W097/36903 (Glaxo Group Limited) discloses pyrrolopyrrolone derivatives, which are inhibitors of human neutrophil elastase. Neutrophil elastase has a wide spectrum of activities in the body, for example, within the lung the enzyme increases mucus production and changes the cellular composition of the epithelium. The enzyme also causes vascular permeability changes within the microcirculation of many tissues and it is a potent destructive agent against a number of connective tissue components. Therefore, pyrrolopyrrolone derivatives are of potential therapeutic benefit in the treatment and amelioration of symptoms of diseases where elastase activity is implicated, such as chronic obstructive pulmonary disease, chronic bronchitis and asthma.

Certain oxazole pyrrolopyrolone derivatives are described in W099/12933; the compound (3S, 3aS, 6aR)-3-isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1- ylmethyl-oxazole-4-carbonyl)-hexahydro-pyrrolo [3,2-b] pyrrol-2-one or a pharmaceutically acceptable salts thereof (e. g. the hydrochloride) is of particular interest.

An important intermediate in the preparation of (3S, 3aS, 6aR)-3-isopropyl-1- methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl-oxazole-4-carbonyl)-hexahydro- pyrrolo [3,2-b] pyrrol-2-one is 2-pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid and carboxylic acid esters and alternatively salts thereof. In turn, an important intermediate in the preparation of the latter compound is 2- (bromomethyl) oxazole-4-carboxylic acid methyl ester and other corresponding halogen derivatives such as the chloro derivative and other esters (such as C, _salkyl esters). According to the invention we provide a novel process for the preparation of a compound of formula I

or a salt thereof or a carboxylic acid ester derivative thereof, wherein L represents a leaving group, which comprises (a) treating a compound of formula 11 wherein R represents COOH or a salt thereof or a derivative thereof and L and L'represent leaving groups with a base such that L'is eliminated and the oxazole ring is formed; and (b) if necessary converting the R moiety to COOH or a salt thereof or a carboxylic acid ester derivative thereof.

Examples of derivatives of carboxylic acid compounds of formula 11 include compounds wherein R represents: CN, a carboxylic acid amide, a carboxylic acid ester or a carboxylic acid thioester.

Preferably R represents a carboxylic acid amide or carboxylic acid ester<BR> particularly COOCH2Ph or a carboxylic acid alkyl ester e. g. COOC, 4 alkyl. Most preferably R represents COOCH3 or COOCH2CH3.

In step (b) conversion processes will be well known to a person skilled in the art e. g. CN and carboxylic acid esters may be converted to COOH by acid catalysed hydrolysis and amides and carboxylic acid thioesters may be converted into COOH by base catalyse hydrolysis. Carboxylic acid esters may be formed from COOH by treatment with an alcohol under conditions of acid or base catalysis.

L preferably represents halogen, more preferably Br or Cl, especially Cl. L' preferably represents halogen, more preferably Br or Cl, especially Cl In one particular embodiment of the invention we provide a nove ! process for the preparation of a compound of formula I or a salt thereof or a carboxylic acid ester derivative thereof, wherein L represents a leaving group, which comprises: (a) treating a compound of formula 11

wherein R represents COOH or a salt thereof or a derivative thereof and L and L'represent leaving groups with a base such that L'is eliminated and the oxazoie ring is formed in a one stage process (without need to isolate the intermediates); and (b) if necessary converting the R moiety to COOH or a salt thereof or a carboxylic acid ester derivative thereof.

Bases that are weak nucleophiles and/or sterically hindered especially tertiary amines are especially suitable for treating the compound of formula 11 in this particular embodiment of the invention.

The preferred base for this embodiment of the invention is diisopropylethylamine (Hunigs base). Typical conditions comprising adding the base in the presence of an inert solvent such as DCM and heating eg to around 50° C for 4-8 hours.

The compound of formula I may be obtained by neutralising the solution and extracting the product into an organic solvent eg. DCM.

In this embodiment of the invention, preferably R represents COOCH2CH3.

In a second particular embodiment of the invention we provide a novel process for the preparation of the compound of formula) or a salt thereof or a carboxylic acid ester derivative thereof which comprises (a) treating a compound of formula 11 with a base together with a nucleophile; (b) eliminating the nucleophile; and

(c) if necessary converting the R moiety to COOH or a salt thereof or a carboxylic acid ester derivative thereof.

In this embodiment preferably R represents COOCH3.

Most particularly according to this second particular embodiment we provide a process for the preparation of a compound of formula I or a carboxylic acid ester derivative thereof, wherein L represents a leaving group, which comprises: (a) treating a compound of formula 11 in the form of a carboxylic acid ester, wherein L and L'represent leaving groups, with a nucleophile; and (b) eliminating the nucleophile.

We prefer to use the compound of formula 11 as an alkyl ester e. g. C, alkyl ester or a benzyl ester, particularly the methyl or ethyl ester, especially the methyl ester.

The nucleophile is preferably an oxygen or a nitrogen nucleophile.

Where the nucleophile is an oxygen nucleophile examples include alcohols e. g.

C1 6alkyl alcohols especially ethanol or methanol particularly methanol. When the nucleophile is an alcohol, particularly suitable bases include carbonates (e. g. potassium carbonate or sodium carbonate) particularly potassium carbonate.

Other examples of oxygen nucleophiles include alkoxides e. g. C16alkoxides (such as potassium or sodium alkoxides) especially ethoxide or methoxide (particularly methoxide, e. g. sodium methoxide). When the oxygen nucleophile is alkoxide, alkoxide may also suitably act as the base.

Suitable bases include alkoxides (e. g. C, 6alkoxides such as potassium or sodium alkoxides, especially ethoxide or methoxide), carbonates (e. g. sodium or potassium carbonate), hydroxides (such as sodium or potassium hydroxide) and amines (e. g. primary amines such as ethylamine, secondary amines such as pyrrolidine and tertiary amines such as diisopropylethylamine alternatively triethylamine).

Where the nucleophile is a nitrogen nucleophile examples include primary amines (such as ethylamine) and secondary amines (e. g. pyrrolidine). When the nucleophile is a nitrogen nucleophile, the nitrogen nucleophile may suitably act as the base.

Particularly preferred conditions are those in which the base is methoxide and the nucleophile is methanol or methoxide.

In the second embodiment preferably step (a) is performed in the presence of a proton source.

When a proton source is provided it may suitably be an alcohol (e. g. a C, 6 alcohol especially ethanol or methanol) or a primary amine (such as ethylamine) or a secondary amine (e. g. pyrrolidine). When the nucleophile is an alkoxide or an alcool, the proton source will preferably be the corresponding or same alcool. When the nucleophile is a nitrogen nucleophile such as a primary or secondary amine the proton source will preferably be the conjugate acid of the same amine.

The reaction may be performed by combining the reagents suitably between 0°C and ambient temperature. An inert solvent such as THF or DCM may also suitably be included, particularly in the absence of an alcohol proton source such as when the nucleophile is a nitrogen nucleophile.

In step (b), elimination will suitably be performed by reflux in a high boiling solvent in the presence of an acid. Suitable solvents include xylene, benzene and toluene especially toluene. Suitable acids include camphor sulphonic acid and toluene sulphonic acid, especially toluene sulphonic acid.

A principal advantage of the process of the invention is that it achieves oxidation of an oxazoline ring to an oxazole ring in a very convenient and efficient manner. More particularly, according to the invention, this transformation may be performed without the need for use of any oxidising agents (which may be environmentally damaging, costly and inefficient). Further advantages include

the fact that the process uses high efficiency and low cost steps. The first embodiment of the invention has the addition advantage that the transformation is achieved in a single stage.

As a further aspect of the invention we provide a process for preparation of a compound of formula I or a salt thereof or a carboxylic acid ester derivative thereof (e. g. a C, 6 alkyl ester thereof) which further comprises the steps of converting it to 2-pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid or a salt thereof or a carboxylic acid ester thereof (e. g. a C, 6 alkyl ester, but preferably the free acid or a salt thereof). Examples of salts thereof include metal salts such as the sodium and potassium salts.

One example process for converting the compound of formula I or a salt thereof or a carboxylic acid ester derivative thereof to 2-pyrrolidin-1-ylmethyl-oxazole-4- carboxylic acid or a salt thereof or a carboxylic acid ester thereof comprises treating it with pyrrolidine in an inert solvent (e. g. DCM or toluene) or alternatively, an alcohol at a temperature suitably between 0°C and ambient or preferably between 0°C and reflux. The compound of formula I is preferably used as a carboxylic ester derivative (e. g. a C, alkyl ester, especially the methyl or ethyl ester). We have found that use of the ethyl ester is particularly satisfactory since this gives a more efficient conversion on treatment with pyrrolidine than other derivatives.

As a further aspect of the invention we provide a process for preparation of a compound of formula I or a salt thereof or a carboxylic acid ester derivative thereof which further comprises the steps of converting it to (3S, 3aS, 6aR)-3- isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl-oxazole-4-carbonyl)- hexahydro-pyrrolo [3,2-b] pyrrol-2-one or a pharmaceutically acceptable salt thereof.

One example process for converting the compound of formula I or a salt thereof or a carboxylic acid ester derivative thereof to (3S, 3aS, 6aR)-3-isopropyl-1- methanesulfonyl4-(2-pyrrolidin-1-ylmethyl-oxazole4-carbonyl) -hexahydro- pyrrolo [3,2-b] pyrrol-2-one or a pharmaceutically acceptable salt thereof comprises preparing 2-pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid or a salt thereof or a carboxylic acid ester thereof e. g. as previously described and then treating this compound as the free acid with (3aS, 6aR)-3-isopropyl-1- methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one under conventional conditions. Typically these include combining the reagents with a coupling agent such as 1- (3-N, N-dimethylaminopropyl)-3-ethylcarbodiimide, preferably also in the presence of 1-hydroxybenzotriazole (HOBT), and an inert solvent such as DMF, MeCN or THF at a temperature suitably between 0 °C and ambient.

Whilst the above example process is satisfactory we have found that a much more satisfactory process involves use in the process of the potassium salt of 2- pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid which as mentioned above can be isolated in highly crystalline form which means that it may be isolated in higher yield. We claim the potassium salt of 2-pyrrolidin-1-ylmethyl-oxazole-4- carboxylic acid as a further aspect of the invention. A preferred preparation of 2-pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid potassium salt comprises preparing methyl 2-(pyrrolidin-1-ylmethyl)-1, 3-oxazole4-carboxylate maleate salt (a crystalline material which facilitates the isolation of the said ester in a subtantially pure form) and converting it to the 2-pyrrolidin-1-ylmethyl-oxazole-4- carboxylic acid potassium salt by treatment with potassium carbonate followed by potassium hydroxide. Alternatively the process can involve use of ethyl 2- (pyrrolidin-1-ylmethyl)-1, 3-oxazole-4-carboxylate maleate salt to form the required potassium salt.

Due to the relative insolubility of this substance in organic solvents we find that the process conditions of the reaction with (3aS, 6aR)-3-isopropyl-1- methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one just described can advantageously be modified to incorporate the step of solubilising the potassium salt of 2-pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid with a lipophilic organic acid in the solvent prior to treatment with (3aS, 6aR)-3-isopropyl-1- methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one. Examples of lipophilic organic acids include toluene sulphonic acid and camphor sulphonic acid and we prefer to use camphor sulphonic acid. By use of such a lipophilic organic acid the conversion to product is achieved with higher efficiency than in its absence.

A preparation of (3S, 3aS, 6aR)-3-isopropyl-1-methanesulfonyl- hexahydropyrrolo [3,2-b] pyrrol-2-one is described as Intermediate 122 in International Patent Application W097/36903.

Compounds of formula 11 in the form of the methyl ester wherein Hal and Hal' represent chlorine may be prepared following Scheme 1: Scheme 1 Step (a) This step may be performed by reaction of the initial compound with sodium methoxide in methanol at low temperature, e. g. around-10 °C (i. e. acetone/ice or salt/ice bath).

Step (b) This step may be performed by combining the reagents in a polar protic solvent, such as methanol, typically at a temperature of around 0 °C. If it should be desired to produce the ethyl ester of the compound of formula 1, then the serine ethyl ester should be used in this reaction. The preferred solvent in this case is methanol also.

The serine ester intermediate used in this step may be in the form of a single enantiomer or a racemic mixture whichever is the most commercially advantageous.

Other compounds of formula 11 may be prepared by analogous methods.

Examples Example 1 (a) Methyl 2,2-dichloroethanimidoate A solution of sodium methoxide (25% w/w in MeOH) (17.1ml) was added to a solution of dichloroacetonitriie (60ml) in methanol (350ml) at-10°C under nitrogen. Stirring took place for 45 minutes at-10°C.

A small aliquot was taken, concentrated in vacuo and analyse by'H n. m. r. This sample showed conversion of dichloroacetonitrile to the title compound. <BR> <BR> <BR> <P> 'H n. m. r. spectroscopy-8H (CDC ! g) 3.88 (3H, s, OCH3), 5.96 (1 H, s, CHCL,), 8.15 (1 H, br s, NH)

(b) Methyl 2- (dichloromethyl)-4, 5-dihydro-1, 3-oxazole-4-carboxylate DL-Serine methyl ester hydrochloride (116g) was added to the mixture following step (a) and the solution allowed to stir gradually warming to room temperature overnight. Dichloromethane (1000ml) was added and the mixture washed with water (350ml) followed by brine (300moi). The organic mixture was concentrated in vacuo to leave an orange oil of the title compound (138.84g). Mass spectrometry-MH+ (calc.) 212, MH+ (obs.) 212 (c) Methyl 2- (chloromethyl)-4-methoxy-4, 5-dihydro-1, 3-oxazole-4-carboxylate To oxazoline product of step (b) (138.4g) in methanol (500mut) at 0°C under nitrogen was added a solution of sodium methoxide (25% w/w in MeOH) (149.7ml) over 30 minutes maintaining the interna temperature of the reaction vessel between 0°C and 10°C. The solution turned pink and a solid precipitate formed. The reaction mixture was stirred, gradually warming to room temperature overnight. The mixture was diluted with dichloromethane (1000ml) and washed with water (500ml) followed by brine (500moi). The organic mixture was concentrated in vacuo to give the title compound (127.08g) Mass spectrometry-MH+ (calc.) 208, MH+ (obs.) 208 (d) Methyl 2- (chloromethyl)-1, 3-oxazole-4-carboxylate The product of step (c) (127.08g) was redissolved in toluene (500ml). Tosic acid monohydrate (10g) was azeotropically dried by slurrying in toluene (100ml) and concentrating in vacuo. The azeotropically dried tosic acid was added to the solution of the product of step (c). The solution was heated to reflux for 30 minutes and cooled to room temperature. The toluene mixture was washed with potassium carbonate solution (500ml, 5% w/v solution) followed by water (200ml) then brine (500mut). The organic solution was concentrated in vacuo to give the title compound (95.47g). Mass spectrometry-MH+ (calc.) 176, MH+ (obs.) 176

Example 2 Preparation of Methyl 2- (pyrrolidin-1-ylmethyl)-1, 3-oxazole-4-carboxylate To Example 1 (d) (95.47g) in toluene (450ml) was added, at 0°C under nitrogen, pyrrolidine (72.12ml). The mixture was allowed to stir, gradually warming to room temperature, overnight. The mixture was extracted with citric acid (500moi, 20% w/v solution) and water (200moi). The combined aqueous extracts were washed with ethyl acetate (100ml). Ethyl acetate (500ml) was added to the aqueous extracts and the aqueous layer basified by the addition of potassium carbonate (216g). The ethyl acetate extracts were separated and the aqueous phase further extracted with ethyl acetate (100ml). The combined organic extracts were washed with brine (200moi) and concentrated in vacuo to give the title compound (87.01g).

Mass spectrometry-MH+ (ca/c.) 211, MH+ (obs.) 211 Example 3 Preparation of 2-Pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid potassium salt (a) Methyl 2, 2-dichloroethaneimidoate Under nitrogen to DCM (495mi) and MeOH (55mi) is added NaOMe in MeOH (1.61ml, 25% w/w solution). The mixture is cooled to-5°C. Dichloroacetonitrile (75g) is added dropwise over ca 45 min. The mixture is stirred for 60 min at 0°C.

(b) Ethyl2- (dichloromethyl)-4, 5-dihydro-1, 3-oxazole-4-carboxylate Serine ethyl ester HCI is added (115.3g) to the product of step (a) and the mixture stirred overnight at 20°C. Water (275ml) is added, the mixture stirred and the DCM layer separated. The aqueous phase is back extracted with DCM (275mi). The combined DCM layers are concentrated to 350moi.

(c) Ethyl 2-(chloromethyl)-1, 3-oxazole4-carboxylate Hunigs base (178ml) is added to the product of step (b) and the mixture heated to ca 50°C for ca 5 hours. The mixture is cooled to 20°C and stirred overnight. DCM (440ml) is added and the mixture cooled to ca 5°C. HCI (2M, 500moi) is added cautiously. The DCM layer is separate and washed with water (250moi).

The mixture is concentrated to 600ml then cooled to 15°C.

(d) Ethyl 2-(pyrrolidin-1ylmethyl)-1, 3-oxazole4-carboxylate Pyrrolidine (113. 4mol) is added to the product of step (c) over 10 minutes and the mixture heated to reflux for 30 minutes. The mixture is chilled to-5°C and stored overnight. The temperature is adjusted to 20°C and K2CO3 (10% w/v, 1000ml) added. The DCM layer is separated, washed with water (200ml) and concentrated at atmospheric pressure to ca 350ml then IPA (300ml) added.

The mixture is further concentrated at atmospheric pressure to 350ml then cooled to 0°C.

(e) Ethyl 2- (pyrrolidin-1-ylmethyl)-1, 3-oxazole-4-carboxylate Maleate salt Maleic acid (78.9g) is added to the product of step (d) as a solution in IPA (400ml) over ca 5 minutes and the resulting precipitate stirred at 0°C-4°C for a further 30 minutes. The solid is filtered at suction and washed with chilled (0°C) IPA (200ml). The filter cake is dried at 50°C in vacuo to give maleate salt (1: 1 stoichiometry of free base and maleic acid) (170.7g, 74% th) as a pale yellow crystalline solid.

(f) 2-Pyrrolidin-1-ylmethyl-oxazole4-carboxylic acid potassium salt Maleate salt (20g) was slurried in DCM (100ml) at 20°C under nitrogen. K2CO3 (100ml, 10% w/v) was added to the product of step (e) dropwise over ca 20 minutes. The DCM layer was separated and washed with water (100ml) then concentrated at atmospheric pressure to 40ml. The solution was cooled to ca

30°C. IMS (100ml) was added and distillation continued at atmospheric pressure to ca 40moi. The solution was cooled to 20°C.

Potassium hydroxide pellets (4.3g, 85% w/w) were dissolved in IMS (40ml). The potassium hydroxide solution was added to the solution of free base ester over <BR> <BR> <BR> <BR> <BR> ca 15 minutes and the solution allowed to stir at ca 20°C overnight. The solution<BR> <BR> <BR> <BR> <BR> <BR> was concentrated to ca 40ml. Acetone (60ml) was added and the slurry stirred at 0°C for 30 minutes then filtered at suction. The solid was washed with chilled (0°C) acetone (40ml) and dried at ca 50°C in vacuo overnight to give title compound (12.41g, 90% th) as a white powder.

Example 4 Preparation of (3S, 3aS, 6aR)-3-Isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1- ylmethyl-oxazole-4-carbonyl)-hexahydro-pyrrolo [3,2-b] pyrrol-2-one hydrochloride (a) 2-Pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid A solution of the compound formed in Example 2 above (22mg) in dioxan (1.5mi) and 1.0M sodium hydroxide (0.3mi) was stirred for 5. Oh. The solution was neutralised (pH ca 7) by the dropwise addition of 2.0M hydrochloric acid.

The solvents were removed in vacuo and the solid residue was dried further in vacuo to give a mixture of the title compound and sodium chloride as a pale yellow solid (40mg). Mass spec MH+ (found) = 197. MH+ (calculated) = 197.

(b) 2-Pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid potassium salt Potassium carbonate (14.8g) was added to a solution of the ethyl ester analogue of the methyl ester in compound formed by step (a) above (24.0g) in ethanol (150m1) and water (150ml). The reaction mixture was refluxed with stirring for 4 hours. The solvent was removed in vacuo. The orange/brown residue was azeotroped with toluene (x3) and then dried in vacuo. The solid

obtained was stirred vigorously with ether (100moi) and filtered off before drying in vacuo to give a mixture of the title compound and potassium bicarbonate as a brown solid (34.5g). This material was used without further purification.

(c) (3S, 3aS, 6aR)-3-Isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl- oxazole-4-carbonyl)-hexahydro-pyrrolo [3,2-b] pyrrol-2-one hydrochloride The compound formed by step (b) above (or alternatively from Example 3) (32.2g) was added rapidly to a stirred solution of 1-hydroxybenzotriazole (13.0g) in acetonitrile (350ml). A solution of (3S, 3aS, 6aR)-3-isopropyl-1- methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one (Intermediate 122 from International Patent Application W097/36903) (21.7g) and 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (37.0g) in acetonitrile (70ml) was then added and the reaction mixture was stirred for 20 hours. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (900mut) and 1.0M sodium carbonate solution (600ml). The aqueous phase was separated and extracted with dichloromethane (150ml).

The combined organics were washed with brine (250mut), dried (MgSO4) and concentrated in vacuo to leave a brown solid. The solid was purified by flash column chromatography (Merck 9385 silica; eluent dichloromethane: ethanol: ammonia 150: 8: 1 to 135: 8: 1) to give a cream solid (29.3g). The solid was dissolved in dichloromethane (150mi) and treated with 1.0M hydrogen chloride in ether (75ml). The solvent was removed in vacuo to leave a solid that was again dissolved in dichloromethane (150moi) and treated with 1.0M hydrogen chloride in ether (75ml). The solvent was removed in vacuo to leave a solid which was recrystallised from acetone to give the title compound (26.3g) as a white solid. Melting point 156-158°C. T. I. C. (Silica; dichloromethane: ethanol: ammonia 100: 8: 1; double elution) Rf = 0.66.

'H NMR (400 MHz; D-6 DMSO): d 8.78 (s, 1H), 4.68 (s, 2H), 4.13 (ddd, J= 11,11,7 Hz, 1H), 4.08 (dd, J=11,10 Hz, 1H), 3.80 (ddd, J=12,10.5,5.5 Hz, 1H), 3.60 (m, 2H), 3.55 (dd, J=12,10.5 Hz, 1H), 3.31 (s, 3H), 3.20 (m, 2H), 3.03 (dd, J=12,2.5 Hz, 1H), 2.88 (md, J=2.5 Hz, 1H), 2.34 (m, 1H), 2.12 (m, 1H), 1.96 (m, 4H), 1.19 (d, J=7 Hz, 3H), 0.98 (d, J=7 Hz, 3H). Contains 0.16 Mol. % acetone.

Infra-red (KBr diffuse reflectance) 3633,3474,3149,3102,2956,2882,2668, 1634,1567,1442,1380,1347,1161,1146,967, 810,547 cm-'.

Mass spec MH+ (found) = 425.186372. MH+ (calculated) = 425.185867 (error 1.2ppm).

Combustion analysis.

Found: C, 48.65; H, 6.39; N, 11.41; S, 6.19; Cl, 7.13%.

C19H28N4OsS. HCI. 0. 75H2O. 0. 2Me2CO requires: C, 48.43; H, 6.57; N, 11.53; S, 6.60; Cl, 7.29%.

Throughout the specification and the claims which follow, unless the context requires otherwise, the word'comprise', and variations such as'comprises'and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.