MXPA00003932A - Synthesis of swainsonine salts - Google Patents

Abstract

A method for synthesizing swainsonine salts and intermediates thereof comprising subjecting a compound of formula (I) wherein R2 and R2'are the same or different and represent alkyl, halogen, alkenyl, alkoxy, cycloalkyl or aryl, to acid hydrolysis in the presence of a C1-4alkanol to obtain a crystalline salt of swainsonine;and optionally, recrystallizing the swainsonine salt from a C1-4alkanol. The reaction may be used in combination with one or more additional reaction steps.

Description

SYNTHESIS OF SALES OF S AINSONINA FIELD OF THE INVENTION The invention relates to methods for synthesizing swainsonin and swainsonin derivatives and particularly swainsonin salts. BACKGROUND OF THE INVENTION The free base of swainsonin is an alkaloid of indolicidin that has biological activity, including the inhibition of many mannosidases. The synthesis of the base-free alkaloid has been described, as in (a) Pearson and Hembre, J. Org. Chem., 1996, 61: 7217-7221; (b) Carpenter, N.M. et al, Tet. Lett. 1989, 30: 7261-7264; (c) Bennett, R.B., III et al, J. Am Chem. Soc. , 1989, 111: 2580-2582; (d) Takahata, M. et al., The Alkaloids ("The Alkaloids"), Vol. 44 Academic Press, New York (1993), at 189; (e) Miller S.A., et al., J. Am Chem. Soc. 1990, 112: 8100-8112; and (f) Cohen, N., et al., J. Am. Chem. Soc. 1983, 105: 3661-3672. The additional synthesis is described in the U.S. Patents. Nos. 5,187,279 (Cha) and 5,075,448 (Fleet). Pearson and Hembre claim to produce 4.5 g of free base swainsonine in 20% produced from the lactone intermediate (2,3-O-isopropylidene-D-erythronolactone) using a method that requires eleven stages, three separation by chromatography and four crystallizations (in 7218, column 2). According to Pearson and Hembre, according to its 1996 publication, attempts to extrapolate even the shortest known synthetic routes have not been successful (in 7217, column 1). SUMMARY OF THE INVENTION The invention presents methods for synthesizing swainsonine its salts and the derivatives of swainsonin and its salts. The advantages of the methods of the invention include high yields, few chromatographic separations, fast reaction times and less expensive reagents. The methods also show the absence of chlorinated solvents, toxic reagents such as osmium tetraoxide and cryogenic intensive energy conditions. In view of the increasing interest in the products of this synthesis, the advantages provided by this method are of considerable commercial significance. The method is particularly useful for large scale processes (eg 200-250 g proportion of final product) and provide stable and high purity products. The methods of the invention have particular application in the synthesis of swainsonin salts. In particular, a disclosed method provides de-swainsonin hydrochloride in 20% yield from the intermediate 2,3-O-isopropylidene-D-erythronolactone. Broadly stated the present invention relates to a method for synthesizing a swainsonin salt comprising: (i) subjecting a compound of the formula I wherein R2 and R2 'are the same or different and represent alkyl, halogen, alkenyl, alkoxy, cycloalkyl or aryl for the acid hydrolysis in the presence of a C ^ alkanol to obtain a crystalline salt of swainsonin; and optionally (ii) recrystallizing the swainsonin salt from a C1_i alkanol. The reaction can be used in combination with one or more of the reaction steps (A) to (G) described herein. The invention specifically contemplates the methods wherein R 2 and R 2 'are the same and represents a C 1 alkyl or wherein R 2 and R 2' represent alkyl or aryl and the other of R 2 and R 2 'represents alkoxy or halogen. In one embodiment the compound of formula I is 1,2-isopropylidenedioxy-8-hydroxyindolizidine (ie, swainsonin acetonide). In a particular embodiment, the invention relates to a method for preparing an isolated and purified crystalline swainsonine hydrochloride salt comprising converting 1,2-isopropylidenedioxy-8-hydroxyindolizidine (ie, swainsonin acetonide) to a hydrochloride salt. by acid hydrolysis in the presence of a Cx_4 alkanol to obtain a crystalline swainsonine hydrochloride salt and optionally recrystallize the salt in a C ^ 4 alkanol. The method of the invention provides a swainsonin hydrochloride preparation having a purity greater than 95%, more preferably 98% and more preferably 99.6%. The invention also provides a method for preparing a swainsonin salt comprising: (A) reacting a lactone of formula II wherein R2 and R2 'are the same or different and represent alkyl, alkenyl, halogen, alkoxy, cycloalkyl or aryl with diisobutylaluminum hydride in an organic solvent preferably selected from the group consisting of toluene, benzene, xylene, chlorobenzene and t-butyl methyl ether to obtain a lactol of formula III wherein R2 and R2 'are as defined above: (B) reacting the lactol of formula III with a phosphonium bromide salt to obtain an olefinic alcohol of formula IV: wherein R2 and R2 'are as defined above and R3 is C1_10 alkyl or aryl; (C) reacting the olefinic alcohol of the formula IV with a phosphine, dialkylazodicarboxylate and azide source to obtain an azide of the formula V wherein R2, R2 'and R3 are as defined above: (D) refluxing the azide of formula V in a high boiling nonreactive solvent (eg, greater than 90 ° C) preferably selected from the group consisting of toluene , benzene, xylene, chlorobenzene and dimethyl formamide (DMF), to form an imino ester of the formula VI wherein R2 R2 'and R3 are as defined above: (E) reacting the imino ester of formula VI with an alkali metal hydroxide in a mixture of water and a non-reactive miscible organic solvent (for example a Cx_4 alkanol or THF) and acidifying the reaction mixture to obtain an acidic imino of formula VII - - wherein R2 and R2 'are as defined above: (F) cyclizing the acid imino of formula VII by reflowing it in an organic solvent preferably selected from the group consisting of toluene, benzene, xylene, chlorobenzene and t-butyl methyl ether, with a catalyst to form an enamide of formula VIII wherein R2 and R2 'are as defined above: (G) reducing the enamide of formula VIII with a borane reagent in an organic solvent preferably selected from the group consisting of toluene, hexane, benzene, xylene, chlorobenzene, mixtures of petroleum ether, ether and t-butyl methyl ether and oxidizing the resulting alkyl borane by peroxide to obtain a protected swainsonin of the formula I; wherein R2 and R2 'are as defined above: (H) subjecting the protected swainsonin to acid hydrolysis in the presence of a Cx_4 alkanol to obtain a crystalline swainsonine salt; and optionally (I) recrystallizing the swainsonin salt from an alkanol 1_i. A method of the invention may further comprise converting the swainsonin salt to swainsonin, and preparing a swainsonin derivative from swainsonin or swainsonin salt. The invention also provides novel methods for preparing intermediates used in the methods of the invention. The intermediates can be used in conventional processes to prepare swainsonin or derivatives thereof. The invention also features a swainsonine salt obtained by a method that includes steps (C), (E), (F), or (H) or a combination thereof for example, steps (F) to (H) , Steps (C), (F) and (H), steps (C) to (H) or steps (A) - (H) as described herein. This synthesis exemplifies the numerous advantages of several individually described transformations of the present invention, namely steps (A) to (H) and in particular steps (C), (E), (G), (F) and (H) ) as described herein. The invention presents the steps described individually and additional combinations thereof.

- - The invention includes individually improved conditions for specific transformations (e.g., stages (C), (E), (F), (G) 0 (H) alone) as well as advantageous combinations thereof to produce synthetic intermediates, including free base, in a commercially variable form. Using the methods of the invention, highly purified and stable isolated preparations of swainsonin salts and salts of swainsonin derivatives can be prepared. Therefore the invention presents swainsonine salts and salts of swainsonin derivatives isolated, purified and stable. DETAILED DESCRIPTION OF THE INVENTION The methods of the invention and the particular improvements thereof can be used in the synthesis of swainsonin, a salt of swainsonin or a derivative of swainsonin or a salt thereof. The methods of the invention can be used particularly to prepare salts of swainsonin halide. A "halide salt" is preferably a hydrochloride, hydrofluoride hydrobromide or hydroiodide salt, preferably a hydrochloride or hydrobromide salt. The methods may be particularly useful in synthesizing crystalline salts, more preferably crystal salts of hydrochloride or swainsonin hydrobromide. A "crystal salt of hydrochloride or swainsonin hydrobromide" includes molecules of hydrochloride or hydrobromide of swainsonin in a unit cell held together by hydrogen bonding interactions. Preferably the crystalline salt of hydrochloride or hydrobromide of swainsonin comprises synthesizing four molecules of hydrochloride or hydrobromide of swainsonin in a unit cell. More preferably the crystalline hydrochloride or hydrobromide salt comprises four molecules of hydrochloride or hydrobromide of swainsonin in a unit cell. A crystalline salt of hydrochloride or hydrobromide of swainsonin has symmetry of separate groups P212121. In a preferred embodiment of the invention, the crystal of the hydrochloride salt or swainsonin hydrobromide comprises ortho-orbital unit cells. The unit cell for a crystal of a swainsonine hydrochloride salt can have the unit cell lengths a = 8.09 ± 0.01A, b = 9.39 ± 0.01A and c = 13.62 ± 0.01Á. Swainsonin derivatives and salts of derivatives can be prepared using the methods described herein and the derivatives and salts prepared by the methods contemplated in the present invention. A "derivative" of swainsonin refers to a compound that possesses a biological activity (either structural or functional) that is substantially similar to the biological activity of swainsonin. The term "derivative" is intended to include "variants" "analogues" or "chemical derivatives" of swainsonin. The term "variant" is intended to refer to a molecule substantially similar in structure and function to the swainsonin or to a portion thereof. A molecule is "substantially similar" to swainsonin if both molecules have substantially similar structures or if both molecules have similar biological activity. The term "analogue" refers to a molecule substantially similar in function to a molecule of swainsonin. The term "chemical derivative" describes a molecule that contains additional chemical residues that are not normally part of the base molecule. Steps (H) and (I) The method of the invention includes subjecting a protected swainsonin of the formula I wherein R and R are the same or different and - represent alkyl, halogen, alkenyl, alkoxy, cycloalkyl or aryl for acid hydrolysis in the presence of a Cx_4 alkanol to obtain a crystalline salt of swainsonin; and optionally recrystallizing the swainsonin salt from C1_alkanol. the invention specifically contemplates the methods wherein R2 and R2 'are the same and represent C2 alkyl or where R2 and R2' represent alkyl or aryl and the other of R2 and R2 'represents alkoxy or halogen. A pure swainsonine salt can be produced by replacing the evaporated water with a C1_i alkanol in continuous or in stages. In this form, a pure swainsonine salt crystallizes out of the alkanol solution as the concentration of water is consumed. In the following and then the term "alkyl", alone or in combination, refers to a branched or linear hydrocarbon radical, typically containing from 1 to 15 carbon atoms, preferably from 1 to 10. Typically alkyl groups and substituted alkyl groups include but are not they limit to methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, 2,2,2-trichloroethyl, and the like. Preferably the alkyl groups are methyl, ethyl and isopropyl. The term "alkoxy" refers to an alkyl or cycloalkyl linked to the main molecular residue through an oxygen atom. Examples of alkoxy groups are methoxy, ethoxy, propoxy, vinyloxy, allyloxy, butoxy, pentoxy, hexoxy, cyclopentoxy and cyclohexoxy. The term "alkenyl", alone or in combination, refers to a branched or linear unsaturated group typically having from 2 to 15 carbon atoms and at least one double bond. Examples of alkenyl groups and substituted alkenyl groups include but are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 1,3-butadiene, hexenyl, pentenyl, 1- phenylethyl, (4-methoxyphenyl) ethyl and the like The term "cycloalkyl" refers to cyclic hydrocarbon groups and includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "halogen", alone or in combination, refers to members of the fluorine, chlorine, bromine or iodine family, preferably chlorine. The term "aplo", alone or in combination, refers to a monocyclic or polycyclic group, preferably - a monocyclic or bicyclic group. An aryl group may be optionally substituted as described herein. Examples of aryl groups and substituted aryl groups are phenyl, benzyl, benzyl ether, p-nitrobenzyl, p-methoxybenzyl, biphenyl, 2,4-dittoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl and naphthyl. The term "alkylidene" as used herein and used herein as an "alkylidene-protected swainsonin" includes methylene, ethylidene, acetonide (isopropylidene), 1-t-butylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-t-chloroethylidene, cyclopentylidene, cyclohexylidene, benzylidene, p-methoxybenzylidene, 2,4-demethoxybenzylidene, 3,4-dimethoxybenzylidene and 2-nitrobenzylidene. One or both of R2, R2 'or R3 having available functional groups can be substituted with one or more substituents including but not limited to the following: alkyl, alkoxy, alkenyl, alkynyl or halogen. In a preferred embodiment of the invention, the compound of the formula I is 1,2-isopropylidenedioxy-8-hydroxydolicidine. The acid hydrolysis can be carried out under anhydrous or non-anhydrous conditions using hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydrogen fluoride, hydrogen chloride or hydrogen bromide. The C 4 alkanols which can be used in the method of the invention include methanol, ethanol, propanol, isopropanol and butanol, preferably a C 1 j alkanol, more preferably isopropanol. In a preferred embodiment, the method is carried out in isopropanol and 6M hydrochloric acid. The reaction can be carried out between -10 ° C to 60 ° C, preferably between 0 ° C and 25 ° C. The method provides a preparation of highly purified crystallized swainsonin salts, preferably swainsonin salts hydrochloride. Step (A) A method of the invention may comprise reacting a lactone of formula II with diisobutylaluminum hydride in an organic solvent to obtain a lactol of formula III. The organic solvent is preferably selected from the group consisting of toluene, benzene, xylene, chlorobenzene and t-butyl methyl ether. Preferably the reaction is carried out using toluene which dries easily and is less volatile than conventional solvents such as THF. The reaction is carried out between -40 ° C and 0 ° C, more preferably between about -20 ° C to -40 ° C. In order to avoid the formation of an undesirable gel reaction product, a small amount of brine (ie concentrated NaCl in a concentration of <) is added to the reaction mixture.l / 2%) or concentrated NaOH. In particular, the NaCl is stirred with the crude reaction products until a precipitate is formed; a drying agent (eg, Na2SO4) is added to the mixture of the water / toluene / THF reaction products and stirred for prolonged periods of time. The resulting hydrated Na2SO4 is easily filtered and the filtrate does not contain aluminum byproducts. The product is isolated as a clear solution. This treatment differs from conventional methods, which use MgSO4 which forms a gel of magnesium and aluminum salts. In one embodiment of the invention, Step (A) comprises (i) reacting 2, 3-O-alkylidene-D-erythrolactone, for example, 2,3-O-isopropylidene-D-eri rolactone ((-) - ( 3aR-cis) -dihydro-2, 2-dimethylfuro [3,4-d] -1,3-dioxol-4 (3aH) -one), with one molar equivalent of diisobutylaluminum hydride in toluene, at about -10 ° C at 0 ° C (in an embodiment of the invention preferably 0 ° C); (ii) (a) add methanol; (ii) (b) add THF and brine; (n) (c) adding disodium sulfate and (11) (d) removing the inorganic salts by precipitation and filtration to produce 2,3-O-alkylene-den-D-eptrosa (the lactol). The lactane of formula II can be prepared from D-isoascorbic acid using a new method (see for example Stages 1 and 2, Scheme IV). In particular, 2,3-O-isopropylidene-D-erythronolactone can be prepared from potassium epigonate and ketone or orthoester with a catalytic acid. The method comprises (a) reacting D-isoascorbic acid with a base (eg, aqueous sodium carbonate) and hydrogen peroxide; and (b) neutralizing the excess base with a protonic acid (for example HCl) at a pH between 3.5 and 4.5, preferably 3.5 and 4.2, more preferably between 3.8 and 4.0 and more preferably 4.0; (c) replacing the water with an irascible organic solvent and filtering the precipitated inorganic salts; (d) adding a catalytic sulfonic acid in a ketone or an orthoester and magnesium sulfate; and (e) crystallizing 2, 3-O-? soprop? l erythronolactone preferentially from ether / hexanes or combinations of t-butyl methyl ether and dnsopropyl ether with hexanes or petroleum ether. Examples of catalytic sulfonic acids include catalytic amounts of p-toluene sulfonic acid, methane sulphonic acid, sulfonic acid, camphor sulphonic acid, sulfonic acid resins, zeolites or acidic clays. The ketone can be acetone, methyl ethyl ketone or cyclohexane, preferably acetone. Examples of orthoesters include trimethyl orthoethyl, orthoformate, orthoacetate, orthobenzoate or ortho propionate. A solvent may be selected so that the same solvent is used in the previous or subsequent steps in the method of the invention. In general it is important to evaporate the solvent as soon as possible to precipitate the undesirable salts. Therefore, in order to isolate the product in high production, it is desirable to precipitate the salts continuously or in stages and simultaneously evaporate the water. Using this procedure, a solution substantially free of salts can be obtained. The method for obtaining the lactone is particularly useful for large-scale processes (for example at approximately 1 Kg. Scale) and to provide a high yield of lactone compound (for example about 77%) compared to the methods of the prior art. Stage (B) - A method of the invention may comprise reacting the lactone compound of the formula III with a phosphonium bromide salt (for example ethyl 4-triphenylphosphonium butyrate bromide salt) to obtain an olefinic alcohol of the formula IV. The phosphonium bromide salt can be prepared using a new method (see for example Scheme IV) which comprises reacting ethyl 4-bromobutyrate with triphenyl phosphine in a high boiling solvent (for example n-butyl acetate or methyl ethyl ketone) at elevated temperatures (e.g. 130 ° C) to form the phosphonium bromide salt. Using this method substantially all the phosphonium bromide salt is precipitated from the solution, in high yield (> 90%). The reaction step preferably uses potassium tert-butoxide as a base instead of compounds such as LDA, lithium hexamethyldisilylamide (HMDS), sodium HMDS and potassium HMDS which are used in conventional methods and are more expensive or difficult to work with. Therefore the reaction can be carried out at temperatures between -15 ° C to -20 ° C. The product is preferably isolated by adding ethanol and heating to reflux to regenerate the desired ethyl ester product from the transferred by-products. Refluxing with any other desired alcohol will produce the corresponding ester product. The reaction gives a yield of about 70-75% which is significantly higher than the methods reported. Step (C) The olefinic alcohol of formula IV can be converted to the azide of formula V using a Mitsunobu reaction. In particular, a method of the invention can comprise reacting an olefinic alcohol of the formula IV with a phosphine source, d alkylazodicarboxylate and azide to obtain an azide of the formula V. The azide product is made as a stable species at low environmental temperatures . Examples of phosphmas that can be used include tpalkyl phosphines such as tnmethylphosphine and tpapl phosphines such as triphenyl phosphine, tribenzyl phosphine and paramethyl phosphine. Examples of dialkylazodicarboxylates that can be used in the process include diethylazodicarboxylate (DEAD), dimethylazodicarboxylate, dibutylazodicarboxylate or dusopropylazodicarboxylate (DIAD). The sources of azide include azido tpmethylsilane (TMS-N3), diphenylphospho- tamide, tetrabutylammonium azide, hydrazoic acid. The reaction may utilize a Corona ether and a metal azide including potassium azide, lithium azide or sodium azide. The reaction - typically uses tetrabutyl ammonium fluoride (TBAF) to remove any byproduct of reaction if TMS-N3 is used. The reaction is generally carried out at low temperatures, for example 10 to -25 ° C. One embodiment of step (C) comprises (i) reacting the olefinic alcohol of formula IV with one molar equivalent of triphenyl phosphine in THF, one molar equivalent of diisopropylazodicarboxylate and trimethylzilylazide to form an alkyl azide product, for example, (+) - (4R, cis) (Z) -2,2-dimethyl-5- (4-carbethoxy-1-butenyl) -1, 3-dioxolane-4-azidomethane and a by-product, for example an olefinic alcohol protected with O- trimethylsilyl; (ii) adding tetrabutylammonium fluoride in THF to the crude azide product; (iii) repeating the treatment described in (i) and (ii), thereby converting a portion of the olefinic alcohol byproduct protected with O-trimethylsilyl to the alkyl azide product. Stage (C) produces the new compound of formula V - - wherein R2, R2 'and R3 are as defined above. In one embodiment R2 and R2 'are the same and represent C1_4 alkyl. In a preferred embodiment, the compound of formula V is ethyl (Z) -5- [(4R_5S) -5- (azidomethyl) -2, 2-dimethyl-1,3-dioxolan-4-yl] -4-pentenoate . Step (D) A method of the invention can comprise refluxing the azide of formula V in a high-boiling non-reactive solvent (eg> 90 ° C) to form an imino ester of formula VI. The solvent may be selected from the group consisting of toluene, benzene, xylene, chlorobenzene and dimethyl formamide. Preferably in a method of the invention the solvent is the same solvent used in previous and subsequent steps and more preferably is toluene. One embodiment of step (D) comprises refluxing the purified azide in toluene at an initial concentration of between 0.30 M and 0.05 M, preferably between 0.1 M and 0.2 M, to form an imino ester, for example, (-) - ( IS, 5R) -3,3-dimethyl-8- (3-carbethoxy-1-propyl) -7-aza-2,4-dioxabicyclo [3.3.0] oct-7-ene. A method of the invention may comprise reacting an imino ester of the formula VI with an alkali metal hydroxide in a mixture of water and a non-reactive miscible organic solvent and acidifying the reaction mixture to obtain an acid imino of the formula VII . Examples of non-reactive miscible organic solvents include C1_i alkanols as described herein and THF. The alkali metal hydroxides that can be used in the reaction include NaOH, LiOH, and KOH. One embodiment of Step (E) comprises (i) reacting an imino ester of formula VI with one molar equivalent of an alkali metal hydroxide in a mixture of water and Cx_4 alkanol (for example ethanol); (ii) acidifying the reaction mixture to about pH 3-7, preferably 6-7, to produce an acidic imino, for example, (-) (1S, 5R) -3,3-dimethyl-8- (3 - carboxy-1-propy1) -7-aza-2,4-dioxabicyclo [3.3.0] oct-7-ene. Step (F) A method of the invention can comprise cyclizing an acidic imino of formula VII by reflowing it in an organic solvent with a catalyst to form an enamide of formula VIII while removing the water formed during the reaction. The organic solvent can be selected from the group consisting of toluene, benzene, xylene, chlorobenzene, and t-butyl methyl ether. Preferably in a method of the invention, the solvent is a solvent used in previous or subsequent steps. The enamide is isolated and dissolved in an anhydride environment using the selected solvent, preferably toluene. The catalyst may be a Lewis acid in particular a carboxylic acid or sulfonic acid including but not limited to formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, trichloroacetic acid, toluene sulfonic acid, camphor sulfonic acid, acid sulfuric acid, methane sulfonic acid, benzoic acid or HCl gas. Preferably the catalyst is a low alkalinity carboxylic acid such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid or trichloroacetic acid. Enamide can be used as a starting material to prepare various swainsonin derivatives, including swainsonine derivatives substituted at positions 5, 6, 7 or 8 or combinations thereof. In one embodiment of the invention, Step (F) comprises cyclizing an acidic imino of the formula VII by reflowing it in toluene with a catalytic amount of a low carboxylic acid in alkalinity to form an enamide, for example, (-) - ( 7S, 8R) -7, 8-0-isopropylidenedioxy-2 -oxo-1-azabicyclo [4.3.0] non-5-ene.

- Step (G) A method of the invention can comprise reducing an enamide of formula VII with a borane reagent in an organic solvent and oxidation (for example oxidation by peroxide) of the resulting alkyl borane to obtain a protected ammonia of the formula I For the reduction, the organic solvent of the group consisting of toluene, THF, benzene, xylene, chlorobenzene, mixtures of petroleum ether, ether, t-butyl methyl ether ethylformate, ethyl acetate / hexane, ethyl acetate / petroleum ether or ethyl acetate can be selected. / heptane. Preferably in a method of the invention the solvent is the same solvent used in previous and subsequent steps and more preferably is toluene. The borane reagent which may be used may be borane-THF complex, borane dimethyl sulfide complex or mono- or disubstituted borane such as methyl- or dimethyl-texil, 9-BBN or monochloroborane. One embodiment of Step (G) of the invention comprises (i) reducing enamide with borane-THF in toluene; (11) crystallize the alkyl? Denod? Ox? -8-hydroxdol? Z? Dma, for example swamsonma acetonide, from t-butyl methyl ether, ethyl acetate, ethyl acetate / hexane , ethyl acetate / petroleum ether or ethyl acetate / heptane.

- DETAILED DESCRIPTION OF THE PREFERRED MODALITIES Swainsonin Halide Salts A preferred method of the invention for preparing a swamsonin halide salt includes steps (A) to (H) as follows. (A) (i) reacting a 2,3-O-alkylidene-D-erythrolactone, for example 2, 3-0-? Soprop? L? Den-D-er? Trolactone ((-) - (3aR-cis ) -d? h? dro-2, 2-dimethylide [3,4-d] -1,3-d? oxol-4 (3aH) -one), with one molar equivalent of diisobutylaluminum hydride in tetrahydrofuran or preferably toluene , at about -10 ° C to 0 ° C in a 0 ° C mode); (A) (n) (a) add methanol, (n) (b) concentrate it to gel, (n) (c) add THF and brine, (n) (d) add disodium sulfate, and (n) (e) remove the inorganic salts by precipitation and filtration to produce 2, 3-0-alkyl? den-D- epistro (the lactol). (B) (i) reacting ethyl 4-bromobutyrate with triphenyl phosphate to form a phosphonium bromide salt; (B) (n) reacting the generated acid from the phosphonium salt with 2, 3-O-alkyl? Den-D-er? Trosa to form an olefinic alcohol; (C) (i) reacting the olefinic alcohol with a molar equivalent of detriphenyl phosphine in THF, a molar equivalent of diisopropylazodicarboxylate and trimethylsilyl azide to form an alkyl azide product, for example, (+) - (4R, cis) (Z) -2, 2-dimethyl-5- (4-carbethoxy-1-butenyl) -1,3-dioxolane-4-azidomethane and a by-product, for example, an olefinic alcohol protected with O-trimethylsilyl; (C) (ii) adding tetrabutylammonium fluoride in THF to the crude azide product. (C) (in) repeating the treatment described in (C) (i) and (C) (ii), thereby converting a portion of the olefinic alcohol byproduct protected with O-trimethylsilyl into the alkyl azide product; (D) refluxing the purified azide in toluene in an initial concentration of between 0.30 M and 0.05 M to form an imino ester for example, (-) - (S, 5 R) -3,3-dimethyl-8- (3- carbetox? -1-propyl) -7-aza-2,4-dioxabicyclo [3.3.0] oct-7-ene; (E) (i) reacting the imino ester with a molar equivalent of an alkali metal hydroxide in a mixture of water and a C ^ alkanol (for example ethanol); (E) (ii) acidifying the reaction mixture at about pH 3-7, preferably 6-7, to produce an acid imino, for example, (-) - (IS, 5R) -3,3-dimethyl-8 - (3-carboxy-1-propyl) -7-aza-2,4-dioxabicyclo [3.3.0] oct-7-ene; (F) cyclizing the acid imino by reflowing it in toluene with a catalytic amount of a low carboxylic acid in alkalinity to form an enamide, for example (-) - (7S, 8R) -7,8-isopropylidenedioxy-2- oxo-l-azabicyclo [4.3.0] non-5-ene; (G) (i) reducing the enamide with the borane-THF complex in toluene followed by oxidation by peroxide; (G) (ii) crystallizing the alkylidenedioxy-8-hydroxyindolizidine, for example swainsonin acetonide, from t-butyl methyl ether, ethylformate, ethyl acetate / hexane, ethyl acetate / petroleum ether or ethyl acetate / heptane; (H) (i) converting aliquilidenedioxy-8-hydroxyindolizidine to swainsonine salt by acid hydrolysis in the presence of a C1.3 alkanol (eg, isopropanol) at room temperature; and optionally (H) (ii) recrystallizing the swainsonin salt in a C ^ alkanol (eg, isopropanol). Methods are provided in particular embodiments for synthesizing swainsonine salts comprising Stage (H); Stages (F) and (H); Stages (G) and (H); Stages (E) and (H); Stages (C) and (H); Stages (C), (D) and (H); Stages (A) (i) and (H); Stages (A) and (H); Stages (B) and (H); Stages (C), (D), (E), (F), (G) and (H); Stages (A), (B), (D) and (H); Stages (A), (B), (C), (D) and (H); o Stages (C), (E), (F) and (H).

- A particular synthesis of swainsonin halide salts, for example, swainsonin hydrobromide or swainsonin hydrochloride are described in Schemes I-III. Scheme I converts D-isoascorbic acid to 2,3-0-isopropylidene-D-erythronolactol through D-erythronolactone. Scheme II takes the lactol for the olefinic azide and Scheme III converts the olefinic azide to swamsonma hydrochloride. In Scheme VI, other specific synthetic routes contemplated by the present invention are shown. Although it is easily recognized that the safest synthesis, of higher cost-efficiency and energy-efficiency uses all the stages described, individual steps can be inserted in the known syntheses such as the synthesis Cha (Supra), to provide the advantages of the stage or stages selected. It will also be appreciated that protected groups other than alkylidene groups (eg, isopropylidene) can be used in the detailed methods described herein. Below the details of the synthesis in the Schemes I-IV and Table A.

SCHEME 1 Stage 1 to solid without mp 64-65 [a] 25 -120 D - add CH3OH to destroy the excess DIBALH - concentrate v diluted with THF - add 0.5% by weight of brine - stir at room temperature until the emulsion is destroyed - add Na2S0 , shake until dry - filter and evaporate to a thin clear oil SCHEME I Stage 4a 1. it is concentrated and allows Ph3P0 / DIAD 2 to crystallize. It is filtered using t-butyl methyl ether as solvent 3. silica filtration (10% TBME / hepatane) - SCHEME I 95% Stage 7 Quantitative 1NaCI the product is in dry toluene and can advance to the next stage Stage 9 mp = 101 ° C Stage 10 -HCl - the reaction is quantitative mp = 190 ° C - the product recovers in > 99% purity from the first cristarzación (91% of product recovered) SCHEME IV Stage 1 D-isoascorbic acid 5. HO evaporated - complete removal of water is critical - removal of water and pH should be moderate to inhibit brown tone Water and salts are removed by repeating (x 3-4 concentration, filtration and washing with 77% hot acetone followed by a final evaporation until drying solid without color mp 64-65-C H25D -120.2 ° (c1, H2O) - concentrate and dilute with THF - add 0.5% by weight of salt water - stir at room temperature until the emulsion is destroyed - add Na2SO0 to dryness - filter and evaporate to a thin clear oil. SCHEME IV CONT. n-BuOAc Ph3P Br '"C02Et * COZEt 130-C, 4 hrs Treatment: EtOAc, vacuum-dried filter -BuOK THF -10 ° C 30 min.

Ph ^ "C02Et 1. -20 to 20fiC for 8 hrs. 2. EtOH, 65QC, 2.5 hrs. 3. AcOH to pH7 4. extraction liq./liq. 5. Silica gel chromatography of / -BuOMe / hexane 4. TBAF (-0.1 equiv.) 5. Traction precipitation by liq./liq traction. of products 6. Silica gel chromatography with EtOAc / hexane - - SCHEME IV CONT. 1. NaOH (1.1 equiv.) H20 / ethanol 2. HCl at pH 6-7 3. evaporated water 1. BH3-THF, Toluene, -5 ° C 2. EtOH 3. H 0, NaOH 4. H 0, NaCl, NaHS0, extraction liq./liq. 5. crystallization HCl - TABLE A ethyl 4-bromobutyrate ethyl 4-bromobutanoate Molecular formula = CgH13Br 02 Br CO Et Molecular weight = 195.054 bp = 80-82 ° C / lOmm Hg 2, 3-O-isopropylidene-D-erythronolactone Molecular formula = C7H10O4 H3C CH, Molecular weight = 158.152 mp = 64-65 ° C [a] D = -120.2 ° (cl, H20) (9C1) CA Index name: Furo [3, 4 -d] -l, 3-dioxol-4 (3aH) -one, dihydro-2,2-dimethyl-, (3aR, 6aR) - Record 25581-41-3 2, 3 -O-isopropi .1; iden- -D-eritronolactol Molecular formula = U7ri12U4 o o Molecular weight = 160.168 mp = 30-32 ° C [a] D = -79.3 ° (cl, H20) (9C1) CA Index name: 1, 3 -Dioxolane-4-carboxaldehyde, 5- (hydroxymethyl) -2, 2-dimethyl- , (4R-cis) Record 51607-16-0 Table A cont. Phosphonium bromide salt Molecular formula = C24H2502PBr Molecular weight = 457,340 Mp = 159-160 ° C (n-BuOAc) (9C1) CA Index name: Phosphonium (4-ethoxy-4-oxobutyl) trif enyl-bromide Register 50479-11-3 Olefinic Alcohol Molecular Formula = C13H2205 Molecular Weight = 258,311 Pale oil [a] D = -29.3 ° (c3.3, CHC13) (9C1) CA Index name: 4-Pentenoic acid, 5- [5- (hydroxymethyl) -2, 2-dimethyl-1, 3-dioxolan - 4 -yl] -, ethyl ester, [4S - [4. alpha. (Z), 5.alfa.]] - Registration 119011-34-6 Olefinic Azide Molecular Formula = C13H21N304 Molecular Weight = 283,324 (+) - (4R, cis) (Z) -2,2-dimethyl-5- (4-carbethoxy-1-butenyl) -1, 3-dioxolane-4-methanol ethyl (Z) -5 - [(4R , 5S) -5- (azidomethyl) -2, 2-dimethyl- -1, 3-dioxolane-4-yl] -4-pentenoate Table A cont. Imino ester Molecular formula = C13H21N 04 Molecular weight = 255.310 (9C1) CA Index Name: 4H-1, 3-Dioxolo [4, 5-c] Pyrrole-6-butanoic acid, 3a, 6a-dihydro-2, 2-dimethyl-, ethyl ester, (3aR-cis) - Registration 119011-33-5 Imino acid Molecular formula = C11H17N 04 Molecular weight = 227.257 (9C1) CA Name of the index: 4H-1, 3-Dioxolo [4, 5-c] pyrrole-6-butanoic acid, 3a, 6a-dihydro-2, 2-dimethyl-, (3aR-cis) -Register 119011 -36-8 Molecular formula = C1: 1H15N 03 Molecular weight = 209,242 (9C1) CA Index name: 1,3 Dioxolo [4,5-a] indolizin-6 (4H) -one, 3a, 7, 8, 9b-tetrahydro-2,2-dimethyl-, (3aR-cis) -Register 130412-70-3 Swainsonin Acetonide Molecular Formula XH19N 03 Molecular Weight 213,274 mp = 101-103 ° C (EtOAc) [a] D = -72.8 ° (c0.4, MeOH) (9C1) CA Index name: 1,3-Dioxolo [4, 5-a] indolizin-9-ol , octahydro-2, 2-dimethyl-, [3aR- (3a. alpha., 9 alpha., 9a. alpha., 9b. alpha.)] - Register 85624-09-5 Table A cont. Swainsonine Molecular formula = C11H19N 03 Molecular weight = 213,274 (9C1) CA Index name: 1, 2, 8-indolizinetriol, octahydro-, [ÍS- (1.alfa., 2. alpha, 8. beta., 8th beta.)] Record 72741-87-8 Swainsonin Hydrochloride Molecular Formula C8H16N 03 Cl Molecular Weight 209,671 Mp = 189-191 ° C [a] D = -66 ° (cl, H20) Name: 1, 2, 8-indolizinio, octahidro-, [ÍS- (1. alf a., 2. alfa., 8. beta., 8th beta.)] -, chloride 4 - . 4 - The following non-limiting examples are illustrative of the present invention: Example I D-Eritronolactone from D-isoascorbic acid With the modifications discussed above, the procedure of H. Cohen et al. (JA .Chem. Soc. (1983), 105: 3661-3672 /? Rg. Synth. (1985), 63: 127-135) using 176.0 g (1.0 mol) of D-isoascorbic acid, 2.5 liters of deionized water , 212 g (2.0 mol) of Na2C03, 220 ml (2.7 mol) 30% H202, and 42 g of Norit A coal. Notably the pH was adjusted to 3.5, in contrast to the Cohen procedure which requires adjusting the pH - 1 with HCl to gasify all the carbonate used. The Cohen process resulted in a very acidic crude product that quickly turned brown as the water evaporated. According to the present invention, a pH of 3.5 was sufficient to gasify the carbonate and resulted in a crude product that was less acidic and therefore less susceptible to browning. Preferably, the pH was adjusted to between 3.9-4.0, as indicated by the suspension of the evolution of carbon dioxide. Alternatively, neutralization with NaOH can also be considered before removing the water.

- The water was removed under vacuum until a coarse mixture of product and insoluble salts was obtained. The mixture was filtered and the residue was washed with hot acetone. The filtrate was concentrated again until the additional insoluble material could be filtered and the residue was rinsed with hot acetone. This process was repeated until no salt could be precipitated. In general, three or four cycles were enough to remove water and salts. The resulting solution was dried under vacuum and the residue was advanced to the next stage. The physical properties of the product are compared with those reported in the literature. EXAMPLE 2 Isopropylidenation of D-Eritronolactone To the crude material of Example 1 dissolved in acetone (1000 ml) was added 100 g of MgSO4 followed by 2.1 g of toluenesulfonic acid monohydrate. After stirring the solution at room temperature for 24 hours, the total consumption of the diol (Rf = 0) to the desired acetonide (Rf = 0.6) was shown by TLC (1: 1: ethyl acetate: toluene). The pH was adjusted, slightly to pH 7 using triethyl amine, while keeping the temperature at 0 ° C. Filtration followed by evaporation of the solvent in vacuo gave a brown oil. The crystallization was carried out at room temperature by adding hexane to the solution of the crude product mixture in diethyl ether. In other tests the product was successfully crystallized from t-butyl methyl ether (TBME) / hexane or TBME / heptane, which is less flammable than dimethyl ether. Filtration, washed with 1: 2 :: ether: hexane and dried in vacuo afforded 149.1 g of white crystalline (77.4%, in 2 steps of D-isoascorbic acid). Very little additional product was detected in the mother liquor. According to the present method, omitting 2,2-dimethoxypropane results in a byproduct of non-detectable methyl ether acyclous or other by-product described by L.A. Flippin and C.H. Heathcock, Org. Synth (1985) 63: 127-135. In a reference test after the Cohen process, which includes dimethoxy propane / acetone, the corresponding secondary product acyclic methyl ester was formed in a yield presumably of -10% due to the large amount of methanol generated by the 2, 2 -dimetoxy propane. The combined modifications of examples 1 and 2 have increased the yield and quality of the product to achieve crystallization at room temperature for a cleaner material. It is recognized that other protected alkylene groups can be readily substituted by isopropylidene. The physical properties of the product are compared to those - reported in the literature. Example 3 2, 3-O-isopropylidene-D-erythronolactol Referring to Examples 3a and 3b the advantages of Examples 3c and 3d are provided for demonstration, the last two methods of the invention described have low energy and low cost requirements. The reaction was essentially quantitative when carried out at 0 ° C in toluene anhydride (Example 3c). Although THF produced a higher exotherm and a lower yield (90%) than toluene, both treatment and solvent withdrawals were easier with THF (Example 3d). It is important to remove as much toluene as possible immediately after reduction and to quench the methanol for large scales (>; 1 Kg). Otherwise, the formation of a thick gel of complex aluminum salts requires the addition of a volume of THF followed by brine. Further stirring is also necessary after the addition of disodium sulfate to maintain the recovery of the product. Without stirring, the desired product can be absorbed or chelated in complexes of aluminum salts within the filter cake. Example 3a 2,3-O-isopropylidene-D-erythronolactone (59 g; 373 mmol) was dissolved in 800 ml of dry toluene (sodium distillate / benzophenone) and the solution cooled to -60 ° C. Diisobutylaluminum hydride (DIBALH; 476 ml; 1M solution in toluene) was added slightly for 1 hour while keeping the temperature low. The mixture was stirred for an additional 1.5 hours at -60 ° C after completing the addition of DIBALH. The reaction was quenched by adding 50 ml of methanol and concentrated to the formation of a gel (~ 200 ml volume of mixture). Terahydrofuran (400 ml) was added, followed by brine (25 ml). The solution gradually became cloudy for approximately 20 minutes until the white solid disappeared. After the addition of anhydrous sodium sulfate powder (100 g), the solution was stirred for 15 minutes and filtered through a glass fiber filter pad. The evaporated filtrate produces the lactol as a thin, slightly yellow oil. The oil was dried under vacuum for two days to yield 58.4 g (97.7% yield) of lactol which crystallized after remaining at room temperature. The reaction was followed by TLC using 1: 1:: toluene: EtOAc. The lactate clearly became lactol with only traces of basal material. Rf = 0.63 for the lactate, Rf = 0.44 for the lactol product. Although the reaction was relatively clean by TLC, the yield obtained according to the original method described by the Cohen method (J. Am. Chem. Soc., 1983) was not reproducible. The extractive treatment was not effective either. The protocol described above was cleaner and faster. Similarly, the reaction and the treatment procedure by Pearson and Hembre (J. Org. Chem., 1996) was not clean and was difficult to treat due to the poor filtration properties of the crude product solution. Example 3b-THF The procedure of Example 3a was graded to 1.0 g of 2,3-O-isopropylidene-D-erythronolactone and the reduction was carried out at -30 ° C. The isolated production was 98%. Example 3c - Toluene at 0 ° C The procedure of Example 3a was graduated to 81.0 g of 2,3-O-isopropylidene-D-erythronolactone and the reduction was carried out at 0 ° C. The reaction was completed in 25 minutes (the total time of the addition of DIBALH) and was clean by TLC. The isolated product was 99%. Example 3d - THF at 0 ° C The procedure of Example 3a was graded to 1.0 g of 2,3-O-isopropylidene-D-erythronolactone and the reduction (1.2-equiv DIBALH) was carried out at 0 ° C in THF resulting in a strong exotherm. The reaction was warmed with 1 ml of methanol. After the addition of 5 ml of brine and stirring for 20 minutes, lOg of NA2SO4 powder was added. After stirring for an additional 30 minutes, the solution was filtered through a glass fiber filter with porosity of 1 miera and the solvent was evaporated. The isolated product was 99%. EXAMPLE 4 Salt of Bromide Ethyl Butyrate 4-Triphenyl Phosphonium An excess of solvent (estimated at 200% -300% by weight of the total reagent) should be used to ensure a mixture of free flowing product by simple filtration and washed with ethyl acetate. There is an undetermined but manageable heat of crystallization associated with the formation of the product. Example 4a Moderate Scale (204.8 g, 1.05 mol) of Ethyl 4-bromobutyrate and (275.0 g, 1048 mol) of triphenylphosphine was heated at 100 ° C for 4 hours and cooled to room temperature. The resulting solid mass was triturated in ethyl acetate, filtered and washed with ethyl acetate to give the desired salt in yield of 431.5 g (90%).

- Example 4b - Large scale A 50 1 flask was charged with 3.65 kg of triphenyl phosphine, 200 ml of ethyl 4-bromobutyrate and 5 liters of n-butyl acetate. The heterogeneous solution was stirred at moderate speed while heating was started. The solution became clear after reaching 63 ° C. After slowly reaching 126 ° C after 2 hours of heating, the reaction mixture was a very thick white mixture. Heating was continued for an additional hour. Then it was cooled to room temperature (for example 2 days), the mixture had hardness of a solid when it was removed from the reaction flask by careful grinding with large spoons. The product was triturated and washed with an ethyl acetate briefly in a large Buchner funnel. The final product was placed in trays and dried in a vacuum oven (70 ° C for 2 days) to remove any butyl acetate, yielding 6.15 kg of light white solid (98%). Example 4c - Reference Examples (5 g scale) Adding 100% (vol / weight) of n-butyl acetate produced, after 3 hours at 80-100 ° C, a quantitatively close yield of the white crystalline filterable solid. Substitution with methylethyl ketone produced a 90% yield after filtration. Upon refluxing it in 4-ethyl acetone overnight (50% and 100% (vol / weight)) it only provides 35% yield of the desired phosphonium salt after cooling and filtration. The yield ranged from 50% to 70% when benzene, toluene, xylene or hexane were used as solvent. Example 5 Chain extension of ittig for olefinic alcohol. Example 5a A stirred suspension of the triphenyl phosphonium bromide salt (5.09 Kg); 10.9 mol; 2 equiv) in THF anhydride (8.51 1) was cooled to 10 ° C. S potassium t-butoxide (1.22 Kg, 11.9 mole) was slowly added in small portions over a period of 20 minutes. Only a slight exotherm (~ 2 ° C) was observed. The solution adopted a yellow to orange color as the addition of potassium t-butoxide progressed. The solution was stirred for an additional 25 minutes while cog to -5 ° C, before the lactol was added. The pure lactol (940 g, 5.88 mol) was dissolved in 500 ml of dry THF and added as drops to the phosphonium salt mixture to prevent the temperature from rising above 0 ° C. The addition of lactol is exothermic, especially at the beginning of the addition. After completing the addition of lactol, the reaction was allowed to reach room temperature overnight with stirring. The reaction seemed to complete in 6 hours. The reaction was cooled to 0 ° C and slightly warmed with 3.5 parts of molar excess of 15% NH 4 Cl (8.2 1). A strong exotherm was observed with the addition of the first 100 ml of 15% NH4C1. The reaction was monitored by TLC 2: 3 :: ethyl acetate: hexane, Rf = 0.44 for lactol, Rf = 0.38 for the product) and appeared to produce a very good conversion for the desired product. However, after quenching, treating and chromatographing, multiple impurities appeared with the desired product. The THF layers were separated from the aqueous layer. The aqueous layer was extracted with toluene (3.5 1, 3 x 2 1). Evaporation of the solvent from the THF layer produced an oil which was redissolved with the above toluene extracts. The combined solution was extracted with water (2 x 2500 ml) and brine (1 x 1000 ml). The organic extracts were dried by MgSO 4, filtered and evaporated to yield a brown syrup containing s triphenyl phosphine oxide. A filtration of only 10% by weight of expected triphenyl phosphine oxide was achieved after stirring the crude product syrup in t-butyl methyl ether at room temperature for 30 minutes. The evaporation of the TBME filtrate and the organic rinses - produced a brown syrup (4 Kg) which produced more Ph3PO after remaining at room temperature over the weekend. Repeated rinses with TBME removed only an additional 8% of the total expected Ph3PO. Silica gel chromatography using TBME / hexane yielded 695 g (45%) of the desired product contaminated with modest amounts of side products. This material was advanced to the next stage of synthesis. Example 5b A three-necked flask adapted with a mechanical stirrer, a distillation funnel and a nitrogen inlet was charged with a phosphonium salt (339 g, 0.85 mol) of Example 4 and dry THF (800 mL). After cog the solution to 0 ° C, potassium t-butoxide (95.4 g, 0.85 mol) was added in portions over a period of 30 minutes. The resulting yellow / orange solution was stirred for an additional 15 minutes before adding a solution of 2,3-0-isopropylidene-D-erythronolactol (68.0 g, 0.425 mol) in dry THF (400 ml) as a dropwise solution. . The internal temperature was maintained between 0-5 ° C. After one hour, TLC (2: 3 :: ethyl acetate: hexane) showed a complete consumption of lactol. The tetrahydrofuran was removed in vacuo. The residue was taken up in toluene (2 1) and rinsed with water (3 x 750 ml) and brine (3 x 750 ml). The organic mixture was dried by MgSO 4, filtered and evaporated to a brown semis. The product was purified by chromatography on silica gel using a gradient (0.5, 10, 20, 30%) of t-butyl methyl ether and isolated as a yellow oil (46 g, 40%). Example 5c - Large Scale Protocol (Scheme V) SCHEME V H C13H2205 MW = 258.311 light oil [a] D = -29.3 ° (c3.3 CHCI3) To a 72 1 flask fitted with a mechanical stirrer, condenser, argon inlet, thermocouple and heating / cooling bath, ethyl 4-triphenylphosphonium butyrate bromide salt (12.8 Kg, 28.0 mole) and anhydrous THF (34) were added. 1) . After cooling the mixture between -15 to -7 ° C under argon, potassium tert-butoxide (3.67 Kg, 32.7 mole) was added at a rate to keep the reaction temperature lower than -5 ° C. After 30 minutes, 2,3-0-isopropyleden-D-erythronolactol (2169 kg, 13.55 mol) dissolved in anhydrous THF (2.4 1) was added dropwise over 2 hours to the orange colored solution so that the reaction temperature was maintained below -5 ° C. The reaction mixture was allowed to warm, with stirring, at room temperature (21 ° C) overnight. Anhydride ethanol (6 1) was added to the resulting mixture. The mixture was then heated to 65-69 ° C for two hours after which the pH dropped from pH 14 to pH 11-12. The solution was cooled and glacial acetic acid oil (630 ml) (temperature: 0 to 5 ° C) was added to adjust the pH to 7. The mixture was transferred to a 50 1 distillation apparatus. The reaction flask was washed with 4 1 of toluene which was added to the distillation flask. The reaction mixture was concentrated under reduced pressure (bath temperature of the vessel at 8 to 20 ° C, about 10 torr, 20 to 30 ° C). Then 20 1 of toluene was added to the residue. About half (11 1) of this mixture was transferred to a 35 1 separatory funnel and washed with 3 x 5 1 of water. During the second water wash, the third dense layer was formed. This third layer was saved and the other washes were discarded with water. The second half was then washed with 3 x 5 liters of water and the third layer of the second wash was combined with the third layer of the first portion. The combined dark oily third layers (3.5 1 total), diluted with 1.5 times their volume in ethyl acetate (5.25 1) were combined. The resulting mixture was washed with water (3.5 1). The ethyl acetate and toluene solutions were combined and concentrated under reduced pressure (15 to 30 ° C to 10 torr) to gauge 11.2 kg of a dark oil. The oil was mixed with 14.6 kg of silica by weight. The 25.8 kg of adsorbed silica was divided into three equal portions (8.6 kg) and each was dry packed individually in a stainless steel MPLC unit on top of a 2.0 kg pad of fresh silica. The silica was compressed in the column with nitrogen at 25 psi for 20 minutes. Each portion was eluted with t-butyl methyl ether: hexane 2: 8, 15 1, followed by 4: 6, 45 1) at a rate of 400 ml / min (2 hours, 15-16 PSI). The combined eluents containing the product (TLC) were concentrated to an oil under reduced pressure. The residue was further dried with stirring at least 10 mm Hg for two hours and overnight without stirring. The resulting yellow oil was transferred to polyethylene containers product 2.63 kg, 10.2 mol, (75%). The NMR results for the final product showed a purity greater than 92% with only triphenylphosphine oxide detectable as a contaminant. Example 6 Preparation of azide by the Mitsunobu reaction A reference example (Example 6a) is provided to demonstrate the advantages of a recycling reaction of the invention described in Example 6b. Example 6a - recycling without alcohol Pure olefinic alcohol (214 g, 828 mmol) and triphenyl phosphine (248 g, 994 mmol, 1.2 equiv) were dissolved in dry THF (4 1). The solution was cooled to 0 ° C and treated dropwise with 1.2 equivalents of DIAD (196 ml) while maintaining the temperature below 5 ° C. Continuing to maintain the temperature, the dropwise treatment with 1.6 equivalents of TMS-azide (175 ml, -1.3 mol) formed a coarse yellow precipitate. The final reaction solution was stored overnight at 4 ° C and treated with tetrabutylammonium fluoride (TBAF) until the ether product TMD was also converted to alcohol. After the concentration, the crude solid product was treated with TBME (600 ml). The insoluble triphenyl phosphine / dicarbisopropoxy hydrazine complex (304 g) was filtered and washed with additional TBME (2 x 150 ml). The TBME was evaporated - to give an orange syrup (505 g) which was filtered in two batches through a short column of silica using an ethyl acetate / hexane gradient to give 157 g (67%) of the desired azide after remove the solvent. A first, similar test on a 25 g scale had a yield of 59%. Example 6b- -Recycling alcohol To a cold solution (0 ° C) and dry THF (500 ml) of the olefinic alcohol (30.0 g); 0.116 mol) and Ph3P (36.5 g, 0.139 mol) was slowly added DIAD (274 ml, 0.139 mol) under argon. Trimethylsilyl azide (185 ml, 0.139 mol) was added dropwise, forming a yellow precipitate. After 20 minutes, the TLC (3: 7 :: ethyl acetate: hexane) showed total alcohol consumption to give the desired azide and the secondary product of TMS ether. Slow addition of 30 ml of TBAF (1 M in THF) resulted in the conversion of the TMS ether from returned to alcohol, as monitored by TLC. The concentrate residue was chromatographed on silica (10-20% TBME / hexane) to give pure azide and the alcohol recovered. After this, the alcohol became more azide. Additional triphenyl phosphine (11g, 0.042 mol), dicarbethoxyhydrazine (DIAD) (83 ml, 0.042 mol) was added. After stirring overnight at 0 ° C, additional TBAF (22 ml, 1 M in THF) was added. After 35 minutes without TMS ether and only a small amount of stirred alcohol was detected by TLC. The solvent was evaporated and after remaining overnight at room temperature the precipitate of the triphenyl phosphine oxide / dicarbisopropoxy hydrazine complex was filtered and washed with TBME to produce a light yellow oil which was chromatographed as before. The total yield of azide = 27.8 g (80%). X H NMR (500 MHz): d (CDC 13): 1.22 (t, 3 H, J = 7.1 Hz) 1.40 (s, 3 H), 1.58 (s, 3 H), 2.42 (m, 4 H), 3.22 (m, 2 H) , 4.18 (q, 2H, j = 7.1 Hz), 4.28 (m, 1H), 5.02 (t, 1H, J = 7.9HZ), 5.45 (t, lH, J = 8.8HZ), 5.64 (m, 1H) . 13 C NMR (125 MHz): d (CDCl 3): 14.2, 23.3, 25.3, 27.8, 33.7, 51.6, 60.5, 72.9, 109.1, 125.6, 133.1, 172.5. ESI-MS: 306.2 (M + Na +), 301.4 (M + NH 4 +), 284.2 (M + H +), 256.0,226.0,208.0. FTIR (cm? Neat): 2985 (m), 2936 (m), 2101 (s, N3), 1734 (s, C = 0), 1372 (m), 1244, 1214, 1163, 1086.

Example 6c (Scheme VI) SCHEME VI To a 72 1 flask loaded with an argon atmosphere, equipped with a mechanical stirrer and an additional funnel was added 2110 g (8.17 mol, 1 equiv) of olefinic alcohol, 34 1 of THF anhydride, and 2.36 kg (9.00 mol, 1.1 equiv) of triphenylphosphine. After the resulting mixture was cooled to -3 ° C, 1.90 kg (~ 9 mol, 1.1 equiv) of diisopropyllazodicarboxylate (DIAD, Aldrich, 95%) was added at a rate to maintain the temperature = 10 ° C. After stirring the mixture at 5-15 ° C for 50 minutes, the reaction mixture was cooled to 0 ° C. To the cooled mixture was added 1.08 kg (~ 9 mol, 1.1 equiv) of trimethylsilyl azide during a period of 25 minutes while maintaining the temperature of the vessel between 1 and 8 ° C. The resulting mixture was stirred for 1 hour at 5 ° C until the alcohol consumption was considered finished by TLC. The reaction was cooled to 5 ° C and a total of 2.2 1 of tetra-n-butyl ammonium fluoride (TBAF, 1 M in THF) was added to completely consume the byproduct of TMS ether formed. The reaction sequence was repeated by first adding 801 g (3.05 mol, 0.37 equiv.) Of triphenyl phosphine and 670 g (3.15 mol, 0.385 equiv.) Of DIAD to the reaction mixture. After the mixture was stirred for 1 hour, then 387 g (3.36 mol, 0.41 equiv.) Of TMS-azide was added at a rate so that the temperature of the vessel was maintained at 0 to 2 ° C. The reaction mixture was stirred for 1 hour. A total of 0.98 1 TBAF (1 M in THF) was then added to consume the TMS ether byproduct. The reaction mixture was allowed to warm to room temperature (20 ° C) overnight with stirring. The THF was removed by vacuum distillation and the reaction vessel was vented with argon. To the resulting residue was added 10 1 of an 80:20 mixture of MTBE: hexanes. The resulting mixture was stirred for 18 hours and filtered. The filter cake (a 1: 1 complex of Ph3PO: dicarbisopropoxy hydrazine complex) was washed with 8 1 of an 8:20 mixture of MTB: hexanes. The filtrates were combined and washed twice with 4 1 of water to remove the tetrabutylammonium salts. The organic phase was concentrated by vacuum distillation to obtain 3060 g of a viscous oil. The residues were mixed with 3.67 Kg of silica gel (230-400 meshes) to gauge a soft flow material. The crude azide was purified by filtration / silica gel chromatography on a large MPLC column (same as for the olefinic alcohol) as follows: The adsorbed silica mixture was divided into two unequal portions. The first 4.59 kg portion was loaded onto a 14.5 x 93 cm long stainless steel column (capacity: 15.9 L) containing 5 kg of clean silica gel. The product was eluted with 24 1 of a mixture of 3% ethyl acetate: hexane and 15 1 of a mixture of 5% ethyl acetate: hexane per 20 psi of nitrogen pressure. A second column was run using the remaining 2.14 kg of silica adsorbed with 1.9 kg of crude azide from the clean silica gel. The fractions containing the product were combined and concentrated by vacuum distillation to gauge 1140 g of product.

Performance = 49%. (> 95% purity by ^ -NMR). Example 7: Azide to Swainsonin Acetonide Example 7a - Cycloaddition to the imino ester The azide (156 g, 0.524 mol) was refluxed in toluene anhydride (3.5 1) for 95 hours. Evaporation of the solvent produced 143 g of crude product which was advanced to the next step without further purification. Thin layer chromatography of the crude product mixture showed complete conversion to the desired product with only minor traces of by-products (basal + Rf = 0.28). This reaction was repeated 5 times at various scales and concentrations (<0.25 M) with consistent events. Example 7b - Saponification of the imino ester The crude imino ester (141 g, 0.55 mol, Example 7) was dissolved in ethanol (800 ml) in a 5 1 flask equipped with a thermocouple, stirrer and additional funnel. An aqueous solution of sodium hydroxide (2 N) was slowly added, 325 ml, 0.62 mol) over a period of 20 minutes while maintaining the temperature below 30 ° C. The mixture (pH ~ 14) was stirred at room temperature for 1 hour until the TLC (3: 2 :: ethyl acetate: hexane) showed the consumption of the ester (Rf = 0.3) to give a new basal material. The mixture was diluted with water (500 ml) and extracted with toluene to remove the minor organic impurities. The aqueous layer was cooled to 0 ° C and neutralized slowly (pH 6.5-7) with hydrochloric acid (55 mL, 2 N). The water evaporated under vacuum (<; 30 ° C) to gauge a crude mixture of the imino acid and desired inorganic salts as a dark waxy oil (156 g). Subsequent tests indicated that the reaction mixture did not need to be diluted with water prior to extraction with an organic solvent. In several small scale attempts, the resulting crude product was a completely white solid and not a dark oil, the latter being caused by some impurities carried by the olefinic alcohol. Example 7c - Condensation / Cyclization of the enamide Toluene (3.5 1) was added to the oil of example 7b. The solution was refluxed for two hours with 45 ml of residual water aziotropically removed with a Dean-Stark trap. Acetic acid (20 ml) was added and the reflux continued for 16 hours. The acetic acid catalysed the condensation that showed to require only 10 hours with acid catalysis, in contrast to the 60 hours needed without acetic acid on a smaller scale (14 g). The TLC showed a complete conversion to the desired enamide without a minor amount of non-reactive basal material. Celite (200 g) and coarse silica gel (150 g) were added to the mixture. After stirring for 30 minutes, the suspension was filtered, the cake was washed with toluene (3 1) and the filtrate was concentrated in vacuo. The crude product (92 g, 80%) was dissolved in anhydrous THF and advanced to the next step without further purification. An alternative (and preferred) treatment after acid catalysis includes filtering the organic salts from the toluene solution and bringing the solution to the next step. Example 7d - Swainsonin acetonide The crude enamide recovered above (90 g, 0.43 mol) was dissolved in anhydrous THF (500 ml), the solution was cooled to 0 ° C and slowly treated with 1.0 M BH3 in THF (1650 ml) and then allowed to reach room temperature while stirring overnight. Through TLC (EtOAc) a new product was propagated with the first solvent without trace of the initial material. The solvent was removed from the pure solution in vacuo. Ethanol (1800 ml) was added followed by NaOH (64 g, 1.4 mol) and 30% hydrogen peroxide (180 ml). The mixture was refluxed for 2 hours. Thin layer chromatography (EtOAc) showed a complete conversion of enamide (Rf = 0.7) for the desired swainsonin acetonide (Rf = 0.3). The basal impurities present in the preparation of enamide were transported completely without any observable change in their amounts or mobility.

The solution was saturated with solid NaCl, and then extracted with ethyl acetate (5 x 350 ml). The organic extracts were dried through MgSO 4, filtered and concentrated in vacuo to yield a completely white solid (48g, 41% - 4 steps in total from the azide). This material was crystallized from TBME to produce 18.6 g of pure product as small white needles. The mother liquor was evaporated and the residue was dissolved in hot ethyl acetate and treated with hot hexane. The solution was inoculated and produced 14.8 g of additional pure product after cooling and filtration. The mother liquor was evaporated and chromatographed to yield 7.4 g of additional pure product (40.8 g total purified). Example 7e Conversion of the imino ester to swainsonin acetonide The imino ester (13.1 g, 51.3 mmol, 95% pure est) was dissolved in ethanol (50 ml). Sodium hydroxide (2N, 35 ml, 68 mmol) was added slowly over a period of 20 minutes while maintaining the temperature below 30 ° C. The mixture was stirred at room temperature for 20 hours. Thin layer chromatography (3: 2 :: ethyl acetate: hexane) showed the consumption of the ester (Rf = 0.3) to give a new basal material.

The mixture was cooled to 0 ° C and adjusted to pH 6.0 with 2N HCl. The ethanol was removed by rotary evaporation (water aspiration; <30 ° C) and the water was removed by lyophilization to gauge a crude mixture of the imino acid and desired inorganic salts as a completely white solid. This crude material, dry toluene (300 ml) and glacial acetic acid (3 ml, 1 equiv) were refluxed under an argon atmosphere for 24 hours or overnight.The water produced by the condensation reaction was removed using a Dean Stark trap Thin layer chromatography (5% MeOH in EtOAc) indicated the consumption of the desired acid imino for the desired enamide (Rf = 0.7) The slightly colored toluene solution was filtered through a glass fiber filter ( to remove the suspended NaCl) and concentrated to 200 ml to ensure the dryness of the solution and remove any traces of remaining acetic acid that may not have been collected in the Dean-Stark trap The resulting solution showed that it did not contain any significant amounts of acid and was used for the next step, Ba or an argon atmosphere, the enamide / toluene solution was cooled to 0 ° C and treated dropwise with BH3 (THF (150 ml, 1M in THF). solution it was allowed to warm to room temperature while stirring overnight (-18 hrs.). The resulting solution was evaporated to dryness to give a light yellow oil. The oil was taken up in ethanol (180 ml) and treated with NaOH (7.2 g, 0.18 mol) followed by 30% H202 (22 ml). This mixture was refluxed for 3 hours and the solvent mixture was evaporated. Brine (30 ml) was added and the product extracted with EtOAc (5 x 50 ml). The combined organic extracts were dried through MgSO4, filtered and evaporated to give 7.58 g (69% crude imino ether, in three steps) of swainsonin acetonide as a completely white crystalline solid. The acetonide swainsonin was recrystallized from ethyl acetate / hexanes to yield 5.5 g (50%). Example 8 Alternate Preparation of Swainsonin Acetonide from Olefinic Azide (Scheme VII) SCHEME VII 4. NaHSQ3 The olefinic azide [1131 g (3.99 mol)] was absorbed in 28 1 of toluene (0.14 molar in azide) and stirred at 106 ° C for 48 hours. The TLC analysis showed that the cyclisation for the imine was complete. The toluene was removed by vacuum distillation. The imine was absorbed in 5.7 1 of ethanol and 2.0 1 (4 mol, 1.02 equiv.) Of 2N NaOH. After the saponification was finished (final pH = 11), as determined by TLC, the reaction was neutralized with 400 ml of 2N HCl (0.8 mol) at pH 6 and left at room temperature overnight. Evaporation by vacuum distillation gave an oily residue. The residue was taken up in 23 l of toluene and the reactor was equipped with a condenser and a Dean Stark trap. The residual ethanol and water were removed as an azeotropic mixture of toluene. Acetic acid (230 ml, ~ 1% v / v of the total) was then added and the ring closure for the enamide was 90% complete within 2 hours as estimated by TLC. The reaction was stirred at reflux overnight. Water and acetic acid were codestilled as an azeotropic mixture. The distillate had a pH of 2 while the solution was pH 5-6 (humidity test strip). After cooling, the mixture was washed with 4 1 of water. The organic phase was dried through magnesium sulfate (1 Kg) and easily filtered through an in-line glass vitrified filter, packed with Celite in a 72 1 flask filled with an argon atmosphere. The filter was rinsed with approximately 1500 ml of toluene. The reaction mixture was cooled to 0 ° C. While maintaining the reaction temperature at = -10 ° C, the borane-THF complex (13.6 1 of 1M in THF, Aldrich, 13.6 mol, 3.4 borane equiv.) Was added slowly. The reaction mixture was allowed to warm to about 10 ° C overnight. The next morning, ethanol (2.8 1) was added (with cooling) at a rate to maintain the reaction mixture = 10 ° C. The solution was then concentrated by vacuum distillation and the resulting residue was dissolved in THF (17 1). NaOH (1.7 1 of 6N) was slowly added to the THF solution followed by the addition of 1.7 1 of 30% hydrogen peroxide at a rate such that the temperature was kept below 35 ° C. The resulting solution was then heated to 63 ° C for about 1.5 hours and then cooled to 30 ° C. The residual peroxide is templated with solid NaHS03 (182 g). The resulting mixture was then saturated with solid NaCl (732 g). The resulting biplace mixture was transferred to a separatory funnel. The organic phase was removed and the aqueous phase was washed three times with 1-2 liters of toluene. The combined organic phases were concentrated by vacuum distillation and dried for 3 days under high vacuum to yield 377.8 g of completely white serous solid. The residue was dissolved in 334 ml of hot ethyl acetate and filtered through a hot filter funnel. The filtrate was allowed to cool to room temperature overnight. The crystallized swainsonine acetonide product was collected by filtration, rinsed with the cold ethyl acetate: hexanes mixture (3 x 50 ml) to gauge an initial crop of crystals which were dried under vacuum for 3 hours (yield 233.8 g). The washes and mother liquors were combined and diluted with 100 ml of ethyl acetate. The resulting mixture was purified by silica gel chromatography using a Biotage Flash 150L MPLC system and eluting progressively with 60:40 to 90:10 hexane: ethyl acetate. The column fractions containing product (TLC) were concentrated by vacuum distillation to gauge 25.4 grams of white solid. This material was dissolved in 50 ml of hot ethyl acetate to which 70 ml of hexanes were added. After cooling to room temperature the resulting crystalline material was collected by vacuum filtration, rinsed twice with 50 ml of a 50:50 mixture of ethyl acetate hexane, and dried under vacuum to gauge 16.9 g of a second crop of swainsonin acetonide. . The combined yield of both crops was 250.7 g, 1.17 mol, 29.3% 'produced from swainsonin acetonide. Both harvests were >98% pure by 'H-NMR. Example 9 - Hydrolysis of Acetonide Swainsonin acetonide (31 g, 0.145 mole was dissolved in isopropanol (300 ml), acid (6N HCl, 300 ml) was added and the solution was stirred overnight at room temperature. thin layer indicated that some acetonide (-20%) did not react.The solvent including acetone byproduct and HCl, was evaporated under vacuum (40-50 ° C) to drive the reaction to completion. in hot isopropanol (150 ml) and allowed to stand while the product crystallized, filtration of the yellow solution gave the final product (28 g, 91%) as a white crystalline solid after vacuum drying (50 ° C) during The melting point was determined to be 189-190 ° C. The hydrolysis reaction was monitored by TLC 7: 2: 1:: EtOAc: MeOH: NH 40 H. Plate visualization was best achieved with iodine. Rf values for swainsonin and acetonide were 0.29 and 0.73, respectively. Specifically, it is important to remove all traces of water to ensure a good production of crystallization. Starting with slightly impure acetonide resulted in a dark coloration (from brown to red to black in some cases) and decreased crystallization production. The crystals thus obtained should be recrystallized. Swainsonin hydrochloride is practically insoluble in isopropanol. Recrystallization can be achieved from a saturated solution of boiling ethanol (denatured) or methanol / ether by dissolving in a minimum part of methanol (~ 10% w / v), filtering and then slowly adding an equivalent amount of diethyl ether ( Recovery of 75-80% clear prisms;). HPLC protocol for purity determination Column: 4.6 x 250 mm, 0.5 cm, Phenomenex, Prodigy 5 ODS-2 Solvent: 5% acetonitrile / 95% aqueous KH2P04 (pH 9.0), 1 ml / min. Detection: UV, 205 nm Retention time: 5.5 minutes EXAMPLE 10 Denatonation reaction SE dissolved swainsonin acetonide (237.4 g, 1.11 mol) in 2-propanol (2.47 1) with stirring in a 22 1 flask equipped with mechanical stirrer, condenser, thermocouple and heating / cooling bath. The vessel was cooled to 7 ° C and a cooled solution of 6N HCl (1.24 1) was slowly added through an addition funnel with stirring. The resulting mixture was allowed to warm to room temperature (19 ° C) with stirring overnight (15 hours). The TLC showed the reaction to be 90% complete. The volume was concentrated to approximately 1.3 1 by vacuum distillation (container temperature 22 to 35 ° C, 20 to 25 torr, 3.6 1 distillate collected). The water was then removed by repeatedly adding 2-propanol and distillation solvent. 2 - . 2 -propanol distilled aggregate precipitate collected temperature observed pressure 3.7 1 3.9 1 22 at 33 ° C 20 -40 torr no 3 . 9 1 3. 8 1 19 at 25 ° C 20 -40 torr no 3 . 8 1 1. 4 1 < 40 ° C N / A yes 2 . 0 1 2 0 1 21 to 24 ° C 20 torr si The reaction mixture was cooled to 19 ° C and the product was collected by filtration through a coarse vitrified glass filtration unit in line. The filter cake was rinsed with 500 ml of cooled 2-propanol (10 to 15 ° C). The filter unit was sealed and evacuated 20 below 1 torr for 4 days) in order to dry the product at a constant weight. The white flaky product was transferred to brown glass bottles and stored under an argon atmosphere. Samples were sent for NMR and analysis. Yield = 217.2 g (89%). Melting point = 188-190 ° C. The crystalline product had the properties reported in PCT / CA98 / 00360. In particular, the hydrochloride salt of (-) - (SS, 2S, 8R, 8aR) -1, 2-8-trihydroxyoctahydro-mdolizma (swainsonin hydrochloride), was a white to completely white crystalline solid, of moleecular weight 209.67, and pKa 7.4. Example 11 - Alternative route for isopropylidene erythronolactone Potassium erythronate (Pfanstiehl Laboratories, aukegan, IL) (2.0 g, 11.5 mmol) was stirred briefly in 50 ml of hot acetone reagent grade (50-55 ° C). After adding p-toluenesulfonic acid (2.3 g), the solution was refluxed for 1.5 hours. The solution was cooled, and the insoluble potassium tosylate and the non-reactive potassium erythronate were removed by filtration. The filtrate was concentrated to remove the water and redissolved in 50 ml of acetone. Magnesium anhydride sulfate (2.5 g) was added and the pH adjusted to 5.5 with p-toluenesulfonic acid. After refluxing for 1.5 hours, the TLC and GC-MS indicated a total conversion, the solution was cooled to room temperature, the solids were removed by filtration, and the filtrate was adjusted to pH 7.0 with a small amount of triethyl amine. After concentration, the residue was redissolved in a minimum of t-butyl methyl ether. Hexane was added until the solution became turbid. After standing for 30 minutes, the cottony solid was filtered and dried in vacuo to yield 1.1 g (60%). No attempt was made to recover more product from the mother liquid. Example 12 - Alternative route for isopropylidene and itronolactone This example was identical to Example 11, except after the first evaporation of acetone to remove the water, 30 ml of toluene was added and evaporated to remove the additional water, before redissolving it in 50 ml. ml of acetone. The isolated product was 1.0 g (56%). This reaction can be improved by, for example, using more p-toluene sulfonic acid (pTSA or other protonic acid such as sulfuric acid) to set a pH below 5.5 (such as between 1.0 and 5.0, or between 2.5 and 4.0); reflowing in acetone more than 1.5 hours; replacing the neutralization of pTSA with a base such as a trimethylamine with a treatment including solid sodium bicarbonate and filtration; or add a little water during the acetone process to improve the solubility. The additional water can be coevaporated with acetone or removed with magnesium sulfate. Other Modalities Based on the examples and description above, a person of ordinary experience in the subject of the invention can easily recognize the essential characteristics of the invention and, without going beyond the spirit and scope thereof, be able to adapt the invention to various uses and conditions.

In particular, the variations and substitutions in the above synthetic transformations will be apparent to those of experience in organic chemistry. All publications, patents and patent applications are hereby incorporated by reference in their entirety to the same extent as if each publication, patent or individual patent application were specifically and individually indicated to be incorporated by reference in its entirety.

Claims (25)

1. CLAIMS 1. A method for synthesizing a swamsonma salt comprising (i) subjecting a compound of the formula I wherein R2 and R2 are the same or different and represent alkyl, halogen, alkenyl, alkoxy, cycloalkyl or aryl for acid hydrolysis in the presence of a Cx 4 alkanol to obtain a crystalline salt of swainson's; and optionally (n) rectalizing the salt of swainsonin from a C14 alkanol. 2. A method as claimed in claim 1 wherein R2 and R2 are the same and represents CX4 alkyl. 3. A method as claimed in claim 1 wherein R2 and R2 represent alkyl or aryl and the other R2 and R2 represents alkoxy or halogen. 4. A method as claimed in claim 1 wherein the compound of formula I is 1,2-O-? Soprop? L? Dend? Ox? -8-h? Drox? Dolic? Dma. 5. A method for preparing a purified and purified crystalline hydrochloride swainsonine salt comprising converting 1,2-isopropylidenedioxy-8-hydroxyindolizidine to a hydrochloride salt by acid hydrolysis in the presence of a C ^ alkanol to obtain a salt of swamsonma crystalline hydrochloride, and optionally recrystallize the salt in a C1.4 alkanol. 6. A method as claimed in any of claims 1 to 5 wherein the acid hydrolysis includes hydrochloric acid. 7. A method as claimed in any of claims 1 to 5 wherein the acid hydrolysis includes hydrogen fluoride or hydrogen bromide. 8. A method for preparing a swainsonin salt comprising: (i) cyclizing an acid imino of the formula VII wherein R2 and R2 'are the same or different and represent alkyl, halogen, alkenyl, alkoxy, cycloalkyl or aryl when refluxing in an organic solvent with a catalyst, to form a compound of formula VIII wherein R2 and R2' are as is defined above (ii) reacting the enamide of formula VIII with borane reagent in an organic solvent, and oxidizing the resulting alkyl borane by peroxide, to obtain a protected swainsonin of formula I; wherein R2 and R3 are as defined above; (iii) subjecting the protected swainsonin to acid hydrolysis in the presence of a C ^ alkanol to obtain a crystalline swainsonine salt; and optionally (iv) recrystallizing the swainsonin salt from a C ^ alkanol. 9. A method for preparing a swainsonine salt comprising: (i) reacting an olefinic alcohol of the formula IV wherein R2 and R2 are the same or different and represent alkyl, halogen, alkenyl, alkoxy, cycloalkyl or aryl R3 is alkyl or aryl Cx 10 with a phosphine source, dialkylazodicarboxylate, and azide to obtain an azide of formula V wherein R2 and R2 are as defined above (11) refluxing the azide of formula V in a high-boiling non-reactive solvent to form an imam ester of formula VI wherein R2 and R2 are as defined above (ni) reacting the same ester of formula VI with an alkali metal hydroxide in a mixture of water and a non-reactive miscible organic solvent and acidifying the reaction mixture to obtain an imino acid of formula VII wherein R2 and R2 'are as defined above (iv) cyclizing the imino acid of formula VII by reflowing it in an organic solvent with a catalyst to form an enamide of formula VIII wherein R2 and R2 'are as defined above: (v) reducing the enamide of formula VIII with borane reagent in an organic solvent and oxidizing the resulting alkyl borane by peroxide to obtain a protected swainsonin of formula I; - - wherein R2 and R2 'are as defined above: (vi) subjecting the protected swainsonin to acid hydrolysis in the presence of a Cx_4 alkanol to obtain a crystalline swainsonine salt; and optionally; (vii) recrystallizing the salt of swainsonin from a C ^ alkanol. 10. A method for preparing a swainsonin salt comprising: (A) reacting a lactone of formula II wherein R2 and R2 'are the same or different and represent alkyl, alkenyl, halogen, alkoxy, cycloalkyl, or aryl with diisobutylaluminum hydride in an organic solvent to obtain a lactol of formula III wherein R2 and R2 'are as defined above: (B) reacting the lactol of formula III with a phosphonium bromide salt to obtain an olefinic alcohol of formula IV: wherein R2 and R are as defined above, and R3 is alkyl or aryl of Cx 10; (C) reacting the olefinic alcohol of formula IV with a source of phosphine, dialkylazodicarboxylate, and azide to obtain an azide of formula V wherein R2 and R are as defined above: (D) refluxing the azide of formula V in a high boiling non-reactive solvent to form an iminoether of formula VI wherein R2 and R2 'and R3 are as defined above: (E) reacting the imino ester of the formula VI with an alkali metal hydroxide in a mixture of water and a non-reactive miscible organic solvent and acidify the reaction mixture to obtain an acid imino of the formula VII wherein R2 and R2 'are as defined above: (F) cyclizing the acid imino of formula VII by reflowing in an organic solvent, with a catalyst to form an enamide of formula VIII wherein R2 and R2 'are as defined above: (G) reducing the enamide of formula VIII with a borane reagent in an organic solvent and oxidizing the resulting alkyl borane by peroxide to obtain a protected swainsonin of formula I; wherein R2 and R2 'are as defined above: (H) subjecting the protected swainsonin to acid hydrolysis in the presence of a C1_i alkanol to obtain a crystalline swainsonine salt; and optionally (I) recrystallizing the swainsonin salt from a C ^ alkanol. 11. A method for preparing a compound of the formula V wherein R and R are the same or different and represent alkyl, halogen, alkenyl, alkoxy, cycloalkyl or aryl, and R3 is alkyl or C1_10 aryl which comprises reacting an olefinic alcohol of formula IV wherein R2, R2 ', and R3 are as defined above with a source of phosphine, dialkylazodicarboxylate, and azide to obtain an azide of formula V 12. A method for preparing a compound of formula VIII wherein R2 and R2 'are the same or different and represent alkyl, halogen, alkenyl, alkoxy, cycloalkyl or aryl, which comprises cyclizing an imino acid of the formula VII. wherein R2 and R2 'as defined above when refluxing in an organic solvent with catalyst, to form a compound of the formula VIII. 13. A compound of the formula V - wherein R2 and R2 'are the same or different and represent alkyl, halogen, alkenyl, alkoxy, cycloalkyl or aryl, and R3 is alkyl or aryl C1_10. 14. Ethyl (Z) -5- [(4R, 5S) -5- (azidomethyl) -2,2-dimethyl-1,3-dioxolan-4-yl] -4-pentenoate. 15. A method for synthesizing swainsonin salts, the method comprising the steps: (H) (i) converting a swainsonine protected from aliquilidene- to the swainsonine salt, by acid hydrolysis in the presence of a C1_3 alkanol solvent at room temperature; and (H) (ii) recrystallizing the swainsonin salt from a C1_3 alkanol solvent. 16. The method of claim 15, further comprising, before step (H), the steps: (E) (i) reacting an imino ester (-) - (ΔS, 5R) -3,3-dialkyl -8- (3-Carbetoxy-1-propyl) -7-aza-2,4-dioxabicyclo [3.3.0] oct-7-ene with one molar equivalent of an alkali metal hydroxide in a mixture of water and a solvent C ^ alkanol, and (E) (ii) acidifying the reaction mixture to about pH 6-7 to produce an acidic imino. The method of claim 15, further comprising, before step (H), the steps: (F) crystallizing an acid imino (-) - (ΔS, 5R) -3, 3-dialkyl-8- ( 3-carboxy-1-propyl) -7-aza-2,4-dioxabicyclo [3.3.0] oct-7-ene by refluxing it in toluene with a catalytic amount of a lower alkyl carboxylic acid to form an enamide. The method of claim 15, further comprising, before step (H), the steps: (G) (i) reducing an enamide of the formula (-) - (7S, 8R) -7, 8- 0-alk l? Denodioxi-2-oxo-l-azabicyclo [4.3.0] -non-5-ene with diborane-THF in toluene; and (G) (ii) crystallizing the crude solid in t-butyl methyl ether or in ethyl acetate / hexane. The method of claim 15, further comprising, before step (H), the steps: (C) (i) reacting the olefinic alcohol (+) - (4R, cis) (Z) -2, 2-dialkyl-5- (4-carbethoxy-1-butenyl) -1,3-dioxolane-4-methanol with one molar equivalent of triphenyl phosphine in THF, one molar equivalent of diisopropylazodicarboxylate, and tpmethylsilyl azide; (C) (ii) adding tetrabutylammonium fluoride in THF to the azide; Y - - (C) (iii) repeating steps (C) (i) and (C) (ii) with the mixture of the reaction product of (C) (ii) to form the azide product. The method of claim 19, further comprising, after step (C), the step: (D) refluxing the azide product, after purification, in toluene at an initial concentration of between 0.30 M and 0.05 M to form an imino ester. The method of claim 15, further comprising, before step (H), the steps: (a) reacting D-isoascorbic acid with aqueous sodium bicarbonate and hydrogen peroxide; and (b) neutralizing the excess carbonate with a protonic acid at a pH between 3.5 and 4.
2. 2. The method of claim 21, further comprising, after (a) and (b), the steps: (c) reacting the crude erythrolactone with a catlytic sulfonic acid in acetone and magnesium sulfate; and (d) crystallizing 2, 3-0-alkylidene erythronolactone from ether / hexanes or t-butyl methyl ether / hexane. 23. The method of claim 15, further comprising, prior to step (H), the steps: (C) (i) reacting the olefinic alcohol with a molar equivalent of triphenyl phosphine in THF, followed by a molar equivalent of dnsopropylazodicarboxylate, and then tpmethylsilyl azide; (C) (11) adding tetrabutylammonium fluoride in THF; and (C) (m) repeating steps (C) (i) and (C) (11) with the reaction product mixture of (C) (11) to form the azide product. (D) refluxing the azide, after purification, in toluene at an initial concentration of between 0.30 and 0.05 M to form the same ester (E) reacting an ammonium ester with a molar excess of an alkali metal hydroxide in a mixture of water and ethanol to then acidify the reaction mixture to about pH 6-7 to produce an acidic acid; (F) cyclizing the acidic term by refluxing it in toluene with a catalytic amount of a lower alkyl carboxylic acid to form the enamide; (G) reducing the enamide with diborane-THF in toluene; and crystallize the crude solid in t-butyl methyl ether or in ethyl acetate / hexane. The method of claim 20, further comprising, prior to step (C), the steps: (A) (i) reacting a 2,3-alkylandeno-D-er-trolactone , with one molar equivalent of diisobutylaluminum hydride in toluene or tetrahydrofuran, at about 0 ° C; (A) (ii) (a) add methanol, (ii) (b) concentrate it to a gel, (ii) (c) add THF and brine, (ii) (d) add disodium sulfate, and (ii) (e) ) remove the inorganic salts by filtration; (B) (i) reacting ethyl 4-bromobutyrate with triphenyl phosphate to form a phosphonium bromide salt; and (B) (ii) reacting the phosphonium salt with 2,3-0-alkylidene-D-erythrose. The method of claim 23, further comprising before step (H), step (e) of preparing 2,3-isopropyledene erythronolactone from potassium erythronate and acetone with catalytic acid.