HK1143982B - Methods and compounds useful for the preparation of sodium glucose co-transporter 2 inhibitors - Google Patents

Description

Methods and compounds for the preparation of sodium-glucose cotransporter 2 inhibitors

this application claims priority to U.S. provisional patent application 60/952,122 filed on 26.7.2008, which is incorporated herein by reference in its entirety.

1. Field of the invention

The present invention relates to a process for the preparation of sodium-glucose cotransporter 2 inhibitors.

2. Background of the invention

Sodium-glucose cotransporter 2(SGLT2) is a transporter that reabsorbs glucose from the filtrate of the kidney and prevents loss of glucose in the urine. Because competitive inhibitors of SGLT2 cause renal excretion of glucose, they are useful in normalizing high blood glucose levels associated with diseases such as diabetes. Handlon, A.L.,ExpertOpin.Ther.Patents15(11)：1531-1540(2005)。

in the search for new drugs that can be used to treat diabetes, a number of SGLT2 inhibitors have been disclosed. See, e.g., Handlon, supra; U.S. Pat. nos. 6,515,117; U.S. patent application publications US2006/0035841, US 2004/0138439. At least one inhibitor is in clinical development as a therapy for type2 diabetes. See, for example, Komoroski, B.et al, "Dapagliflozin (BMS-512148), aSelectiveInhibitorofheSodium-GlucoseUptake Transporter2(SGLT2), ReduccesFastSerumGlucoseandGlucoseExcursion type2diabetes MelitsAspientsOver 14 Days"AmericanDiabetesAssn.67 ^th ScientificSessions，Abstract0188-OR(2007)。

3. Summary of the invention

The present invention includes methods of making certain SGLT2 inhibitors, as well as compounds useful in the methods.

One embodiment of the present invention includes a process for preparing a compound of formula I:

the substitution of the compound is as defined herein, the method comprising reacting a compound of formula II:

with a base under suitable conditions.

The invention also includes various intermediates useful in the preparation of SGLT2 inhibitors, including compounds of formula I.

4. Description of the drawings

Certain aspects of the invention may be understood with reference to the drawings.

FIG. 1 is an X-ray diffraction pattern of a crystalline solid form of (2S, 3S, 4R, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylthio) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate. The spectra were obtained using a RigakuMiniFlex diffractometer (Cu (1.54060)) Radiation).

FIG. 2 is (4-chloro-3- (4-ethoxybenzyl) phenyl) ((3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d)][1，3]Dioxolan-5-yl) methanone. The spectra were obtained using a RigakuMiniFlex diffractometer (Cu (1.54060)) Radiation).

FIG. 3 shows ((3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d ]][1，3]X-ray diffraction pattern of a crystalline solid form of dioxolan-5-yl) (morpholinyl) methanone. The spectra were obtained using a RigakuMiniFlex diffractometer (Cu (1.54060)) Radiation).

FIG. 4 is an X-ray diffraction pattern of a crystalline solid form of 1-chloro-2- (4-ethoxybenzyl) -4-iodobenzene. The spectra were obtained using a RigakuMiniFlex diffractometer (Cu (1.54060)) Radiation).

5. Detailed description of the invention

Novel compounds that inhibit sodium-glucose cotransporter 2(SGLT2) have recently been disclosed. See U.S. provisional application 60/848,156 filed on 29/9/2006 and U.S. provisional application 60/905,714 filed on 8/3/2007. The present invention is based in part on the discovery of novel methods for preparing those compounds. The specific process of the invention allows for large scale production of the compounds.

5.1 definition

Unless otherwise specified, the term "alkenyl" refers to straight, branched, and/or cyclic hydrocarbons having from 2 to 20 (e.g., 2 to 10 or 2 to 6) carbon atoms and including at least one carbon-carbon double bond. Representative alkenyl groups include vinyl, allyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2, 3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, and 3-decenyl.

Unless otherwise indicated, the term "hydrocarbyloxy" refers to an-O-hydrocarbyl group. Examples of hydrocarbyloxy groups include, but are not limited to, -OCH₃、-OCH₂CH₃、-O(CH₂)₂CH₃、O(CH₂)₃CH₃、-O(CH₂)₄CH₃and-O (CH)₂)₅CH₃。

Unless otherwise specified, the term "hydrocarbyl" refers to straight, branched, and/or cyclic ("cyclic") hydrocarbons having 1 to 20 (e.g., 1 to 10 or 1 to 4) carbon atoms. Hydrocarbyl groups having 1 to 4 are referred to as "lower hydrocarbyl". Examples of hydrocarbyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4-dimethylpentyl, octyl, 2, 4-trimethylpentyl, nonyl, decyl, undecyl, and dodecyl. The cycloalkyl group may be monocyclic or polycyclic, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Further examples of hydrocarbyl moieties have linear, branched, and/or cyclic moieties (e.g., 1-ethyl-4-methyl-cyclohexyl). The term "hydrocarbyl" includes saturated hydrocarbons as well as alkenyl and alkynyl moieties.

Unless otherwise indicated, the term "alkylaryl" or "alkyl-aryl" refers to an alkyl moiety bound to an aryl moiety.

Unless otherwise indicated, the term "alkylheteroaryl" or "alkyl-heteroaryl" refers to an alkyl moiety bound to a heteroaryl moiety.

Unless otherwise indicated, the term "hydrocarbyl heterocycle" or "hydrocarbyl-heterocycle" refers to a hydrocarbyl moiety bound to a heterocyclic moiety.

Unless otherwise specified, the term "alkynyl" refers to a straight, branched, or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 20 or 2 to 6) carbon atoms and including at least one carbon-carbon triple bond. Representative alkynyl moieties include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl and 9-decynyl.

Unless otherwise indicated, the term "aryl" refers to an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen atoms. The aryl moiety may comprise multiple rings joined or fused together. Examples of aryl moieties include, but are not limited to, anthracenyl, azulenyl, biphenyl, fluorenyl, indane, indenyl, naphthyl, phenanthryl, phenyl, 1, 2, 3, 4-tetrahydronaphthalene, and tolyl.

Unless otherwise indicated, the term "arylalkyl" or "aryl-alkyl" refers to an aryl moiety bound to an alkyl moiety.

Unless otherwise indicated, the terms "halogen" and "halo" include fluorine, chlorine, bromine, and iodine.

Unless otherwise specified, the term "heterohydrocarbyl" refers to a hydrocarbyl moiety (e.g., linear, branched, or cyclic) in which at least one carbon atom of the hydrocarbyl moiety has been replaced with a heteroatom (e.g., N, O or S).

Unless otherwise specified, the term "heteroaryl" refers to an aryl moiety wherein at least one carbon atom of the aryl moiety has been replaced with a heteroatom (e.g., N, O or S). Examples include, but are not limited to, acridinyl, benzimidazolyl, benzofuranyl, benzisothiazolyl, benzisoxazolyl, benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furanyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, 2, 3-naphthyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl, and triazinyl.

Unless otherwise indicated, the term "heteroarylalkyl" or "heteroaryl-alkyl" refers to a heteroaryl moiety bound to an alkyl moiety.

Unless otherwise indicated, the term "heterocycle" refers to an aromatic, partially aromatic or non-aromatic, monocyclic or polycyclic ring or ring system consisting of carbon, hydrogen, and at least one heteroatom (e.g., N, O or S). The heterocyclic ring may include multiple (i.e., two or more) rings that are fused or joined together. Heterocycles include heteroaryls. Examples include, but are not limited to, benzo [1, 3] dioxolyl, 2, 3-dihydro-benzo [1, 4] dioxin yl, 1, 2-naphthyridinyl, furanyl, hydantoinyl, morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, and valerolactanyl.

Unless otherwise indicated, the term "heterocyclylalkyl" or "heterocycle-alkyl" refers to a heterocyclic moiety bound to an alkyl moiety.

Unless otherwise indicated, the term "heterocycloalkyl" refers to a non-aromatic heterocycle.

Unless otherwise indicated, the term "heterocycloalkylalkyl" or "heterocycloalkyl-alkyl" refers to a heterocycloalkyl moiety bound to an alkyl moiety.

Unless otherwise indicated, the term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, citric acid, malic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, fumaric acid,Glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Thus, examples of specific salts include hydrochloride and mesylate salts. Others are known in the art. See, for example, Remington's pharmaceutical sciences, 18^thed. (Mack publishing, Easton PA: 1990) and Remington: the science and practice of pharmacy, 19^thed.(MackPublishing，EastonPA：1995)。

Unless otherwise indicated, the term "stereoisomeric mixtures" includes racemic mixtures as well as stereoisomerically enriched mixtures (e.g., R/S ═ 30/70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35, and 70/30).

Unless otherwise indicated, the term "stereomerically pure" refers to a composition that includes one stereoisomer of a compound and is substantially free of other stereoisomers of the compound. For example, a stereomerically pure composition of a compound having one stereocenter is substantially free of the opposite stereoisomer of the compound. A stereomerically pure composition of a compound having two stereocenters is substantially free of other diastereomers of the compound. Typical stereoisomerically pure compounds include greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound.

Unless otherwise indicated, the term "substituted" when used to describe a chemical structure or moiety refers to a derivative of that structure or moiety wherein one or more of its hydrogen atoms is replaced by an atom, chemical moiety or functional group such as, but not limited to: alcohols, aldehydes, hydrocarbyloxy, alkanoyloxy, hydrocarbyloxycarbonyl, alkenyl, hydrocarbyl (e.g., methyl, ethyl, propyl, t-butyl), alkynyl, hydrocarbonyloxy (-OC (O) hydrocarbyl), amide (-C (O) NH-hydrocarbyl-or-hydrocarbylNHC (O) hydrocarbyl), amidino (-C (NH) NH-hydrocarbyl or-C (NR) NH-hydrocarbyl₂) Amines (primary, secondary and tertiary amines, such as alkylamino, arylamino, arylalkylamino), aroyl, aryl, aryloxy, azo, carbamoyl (-NHC (O) O-hydrocarbyl-or-OC (O) NH-hydrocarbyl), methionyl (e.g., CONH₂And CONH-alkyl, CONH-aryl and CONH-arylalkyl), carbonyl, carboxyl, carboxylic acid anhydride, carboxylic acid chloride, cyano, ester, epoxide, ether (e.g., methoxy, ethoxy), guanidino, halo, haloalkyl (e.g., -CCl)₃，-CF₃，-C(CF₃)₃) Heterocarbyl, hemiacetal, imines (primary and secondary imines), isocyanates, isothiocyanates, ketones, nitriles, nitro, oxo, phosphodiesters, sulfides, sulfonamides (e.g., SO)₂NH₂) Sulfones, sulfonyl groups (including hydrocarbyl sulfonyl, arylsulfonyl and arylalkylsulfonyl groups), sulfoxides, thiols (e.g., mercapto, thioether) and ureas (-NHCONH-hydrocarbyl-).

The term "comprising" means "including but not limited to" unless otherwise specified. Similarly, the term "such as" means "such as but not limited to".

Unless otherwise indicated, one or more adjectives immediately preceding a series of nouns are considered to modify each noun. For example, the expression "optionally substituted alkyl, aryl or heteroaryl" has the same meaning as "optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl".

It is noted that the chemical moieties that form part of the larger compound may be described herein by their name as a single molecule or by the name commonly used for their free radicals. For example, the terms "pyridine" and "pyridyl" have the same meaning when used to describe a group attached to another chemical moiety. Thus, the two phrases "XOH, wherein X is pyridyl" and "XOH, wherein X is pyridine" have the same meaning and include the compounds pyridine-2-ol, pyridine-3-ol and pyridine-4-ol.

It is noted that a structure or a part of a structure is to be interpreted as including all stereoisomers of it, if the stereochemistry of the structure or the part is not indicated, for example, by bold or dashed lines. In addition, any atom having an unsaturated valence represented in the figure is assumed to be attached to a sufficient hydrogen atom to satisfy its valence. In addition, chemical bonds represented by a solid line parallel to a dashed line include single and double bonds (e.g., aromatic), provided that valency permits.

5.2 methods

The present invention includes methods of preparing compounds of formula I:

wherein: y is O, S, NR₄Or C (R)₄)₂；Z₁Is O, S, SO or SO₂(ii) a Each R₁Independently hydrogen, halogen, cyano, OR_1A、SR_1AOr an optionally substituted hydrocarbyl group; each R_1AIndependently hydrogen or an optionally substituted hydrocarbyl or aryl group; each R₂Independently hydrogen, halogen, cyano, OR_2A、SR_2AOr an optionally substituted hydrocarbyl group; each R_2AIndependently hydrogen or an optionally substituted hydrocarbyl or aryl group; r₃Is an optionally substituted hydrocarbyl, aryl or heterocyclic ring; each R₄Independently hydrogen or an optionally substituted hydrocarbyl or aryl group; n is 1 to 3; and mIs 1-3.

Specific methods are shown in scheme 1 below:

reaction scheme 1

Wherein each P₁Independently a hydroxyl protecting group that is stable under acidic conditions. In this process, the compound of formula II (a) is oxidized to give the compound of formula II, which is then contacted with a base to give the compound of formula I. Suitable oxidation conditions are known in the art and include the use of peroxy compounds such as m-chloroperoxybenzoic acid, peroxyacetic acid, ozone, mixtures of the following: hydrogen peroxide or a hydrogen peroxide complex (e.g., urea hydrogen peroxide) with an anhydride (e.g., phthalic anhydride). Suitable bases are also known in the art and include alkoxides, hydroxides, carbonates, and amines.

Of course, various moieties (e.g., R) are provided herein₁-R₃) Potentially reactive moieties included in the definition of (a) may be protected using methods known in the art. In addition, the final product may undergo further reactions known in the art to yield other compounds encompassed by formula I. The final product may also be crystallized. In one method, the product is co-crystallized with an amino acid (e.g., L-phenylalanine, L-phenylglycine, L-arginine).

For all of the general structures and reactions disclosed herein (e.g., as disclosed in schemes 1-3), where appropriate, certain embodiments of the invention result in Y being C (R)₄)₂. In other embodiments, Z₁Is S, SO or SO₂. In other embodiments, each P is₁Independently C (O) R₅Wherein each R is₅Independently a hydrocarbyl, aryl, hydrocarbyl aryl or arylalkyl group. P₁Examples of (b) include acetyl, benzoyl and pivaloyl. In other placesIn embodiments, R₁Is OR_1AAnd R_1AIs for example optionally substituted lower alkyl. In other embodiments, R₂Is halogen. In other embodiments, R₃Is a lower alkyl group (e.g., methyl or ethyl). In other embodiments, R₄Is hydrogen. In other embodiments, m is 1. In other embodiments, n is 1.

In one embodiment, Y is CH₂，Z₁Is S or SO₂，R₁Is ethoxy, R₂Is chlorine, and R₃Is methyl. For example, in a particular method, the compound of formula I is represented by the formula:

in another embodiment, Y is CH₂，Z₁Is S or SO₂，R₁Is ethoxy, R₂Is chlorine, and R₃Is ethyl. For example, in a particular method, the compound of formula I is represented by the formula:

in a specific embodiment, the compound of formula ii (a) is of formula ii (b), which may be prepared as shown in scheme 2:

reaction scheme 2

Wherein X is bromine, iodine, alkylsulfonyl or alkoxysulfonyl. Suitable reaction conditions are known in the art. For example, basic conditions may be used (e.g., using a base such as N, N-diisopropylethylamine). In one method, the compound of formula ii (b) is represented by the formula:

one specific compound of formula II (b) is (2S, 3S, 4R, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylthio) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate:

the particular crystalline form of this compound has a melting point of about 156 ℃ as measured by Differential Scanning Calorimetry (DSC) (onset temperature). The crystalline form provides an X-ray powder diffraction (XRPD) pattern having one or more peaks at about 7.7, 11.9, 12.4, 16.9, 19.5, 19.9, 21.9, 23.2, 24.1, and/or 27.7 degrees 2 Θ. As is well known to those skilled in the art, the relative intensities of the peaks in the X-ray diffraction pattern of a crystalline form may vary depending on how the sample is prepared and how the data is collected. Accordingly, an example of an XRPD pattern of this crystalline form is provided in fig. 1.

In general, the compounds of formula ii (a) can be prepared by the process shown in scheme 3 below:

reaction scheme 3

Wherein: each P₂Independently a hydroxy protecting group stable under acidic conditions, or two P₂Taken together to form a single protecting group; x' is chlorine, bromine or iodine; and X' is a leaving group (e.g., amino, hydrocarbyloxyamino, hydroxyl, halogen, hydrocarbyloxy, phenoxy, carboxyl, sulfonyl). In a particular method, each P₂Independently C (O) R₆Or two of P₂Taken together to form C (R)₆)₂Wherein each R is₆Independently a hydrocarbyl, aryl, hydrocarbyl aryl or arylalkyl group.

In this process, the compound of formula II (a) may be obtained by contacting a compound of formula II (d) with a reagent and the reaction conditions depend on Z₂The nature of (c). For example, a compound of formula II (d) may be contacted with a Lewis acid (e.g., trimethylsilyltriflate) and thiourea to provide a compound wherein Z is₂Compounds that are S (e.g., formula II (c), as shown in scheme 2 above). The compound of formula II (d) may be contacted with a hydroxy compound under acidic conditions to give a compound wherein Z₂A compound which is O.

By reacting a compound of the formula II (e) with P₁-X' "is chloro, bromo, iodo, alkylcarboxyl, a hydrocarbylsulfonyl or hydrocarbyloxysulfonyl to obtain the compound of formula ii (d). Suitable reaction conditions are known in the art. For example, the reaction may be catalyzed by a base such as pyridine. In certain embodiments, the compounds of formula ii (d) are represented by the following formula:

and P is₁Salts are, for example, acid chlorides or acetic anhydride.

The compound of formula ii (e) may be prepared by contacting a compound of formula iii (a) with an acid under conditions sufficient to provide a compound of formula ii (e). Suitable acids are known in the art and include acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, and toluenesulfonic acid.

The compounds of formula iii (a) may be prepared by reducing compounds of formula iii (b). Suitable reducing conditions are known in the art and include the use of cerium chloride and sodium borohydride, borane complexes, enzymatic reduction, and hydrogenation or transfer hydrogenation. In certain embodiments, the compounds of formula iii (b) are represented by the formula:

specific compounds of formula III (b) are (4-chloro-3- (4-ethoxybenzyl) phenyl) ((3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d ] [1, 3] dioxolan-5-yl) methanone:

the particular crystalline form of this compound has a melting point of about 113 ℃ as measured by DSC (onset temperature). The crystalline form provides an X-ray powder diffraction (XRPD) pattern having one or more peaks at about 7.6, 13.2, 17.0, 17.4, 18.6, 19.5, 20.5, 20.8, and/or 23.2 degrees 2 Θ. An example of an XRPD pattern of this form is provided in fig. 2.

The compound of formula iii (b) may be prepared by coupling a compound of formula IV with a compound of formula V. Suitable coupling conditions are well known in the art and include the use of metallation reagents (e.g., magnesium or lithium) or transmetallation reagents such as magnesium reagents (e.g., hydrocarbyl magnesium halides, dihydrocarbyl magnesium, lithium trihydrocarbyl magnesium halides) and organolithium reagents (e.g., n-butyllithium, sec-butyllithium, tert-butyllithium). Thus, compounds of formula iii (b) may be prepared using compounds of formula iv (a) under suitable conditions:

where M is a suitable metal, such as Na, K, Li or Mg, X' is Cl, Br or I, and p is 0, 1 or 2, depending on the metal.

In particular methods, the compound of formula V is such that X "is amino (e.g., morpholinyl). Specific compounds of formula V are ((3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d ] [1, 3] dioxolan-5-yl) (morpholinyl) methanone:

the particular crystalline form of this compound has a melting point of about 136 ℃ as measured by DSC (onset temperature). The crystalline form provides an XRPD pattern having one or more peaks at about 9.0, 16.9, 17.6, 18.2, 18.4, 18.8, and/or 22.7 degrees 2 Θ. An example of an XRPD pattern of this form is provided in figure 3.

This particular compound of formula V can be prepared by a method such as that shown in scheme 4:

reaction scheme 4

Suitable reaction conditions are well known in the art and include those described below in the examples. Typically, L- (-) -xylose is cyclized under conditions sufficient to afford compound 1, then oxidized to afford compound 2, which is then contacted with morpholine under conditions sufficient to afford ((3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d ] [1, 3] dioxolan-5-yl) (morpholinyl) methanone. The present invention includes compounds of formulas 1 and 2, including crystalline forms thereof.

Returning to scheme 3, in certain processes of the invention, the compound of formula IV is represented by the following formula:

a specific compound of formula IV is 1-chloro-2- (4-ethoxybenzyl) -4-iodobenzene:

a particular crystalline form of this compound has a melting point (as determined by mp apparatus) of about 65 ℃. The crystalline form provides an XRPD pattern having one or more peaks at about 5.1, 13.5, 15.2, 20.3, 22.2, and/or 27.0 degrees 2 Θ. An example of an XRPD pattern of this form is provided in figure 4.

Particular compounds of formula iv (a) include those represented by the following formula:

more specific compounds are represented by the formula:

specific compounds of formula IV (a) are (4-chloro-3- (4-ethoxybenzyl) phenyl) magnesium iodide and (4-chloro-3- (4-ethoxybenzyl) phenyl) magnesium chloride, as shown below:

the compounds of formulae IV and V may be prepared by those methods disclosed below as well as methods known in the art. See, for example, U.S. Pat. nos. 6,515,117; davis, n.j. et al,TetrahedronLetters34(7)：1181-4(1993)。

6. examples of the embodiments

Various aspects of the present invention can be understood from the following examples, but are not intended to limit the scope of the present invention.

6.1 Synthesis of ((3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d ] [1, 3] dioxan-5-yl) (morpholinyl) methanone

To a 12L three-necked round bottom flask equipped with a mechanical stirrer, a rubber septum with temperature sensor, and a gas bubbler was added L- (-) -xylose (504.40g, 3.360mol), acetone (5L, reagent grade), and anhydrous MgSO₄Powder (811.23g, 6.740mol/2.0 eq). The suspension was stirred at ambient temperature and then concentrated H was added₂SO₄(50mL, 0.938mol/0.28 equiv). A mild exotherm was observed (temperature increased to 24 ℃ over about 1 hour) and the reaction was stirred at ambient temperature overnight. After 16.25 hours, TLC showed that all L-xylose had been consumed, the major products were diacetone and some (3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2, 2-dimethyltetrahydrofuro [2, 3-d ] was][1，3]Dioxolan-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500mL each). The yellow filtrate under stirring is treated with concentrated NH₄OH solution (39mL) was neutralized to pH 8.7. After stirring for 10 minutes, suspended solids were removed by filtration. The filtrate was concentrated to give the crude diacetone intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5L of water stirred in a 5L three necked round bottom flask equipped with a mechanical stirrer, a rubber septum with temperature sensor and a gas bubbler. The pH was adjusted from 9 to 2 with 1N hydrochloric acid (142mL) and stirred at room temperature for 6 hours until GC showed sufficient conversion of the diacetone intermediate to (3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2, 2-dimethyltetrahydrofuro [2, 3-d ]][1，3]Dioxolan-6-ol. By adding 50% w/wK₂HPO₄The reaction was neutralized with aqueous solution until pH 7. The solvent was then evaporated and ethyl acetate (1.25L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to give an orange oil, which was dissolved in 1L of methyl tert-butyl ether. This solution had KF0.23 wt% water, which was concentrated to give (3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2, 2-dimethyltetrahydrofuro [2, 3-d ]][1，3]Dioxolan-6-ol as orange oilMaterial (551.23g, 86% yield, 96.7 area% purity by GC).¹HNMR(400MHz，DMSO-d₆)1.22(s，3H)1.37(s，3H)3.51(dd，J＝11.12，5.81Hz，1H)3.61(dd，J＝11.12，5.05Hz，1H)3.93-4.00(m，1H)3.96(s，1H)4.36(d，J＝3.79Hz，1H)4.86(br.s.，2H)5.79(d，J＝3.54Hz，1H)。¹³CNMR(101MHz，DMSO-d₆)26.48，27.02，59.30，73.88，81.71，85.48，104.69，110.73。

To (3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2, 2-dimethyltetrahydrofuro [2, 3-d ] at 20 deg.C][1，3]Dioxolan-6-ol (25.0g, 131mmol) in acetone (375mL, 15 fold) and H₂NaHCO was added to a solution in O (125mL, 5X)₃(33.0g, 3.0 equiv.), NaBr (2.8g, 20 mol%) and TEMPO (0.40g, 2 mol%). The mixture was cooled to 0-5 ℃ and then solid trichloroisocyanuric acid (TCCA, 30.5g, 1.0 eq.) was added in portions. The suspension was stirred at 20 ℃ for 24 hours. Methanol (20mL) was added and the mixture was stirred at 20 ℃ for 1 hour. A white suspension is formed. The mixture was filtered and washed with acetone (50mL, 2 fold). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300mL, 12 x3) and the combined organic layers were concentrated to give an oily mixture containing some solid residue. Acetone (125mL, 5 fold) was added and the mixture was filtered. The acetone solution was then concentrated to give the desired acid ((3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d)][1，3]Dioxolane-5-carboxylic acid) as a yellow solid (21.0g, 79%).¹HNMR (methanol-d)₄)，6.00(d，J＝3.2Hz，1H)，4.72d，J＝3.2Hz，1H)，4.53(d，J＝3.2Hz，1H)，4.38(d，J＝3.2Hz，1H)，1.44(s，3H)，1.32(s，3H)。

To (3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d][1，3]To a solution of dioxolane-5-carboxylic acid (5.0g, 24.5mmol) in THF (100mL, 20 fold) was added TBTU (11.8g, 1.5 equiv.), N-methylmorpholine (NMM, 4.1mL, 1.5 equiv.) and the mixture was stirred at 20 ℃ for 30 minutes. Morpholine (3.2mL, 1.5 equivalents) was then added and the reaction mixture was stirred at 20 ℃ for an additional 6 hours. By filteringThe solid was filtered off and the filter cake was washed with THF (10mL, 2 x 2). The organic solution was concentrated in vacuo and the residue was purified by silica gel column chromatography (hexane: EtOAc, from 1: 4 to 4: 1) to give 4.3g of the desired morpholinamide (64%) as a white solid.¹HNMR(CDCl₃)，6.02(d，J＝3.2Hz，1H)，5.11(brs，1H)，4.62(d，J＝3.2Hz，1H)，4.58(d，J＝3.2Hz，1H)，3.9-3.5(m，8H)，1.51(s，3H)，1.35(s，3H)。

6.2 Synthesis options for ((3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d ] [1, 3] dioxan-5-yl) (morpholinyl) methanone

Diol (3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2, 2-dimethyltetrahydrofuro [2, 3-d)][1，3]A solution of dioxolan-6-ol in acetonitrile (5.38kg, 65% w/w, 3.50kg active, 18.40mol), acetonitrile (10.5L) and TEMPO (28.4g, 1 mol%) was added to K₂HPO₄(0.32kg, 1.84mol) and KH₂PO₄(1.25kg, 9.20mol) in water (10.5L). Preparation of NaClO under Cooling₂(3.12kg, 80% w/w, 27.6 mol, 1.50eq) in water (7.0L) and K₂HPO₄(2.89kg, 0.90eq) in water (3.0L). Bleach (3.0L, about 6% household grade) was mixed with K₂HPO₄The solutions were mixed. Adding about 20% NaClO₂Solution (1.6L) and bleaching agent/K₂HPO₄Solution (400mL, 1 mol%). The remaining portions of both solutions were added simultaneously. The reaction mixture turned dark reddish brown and a slow exotherm was observed. NaClO₂The addition rate of the solution was about 40mL/min (3-4 hours addition) and bleach/K₂HPO₄The addition rate of the solution was about 10-12mL/min (10 hours addition) while maintaining the batch at 15-25 ℃. An additional addition of TEMPO (14.3g, 0.5 mol%) was made every 5-6 hours until the reaction was complete (usually two additions were sufficient). The headspace was purged with nitrogen to an aqueous scrubber to keep the yellow-green gas from accumulating in the vessel. The reaction mixture was cooled to < 10 ℃ and was treated with three portions of Na over1 hour₂SO₃(1.4kg, 0.6eq) quench. Then mixing the reactionSubjecting the mixture to H treatment at 5-15 deg.C₃PO₄Acidification is carried out until pH reaches 2.0-2.1 (2.5-2.7L). The layers were separated and the aqueous layer was extracted with acetonitrile (10.5Lx 3). The combined organic layers were concentrated in vacuo (-100- & lt 120 & gttorr) at < 35 ℃ (28-32 ℃ vapor, 45-50 ℃ bath temperature) to a small amount (-6-7L) and then rinsed with acetonitrile (40L) until the KF of the solution reached < 1% upon dilution with acetonitrile to a volume of about 12-15L. Morpholine (1.61L, 18.4mol, 1.0eq) was added over 4-6 hours and the slurry was aged under nitrogen overnight. The mixture was cooled to 0-5 ℃ and aged for 3 hours, then filtered. The filter cake was washed with acetonitrile (10L). Drying under flowing nitrogen gas gave 4.13kg of ((3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d)][1，3]Morpholine salt of dioxolane-5-carboxylic acid as a white solid (92-94% purity based on¹HNMR assay, containing 1, 4-dimethoxybenzene as internal standard), yield 72-75% after purity correction.¹HNMR(D₂O)5.96(d，J＝3.6Hz，1H)，4.58(d，J＝3.6Hz，1H)，4.53(d，J＝3.2Hz，1H)，4.30(d，J＝3.2Hz，1H)，3.84(m，2H)，3.18(m，2H)，1.40(s，1H)，1.25(s，1H)。¹³HNMR(D₂O)174.5，112.5，104.6，84.2，81.7，75.0，63.6，43.1，25.6，25.1。

((3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d)][1，3]Morpholine salt of dioxolane-5-carboxylic acid (7.85kg, 26.9mol), morpholine (2.40L, 27.5mol) and boric acid (340g, 5.49mol, 0.2eq) were added to toluene (31L). The resulting slurry was degassed and heated to reflux under nitrogen using a Dean-Starktrap trap (Dean-Starktrap) for 12 hours, then cooled to room temperature. The mixture was filtered to remove insoluble material and the filter cake was washed with toluene (5L). The filtrate was concentrated to about 14L and washed with toluene (. about.80L) to remove excess morpholine. When the final volume reached-12L, heptane (14L) was slowly added at 60-70 ℃. The resulting slurry was gradually cooled to room temperature and aged for 3 hours. It was filtered and washed with heptane (12L) and dried under nitrogen to give a pale pink solid (6.26kg, 97% purity, 98% yield). Melting point: 136 Deg.C (DSC).¹HNMR(CDCl₃)，6.02(d，J＝3.2Hz，1H)，5.11(brs，1H)，4.62(d，J＝3.2Hz，1H)，4.58(d，J＝3.2Hz，1H)，3.9-3.5(m，8H)，1.51(s，3H)，1.35(s，3H)。¹³CNMR (methanol-d)₄)26.84，27.61，44.24，47.45，68.16，77.14，81.14，86.80，106.87，113.68，169.05。

6.1 Synthesis of chloro-2- (4-ethoxybenzyl) -4-iodobenzene

A 2L three-necked round bottom flask equipped with a mechanical stirrer, a rubber septum with temperature sensor, and a constant pressure addition funnel with gas bubbler was charged with 2-chloro-5-iodobenzoic acid (199.41g, 0.706mol), dichloromethane (1.2L, KF ═ 0.003 wt% water) and the suspension was set to stir at ambient temperature. N, N-dimethylformamide (0.6mL, 1.1 mol%) was added followed by oxalyl chloride (63mL, 0.722mol, 1.02 eq.) over 11 minutes. The reaction was stirred at ambient temperature overnight and the reaction became a solution. After 18.75 hours, additional oxalyl chloride (6mL, 0.069mol, 0.10 eq) was added to consume unreacted starting material. After 2 hours, the reaction mixture was concentrated in vacuo to give crude 2-chloro-5-iodobenzoyl chloride as a pale yellow foam which was directly subjected to the next step.

A jacketed 2L three-neck round bottom flask equipped with a mechanical stirrer, a rubber septum with temperature sensor, and a constant pressure funnel with a gas bubbler was charged with aluminum chloride (97.68g, 0.733mol, 1.04 eq.), dichloromethane (0.65L, KF ═ 0.003 wt% water) and the suspension was set to stir under nitrogen and cooled to about 6 ℃. Ethoxybenzene (90mL, 0.712mol, 1.01 equiv.) was then added over 7 minutes, maintaining the internal temperature below 9 ℃. The resulting orange solution was diluted with dichloromethane (75mL) and cooled to-7 ℃. A solution of 2-chloro-5-iodobenzoyl chloride (. ltoreq.0.706 mol) in 350mL of dichloromethane was then added over 13 minutes, maintaining the internal temperature below +3 ℃. The reaction mixture was heated slightly and held at +5 ℃ for 2 hours. HPLC analysis showed the reaction was complete and the reaction was quenched to 450mL of 2N hydrochloric acid pre-cooled (. about.5 ℃ C.) in a jacketed round bottom flask with stirring. The quenching was carried out in multiple portions over 10 minutes, maintaining the internal temperature below 28 ℃. The quenched biphasic mixture was stirred at 20 ℃ for 45 minutes and the lower organic phase was washed with 1N hydrochloric acid (200mL), saturated aqueous sodium bicarbonate (twice, 200 mL/time), and saturated aqueous sodium chloride (200 mL). The washed extract was concentrated on a rotary evaporator to give crude (2-chloro-5-iodophenyl) (4-ethoxyphenyl) methanone as an off-white solid (268.93g, 99.0 area% by HPLC at 220nm, 1.0 area% regioisomer at 200nm, 98.5% "as is" yield).

A 1L three-necked round bottom flask equipped with a mechanical stirrer, a rubber septum with temperature sensor, and a gas bubbler was charged with crude (2-chloro-5-iodophenyl) (4-ethoxyphenyl) methanone (30.13g, 77.93mmol), acetonitrile (300mL, KF ═ 0.004 wt% water) and the suspension was set to stir under nitrogen and cooled to about 5 ℃. Then triethylsilane (28mL, 175.30mmol, 2.25 equiv.) was added followed by boron trifluoride-diethyl etherate (24mL, 194.46mmol, 2.50 equiv.) which was added over about 30 seconds. The reaction was warmed to ambient temperature over 30 minutes and stirred for 17 hours. The reaction was diluted with methyl tert-butyl ether (150mL) and saturated aqueous sodium bicarbonate (150mL) was added over about 1 minute. The biphasic solution was stirred at ambient temperature for 45 minutes, with gentle evolution of gas noted. The above organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (100mL) and with a saturated aqueous solution of sodium chloride (50 mL). The washed extract was concentrated on a rotary evaporator to about half its original volume and diluted with water (70 mL). Further concentration in vacuo at 45 ℃ until white particles formed, which were cooled to ambient temperature with stirring. After about 30 minutes at ambient temperature, the suspended solid was isolated by filtration, washed with water (30mL) and dried under vacuum at 45 ℃. After about 2.5 hours, 1-chloro-2- (4-ethoxybenzyl) -4-iodobenzene was obtained as a slightly waxy white granular powder. (28.28g, 98.2 area% by HPLC at 220nm, 97.4% "as is" yield).

6.4 Synthesis of (4-chloro-3- (4-ethoxybenzyl) phenyl) ((3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d ] [1, 3] dioxan-5-yl) methanone

To a solution of 1-chloro-2- (4-ethoxybenzyl) -4-iodobenzene (500mg, 1.34mmol) in THF (5.0mL) at 0-5 deg.C was added i-PrMgCl (2.0MinTHF, 1.0mL, 2.00mmol) and the mixture was stirred at 0-5 deg.C for 1.5 h. (3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d ] is added dropwise at 0-5 DEG C][1，3]Dioxolan-5-yl) (morpholinyl) methanone (146.5mg, 0.536mmol) in THF (1.0mL) and the mixture is kept stirring for 1 h, warmed to 20 ℃ and stirred at 20 ℃ for 2 h. The reaction was quenched with saturated aqueous NH4Cl solution, extracted with MTBE and washed with brine. The organic layer was concentrated and the residue was purified by silica gel column chromatography to give the desired ketone (178mg, 76%) as a white solid.¹HNMR(CDCl₃)7.88(dd，J＝8.4，2.0Hz，1H)，7.82(d，J＝2.0Hz，1H)，7.50(d，J＝8.4Hz，1H)，7.12(d，J＝8.4Hz，2H)，6.86(d，J＝8.4Hz，2H)，6.07(d，J＝3.2Hz，1H)，5.21(d，J＝3.2Hz，1H)，4.58(d，J＝3.2Hz，1H)，4.56(d，J＝3.2Hz，1H)，4.16(d，J＝7.2Hz，2H)，4.03(q，J＝7.2Hz，2H)，1.54(s，3H)，1.42(t，J＝7.2Hz，3H)，1.37(s，3H)。

6.5 alternative Synthesis of (4-chloro-3- (4-ethoxybenzyl) phenyl) ((3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d ] [1, 3] dioxan-5-yl) methanone

A20L reactor equipped with mechanical stirrer, temperature controller and nitrogen inlet was charged with iodide (3.00kg, 8.05mol) and THF (8L, 4 times the morpholinylamide) at room temperature and cooled to-5 ℃. To the above solution was added i-PrMgCl in THF (Aldrich2M, 4.39L, 8.82mol) dropwise over 3 hours at-5 ℃. This grignard solution was used in the following ketone formation.

To a 50L reactor equipped with a mechanical stirrer, temperature controller and nitrogen inlet was added morpholinylamide (HPLC purity 97 wt%, 2.01kg, 7.34mol) and THF (11L, 5.5 fold) at room temperature and stirred at room temperature for 45 minutes and at 30 ℃ for 15 minutes. The homogeneous solution was then cooled to-25 ℃. To this solution was added t-BuMgCl in THF (Aldrich1M, 7.32L, 7.91mol) over 3 hours at-25 ℃. The above Grignard solution was then added to this solution at-20 ℃ over 41 minutes. The resulting solution was further stirred at-20 ℃ before quenching. The reaction mixture was added to 10 wt.% NH at 0 ℃ with vigorous stirring₄Aqueous Cl (10L, 5X) and stirred at 0 ℃ for 30 min. To this mixture was added 6n hcl (4L, 2 fold) slowly at 0 ℃ to give a clear solution, which was stirred at 10 ℃ for 30 minutes. After phase separation, the organic layer was washed with 25 wt% aqueous NaCl (5L, 2.5 times). The organic layer was concentrated to a 3-fold solution under conditions of (200 mbar, bath temperature 50 ℃). EtOAc (24L, 12X) was added and evaporated to a 3X solution under conditions of (150 mbar, bath temperature 50 ℃ C.). After removal of solids by filtration through refining, EtOAc (4L, 2 fold) was added and concentrated to dryness (150 mbar, bath temperature 50 ℃). The wet cake was then transferred to a 50L reactor equipped with a mechanical stirrer, temperature controller and nitrogen inlet. After addition of EtOAc, the suspension was heated at 70 ℃ to give a 2.5-fold homogeneous solution. Heptane (5L, 2.5 times) was slowly added to the resulting homogeneous solution at the same temperature. The homogeneous solution was seeded and heptane (15L, 7.5 fold) was added slowly at 70 deg.C to give a slightly cloudy solution. After stirring at 70 ℃ for 0.5 h, the suspension was slowly cooled to 60 ℃ and stirred at 60 ℃ for 1 h. The suspension was then slowly cooled to room temperature and stirred at the same temperature for 14 hours. The crystals were collected and washed with heptane (8L, 4 fold) and dried under vacuum at 45 ℃ to afford the desired ketone as a fluffy solid (2.57kg, 100% by weight by HPLC, 81% yield corrected for purity).

6.6 Synthesis of (2S, 3S, 4R, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylthio) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate

To ketone (4-chloro-3- (4-ethoxybenzyl) phenyl) ((3aS, 5R, 6S, 6aS) -6-hydroxy-2, 2-dimethyltetrahydrofuro [2, 3-d ]][1，3]Dioxolan-5-yl) methanone (114.7g, 0.265mol) in MeOH (2L, 17X) was added CeCl₃·7H₂O (118.5g, 1.2 eq) and the mixture was stirred at 20 ℃ until all the solid had dissolved. The mixture was then cooled to-78 ℃ and the NaBH was added₄(12.03g, 1.2 equivalents) were added in portions so that the temperature of the reaction did not exceed-70 ℃. The mixture was stirred at-78 ℃ for 1 hour, slowly warmed to 0 ℃ and saturated NH₄Aqueous Cl (550mL, 5 fold) was quenched. The mixture was concentrated in vacuo to remove MeOH, then extracted with EtOAc (1.1L, 10 x2) and washed with brine (550mL, 5 x). The combined organics were concentrated in vacuo to afford the desired alcohol as a colorless oil (crude, 115 g). To this colorless oil, AcOH (650mL) and H were added₂O (450mL) and the mixture was heated to 100 ℃ and stirred for 15 hours. The mixture was then cooled to room temperature (20 ℃) and concentrated in vacuo to afford a yellow oil (crude product,. about.118 g). To this crude oil was added pyridine (500mL) and the mixture was cooled to 0 ℃. Then, Ac was added₂O (195mL, 8.0 equiv.) and the mixture was warmed to 20 ℃ and stirred at 20 ℃ for 2 hours. Reaction with H₂O (500mL) was quenched and diluted with EtOAc (1000 mL). The organic layer was separated and concentrated in vacuo to remove EtOAc and pyridine. The residue was diluted with EtOAc (1000mL) and treated with NaHSO₄Aqueous (1N, 500mL, x2) and brine (300 mL). The organic layer was concentrated to give the desired tetraethyl ester salt intermediate as a yellow foam (-133 g).

To a solution of tetraacetate (133g, 0.237mol, assumed to be pure) and thiourea (36.1, 2.0 equivalents) in dioxane (530mL, 4 fold) was added trimethylsilyl triflate (TMSOTf) (6 times)4.5mL, 1.5 equivalents) and the reaction mixture was heated to 80 ℃ for 3.5 hours. The mixture was cooled to 20 ℃ and MeI (37mL, 2.5 equiv.) and N, N-Diisopropylethylamine (DiPEA) (207mL, 5.0 equiv.) were added and the mixture was stirred at 20 ℃ for 3 h. The mixture was then diluted with methyl tert-butyl ether (MTBE) (1.3L, 10 fold) and washed with H₂O wash (650mL, 5X 2). The organic layer was separated and concentrated in vacuo to afford a yellow solid. MeOH (650mL, 5 fold) was added to this yellow solid and the mixture was slurried for an additional 2 hours at 60 deg.C, then cooled to 0 deg.C and stirred for 1 hour at 0 deg.C. The mixture was filtered and the filter cake was washed with MeOH (0 ℃, 70mL, x 3). The filter cake was dried overnight under vacuum at 45 ℃ to give the desired triacetate (2S, 3S, 4R, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylthio) tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (88g, 60% over 4 steps) as a pale yellow solid.¹HNMR(CDCl₃)7.37(d，J＝8.0Hz，1H)，7.20(dd，J＝8.0，2.0Hz，1H)，7.07(m，2H)，6.85(m，2H)，5.32(t，J＝9.6Hz，1H)，5.20(t，J＝9.6Hz，1H)，5.05(t，J＝9.6Hz，1H)，4.51(d，J＝9.6Hz，1H)，4.38(d，J＝9.6Hz，1h)，4.04(m，2H)，2.17(s，3H)，2.11(s，3H)，2.02(s，3H)，1.73(s，3H)，1.42(t，J＝7.2Hz，3H)。

6.7 alternative Synthesis of (2S, 3S, 4R, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylthio) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate

40L of LMeOH was added to a 50L reactor under a nitrogen atmosphere followed by ketone (2.50kg, 5.78mol) and CeCl₃·7H₂O (2.16kg, 1.0 equiv). Methanol (7.5L) was added as a rinse (47.5L in total, 19 times). Freshly prepared NaBH was slowly added (35 min) at 15-25 deg.C₄(87.5g, 0.4 eq.) in 1N aqueous NaOH solution (250 mL). The mixture was then stirred for 15 minutes. HPLC analysis of the reaction mixture showed a diastereomer ratio of about 90: 10. Reaction with 10 wt.% NH₄Aqueous Cl (2.5L, 1 fold) was quenched and the mixture was concentrated to 5 fold in vacuo, diluted with water (10L, 4 fold) and MTBE (12.5L, 5 fold). The mixture was cooled to 10 ℃ and 6N was addedHydrochloric acid until the pH of the mixture reached 2.0. Stirring was continued for 10 minutes and the layers were separated. H for organic layer₂O wash (5L, 2 fold). The combined aqueous layers were extracted with MTBE (12.5L, 5 fold). The combined organic layers were washed with brine (2.5L, 1 fold) and concentrated in vacuo to 3 fold. MeCN (15L, 6 fold) was added. The mixture was again concentrated to 10L (4 fold) and any solid residue was removed by polish filtration. The filter cake was washed with a minimum amount of MeCN.

The organic filtrate was transferred to a 50L reactor and 20 mol% H prepared beforehand was added₂SO₄Aqueous solution (61.8mL 98% concentrated H₂SO₄And 5LH₂O). The mixture was heated to 80 ℃ for 2 hours and then cooled to 20 ℃. Saturated K for reaction₂CO₃The aqueous solution (5L, 2 fold) was quenched and diluted with MTBE (15L, 6 fold). The organic layer was separated, washed with brine (5L, 2 fold) and concentrated in vacuo to 5L (2 fold). MeCN (12.5L, 5 fold) was added and the mixture was concentrated to 7.5L (3 fold).

The MeCN solution of (3S, 4R, 5R, 6S) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) tetrahydro-2H-pyran-2, 3, 4, 5-tetraol described above was cooled to 10 ℃, dimethylaminopyridine (17.53g, 2.5 mol%) was added followed by slow addition of acetic anhydride (3.23L, 6.0 equivalents) and triethylamine (5L, 2 fold, 6.0 equivalents) such that the temperature of the mixture was maintained below 20 ℃. The reaction was then warmed to 20 ℃ and stirred for 1 hour, diluted with MTBE (15L, 6 fold). The mixture was slowly quenched with water (7.5L, 3X). Separating the organic layer and sequentially treating with KHCO₃Saturated aqueous solution (5L, 2 times), 1NNaHSO₄(5L, 2 fold) and brine (5L, 2 fold).

The organic layer was then concentrated to 5L (2 fold) in vacuo. MeCN (12.5L, 5 fold) was added and the solution was concentrated to 7.5L (3 fold) (KF ═ 0.08%). Dioxane (12.5L, 5 fold) was added and the solution was concentrated to 7.50L (3 fold) (KF ═ 0.02%). Any residual solids were removed by polishing filtration and the filter cake was washed with a minimum amount of dioxane (500 mL).

To the above filtrate was added thiourea (880g, 2.0 equivalents) and TMSOTf (1.57L, 1.5 equivalents). The reaction mixture was heated to 80 ℃ for 3 hours (> 97% conversion). The mixture was cooled to 20 ℃ and iodomethane (541mL, 1.5 equivalents) and diisopropylethylamine (3.02L, 3.0 equivalents) were added and the mixture was stirred at 20 ℃ for 18 h. Additional methyl iodide (90mL, 0.25 eq) was added and the mixture was stirred at 20 ℃ for 1 hour. The mixture was then diluted with MTBE (25L, 10 fold) and washed with water (12.5L, 5 fold x 2). The organic layer was separated and concentrated in vacuo to 5L (2 fold). MeOH (12.5L, 5X) was added and the mixture was concentrated to 5X to give a slurry. The mixture was then heated at 60 ℃ for 1 hour and cooled to 0 ℃ and stirred at 0 ℃ for 1 hour. The mixture was filtered and the filter cake was washed with MeOH (0 ℃, 2.5L, 1 x2, 1.0L, 0.4 x). The filter cake was dried under vacuum at 45 ℃ overnight to give the desired triacetate (1.49kg, 47% overall yield over 4 steps) as a pale yellow/off-white solid.

6.8 Synthesis of (2S, 3R, 4R, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylthio) tetrahydro-2H-pyran-3, 4, 5-triol

To a slurry of (2S, 3S, 4R, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylthio) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate (90.0g, 0.164mol) in MeOH (900mL, 10 fold) at 20 ℃ was added NaOMe-containing MeOH (25 wt%, 18mL, 0.2 fold) and the mixture was stirred at 20 ℃ for 2 hours until all solids were hours. The mixture was then concentrated to 300mL and added to H₂O (1L) and stirred for 1 hour. The solid was filtered and washed with H₂O wash (100mL, x3) and the filter cake was dried under vacuum at 45 ℃ overnight to give the desired methyl sulfide (67.0g, 95%).¹HNMR(CDCl₃)7.38(d，J＝8.4Hz，1H)，7.22(m，2H)，7.11(d，J＝8.8Hz，2H)，6.83(d，J＝8.8Hz，2H)，4.35(d，J＝9.6Hz，1H)，4.15(d，J＝9.6Hz，1H)，4.10-3.95(m，3H)，3.64(t，J＝8.8Hz，1H)，3.50(m，2H)，2.73(brs，3H)，2.17(s，3H)，1.40(t，J＝7.2Hz，3H)。

Preparation of form 1 crystals of anhydrous (2S, 3R, 4R, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylthio) tetrahydro-2H-pyran-3, 4, 5-triol

To a 50L reactor, MeOH (12L) and the triacetate (1.70Kg, 3.09mol) were added under a slightly positive pressure of nitrogen atmosphere. Methanol (5L) was added as a rinse. The slurry was then charged with NaOMe-containing MeOH (25 wt%, 340mL, 0.2 fold) over 15 minutes at 20 ℃ and the mixture was stirred at 20 ℃ for 2 hours until all solids disappeared. Water (25.5L, 15 fold) was added slowly to the mixture over 45 minutes, and 5g seed crystals were added (DSC123 ℃). A solid precipitated and the mixture was stirred at 20 ℃ for 1 hour, cooled to 0 ℃ and stirred for 30 minutes. The solid was filtered and washed with water (1.7L, 1X 2) and the filter cake was dried under vacuum at 45 ℃ overnight to give the title compound (melting point determined by DSC peak ≈ 123 ℃; 1.28Kg, 97.7% yield).

Preparation of form 2 crystals of anhydrous (2S, 3R, 4R, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylthio) tetrahydro-2H-pyran-3, 4, 5-triol

To a 50L reactor, MEK (2-butanone, 4L) and form 1 (1.49Kg) of (2S, 3R, 4R, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylthio) tetrahydro-2H-pyran-3, 4, 5-triol are added under a slightly positive pressure of nitrogen. MEK (3.45L) was added as a rinse. The mixture was heated to 80 ℃ and heptane (14.9L, 10 fold) was added slowly over 1.5 hours. Solids began to precipitate and heptane (14.9L, 10 fold) was added to the mixture over 6 hours. The mixture was stirred at 80 ℃ for 15 hours. The mixture was cooled to 20 ℃ over 3 hours and stirred at 20 ℃ for 1 hour. The solid was filtered and the filter cake was washed with MEK/heptane (2.5: 7.5, v/v, 1.49L, 1X 2), dried under nitrogen for 12 hours and dried under vacuum at 50 ℃ for 24 hours to give the title compound as a white solid (melting point. apprxeq.134 ℃ C.; 1.48Kg, 98% recovery by DSC peak).

6.11 alternative preparation of Anhydrous (2S, 3R, 4R, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylthio) tetrahydro-2H-pyran-3, 4, 5-triol form 2 crystals

The triacetate (10kg) and methanol (75kg) were charged to a 250L reactor. Sodium methoxide (1.6kg, 30% solution) was added and rinsed with 5kg of methanol. The mixture was stirred at room temperature for at least 2 hours or until the reaction was complete. Charcoal (DarcoG-60, 1kg) was added and rinsed with 5kg of methanol. The mixture was heated at 40 ℃ for 1 hour, cooled to room temperature, and filtered through celite. The filter cake was washed with methanol (10 kg). Water (100kg) was added and the mixture was concentrated in vacuo. MTBE (200kg) and water (50kg) were added and the phases separated. The organic layer was washed with water (100kg) and concentrated in vacuo. MEK (100kg) was added and about the same solvent was distilled under vacuum. This MEK addition and distillation was repeated to dry the solution. Sufficient MEK was added to produce a solution of (2S, 3R, 4R, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylthio) tetrahydro-2H-pyran-3, 4, 5-triol in 50 LMEK. This solution was polish filtered and heptane (100L) was added at about 80 ℃. Seed crystals of type2 (0.1kg) were added followed by slow addition of heptane (100L) at 80 ℃. Heating at 80 ℃ was continued for 8 hours, cooling to 20 ℃ over a period of at least 3 hours, holding at this temperature for at least 2 hours, filtration and washing with MEK/heptane. The filter cake was dried under vacuum at 50 ℃ to give the title compound as a white solid (6.6kg, 86% yield).

6.12 Synthesis of (2S, 3R, 4R, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylsulfonyl) tetrahydro-2H-pyran-3, 4, 5-triol

To a mixture of urea hydrogen peroxide (UHP, 92.34g, 6.0 equivalents) and phthalic anhydride (72.70g, 3.0 equivalents) was added MeCN (720mL) and MeOH (180 mL). The mixture was stirred at 20 ℃ until all solids were dissolved. Then a solution of (2S, 3S, 4R, 5S, 6R) -2- (4-chloro-3- (4-ethoxybenzyl) phenyl) -6- (methylthio) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate (90.00g, 0.163mol) in MeCN (540mL, 6 fold) was added andthe mixture was stirred at 20 ℃ for 7 hours. The mixture was diluted with EtOAc (900mL, 10 fold) and saturated NaHCO₃Aqueous solution (900mL, 450mL) and H₂O (450mL) wash. The organic layer was then concentrated in vacuo to afford a white solid (-95 g). To the above white solid add MeOH (900mL), then add NaOMe containing MeOH (25 wt%, 18mL, 0.2 times) and the mixture at 20 ℃ stirring for 3 hours, until all the solid disappeared. The mixture was concentrated to 300mL and added slowly to H with stirring_2O(1350 mL). Stirring was continued for 1 hour. The solid was filtered and the filter cake was taken up with H₂O wash (90mL, x2) and dry under vacuum at 45 ℃ overnight to give the desired sulfone (71.4g, 96%).¹HNMR(CDCl₃)7.35(d，J＝8.4Hz，1H)，7.20(m，2H)，7.081(d，J＝8.8Hz，2H)，6.78(d，J＝8.8Hz，2H)，4.58(brs，1H)，4.51(brs，1H)，4.42(d，J＝9.6Hz，1H)，4.24(d，J＝9.6Hz，1H)，4.10-3.90(m，4H)，3.74(m，1H)，3.54(m，1H)，3.36(brs，1H)，2.81(s，3H)，1.37(t，J＝7.2Hz，3H)。

All publications (e.g., patents and patent applications) cited above are hereby incorporated by reference in their entirety.

Claims (2)

1. A compound of the formula:

or a salt thereof.

2. The compound of claim 1, represented by the formula: