GB1585316A - Erythromycin a intermediates - Google Patents

Description

PATENT SPECIFICATION

: ( 21) Application No 34309/79 ( 22) Filed 2 Feb 1978 f ( 62) Divided out of No 1 585 315 ( 31) Convention Application No 765 480 : ( 32) Filed 4 Feb 1977 ke ( 31) Convention Application No 856 479 ( 32) Filed 1 Dec 1977 in ( 33) United States of America (US) ( 44) Complete Specification published 25 Feb 1981 ( 51) INT CL 3 C 07 H 17/08 ( 52) Index at acceptance C 2 C 1485 1672 178 X 214 215 247 253 25 Y 28 X 30 Y 323 32 Y 346 351 352 360 362 363 364 366 368 36 Y 620 625 628 633 635 638 643 644 645 670 672 760 761 767 769 AA AB LK LY LZ ( 11) 1585316 ( 54) ERYTHROMYCIN A INTERMEDIATES ( 71) We, PFIZER INC, a Corporation organised under the laws of the State of Delaware, United States of America, of 235 East 42nd Street, New York, State of New York, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to.

be performed, to be particularly described in and by the following statement:-

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-erythromycin A antibacterial agents as described in our co-pending British Patent Application No 4165/78 (Serial No 1585315).

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 structure:

Erythromycin R A -OH B -H The structure reveals that the antibiotic is comprised of three 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, as herein described, the macrolide ring While the numbering system of the macrolide ring is in unprimed numbers, that of the desosamine is in primed numbers and that of cladinose in double-primed numbers.

Numerous derivatives of erythromycin have been prepared in an effort to 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 ( 19 p discloses 4 "-deoxy-4 "-oxo-erythromycin A 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 1,341022) Sulfonamide derivatives of erythromycylamine are reported in U S Patent No 3 983,103 to be useful as antibacterial agents Other derivatives are also renorted (Ryden, et al, 1 Med Chem, 16, 1059 ( 1973), and Massey, et al, 7 Med Chem, 17, 105 ( 1974)), to have in vitro and in vivo antibacterial activity.

As described in our co-pending British Patent Application No 4165/78 (Serial No 1585315), certain novel 4 "-deoxy-4 "-amino-erythromycin A derivatives have been found to be useful as antibacterial agents These antibacterial agents have the formulae:

-30 R 3 o,,r R 40 ilgl or 930 -e H 3 III IV and the pharmaceutically acceptable acid addition salts thereof, wherein R 1 and R 4 are each hydrogen or alkanoyl of two or three carbon atoms; R 2 is alkanoyl of two or three carbon atoms; and R 3 is hydrogen; or R 2 and R, taken together are 0 11 -C-; or R 8 and R 4 taken together are O 11 20 -C- 20 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:

R 2 orP 1310 " N(j N or N" L 3 l ''"" X (' oo f R 3 < wherein R 1 is hydrogen or alkanoyl of two or three carbon atoms; R 2 is alkanoyl of two or three carbon atoms; Y is 1,585,316 0 /t N-OH or N-O-GCHCI; and R, is hydrogen or R 2 and Ra when taken together are 0 U -C-.

Preferred compounds of the formula I are those wherein R 1 is hydrogen or acetyl.

Preferred compounds of the formula II are those wherein R 1 is hydrogen and also those wherein R, is acetyl.

Also within the scope of the present invention are processes for preparing the compounds of the formulae:

0 /\ by,, Ho W 9 A H O,0 l 010 ll whichomprissreacing Ioleo a compound sc f IA IIA wherein Ac and R, are each alkanoyl of two or three carbon atoms; and Rais hydrogen; or R& and R,, when taken together are Ho which comprises reacting 1 mole of a compound selected from 4 o,,,, MO and I, II' 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 I' and II' wherein the reaction-inert-solvent is methylene chloride.

A second process within the scope of the present invention comprises the preparation of compounds of the formulae:

1,585,316 4 1,585,316 4 I and o IA IIA wherein Ac and R 2 are each alkanoyl of two or three carbon atoms; and R 3 is hydrogen; or R, and R& when taken together are O which comprises reacting 1 mole of a compound selected from 5 _ _ WHO,,,, 140)\t O O o Q O fl \ 9 O I 40 <and R 3 O).

with at least one mole each of N-chlorosucccinimide and dimethylsulfide in a reactioninert-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 10 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 4 "-position where noted, are those of the naturally occurring erythromycin A.

The selective oxidation of I' and II' to IA and IIA, respectively, is the first of S 15 the processes of the present invention and comprises reacting the compounds I' and I" with trifluoroacetic anhydride and dimethylsulfoxide followed by the addition of a tertiary amine such as triethylamine.

In practice, the trifluoroacetic anhydride and dimethylsulfoxide are initially combined in a relation-inert-solvent at about -65 C After ten to fifteen minutes 20 the alcohols I' 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 trifluoroacetic 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 25 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 trifluoroacetic anhydride and dimethylsulfoxide are required.

Experimentally, it is advantageous to employ a 1-5 fold excess of the anhydride 30 and dimethylsulfoxide in order to hasten the completior of the reaction The tertiary 1,585,316 5 amine employed should correspond to the molar amount of trifluoroacetic anhydride used.

The reaction-insert-solvent utilized in this process should be 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, 5 it is preferred that, in addition to having the above characteristics, said solvent possesses 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 10 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 ' O acetyl 4 "deoxy 4 " oxo erythromycin A, 11,2 ' di O acetyl 4 " deoxy 4 " oxoerythromycin A 6,9-hemiketal and 2 ' O acetyl 4 " deoxy 4 " oxo erythromycin A 6,9-hemiketal 11,12-carbonate ester 15 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 minutes.

As to the order of addition of the retagents, it is preferred that the trifluoroacetic 20 anhydride is 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 kent below -30 C This is in accordance with the teaching of Omura, et at, l Org Chem, 41, 957 ( 1976).

The second process represents an oxidation reaction wherein the 4 "hvdroxy sub 25 stituent of I' and I", wherein Ac and R 2 are each alkanoyl of two or three carbon 25 atoms, Rs is hydrogen, and R 2 and R% when taken together are 0 is oxidized to form a 4 "-deoxy-4-oxo-erythromycin A compound.

The process comprises the use of N-chlorosuccinimide and dimethtylsulfide as 30 the oxidizing agent In practice, these two reagents are first combined in a reactioninert-solvent at about O C After ten to twenty minutes the temperature is lowered to 0 to -25 C and the alcohol substrate I' or I" 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 35 Regarding the quantities of reactants, for each mole of 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 40 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 45 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 solvents The especially preferred solvent for the claimed process is toluene-benzene 50 The preferred compounds prepared by this process are 11,2 ' di O acetyl4 " deoxy 4 " oxo erythromycin A 6,9 hemiketal, 2 ' O acetyl 4 " deoxy4 " oxo erythromycin A 6,9 hemiketal 11,12 carbonate ester and 2 ' Oacetyl 4 " deoxy 4 " oxo erythromycin A.

Reaction time is not critical and is dependent on concentration, reaction tem 55 perature 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 I' or I" be added to the premixed succinimide derivative and dimethylsulfide 60 Both the herein described processes are viewed as unique because of the selectivity of the oxidation which takes place exclusively at the 4 "-hydroxy substituent, leaving other secondary alcohols in the molecule unaffected.

The 4 "-deoxy-4 "-oxo compounds of the formula:

i-jo -5 N(Co n wherein R, and R 2 are each alkanoyl of two or three carbon atoms and R, is hydrogen are also prepared according to the invention by treating a compound of the formula:

NOO wherein Y is O and R 1 is alkanoyl or two or three carbon atoms, with an alkanoic anhydride (R,)20 and pyridine 2 O 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 15 Removal of the alkanoyl moiety at the 2 '-position of the intermediate ketones I (Y=O) and II is carried out through a solvolysis reaction wherein the 2 ' 0alkanovl 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 20 Formula I (Y=O) and II wherein R, is hydrogen.

Compounds of the formula (I) in which R 1 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 inter 25 mediates leading to the 4 "-deoxy-4 "-amino-erythromycin A antibacterial agents of the present invention of formulae III and IV Preferred as intermediates in this group are 2 ' O acetyl 4 " deoxy 4 " oxo erythromycin A, 6,9 hemiketal, 11,12 carbonate ester and 4 " deoxy 4 " oxo erythromycin A, 6,9 hemiketal, 11,12 carbonate ester 30 Several synthetic pathways can be employed in the preparation of the antibacterial agents of Formula III and IV from the requisite components of the Formulae I and II as described in our copending British Patent Application No 4165/78 (Serial No 1585315).

1,585,316 The oximes of the ketones I (Y=O) 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 5 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 by basification to p H 9 5 and extraction with a water-immiscible solvent such as ethyl acetate 10 Alternatively, the reaction mixture can be filtered and the filtrate concentrated in vacuo to dryness The residue is subsequently partitioned between water at p H 9.0-9 5 and a water-immiscible solvent.

Preparation of the O-acetyloxime compounds of Formula I C 11 (Y= N-O-CCH-3) 15 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 of triethylamine The use of an excess of the anhydride and pyridine aid in the completion of the reaction and an excess of 30-40 %, is preferred The reaction is best conducted in an aprotic solvent such as benzene or ethyl acetate at room 20 temperature overnight On completion of the reaction, water is added, the p H 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 ' Oacetyl 4 " deoxy 4 " oxo erythromycin A oxime, 2 ' O acetyl 4 " deoxy 25 4 " oxo erythromycin A O-acetyloxime, 4 " deoxy 4 " oxo erythromycin A oxime and 4 " deoxy 4 " oxo erythromycin A O-acetyloxime.

The following examples are provided solely for the purpose of illustration and not to be construed as limitations of this invention:

EXAMPLE 1 30

2 '-O-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 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 35 slurry is added dropwise a solution of 1 0 g of 2 '-O-acetylerythromycin A ethyl acetate, obtained by recrystallization of 2 '-O-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 min 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 40 bath is removed After stirring for 15 min the solution is added to 10 ml of water and the p H of the aqueous phase adjusted to 10 The organic phase is separated, washed successively with water ( 3 X 10 ml) and the 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 chloridehexane gives 45 320 mg of the purified product, m p 105-108 C.

NMR ( 8, CDC 13): 3 28 ( 3 H)s, 2 21 ( 6 H)s and 2 02 ( 3 H)s.

In a similar manner, starting with 2 '-O-propionylerythromycin A ethyl acetate and following the above procedure gives 2 '-O-propionyl-4 "-deoxy-4 "-oxoerythromycin A 50 EXAMPLE 2.

4 "-Deoxy-4 "-oxo-erythromycin A.

A solution of 40 g of 2 '-O-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 recrystallized from methylene chloridehexane, 55 3.44 g, m p 170 5-172 5 C.

NMR (,8, CD Cl,): 3 36 ( 3 H)s and 2 33 ( 6 H)s.

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

1,585,316 EXAMPLE 3.

2 '-O-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 hrs The solution is added to 100 ml of water and 5 the p H of the aqueous phase raised to 9 5 by the addition of 6 N 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 10

2 '-O-Acetyl-4 "-deoxy-4 "-oxo-erythromycin A oxime.

To 500 ml of methanol is added 10 8 g of 2 '-O-acetyl-4 "-deoxy-4 "-oxoerythromycin A, 1 94 g of hydroxylamine hydrochloride and 11 0 g of barium carbonate, and the resulting suspension stirred at room temperature for 3 5 hrs The mixture is filtered and the filtrate concentrated under reduced pressure The residual 15 foam is taken up in ethyl acetate which is subsequently washed with water at p H 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 ( 8, CDC 13): 3 33 ( 3 H)s, 2 30 ( 6 H)s and 2 06 ( 3 H)s.

EXAMPLE 5 20

2 '-O-Acetyl-4 "-deoxy-4 "-oxo-erythromycin A O-acetyloximine.

To a solution of 330 mg of 2 '-O-acetyl-4 "-deoxy-4 "-oxo-erythromycin 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 Al of acetic anhydride and 23 4 ul of triethylamine are added and the stirring con 25 tinued for 4 hrs The reaction mixture is added to water and the p H 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 (,A, CDC 13): 3 38 ( 3 H)s, 2 25 ( 6 H)s, 2 20 ( 3 H)s, 2 05 ( 3 H)s and 1 56 ( 3 H)s 30 In a similar manner by substituting 2 '-O-propionyl-4 "-deoxy-4 "-oxoerythromycin oxime and 4 "-deoxy-4 "-oxo-erythromycin A oxime for 2 '-O-acetyl-4 "-deoxy4 "-oxo-erythromycin A oxime in the above procedure, the respective Oacetyl derivatives are prepared.

EXAMPLE 6 35

11,2 '-Di-O-acetyl-4 "-deoxy-4 "-oxo-erythromycin A 6,9-hemiketal.

A solution of 10 g of 2 '-O-acetyl-4 "-deoxy-4 "-oxo-erythromycin A is 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 40 of water and 100 ml of chloroform The p H of the aqueous layer is raised to 9 0 and the chloroform separated, dried over sodium sulfate and concentrated to dryness.

NMR ( 8, CD Ch 3): 3 33 ( 3 H)s, 2 26 ( 6 H)s, 2 10 ( 3 H)s, 2 03 ( 3 H)s and 1 55 ( 3.H)s.

EXAMPLE 7 45

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:

1,585,316 9 1,585,3169 RR 2 0 O O O CH 3 C CHSCH 2 CO O ti II CH 3 CH 2 C C 3 CHCCO O CH 3 CHGC CH-CEXAMPLE 8 5

1-O-Acetvl-4 "-deoxv-4 "-oxo-erythromvcin A 6,9-hemiketal.

A solution of 3 O g of 11,2 '-di-O-acetyl-4 "-deoxy-4 "-oxo-erythromycin A 9,6hemiketal in 50 ml of methanol is stirred under a nitrogen atmosphere overnight.

The solvent is removed in vacuo to give the desired product ( 3 0 g) as a yellow foam 10 NMR ( 8, CDC 13): 3 35 ( 31-1)s, 2 31 ( 6 H)s, 2 13 ( 3 H) and 1 55 ( 3 H) s.

In a similar manner, the compounds of Example 7 are converted by the procedure of Example 8 to 11-O-acetyl-4 "-deoxy-4 "-oxo-erythromycin A 6,9hemiketal and 11O-propionyl-4 "-deoxy-4 "-oxo-erythromycin A 6,9-hemiketal.

EXAMPLE 9 15

2 '-O-Acetylerythromycin A 6,9-hemiketal 11,12-carbonate ester.

To a solution of 13 2 g of erythromycin A 6,9-hemiketal 11,12-carbonate 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 hrs The solution is poured into 200 ml of water and the aqueous phase basified to p H 9 0 The benzene layer is 20 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 ( 8, CDC 1,): 3 36 ( 3 H)s, 2 30 ( 6 H)s, 2 06 ( 3 H)s and 1 61 ( 3 H) s.

In a similar manner, by substituting an equivalent amount of propionic anhydride 25 for acetic anhydride in the procedure of Example 9, 2 '-Opropionylerythromycin A 6,9-hemiketal 11,12-carbonate ester is prepared.

EXAMPLE 10.

2 '-O-Acetyl-4 "-deoxy-4 "-oxo-erythromycin A 6,9-hemiketal 11,12carbonate ester.

To a suspension of 6,19 g of N-chlorosuccinimide in 150 ml of toluene and 30 ml of benzene cooled to -5 C is added 4 46 ml of dimethylsulfide After stirring for 20 min 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 hrs At the end of 35 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 40 Filtration and drying of the product gives 11 3 g of crystalline material, m p 212213 5 C.

NMR ( 8, CDCI): 5 26 ( 1 H)t, 3 36 ( 3 H)s, 2 30 ( 6 H)s, 2 13 ( 3 H)s, 1 63 ( 3 H)s and 1 50 ( 3 H)s.

Similarly, 2 '-O-propicnyl-4 "-deoxy-4 "-oxo-erythromycin A 6,9-hemiketal 11,12 45 carbonate ester is prepared by the procedure of Example 10 by the replacement of the 2 '-O-acetyl ester with an equivalent amount of 2 '-O-propionylerythromycin A 6,9-hemiketal 11,12-carbonate ester.

1,585,316 1,585,316 10 EXAMPLE 11.

4 "-Deoxy-4 "-oxo-erythromycin A 6,9-hemiketal 11,12-carbonate ester.

42.9 g of 2 '-O-acetyl-4 "-deoxy-4-oxo-erythromycin A 6,9-hemiketal 11 12carbonate ester is added to 800 ml of methanol and the resulting solution stirred at rocm temperature for 72 hrs On removal of the solvent in vacuc there remains 5 41 g of the product as a white foam The residual material is dissolved in about ml of acetone followed by the careful addition of water to the precipitation point.

The resulting crystalline solid is stirred for 40 min, and this then filtered and dried to give 34 2 g of desired product, m p 186 5-188 C.

NMR ( 8, CDCI): 5 66 ( 1 H)s, 3 35 ( 3 H)s, 2 35 ( 6 H)s, 1 45 ( 3 H 1)s and 10 1.51 ( 3 H)s.

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

Claims (1)

1. WHAT WE CLAIM IS: 15

   1 A compound of the formula:l R 1 < 0,N& ) N (CH 3), cabo R 20 am is or NO 1 l À oo Ia 0 I '"-'o 3 1 wherein R, is hydrogen or alkanoyl having two or three carbon atoms; R, is hydrogen or alkanoyl having two or three carbon atoms; R, is alkanoyl having two or three carbon atoms; Y is 20 N-OH and N-O-CCHC; and R, is hydrogen; or Rs and R, when taken together are 0 111 -C.

   2 A compound of the formula (I) as claimed in claim 1, wherein R 1 is hydrogen or acetyl 25 3 The compound of the formula:4 The compound of the formula:4 The compound of the formula:The compound of the formula:6 The compound of the formula:H 0/, 7 A compound of the formula (II) as claimed in claim 1, wherein R, is hydrogen or acetyl.

   8 The compound of the formula:0 iiif 1 n A 16 .1 HI O 1,585,316 9 The compound of the formula:CH 3 A process for preparing a compound of the formula:0 o '0 "or wherein Ac and R 2 are each alkanoyl of two or hydrogen; or R 2 and R, taken together are three carbon atoms; and R, is -L, which comprises reacting 1 mole of a compound of the formula:4 otin,, or I, 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:Mo.

   1,585,316 HFO and 3 IA IIA wherein Ac and R 2 are each alkanoyl having two or three carbon atoms; and R, is hydrogen; or R, and R 3 taken together are -C; which comprises reacting 1 mole of a compound of the formula:so i, O r N',i Qo;< $;'," ' 2Ji 0 Noz, 14 g %I O 3 ad,' ' B Q I' ' "oc /'"o O o 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.

   12 A process as claimed in claim 10 or 11 wherein the tertiary amine is triethvlamine.

   13 A process for preparing a compound of the formula (I) as claimed in claim 1 in which Y is 0 O N-OH or N-O-C-C H, s 15 which comprises reacting the corresponding compound of the formula (I) in which Y is O with hydroxyamine hydrochloride, followed by acetylation when a compound in which Y is 0 Il N-O-CCH, is desired.

   14 A process for preparing a compound of the formula (II) as claimed in claim 1 wherein R 1 and R 2 are alkanoyl of 2 or 3 carbon atoms and R, is hydrogen, which comprises reacting a compound of the formula (IA) as defined in claim 10 with an alkanoic anhydride of the formula (R 2)20 in the presence of pyridine.

   14 1,585,316 14 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 1 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 5 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 10 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 Examrnles 4 and 5.

   20 A process as claimed in claim 14 substantially as hereinbefore described in 15 Examnles 6 and 7.

   21 A process as claimed in claim 11 substantially as hereinbefore described in Examnle 10.

   22 A process as claimed in claim 16 substantially as hereinbefore described in Examnle 9 20 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 10 to 22.

   P C C GRAHAM, Chartered Patent Agent.

   Agent for the Applicants.

   Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1981.

   Published by the Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.