AU9774298A

AU9774298A - Aryloxymethyl carbapenem antibacterials

Info

Publication number: AU9774298A
Application number: AU97742/98A
Authority: AU
Inventors: Helen Chen; Frank P. Dininno
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1997-09-17
Filing date: 1998-09-14
Publication date: 1999-04-05
Also published as: EP1023293A1; EP1023293A4; CA2304267A1; JP2002503638A; WO1999014217A1

Description

WO 99/14217 PCT/US98/19015 ARYLOXYMETHYL CARBAPENEM ANTIBACTERIALS 5 BACKGROUND OF THE INVENTION The present invention relates to carbapenem antibacterial agents in which the carbapenem nucleus is substituted at the 2-position with an aryl platform, linked through 10 a CH2-O- group. The aryl platform is further substituted with various substituent groups, typically including at least one cationic group. The carbapenems of the present invention are useful against gram positive microorganisms, especially methicillin 15 resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). The antibacterial compounds of the present invention thus comprise an important contribution to therapy for treating infections caused by these difficult 20 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. 25 SUMMARY OF THE INVENTION The present invention relates to a compound represented by formula I:

(R)

3 PHH R

H

3 C N CH 2 -O x 0 C 02M I

(R)

3 30 or a salt or hydrate thereof, wherein: WO 99/14217 PCT/US98/19015 -2

R

1 represents H or methyl; CO2M represents a carboxylic acid, a carboxylate anion, 5 a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group; P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group; 10 X is present or absent, and when present, represents members selected from the group consisting of: CH 2 , C(R)2, C=CR 2 , O, S(0)x, with x equal to 0, 1 or 2, C(0), CO 2 , OCO and NR; 15 each R group is independently selected from: hydrogen; halo; -CN; -NO2; -NRaRb; -ORc; -SRc; -C(0)NRaRb; -C(0)ORh; S(0)Rc; -SO 2 Rc; -SO 2 NRaRb; -NRaSO 2 Rb; -C(0)Ra; -OC(O)Ra; OC(0)NRaRb; -NRaC(O)NRbRc; -NRaCO 2 Rh; -OCO 2 Rh; NRaC(0)Rb; -C1-6 straight- or branched-chain alkyl, unsubstituted or 20 substituted with one to four Rd groups; -A-(CH 2 )n-Q and -C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; A represents O, S or -CH2-; 25 n represents an integer 0-3; each R a , Rb and Rc independently represents hydrogen, -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups, or -C3-7 cycloalkyl, unsubstituted or 30 substituted with one to four Rd groups; or R a and Rb taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of 0, S, NRc, with Rc as defined above, or -C(0)-, said ring being unsubstituted or substituted with one to four R i groups; 35 or Rb and Rc taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by WO 99/14217 PCT/US98/19015 -3 one to three of O, S, NRa, with R a as defined above, or -C(O)-, said ring being unsubstituted or substituted with one to four R i groups; each Rd independently represents halo; -CN; -NO2; 5 NReRf; -ORg; -SRg; -CONReRf; -COORg; -SORg; -SO 2 Rg; -SO 2 NReRf; -NReSO 2 Rf; -CORe; -NRe CORf; -OCORe; -OCONReRf; NReCONRfRg; -NReCO 2 Rh; -OCO 2 Rh; -C(NRe)NRfRg; NReC(NH)NRfRg or -NReC(NRf)Rg; 10 Re, Rf and Rg represent hydrogen; -R*; -C1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R i groups; or Re and R f taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by 15 one to three of O, S, -C(0)- or NRg with Rg as defined above, said ring being unsubstituted or substituted with one to four R i groups; each R i independently represents halo; -CN; -NO2; phenyl; -NHSO 2 Rh; -ORh, -SRh; -N(Rh) 2 ; -N+(Rh) 3 ; -C(0)N(Rh) 2 ; 20 SO 2 N(Rh) 2 ; heteroaryl; heteroarylium; -CO 2 Rh; -C(0)Rh; -OCORh; NHCORh; guanidinyl; carbamimidoyl or ureido; each Rh independently represents hydrogen, a -C1-6 straight or branched-chain alkyl group, a -C3-C6 cycloalkyl group or 25 phenyl, or when two Rh groups are present, said Rh groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, -C(0)-, NH and NCH3; 30 Q is selected from the group consisting of:

(CH

2 )b ~N-,@ VN \ , N , N N-R x and NRxRYRz o\ g L (CH 2 )a wherein: aandb are 1,2 or3; WO 99/14217 PCT/US98/19015 -4 L- is a pharmaceutically acceptable counterion; c represents O, S or NRS; 3, 8, k, t and a represent CRt, N or N+R s , provided that no more than one of 3, 8, k, 4 and a is N+Rs; 5 each R s independently represents hydrogen; phenyl or C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; 10 each Rt independently represents hydrogen; halo; phenyl; -CN; -NO2; -NRURV; -ORu; -SRu; -CONRuRv; -COORh; SORu; -SO 2 Ru; -SO2NRuRv; -NRuSO 2 Rv; -CORu; -NRuCORv; OCORu; -OCONRuRv; -NRuCO 2 Rv; -NRuCONRvRw; -OCO 2 Rv; -C1_ 6 straight- or branched-chain alkyl, unsubstituted or substituted with 15 one to four R i groups; Ru and Rv represent hydrogen or -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; 20 or Ru and R v together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRw or -C(0)-, said ring being unsubstituted or substituted with one to four R i groups; 25 each Rw independently represents hydrogen; -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; C3-6 cycloalkyl optionally substituted with one to four R i groups; phenyl optionally substituted with one to four R i groups, or heteroaryl optionally substituted with 1-4 Ri groups; 30 or Rh and Rw taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3; Rx represents hydrogen or a C1-8 straight- or branched 35 chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRw, N+RhRw, or -C(O)-, said chain being unsubstituted or WO 99/14217 PCT/US98/19015 -5 substituted with one to four of halo, CN, NO2, ORw, SRw, SORw,

SO

2 Rw, NRhRw, N+(Rh) 2 Rw, -C(O)-Rw, C(O)NRhRw, SO 2 NRhRw,

CO

2 RW, OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRw, or a phenyl or heteroaryl group which is in turn optionally substituted 5 with from one to four R i 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 i groups; RY and Rz represent hydrogen; phenyl; -C1-6 straight or 10 branched chain alkyl, unsubstituted or substituted with one to four R i groups, and optionally interrupted by O, S, NRw, N+RhRw or -C(O)-; or Rx and RY together with any intervening atoms 15 represent a 4-6 membered saturated ring optionally interrupted by O, S, SO2, NRw , N+RhRw or -C(O)-, unsubstituted or substituted with 1 - 4 Ri groups, and when Rx and RY together represent a 4-6 membered ring as defined above, Rz is as defined above or Rz represents an 20 additional saturated 4-6 membered ring fused to the ring represented by Rx and RY taken together, optionally interrupted by O, S, NRw or C(O)-, said rings being unsubstituted or substituted with one to four

R

i groups. 25 Pharmaceutical compositions and methods of treatment are also included. DETAILED DESCRIPTION OF THE INVENTION The invention is described herein in detail using the 30 terms defined below unless otherwise specified. Carboxylate anion refers to a negatively charged group -COO-. The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon 35 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 WO 99/14217 PCT/US98/19015 -6 substituted, alkyl groups may be substituted with up to four substituent groups, selected from Rd and R i , 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 5 "branched alkyl group". Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused. 10 The term "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. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. The term "alkynyl" refers to a hydrocarbon radical 15 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., 20 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 25 phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl. The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic 30 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 1 to 3 additional carbon atoms are optionally 35 replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of this type are pyrrole, pyridine, oxazole, thiazole and oxazine. Additional WO 99/14217 PCT/US98/19015 -7 nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole. Examples include the following: NH N NHN pyrrole (pyrrolyl) imidazole (imidazolyl) thiazole (thiazolyl) NO O S oxazole (oxazolyl) furan (furyl) thiophene (thienyl) N---\ NH NH triazole (triazolyl) pyrazole (pyrazolyl) isoxazole (isoxazolyl) oN N N N isothiazole (isothiazolyl) pyridine (pyridinyl) pyrazine (pyrazinyl) NNN pyridazine (pyridazinyl) pyrimidine (pyrimidinyl) N~N N-'z - N K N) 5 triazine (triazinyl) Heteroarylium refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge. Examples include the following: 10 WO 99/14217 PCT/US98/19015 -8 +:r-N-CH 3 ---N / ..- N / N+ + Nz / + N 0 N-CH3

OH

3

CH

3 + N C N N+ N N NN IN z" . "CH3 K-N N

CH

3 When a charge is shown on a particular nitrogen atom in a ring which contains one or more additional nitrogen 5 atoms, it is understood that the charge may reside on a different nitrogen atom in the ring by virtue of charge resonance that occurs. + C N N_ ,N +_H I N-CH 3 10 and I""N-CH N

+

H N 3 , = N-- CH 3 K:: NOH 3 + N±H3

+

WO 99/14217 PCT/US98/19015 -9 The term "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 5 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), 10 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. 15 The term "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 1

-C

4 alkyl-O-, with the alkyl group 20 optionally substituted as described herein. Guanidinyl refers to the group: H 2 NC(NH)NH-. Carbamimidoyl refers to the group: H 2 NC(NH)-. Ureido refers to the group: H 2 NC(0)NH-. When a group is termed "substituted", unless 25 otherwise indicated, this means that the group contains from 1 to 4 substituents thereon. With respect to R, R a , Rb and Rc, the substituents available on alkyl groups are selected from the values of Rd. Many of the variable groups are optionally substituted with up to four R i groups. With respect to R e , R f and Rg, when these 30 variables represent substituted alkyl, the substituents available thereon are selected from the values of R i . When a functional group is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for 35 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.

WO 99/14217 PCT/US98/19015 -10 W. et al. Protective Groups in Organic Synthesis Wiley, New York (1991). Examples of suitable protecting groups are contained throughout the specification. When a group is "optionally interrupted", this 5 includes one or more of the interrupting moieties in combination, as well as said moieties located at either or both ends of the chain. Thus, it includes terminating the group as well. In some of the carbapenem compounds of the present invention, M is a readily removable carboxyl protecting group, 10 and/or P represents a hydroxyl which is protected by a hydroxyl protecting group. Such conventional protecting groups consist of known groups which are used to protectively block the hydroxyl or carboxyl group during the synthesis procedures described herein. These conventional blocking groups are readily removable, i.e., 15 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 20 and a nucleophile and catalytic hydrogenation. Examples of carboxyl protecting groups include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl such as t-butyldimethylsilyl (TBDMS), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p-nitrobenzyl, 4-pyridylmethyl 25 and t-butyl. Examples of suitable C-6 hydroxyethyl protecting groups include triethylsilyl, t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl, p nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like. 30 The carbapenem compounds of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms for the treatment of bacterial infections in animal and human subjects. The term "pharmaceutically acceptable ester, salt or hydrate," refers to those salts, esters and hydrated 35 forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist. i.e., those which are substantially non-toxic and which may favorably affect the WO 99/14217 PCT/US98/19015 -11 pharmacokinetic properties of said compounds, such as palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of 5 crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug. Conveniently, pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers. Thus, the present invention is also concerned with 10 pharmaceutical compositions and methods of treating bacterial infections utilizing as an active ingredient the novel carbapenem compounds. With respect to -CO2M, which is attached to the carbapenem nucleus at position 3, this represents a carboxylic 15 acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a protecting group (M represents a carboxyl protecting group). The pharmaceutically acceptable salts referred to 20 above may take the form -COOM, where M is a negative charge, which is balanced by a counterion, e.g., an alkali metal cation such as sodium or potassium. Other pharmaceutically acceptable counterions may be calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, 25 tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc. The pharmaceutically acceptable salts referred to above also include acid addition salts. Thus, the Formula I compounds can be used in the form of salts derived from 30 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, 35 glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- WO 99/14217 PCT/US98/19015 -12 naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. The pharmaceutically acceptable esters are such as 5 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 10 methoxymethyl, and others described in detail in U.S. Pat. No. 4,479,947. These are also referred to as "biolabile esters". Biolabile esters are biologically hydrolizable, and may be suitable for oral administration, due to good absorption through the stomach or intestinal mucosa, resistance to gastric acid 15 degradation and other factors. Examples of biolabile esters include compounds in which M represents an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl 20 group. These groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups. The following M species are examples of biolabile ester forming moieties.: acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1 isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, 25 phthalidyl and (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl. L- can be present or absent as necessary to maintain the appropriate charge balance. When present, L- represents a pharmaceutically acceptable counterion. Most anions derived from inorganic or organic acids are suitable. Representative 30 examples of such counterions are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, benzenesulfonate, bromide, citrate, camphorate, camphorsulfonate, chloride, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, lactobionate, malate, 35 maleate, mandelate, methanesulfonate, pantothenate, pectinate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, WO 99/14217 PCT/US98/19015 -13 stearate, succinate, sulfate, tartrate and tosylate. Other suitable anionic species will be apparent to the ordinarily skilled chemist. Likewise, when L represents a specie with more than one negative charge, such as malonate, tartrate or 5 ethylenediaminetetraacetate (EDTA), an appropriate number of carbapenem molecules can be found in association therewith to maintain the overall charge balance and neutrality. When the side chain is neutral, and the 3-carboxylate is in the form of an anion, the molecule is charge balanced by the 10 presence of an appropriately charged group, such as L'. Suitable positively charged groups include cations, such as sodium, potassium, calcium, magnesium and the like. Protonated moieties are also acceptable, such as tetraalkylammonium and the like. 15 A subset of compounds of the invention which is of particular interest is described with reference to formula I wherein R 1 represents methyl. Within this subset, all other variables are as originally defined. 20 Another subset of compounds of the invention which is of particular interest is described with reference to formula I wherein CO2M represents a carboxylic acid or a carboxylate anion. Hence, M in this instance represents a negative charge which will be balanced 25 by a positively charged group, such as in the positively charged R group. Likewise, if the positively charged R group contains more than one positive charge, a negatively charged counterion may be present which in combination with the carboxylate anion, provides overall charge neutrality. 30 Another subset of compounds of the invention which is of particular interest is described with reference to formula I wherein P represents hydroxyl or hydroxyl protected by hydroxyl-protecting group. Within this subset, all other variables are as originally 35 defined.

WO 99/14217 PCT/US98/19015 -14 Another subset of compounds of the invention which is particular interest is described with reference to formula I wherein at least one of the R groups attached to the phenyl ring contains a positively charged moiety. More particularly, one of the 5 R groups represents -A-(CH 2 )n-Q, and the remaining R groups represent hydrogen or another value of R other than -A-(CH 2 )n-Q. Within this subset, A, n, Q and all other variables are as originally defined. 10 Another subset of compounds of the invention which is of particular interest is described with reference to formula I one of the R groups represents -A-(CH 2 )n-Q, and A represents -CH 2 -. Within this subset, all other variables are as originally defined. 15 Another subset of compounds of the invention which is of particular interest is described with reference to formula I wherein one of the R groups represents -A-(CH 2 )n-Q, and n represents 0 or 1. Within this subset, all other variables are as originally defined. 20 Another subset of compounds of the invention which is of particular interest is described with reference to formula I wherein one of the R groups represents -A-(CH 2 )n-Q, and Q represents _® e' - (x (-

(Y

7N\or H \1 25 ao represents O, S or NRS; and 3, 5, X, t and c represent CRt, N or N+Rs, provided that no more than one of 13, 8, X, p. and T is N+Rs, balanced by L which is a pharmaceutically acceptable counterion, and R s is as 30 originally defined. Within this subset, all other variables are as originally defined. Another subset of compounds of the invention which is of particular interest is described with reference to formula I wherein WO 99/14217 PCT/US98/19015 -15 one of the R groups represents -A-(CH 2 )n-Q, and Q is selected from the group consisting of: (CH2)b -SN N-Rx and RxRYRz L (CH 2 )a 5 a and b are 2; L- is a pharmaceutically acceptable counterion; and Rx, RY and Rz are as originally defined. Within this subset, all other variables are as originally defined. 10 A more preferred subset of compounds of the invention which is of interest is described with reference to formula I wherein one of the R groups represents -A-(CH 2 )n-Q, and Q is (CH2)b (0(C N- NR x / \ 15 L (CH 2 )a Within this subset, all other variables are as originally defined. Another subset of compounds of the invention which is of 20 particular interest is described with reference to formula I wherein one of the R groups represents -A-(CH 2 )n-Q, and Q is wherein: 25 0x represents O, S or NRs; P, 5, X, g and ac represent CRt, N or N+R s , provided that nomore than one of P, 5, X, R and Y is N+R s , balanced by L-,which is a pharmaceutically acceptable counterion, and WO 99/14217 PCT/US98/19015 -16 all other variables are as originally defined. Representative examples of compounds of the invention are as follows: TABLE 1 Cpd No. Compound S 2 allylO 2 C O H H O 0 0 N C02allyl C 02- X ON 4 allayI-O H H| - S 3 HOHH 0 tO CN X X C2-allyl 4 allyl-O H H N/ X 0

C

2 aI y WO 99/14217 PCT/US98/19015 -17 OH S 5 ally-O2CO H H 0 N

CO

2 allyl / N s HN 'N 6 HH *0 NN 0 CO2

N

~ ~ 1CONH 2 e 7 HOHH N OCO2

NCONH

2 0 8 S allyl-O H H NC C 0 2 -allyl WO 99/14217 PCT/US98/19015 -18 OH S 9 allylO 2 CO H H o N/

CO

2 allyl G N

/CONH

2 10 S HOHH Os-O HOH H 11 - 0 (N O E CC022 X S

-

HO H H N! O / o HO H HC0 12 J, 0 N/ o

CO

2-

X

+

WO 99/14217 PCT/US98/19015 -19 N } CONH2 SyO XE 13 HOHH 0 N o G

CO

2 ON CONH2 / 0 o allyIO 2 CO H H 14 O N OH 0

CO

2 allyl N NG) CONH 2 NZ/ Si O OX HO H H 15 0 N o e CO2 0 HO H H 16 O N 0 0 C02 X+ WO 99/14217 PCT/US98/19015 -20 N D CONH 2 /8 HO H H 17 0 O N 0 E

CO

2 CH2=CHCH202CO H H 18

CO

2 CH2CH=CH2 19 HO H H N/ 0 C 02X OSiPh 2 CMe 3 CH2=CHCH20 2 C H H 200 NC O CO2CH2CH=CH2 WO 99/14217 PCT/US98/19015 -21 OH 21 CH 2

=CHCH

2 02CO H H 00 N / C020

H

2

CH=CH

2 0 /"N Me N

CH

2

=CHCH

2 02CO H H HHe 00 N C O 2

CH

2

CH=CH

2 S M/NMe HO HH 23 o / 020 0

CH

2

=CHCH

2 02C H H 24 N 2H2CH2 0 CO2CH2CH=CH2 WO 99/14217 PCT/US98/19015 -22 HO HH 0 N/ C 0 2 - X+ 26 CH2=CHCH202CO H H N CO2CH2CH=CH 2 HO HH O N/ 0

CO

2-

X

+ /C CO2CH3 02 H 280 28 CO2CH 2 CH=CH2 WO 99/14217 PCT/US98/19015 -23 29 C 0 2

CH

3 9'HO 2H

N

7 O~ SC 0 2-

X

+ 02 HH C2CH3 300 CO2CH2CH=CH2 C O2C H 3 HO 31 HH N/ 0 C 0 2 - X+ OTBS 02 H Hl CO2CH2CH=CH2 WO 99/14217 PCTIUS98/19015 -24 OH 332C H H N 0 CO2CH2CH=CH 2 C H 3 N N 34 0 N/ 0 O 020 H 2 CH=0H 2

OH

3 N N 35 HO H H 0 0 0 C-0 0 00 0 CO2CH 2

CH=CH

2 WO 99/14217 PCT/US98/19015 -25 37 O2 -o HH H 02 37 o CO2CH 2

CH=CH

2 0 N CONH 2 %-/"o 0o./ 2 / / N 2X 38 2CO S 22X H H O N/ 0 C O 2

CH

2

CH=CH

2 0 N CONH 2 x 00 HO 39 H H / C02 0 2C H 2 OTBS HHC C 40 'r 0 CO2CH 2 CH=CH2 WO 99/1 4217 -2-PCT/US98/1901 5 -CH20H 41 H H 0 N! 0 CO2CH2CH=CH 2 -C H 2 0OH HOH 00 C 02 X+ TBS K0 43 CH 2 =CHCH2O 2 C H 0

CO

2 CH2CH=0H2 H 44 0H 2 =CHCH2O 2 C H

CO

2 CH2CH=0H2 WO 99/14217 PCT/US98/19015 -27 Ms 45

CH

2 =CHCH2O 2 C H H 0 0 C0 2 CH2CH=CH2 K- 0 46 0H 2 =0H0H20 2 C 0

CO

2 CH2CH=CH2

OH

3 rN ®N 47 0H 2

=CHCH

2

O

2 00 H H N/ 0

OO

2

CH

2

CH=CH

2 WO 99/14217 PCTIUS98/19015 -28 S

N/-CONH

2 2 X 0 48 0 H2=CHCH 2

O

2 0 0 H H

N

7 0 o O 2

CH

2

CH=CH

2 N2) X0 0 o H 2

=CHCH

2

O

2 C 0 49 H H0

N

7 0 0020

H

2 CH=0H 2

CH

2

CH

2 00NH 2 N XG 0 CH2=CHCH 2 02O 0 HH 'Z 0

N

7 0

CO

2

CH

2

CH=CH

2 WO 99/14217 PCT/US98/19015 -29 CH3 N 0 51 HO HH /O 51 o 002 00

NG

) /

C

ONH

2 N X 0 52 HOHH 0 N / 0 N HO HH 53 0 0 N/ O 0 WO 99/14217 PCT/US98/19015 -30 CH2CH2CONH 2 N 54 HOH H HH * 0 0 002 OH 0 55 0 2CO H H 0 0 CO2CH2CH=CH2 N/"CONH 2 2X N 02CO H H * 0 N/ 0 C0 2 C H 2

CH=CH

2 WO 99/14217 PCT/US98/19015 -31 0I N" CONH 2 x N 0.N 57 HOH N/ 0 C 02

CH

3 N oX N 58 K 0 HH 0 N/ 0 C02CH 2

CH=CH

2 WO 99/14217 -32- PCT/US98/19015

OH

3 590 HO 0 C020 OH 02C

C

0 2CH3 60 71H 0 0 CO2CH 2

CH=CH

2 2X® N 61 7' ~ 0 2 C H 3 0 2 0 H H 0 N/ C 0 2 C H 2 CH=0H 2 WO 99/14217 PCTIUS98/19015 -33

NCONH

2 ON x ( 62 HOC 2H H H 0 N 0 C2

OH

3 KN 63 0 0 2 H 0 C0 2 0H 3 00 C O 2

CH

2

CH=CH

2 WO 99/14217 PCT/US98/19015 -34

CH

3 K N C00 2 CH3 64HOH H 64 HH j 10 N // 0 020O O O O0 CO2CH2CH=CH 2 HO HH 660 N0

CO

2- X + X+ and X represent appropriately charged counterions which are present to provide overall charge balance. The compounds of the present invention are prepared by 5 reacting a suitably protected, activated 2-hydroxymethyl-carbapen-2 em-3-carboxylate with an appropriately substituted phenyl ring, and then removing any protecting groups which are present to afford the WO 99/14217 PCT/US98/19015 -35 desired final product. The process is illustrated by the following generic schemes: FLOW SHEET A P H H R1 OH . (R)3 H39C OH N / + (R) 3 O ** X Al CO 2 P A2 PH H R1i (R)3 Mitsunobu Reaction H3 O H3C

RO

2

CN=NCO

2 R N R'3P O X Solvent A3 C0 2 P (R)3 HO H H R1 (R ) 3 Deprotection H3 O (Ph 3

P)

4 Pd H 3 C Ph 3 P O X

CO

2 Na A4 C02- (R)3 (R)3 CO2H CH2CI2 EtOAc WO 99/14217 PCT/US98/19015 -36 FLOW SHEET B H H R1 OH .. (R)2 OHH H3COH N/ (R) 3 A(CH2)nOSiR 3 0 x Al CO2P** A5) I-- A(CH2)nOSiR 3 PH H RI x Mitsunobu Reaction H3 .H3C0j RO2CN=NCO 2 R N / (R) 3 R'3P 0 Solvent A6 CO2P** R)2 P 1 A(CH2)nOH HH R Desilylation H 3 C 0I (R) -/ (R)3

BU

4 NF N HOAc O Solvent A7 CO2P* - A(CH2)n Q + Activation P R SDisplacement H H R Deprotection H3C / (R) 3 0 O02 A8 CO2" A8 With reference to the Flow Sheets above, P, R, R 1 , A, Q and n are as defined with respect to the compounds of formula I. P** 5 is a carboxyl covering group. The side chain A2 or A5 is initially reacted with a suitably protected carbapen-2-em-3-carboxylate having an activated hydroxymethyl group at the 2-position. The carbapenem nucleus having a hydroxymethyl 10 substituent at position 2 can be obtained in accordance with Schmitt, WO 99/14217 PCT/US98/19015 -37 S. M. et al., J. Antibiotics 41(6): 780-787 (1988), the teachings of which are incorporated herein by reference. 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, 5 trichloroethyl, 2-trimethylsilylethyl and the like. Furthermore, the hydroxyl group of the 6-(hydroxyethyl) side-chain is protected with a hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl, allyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2 10 trichloroethoxycarbonyl and the like. The addition of the side chain to the carbapenem is accomplished by treating a solution of the hydroxymethyl carbapenem Al and the side chain A2 or A5 in a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, 15 dimethylformamide (DMF), benzene, dimethylsulfoxide (DMSO), and the like with a combination of reagents that comprise the Mitsunobu reaction ( for a review see: Hughes, D.L. Organic Reactions, Paquette, L. ed., Vol. 42, John Wiley & Sons, USA, 1992. ) such as an azodicarboxylate like diethylazodicarboxylate (DEAD), 20 diisopropyldiazodicarboxylate(DIAD), and tetramethyldiazodicarboxamide (TMAD), or the like, and a tri substituted phosphine, such as triphenylphosphine, tri-n butylphosphine, and the like, at a temperature between about -20 oC and 35 oC for about 5 to 90 minutes. 25 Alternatively, the naphthosultam and carbapenem can be simultaneously added to a preformed complex of the diazocarboxylate and phosphine. Once the naphthosultam, carbapenem, and activating reagent(s) have been mixed, the reaction is allowed to proceed at a temperature between about -20 oC and 35 'C 30 for about 5 to 90 minutes. The resulting mixture is then subjected to a standard work-up procedure to afford a crude methyl substituted carbapenem which is purified, if necessary, by recrystallization or by chromatography on silica gel, eluting with a suitable solvent or 35 mixture of two or more solvents, such as hexane, ethyl acetate, ether, benzene, dichloromethane, chloroform, acetone, methanol and the like.

WO 99/14217 PCT/US98/19015 -38 Modification of the side chain, which is generally necessary to introduce the charged substituent, is best accomplished before reacting the carbapenem and the side chain, as in Flow Sheet B. Afterwards, the removal of protecting groups on the hydroxyethyl 5 side chain and/or 3-carbapenem carboxylate can be accomplished. For compounds which contain a hydroxyl group in the side chain, a positively charged substituent may be introduced into the side chain by first activating the hydroxyl group. This entails converting it to a suitable leaving group such as a triflate, mesylate, tosylate, iodide, 10 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-methyl-diazabicyclooctane, 1 (carbamoylmethyl)-4-aza- 1-azoniabicyclo[2.2.2] octane, 1-(3 hydroxyprop-1-yl)-4-aza- 1-azoniabicyclo [2.2.2] octane, pyridine, 15 morpholine and the like which contains a nitrogen atom that can act as a nucleophile. Alternatively, in some cases, the charged substituent may be incorporated in the side chain after addition of the side chain to the carbapenem, or after deprotection. Introduction of the charged moiety Q before deprotection is greatly preferred. 20 In some cases, activation of the hydroxyl group and displacement by Q to produce A8 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 25 leaving group is accomplished by treating the hydroxyl substituted compound in a suitable solvent such as dichloromethane, tetrahydro furan, ether, benzene, and the like with an activating reagent, such as trifluoromethanesulfonic anhydride, methanesulfonic anhydride, toluenesulfonic anhydride, methanesulfonyl chloride, 30 benzenesulfonyl chloride, toluenesulfonyl chloride, and the like in the presence of a suitable base such as triethylamine, tributylamine, diisopropylethylamine and the like at a temperature between about -100 0 C and 0OC for about 5 to 120 minutes. The intermediate thus obtained contains a leaving group, which may be converted to an 35 alternative leaving group, iodide, by treating a solution of the intermediate in a suitable solvent such as acetone, methyl ethyl WO 99/14217 PCT/US98/19015 -39 ketone, and the like at about -10oC to 50 0 C with an excess of sodium iodide or potassium iodide for about 0.25 to 24 hours. In many cases, the iodide is obtained in sufficiently pure form that it may be used without further purification. For ease of 5 handling, 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. In some cases, activation and displacement of the hydroxyl group may be 10 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 15 activated intermediate is treated with 1-3 molar equivalents of compound Q at a temperature between about -78 0 C and 50 0 C for about 15 to 120 minutes. In some cases, it is desirable to form the activated intermediate in one solvent, isolate the activated intermediate, and conduct the displacement reaction in a different solvent. In other 20 cases, 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. In cases where the displacement reaction is best accomplished by using the iodide, a solution of the iodide is combined 25 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. Although the reaction will proceed in the absence of the silver salt, the reaction proceeds more rapidly in the 30 presence of the silver salt. In addition, the silver salt assists in the removal of the displaced iodide from the reaction mixture which can improve the efficiency of subsequent steps. The resulting mixture is then subjected to a standard work-up procedure familiar to those skilled in the art to afford a crude product which is purified, if 35 necessary, by recrystallization or chromatography. An alternative method for introducing a positive charge into the side chain may be applied to side chains that contain a WO 99/14217 PCT/US98/19015 -40 nitrogen atom which may be quaternized by reaction with a suitable alkylating reagent, such as methyl iodide, methyl bromide, benzyl trichloroacetimidate, methyl trifluoromethanesulfonate, triethyloxonium tetrafluoroborate, and the like. Quaternization of the 5 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 synthesis of the target compound is completed by removing any protecting groups which are present in the 10 penultimate intermediate using standard techniques. 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. 15 The final product may be characterized structurally by standard techniques such as NMR, IR, MS, and UV. For ease of handling, 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 20 antibacterial agents active against various Gram-positive and to a lesser extent Gram-negative bacteria, and accordingly find utility in human and veterinary medicine. Many of compounds of the present invention are biologically active against MRSA/MRCNS. In vitro antibacterial 25 activity is predictive of in vivo activity when the compounds are administered to a mammal infected with a susceptible bacterial organism. Using standard susceptibility tests, the compounds of the invention are determined to be active against MRSA. 30 The compounds of the invention can be formulated in pharmaceutical compositions by combining the compound with a pharmaceutically acceptable carrier. Examples of such carriers are set forth below. The compounds may be employed in powder or 35 crystalline form, in liquid solution, or in suspension. They may be administered by a variety of means; those of principal interest WO 99/14217 PCT/US98/19015 -41 include: topically, orally and parenterally by injection (intravenously or intramuscularly). Compositions for injection, a preferred route of delivery, may be prepared in unit dosage form in ampoules, or in 5 multidose containers. The injectable compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain various formulating agents. Alternatively, the active ingredient may be in powder (lyophilized or non-lyophilized) form for reconstitution at the time of delivery 10 with a suitable vehicle, such as sterile water. In injectable compositions, the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included. 15 Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders. Oral compositions may take such forms as tablets, 20 capsules, oral suspensions and oral solutions. The oral compositions may utilize carriers such as conventional formulating agents, and may include sustained release properties as well as rapid delivery forms. The dosage to be administered depends to a large 25 extent upon the condition and size of the subject being treated, the route and frequency of administration, the sensitivity of the pathogen to the particular compound selected, the virulence of the infection and other factors. Such matters, however, are left to the routine discretion of the physician according to principles of 30 treatment well known in the antibacterial arts. Another factor influencing the precise dosage regimen, apart from the nature of the infection and peculiar identity of the individual being treated, is the molecular weight of the compound. The compositions for human delivery per unit 35 dosage, whether liquid or solid, may contain from about 0.01% to as high as about 99% of active material, the preferred range being from about 10-60%. The composition will generally contain from WO 99/14217 PCT/US98/19015 -42 about 15 mg to about 2.5 g of the active ingredient; however, in general, it is preferable to employ dosage amounts in the range of from about 250 mg to 1000 mg. In parenteral administration, the unit dosage will typically include the pure compound in sterile 5 water solution or in the form of a soluble powder intended for solution, which can be adjusted to neutral pH and isotonic. The invention described herein also includes a method of treating a bacterial infection in a mammal in need of such treatment comprising administering to said mammal a 10 compound of formula I in an amount effective to treat said infection. The preferred methods of administration of the Formula I antibacterial compounds include oral and parenteral, e.g., i.v. infusion, i.v. bolus and i.m. injection. 15 For adults, about 5-50 mg of Formula I antibacterial compound per kg of body weight given one to four times daily is preferred. The preferred dosage is 250 mg to 1000 mg of the antibacterial given one to four times per day. More specifically, for mild infections a dose of about 250 mg two or three times daily 20 is recommended. For moderate infections against highly susceptible gram positive organisms a dose of about 500 mg three or four times daily is recommended. For severe, life-threatening infections against organisms at the upper limits of sensitivity to the antibiotic, a dose of about 1000-2000 mg three to four times daily 25 may be recommended. For children, a dose of about 5-25 mg/kg of body weight given 2, 3, or 4 times per day is preferred; a dose of 10 mg/kg is typically recommended. The compounds of Formula I are of the broad class 30 known as carbapenems. Many carbapenems are susceptible to attack by a renal enzyme known as dehydropeptidase (DHP). This attack or degradation may reduce the efficacy of the carbapenem antibacterial agent. Many of the compounds of the present invention, on the other hand, are less subject to such attack, and 35 therefore may not require the use of a DHP inhibitor. However, such use is optional and contemplated to be part of the present invention. Inhibitors of DHP and their use with carbapenems are WO 99/14217 PCT/US98/19015 -43 disclosed in, e.g., [European Patent Application Nos. 79102616.4, filed July 24, 1979 (Patent No. 0 007 614); and 82107174.3, filed August 9, 1982 (Publication No. 0 072 014)]. The compounds of the present invention may, where 5 DHP inhibition is desired or necessary, be combined or used with the appropriate DHP inhibitor as described in the aforesaid patents and published application. The cited European Patent Applications define the procedure for determining DHP susceptibility of the present carbapenems and disclose suitable 10 inhibitors, combination compositions and methods of treatment. A preferred weight ratio of Formula I compound: DHP inhibitor in the combination compositions is about 1:1. A preferred DHP inhibitor is 7-(L-2-amino-2-carboxy ethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic 15 acid or a useful salt thereof. The invention is further described in connection with the following non-limiting examples. EXAMPLE 1 20 PREPARATION OF 1-HYDROXYDIBENZOTHIOPHENE OH 6 So Step A: A stirred mixture of 3-methoxy benzenethiol (0.5 g, 3.6 mmoles), 1-fluoro-2-nitrobenzene (0.5 g, 3.6 mmoles), 37% KF/A1203 25 (1.4755 g, 3 w/w) , and 18-crown-6 (0.1255 g, 0.36 mmoles) in sieve dried acetonitrile (5 mL) was refluxed at 90 0 C under a N2 atmosphere for 1 hr. The reaction was allowed to cool to ambient temperature. The insoluble solids present in the reaction were filtered off and washed with EtOAc. The filtrate was collected and concentrated in 30 vacuo to give a black/red solid (1.1487 g). The product was purified by plate layer chromatography with a mixture of 2:1 hexane/CH2Cl2 to afford the desired product as a yellow solid (0.7095 g).

WO 99/14217 PCT/US98/19015 -44 1 H NMR (CDCl3) 5: 3.82 (s, 3H), 6.90 (dd, 1H), 7.01 (dd, 1H), 7.12-7.23 (m, 3H), 7.33-7.39 (m, 2H), 8.22 (dd, 1H). Step B: 5 To a stirred solution of the product obtained from Step A (0.7095 g, 2.7 mmoles) in absolute EtOH (7 mL) was added SnC12*H20 (1.8563 g, 8.1 mmoles). The resulting mixture was refluxed at 90 0 C for 1.5 hrs under an atmosphere of N2. The reaction was cooled to ambient temperature, poured into a mixture of ice, brine, and 5 N 10 NaOH, and extracted with EtOAc (2X). The organic layers were combined, washed with brine, and dried over Na2SO4. Concentration in vacuo afforded the desired product as a yellow oil (0.6826 g). The product was purified by plate layer chromatography with 1:1 CH2C12/hexane to give the desired amine (0.52 g, quantitative yield). 15 1 H NMR (CDC13) 8: 3.72 (s, 3H), 4.29 (br s, 2 H), 6.62-6.69 (m, 3H), 6.73-6.80 (m, 2H), 7.11 (t, 1H), 7.21 (t, 1H), 7.44 (dd, 1H). Step C: To a thick slurry of the amine (0.277 g, 1.74 mmoles) 20 from Step B in 2 N HC1 (1.76 mL) and HOAc (0.54 mL) was added absolute EtOH (1.76 mL) to solubilize the mixture. The stirred mixture was cooled to 0 0 C and a solution of NaNO2 (0.1552 g, 2.09 mmoles) in water (0.2 mL) was added under N2. The resulting light brown solution was stirred at 0OC for 20 min. before adding a 93.1 25 mg/mL aqueous solution of KPF6 (2.7 mL). Upon addition, yellow solid immediately precipitated out of solution. The yellow/brown solid was collected by vacuum filtration and washed with cold water (2X) and cold Et20 (3X). After drying in vacuo over 18 hrs, the diazonium salt was collected as a yellow solid (0.3149 g). 30 1 H NMR (d6-acetone) 5: 3.83 (s, 3H), 7.16 (dd, 1H), 7.27 (s, 1H), 7.27-7.30 (dd, 1H), 7.47 (t, 1H), 7.79 (d, 1H), 7.88 (t, 1H), 8.18 (t, 1H), 8.84 (dd, 1H). Step D: 35 A solution of FeSO4O7H20 (0.2258 g, 0.81 mmoles) in distilled water (3 mL) was heated to 100 0 C. The diazonium salt from Step C was added in one portion and the resulting mixture was WO 99/14217 PCT/US98/19015 -45 stirred at 100oC under N2. Gas evolution was observed for the first 5 10 min. of the reaction. With time, the product oiled out of solution. After 30 min., the reaction was partitioned between EtOAc and ice/brine. The organic layer was collected, dried over Na2SO4, and 5 concentrated in vacuo to give a green/brown oil (0.3317 g). The crude material was purified by plate layer chromatography with 20% CH2C12/hexane to afford the desired product as a white solid (0.040 g). 1 H NMR (CDC13) 5: 4.07 (s, 3H), 6.89 (d, 1H), 7.36-7.45 (m, 4H), 7.80 (dd, 1H), 8.64 (dd, 1H). 10 Step E: To a stirred solution of the dibenzothiophene (0.040 g, 0.19 mmoles) isolated from Step D in HOAc (2.5 mL) was added 40% HBr (0.65 mL, 5.6 mmoles) under N2. The reaction was heated to 15 130'C for 20 hrs. The resulting green solution was partitioned between EtOAc and ice/brine. The organic layer was washed with sat. NaHCO3 (2X) and brine. The EtOAc extract was dried over Na2SO4 and concentrated in vacuo to give an off-white solid (0.0366 g). Purification by plate layer chromatography with 1:1 hexane/CH2Cl2 20 afforded the desired phenol as a white solid (0.0294 g). 1 H NMR (CDCl3) 8: 5.53 (s, 1H), 6.77 (d, 1H), 7.26 (t, 1H), 7.43-7.49 (m, 3H), 7.82 (dd, 1H), 8.63 (dd, 111). EXAMPLE 2 25 PREPARATION OF CARBAPENEM 1 S allyl 2 0CO H H 0 N 0 C O2allyl A solution of 1-hydroxybenzothiophene (0.0294 g, 0.15 30 mmoles), the bis-allyl protected carbinol (0.0684 g, 0.19 mmoles), and triphenylphosphine (0.0592 g, 0.22 mmoles) in distilled THF (1.5 mL) was cooled to 0 0 C and placed under a N2 atmosphere. To this stirred WO 99/14217 PCT/US98/19015 -46 solution was added dropwise diisopropylazodicarboxylate (0.06 mL, 0.22 mmoles). The reaction was stirred for 1 hr, and concentrated in vacuo. The residue was purified by plate layer chomatography with double elution using 20% hexane/CH2C12 to afford the coupled 5 product as a yellow oil (0.037 g). 1H NMR (CDC13) 8: 1.28 (d, 3H), 1.43 (d, 3H), 3.40 (m, 2H), 4.18 (dd, 1H), 4.58-4.63 (dd, 2H), 4.74-4.93 (m, 2H), 5.00 (d, 1H), 5.09 (m, 1H), 5.22-5.52 (m, 4H), 5.84-6.07 (m, 3H), 6.87 (d, 1H), 7.33 (t, 1H), 7.43-7.50 (m, 3H), 7.83 (dd, 1H11), 8.57 (dd, 1H). 10 EXAMPLE 3 PREPARATION OF CARBAPENEM 2 S HO H H N! C O2Na 15 To a solution of carbapenem 1 (0.037 g, 0.068 mmoles) in 1:1 CH2CI2/EtOAc (1 mL) was added under N2, 2-ethylhexanoic acid (0.01 mL, 0.074 mmoles), 0.5 M solution of sodium-2-ethyl-hexanoate (0.15 mL, 0.074 mmoles), triphenylphosphine (0.0115 g, 0.004 20 mmoles), and Pd(PPh3)4 (0.0175g, 0.001 mmoles) in that order. The reaction was stirred at ambient temperature for 5 min. and then stirred at 0OC for another 30 min. The product was precipitated out of solution with addition of Et20 (5 mL). The resulting mixture was centrifuged and the supernatent discarded. The product was 25 triturated with additional Et20 (5 mL) and dried in vacuo to give a white/orange solid (0.0146 g). The crude material was purified by reverse phase plate layer chromatography with 7:3 H20/CH3CN. The desired product was eluted off the silica gel with 4:1 CH3CN/H20. Lyophilization gave the final compound as a white solid (0.023 g).

WO 99/14217 PCT/US98/19015 -47 1 H NMR (5:2 D20/CD3CN) 5: 1.43 (t, 6H), 3.59-3.63 (m, 2H), 4.36-4.44 (m, 2 H), 5.24 (d, 1H), 6.05 (d, 1H), 7.35 (d, 1H), 7.70-7.83 (m, 4H), 8.19 (dd, 1H), 8.93 (dd, 1H). 5 EXAMPLE 4 PREPARATION OF 1-HYDROXY-5-T BUTYLDIMETHYLSILYLOXYMETHYL DIBENZOTHIOPHENE OH S OTBS 10 Step A: 2-Bromo-3-nitrotoluene and 3-methoxy benzenethiol were coupled using the procedures described in Example 1 (Step A) to afford the desired product as a yellow oil. 15 1 H NMR (CDCl3) 5: 2.38 (s, 3H), 3.73 (s, 3H), 6.62-6.66 (m, 2H), 6.68 (dd, 1H), 7.11 (t, 1H), 7.39 (m, 2H), 7.53 (dd, 1H). Step B: The coupled product from Step A was reduced to its 20 corresponding amine using the procedures described in Example 1 (Step B). The amine was obtained as a green/yellow oil. 1 H NMR (CDC13) 5:2.39 (s, 3H), 3.71 (s, 3H), 6.58-6.65 (m, 3H), 6.71-6.76 (m, 2H), 7.09 (q, 2H). 25 Step C: Utilizing the procedure described in Example 1 (Step C), the amine from Step B was converted to its diazonium salt. The product was isolated as a green/yellow solid. 1 H NMR (d6-acetone) 5: 2.49 (s, 3H), 3.78 (s, 3H), 6.97-7.02 30 (m, 3H), 7.35 (t, 1H), 8.04 (t, 1H), 8.31 (d, 1H), 8.87 (d, 1H).

WO 99/14217 PCT/US98/19015 -48 Step D: To a solution of the diazonium salt (0.9275 g, 2.3 mmoles) obtained from Step C in anhydrous DMSO (20 mL) was added 3A molecular sieves. The mixture was heated to 60 0 C and stirred for 1 5 hr. The orange mixture was filtered and the molecular sieves washed well with EtOAc. The filtrate was collected and washed with H20 (4X) followed by brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a dark red/orange oil. The crude material was purified by plate layer chromatography with 2:1 10 hexane/CH2C12 to give the desired dibenzothiophene as a white solid (0.1047 g). 1 H NMR (CDCl3) 8: 2.58 (s, 3H), 4.08 (s, 3H), 6.91 (d, 1H), 7.25 (d, 1H), 7.36 (t, 2H), 7.47 (d, 1H), 8.50 (d, 1H). 15 Step E: Utilizing the procedure described in Example 1 (Step E), the product from Step D was demethylated to give the phenol as a white solid. 1 H NMR (CDC13) 8: 2.58 (s, 3H), 6.77 (d, 1H), 7.24-7.31 (2d, 20 2H), 7.38 (t, 1H), 7.43 (t, 1H), 8.48 (d, 1H). Step F: To a solution of the phenol (0.076 g, 0.35 mmoles) from Step E in CH2C12 (1 mL) was added NEt3 (0.059 mL, 0.42 mmoles) at 25 0OC under N2. The reaction was stirred for 10 min. before adding acetyl chloride (0.027 mL, 0.39 mmoles). The reaction was then stirred at 0OC for another 15 min. and poured into ice/H20. The mixture was extracted with EtOAc. The organic layers were washed with 1 N HC1 followed by brine, and dried over Na2SO4. 30 Concentration in vacuo gave the desired product as a light brown oil (0.1163 g, quantitative yield). 1 H NMR (CDC13) 6: 2.53 (s, 3H), 2.57 (s, 3H), 7.19 (d, 1H), 7.27 (d, 1H), 7.38 (t, 1H), 7.43 (t, 1H), 7.73 (d, 1H), 8.08 (d, 1H). 35 Step G: The acetylated product (0.0902, 0.35 mmoles) obtained from Step F was dissolved in CCl4 (0.5 mL) and placed under a N2 WO 99/14217 PCT/US98/19015 -49 atmosphere. NBS (0.0817 g, 0.46 mmoles) was added followed by a crystal of AIBN. The reaction was heated to 80'C for 23 hrs. The reaction was poured into ice/brine and extracted with EtOAc. The organic layers were washed with 5% Na2S203 and brine. 5 Concentration in vacuo gave the crude product as a yellow oil (0.2085 g). The oil was purified by plate layer chromatography with 1:1 hexane/CH2Cl2 to afford the alkyl bromide as a yellow solid (0.0895 g). 1 H NMR (CDCl3) 8: 2.53 (s, 3H), 4.77 (s, 2H), 7.23 (d, 1H), 7.46-7.52 (m, 3H), 7.76 (d, 1H), 8.22 (dd, 1H). 10 Step H: The alkyl bromide (0.0895 g, 0.27 mmoles) from Step G was combined with KOAc (0.0541 g, 0.53 mmoles) in sieve-dried DMF (1 mL) and heated to 100'C for 1 hr. The reaction was poured into 15 ice/H20 and extracted with EtOAc. The organic layers were washed with additional H20 (2X) and brine, and dried over Na2SO4. Concentration in vacuo gave an orange/red oil (0.114 g). The oil was purified by plate layer chromatography with 3:1 CH2Cl2/hexane to give a pale yellow solid (0.0635 g). 20 1 H NMR (CDC13) 6: 2.17 (s, 3H), 2.55 (s, 3H), 5.38 (s, 2H), 7.21 (d, 1H), 7.44-7.49 (m, 3H), 7.73 (d, 1H), 8.22 (dd, 1H). Step I: A yellow mixture of the product (0.0635 g, 0.2 mmoles) 25 from Step H, 5 N NaOH (0.1 mL, 0.42 mmoles), and absolute EtOH (1 mL) was heated to 70 0 C under N2 for 15 min. The reaction was partitioned between EtOAc and ice/1 N HC1. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give an orange solid (0.0637 g). The solid was purified by plate layer 30 chromatography with 5% EtOAc/CH2C12 to give the desired product as a slightly orange solid (0.0335g). 1H NMR (CDCl3+CD3OD) 5: 4.76 (s, 2H), 6.71 (d, 1H), 7.07 (t, 1H), 7.17 (d, 1H), 7.24-7.28 (m, 2H), 8.45 (d, 1H). 35 Step J: To a flask charged with the phenol (0.0335 g, 0.16 mmoles) from Step I was added a solution of TBSC1 (0.0305 g, 0.17 WO 99/14217 PCT/US98/19015 -50 mmoles) in DMF (0.5 mL) under N2. The reaction was cooled to 0OC and stirred for 10 min. before adding dropwise a solution of imidazole (0.0137g, 0.19 mmoles) in DMF (0.25 mL). The solution was stirred at 0OC for 1 h. The reaction was partitioned between EtOAc and ice/1 N 5 HC1. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a light brown oil. The oil was purified by plate layer chromatography with 3:1 CH2Cl2/hexane to afford the TBS-protected alcohol as a light yellow solid (0.0416 g). 1 H NMR (CDC13) 6: 0.15 (s, 3H), 0.98 (s, 6H), 4.97 (s, 2H), 10 6.76 (d, 1H), 7.26 (t, 1H), 7.45-7.48 (m, 3H), 8.55 (dd, 1H). EXAMPLE 5 PREPARATION OF CARBAPENEM 3 OH S ally 2 0 CH H 0 N! 0 CO2allyl 15 Step A: Utilizing the procedure from Example 2, 1-hydroxy-5-t butyldimethylsilyloxymethyl dibenzothiophene was coupled with bis allyl carbinol to afford the desired product as a yellow/orange oil after 20 plate layer chromatography with 3:1 CH2Cl2/hexane. 1 H NMR (CDC13) 5: 0.15 (s, 3H), 0.98 (s, 6H), 1.27 (d, 3H), 1.41 (d, 3H), 3.41-3.44 (m, 2H), 4.14 (dd, 1H), 4.56-4.58 (m, 2H), 4.75-4.85 (m, 2H), 4.96 (s, 2H), 4.98 (d, 1H), 5.08-5.12 (m, 1H), 5.21-5.48 (m, 4H), 5.80-6.03 (m, 3H), 6.86 (d, 1H), 7.32 (t, 1H), 7.46-7.49 (m, 3H), 8.51 (dd, 25 1H). Step B: To a solution of the adduct (0.0572 g, 0.083 mmoles) obtained from Step A in distilled THF (1 mL) was added HOAc (0.028 30 mL, 0.496 mmoles) followed by 1 M TBAF in THF (0.25 mL, 0.248 mmoles). The reaction was stirred at ambient temperature for 3 hrs.

WO 99/14217 PCT/US98/19015 -51 The reaction was partitioned between EtOAc and H20/brine. The organic layer was washed with sat. NaHCO3 (2X) and brine, and dried over Na2SO4. After removing the solvent in vacuo, a yellow oil was obtained (0.053 g). The oil was purified by plate layer 5 chromatography with double elution using 5% EtOAc/CH2C12 to afford the desired phenol as a yellow/orange oil (0.0349 g). 1 H NMR (CDC13) 6: 1.27 (d, 3H), 1.41 (d, 3H), 3.41-3.44 (m, 2H), 4.14 (dd, 1H), 4.56-4.58 (m, 2H), 4.75-4.85 (m, 2H), 4.96 (d, 2H), 4.98 (d, 1H), 5.08-5.12 (m, 1H), 5.21-5.48 (m, 4H), 5.80-6.03 (m, 3H), 6.86 10 (d, 1H), 7.32 (t, 1H), 7.46-7.49 (m, 3H), 8.51 (dd, 1H). EXAMPLE 6 PREPARATION OF CARBAPENEM 4 N 'N S Ho H 0 No 0 CO2 15 Step A: To a solution of carbapenem 3 (0.0349 g, 0.060 mmoles) in sieve-dried CH2Cl2 (1 mL) was added 1-methyl imidazole (0.011 mL, 0.13 mmoles) at -20 0 C followed by Tf20 (0.011 mL, 0.066 mmoles). The 20 reaction was stirred at -20 0 C for 1.5 h and then partitioned between ice/H20 and CH2C12. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a pale yellow oil (0.0562 g). The oil was redissolved in CH2C12 (0.5 mL) and the product was precipitated out with Et20 as an oil. The mixture was 25 centrifuged and the supernatent discarded. The oil was washed with Et20 and dried in vacuo (0.0462 g, quantitative yield). 1H NMR (CDCl3) 8:1.27 (d, 3H), 1.42 (d, 3H), 3.36-3.47 (m, 2H), 3.96 (s, 3H), 4.17 (dd, 1H), 4.56-4.60 (m, 2H), 4.71-4.90 (m, 2H), 4.99 (d, 1H), 5.06-5.16 (m, 1H), 5.21-5.49 (m, 4H), 5.62 (s, 2H), 5.79-6.05 (m, WO 99/14217 PCT/US98/19015 -52 3H), 6.89 (d, 1H11), 7.23-7.27 (m, 2H), 7.35 (t, 1H), 7.44 (d, 1H), 7.49-7.60 (m, 2H), 8.57 (dd, 1H), 9.31 (s, 1H). Step B: 5 The product from Step A was deblocked using the procedures described in Example 3 to afford the final compound as a white solid after lyophilization. 1 H NMR (5:2 D20/CD3CN) 8: 1.42-1.46 (2d, 6H), 3.57-3.62 (m, 2H), 4.07 (s, 3H), 4.33-4.43 (m, 2H), 5.23 (d, 1H), 5.88 (s, 2H), 6.02 10 (d, 1H11), 7.37 (d, 1H), 7.67-7.91 (m, 6H), 8,98 (d, 1H). EXAMPLE 7 PREPARATION OF CARBAPENEM 5 N ,C ONH 2 S Cl HO H H 0 N' 0G 15 Co02 Step A: To a stirred solution of carbapenem 3 (0.0895 g, 0.16 mmoles) in sieve-dried CH2C12 (1.5 mL) was added NEt3 (0.032 mL, 20 0.23 mmoles) at -6 0 C under N2 followed by dropwise addition of MsC1 (0.016 mL, 0.20 mmoles). The reaction was stirred at -6oC for 15 min., and then poured into ice/1 M HC1. The resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a pale yellow oil 25 (0.1027 g, 98% yield). The crude mesylate was dissolved in acetone (2 mL) and cooled to O'C. Nal (0.0465 g, 0.31 mmoles) was added in one portion under N2. With time the reaction became increasingly yellow. The reaction was stirred at 0°C for 1 hr and then partitioned between ice/brine and EtOAc. The organic layer was dried over 30 Na2SO4 and concentrated in vacuo to afford the alkyl iodide as a yellow oil (0.1045 g).

WO 99/14217 PCT/US98/19015 -53 1 H NMR (CDC13) 8:1.27 (d, 3H), 1.41 (d, 3H), 3.35-3.42 (m, 1H), 3.43 (dd, 1H), 4.14 (dd, 1H), 4.57-4.59 (m, 2H), 4.68 (s, 2H), 4.71 4.89 (m, 2H), 4.99 (d, 2H), 5.06-5.13 (m, 1H), 5.21-5.51 (m, 4H), 5.80-6.03 (m, 3H), 6.86 (d, 1H), 7.32-7.52 (m, 4H), 8.49 (d, 1H). 5 Step B: To a solution of the alkyl iodide (0.1045 g, 0.15 mmoles) obtained from Step A in sieve-dried acetonitrile (2 mL) was added dabco acetamide triflate salt (0.0481 g, 0.15 mmoles) followed by 10 AgOTf (0.0394 g, 0.15 mmoles) at ambient temperature under N2. Upon addition of AgOTf, a yellow precipitate formed. The resulting mixture was stirred for 40 min. and filtered through a celite pad. The celite was washed well with acetonitrile and the filtrate concentrated in vacuo. The residue was dissolved in acetone (4 mL) 15 and filtered through a cotton plug into a centrifuge tube. The solution was reconcentrated under a stream of N2 to give a rose-colored oil (0.1585 g, quantitative yield). 1H NMR (d6-acetone) 8: 1.35-1.41 (2d, 6H), 3.56-378 (m, 2H), 3.34 (dd, 1H), 4.34 (dd, 1H), 4.52-4.88 (m, 18H), 5.01-5.57 (m, 8H), 20 5.80 (d, 1H), 5.87-6.05 (m, 2H), 7.18 (d, 1H), 7.20-7.25 (bs, 1H), 7.53 (t, 1H), 7.62-7.71 (m, 3H), 7.86 (d, 1H), 8.91 (d, 1H). Step C: The product (0.0696 g, 0.068 mmoles) from Step B was 25 deblocked using the procedure described in Example 3 with the exception of sieve-dried DMF as the solvent. The reaction became increasingly cloudy over time. After 1 hr, the reaction was cooled to O'C and the product was further precipitated with the addition of acetone. The crude material (0.0377 g) was collected as a hexanoate 30 salt after washing with acetone and centrifugation. The compound was dissolved in a minimal amount of H20 and purified via a reverse-phase HPLC equipped with a 10 mL column of MacroPrep ion exchange resin in conjunction with a 10 mL column of Amberchrom CG 161. 35 The following HPLC conditions used are listed below: WO 99/14217 PCT/US98/19015 -54 Macroprep column Time [mini Flow rate[mL/min] Eluant 0-5 10 water 5 5-10 10 5% NaCl 10-30 15 5% NaCl Amberchrom CG 161 column Time[min] Flow rate [mL/min] Eluant 10 [linear gradient 0-15 10 water 15-20 10 100% H 2 0 to 60:40

CH

3

CN/H

2 0 15 After lyophilization, the final compound was obtained as a white solid (0.0155 g). 1 H NMR (5:2 D20/CD3CN) 8: 1.47 (d, 6H), 3.60-3.67 (m, 2H), 4.33-4.82 (m, 16H), 5.24-5.31 (m, 3H), 6.02 (d, 1H), 7.42 (d, 1H), 7.78-7.96 (m, 4H), 9.07 (dd, 1H). 20 EXAMPLE 8 PREPARATION OF 1-HYDROXY-5-T BUTYLDIMETHYLSILYLOXYPROPYL DIBENZOTHIOPHENE OH S 25 TBSO Step A: The acetylated dibenzothiophene (0.3985, 1.55 mmoles) obtained from Example 4 (Step F) was dissolved in CCl4 (5 mL) and place under a N2 atmosphere. Recrystallized NBS (0.3051 g, 1.7 30 mmoles) was added followed by a crystal of AIBN. The reaction was heated to 80 0 C for 23 hrs. Additional NBS (0.3067 g, 1.7 mmoles) was WO 99/14217 PCT/US98/19015 -55 added to the reaction and the mixture was stirred at 80 0 C for another 6.5 hrs. The reaction was poured into ice/brine and extracted with EtOAc. The organic layers were washed with 5% Na2S203 and brine. Concentration in vacuo gave an orange solid (0.5974 g). By 1 H NMR 5 analysis, the crude product contained a 3:1 mixture of the desired dibrominated product to the monobrominated product or 74% yield of dibrominated product. 1 H NMR (CDCl3) 6: 2.55 (s, 3H), 6.96 (s, 1H), 7.25 (d, 1H), 7.48-7.50 (m, 2H), 7.76 (t, 2H), 8.24 (d, 1H). 10 Step B: The crude alkyl bromide (0.4670 g, 1.1 mmoles) from Step A was dissolved in sieve-dried DMF (5 mL) and placed under N2. KOAc (0.3396 g, 3.4 mmoles) was added in one portion and the 15 reaction was heated to 100oC. After 1.5 hrs, The reaction was partitioned between EtOAc and H20. The organic layer was washed with water (3X) and brine, dried over Na2SO4, and concentrated in vacuo to give a brown/yellow oil (0.6382 g). The oil was purified by plate layer chromatography with 4 elutions using 3:2 CH2C12/hexane 20 to give 2 major fractions: 1) the triacetate compound (0.1403 g) and 2) a mixture of the diacetate compound and the aldehyde (0.2077 g). 1 H NMR (CDC13) 5: 2.18 (s, 6H), 2.55 (s, 3H), 7.23 (d, 1H), 7.47 (t, 2H), 7.61 (d, 1H), 7.75 (d, 1H), 7.93 (s, 1H), 8.31 (dd, 1H). 25 Step C: The fraction from Step B containing the triacetate compound (0.1255 g, 0.4 mmoles) was suspended in absolute EtOH (2 mL) and 5 N NaOH (0.15 mL, 0.8 mmoles) was added under N2. The reaction was heated to 70oC for 20 min. then poured into ice/1 M HC1. 30 The mixture was extracted with EtOAc. The organic layer was collected, washed with brine, dried over Na2SO4, and cocentrated in vacuo to give an orange solid (0.1065 g). The solid was purified by plate layer chromatography with 5% EtOAc/CH2C12 to afford the clean aldehyde as a yellow solid (0.0756 g). 35 1 H NMR (CDCl3+d6-acetone) 8: 6.73 (d, 1H), 7.07 (t, 1H), 7.21 (d, 1H), 7.40 (t, 1H), 7.73 (d, 1H), 8.78 (dd, 1H), 9.00 (bs, 1 H), 10.04 (s, 1H).

WO 99/14217 PCT/US98/19015 -56 Step D: The fraction from Step B containing a mixture of the diacetate compound and the aldehyde (0.2077 g, 0.77 moles) was 5 submitted under the same reaction conditions described in Step C. The resulting mixture of aldehyde and diol was separated by plate layer chromatography with 5% EtOAc/CH2C12 to give 0.0895 g of clean aldehyde. 10 Step E: The aldehydes from Step C and Step D were combined and acetylated using the procedures described in Example 4 (Step F). The reaction was stirred at O'C for a total of 30 min. The desired product was isolated as tan solid. 15 1 H NMR (CDC13) 8: 2.57 (s, 3 H), 7.29 (d, 1 H), 7.50 (t, 1 H), 7.65 (t 1H), 7.82 (d, 1H), 7.99 (dd, 1H), 8.54 (dd, 1H), 10.29 (s, 1H). Step F: The acetylated product (0.1572 g, 0.58 mmoles) from Step 20 E was dissolved in CH2C12 (3 mL) and methyl (triphenylphosphoranylidene)-acetate (0.2141 g, 0.64 mmoles) was added under N2. The mixture was stirred at ambient temperature for 1.5 hrs. The reaction was concentrated in vacuo to give a white/yellow solid. The solid was purified by plate layer 25 chromatography with 5% hexane/CH2Cl2 to give the desired ester as a white solid (0.1688g). 1 H NMR (CDCl3) 5: 2.54 (s, 3 H), 3.86 (s, 3H), 6.67 (d, 1H), 7.24 (d, 1H), 7.48 (t 2H), 7.66 (d, 1H), 7.77 (d, 1H), 7.95 (d, 1H), 8.28 (d, 1H). 30 Step G: To a solution of the ester obtained from Step F (0.1688 g, 0.51 mmoles) in 1:1 EtOAc/EtOH was added 10% Pd/C (0.0186, 10% w/w). The resulting mixture was degassed with N2 and 35 hydrogenated under atmospheric H2 pressure for 3 hrs. The reaction was degassed with N2 and the catalyst removed by filtering through a WO 99/14217 PCT/US98/19015 -57 celite pad. The filtrate was concentrated in vacuo to give a white/yellow solid (0.1595 g). 1 H NMR (CDCl3) 8: 2.53 (s, 3 H), 2.80 (t, 2H), 3.21 (t, 2H), 3.70 (s, 3H), 7.21 (t, 1H), 7.31 (d, 1H), 7.40-7.49 (m, 2H), 7.73 (dd, 1H), 5 8.12 (dd, 1H). Step H: The alkyl ester isolated from Step G (0.1595 g, 0.49 mmoles) was dissolved in absolute EtOH (2 mL), and 5 N NaOH (0.29 10 mL, 1.5 mmoles) was added under N2. The resulting yellow mixture was heated to 70'C. After 1 hr, the reaction was partitioned between ice/1 M HC1 and EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to afford the desired acid as a pale yellow solid (0.1614 g, quantitative yield). 15 1 H NMR (CDCl3+d6-acetone) a: 2.77 (t, 2H), 3.15 (t, 2H), 6.81 (d, 1H), 7.18-7.26 (m, 2H), 7.32 (t, 1H), 7.32 (d, 1H), 8.52 (d, 1H). Step I: To a solution of the carboxylic acid generated in Step H 20 (0.1614, 0.49 mmoles) in distilled THF (5 mL) was added dropwise a 1 M solution of BH3.THF in THF (0.98 mL, 0.98 mmoles). Upon addition, gas evolution was observed. With time, the reaction became a cloudy green mixture. The reaction was stirred at ambient temperature for a total of 2 hrs. The reaction was quenched with 25 dropwise addition of MeOH until no further gas evolution was observed. The reaction mixture was concentrated in vacuo and the residue was purified by plate layer chromatography with 5% EtOAc/CH2Cl2 to give the desired diol as a white solid (0.1065 g). 1H NMR (CDCl3+d6-acetone) 8: 1.88 (m, 2H), 2.81 (t, 2H), 30 3.57 (t, 2H), 6.74 (d, 1H), 7.08 (t, 2H), 7.10 (d, 1H), 7.21-7.27 (m, 2H), 8.42 (d, 1H), 8.69 (bs, 1 H). Step J: Utilizing the procedure described in Example 4 (Step J), 35 the diol obtained from Step I was selectively protected at the primary alcohol position to give the desired TBS-protected product as a yellow oil after plate layer chromatography with 5% EtOAc/CH2C12.

WO 99/14217 PCT/US98/19015 -58 1 H NMR (CDC13) 8: 0.07 (s, 3H), 0.92 (s, 6 H), 1.99 (m, 2H), 2.92 (t, 2H), 3.70 (t, 2H), 6.74 (d, 1H), 7.24-7.27 (m, 2H), 7.38-7.43 (m, 2H), 8.48 (d, 1H). 5 EXAMPLE 9 PREPARATION OF CARBAPENEM 6 OH 1S alylo 2 0CO H H O N! 0 C 02allyl 10 Step A: 1-Hydroxy-5-t-butyldimethylsilyloxypropyl dibenzothiophene was coupled with the bis-allyl protected carbinol using the procedure described in Example 2 to give the adduct as a yellow oil after plate layer chromatography with 3:1 CH2Cl2/hexane. 15 1 H NMR (CDC13) 5: 0.09 (s, 3H), 0.94 (s, 6H), 1.29 (d, 3H), 1.43 (d, 3H), 1.98 (m, 2H), 2.93 (t, 2H), 3.35-3.48 (m, 2 H), 3.70 (t, 2H), 4.17 (dd, 1H), 4.58-4.63 (m, 2H), 4.74-4.93 (m, 2H), 5.00 (d, 1H), 5.09-5.18 (m, 1H), 5.22-5.52 (m, 4H), 5.84-6.07 (m, 3H), 6.87 (d, 1H), 7.26-7.51 (m, 4H), 8.43 (dd, 1H). 20 Step B: The adduct from Step A was desilylated following the procedures presented in Example 5 (Step B) with the exception that the reaction was stirred for 4.5 hrs. The desired alcohol was isolated. 25 1 H NMR (CDC13) 5: 1.29 (d, 3H), 1.43 (d, 3H), 1.98 (m, 2H), 2.93 (t, 2H), 3.35-3.48 (m, 2 H), 3.70 (m, 2H), 4.17 (dd, 1H), 4.58 4.63 (m, 2H), 4.74-4.93 (m, 2H), 5.00 (d, 1H), 5.09-5.18 (m, 1H), 5.22-5.52 (m, 4H), 5.84-6.07 (m, 3H), 6.87 (d, 1H), 7.26-7.51 (m, 4H), 8.43 (dd, 1H).

WO 99/14217 PCT/US98/19015 -59 EXAMPLE 10 PREPARATION OF CARBAPENEM 7 -N,, CONH 2 cP - S HO H H 0 CO2 5 Step A: To a solution of carbapenem 6 (0.0561 g, 0.093 mmoles) in sieve-dried CH2Cl2 (1 mL) at -8 0 C was added 2,6-lutidine (0.016 mL, 0.14 mmoles) under N2 followed by Tf20 (0.017 mL, 0.10 mmoles). 10 After 25 min., additional Tf20 (1.1X) and 2,6-lutidine (1.5X) was added to the reaction. The reaction was stirred for another 10 min before partitioning the reaction between EtOAc and ice/1 M HC1. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude triflate as a yellow oil (0.0778 15 g, quantitative yield). 1 H NMR (CDC13) 8: 1.29 (d, 3H), 1.43 (d, 3H), 2.31 (m, 2H), 3.02 (t, 2H), 3.35-3.48 (m, 2 H), 4.17 (dd, 1H), 4.58-4.63 (m, 4H), 4.74-4.93 (m, 2H), 5.00 (d, 1H), 5.09-5.18 (m, 1H), 5.22-5.52 (m, 4H), 5.84-6.07 (m, 3H), 6.89 (d, 1H), 7.26-7.52 (m, 4H), 8.44 (dd, 1H). 20 Step B: To a solution of the triflate obtained from Step A (0.0778 g, 0.093 mmoles) in sieve-dried CH3CN was added dabco acetamide triflate salt (0.0298 g, 0.093 mmoles) under N2. The reaction was 25 stirred at ambient temperature for 1 hr and 20 min. The reaction was concentrated in vacuo to give a rose-colored oil (0.106 g). The oil was dissolved in acetone (2.5 mL) and the product was precipitated out of solution with the addition of Et20 (8 mL). The solid was isolated by centrifugation and rewashed with Et20 to give the desired 30 product (0.0788 g).

WO 99/14217 PCT/US98/19015 -60 1 H NMR (d6-acetone) 8: 1.38 (d, 6H), 2.51 (min, 2H), 3.05 (t, 2H), 3.54 (min, 1H), 3.69-3.77 (min, 2H), 4.00 (min, 2H), 4.32-4.88 (min, 19H), 5.10-5.51 (min, 6H), 5.78 (d, 1H), 5.87-6.06 (min, 2H), 7.09 (d, 1H), 7.23 (bs, 1H), 7.43-7.51 (min, 3H), 7.57 (d, 1H), 7.68 (bs, 1H), 8.59 (dd, 1H). 5 Step C: The dabco quat from Step B was deallylated following the procedures described in Examples 7 (Step C) to afford the desired product as a white solid. 10 1 H NMR (5:2 D20/CD3CN) 8: 1.40 (d, 6H), 2.44 (min, 2H), 3.16 (t, 2H), 3.60-3.69 (min, 2H), 3.78 (min, 2H), 4.09-4.82 (min, 16H), 5.28 (d, 1H), 5.97 (d, 1H), 7.31 (d, 1H), 7.59 (d, 1H), 7.67-7.79 (min, 3H), 8.78 (d, 1H). 15 EXAMPLE 11 PREPARATION OF CARBAPENEM 8 Ss-O HO H H 0 CO2Na Step A: 20 A solution of carbapenem 1 (0.099 g, 0.18 mmoles) in CH2C12 (2 mL) was cooled to 0 0 C and a solution of 85 wt% MCPBA (0.0436 g, 0.20 mmoles) in CH2C12 (2 mL) was added over 10 min. via a dropping funnel. The reaction was allowed to stir at 0OC for 30 min. The reaction was quenched with 5% Na2S203 and extracted with 25 EtOAc. The organic layer was washed with 5% Na2S203 and brine, dried over Na2SO4, and concentrated in vacuo to give a yellow oil (0.093 g). The oil was purified by plate layer chromatography with 10% EtOAc/CH2C12 to afford the sulfoxide as a mixture of diastereomers (0.0496 g).

WO 99/14217 PCT/US98/19015 -61 1H NMR (CDC13) 8: 1.26 (d, 3H), 1.41 (dd, 3H), 3.25-3.49 (m, 2H), 4.17 (m, 1H11), 4.57 (m, 2H), 4.71-5.51 (m, 8H), 5.76-6.05 (m, 3H), 7.06 (t, 1H), 7.40-7.64 (m, 4H), 7.97 (d, 1H), 8.16 (dd, 1H). 5 Step B: The final compound was isolated in 60% yield after submitting the sulfoxide obtained in Step A to the conditions described in Example 3. 1 H NMR (5:2 D20/CD3CN) 6: 1.45 (d, 6H), 3.52-3.63 (m, 10 2H), 4.36-4.44 (m, 2 H), 5.20 (dd, 1H), 6.03 (dd, 1H), 7.63 (d, 1H), 7.81 7.93 (m, 3H), 7.98 (t, 1H), 8.28 (d, 1H), 8.60 (d, 1H). EXAMPLE 12 PREPARATION OF CARBAPENEM 9 15 0 o!: 0 CO2Na The sulfone was prepared in an analogous manner to Example 11 using 3 equivalents of MCPBA in the oxidation step 20 (Example 11, Step A). The final compound was isolated as a white solid. 1 H NMR (5:2 D20/CD3CN) 8: 1.50 (2d, 6H), 3.59 (m, 1H), 3.67 (dd, 1H), 4.43 (dd, 1H), 4.45 (m, 1H), 5.30 (d, 1H), 6.11 (d, 1H), 7.77 (d, 1H), 7.80 (d, 1H11), 7.92 (t, 2H), 8.10 (t, 1H), 8.21 (d, 1H), 8.69 (d, 1H). 25 WO 99/14217 PCT/US98/19015 -62 EXAMPLE 13 PREPARATION OF CARBAPENEM 10 N ' CONH 2 SyO Cl 0 HO H H o 0 0 E C02 5 To a solution of carbapenem 5 (0.0100 g, 0.016 mmoles) in 1:1 acetone/H20 (1 mL) was added 0.44 mL of a stock solution (0.024 g/mL) of dimethyl dioxirane in acetone at 0°C under N2. The reaction was followed by reverse-phase HPLC. After 50 min., an additional 0.040 mL of dimethyl dioxirane was added to the reaction. The 10 reaction was stirred for another 20 min., then concentrated in vacuo. The aqueous residue was lyophilized to give the sulfoxide in 54% purity by 1 H NMR and UV as a white solid (0.0071 g). 1 H NMR (5:2 D20/CD3CN) 8: 1.45 (m, 6H), 3.27-3.61 (m, 2H), 4.28-4.82 (m, 16 H), 5.04-5.46 (m, 3H), 5.73-5.93 (m, 1H), 7.53-8.15 15 (m, 5H), 8.62-8.71 (m, 1H). EXAMPLE 14 PREPARATION OF CARBAPENEM 11 / N §\ . CONH 2 allyl 2 0CO H H 0 N 0 20 C 0211yI Step A: Carbapenem 3 was treated with 3 equivalents of a 0.057 M solution of dimethyl dioxirane in acetone in the same manner WO 99/14217 PCT/US98/19015 -63 described in Example 13 with the exception that the reaction was complete within 20 min. Purification of the crude material by plate layer chromatography with 15% EtOAc/CH2Cl2 gave the desired sulfone in quantitative yield. 5 1 H NMR (CDC13) 8:1.23 (d, 3H), 1.43 (d, 3H), 3.27 (m, 1H), 3.45 (dd, 1H), 4.19 (dd, 1H), 4.58-4.91 (m, 4H), 4.94 (d, 1H), 5.08 5.51 (min, 7H), 5.78 (d, 1H), 5.83-6.05 (m, 2H), 7.11 (dd, 1H), 7.44-7.66 (m, 4H), 8.12 (d, 1H). 10 Step B: The sulfone generated in Step A was converted to the alkyl iodide following the procedures described in Example 7 (Step A) with the exception that initial mesylation was complete after 35 min. and 5 equivalents of Nal at ambient temperature for 4.5 hrs was 15 necessary to drive the reaction to completion. The iodide was isolated in quantitative yield as a red/orange oil. 1 H NMR (CDC13) 8:1.23 (d, 3H), 1.41 (d, 3H), 3.24 (m, 1H), 3.45 (dd, 1H), 4.19 (dd, 1H), 4.58-4.90 (m, 4H), 4.78 (s, 2H), 4.93 (d, 1H), 5.07-5.51 (m, 5H), 5.78 (d, 1H), 5.83-6.05 (min, 2H), 7.11 (min, 1H), 20 7.44-7.59 (min, 4H), 8.06 (d, 1H). Step C: Utilizing the procedure from Example 7 (Step B) with the exception that the reaction was stirred at ambient temperature for 19 25 hrs, the dabco quaternized carbapenem was prepared by reacting the alkyl iodide isolated from Step B with the dabco acetamide triflate salt. 1 H NMR (d6-acetone) 8: 1.35 (d, 6H), 3.50 (m, 1H), 3.72 (dd, 1H), 4.34 (dd, 1H), 4.58-4.87 (min, 18H), 5.09-5.50 (m, 8H), 5.77 (d, 30 1H), 5.89-6.05 (m, 2H), 7.22 (bs, 1H), 7.52 (t, 2H), 7.66-7.76 (m, 3H), 7.93 8.02 (min, 2H), 8.69 (dd, 1H).

WO 99/14217 PCT/US98/19015 -64 EXAMPLE 15 PREPARATION OF CARBAPENEM 12 \ ON NoDCONH 2 S GOTf HO H H0 * 0 N! 0 ( o- ,o C02 5 A mixture of carbapenem 11 (0.0761 g, 0.072 mmoles), triphenylphosphine (0.028 g, 0.011 mmoles), Pd(PPh3)4 (0.0047 g, 0.036 mmoles), and dimedone (0.0302 g, 0.20 mmoles) in sieve-dried DMF (1 mL) was sparged with N2. iPr2NEt (0.037 mL, 0.20 mmoles) was then added. The reaction was stirred at ambient temperature for 10 1 hr. The product was precipitated out of solution with Et20 (6 mL). The mixture was centrifuged and the supernatent was discarded. The solid pellet was washed with Et20 and recentrifuged. The pellet was collected and dried in vacuo to give an off-white solid (0.050 g). 0.012 g of the crude material was purified on reverse phase HPLC by 15 eluting the compound through a 10 mL column of Amberchrom CG 161 with a linear gradient (100% water to 40:60 CH3CN/I-H20 over 35 min). The aqueous fractions were lyophilized to give the desired product in 82% purity (0.0082 g). 1 H NMR (5:2 D20/CD3CN) 5: 1.44 (t, 6H), 3.52-3.61 (m, 20 1H), 3.66 (dd, 1H), 4.49-4.86 (m, 16H), 5.29-5.40 (m, 3H), 6.03 (d, 1H), 7.79-7.84 (2d, 2H), 7.95-8.03 (m, 2H), 8.21 (t, 1H), 8.90 (d, 1H). EXAMPLE 16 PREPARATION OF 1-HYDROXY-5-T 25 BUTYLDIMETHYLSILYLOXYMETHYL DIBENZOFURAN OH 0O

TBSO

WO 99/14217 PCT/US98/19015 -65 Step A: To a mixture of 2,6-difluoronitrobenzene (1.0 g, 6.3 mmoles) in MeOH (10 mL) was added a 4.4 M solution of NaOMe in MeOH (1.57 mL, 6.9 mmoles). The mixture was heated to 70'C for 20 5 min. The resulting orange reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed with H20 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a pale yellow solid. The solid was purified by plate layer chromatography with 1:1 hexane/CH2C12 to 10 give clean product as a pale yellow solid (1.0559 g). 1 H NMR (CDC13) 8: 3.89 (s, 3H), 6.77-6.85 (min, 2H), 7.36 7.41 (min, 1H). Step B: 15 The methoxy nitrobenzene isolated from Step A was coupled with o-cresol (0.64 mL, 6.2 mmoles) using the procedures described in Example 1 (Step A) with the exception that the reaction time was 3 hrs. After purification by plate layer chromatography with 1:1 hexane/CH2C12, the desired adduct was obtained as a pale 20 yellow solid. 1 H NMR (CDCl3) 8: 2.18 (s, 3H), 3.91 (s, 3H), 6.27 (d, 1H), 6.66 (d, 1H), 6.98 (d, 1H), 7.10-7.27 (min, 4H). Step C: 25 The adduct from Step B (1.3924 g, 5.4 mmoles) was hydrogenated under 40-46 psi of H2 in a Parr Shaker for 5 days using 10% Pd/C (0.139 g, 10 w/w) in 1:1 EtOH/EtOAc. The catalyst was filtered off through a celite pad and the filtrate was concentrated in vacuo. The product was obtained as a yellow oil (1.2833 g, quantitative 30 yield). 1 H NMR (CDC13) 5: 2.30 (s, 3H), 3.88 (s, 3H), 6.36 (m, 1H), 6.60 (min, 2H), 6.79 (d, 1H), 6.97 (t, 1H), 7.08 (t, 1H), 7.21 (d, 1H). Step D: 35 The amine from Step C was converted to its KPF6 diazonium salt using the procedures described in Example 1 (Step C). The product was isolated as a yellow solid.

WO 99/14217 PCT/US98/19015 -66 1 H NMR (d6-acetone) 8: 2.26 (s, 3H11), 4.36 (s, 3H), 6.57 (d, 1H), 7.25 (d, 1H11), 7.32 (d, 1H), 7.38 (t, 2H), 7.46 (dd, 1H), 8.17 (t, 1H). Step E: 5 A mixture of 0.438 g (0.48 mmoles) of Pd2(dba)3 in anhydrous DMSO (30 mL) was heated to 100 0 C under N2 and the diazonium salt from Step D (1.8489 g, 4.8 mmoles) was added in one portion, resulting in significant gas evolution. The reaction was stirred at 100 0 C for 40 min and then filtered through celite. The 10 filtrate was paritioned between EtOAc and water. The organic layer was washed well with H20 (2X) followed by brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a black solid. The solid was purified by plate layer chromatography with 2:1 hexane/CH2C12 to give the desired product as a white solid (0.4335 g). 15 1H NMR (CDCl3) 8: 2.59 (s, 3H), 4.05 (s, 3H), 6.77 (d, 1H), 7.20-7.27 (m, 3H), 7.35 (t, 1H11), 7.95 (dd, 1H). Step F: The dibenzofuran from Step E was demethylated and 20 acetylated using the procedures described in Example 1 (Step E) and Example 4 (Step F) respectively. The desired product was obtained as a white solid over the 2 steps. 1 H NMR (CDC13) 8: 2.50 (s, 3H), 2.58 (s, 3H), 7.11 (dd, 1H), 7.21-7.30 (min, 2H), 7.41-7.50 (m, 2H), 7.64 (dd, 1H). 25 Step G: 0.1126 g (0.49 mmoles) of acetylated dibenzofuran from Step F, recrystallized NBS (0.0970 g, 0.54 mmoles), benzoyl peroxide (0.0271 g, 0.099 mmoles), and CC14 (3 mL) were combined under N2 30 and heated to 100'C. In addition to heating, the reaction was illuminated with a sun lamp. Within 30 min., the reaction became dark purple. After 2 hrs, another 0.3 equivalents of NBS and 0.0312 g of benzoyl peroxide were added. The reaction was heated for another 2 hrs, and then partitioned between EtOAc and 5% Na2S203. The 35 organic layer was washed with H20 and brine, dried over Na2SO4, and concentrated in vacuo to give a dark purple solid. The solid was WO 99/14217 PCT/US98/19015 -67 purified by plate layer chromatography with 2:1 CH2C12/hexane to afford the desired alkyl bromide as an off-white solid (0.081 g). 1 H NMR (CDCl3) 8: 2.50 (s, 3H), 4.84 (s, 2H), 7.16 (dd, 1H), 7.30 (t, 1H), 7.47-7.55 (m, 3H), 7.77 (dd, 1H). 5 Step H: The diacetate was prepared after plate layer chromatography with 2:1 CH 2 C1 2 /hexane, from the alkyl bromide of Step G using the procedures described in Example 4 (Step H). 10 1 H NMR (CDCl3) 8: 2.14 (s, 3H), 2.51 (s, 3H), 5.49 (s, 2H), 7.15 (dd, 1H), 7.32 (t, 1H), 7.44-7.52 (m, 3H), 7.80 (dd, 1H). Step I: The diacetate from Step H was treated under the same 15 conditions as Example 4 (Step I) to give the crude diol. 1H NMR (CDC13+CD3OD) 6: 5.00 (s, 2H), 6.67 (d, 1H), 7.03 (d, 1H), 7.19-7.30 (m, 2H), 7.38 (dd, 1H), 8.02 (dd, 1H). Step J: 20 The diol from Step I was selectively protected at the primary position using the procedures described in Example 4 (Step J) to give the desired product as a white solid after plate layer chromatography with 2:1 CH2Cl2/hexane. 1H NMR (CDCl3) 8: 0.15 (s, 3H), 0.97 (s, 6H), 5.15 (s, 2H), 25 6.68 (d, 1H), 7.15 (d, 1H), 7.25 (t, 1H), 7.33 (t, 1H), 7.53 (d, 1H), 7.98 (d, 1H).

WO 99/14217 PCT/US98/19015 -68 EXAMPLE 17 PREPARATION OF CARBAPENEM 13 N N.CON H 2 HO H H H .7 0 N! o C 02 Step A: 5 The carbapenem adduct was prepared by coupling 1 hydroxy-5-t-butyldimethylsilylmethyl dibenzofuran with bis-allyl protected carbinol in an analogous manner to Example 2 to give the desired product as a light purple oil. 1 H NMR (CDCl3) 5: 0.15 (s, 3H), 0.97 (s, 6H), 1.30 (d, 3H), 10 1.44 (d, 3H), 3.46 (dd, 1H), 3.49 (m, 1H), 4.20 (dd, 1H), 4.60 (dd, 2H), 4.72-4.91 (m, 2H), 4.96 (d, 1H), 5.09-5.51 (m, 5H), 5.13 (s, 2H), 5.73 (d, 1H), 5.85-6.07 (m, 2H), 6.77 (d, 1H), 7.21 (t, 1H), 7.31-7.40 (m, 2H), 7.52 (t, 1H), 7.92 (d, 1H). 15 Step B: Desilylation of the carbapenem from Step A was accomplished using the procedures described in Example 5 (Step B) to give the desired alcohol as a yellow oil. 1 H NMR (CDC13) 5: 1.30 (d, 3H), 1.44 (d, 3H), 3.46 (dd, 20 1H), 3.49 (m, 1H), 4.20 (dd, 1H), 4.60 (dd, 2H), 4.72-4.91 (m, 2H), 4.96 (d, 1H), 5.08 (s, 2H), 5.10 (m, 1H), 5.24-5.51 (m, 4H), 5.73 (d, 1H), 5.85-6.07 (m, 2H), 6.70 (d, 1H), 7.23-7.50 (m, 4H), 8.03 (dd, 1H11). Step C: 25 The alcohol from Step B was converted to its corresponding alkyl iodide following procedures presented in Example 7 (Step A). 1 H NMR (CDC13) 8: 1.30 (d, 3H), 1.44 (d, 3H), 3.46 (dd, 1H), 3.49 (m, 1H), 4.20 (dd, 1H), 4.60 (m, 2H), 4.71-4.89 (m, 2H), 4.75 (s, WO 99/14217 PCT/US98/19015 -69 2H), 4.95 (d, 1H), 5.09-5.49 (m, 5H), 5.73 (d, 1H), 5.85-6.07 (m, 2H), 6.77 (d, 1H), 7.23-7.48 (m, 4H), 7.92 (d, 1H). Step D: 5 Utilizing the procedures presented in Example7 (Steps B and C), the alkyl iodide from Step C was displaced by dabco acetamide triflate salt and deallylated to afford the final compound. Purification of the crude product was achieved on reverse-phase HPLC by eluting the compound through a 10 mL column of Amberchrom CG 161 with 10 a linear gradient (100% water to 40:60 CH3CN/H20 over 45 min). 1 H NMR (5:2 D20/CD3CN) 5: 1.41 (d, 6H), 3.59-3.70 (m, 2H), 4.23-4.82 (m, 16H), 5.16 (d, 1H), 5.29 (s, 2H), 5.89 (d, 1H), 7.24 (d, 1H), 7.53 (d, 1H), 7.73-7.89 (m, 3H), 8.51 (d, 1H). 15 EXAMPLE 18 PREPARATION OF CARBAPENEM 14 CH2=CHCH202CO HH CO 2 CH2CH=CH2 Step A: Preparation of 3-hydroxybiphenyl 20 A stirred mixture of 660mg(3mmol) of 3-iodophenol, 439mg (3.6mmol) phenylboronic acid, and 173mg (0.15mmol) tetrakistriphenylphosphine in 10mL of toluene, 5mL ethanol, and 6mL 2M sodium carbonate (aqueous) was heated at 1000C in an inert atmosphere of nitrogen for 15 minutes. The cooled mixture was 25 partitioned between EtOAc, ice, and brine and the organic phase was separated, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by plate layer chromatography (PLC) using CH2Cl2 as the eluant to give 430mg of the title product. 30 WO 99/14217 PCT/US98/19015 -70 Step B: Following the procedure outlined in Example 2 and using 28.2mg (0.165mmol) of 3-hydroxybiphenyl there was obtained after plate layer chromatography using methylene chloride as the 5 eluant, 58.9mg of carbapenem 14, containing some 3 hydroxybiphenyl, which was used without further purification. 1 H NMR (CDCl3) 5: 1.26 (d, J=7.3Hz,3H), 1.47 (d, J=6.3Hz, 3H), 3.47 (dd, J=3.0, 11Hz, 1H-6), 3.50 (m, 1H-1), and 4.2 (dd, J=3.0, 10Hz, 1H11-5). 10 EXAMPLE 19 PREPARATION OF CARBAPENEM 15 HO 0 CO2Na 15 Following the procedure outlined in Example 3 and using the carbapenem derivative prepared in Example 18, 9.4mg of carbapenem 15 was obtained after purification by reverse phase plate layer chromatography using water-acetonitrile (7:3) as eluant and lyophilization. 20 IR (nujol) : 1750 and 1596 cm- 1 ; 1H NMR (D20-CD3CN,5:2) 8: 1.43 (d, J=7.3Hz, 3H), 1.5 (d, J=6.3Hz, 3H), 3.56 (m, 1H-1), 3.62 (dd, J= 2.8, 5.7Hz, 1H-6), 4.36 (dd, J= 2.6, 9.9Hz, 1H-5), 4.45 (m, 1H11-8), 5.06 (d, J=13.8Hz), 1H), 5.85 (d, J=13.8Hz, 1H), 7.28-7.96 (m, 9 ArH); 25 UV: Xmax 252nm(H20).

WO 99/14217 PCT/US98/19015 -71 EXAMPLE 20 PREPARATION OF CARBAPENEM 16 OSiPh 2 CMe 3 CH2=CHCH202CHH H H 0 N/ O CO2CH2CH=CH2 Step A: Preparation of 4'-t-butyldiphenylsilyloxymethyl-3 5 hydroxybiphenyl As described in Example 18, step A, 391mg (1 mmol) of 4 t-butyldiphenylsilyloxymethylboronic acid (prepared as exemplified in US 5,192,758) and 220 mg (1 mmol) of 3-iodophenol gave 354.3mg of the title compound. 10 Step B: Following the procedure of Example 2, 153.5mg (0.35mmol) of 4'-t-butyldiphenylsilyloxymethyl-3-hydroxybiphenyl was utilized to prepare 89.2mg of carbapenem 16 containing some of 15 the latter which was used without further purification. EXAMPLE 21 PREPARATION OF CARBAPENEM 17 0 H CH2=CHCH 2 02CO H H 0 CO2CH2CH=CH 2 20 To a stirred solution of carbapenem 16, prepared in Example 20, in lmL of THF at 0oC was added sequentially 19.5mL (0.34mmol) of acetic acid and 227mL (0.23mmol) of a 1.0 M solution of tetrabutylammonium fluoride in THF. The resulting mixture was WO 99/14217 PCT/US98/19015 -72 stirred with the ice-water bath removed for six hours. The mixture was partitioned between ether, ice-water, and saturated NaHCO3 solution and the organic phase separated, washed with brine, dried over Na2SO4, filtered, and evaporated. Purification by plate layer 5 chromatography using CH2C12-EtOAc(10:1) as eluant provided 19.7mg of carbapenem alcohol. IR (CH2C12): 3604,1779, 1746, and 1719cm-1; 1 H NMR (CDC13) 8:1.26 (d, J=7.2Hz,3H), 1.46 (d, J=6.3Hz, 3H), 1.72 (t, J=5.7Hz, 1-OH), 3.45 (dd, J=3.0, 8.1Hz, 1H-6), 10 3.50 (m, 1H-1), 4.19 (dd, J=3.0, 10Hz, 1H-5), 5.13 (m, 1H-8), 4.75 (d, J=5.7Hz, 2H), 6.86-7.6 (m, 8 ArH). EXAMPLE 22 PREPARATION OF CARBAPENEM 18 ( /"NMe \ ®OTf

CH

2

=CHCH

20 2 CO H H N 0 15 CO2CH 2 CH=CH2 To a stirred solution of 19.7mg (0.036 mmol) of the carbapenem 17 from Example 21 and 6.3mL (0.079 mmol) of N methylimidazole in 1 mL of sieve dried CH2C12 at -230C in an inert atmosphere of nitrogen was added 6.7mL (0.0396 mmol) of neat triflic 20 anhydride. The resulting mixture was stirred at -230C for 70 minutes and then partitioned between water and CH2CI2 and the organic phase was separated, dried over Na2SO4, filtered, and evaporated to give 26.3mg of a colorless foam. 1 H NMR (CDC13) 8: 1.25 (d, J=7.4Hz,3H), 1.45 (d, 25 J=6.2Hz, 3H), 3.45 (dd, J=3.0, 8.1Hz, 1H-6), 3.50 (m, 1H-1), 3.97 (s, N CH3), 4.19 (dd, J=3.1, 10Hz, 1H-5), 5.13 (m, 1H-8), 5.4 (s, 2H), 6.88-7.66 (m, 10 ArH), 9.32 (bs, 1H).

WO 99/14217 PCT/US98/19015 -73 EXAMPLE 23 PREPARATION OF CARBAPENEM 19 //NMe HO HH 0 / C020 Following the procedure outlined in Example 3, the 5 carbapenem 18 prepared in Example 22 was deallylated to provide 9.5mg of 19 after purification by reverse phase chromatography (RP PLC) using water-acetonitrile (7:3) as eluant and lyophilization. IR (nujol): 1754, 1589cm- 1 ; 1 H NMR (D20-CD3CN,5:2) 8: 1.44 (d, J=7.3Hz, 3H), 1.5 (d, 10 J=6.5Hz, 3H), 3.54 (m, 1H-1), 3.62 (dd, J= 2.9, 5.7Hz, 1H-6), 4.14 (s, N CH3), 4.33 (dd, J= 2.6, 9.97Hz, 1H-5), 4.45 (m, 1H-8), 5.07 (d, J=14.3Hz), 1H), 5.68 (s, 2H), 5.88 (d, J=14.3Hz, 1H), 7.3-8.02 (m, 10 ArH); UV: Xmax 258nm(H20). 15 EXAMPLE 24 PREPARATION OF CARBAPENEM 20

CH

2

=CHCH

2 02C H CO2CH2CH=CH2 As previously described in Example 2, 33.1mg (0.168mmol) of commercially available 4-hydroxyfluoren-9-one gave 20 44.2mg of carbapenem 20 containing some of the latter which was used without further purification.

WO 99/14217 PCT/US98/19015 -74 EXAMPLE 25 PREPARATION OF CARBAPENEM 21 HO N0 CO2Na Using the procedure described in Example 3, 5 carbapenem 20 prepared in Example 24 was deallylated to provide 12.5mg of carbapenem 21 after RP-PLC and lyophilization. IR (nujol): 1754, 1712, 1593cm-1; 1 H NMR (D20-CD3CN,5:2) 8:1.48 (d, J=7.3Hz, 3H), 1.49 (d, J=7.7Hz, 3H), 3.62 (min, 1H-1), 3.65 (min, 1H-6), 4.42 (min, 1H-5), 4.47 10 (m, 1H-8), 5.15 (d, J=13.5Hz), 1H), 5.95 (d, J=13.5Hz, 1H), 7.5-8.08 (m, 7 ArH); UV: Xmax 253nm(H20). EXAMPLE 26 PREPARATION OF CARBAPENEM 22 CH2=CHCH202C H H 0 15

CO

2

CH

2

CH=CH

2 Step A: Preparation of 4-Hydroxy-fluorene A partial solution of 196.2mg (1 mmol) of 4-hydroxy fluoren-9-one in 2mL EtOAc and 3 mL EtOH with 40mg 10% Pd/C was stirred under a balloon of hydrogen for 27.5 hours. The catalyst was 20 removed by filtration through celite, washed well with EtOAc, and the filtrate evaporated. The residue was purified by plate layer chromatography with CH2C12-EtOAc(50:1) to give 102.7mg of the title substance. 1 H NMR (d6-acetone) 5: 3.88 (s, CH2).

WO 99/14217 PCT/US98/19015 -75 Step B: Using the procedure outlined in Example 2, 29.7mg (0.16 mmol) of 4-hydroxyfluorene, prepared above, provided 57.2mg of 5 carbapenem 22, which contained a small amount of the latter, and was used without further purification. 1 H NMR (CDCl3) 8:1.28 (d, J=7.3Hz,3H), 1.43 (d, J=6.3Hz, 3H), 3.43 (dd, J=3.0, 7.9 Hz, 11H-6), 3.50 (m, 11H-1), 3.91 (s, 2H), 4.17 (dd, J=3.0, 10Hz, 1H-5), 5.13 (m, 1H-8), 4.91 (d, J=14.1Hz, 1H), 5.74 10 (d, J= 14.1 Hz), 6.83-8.05 (m, 7ArH). EXAMPLE 27 PREPARATION OF CARBAPENEM 23 HOH H HH O N 0 CO2Na 15 Using the deallylation procedure described in Example 3 and the material prepared in the above example, 19mg of carbapenem 23 was produced after purification and lyophilization. IR (nujol): 1753, 1582cm- 1 ; 1 H NMR (D20-CD3CN,5:2) 8:1.44 (app. d, 6H), 3.61 (m, 20 111H-1 & 1H-6), 4.17 (s, 2H11), 4.33 (m, 1H-5), 4.42 (m, 1H11-8), 5.16 (d, J=13.8Hz), 1H), 5.99(d, J=13.8Hz, 1H11), 7.27-8.42 (m, 7 ArH); UV: kmax 269nm(H20). EXAMPLE 28 25 PREPARATION OF CARBAPENEM 24 WO 99/14217 PCT/US98/19015 -76 0- C20H3 02COH H / CO2CH 2 CH=CH2 Step A: Preparation of 4-Hydroxy-9-carbomethoxy-fluorylidene A stirred mixture of 401mg (2 mmol) of 4-hydroxy fluoren-9-one and 1.37g (4.1mmol) of methyl 5 (triphenylphosphoranylidene)-acetate in 10mL of toluene was refluxed under an atmosphere of nitrogen for 65.5 hours. The cooled reaction mixture was evaporated and the residue purified by plate layer chromatography using CH2Cl2-EtOAc (50:1) as eluant to give 433mg of the title compound as a mixture of isomers. 10 1 H NMR (CDC13) 8:3.87 (s, 3H), 3.88 (s, 3H), 6.74-8.89 (m, 8H). Step B: As previously described in Example 2, 39.2mg 15 (0.156mmol) of fluorylidene prepared in Step A was converted into 75.7mg of carbapenem 24 as a mixture of isomers and containing some of the latter, which was used without further purification. 1 H NMR (CDCl3) 8:1.25 (m, 3H), 1.42 (d, J=6.3Hz, 3H), 3.40 (m, 1H-1), 3.43 (m, 1H-6), 3.85 (s, 3H), 3.86 (s, 3H), 4.18 (m, 1H-5), 20 5.11 (m, 1H-8), 6.7-8.88 (m, 8H). EXAMPLE 29 PREPARATION OF CARBAPENEM 25 / ,~ CO2CH3 HO H 02Na WO 99/14217 PCT/US98/19015 -77 Using the procedure described in Example 3 and the material prepared in Example 28, 15.4 mg of carbapenem 25 was produced as a mixture of geometric isomers. IR (nujol): 1751, 1717, 1630, 1586cm- 1 ; 5 1 H NMR (D20-CD3CN,5:2) 8: 1.48 (app. t, 6H), 3.63 (m, 1H1-1 & 1H1-6), 4.13 (s, 3H), 4.4(m, 1H-5), 4.46 (min, 1H-8), 5.16 (d, J=13.9Hz), 1H), 5.97(d, J=13.9Hz, 1H), 7.08-8.88 (m, 8H); UV: kmax 330, 263nm(H20). 10 EXAMPLE 30 PREPARATION OF CARBAPENEM 26 02C C02CH 3 0 2 H H CO2CH2CH=CH2 Step A: Preparation of 4-Hydroxy-9-carbomethoxymethyl-fluorene A stirred mixture of 348mg (1.38 mmol) of the 15 fluorylidene derivative prepared in Example 28, Step A, and 50mg of 10% Pd/C in 10mL of EtOAc-EtOH (1:1) was hydrogenated under balloon pressure at ambient temperature for 2.5 hours. The catalyst was removed by filtration through celite, washed well with EtOAc, and the filtrate evaporated and dried in vacuo to give 348.5mg of the 20 title product. 1H NMR (CDC13) 8: 2.77 (d, J=7.3Hz, 2H), 3.79 (s, 3H), 4.42 (t, J=7.3Hz,1H), 5.6 (s, OH), 6.72-8.09 (min, 7ArH). Step B: 25 As previously described in Example 2, 53mg (0.208 mmol) of the fluorene derivative prepared above provided after purification by PLC eluting with CH2C12-EtOAc (50:1), 88mg of carbapenem 26 , as an equimixture of diastereomers, and containing a little phenolic starting material, which was used without further 30 purification.

WO 99/14217 PCT/US98/19015 -78 1 H NMR (CDC13) 8: 1.28 (d, J=7.3Hz, 3H), 1.44 (2d's, 3H), 2.75 (2d's, 2H), 3.43 (m, 1H-1 & 1H-6), 3.85 (s, 3H), 3.78 (2s's, 3H), 4.18 (2dd's, 1H-5), 4.41 (t, J=7.3Hz, 1H), 5.11 (m, 1H-8), 6.84-8.04 (m, 7ArH). 5 WO 99/14217 PCT/US98/19015 -79 EXAMPLE 31 PREPARATION OF CARBAPENEM 27 CO2CH3 HO HH N 0 CO2Na 5 Using the procedure described in Example 3 and the material prepared in the previous example, 28.3mg of carbapenem 27 was produced after RP-PLC purification and lyophilization. IR(nujol): 1754, 1737, 1603, 1584cm- 1 ; 1H NMR (D20-CD3CN,5:2) 5:1.48 (app. d, 6H), 3.14 ( d, 10 J=6.9Hz, 2H), 3.65 (m, 1H-1 & 1H-6), 3.97 (s, 3H11), 4.4 (m, 1H-5), 4.46 (m, 1H-8), 4.63 (t, J= 6.9Hz, 1H), 5.18 (d, J=13.9Hz), 1H), 5.99(d, J=13.9Hz, 1H), 7.33-8.42 (m, 7ArH); UV: Xmax 270nm(H20). 15 EXAMPLE 32 PREPARATION OF CARBAPENEM 28 \OTBS -02 HH N 0 CO2CH 2

CH=CH

2 Step A: Preparation of 4-Hydroxy-9-hydroxyethyl-fluorene To a stirred solution of 277.5mg (1.09mmol) of the ester 20 prepared in Step A of Example 30 in 5mL of anhydrous THF at 0oC was added dropwise 1.1mL (1.1mmol) of a 1M solution of lithium aluminum hydride in ether. The resulting mixture was stirred at 0 0 C under nitrogen for 1.5 hours and then carefully quenched with Glaubers salt. The mixture was partitioned between EtOAc, ice, 2N 25 HC1, and brine and the organic phase was separated, washed with WO 99/14217 PCT/US98/19015 -80 brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by PLC with CH2Cl2-EtOAc (10:1) to give 236.8mg of the title compound. 1 H NMR (CDCl3) 6: 2.33 (q, J= 6.8Hz, 2H), 3.57 (t, J= 5 6.8Hz, 2H), 4.13 (t, J=6.8Hz), 6.08 (s, OH), 6.68-8.13 (m, 7ArH). Step B: Preparation of 4-Hydroxy-9-silyoxyethyl-fluorene A mixture of 236.8mg (1.05mmol) of carbinol, prepared in the previous example, 173.5mg (1.15mmol) of t 10 butyldimethylchlorosilane, and 85.5mg (1.26mmol) of imidazole in 5mL of sieve-dried DMF was stirred at 0oC under nitrogen for 40 minutes. The mixture was partitioned between EtOAc, ice, 2N HC1, and the organic phase was separated, washed twice with ice-water and then with brine, dried over Na2SO4, filtered, and evaporated. The 15 residue was purified by PLC with CH2Cl2-EtOAc (50:1) to give 325.1mg of the title compound. 1 H NMR (CDC13) 8: 0.03 (s, 6H), 0.88 (s, 9H), 2.19(m, 2H), 3.67 (t, J= 6.8Hz, 2H), 4.13 (t, J=6.4Hz), 5.12 (s, OH), 6.71-8.10 (m, 7ArH). 20 Step C: Using the procedure described in Example 2 and the material prepared in the above example, 478.1mg of carbapenem 28 was produced as an equimixture of diastereomers after PLC using 25 CH2C12-EtOAc (50:1) as eluant. 1 H NMR (CDCl3) 6: 0.05 (s, 6H), 0.86 (s, 9H), 1.28 (d, J=7.3Hz, 3H), 1.44 (d, 3H), 2.14 (m, 2H), 3.44 (min, 1H-1 & 1H-6), 3.65 (m, 2H), 4.11 (m, 1H), 4.20 (2dd's, 1H-5), 5.12 (min, 1H-8), 6.81-8.05 (m, 7ArH). 30 WO 99/14217 PCT/US98/19015 -81 EXAMPLE 33 PREPARATION OF CARBAPENEM 29 \OH HH N 0 CO2CH2CH=CH 2 Using the procedure outlined in Step B of Example 5 and 5 the material prepared in the above example, 220.9mg of the title carbapenem was produced after purification by PLC using CH2C12 EtOAc(10:1) as eluant. 1 H NMR (CDCl3) 6: 1.28 (2dd's, J=7.3Hz, 3H), 1.44 (app. t, 3H), 2.29 (m, 2H), 3.46 (min, 1H-1 & 1H-6), 3.56 (min, 2H), 4.12 (min, 1H), 10 4.20 (2dd's, 1H-5), 5.12 (m, 1H-8), 6.82-8.04 (m, 7ArH). EXAMPLE 34 PREPARATION OF CARBAPENEM 30

CH

3 N ~~O2OH H - OTf® NN 02C0 00 15 CO2CH 2 CH=CH2 To a stirred mixture of 51.5mg (0.09mmol) of carbinol 29, prepared in the previous example, and 16.2mg (0.2mmol) of N methyl-imidazole in lmL of sieve-dried CH2C12 at 00C was added dropwise 27.9mg (0.99 mmol) of neat triflic anhydride. The mixture 20 was stirred at OOC for 20 minutes and then with the ice-water bath removed for 3 hours. The mixture was partitioned between H20 and CH2C12 and the organic phase was separated, dried over Na2SO4, filtered, evaporated, and dried in vacuo. The residue was taken up in a minimum amount of CH2Cl2 and carbapenem 30 was precipitated WO 99/14217 PCT/US98/19015 -82 by the addition of Et20. After decantation of the supernatant and drying in vacuo, 49.7mg of imidazolium salt 30 was obtained. 1H NMR (CDCl3) 8: 1.26 & 1.30 (2d's, J=7.3Hz, 3H), 1.42 & 1.45 (2d's, J=6.4Hz, 3H), 2.87 (m, 2H), 3.34 & 3.60 (2m's, 1H-1), 3.45 5 (2dd's, 1H-6), 3.72 & 3.73 (2s's, N-CH3), 3.76 (m, 2H), 4.15 & 4.31 (2dd's, 1H11-5), 4.2 (m, 1H), 5.12 (m, 1H-8), 6.54-7.99 (m, 9H), 8.6 & 8.66 (2s's, 1H). EXAMPLE 35 10 PREPARATION OF CARBAPENEM 31

CH

3 N N H SHH N CCO2 Using the procedure described in Example 3 and the carbapenem prepared in the above example, 14.8mg of carbapenem 31 was produced. 15 IR (nujol): 1756, 1595, 1583cm-1; 1H NMR (D20-CD3CN,5:2) 8: 1.5 (m, 6H), 3.1 (m, 2H11), 3.6 (m, 1H-1), 3.7 (2dd's, 1H11-6), 3.8(2s's, 3H11), 4.05 (m, 2H), 4.35-4.45 (m, 3H11), 5.18 & 5.25 (2d's, 1H11), 5.98 (app. t, 1H11), 7.2-8.42 (m, 7ArH); UV: Xmax 271nm(H20). 20 WO 99/14217 PCT/US98/19015 -83 EXAMPLE 36 PREPARATION OF CARBAPENEM 32 \ OMs H H O N CO2CH 2

CH=CH

2 5 To a stirred solution of 220.9mg (0.39 mmol) of carbapenem carbinol 29, prepared in Example 33, in 3mL of sieve dried CH2C12 at 0oC was added sequentially 58.5mg (0.58 mmol) of triethylamine and 57.4mg (0.5 mmol) of mesyl chloride. The mixture was stirred further for 11 minutes, and the mixture was partitioned 10 between EtOAc, ice, 2N HC1, and brine and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 249.3mg of carbapenem 32 which was used without further purification. 1 H NMR (CDCl3) 5: 2.760 & 2.765 (2s's, OSO2CH3). 15 EXAMPLE 37 PREPARATION OF CARBAPENEM 33 H H 0 CO2CH 2

CH=CH

2 A mixture of 240.8mg (0.37 mmol) of carbapenem 32, 20 prepared in the previous example, and 249.6mg (1.6 mmol) of sodium iodide in 3 mL acetone was stirred at ambient temperature for 55 hours. The mixture was partitioned between EtOAc, ice, 5% aqueous sodium thiosulfate, and brine and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried WO 99/14217 PCT/US98/19015 -84 in vacuo to give 244.2mg of carbapenem 33 which was used without further purification. 1 H NMR (CDC13) 8: 2.53 (min, 2H), 3.0 (min, 2H). 5 EXAMPLE 38 PREPARATION OF CARBAPENEM 34 0 N CONH 2 N -' 2 OTf H H N/0 0 CO2CH2CH=CH 2 A mixture of 136.6mg (0.2mmol) of carbapenem 33, 63.9mg (0.2mmol) of N-acetamidodiazoniabicyclooctane triflate, and 10 51.3mg (0.2mmol) of silver triflate in 1.5mL of acetonitrile was stirred at ambient temperature for 25 hours. The insoluble AgI was removed by filtration through celite, and the filtrate evaporated and dried in vacuo. The residue was taken up in acetone, refiltered, and the filtrate concentrated. Upon the addition of Et20, the title compound 15 separated, and it was again reprecipitated from acetone, and dried in vacuo to give 150.2mg of 34, containing some of the starting salt, which was used without further purification. 1 H NMR (d6-acetone) 6: 4.27 (min, 6H), 4.49 (min, 6H), 4.61 (min, 2H). 20 WO 99/14217 PCT/US98/19015 -85 EXAMPLE 39 PREPARATION OF CARBAPENEM 35 N -CONH2 0D C1 HO 00 C C02 0 Using the procedure described in Example 3 and 5 carbapenem 34, prepared in the foregoing example, 15.7mg of carbapenem 35 was produced after purification on macroprep and amberchrom 161 resins. IR (nujol): 1749, 1695, 1583cm- 1 ; 1 H NMR (D20-CD3CN,5:2) 5:1.44 (m, 6H), 2.92 (m, 2H), 10 3.18 (m,2H), 3.5-3.75 (m, 1H-1 & 1H-6), 4.0(m, 6H), 4.35 (m, 6H), 5.07 5.18 (2d's, 1H), 5.88-5.96 (2d's, 1H), 7.28-8.37 (m, 7ArH); UV: Amax 271nm(H20). EXAMPLE 40 15 PREPARATION OF CARBAPENEM 36 02C H- H 2 0TBS 02 CO2CH 2

CH=CH

2 Step A: Preparation of 4-Acetoxy-9-(2-t-butyldimethylsilyloxyethyl) fluorene To a stirred solution of a mixture of 1.91g (5.6 mmol) of 20 the phenol, prepared in Step B of Example 32, and 736.6mg (7.28 mmol) of triethylamine in 20mL of CH2Cl2 at 00C was added 527.5mg (6.72 mmol) of neat acetyl chloride and the mixture was stirred further for 0.5 hour. The mixture was partitioned between EtOAc, ice, IN HC1, and brine and the organic phase was separated, washed WO 99/14217 PCT/US98/19015 -86 with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 2.14g of crude product which was used without further purification. 1 H NMR (CDCl3) 5: 0.86 (s, 9H), 2.47 (s, 3H). 5 Step B: Preparation of 4-Acetoxy-9-bromo-9-(2-t butyldimethylsilyloxyethyl)-fluorene A mixture of 2.14g (5.6 mmol) of material prepared in the previous step, 1.2g (6.72 mmol) of N-bromosuccinimide, and a pinch of AIBN in 20mL of carbon tetrachloride was refluxed under 10 nitrogen for 1.5 hours. The cooled mixture was partitioned between EtOAc, ice, 5% aqueous sodium thiosulfate, and brine and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give the crude, title product which was used without further purification. 15 1 H NMR (CDCl3) 8: 0.73 (s, 9H), 2.47 (s, 3H), 2.91 (m, 2H), 3.20 (min, 2H). Step C: Preparation of 4-Acetoxy-9-E,Z-t-butyldimethylsilyloxyethenyl fluorene 20 A mixture of the crude product from the previous step, 913mg (10.9 mmol) of NaHCO3, and 1.54g (5.98 mmol) of silver triflate in 25mL DMSO was stirred at room temperature for 15 minutes. The mixture was diluted with EtOAc, filtered through celite to remove the insoluble materials, and washed thoroughly with EtOAc. The filtrate 25 was partitioned between EtOAc, ice, and brine and the organic phase was separated, washed twice with ice-water, and then with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by PLC eluted with CH2C12-hexanes (1:1) gave 1.22g of product, as a mixture of geometric isomers. 30 1 H NMR (CDC13) 5: 0.17 (s, 6H), 0.98 (s, 9H), 2.48 (s, 3H), 5.02 (min, 2H). Step D: Preparation of 4-Hydroxy-9-E,Z-t butyldimethylsilyloxyethenyl-fluorene 35 To a stirred, warm solution of 1.19g (3.13 mmol) of acetate, prepared in the previous step, in 20mL EtOH was added WO 99/14217 PCT/US98/19015 -87 dropwise 0.77mL (3.85 mmol) of a 5N solution of sodium hydroxide in water. The resulting dark solution was stirred further for 5 minutes and then partitioned between EtOAc, ice, IN HC1, and brine. The organic phase was separated, washed with brine, dried over Na2SO4, 5 filtered, evaporated, and dried in vacuo. Purification by PLC eluted with CH2C12 gave 890.0mg of product, as a mixture of geometric isomers. 1 H NMR (CDC13) 8: 0.15 (s, 6H), 0.96 (s, 9H), 4.98 (m, 2H), 5.18 & 5.22 (2s's, 1-OH), 6.68-8.1 (m, 8H). 10 Step E: Using the procedure outlined in Example 2 and 423.7mg (1.25mmol) of the mixture of phenols prepared in the previous step, 555mg of carbapenem 36 was produced which contained a little of the 15 starting phenol and was used without further purification. 1 H NMR (CDC13) 8: 0.15 (s, 6H), 0.95 (s, 9H), 1.27 (d, J=7.3Hz), 1.43 (d, 6.3Hz), 3.44 (m, 1H-1 & 1H-6), 4.17 (m, 1H1-5), 5.12 (m, 1H-8), 6.77-8.1 (m, 8H). 20 EXAMPLE 41 PREPARATION OF CARBAPENEM 37 0C CH20H 02Z~CO H H N 0 CO2CH2CH=CH 2 To a stirred solution of a mixture of carbapenem 36, prepared in the prior example, and 292mg (4.86mmol) of acetic acid 25 in 10mL of THF was added 2.43mL (2.43mmol) of a 1M solution of tetrabutylammonium fluoride in THF. The mixture was stirred further for 1.25 hour, and then partitioned between EtOAc, ice, saturated NaHCO3 solution, and brine. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, 30 evaporated, and dried in vacuo. Purification by PLC eluted with WO 99/14217 PCT/US98/19015 -88 CH2C12-EtOAc (10:1) gave 306mg of product 37, as a mixture of geometric isomers. 1 H NMR (CDC13) 8: 1.27 (d, J=7.3Hz), 1.43 (d, J=6.3Hz), 3.44 (m, 1H-1 & 1H-6), 4.18 (m, 1H-5), 5.12 (m, 1H-8), 6.81-8.04 (m, 8H). 5 EXAMPLE 42 PREPARATION OF CARBAPENEM 38 K- H 2 0H HO HH 0 No 0

CO

2 Na Using the procedure described in Example 3, 27.6mg 10 (0.048mmol) of carbapenem 37 in lmL of CH2C12-DMF provided 16.2mg of carbapenem 38 after RP-PLC developed with water acetonitrile (3:1). IR (nujol): 1747, 1599cm- 1 ; 1 H NMR (D20-CD3CN,5:2) 8: 1.49 (m, 6H), 3.65 (m, 1H-1 15 & 1H-6), 4.4 (m, 1H)-5, 4.48 (m, 1H-8), 5.22(m, 3H), 6.03 (m, 1H), 7.17 8.43 (m, 8H); UV: Xmax 261nm(H20). EXAMPLE 43 20 PREPARATION OF CARBAPENEM 39 TBS 70

CH

2 =CHCH202

CO

2 CH2CH=CH2 Step A: Preparation of 2-Methoxy-6-carbomethoxy-4'-t-butyl diphenylsilyloxymethylbiphenyl WO 99/14217 PCT/US98/19015 -89 Using the procedure described in Step A of Example 18, 10.0g (34.2mmol) of methyl-2-iodo-3-methoxybenzoate (prepared as outlined by W. M. Stanley, E. McMahon, and R. Adams, J. Amer. Chem. Soc. 1933, 55, 706) was refluxed for 5 hours to give after 5 chromatography on silica gel with CH2C12-hexanes (2:1) 12.1lg of the title compound. 1 H NMR (CDCl3) 8: 1.14 (s, 9H), 3.57 (s, 3H), 3.78 (s, 3H), 7.1-7.77 (min, ArH). 10 Step B: Preparation of 2-Methoxy-4'-hydroxymethylbiphenyl-6 carboxylic acid A stirred mixture of 6.0g (11.7mmol) of biphenyl derivative prepared in Step A and 4.7mL of 5N NaOH in 100mL of EtOH was refluxed in an inert atmosphere of nitrogen for 4 hours. 15 The mixture was partitioned between EtOAc, ice, 2N HC1, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Upon addition of a little CH2Cl2 the product crystallized and after the addition of some hexanes 1.95g of the product was collected by filtration and dried in 20 vacuo. 1 H NMR (d6-acetone) 8: 3.74 (s, 3H), 4.64 (s, 2H), 7.17-7.44 (min, 7ArH). Step C: Preparation of 4-Methoxy-7-chloromethyl-fluoren-9-one 25 To a stirred suspension of 2.0g (7.74mmol) of acid prepared in Step B in 40mL of sieve- dried CH2Cl2 at 0OC was added all at once 3.55g (17.0mmol) of phosphorous pentachloride and the mixture was stirred further for 5 minutes, and then for 1 hour with the ice-water bath removed. The homogenous solution was recooled to 30 0 0 C, and 1.55g (11.6mmol) of A1C13 was added all at once. The resulting mixture was stirred further for 0.5 hour and then partitioned between EtOAc, ice, and brine. The organic phase was separated, washed with brine and saturated NaHCO3, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 2.04g of the 35 title material as a yellow solid, which was used without further purification. IR (CH2Cl2): 1717.5cm-1; WO 99/14217 PCT/US98/19015 -90 1 H NMR (CDC13) 6: 3.90 (s, 3H), 4.53 (s, 2H), 6.94-7.68 (inm, 6ArH). Step D: Preparation of 4-Methoxy-7-acetoxymethyl-fluoren-9-one 5 A mixture of 2.0g (7.7mmol) of material prepared in Step C and 1.52g (15.5mmol) of potassium acetate in 30mL of DMF was stirred at 100 0 C under nitrogen for 36 minutes. The cooled mixture was partitioned between EtOAc and ice-water and the organic phase was separated, washed twice with ice-water, and then with brine, 10 dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 2.17g of the title material as a yellow solid, which was used without further purification. IR (CH2C12): 1742, 1718cm-1; 1H NMR (CDCl3) 5: 2.12 (s, 3H), 3.99 (s, 3H), 5.10 (s, 2H), 15 7.04-7.81 (min, 6ArH). Step E: Preparation of 4-Methoxy-7-hydroxymethyl-fluoren-9-one A stirred mixture of the acetate prepared above and 3.07mL (15.4mmol) of 5N NaOH in 100mL of EtOH was refluxed 20 under nitrogen for 10 minutes. The cooled mixture was partitioned between EtOAc, ice-water and 2N HC1, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 2.07g of the title material as a yellow solid, which was used without further purification. 25 1 H NMR (CDC13) 5: 3.96 (s, 3H), 4.68 (s, 2H), 7.01-7.77 (m, 6ArH). Step F: Preparation of 4-Methoxy-7-formyl-fluoren-9-one To a stirred suspension of 1.85g (7.69mmol) of carbinol 30 from Step E in 50mL CH2Cl2 was added 270.1mg (0.769mmol) of tetrapropylammonium perruthenate. After stirring for 5 minutes, 1.35g (11.5mmol) of solid N-methyl-morpholine-N-oxide was added all at once, and the resulting mixture stirred further for 5 minutes. The dark solution was passed over a column of florisil eluted with 35 CH2C12-EtOAc (10:1) to give 1.42g of the title aldehyde as a yellow solid.

WO 99/14217 PCT/US98/19015 -91 IR (CH2Cl2): 1720, 1698cm- 1 ; 1 H NMR (CDC13) 6: 4.02 (s, 3H), 7.09-8.1 (m, 6ArH), 10.0 (s, 1H). 5 Step G: Preparation of 4-Hydroxy-7-formyl-fluoren-9-one A stirred mixture of the methylether from the previous step and 30mL of 48%HBr in 15mL of acetic acid was heated at 130 0 C under nitrogen for 7 hours. The cooled mixture was poured onto ice water and the separated product collected by suction filtration, 10 washed well with water, and dried in vacuo to give 0.94g of the title compound. 1H NMR (d6-acetone) 8: 7.18-8.15 (m, 6ArH), 9.8 (s, 1 OH), 10.07 (s,1-CHO). 15 Step H: Preparation of 4-Hydroxy-7-hydroxymethyl-fluoren-9-one A stirred mixture of 405.2mg (1.8mmol) of aldehyde prepared in Step G and 804.3mg (3.8mmol) of sodium triacetoxyborohydride in 27mL of anhydrous THF was refluxed under nitrogen for 1 hour. The cooled mixture was partitioned between 20 EtOAc, ice-water and saturated NaHCO3, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by PLC with CH2C12 EtOAc (2:1) yielded 303.7mg of the crystalline, title product. 1 H NMR (d6-acetone) 8: 4.66 (s,2H), 7.08-7.86 (m, 6ArH), 25 9.38 (s, 1-OH). Step I: Preparation of 4-Hydroxy-7-t-butyldimethylsilyloxymethyl fluoren-9-one A mixture of 332.2mg (1.47mmol) of the diol from Step H, 30 243.5mg (1.61mmol) of t-butyldimethylchlorosilane, and 120mg (1.76mmol) of imidazole in 8mL of sieve dried DMF was stirred at 0OC for 45 minutes. The mixture was partitioned between EtOAc, ice water and 2N HC1, and the organic phase was separated, washed twice with ice-water, and then with brine, dried over Na2SO4, 35 filtered, evaporated, and dried in vacuo. Purification by PLC using CH2C12-EtOAc (50:1) gave 447.4mg of the title material.

WO 99/14217 PCT/US98/19015 -92 1 H NMR (d6-acetone) 8: 0.14 (s, 6H), 0.95 (s, 9H), 4.81 (s,2H), 7.08-7.86 (m, 6ArH), 9.35 (bs, 1-OH). Step J: 5 Using the procedure given in Example 2, 127.1mg (0.37mmol) of the phenol prepared in Step I provided 99.5mg of carbapenem derivative 39 which contained a little of the latter and some SN2' product and was used without further purification. 1 H NMR (CDC13) 8: 0.1 (s, 6H), 0.93 (s, 9H), 1.27 (d, 10 J=7.3Hz), 1.43 (d, 6.3Hz), 3.44 (m, 1H-1 & 1H-6), 4.21 (dd, 1H-5), 5.12 (m, 1H1-8), 6.86-7.76 (m, 6H). EXAMPLE 44 PREPARATION OF CARBAPENEM 40 H KO

CH

2 =CHCH202C N 0 15

CO

2 CH2CH=CH2 Using the procedure detailed in Example 5, Step B, the carbapenem prepared in the previous example was desilylated to provide 52.7mg of carbapenem 40 after PLC with CH2Cl2-EtOAc (2:1). 1H NMR (CDC13) 8:1.29 (d, J=7.4Hz), 1.45 (d, 6.3Hz), 3.44 20 (m, 1H-1 & 1H-6), 4.22 (dd, 1H-5), 5.13 (m, 1H-8), 7.0-7.78 (m, 6H).

WO 99/14217 PCT/US98/19015 -93 EXAMPLE 45 PREPARATION OF CARBAPENEM 41 OMs

CH

2 =CHCH202C H H N 0 0

CO

2 CH2CH=CH2 Using the procedure described in Example 36, the 5 carbapenem prepared in Example 44 was converted into the corresponding mesylate 41 (59mg). 1 H NMR (CDCl3) 8:1.27 (d, J=7.4Hz, 3H), 1.45 (d, J=6.3Hz, 3H), 3.0 (s, 3H), 3.44 (m, 1H-1 & 1H-6), 4.22 (dd, 1H-5), 4.90 (d, J=14.8Hz, 1H), 5.13 (m, 1H-8), 5.24 (s, 2H), 5.73 (d, J=14.8Hz, 1H), 10 7.03-7.82 (m, 6H). EXAMPLE 46 PREPARATION OF CARBAPENEM 42 70

CH

2 =CHCH202C N 0

CO

2 CH2CH=CH2 15 Carbapenem 41 (58.7mg, 0.09mmol) and 27.1mg (0.18mmol) of sodium iodide in lmL of acetone was stirred at 0 0 C for 1.25 hour. The mixture was partitioned between EtOAc, ice-water and brine, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 20 63.3mg of carbapenem 42; as a yellow foam, which was used without further purification.

WO 99/14217 PCT/US98/19015 -94 1 H NMR (CDC13) 8:1.30 (d, J=7.2Hz, 3H), 1.45 (d, J=6.3Hz, 3H), 3.44 (m, 1H-1 & 1H-6), 4.22 (dd, 1H-5), 4.47 (s,2H), 4.90 (d, J=14.8Hz, 1H), 5.13 (m, 1H-8), 5.24 (s, 2H), 5.73 (d, J=14.8Hz, 1H), 7.01-7.78 (m, 6H). 5 EXAMPLE 47 PREPARATION OF CARBAPENEM 43 CH3 N OTf CH2=CHCH202CO HH N 0 CO2CH2CH=CH 2 Using the procedure described in Example 22, 40.5mg 10 (.07mmol) of carbapenem 40 provided 55.5mg of salt 43. 1 H NMR (CDC13) 8:1.26 (d, J=7.3Hz, 3H), 1.41 (d, J=6.2Hz, 3H), 3.44 (m, 1H-1 & 1H-6), 3.96 (s, N-CH3), 4.2 (dd, 1H-5), 5.13 (m, 1H-8), 5.39 (s, 2H), 5.65 (d, J=14.7Hz, 1H), 6.97-7.70 (m, 8H), 9.29 (s, 1H). 15 WO 99/14217 PCT/US98/19015 -95 EXAMPLE 48 PREPARATION OF CARBAPENEM 44 CONH2 2 OTf 0 CH2=CHCH202CO Io CO2CH2CH=CH2 Using the procedure of Example 38, the carbapenem 38 5 prepared in Example 42 in lmL acetonitrile after 0.5 hour was converted to 88.2mg of carbapenem 44, which contained a little of the dabco acetamide starting material and was used without further purification. 1 H NMR (d6-acetone) 8: 1.38 (app t, 6H), 4.4 (m, 6H), 4.54 10 (m, 6H), 4.64 (s, 2H), 5.14 (s, 2H), 5.69 (d, J=13.8Hz, 1H), 7.3-8.05 (m, 6H). EXAMPLE 49 PREPARATION OF CARBAPENEM 45 N ~~0

CH

2

=CHCH

2 02 H H" 0 0 15 CO2CH2CH=CH 2 A mixture of 77.8mg (0.114mmol) of carbapenem iodide 42 and 12.8mg (0.114mmol) of dabco in lmL acetonitrile was stirred at room temperature for 0.5 hour and then at 0OC for 1.25 hour. The acetonitrile was evaporated and the residue partitioned between WO 99/14217 PCT/US98/19015 -96 water and methylene chloride. The methylene chloride layer was separated , dried over sodium sulfate, filtered, and evaporated to give 86.4mg of carbapenem 45. 1 H NMR (CDC13) 5:1.29 (d, J=7.3Hz,3H), 1.44 (d, J=6.4Hz, 5 3H11), 3.19 (m, 6H), 3.75 (m,6H), 3.44 (m, 1H-1 & 1H-6), 4.28 (dd, 1H-5), 5.45 (d, J=14.5Hz, 1H),5.65 (d, J=14.5Hz, 1H), 6.93-7.92 (m, 8H). EXAMPLE 50 PREPARATION OF CARBAPENEM 46

CH

2

CH

2

CONH

2 N 17 0 0 CH2=CHCH202CO 2 HH N 0 10

CO

2 CH2CH=CH 2 To a solution of 102.2mg (0.15mmol) of carbapenem iodide 42 in lmL of acetonitrile was added a solution of 22.9mg (0.165mmol) of N-2-carboxamidoethylimidazole in 0.275mL DMF and 0.085mL methanol and the mixture was stirred at room temperature 15 for 19 hours. The volatiles were evaporated and the residue taken up in minimum amount of methylene chloride and the product precipitated by the addition of Et20. Repetition of this process and drying gave 116.1mg of carbapenem 46. 1H NMR (CDC13) 5:1.28 (d, J=7.2Hz,3H), 1.44 (d, J=6.3Hz, 20 3H), 3.16 (m, 2H), 3.44 (m, 1H-1 & 1H-6), 4.27 (dd, 1H-5), 4.64 (m,2H), 5.59 (s, 2H), 6.21 (bs, 2NH), 6.93-7.8 (m, 8H), 9.82 (bs, 1H).

WO 99/14217 PCT/US98/19015 -97 EXAMPLE 51 PREPARATION OF CARBAPENEM 47 CH3 N 002 0 HO HH o N OCO2® Following the procedure outlined in Example 3, the 5 carbapenem 43 prepared in Example 47 was deallylated to provide 11.4mg of 47 after purification by reverse phase chromatography (RP PLC) using water-acetonitrile (7:3) as the eluant and lyophilization. IR (nujol): 1751, 1716, 1593cm- 1 ; 1 H NMR (D20-CD3CN,5:2) 8: 1.39 (d, J=7.4Hz, 3H), 1.45 10 (d, J=6.4Hz, 3H), 3.54 (m, 1H-1), 3.59 (dd, J= 2.8 5.7Hz, 1H-6), 4.09 (s, N-CH3), 4.45 (m,1H-5 & 1H-8), 5.0 (d, J=13.6Hz, 1H), 5.58 (s, 2H), 5.78 (d, J=13.6Hz, 1H), 7.31-7.93 (m, 8ArH); UV: kmax 256nm(H20).

WO 99/14217 PCT/US98/19015 -98 EXAMPLE 52 PREPARATION OF CARBAPENEM 48 D N CONH2 0 OTf HO HH N C02 Using the procedure described in Example 7, Step C, 5 and carbapenem 44, prepared in the Example 48, 7.6mg of carbapenem 48 was produced with Et20 precipitation and purification on amberchrom 161 resin. IR (nujol): 1747, 1706, 1688, 1591cm-1; 1 H NMR (D20-CD3CN,5:2) 5: 1.47 (d, J=7.2Hz, 3H), 1.52 10 (d, J=6.3Hz, 3H), 3.61-3.70 (m, 1H-1 & 1H-6), 4.27 (m, 6H), 4.47 (m, 6H), 5.07- 5.18 (2d's, 1H), 5.88-5.96 (2d's, 1H), 7.28-8.37 (m, 7ArH); UV: Xmax 268nm(H20). EXAMPLE 53: 15 PREPARATION OF CARBAPENEM 49 N 0N' HO HH - 0 N/ O 02 Using the procedure described in Example 3, except the solvent was DMF, and carbapenem 46, prepared in Example 50, 20mg of carbapenem 49 was produced.

WO 99/14217 PCT/US98/19015 -99 IR (nujol): 1754, 1711, 1595cm- 1 ; 1 H NMR (D20-CD3CN,5:2) 8: 1.43 (d, J=6.9Hz, 3H), 1.48 (d, J=6.3Hz, 3H), 3.37 (m, 6H), 3.62 (m, 6H), 4.68 (bs, 2H), 5.06 (d, J=13.4Hz,1H), 5.83 (d, J=13.4Hz,1H), 7.38-8.0 (m, 6ArH); 5 UV: Xmax 257nm(H20). EXAMPLE 54 PREPARATION OF CARBAPENEM 50 CH2CH2CONH 2 N HO HH ~o N 00 CO2 0 10 Using the procedure described in Example 3, except the solvent was DMF, and carbapenem 45, prepared in the Example 49, 34.8mg of carbapenem 50 was produced. IR (nujol): 1755, 1715,1688,1678,1592cm- 1 ; 1 H NMR (D20-CD3CN, 5:2) 8: 1.39 (d, J=6.2Hz, 3H), 1.45 15 (d, J=6.3Hz, 3H), 3.08 (t, J=6.5Hz, 2H), 3.52 (m, 1H-1), 3.6 (dd, 1H-6), 4.4 (m, H-5 & H-8), 4.68 (t, J=6.5Hz, 2H), 5.0 (d, J=13.8Hz,1H), 5.58 (s, 2H), 5.75 (d, J=13.3Hz,1H), 7.28-7.9(m, 8ArH); UV: Xmax 257nm(H20).

WO 99/14217 PCT/US98/19015 -100 EXAMPLE 55 PREPARATION OF CARBAPENEM 51 OH HH 0 0 CO2CH 2 CH=CH2 Step A: Preparation of 4-Acetoxy-7-formyl-fluoren-9-one 5 To a stirred suspension of 1.53g (6.83mmol) of 4-hydroxy 7-formyl-fluoren-9-one, prepared in Step G of Example 43, in 25mL THF at 00C was added 1.24mL (8.88mmol) of triethylamine and 0.58mL (8.2mmol) of acetyl chloride. The mixture was stirred further for 0.5 hour and then partitioned between EtOAc, ice, IN HC1, and 10 brine. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by chromatography on silica gel using methylene chloride as eluant gave 1.46g of the title compound. IR (CH2C12): 1772, 1724, 1702, 1618,1606cm-1; 15 1H NMR (CDC13) 8: 2.48 (s, 3H), 7.38-8.15 (min, 6ArH), 10.0 (s, 1H). Step B: Preparation of 4-Acetoxy-7-(E-2-carbomethoxyvinyl)-fluoren-9 one 20 A mixture of 1.46g (5.49mmol) of aldehyde, prepared in Step A, and 2.02g (6.04mmol) of methyl (triphenylphosphoranylidene)-acetate in 25mL of methylene chloride was stirred at room temperature for 1 hour, during which time product precipitation was progressive. Ether-hexanes (2:1, 20mL) 25 was added and the yellow solid was collected by suction filtration, washed with 60mL of ether-hexanes (2:1), and dried in vacuo to give 1.43g of the title material.

WO 99/14217 PCT/US98/19015 -101 1 H NMR (CDCl3) 5: 2.48 (s, 3H), 3.82 (s, 3H), 6.49 (d, J=16Hz, 1H), 7.30-7.87 (m, 6ArH), 7.68 (d, J=16Hz, 1H). Step C: Preparation of 4-Acetoxy-7-(2-carbomethoxyethyl)-fluoren-9 5 one The material prepared above in Step B, 1.11g (3.45mmol) and 267mg of 5%Rh/C in 60mL methylene chloride and 12mL methanol was stirred under balloon pressure of hydrogen for 5 hours. The catalyst was removed by filtration through celite, washed 10 well with methylene chloride, and the filtrate evaporated and dried in vacuo to give 1. 1g of product which was used without further purification. 1 H NMR (CDC13) 6: 2.46 (s, 3H), 2.65 (t, J=7.5Hz, 2H), 2.98 (t, J=7.5Hz, 2H), 3.67 (s, 3H), 7.23-7.56 (min, 6ArH). 15 Step D: Preparation of 2-(4-Hydroxy-7-fluoren-9-one)propionic acid A stirred mixture of 1.27g (3.92mmol) of ester, prepared in Step C above, and 2.43mL (12.2mmol) of 5N NaOH in 30 mL of EtOH was refluxed under nitrogen for 70 minutes. The cooled mixture was 20 partitioned between EtOAc, ice, 2N HC1, and brine, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 1.04g of the title acid. 1 H NMR (d6-acetone) 6: 2.67 (t, J=7.5Hz, 2H), 2.97 (t, J=7.5Hz, 2H), 7.08-7.80 (min, 6ArH), 9.37 (s, bs, 1H). 25 Step E: Preparation of 4-Hydroxy-7-(3-hydroxypropyl)-fluoren-9-ol To a stirred suspension of the acid (905.1mg,3.38mmol), prepared above in Step D, in 30mL of anhydrous THF at ambient temperature was added cautiously 10.1mL of IM borane-THF in THF. 30 The resulting mixture was stirred further for 2 hours and carefully quenched with methanol. The mixture was evaporated and the residue partitioned between EtOAc, ice, saturated NaHCO3, and brine, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 35 0.96g of the title triol.

WO 99/14217 PCT/US98/19015 -102 1 H NMR (d6-acetone) 8: 1.85 (m, 2H), 2.74 (t, J=7.4Hz, 2H), 3.60 (t, J=7.4Hz, 2H),5.49 (d, J=6.1Hz, 1H), 6.83-7.91 (m, 6ArH), 8.88 (s, 1H). 5 Step F: Preparation of 4-Hydroxy-7-(3-hydroxypropyl)-fluoren-9-one A stirred mixture of 870mg (3.38mmol) of triol, prepared in Step E, and 958mg (13.5mmol) of manganese dioxide in 20mL of acetone was refluxed for 17 hours. The cooled mixture was filtered through celite, washed well with acetone, and the filtrate evaporated 10 and dried in vacuo to give 832.2mg of the title compound, as a brick red solid. 1 H NMR (d6-acetone) 8: 1.85 (m, 2H), 2.74 (t, J=7.4Hz, 2H), 3.59 (m, 2H), 7.06-7.79 (m, 6ArH), 9.30 (s,1H). 15 Step G: Preparation of 4-Hydroxy-7-(3-t-butyldimethylsilyloxypropyl) fluoren-9-one A mixture of 832.2mg (3.28mmol) of diol, prepared in Step F above, 543.2mg (3.6mmol) of t-butyldimethylchlorosilane, and 267.7mg (3.9mmol) of imidazole in 10mL sieve-dried DMF was stirred 20 at 0 OC for 45 minutes. The mixture was partitioned between EtOAc, ice, and 2N HC1, and the organic phase was separated, washed twice with ice-water and then with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography using an elution gradient of methylene chloride-ethyl acetate (50:1 to 25 10:1) to give 1.05g of the title product. 1 H NMR (CDC13) 8: 0.04 (s, 6H), 0.89 (s, 9H), 1.84 (m, 2H), 2.68 (t, J=6.3Hz, 2H), 3.62 (t, J=6.3Hz, 2H), 5.25 (bs, 1H),5.7 (d, J=15Hz, 1H), 6.98-7.61 (m, 6ArH) 30 Step H: Mitsunobu Reaction Using the general procedure described in Example 2 and 109.8mg (0.3mmol) of phenol, prepared in Step G, 165.4mg of the carbapenem adduct was produced. 1 H NMR (CDC13) 8: 0.03 (s, 6H), 0.89 (s, 9H), 1.27 (d, 35 J=7.3Hz, 3H), 1.43 (d, J=6.3Hz, 3H), 1.84 (m, 2H), 2.68 (t, J=7.6Hz, 2H), WO 99/14217 PCT/US98/19015 -103 3.44 (m, 1H-1 & 1H-6), 3.62 (t, J=6.2Hz, 2H), 4.21 (dd, 1H-5), 5.12 (m, 1H-8), 5.7 (d, J=15Hz, 1H), 6.86-7.76 (m, 6H). Step I: Desilylation 5 Using the general procedure outlined in Example 21, the carbapenem prepared in the previous step provided 103.4mg of carbapenem 51. 1 H NMR (CDC13) 8:1.27 (d, J=7.3Hz, 3H), 1.43 (d, J=6.3Hz, 3H), 1.87 (m, 2H), 2.72 (t, J=7.3Hz, 2H), 3.44 (m, 1H-1 & 1H 10 6), 3.67 (t, J=6.3Hz, 2H), 4.21 (dd, 1H-5), 5.12 (m, 1H-8), 5.7 (d, J= 15Hz, 1H), 6.97-7.62 (m, 6H).

WO 99/14217 PCT/US98/19015 -104 EXAMPLE 56 PREPARATION OF CARBAPENEM 52 ND CONH2 eN 2OTf 0 02CO HH N OO 0 CO2CH 2 CH=CH2 Step A: Triflate Formation 5 Using the general procedure outlined in Step A of Example 10, 58.2mg (0.097mmol) of alcohol 51, prepared in Example 55, was converted into 70.4mg of the corresponding triflate. Step B: Displacement Reaction 10 Using the general procedure outlined in Step B of Example 10, the crude triflate from Step A was converted into 81.3mg of crude carbapenem 52, which was used without further purification.

WO 99/14217 PCT/US98/19015 -105 EXAMPLE 57 PREPARATION OF CARBAPENEM 53 N 'CONH 2 " C02® N 0 HO

HH

0 N 0 C02 Using the general procedure outlined in Step C of 5 Example 7, the crude carbapenem salt 52 was converted into 20.3mg of carbapenem 53, after resin chromatography on amberchrom CG 161. IR (nujol): 1753, 1704,1592cm-1; 1H NMR (D20-CD3CN, 5:2) : 1.09 (m), 1.43 (d, J=7.4Hz, 10 3H), 1.48 (d, J=6.3Hz, 3H), 1.65 (m), 2.94 (m, 2H), 3.56 (m, 1H-1), 3.63 (dd, 1H-6), 3.83 (m), 4.2 (m), 4.45 (m), 5.01 (d, J=14Hz,1H), 5.58 (s, 2H), 5.8 (d, J=14Hz,1H), 7.36-7.83(m, 8ArH); UV: Xmax 257nm(H20).

WO 99/14217 PCT/US98/19015 -106 EXAMPLE 58 PREPARATION OF CARBAPENEM 54

CH

3 N ®OTf N /,d O 0 2 H 0 N 0 CO2CH 2 CH=CH2 Using the procedure described in Example 22, 48.7mg 5 (.08mmol) of carbapenem 51 provided 54.3mg of salt 54. 1 H NMR (CDC13) 5:1.29 (d, J=7.4Hz,3H), 1.44 (d, J=6.3Hz, 3H), 2.25 (min, 2H), 2.72 (min, 2H), 3.44 (min, 1H-1 & 1H-6), 3.98 (s, N-CH3), 5.13 (min, 1H-8), 5.68 (d, J=14.9Hz, 1H), 6.99-7.65 (min, 8H), 9.2 (s, 1H). 10 EXAMPLE 59 PREPARATION OF CARBAPENEM 55

CH

3 N 0/O HO HH 0 N/ 020 Following the procedure outlined in Example 3, the carbapenem 54 prepared in Example 58 was deallylated to provide 15 14mg of 55 after purification by reverse phase chromatography (RP PLC) using water-acetonitrile (7:3) as eluant and lyophilization. IR (nujol): 1753, 1709, 1594cm- 1

;

WO 99/14217 PCT/US98/19015 -107 1 H NMR (D20-CD3CN,5:2) 8: 1.43 (d, J=7.4Hz, 3H), 1.48 (d, J=6.3Hz, 3H), 2.38 (m, 2H), 2.87 (m, 2H), 3.54 (m, 1H-1), 3.62 (dd,1H-6), 4.06 (s, N-CH3), 4.45 (m, 4H), 5.05 (d, J=14.3Hz, 1H), 5.84 (d, J=14.3Hz, 1H), 7.36-7.81 (m, 8ArH), 8.9 (bs, 1H). 5 UV: Xmax 258nm(H20). EXAMPLE 60 PREPARATION OF CARBAPENEM 56 OH

O

0 0 2CH3 0 0 CO2CH 2

CH=CH

2 10 Step A: Preparation of 4-Hydroxy-7-(3-t-butyldimethylsilyloxypropyl) 9-carbomethoxy-fluorylidene A stirred mixture of 110.4mg (0.3mmol) of fluorenone derivative prepared in Step G of Example 55 and 250.8mg (0.75mmol) of methyl-(triphenylphosphoranylidene)-acetate in 3mL of p-xylene 15 was refluxed under nitrogen for 21 hours. The cooled mixture was evaporated and the residue purified by PLC with CH2C12-EtOAc (50:1) to give 90mg of the title compound as a mixture of geometric isomers. 1 H NMR (CDCl3) 8: 0.07 (s, 6H), 0.92 (s, 9H11), 1.87 (m, 2H), 2.73 (m, 2H), 3.65 (t, 2H), 3.87 (s, 3H), 6.71-8.74 (m, 7H). 20 Step B: Mitsunobu Reaction Using the general procedure described in Example 2 and 180.6mg (0.42mmol) of phenol, prepared in Step A, 288.4mg of the carbapenem was produced, as a mixture of geometric isomers. 25 1 H NMR (CDCl3) 8: 0.04 (s, 6H), 0.89 & 0.90 (s's, 9H), 1.27 (2d's, 3H)), 1.43 (d, 6.5Hz,3H), 1.86 (m, 2H11), 2.73 (m, 2H), 3.44 (m, 1H-1 & 1H11-6), 3.66 (m, 2H), 3.85 (s, 3H), 4.17 (2dd's, 1H11-5), 5.12 (m, 1H-8), 5.45 (d, 1H), 5.71 (d, J=15Hz, 1H), 6.69-8.74 (m, 7H11).

WO 99/14217 PCT/US98/19015 -108 Step C: Desilylation Using the general procedure outlined in Example 21, the carbapenem (268.9mg) prepared in the previous step provided 5 171.6mg (75%) of carbapenem 56. 1H NMR (CDCl3) 6: 1.27 (d, J=7.3Hz, 3H), 1.43 (d, J=6.3Hz, 3H), 1.95 (m, 2H), 2.78 (m, 2H), 3.44 (m, 1H-1 & 1H-6), 3.67 (t, J=6.3Hz, 2H), 3.86 (s, 3H), 4.21 (dd, 1H1-5), 5.12 (m, 1H-8), 5.45 (d, 1H), 5.7 (d, 1H11), 6.72-8.77 (m, 7H). 10 EXAMPLE 61 PREPARATION OF CARBAPENEM 57 N CONH 2 ® N 20Tf 0CO2CH3 02 OO o-o N" 0 CO2CH 2

CH=CH

2 Step A: Triflate Formation 15 Using the general procedure outlined in Step A of Example 10, 48.4mg (0.074mmol) of alcohol 56, prepared in Example 60, was converted into 65.6mg of the corresponding triflate. Step B: Displacement Reaction 20 Using the general procedure outlined in Step B of Example 10, the crude triflate from Step A was converted into 78mg of crude carbapenem 58, which was used without further purification.

WO 99/14217 PCT/US98/19015 -109 EXAMPLE 62 PREPARATION OF CARBAPENEM 58 N

CONH

2 N C0 SCO2CH3 HOH H H 0 N Using the general procedure outlined in Step C of 5 Example 7, the crude carbapenem salt 57 was converted into 17.9mg of carbapenem 58, after resin chromatography on amberchrom CG 161. IR (nujol): 1751, 1699, 1584cm-1; 1 H NMR (D20-CD3CN,5:2) 5:1.09 (m), 1.5 (m, 6H), 1.65 10 (m), 2.94 (m, 2H), 3.56 (m, 1H-1 & 1H-6), 3.83 (m), 4.11 (s, 3H), 4.2 (m), 4.45 (m), 5.07 (d, J=13.6Hz,1H), 5.88 (d, J=13.6Hz,1H), 7.3-8.69(m, 7H); UV: ?max 330, 266nm(H20).

WO 99/14217 PCT/US98/19015 -110 EXAMPLE 63 PREPARATION OF CARBAPENEM 59 CH3 ®0Tf / 02CO 02CH 3 HH 0 N 0 CO20CH2CH=CH2 Using the procedure described in Example 22, 70.2mg 5 (.011mmol) of carbapenem 56 provided 68.4mg of salt 59. 1H1 NMR (CDCl3) 8:1.28 (m, 3H), 1.44 (m, 3H), 2.25 (m, 2H), 2.72 (m, 2H), 3.44 (m, 1H-1 & 1H-6), 3.87 (s, 3H), 3.93 (s, N-CH3), 4.2 (m, 2H), 5.13 (m, 1H-8), 6.73-9.16 (m, 9H). 10 EXAMPLE 64 PREPARATION OF CARBAPENEM 60

CH

3 N H CO 2 CH3 HO

HH

0 Following the procedure outlined in Example 3, the carbapenem 59 prepared in Example 64 was deallylated to provide 15 31.3mg of 60 after purification by reverse phase chromatography (RP PLC) using water-acetonitrile (7:3) as the eluant and lyophilization. IR (nujol): 1753, 1715, 1587cm- 1

;

WO 99/14217 PCT/US98/19015 -111 1 H NMR (D20-CD3CN,5:2) 8:1.44 (m,6H), 2.38 (m, 2H), 2.87 (m, 2H), 3.54 (m, 1H-1 & H-6), 4.00, 4.02, 4.07, 4.09 (s's, 6H), 4.45 (m, 4H), 5.09 (d, J=14Hz, 1H), 5.88 (d, J=14Hz, 1H), 7.28-8.84 (m, 9H). UV: kmax 332, 268nm(H20). 5 EXAMPLE 65 PREPARATION OF CARBAPENEM 61 0 020 H H N 0 0 CO2CH2CH=CH 2 Step A: Preparation of Methyl-2,2'-dimethoxy-biphenyl-6-carboxylate 10 Using the procedure outlined in Step A of Example 18, 201.7mg (0.69mmol) of methyl-2-iodo-3-methoxy-benzoate and 125.9mg (0.82mmol) of 2-methoxy-phenylboronic acid gave after 27 hours of reflux a quantitative yield of the title substance. 1 H NMR (CDC13) 5:3.56 (s, 3H), 3.71 (s, 3H11), 3.73 (s, 3H), 15 6.95-7.47 (m, 7H11). Step B: Preparation of 2,2'-dimethoxy-biphenyl-6-carboxylic acid A stirred mixture of 188.4mg (0.69mmol) of ester prepared in Step A and 0.28mL (1.39mmol) of 5N NaOH in 2mL of 20 ethanol was refluxed under nitrogen for 1.5 hours. The mixture was partitioned between EtOAc, ice, 2N HC1, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo to give 171.6mg of the title acid which was used without further purification. 25 1 H NMR (d6-acetone) 8:3.66 (s, 3H), 3.71 (s, 3H), 6.79-7.48 (m, 7H). Step C: Preparation of 12-Methoxy-3,4-benzocoumarin To a stirred suspension of 171.6mg (0.67mmol) of acid 30 prepared in Step B in 2mL of sieve-dried CH2Cl2 at 0 0 C was added all at once 173.1mg (0.83mmol) of phosphorous pentachloride and the WO 99/14217 PCT/US98/19015 -112 mixture was stirred further for 5 minutes, and then for 1 hour with the ice-water bath removed. The homogeneous solution was recooled to OOC, and 133mg (0.99mmol) of AIC13 was added all at once. The resulting mixture was stirred with the ice-water bath removed for 1 5 hour and then partitioned between EtOAc, ice, and brine. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by PLC with hexanes-methylene chloride (2:1) provided 134.7mg of the title compound. 10 1 H NMR (CDCl3) 8: 3.99 (s, 3H), 7.21-8.87 (min, 7ArH). Step D: Preparation of 12-Hydroxy-3,4-benzocoumarin The methylether from Step C in lmL acetic acid and 3.4mL 48%HBr was stirred at 130 0 C for 5 hours. The cooled solution 15 was treated with water and the insoluble product collected by filtration, washed well with water, and dried in vacuo to give 131.3mg of the title product, which was used without further purification. 1 H NMR (d6-acetone) 8: 7.33-9.16 (m, 7H), 9.97 (s, 1H). 20 Step E: Mitsunobu Reaction Using the general procedure described in Example 2 and 53mg (0.025mmol) of phenol, prepared in Step D, 35.5mg of carbapenem 61 was produced, which contained some of the C-3 isomer and was used without further purification. 25 EXAMPLE 66 PREPARATION OF CARBAPENEM 62 0 HO HH 0 N 0 CO2Na Using the procedure described in Example 3 and the 30 material prepared in Step E of the previous example, 6.6mg of WO 99/14217 PCT/US98/19015 -113 carbapenem 62 was produced after RP-PLC purification, elution with water-acetonitrile (4:1), and lyophilization. IR (nujol): 1754, 1726, 1598cm-1; 1 H NMR (D20-CD3CN,5:2) 8: 1.41 (d, J=7.2Hz, 3H), 1.45 5 (d, J=6.3Hz, 3H), 3.47(m, 1H-1), 3.61 (dd, 1H-6), 4.34 (dd, 1H-5), 4.42 (m, 1H-8), 5.2 (d, J=13.5Hz, 1H), 6.0 (d, J=13.5Hz, 1H), 7.56-9.18 (m, 7ArH); UV: kmax 332, 262nm(H20).

Claims

1. A compound represented by formula I: (R) 3 PH H H3C N / CH 2 -O X N/ x 0 CO 2 M 5I (R) 3 or a salt or hydrate thereof, wherein: R 1 represents H or methyl; 10 CO 2 M represents a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group; 15 P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group; X is present or absent, and when present, represents a members selected from the group consisting of: CH 2 , C(R)2, CCR 2 , 20 O, S(0)x, with x equal to 0, 1 or 2, C(0), C0 2 , OCO and NR; each R group is independently selected from: hydrogen; halo; -CN; -NO 2 ; -NRaRb; -ORc; -SRc; -C(0)NRaRb; -C(0)ORh; S(O)Rc; -SO 2 Rc; -SO 2 NRaRb; -NRaSO 2 Rb; -C(O)Ra; -OC(O)Ra; 25 OC(O)NRaRb; -NRaC(O)NRbRc; -NRaCO 2 Rh; -OCO 2 Rh; -NRaC(O)Rb; C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups; -A-(CH 2 )n-Q and -C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; 30 A represents O, S or-CH2-; WO 99/14217 PCT/US98/19015 -115 n represents an integer 0-3; each R a , Rb and Rc independently represents hydrogen, -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted 5 with one to four Rd groups, or -C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups; or R a and Rb taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRc, with Rc as defined above, or -C(O)-, said 10 ring being unsubstituted or substituted with one to four Ri groups; or Rb and Rc taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of 0, S, NRa, with R a as defined above, or -C(0)-, said ring being unsubstituted or substituted with one to four R i groups; 15 each Rd independently represents halo; -CN; -NO 2 ; NReRf; -ORg; -SRg; -CONReRf; -COORg; -SORg; -SO 2 R9; -SO 2 NReRf; NReSO 2 Rf; -CORe; -NRe CORf; -OCORe; -OCONReRf; -NReCONRfRg; -NReCO 2 Rh; -OCO 2 Rh; -C(NRe)NRfRg; -NReC(NH)NRfRg or 20 NReC(NRf)Rg; R e , R f and R9 represent hydrogen; -R*; -C1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four R i groups; 25 or Re and R f taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of 0, S, -C(O)- or NRg with Rg as defined above, said ring being unsubstituted or substituted with one to four Ri groups; 30 each R i independently represents halo; -CN; -NO2; phenyl; -NHSO 2 Rh; -ORh, -SRh; -N(Rh) 2 ; -N+(Rh) 3 ; -C(O)N(Rh) 2 ; SO 2 N(Rh) 2 ; heteroaryl; heteroarylium; -CO 2 Rh; -C(O)Rh; -OCORh; NHCORh; guanidinyl; carbamimidoyl or ureido; 35 each Rh independently represents hydrogen, a -C1-6 straight or branched-chain alkyl group, a -C3-C6 cycloalkyl group or phenyl, or when two Rh groups are present, said Rh groups may be WO 99/14217 PCT/US98/19015 -116 taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, -C(O)-, NH and NCH3; 5 Q is selected from the group consisting of: (CH 2 )b NN , I , SN o , N-Rx and NRxRYRz N IaCd L (CH 2 )a wherein: a and b are 1, 2 or 3; L- is a pharmaceutically acceptable counterion; 10 ox represents O, S or NRS; P, 8, X, p. and a represent CRt, N or N+R s , provided that no more than one of 3, 8, X, g and ay is N+Rs; each Rs independently represents hydrogen; phenyl or 15 C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; each Rt independently represents hydrogen; halo; phenyl; -CN; -NO 2 ; -NRuRv; -ORu; -SRu; -CONRuRv; -COORh; -SORu; 20 -SO 2 Ru; -SO 2 NRuRv; -NRuSO 2 Rv; -CORu; -NRuCORv; -OCORu; OCONRuRv; -NRuCO 2 Rv; -NRuCONRvRw; -OCO 2 Rv; -C1-6 straight or branched-chain alkyl, unsubstituted or substituted with one to four R I groups; 25 Ru and Rv represent hydrogen or -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or Ru and R v together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by 30 one or more of O, S, NRw or -C(O)-, said ring being unsubstituted or substituted with one to four R i groups; WO 99/14217 PCT/US98/19015 -117 each Rw independently represents hydrogen; -C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four R i groups; C3-6 cycloalkyl optionally substituted with one to four R i groups; phenyl optionally substituted with one to four R i 5 groups, or heteroaryl optionally substituted with 1-4 Ri groups; or Rh and Rw taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3; 10 Rx represents hydrogen or a C1-8 straight- or branched chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRw, N+RhRw, or -C(0)-, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, OR w , SRw, SOR w , SO2R w , NRhRw, N+(Rh) 2 Rw, -C(O)-Rw, C(0)NRhRw, SO 2 NRhRw, 15 CO 2 Rw, OC(0)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRw, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four R i 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 i groups; 20 RY and Rz represent hydrogen; phenyl; -C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four R i groups, and optionally interrupted by O, S, NRw, N+RhRw or -C(O)-; 25 or Rx and RY together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO2, NRw , N+RhRw or -C(O)-, unsubstituted or substituted with 1 - 4 Ri groups, 30 and when Rx and RY together represent a 4-6 membered ring as defined above, Rz is as defined above or Rz represents an additional saturated 4-6 membered ring fused to the ring represented by Rx and RY taken together, optionally interrupted by O, S, NRw or C(0)-, said rings being unsubstituted or substituted with one to four 35 R i groups. WO 99/14217 PCT/US98/19015 -118

2. A compound in accordance with claim 1 wherein R 1 represents methyl.

3. A compound in accordance with claim 1 wherein 5 CO 2 M represents a carboxylic acid or a carboxylate anion.

4. A compound in accordance with claim 1 wherein P represents hydroxyl or hydroxyl protected by hydroxyl 10 protecting group.

5. A compound in accordance with claim 1 wherein one R group represents -A-(CH 2 )n-Q, and A, n and Q are as originally defined. 15

6. A compound in accordance with claim 5 wherein A represents -CH 2 -.

7. A compound in accordance with claim 5 wherein 20 n represents 0 or 1.

8. A compound in accordance with claim 5 wherein Q represents -N i or N II 25 wherein: a represents O, S or NRs; P, 5, k, 4 and a represent CRt, N or N+R s , provided that nomore than one of P, 8, X, g and ac is N+Rs, balanced by L- which is 30 a pharmaceutically acceptable counterion, and RS is as originally defined.

9. A compound in accordance with claim 5 wherein Q is selected from the group consisting of: 35 WO 99/14217 PCT/US98/19015 -119 (CH2)b N N-Rx and NRxRYRz e \ / L (CH 2 )a a and b are 2; 5 L- is a pharmaceutically acceptable counterion; and Rx, RY and Rz are as originally defined.

10. A compound in accordance with claim 9 wherein 10 Q is (CH2)b N N- Rx /\ / L (CH 2 )a

11. A compound in accordance with claim 5 wherein 15 Q is wherein: 0x represents O, S or NRs; 20 3, 5, X, R and a represent CRt, N or N+R s , provided that nomore than one of 13, 5, k, 4 and a is N+Rs, balanced by L-,which is a pharmaceutically acceptable counterion, and all other variables are as originally defined. 25

12. A compound in accordance with claim 1 falling within the following table: WO 99/14217 PCT/US98/19015 -120 TABLE 1 Cpd No. Compound S 2 allylO 2 CO H H N/ 0 CO 2 allyl - S -- s 3 HOHH 'Z0 NZ 0 C 02 X + N N C -al S 4 allyl-O H H N /X 0 00 2 -alyI WO 99/14217 PCT/US98/19015 -121 OH S 5 allyI-O 2 C O H H N/ 0 CO 2 allyl N N H S 6 oH 0 Co 2 N2 C0NCONH 2 7 HOHH O 002 N' 0 CD CO2 kNZCONH2 8 S allyl-O H H NZ O C O2-allyl WO 99/14217 PCT/US98/19015 -122 OH S 9 allylO 2 CO H H 0 CO 2 allyl G N-Lt S'N~ CONH 2 10 S HO H O s o NN 00 02 2 x O/\o C O0 HO H H N/ C 2 - X + HO H HC0 12 0 N/ O CO2- X' WO 99/14217 PCT/US98/19015 -123 N __/CONH 2 S O X 13 HOHH OO all2OH H/ N C02 O , N CONH2 allyIO 2 CO H H 14 O N 0 o o..x C0 2 a2yI HO H H 15 O N! CO2NH HO HOH H-0 16 O N 0 0 O 7 CO2 X + WO 99/14217 PCT/US98/19015 -124 N CONH 2 O- XX HO H H 17 O20 N! 0 Q C02 CH2=CHCH20200 H H 18 o CO 2 CH2CH=CH2 19 HOH H N/ 0 C 02 X+ OSiPh 2 CMe 3 CH2=CHCH202C 0 o CO2CH2CH=CH2 WO 99/14217 PCT/US98/19015 -125 OH 21 CH 2 =CHCH 2 02CO H H 00 0 C020 H 2 CH=CH 2 e //-NMe N CH 2 =CHCH 2 02CO H H 0 /0_'N NMe NN H=CHCHCO20O HO 23 N 0 CH2CCHCH22C H HH 00 24 o 0 CO2CH2CH=CH2 WO 99/14217 -2-PCT/US98/1 9015 -126 HO H H 00 0 0 CH2=CHHH2HCH 2 N/ 0 CHO %z7~02C0H H 27 0 CO2CH 2 CH=CH2 WO 99/14217 -2-PCTIUS98/1 9015 HOH N 7 300 30 N" 0 CO2CH2CH=CH2 HO C 0 2 CH 3 31 HOH N/ 0 C002- X+ 7 OTBS H H 0 C020H 2 CH=CH 2 WO 99/14217 PCT/US98/19015 -128 OH " O2cO HH 33 o2 O N 7 0 CO2CH2CH=CH 2 C H 3 N N 34 G 020 H 2 CH= H 2 OH 3 NN O 7 OOMs NH= HH 0 CO2CH 2 CHCH 2 WO 99/14217 PCT/US98/19015 -129 02C"'H H J / O \7 37 o H 00 CO2CH2CH=CH2 N CONH 2 N 3802 0 0 H H 0 NN O CO2CH2CH=CH2 N CONH2 ox HO 39 HO H 0O O~ C 0 2 ,'- CH 2 OTBS 020H 40 /0O CO2CH 2 CH=CH2 WO 99/14217 PCT/US98/1 9015 -130 -CH20H 41 ~~2 OH H N/ 0 CO2CH2CH=0H 2 HO 2 O HH 00 43 CH 2 =0H0H20 2 0 I N 7 0 C0 2 CH2CH=CH2 H K0 44 0H 2 =CHCH20 2 C H N" on C0 2 CH2CH=CH2 WO 99/14217 PCT/US98/19015 -131 OMs 45 CH 2 =CHCH2O 2 C H H 0 N 7 0 CO 2 CH2CH=CH2 17 0 46 CH 2 =CH0H20 2 C H JN 0 CO 2 CH2CH=0H2 OH 3 N/N 00 CO0 2 C H 2 CH=0H 2 WO 99/14217 PCT/US98/19015 -132 N/-"CON H 2 2X 0 48 CH2=CHCH202CO H H NN O C02CH2CH=CH 2 00O20 H 2 CH=GH 2 CH 2 C H 2 CON H 2 x0 CH 2 =CHCH 2 02CO H H H H 49 0 N 0 CO 2 CH 2 CH=CH 2 CH2CH2CONH2 N CH2=CHCH202COHH N/ 0 COCH2CH=CH2 WO 99/14217 PCT/US98/19015 -133 CH3 N O/ 0 51 HO H H o Nx 00 522 HOD 0co0 N "CONH2 No 2 N X 170 HO 52 HOH NY o CO2 O HH 53 0 0 N/ O02C WO 99/14217 PCT/US98/19015 -134 CH2CH2CONH 2 N 0 54 HOHH O / C02G OH " O 2 CH H 0 CO2CH 2 CH=CH2 N/CONH2 ('-I/N 2X® N 56 0 0 O2CO0 H H 0 N/ 0 C02CH 2 CH=CH 2 WO 99/14217 PCT/US98/19015 -135 N1 CONH 2 g N2 Xm ON x S 00 57 HO H H N/ O~ C 0 2 " CH 3 N oX N> 58 0 0200 HH 00 0Ho N O C02C H2CH=CH 2 WO 99/14217 PCT/US98/19015 -136 OH 3 N O ° / O 59 0 HO H HH 0O N C020 OH 02C0 CO2CH3 60 0 0 0 CO2CH 2 CH=CH 2 N/"CONH2 2 X N 61 02CO CO 2 CH 3 H H 0 N/ 0 C0 2 C H 2 CH=CH 2 WO 99/14217 PCT/US98/19015 -137 N CONH 2 N X 62 SC0 2 C H 3 HO HH 0 N 7 0 C 02 CH 3 N X N 63 020C 0 C0 O 2 CH 3 HH 0 N 7 0 CO0 2 CH 2 CH=CH 2 WO 99/14217 PCT/US98/19015 -138 CH 3 N CCH COHCHa HOO N/o C020 0 2C H HO 6HH / 0 CO2CH2CH=CH 2 HOO 66 0 O N C0 2 - X + wherein X + and X- represent appropriately charged counterions.

13. A pharmaceutical composition which is 5 comprised of a compound in accordance with claim 1, or a pharmaceutically acceptable salt or hydrate thereof, in combination with a pharmaceutically acceptable carrier. WO 99/14217 PCT/US98/19015 -139

14. A pharmaceutical composition which is made by combining a compound in accordance with claim 1 or a pharmaceutically acceptable salt or hydrate thereof, with a pharmaceutically acceptable carrier. 5

15. A pharmaceutical composition in accordance with claim 12 further comprised of a compound which inhibits dehydropeptidase. 10

16. A method of treating or preventing a bacterial infection in a mammalian patient in need of such therapy, comprising administering to said patient an anti-infective amount of a compound as defined in claim 1.