WO2019113646A1 - Procédé de sulfatation - Google Patents

Procédé de sulfatation Download PDF

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Publication number
WO2019113646A1
WO2019113646A1 PCT/AU2018/051338 AU2018051338W WO2019113646A1 WO 2019113646 A1 WO2019113646 A1 WO 2019113646A1 AU 2018051338 W AU2018051338 W AU 2018051338W WO 2019113646 A1 WO2019113646 A1 WO 2019113646A1
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compound
sulfation
participating
participating component
component
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PCT/AU2018/051338
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English (en)
Inventor
Mark Von Itzstein
Chih-Wei Chang
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Griffith University
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Priority claimed from AU2017905016A external-priority patent/AU2017905016A0/en
Application filed by Griffith University filed Critical Griffith University
Publication of WO2019113646A1 publication Critical patent/WO2019113646A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B45/00—Formation or introduction of functional groups containing sulfur
    • C07B45/02—Formation or introduction of functional groups containing sulfur of sulfo or sulfonyldioxy groups

Definitions

  • the invention relates to the field of synthetic chemistry. More particularly, this invention relates to a method of N- or O-sulfation of a compound.
  • Sulfation reactions have been used for the synthesis of a wide variety of sulfated materials including sulfated surfactants, sulfated glycosaminoglycans (GAG) and GAG mimetics as well as sulfated polysaccharides generally, including Fondaparinux Sodium and Pentosan Sulfate.
  • a number of sulfated compounds are undergoing clinical trials for the treatment of cancers, including heterogeneous phosphomannopentaose sulfate, as described in WO 1996/033726, and homogeneous sulfated polyglucoside, as described in WO 2009/049370.
  • the preparation of ursodeoxycholic acid di-sodium 3,7-disulfate is also described in WO 2004/092193.
  • the O-sulfation of hydroxyl groups of sulfation precursors generally involves the use of a sulfur trioxide trimethylamine complex (SO 3 .TMA) or sulfur trioxide triethylamine complex (SO 3 .TEA) in DMF and heating of the reaction mixtures at 50-60 °C (Al-Horani et al., Tetrahedron 2010, 66 (16), 2907-2918).
  • SO 3 .TMA sulfur trioxide trimethylamine complex
  • SO 3 .TEA sulfur trioxide triethylamine complex
  • O-sulfation with a sulfur trioxide pyridine complex (S0 3 .Py) using either pyridine or DMF as a solvent has been used in some cases.
  • WO 2015/01 1519 describes a process for the production of Fondaparinux sodium and discloses a sulfation step using a sulfur trioxide- amine complex, such as SO3.TMA or SO3.TEA. This is stated to be a preferred approach to the use of SOsPyr which led to impurities including desulfation products.
  • the sulfation step occurs in the presence of DMAc.
  • W02003020735 discloses the sulfation of low molecular weight saccharides derived from glycosaminoglycans using a sulphating reagent within a dipolar aprotic solvent selected from pyridine, pyridine-DMF, and pyridine-DMSO.
  • This method is said to provide a more efficient and high-yielding process when compared to prior art methods (Petitou et al., U.S. Patent No. 5,013,724) which require a conversion of the glycosaminoglycan into an organic amine salt before sulfation. Nonetheless, it still suffers from the requirement for tedious work up and solvent removal procedures.
  • a method of N- or O-sulfation of a compound including the steps of:
  • the compound comprises at least one of a nitrogen- containing functional group or an oxygen-containing functional group.
  • the nitrogen-containing functional group is selected from an amine, amide, sulfonamide, imine and /V-oxide. It is highly preferred that the nitrogen-containing functional group is an amine.
  • the nitrogen-containing functional group is an -Nhh group.
  • the oxygen-containing functional group is hydroxyl
  • the compound displays one or more free hydroxyl groups for sulfation.
  • the at least one participating component may be an electron donor molecule and/or a polar aprotic compound.
  • the at least one participating component may be selected from the group consisting of heterocycles, formamides, phosphoramides, sulfoxides, anilides, and ethers.
  • the at least one participating component is a heterocycle it is selected from oxygen and/or nitrogen-containing five to seven- membered heterocycles which may optionally be substituted or fused with one or more further five to seven-membered rings which may themselves be heterocyclic, carbocyclic, aryl or heteroaryl.
  • the at least one participating component may be selected from the group consisting of A/,A/-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), morpholine, /V-formylmorpholine, /V-formylpiperidine, N- methylformanilide, 1 -formylpyrrolidine, 2-bromopyridine, and hexamethylphosphoramide (HMPA).
  • DMF A/,A/-dimethylformamide
  • DMSO dimethyl sulfoxide
  • morpholine /V-formylmorpholine
  • /V-formylpiperidine N- methylformanilide
  • 1 -formylpyrrolidine 1 -formylpyrrolidine
  • 2-bromopyridine 2-bromopyridine
  • HMPA hexamethylphosphoramide
  • the at least one non-participating component may be a non-polar aprotic compound.
  • the at least one non-participating component may be selected from the group consisting of haloalkyl, nitrile, nitroalkyl, heterocyclic, alcohol, aqueous alcohol, water, ester and optionally substituted aryl
  • the at least one non-participating component may be selected from the group consisting of 1 ,2-dichloroethane (DCE), dichloromethane (DCM), chlorobenzene, toluene, methanol, ethanol, water, methanol/water blends, acetonitrile, acetone, nitromethane, tetrahydrofuran, chloroform, 1 ,2,3,4-tetrahydro-naphthalene, trans- 1 ,2-dichloroethylene, c/s-1 ,2- dichloroethylene, xylenes, butyl acetate and ethyl acetate.
  • DCE ,2-dichloroethane
  • DCM dichloromethane
  • chlorobenzene toluene
  • methanol ethanol
  • ethanol water
  • methanol/water blends acetonitrile
  • acetone nitromethane
  • tetrahydrofuran chloroform
  • the method may further include the step of precipitating the N- or O- sulfated compound from the co-solvent system.
  • the precipitating may be triggered by addition of further amounts or non-participating solvent which may be the same or different to the non participating solvent used in the sulfation reaction.
  • the N- or O-sulfated compound may be present as an amine salt at the point of precipitation from the co-solvent system. That is, the sulfated compound of step (b) may be precipitated from the co-solvent system as an amine salt.
  • FIG 1 A is a graphical representation demonstrating S-N bond dissociation of a SO3.TMA complex in the presence of A/,A/-dimethylformamide as a participating component;
  • FIG 1 B shows real-time 1 FI NMR detection of dissociation of the S-N bond demonstrated in FIG 1 A; a mixture of S03.Me3N (6.95 mg, 50 mitioI) and DMF (1 1 .5 mI_, 150 mitioI) with CD 3 CN (0.5 ml_) in 5 mm NMR tube was sonicated for 1 min and subsequently measured in 1 FI NMR at 50 ° C. For the control experiment, S03.Me3N remained intact in the absence of DMF at 50 ° C for 24 h;
  • FIG 2A is a graphical scheme regarding a postulated mechanism for O-sulfation according to the present invention.
  • FIG 2B is a general scheme postulating the role of the participating/non-participating components in the present sulfation method as applied to /V-sulfation;
  • FIG 3 shows 1 FI-NMR monitoring of sulfation of methyl a-D-glucoside performed in neat DMF at 60 ° C.; the experimental procedure was to place SO 3 .TMA (1 .5 eq per OFI, 3.6 mmol, 500 mg) and glycoside (129 mg, 0.6 mmol) in 2-necked round flask, the flask was charged with Ar balloon and degassed for 3 times after which time 30 ml_ of anhydrous DMF was added into the flask and the resulting reaction was heated at 60 ° C and monitored via 1 FI NMR at different time courses.
  • SO 3 .TMA (1 .5 eq per OFI, 3.6 mmol, 500 mg
  • glycoside 129 mg, 0.6 mmol
  • the present invention is predicated, at least in part, on the finding that the desulfation of sulfated product in a reaction mixture may be reduced, the work up procedure may be greatly simplified and the overall yield of product may be improved by the use of a co-solvent system comprising a participating component and a non-participating component during the sulfation reaction.
  • a co-solvent system comprising a participating component and a non-participating component during the sulfation reaction.
  • the participating component for example DMF as is commonly used as solvent in a standard sulfation reaction, interacts with the sulfating reagent to improve reactivity and help achieve the sulfated product and then solubilises this product.
  • the present invention employs the use of a non participating component which is postulated to assist in actively removing or sequestering the participating component away from the sulfated product. This has benefits in decreasing the likelihood or extent of desulfation of the sulfated product and, importantly, can result in precipitation of the sulfated product thereby allowing for simple collection.
  • FIG 2A This theory is graphically represented in FIG 2A, and the role of the participating and non-participating components is further set out in in relation to /V-sulfation in FIG 2B, which demonstrates the sulfation of a generic hydroxyl- containing organic compound (R-OFI) using SO3.W (where W could be, for example, TMA) with e.g. DMF (represented as X in FIG 2A) as the participating component and e.g. DCE (represented as Y in FIG 2A) as the non-participating component.
  • W could be, for example, TMA
  • DMF represented as X in FIG 2A
  • DCE represented as Y in FIG 2A
  • the non-participating component may be, for example, MeOH and water.
  • the postulated mechanism involves the replacement of the trimethylamine portion (W) of the sulfating reagent with DMF (X) to form a more reactive sulfating agent (as perFIG 2A). This reacts with the R-OH group to form the sulfated product as shown in FIG 2A. It is the presence of the non-participating component, such as DCE, which, due to its miscibility with the participating component, sequesters the participating component and encourages the sulfated product to precipitate out of the co-solvent system. In the example shown, the sulfated product precipitates out as the amine salt.
  • DCE non-participating component
  • the term “participating component’ refers to a component of a co-solvent system which is actively involved in the sulfation reaction. Specifically, the term is used for a component of the co-solvent system which forms a complex with the SO3 component of the sulfating reagent during the sulfation reaction to form a more reactive sulfating intermediate. For example, in the reaction shown in FIG 2A the participating component forms a complex with the SO3 component of the SO3.TMA sulfating reagent during the sulfation reaction. Whether or not a given molecule is acting as a participating component can be ascertained in the following manner.
  • FIG 1 B indicates a reliable way in which the continuing dissociation of the S-N bond (generically indicated in FIGs 2A and 2B as S-W) of the sulfating complex in the presence of the participating component can be monitored.
  • the breaking of this bond and the action of the participating component within this is a key part of the sulfation reaction.
  • This reaction and monitoring thereof allows a person skilled in the art to run a simple test to ascertain if, indeed, they have a compound or solvent which is acting as a participating component in a sulfation reaction.
  • the participating component may or may not be acting as a bulk solvent in that it may be present only in catalytic amounts in the co-solvent system.
  • non-participating component refers to a component of a co-solvent system which is not actively involved in the sulfation reaction perse. Specifically, the term is used for a component of the co-solvent system which does not form a complex with the SO3 component of the sulfating reagent during the sulfation reaction to form a more reactive sulfating intermediate.
  • the converse of the approach set out for testing whether or not a component of the co-solvent system may be used to identify whether or not a component is a non-participating solvent. That is, the same test may be used with a negative result indicating a non-participating component.
  • the ability to precipitate the sulfated product also indicates the presence of a successful non participating component.
  • the term “polar aprotic compound” refers to a compound possessing sufficient polarity and, more importantly, sufficient electron-donating capability to act as a participating component and react with the sulfating reagent to form an intermediate, as described herein.
  • the polar aprotic compound may be a polar aprotic solvent although it need not always be so.
  • A/,A/-diphenylformamidine may be capable of acting as a polar aprotic compound and a participating component even though it is solid at room temperature and so may not be considered to be a traditional solvent.
  • a polar aprotic compound has sufficient electron-donating capability to act as a participating component can be determined experimentally using the testing procedure described herein.
  • the compound comprises at least one of a nitrogen- containing functional group or an oxygen-containing functional group.
  • the nitrogen-containing functional group is selected from an amine, amide, sulfonamide, imine and /V-oxide. It is highly preferred that the nitrogen-containing functional group is an amine.
  • the nitrogen-containing functional group is an -Nhh group.
  • the oxygen-containing functional group is hydroxyl
  • the compound may be modified to present the oxygen-containing or nitrogen-containing functional groups. Further, the compound may have such groups but presented in a form whereby they are not available for sulfation, for example protected with a suitable protecting group. The relevant group may be removed by conventional chemical reactions prior to being exposed to the sulfation reagent and so all such compounds may be suitable for use in the present method.
  • the compound displays one or more free hydroxyl groups for O-sulfation thereof. It will be appreciated that the compound may initially have the hydroxyl group protected but this protecting group may be removed prior to the sulfation.
  • the compound may be selected from the group consisting of a carbohydrate, a carboxylic acid, an alkanol, a haloalkanol, an aldehyde, a phenol or other hydroxyl-substituted aryl, a sulfonic acid, a hydroxyl-substituted heteroaryl, a hydroxyl-substituted heterocycle, a thioalkanol, a diol, triol or polyol, and a sterol.
  • the co-solvent system may comprise one or more additional solvents or components beyond the at least one participating component and at least one non-participating component.
  • the at least one participating component may, in certain embodiments, be two, three or four participating components.
  • the non-participating component may, in certain embodiments, be two, three or four non-participating components.
  • the co-solvent system may comprise only one participating component.
  • the co-solvent system may comprise only one participating component and either one or two non-participating components.
  • the at least one participating component may be an electron donor molecule and/or a polar aprotic compound.
  • the at least one participating component may be an aprotic dipolar compound.
  • the at least one participating component may be selected from the group consisting of heterocycles, formamides, phosphoramides, sulfoxides, anilides, and ethers.
  • the at least one participating component is a heterocycle it is selected from oxygen and/or nitrogen-containing five to seven- membered heterocycles which may optionally be substituted or fused with one or more further five to seven-membered rings which may themselves be heterocyclic, carbocyclic, aryl or heteroaryl.
  • the at least one participating component may be selected from the group consisting of A/,A/-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), morpholine, /V-formylmorpholine, /V-formylpiperidine, N- methylformanilide, 1 -formylpyrrolidine, 2-bromopyridine, and hexamethylphosphoramide (HMPA).
  • DMF A/,A/-dimethylformamide
  • DMSO dimethyl sulfoxide
  • morpholine /V-formylmorpholine
  • /V-formylpiperidine N- methylformanilide
  • 1 -formylpyrrolidine 1 -formylpyrrolidine
  • 2-bromopyridine 2-bromopyridine
  • HMPA hexamethylphosphoramide
  • the at least one participating component may be a component or solvent also associated with the sulfating reagent.
  • the at least one participating component may be pyridine.
  • the co-solvent system comprises the pyridine as the at least one participating component with the non-participating component also present, for example as DCE.
  • the participating component may not be a component of the sulfating reagent. That is, the participating component will be added as an additional and separate component to any equivalent component of the sulfating reagent. This separation may be particularly so if the reaction is to be microwave assisted.
  • the participating component may, in certain embodiments, be considered to be the /V-sulfation precursor itself.
  • the co-solvent system is formed comprising of both the participating and non-participating components.
  • the at least one non-participating component may be selected from the group consisting of haloalkyl, nitrile, alcohol, aqueous alcohol, water, nitroalkyl, heterocyclic, ketone, optionally substituted aryl and ester.
  • the at least one non-participating component may be selected from the group consisting of 1 ,2-dichloroethane (DCE), dichloromethane (DCM), chlorobenzene, toluene, methanol, ethanol, water, methanol/water blends, acetonitrile, acetone, nitromethane, tetrahydrofuran, chloroform, 1 ,2,3,4-tetrahydro-naphthalene, trans- 1 ,2-dichloroethylene, c/s-1 ,2- dichloroethylene, xylenes, butyl acetate and ethyl acetate.
  • DCE ,2-dichloroethane
  • DCM dichloromethane
  • chlorobenzene toluene
  • methanol ethanol
  • ethanol water
  • methanol/water blends acetonitrile
  • acetone nitromethane
  • tetrahydrofuran chloroform
  • the at least one non-participating component may be two or more components selected from the groups already described.
  • a combination of non-participating components may be useful such as, for example, ethyl acetate and acetonitrile.
  • the non-participating component is an alcohol or aqueous alcohol.
  • Methanol and water or blends thereof may be particularly preferred.
  • methanol and water may act as non participating components which enable the solubilizing of all reactants and which compromise the selectivity between the NFh and OFI functionalities. Therefore, in one embodiment, the non-participating component for /V-sulfation may be selected from polar aprotic molecules including, but not limited to, alcohols, including methanol, and water.
  • the non-participating component for /V-sulfation may not be limited to polar protic solvents and may, in certain embodiments, be selected from non-polar aprotic solvents including DCE, DCM, Acetonitrile, EtOAc and the like.
  • the sulfation may, in one embodiment, be a selective /V-sulfation in the presence of hydroxyl groups on the compound.
  • the nitrogen of, for example, a free amino group is more nucleophilic than an oxygen of a hydroxyl and so the amine nitrogen can be selectively sulfated.
  • Conditions of either one or both of the participating component and non-participating component may be manipulated to favour the /V-sulfation.
  • the base may be an amine base, a carbonate base or a bicarbonate base.
  • Preferred bases may include trialkylamines, such as triethylamine, and sodium and/or potassium carbonates and bicarbonates.
  • the base is an additional component in the reaction mixture. That is, in embodiments, neither the participating component nor the non participating component is an alkylamine bases, particularly not a trialkylamine.
  • the base may act as an acid scavenger to neutralize the increasing acidity derived from the generated acid due to the potential volatilization of the W component during the course of the reaction. If the basicity of the base is stronger than W, then the W+H cation would be replaced by H+base as the more stable salt. Therefore, the base may be selected from any suitable inorganic or organic base including but not limited to triethylamine and sodium and potassium carbonates and bicarbonates.
  • the participating and/or non-participating component is not a base.
  • the non-participating component may not be an amine base.
  • the non-participating component may not be selected from heterocyclic amine bases, such as pyridine.
  • the non-participating component is not an alkylamine, including TEA and TMA. While such an amine may assist in the breaking of the key S-W bond (preferably an S-N bond) of the sulfating reagent an analogous reagent is formed and so O-sulfation is not achieved.
  • the method may further include the step of precipitating the N- or O- sulfated compound from the co-solvent system. This step is linked to the level of miscibility of the at least one participating component and at least one non participating component, as discussed further below. Further non-participating component may be added to the post-reaction mixture to achieve precipitation. That further non-participating component may be the same as or different to the non-participating component present during the sulfation reaction.
  • the N- or O-sulfated compound may be present as an amine salt or pyridinium at the point of precipitation from the co-solvent system. That is, the sulfated compound of step (b) may be precipitated from the co-solvent system as an amine or pyridinium salt.
  • the precipitation of the N- or O-sulfated compound may be achieved in a number of ways such as, for example, by variation of the alkyl chain length associated with the amine functionality which can allow for tailoring of precipitation based upon the polarity of the co-solvent system.
  • the step of precipitating the N- or O-sulfated compound from the co-solvent system may not require the addition of a further solvent which is not already part of the co-solvent system in which the sulfation reaction occurred. That is, the precipitation step does not necessarily require the addition of a further solvent to crash out the sulfated product. It will be appreciated, however, that in some embodiments it may be desirable or efficient to add additional post-reaction non-participating component to improve the yield of product by encouraging precipitation of product.
  • the at least one participating component and at least one non-participating component are at least partially miscible.
  • the at least one participating component and at least one non-participating component are miscible. They will suitably be miscible such that they can be mixed, in all concentrations, to form a homogeneous solution. Miscibility can be ascertained or predicted from one of many solvent miscibility tables available in the literature or can be simply tested by an experiment mixing the two components in a variety of ratios and miscibility visibly determined.
  • the benefit of a high level of miscibility between the at least one participating component and at least one non-participating component is that the at least one non-participating component is better able to sequester the at least one participating component which makes it more likely that the sulfated reaction product will precipitate from the reaction. While not an essential step in the present method, distinct advantages in operation are achieved by the precipitation of the reaction product.
  • the method may therefore also include the step of collecting the solid sulfated product.
  • the collecting may be by simple filtration. This is a significant advantage compared with attempting to extract the sulfated product from a significant volume of DMF, as occurs in prior art sulfation approaches. Apart from the cost and time savings, there is a significant risk of desulfation of the sulfated product during neutralisation and DMF removal in prior art approaches.
  • the present method therefore assists greatly in preserving the sulfated product.
  • FIG 3 demonstrates the desulfation side reaction which occurs with extended heating times in convention reaction approaches. The present approach and, particularly, employing precipitation of the product can greatly reduce or avoid this issue.
  • the method does not include the step of column chromatography for removal of solvent, such as DMF.
  • the ratio of the at least one participating component to the at least one non-participating component in the co-solvent system is between 10:1 to 0.1 :1000 including between 10:1 to 0.1 :500, 10:1 to 0.1 :250, 10:1 to 0.1 :100, 10:1 to 0.1 :50, 10:1 to 0.1 :25, 5:1 to 0.1 :500, 5:1 to 0.1 :250, 5:1 to 0.1 :100, 5:1 to 0.1 :50, 5:1 to 0.1 :25, 1 :1 to 0.1 :500, 1 :1 to 0.1 :250, 1 :1 to 0.1 :100, 1 :1 to 0.1 :50, 1 :1 to 0.1 :25, 10:1 to 1 :500, 10:1 to 1 :250, 10:1 to 1 :1 00, 10:1 to 1 :50, 10:1 to 1 :25, 5:1
  • adjusting the ratio of the at least one participating component to the at least one non-participating component in the co-solvent system can influence the course of the reaction and can reduce the incidence of unwanted side reactions as well as assisting in optimising reaction yield.
  • the optimal ratio may vary depending on the substrate to be sulfated but can be identified by simultaneously running a number of reactions, preferably on a small scale, varying only that ratio. This routine testing will then indicate a preferred range of ratio of the at least one participating component to the at least one non-participating component in the co-solvent system which can be applied to scaled up reactions.
  • the participating component may be formed during the reaction by the breaking of the S-W bond (as per FIG 2A, typically an S-N bond) of the sulfating reagent with the W component effectively becoming the participating component.
  • S-W bond as per FIG 2A, typically an S-N bond
  • S0 3 .Pyr will release pyridine to act as a participating component under certain conditions.
  • the sulfating reagent may be selected from those which are commonly used in sulfation reactions and particularly those applicable to sulfation of carbohydrates.
  • the sulfating reagent may be of formula SO 3 .W wherein W may be selected from, but is not limited to, formamide, sulfoxide, phosphoramide, dioxane, pyridine and alkylamine. Specifically, W may be selected from TMA, TEA, Pyr, DMF and 1 ,4-Dioxane. W may be any electron- donating molecule or species.
  • Suitable sulfating reagents may be selected from, but are not limited to, S03.Pyr and SO3.NR1 R2R3 which latter general reagent class includes where each R is independently selected from C1 -C6 alkyl and the formula includes sulfating reagents such as SO 3 .TMA and SO 3 .TEA.
  • the method may further include the step of treating the sulfated product with a base.
  • a base This may be useful to convert the sulfated product salt form into a more desirable form.
  • the sulfating reagent is S0 3 .Pyr then the sulfated product will be a pyridine salt. It may be desirable to convert this into a more preferred salt which can be achieved by addition of a suitable base such as NaOFI, NaFIC0 3 , TMA and TEA, for example.
  • the method of the first aspect may include heating of the reaction mixture comprising the co-solvent system, the compound to be sulfated and the sulfating reagent. The heating may be the typical application of heat e.g. via an oil bath, heating mantle or the like. Microwave heating may be acceptable in some circumstances but is not preferred as it can lead to significant desulfation of the product.
  • the method of the first aspect does not involve microwave heating. That is, the sulfation reaction mixture is not contacted with microwave radiation or does not require microwave radiation for the sulfation reaction to be substantially complete. Microwave radiation may be useful in some N-sulfation reactions to replace multiple sulfation cycles or reduce the need for such repetition but it is an advantage of the present inventive method that such microwave radiation is not required to achieve sulfation in excellent yield.
  • the reaction mixture is heated at between 50°C to 140°C.
  • the reaction mixture is heated at between 60°C to 130°C, including between 70°C to 120°C, 75°C to 1 10°C and 80°C to 100°C.
  • the choice of optimal temperature may depend on, for example, the proportion of non-participating solvent in that highly-sulfated products with a higher proportion of non-participating solvent in the reaction are more tolerant to high temperatures. The choice of temperature is therefore a balance between sufficient heating to spur the reaction and a temperature which does not increase desulfation.
  • the method may include the step of selecting the conjugate base forming part of the sulfating reagent.
  • trimethylamine is volatile and can easily escape the reaction mixture thereby increasing the acidity of the mixture which increases the risk of desulfation of the sulfated product. It may therefore be desirable to select a conjugate base which is less volatile to thereby avoid the issue of a lowering of pH.
  • an N- or O-sulfated compound when synthesised by the method of the first aspect.
  • N- or O-sulfated compound will clearly be a sulfated analogue of the compound classes set out for the first aspect.
  • the N- or O-sulfated compound may be a persulfated compound.
  • the present method may present one or more advantages over prior art approaches (typically heating the substrate in DMF with the sulfating reagent) which may be selected from (i) improved yield; (ii) higher degree of sulfation of product; (iii) simpler work up procedure to obtain final sulfated product; (iii) reduced reaction time; (iv) reduced solvent usage; (v) reduced overall synthesis/manufacturing cost; (vi) purer sulfated product due to less partially sulfated products; (vii) improved precipitation or aggregation of solid sulfated product when compared with a similar reaction employing only the participating component and not the non-participating component; and (viii) reduced product degradation and/or desulfation.
  • Step 1 A mixture of 4-Tolyl 6-0-acetyl-2-0-benzoyl-3-0-benzyl-1 - thio- -D-glucopyranoside (52 mg, 100 mitioI), SO 3 .TMA (69.5 mg, 500 mitioI) and additive (300 mmol) in anhydrous 1 ,2-dicholoroethane (DCE, 1 ml_) was heated under Ar at 80 °C for 30 min. Upon cooling, 100 mI_ of reaction mixture withdrawn from each reaction was directly concentrated in vacuum for 30 min to furnish the crude products dissolved in CDCI 3 for measurement of conversion in 1 H NMR. These results are recorded in Table 1.
  • Step 2 A mixture of 4-Tolyl 6-0-acetyl-2-0-benzoyl-3-0-benzyl-1 - thio- -D-glucopyranoside (26 mg, 50 mitioI), SO 3 .TMA (35 mg, 250 mitioI) and in anhydrous solvent (2 ml_) was heated under Ar at 60 °C for 5 h. Upon cooling, 100 mI_ of reaction mixtures withdrawn from each reaction was directly concentrated in vacuum for 30 min to furnish the crude products dissolved in CDCI 3 for measurement of conversion in 1 H NMR. These results are recorded in Table 2.
  • the collected fractions were lyophilized to yield the sulfated methyl a-D-glucoside as a glassy solid (563 mg, 93.5%). This indicates that pyridine released from the sulfating reagent can act as the participating component and so this does not necessarily need to be added separately at the start of the reaction.
  • Table 5 indicates the results from optimisation of conditions for selective /V-sulfation in the presence of a free hydroxyl. It is an advantage of the present method that the choice of participating and non-participating component can be tailored to favour such a selective approach.
  • the reaction was quenched with 1 M NaHC0 3 (3 ml_) and the pH was maintained at 9.5. After stirring for 10 min, the reaction mixture was concentrated with toluene. The final solid residue was dissolved in water, filtered with a pad of cotton and passed through an ion-exchange column of DOWEX 50W-X8 (Na form). The collected fractions were concentrated to give the product mixture as sodium salt which was further purified through Sephadex G25. The combined fractions was lyophilized to furnish the /V-sulfated product P-14b as sodium form (258 mg, 91 .8% yield).
  • the resulting pure product was obtained as a white solid with trimethyllammonium salt which was dissolved in de-ionized water and directly subjected to ion-exchange column (Na form of DOWEX 50Wx8). The combined fractions were lyophilized to yield the final sulfated product P-18 as sodium salt (88 mg, 65.6% yield).
  • the resulting pure product was obtained as a white solid with trimethylammonium salt which was dissolved in de-ionized water and directly subjected to ion-exchange column (Na form of DOWEX 50Wx8). The combined fractions were lyophilized to yield the final sulfated product P-19 as sodium salt (36 mg, 47.3% yield).
  • the resulting solid was dissolved in de ionized water and directly subjected to ion-exchange column Na form of DOWEX 50Wx8 and further purified through SEC Sephadex G25.
  • the collected fractions were lyophilized to furnish the product P-22 as a white solid with sodium salt (36.9 g, 65.7%).

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Abstract

L'invention concerne un procédé de N- ou de O-sulfatation d'un composé par l'utilisation d'un système de co-solvant comprenant un constituant participant et un constituant non participant, pendant la réaction de sulfatation, ledit procédé permettant ainsi au constituant non participant de séquestrer de manière active le constituant participant en l'éloignant du produit de réaction sulfaté. Ceci présente des avantages en terme de diminution de la probabilité ou de l'étendue de la désulfatation du produit sulfaté et peut entraîner la précipitation du produit sulfaté, ce qui permet une collecte simple.
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WO2022116981A1 (fr) * 2020-12-01 2022-06-09 远大医药（中国）有限公司 Application d'un composé de cellobioside polyanionique

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