Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• This invention relates to a novel pharmaceutical composition and to certain > novel compounds, to a process for preparing such composition and compounds and to the use of such a composition and compounds in medicine.
• a a represents a substituted or unsubstituted aromatic heterocyclyl group
• R a represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
• Rb and R c each represent hydrogen or R ⁇ and R c together represent a bond;
• a ⁇ represents a benzene ring having in total up to five substituents; and
• n' represents an integer in the range of from 2 to 6.
• EP 0306228 is 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter
• WO94/05659 discloses certain salts of Compound (I) including the 5 maleate salt.
• the invention provides a pharmaceutical composition which composition comprises an effective non-toxic amount of a compound of formula (I): or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein:
• a 1 represents OH or -OSO 2 OH
• R! represents a hydrogen atom or a C ⁇ -6 alkyl group
• R2 and R ⁇ each represent hydrogen or R ⁇ and R ⁇ together represent a bond; and a pharmaceutically acceptable carrier therefor.
• a ⁇ represents OH
• a 1 represents -OSO 2 OH.
• R! represents a C ⁇ -6 alkyl group, especially a methyl group.
• R ⁇ and R ⁇ each represent hydrogen.
• the moiety A!-(C5H3N)-NR 1 - represents a group of formula (a):
• a ⁇ and R! are as defined in relation to formula (I).
• the invention also provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, in solid form.
• the invention also provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, in purified form.
• the invention also provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, in crystalline form.
• the invention also provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, in pharmaceutically acceptable form.
• certain of the compounds of formula (I) are novel and hence the invention also provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof; providing that formula (I) does not encompass 5-(4- ⁇ 2-[(5-hydroxy- pyridin-2-yl)-methyl-amino]-ethoxy ⁇ -benzyl)-thiazolidine-2,4-dione and/or providing formula (I) does not encompass sulfuric acid mono-[6-( ⁇ 2-[4-(2,4-dioxo-thiazolidin-
• Suitable pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable acids or bases.
• Suitable pharmaceutically acceptable salts derived from bases include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine,
• metal salts such as for example aluminium
• alkali metal salts such as lithium, sodium or potassium
• alkaline earth metal salts such as calcium or magnesium
• ammonium or substituted ammonium salts for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethy
• Suitable pharmaceutically acceptable acids derived from bases include acid addition salts.
• Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, ⁇ -keto glutarate and ⁇ -glycerophosphate.
• pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide
• pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, ⁇ -keto glutarate and ⁇ -glycerophosphate.
• Suitable pharmaceutically acceptable solvates include hydrates.
• a compound of formula (I) may exist in one of several tautomeric forms, all of which are encompassed by the present invention. It will also be appreciated that the compounds of formula (I) can have at least one chiral carbon atom and hence can form two or more stereoisomers.
• the present invention encompasses all isomeric forms of the compounds of formula (I), including any stereoisomeric forms thereof, whether as individual isomers or as mixtures of isomers.
• "alkyl” whether present alone or as part of other groups such as alkoxy or aralkyl groups, are alkyl groups having straight or branched carbon chains, containing up to 12 carbon atoms.
• Suitable alkyl groups are C ⁇ . alkyl groups e.g. methyl, ethyl, ⁇ -propyl, i_s ⁇ -propyl, ⁇ -butyl, iso- butyl or tert-butyl groups.
• the term 'conditions associated with diabetes' includes those conditions associated with the pre-diabetic state, conditions associated with diabetes mellitus itself and complications associated with diabetes mellitus.
• the term 'conditions associated with the pre-diabetic state' includes conditions such as insulin resistance, impaired fasting glucose, impaired glucose tolerance and hyperinsulinaemia.
• 'Conditions associated with diabetes mellitus itself include hyperglycaemia, insulin resistance and obesity. Further conditions associated with diabetes mellitus itself include hypertension and cardiovascular disease, especially atherosclerosis and conditions associated with insulin resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome and steroid induced insulin resistance and gestational diabetes.
• 'Complications associated with diabetes mellitus' includes renal disease, especially renal disease associated with Type 2 diabetes, neuropathy and retinopathy.
• Renal diseases associated with Type 2 diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.
• nephropathy glomerulonephritis
• glomerular sclerosis glomerular sclerosis
• nephrotic syndrome hypertensive nephrosclerosis
• end stage renal disease end stage renal disease.
• the term 'pharmaceutically acceptable' embraces compounds, compositions and ingredients for both human and veterinary use: for example the term
• 'pharmaceutically acceptable salt embraces a veterinarily acceptable salt.
• the invention also provides a process for the preparation of the compounds of formula (I), which process comprises reacting a compound of formula (II):
• R ⁇ and R ⁇ are as defined in relation to the compounds of formula (I) and I_l represents a leaving group, especially a halogen atom such as a fluorine atom, with a compound of formula (HI):
• R! is as defined in relation to formula (I) and A ⁇ represents A* as defined in relation to formula (I) or a protected form thereof; and thereafter, if required, carrying out one or more of the following optional steps:
• a ' is OH or, preferably, a protected form thereof such as a benzylated form.
• the compound of formula (HI) is used in an activated form, generally prepared in situ in the relevant reaction.
• a suitable activated form of a compound of formula (HI) is an anionic form such as a salted form and especially an alkali metal salted form, for example a potassium salt.
• the activated form of the compound of formula (El) may be prepared by any appropriate conventional procedure.
• the anionic form of the compound of formula (HI) may be prepared by treating the compound of formula (El) with a base, such as a metal alkoxide, for example potassium tert-butoxide.
• the reaction conditions for the reaction between the compounds of formulae (II) and (HI) are generally the appropriate, conventional conditions.
• the reaction between the compound of formula (II) and a salted form of a compound of formula (HI) may be carried out in an aprotic solvent, such as dimethylformamide, at any temperature providing a suitable rate of formation of the required product, conveniently at an elevated temperature for example 60°C.
• the compounds of formulae (II) and (HI) are known compounds or they are prepared by methods analogous to those used to prepare known compounds, for example those disclosed in EP0306228.
• Compound (H) wherein i represents F and R2 together with R ⁇ represents a bond can also be prepared using methods disclosed by Steblyuk et al. (Fiziol. Akt. Veshchestva, 11, 97-101, 1979).
• the above mentioned conversion of a compound of formula (I) into a further compound of formula (I) includes:
• Suitable conversions (a) include the conversion of a compound wherein A s OH into a compound wherein A ⁇ is -OSO 2 OH, which conversion may be carried out using pyridine/sulphur trioxide complex in a solvent such as pyridine, at any convenient temperature providing a suitable rate of formation of the required product, for example at ambient temperature.
• Suitable conversions (b) may be carried out using any appropriate conventional reduction procedure, for example by use of catalytic reduction using for example a 10% palladium-on-carbon catalyst in an alkanolic solvent such as ethanol, by use of a metal/solvent system such as magnesium metal/methanol as described in Tet. Lett. 1986, 27, 2409 or by use of a metal borohydride, such as lithium borohydride (generally used in stoichiometric excess) in an aprotic solvent such as tetrahydrofuran and pyridine, typically at an elevated temperature as described in International Patent Application, Publication Number WO98/37073.
• a metal borohydride such as lithium borohydride (generally used in stoichiometric excess) in an aprotic solvent such as tetrahydrofuran and pyridine
• any reactive group in the substrate molecule may be protected, according to conventional chemical practice.
• suitable protecting groups are those used conventionally in the art.
• suitable hydroxyl protecting groups include benzyl or trialkylsilyl groups.
• the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
• a benzyloxy group may be prepared by treatment of the appropriate compound with a benzyl halide, such as benzyl bromide, and thereafter, if required, the benzyl group may be conveniently removed using mild acidic hydrolysis using, for example, hydrogen chloride in acetic acid.
• the present invention accordingly provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.
• the present invention provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment Type 2 diabetes or conditions associated with Type 2 diabetes.
• the compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof is administered as a pharmaceutical composition of the invention also comprising a pharmaceutically acceptable carrier.
• composition of the invention is prepared by admixing a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, preferably an effective non-toxic amount thereof, with a pharmaceutically acceptable carrier.
• compositions of the present invention may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
• pharmaceutical compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged.
• compositions for oral administration are unit dosage forms such as tablets and capsules.
• Other fixed unit dosage forms, such as powders presented in sachets, may also be used.
• the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.
• Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate.
• composition will be formulated in unit dose form.
• unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg.
• the present invention further provides a method for the treatment of Type 2 diabetes or conditions associated with Type 2 diabetes in a human or non-human mammal which comprises administering an effective, non-toxic, amount of a compound of the general formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof to a human or non-human mammal in need thereof.
• a method for the treatment of Type 2 diabetes or conditions associated with Type 2 diabetes in a human or non-human mammal which comprises administering an effective, non-toxic, amount of a compound of the general formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof to a human or non-human mammal in need thereof.
• the compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg.
• the active ingredient may be administered by mouth, usually once or twice a day and in an amount in the range of from about 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg. Similar dosage regimens are suitable for the treatment and/or prophylaxis of hyperlipidaemia in non-human mammals.
• the present invention provides the use of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of Type 2 diabetes or conditions associated with Type 2 diabetes. No toxicological effects have been established for the compounds of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of Type 2 diabetes or conditions associated with Type 2 diabetes. No toxicological effects have been established for the compounds of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of Type 2 diabetes or conditions associated with Type 2 diabetes. No toxicological effects have been established for the compounds of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof,
• the blood glucose lowering activity of the present compounds can be determined using standard tests such as the Oral Glucose Tolerance Test in C57bll/6 obese (ob/ob) mice, for example using methodology disclosed in EP0306228.
• 2,5-Dibromopyridine (27.93g) and 2-(methylamino)ethanol (36.15g) were heated under nitrogen at 150°C for 5 hours with stirring.
• the reaction mixture was cooled to room temperature and added to brine (490mL) followed by extraction with ethyl acetate (245mL x 3).
• the combined organic phases were washed with brine (245mL) and dried over sodium sulphate.
• PNMR in dimethylsulphoxide, DMSO: ⁇ H 3.00 (3H, s. NCH 3 ), 3.53 (4H, t, NCH 2 . OCH 2 ), 4.66 ( 1H. bs, OH), 6.60 ( 1H, d, ArH), 7.59 (2H. dd. ArH), 8.10 ( 1H, d, ArH).
• Infrared (nujol): v max 2954, 2928, 2884, 2856, 1620, 1570, 1506, 1472, 1463, 1439, 1416, 1388, 1360, 1318, 1256, 1205, 1135, 1102, 1071, 1018, 1006, 993, 974, 938, 926, 900, 836, 809, 777, 741, 713, 695, 662 and 650 cm" 1 .
• the product was chromatographed on silica, eluting initially with ethyl acetate/60- 80° petrol, 1: 1 by volume, then with ethyl acetate/60-80 o petrol, 7:3 by volume.
• the product-rich fractions were combined and evaporated under reduced pressure to give a yellow oil. This was dried by adding toluene (lOOmL x 2) and re-evaporating, finally drying under high vacuum.
• the product crystallised as a cream-coloured solid.
• reaction mixture was poured into a mixture of 1M HC1 (72mL) and water (1160mL) with stirring to give a pale yellow suspension.
• the pH was 6.5. Stirring was continued for 30 minutes before the solid was filtered off, washed with water (lOOmL), and sucked dry on the filter.
• the paste-like damp solid was suspended in denatured ethanol (lOOmL) and heated to reflux with stirring. After 30 minutes at reflux temperature the reaction mixture was allowed to cool slowly to 30°C when cooling was applied to take the final temperature to 10°C. The solid was filtered off and washed on the filter with denatured ethanol (25mL, lOmL), then dried in a fan oven at 50°C overnight.
• Infrared (nujol): v max 1730, 1695, 1601, 1564, 1545, 1508, 1406, 1336, 1312, 1287, 1251, 1230, 1208, 1188, 1163, 1075, 1028, 973, 896, 862, 848, 823, 813, 804, 796, 741, 716, 697, 686, 651, 631, 606, 552, 542, 520 cm" 1 .
• the solid was filtered off and washed thoroughly with until the filtrate was colourless.
• the solid was azeotropically dried using toluene (lOOmL) and evaporating under reduced pressure. This was repeated once.
• the dry residue was extracted by heating it with ethyl acetate (500mL) to reflux temperature and filtering the hot mixture. This procedure was repeated on insoluble material with more ethyl acetate (500mL).
• the combined filtrates were evaporated to a white solid which was dried with toluene ( lOOmL x 2) as above, then under high vacuum.
• Example 1 5-(4- ⁇ 2-[f5-Hvdroxy-pyridin-2-yl)-methyl-amino1-ethoxy ⁇ -benzyl)- thiazol_dine-2.4-dione
• Example 2 The product from Example 1 (3.40g) and pyridine-sulphur trioxide complex (4.53g) were dissolved in pyridine (230mL) and stirred at room temperature under nitrogen for 26 hours. The solvent was removed under reduced pressure and toluene (70mL) was added to the residue and re-evaporated. This was repeated with more toluene (70mL). The residue was then treated with methanol (140mL) and heated to reflux with stirring until dissolved and the hot solution filtered. On cooling at room temperature over 16 hours, a precipitate formed. The mixture was further cooled in a refrigerator (4 - 5°C) for a further 26 hours before the solid was collected by filtration and washed with methanol (20mL) to give crude product. Yield 3.14g, 6.93mmol, 76.1%
• the crude product (3.14g) was suspended in a mixture of water (250mL) and methanol (50mL) and heated to reflux with stirring. The resulting yellow solution was heated for at least 30 minutes until all the solid had dissolved when it was filtered hot. The filtrate was allowed to cool to room temperature and stand for at least 20 hours. The resulting cream coloured solid was filtered off, washed with water (30mL x 2), and dried at the pump.

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