WO2010004269A2 - Synthèse stéréospécifique - Google Patents

Synthèse stéréospécifique Download PDF

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WO2010004269A2
WO2010004269A2 PCT/GB2009/001684 GB2009001684W WO2010004269A2 WO 2010004269 A2 WO2010004269 A2 WO 2010004269A2 GB 2009001684 W GB2009001684 W GB 2009001684W WO 2010004269 A2 WO2010004269 A2 WO 2010004269A2
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general formula
compound
alkyl
alkenyl
alkynyl
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PCT/GB2009/001684
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English (en)
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WO2010004269A3 (fr
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Alexander Charles Weymouth-Wilson
George W. J. Fleet
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Dextra Laboratories Limited
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Priority claimed from GB0812605A external-priority patent/GB0812605D0/en
Priority claimed from GB0812609A external-priority patent/GB0812609D0/en
Priority claimed from GB0812613A external-priority patent/GB0812613D0/en
Application filed by Dextra Laboratories Limited filed Critical Dextra Laboratories Limited
Publication of WO2010004269A2 publication Critical patent/WO2010004269A2/fr
Publication of WO2010004269A3 publication Critical patent/WO2010004269A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02—Preparation by ring-closure or hydrogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin

Definitions

  • 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).
  • DNJ deoxynojirimycin
  • DIJ 1- deoxyidonojirimycin
  • 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 ® ).
  • 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- ⁇ -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.
  • 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.
  • 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
  • the process is advantageous because the starting material is glucurono-3,6-lactone is readily available at relatively low cost.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • heteroaryl refers 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.
  • 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.
  • halo refers to fluoro, chloro, bromo or iodo.
  • 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.
  • 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.
  • 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).
  • 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 stereo
  • 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.
  • 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:
  • 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):
  • 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;
  • 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
  • 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.
  • 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.
  • step iii(a/b) the leaving group is removed, which leads to a reversal of the stereochemistry at this position of the lactone ring.
  • 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.
  • 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).
  • m is 0 so that the phenyl groups are unsubstituted.
  • 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.
  • R 2 is methyl or ethyl so that the base would be sodium methoxide in methanol or sodium ethoxide in ethanol.
  • improved yields may be obtained using organic bases, especially amine bases such as triethylamine.
  • 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.
  • 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.
  • 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:
  • Step iii(a/b) is as described above for the synthesis of L-iduronic acid.
  • 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.
  • step v(b) 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, ⁇ /-dimethylformamide and at reduced temperature, for example -30 to O 0 C. More suitably, the temperature is about -2O 0 C.
  • 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.
  • a polar organic solvent such as dichloromethane
  • 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.
  • 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.
  • step iii(c) the compound of general formula (IV) is reacted with sodium azide to give a compound of general formula (Vc).
  • 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.
  • 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, ⁇ /-dimethylformamide and at reduced temperature, for example -3O 0 C to O 0 C. More suitably, the temperature is about -2O 0 C.
  • 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).
  • DIBAL-H diisobutyl aluminium hydride
  • the reaction may be carried out in a polar organic solvent such as dichloromethane and at reduced temperature, for example about -78 0 C.
  • 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.
  • 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.
  • 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 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.
  • Diphenyl diazomethane (2.6 g, 13.3 mmol) was added to a hot (110 0 C) solution of 1 ,2-O- benzylidene- ⁇ -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.
  • 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.
  • Steps 1 to 3 of the process were carried out in an identical manner to Example 1.
  • 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.
  • 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.
  • 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- ⁇ -D- glucurono-3,6-lactone
  • 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- ⁇ -O-trifluoromethanesulfonyl- ⁇ -D-glucurono-S.e- lactone (1.5 g, 97%) as a brown solid.
  • 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- ⁇ -L-idurono-3,6-lactone (700 mg, 65%) as a brown solid.
  • 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- ⁇ -D-idofuranose (370 mg, 53% over two steps) as a white solid.

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Abstract

La présente invention concerne un procédé de préparation d’un composé de formule générale (IV) dans laquelle OX, R3 et R3’ sont tels que définis dans le présent document; et l’utilisation de composés de formule générale (IV) en tant qu’intermédiaires dans des procédés de synthèse stéréospécifique de molécules biologiquement actives.
PCT/GB2009/001684 2008-07-10 2009-07-07 Synthèse stéréospécifique WO2010004269A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB0812605A GB0812605D0 (en) 2008-07-10 2008-07-10 Process for preparation of iduronic acid
GB0812613.8 2008-07-10
GB0812609A GB0812609D0 (en) 2008-07-10 2008-07-10 Process for the preparation of deoxynojirimycin
GB0812609.6 2008-07-10
GB0812605.4 2008-07-10
GB0812613A GB0812613D0 (en) 2008-07-10 2008-07-10 Process for the preparation of 1-deoxyidonojirimycin

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WO2010004269A2 true WO2010004269A2 (fr) 2010-01-14
WO2010004269A3 WO2010004269A3 (fr) 2010-11-18

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Publication number Priority date Publication date Assignee Title
WO2016177908A3 (fr) * 2015-05-07 2016-12-29 L'oreal Procede de traitement des matieres keratiniques a partir de derives de c-glycosides amides, acides ou ester, et la composition cosmetique les contenant
FR3060566A1 (fr) * 2015-05-07 2018-06-22 L'oreal Procede de preparation de derives de c-glycosides et composes intermediaires
US11045411B2 (en) 2015-05-07 2021-06-29 L'oreal Process for treating keratin materials using amide, acid or ester c-glycoside derivatives, and cosmetic composition containing same

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