The present invention relates to the synthesis of compounds which are useful intermediates in the stereospecific synthesis of a number of useful compounds, for example, L-iduronic acid and derivatives thereof, deoxynojirimycin (DNJ) and 1- deoxyidonojirimycin (DIJ).

L-iduronic acid is a component of glycosaminoglycans, in particular of linear sulfated oligosaccharides such as heparin, dermatan sulfate and heparin sulfate. It is also an intermediate in the synthesis of antithrombolytic pentasaccharides such as fondaparinux (ARIXTRA ^® ) and enoxaparin (LOVENOX ^® , CLEXANE ^® ).

Processes for the synthesis of iduronic acid are known but tend to be both complex and low yielding. Examples of prior art synthetic routes include that described by Hinou et al, Tetrahedron Letters, 40(8), 19 February 1999, 1501-1504. This describes a route for the synthesis of iduronic acid using trehalose as the disaccharide starting material.

Lohman et a/ describe a synthetic route to iduronic acid (J. Org. Chem., 68 (19), 7559 - 7561 , 2003), which is said to be an efficient route to the iduronic acid derivative 3-0- benzyl-1 ,2-0-isopropylidene-α-L-idopyranosiduronate from diacetone glucose. This "efficient" reaction has nine steps and an overall yield of the product of 36%. The paper acknowledges that the production of protected uronic acid building blocks has proved to be particularly challenging.

1 -deoxynojirimycin is a sugar analogue in which the ring oxygen atom has been replaced by a basic nitrogen atom. The compound is an antibiotic which is known to have activity as a glucosidase inhibitor. Other uses have also been suggested, for example EP0282618 teaches that 1 -deoxynojirimycin has anti-HIV activity.

Prior art processes for the synthesis of this compound have been complex and relatively low yielding. The inventors have now developed an improved process, which is relatively short, having only 8 steps, is high yielding, with an overall yield of at least about 54%, is suitable for use on an industrial scale and uses inexpensive starting materials. There are many literature examples for the synthesis of DNJ. One example is a publication by George Fleet, Tetrahedron 1987, 43, 979 where DNJ is synthesised from a bicyclic lactam with an overall lower yield than the process of the present invention.

DIJ is a sugar analogue in which the ring oxygen atom has been replaced by a basic nitrogen atom. The compound is an antibiotic which is known to have activity as a glucosidase inhibitor. Other uses have also been suggested, for example EP0282618 teaches that 1-deoxyidonojirimycin has anti-HIV activity.

It is important to be able to synthesise compounds such as these stereospecifically and in high yield and the inventors have found these objectives can be achieved via a novel route.

Therefore, in a first aspect of the invention, there is provided a process for the synthesis of a compound of general formula (IV):

(IV) wherein:

R ³ and R ^3' are each independently hydrogen, Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, aryl or heteroaryl, any of which may be substituted with one or more substituents chosen from halo, OR ¹⁰ or N(R ¹⁰ ) ₂ , NO ₂ , aryl or additionally for aryl groups with C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl any of which may optionally be substituted with halo, OR ¹⁰ or N(R ¹⁰ ) ₂ ; wherein each R ¹⁰ is independently hydrogen or C ₁ -C ₆ alkyl; provided that R ³ and R ³ are not both hydrogen; or alternatively, R ³ and R ³ may together with the carbon atom to which they are attached form a 5 to 7 membered carbocyclyl or heterocyclyl ring, optionally substituted with halo, OR ¹⁰ or N(R ¹⁰ ) ₂ ; and OX represents a leaving group;

the process comprising the steps of: i. reacting glucurono-3,6-lactone having the formula:

with a compound of general formula (II):

O

R ³ ^R ^3'

(H) wherein R ³ and R ³ are as defined for general formula (IV);

to give a compound of general formula (III):

(III) wherein R ³ and R ³ are as defined above for general formula (IV);

ii. introducing a leaving group OX into the compound of general formula (III) to give a compound of general formula (IV) as defined above.

The process is advantageous because the starting material is glucurono-3,6-lactone is readily available at relatively low cost.

In addition, the advantage of compounds as general formula (IV) as synthetic intermediates is that the stereochemistry is fixed at all positions except for that of the leaving group OX. An SN2 nucleophilic substitution at this position will give rise to a product in which the stereochemistry is reversed. If it is necessary to retain the stereochemistry at this position, the OX group can be replaced by OH in an SN2 nucleophilic substitution reaction, following which a new OX group is introduced, with the reversed stereochemistry being retained. On nucleophilic substitution to replace the new OX group, the stereochemistry can again be reversed so that the product will have the same stereochemistry at this position as that of the compound of general formula (IV). This means that it is possible to synthesise products in which the stereochemistry at this particular position can be selected. The nucleophilic substitution reaction may be up to 100% stereospecific, depending on the choice of leaving group. This means that a very high proportion of the product, indeed up to 100%, will have the required stereochemistry.

In the present specification "C ₁ -C ₆ alkyl" refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms, and which may be optionally substituted by one or more halogen atoms. Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl, n-hexyl and trifluoromethyl.

"C ₂ -C ₆ alkenyl" refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and containing at least one carbon-carbon double bond, and which may be optionally substituted by one or more halogen atoms. Examples include ethenyl, 2- propenyl, and 3-hexenyl.

"C ₂ -C ₆ alkynyl" refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and containing at least one carbon-carbon triple bond, and which may be optionally substituted by one or more halogen atoms. Examples include ethynyl, 2- propynyl, and 3-hexynyl.

The terms "carbocyclic" and "carbocyclyl" refer to a non aromatic ring system having from 3 to 8 ring atoms, all of which are carbon atoms, which may contain one or more carbon- carbon double bond and which may be optionally substituted by one or more halogen atoms. Examples of carbocyclic ring systems include cyclopropyl, cyclopentyl, cyclohexyl and cyclohexenyl.

The terms "heterocyclic" and "heterocyclyl" refer to a non aromatic ring system having 3 to 8 ring atoms, one or more of which is a hetero atom selected from N, O and S. Examples include tetrahydrofuran, morpholine, piperidine, piperazine, imidazoline, dioxane and pyrrolidine.

The terms "aromatic" and "aryl" refer to ring systems having a single ring or two fused rings and from 5 to 10 ring carbon atoms and which has aromatic character. In bicyclic systems, only one of the rings must have aromatic character with the other ring optionally being partially saturated. Examples of aromatic ring systems include phenyl, naphthalene, and indane.

The terms "heteroaromatic" and "heteroaryl" refer to ring systems having a single ring or two fused rings and from 5 to 10 ring atoms, at least one of which is a heteroatom selected from N, O and S. In bicyclic systems, only one of the rings must have aromatic character with the other ring optionally being partially saturated. Examples of heteroaromatic ring systems include pyridine, pyrimidine, furan, thiophene, indole, isoindole, benzofuran, benzimidazole, benzimidazoline, benzodioxole, benzodioxane, quinoline, isoquinoline, tetrahydroisoquinoline, quinazoline, thiazole, benzthiazole, benzoxazole, indazole and imidazole ring systems.

In the present specification, "halo" refers to fluoro, chloro, bromo or iodo.

In step i. of the process defined above, the compound of general formula (II) may be present in excess, for example in a molar excess of from 5 to 12 equivalents, more usually from about 7 to 10 molar equivalents and often about 8.5 to 9.5 molar equivalents.

The reaction may be conducted using an agent such as zinc chloride and in a water- miscible organic solvent such as ethanol or methanol.

In particularly suitable compounds of general formula (II):

R ³ and R ³ are both methyl or ethyl; or one of R ³ and R ³ is hydrogen and the other is phenyl optionally substituted with one or more substituents chosen from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or halo; wherein the alkyl, alkenyl or alkynyl groups are optionally substituted with one or more halo substituents; or

R ³ and R ³ together form a cyclopentyl or cyclohexyl ring system optionally substituted by halo.

In step ii. of the process, the reaction may be conducted using any suitable reagent for the introduction of a leaving group such as toluene sulfonyl (tosyl), methyl sulfonyl (mesyl), 4- nitrobenzenesulfonyl (nosyl) and trifluoromethanesulfonyl (triflyl). These leaving groups are well known and can be introduced by reacting the compound of general formula (III) with a known agent such as tosyl chloride, mesyl chloride, nosyl chloride, triflic acid or triflic anhydride. Triflate is particularly suitable as nucleophilic substitution of this leaving group leads to a product in which the stereochemistry reversed.

The reaction should be carried out in dry conditions and in the presence of a weak base, particularly a tertiary amine or pyridine or a pyridine derivative such as 2,6-di-t-butyl-4- methylpyridine. The reaction temperature is typically from -4O ⁰ C to O ⁰ C with a temperature of about -3O ⁰ C being particularly suitable. Suitable solvents include polar organic solvents, particularly halogenated solvents such as dichloromethane.

One example of the use of compounds of general formula (IV) is in the production of L- iduronic acid and derivatives thereof. The overall synthesis of the product is a seven step method with a high overall yield. It also has the advantage of being more versatile than prior art processes as it can be used to synthesise a much wider range of derivatives of iduronic acid than is possible with known processes. Therefore, the process of invention may optionally comprise the additional steps of:

iii(a/b) removing the leaving group to obtain a compound of general formula (Va/b):

(Va/b) wherein R ³ and R ³ are as defined above for general formula (IV);

iv(a) reacting the compound of general formula (Va/b) with a compound of general formula (Via):

(Via) wherein each R ⁴ independently represents C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or halo; wherein the alkyl, alkenyl or alkynyl groups are optionally substituted with one or more halo substituents; m is 0 to 4; to give a compound of general formula (VII):

(Vila) wherein R ³ and R ³ are as defined above for general formula (IV) and R ⁴ and m are as defined above for general formula (Via);

v(a) conducting a lactone ring opening reaction on the compound of general formula (VII) using a base in a solvent of formula (Xa):

R ² OH (Xa)

wherein R ² is H, Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, aryl; any of which may optionally be substituted with one or more substituents; wherein optional substituents for alkyl, alkenyl and alkynyl groups are halo, aryl or substituted aryl substituents and optional substituents for aryl groups are Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or halo substituents;

to obtain a compound of general formula (Villa):

(Villa) wherein R ³ and R ³ are as defined above for general formula (IV) and R ⁴ and m are as defined above for general formula (Via); and R ² is as defined above for general formula (I);

vi(a) Reacting the compound of general formula (Villa) with a protecting agent which substitutes an OH group with an OR ¹ group to give a compound of general formula (IXa):

(IXa) wherein R ³ and R ³ are as defined above for general formula (IV), R ⁴ and m are as defined above for general formula (Vl), R ² is as defined above for general formula (Xa); and R ¹ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, aryl, -C(O)C ₁ -C ₆ alkyl, -C(O)C ₂ -C ₆ alkenyl, -C(O)C ₂ -C ₆ alkynyl, -C(O)aryl, any of which may optionally be substituted with one or more substituents; wherein optional substituents for alkyl, alkenyl and alkynyl groups are halo, aryl or substituted aryl substituents and optional substituents for aryl groups are C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or halo substituents; vii(a) deprotecting the compound of general formula (IXa) to give a compound of general formula (Ia):

(Ia) wherein:

R ¹ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, aryl, -C(O)C ₁ -C ₆ alkyl, -C(O)C ₂ -C ₆ alkenyl, -C(O)C ₂ -C ₆ alkynyl, -C(O)aryl, any of which may optionally be substituted with one or more substituents;

R ² is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, aryl; any of which may optionally be substituted with one or more substituents; wherein optional substituents for alkyl, alkenyl and alkynyl groups are halo, aryl or substituted aryl substituents and optional substituents for aryl groups are C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or halo substituents.

One advantage of the process of the invention is that the compound of general formula (Ia) can have any one of a large number of R ¹ groups. It was not possible to introduce such a wide variety of R ¹ groups using previous methods.

In the compounds of general formula (Ia) it is preferred that R ¹ is not hydrogen as this makes the iduronic acid or derivative thereof more difficult to use for further reactions. It is also preferred that R ² is not hydrogen but this is less critical.

In step iii(a/b), the leaving group is removed, which leads to a reversal of the stereochemistry at this position of the lactone ring. Surprisingly, this reversal of stereochemistry seems to be most effective when the leaving group is a triflate group and does not occur so cleanly with other leaving groups such as methane sulfonate and toluene sulfonate.

The most suitable agents for removing the leaving group are group (I) metal salts of trihaloacetate, for example caesium, potassium and, in particular sodium salts. The most suitable trihaloacetate salts are trifluoroacetates. Sodium trifluoroacetate is a particularly useful reagent for this reaction. A suitable solvent for the reaction is tetrahydrofuran. In step iv(a), the lactone of general formula (Va) is reacted with a diphenyldiazomethane derivative of general formula (Via) to give a protected compound of general formula (Vila). In the compound of general formula (Via), it is preferred that m is 0 so that the phenyl groups are unsubstituted.

The use of diphenyldiazomethane derivatives as protecting groups is described in detail by Best et a/, Tet. Lett., 49, (2008), 2196-2199. It is a particularly useful protection method as it ensures that the correct stereochemistry is retained and the required product is obtained in high yield.

Suitable solvents for the reaction include a range of organic solvents such as toluene and acetonitrile.

The compound of general formula (Vila) is treated with a base to open the lactone ring as set out in step v(a). The base may be a metal alkoxide in an alcoholic solvent and may be of the formula: MOR ² /R ² OH, where R ² is as defined in general formula (Ia) and M is a group (I) metal ion, especially sodium. Typically, in this case R ² is methyl or ethyl so that the base would be sodium methoxide in methanol or sodium ethoxide in ethanol. However, improved yields may be obtained using organic bases, especially amine bases such as triethylamine.

In step vi(a) the free hydroxyl group of the compound of general formula (Villa) is protected using a suitable protecting group R ¹ O. Suitable protecting groups for saccharide hydroxyl groups are well known and are described, for example, in "Protecting Groups in Organic Synthesis", Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc. Examples of such groups include C ₁ -C ₆ alkyl, benzyl or aryl ether or ester groups such as benzyloxy or acetate, protecting groups. The protecting group may be introduced according to standard conditions familiar to those of skill in the art.

The final step of the process is step vii(a) in which all of the protecting groups are removed apart from that introduced in step vi(a), following which the compound rearranges to the pyranose form.

Deprotection may be achieved using any one of the numerous known methods for removing benzylidene groups and diphenylmethoxy groups. Examples of such methods include hydrogenolysis, acid hydrolysis and oxidation.

A further use for the compounds of general formula (IV) is as an intermediate in the synthesis of 1-deoxonojirimycin. As explained above, the synthesis of 1-deoxonojirimycin according to the present invention is relatively short, having only 8 steps, is high yielding, with an overall yield of at least about 54%, is suitable for use on an industrial scale and uses inexpensive starting materials. Therefore, the process of the invention optionally comprises the additional steps of:

iii(a/b) removing the leaving group to obtain a compound of general formula (Va/b):

(Va/b) wherein R ³ and R ³ are as defined above for general formula (IV);

iv(b) introducing a leaving group into the compound of general formula (Va/b) to give a compound of general formula (VIb):

(VIb) wherein R ³ and R ³ are as defined above for general formula (IV); and OX is a leaving group;

v(b) reacting the compound of general formula (VIb) with sodium azide to form a compound of general formula (VIIb):

(VIIb) wherein R ³ and R ³ are as defined above for general formula (IV);

vi(b) reducing the compound of general formula (VIIb) to give a compound of general formula (VIIIb)

(VIIIb) wherein R ³ and R ³ are as defined above for general formula (IV);

vii(b) ring opening the compound of general formula (VIIIb) under reducing conditions to give a compound of general formula (IXb):

(IXb) wherein R ³ and R ³ are as defined above for general formula (IV); and

viii(b) reacting the compound of general formula (IXb) to remove the ylidene protecting group and obtain 1-deoxynojirimycin (formula (Ib)):

(Ib) or a salt thereof.

Step iii(a/b) is as described above for the synthesis of L-iduronic acid.

In step iv(b), the compound of general formula (Va/b) is again reacted to introduce a leaving group OX under the conditions described for step (ii), with suitable leaving groups being the same as those described for step (ii), i.e. tosyl, mesyl, nosyl and triflyl. Following this, the derivative of general formula (VIb) is reacted with sodium azide in step v(b) to give a compound of general formula (VIIb). The stereochemistry is again reversed to ensure that the azide group in the compound of general formula (VIIb) is in the orientation required in the final product.

The reaction with sodium azide may be carried out in an polar organic solvent, for example N, Λ/-dimethylformamide and at reduced temperature, for example -30 to O ⁰ C. More suitably, the temperature is about -2O ⁰ C.

In step vi(b) the compound of general formula (VIIb) is reduced to give a compound of general formula (VIIIb). Typical reducing agents for this step are sources of hydride ions, for example di-tert-butyl aluminium hydride, Red Al, moderated Red Al, Selectrides and more preferably, diisobutyl aluminium hydride (DIBAL-H).

The reaction may be carried out in a polar organic solvent such as dichloromethane and at reduced temperature, for example about -78 ⁰ C.

Following step vi(b), the crude lactol of general formula (VIIIb) may be reacted without further purification in a ring opening reaction to give a compound of general formula (IXb). Suitable ring opening reagents are reducing agents, for example acetyl (sodium triacetoxyborohydride, (NaBH(OCOCH ₃ ) ₃ ) or cyano (sodium cyanoborohydride (NaCNBH ₃ )) and especially sodium borohydride. The ring opening reaction of step vii(b) may be conducted at reduced temperature, typically -3O ⁰ C to O ⁰ C, particularly -2O ⁰ C to - 1O ⁰ C. The reaction solvent will generally be chosen so that it is miscible with water, for example ethanol and, more usually, methanol. In the final step viii(b) of the reaction, the ylidene protecting group is removed from the compound of general formula (IXb) to give the required product, 1-deoxynojirimycin. The protecting group may be removed using any known method, for example hydrogenation, acid hydrolysis or oxidation. Catalytic hydrogenation has proved to be particularly successful and may be carried out using any suitable catalyst, for example a platinum or palladium catalyst, typically Pd/C. The reaction is suitably carried out in an aqueous solvent under acid conditions, for example in the presence of hydrochloric acid, and this leads to the production of a salt of 1-deoxynojirimycin. When hydrochloric acid is present, the product may be isolated as the hydrochloride salt.

The hydrogenation may be conducted at a pressure of about 30-60 psi and may proceed for several days, typically 2-5 days, for example 3 days.

A further use for the compounds of general formula (IV) is as an intermediate in the synthesis of 1-deoxyidonojirimycin. As with the previous process, this synthesis is relatively short, having only six steps in total and is also high yielding. Therefore, the process of the invention optionally contains the additional steps of:

iii(c) reacting the compound of general formula (IV) with sodium azide to form a compound of general formula (VIIc):

(VIIc) wherein R ³ and R ³ are as defined above for general formula (IV);

iv(c) reducing the compound of general formula (VIIc) to give a compound of general formula (VIIIc)

(VIIIc) wherein R ³ and R ³ are as defined above for general formula (IV);

v(c) ring opening the compound of general formula (VIIIc) under reducing conditions to give a compound of general formula (IXc):

(IXc) wherein R ³ and R ³ are as defined above for general formula (IV); and

vi(c) reacting the compound of general formula (IXc) to remove the ylidene protecting group and obtain 1-deoxyidonojirimycin (formula (Ic)):

(Ic) or a salt thereof.

In step iii(c), the compound of general formula (IV) is reacted with sodium azide to give a compound of general formula (Vc). During this reaction, the stereochemistry is reversed to ensure that the azide group in the compound of general formula (Vc) is in the orientation required in the final product. Surprisingly, this reversal of stereochemistry seems to be most effective when the leaving group is a triflate group and does not occur so cleanly with other leaving groups such as methane sulfonate and toluene sulfonate.

The reaction with sodium azide may be carried out in an polar organic solvent, for example N, Λ/-dimethylformamide and at reduced temperature, for example -3O ⁰ C to O ⁰ C. More suitably, the temperature is about -2O ⁰ C.

In step iv(c) the compound of general formula (VIIc) is reduced to give a compound of general formula (VIIIc). Typical reducing agents for this step are sources of hydride ions, for example di-tert-butyl aluminium hydride, Red Al, moderated Red Al, Selectrides and, more suitably, diisobutyl aluminium hydride (DIBAL-H). The reaction may be carried out in a polar organic solvent such as dichloromethane and at reduced temperature, for example about -78 ⁰ C.

Following step iv(c), the crude lactol of general formula (VIIIc) may be reacted without further purification in a ring opening reaction to give a compound of general formula (IXc). Suitable ring opening reagents are reducing agents, for example acetyl (sodium triacetoxyborohydride, (NaBH(OCOCH ₃ ) ₃ ) or cyano (sodium cyanoborohydride (NaCNBH ₃ )) and especially sodium borohydride. The ring opening reaction of step v(c) may be conducted at reduced temperature, typically -3O ⁰ C to O ⁰ C, particularly -2O ⁰ C to - 10 ⁰ C. The reaction solvent will generally be chosen so that it is miscible with water, for example ethanol and, more usually, methanol.

In the final step vi(c) of the reaction, the benzylidene protecting group is removed from the compound of general formula (IXc) to give the required product, 1-deoxyidonojirimycin. The protecting group may be removed using any known method, for example hydrogenation, acid hydrolysis or oxidation. Catalytic hydrogenation has proved to be particularly successful and may be carried out using any suitable catalyst, for example a platinum or palladium catalyst, typically Pd/C. The reaction is suitably carried out in an aqueous solvent under acid conditions, for example in the presence of hydrochloric acid, and this leads to the production of a salt of 1-deoxyidonojirimycin. When hydrochloric acid is present, the product may be isolated as the hydrochloride salt.

The hydrogenation may be conducted at a pressure of about 30-60 psi and may proceed for several days, typically 2-5 days, for example 3 days.

The compounds DNJ (Ib) and DIJ (Ic) are stereoisomers and are identical except for the single difference in stereochemistry. Similarly compounds of general formulae (VIIb), (VIIb) and (IXb) are identical to the compounds of general formulae (VIIc), (VIIIc) and (IXc) apart from the single difference in stereochemistry and steps v(b), vi(b), vii(b) and viii(b) are essentially the same as steps iii(c), iv(c), v(c) and vi(c). The two additional steps iii(a/b) and iv(b) carried out in the process for the preparation of DNJ are carried out in order to reverse the stereochemistry at the position of the leaving group OX. The invention will now be described in more detail with reference to the following examples.

Example 1 - Synthesis of methyl 3-O-acetyl-L-idopyranuronate

Step 1 - Preparation of 1,2-O-benzylidene-α-D-glucurono-3,6-lactone

To a mixture of zinc chloride (464 g, 1.2 equiv.) in benzaldehyde (2.5 L, 8.7 equiv.) was added glucurono-3,6-lactone (500 g, 1.0 equiv.) in one portion and the mixture was stirred at room temperature for three days. The reaction was split into halves for ease of processing. Each half was diluted with Et ₂ O (2 L) and washed with water (3 * 0.75 L). The two organic phases were recombined and evaporated first at 40 ⁰ C and then at 60 ⁰ C under vacuum down to approx 1.5 L. MeOH (0.5 L) was added and the solution was washed with petrol (2 * 1 L). The separated MeOH phase was then evaporated to a syrup and crystallized by the addition of 4:1 petrol: EtOAc (1 L) with vigorous stirring (1 h). The solid was collected by filtration and dried in-vacuo at 50 ⁰ C affording the title product as beige crystals (730 g, 97%) in a 4:1 ratio of benzylidene conformers where the major product is believed to be 1 ,2-0-(S)-benzylidene-α-D-glucurono-3,6-lactone. R _f = 0.16 (7:3, petrol/acetone).

Steps 2 and 3 - Preparation of 1,2-O-benzylidene-β-L-idurono-3,6-lactone

In a 5 L 3-neck flask equipped with and overhead stirrer, thermometer, 500 mL dropping funnel and drying tube was charged 1 ,2-O-benzylidene-α-D-glucurono-3,6-lactone (4:1 ratio of benzylidene conformers) (449 g, 1 equiv.) followed by pyridine (411 mL, 3 equiv.) and dichloromethane (3.4 L, 0.5 M). The mixture was stirred until dissolved and then cooled to -30 ⁰ C in an acetone/CO ₂ bath. Trifluoromethanesulfonic anhydride (315 mL, 1.1 equiv.) was added over a period of approximately 30 min and then stirring was continued for a further 10 min at -30 ⁰ C. TLC (7:3, petrol/acetone) showed complete conversion to the triflate (R _f = 0.50). The reaction mixture was poured onto 3 L of 2 M aqueous HCI (at room temperature), stirred vigorously for 5 min and then separated. The organic phase was evaporated to a thick syrup which was re-dissolved in DMF (1.1 L). With overhead stirring sodium trifluoroacetate (347 g, 1.5 equiv.) was added in a single portion and the reaction stirred for 20 min. N. B. During this time the exotherm from the reaction caused the temperature to reach 50 °C. The reaction was then quenched by pouring onto sat. aqueous NaHCO ₃ (4 L) and then extracting into EtOAc (3 x 2 L). The combined organic phases were then washed with brine (3 * 1 L) and evaporated to thick syrup. MTBE (350 mL) was added, mixed at 50 ⁰ C for 30 min and then cooled to room temperature. The solid was collected by filtration and dried to afford the title compound as an off-white powder (104 g, 23%) in a 95:5 mix of benzylidene conformers. The mother liquor from the filtration was evaporated, re-dissolved in Et ₂ O (1.2 L), washed with brine (2 * 0.5 L) and evaporated to a thick syrup (283 g, 63%). The syrup contained the title compound as a 7:3 mix of benzylidene conformers. R _f = 0.27 (7:3, petrol/acetone).

Step 4 - Preparation of 1,2-O-benzylidene-5-O-diphenylmethyl-D-L-idurono-3,6- lactone

59%

Diphenyl diazomethane (2.6 g, 13.3 mmol) was added to a hot (110 ⁰ C) solution of 1 ,2-O- benzylidene-β-L-idurono-3,6-lactone (2.0 g, 7.6 mmol) in toluene in one portion. After 1 h the dark purple colour had faded to a light yellow solution. The reaction mixture was further heated for 5 h, cooled and then the solvent evaporated. The crude residue was purified (biotage chromatography, toluene/acetone) to give 1 ,2-O-benzylidene-5-O- diphenylmethyl-D-L-idurono-3,6-lactone as a pale yellow solid (1.9 g, 59%). Step 5 - Preparation of i^-O-benzylidene-S-O-acetyl-δ-O-diphenylmethyl glucofuranuronic acid methyl ester

Triethylamine (5 ml.) was added to a solution of 1 ,2-O-benzylidene-5-O-diphenylmethyl-D- L-idurono-3,6-lactone (1.05 g, 2.4 mmol) in dichloromethane/ methanol (5 mL_/10 ml.) and the reaction mixture was left to stand at -20 ⁰ C overnight. The solvent was evaporated using high vacuum at 0 ⁰ C to give a syrup. Acetic anhydride (2 mL) was added drop-wise to a solution of the crude syrup in pyridine (10 mL) at 0 ⁰ C. The reaction mixture was stirred for 2h at room temperature and left to stand for 18 h at 5 ⁰ C. The solvent was evaporated in vacuo to give a thin syrup which was partitioned between water (15 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was washed with EtOAc (2 x 20 mL). The combined organic extracts were evaporated in vacuo and the crude residue was purified (biotage, petrol/EtOAc, 4/1) to give 1 ,2-O-benzylidene-3-O-acetyl-5-O- diphenylmethyl glucofuranuronic acid methyl ester as a light yellow syrup.

Step 6 - Preparation of methyl 3-O-acetyl-L-idopyranuronate

Pd/C (10% w/w, 61 mg) was added to a solution of 1 ,2-O-benzylidene-3-O-acetyl-5-O- diphenylmethyl glucofuranuronic acid methyl ester (290 mg) in MeOH (40 mL) and the reaction mixture was hydrogenated at 9 bar for 3 days. Celite was added, the reaction mixture was filtered and concentrated in vacuo to give methyl 3-O-acetyl-L- idopyranuronate as a colourless oil. Example 2 - Synthesis of 1-deoxynoiirimycin

Steps 1 to 3 of the process were carried out in an identical manner to Example 1.

Steps 4 and 5 - Production of 5-azido-5-deoxy-1,2-O-benzylidene-α-D-glucurono-3,6- lactone

In a 5 L 3-neck flask equipped with and overhead stirrer, thermometer, 500 ml. dropping funnel and drying tube was charged 1 ,2-0-benzlidene-β-L-idurono-3,6-lactone (mixture of benzylidene conformers) (369 g, 1 equiv.) followed by pyridine (338 ml_, 3 equiv.) and dichloromethane (2.8 L, 0.5 M). The mixture was stirred until dissolved and then cooled to -30 ⁰ C in an acetone/CO ₂ bath. Trifluoromethanesulfonic anhydride (258 ml_, 1.1 equiv.) was added over a period of approximately 30 min and then stirring was continued for a further 20 min at -30 ⁰ C. TLC (7:3, petrol/acetone) showed complete conversion to the triflate (R _f = 0.53). The reaction mixture was poured onto 2 L of 2 M aqueous HCI (at room temperature), stirred vigorously for 5 min and then separated. The organic phase was evaporated to a thick syrup which was re-dissolved in DMF (1.4 L) and then cooled to -20 ⁰ C with overhead stirring. Sodium azide (95 g, 1.05 equiv.) was added in a single portion and the reaction stirred for 60 min at -20 ⁰ C. Ether (1 L), brine (1 L) and water (1 L) were added to the reaction mixture and the layers separated. The aqueous layer was extracted with ether (3 x 1 L) and the combined organic phases were washed with brine (3 x 1 L), evaporated in vacuo at 25 ^C C to a brown syrup. The crude material was purified by column chromatography (petrol: EtOAc) to give 5-azido-5-deoxy-1 ,2-0-benzylidene-α-D-glucurono- 3,6-lactone as a yellow syrup (305 g, 76% over 2 steps)

Steps 6 and 7 - Production of δ-azido-δ-deoxy-i^-O-benzylidene-α-D-glucofuranose

5-Azido-5-deoxy-1 ,2-0-benzylidene-a-D-glucurono-3,6-lactone (7.7 g, 27 mmol) was dissolved in DCM (35 mL) and cooled to -78°C. DIBAL solution (1.0 M in hexanes, 31 mL, 31 mmol) was then added over a period of 20 min. and the reaction mixture stirred at - 78°C. TLC analysis (70:30 petrol/EtOAc) after a further 40 min. revealed the complete consumption of starting material (R _f 0.57) and the formation of a major product (R _f 0.34). The reaction mixture was then diluted with DCM (210 ml_), treated with a saturated aqueous potassium sodium tartrate solution (280 ml_) and stirred for 20 h at RT. The organic layer was then collected and the aqueous extracted with 5 * 200 ml. DCM, the combined organic fractions were concentrated under reduced pressure to afford the crude lactol (8.9 g). This material was dissolved in methanol (70 mL) and cooled to -20°C. Sodium borohydride (267 mg, 7 mmol) was then added portionwise, not allowing the internal temperature to rise above -10 ^c C. The reaction mixture was then stirred at -10 ⁰ C for 1 h, cooled to -20 ⁰ C and treated with a further portion of sodium borohydride (120 mg, 3 mmol). The reaction was then stirred for a further hour at -10 ⁰ C ₁ after which TLC analysis (70:30 petrol/EtOAc) revealed the absence of starting material (R _f 0.41) and the formation of a major product (R _f 0.22). The reaction mixture was then neutralized with glacial acetic acid and concentrated under reduced pressure. Purification by flash column chromatography (70:30 petrol/EtOAc to 100% EtOAc) afforded 5-azido-5-deoxy-1 ,2-O- benzylidene-α-D-glucofuranose (4.9 g, 63% over two steps) as a white solid.

Step 8 - Production of 1-Deoxynojirimycin hydrochloride

H ₂ , Pd/C 10%, HCl ( / ^0H H-Cl δ-Azido-i ^-O-benzylidene-δ-deoxy-α-D-glucofuranose (2.8 g, 9.6 mmol) was suspended in water (38 mL) and acidified with HCI (1.25 M in MeOH, 8.5 mL). The reaction mixture was treated with Pd/C (10% w/w, 1.0 g, 0.9 mmol) and shaken under H ₂ (40-50 psi). After 1 h the solution was reacidified to pH 1 with HCI (1.25 M in MeOH, 8.5 mL), treated with an additional portion of Pd/C (10% w/w, 1.0 g, 0.9 mmol) and resubmitted to the same reaction conditions (the pressure of H ₂ was maintained at 40-50 psi). After 3 days TLC analysis (14:3:1 :1 :1 IMS/water/pyridine/AcOH/n-BuOH) showed the complete consumption of starting material (R _f 0.95) and the formation of a major product (R _f 0.50). The reaction mixture was filtered, acidified to pH 2 with 32% aqueous HCI and concentrated under reduced pressure. The resulting oil slowly crystallised to give 1-deoxynojirimycin hydrochloride (1.9 g, quant.) as a white solid. Example 3 - Synthesis of 1-Deoxyidonoiirimycin

Step 1 of the process was carried out in an identical manner to Step 1 of Example 1. Step 2 - Preparation of 1,2-O-benzylidene-5-O-trifuoromethanesulfonyl-α-D- glucurono-3,6-lactone

1 ,2-0-Benzylidene-α-D-glucurono-3,6-lactone (1.0 g, 3.8 mmol) was dissolved in DCM (13 ml_) and pyridine (0.90 ml_, 11.4 mmol) was added. The solution was cooled to -30 ⁰ C and trifluoromethanesulfonic anhydride (0.75 ml_, 4.5 mmol) was added over a period of 20 min., after which the reaction mixture was stirred at -30 ⁰ C for a futher 40 min. TLC analysis (1 :1 petrol/EtOAc) showed complete consumption of starting material (R _f 0.11) and formation of a major product (R _f 0.83). The reaction mixture was quenched with aqueous HCI (2 M, 7 ml_), the organic fraction washed with water and concentrated under reduced pressure to afford 1 ^-O-benzylidene-δ-O-trifluoromethanesulfonyl-α-D-glucurono -S.e- lactone (1.5 g, 97%) as a brown solid.

Step 3 - Preparation of 1,2-O-benzylidene-5-azido-5-deoxy-β-L-idurono-3,6-lactone

i ^-O-Benzylidene-δ-O-trifuoromethanesulfonyl-α-D-glucurono- S.Θ-lactone (1.5 g, 3.7 mmol) was dissolved in DMF (7 ml.) and the resulting solution was cooled to -2O ⁰ C. Sodium azide (281 mg, 4.3 mmol) was added in one portion, and the reaction mixture was stirred at -2O ⁰ C for 1 h. TLC analysis (80:20 petrol/EtOAc) showed complete consumption of starting material (R _f 0.47) and formation of a major product (R _f 0.58). The reaction mixture was quenched with 5% aqueous NaCI (7 mL) and extracted with Et ₂ O (4 * 10 mL). The organic fractions were washed with water, concentrated under reduced pressure and purified by column chromatography (70:30 petrol/EtOAc) to afford 1 ,2-O-benzylidene-5- azido-5-deoxy-β-L-idurono-3,6-lactone (700 mg, 65%) as a brown solid.

Steps 4 and 5 - Preparation of 5-azido-5-deoxy-1,2-O-benzylidene-α-D-idofuranose DIBALH ^, DCM

5-Azido-5-deoxy-1 ,2-O-benzylidene-a-D-idurono-3,6-lactone (7.7 g, 27 mmol) was dissolved in DCM (5 ml_) and cooled to -78°C. DIBAL solution (1.0 M in hexanes, 2.7 mL, 2.7 mmol) was then added over a period of 10 min. and the reaction mixture stirred at - 78°C. TLC analysis (80:20 petrol/EtOAc) after 1 h revealed the complete consumption of starting material (R _f 0.68) and the formation of a major product (R _f 0.19). The reaction mixture was then diluted with DCM (18 mL), treated with a saturated aqueous potassium sodium tartrate solution (24 mL) and stirred for 20 h at RT. The organic layer was then collected and the aqueous layer extracted with 4 * 15 mL DCM, the combined organic fractions were concentrated under reduced pressure to afford the crude lactol. This material was dissolved in methanol (6 mL) and cooled to -20 ⁰ C. Sodium borohydride (25 mg, 0.7 mmol) was added and the reaction mixture was stirred at -10 ⁰ C for 1 h. TLC analysis (70:30 petrol/EtOAc) revealed the absence of starting material (R _f 0.53) and the formation of a major product (R _f 0.10). The reaction mixture was then neutralized with glacial acetic acid/triethylamine and concentrated under reduced pressure. Purification by flash column chromatography (70:30 to 40:60 petrol/EtOAt) afforded 5-azido-5-deoxy-1 ,2- O-benzylidene-α-D-idofuranose (370 mg, 53% over two steps) as a white solid.

Step 6 - Preparation of L-1-deoxyidonojirimycin hydrochloride

5-Azido-1 ,2-0-benzylidene-5-deoxy-β-L-idofuranose (350 mg, 1.19 mmol) was suspended in water (15 mL) and acidified with HCI (1.25 M in MeOH, 2 mL). The reaction mixture was treated with Pd/C (10% w/w, 137 mg, 0.13 mmol) and shaken under H ₂ (40-50 psi). After 2 days TLC analysis (14:3:1 :1 :1 IMS/water/pyridine/AcOH/n-BuOH) showed the complete consumption of starting material (R _f 0.90) and the formation of a major product (R _f 0.62). The reaction mixture was filtered, acidified to pH 2 with 32% aqueous HCI and concentrated under reduced pressure to give L-1-deoxyidonojirimycin hydrochloride (400 mg, quant.) as a syrup.