Process for the preparation of 7-alkoxyalkyl-1,2,4-triazolo[1,5-A] pyrimidine derivatives

An improved process for the preparation of 1,2,4-triazolo[1,5-a]pyrimidine compounds comprising the reaction involving a compound of formula II ##STR1## and a compound of formula III ##STR2## in the presence of an oxidizing agent and a reducing agent, wherein a metal salt is added to form a complex with the oxidized reducing agent produced in the process, and this complex is separated from the desired product.

The present invention relates to an improved process for the preparation of
 certain 1,2,4-triazolo[1,5a]pyrimidines which are useful in the treatment
 and/or prophylaxis of seizures, neurological disorders such as epilepsy
 and/or conditions in which there is neurological damage such as stroke,
 brain trauma, head injuries and haemorrhage.
 Compounds of Formula A
 ##STR3##
 in which R, represents H or optionally substituted alkyl, alkoxy or
 alkanoyl; R.sub.2 and R.sub.3 independently represent H or optionally
 substituted alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl or
 sulphonyl; R.sub.4 and R.sub.5 independently represent H, alkyl or
 together with the carbon atom to which they are attached represent
 optionally substituted cycloalkylidene; and R.sub.6, R.sub.7 and R.sub.8
 independently represent H, halo hydroxy, mercapto, cyano or optionally
 substituted alkyl, alkanoyl, alkoxy, alkoxycarbonyl, carboxy, alkanoyloxy,
 alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino,
 sulphamoyl, carbamoyl, alkylcarbanoyl or alkanoylamino; processes for
 their preparation, and their use in the treatment and/or prophylaxis of
 seizures, neurological disorders such as epilepsy and/or conditions in
 which there is neurological damage such as stroke, brain trauma, head
 injuries and haemorrmage are described in WO95/10521 (Knoll AG).
 In WO95/10521, there is a disclosure of the preparation of compounds of
 formula A by coupling alcohols of formula B
 ##STR4##
 with phenols of formula C
 ##STR5##
 in the presence of a redox coupling agent which, for example, in the
 "Mitsunobu" reaction is diethyl azodicarboxylate with triphenylphosphine.
 This reaction leads to the production of triphenylphosphine oxide which is
 separated from the compound of formula A by flash column chromatography on
 silica gel.
 The "Mitsunobu" reaction using a redox couple, in which the reducing agent
 is triphenylphosphine, is a very good method for producing chiral
 compounds of formula A because it results in generally good yields with
 high stereoselectivity (inversion) and is relatively simple to carry out
 since the alcohol activation and displacement reactions take place in a
 single transformation--usually at room temperature. However, the resultant
 formation of triphenylphosphine oxide is a disadvantage because it is
 difficult to remove from the desired product. Flash column chromatography
 is an acceptable laboratory-scale solution to this problem, but is not
 practicable on an industrial scale in terms of cost, time efficiency and
 ease of handling.
 One solution to the problem is to use for example a basic phosphine, such
 as diphenyl(2-pyridyl)phosphine or
 (4dimethylamirophenyl)diphenylphosphine, as the reducing agent in the
 redox couple. This facilitates product isolation since the resulting
 phosphine oxide is removed by aqueous acid washing. However, these basic
 phosphines may not be suitable for chiral compounds of formula A since the
 acid washing may cause racemisation of the chiral centre, and some
 compounds of formula A are soluble in strong acid so that separation from
 the phosphine oxide would not be achieved by acid washing. Furthermore,
 use of these basic phosphines is not commercially viable on a production
 scale. In addition, the yield can be substantially reduced by using a
 reducing agent other than triphenylphosphine. Polymer-bound phosphines may
 also be used to avoid the formation of triphenylphosphine oxide. However,
 these phosphines are expensive and the reaction is significantly slower so
 that time and cost efficiency are compromised.
 Surprisingly, we have now found a means of reducing the level of
 triphenylphosphine oxide from the desired compound of formula A which is
 inexpensive, quick, requires mild conditions and neutral pH, and is very
 easy to carry out both on a laboratory scale and on a production scale.
 This new process enables the use of triphenylphosphine in the redox couple
 (thus resulting in good stereospecificity and yield) and the efficient
 removal of the unwanted triphenylphosphine oxide. The process can also be
 applied to other tri-substituted phosphine redox couples if desired, since
 it is effective at reducing the levels of other phosphine oxides. Other
 elements of group V of the periodic table, such as arsenic and antimony,
 are also able to form tri-substituted compounds (arsines and stibines)
 which may be used as reducing agents. The process of the present invention
 may also be applied to reducing the level of the oxides of such compounds.
 It will be understood that for the remainder of this document, the term
 "tri-substituted phosphine, arsine and/or stibine" refers to
 tri-substituted phosphine, arsine and/or stibine in which the substituents
 are organic moieties.
 The present invention comprises a process for the preparation of compounds
 of formula I
 ##STR6##
 including pharmaceutically acceptable salts, solvates, racemates,
 enantiomers, diastereoisomers and mixtures thereof in which:
 R.sub.1 represents H or one of the following groups (optionally substituted
 with one or more of halo, cyano, hydroxy or amino): C.sub.1-6 alkyl,
 C.sub.1-6 alkoxy or C.sub.1-6 alkanoyl;
 R.sub.2 and R.sub.3 independently represent H or one of the following
 groups (optionally substituted with one or more of halo, cyano, hydroxy or
 amino): C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, C.sub.1-6
 alkylthio, C.sub.1-6 alkylsulphinyl or C.sub.1-6 alkylsulphonyl;
 R.sub.4 and R.sub.5 independently represent H, C.sub.1-6 alkyl or R.sub.4
 and R.sub.5 combined together with the carbon atom to which they are
 attached represent C.sub.3-6 cycloalkylidene (each alkyl or cydoalkylidene
 being optionally substituted with one or more of halo, cyano, hydroxy,
 amino or C.sub.1-6 -alkyl); and
 R.sub.6, R.sub.7 and R.sub.8 independently represent H, halo, hydroxy,
 mercapto, nitro, cyano or one of the following groups (optionally
 substituted with one or more of halo, cyano, hydroxy or amino; and any
 nitrogen atom being optionally substituted with one or more C.sub.1-6
 alkyl): C.sub.1-6 alkyl, C.sub.1-6 alkanoyl, C.sub.1-7 alkoxy, C.sub.2-6
 alkoxycarbonyl, carboxy, C.sub.1-6 alkanoyloxy, C.sub.1-6 alkyfthio,
 C.sub.1-6 alkylsulphinyl, C.sub.1-6 alkylsulphonyl, C.sub.1-6
 alkyl-sulphonylamino, sulphamoyl, carbamoyl, C.sub.2-6 ikylcarbamoyl or
 C.sub.1-6 alkanoylamino; said process comprising the reaction involving an
 alcohol of formula II
 ##STR7##
 in which R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined
 above, with a phenol of formula III
 ##STR8##
 in which R.sub.6, R.sub.7 and R.sub.8 are as defined above, in the presence
 of an inert diluent and at least one redox couple comprising an oxidising
 agent and a reducing agent which is selected from a tri-substituted
 phosphine, arsine or stibine wherein the reducing agent becomes oxidised;
 wherein
 a) a metal salt is added to form a complex or complexes with the oxidised
 reducing agent or agents produced in the process, and
 b) the resultant complex or complexes is/are separated from the desired
 product.
 It will be understood that the oxidising agent becomes reduced during the
 process, and that the reduced oxidising agent may be removed from the
 desired product either before or after steps a) and b) are carried out.
 Preferably, the reduced oxidising agent is removed from the desired
 product after steps a) and b) are carried out.
 It will be understood that any group mentioned herein which contains a
 chain of three or more atoms signifies a group in which the chain may be
 straight or branched. For example, an alkyl group may comprise propyl
 which includes n-propyl and isopropyl and butyl which includes n-butyl,
 sec-butyl, isobutyl and tert-butyl. The total number of carbon atoms is
 specified herein for certain substituents, for example C.sub.1-6 alkyl
 signifies an alkyl group having from 1 to 6 carbon atoms. The term `halo`
 as used herein signifies fluoro, chloro, bromo and iodo. The term `halide`
 as used herein signifies fluoride, chloride, bromide or iodide. The term
 `optionally substituted` as used herein, unless immediately followed by a
 list of one or more substituent group or groups, means optionally
 substituted with one or more of halo, cyano, hydroxy, amino or C.sub.1-6
 alkyl. When the phenyl ring substituents R.sub.6, R.sub.7 and R.sub.8 are
 other than H, the substituent may replace any H attached to a carbon atom
 in the ring and may be located at any such position of the ring, ie up to
 three of positions 2, 3, 4, 5 or 6.
 Certain compounds of formula I may form salts with organic or inorganic
 acids and or bases. As stated above, reference herein to compounds of
 formula I includes all salts of compounds of formula I which are
 pharmaceutically acceptable.
 The term "inert diluent" means a diluent commonly used by those skilled in
 the art which is inert to the reaction conditions. Preferably the inert
 diluent is a solvent or mixture of solvents selected from tetrahydrofuran,
 diethyl ether, 1,4dioxane, toluene, acetonitrile, dichloromethane,
 dimethylfornamide, diisopropyl ether, t-butyl methyl ether, and ethyl
 acetate.
 The separation of the resultant complex or complexes from the desired
 product [step b) of the present invention] may be achieved by one of the
 following methods. In cases where the complex precipitates out of the
 solution, the separation may be achieved by filtration, decantation, or
 centrifugation. Preferably, separation is achieved by filtration. It will
 be understood that the desired product may then be obtained from the
 filtrate for example by evaporation or crystallisation. Alternatively, if
 the complex is soluble in the inert diluent, and therefore does not
 precipitate out of the solution, the inert diluent may be removed by
 evaporation and replaced by a solvent, in which the complex and the
 desired product have different solubilities. Suitably the solvent is
 selected from water, methanol, ethanol and/or propan-2-ol and/or any of
 the inert diluents listed previously herein, or it may be a mixture of any
 of these. When the desired product is more soluble than the complex, for
 example when the solvent is toluene, the insoluble complex can be
 separated and the desired product obtained as described above.
 Alternatively, when the complex is more soluble than the desired product,
 for example when the solvent is propan-2-ol, the insoluble desired product
 can then be separated by filtration, decantation, or centrifugation.
 Optionally, further purification of the desired product may be carried out
 after steps a) and b). Further purification may comprise, for example
 trituration with a suitable solvent, for example a C.sub.1-4 alcohol or
 mixture thereof, preferably a propanol, most preferably propan-2-, and/or
 crystallisation from such a suitable solvent. Preferably, the further
 purification comprises trituration with propan-2-ol or crystallisation
 from propan-2-ol.
 It will be appreciated by those skilled in the art that steps a) and b) of
 the process may be carried out iteratively if desired. Preferably, steps
 a) and b) of the process are carried out until the level of
 tri-substituted phosphine, arsine and/or stibine oxide has been reduced
 sufficiently to enable the desired product to be isolated by the further
 purification described above, in a form which is substantially free of
 tri-substituted phosphine, arsine and/or stibine oxide. Preferably, the
 level of tri-substituted phosphine, arsine and/or stibine oxide is reduced
 to 15% of the product mixture or less. Most preferably, the level of
 tri-substituted phosphine, arsine and/or stibine oxide is reduced to
 substantially 0% (wherein no triphenylphosphine oxide is detectable by Gc
 or HPLC analysis).
 The metal salt of step a) may be added during or after the reaction
 involving the compounds of formulae II and III, subsequent to an inert
 diluent change after completion of the reaction involving the compounds of
 formulae II and III, or after removal of the reduced oxidising agent.
 Preferably, the metal salt is added after the reaction involving the
 compounds of formulae II and III.
 It will be appreciated that the phrase "a metal salt is added" in step a)
 is intended to include the addition of a metal salt and/or the addition of
 reactants suitable for the formation of a metal salt in situ, for example
 a metal and an acid, or a metal oxide and an acid. The present invention
 therefore includes both the above additions.
 Preferably the metal salt is added in a quantity ranging from 0.25 to 5
 molar equivalents of the reducing agent, more preferably in a quantity
 ranging from 1.5 to 3 molar equivalents of the reducing agent Preferably,
 the compounds of formula II and III, and the oxidising agent and the
 reducing agent are present in about equimolar quantities.
 Preferably the reaction involving compounds of formula 11 and III is
 carried out at a temperature in the range -20 to 100.degree. C., more
 preferably in the range -10 to 40.degree. C.
 Preferably, when step a) is carried out after the reaction involving the
 compounds of formula II and III, the mixture is brought to a temperature
 in the range 0 to 120.degree. C., preferably at 20 to 120.degree. C., most
 preferably the mixture is heated under reflux at the boiling point
 temperature of the inert diluent, for up to 16 hours, preferably for up to
 6 hours, more preferably for 1 to 4 hours, subsequent to the addition of
 the metal salt, then the mixture is cooled to a temperature in the range
 -100.degree. C. to ambient temperature.
 The metal salt may be a halide (for example fluoride, chloride, bromide or
 iodide), sulphate, nitrate, perchlorate, bicarbonate, carbonate, acetate,
 citrate or benzoate salt of an alkali, alkaline earth, group IIb,
 transition or lanthanide metal, or a solvate thereof, for example a
 hydrate or organic solvate. Preferably the metal is selected from lithium,
 sodium, potassium, magnesium, calcium, barium, strontium, samarium (III),
 zinc, iron (II), iron (III), manganese (II), cobalt (II), cobalt (III),
 nickel, copper (I) and copper (II). Preferably, the metal salt is a halide
 salt of magnesium, copper (I), manganese (II), iron (III), samarium (III)
 or zinc. More preferably the salt is the chloride salt or iodide salt,
 most preferably the chloride salt. Preferably the metal salt is magnesium
 chloride, copper (I) chloride, or zinc chloride. It is desirable that the
 metal salt is low in cost, toxicity, Lewis acidity and oxidising ability.
 Especially preferred is magnesium chloride.
 The salt may be added to the mixture in the form of powder, pellets, or a
 solution or slurry in an inert diluent In one preferred form magnesium
 chloride is added as a powder.
 The redox couple may be any of those known in the art as suitable for this
 type of reaction. Preferably the reducing agent is a phosphine. For
 example, the reducing agent may be selected from tris(C.sub.1-4
 akyl)phosphine, triphenylphosphine, tris(3-chlorophenyl)phosphine,
 tris(4-chlorophenyl)phosphine, tris(3-methylphenyl)-phosphine,
 tris(4-methylphenyl)phosphine, tris(3-methoxyphenyl)phosphine,
 tris(4-methoxyphenyl)phosphine, phenoxydiphenylphosphine and
 diphenoxyphenylphosphine. Preferably, the oxidising agent is selected from
 di(C.sub.1-5 alkyl) azodicarboxylate, di(C.sub.1-5 alkyl) azodicarboxamide
 (N-substituted by R.sub.1 and R.sub.2 which may independently represent H
 or a straight or branched C.sub.1-8 alkyl or cyclic C.sub.3-8 alkyl group
 or R.sub.1 and R.sub.2 together represent a C.sub.4-6 alkylene chain),
 polymer (such as polystyrene) supported methyl azodicarboxylate (as
 described in JACS, 111, p3973-3976, 1989),
 4methyl-1,2,4triazolidine-3,5-dione, dibenzoylperoxide, dimethyl
 ketomalonate and 3methylbenzothiazole-2-selone. Preferably, the redox
 couple is triphenylphosphine with diisopropyl azodicarboxylate or diethyl
 azodicarboxylate.
 Therefore, the present invention provides a process for the preparation of
 7-[1-(4-chlorophenoxy)ethyl]-1,2,4triazolo[1,5-a]pyrimidine including the
 racemate, enantiomers and mixtures thereof, said process comprising the
 reaction involving the compound of formula II which is
 1-(1,2,4triazolol[1,5-a]pyrimidin-7-yl)ethanol, including the racemate,
 enantiomers and mixtures thereof, and the compound of formula III which is
 4chlorophenol in the presence of an inert diluent and at least one redox
 couple comprising an oxidising agent, which is dilsopropyl
 azodicarboxylate or diethyl azodicarboxylate, and a reducing agent, which
 is triphenylphosphine, wherein the reducing agent becomes oxidised;
 wherein
 a) a halide salt of magnesium, copper (I), iron (III), samarium (III) or
 zinc is added after the reaction involving the compounds of formulae II
 and III to form a complex or complexes with the oxidised reducing agent or
 agents produced in the process, and
 b) the resultant complex or complexes is/are separated from the desired
 product by filtration, and optionally further purification of the desired
 product is carried out by trituration with propan-2-ol and/or
 crystallisation from propan-2-ol.
 Preferably, the compound of formula II is
 1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol, most preferably it is
 (S)-1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol.
 Preferably, the compound of formula III is 4-chlorophenol.
 Preferably, the compound of formula I is
 7-[1-(4-chlorophenoxy)ethylo-1,2,4-triazolo[1,5-a]pyrimidine, most
 preferably it is
 (R-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine.
 Suitably, the process reduces the level of tri-substituted phosphine,
 arsine and/or stibine oxide by at least 20%. Preferably the level of
 tri-substituted phosphine, arsine and/or stibine oxide is reduced by at
 least 30%. More preferably the level of tri-substituted phosphine, arsine
 and/or stibine oxide is reduced by at least 50%. Especially preferably,
 the level of tri-substituted phosphine, arsine and/or stibine oxide is
 reduced by at least 70%. Most preferably the level of tri-substituted
 phosphine, arsine and/or stibine oxide is reduced by at least 85%. The
 percentage reduction is calculated by comparing the % of oxide present, by
 normalisation by gas-liquid chromatography, in the product mixture before
 and after the process of the present invention is carried out.
 The invention will now be illustrated by the following non-limiting
 examples. The examples are illustrative only, and have not necessarily
 been carried out under optimal conditions. The final product of each
 example was characterised using one or more of the following techniques:
 elemental analysis; infra-red spectroscopy; nuclear magnetic resonance
 spectroscopy (nmr); gas-liquid chromatography (Gc); and high performance
 liquid chromatography (HPLC). Temperatures are given in degrees Celsius.
 Under Gc analysis, triphenylphosphine oxide and the complexes comprising
 triphenylphosphine oxide may have the same retention time so that figures
 for percentage triphenylphosphine oxide levels after complexation may
 refer to total triphenylphosphine oxide levels (both free and complexed).

EXAMPLE 1
 A solution of diisopropyl azodicarboxylate (27.2 g, 1.1 eq) in dry
 tetrahydrofuran (40 ml) was added over 45 minutes to a stirred mixture of
 1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (20 g), 4-chlorophenol
 (17.2 g, 1.1 eq), triphenylphosphine (35.2 g, 1.1 eq) and tetrahydrofuran
 (240 ml) under nitrogen at 0-50.degree. C. and then stirred overnight at
 ambient temperature. Water (4 ml, 1.85 eq) was added and the mixture
 heated under reflux for 30 minutes. Magnesium chloride (28 g, 2.5 eq) was
 added and the stirred mixture heated under reflux for 2.5 hours, cooled to
 0.degree. C. and filtered, washing the filter pad with tetrahydrofuran
 (2.times.50 ml). The solvent was removed in vacuo and the residual oil
 triturated with ethyl acetate (300 ml) then diluted with t-butyl methyl
 ether (100 ml. The mixture was filtered and the filter pad washed with a
 3:1 mixture of ethyl acetate and t-butyl methyl ether (2.times.50 ml). The
 filtrate was washed with water (2.times.100 ml), sodium hydroxide (0.5 M,
 2.times.50 ml), brine (50 ml), and dried (MgSO.sub.4). The solvent was
 removed in vacuo to give a residue. This was triturated with propan-2-ol
 (40 ml), left to stand overnight at &lt;50 C., then filtered to give a solid
 (27 g).
 Propan-2-ol (50 ml) was added to the solid and the mixture allowed to stand
 at 0.degree. C. overnight. The mixture was filtered and the solid washed
 with cold (0.degree. C.) propan-2-ol (2.times.10 ml) to give
 7-[1-(4-chlorophenoxy)ethyl 1,2,4-triazolol[1,5-a]pyrimidine (26 g) which
 was analysed for triphenylphosphine oxide content
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 After crystallisation: 0%
 EXAMPLE 2
 Example 1 was repeated but using
 (S)-1-(1,2,4-triazolo[1,5a]-pyrimid-7-yl)ethanol (4.2 g) as starting
 material. After ethyl acetatelt-butyl methyl ether trituration, a crude
 product (10.9 g) was isolated which was triturated with propan-2-ol (10
 ml) at &lt;5.degree. C. for 2 hours; a solid (4.8 g) was isolated by
 filtration, crystallised from propan-2-ol (total volume 8 ml) and the
 crystals washed with propan-2-ol (2.times.1 ml) to give crystals (4.5 g)
 and residue (0.4 g) which were analysed for triphenylphosphine oxide
 content.
 The crystals and residue were recombined and recrystallised from
 propan-2-ol (25 ml) to give residue (2.6 g) and
 (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5a]pyrimidine (2.4 g),
 35%, optical rotation [.alpha.].sub.D =143.degree. (c=1.05, methanol)
 which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 After 1st crystallisation: 0%
 After recrystallisation: 0%
 EXAMPLE 3
 A solution of dilsopropyl azodicarboxylate (6.17 g) in dry tetrahydrofuran
 (10 ml) was added dropwise to a stirred mixture of
 1-(1,2,4-triazolo[1,5a]pyrimidin-7-yl)ethanol (5 g, 30 mmol),
 4-chlorophenol (3.92 g), triphenyiphosphine (8 g) and ethyl acetate (70
 ml) under nitrogen at 0-5.degree. C. and stirred overnight at ambient
 temperature. Magnesium chloride (5.8 g, 2 eq) was added and the stirred
 mixture heated under reflux for 2 hours. t-Butyl methyl ether (50 ml) was
 added and the mixture cooled to 0.degree. C., filtered and the filter pad
 washed with a 6:4 mixture of ethyl acetate and t-butyl methyl ether (100
 ml. The filtrate was washed with water (2.times.100 ml), sodium hydroxide
 solution (1M, 4.times.25 ml), brine (30 ml), dried (MgSO.sub.4) and the
 solvent evaporated to give a solid (13.6 g) which was analysed for
 triphenylphosphine oxide content.
 The solid was recrystallised from propan-2-ol (35 ml) with seeding to yield
 7-[1-(4-chlorophenoxy)ethyl-1,2,4-triazolo]-1,5a]pyrimidine (3.4 g), 43%,
 which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 After complexation: 5.7%
 After crystallisation: 0.49%
 EXAMPLE 4
 A solution of diisopropyl azodicarboxylate (11 g, 1.1 eq) in toluene (20
 ml) was added dropwise to a stirred mixture of
 1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (8.1 g, recrystallised from
 tetrahydrofuran, 49 mmol), 4-chlorophenol (6.35 g, 1 eg),
 triphenylphosphine (12.95 g, 1 eq) and toluene (200 ml) under nitrogen at
 0-5.degree. C. and the mixture then stirred at ambient temperature
 overnight. Magnesium chloride (9.5 g, -.about.2 eq) was added and the
 stirred mixture heated under reflux for 1.5 hours, cooled to -5.degree. C.
 and filtered, washing the filter pad with further toluene (2.times.50 ml).
 ml). The combined filtrate was washed with water (2.times.200 ml), sodium
 hydroxide solution (1M, 2.times.50 ml), and then water (2.times.50 ml) and
 then the solvent evaporated. Propan-2-ol (50 ml) was added to the residue
 and the solvent evaporated; this was repeated. The residue was dissolved
 in propan-2-ol (50 ml), seeded with a crystal of product, and left to
 stand at 0-5.degree. C. for 72 hours. The product was collected by
 filtration, washed with cold propan-2-ol (2.times.20 ml) and dried in
 vacuo to yield 7-[1-(4-chlorophenoxy)ethyl]1,2,4-triazolo[1,5-a]pyrimidine
 (7.1 g, 53%), which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 After crystallisation: 0.4%
 EXAMPLE 5
 A solution of diisopropyl azodicarboxylate (4.47 g, 1.05 eq) in
 tetrahydrofuran (10ml) was added dropwise to a stirred mixture of
 1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (3.45 g),
 triphenylphosphine (5.52 g) and 5'-chloro-2'-hydroxyacetanilide (3.9 g) in
 tetrahydrofuran (100 ml) at 0-5.degree. C. under nitrogen and the mixture
 then stirred at ambient temperature overnight. Water (0.3 ml) was added
 and the stirred mixture heated under reflux for 15 minutes. Magnesium
 chloride (5 g; 2.5 eq) was added and the stirred mixture heated under
 reflux for 2 hours, then cooled to 0.degree. C. and filtered, washing the
 filter pad with tetrahydrofuran (25 ml). The solvent was evaporated, and
 the residue was dissolved in water (100 ml) and ethyl acetate (200 ml).
 The organic layer was washed with water (100 ml), sodium hydroxide (1M,
 2.times.50 ml) and brine (50 ml), then dried (MgSO.sub.4) and the solvent
 evaporated. The residue was dissolved in warm propan-2-ol (45 ml) and
 allowed to crystallise at 5.degree. C. overnight; the crystals formed were
 washed with propan-2-ol (2.times.10 ml) and dried in vacuo to yield
 5'chloro-2'-[1-(1,2,4triazolo[1,5a]pyrimidin-7-yl)ethoxy]acetanilide (4.66
 g), 67% which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by nmr analysis
 After crystallisation: 0%
 EXAMPLE 6
 A solution of diisopropyl azodicarboxylate (12.18 g, 1.1 eq) in toluene (42
 ml) was added dropwise to a stirred mixture of
 1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (8.9 g), triphenylphosphine
 (14.33 g) and 4-chloro-2-nitrophenol (9.5 g, 1 eg) in toluene (140 ml) at
 0-5.degree. C. under nitrogen and the mixture stirred for 1 hour, warmed
 to ambient temperature and then left to stand overnight. The solvent was
 evaporated, and the residue dissolved in tetrahydrofuran (200 ml).
 Magnesium chloride (11 g; 2 eq) was added and the stirred mixture heated
 under reflux for 1.5 hours, cooled to ambient temperature and filtered.
 The filtrate solvent was evaporated and the residue partitioned between
 ethyl acetate (400 ml) and water (200 ml). The organic layer was washed
 with water (200 ml), then sodium hydroxide (1M, 100 ml) and brine (100
 ml), dried (MgSO.sub.4) and the solvent evaporated. The residue was
 triturated with boiling propan-2-ol (200 ml), cooled and filtered to give
 7-[1-(4chloro-2-nitrophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine, (10
 g), 57%, mp 158.degree. C. which was analysed for triphenylphosphine oxide
 content.
 % Triphenylphosphine oxide content by nmr analysis
 After propan-2-ol trituration: 0%
 EXAMPLE 7
 The solvent was evaporated from a mixture of
 (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidne (1 g) and
 triphenylphosphine oxide (1 g) in ethanol (25 ml), then samples were taken
 and evaporated, and the residues were analysed by nmr, Gc, HPLC. The
 mixture was redissolved in ethanol (25 ml), and magnesium chloride (0.7 g,
 .about.2 eq) added. The mixture was stirred for 1 hour then the solvent
 evaporated to give an oil; this was redissolved in ethanol (25 ml,) and
 the solvent evaporated; ethyl acetate (20 ml) was added to the residue,
 then the solvent was evaporated to give a solid. The solid was then
 extracted with a 2:1 mixture of ethyl acetate and petroleum ether (b.p.
 40-60.degree. C.) (2.times.15 ml) and the mixture filtered. Evaporation of
 the filtrate solvent yielded
 (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine (0.55 g)
 as a solid. The filter pad was then washed with ethyl acetate (2.times.10
 ml) and the solvent evaporated to yield further product (0.11 g). The
 product was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 Before complexation: 61.2%
 After complexation: 2.1%
 EXAMPLE 8 - PRODUCTION SCALE
 A reactor was loaded with 4chlorophenol (2.89 kg),
 (S)-1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (3.69 kg),
 triphenylphosphine (5.9 kg) and tetrahydrofuran (69I). The suspension was
 cooled to 5-10.degree. C. and diisopropyl azodicarboxylate (4.79 kg) was
 added over 2 hours. After complete addition of diisopropyl
 azodicarboxylate the solution was stirred while warming to ambient
 temperature. Magnesium chloride (anhydrous; 4.3 kg; .about.2 eq) was added
 and the reaction mixture was heated under reflux for 1 hour. Cooling to
 10.degree. C. yielded a suspension which was collected by filtration. The
 filter pad was washed with tetrahydrofuran (10 I). The mother liquor was
 refilled into the reactor and tetrahydrofuran replaced with toluene by
 distillation of inert diluent (100 I) and addition of toluene (100 I) at
 the same rate. When the inert diluent exchange was complete the solution
 was cooled to ambient temperature and extracted twice with water. The
 organic phase was separated, filtered, then charged to the reaction
 vessel. Toluene (64 I) was distilled off, propan-2ol (128 I) added, and
 the solvent mixture (123 I) was then distilled off. After this solvent
 exchange the reaction mixture was slowly cooled to ambient temperature for
 crystallization of the product. The product was filtered off and washed
 with propan-2-ol (10 I).
 (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine, (2.29
 kg) was isolated after drying in vacuo at 40.degree. C. HPLC-analysis:
 99.92%; chiral HPLC: ee=100%. No triphenylphosphine oxide was detectable
 by HPLC analysis.
 EXAMPLE 9
 A solution of diisopropyl azodicarboxylate (6.18 g, 1.1 eq) in dry
 tetrahydrofuran (11 ml) was added dropwise at 0-5.degree. C. over 1 hour
 to a stirred mixture of 1-(1,2,4-triazolo[1,5-a]pyrmidin-7-yl)ethanol
 (5.008 g), 4-chlorophenol (3.929 g, 1.1 eg), triphenylphosphine (8.021 g,
 1.1 eq) and dry tetrahydrofuran (61 ml) under nitrogen, and then stirred
 overnight at ambient temperature. A sample of the mixture was evaporated
 and the residue was analysed by Gc for triphenylphosphine oxide content.
 A sample (27 ml) of the mixture was taken. Magnesium chloride (1.9 g, 2 eq)
 was added at ambient temperature and stirred overnight. The mixture was
 cooled to 0.degree. C. for one hour then filtered, and the filter pad
 washed with tetrahydrofuran (10 ml). The solvent was removed from the
 filtrate in vacuo. The residue was dissolved in toluene (20 ml) and the
 resulting solution filtered. The filtrate was washed with water (20 ml)
 and the organic layer was separated. The organic solvent was removed in
 vacuo to yield a residue (4.23 g) which was analysed for
 triphenylphosphine oxide content.
 Ice cold propan-2-ol (5 ml) was added to the residue, and the resulting
 mixture was left at 0.degree. C. overnight. The mixture was then filtered,
 and the filter pad washed with ice cold propan-2-ol (2 ml), to yield
 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine (0.81 g; 29%)
 which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis.
 Before complexation: 50.5%
 After complexation: 17.1%
 After propan-2-ol trituration: 0%
 EXAMPLE 10
 A sample (27 ml) of the mixture from the reaction described in example 9
 was taken, and magnesium chloride (1.9 g, 2 eq) was added. The mixture was
 heated under reflux for 30 minutes, then cooled to 0.degree. C. for one
 hour and filtered, and the filter pad washed with tetrahydrofuran (10 ml).
 The solvent was removed from the filtrate in vacuo. The residue was
 extracted with toluene (20 ml) and the resulting mixture filtered. The
 filtrate was washed with water (20 ml) and the organic layer was
 separated. The organic solvent was removed in vacuo to yield a residue
 (3.25 g) which was analysed for triphenylphosphine oxide content.
 Ice cold propan-2-ol (5 EQ was added to the residue, and the resulting
 mixture was left at 0.degree. C. overnight. The mixture was then filtered,
 and the filter pad washed with ice cold propan-2-ol (2 ml), to yield
 7-[1-(4chlorophenoxy)ethyl]1,2,4-triazolo[1,5a]pyrimidine pyrimidine (1.12
 g; 39%) which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation Gc analysis.
 Before complexation: 50.5%
 After complexation: 7.0%
 After propan-2-ol trituration: 0%
 EXAMPLE 11
 A sample (27 ml) of the mixture from the reaction described in example 9
 was taken, and magnesium chloride (0.475 g, 0.5 eq) was added. The mixture
 was heated under reflux for 2.5 hours. The mixture was cooled to 0.degree.
 C. for one hour and then filtered, and the filter pad washed with
 tetrahydrofuran (10 ml). The solvent was removed from the filtrate in
 vacuo. The residue was dissolved in toluene (20 ml) ml) and the resulting
 solution filtered. The filtrate was washed with water (20 ml) and the
 organic layer was separated. The organic solvent was removed in vacuo to
 yield a residue (4.77 g) which was analysed for triphenylphosphine oxide
 content.
 Ice cold propan-2ol (5 ml was added to the residue, and the resulting
 mixture was left at 0.degree. C. overnight. The mixture was then filtered,
 and the filter pad washed with ice cold propan-2-ol (2 ml), to yield
 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5a]pyrimidine (0.91 g; 32%)
 which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation Gc analysis.
 Before complexation: 50.5%
 After complexation: 28.1%
 After propan-2-ol trituration: 0%
 EXAMPLE 12
 A solution of dilsopropyl azodicarboxylate (1.23 g) in dichloromethane (2
 ml) was added dropwise over one hour to a mixture of
 1-(1,2,4-triazolo[1,5a]pyrimidin-7-yl)ethanol (1.01 g), 4-chlorophenol
 (0.78 g), triphenylphosphine (1.61 g) and dichloromethane (12 ml) under
 nitrogen at 0-5.degree. C. and then stirred overnight at ambient
 temperature. Magnesium chloride (1.14 g, 2 eq) was added and the mixture
 heated under reflux for two hours, cooled to 0.degree. C. for 30 minutes
 and filtered, washing the filter pad with dichloromethane. The solvent was
 removed in vacuo, and the residue dissolved in toluene (20 ml). The
 mixture was filtered, water (20 ml) was added and then the organic layer
 was separated. The solvent was removed in vacuo to yield a solid (2.40 g)
 which was analysed for triphenylphosphine oxide content.
 Propan-2-ol (5 ml) was added to the solid and the mixture allowed to stand
 at 0-5.degree. C. for 3 days. The mixture was filtered and the solid
 washed with cold (0.degree. C.) propan-2ol (2 ml) to give
 7-[1-(4chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine (0.361 g; 22%)
 which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 Before complexation: 50.5%
 After complexation: 22.7%
 After propan-2-ol trituration: 0.1%
 EXAMPLE 13
 A solution of diisopropyl azodicarboxylate (6.17 g) in dry tetrahydrofuran
 (7 ml) was added slowly dropwise to a stirred mixture of
 1-(1,2,4-trazolol[1,5-a]pyrimidin-7-yl)ethanol (5 g), 4-chlorophenol (3.92
 g) and triphenylphosphine (8.02 g) in dry tetrahydrofuran (60 ml) under
 nitrogen at 5-10.degree. C. The mixture was stirred for 30 minutes at
 5-10.degree. C. under nitrogen, then the mixture was allowed to warm to
 ambient temperature. The mixture was then stirred at ambient temperature
 for one hour. The solvent was removed in vacuo to yield a residue (23.4 g)
 which was analysed for triphenylphosphine oxide content.
 A sample (2.01 g) of the residue was taken, and zinc chloride (0.38 g, 1.1
 eq) and ethanol (30 ml) were added. The mixture was heated under reflux
 for 30 minutes, then cooled to ambient temperature, filtered and the
 filter pad washed with ethanol (10 ml). The solvent was removed from the
 filtrate in vacuo. Toluene (20 ml) was added to the residue, and the
 mixture was filtered. Water (20 ml) was added and the organic layer
 separated. The solvent was removed in vacuo to yield the residue (1.53 g)
 which was analysed for triphenylphosphine oxide content.
 Propan-2-ol (5 ml) was added to the residue and the mixture allowed to
 stand at 0-5.degree. C. for 3 days. The mixture was filtered and the solid
 collected was washed with cold (0.degree. C.) propan-2-ol (2 ml) to give
 7-[1-(4chlorophenoxy)ethyl]-1,2,4triazolo[1,5-a]pyrimidine (0.132 g; 25%)
 which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 Before complexation: 49.4%
 After complexation: 14.6%
 After propan-2ol trituration: 0%
 EXAMPLE 14
 A sample (2.00 g) of the residue from the Mitsunobu reaction described in
 example 13 was taken, and manganese (II) chloride tetrahydrate (0.55 g,
 1.1 eq) and tetrahydrofuran (30 ml) were added. The mixture was heated
 under reflux for 2 hours, cooled to ambient temperature, filtered and the
 filter pad washed with tetrahydrofuran (10 ml). The solvent was removed
 from the filtrate in vacuo. Toluene (20 ml) was added and the mixture was
 filtered. Water (20 ml) was added to the filtrate. The organic layer was
 separated and the solvent removed in vacuo to yield a residue (0.80 g)
 which was analysed by Gc for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 Before complexation: 49.4%
 After complexation: 28.4%
 EXAMPLE 15
 A sample (2.00 g) of the residue from the Mitsunobu reaction described in
 example 13 was taken, and magnesium chloride mono(ethyl acetate) (0.95 g,
 2 eq) and ethyl acetate (20 ml) were added. The mixture was heated under
 reflux for 2 hours, then cooled to ambient temperature, filtered and the
 filter pad washed with ethyl acetate (10 ml). Water (20 ml) was added and
 the organic layer separated. The solvent was removed in vacuo to yield a
 residue (2.54 g) which was analysed by Gc for triphenylphosphine oxide
 content.
 Propan-2-ol (5 ml) was added to the solid and the mixture allowed to stand
 at 0-5.degree. C. for 3 days. The mixture was filtered and the solid
 washed with cold (0.degree. C.) propan-2-ol (2 ml) to give
 7-[1-(4chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine (0.234 g; 33%)
 which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 Before complexation: 49.4%
 After complexation: 14.9%
 After propan-2-ol trituration: 0.6%
 EXAMPLE 16
 A sample (2.00 g) of the residue from the Mitsunobu reaction described in
 example 13 was taken, and propan-2-ol (5 ml) was added. The mixture was
 allowed to stand at 0-5.degree. C. for 1.5 hours. The mixture was filtered
 and solid washed with cold (0.degree. C.) propan-2-ol (2 ml) to yield a
 solid which was analysed by Gc for triphenylphosphine oxide content.
 Magnesium chloride (0.55 g, 2.2 eq) and tetrahydrofuran (30 ml) were added
 and the mixture heated under reflux for 2 hours. The mixture was cooled to
 0.degree. C. for one hour, filtered and the filter pad washed with
 tetrahydrofuran (10 ml). The solvent was removed in vacuo. Toluene (20 ml)
 was added and the mixture was filtered. Water (20 ml) was added to the
 filtrate, and organic layer was separated. The solvent was removed in
 vacuo to yield a solid (0.56 g) which was analysed by Gc for
 triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 Before trituration: 49.4%
 After propan-2do trituration: 65.0%
 After complexation: 7.7%
 EXAMPLE 17
 A sample (2.00 g) of the residue from the Mitsunobu reaction described in
 example 13 was taken, and tetrahydrofuran (30 ml) and a solution of
 magnesium chloride (0.55 g, 2 eq) in methanol (10 ml) were added to the
 mixture. The mixture was stirred for 2.5 hours at ambient temperature. The
 solvent was removed in vacuo, toluene (70 ml) was added and the mixture
 was filtered. The solvent was removed in vacuo to yield a solid (1.11 g)
 which was analysed by Gc for triphenylphosphine oxide content.
 Propan-2-ol (5 ml) was added to the solid and the mixture allowed to stand
 at 0-5.degree. C. for 3 days. The mixture was filtered and the solid
 washed with cold (0.degree. C.) propan-2-ol (2 ml) to give
 7-[1-(4-chlorophenoxy)ethyl]1,2,4-triazolo[1,5-a]pyrimidine (0.036 g; 5%)
 which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 Before complexation: 49.4%
 After complexation: 25.1%
 After propan-2-ol trituration: 0.2%
 EXAMPLE 18
 A sample (2.00 g) of the residue from the Mitsunobu reaction described in
 example 13 was taken, and zinc iodide (0.89 g, 1.1 eq) and ethanol (30 ml)
 were added. The mixture was heated under reflux for 2 hours, then cooled
 to 0.degree. C. for one hour. The mixture was filtered and the filter pad
 washed with ethanol (10 ml). The solvent was removed in vacuo, toluene (20
 ml) was added to the residue and the mixture was filtered. Water (20 ml)
 was added and the organic layer was separated. The solvent was removed in
 vacuo to yield a solid (1.37 g) which was analysed by Gc for
 triphenylphosphine oxide content.
 Propan-2-ol (5 ml) was added to the solid and the mixture allowed to stand
 at 0-5.degree. C. for 3 days. The mixture was filtered and the solid
 washed with cold (0.degree. C.) propan-2-ol (2 ml) to give
 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolol[1,5-a]pyrimidine (0.291 g)
 which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 Before complexation: 49.4%
 After complexation: 41.8%
 After propan-2-ol trituration: 15.1%
 EXAMPLE 19
 A sample (2.00 g) of the residue from the Mitsunobu reaction described in
 example 13 was taken, and copper (I) chloride (0.28 g, 1.1 eq) and
 tetrahydrofuran (30 ml) were added. The mixture was heated under reflux
 for 2 hours, then cooled to 0.degree. C. for one hour, filtered and the
 filter pad washed with tetrahydrofuran (10 ml). The solvent was removed in
 vacuo, toluene (20 ml) was added and the mixture was filtered. Water (20
 ml) was added and the organic layer was separated and dried over magnesium
 sulphate. The organic solvent was removed in vacuo to yield a solid (1.38
 g) which was analysed by Gc for triphenylphosphine oxide content.
 Propan-2-ol (5 ml) was added to the solid and the mixture allowed to stand
 at 0-5.degree. C. for three days. The mixture was filtered and the solid
 washed with cold (0.degree. C.) propan-2-ol (2 ml) to give 7-[1
 -(4chlorophenoxy)ethyl]-1,2,4triazolo[1,5-a]pyrimidine (0.442 g; 63%)
 which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 Before complexation: 49.4%
 After complexation: 43.6%
 After propan-2-ol trituration: 0.2%
 EXAMPLE 20
 A sample (2.00 g) of the residue from the Mitsunobu reaction described in
 example 13 was taken, and iron (III) chloride (0.45 g, 1.1 eq) and
 tetrahydrofuran (30 ml) were added. The mixture was heated under reflux
 for 2 hours, cooled to 0.degree. C. for one hour, filtered and the filter
 pad washed with tetrahydrofuran (10 ml). Toluene (20 ml) was added to the
 filtrate and the mixture was filtered. Water (20 ml) was added to the
 filtrate and organic layer was separated. The organic layer was dried over
 magnesium sulphate, and the solvent removed in vacuo to yield a solid
 (1.08 g) which was analysed by Gc for triphenylphosphine oxide content.
 Propan-2-ol (5 ml) was added to the solid and the mixture allowed to stand
 at 0-5.degree. C. for 3 days. The mixture was filtered and the solid
 washed with cold (0.degree. C.) propan-2-ol (2 ml) to give
 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine (0.186 g;
 27%) which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 Before complexation: 49.4%
 After complexation: 36.5%
 After propan-2-ol trituration: 0.8%
 EXAMPLE 21
 Diethyl azodicarboxylate (1.06 g) in tetrahydrofuran (2 ml) was added
 dropwise over 1 hour to a mixture of
 1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (1.00 g), 4-chlorophenol
 (0.78 g), triphenylphosphine (1.62 g) and tetrahydrofuran (12 ml) which
 was stirred under nitrogen at 0-5.degree. C. The mixture was allowed to
 stand overnight at ambient temperature. Magnesium chloride (1.14 g, 2 eq)
 was added, and the mixture was heated under reflux for 2 hours then cooled
 to 0.degree. C. for one hour. The mixture was littered and the filter pad
 washed with tetrahydrofuran (10 ml). The solvent was removed from the
 filtrate in vacuo. Toluene (20 ml) was added and the mature was filtered.
 Water (20 ml) was added to the filtrate and the organic layer was
 separated. The solvent was removed in vacuo to yield a solid (1.16 g)
 which was analysed by Gc for triphenyiphosphine oxide content.
 Propan-2-ol (5 ml) was added to the solid and the mixture allowed to stand
 at 0-5.degree. C. for 3 days. The mixture was filtered and the solid
 washed with cold (0.degree. C.) propan-2-ol (2 ml) to give
 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5a]pyrimidine (0.61 g; 36%)
 which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 Before complexation: 50.5%
 After complexation: 9.5%
 After propan-2-ol trituration: 0.2%
 EXAMPLE 22
 A sample (2.00 g) of the residue from the Mitsunobu reaction described in
 example 13 was taken, and tetrahydrofuran (30 ml) and magnesium chloride
 hexahydrate (1.04 g, 2 eq) were added. The mixture was heated under reflux
 for 2 hours, then cooled to 0.degree. C. for one hour and filtered, and
 the filter pad washed with tetrahydrofuran (10 ml). The solvent was
 removed in vacuo, toluene (20 ml) was added and the mixture was filtered.
 Water (20 ml) was added to the filtrate and the organic layer was
 separated. The solvent was removed in vacuo to yield a solid (0.95 g)
 which was analysed by Gc for triphenylphosphine oxide content.
 Propan-2-ol (5 ml) was added to the solid and the mixture allowed to stand
 at 0-5.degree. C. for 3 days. The mixture was filtered and the solid
 washed with cold (0.degree. C.) propan-2-ol (2 ml) to give
 7-[1-(4chlorophenoxy)ethyl]-1,2,4-triazolo[1,5a]pyrimidine (0.153 g; 22%)
 which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 Before complexation: 49.4%
 After complexation: 27.4%
 After propan-2-ol trituration: 0.35%:
 EXAMPLE 23
 A sample (2.00 g) of the residue from the Mitsunobu reaction described in
 example 13 was taken, and tetrahydrofuran (30 ml) and samarium (III)
 chloride (1.31 g, 2 eg) were added. The mixture was heated under reflux
 for 2 hours, then cooled to 0.degree. C. for 2 hours, filtered and the
 filter pad washed with tetrahydrofuran (10 ml). The solvent was removed in
 vacuo, toluene (20 ml) added and the mixture was filtered. Water (20 ml)
 was added and the organic layer was separated. The solvent was removed in
 vacuo to yield a solid (0.1 g) which was analysed for triphenylphosphine
 oxide content.
 % Triphenylphosphine oxide content by normnalisation by Gc analysis
 Before complexation: 49.4%
 After complexation: 2.0%
 EXAMPLE 24
 A solution of diisopropyl azodicarboxylate (1.23 g) in tetrahydrofuran (2
 ml) was added over 10 minutes to a stirred mixture of 4-chlorophenol (0.78
 g), triphenylphosphine (1.62 g) and tetrahydrofuran (12 ml) under nitrogen
 at 0-5.degree. C. Magnesium chloride (1.14 g, 2 eq) and
 1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (1.00 g) were added and the
 mixture was stirred under nitrogen at ambient temperature overnight The
 mixture was heated under reflux for 2 hours, then allowed to cool to
 0.degree. C. for one hour, filtered and the filter pad washed with
 tetrahydrofuran (10 ml). The solvent was removed in vacuo. Toluene (20 ml)
 was added to the residue and the mixture was filtered. Water (20 ml) was
 added and the organic layer was separated. The solvent was removed in
 vacuo to yield a solid (2.06 g) which was analysed by Gc for
 triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 After complexation: 34.7%
 EXAMPLE 25 - LAB SCALE SYNTHESIS WHICH IS SCALABLE TO PRODUCTION SCALE
 The reactor was loaded with 4-chlorophenol (58.5 g),
 (S)1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (50 g),
 triphenylphosphine (85 g) and toluene (900 ml). The suspension was cooled
 to 5-10.degree. C. and diisopropyl azodicarboxylate (65 ml) was added over
 2 hours. After complete addition of diisopropyl azodicarboxylate the
 solution was stirred while warming to ambient temperature. The reaction
 mixture was re-cooled to 0.degree. C. and filtered. The filtrate,
 magnesium chloride (anhydrous; 31.1 g) and celite (25.5 g) were combined
 in the reactor. Toluene (500 ml) was distilled off and the remaining
 mixture was cooled to 0.degree. C. The suspension formed was removed by
 filtration. Further magnesium chloride (2.6 g) and celite (2.5 g) were
 added to the filtrate. Toluene (200 ml) was removed by distillation. The
 residue was cooled to 0.degree. C. and filtered. The filtercake was washed
 with toluene. The reactor was loaded with the filtrate, and toluene was
 removed by azeotropic distillation with propan-2-ol. The product
 crystallised from propan-2-ol at 40.degree. C. while cooling to 20.degree.
 C. The product was collected by filtration and washed with propan-2-ol.
 After drying, the product
 (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine (61.1 g)
 was obtained (yield: 73.6%; HPLC analysis: 99.1%; chiral HPLC: ee=100%).
 No triphenylphosphine oxide was detectable by HPLC analysis.
 Comparative Example 1
 This experiment was conducted to compare the effect of trituration with
 propan-2-ol on a mixture, comprising desired product, triphenylphosphine
 oxide and dihydro-diisopropyl azodicarboxylate, which either has or has
 not been subjected to the addition of a metal salt.
 A mixture of 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine
 (0.274), triphenylphosphine oxide (0.19 g) and dihydro-diisopropyl
 azodicarboxylate (0.32 g) [29%, 28% and 17.2% by normalisation by Gc
 analysis respectively] was triturated with propan-2-ol (2 ml) and cooled
 to 0.degree. C. for three hours. The mixture was filtered, and the filter
 pad washed with ice cold propan-2-ol (2 ml), to yield
 7-[1-(4-chlorophenoxy)ethyl]-1,2,4triazolo[1,5-a]pyrimidine (0.269 g)
 which was analysed for triphenylphosphine oxide content.
 % Triphenylphosphine oxide content by normalisation by Gc analysis
 Before propan-2-ol trituration: 28%
 After propan-2-ol trituration: 9.1%
 Although the percentage of triphenylphosphine oxide in the sample has been
 reduced by the trituration process, there is still 9.1% present. This can
 be compared with the result seen in example 11, where the percentage
 triphenylphosphine oxide after complexation with magnesium chloride was
 28.1% which reduced to 0% after trituration with propan-2-ol. It is thus
 apparent that greater triphenylphosphine oxide removal can be achieved in
 a mixture which has been subjected to the addition of a metal salt than in
 one which has not.
 Comparative Example 2
 A series of ten laboratory scale reactions in which diethyl
 azodicarboxylate was added at 3-6.degree. C. to a mixture of
 triphenylphosphine, 4-chlorophenol, and
 (S)-1-(1,2,4-triazolol[1,5-a]pyrimidin-7-yl)ethanol in tetrahydrofuran was
 carried out. The mixtures were stirred at ambient temperature for 3-4
 hours, then the product obtained by standard work-up procedures.
 The standard work-up procedures comprised removing the solvent and
 dissolving the residue in diethyl ether, washing with aqueous sodium
 hydroxide, water, and saturated brine, drying over magnesium sulphate and
 removing the solvent; triturating the residue with diethyl ether and
 removing the solid; passing the filtrate through a silica gel pad using
 diethyl ether as eluant; combining the relevant fractions and removing the
 solvent to yield a residue which was analysed by HPLC; combining samples
 still containing triphenylphosphine oxide and further purifying by
 recrystallisations, passing through silica gel pads using diethyl ether as
 eluant, and/or hot filtering with propan-2-ol. A sample of
 (R-7-[1-(4chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine (165.5 g),
 in which no triphenylphosphine oxide was detectable, was obtained.
 It is evident from the above details that many manipulations were required
 before the triphenylphosphine oxide could be adequately removed to yield
 pure product. Such elaborate procedures are not suitable for scaling up to
 industrial scale syntheses. This can be compared with example 8 where an
 industrial scale synthesis is described in which the addition of magnesium
 chloride after the main reaction is complete reduces the number of
 manipulations required to obtain pure product. A similar comparison may be
 made with example 25. These comparisons illustrate the advantage of the
 present invention.