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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

• the invention described herein relates to processes for preparing macrolide antibacterial agents.
• the invention relates to intermediates and processes for preparing ketolides and other macrolides that include a 1,2,3-triazole substituted side chain.
• Erythromycin was the first compound of this class to be introduced into clinical practice. Since then, additional macrolides, including ketolides have garnered much attention for their ability to treat a wide range of disease states. In particular, macrolides are an important component of therapies for treating bacterial, protozoal, and viral infections. In addition, macrolides are often used in patients allergic to penicillins.
• macrolide compounds have been found to be effective for the treatment and prevention of infections caused by a broad spectrum of bacterial and protozoal infections. They are also useful for infections of respiratory tract and soft tissue infections. Macrolide anitbiotics are found to be effective on beta-hemolytic streptococci, pneumococci, staphylococci and enterococci. They are also found to be effective against mycoplasma, mycobacteria, some rickettsia, and chlamydia.
• Macrolide compounds are characterized by the presence of a large lactone ring, which is generally a 14, 15, or 16-membered macrocyclic lactone, to which one or more saccharides, including deoxy sugars such as cladinose and desosamine, may be attached.
• erythromycin is a 14-membered macrolide that includes two sugar moieties.
• Spiramycin belongs to a second generation of macrolide compounds that include a 16- membered ring.
• Third generation macrolide compounds include for example semi-synthetic derivatives of erythromycin A, such as azithromycin and clarithromycin.
• ketolides represent a newer class of macro lide antibiotics that have received much attention recently due to their acid stability, and most importantly due to their excellent activity against organisms that are resistant to other macro lides.
• ketolides are 14-membered ring macro lide derivatives characterized by a keto group at the C-3 position (Curr. Med. Chem., "Anti-Infective Agents," 1 : 15-34 (2002)).
• telithromycin U.S. Patent No. 5,635,485
• telithromycin U.S. Patent No. 5,635,485
• Liang et al. describes compounds including those of formula (I):
• R 1 is a monosaccharide or polysaccharide
• A is -CH 2 -, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(O)2NH-, -C(O)NHS(O)2-;
• B is -(CH 2 )D- where n is an integer ranging from 0-10, or B is an unsaturated carbon chain of 2-10 carbons, which may contain any alkenyl or alkynyl group;
• C represents 1 or 2 substituents independently selected in each instance from hydrogen, halogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl, ureyl, and carbamoyl, each of which is optionally substituted;
• W is hydrogen, F, Cl, Br, I, or OH
• R 1 is a monosaccharide or polysaccharide
• A is -CH 2 -, -C(O)-, -C(O)O-, -C(O)NH-, -S(O)2-, -S(0)2NH-, -C(0)NHS(0)2-;
• B is -(CH 2 ) n - where n is an integer ranging from 0-10, or B is an unsaturated carbon chain of 2-10 carbons, which may contain any alkenyl or alkynyl group;
• C represents 1 or 2 substituents independently selected in each instance from hydrogen, halogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, heteroarylalkyl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl, ureyl, and carbamoyl, each of which is optionally substituted;
• W is hydrogen, F, Cl, Br, I, or OH
• R 1 is a monosaccharide that includes an optionally protected 2'-hydroxy group.
• R 1 is a monosaccharide that includes a protected 2'-hydroxy group, where the protecting group is a sterically hindered acyl group, such as a branched alkyl, aryl, heteroaryl, arylalkyl, arylalkyl, or heteroarylalkyl acyl group, each of which is optionally substituted.
• -A-B- is alkylene, cycloalkylene, or arylene; and C is optionally substituted aryl or heteroaryl.
• R 1 is desosamine; -A-B- is 1,4-butylene and C is 4-(3-aminophenyl).
• W is F.
• R 1 is desosamine that includes a protected 2'-hydroxyl group, where the protecting group is a sterically hindered acyl group.
• the sterically hindered acyl group is benzoyl or substituted benzoyl.
• R la is a sterically hindered acyl group, and A, B, C, and V are as described herein.
• -A-B- is alkylene, cycloalkylene, or arylene; and C is optionally substituted aryl or heteroaryl.
• R la is benzoyl; -A-B- is 1,4- butylene and C is 4-(3-aminophenyl).
• A, B, C, and V are as described herein.
• -A-B- is alkylene, cycloalkylene, or arylene; and C is optionally substituted aryl or heteroaryl.
• -A-B- is 1,4-butylene and C is 4-(3-aminophenyl).
• R 1 is a monosaccharide that includes a 2'-hydroxyl group, and V, W, X, and Y are as defined herein, with a sterically hindered acylating agent R la -L, wherein R la is a sterically hindered acyl group and L is a leaving or activating group, to form the corresponding 2'-acyl derivative.
• the process includes the step of (a) reacting compound (1) with a sterically hindered acylating agent to form the corresponding 2'-acyl or 2',4"-diacyl derivative, compound (2), as follows:
• W and R la are as defined herein.
• a process for preparing a compound of formula (I), (II), or (III) comprising the step of (b) reacting a compound of formula (IV) with a carbonylating reagent to form a compound of formula (V): where L is a leaving group, and R 1 , V, W, X, and Y are as defined herein.
• the process includes the step of (b) reacting compound (2) with carbonyldiimidazole to prepare compound (3):
• R la and W are as defined herein.
• a process for preparing a compound of formula (I), (II), or (III) comprising the step of (c) reacting a compound of formula (V) with a compound of formula N 3 -B-A-NH 2 to obtain a compound of formula (VI):
• R 1 , A, B, V, W, X, and Y are as described herein.
• a and B are taken together to form alkylene, cycloalkylene, including spirocycloalkylene, or arylene, each of which is optionally substituted.
• the process includes the step of (c) reacting compound (3) with N 3 -B-A-NH 2 to obtain compound (4):
• R la , A, B, and W are as described herein.
• a process for preparing a compound of formula (I), (II), or (III) comprising the step of (d) reacting a compound of formula (I), where X is hydrogen and Y is OR 7 ; where R 7 is a monosaccharide or disaccharide with an acid to prepare the corresponding compound of formula (I) where R 7 is hydrogen.
• the process includes the step of (d) reacting compound (4) with an acid to prepare compound (5):
• R la , A, B, and W are as described herein.
• the process includes the step of (e) oxidizing compound (5) with an oxidizing agent to prepare compound (6): where R , 1a a , A, B, and W are as described herein.
• a process for preparing a compound of formula (I), (II), or (III) comprising the step of (f) reacting a compound of formula (I), where W is hydrogen, with a fluorinating agent to prepare the corresponding compound of formula (I) where W is F.
• the process includes the step of (f) reacting compound (6) with a fluorinating agent to prepare compound (7):
• R , 1a a , A, and B are as described herein.
• a process for preparing a compound of formula (I), (II), or (III) comprising the step of converting the azide group on a compound of formula (VI) into the corresponding compound of formula (I) having a 1,2,3- triazole group.
• a process is described for preparing a compound of formula (I), (II), or (III) comprising the step of (g) reacting a compound of formula (VI) with an R 4 ,R 5 - substituted alkyne to obtain a compound of formula (VII):
• R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, and heteroaryl, each of which is optionally substituted, and R 1 , A, B, V, W, X, and Y are as described herein. In one aspect, both R 4 and R 5 are not hydrogen. In another aspect, at least one of R 4 and R 5 is hydrogen. In one variation, A and B are taken together to form alkylene, cycloalkylene, including spirocycloalkylene, or arylene, each of which is optionally substituted.
• the process includes the step of (g) performing a Huisgen cyclization in the presence of a copper catalyst and base on compound (7) to prepare compound (8):
• R , 1a a , A, and B are as described herein.
• a process for preparing a compound of formula (I) comprising the step (h) of reacting a compound of formula (I), where R 1 is a monosaccharide or polysaccharide having a acyl protecting group, with an alcohol to prepare the corresponding deprotected compound of formula (I).
• a process is described for preparing a compound of formula (III) comprising the step of reacting a compound of formula (II) with an alcohol.
• the process includes the step of (h) reacting compound (8) with an alcohol to prepare compound (9):
• the processes described herein may be advantageously performed simply and cost-effectively. It is further appreciated that the processes described herein may be scaled to large production batches. It is further appreciated that the processes described herein are performed in fewer steps than conventional processes. It is further appreciated that the processes described herein are performed in more convergent steps and fewer linear steps than conventional processes. It is further appreciated that the processes described herein may concomitantly produce fewer or different side products than known processes. It is further appreciated that the processes described herein may yield compounds described herein in higher purity than known processes.
• R 1 is a monosaccharide or polysaccharide.
• the monosaccharide is an aminosugar or a derivative thereof, such as a mycaminose derivatized at the C-4' position, desosamine, a 4-deoxy-3-amino-glucose derivatized at the C-6' position, chloramphenicol, clindamycin, and the like, or an analog or derivative of the foregoing.
• the polysaccharide is a disaccharide, such as a mycaminose derivatized at the C-4' position with another sugar or a 4-deoxy-3-amino-glucose derivatized at the C-6' position with another sugar, a trisaccharide, such as an aminosugar or halosugar, or an analog or derivative of the foregoing.
• R 1 is desosamine, or an analog or derivative thereof. It is to be understood that in this and other embodiments, derivatives include protected forms of the monosaccharide or polysaccharide.
• R 1 is a monosaccharide that includes a 2'-hydroxyl group
• V, W, X, and Y are as defined herein, with a sterically hindered acylating agent R la -L, wherein R la is a sterically hindered acyl group and L is a leaving or activating group, to form the corresponding 2'-acyl derivative.
• R la is a sterically hindered acylating agent
• L is a leaving or activating group
• the process includes the step of (a) reacting compound (1) with a sterically hindered acylating agent to form the corresponding 2'-acyl or 2',4"-diacyl derivative, compound (2), as follows: wherein W and R , 1a a are as defined herein.
• W is F.
• R la is an optionally substituted benzoyl group
• step (a) includes benzoic anhydride, or an equivalent activated benzoylating reagent capable of forming the benzoyl ester at the 2' or both the 2' and 4' positions of a compound of formula (IV), or alternatively compound (1).
• Illustrative bases include but are not limited to inorganic bases, such as sodium and potassium bicarbonates and carbonates, sodium and potassium hydroxides, and the like, and mixtures thereof; and amine bases, such as pyridine, dimethylaminopyridine (DMAP), triethylamine (TEA), diisopropylethylamine (DIPEA, H ⁇ nigs base), l,4-diazabicyclo[2.2.2]octane (DABCO), and the like, and mixtures thereof.
• the reaction may be performed at a variety of temperatures, such as in the range from about O 0 C to about 60 0 C, and illustratively at about 10 0 C to about 30 0 C.
• a process for preparing a compound of formula (I), (II), or (III) comprising the step of (b) reacting a compound of formula (IV) with a carbonylating reagent to form a compound of formula (V):
• Step (d) is generally performed in a solvent such as water, a polar organic solvent, including alcohols such as methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol, and the like, and mixtures thereof.
• Step (d) may be performed at a wide variety of temperatures, including temperatures in the range from about 0 0 C to about 70 0 C, and illustratively in the range from about 20 0 C to about 6O 0 C.
• the oxidizing agent is selected from Swern conditions such as DMSO/EDAC ⁇ Cl/pyridine-TFA, Dess-Martin conditions, Corey-Kim conditions, such as dimethylsulfide/N-chlorosuccinimide, Jones reagent and other chromium oxidizing agents, permanganate and other manganese oxidizing agents, Ni(Ac)2/hypochlorite, and others.
• the oxidation is carried out using the Dess-Martin periodinane in methylene chloride at a temperature from about 5°C to about 30 0 C utilizing a mole-equivalent ratio of Dess-Martin periodinane to compound (5) of from about 3.3 to 1 to about 1.3 to 1.
• the oxidation is carried out using the Dess-Martin periodinane in methylene chloride at a temperature from about 5°C to about 30 0 C utilizing a mole-equivalent ratio of Dess-Martin periodinane to compound (5) of about 1.3 to 1.
• the process includes the step of (f) reacting compound (6) with a fluorinating agent, such as (PhSC ⁇ N-F (NFSI or N- fluorosulfonimide), F-TEDA, F-TEDA-BF 4 , l-fluoro-4-hydroxy-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), and the like, in the presence of solvent and base, such as t-BuOK, to prepare compound (7):
• a fluorinating agent such as (PhSC ⁇ N-F (NFSI or N- fluorosulfonimide), F-TEDA, F-TEDA-BF 4 , l-fluoro-4-hydroxy-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), and the like
• Illustrative substituted alkynes include alkynes substituted with aromatic groups, substituted aromatic groups, heterocyclic groups, substituted heterocyclic groups, alkyl groups, branched alkyl groups, substituted alkyl groups, such as alkyl groups substituted with amino groups, including primary, secondary, and tertiary amino groups, one or more halogens, hydroxyls, ethers, including alkyl and aromatic ethers, ketones, thioethers, esters, carboxylic acids, cyanos, epoxides, and the like.
• R 1 is a monosaccharide that includes a 2'-hydroxyl group acylated with a sterically hindered acylating agent R la -L, wherein R la is a sterically hindered acyl group and L is a leaving or activating group; and A, B, and W are as defined herein.
• the steps (a), (b), (c), (d), (e), (f), (g), and (h) are performed as described herein.
• the processes described herein are useful for preparing compounds of formulae (I), (II), and (III) in higher yields and/or purity than conventional processes.
• the processes described herein allow for the direct introduction of an azide side chain onto the macro lide without requiring the prior activation of a side chain hydroxyl group, such as by using tosyl chloride or an equivalent activating group, and subsequent conversion into the corresponding side chain azide group.
• the direct introduction of the azide side chain as described herein reduces the overall number of synthetic steps that must be performed in preparing compounds of formulae (I), (II), and (III).
• Conventional syntheses disclose the introduction of a side chain containing an alcohol group that must be converted into the azide in a linear sequence in at least two steps.
• the adsorbent solid is selected from a reverse-phase adsorbent, silica gel, alumina, magnesia-silica gel, or the like
• the elutant is selected from ethyl acetate, isopropyl acetate, methylene chloride, heptane, cyclohexane, toluene, acetonitrile, methanol, isopropanol, ethanol, THF, water or the like, or combinations thereof.
• the solid adsorbent is magnesia-silica gel.
• the processes described herein improve the purity of the compounds of formulae (I), (II), and (III) described herein, and/or improve the purification of the compounds described herein.
• the processes described herein include the use of a sterically hindered acyl group that functions both to protect a hydroxyl group on the saccharide moieties of the macro lide and also functions to provide more effective purification of the compounds. For example, it has been discovered that performing the Huisgen cyclization leads to a mixture of triazole compound of formula (VII) and unreacted ethyne compound.
• heteroaryl refers to optionally substituted aromatic ring systems having one or more heteroatoms such as, for example, oxygen, nitrogen, sulfur, selenium and phosphorus.
• heteroaryl may include five- or six-membered heterocyclic rings, poly cyclic heteroaromatic ring systems and polyheteroaromatic ring systems.
• Example 2 Preparation of 10,11 -anhydro-2',4"-di-O-benzoyl- 12-0- imidazolylcarbonyl-6-O-methylerythromycin A.
• Dimethylformamide (DMF, 100 mL) was added to 2',4"-di-O-benzoyl-6-O-methylerythromycin A at 25-35°C, then 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU 6.4 g) was added to the reaction mixture and stirred at ambient temperature.
• l,l'-Carbonyldiimidazole (CDI, 17 g) was added to the reaction and it was stirred until completion at ambient temperature.
• the title compound is isolated by addition of water, and collecting the resulting precipitate.
• the solid was treated with dichloromethane followed by extraction and removal of solvent to give the title compound.
• the mole-equivalent ratio of 4-azido butyl amine to 10,1 l-anhydro-2',4"-di-O-benzoyl-12-O- imidazolylcarbonyl-6-O-methylerythromycin A is optionally selected to be from about 4 to 1 to about 3 to 1.
• the molar ratio of DBU to 10,1 l-anhydro-2',4"-di-O-benzoyl- 12-0- imidazolylcarbonyl-6-O-methylerythromycin A is optionally selected to be from about 1 to 1 to about 0.75 to 1.
• Example 5 Preparation of 1 l-N-(4-Azidobutyl)-5-(2'-benzoyldesosaminyl)-3- oxo-6-O-methylerythronolide A 11,12-cyclic carbamate.
• Dichloromethane 50 mL was added to N-chlorosuccinimide (2 g) under nitrogen at room temperature cooled to 0 0 C.
• Dimethylsulfide (1.8 mL) was added slowly to the reaction mixture at 0 0 C under stirring.
• the reaction mixture was quenched with 5 % aqueous sodium hydroxide solution.
• the organic layer was washed with water and sat. solution of sodium chloride.
• the solvent was removed by distillation of the organic layer and the product was isolated from a mixture of diisopropyl ether and hexane.
• the separated solid was filtered and dried under vacuum at 30-35 0 C to give the title compound.
• the mole-equivalent ratio of Dess-Martin periodinane to 1 l-N-(4-azidobutyl)- 5-(2'-benzoyldesosaminyl)-3-hydroxy-6-O-methylerythronolide A 11,12-cyclic carbamate is optionally from about 3.3 to 1 to about 1.3 to 1.
• the material is converted to a salt by addition of an acid followed by precipitation of the salt.
• Analysis of the material indicated the title compound with >98% purity. Examples 1-8 were repeated to prepare a 5 kg sample of the title compound of Example 8. It was determined that the large sample contained less than about 0.1% aminophenylethynes, or about 0.07% aminophenylethynes.
• Example 9 Purification of 1 l-N-(3-amino-phenyl-l-ylmethyl-[l,2,3]-triazole-l- yl]butyl)-5-desosaminyl-3-oxo-2-fluoro-erythronolide A, 11,12-cyclic carbamate. Florisil (21 kg) was loaded into a column containing 63 L of ethyl acetate.
• the filtrate is slowly added to a solution of aqueous ammonia (0.79 L ammonia in 28 L water) at 10-25 0 C.
• aqueous ammonia (0.79 L ammonia in 28 L water) at 10-25 0 C.
• the resulting mixture is stirred for 30 minutes and the solid is collected by centrifugation.
• the solid was dried at 45-50 0 C until the moisture content was not more than 1.5%.
• Example 9A 1 l-N-(3-amino-phenyl-l-ylmethyl-[l,2,3]-triazole-l-yl]butyl)-5- desosaminyl-3-oxo-2-fluoro-erythronolide A, 11,12-cyclic carbamate is optionally purified by dissolving material in a minimum amount of a solvent and adding an acid to the mixture to form a solid that precipitates from the solvent or precipitates after addition of a second solvent to the acidified mixture.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biochemistry (AREA)
• Molecular Biology (AREA)
• Genetics & Genomics (AREA)
• Biotechnology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Animal Behavior & Ethology (AREA)
• Oncology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Communicable Diseases (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Saccharide Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Related Child Applications (2)

Publications (1)

Family

ID=40580003

Family Applications (1)

Country Status (9)

Cited By (16)

Families Citing this family (8)

Citations (4)

Family Cites Families (147)

• 2008
  • 2008-10-23 CN CN201610086292.4A patent/CN105732745A/zh active Pending
  • 2008-10-23 AU AU2008316830A patent/AU2008316830B2/en not_active Ceased
  • 2008-10-23 US US12/739,652 patent/US9453042B2/en not_active Expired - Fee Related
  • 2008-10-23 JP JP2010531238A patent/JP5698979B2/ja active Active
  • 2008-10-23 EP EP08841217A patent/EP2214484A4/en not_active Withdrawn
  • 2008-10-23 CA CA2703475A patent/CA2703475A1/en not_active Abandoned
  • 2008-10-23 CN CN200880123646.1A patent/CN101917850B/zh not_active Expired - Fee Related
  • 2008-10-23 WO PCT/US2008/080936 patent/WO2009055557A1/en not_active Ceased
• 2010
  • 2010-04-22 IL IL205254A patent/IL205254A/en active IP Right Grant
• 2014
  • 2014-11-10 JP JP2014227753A patent/JP6167095B2/ja active Active
• 2016
  • 2016-06-01 AU AU2016203649A patent/AU2016203649A1/en not_active Abandoned
  • 2016-09-12 US US15/262,277 patent/US10131684B2/en active Active
  • 2016-12-23 HK HK16114635.4A patent/HK1226411A1/zh unknown
• 2017
  • 2017-06-26 JP JP2017124117A patent/JP6845099B2/ja active Active
• 2018
  • 2018-10-10 US US16/155,939 patent/US20190241602A1/en not_active Abandoned
• 2019
  • 2019-05-15 JP JP2019092242A patent/JP2019147827A/ja active Pending

Patent Citations (4)

Non-Patent Citations (4)

Also Published As

Similar Documents

Legal Events