Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
  • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• This invention relates to 3-O-glycosyl 16-membered macrolide antibacterials, such as 2'',4'',4'''- tri-O-acetyl-O-(4'-O-phenoxyacetyl- ⁇ -L-cladinosyl)-(1 ⁇ 3)- desmycosin and O- ⁇ -L-cladinosyl-(1 ⁇ 3)-12,13-dehydro- 12,13-deoxorosaramicin, related derivatives, pharmaceutically acceptable acid addition salts thereof, pharmaceutical compositions containing them and a method of eliciting an antibacterial response using the novel antibacterials or pharmaceutical compositions containing them.
• macrolide antibacterials such as 2'',4'',4'''- tri-O-acetyl-O-(4'-O-phenoxyacetyl- ⁇ -L-cladinosyl)-(1 ⁇ 3)- desmycosin and O- ⁇ -L-cladinosyl-
• 3-O-glycosyl derivatives are found among the naturally occurring 12- and 14-membered macrolides.
• methymycin is disclosed in J. Am. Chem. Soc, 1956, 78, p. 6390
• neomethymycin is disclosed in Tetrahedron, 1958, 3 , p. 255.
• 14-membered macrolides erythromycin is disclosed in J. Am. Chem. Soc., 1957, 79, p. 6062; oleandomycin is disclosed in J. Am. Chem. Soc., I960, 82, p. 3225; and lankamycin is disclosed in J. Am. Chem. Soc, 1970, 92, P. 4129.
• 3-O-glycosyl 16-membered macrolide antibacterials available synthetically or occuring naturally.
• R 1 is a glycosyl group, represented by the formula II:
• R q and each R t are independently hydrogen, hydroxy, acyloxy, loweralkoxy, aralkoxy, N- loweralkylamino-carbonyloxy, N-aralkylamino carbonyloxy, or arylsulfonyloxy (-OSO 2 Ar) and R s and R w are independently hydrogen, lower alkyl or -CH 2 OH; or represented by the formula IIA:
• each R a is independently hydrogen, lower alkyl, or CH 2 OH and each R b is independently hydrogen, hydroxy, acyloxy, lower alkoxy, aralkoxy, N- loweralkylaminocarbonyloxy, N-aralkylaminocarbonyloxy or arylsulfonyloxy and n is 1, 2, 3, or 4;
• R 2 is hydrogen or an acyl group
• X is hydrogen, hydroxy, an acyloxy group
• R 2 is independently as defined hereinabove;
• m 0,1, or 2 and Q is independently CR 3 R 4 , NR 3 ,
• R 3 and R 4 are independently hydrogen, lower alkyl, aralkyl, G-substituted aralkyl, aryl and G-substituted aryl wherein G is independently one or more of halogen, trifluoromethyl, lower alkoxy or (C 2 -C 7 )alkanoyl; is a 12,13 double bond or a 12,13-oxo moiety; Z is hydrogen, hydroxy, an acyloxy group, a N,N-di(loweralkyl) amino group,
• R 2 is def ined above and R 5 and R 6 are independently hydrogen , lower alkyl or acyl groups ; or a pharmaceutically acceptable acid addition salt thereof .
• R 1 is an ⁇ - L-glycosyl group represented by formula II .
• R 1 is ⁇ -L -clandinosyl or tetrahydropyranyl
• X is hydrogen , hydroxy, or
• R 2 is as defined previously, Y is menthyl or formyl, Z is hydrogen, acyloxy, hydroxy, or wherein R 2 , R 5 and R 6 are as defined previously.
• R 2 is as defined previously, X is hydroxy or acyloxy, is a 12,13 double bond, and Z is
• R 2 , R 5 and R 6 are as defined previously.
• Especially compounds within the class are those wherein
• X is hydroxy or acetyl
• Z is
• R is acetyl
• the invention also includes the use of a compound of formula I for the preparation of a pharmaceutical composition useful for treating bacterial infection and a method for making a pharmaceutical composition comprising mixing a compound of formula I with a pharmaceutically acceptable carrier.
• the compounds of this invention show high serum levels and are useful as antibacterials against susceptible bacterial infections, especially those caused by Gram-positive organisms.
• This invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising an antibacterially effective amount of a compound represented by formula I in admixture with a pharmaceutically acceptable carrier therefor.
• This invention further provides a method of eliciting an antibacterial effect against susceptible bacterial infections, wherein an antibacterially effective amount of a compound represented by formula I or pharmaceutical compositions thereof is administered to an animal having a susceptible bacterial infection.
• the compounds of this invention have stereochemical configuration indicated for the structure of compounds of formula I, and it is to be understood that the stereochemical configuration is identical to that of tylosin.
• the stereochemistry of the 12,13-oxo moiety, when present in the compounds of formula I, is indicated below:
• acyl group means (C 2 -C 7 )alkanoyl; (C 2 -C 7 )alkanoyl substituted by chloro, lower alkoxy, aryl, aralkoxy, or aryloxy; aroyl; and substituted aroyl; said aroyl substituents being one or more of halogen, nitro, lower alkoxy, or lower alkyl,
• acyloxy means the "acyl group" as defined herein univalently bonded to divalent oxygen and includes inter alia, acetyloxy, butyryloxy, iso- valeryloxy, phenylacetyloxy, benzoyloxy, p-methoxybenzoyloxy.
• lower alkyl as used herein means straight and branched-chain alkyl groups of one to six carbons including methyl, ethyl, propyl, butyl, pentyl, hexyl and the corresponding branched-chain isomers thereof such as iso-propyl, tert- or sec-butyl, iso- valeryl and iso-hexyl.
• Methyl is the preferred alkyl group .
• lower alkoxy means “lower alkyl” groups univalently bonded to divalent oxide and includes inter alia, methoxy, ethoxy, and propoxy.
• aryl means phenyl and biphenyl optionally substituted by lower alkyl.
• halogen means fluoro, chloro and bromo, preferably fluoro and chloro.
• aralkyl means lower alkyl substituted by aryl including benzyl, ⁇ - and ⁇ -phenethyl and ⁇ - and ⁇ -(o-tolyl)ethyl.
• Aralkoxy refers to "aralkyl” as defined hereinabove univalently bonded to divalent oxygen.
• aryloxy refers to phenoxy and biphenyloxy.
• (C 2 -C 7 )alkanoyl means carbonyl groups univalently bonded to "lower alkyl” groups and includes acetyl, propionyl, butyryl, iso-butyryl and iso-valeryl.
• the preferred (C 2 -C 7 ) alkanoyl groups are acetyl, butyryl, iso-valeryl for R 1 , R 2 , R 3 , R 4 , R 5 , and
• Typical suitable chloro-substituted (C 2 -C 7 ) alkanoyl groups include 2-chloro(C 2 -C 7 ) alkanoyl such as 2-chloroacetyl and 2-chloropropanoyl.
• Typical suitable lower alkoxy (C 2 -C 7 ) alkanoyls include methoxyacetyl, ethoxyacetyl, 2- and 3-methoxypropanoyl, and propoxyacetyl.
• Typical suitable aryl-substi tuted (C 2 -C 7 ) alkanoyl groups include phenylacetyl and biphenylacetyl.
• Typical suitable aryloxy-substituted ( C 2 -C 7 ) alkanoyls include phenoxyacetyl and biphenyloxyacetyl.
• aroyl means substituted and unsubstituted benzoyl wherein the substituents are one or more of halogen, nitro, lower alkoxy or lower alkyl.
• suitable substituted benzoyl include p-fluoro benzoyl, 3-chlorobenzoyl, 4-nitrobenzoyl, 3-nitrobenzoyl, p-ethoxybenzoyl, 3-chloro-4-nitrobenzoyl, 3-fluoro-4-methoxybenzoyl, 3-nitro-4-ethylbenzoyl and 3-chloro-4-methylbenzoyl.
• Typical suitable G-substituted aryl groups include 4-fluorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl, 4-ethoxyphenyl, 4-acetylphenyl and 3- chloro-4-methoxyphenyl.
• Typical suitable G-substituted aralkyl groups include 4-fluorobenzyl, 3-chlorophenylethyl, 4-methoxy- ⁇ -phenethyl, and 4-trifluoromethylbenzyl.
• N,N-di(loweralkyl)amino means two "lower alkyl groups", each univalently bonded to a trivalent nitrogen atom, including dimethylamino, diethylamino, di-n-propylamino, methylpropylamino and diisopropylamino.
• lower alkoxycarbonyloxy as used herein means “lower alkoxy” groups univalently bonded
• aralkoxycarbonyloxy as used herein means an "aralkyl group" univalently bonded to a divalent oxide which in turn is univalently bonded to the carbonyl carbon of the carbonyloxy moiety including phenethoxycarbonyloxy, benzyloxycarbonyloxy, and o-tolylethoxycarbonyloxy.
• N-loweralkylaminocarbonyloxy means one or two "lower alkyl group" univalently bonded to the trivalent amino moiety, -N- which in turn is univalently bonded to the carbonyl carbon of a carbonyloxy moiety, including N-methylaminocarbonyloxy N,N-dimethylaminocarbonyloxy, N-iso-propyl aminocarbonyloxy N,N-methylethylaminocarbonyloxy and N- tert-butylaminocarbonyloxy.
• N-aralkylaminocarbonyloxy as used herein means one or two “aralkyl group” univalently
• a trivalent nitrogen i.e. -N- which in turn is univalently bonded to the carbonyl carbon of the carbonyloxy moiety, including N-benzylaminocarbonyloxy, N - ( ⁇ -phenethyl)aminocarbonyloxy and N-o-tolylethylaminocarbonyloxy.
• arylsulfonyloxy means "aryl" univalently bonded to the sulfur in sulfonyloxy including phenylsulfonyloxy and biphenyl sulfonyloxy.
• R a is preferably hydrogen or methyl.
• R b is preferably hydrogen or loweralkoxy.
• Typical suitable acyclic glycosyl groups represented by formula IIA include -CH 2 -O-CH 2 CH 3 , -CH(CH 3 )-O-CH(CH 3)2 , -CH 2 -O-(CH 2 ) 2 CH 3 , -CH 2 -O-(CH 2 ) 3 -CH 3 , -CH(CH 3 )-O-CH 2 CH(CH3) 2 , -CH 2 -O-(CH 2 ) 4 -CH 3 , -CH(CH 3 )-O- CH(CH 3 )-(CH 2 ) 3 -CH 3 , -CH 2 -O-CH 2 -CH(OCH 3 )CH 3 , -CH 2 -O- CH(CH 2 OH)-CH 3 or -CH(CH 3 )-O-CH(CH 2 OH)(CH 2 ) 3 CH 3 .
• R t is preferably hydrogen, hydroxy, lower alkoxy, for example methoxy, or acyloxy, for example acetyloxy, butyryloxy or iso-valeryloxy.
• R s and R w may be in the axial or equatorial position.
• R s is preferably hydrogen or methyl;
• R w is preferably methyl.
• the preferred glycosyl groups include the following ⁇ -L-glycosyl groups represented by formulas IIB, IIC and IID
• R s and R w are independently hydrogen or methyl and wherein R is hydroxy, lower alkoxy or lower acyloxy and R t is hydrogen, hydroxy, lower alkoxy or acyloxy:
• ⁇ -L - glycosyl groups of formula IIB, IIC, and IID are ⁇ -L-cladinosyl, 4-O-acyl- ⁇ -L-cladinosyl, ⁇ -L-digitoxsyl, 3-O-methyl- ⁇ -L-digitoxsyl, 3,4-di-O-acyl- ⁇ -L-digitoxsyl, 3,4-di-O-acyl- ⁇ -L-mycarosyl,4-O-acyl- ⁇ -L-oleandrosyl, and 3-tetrahydropyranyl.
• the ⁇ -L-cladinosyl group may be obtained by acid cleavage of erythromycin-A [See Example 1(a)].
• the preparations of ⁇ -L-digitoxose and 3-O-methyl- ⁇ -L-digitoxose are disclosed by J.S. Brimacombe et al. in J. Chem.
• Typical suitable starting materials for preparation of the compounds of this invention include any of the known 16-membered macrolides having a free or potentially free hydroxy group at the C-3 carbon as defined in formula I and which may possess other reactive tertiary, secondary or primary hydroxy groups suitably protected as described hereinafter.
• Typical suitable starting materials useful in preparation of the compounds of the present invention include the following known antibiotics or those that are readily preparable from known antibiotics.
• the preparation of desmycosin and that of tylosln are described by R. L. Hamill et al. in U.S. Patent No. 3,178,341.
• the preparation of macrocin and that of lactenocin are described by R. L. Hamill et al.. in U.S. Patent No.
• Cirramycin A 1 is prepared as described by H. Koshiyama et al., J. Antibiotics Ser. A16, 59-66 (1963) and S. Nash et al . in U.S. Patent No. 4,252,898.
• Antibiotic M-4365 G 2 can be prepared by the method described by T. Furumai et al. in J. Antibiotics, 30, 443-449 (1977) or as described by A. K. Ganguly in U.S. Patent No. 3,975,372.
• the preparation of 9-dihydrodesmycosin is described by E.H. Massey in U.S. Patent No. 3,769,273.
• the formyl group in desmycosin, DMOT, tylosin, 12,13-deoxo-12,13-dehydrorosaramicin or DMT can be replaced by hydrogen by use of tris (triphenylphosphine) rhodium chloride, in accordance with the procedure described in U.S. Patent No. 4,345,069, to give the corresponding 19-deformyl derivative, e.g. 19-deformyldesmycosin.
• epoxidation of the 12,13 double bond in for example, tylosin, DMT, 19-deformyl DMT, DMOT or 19-deformyl DMOT may be performed using m-chloroperbenzoic acid as described in U.S. Patent No. 4,477,443 (Examples 58-61) to give the corresponding 12,13-oxo derivative, e.g. 12,13-oxotylosin, 12,13-oxo DMT, 19-deformyl-12,13- oxoDMT, 12,13-oxo DMOT and 19-deformyl-12,13-oxoDMOT.
• suitable starting materials useful for preparation of the compounds of this invention may be obtained by modification of the suitable starting materials hereinabove such as 19-deformyl DMT by well known techniques to convert the free hydroxy group at the 23-carbon in such compounds into compounds wherein the 23-carbon is attached to acyloxy-N,N-di(lower alkyl)amino, lower alkoxycarbonyloxy, aralkoxycarbonyloxy, N-loweralkylaminocarbonyloxy or N-aralkylaminocarbonyloxy.
• suitable starting materials hereinabove such as 19-deformyl DMT by well known techniques to convert the free hydroxy group at the 23-carbon in such compounds into compounds wherein the 23-carbon is attached to acyloxy-N,N-di(lower alkyl)amino, lower alkoxycarbonyloxy, aralkoxycarbonyloxy, N-loweralkylaminocarbonyloxy or N-aralkylaminocarbonyloxy.
• L is a leaving group and R 1 is as previously defined, wherein any reactive groups are protected, if necessary or desired, followed if necessary or desired by one or more of the following steps:
• the preferred leaving group, L is pyridyl-2-thio.
• the Glycosylation Reaction The glycosyl groups are attached to the free hydroxyl group at the C-3 carbon of the 16-membered macrolide starting materials by use of the procedures known in the art. For example, the procedure of Tatsuta, Carb. Research 1977, 54 , p. 85 or of R. B. Woodward et al., J. Am. Chem. Soc. 1981, 103, p. 3215 may be used.
• a suitably protected glycosyl group e.g., l-deoxy-1-(pyridyl-2-thio)- ⁇ and/or ⁇ -L-glycoside such as the 1-S-pyridyl derivative of L-cladinose is reacted with a 16-membered macrolide having a free hydroxyl group at the C-3 carbon (and with other reactive tertiary, secondary and/or primary hydroxyl groups suitably protected) in the presence of anhydrous silver perchlorate or anhydrous silver trifluoromethylsulfonate in an anhydrous aprotic solvent such as acetonitrile. Reaction temperatures of 20-25°C for 20-30 hours are conveniently used.
• any other free hydroxy groups are conveniently protected as acyl derivatives by use of (C 1 -C 5 )alkanoic anhydrides, such as, acetic anhydride in the presence of added base such as pyridine, or as the silyl ethers. Standard deprotection techniques which are well known are used to remove the acyl or silyl protecting groups.
• more labile acyl protecting groups such as aryloxyacyl, haloacetyl, alkoxyacetyl, formyl or haloalkoxycarbonyl may be used. Since very mild basic conditions are employed to remove these more labile acyl groups, the lactone moiety is not adversely affected. In this manner, more labile protecting groups such as phenoxyacetyl may be used for protecting the hydroxyl groups in the glycoside group.
• phenoxyacetyl chloride in the presence of pyridine is reacted with L-digitoxose to form 1,3,4-tri- O-phenoxyacetyl- ⁇ - and - ⁇ -L-digitoxose.
• the 1-O- phenoxyacetyl group is removed by treatment at ambient temperatures, e.g., 25°C with aqueous HC1 e.g. 0.
• DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
• organic trisubstituted nitrogen base refers to acyclic tertiary amines, pyridine and lower alkyl substituted pyridines and bicyclic tertiary amines.
• Typical suitable acyclic tertiary aliphatic amines include tri(lower alkyl) amines such as trimethylamine, triethylamine, tri-n-propylamine and dimethyl-sec-butylamine. Triethylamine is the preferred acyclic tertiary amine.
• Typical suitable substituted pyridines include 2-, 3- and 4-methylpyridine.
• Typical suitable bicyclic tertiary amines include 1,5-diazabicyclo[4.4.0]non-5-ene, hereinafter "DBN” and 1,8- diazabicyclo[5.4.0]undec-7-ene, hereinafter "DBU".
• DBN 1,5-diazabicyclo[4.4.0]non-5-ene
• DBU 1,8- diazabicyclo[5.4.0]undec-7-ene
• lower alkanol refers to straight and branched-chain alcohols of one to six carbons such as methanol, ethanol, n- and iso-propanol. Methanol is preferred.
• the 4-O-acylcladinosyl derivatives (Vla-c) of the compounds of formulas Ia-c are prepared by selectively removing the acyl group from the 2'' position of the desosaminyl sugar by treating compounds Va-c with a lower alkanol, normally methanol, at 25°C for 16 hours.
• a lower alkanol normally methanol
• the 3-O- ⁇ -glycosyl 16-membered macrolide antibacterials of this invention wherein the glycosyl group, R 1 , is represented by formula II may be prepared as described in Example 20.
• the 3-O-glycosyl 16-membered macrolide antibacterials of this invention wherein the glycosyl group, R 1 , is represented by the formula IIA may be prepared as described in Example 18.
• This invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of the present invention or its pharmaceutically acceptable acid addition salts in admixture with a pharmaceutically acceptable carrier.
• the compounds of the present invention are capable of forming pharmaceutically acceptable acid addition salts with inorganic and organic acids.
• pharmaceutically acceptable acid addition salts means those salts that do not exhibit toxic manifestations at normal therapeutic doses.
• Exemplary of such salts are those formed by reaction of the compounds of this invention with acids such as hydrochloric, sulfuric, phosphoric, citric, acetic, propionic, tartaric, maleic, benzoic, cyclopropylcarboxylic, adamantylcarboxylic, lauryl sulfonic, glucoheptonic, stearic, lactobionic and the like.
• Pharmaceutically acceptable acid addition salts may be prepared by methods generally used in the art such as by adding a stoichiometric amount of acid to a solution of a compound of the invention in an inert organic solvent and isolating the salt by art known methods such as precipitation of the salt with a solvent wherein the salt is not appreciably soluble, e.g. diethyl ether.
• An inert organic solvent is one which does not react with the antibacterial, the acid or the salt under conditions of the reaction.
• Typical pharmaceutically acceptable carriers suitable for use in the formulations described are exemplified by sugars such as lactose, sucrose, mannitol and sorbitol; starches such as corn starch, tapioca starch and potato starch; cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinyl pyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such, as magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants, ethylene glycol polymers; betacyclodextrin; fatty acids, hydrolyzed cereal solids; water, polyalkylene glycols; gums; and petroleum ; as well as other
• This invention also embraces a method of eliciting an antibacterial effect against susceptible bacterial infections which comprises administering to an animal, preferably a warm-blooded animal such as man having a susceptible bacterial infection an antibacterially effective amount of a compound of formula I or a pharmaceutical composition thereof.
• the compounds of this invention may be administered orally, intramuscularly, topically or intraveneously. Administration may be effected by any of the conventional methods, i.e., by the use of tablets, capsules, and suspensions, solutions, creams, ointments or injectables. Each of the dosage forms can be formulated utilizing non-toxic pharmaceutically acceptable exc ipients conventionally known in the art.
• the compounds of this invention are preferably administered intravenously at doses of from about 5 to about 50 mg per kg per day, preferably from about 15 to about 30 mg per kg per day, in single or divided doses.
• the compounds of this invention may also be administeredorally at doses of from about 15 mg/kg to 50 mg/kg or subcutaneously at doses of about 15 mg/kg to 30 mg/kg.
• the compounds of this invention elicit an antibacterial effect against a wide variety of bacterial species, but are generally more active against strains of Gram-positive bacteria.
• Exemplary of the bacteria against which the compounds of this invention are active are various strains of Staphylococci and Streptococci.
• the compounds of the invention have enhanced (IV) serum levels and a similar spectrum of antibacterial activity to that of the corresponding parent 16-membered macrolide having a free C-3 hydroxyl group.
• the compounds are also active against erythromycin-resistant strains of Staphylococci and methicillin-susceptible and methicillin-resistant strains of Staphylococci.
• the antibacterial activity of the compounds of this invention is determined by testing against a variety of pathogens using standard antibacterial dilution assays in Mueller-Hinton agar, the activity being expressed as the Minimum Inhibitory Concentration (MIC, meg./ml., 24 hours).
• MIC Minimum Inhibitory Concentration
• the geometric mean MIC's of the compounds of this invention are in the range of about 0.088 to 27.
• Erythromycin A (Merck Index, 10th Edition Entry No. 3624) (50g) was dissolved in IN aqueous hydrochloric acid (70 mL) and water (500 mL) and the mixture subjected to liquid-liquid extraction using diethyl ether for 99 h. The ether extract was evaporated to dryness to give L-cladinose (11.7g, 97%) as a colorless viscous oil.
• 1,4-Di-O-actyl- ⁇ -L-cladinose (2.18g) was dissolved in 0.1N aqueous hydrochloric acid (245 mL) and the mixture was allowed to remain at 25°C for 1 h. The mixture was extracted with diethyl ether and the ether layer was retained. The aqueous acid layer was neutralized and extracted with dichloromethane. The latter was combined with the ether extract and dried (MgSO4), filtered and evaporated to dryness to give 4-O-acetyl- ⁇ - and ⁇ -L-cladinose (1.86g, 100%) as a colorless gum that was used without further purification.
• 4-O-Acetyl-L-cladinose (1.84g) was dissolved in dry dichloromethane (25 mL) and the solution was cooled to 13°C. After 30 minutes a chilled solution of 2,2'-dipyridyldisulphide (Aldrithiol-2) (2.8g) and tri-n-butylphosphine (3.45g) in dry dichloromethane (30 mL) was added in one portion. The mixture was allowed to remain at 13°C under dry argon for 19 h.
• Aldrithiol-2 2,2'-dipyridyldisulphide
• 3.45g tri-n-butylphosphine
• 1,4-Di-O-phenoxyacetyl- ⁇ -L-cladinose (63.35 g) was dissolved in acetonitrile (4.5 L) and 0. IN hydrochloric acid (4.158 L) was added and the mixture was stirred at 25°C for 18 h.
• the reaction mixture was neutralized to pH 7.3 and the acetonitrile was evaporated in vacuo.
• the resulting aqueous solution was extracted with diethyl ether (2 ⁇ 1.5 L) and then with dichloromethane (2 ⁇ 1.5 L). The combined organic extracts were evaporated to dryness and the residue was chromotographed on a preparative HPLC using two silica gel cartridges.
• the mixture was evaporated to dryness and the residue was extracted with ethyl acetate and filtered.
• the ethyl acetate extract was evaporated to dryness and the residue was taken up in dichloromethane and washed with water the pH being adjusted to 10.
• the organic layer was dried (MgSO 4 ), filtered and evaporated to dryness.
• the residue was chromatographed on a silica gel column (60x2.5 cm.) using 5% increasing to 20% ethyl acetate in dichloromethane (v/v) as the eluant.
• Desmycosin (Merck Index, Tenth Edition p. 1405) (18.9 g) was dissolved in degassed benzene (580 mL) and tris (triphenylphosphine)rhodium chloride (29.5 g.) was added. The mixture was heated under dry nitrogen at 90°C for 16 h. The mixture was diluted with ethyl acetate and extracted twice with 0.2N hydrochloric acid. The aqueous acid layer was adjusted to pH 10 and extracted with dichloromethane. The latter was dried (MgSO 4 ), filtered and evaporated to dryness.
• 19-Deformyldesmycosin (12 g) was dissolved in dry acetone (100 mL) and acetic anhydride (7.6 mL) was added. The mixture was allowed to remain at 25 °C for 17 h. The solution was evaporated to dryness and the residue was azeotroped with toluene to give 2',4'-di-O-acetyl-19-deformyldesmycosin (11.5 g., 86%) as a colorless amorphous solid that was used without further purification.
• the mixture was evaporated to dryness and the residue was extracted with ethyl acetate and filtered.
• the ethyl acetate was removed in vacuo and the residue was taken up in dichloromethane and washed with water, the pH being adjusted to 10.
• the organic layer was dried (MgSO 4 ), filtered and evaporated to dryness.
• the residue was chromatographed on a silica gel column (30x2.5 cm) using 5% increasing to 20% ethyl acetate in dichloromethane (v/v) as the eluant.
• the reaction mixture was evaporated to dryness and the residue was taken up in dichloromethane and washed with 5% aqueous sodium bicarbonate.
• the dichloromethane layer was filtered, washed with water, dried (Na 2 SO 4 ), filtered and evaporated to dryness.
• the residue was triturated with ethyl acetate and filtered.
• the solids were washed with ethyl acetate and the combined filtrates were evaporated to dryness.
• the residue was chromatographed on a silica gel column (200 g.) using 10%, 20%, 25% and finally 45% acetone in toluene (v/v) as the eluant to give a ca.
• 2-Methoxy-1-butanol (prepared by standard methods known in the art, for example those described in CA, 1984, Vol. 101, 6616f and CA, 1984, Vol. 100, 209159 m.) is reacted with formaldehyde and 90% HCl to give 2-methoxy-1-butyloxymethyl chloride.
• the latter reacts with 2'-O-acetyl-12,13-dehydro-12,13-deoxorosaramicin of Example 2(a) in the presence of a tertiary amino base, followed by reaction with a lower alkanol such as methanol, to give the title compound.

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