IE46662B1 - Erythromycin a intermediates - Google Patents

Description

This invention relates to certain novel erythromycins and to processes for their preparation. The erythromycins are useful intermediates in the preparation of certain 4-deoxy-4-amino-erythro mycin A antibacterial agents as described in Patent Specification No. 46661.

Erythromycin is an antibiotic formed during the culturing of a strain of Streptomyces erythreus in a suitable medium as taught in U.S. Patent No. 2,653,899. Erythromycin, which is produced in two forms, A and B, is represented by the following structurej ' Erythromycin R A -OH Β -H The structure reveals that the antibiotic is comprised of three 15 main portions: a sugar fragment known as cladinose, a second sugar moiety containing a basic amino substituent known as desosamine and a fourteen membered lactone ring referred to as erythronolide A or B - 3 or, as herein described, tlie macrolide ring. While fhe numbering system of the macrolide ring is in unpriced iini'ibers, that of the dvKos.-niiino is in primed numbers and that of rl.idinose in doublepi lined numbers. thiiueroiiii del ivat ives of erythromycin have been prepared in an effort lo modify its biological or pharmacodynamic properties.

U.S. Patent No. 3,417,077 describes the reaction product of erythromycin and ethylene carbonate as a very active antibacterial agent. U.S. Patent No. 3,884,903 discloses 4-deoxy-4-oxoerythromycin Λ and B derivatives as being useful as antibiotics.

Erythromycylamine, the 9-amino derivative of erythromycin A, has been the subject of considerable investigation (British Patent No. 1,100,504, Tetrahedron Letters, 1645 (1967) and Croatica Chemica Acta, 39, 273 (1967)) and some controversy as to its structural identity (Tetrahedron^ Letters, 157 (1970) and British Patent NO. 1,341,022). Sulfonamide derivatives of erythromycylamine are reported in O.S. Patent No. 3,983,103 to be useful as antibacterial agents. Other derivatives are also reported (Ryden, et aj_, J. Med. Qiem., 16, 1059 (1973) and Massey, et al, .1. Med. Chem., 17, 105 (1974)) to have in vitro and in vivo antibacterial activity.

As described ir. Patent Specification No. 46661 certain novel 4,,-deo3y-4-antino-erythran’ycin A derivatives have been found to be useful as antibacterial agents. These antibacterial agents have the formulae: - 4 46662 III IV and the pharmaceutically acceptable acid addition salts thereof, wherein R^ and R^ are each hydrogen or alkanoyl of two or three carbon atoms; R^ is alkanoyl of two or three carbon atoms; and R^ is hydrogen; or R^ and R^ taken together are or and R^ taken together are -C-.

According to the present invention, there are provided compounds useful as intermediates leading to the antibacterial agents of Formulae III and IV, of the formula: I II - 5 wherein R. is hydrogen or alkanoyl of two or three carbon atoms; R, is alkanoyl of two or three carbon atoms; Y is N-OH or N-O-CCH. s and Rg is hydrogen; or Rg and Rg when taken together are -C-.

Preferred compounds of the formula I are those wherein Rj is hydrogen or acetyl.

Preferred compounds of the formula II are those wherein Rj is hydrogen and also those wherein Rj is acetyl.

Also within the scope of the present invention are processes for preparing the compounds of the formulae: IA IIA wherein Ac and Rg are each alkanoyl of two or three carbon atoms; p and Rg is hydrogen; or Rg and Rg when taken together are -0-, which a. comprises reacting 1 mole of^compound selected from: with at least one mole each of dimethylsulfoxide and trifluoroacetic anhydride in a reaction-inert-solvent at -30 to -65°C. followed by contacting the reaction mixture with at least one mole of a tertiary amine such as triethylamine.

A preferred feature of this process is the oxidation of the compounds of Formula X' and II' wherein the reaction-inert-solvent is methylene chloride.

A second process within the scope of the present invention 10 comprises the preparation of compounds of the formulae: IA IIA ν.' - Ί wherein Ac and Rj are each alkanoyl of two or three carbon atoms; and Rj is hydrogen; or Rj and Rj when taken together are -2-, which comprises reacting 1 mole of a compound selected from: 1' II' with at least one mole each of N-chlorosuccinimide and dimethylsulfide in a reaction-inert-solvent at 0 to -25°C, followed by contacting the reaction mixture with at least one mole of a tertiary amine such as triethylamine.

A preferred feature of the claimed process is the use of toluene and benzene as the reaction-inert solvent.

Throughout the present invention, the stereochemical designation of the substituents on the sugars and macrolide ring, with the exception of epimerisation at the ^''-position where noted, are those of the naturally occurring erythromycin A.

The selective oxidation of I’ and IX' to IA and IIA, respectively, is the first of the processes of the present invention and comprises - 8 reacting the compounds 1' and II' with trifluoroacetie anhydride and dimethylsulfoxide followed by the addition of a tertiary amine such as triethylamine.

In practice, the trifluoroacetie anhydride and dimethylsulfoxide are initially combined in a reaction-inert-solvent at about -65°C. After ten to fifteen minutes the alcohols 1' and II' are added at such a rate that the temperature is maintained at about -65°C. and does not rise above -30°C. At temperatures above -30°C. the trifluoroacetie anhydride - dimethylsulfoxide complex is_not stable. The reaction temperature is maintained between -30 and -65°C. for about fifteen minutes and is then lowered to about -70°C. A tertiary amine is added all at once and the reaction mixture allowed to warm during a ten to fifteen minute period. The reaction mixture is subsequently treated with water and worked up.

Regarding the quantities of reactants, for each mole of alcohol substrate employed, one mole each of the trifluoroacetie anhydride and dimethylsulfoxide are required. Experimentally, it is advantageous to employ a 1-5 fold excess of the anhydride and dimethylsulfoxide in order to hasten the completion of the reaction. The tertiary amine employed should correspond to the molar amount of trifluoroacetie anhydride used.

The reaction-inert-solvent utilized in this process should he one which. appreciably solubilizes the reactants and does not react to any great extent with either the reactants or the products formed. Since this oxidation process is conducted at -30 to -65°C., it is preferred - 9 that, in addition to having the above characteristics, said solvent possess a freezing point below the reaction temperature. Such solvents or mixtures thereof which meet these criteria are toluene, methylene chloride, ethyl acetate, chloroform and tetrahydrofuran.

Solvents which meet the above requirements but which have a freezing point above the reaction temperature can be employed in minor amounts in combination with one of the preferred solvents.

The especially preferred solvent for this process is; methylene chloride. ~ The preferred compounds prepared by this process are 2'-Oacetyl-4-deoxy-4-oxo-erythromycin A, ll,2'-di-0-acetyl-4-deoxy4-oxo-erythromycin A 6,9-hemiketal and 2'-0-acetyl-4-deoxy-4oxo-erythromycin A 6,9-hemiketal 11,12-carbonate ester.

The reaction time is not critical and is dependent on reaction temperature and the inherent reactivity of the starting reagents.

At temperatures of -30 to -65°C., the reaction is complete in fifteen to thirty minttes.

As to the order of addition of the reagents, it is preferred that the trifluoroacetic anhydride be combined with the dimethylsulfoxide followed by the addition of the requisite alcohol substrate. It is further suggested, as hereinbefore mentioned, that the temperature of the reaction mixture is kept below -30°C. This is in accordance with the teaching of Cmura, et al., J. Org. Chem., 41, 957 (1976).

The second process represents an oxidation reaction wherein the 4-hydroxy substituent of 1' and II', wherein Ac and are each alkanoyl of two or three carbon atoms, R, is hydrogen, and R„ and R, § when taken together are -C-, is oxidized to form a 4-deoxy-4-oxoerythromycin A compound. - 10 The process comprises the use of N-chlorosuccinimide and dimethyl-sulfide as the oxidizing agent. In practice, these two reagents are first combined in a reaction-inert-solvent at about 0°C. After ten to twenty minutes the temperature is lowered to 0 to —25°C. and the alcohol substrate 1' or II* is added, while maintaining the aforementioned temperature. After two to four hours reaction time, a tertiary amine, such as triethylamine, is added and the reaction mixture hydrolyzed and worked up.

Regarding the quantities of reactants, for each mole ef alcohol substrate employed, one mole each of the N-chlorosuccinimide and dimethylsulfide are required. Experimentally, it is advantageous to employ a 1-20 fold excess of the succinimide and sulfide reactants in order to hasten the completion of the reaction. The amount of tertiary amine employed should correspond to the molar amount of succinimide used.

The reaction-inert-solvent utilized in the claimed process should be one which appreciably solubilizes the reactants and does not react to any appreciable extent with either the reactants or the products formed. Since the reaction is conducted at 0 to -25°C., it is preferred that, in addition to having the above characteristics, it should possess a freezing point below the reaction temperature.

Such solvents or mixtures thereof which meet these criteria are toluene, ethyl acetate, chloroform, methylene chloride or tetrahydrofuran. Solvents which meet the above requirements but which have a freezing point above the reaction temperature can also be employed in minor amounts in combination with one or more of the preferred - 11 solvents. The especially preferred solvent for the claimed process is toluene-benzene.

The preferred compounds prepared by this process are ll,2'-di-0acetyl-4-deoxy-4-oxo-erythromycin A 6,9-hemiketal, 2'-0-acetyl-4~ deoxy-4-oxo-erythromycin A 6,9-hemiketal 11,12-carbonate ester and 2'- 0-acetyl-4-deoxy-4-oxo-erythromycin A.

Reaction time is not critical and is dependent on concentration, reaction temperature and the inherent reactivity of the reagents. At a reaction temperature of 0 to -25°C. the reaction time is about two to four hours.

Regarding the order of addition, as previously mentioned, it is preferred that the alcohol substrate 1' or II' be added to the premixed succinimide derivative and dimethylsulfide.

Both the herein described processes are viewed as unique because IS of the selectivity of the oxidation which takes place exclusively at the 4-hydroxy substitutent, leaving other secondary alcohols in the molecule unaffected.

The 4-deoxy-4-oxo compounds of the formula: II - 12 10 wherein and Rg are each alkanoyl of two or three carbon atoms and Rg is hydrogen are also prepared according to the invention by treating a compound of the formula: '^3, D I wherein Y is 0 and R^ is alkanoyl of two or three carbon atoms, with an alkanoic anhydride (Rg)gO and pyridine.

In practice, the ketone I is contacted with an excess of the anhydride in pyridine as the solvent. It is preferred that as much as a four fold excess of the anhydride be employed in the reaction.

The reaction is conveniently carried out at ambient temperature. At this reaction temperature the reaction time is about twelve to twenty-four hours.

Removal of the alkanoyl moiety at the 2'-position of the intermediate ketones I (Y = 0) and II is carried out through a solvolysis reaction wherein the 2'-0-alkanoyl-4-deoxy-4-oxo-erythromycin A is stirred with an excess of methanol, typically overnight at room temperature. Removal of the methanol and subsequent purification, where necessary, of the residual product provides for compounds of Formulae I (Y = 0) and II wherein R^ is hydrogen. - 13 Compounds of the formula (I) in which R^ is alkanoyl of 2 or 3 carbon atoms may be prepared by acetylating or propionylating the corresponding compound of the formula (I) in which R^ is H.

As previously mentioned, the compounds of Formulae I and II are useful intermediates leading to the 4-deoxy-4-amino-erythromycin A antibacterial agents of formulae III and IV. Preferred as intermediates in this group are 2'-0-acetyl-4deoxy-4-oxo-erythromycin A 6,9-heraiketal 11,12-carbonate ester and 4-deoxy-4-oxo-erythromycin A 5,9-hemiketal 11,12-carbonate ester.

Several synthetic pathways can be employed in the preparation of the antibacterial agents of Formulae III and IV from the requisite compounds of the formula I and II as described in Patent Snecificaticn No. 46661.

The oximes of the ketones I (Y = 0) are prepared by reacting said ketones with hydroxylamine hydrochloride, typically in the presence of barium carbonate in methanol or isopropanol at room temperature. In practice, it is preferred that an excess of hydroxylamine be employed, and as much as a three fold excess provides the desired intermediate in good yields. Employing ambient temperatures and an excess of the hydroxylamine allows for the preparation of the desired oxime derivative in a reaction period of one to three hours. The barium carbonate is used in molar quantities twice that of the hydroxylamine hydrochloride employed. The product is isolated by addition of the reaction mixture to water followed hy basification to pH 9.5 and extraction with a water-immiscible solvent such as ethyl acetate. - 14 Alternatively, the reaction mixture can be filtered and the filtrate concentrated in vacuo to dryness. The residue is subsequently partitioned between water at pH 9.0-9.5 and a waterimmiscible solvent.

Preparation of the O-acetyloxime compounds of Formula I 0 (Y = N-O-CCH^) is effected by acetylation of the corresponding oxime. Experimentally, one mole of the oxime is reacted with one mole of acetic anhydride in the presence of one mole of pyridine or triethylamine. The use of an excess of the anhydride and pyridine aid in the completion of the reaction and an excess of 30-402 is preferred. The reaction is best conducted in an aprotic solvent such as benzene or ethyl acetate at room temperature overnight. On completion of the reaction, water is added, the pH adjusted to 9.0 and the product separated in the solvent layer.

The preferred oxime and oxime derivatives which are useful intermediates leading to the 4-deoxy-4-amino-erythromycin A antibacterial agents include 2'-0-acetyl-4-deoxy-4-oxo-erythromycin A oxime, 2'-0-acetyl-4-deoxy-4-oxo-erythromyein A O-acetyloxime, 4-deoxy4-oxo-erythromycin A oxime and 4-deoxy-4-oxo-erythromycin A 0acetyloxime.

The following examples are provided solely for the purpose of illustration and not to be construed as limitations of this invention: EXAMPLE 1 2'-0-Acetyl-4-deoxy-4-oxo-erythromycin A To 3 ml of methylene chloride and 0.328 ml. of dimethylsulfoxide cooled to about -65°C. and maintained under a nitrogen atmosphere is V·' - 15 added 0.652 ml. of trifluoroacetic anhydride. After about a minute a white slurry forms indicating the presence of the trifluoroacetic anhydride - dimethylsulfoxide complex. To the resulting slurry is added dropwise a solution of 1.0 g. of 2'-0-acetylerythromycin A. ethyl acetate, obtained by recrystallization of 2'-0-acetylerythromycin A from ethyl acetate, in 7 ml. of methylene chloride keeping the temperature at about -65°C. The resulting mixture is stirred for 15 minutes at about -60°C. and is then cooled to -70°C. Triethylamine (1.61 ml.) is added rapidly to the reaction mixture and the cooling bath is removed. After stirring for 15 minutes the solution is added to 10 ml. of water and the pH of the aqueous phase adjusted to 10.

The organic phase is separated, washed successively with water (3 x 10 ml.) and brine solution (1 x 10) and dried over sodium sulfate. Removal of the solvent under reduced pressure gives 929 mg. of the crude product. Recrystallization from methylene chloride - hexane gives 320 mg. of the purified product, m.p. 105-108°C.

NMR (£ , CDClj): 3.28 (3H)s, 2.21 (6H)s and 2.03 (3H)s.

In a similar manner, starting with 2'-O-propionylerythromycin A. ethyl acetate and following the above procedure gives 2'-0~propionyl20 4-deoxy-4-oxo-erythromycin A.

EXAMPLE 2 4-Deoxy-4-oxo-erythromycin A A solution of 4.0 g. of 2'-0-acetyl-4-deoxy-4-oxo-erythromycin A in 75 ml. of methanol is stirred at ambient temperature for 20 hours. The solvent is removed in vacuo and the residual white foam - 16 recrystallized from methylene chloride - hexane, 3.44 g., m.p. 170.5172.5°C.

HMR (g , CDClg): 3.36 (3H)s and 2.33 (6H)s.

A product identical with the above is isolated when 2'-O5 propionyl-4-deoxy-4-oxo-erythromycin A is treated with methanol at room temperature.

EXAMPLE 3 21 -0-Acetyl-4'’-deoxy-4-oxo-erythromycin A To a stirring solution of 13.7 g. of 4-deoxy-4-oxo-erythromycin A in 100 ml. of ethyl acetate is added 2.3 ml. of acetic anhydride and the resulting reaction mixture stirred at room temperature for 2 hours. The solution is added to 100 ml. of water and the pH of the aqueous phase raised to 9.5 by the addition of 615 sodium hydroxide solution. The organic layer is separated, dried over sodium sulfate and concentrated to give 14.5 g. of a white foam identical, after recrystallization from methylene chloride - hexane, with the product of Example 1.

EXAMPLE 4 21-0-Acetyl-4-deoxy-4-oxo-erythromycin A oxime To 500 ml, of methanol is added 10.8 g’. of 2'-O-acety 1-4deoxy-4-oxo-erythromycin A, 1.Q4 g. of hydroxylamine hydrochloride and 11.0 g. of barium carbonate, and the resulting suspension stirred at room temperature for 3.5 hours. The mixture is filtered and the filtrate concentrated under reduced pressure. The residual foam - 17 is taken up in ethyl acetate which is subsequently washed with water at pH. 9.5. The organic phase is separated, dried over sodium sulfate and concentrated in vacuo to give 10.6 g. of the desired product.

NMR (ξ , CDClg): 3.33 (3K)s, 2.30 (6H)s and 2.06 (3H)s.

EXAMPLE 5 2l-0-Acetyl-4-deoxy-4-oxo-erythromycin A O-acetyloxime To a solution of 330 mg. of 2’-0-acetyl-4''-deox_y-4-oxoerythromycin A oxime in 30 ml. of ethyl acetate is added-with stirring 64.2 microlitres of acetic anhydride, and the reaction mixture stirred overnight at room temperature. An additional 15.8 /il of acetic anhydride and 23.4 yul of triethylamine are added and the stirring continued for 4 hours. The reaction mixture is added to water and the pH adjusted to about 9.0. The ethyl acetate layer is separated, dried over sodium sulfate and concentrated under vacuum to give 300 mg. of the desired product.

NMR ( ξ . CDClj): 3.38 (3H)s, 2.26 (6H)s, 2.20 (3H)s, 2.05 (3H)s and 1.56 (3H)s.

Xn a similar manner hy substituting 2'-0-propionyl-4-deoxy-4oxo-erythromycin A oxime and 4-deoxy-4-oxo-erythromycin A oxime for 2'-0-acetyl-4-deoxy-4-oxo-erythromycin A oxime in the above procedure, the respective 0-acetyl derivatives are prepared. 6 6 6 2 - 18 EXAMPLE 6 ll,2'-Di-0-acetyl-4-deoxy-4-oxo-erythromycin A 6,9-hemiketal A solution of 10 g. of 2'-0-acetyl-4-deoxy-4-oxo-erythromycin A in 250 ml. of pyridine is treated with 40 ml. of acetic anhydride and the resulting reaction mixture allowed to stand at room temperature for 10 days. The bulk of the solvent is removed in vacuo and the ? remaining concentrate added to a mixture of 150 ml. of water and 100 ml. of chloroform. The pH of the aqueous layer is raised to 9.0 and the chloroform separated, dried over sodium sulfate and concentra10 ted to dryness.

NMR (£ , CDClg): 3.33 (3H)s, 2.26 (6H)s, 2.10 (3H)s, 2.03 (3H)s and 1.55 (3H)s.

I EXAMPLE 7 Starting with the appropriate 4-deoxy-4-oxo-erythromycin A and requisite alkanoic anhydride and employing the procedure of Example 6, the following compounds are synthesized: °«3 Ο Ο II II CHjC- θ CHjCHjCW CVH,i0 0 II II CHjCHjC- CHCEXAMPLE 8 ll-Q-Acetyl-4-deoxy-4-o::o-erythro!nycin A 6,9-hemiketal A solution of 3.0 g. of ll)2,-di-0-acetyl-4-deoxy-4-oxo5 erythromycin A 9,6-hemiketal in 50 ml. of methanol is stirred under a nitrogen afSmsphere overnight. The solvent is removed in vacuo to give the desired product (3.0 g.) as a yellow foam.

NMR ( £ , CDClj): 3.35 (3H)s, 2.31 (6H)s, 2.13 (3H) and 1.55 (3H)s. - 20 In a similar manner, the compounds of Example 7 are converted by the procedure of Example 8 to ll-O-acetyl-4-deoxy-4-oxo-erythro mycin A 6,9-hemfketal and 11-0-ρΓορίοηγ1-4-ά6θχγ-4-οχο-Β^ί1π:οπ^α1η A 6,9-hemiketal EXAMPLE 9 2'-0-Acetylerythromycin A 6,9-hemiketal 11,12-carbonate ester To a solution of 13.2 g. of erythromycin A 6,9-hemiketal 11,12carbonate ester (U'.S. 3,417,077) in 150 ml. of benzene_is added 1.8 ml. of acetic anhydride, and the reaction mixture stirred at room temperature for 1.5 hours. The solution is poured into 200 ml. of water and the aqeuous phase basified to pH 9.0. The benzene layer is separated, dried over sodium sulfate and concentrated in vacuo to 15.3 g. of a white foam. On trituration with 50 ml. of diethyl ether the foam crystallizes. Filtration and drying of the product gives 12.6 g. of pure product, m.p. 224.5-228.5°C.

NMR ( , CDClg): 3.36 (3H)s, 2.30 (6H)s, 2.06 (3H)s and 1.61 (3H)s.

In a similar manner, by substituting an equivalent amount of propionic anhydride for acetic anhydride in the procedure of Example 9, 2'-0-propionylerythromycin A 6,9-hemiketal 11,12-carbonate ester is prepared. - 21 example 10 2l-0-Acetyl-4-deoxy-4-oxo-erythroinycin A 6,9-hemiketal 11,12-carbonate ester To a suspension of 6.19 g. of N-chlorosuccinimide in 150 ml. of toluene and 50 ml. of benzene cooled to -5°C. is added 4.46 ml. of dimethylsulfide. After stirring for 20 minutes the resulting suspension is cooled to -25°C. and 12.4 g. of 2'-O-acetylerythromycin A 6,9-hemiketal 11,12-carbonate ester, partially dissolved in 80 ml. of toluene, is added dropwise. The temperature, which is maintained between -19 to -25°C. during the addition, is kept at -25°C. for 2 hours. At the end of this period 6.79 ml. of triethylamine is added all at once. The cooling bath is removed and the temperature allowed to rise to -10°C. The reaction mixture is then poured into water and the aqueous phase adjusted from 8.4 to 9.0. The organic layer is separated, dried over sodium sulfate and concentrated under vacuum to a white foam (14.0 g.). Trituration of the residue with diethyl ether causes the foam to crystallize. Filtration and drying of the product gives 11.3 g. of crystalline material, m.p. 212-213.5°C.

NMR (£ , CDC13): 5.26 (lH)t, 3.36 (3H)s, 2.30 (6H)s, 2.13 (3H)s, 1.63 (3H)s and 1.50 (3H)s.

Similarly, 2'-0-propionyl-4-deoxy-4-oxo-erythromycin A 6,9hemiketal 11,12-carbonate ester is prepared by the procedure of Example 10 hy the replacement of the 2'-0-acetyl ester with an equivalent amount of 2'-0-propionylerythromycin A 6,9-hemiketal 11,12-carbonate ester. - 22 EXAMPLE 11 4-Deoxy-4-oxo-erythromycin A 6,9-hemiketal 11,12-carbonate ester 42.9 g. of 2'-0-acetyl-4-deoxy-4-oxo-erythromycin A 6,95 hemiketal 11,12-carbonate ester is added to 800 ml. of methanol and the resulting solution stirred at room temperature for 72 hours.

On removal of the solvent in vacuo there remains 41 g. of the product as a white foam. The residual material is dissolved in about 100 ml. of acetone followed by the careful addition of water to the precipi10 tation point. The resulting crystalline solid is stirred for 40 minutes, and this then filtered and dried to give 34.2 g. Of desired product, m.p. 186.5-188°C.

NMR ( £ , CDClg): 5.66 (IH)t, 3.35 (3H)s, 2.35 (6H)s, 1.65 (3H)s and 1.51 (3H)s.

In a similar manner the same product is obtained when an equivalent amount of 2'-0-propionyl-4-deoxy-4-oxo-erythromycin A 6,9hemiketal 11,12-carbonate ester is employed in the above procedure in place of the 2'-0-acetyl ester.

Claims (10)

1. A compound of the fortnula:- wherein R^ is hydrogen or alkanoyl having two or three carbon atoms;

2. A compound of the formula (I) as claimed in claim 1, wherein R^ is hydrogen or acetyl.

3. The compound of the formula :10 - 24

4. The compound of the formula: 5. With at least one mole each of N-chlorosuce’oimide and dimethylsulfide in a reaction inert solvent at 0 to -25°C, followed by contacting the reaction mixture with at least one mole of a tertiary amine. 12. A process as claimed in claim 10 or 11 wherein the tertiary amine is triethylamine. 10 13. A process for preparing a compound of the formula (I) as claimed in claim 1 in which Y is N-OH or N-O-ci-CHj, which comprises reacting the corresponding compound of the formula (I) in which Y is 0 with hydroxylamine hydrochloride, followed by acetylation when 0 a compound in which Y is Ν-Ο&Η^ is desired. 15 14. A process for preparing a compound of the formula (II) as claimed in claim 1 wherein R^ and Rj are alkanoyl of 2 or 3 carbon atoms and R^ is hydrogen, which comprises reacting a compound of the formula (XA) as defined in claim 10 with an alkanoic anhydride of the formula (R,)^ in the presence of pyridine. - 28 15. A process for preparing a compound of the formula (I) or (II) as claimed in claim 1 wherein R^ is hydrogen, which comprises treating the corresponding compound of the formula (I) or (II) in which R^ is alkanoyl of 2 or 3 carbon atoms with an excess of methanol. 16. A process for preparing a compound of the formula (I) as claimed in claim 1 wherein R^ is alkanoyl of 2 or 3 carbon atoms, which comprises acetylating or propionylating the corresponding compound of the formula (I) in which R^ is hydrogen. 17. A process as claimed in claim 10 substantially as hereinbefore described in Example 1. 18. A process as claimed in claim 15 substantially as hereinbefore described in either of Examples 8 and 11. 19. A process as claimed in claim 13 substantially as hereinbefore described in Examples 4 and 5. 20. A process as claimed in claim 14 substantially as hereinbefore described in either of Examples 6 and 7. 21. A process as claimed in claim 11 substantially as hereinbefore described in Example 10. 22. A process as claimed in claim 16 substantially as hereinbefore described in Example 9. 23. A compound of the formula (I) or (II) as claimed in claim 1 which has been prepared by a process as claimed in any one of claims 5 with at least one mole each of dimethylsulfoxide and trifluoroacetic anhydride in a reaction-inert solvent at -30 to -65°C, followed by contacting the reaction mixture with at least one mole of a tertiary amine. 11. A process for preparing a compound of the formula:- IA IIA - 27 wherein Ac and R., are each alkanoyl having two or three carbon and taken together are -C-; of a compound of the formula:atoms; and R.j is hydrogen; or R^ which comprises reacting 1 mole

5. The compound of the formula: cch^ 5 R„ is alkanoyl having two or three carbon atoms; Y is N-OH or p 0 N-O-CCHg; and Rg is hydrogen; or R. ; and Rg when taken together are -C-.

6. The compound of the formula: - 25

7. A compound of the formula OI) an claimed hi claim 1, wherein R^ is hydrogen or acetyl.

8. The compound of the formula:-

9. The compound of the formula :- 10. A process for preparing a compound of the formula:- - 26 wherein Ac and Rg are each alkanoyl of two or three carbon atoms; and Rg is hydrogen; or Rg and Rg taken together are -ίζ-, which comprises reacting 1 mole' of a compound of the formula:-

10. To 22.