WO2001000624A1 - Procede de synthese de carbapenems naphthosultam - Google Patents

Procede de synthese de carbapenems naphthosultam Download PDF

Info

Publication number
WO2001000624A1
WO2001000624A1 PCT/US2000/016993 US0016993W WO0100624A1 WO 2001000624 A1 WO2001000624 A1 WO 2001000624A1 US 0016993 W US0016993 W US 0016993W WO 0100624 A1 WO0100624 A1 WO 0100624A1
Authority
WO
WIPO (PCT)
Prior art keywords
groups
substituted
unsubstituted
branched
straight
Prior art date
Application number
PCT/US2000/016993
Other languages
English (en)
Inventor
Edward J. J. Grabowski
John Y. L. Chung
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU58813/00A priority Critical patent/AU5881300A/en
Publication of WO2001000624A1 publication Critical patent/WO2001000624A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/02—Preparation
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for synthesizing carbapenem intermediates and compounds produced.
  • hydroxymethylcarbapenems are substituted at the 2-position through a CH2 link with various sidechains to prepare anti-methicillin resistant Staphylococcus aureus (MRSA) compounds.
  • MRSA anti-methicillin resistant Staphylococcus aureus
  • the intermediate compounds are included as well.
  • Examples of carbapenems which are substituted with a naphthosultam-containing side chain at the 2-position are found in Schmitt, S. M. et al., J. Antibiotics 41(6): 780-787 (1988) and U. S. Patent No. 5,756,725, issued May 26, 1998, the teachings of which are hereby incorporated by reference.
  • European applications 0330108, 0102239, 0212404, 0695753 and 0476649 also disclose methods for synthesizing various antibiotic derivatives.
  • carbapenems are useful against gram positive microorganisms, especially methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). These antibacterials thus comprise an important contribution to therapy for treating infections caused by these difficult to control pathogens. There is an increasing need for agents effective against such pathogens (MRSA/MRCNS) which are at the same time relatively free from undesirable side effects.
  • MRSA methicillin resistant Staphylococcus aureus
  • MRSE methicillin resistant Staphylococcus epidermidis
  • MRCNS methicillin resistant coagulase negative Staphylococci
  • This invention relates to a novel method for making late stage MRSA carbapenem intermediates via a one-pot nitromethylation-allylation protocol or a similar process thereof, which avoids the disadvantages associated with the Stille Coupling and Wittig methods.
  • the claimed process uses safe and readily available reagents to achieve the transformation in a short sequence of steps.
  • R represents H or methyl
  • P* represents H, negative charge, or a carboxy protecting group; P represents hydrogen, or hydroxy-protecting group; and each R is independently selected from: -R*; -Q; hydrogen; halo; - CN; -NO 2 ; -NR a R b ; -OR c ; -SR C ; -C(O)NR a R b ; -C(O)OR h ; -S(O)R c ; -SO 2 R c ; - SO 2 NR a R b ; -NR a SO 2 R b ; -C(O)R a ; -OC(O)R ; -OC(O)NR a R b ; -NR a C(O)NR b R ; - NR a CO 2 R h ; -OCO 2 R h ; -NR a C(O)R b ; -Ci -6 straight- or branched-
  • R e , R f andR g represent hydrogen; -R*; -Ci -6 straight- or branched- chain alkyl unsubstituted or substituted with one to four R 1 groups; or R e and R f taken together with any intervening atoms represent a 4-6 membered saturated ⁇ ng optionally interrupted by one to three of O, S, -C(O)- or NRg with RS as defined above, said ⁇ ng being unsubstituted or substituted with one to four R 1 groups, each R 1 independently represents halo; -CN; -NO2; phenyl; -NHSO2R h ; -OR h , -SR h ; -N(R h )2; -N+(R h )3; -C(O)N(R h )2; -SO2N(R h )2; heteroaryl; heteroarylium; -CO2R h ; -C
  • Q is selected from the group consisting of:
  • a and b are 1, 2 or 3;
  • L ⁇ is a pharmaceutically acceptable counte ⁇ on; ⁇ represents O, S or NR S ; ⁇ , ⁇ , ⁇ , ⁇ and ⁇ represent CR*, N or N + R s , provided that no more than one of ⁇ , ⁇ , ⁇ , ⁇ and ⁇ is N + R s ;
  • R* is selected from the group consisting of:
  • d represents O, S or NR k ;
  • e, g, x, y and z represent CR m , N or N + R k , provided that no more than one of e, g, x, y and z in any given structure represents N + R k ;
  • R n and R° represent hydrogen, phenyl; -Ci-6 straight- or branched- cham alkyl unsubstituted or substituted with one to four R 1 groups; each R s independently represents hydrogen; phenyl or -Ci -6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R 1 groups; each R l independently represents hydrogen; halo; phenyl; -CN; -NO 2 ; - NR U R V ; -OR u ; -SR U ; -CONR u R v ; -COOR h ; -SOR u ; -SO 2 R u ; -SO 2 NR u R v ; - NR u SO 2 R v ; -COR u ; -NR u COR ; -OCOR u ; -OCONR u R v ; -NR u CO 2 R v
  • R u and R v represent hydrogen or -C1 -6 straight- or branched-cham alkyl, unsubstituted or substituted with one to four R 1 groups; or R u and R v together with any intervening atoms represent a 4-6 membered saturated ⁇ ng optionally interrupted by one or more of O, S, NR W or - C(O)-, said ⁇ ng being unsubstituted or substituted with one to four R 1 groups; each R w independently represents hydrogen; -Ci -6 straight- or branched-cham alkyl, unsubstituted or substituted with one to four R 1 groups, C3.6 cycloalkyl optionally substituted with one to four R 1 groups; phenyl optionally substituted with one to four R 1 groups, or heteroaryl optionally substituted with 1-4 R 1 groups; or R n and R w taken together with any intervening atoms represent a 5- 6 membered saturated ⁇ ng, optionally interrupted by one or two of O, S
  • R x represents hydrogen or a C1 -8 straight- or branched- chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NR W , N+R h R , or -C(O)-, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, OR w , SR W , SOR , SO2R w , NR h R , N+(R h )2R w , -C(O)-R w , C(O)NR h R w ,
  • SO2NR h R CO2R w , OC(O)R w , OC(O)NR h R , NR h C(O)R , NR h C(O)NR h R , or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R 1 groups or with one to two C1.3 straight- or branched- chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four R 1 groups; RY and R z represent hydrogen; phenyl; -C ⁇ _6 straight or branched chain alkyl, unsubstituted or substituted with one to four R 1 groups, and optionally interrupted by O, S, NR , N+R h R w or -C(O)-; or R x and R together with any intervening atoms represent a 4-6 membered saturated ⁇ ng optionally interrupted by O, S, SO2, NR W , N+R h
  • R, P and P* are as previously defined and R ⁇ represents halo, SOEt, OTf, or OP(O)(OR")2, wherein R" represents Ci-6 alkyl, aryl or benzyl.
  • alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl. When substituted, alkyl groups may be substituted with up to four substituent groups, selected from R" and R as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group”. Cycloalkyl is a specie of alkyl containing from 3 to
  • alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond.
  • Prefe ⁇ ed alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
  • alkynyl refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond.
  • Preferred alkynyl groups include ethynyl, propynyl and butynyl.
  • Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like.
  • An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms.
  • the preferred aryl groups are phenyl, naphthyl and phenanthrenyl.
  • Aryl groups may likewise be substituted as defined. Prefe ⁇ ed substituted aryls include phenyl and naphthyl.
  • heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from
  • additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein.
  • nitrogen heteroatoms examples include pyrrole, pyridine, oxazole, thiazole and oxazine.
  • Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole. Examples include the following:
  • Heteroarylium refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge. Examples include the following:
  • heterocycloalkyl refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by hetero atoms.
  • the terms “quaternary nitrogen” and “positive charge” refer to tetravalent, positively charged nitrogen atoms including, e.g., the positively charged nitrogen in a tetraalkylammonium group (e. g. tetramethylammonium), heteroarylium, (e.g., N-methyl- pyridinium), basic nitrogens which are protonated at physiological pH, and the like. Cationic groups thus encompass positively charged nitrogen-containing groups, as well as basic nitrogens which are protonated at physiologic pH.
  • heteroatom means O, S or N, selected on an independent basis.
  • Halogen and "halo" refer to bromine, chlorine, fluorine and iodine.
  • Alkoxy refers to C j -C4 alkyl-O-, with the alkyl group optionally substituted as described herein.
  • protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al. Protective Groups in Organic Synthesis Wiley, New York (1991). Examples of suitable protecting groups are contained throughout the specification.
  • P and P* represent hydroxyl and carboxyl protecting groups, respectively. These groups are generally removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst and a nucleophile and catalytic hydrogenation.
  • carboxyl protecting groups P* include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl groups such as t-butyldimethylsilyl (TBDMS), trimethylsilyl, (TMS), triethylsilyl (TES), and trimethylsilylethyl, phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p- nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, and t-butyl.
  • TDMS t-butyldimethylsilyl
  • TMS trimethylsilyl
  • TES triethylsilyl
  • phenacyl p-methoxybenzyl
  • o-nitrobenzyl p-methoxyphenyl
  • p-methoxyphenyl p-methoxyphenyl
  • Suitable hydroxy protecting groups P include TMS, TES, TBDMS, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.
  • -CO2P* which is attached to the carbapenem nucleus at position 3, this can represent a carboxylic acid group (P* represents H), a carboxylate anion (P* represents a negative charge), a pharmaceutically acceptable ester (P* represents an ester forming group) or a carboxylic acid protected by a protecting group (P* represents a carboxyl protecting group).
  • the pharmaceutically acceptable salts referred to above may take the form -COO P*, where P* is a negative charge, which is balanced by one or more counterions as needed, e.g., an alkali metal cation such as sodium or potassium.
  • Counterions may be calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.
  • the pharmaceutically acceptable salts referred to above also include phosphate, sulfate and acid addition salts.
  • the Formula 4 compounds can be used in the form of salts derived from inorganic or organic acids. Included among such salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
  • the pharmaceutically acceptable esters are such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,438. Included within such pharmaceutically acceptable esters are those which are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others described in detail in U.S. Pat. No. 4,479,947. These are also refe ⁇ ed to as "biolabile esters". Suitable nucleophiles of this invention are selected from compounds of the structural formula 7, 7a, 7b, and 7c
  • Rl is as described above.
  • Suitable carbon acids include nitromethane (CH 3 NO 2 ), methyl triflone (CF 3 SO 2 CH 3 ; prepared from MeMgCl/CF 3 SO 2 F) and trimethyl sulfoxonium chloride (Me3SOI), preferably nitromethane.
  • CH 3 NO 2 nitromethane
  • CF 3 SO 2 CH 3 methyl triflone
  • Me3SOI trimethyl sulfoxonium chloride
  • Suitable bases include trialkylamines such as triethylamine, trimethylamine, ethyldimethylamine, tri-n-propylamine and the like, tetramethylguanidine (TMG) and its analogs, l,8-diazabicyclo[5.4.0.]undec-7-ene (DBU) and its analogs, pyridine, lutidine, collidine, 4-dimethylaminomethyl-pyridine, inorganic carbonates and bicarbonates such as sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, and the like and tartrates such as potassium sodium tartrate, potassium tartrate, potassium bitartrate, sodium tartrate, sodium bitartrate and the like.
  • Preferable bases are tetramethylguanidine and (TMG), l,8-diazabicyclo[5.4.0.]undec-7-ene (DBU).
  • Suitable palladium (Pd) catalyst are those which contain a palladium and a phosphine ligand source or a phosphite ligand source.
  • ligands are triphenylarsine, trifurylphosphine, trialkylphosphites (P(OR + ) 3 ; wherein R + is C 1-10 alkyl), such as triethylphosphite, tributylphosphite, trimethylphosphite, tri- isopropylphosphite and the like, triarylphosphite such as triphenylphosphite (referred to as P(OPh) 3 or TPP) and the like, DPPE, DPPP, preferably Pd(OAc) 2 , and Pd(PPh 3 ) 4 .
  • P(OPh) 3 or TPP triphenylphosphite
  • catalysts containing ligands are Pd(OAc) 2 /(P(OR + ) 3 , Pd 2 (DBA) 3 /TPP and the like.
  • Solvents useful in the claimed invention include toluene, C 1-6 alcohols such as isopropyl alcohol, methanol, ethanol, hexanol, butanol, and the like, acetronitrile, tetrahydrofuran (THF), ether, ester such as ethyl acetate, isopropylacetate and the like,N,N,N',N'-tetraalkylureas such as 1,1,3,3-tetramethylurea, 1,3-dimethyl- 2-imidazolidinone, l,3-dimethyl-3,4,5,6-tertrahydro-2(lH)-pyrimidinone benzene (DMPU) and the like, hexamethylphosphoramide (HMPA), dimethylformamide, N- methylpyrolidin
  • the reaction can be carried out in two independent steps or preferably as a tandem carbon acid addition/elimination reaction followed by palladium catalyze allylation reaction in a one-pot process.
  • the temperature range of the reaction is generally at about -100°C to about 60°C, preferably about -25°C to about 25°C.
  • P represents a member selected from the group consisting of: TMS, TES, TBDMS, trimethylsilylethyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichlorethyl and 2,2,2-trichloroethyloxycarbonyl.
  • P* represents a member selected from the group consisting of: allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl groups such as t-butyldimethylsilyl (TBDMS), trimethylsilyl, (TMS), triethylsilyl (TES), trimethylsilylethyl, phenacyl, p- methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p-nitrobenzyl (PNB), 4- pyridylmethyl, 2,2,2-trichlorethyl and t-butyl.
  • TDMS t-butyldimethylsilyl
  • TMS trimethylsilyl
  • TES triethylsilyl
  • PPB 4- pyridylmethyl, 2,2,2-trichlorethyl and t-butyl.
  • Still other processes that are of particular interest are those described above wherein R represents methyl. Still other processes that are of particular interest are those described above wherein at least one Rl represents C 1-6 alkoxy or-Ci-6 straight or branched chain alkyl group, substituted with one to four R" groups, wherein one Rd group represents -R* or Q. Still other processes that are of particular interest are those described above wherein R2 represents SOEt, OTf, or OP(O)(OR")2, preferably OTf, wherein R' and R" independently represent Ci _6 alkyl, aryl or benzyl .
  • An aspect of this embodiment is realized when the base is selected from DBU and TMG, the solvent is DMPU or HMPA, the palladium catalyst is Pd(OAc) 2 and the ligand is (EtO) 3 P.
  • a carbapenem of formula A is reacted with a carbon acid in the presence of a base at about -25 °C to about 25 °C, followed by partial neutralization with acid, treatment with naphthosultam, a palladium catalyst, and a phosphite reagent and aged at 0-50 °C to furnish C.
  • the naphthosultam side chain group is reacted with a carbon acid in the presence of a base at about -25 °C to about 25 °C, followed by partial neutralization with acid, treatment with naphthosultam, a palladium catalyst, and a phosphite reagent and aged at 0-50 °C to furnish C.
  • SCG naphthosultam side chain group
  • the carbapenem nucleus A having a -OTf or -OPO(OPh) 2 substituent at position 2 can be obtained in accordance with Schmitt, S. M. et al., J. Antibiotics 41(6): 780-787 (1988) or Yasuda, N. et al., Tet. Lett. 40(3) 427-430 (1998).
  • the compounds disclosed in U. S. Patent No. 5,756,725, issued May 26, 1998 can also be prepared in accordance with the invention herein.
  • the carboxylic acid group at C-3 of the carbapenem is generally protected as a carboxyl protecting group such as p- nitrobenzyl (PNB), allyl, p-methoxybenzyl, trichloroethyl, 2-trimethylsilylethyl, and the like.
  • PNB p- nitrobenzyl
  • allyl allyl
  • p-methoxybenzyl trichloroethyl
  • 2-trimethylsilylethyl 2-trimethylsilylethyl
  • the hydroxyl group of the ⁇ -(hydroxyethyl) side-chain is optionally protected with a hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl, allyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-trichloroethoxycarbonyl and the like.
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TDMS tert-butyldimethylsilyl
  • TDPS tert-butyldiphenylsilyl
  • acetyl acetyl, allyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, benzyloxycarbonyl,
  • the addition of the naphthosultam side chain group (SCG) to the carbapenem B is accomplished by reacting the carbapenem B with the naphthosultam side chain group in a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, DMPU, NMP, NEP, nitromethane, dimethylformamide (DMF), benzene, dimethylsulfoxide (DMSO), and the like, preferably DMPU or HMPA, in the presence of a palladium catalyst sytem, described above, at a temperature between about 0 °C and 150 °C, preferably about 15 °C to about 50 °C, and most preferably about 20°C to about 35°C, for about 5 to 120 minutes followed by an appropriate workup and isolation procedure familiar to those skilled in the art to yield the compounds of 6.
  • a base, described above, can also be optionally added to the process.
  • the preferable palladium catalyst system is one which includes a ligand.
  • catalyst systems are Pd(OAc) 2 /TPP, Pd 2 (DBA) 3 /TPP, Pd(OAc) 2 /triethylphosphite, Pd(OAc) 2 /trifurylphosphine, Pd 2 (DBA) 3 /trifurylphosphine, Pd 2 (DBA) 3 /triethylphosphite and the like, with an optimal palladium level of about 0.1 mole% to about 15 mole%, preferably about 0.5 mole% to about 10 mole% and an optimal ligand level of about 0.3 mole% to about 45 mole%, preferably about 15 to about 30 mole .
  • the temperature range is about 0 °C to about 35 °C, which allows for direct coupling of a charged (i.e., at least one R is charged) substituted naphthosultam to the carbapenem carbonate.
  • the compounds of 2 can be prepared by modifying the naphthosultam side chain of 6 as desired, and then removing any protecting groups which are present to afford the desired final product as taught in U. S. Patent No. 5,756,725, herein incorporated by reference.
  • a positively charged substituent may be introduced into the side chain by first activating the hydroxyl group by converting it to a suitable leaving group such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like, and then displacing the resulting leaving group with a compound Q*, such as N-methyl- imidazole, N-(2-hydroxyethyl)-imidazole, N-mefhyl-diazabicyclooctane, 1-
  • a suitable leaving group such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like
  • the charged substituent may be incorporated in the naphthosultam side chain before addition of the naphthosultam to the carbapenem, which is prefe ⁇ ed when a trialkylphosphite or triarylphosphite ligand is employed in the catalyst system.
  • the charged substituent may be introduced after deprotection of 6. However, introduction of the charged substituent by modification of 6 before deprotection is greatly prefe ⁇ ed. In some cases, activation of the hydroxyl group and displacement by
  • Q* to produce 2 may be accomplished in a single step by taking advantage of the basic character of compound Q* and using it as a base in the activation reaction.
  • the conversion of the hydroxyl group to a suitable leaving group is accomplished by treating the hydroxyl substituted compound in a suitable solvent such as dichloromethane, dichloroethane, toluene, tetrahydrofuran, ether, acetonitrile, benzene, and the like with an activating reagent, such as trifluoromethanesulfonic anhydride, methanesulfonic anhydride, toluenesulfonic anhydride, methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, and the like in the presence of a suitable base such as triethylamine, tributylamine, lutidine, diisopropylethylamine, and the like at a temperature of between about -100°C and about 0°C for about 5 to about 120 minutes.
  • a suitable solvent such as dichloromethane, dichloro
  • the intermediate thus obtained contains a leaving group, which may be converted to an alternative leaving group, iodide, by treating a solution of the intermediate in a suitable solvent such as acetone, methyl ethyl ketone, and the like at about -10°C to about 50°C with an excess of sodium iodide or potassium iodide for about 0.25 to about 24 hours.
  • a suitable solvent such as acetone, methyl ethyl ketone, and the like at about -10°C to about 50°C with an excess of sodium iodide or potassium iodide for about 0.25 to about 24 hours.
  • the iodide is obtained in sufficiently pure form that it may be used without further purification.
  • the iodide if not crystalline, may be lyophilized from benzene to afford an amorphous, easily handled, solid.
  • the activated hydroxyl group or iodide is displaced by reacting the activated intermediate with reagent Q*.
  • activation and displacement of the hydroxyl group may be accomplished in a single step.
  • the activating reagent is added to a solution of the hydroxyl substituted compound in the presence of a suitable base in a suitable solvent such as dichloromethane, tetrahydrofuran, ether, DMF, benzene, acetonitrile, DMSO, and the like as described in the preceding paragraphs.
  • the resulting activated intermediate is treated with 1-3 molar equivalents of compound Q* at a temperature of between about -78°C and about 50°C for about 15 to about 120 minutes.
  • the activated intermediate in one solvent, isolate the activated intermediate, and conduct the displacement reaction in a different solvent.
  • the displacement may be conducted without isolation of the intermediate and, in cases where Q* is also used as a base, may even be concurrent with the formation of the activated intermediate.
  • a solution of the iodide is combined with an approximately equivalent amount (0.9 - 1.05 molar equivalents) of compound Q*.
  • a silver salt of a non- nucleophilic acid such as silver trifluoromethanesulfonate, silver tetrafluoroborate and the like is then added.
  • the reaction will proceed in the absence of the silver salt, the reaction proceeds more rapidly in the presence of the silver salt.
  • the silver salt assists in the removal of the displaced iodide from the reaction mixture which can improve the efficiency of subsequent steps.
  • An alternative method for introducing a positive charge into the side chain may be applied to side chains (i.e. R 1 groups) that contain a nitrogen atom which may be quaternized by reaction with a suitable alkylating reagent AR, such as methyl iodide, methyl bromide, benzyl trichloroacetimidate, bromoacetamide, chloroacetamide, methyl trifluoromethanesulfonate, triethyloxonium tetrafluoroborate, and the like. Quatemization of the nitrogen atom in the side chain is effected by treating a solution of the compound with a slight excess (1.05 to 1.2 molar equivalents) of the alkylating reagent.
  • the conversion of the hydroxyl group to a suitable leaving group can be accomplished by triflation which can be carried out in dichloromethane, dichloroethane, toluene, and the like using lutidine as a base.
  • An aqueous citric acid work-up can be used to remove the lutidine followed by a solvent switch into a solvent such as acetonitrile.
  • the activated hydroxyl group is displaced by reacting the activated intermediate with a reagent Q* such as DABCO acetamide to yield a protected DABCO coupled product.
  • the synthesis of the target compound is completed by removing any protecting groups which are present in the penultimate intermediate using standard techniques which are well known to those skilled in the art.
  • the hydroxy protected substituent can be deprotected by reacting the hydroxy protected penultimate intermediate with an acid such HC1, H 2 SO 4 , MsOH, TFA, H 3 PO 4 , TsOH and the like or fluoride anion such as TBAF, HF-pyridine, ammonium fluoridate and the like.
  • the carboxy protected substituent can be deprotected by hydrogenolysis (H 2 ) in the presence of palladium on carbon, Raney Ni, Pd(OH) 2 /carbon, palladium on Al 2 O 3 , platinum on carbon catalyst and the like followed by reduction with a metal such as zinc and photolysis (by photolysis methods known in the art).
  • the deprotected final product is then purified, as necessary, using standard techniques such as ion exchange chromatography, HPLC on reverse phase silica gel, MPLC on reverse phase polystyrene gel, and the like or by recrystallization.
  • the final product may be characterized structurally by standard techniques such as NMR, IR, MS, and UV.
  • the final product if not crystalline, may be lyophilized from water to afford an amorphous, easily handled solid.
  • the compounds of the present invention are valuable intermediates for antibacterial agents, such as those described in USSN 08/825,786, that are active against various Gram-positive and to a lesser extent Gram-negative bacteria, and accordingly find utility in human and veterinary medicine.
  • the TES-protected enol triflate was prepared in a similar fashion as above starting from the TES-protected diazo compound except that the CH 2 C1 2 extracts were filtered through a silica pad (2X weight of the starting diazo compound) before crystallization.
  • the mixture was quenched into a stirring mixture of MTBE (100 mL) and ice cold 0.25 M pH 7 phosphate buffer (100 mL).
  • the organic phase was washed with 0.1 M phosphate buffer (90 mL) and brine (60 mL), and then dried (Na 2 SO 4 ).
  • the organic was diluted with half volume of hexane and filtered through a pad of silica 60 (8 g), and the filter cake was washed with 1:1 EtOAc/hexane (60 mL).
  • the filtrate was concentrated to dryness to give the product as a yellow oil (0.32 g, ⁇ 80wt% pure, ⁇ 60% yield).
  • the TES-protected product was prepared in a similar fashion as above starting from the TES-protected enol triflate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un procédé de synthèse d'un composé de carbapenem de la formule (6) dans laquelle: R représente H ou méthyle, P et P* représentent indépendamment H ou des groupes protecteurs et chaque R1 est indépendamment sélectionné parmi: H, halo, OH, OP, P étant un groupe protecteur, C¿1-6? alkyle ou C1-6 alkyle substitué par 1-3 de halo, OH, OP, NH2, NHC1-4 alkyle ou N(C1-4 alkyl)2.
PCT/US2000/016993 1999-06-25 2000-06-21 Procede de synthese de carbapenems naphthosultam WO2001000624A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58813/00A AU5881300A (en) 1999-06-25 2000-06-21 Synthetic process for naphthosultam carbapenems

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US14110499P 1999-06-25 1999-06-25
US60/141,104 1999-06-25
US14624999P 1999-07-29 1999-07-29
US60/146,249 1999-07-29

Publications (1)

Publication Number Publication Date
WO2001000624A1 true WO2001000624A1 (fr) 2001-01-04

Family

ID=26838795

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/016993 WO2001000624A1 (fr) 1999-06-25 2000-06-21 Procede de synthese de carbapenems naphthosultam

Country Status (2)

Country Link
AU (1) AU5881300A (fr)
WO (1) WO2001000624A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998051677A1 (fr) * 1997-05-13 1998-11-19 Merck & Co., Inc. Procede de synthese pour composes intermediaires de carbapenem

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998051677A1 (fr) * 1997-05-13 1998-11-19 Merck & Co., Inc. Procede de synthese pour composes intermediaires de carbapenem

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YOSHIOKA ET AL.: "An efficient method for the preparation of carbapenem derivatives with C-2 carbon side chains from PS-5 and OA-6129 compounds", J. CHEM. SOC. CHEM. COMMUN.,, 1984, pages 1513 - 1514, XP002931073 *

Also Published As

Publication number Publication date
AU5881300A (en) 2001-01-31

Similar Documents

Publication Publication Date Title
EP0906313B1 (fr) Composes antibacteriens a base de carbapenem, compositions contenant de tels composes et methodes de traitement
WO2001000624A1 (fr) Procede de synthese de carbapenems naphthosultam
US6399597B1 (en) 1,8-naphthosultamylmethyl carbapenem antibacterial compounds, compositions containing such compounds and methods treatment
WO1999012928A1 (fr) Antibacteriens du type 3-(iodophenoxymethyl) carbapenem
EP1104424B1 (fr) Procede permettant la synthese d'intermediaires de carbapenems
AU4184497A (en) Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment
AU4216199A (en) Benzothiazolythiomethyl carbapenem antibacterial
EP1023062B1 (fr) Carbapenemes antibacteriens, compositions et methodes de traitement
WO1999062878A1 (fr) Composes antibacteriens de carbapenem, compositions renfermant ces composes, et methodes de traitement
EP1028962B1 (fr) Composes antibacteriens carbapenems, compositions contenant ces composes et methodes de traitement
AU4490597A (en) Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment
EP1090000A1 (fr) Antibacteriens naphtho 1,8-de]thiasin-2-yl methyl carbapenem
EP1027352A1 (fr) Composes antibacteriens de la classe des carbapenemes, compositions et procedes de traitement
WO1996004282A1 (fr) Composes de carbapenems, compositions et procedes de traitement
US6294529B1 (en) Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment
WO1999009032A1 (fr) Carbapenems avec derive de naphtosultame lie par methylene
WO1999067241A1 (fr) Antibacteriens de carbapenem (heterocycliques) substitues par methyle
WO1999020269A1 (fr) Carbapenemes antibacteriens, compositions et methodes de traitement
JP2002518446A (ja) カルバペネム抗菌性化合物、前記化合物を含む組成物及び治療方法
JP2001519352A (ja) カルバペネム系抗菌化合物、該化合物を含有する組成物および治療方法
EP1089730A1 (fr) Composes antibacteriens a base de carbapenem, compositions renfermant ces composes et methodes therapeutiques
WO1999067240A1 (fr) Antibacteriens a base de carbapenem a substitution methyle (heterocyclique)

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref country code: AT

Ref document number: 2000 9124

Date of ref document: 20010125

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 20009124

Country of ref document: AT

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP