MXPA06011276A - Synthesis of boronic ester and acid compounds - Google Patents

Abstract

The invention relates to the synthesis of boronic ester and acid compounds. More particularly, the invention provides improved synthetic processes for the large-scale production of boronic ester and acid compounds, including the peptide boronic acid proteasome inhibitor bortezomib.

Description

SYNTHESIS OF ESTER AND BORIC ACID COMPOUNDS (File of the President No. MPI04-044P1R WO M) BACKGROUND OF THE INVENTION Field of the Invention This invention relates to the synthesis of ester and boric acid compounds. More particularly, the invention relates to large-scale synthetic processes for the preparation of ester and boric acid compounds by redisposition promoted by Lewis acid from "ato" boron complexes. BACKGROUND OF THE INVENTION The boric acid and ester compounds show a variety of useful biological activities. Shenvi et al. , U.S. Patent No. 4,499,082 (1985), discloses that peptide boric acids are inhibitors of certain proteolytic enzymes. Kettner and Shenvi, U.S. Patent No. 5,187,157 (1993), U.S. Patent No. 5,242,904 (1993), and U.S. Patent No. 5,250,720 (1993), describe a class of boric acids of peptides that inhibit trypsin-like proteases. Kleeman et al. , U.S. Patent No. 5,169,841 (1992), discloses N-terminal modified peptide boric acids that inhibit the action of renin. Kinder et al. , U.S. Patent No. 5,106,948 (1992), discloses that certain tripeptide boric acid compounds inhibit the growth of cancer cells. More recently, boric acid and ester compounds have shown promise as inhibitors of the proteasome, a multicatalytic protease responsible for most intracellular protein conversions. Ciechanover, Cell, 79: 13-21 (1994), describes that the proteasome is the proteolytic component of the ubiquitin-proteasome pathway, where proteins are the target of degradation by conjugation with multiple ubiquitin molecules. Ciechanover also describes that the ubiquitin-proteasome pathway plays a key role in a variety of important physiological processes. Ada s et al. , U.S. Patent No. 5,780,454 (1998), U.S. Patent No. 6,066,730 (2000), U.S. Patent No. 6,083,903 (2000), U.S. Patent No. 6,297,217 (U.S. Pat. 2001), U.S. Patent No. 6,548,668 and U.S. Patent No. 6,617,317 (2003), incorporated herein by reference in their entirety, describe peptide and ester compounds of boric acid useful as proteasome inhibitors. . The references also describe the use of ester and boric acid compounds to reduce the rate of degradation of muscle proteins, to reduce the activity of NF-β B in a cell, to reduce the rate of degradation of the p53 protein in a cell , to inhibit the degradation of cyclin in a cell, to inhibit the growth of a cancer cell, to inhibit antigen presentation in a cell, to inhibit NF-? B-dependent cell adhesion and to inhibit HIV replication. Albanell and Adams, Drugs of the Future 27: 1079-1092 (2002), describes that one of such peptide proteasome inhibitors of boric acid, bortezomib (W-2-pyrazine-carbonyl-L-phenylalanine-L-leucinaboric acid), shows significant antitumor activity in human tumor xenograft models and is under clinical evaluation. Richardson et al. , New Engl. J. Med., 348: 2609 (2003), reports the results of a 2-phase study of bortezomib, which shows its efficacy in the treatment of refractory multiple myeloma and relapse. Studies of boric acid protease inhibitors have advanced greatly through the development of chemistry for the preparation of functionalized boric acid compounds, particularly alpha-halo- and alpha-aminoboronic acids. Matteson and Majumdar, J. Am. Chem. Soc. , 102: 7590 (1980), describes a process for preparing alpha-chloroboric esters by homologation of boric esters, and Matteson and Ray, J. Am. Chem. Soc, 102: 7591 (1980), reports that chiral control of the homologation reaction can be achieved by the use of boricol pinioniol esters. The preparation of alpha-amino-boric acid and ester compounds from corresponding alpha-chloroboric esters has also been reported (Matteson et al., J. Am. Chem. Soc., 103: 5241 (1981); Shenvi, US Pat. United States No. 4,537,773 (1985)). Matteson and Sadhu, U.S. Patent No. 4,525,309 (1985), describes an improved process for the homologation of boric esters by rearrangement of the intermediate "ato" boron complex in the presence of a Lewis acid catalyst. Lewis acid is reported to promote the rearrangement reaction and to minimize epimerization at the alpha-carbon atom. However, rigorous water exclusion and careful control of Lewis acid stoichiometry are required to obtain optimum results. These characteristics make the reaction difficult to perform satisfactorily on a production scale, and limit the availability of the pharmaceutically important ester and boric acid compounds, such as bortezomib. Thus, a need remains in the art for improved methods for the large scale production of ester and boric acid compounds. DESCRIPTION OF THE INVENTION The present invention provides improved synthetic processes for the large scale production of ester and boric acid compounds. These processes offer increased yield and purity, increased throughput and ease of handling compared to prior art methods. Notably, the processes described in this document are suitable for large-scale batch production, on a multi-kilogram scale that is limited only by the size of the manufacturing capabilities available. The processes of the invention are particularly advantageous for the synthesis of chiral ester and boric acid compounds, including ester compounds and alpha-aminoboronic acid. Regardless of the scale, the desired products are produced with a much higher chemical and stereochemical purity. The patents and the specific bibliography indicated in this document establish the knowledge that is available to those skilled in the art. Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as is commonly understood by one skilled in the art to which this invention relates. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described herein. The patents, requests and references issued that are cited in this document are incorporated as reference to the same extent as if each one was specifically and individually indicated as a reference. In the case of inconsistencies, you will control the present description, including the definitions. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. The term "approximately" is used in this document to indicate approximately, in the region of, more or less or around. When the term "approximately" is used together with a numerical range, modify that interval by extending the upper and lower limits of the numerical values indicated. In general, the term "approximately" is used in this document to modify a numerical value above and below the value established by a variance of 10%. The term "comprises" is used in this document to indicate "includes, but is not limited to". The term "aliphatic", as used herein, means a straight chain, branched or cyclic hydrocarbon C? _? 2 that is completely saturated or that contains one or more units of unsaturation, but is not aromatic. For example, suitable aliphatic groups include linear, branched or cyclic saturated or unsaturated alkyl, alkenyl or alkynyl groups and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl. In various embodiments, the aliphatic group has 1-12, 1-8, 1-6, or 1-4 carbons.

The terms "alkyl", "alkenyl" and "alkynyl", used alone or as part of a larger moiety, refer to a straight and branched chain aliphatic group having from 1 to 12 carbon atoms, which is optionally substituted with one, two or three substituents. For the purposes of the present invention, the term "alkyl" will be used when the carbon atom linking the aliphatic group with the rest of the molecule is a saturated carbon atom. However, an alkyl group can include unsaturation in other carbon atoms. Thus, alkyl groups include, without limitation, methyl, ethyl, propyl, allyl, propargyl, butyl, pentyl, and hexyl. For the purposes of the present invention, the term "alkenyl" will be used when the carbon atom linking the aliphatic group with the rest of the molecule forms part of a carbon-carbon double bond. Alkenyl groups include, without limitation, vinyl, 1-propenyl, 1-butenyl, 1-pentenyl and 1-hexenyl. For the purposes of the present invention, the term "alkynyl" will be used when the carbon atom linking the aliphatic group with the rest of the molecule forms part of a carbon-carbon triple bond. Alkynyl groups include, without limitation, ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl and 1-hexynyl. The terms "cycloalkyl", "carbocycle", "carbocyclyl", "carbocycle" or "carbocyclic", used alone or as part of a larger moiety, mean a system of saturated or partially unsaturated cyclic aliphatic rings having from 3 to 14 members , wherein the aliphatic ring system is optionally substituted. Cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl and cyclooctadienyl. In some embodiments, the cycloalkyl has 3-6 carbons. The terms "cycloalkyl", "carbocycle", "carbocyclyl", "carbocycle" or "carbocyclic" also include aliphatic rings that condense to one or more aromatic or non-aromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, where the radical or point of Union is in the aliphatic ring. The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" refer to an alkyl, alkenyl or alkoxy group, as the case may be, substituted with one or more halogen atoms. As used herein, the term "halogen" or "halo" means F, C, Br or I. Unless otherwise indicated, the terms "alkyl", "alkenyl" and "alkoxy" include haloalkyl, haloalkenyl and haloalkoxy groups, including, in particular, those with 1-5 fluorine atoms. The terms "aryl" and "ar-", used alone or as part of a larger moiety, for example, "aralkyl", "aralkoxy" or "aryloxyalkyl", refer to a C6- aromatic moiety. comprising one to three aromatic rings, which are optionally substituted. Preferably, the aryl group is an aryl group Ce-1- The aryl groups include, without limitation, phenyl, naphthyl and anthracenyl. The term "aryl", as used herein, also includes groups in which an aromatic ring is condensed to one or more non-aromatic rings, such as indanyl, phenanthridinyl or tetrahydronaphthyl, where the radical or point of attachment is in the aromatic ring. The term "aryl" can be used interchangeably with the term "aryl ring". An "aralkyl" or "arylalkyl" group comprises an aryl group covalently bonded to an alkyl group, any of which is optionally substituted. Preferably, the aralkyl group is aryl (A-e) C6-10 alkyl, including, without limitation, benzyl, phenethyl and naphthylmethyl. The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, eg, heteroaralkyl or "heteroaralkoxy", refer to groups having from 5 to 14 ring atoms, preferably 5, 6, 9 or 10 atoms in the ring; having 6, 10 or 14 p-electrons shared in a cyclic series; and having, in addition to carbon atoms, from one to four heteroatoms selected from the group consisting of N, O and S. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl , isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazole, benzthiazolyl, purinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinoxalinyl, naphthyridinyl, pteridinyl , carbazolyl, acridinyl and phenazinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is condensed to one or more non-aromatic rings, where the radical or point of attachment is in the heteroaromatic ring. Non-limiting examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido [3,4-d] pyrimidinyl. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic", including those terms rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, wherein the alkyl and heteroaryl portions are independently optionally substituted. As used herein, the terms "heterocycle", "heterocyclyl" or "heterocyclic radical" refer to a 7- to 7-membered monocyclic or 7 to 10 membered monocyclic heterocyclic moiety that is saturated or partially unsaturated and that has, in addition to carbon atoms, one or more, preferably from one to four, heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur heteroatoms are optionally oxidized and the nitrogen atoms are optionally quaternized. The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl and morpholinyl. The terms "heterocycle", "heterocyclyl" and "heterocyclic radical", as used herein, also include groups in which a non-aromatic ring containing heteroatoms is condensed to one or more aromatic or non-aromatic rings, such as indolinyl , chromanyl, phenanthridinyl or tetrahydroquinolinyl, where the radical or point of attachment is in the non-aromatic ring containing heteroatoms. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl moieties are independently optionally substituted. As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between the ring atoms. The term "partially unsaturated" is intended to encompass rings having one or multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein. The term "substituted", as used herein, means that one or more hydrogen atoms are replaced from the indicated moiety, with the proviso that the substitution results in a chemically feasible or stable compound. A stable or chemically feasible compound is one in which the chemical structure is not substantially altered when maintained at a temperature of 40 ° C or less, in the absence of moisture or other chemically reactive conditions, for at least a week, or a compound that maintains its integrity for sufficient time to be useful for the synthetic processes of the invention. The phrase "one or more substituents", as used herein, refers to a number of substituents that is one to the maximum number of possible substituents based on the number of available binding sites, provided they are met. the previous conditions of stability and chemical feasibility. An "aryl group" including the aryl moiety of aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including the heteroaryl moiety in heteroaralkyl and heteroarylalkoxy and the like) can contain one or more substituents Examples of suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group include -halo, -N02, -CN, -R *, -OR *, -SR °, -N (R +) 2, NR + C (0) R *, -NR + C (0) N (R +) 2, -NR + C02R °, -0-C02R *, -0-C (0) R *, -C02R *, -C (0) R *, -C (0) N (R +), -OC (O) N (R +) 2, -S (0) 2R °, -S02N (R +) 2, -S (0) R ° and -NR + S02N (R +) 2- Each R + is independently selected from the group consisting of R *, -C (0) R *, -C02R * and -S02R * or two R + in the same nitrogen atom, taken together with the nitrogen atom, form an aromatic or non-aromatic ring of 5-8 members having, in addition to nitrogen, 0-2 heteroatoms in the ring selected from N, O and S. Each R * is independently hydrogen or an aliphatic, aryl, heteroaryl or heterocyclyl group optionally replaced. Each R ° is independently an optionally substituted aliphatic or aryl group. An aliphatic group may also be substituted with one or more substituents. Examples of suitable substituents on the saturated carbon of an aliphatic group or a non-aromatic heterocyclic ring include, without limitation, those listed above for the unsaturated carbon of an aryl or heteroaryl group. The present inventors have discovered that the requirement for scrupulously dry equipment, solvents and reagents which characterize the procedures described above for the Lewis acid promoted rearrangement of the "ato" boron complexes can be obtained by the use of an ether solvent having a low miscibility with water. Strikingly, the use of such a solvent allows the reaction to be performed on a multi-kilogram scale without deteriorating yield or purity. In essence, the scale of the reaction is limited only by the size of the manufacturing capabilities available. In one aspect, therefore, the inventors provide a large-scale process for preparing a boric ester compound of formula (I): wherein: R1 is an optionally substituted aliphatic, aromatic or heteroaromatic group; R2 is hydrogen, a nucleofugic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; R3 is a nucleophilic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; and each of R4 and R5, independently, is an optionally substituted aliphatic, aromatic or heteroaromatic group or R4 and R5, taken together with the oxygen and boron atoms involved, form an optionally substituted 5 to 10 membered ring having 0 -2 more heteroatoms in the ring selected from N, O or S. The process comprises the steps: (a) providing a complex "ato" boron of formula (II): wherein Y is a nucleofugic group; M + is a cation; and each of R1 to R5 is as defined above; and contacting the "ato" boron complex of formula (JJ) with a Lewis acid under conditions that produce the boronic ester compound of formula (J), said contacting step being carried out in a reaction mixture comprising: (i) ) a coordination ether solvent having a low miscibility with water; or (ii) an ether solvent having a low miscibility with water and a co-solvent of coordination. The processes previously reported for the rearrangement of complex "ato" boron promoted by Lewis acid employ tetrahydrofuran, an ether solvent that is completely miscible with water. The failure to use equipment, solvents and reagents rigorously dried in these processes results in a drastic reduction in the diastereomeric ratio. The hygroscopic Lewis acids, in particular, should typically be flame-dried immediately before use in the reaction. Although techniques for performing moisture sensitive reactions are familiar to those skilled in the art and are routinely practiced on a laboratory scale, such reactions are costly and difficult to scale. In addition, attempts to scale prior art processes usually result in further deterioration in the diastereomeric ratio during treatment and isolation of the product boric ester compound. Matteson and Erdiik, Organometallics, 2: 1083 (1983), reports that exposure of alpha-haloboronic ester products to free halide ions results in epimerization at the alpha-carbon center. Without wishing to be bound by a theory, the present inventors believe that epimerization is particularly problematic during the reaction treatment and / or subsequent steps. For example, it is believed that epimerization occurs during the concentration of the reaction mixture to remove the tetrahydrofuran solvent and exchange it for a water-immiscible solvent. Failure to completely remove tetrahydrofuran also negatively impacts the diastereomeric relationship during subsequent aqueous washes. Exposure of the product to a halide ion during these steps is difficult to avoid, particularly when the reaction is carried out on a large scale.

The present inventors have discovered that the rearrangement of the "ato" boron complexes is done selling in an ether solvent having low miscibility with water. The use of such solvents obviates the need for solvent exchange prior to aqueous washes, and the organic soluble product is efficiently shielded from the aqueous halide ion during washings, even if carried out on a large scale. Preferably, the solubility of the water in the ether solvent is less than about 5% w / wt, more preferably less than about 2% w / w. In various embodiments, the ether solvent having low miscibility with water constitutes at least about 70%; at least about 80%, at least about 85%, at least about 90% or at least about 95% v / v of the reaction mixture. The ether solvent is preferably one which is suitable for conventional use in large scale production. As used in this document, the term "large scale" refers to a reaction using at least about five mole of at least one starting material. Preferably, a large-scale process uses at least about 10, 20, 50 or 100 mol of at least one starting material. For the purposes of the invention, the term "ether" refers to any of a class of chemical compounds characterized by having an oxygen atom attached to two carbon atoms. An "ether solvent" is an ether compound that is in liquid form at the desired reaction temperature and that is capable of dissolving the starting material (s) and / or product (s) of the reaction. Non-limiting examples of ether solvents suitable for use in the processes of the invention include tert-butyl methyl ether, tert-butyl ethyl ether, tert-amyl methyl ether and isopropyl ether. In one embodiment, the reaction mixture further comprises a coordination co-solvent. In another embodiment, the ether solvent having low miscibility with water is sufficiently coordinating that a co-solvent of coordination is not necessary. For the purposes of the invention, the terms "coordination co-solvent" and "coordination solvent" refer to a solvent that is capable of coordinating the Lewis acid and solvate the ionic components of the reaction. The hindered ether solvents, such as tert-butyl methyl ether, are poorly coordinating and are preferably used with a co-solvent of coordination. Non-limiting examples of coordination co-solvents for use in the practice of the invention include tetrahydrofuran, dioxane, water and mixtures thereof. In some embodiments, the reaction mixture comprises at least about 5% or at least about 10% of a coordination co-solvent. Preferably, the amount of a water miscible coordination co-solvent present in the reaction mixture is not so great as to interfere with phase separation during the reaction or treatment. In various embodiments, the coordination co-solvent does not constitute more than about 20%, about 15% or about 10% v / v of the reaction mixture. As used herein, the term "nucleofugal" refers to any group that is capable of undergoing nucleophilic displacement under the conditions of rearrangement of the present process. Such nucleophilic groups are known in the art. Preferably, the nucleofugic group is a halogen, more preferably chlorine or bromine. In the course of the rearrangement reaction which converts the "ato" boron complex of formula (JJ) into the boronic ester compound of formula (I), the nucleophilic group Y is released as YA by way of example, when Y is chlorine , the chloride ion is released in step (b) The variable M + is any cationic counter ion for the tetravalent boron atom negatively charged in the "ato" boron complex of formula (IX). In some preferred embodiments, M + is selected from the group consisting of Li +, Na + and KA. A person skilled in the art will recognize that the M + Y ~ salt is formed co or a by-product in the rearrangement reaction of step (b). The variable R1 is preferably a group with good migratory fitness. In some embodiments, R1 is aliphatic C? -8, aryl C6_? 0 or (aryl C6-? O) (aliphatic C? _6), any of which is optionally substituted. In certain embodiments, R1 is C4-4 aliphatic, particularly isobutyl. The variable R2 is preferably hydrogen, a nucleophilic group or an optionally substituted C? _8 aliphatic group, C6_? O aryl or (C6-? O aryl) (C? _6 aliphatic). The variable R3 is preferably a nucleophilic group or an optionally substituted aliphatic group C] _8, aryl C3-ao or (aryl C6-? O) (aliphatic C? _6). One skilled in the art will recognize that functional substituents can be present on any of R1, R2 or R3, with the proviso that the functional substituent does not interfere with the formation of the "ato" boron complex of formula (JJ). An embodiment of the invention relates to a process for preparing a boronic ester compound of formula (I), in which R3 is a nucleofugic group. Such compounds are useful as intermediates for the synthesis of alpha-substituted boric acid and ester compounds, including ester compounds and alpha-aminoboronic acid, as described below. In certain preferred embodiments, R3 is a nucleofugic group and R2 is hydrogen.

The variables R4 and R5 can be the same or different. In some embodiments, R4 and R5 are attached directly, so that R4 and R5, taken together with the intervening oxygen and boron atoms, form an optionally substituted 5- to 10-membered ring, which may have 0-2 more heteroatoms in the ring selected from N, O or S. In some embodiments, the ring is a 5- or 6-membered ring, preferably a 5-membered ring. The present invention is particularly advantageous for the redisposition promoted by Lewis acid of the "ato" boron complexes of formula (JJ), in which R4 and R5 are directly linked and together they are a chiral residue. An embodiment of the invention relates to the rearrangement of such chiral "ate" boron complexes to provide a boric ester compound of formula (J) wherein the carbon atom having R1, R2 and R3 is a chiral center. The rearrangement reaction is preferably performed with a high quality stereodirection by the residue R4-R5 to provide the boronic ester compound of formula (J) having a diastereomeric ratio at the carbon atom having R1, R2 and R3 of less about 96: 4 in relation to the chiral center in the chiral moiety R4-R5. Preferably, the diastereomeric ratio is at least about 97: 3. The terms "stereoisomer," "enantiomer," "diastereomer," "epimer," and "chiral center," are used herein in accordance with the meaning that is given for each of them in conventional use by those skilled in the art. The technique. In this way, stereoisomers are compounds that have the same atomic connectivity, but differ in the spatial organization of atoms. Enantiomers are stereoisomers that have a mirror image relationship, that is, the stereochemical configuration in all corresponding chiral centers is opposite. Diastereomers are stereoisomers that have more than one chiral center, which differs from one another in that the stereochemical configuration of at least one, but not all, of the corresponding chiral centers is opposite. The epimers are diastereomers that differ in the stereochemical configuration only in a chiral center. As used herein, the term "diastereomeric ratio" refers to the ratio between diastereomers that differ in the stereochemical configuration at a chiral center, relative to a second chiral center on the same molecule. By way of example, a chemical structure with the chiral centers provides four possible stereoisomers: R * R, R * S, S * R and S * S, where the asterisk indicates the corresponding chiral center in each stereoisomer. The diastereomeric ratio for such a mixture of stereoisomers is the ratio of one diastereomer and its enantiomer to the other diastereomer and its enantiomer = (R * R + S * S): (R * S + S * R). One skilled in the art will recognize that other stereoisomers are possible when the molecule has more than two chiral centers. For the purposes of the present invention, the term "diastereomeric ratio" has the same meaning with respect to compounds with multiple chiral centers as it does with respect to a compound having two chiral centers. In this way, the term "diastereomeric ratio" refers to the ratio of all compounds having R * R or S * S configuration at the specified chiral centers. For convenience, this relationship is referred to herein as a diastereomeric relationship in the carbon of the asterisk, in relation to the specified second chiral center. The diastereomeric ratio can be measured by any suitable method to distinguish between diastereomeric compounds having different relative stereochemical configurations at the specified chiral centers. Such methods include, without limitation, methods of nuclear magnetic resonance (NMR), gas chromatography (GC) and high performance liquid chromatography (HPLC). As discussed previously, an embodiment of the invention relates to processes that provide a boronic ester compound of formula (J) having a diastereomeric ratio at the carbon atom having R1, R2 and R3 of at least 96: 4 relative to the center Chiral of the chiral residue R4-R5. One of skill in the art will recognize that the chiral center R4-R5 may itself contain more than one chiral center. When R4-R5 has no more than one chiral center, it preferably has high diastereomeric purity, and the diastereomeric ratio at the carbon atom having R1, R2 and R3 can be measured in relation to any of the chiral centers of R4-R5. In the processes of the invention, the chiral moiety R4-R5 preferably has a high level of enantiomeric purity. For purposes of the invention, the term "enantiomeric purity" is used to indicate "enantiomeric excess," which is the amount by which the major enantiomer is in excess of the minor enantiomer, expressed as a percentage of the total. Preferably, the chiral moiety R-R5 has an enantiomeric purity of at least about 98%, more preferably at least about 99%, even more preferably at least about 99.5%, and more preferably at least about 99.9%. When the chiral residues R4-R5 have a very high enantiomeric purity, the diastereomeric ratio at the carbon atom having R1, R2 and R3 approximates the epimeric ratio at that center, ie, diastereomeric ratio = (R * R) : (S * R) or. { R * S): (S * S) =. { R *): (S *). As used herein, the term "epimeric ratio" refers to the ratio of the product having an absolute stereochemical configuration at a given chiral center so that the product has the opposite absolute stereochemical configuration at the corresponding chiral center. Preferably, the products have a stereochemical configuration identical to all other corresponding chiral centers. In one embodiment, therefore, the invention relates to the rearrangement of a chiral "ate" boron complex of formula (JJ) to provide a boronic ester compound of formula (J) wherein the epimeric ratio in the carbon having R1, R2 and R3 is at least about 96: 4, more preferably at least about 97: 3. Lewis acids suitable for use in the practice of the invention are those capable of complexing with the nucleophilic group to facilitate its displacement after the migration of R1. Preferably, the Lewis acid is also capable of coordinating with an oxygen atom bound to boron. Non-limiting examples of suitable Lewis acids include zinc bromide, zinc chloride, ferric bromide and ferric chloride. In certain preferred embodiments, the Lewis acid is zinc chloride. The contacting step is preferably carried out at low temperature, but can be carried out at room or high temperature. The selection of a reaction temperature will depend greatly on the Lewis acid used, as well as on the migratory ability of the residue R1. A person skilled in the art will be able to select a suitable temperature in view of the reaction conditions that are used. In some embodiments, the contacting step is carried out at a reaction temperature of at least about -100 ° C, -78 ° C or -60 ° C. In some embodiments, the contacting step is performed at a reaction temperature that is not greater than about 80 ° C, 40 ° C or 30 ° C. Any range encompassing these high and low temperatures is included within the scope of the invention. Preferably, the contacting step is carried out at a reaction temperature in the range of about -100 ° C to about 80 ° C, about 70 ° C to about 40 ° C, about -60 ° C to about 30 ° C. , or from about -50 ° C to about 30 ° C. In certain preferred embodiments, the contact stage begins at low temperature, preferably in the range of -70 ° C to about -30 ° C, and then the reaction mixture is allowed to warm, preferably at room temperature.

Surprisingly, the process of the present invention does not require special precautions to avoid the presence of water during the redisposition reaction itself. In some embodiments, wet Lewis acid is used, with minimal deterioration of the diastereomeric ratio. When used with respect to Lewis acid, the term "wet" means that the water content of Lewis acid is greater than about 100, 200, 500 or 1,000 ppm. Remarkably, the Lewis acid can be added to the reaction mixture in the form of an aqueous solution with no harmful impact on the diastereomeric ratio. In some embodiments, therefore, the process of the invention requires the steps: (a) providing a solution comprising an "ate" boron complex of formula (JJ) and (i) a coordination ether solvent having a low miscibility with water; or (ii) an ether solvent having a low miscibility with water and a coordination co-solvent; and adding to the solution of step (a) a Lewis acid solution comprising water and a Lewis acid. In other embodiments, the Lewis acid solution comprises tetrahydrofuran and a Lewis acid. In this way, unlike the prior art processes, the process of the invention is easily flexible to large scale production. In various embodiments, about 5, 10, 20, 50, 100, 500 or 1000 mol of "ato" boron complex of formula (JJ) are contacted with a Lewis acid under conditions that provide the boronic ester compound of formula (J) The invention also provides a composition comprising a boronic ester compound of formula (I), as described herein, and an ether solvent having low miscibility with water. The composition preferably comprises at least about 5, 10, 20, 50, 100, 500 or 1000 mol of boronic ester compound of formula (J). In certain embodiments, R4 and R5 together are a chiral moiety, and the compound of formula (J) present in the composition has a diastereomeric ratio of at least about 96: 4 at the carbon atom having R1, R2 and R3, in relation to the chiral center in the chiral moiety R4-R5.

The treatment of the reaction preferably comprises washing the reaction mixture with an aqueous solution and the concentrate of the washed reaction mixture by removing the solvents to produce a residue comprising the boronic ester compound of formula (J). Preferably, the residue comprises at least about 5, 10, 20, 50, 100, 500 or 1000 mol of the boronic ester compound of formula (J). In embodiments where R4-R5 is a chiral moiety, the boronic ester compound of formula (J) present in the residue preferably has a diastereomeric ratio of at least 96: 4 at the carbon atom having R1, R2 and R3, in relation to the chiral center in the chiral moiety R-R5. More preferably, the diastereomeric ratio is at least about 97: 3. The "ato" boron complex of formula (JJ) can be prepared by any known method, but is preferably prepared by reaction of a boric ester of formula (III): with a reagent of formula (XV): wherein each of M +, Y and R1 to R5 are as defined for the complex "ato" boron of formula (JJ). In some embodiments, the reaction is carried out at a reaction temperature of at least about -100 ° C, -78 ° C or -60 ° C. In some embodiments, the reaction is carried out at a reaction temperature not higher than about 0 ° C, -20 ° C or -40 ° C. Any range encompassing these high and low temperatures is included within the scope of the invention. The reaction is preferably carried out at a reaction temperature in the range of about -100 ° C to about 0 ° C, about -78 ° C to about -20 ° C, or about -60 ° C to about -40 ° C. In some embodiments, the "ato" boron complex of formula (JJ) is prepared in a solution comprising an ether solvent having low miscibility with water, and the reaction mixture is treated directly with a Lewis acid to perform the rearrangement with the boron ester compound of formula (J). In some embodiments, the reagent of formula (JV) is formed in situ. Such embodiments include the steps: (i) providing a solution comprising a boric ester of formula (JJJ), as defined above and a compound of formula (V): R2 R3 Y (V) wherein R2 and R3 are as defined above for the formula reagent (JV); and (ii) treating the solution with a strong and sterically hindered base to form the "ato" boron complex of formula (JX).

In some embodiments, the sterically hindered base is an alkali metal dialkylamide base of formula MN (R *) 2, wherein M2 is Li, Na or K and each R # is independently a branched or cyclic C3_6 aliphatic. The in situ formation of reagent of formula (XV) is especially advantageous in those embodiments where Y is a nucleofugic group, due to the instability of the reagent of formula (JV). The boric ester of formula (JJJ) can be prepared by any known method, but is typically prepared by esterification of the corresponding boric acid compound, i.e., by the methods described in Brown et al. , Organometallic, 2: 1311-1316 (1983). The cyclic boric esters of formula (JJJ) are preferably prepared by: (a) providing a solution comprising: (i) a boric acid compound of formula R1-B (OH) 2; (ii) a compound of formula HO-R-R5-OH, wherein R4 and R5, taken together, are an optionally substituted linking chain comprising 2-5 carbon atoms and 0-2 heteroatoms selected from the group consisting by O, N and S; and (iii) an organic solvent that forms an azeotrope with water; and (b) heating the solution to reflux with azeotropic removal of the water. As used with respect to R 4 and R 5, the term "linking chain" refers to the shorter linear chain of atoms connecting the oxygen atoms to which R 4 and R 5 are attached. The linker chain is optionally substituted at any atom in the chain, and one or more atoms in the chain may also be part of a ring system that is spiro a, fused to, or joins the linear link chain. By way of example, but without limitation, in some embodiments, the compound of formula HO-R4-R5-OH is pinanediol, which has the structure In such embodiments, the linking chain R4-R5 comprises two carbon atoms, which together form one side of the bicyclo [3, 1, 1] heptane ring system, and one of which is further substituted with a methyl group. In some embodiments, the compound of the formula HO-R4-R5-OH is a chiral diol, preferably one having a high diastereomeric and enantiomeric purity. One skilled in the art will appreciate that in such an embodiment, the compound of the formula HO-R4-R5-OH is employed as a chiral auxiliary to direct the stereochemical configuration on the carbon having R1, R2 and R3. Chiral diols useful as chiral auxiliaries in inorganic synthesis are well known in the art. Non-limiting examples include 2,3-butanediol, preferably (2R, 3R) - (-) -2, 3-butanediol or (2S, 3S) - (+) - 2, 3-butanediol; pinanediol, preferably (1R, 2R, 3R, 5S) - (-) -pinanodiol or (1S, 2S, 3S, 5R) - (+) - p-nanediol; 1,2-cyclopentanediol, preferably (SS, 2S) - (+) - trans-1,2-cyclopentanediol or (IR, 2R) - (-) - trans-1,2-cyclopentanediol; 2,5-hexanediol, preferably (2S, 5S) -2,5-hexanediol or (2R, 5R) -2,5-hexanediol; 1,2-dicyclohexyl-1,2-ethanediol, preferably (IR, 2) -1,2-dicyclohexyl-1,2-ethanediol or (1S, 2S) -1,2-dicyclohexyl-1,2-ethanediol; hydrobenzoin, preferably (S, S) - (-) - hydrobenzoin or (R, R) - (+) - hydrobenzoin; 2,4-pentanediol, preferably (R, R) - (-) -2,4-pentanediol or (S, S,) - (+) -2,4-pentanediol; - Erythronic lactone, preferably? -D-eritronic lactone. Carbohydrates can also be used as chiral diols, for example a 1, 2, 5, 6-symmetrically protected mannitol. Non-limiting examples of organic solvents suitable for use in the esterification reaction include acetonitrile, toluene, hexane, heptane and mixtures thereof. In some embodiments, the organic solvent is an ether solvent, preferably an ether solvent solvent having low miscibility with water. In certain preferred embodiments, the esterification reaction is carried out in an ether solvent having low miscibility in water, and the solution of the product comprising the boric ester of formula (JJJ) is used directly in the next step, without isolation of the boric ester. As indicated above, the process of the present invention for the first time allows the treatment of large-scale reactions without significant deterioration in the diastereomeric ratio. In another aspect, therefore, the invention provides a composition comprising at least about 5, 10, 20, 50, 100, 500 or 1000 mol of a boronic ester compound of formula (J): in which: R1 is an optionally substituted aliphatic, aromatic or heteroaromatic group; R2 is hydrogen, a nucleofugic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; R3 is a nucleophilic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; and R4 and R5, taken together with the oxygen and boron atoms involved, form an optionally substituted 5 to 10 membered chiral ring having 0-2 more heteroatoms in the ring selected from N, 0 or S; wherein the carbon atom to which R1, R2 and R3 are attached is a chiral center, having a diastereomeric ratio of at least about 96: 4, preferably at least about 97: 3, with respect to the chiral center in the chiral moiety R -R5 The preferred values for R1 to R3 are as described above. Preferably, the solvents constitute less than about 30% w / w, 20% w / w, 10% w / w or 5% w / w of the composition according to this aspect of the invention. In some embodiments, the boronic ester compound of formula (J) constitutes at least about 70% w / w, 80% w / w, 90% w / w or 95% w / w of the composition. An embodiment refers to the composition described above, wherein at least one of the following characteristics is present: (a) R3 is chlorine; (b) the boric ester compound (J) is (c) R "is hydrogen, and (d) R1 is aliphatic C? _4 All the boronic ester compound of formula (J) present in the composition can be produced in a single batch embodiment .For the purposes of the invention, the term "batch embodiment" refers to the execution of a synthetic process, wherein each stage of the process is performed only once Preferably, the boronic ester compound of formula (J) present in the composition is prepared in a single embodiment batch process according to the first aspect of the invention A person skilled in the art will appreciate that the preparation of a given quantity of product by a single batch embodiment of a large-scale process is more efficient and provides a more homogeneous product that the preparation of the same amount of product by repeated execution of a small-scale process The boric ester compounds of formula (J) in which R3 is a nucleofugic group are useful. iles as intermediates for the synthesis of alpha-aminoboronic ester compounds. In another aspect, therefore, the invention provides a large scale process for preparing an alpha-aminoboronic ester, preferably by a process comprising the steps: (a) providing an "ate" boron complex of formula (JJ): where Y is a nucleofugal group; M + is a cation; R1 is an optionally substituted aliphatic, aromatic or heteroaromatic group; R "is hydrogen, R3 is a nucleofugic group, and each of R4 and R5, independently, is an optionally substituted aliphatic, aromatic or heteroaromatic group or R4 and R5, taken together with the intervening oxygen and boron atoms, form a optionally substituted 5 to 10 membered ring having 0-2 more heteroatoms in the ring selected from N, O or S; (b) contacting the boron complex "ato" of formula (JJ) with a Lewis acid under conditions producing the boric ester compound of formula (J): R3 ^ B '° R4 ORR5 (j) wherein each of R1 to R5 is as defined above, said contact step being carried out in a reaction mixture comprising: (i) a coordinating ether solvent having a low miscibility with water; or (ii) an ether solvent having a low miscibility with water and a coordination co-solvent; and (c) treating the boronic ester compound of formula (I) with a reagent of formula M1-N (G) 2, wherein M1 is an alkali metal and each G individually or together is an amino group protecting group to form an by-product of formula M1-R3 and a compound of formula (VJJJ): (VJJJ) wherein each of G and R1 to R5 are as defined above; and (d) removing the G groups to form a compound of formula (VXX): or an acid addition salt thereof. In some embodiments, in step (c), the boric ester compound formula (J) is treated with a reagent of formula M1-N (Si (R6) 3) 2 wherein M1 is an alkali metal and each R6 is independently selected from the group consisting of alkyl, aralkyl and aryl, wherein the aryl or aryl portion of the aralkyl is optionally substituted. The reaction of the boronic ester compound of formula (J) with the reagent of formula M1-N (G) 2 is preferably carried out at a reaction temperature in the range of about ~ 100 ° C to about 50 ° C, preferably about -50 ° C to about 25 ° C and more preferably from about -30 ° C to about 0 ° C. In some embodiments, R3 is halo, preferably chloro, and M1 is Li. To facilitate the isolation of the product of formula (VJJJ), the reaction mixture preferably comprises an organic solvent in which the by-product M1-R3 has low solubility. Non-limiting examples of suitable organic solvents include methylcyclohexane, cyclohexane, heptane, hexane and toluene. In some embodiments, step (c) further comprises filtering the reaction mixture to remove M "AR3 and providing a filtrate comprising the compound of formula (VXXX) .Preferably, the filtrate is used directly in step (d). In those embodiments in which the reaction mixture comprises an organic solvent in which the by-product M1-R3 has low solubility, the reaction mixture may further comprise a solvent in which the by-product M1-R3 has a high solubility. In some cases, the solvent in which the by-product M1-R3 has a high solubility is preferably removed before filtering the reaction mixture, For example, in some embodiments, a reagent of the formula is added to the reaction mixture. M1- (Si (R6) 3) 2 in the form of a solution comprising tetrahydrofuran In such embodiments, step (c) preferably further comprises removing the tetrahydrofuran before filtering of reaction mixture. Those skilled in the art will know that there are several methods that can be used to remove protecting groups G in the compound (VJJJ), including, for example, aqueous hydrolysis or acid treatment. The alpha-aminoboronic ester product of formula (VJJ) has low solubility and is preferably immediately derived (Matteson et al., J. Am. Chem. Soc., 103: 5241 (1981)) or isolated in the form of a sodium salt. addition of acids. In some embodiments, step (d) comprises treating the compound of formula (VJJJ) with an acid and isolating the compound of formula (VJJ) in the form of the acid addition salt. In certain preferred embodiments, the acid is trifluoroacetic acid, and the compound of formula (VJJ) is isolated in the form of the trifluoroacetic acid addition salt.

As discussed above, the processes of the invention are particularly suitable for preparing alpha-aminoboronic ester compounds of formula (VJJ), wherein the alpha carbon is a chiral center. Thus, an embodiment of the invention relates to a large scale process for preparing an alpha-aminoboronic ester compound of formula (VJJa) or. { Vllb): or an acid addition salt thereof, wherein: R1 is an optionally substituted aliphatic, aromatic or heteroaromatic group; and R4 and R5, taken together with the oxygen and boron atoms involved, form an optionally substituted chiral cyclic boronic ester; said process comprising: (a) providing a complex "ato" boron of formula (JJa) or (Hb): YY £ f "OR4M + Y? -O.R4M + OR5 (JJa) OR5 (jjjb) where Y is a nucleophilic group, M + is a cation, R2 is hydrogen, R3 is a nucleofugic group, and R4 and R5 are as defined above, (b) contacting the boron complex "ato" of formula (JJa) or (I Ib) with a Lewis acid under conditions that produce a boric ester compound of formula (Xa) or (Xb): wherein one of R1 to R5 is as defined above, said contacting step being carried out in a reaction mixture comprising: (i) a coordination ether solvent having a low miscibility with water; or (ii) an ether solvent having a low miscibility with water and a coordination co-solvent; and (c) treating the boronic ester compound of formula (Xa) or (Ib) with a reagent of formula M-L-N (G) 2? where M1 is an alkali metal and G is an amino group protecting moiety, to form a compound of formula (VJJJa) or (VlIJb): (VI I Ib) where each of G and R1 to R5 are as defined above; and (d) removing the G groups to form a compound of the formula (VJJa) or (Vllb): or an acid addition salt thereof. The preferred values for Y, M +, R1 to R5 and G are as described above. The compound of formula (VJJa) or (VlIJb) preferably has a diastereomeric ratio at the alpha carbon of at least about 96: 4, more preferably at least about 97: 3, with respect to the chiral center in the chiral moiety R4-R5. The alpha-aminoboronic ester compounds of formula (VJJ) are synthetic intermediates useful for the preparation of peptidylboronic ester compounds. In some embodiments, therefore, the process according to this aspect of the invention further comprises coupling the compound of formula (VJJ) with a compound of formula (IX): R7 pltfVO (XX) wherein: P1 is a moiety amino group blocker; R7 is selected from the group consisting of hydrogen, aliphatic C? -? Or, aryl Ce_10 optionally substituted or aliphatic C? _6-R8; and R8 is selected from the group consisting of alkoxy, alkylthio, optionally substituted aryl, heteroaryl and heterocyclyl groups and optionally protected amino groups, hydroxy and guanidino; and X is OH or a leaving group; to form a compound of formula (X): wherein each of P1, R1, R4, R5 and R7 is as defined above. The leaving group X is any group capable of nucleophilic displacement by the alpha-amino group of the compound of formula (VJI). In some embodiments, the -C (0) -X moiety is an activated ester, such as a 0- (W-hydroxysuccinimide) ester. In some embodiments, an activated ester is generated in situ by contacting a compound of formula (XX), wherein X is OH, with a peptide coupling reagent. Examples of suitable peptide coupling reagents include, but are not limited to, carbodiimide reagents, for example, dicyclohexylcarbodiimide (DCC) or 1- (3-dimethyl-aminopropyl) -3-ethylcarbodiimide (EDC); phosphonium reagents, for example, benzotriazol-1-yloxytris- (dimethylamino) -phosphonium hexafluorophosphate (BOP reagent); and uronium reagents, for example, O- (IH-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU). Those skilled in the art will also know that there are methods that allow direct coupling of silylproteinated amines, without a prior deprotection step. In such procedures, the silyl groups are removed in situ under coupling reaction conditions. In such embodiments of the present invention, therefore, a compound of formula (VJJJ) is contacted with a compound of formula (IX) under conditions that remove the (R6) 3Si groups in situ and form a compound of formula ( X) For the purposes of the invention, the term "amino group blocking moiety" refers to any group used to derive an amino group, especially an N-terminal amino group of a peptide or amino acid. The term "amino group blocking moiety" includes, but is not limited to, protecting groups that are commonly employed in organic synthesis, especially peptide synthesis. See, for example, Gross and Mienhoffer, eds., The Peptides, Vol. 3, Academic Press, New York, 1981, p. 3-88; Green and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, Inc., New York, 1999. Unless otherwise indicated, however, it is not necessary for an amino group blocking moiety that is easily cleavable. Amino group blocking moieties include, for example, alkyl, acyl, alkoxycarbonyl, aminocarbonyl and sulfonyl moieties. In some embodiments, the amino group-blocking moiety is an acyl moiety derived from an amino acid or peptide, or a derivative or analog thereof. As used herein, the term "amino acid" includes amino acids that are found in nature and not naturally occurring. For purposes of the invention, a "derivative" of an amino acid or peptide is one in which a functional group, for example, a hydroxy, amino, carboxy or guanidino group at the N-terminus or on a side chain, is modified with a blocking group. As used herein, an "analogue" of an amino acid or peptide is one that includes a modified backbone or side chain. The term "peptide analogue" is intended to include peptides in which one or more stereocenters are reversed and one or more peptide bonds are replaced with a peptide isostere. In some embodiments, P1 is a cleavable protecting group. Examples of cleavable protecting groups include, without limitation, acyl protecting groups, for example, formyl, acetyl (Ac), succinyl (Suc) or methoxysuccinyl (MeOSuc) and urethane protecting groups, for example, tert-butoxycarbonyl (Boc) , benzyloxycarbonyl (Cbz) or fluorenylmethoxycarbonyl (Fmoc).

In some of those embodiments, the process according to this aspect of the invention also comprises the steps: (f) removing the protecting group P1 to form a compound of formula (XJ): or an acid addition salt thereof, wherein each of R1, R4, R5 and R7 is as defined above; Y (g) coupling the compound of formula (XJ) with a reagent of formula P2-X, wherein P2 is any amino group blocking moiety, as described above and X is a leaving group, to form a compound of formula (XII): wherein each of P2, R1, R4, R5 and R7 are as defined above. One skilled in the art will recognize that in those embodiments in which P2 is an acyl group, including, for example, an acyl residue derived from an amino acid or peptide or an analogue or a derivative thereof, the leaving group X can be generated in situ. , as discussed above for the compound of formula (JX).

In each of the compounds (X) and (XII), the boric acid residue is protected in the form of a boric ester. If desired, the boric acid moiety can be deprotected by any method known in the art. Preferably, the boric acid moiety is deprotected by transesterification in a biphasic mixture. More preferably, the deprotection step of boric acid comprises the steps: (i) providing a biphasic mixture comprising the boronic ester compound of formula (X) or (XII), an organic boric acid acceptor, a lower alkanol, an C5-8 hydrocarbon solvent and an aqueous mineral acid; (ii) stirring the biphasic mixture to provide the corresponding deprotected boric acid compound of formula (Xa) or (XXXX): (iii) separating the solvent phases; and (iv) extracting the compound of formula (Xa), (XJJJ) or a boric acid aldehyde thereof, in an organic solvent. The organic boric acid acceptor of step (i) is preferably aliphatic. aryl or ar (aliphatic) boric acid. In some embodiments, the boric acid acceptor is selected from the group consisting of phenylboronic acid, benzylboric acid, butylboric acid, pentylboronic acid, hexylboric acid, and cyclohexylboric acid. In certain embodiments, the boric acid acceptor is isobutylboronic acid. In some embodiments, the boric acid acceptor is selected so that the boronic ester compound of formula (III) is formed as a byproduct of the deprotection reaction. The boronic ester compound of formula (III) can then be used in another batch embodiment of the process described above. In such embodiments, the R4-R5 moiety is recycled efficiently, which can be particularly advantageous if R4-R5 is an expensive chiral moiety. To improve the purity of the product, the aqueous phase containing the compound of formula (Xa) or (XIII) is preferably washed to remove the neutral organic impurities before the extraction step (iv). In such embodiments, step (iii) preferably comprises the steps: (1) separating the solvent phases; (2) adjust the aqueous phase to basic pH; (3) washing the aqueous phase with an organic solvent; and (4) adjusting the aqueous phase to a pH of less than about 6. In some embodiments, the invention relates to an improved process for making the proteasome inhibitor bortezomib. Thus, in one embodiment, the invention provides a large-scale process for forming a compound of formula (XIV): or an aldehyde of boric acid thereof. The process comprises the steps: (a) providing a complex "ato" boron of formula (XV): in which: R3 is a nucleofugic group; And it is a nucleofugal group; and M + is an alkali metal; (b) contacting the complex "ato" boron of formula (XV) with a Lewis acid under conditions that produce a boronic ester compound of formula (XVJ): said contacting step being carried out in a reaction mixture comprising: (i) a coordination ether solvent having a low miscibility with water; or (ii) an ether solvent having a low miscibility with water and a coordination co-solvent; (c) treating the boronic ester compound of formula (XVJ) with a reagent of formula M1-N (G) 2, wherein M1 is an alkali metal and each G individually or together is an amino group protecting group, to form an compound of formula (XVJJ): (d) removing the G groups to form a compound of the formula (XVJJJ): XVJJJ) or an acid addition salt thereof; (e) coupling the compound of formula (XVJJX) with a compound of formula (XIX); wherein: P1 is a cleavable amino group protecting moiety; and X is OH or a leaving group; to form a compound of formula (XX): wherein P1 is as defined above; (f) removing the protecting group P1 to form a compound of the formula (XXJ): or an acid addition salt thereof; (g) coupling of the compound of formula (XXJ) with a reagent of formula (XXJJ) (XXII) wherein X is OH or a leaving group, to form a compound of formula (XXIII): (XXIII); Y (h) deprotecting the boric acid residue to form the compound of formula (XJV) or a boric acid aldehyde thereof. In some embodiments, the process is characterized by at least one of the following characteristics (1) - (5). In certain preferred embodiments, the process is characterized by the five characteristics (l) - (5) shown below. (1) In the "ato" boron complex of formula (XV), R3 and Y are both chloro. (2) The coupling step (e) comprises the steps: (i) coupling the compound of formula (XVJJJ) with a compound of formula (XIX) wherein X is OH in the presence of 2- (1H-benzotriazole tetrafluoroborate -1-yl) -1, 1, 3, 3-tetramethyluronium (TBTU) and a tertiary amine in dichloromethane; (ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and (iii) performing an aqueous wash of the ethyl acetate solution. (3) The step of removing the protecting group (f) comprises the steps: (i) treating the compound of formula (XX) with HCl in ethyl acetate; (ii) adding heptane to the reaction mixture; and (iii) isolating by crystallization the compound of formula (XXJ) in the form of its HCl addition salt. (4) The coupling step (g) comprises the steps: (i) coupling the compound of formula (XXJ) with 2-pyrazine carboxylic acid in the presence of TBTU and a tertiary amine in dichloromethane; (ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and (iii) performing an aqueous wash of the ethyl acetate solution. (5) The step of deprotection of boric acid (h) comprises the steps: (i) providing a biphasic mixture comprising the compound of formula (XXJJJ), an organic boric acid acceptor, a lower alkanol, a hydrocarbon solvent C5_ s and an aqueous mineral acid; (ii) stirring the biphasic mixture to produce the compound of formula (XJV); (iii) separating the solvent phases; and (iv) extracting the compound of formula (XJV) or a boric acid aldehyde thereof, in an organic solvent. Preferably, step (h) (iii) comprises the steps: (1) separating the solvent phases; (2) adjust the aqueous phase to basic pH; (3) washing the aqueous phase with an organic solvent; and (4) adjusting the aqueous phase to a pH of less than about 6; In another embodiment, the invention relates to a large scale process for forming a compound of formula (XJV) or an aldehyde of boric acid thereof, the steps comprising: (aa) coupling a compound of formula (XVJJJ): (VJJJ) or an acid addition salt thereof, with a compound of formula (XJX): wherein: P1 is a cleavable amino group protecting moiety; and X is OH or a leaving group; to form a compound of formula (XX): (XX) wherein P1 is as defined above, said coupling step (aa) comprising the steps: (i) coupling the compound of formula (XVXXX) with a compound of formula (XXX) wherein X is OH in the presence of 2- (IH-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and a tertiary amine in dichloromethane; (ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and (iii) performing an aqueous wash of the ethyl acetate solution; (bb) removing the protecting group P1 to form a compound of the formula (XXX): or an acid addition salt thereof, said step of removing the protecting group (bb) comprising the steps: (i) treating the compound of formula (XX) with HCl in ethyl acetate; (ii) adding heptane to the reaction mixture; and (iii) isolating the compound of formula by crystallization (XXJ) in the form of its HCl addition salt; (ce) coupling the compound of formula (XXJ) with a reagent of formula (XXJJ) (XXJJ) wherein X is OH or a leaving group, to form a compound of formula (XXXXX): (XXIII), said coupling step (ce) comprising the steps: (i) coupling the compound of formula (XXJ) with 2-pyrazinecarboxylic acid in the presence of TBTU and a tertiary amine in dichloromethane; (ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and (iii) performing an aqueous wash of the ethyl acetate solution; and (dd) deprotecting the boric acid moiety to form the compound of formula (XJV) or a boric acid aldehyde thereof, said deprotection step (dd) comprising the steps: (i) providing a biphasic mixture comprising the compound of formula (XXJ J), an organic boric acid acceptor, a lower alkanol, a C5-8 hydrocarbon solvent and an aqueous mineral acid; (ii) stirring the biphasic mixture to produce the compound of formula (XJV); (iii) separating the solvent phases; and (iv) extracting the compound of formula (XJV) or a boric acid aldehyde thereof, in an organic solvent. Preferably, step (dd) (iii) comprises the steps: (1) separating the solvent phases; (2) adjust the aqueous phase to basic pH; (3) washing the aqueous phase with an organic solvent; and (4) adjusting the aqueous phase to a pH of less than about 6; The efficiency of the processes described above is improved by telescopic steps, for example, by bringing the reaction mixture or solution of product treated with a reaction directly to the next reaction, without isolation of the intermediate product. For example, in some embodiments, step (e) (iii) or (aa) (iii) produces an ethyl acetate solution comprising a compound of formula (XX) and the ethyl acetate solution is directly subjected to step (f) or (bb) to effective conditions for removing the protecting group P1. In some of those embodiments, the protecting group P1 is an acid-stable protective group, for example, tert-butoxycarbonyl (Boc) and the ethyl acetate solution of step (e) (iii) or (aa) (iii) is treated with acid. In certain preferred embodiments, the ethyl acetate solution of step (a) (iii) or (aa) (iii) is azeotropically dried and then treated with gaseous HCl. When the deprotection step (f) or (bb) is carried out under anhydrous conditions, as described above, the product of formula (XXJ) can be isolated by crystallization of the reaction mixture in the form of its HCl addition salt. Crystallization of the product salt is promoted by the addition of a hydrocarbon solvent such as n-heptane. In some embodiments, the reaction mixture is partially concentrated prior to the addition of the hydrocarbon solvent. The present inventors have discovered that the crystallization of the compound of formula (XXX) in this manner effectively removes any tripeptide impurities that may have formed during the coupling step (e) or (aa). Such impurities are difficult to remove in the later stages of the synthesis. It is possible to further abbreviate the process by bringing the product mixture from the coupling stage (g) or (ce) directly to the deprotection step of the boric acid residue (g) or (dd). Preferably, the organic solvent of the coupling step is first replaced with ethyl acetate in order to facilitate aqueous washing. A second exchange of solvent in a hydrocarbon solvent then allows the solution of the product of step (g) or (ce) to be used directly in the deprotection step of biphasic boric acid (h) or (dd), without isolation of the compound of formula (XXIII). Alternatively, a more convergent approach can be adopted for the synthesis of the compound of formula (XJV). Thus, in another embodiment, the invention provides a large-scale process for forming a compound of formula (JV) or an aldehyde of boric acid thereof. The process comprises the steps: (a) providing a complex "ato" boron of formula (XV): wherein: R3 is a nucleofugic group; And it is a nucleofugal group; and M + is an alkali metal; (b) contacting the complex "ato" boron of formula (XV) with a Lewis acid under conditions that produce a boronic ester compound of formula (XVJ): said contacting step being carried out in a reaction mixture comprising: (i) a coordination ether solvent having a low miscibility with water; or (ii) an ether solvent having a low miscibility with water and a coordination co-solvent; (c) treating the boronic ester compound of formula (XVJ) with a reagent of formula M1-N (Si (R6) 3) 2, wherein M1 is an alkali metal and each Rd is independently selected from the group consisting of alkyl, aralkyl and aryl, wherein the aryl or aralkyl portion is optionally substituted, to form a compound of formula (XVJJ): (XVJJ) (d) removing the (R) 3Si groups to form a compound of the formula (XVJXX): (XVXIJ) or an acid addition salt thereof; (e ') coupling the compound of formula (XVJJJ) with a compound of formula (XlXa): wherein X is OH or a leaving group, to form a compound of formula (XXIII): (XXIII); Y (f ') deprotecting the boric acid residue to form the compound of formula (XJV) or a boric acid aldehyde thereof. In some embodiments, the process is characterized by at least one of the following characteristics (1) - (3). In certain preferred embodiments, the process is characterized by the three characteristics (l) - (3) shown below. (1) In the "ato" boron complex of formula (XV), R3 and Y are both chloro. (2) The coupling step (e1) comprises the steps: (i) coupling the compound of formula (XVJXX) with a compound of formula (XXXa) wherein X is OH in the presence of 2- (IH-benzotriazole tetrafluoroborate -l-yl) -1, 1, 3, 3-tetramethyluronium (TBTU) and a tertiary amine in dichloromethane; (ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and (iii) performing an aqueous wash of the ethyl acetate solution. (3) The step of deprotection of boric acid (f) comprises the steps: (i) providing a biphasic mixture comprising the compound of formula (XXJJJ), an organic boric acid acceptor, a lower alkanol, a hydrocarbon solvent C5_ and an aqueous mineral acid; (ii) stirring the biphasic mixture to produce the compound of formula (XJV); (iii) separating the solvent phases; and (iv) extracting the compound of formula (XJV) or a boric acid aldehyde thereof, in an organic solvent. Preferably, step (f) (iii) comprises the steps: (1) separating the solvent phases; (2) adjust the aqueous phase to basic pH; (3) washing the aqueous phase with an organic solvent; and (4) adjusting the aqueous phase to a pH of less than about 6; In step (h) (iv), (dd) (iv) or (f) (iv) of the processes described above, the compound of formula (XIV) or a boric acid aldehyde thereof, is preferably extracted in acetate of ethyl and crystallized by the addition of hexane or heptane. In some embodiments, the process further comprises isolating the boric acid anhydride of the compound of formula (XXV), preferably a trimeric boronic acid anhydride of formula (XXXV): The processes of the invention allow the large-scale manufacture of bortezomib of very high chemical purity and stereochemistry. The prior processes of the technique limited the scale and produced the product with a lower total purity. In still another aspect, therefore, the invention provides a composition comprising at least one kilogram of a compound of formula (XXIV): The compound of formula (XXIV) is preferably prepared according to the process described above, and preferably constitutes at least 99% w / w of the composition according to this aspect of the invention. EXAMPLES Abbreviations BOC tert-butoxycarbonyl D.l. deionized DMF AA7-dimethylformamide GC gas chromatography GC-MS gas chromatography-hour mass spectrometry HDPE high-density polyethylene HPLC high-performance liquid chromatography LDA diisopropylamide lithium LOD lost on drying min minutes MTBE t-butyl methyl ether RP-HPLC high performance liquid chromatography and reverse phase RPM revolutions per minute TBTU O-benzotriazol-1-yl- N, N, N 'tetrafluoroborate , N '-tetramethyluronium THF tetrahydrofuran Example 1: Manufacturing process of trifluoroacetate-3-methylbutane-1-boronate of (IR) - (S) -pinanodiol 1-ammonium (IS) - (S) -pinanodiol l-chloro-3-methylbutane-l-boronate 1 2-Methylpropane-l-boronate (S) -phenynediol (12.0 kg, 50.8 mol) was charged to a reaction vessel maintained under a nitrogen atmosphere. 2. Tert-butyl methyl ether (53 kg) and dichloromethane (22.5 kg) were charged and the resulting mixture was cooled to -57 ° C with stirring. 3. Diisopropylamine (6.7 kg) was charged to another reaction vessel maintained under a nitrogen atmosphere. 4. Tert-butyl methyl ether (27 kg) was charged to the diisopropylamine and the resulting mixture was cooled to -10 ° C with stirring. 5. N-Hexyllithium in hexane (33.2% by weight solution) (17.6 kg) was added to the diisopropylamine mixture over a period of 57 minutes, while the reaction temperature was maintained from -10 ° C to -7 ° C. 6. This mixture (LDA mixture) was stirred for 33 minutes at -9 ° C to -7 ° C before use. 7. Zinc chloride (12.1 kg) was charged to a third reaction vessel maintained under a nitrogen atmosphere. 8. Tert-Butyl methyl ether (16 kg) was charged to the zinc chloride and the resulting mixture was heated to 30 ° C with stirring. 9. Tetrahydrofuran (53 kg) was added to the zinc chloride suspension for a period of 18 minutes, while the reaction temperature was maintained at 35 ° C to 40 ° C. 10. This mixture (mixture of ZnCl 2) was stirred for 4 hours and 28 minutes at 38 ° C to 39 ° C until used. 11. The LDA mixture (# 3-6) was added over a period of 60 minutes to the reaction vessel containing 2-methylpropane-1-boronate (S) -pinenediolboronate, while the reaction temperature was maintained at - 60 ° C to -55 ° C. 12. A rinse of tert-butyl methyl ether (10 kg) was used to complete the addition. 13. The reaction mixture was stirred for a further 20 minutes at -59 ° C to -55 ° C. 14. The reaction mixture was heated to -50 ° C for a period of 11 minutes. 15. The ZnCA mixture (from # 7-10) was added over a period of 48 minutes to the reaction vessel containing 2-methylpropane-1-boronate (S) -pinenediol and the LDA mixture, while the reaction was maintained from -50 ° C to -45 ° C. 16. A rinse of tert-butyl methyl ether (10 kg) was used to complete the addition. 17. The reaction mixture was stirred for a further 30 minutes at -45 ° C to -40 ° C and then heated at 10 ° C for a period of 81 minutes. 18. A 10% solution of sulfuric acid (72 kg) was added to the reaction vessel over a period of 40 minutes, while the reaction temperature was maintained from 10 ° C to 21 ° C. 19. The reaction mixture was stirred for 16 minutes at room temperature, before removing the aqueous phase. 20. The organic phase was washed successively with deionized water (D.l.) (32 kg), and a 10% solution of sodium chloride (26.7 kg), each wash involving vigorous stirring for 15 to 17 minutes at room temperature. 21. The reaction mixture was concentrated under reduced pressure (Pmin = 81 mbar), maintaining an external temperature (jacket / bath) of 50 ° C to 55 ° C, providing a residue which was dissolved in methylcyclohexane (56 kg). 22. The reaction mixture was heated to reflux (in a Dean-Stark type condenser for water separation) under reduced pressure (pmin-67 mbar), maintaining an external temperature (jacket / bath) of 50 ° C to 55 ° C. ° C for 2 hours and 7 minutes, until no more water was separated. 23. Approximately 35 1 of the solvents were removed by distillation under reduced pressure (Pmm = 81 mbar), maintaining an external temperature (jacket / bath) of 50 ° C to 55 ° C. 24. The resulting dry methylcyclohexane mixture containing l-chloro-3-methylbutane-l-boronate of (SS) - (S) -phenynediol was cooled to 14 ° C. 1-Bis (trimethylsilyl) amino-3-methylbutane-1-boronate of (1R) - (S) -phenynediol 1. Lithium bis (trimethylsilyl) amide was charged to tetrahydrofuran (20% solution)., 4% by weight), (41.8 kg) in a reaction vessel maintained under a nitrogen atmosphere and cooled to -19 ° C with stirring. 2. The mixture of methylcyclohexane containing l-chloro-3-methylbutane-1-boronate of (1S) - (S) -phenynediol was added over a period of 55 minutes, while the reaction temperature was maintained at -19 °. C at -13 ° C. 3. A methylcyclohexane rinse (5 kg) was used to complete the addition. 4. The reaction mixture was stirred for a further 65 minutes at -13 ° C to -12 ° C and then heated at 25 ° C for a period of 25 minutes. 5. A suspension of Celite (2.5 kg) in methylcyclohexane (22 kg) was added to the reaction mixture. 6. The reaction mixture was concentrated under reduced pressure (Pimn = 25 mbar), maintaining an external temperature (jacket / bath) of 45 ° C to 50 ° C, providing a residue which was dissolved in methylcyclohexane (36 kg). 7. Then, a sample was withdrawn for the assay in process for the content of tetrahydrofuran by GC. 8. The tetrahydrofuran assay was 0.58%. 9. The solids were removed by filtration and the filtrate was filtered through a pad of silica gel (2.0 kg). 10. Both filter units were washed with isopropyl ether (30 kg). 11. The resulting methylcyclohexane / isopropyl ether mixture containing 1-bis (trimethylsilyl) amino-3-methylbutane-1-boronate of (IR) - (S) -phenynediol was stored in a container at room temperature until it was used in the next stage. Trifluoroacetate-3-methylbutane-1-boronate (IR) - (S) -phenynediol-1-ammonium 1. Trifluoroacetic acid (12 kg) was charged to another reaction vessel maintained under a nitrogen atmosphere. 2. Isopropyl ether (78 kg) was charged to trifluoroacetic acid and the resulting mixture was cooled to -10 ° C with stirring. 3. The methylcyclohexane / isopropyl ether mixture containing 1-bis (trimethylsilyl) amino-3-methylbutane-l-boronate of (IR) - (S) -phenynediol was added over a period of 53 minutes causing precipitation of the product, while the reaction temperature was maintained from -10 ° C to -5 ° C. 4. An isopropyl ether rinse (5 kg) was used to complete the addition. 5. The reaction mixture was stirred for 8 hours and 20 minutes more than -9 ° C to -7 ° C. 6. The solid was collected by filtration, washed with isopropyl ether (70 kg) in two portions and dried under reduced pressure (pmin = 56 mbar) from 41 ° C to 42 ° C for 2 hours and 15 minutes. 7. The solid was stirred with water D.l. (60 kg) for 24 minutes at room temperature, before the water D.l. was removed by filtration. 8. The solid was washed with water D. (12 kg). 9. The solid was then dried under vacuum (pmin = 4 mbar) at 40 ° C to 44 ° C for 9 hours and 22 minutes, after which the loss after drying was 0.51%, which satisfies the requirement of < 1% . 10. Then, the intermediate, 1-ammonium trifluoroacetate-3-methylbutane-1-boronate of (IR) - (S) -phenylene diol, crude, was packed in unitary polyethylene bags in polypropylene drums and marked. The yield was 72%. Recrystallization of 1-ammonium trifluoroacetate-3-methylbutane-1-boronate from (IR) - (S) -phenynediol, crude 1. Charged 1-ammonium trifluoroacetate-3-methylbutane-l-boronate from (IR) - (S) pinanediol, crude, (13 kg) in a reaction vessel maintained in a nitrogen atmosphere. 2. Trifluoroacetic acid (31 kg) was charged to the reaction vessel and the resulting mixture was cooled to 4 ° C with stirring. 3. When all of the solid was dissolved leaving a slightly cloudy mixture, isopropyl ether (29 kg) was added over a period of 57 minutes, while the reaction temperature was maintained at 2 ° C to 3 ° C. 4. After the addition was complete, the mixture was filtered through a filter in a receiving vessel maintained under a nitrogen atmosphere. 5. The reactor and the filter were rinsed with a mixture of trifluoroacetic acid (3.8 kg) and isopropyl ether (5 kg).

The rinse was added to the filtrate. 6. Isopropyl ether (126 kg) was added over a period of 15 minutes causing the product to precipitate, while the reaction temperature was maintained from 16 ° C to 18 ° C. 7. The mixture was stirred at 16 ° C to 18 ° C for 15 min, then cooled to -5 ° C over a period of 67 minutes and stirred at -3 ° C to -5 ° C under a nitrogen atmosphere. for 89 minutes. 8. The solid was then isolated by filtration, washed in two portions with isopropyl ether (48 kg) and dried under vacuum (pmin = 2 mbar) from 34 ° C to 40 ° C for 2 hours and 55 minutes, after which the loss after drying was 0.32%, which satisfies the requirement of < 0.5%. 9. Then, the product, l-ammonium trifluoroacetate-3-methylbutane-1-boronate (IR) - (S) -pinanodiol, was packed in double polyethylene bags in fiber barrels and marked. The yield was 86%. Example 2: Manufacturing process of N- (2-pyrazine-carbonyl) -L-phenylalanine-L-leucine-boric anhydride N-BOC-L-phenylalanine-L-leucine-boronate (1S), S, 3R, 5S) -pinanodiol 1. In a fuming layer, a three-neck glass reaction flask equipped with a Claisen head temperature log and a mechanical stirrer was flushed with nitrogen. 2. 1-ammonium trifluoroacetate-3-methylbutane-1-boronate (IR) - (S) -pinenediol (2.0 kg) was charged to the flask. 3. BOC-L-phenylalanine (1.398 kg) was charged into the flask. 4. 2- (lH-Benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium, TBTU (1,864 kg) tetrafluoroborate was charged to the flask.

. Dichloromethane (15.8 1) was charged into the flask. 6. The resulting motor was adjusted to provide agitation at 260 RPM. 7. Using an ice / water cooling bath, the reaction mixture was cooled to 1.0 ° C, maintaining a nitrogen atmosphere. 8. N, N-diisopropylethylamine (2.778 l) was charged to a glass flask and transferred to the reaction mixture over a period of 117 minutes using a peristaltic pump maintaining a range of the reaction temperature of 0.7 ° C - 2.1 ° C. The total addition rate was 23.7 ml / min. 9. A dichloromethane rinse (0.2 1) was used from the flask in the reaction mixture to complete the addition. 10. The reaction mixture was stirred for a further 35 minutes.

The temperature at the beginning of this time was 1.8 ° C, and 2.5 ° C at the end. 11. Next, a sample was withdrawn for in-process assay by high-performance liquid chromatography and reverse-phase chromatography (RP-HPLC). It was determined that the conversion percentage was 99.3%. 12. The reaction mixture was transferred in approximately two equal parts to two rotary evaporator flasks. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, maintaining an external bath temperature of 29-30 ° C. 13. Ethyl acetate (4.01) was divided into two approximately equal portions and charged into the two rotary evaporator flasks. 14. The mixtures from each flask were again concentrated under reduced pressure using a rotary evaporator, maintaining an external bath temperature of 29-30 ° C. 15. The residues from each rotary evaporator flask were then transferred to the reaction flask using ethyl acetate (13.34 1). 16. In a glass flask equipped with an agitator, a 1% aqueous solution of phosphoric acid was prepared by mixing water D. (13.18 1) and phosphoric acid (0.160 kg). 17. In a glass flask equipped with a stirrer, a 2% aqueous solution of potassium carbonate (12.0 1) was prepared by mixing water D. (11.76 1) and potassium carbonate (0.24 kg). 18. In a glass flask equipped with an agitator, a 10% aqueous solution of sodium chloride (13.34 1) was prepared by mixing water D. (13.34 1) and sodium chloride (1.334 kg). 19. D. I (13.34 1) water containing the ethyl acetate solution was charged to the reaction flask and the mixture was stirred at 380 RPM for 7 minutes. The phases were allowed to separate and the aqueous phase (bottom layer) was transferred under vacuum to a suitable flask and discarded. 20. Again, D.I. (13.34 1) water was charged to the reaction flask containing the ethyl acetate solution and the mixture was stirred at 385 RPM for 7 minutes. The phases were allowed to separate and the aqueous phase (bottom layer) was transferred under vacuum to a suitable flask and discarded. 21. The 1% solution of phosphoric acid prepared in Step 16 was charged into the reaction flask containing the ethyl acetate solution and the mixture was stirred at 365 RPM for 7 minutes. The phases were allowed to separate and the acidic aqueous phase (bottom layer) was transferred to a suitable flask and discarded. 22. The 2% potassium carbonate solution prepared in Step 17 was charged into the reaction flask containing the ethyl acetate solution and the mixture was stirred at 367 RPM for 7 minutes. The phases were allowed to separate and the basic aqueous phase (bottom layer) was transferred to a suitable flask and discarded. 23. The 10% solution of sodium chloride prepared in Step 18 was charged into the reaction flask containing the ethyl acetate solution and the mixture was stirred at 373 RPM for 6 minutes. The phases were allowed to separate and the aqueous phase (bottom layer) was transferred to a suitable flask and discarded. 24. The ethyl acetate solution was transferred to a rotary evaporator flask and concentrated under reduced pressure using a rotary evaporator, maintaining a bath temperature of 29-30 ° C, to provide a residue. 25. Then, the residue was redissolved in ethyl acetate (4.68 1). 26. The solution was concentrated in vacuo using a rotary evaporator, maintaining a bath temperature of 29-30 ° C, to again provide a residue. 27. Again, the residue was then redissolved in ethyl acetate (4.68 1) and samples were taken for the determination of the water content by Karl Fisher titration. The water content of the two samples was determined as 0.216% and 0.207%. 28. Using a further amount of ethyl acetate (12.66 1), the mixture was transferred from the rotary evaporator flask to a dry reaction flask equipped with a temperature log, a mechanical stirrer and a vitrified gas dispersion tube, and purged with nitrogen. L-phenylalanine-L-leucine boronate of (1S, 2S, 3R, 5S) -pinanodiol, HCl salt 1. The ethyl acetate solution containing N-BOC-L-phenylalanine-L-leucine boronate (IS) , 2S, 3R, 5S) -pinanodiol was cooled using an ice / water cooling bath at -0.9 ° C. 2. Hydrogen chloride gas (1.115 kg) was bubbled into the reaction mixture over a period of 1.48 hours. The temperature at the beginning of the addition was -0.9 ° C, and 6.8 ° C at the end. 3. Then, the reaction was allowed to warm to 14.4 ° C for 50 minutes, while maintaining a nitrogen atmosphere. 4. A sample was withdrawn for the in-process assay by RP-HPLC. The conversion percentage was 68.9% (area%). 5. The reaction was stirred for 35 minutes. The temperature at the beginning was 14 ° C and 14.8 ° C at the end. 6. A sample was withdrawn for the assay in process by RP-HPLC. The conversion percentage was 94.7% (area%). 7. The reaction was stirred for approximately 50 more minutes, maintaining a temperature of 10 ° C ± 5 ° C. 8. A sample was withdrawn for the in-process assay by RP-HPLC. The conversion percentage was 97.3%. 9. The reaction was stirred for approximately 50 more minutes, maintaining a temperature of 10 ° C ± 5 ° C. The final temperature was 14.6 ° C. 10. A sample was withdrawn for the in-process assay by RP-HPLC. The total reaction time after the addition of hydrogen chloride gas was four (4) hours. 11. The conversion percentage was 99%. 12. A suspension was observed. 13. N-heptane (8.8 1) was charged into the reaction mixture. 14. The suspension was stirred for 2 hours. The temperature at the beginning of the stirring time was 12.7 ° C, and 15.3 ° C at the end. 15. The solid was isolated by filtration on a Buchner funnel coated with a layer of polypropylene filter paper. 16. The solid was washed with n-heptane (4.68 1). 17. In one lid, the solid was transferred to three drying trays no more than 1"deep and air dried for 1 hour 18. Then, the solid was dried at <35 ° C at a vacuum of 27 ° C. "Hg for 16 hours and 28 minutes in a vacuum oven equipped with a vacuum gauge and temperature record. 19. The solid was sampled from each drying tray to determine the% loss after drying. It was determined that the LOD was 0%, 0.02%, and 0.02% for the three samples taken.

. Then, L-phenylalanine-L-leucine boronate (1S, 2S, 3R, 5S) -Pinanodiol, HCl salt in double poly bags in fiber drums were packaged and labeled and sampled. 21. The isolated yield was 1.87 kg, 79.1%. The intermediate was stored at 2-8 ° C until it was used in the additional manufacture. N- (2-Pyrazinecarbonyl) -L-phenylalanine-L-leucine boronate of (1S, 2S, 3R, 5S) -pinanodiol 1. In a fuming layer, a three-neck glass reaction flask was flushed with nitrogen thoroughly. with a Claisen head, temperature log and a mechanical agitator. 2. L-phenylalanine-L-leucine boronate (1S, S, 3R, 5S) -pinenediol, HCl salt (1.85 kg) was charged into the flask. 3. 2-Pyrazinecarboxylic acid (0.564 kg) was charged into the flask. 4. 2- (H-Benzotriazol-1-yl) -1,3,3-tetramethyluronium tetrafluoroborate, TBTU (1,460 kg) tetrafluorophosphate was charged into the flask. 5. Dichloromethane (18.13 1) was charged to the flask. 6. The agitation motor was adjusted to provide agitation at 272 RPM. 7. Using a cooling bath, the reaction mixture was cooled to -1.2 ° C. 8. N, N-diisopropylethylamine (1.865 kg) was charged in a glass flask and transferred to the reaction over a period of 50 minutes using a peristaltic pump maintaining a reaction temperature range of -1.2 ° C to 2 ° C. , 8 ° C. 9. A dichloromethane rinse (0.37 1) was used from the flask in the reaction mixture to complete the addition. 10. The reaction mixture was allowed to warm and stirred for an additional 81 minutes. 11. The temperature at the beginning of the agitation time was 15 ° C, and 24.9 ° C at the end. 12. Afterwards, a sample was withdrawn for the in-process assay by RP-HPLC. It was determined that the conversion percentage was 99.9%. 13. The reaction mixture was transferred in approximately two equal halves to two rotary evaporator flasks.

The reaction mixture was concentrated under reduced pressure using two rotary evaporators, maintaining an external bath temperature of 33-34 ° C. 14. Ethyl acetate (12.95 1) was divided into two approximately equal portions and rotary evaporators were charged into the two flasks. 15. Thereafter, the mixtures in each flask were concentrated under reduced pressure using a rotary evaporator, maintaining an external bath temperature of 33-34 ° C. 16. Then, the residues from each rotary evaporator flask were transferred to the reaction flask using ethyl acetate (12.95 1). 17. In a glass flask equipped with a stirrer, a 1% aqueous solution of phosphoric acid was prepared (12.34 1) mixing water D. I. (12.19 1) and phosphoric acid (0.148 kg). 18. In a glass flask equipped with an agitator, a 2% aqueous solution of potassium carbonate (12.34 1) was prepared by mixing water D. (12.09 1) and potassium carbonate (0.247 kg). 19. In a glass flask equipped with an agitator, a 10% aqueous solution of sodium chloride (12.34 1) was prepared by mixing water D. (12.34 1) and sodium chloride (1.234 kg). 20. Water D. (12.34 1) was charged to the reaction flask containing the ethyl acetate solution and the mixture was stirred at 382 RPM for 7 minutes. The phases were allowed to separate and the aqueous phase (bottom layer) was transferred to a suitable flask and discarded. 21. Again, D.I. (12.34 1) water was charged to the reaction flask containing the ethyl acetate solution and the mixture was stirred at 398 RPM for 7 minutes. The phases were allowed to separate and the aqueous phase (bottom layer) was transferred to a suitable flask and discarded. 22. The 1% solution of phosphoric acid prepared in Step 17 was charged into the reaction flask containing the ethyl acetate solution and the mixture was stirred at 364 RPM for 8 minutes. The phases were allowed to separate and the acidic aqueous phase (bottom layer) was transferred to a suitable flask and discarded. 23. The 2% potassium carbonate solution prepared in Step 18 was charged into the reaction flask containing the ethyl acetate solution and the mixture was stirred at 367 RPM for 8 minutes. The phases were allowed to separate and the basic aqueous phase (bottom layer) was transferred to a suitable flask and discarded. 24. The 10% solution of sodium chloride prepared in Step 19 was charged into the reaction flask containing the ethyl acetate solution and the mixture was stirred at 374 RPM for 8 minutes. The phases were allowed to separate and the aqueous phase (bottom layer) was transferred to a suitable flask and discarded. 25. The ethyl acetate solution was transferred in vacuo into approximately two halves equal to the two rotary evaporator flasks and concentrated under reduced pressure using a rotary evaporator, maintaining an external bath temperature of 34 ° C. 26. N-heptane (14.8 1) was divided into two approximately equal portions and rotary evaporators were charged into the two flasks. Then, the mixtures of each flask were concentrated under reduced pressure using a rotary evaporator, maintaining an external bath temperature of 34 ° C. N- (2-pyrazine-carbonyl) -L-phenylalanine-L-leucine-boronic anhydride 1. In a glass flask equipped with a stirrer, a 1 N solution of hydrochloric acid (22.2 1) was prepared by mixing water DI (20.36 1) and hydrochloric acid (1.84 kg). 2. In a glass flask equipped with a stirrer, a 2 N solution of sodium hydroxide (12.03 1) was prepared by mixing water D. (12.03 1) and sodium hydroxide (0.962 kg). 3. Then, the residues containing N- (2-pyrazine-carbonyl) -L-phenylalanine-L-leucine boronate of (1S, 2S, 3R, 5S) -phenynediol in each rotary evaporator flask were transferred to a reaction flask of Three-neck glass equipped with a temperature register and a mechanical stirrer, using n-heptane (14.8 1) and methanol (14.8 1). 4. The agitation motor was adjusted to provide agitation at 284 RPM. 5. 2-Methylpropanoboric acid (0.672 kg) was charged to the flask. 6. 1 N hydrochloric acid prepared in Step 1 (11.2 1) was charged to the flask. 7. The agitation motor was adjusted to provide agitation at 326 RPM. 8. The reaction mixture was stirred for 16.38 hours. The temperature of the starting batch was 28.6 ° C, and the final temperature of the batch was 21.6 ° C. 9. Next, a sample was withdrawn for the in-process assay by RP-HPLC. 10. It was determined that the conversion percentage was 100%. 11. The stirring was stopped and the biphasic mixture allowed to separate. 12. The n-heptane phase (upper layer) was transferred to a suitable flask and discarded. 13. N-heptane (5.37 1) was charged into the reaction flask and the mixture was stirred at 381 RPM for 6 minutes. The phases were allowed to separate and the n-heptane phase (upper layer) was transferred to a suitable flask and discarded. 14. Again, n-heptane (5.37 1) was charged into the reaction flask and the mixture was stirred at 340 RPM for 6 minutes. The phases were allowed to separate and the n-heptane phase (upper layer) was transferred to a suitable flask and discarded.

. The aqueous methanol solution was transferred in approximately two equal halves to the two rotary evaporator flasks and concentrated under reduced pressure using a rotary evaporator, maintaining an external bath temperature of 33-34 ° C. 15 1 of methanol was collected. 16. Dichloromethane (5.37 1) was used to transfer the residue from the rotary evaporator flasks to the reaction flask. 17. 2 N sodium hydroxide (11.2 1) prepared in Step 2 was charged into the flask. 18. The dichloromethane phase (lower layer) was transferred to a suitable flask and discarded. 19. Dichloromethane (5.37 1) was charged into the flask and the mixture was stirred at 374 RPM for 6 minutes. The phases were allowed to separate and the dichloromethane phase (lower layer) was transferred to a suitable flask and discarded. 20. Again, dichloromethane (5.37 1) was charged into the flask and the mixture was stirred at 368 RPM for 8 minutes. The phases were allowed to separate and the dichloromethane phase (lower layer) was transferred to a suitable flask and discarded. 21. Dichloromethane (5.37 1) was charged into the flask. 22. 1 N Hydrochloric acid (10.7 1) was charged to the flask with stirring. It was determined that the pH of the aqueous phase was 6. 23. Agitation was discontinuous and the phases were allowed to separate. 24. The dichloromethane phase (lower layer) was transferred under vacuum to a glass receiving flask. 25. Dichloromethane (5.37 1) was charged into the flask and the mixture was stirred at 330 RPM for 6 minutes. The phases were allowed to separate and the dichloromethane phase (lower layer) was transferred to a glass receiving flask. 26. Again, dichloromethane, (5.37 1) was charged to the flask and the mixture was stirred at 335 RPM for 6 minutes. The phases were allowed to separate and the dichloromethane phase (lower layer) was transferred to a glass receiving flask. 27. The dichloromethane extracts were combined and transferred in approximately two halves equal to the two rotary evaporator flasks and concentrated under reduced pressure using a rotary evaporator, maintaining an external bath temperature of 33-34 ° C. 28. Ethyl acetate (12.95 1) was divided into two approximately equal portions and rotary evaporators were charged into the two flasks. Then, the mixtures in each flask were concentrated under reduced pressure using a rotary evaporator, maintaining an external bath temperature of 45-46 ° C. 29. Again, ethyl acetate was divided (12, 95 1) in two approximately equal portions and loaded in the two rotary evaporator flasks. Then, the mixtures of each flask were concentrated under reduced pressure using a rotary evaporator, maintaining an external bath temperature of 45-46 ° C, until approximately 10% of the original volume remained. 30. N-heptane (10.2 1) was divided into two approximately equal portions and the rotary evaporators were charged to the two flasks, and the suspension was stirred under a nitrogen atmosphere for 2.67 hours at 22-23 ° C. 31. The solid was isolated by filtration in a Buchner funnel, coated with a layer of polypropylene filter paper. 32. The solid was washed with n-heptane (2.96 1). 33. In a lid, the solid was transferred to four drying trays and air-dried for 1.25 hours. 34. The solid was then dried at 36-50 ° C under a vacuum of 27"Hg for 18 hours and 27 minutes in a vacuum oven equipped with a vacuum gauge and a temperature log 35. The solid was sampled from each tray to determine the% loss of drying (LOD) .The LOD was determined to be 0.38%, 0.62%, 0.71%, and 0.63% in the four samples taken. 36. N- (2-pyrazine-carbonyl) -L-phenylalanine-L-leucine-boric acid, raw, was packed in two bottles of 5 1, HDPE, unmanufactured and wide-mouthed and labeled. 37. The isolated yield was 1,314 kg, 83%. Recrystallization of anhydride N- (2-Pyrazinecarbonyl) -L-phenylalanine-L-leucine boronic-anhydride, crude 1. In a lid, a glass reaction flask equipped with a mechanical stirrer, a reflux condenser was flushed with nitrogen. and a temperature record. 2. ethyl acetate (21 1) was charged into the flask. 3. The ethyl acetate was heated to 66.8 ° C under a nitrogen atmosphere, using a hot water / steam bath. 4. N- (2-pyrazine-carbonyl) -L-phenylalanine-L-leucine-boronic anhydride anhydride (1.311 kg) was slowly charged into the reaction flask. A change occurred during a period of 3 minutes. 5. The mixture was stirred for 1 minute until all the solid dissolved. The temperature of the solution was 64 ° C. 6. The heat source was removed and the mixture cooled slowly to 60 ° C using a cold bath. 7. The hot ethyl acetate solution was transferred into a receiving flask by multiple pipes and a polyethylene line filter capsule using a peristaltic pump. 8. The mixture was allowed to cool to 27.2 ° C and was allowed to stand under a nitrogen atmosphere without stirring for 17.75 hours. The final recorded temperature was 20.5 ° C. 9. The mixture was cooled using an ice / water bath with stirring for 2.33 hours. The temperature at the beginning of the agitation time was 3.8 ° C and -2.8 ° C at the end. 10. The solid was isolated by filtration in a Buchner funnel coated with a layer of polypropylene filter paper. The filtrate was collected in a collection flask. 11. The solid was washed with ethyl acetate (2.62 1) and cooled to 4.7 ° C. 12. In one lid, the solid was transferred to two drying trays. 13. The solid was then dried at 51-65 ° C under a vacuum of 27"Hg for 19 hours and 10 minutes in a vacuum oven equipped with a vacuum gauge and a temperature record. sampled to determine the% loss after drying (LOD) The LOD was determined to be 0.65% and 0.62% for the two samples taken 15. N- (2-pyrazine-carbonyl) anhydride was packed L-phenylalanine-L-leucine-boricum in four amber 3 1 wide mouth bottles, Type 3, with Teflon Coated Lids and marked 16. The isolated yield was 1,132 kg, 86.3%. 17. N- (2-pyrazine-carbonyl) -L-phenylalanine-L-leucine-boric anhydride anhydride was stored at -25 to -15 ° C. Example 3: Convergent Synthesis of N- (2-Pyrazinecarbonyl) -L-phenylalanine-L-leucine-boronic anhydride N- (2-Pyrazinecarbonyl) -L-phenylalanine-L-leucine-boronate of (1S, S, 3R, 5S ) -pinanodiol A solution of 1-ammonium trifluoroacetate-3-methylbutane-l-boronate of (IR) - (S) -phenynediol (13.97 g) and JV7"- hydroxysuccinimide (6.23 g) in 66 ml of DMF was cooled to -5 ° C, followed by the addition of dicyclohexylcarbodiimide (10.83 g) The resulting suspension was stirred for one hour at a temperature of -5 to 0 ° C. To a solution of N- (2- pyrazine-carbonyl) -L-phenylalanine (19.52 g, prepared by coupling the preformed succinimide ester of pyrazinecarboxylic acid with L-phenylalanine in dioxane-water) in 62 ml of DMF was added N-methylmorpholine (5.7 ml ) at a temperature of 0 ° C, and the resulting solution was added to the suspension.The suspension was adjusted to pH 7 by the addition of, 7 ml more of N-methylmorpholine and stirred overnight, slowly increasing the temperature to 21 ° C. After filtration, the filter cake was washed twice with MTBE and the combined filtrates were diluted with 950 ml of MTBE. The organic phase was washed with 20% aqueous citric acid (3 x 150 ml), 20% aqueous NaHCO 3 (3 x 150 ml) and brine (2 x). The organic phase was dried over Na 2 SO 4, filtered and concentrated to yield 25.5 g (95.5%) of the title compound as a foam. As indicated by tic, this material contained some minor impurities, including about 2% cyclohexylurea.

N- (2-pyrazine-carbonyl) -L-phenylalanine-L-leucine-boronic anhydride A solution of N- (2-pyrazine-carbonyl) -L-phenylalanine-L-leucine-boronate of (1S, 2S, R , 5S) -phenynediol (25.2 g) in 207 ml of MeOH and 190 ml of hexane was cooled to 15 ° C, and 109.4 ml of 1 N HCl were added in portions, maintaining the temperature between 15 and 25 ° C. Then, 2-methylpropanoboric acid (8.67 g) was added with vigorous stirring, and stirring of the biphasic mixture was continued overnight. After separation of the two phases, the lower phase was extracted once with 75 ml of hexane. Then, the lower phase was concentrated in vacuo until it became turbid, followed by the addition of 109.4 ml of 2 N NaOH and 100 ml of Et20. The two phases were separated and the lower phase was extracted with Et20 (4 x 100 ml each) and then brought to pH 6.0 by the addition of 109 ml of 1 N HCl. After extraction with 100 ml of acetate of ethyl, the lower phase was adjusted to pH 6.0 with 1 N HCl and extracted once more with 75 ml of ethyl acetate. The combined ethyl acetate phases were washed with semi-saturated brine (2 x 25 ml) and brine (2 x 25 ml), dried over Na 2 SO, filtered and concentrated to yield 15.3 g (81.8%). ) of crude N- (2-pyrazine-carbonyl) -L-phenylalanine-L-leucine-boric anhydride in the form of a foam. The crude material was dissolved in 150 ml of ethyl acetate and concentrated in vacuo to a suspension, followed by the addition of 150 ml of MTBE. The suspension was stored at 2 to 8 ° C overnight, filtered, washed twice with MTBE and dried under high vacuum, yielding 10.69 g (57.2%) of N- (2-pyrazine-) anhydride. carbonyl) -L-phenylalanine-L-leucine-boric in the form of a white solid. Example 4: Measurement of the Diastereomeric Ratio of 1-ammoniotriflu? 3oacetate-3-methylbutane-1-boronate of (IR) - (1S, 2S, 3J, 5S) -pinanodiol The diastereomeric purity of 1-ammoniotrifluoroacetate-3-methylbutane -1-boronate of (IR) - (SS, 2S, 3R, 5S) -phenynediol (compound 1) was determined by non-chiral gas chromatography (GC). Acetonitrile products (p.a. Bruker or equivalent) Chemicals: Tetradecane (internal standard) (Fluka puriss or equivalent) Trifluoroacetic anhydride (TFAA) (pa Merck or equivalent) Instrumental: Trace-GC system 2000 or equivalent Mobile phase: H2 Solvent A (with Approximately 300 mg of tetradecane internal standard ) weighed to an accuracy of 0.1 mg in a 100 ml volumetric flask. 1.5 ml of TFAA were added and the flask was brought to volume with acetonitrile. Preparation of the sample Weigh approximately sample: 150 mg of the sample (within 0.1 mg) in a 10 ml volumetric flask. The flask was brought to volume with Solvent A. The solution was stored for 15 minutes before injection.

GC Parameters: Column: Rtx-200 film; 105 m x 0.25 mm d.i. x 0.25 μm Mobile phase: H2 P ogram of 130 ° C (0.5 min); 0.5 ° C / min at 200 ° C (0 Temp.: min); 30 ° C / min at 300 ° C (2 min) Fl uj o: 0.9 ml / min (condensed flow) Temperature of 250 ° C injector: Temperature of 250 ° C (FID) Detecto: Filter: 1: 50 Volume 1 μl Injectable: Substances Compound 1 1-ammonium trifluoroacetate-3-methylbutane-l-boronate (IR) - (ΔS, 2S, 3R, 5S) -phenynediol Compound 2 1-ammonium-trifluoroacetate-3-methylbutane-1-boronate (1S) - (1S, 2S, 3R, 5S) -phenynediol Stability of the solution A stock solution of compound 1 was prepared by weighing 150.13 mg of compound 1 into a 10 ml volumetric flask and bringing it to volume with solvent A. The stability of this solution was tested at room temperature for 48 hours. The stock solution was filled in 6 separate GC vials. Injections in the GC system were made from these vials after 0, 12, 24, 48 and 72 hours (double injection of each vial.) The% area of compound 1 and compound 2 was determined. No changes were observed in the % area, indicating that the solution is stable during 72 hours at room temperature. Specificity Approximately 150 mg of a sample comprising Compound 1 and Compound 2 was dissolved in Solvent A and injected into the GC chromatography system. The peak for compound 1 was well separated from the peak for compound 2. Verification of peak purity by GC-MS showed that no other components were co-eluted with compound 1 or compound 2. Limit of detection Limit of Detection (LOD) was defined as the concentration at which the signal of compound 1 showed a signal at noise ratio of at least 3: 1. An earlier blank measurement was made to show that other peaks did not interfere. The signal to noise ratio was calculated by the equation: SINE = - H (^ siSnal) H aseliné) S / N = signal at noise ratio H (signal) = signal height for compound 1 [mm] H (reference) = height of the reference signal [mm] A sample concentration of 0.05% of the concentration of the conventional test sample was injected and showed a noise ratio signal of 4.3. Therefore, the limit of detection is 0.0075 mg / ml. Quantitation limit The limit of quantitation (LOQ) was defined as the concentration at which the signal of compound 1 showed a noise ratio signal of at least 10: 1. The noise ratio signal was calculated as described above. A sample concentration of 0.1% of the conventional sample concentration was injected and showed a noise ratio signal of 10.1. Therefore, the limit of quantification is 0.015 mg / ml. Example 5: Purity test for N- (2-pyrazine-carbonyl) -L-phenylalanine-L-leucine-boric anhydride The purity of N- (2-pyrazine-carbonyl) -L-phenylalanine-L-leucine-boric anhydride (compound 3) was assayed by reverse phase HPLC. Reagents: Water, HPLC quality Acetonitrile, HPLC quality Formic acid, ACS quality, pure > 98% Hydrogen peroxide at 3%, quality of ACS or equivalent Inspire to the Chroma to gra fí a Autosampler capable of releasing high liquid injections of 20 μl and maintaining a temperature resolution of 5 ° C Pump capable of releasing the gradient at 1.0 ml / min. UV detector capable of controlling waste water at 270 nm Column chromatographic column of Symmetry C18, 250 mm x 4.6 mm ID, 5 μm, Waters, Cat. WAT054275. Preparation of the sample Weigh out approximately sample: 50 mg of compound 3 in a 50 ml volumetric flask. Mobile Phase B (5 ml) was added and the mixture was sonic to dissolve compound 3 (approximately 30-60 seconds). The solution was allowed to reach room temperature, diluted to volume with Mobile Phase A and mixed well. Each sample was prepared in duplicate and was stable for 7 days, when stored at 2-8 ° C protected from light. HPLC parameters: Mobile phase A: acetonitrile / water / formic acid, 30: 70: 0.1 (v / v / v), degassed Mobile phase B: acetonitrile / water / formic acid, 80: 20: 0.1 ( v / v / v), degassing Flow rate: 1.0 ml / min Detector: UV at 270 nm Volume of 20 μl injection: Temp. of column: Temp. of Tray 5 ° C of sample: Program Time% A% B gradient: 0 100 0 15 100 0 30 0 100 45 0 100 47 100 0 55 100 0 Substances Compound 3 Anhydride N N-- ((22- ~ pyrazine-carbonyl ) -L- phenylalanine-L-leucine-boric anhydride Compound 4 N- (2-pyrazine-carbonyl) -L-phenylalanine-D-leucine-boric anhydride Compound 5 N- (2-pyrazine-carbonyl) -L-phenylalanine-D-1-boric anhydride The reaction time of compound 3 was typically between 10 and 14 minutes when an HPLC system with a volume of 1.3 minutes was used. Compounds 4 and 5 co-eluted at the longest retention time, with a resolution of > 2.0. The relative retention of compound 3 in a sample chromatogram with respect to the standard chromatogram was calculated according to the following equation: tinues tsttl Where: Rx = relative retention Aues = retention time of the peak of compound 3 in the sample chromatogram, minutes tstd = retention time of the drug substance peak in the nearest previous conventional chromatogram, minutes The test results were calculated for each sample according to the following equation: Amues Wsld XP 1 Voessayo = xxx lOO Asid Wmues ÍIOO - S 100 Where : Aiuues = peak area response of compound 3 in the sample preparation gtd = response to the main peak area of compound 3 in the standard treatment preparation Wstd = weight of the standard, mg P = purity assigned to the standard (decimal format) ) Wmues = weight of the sample, mg M = moisture content of the sample,% 100 = conversion to percentage Relative retention and the impurity levels of each sample were calculated according to the following equations: Where: Rr = relative retention ti = retention time of the individual impurity tds = retention time of the peak of compound 3 Where: Ii = individual impurity i = response to the peak area of the individual impurity in the sample preparation Astd,?% = Average peak response of compound 3 in the conventional preparation at 1% std = standard weight, mg " "sample weight of the sample, mg P assigned purity of the standard (decimal format) DF dilution factor, 1/100 RFi = relative response factor of the individual impurity 100 = conversion to the percentage factor When tested by this method, the N- (2-pyrazine-carbonyl) -L-phenylalanine-L-leucinaboric anhydride of Example 2 showed total impurities of less than 1%. Although the above invention has been described in detail for purposes of clarity and understanding, these particular embodiments should be considered as illustrative and not restrictive. A person skilled in the art will appreciate, from a reading of this description, that various changes in shape and detail can be made without departing from the true scope of the invention and the appended claims.

Claims (91)

1. 1. A large-scale process for preparing a boric ester compound of formula (X): wherein: R1 is an optionally substituted aliphatic, aromatic or heteroaromatic group; R2 is hydrogen, a nucleofugic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; R3 is a nucleophilic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; and each of R4 and R5, independently, is an optionally substituted aliphatic, aromatic or heteroaromatic group or R4 and R5, taken together with the oxygen and boron atoms involved, form an optionally substituted 5 to 10 membered ring having 0 -2 more heteroatoms in the ring selected from N, O or S; said process comprising the steps: (a) providing a complex "ato" boron of formula (JJ): 3 RY2 £ AOR4 OR BR "55 M +: JJ) where Y is a nucleofugic group, M + is a cation, and each of R1 to R5 is as defined above, and (b) put in contacting the "ato" boron complex of formula (XX) with a Lewis acid under conditions that produce the boronic ester compound of formula (J), said contacting step being carried out in a reaction mixture comprising: (i) a solvent of coordinating ether having a low miscibility with water; or (ii) an ether solvent having a low miscibility with water and a co-solvent of coordination.

2. The process of claim 1, wherein the reaction mixture comprises a coordination co-solvent.

3. The process of claim 2, wherein the coordination co-solvent is selected from the group consisting of tetrahydrofuran, dioxane, water, and mixtures thereof.

4. The process of claim 0, wherein the coordination co-solvent does not constitute more than about 20% v / v of the reaction mixture.

5. The process of claim 0, wherein the coordination solvent does not constitute more than about 15% v / v of the reaction mixture.

6. The process of claim 1, wherein the solubility of water in the ether solvent having a low miscibility with water is less than about 2% w / w.

7. The process of claim 0, wherein the ether solvent having a low miscibility with water is selected from the group consisting of tert-butyl methyl ether, tert-butyl ethyl ether, tert-amyl methyl ether, isopropyl ether, and mixtures of the same.

8. The process of claim 0, wherein the ether solvent having a low miscibility with water constitutes at least about 70% v / v of the reaction mixture.

9. The process of claim 1, wherein at least about 5 moles of the "ato" boron complex of formula (JJ) are provided in step (a).

10. The process of claim 1, wherein at least about 20 moles of the "ato" boron complex of formula (JJ) are provided in step (a).

11. The process of claim 1, wherein at least about 50 moles of the "ato" boron complex of formula (JJ) are provided in step (a).

12. The process of claim 1, wherein at least about 100 moles of the "ato" boron complex of formula (JJ) are provided in step (a).

13. The process of claim 1, wherein the Lewis acid is selected from the group consisting of zinc chloride, zinc bromide, ferric chloride, and ferric bromide.

14. The process of claim 0, wherein the Lewis acid is wet.

15. The process of claim 0, wherein in step (a) the "ato" boron complex of formula (JJ) is provided in a solution comprising an ether solvent having a low miscibility with water, and the contacting step ( b) comprises the steps: (i) providing a solution comprising a Lewis acid and tetrahydrofuran; and (ii) adding the Lewis acid solution to the "ato" boron complex solution of formula (JJ) of step (a).

16. The process of claim 0, wherein in step (a) the "ato" boron complex of formula (JJ) is provided in a solution comprising an ether solvent having a low miscibility with water, and the contacting step ( b) comprises the steps: (i) providing a solution comprising a Lewis acid and water; and (ii) adding the Lewis acid solution to the "ato" boron complex solution of formula (JJ) of step (a).

17. The process of claim 1, wherein Y is a halogen.

18. The process of claim 1, wherein Y is chloro.

19. The process of claim 1, wherein R1 is aliphatic C? _8, aryl C6-? Or / or (aryl C6-? O) (aliphatic C? _6) •

20. The process of claim 1, wherein M + is selected from the group consisting of Li +, Na +, and K "A

21. The process of claim 1, wherein R4 and R5, taken together with the oxygen and boron atoms involved, form an optionally substituted 5-membered ring.

22. The process of claim 0, wherein R4 and R5 together are a chiral moiety.

23. The process of claim 0, wherein the "ato" boron complex of formula (JJ) is:

24. The process of claim 0, wherein step (b) provides the boronic ester compound of formula (J) wherein the carbon atom bearing R1, R2, and R3 is a chiral center having a diastereomeric ratio of at least about 96: 4 with respect to a chiral center in the chiral moiety R4-R5.

25. The process of claim 0, wherein step (b) provides the boronic ester compound of formula (J) wherein the carbon atom bearing R1, R2, and R3 is a chiral center having a diastereomeric ratio of at least about 97: 3 with respect to a chiral center in the chiral moiety R4-R5.

26. The process of claim 0, characterized by at least one of the following characteristics: (a) the contacting step (b) is carried out in a reaction mixture comprising tert-butyl methyl ether; (b) the Lewis acid is zinc chloride; (c) at least about 5 moles of the boric ester of formula (JJ) are provided in step (a); (d) the contact step (b) is carried out at a reaction temperature in the range of about -60 ° C to about -30 ° C; (e) Lewis acid is moist; (f) And it is chlorine; (g) R3 is chloro; (h) R2 is hydrogen; and R is aliphatic C? _4

27. The process of claim 0, characterized by at least two of the features (a) - (h).

28. The process of claim 0, characterized by at least three of the features (a) - (h).

29. The process of claim 0, characterized by the eight features (a) - (h) in their entirety.

30. The process of claim 0, further comprising: (c) washing the reaction mixture with an aqueous solution; and (d) concentrating the washed reaction mixture by removing the solvents to give a residue comprising the boronic ester compound of formula (J).

31. The process of claim 0, wherein the residue comprises at least about five moles of the boronic ester compound of formula (J).

32. The process of claim 0, wherein the boronic ester compound of formula (J) present in the residue has a diastereomeric ratio of at least about 96: 4 at the carbon atom carrying R1, R2, and R3, with respect to a chiral center in the chiral residue R4-R5.

33. The process of claim 0, wherein the boronic ester compound of formula (J) present in the residue has a diastereomeric ratio of at least about 97: 3 at the carbon atom carrying R1, R2, and R3, with respect to a chiral center in the chiral residue R4-R5.

34. A composition comprising an ether solvent having a low miscibility with water and at least about ten moles of a boric ester compound of formula (J): R OR 5: D wherein: R 1 is an optionally substituted aliphatic, aromatic or heteroaromatic group; R2 is hydrogen, a nucleofugic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; R3 is a nucleophilic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; and each of R4 and R5, independently, is an optionally substituted aliphatic, aromatic or heteroaromatic group or R4 and R5, taken together with the oxygen and boron atoms involved, form an optionally substituted 5 to 10 membered ring having 0 -2 more heteroatoms in the ring selected from N, O or S.

35. A composition comprising an ether solvent having a low miscibility with water and at least about ten moles of a boronic ester compound of formula (X): wherein: R is an optionally substituted aliphatic, aromatic or heteroaromatic group; R2 is hydrogen, a nucleofugic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; R3 is a nucleophilic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; and each of R4 and R5, independently, is an optionally substituted aliphatic, aromatic or heteroaromatic group or R4 and R5, taken together with the oxygen and boron atoms involved, form an optionally substituted 5 to 10 membered ring having 0 -2 more heteroatoms in the ring selected from N, O or S. where the carbon atom to which R1, R2, and R3 are attached is a chiral center, which has a diastereomeric ratio of at least about 96: 4, with respect to to a chiral center in the chiral residue R4-R5.

36. A composition comprising an ether solvent having a low miscibility with water and at least about ten moles of a boronic ester compound of formula (J):, R 1 R 2 ', R B. R 4' ^ B 'OR 5 (J ) wherein: R1 is an optionally substituted aliphatic, aromatic or heteroaromatic group; R2 is hydrogen, a nucleofugic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; R3 is a nucleophilic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; and each of R4 and R5, independently, is an optionally substituted aliphatic, aromatic or heteroaromatic group or R4 and R, taken together with the oxygen and boron atoms involved, form an optionally substituted 5 to 10 membered ring having 0 -2 more heteroatoms in the ring selected from N, 0 or S. where the carbon atom to which R1, R2, and R3 are attached is a chiral center, which has an epimeric ratio of at least about 96: 4,

37. The composition of any one of claims 0-0, wherein the solubility of water in the ether solvent is less than about 2% w / w.

38. The composition of any one of claims 0-0, wherein the ether solvent is selected from the group consisting of tert-butyl methyl ether, tert-butyl ethyl ether, tert-amyl methyl ether, isopropyl ether, and mixtures thereof .

39. The composition of any one of claims 0-0, wherein R1 is aliphatic A-s, aryl C6-? O, or (aryl C-? O) (aliphatic C? -?).

40. The composition of any one of claims 0-0, characterized by at least one of the following characteristics: (a) R3 is chlorine; (b) R2 is hydrogen; and (C) R1 is aliphatic C? _

41. The composition of any one of claims 0-0, wherein R4 and R5, taken together with the oxygen and boron atoms involved, form an optionally substituted 5-membered ring.

42. The composition of any one of claims 0-0, wherein the compound of formula (J) is

43. A composition comprising at least about ten moles of a boronic ester compound of formula (J): wherein: R1 is an optionally substituted aliphatic, aromatic or heteroaromatic group; R2 is hydrogen, a nucleofugic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; R3 is a nucleophilic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; and each of R4 and R5, independently, is an optionally substituted aliphatic, aromatic or heteroaromatic group or R4 and R5, taken together with the oxygen and boron atoms involved, form an optionally substituted 5 to 10 membered ring having 0 -2 more heteroatoms in the ring selected from N, O or S. wherein the carbon atom to which R1, R ", and R3 are attached is a chiral center, having a diastereomeric ratio of at least about 96: 4, with respect to a chiral center in the chiral moiety R4-R5, and where the boronic ester compound of formula (J) constitutes at least about 70% w / w of the composition.

44. The composition of claim 0 comprising at least about 20 moles of the boronic ester compound of formula (J).

45. The composition of claim 0, wherein the carbon atom to which R1, R2, and R3 are attached has a diastereomeric ratio of at least about 97: 3, with respect to a chiral center in the chiral moiety R4-R5.

46. The composition of claim 0, wherein all the boronic ester compound of formula (J) present in the composition is produced in a single batch.

47. The composition of claim 0, wherein all the boronic ester compound of formula (J) present in the composition is produced in a single batch of the process according to claim 1. *

48. The composition of claim 0, wherein there is present at least one of the following characteristics: (a) R3 is chlorine; (b) the boronic ester compound of formula (J) is: (c) R2 is hydrogen; and: d) R is aliphatic C? -q

49. A large-scale process for preparing a boric ester compound of formula (J): wherein: R1 is an optionally substituted aliphatic, aromatic or heteroaromatic group; R2 is hydrogen, a nucleofugic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; R3 is a nucleophilic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; and each of R4 and R5, independently, is an optionally substituted aliphatic, aromatic or heteroaromatic group or R4 and R5, taken together with the oxygen and boron atoms involved, form an optionally substituted 5 to 10 membered ring having 0 -2 more heteroatoms in the ring selected from N, 0 or S; said process comprising: (a) providing a solution comprising: (i) a boric ester of formula (JJJ): ^ ts OR 4 OR 5 (JJJ) wherein R, R, and R are as defined above; and (ii) an ether solvent having a low miscibility with water; (b) treating the solution with a reagent of formula (JV): R3 Ri Y? M ':? ) to form a complex or "ato" boron of formula (J): R3 AY -é BV "= M + OR5 (jj) in which: Y is a nucleophilic group, M + is a cation, and each of R1 to R5 is as defined above, and (c) put in contact the boron complex "ato" of formula (JJ) with a Lewis acid under conditions giving the boronic ester compound of formula (J), said contacting step being carried out in a reaction mixture comprising: (i) an ether coordination solvent having a low miscibility with water; or (ii) an ether solvent having a low miscibility with water and a co-solvent of coordination.

50. A large scale process for preparing a boric ester compound of formula (J): R2R1 R3% OR4 OR5 (j) in which: R1 is an optionally substituted aliphatic, aromatic or heteroaromatic group; R2 is hydrogen, a nucleofugic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; R3 is a nucleophilic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; and each of R4 and R5, independently, is an optionally substituted aliphatic, aromatic or heteroaromatic group or R4 and R5, taken together with the oxygen and boron atoms involved, form an optionally substituted 5 to 10 membered ring having 0 -2 more heteroatoms in the ring selected from N, O or S; said process comprising: (a) providing a solution comprising: (i) a boric ester of formula (JJJ): Rl ^ OR4 R5 (JJJ) wherein R1, R4, and R5 are as defined above; (ii) a compound of formula (V): R2 R3 and Y H (V) where Y is a nucleofugic group, and R2 and R3 are as defined above; and (iii) a solvent comprising: (aa) an ether coordination solvent having a low miscibility with water; or (bb) an ether solvent having a low miscibility with water and a coordination co-solvent; (b) treating the solution of step (a) with a strong base, with spherical impedts, to form a complex "ato" boron of formula (XX): where M + is a cation derived from the base, and each of Y and R1 to R5 are as defined above; and (c) contacting the "ato" boron complex of formula (II) with a Lewis acid in a solution comprising an ether solvent having a low miscibility with water to form the boronic ester compound of formula (X ).

51. A large-scale process for preparing a boric ester compound of formula (I): wherein: R1 is an optionally substituted aliphatic, aromatic or heteroaromatic group; R2 is hydrogen, a nucleofugic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; R3 is a nucleophilic group or an optionally substituted aliphatic, aromatic or heteroaromatic group; and R 4 and R 5, taken together, form an optionally substituted linking chain comprising 2-5 carbon atoms and 0-2 heteroatoms selected from the group consisting of O, N, and S; said process comprising: (a) providing a solution comprising: (i) a boric acid compound of formula (VX): Rl .AH B OH (VI) where R1 is as defined above; (ii) a compound of formula HO-R4-R5-OH, wherein R4 and R5 are as defined above; and (iii) an organic solvent that forms an azeotrope with water; (b) heating the solution from step (a) to reflux, with azeotropic removal of the water, to form a boric ester of formula (XXX): R ^ OR4 (III) where R1, R4, and R5 are as defined above; (c) providing a solution comprising: (i) the boric ester of formula (III); (ii) a compound of formula (V): R2 R3 LH Y (v) where Y is a nucleofugic group, and R2 and R3 are as defined above; and (iii) a solvent comprising: (aa) an ether coordination solvent having a low miscibility with water; or (bb) an ether solvent having a low miscibility with water and a coordination co-solvent; (d) treating the solution of step (c) with a strong base, with steric hindrances, to form a boron complex "ato" of formula (XX): where M + is a cation derived from the base, and each of Y and R1 to R5 are as defined above; and (e) contacting the "ato" boron complex of formula (XI) with a Lewis acid in a solution comprising an ether solvent having a low miscibility with water to form the boronic ester compound of formula (X ).

52. The process of claim 0 or 0, wherein the sterically hindered base is an alkali metal dialkylamide base of formula M2N (R #) 2, wherein M2 is selected from the group consisting of Li, Na, and K, and each R *, independently, is a branched or cyclic C3_6 aliphatic.

53. The process of claim 0, wherein the organic solvent in step (a) is selected from the group consisting of acetonitrile, toluene, hexane, heptane, and mixtures thereof.

54. The process of claim 0, wherein the organic solvent in step (a) is an ether solvent having a low miscibility with water.

55. The process of claim 0, wherein the solutions in each of steps (a) and (c) comprise the same ether solvent.

56. The process of claim 0, wherein step (b) provides a product solution comprising the boric ester of formula (XXX), and the product solution of step (b) is used in step (c) without isolating the boric ester of formula (XXX).

57. A large scale process for preparing an aminoboronic ester compound of formula (VXX): R 1 H2N ErOR 4 OR 5 (vxx) or an acid addition salt thereof, wherein: wherein: R 1 is an aliphatic, aromatic or heteroaromatic group optionally substituted; and each of R4 and R5, independently, is an optionally substituted aliphatic, aromatic or heteroaromatic group or R4 and R5, taken together with the oxygen and boron atoms involved, form an optionally substituted 5 to 10 membered ring having 0 -2 more heteroatoms in the ring selected from N, O or S comprising said process: (a) providing a boron complex "ato" of formula (JJ): where Y is a nucleofugal group; M + is a cation; R "is hydrogen, R3 is a nucleofugic group, and each of R1, R4, and R5 are as defined above, (b) contacting the" ato "boron complex of formula (XJ) with a Lewis acid. under conditions giving the boronic ester compound of formula (J): S? : R1 4 R3"., OR B 'OR5 (j) wherein each of R1 to R5 is as defined above, said contacting step being carried out in a reaction mixture comprising: (i) a coordination solvent of ether having a low miscibility with water, or (ii) an ether solvent having a low miscibility with water and a co-solvent of coordination, (c) treating the boric ester compound of formula (J) with a reagent of formula M1-N (Si (R6) 3) 2, wherein M1 is an alkali metal and each R6 independently is selected from the group consisting of alkyl, aralkyl, and aryl, wherein the aryl or aryl portion of the aralkyl is optionally substituted, to form a by-product of formula M1-R3 and a compound of formula (VJIJ): R1 (G) 2IS EGOR4 OR5 (viii) wherein each G and R1 to R5 are as defined above, and (d) removing the G groups to form a compound of formula (VII): or an acid addition salt thereof.

58. The process of claim 0, wherein the reaction mixture in step (c) comprises an organic solvent in which the byproduct M1-R3 has poor solubility.

59. The process of claim 0, wherein M1 is Li and R3 is Cl.

60. The process of claim 0, wherein the reaction mixture in step (c) comprises an organic solvent selected from the group consisting of methylcyclohexane, cyclohexane, heptane, hexane, toluene, and mixtures thereof.

61. The process of claim 0, wherein the reaction in step (c) is carried out at a reaction temperature in the range of about -100 ° C to about 50 ° C.

62. The process of claim 0, wherein the reaction temperature is in the range of about -50 ° C to about 25 ° C.

63. The process of claim 0, wherein the reaction temperature is in the range of about -30 ° C to about 0 ° C.

64. The process of claim 0, wherein step (d) comprises treating the compound of formula (VXXX) with an acid and isolating the compound of formula (VXX) in the form of the acid addition salt.

65. The process of claim 0, wherein the acid is trifluoroacetic acid.

66. The process of claim 0, wherein step (c) further comprises filtering the reaction mixture to provide a filtrate comprising the compound of formula (VXXX).

67. The process of claim 0, wherein in step (c), the reagent of formula M1-N (Si (Rd) 3) 2 is added to the reaction mixture in the form of a solution comprising tetrahydrofuran, and the step ( c) further comprises removing the tetrahydrofuran before filtering the reaction mixture.

68. The process of claim 0, wherein the filtrate is used directly in step (d).

69. The process of claim 0, further comprising the step: (e) coupling the compound of formula (VJ) with a compound of formula (JX): R7 0 (IX) where: P1 is a moiety that blocks the amino group; R7 is selected from the group consisting of hydrogen, Ci-io aliphatic / optionally substituted Ce-io aryl, or Ci-β-8 aliphatic; and R8 is selected from the group consisting of alkoxy, alkylthio, optionally substituted aryl, heteroaryl, and heterocyclyl groups, and optionally protected amino, hydroxy, and guanidino groups; and X is OH or a leaving group; to form a compound of formula (X): where each of P1, R1, R4, R5, and R7 is as defined above.

70. The process of claim 0, wherein P1 is a cleavable protecting group.

71. The process of claim 0, further comprising the steps: (f) cleaving the protecting group P1 to form a compound of the formula (XJ): or an acid addition salt thereof, wherein each of R1, R4, R5, and R7 is as defined above; (g) coupling the compound of formula (XI) with a reagent of formula P2-X, where P2 is a moiety that blocks the amino group and X is a leaving group, to form a compound of formula (XII): wherein each of P2, R1, R4, R5, and R7 are as defined above; and (h) deprotecting the boric acid residue to form a compound of formula (XJJJ): or a boric acid anhydride thereof, wherein each of P1, R1, and R7 are as defined above.

72. A large-scale process for preparing an aminoboronic ester compound of formula (VJIa) or (Vllb): R1 R1 H2N- ^ B'OR4 H2N- ^ B-OR4 OR5 (VJJa) OR5 (Vllb) or an addition salt of acids thereof, wherein: R1 is an optionally substituted aliphatic, aromatic or heteroaromatic group; and R4 and R5, taken together with the oxygen and boron atoms involved, form an optionally substituted chiral cyclic boronic ester; said process comprising: (a) providing a complex "ato" boron of formula (JJa) or (I Ib): wherein Y is a nucleofugic group; M + is a cation; R2 is hydrogen; R3 is a nucleofugic group; and R4 and R5 are as defined above; (b) contact the boron complex "ato" of formula (JJa) or (llb) with a Lewis acid under conditions giving a boronic ester compound of formula (Ja) or (Ib): wherein each of R1 to R5 is as defined above, said contacting step being carried out in a reaction mixture comprising: (i) an ether coordination solvent having a low miscibility with water; or (ii) an ether solvent having a low miscibility with water and a coordination co-solvent; (c) treating the boronic ester compound of formula (Ja) or (Jb) with a reagent of formula M1-N (G) 2, wherein M1 is an alkali metal and each G is a protective moiety of the amino group, to form a compound of formula (Villa) or (VlIZb): R1 R1 (G) 2N B'OR4 (G) 2N ^ ETOR4 OR5 (Villa) OR5 (yjjjjb) where each G and R1 to R5 are as defined above; and (d) removing the G groups to form a compound of the formula (VJJa) or (Vllb): or an acid addition salt thereof

73. A large-scale process for forming a compound of formula (XJV): or a boric acid anhydride thereof, said process comprising: (a) providing an "ate" boron complex of formula (XV): where: M + is an alkali metal; (b) contacting the "ato" boron complex of formula (XV) with a Lewis acid under conditions giving a boronic ester compound of formula (XVJ): said contacting step being carried out in a reaction mixture which it comprises an ether solvent having a low miscibility with water; (c) treating the boric ester compound of formula (XVJ) with a reagent of formula M1-N (G) 2, where M1 is an alkali metal and each G individually or together is a protecting group of the amino group, to form a compound of formula I XVII): (d) removing the G groups to form a compound of the formula (XVJJJ): [XVJJJ) or an acid addition salt thereof; (e) coupling the compound of formula (XVJJJ) with a compound of formula (XIX); wherein P1 is a protective moiety of the cleavable amino group; and X is OH or a leaving group; to form a compound of formula (XX): where P1 is as defined above; (f) removing the protecting group P1 to form a compound of formula (XXI): or an acid addition salt thereof; (g) coupling the compound of formula (XXI) with a reagent of formula (XX J) where X is an OH or a leaving group, to form a compound of formula (XXIII): (XXIII); and (h) deprotecting the boric acid residue to form the compound of formula (XJV) or a boric acid anhydride thereof.

74. The process of claim 0, characterized by at least one of the following characteristics (l) - (5): (1) in the boron complex "ato" of formula (XV), R3 and Y are both chlorine; (2) the coupling step (e) comprises the steps: (i) coupling the compound of formula (XVJ) with a compound of formula (XIX) wherein X is OH in the presence of 2- (1H-benzotriazole-1-tetrafluoroborate) -yl) -1, 1, 3, 3-tetra-ethyluronium (TBTU) and a tertiary amine in dichloromethane; (ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and (iii) performing an aqueous wash of the ethyl acetate solution. (3) the step of removing the protecting group (f) comprises the steps: (i) treating the compound of formula (XX) with HCl in ethyl acetate; (ii) adding heptane to the reaction mixture; and (iii) isolating by crystallization the compound of formula (XXJ) in the form of its HCl addition salt; (4) the coupling step (g) comprises the steps: (i) coupling the compound of formula (XXJ) with 2-pyrazine carboxylic acid in the presence of TBTU and a tertiary amine in dichloromethane; (ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and (iii) performing an aqueous wash of the ethyl acetate solution; and (5) the step of deprotecting the boric acid (h) comprises the steps: (i) providing a biphasic mixture comprising the compound of the formula (XXIII), an organic boric acid acceptor, a lower alkanol, a C5_8 hydrocarbon solvent , and an aqueous mineral acid; (ii) stirring the biphasic mixture to give the compound of formula (XXV); (iii) separating the solvent layers; and (iv) extracting the compound of formula (XIV), or a boric acid anhydride thereof, in an organic solvent.

75. The process of claim 0, characterized by the five characteristics (l) - (5) in its entirety.

76. The process of claim 0, wherein step (h) (iii) comprises the steps: (1) separating the solvent layers; (2) adjust the aqueous layer to basic pH; (3) washing the aqueous layer with an organic solvent; and (4) adjusting the aqueous layer to a pH of less than about 8,

77. The process of claim 0, wherein in step (h) (iii) (3), the aqueous layer is washed with dichloromethane.

78. The process of claim 0, wherein in step (h) (iv), the compound of formula (XJV), or a boric acid anhydride thereof, is extracted into dichloromethane, the solvent is changed to ethyl acetate, and the compound of formula (XJV), or a boric acid anhydride thereof, is crystallized by the addition of hexane or heptane.

79. The process of claim 0, wherein the addition of hexane or heptane results in the crystallization of a cyclic trimeric boric acid anhydride of formula (XXJV):

80. A large-scale process for forming a compound of formula (XJV): or a boric acid anhydride thereof, comprising the steps: (aa) coupling a compound of formula (XVJ): (XVIII) or an acid addition salt thereof, with a compound of formula (XXX): wherein: P1 is a protective moiety of the cleavable amino group; and X is OH or a leaving group; to form a compound of formula (XX): wherein P1 is as defined above, said coupling step (aa) comprising the steps: (i) coupling the compound of formula (XVJJJ) with a compound of formula (XIX) wherein X is OH in the presence of tetrafluoroborate of 2- (1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium (TBTU) and a tertiary amine in dichloromethane; (ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and (iii) performing an aqueous wash of the ethyl acetate solution; (bb) removing the protecting group P1 to form a compound of the formula (XXJ): or an acid addition salt thereof, said step (bb) comprising removing the protecting group the steps: (i) treating the compound of formula (XX) with HCl in ethyl acetate; (ii) adding heptane to the reaction mixture; and (iii) isolating by crystallization the compound of formula (XXI) in the form of its HCl addition salt; (ce) coupling the compound of formula (XXI) with a reagent of formula (XXJJ) where X is an OH or a leaving group, to form a compound of formula (XXJII): (XXIII), said coupling step (ce) comprising the steps: (i) coupling the compound of formula (XXI) with 2-pyrazine carboxylic acid in the presence of TBTU and a tertiary amine in dichloromethane; (ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and (iii) performing an aqueous wash of the ethyl acetate solution; and (dd) deprotecting the boric acid residue to form the compound of formula (XJV) or a boric acid anhydride thereof, said deprotection step (dd) comprising the steps: (i) providing a biphasic mixture comprising the compound of formula (XXIII), an organic boric acid acceptor, a lower alkanol, a C5-8 hydrocarbon solvent, and aqueous mineral acid; (ii) stirring the biphasic mixture to give the compound of formula (XJV); (ii) separating the solvent layers; and (iv) extracting the compound of formula (XIV), or a boric acid anhydride thereof, in an organic solvent.

81. The process of claim 0, wherein step (dd) (iii) comprises the steps: (1) separating the solvent layers; (2) adjust the aqueous layer to basic pH; (3) washing the aqueous layer with an organic solvent; and (4) adjusting the aqueous layer to a pH of less than about 8.

82. The process of claim 0, where in the stage (dd) (iv), the compound of formula (XJV), or a boric acid anhydride thereof, is extracted into dichloromethane, the solvent is changed to ethyl acetate, and the compound of formula (XJV), or an anhydride of boric acid thereof, is crystallized by the addition of hexane or heptane.

83. The process of claim 0, wherein the addition of hexane or heptane results in the crystallization of a cyclic trimeric boric acid anhydride of formula (XXJV):

84. A large-scale process for forming a compound of formula (XIV): or a boric acid anhydride thereof. Understanding the process the stages: (a) provide a complex "ato" boron of formula (XV): wherein: R is a nucleofugic group; And it is a nucleofugal group; and M + is an alkali metal; (b) contacting the complex "ato" boron of formula (XV) with a Lewis acid under conditions giving a boric ester compound of formula (XVJ): said contacting step being carried out in a reaction mixture comprising: (i) an ether coordination solvent having a low miscibility with water; or (ii) an ether solvent having a low miscibility with water and a coordination co-solvent; (c) treating the boronic ester compound of formula (XVI) with a reagent of formula M1-N (Si (R6) 3) 2, wherein M1 is an alkali metal and each R6 is independently selected from the group consisting of alkyl, aralkyl, and aryl, wherein the aryl or aryl portion of the aralkyl is optionally substituted, to form a compound of the formula (XVJJ): ((dd)) rreettiirraarr 1los (R6) 3 Si to form a compound of formula (XVJJJ): (XVJJJ) or an acid addition salt thereof; (ep) coupling the compound of formula (XVJJJ) with a compound of formula (XlXa): wherein X is OH or a leaving group, to form a compound of formula (XXIII): (XXIII); Y (f) deprotecting the boric acid residue to form the compound of formula (XIV) or a boric acid anhydride thereof.

85. The process of claim 0, characterized by at least one of the following characteristics (l) - (3): (1) In the "ato" boron complex of formula (XV), R3 and Y are both chloro. (2) The coupling step (e ') comprises the steps: (i) coupling the compound of formula (XVIIJ) with a compound of formula (XJXa) wherein X is OH in the presence of 2- (1H-benzotriazole- tetrafluoroborate) 1-yl) -1,3,3,3-tetramethyluronium (TBTU) and a tertiary amine in dichloromethane; (ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and (iii) performing an aqueous wash of the ethyl acetate solution. (3) Understanding the stage of deprotecting boric acid (f) the steps: (i) providing a biphasic mixture comprising the compound of formula (XXJJJ), an organic boric acid acceptor, a lower alkanol, a C5 hydrocarbon solvent 8, and aqueous mineral acid; (ii) stirring the biphasic mixture to give the compound of formula (XJV); (iii) separating the solvent layers; and (iv) extracting the compound of formula (XJV), or a boric acid anhydride thereof, in an organic solvent.

86. The process of claim 0, wherein step (f) (iii) comprises the steps: (1) separating the solvent layers; (2) adjust the aqueous layer to basic pH; (3) washing the aqueous layer with an organic solvent; and (4) adjusting the aqueous layer to a pH of less than about 8.

87. The process of claim 0, wherein in step (f) (iii) (3), the aqueous layer is washed with dichloromethane.

88. The process of claim 0, wherein in step (f) (iv), the compound of formula (XJV), or a boric acid anhydride thereof, is extracted into dichloromethane, the solvent is changed to ethyl acetate, and the compound of formula (XJV), or a boric acid anhydride thereof, is crystallized by the addition of hexane or heptane.

89. The process of claim 0, wherein the addition of hexane or heptane results in the crystallization of a cyclic trimeric boric acid anhydride of formula (XXXV):

90. A composition comprising at least one kilogram of a compound of formula (XXJV): wherein the compound of formula (XXJV) is prepared according to the process of claim 0 or 0.

91. A composition comprising at least one kilogram of a compound of formula (XXJV): wherein the compound of formula (XXJV) constitutes at least 99% w / w of the composition.