GB2194789A - Antibacterial agent intermediates - Google Patents

Antibacterial agent intermediates Download PDF

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GB2194789A
GB2194789A GB08721346A GB8721346A GB2194789A GB 2194789 A GB2194789 A GB 2194789A GB 08721346 A GB08721346 A GB 08721346A GB 8721346 A GB8721346 A GB 8721346A GB 2194789 A GB2194789 A GB 2194789A
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compound
formula
amino
cephem
give
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GB2194789B (en
GB8721346D0 (en
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Haruhiro Yamashita
Masahisa Oka
Takayuki Naito
Jun Okumura
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Bristol Myers Co
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Bristol Myers Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Description

1 1 1 GB2194789A 1
SPECIFICATION
Antibacterial agent intermediates Summary of the Invention This application relates to 7-[2-(5-amino-1,2,4thiadiazol-3-yi)-2-(substituted)iminoacetamidol-3[3-(quaternaryammonio)-1propen-l-yil-3-cephem-4-carboxylates of the formula
S N C - CONH % 11 H N H R HN--\s/ \ OR2 0 in which R' and R2 are as defined herein and -ON-Q is a quaternary ammonio group as defined herein, and to salts and esters thereof. This invention also relates to processes for the preparation of the compounds of Formula 1, to pharmaceutical compositions containing at least one compound of Formula 1, and to intermediates in their preparation.
The present Application has been divided out from Application No.85.08846 (2157293) 1 Background and Prior Art
A) U.S. Patent 4,390,534, issued June 28, 1983 to Tsutomu Teraji et aL, discloses cephem 25 and cepharn compounds of the formula R1 S-CONH S R3 R4 S / RS wherein RI is amino or protected amino; R2 is hydrogen, acyl, optionally substituted aryl, substituted alkyl, alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkenyl or an 0- or Scontaining 5-membered heterocyclic ring substituted with oxo group(s); R3 is hydrogen or alkyl; R4 is hydrogen, acyloxyalkyl, acylthioalkyl, optionally substituted pyriclinioalkyl, optionally substituted heterocyclythioalkyl, alkyl, halogen, hydroxy or optionally substituted thiazolioalkyl; and R5 is carboxy or protected carboxy; provided that R5 is COO- when R4 is optionally substituted pyriclinioalkyl or optionally substituted thiazolioalkyl; and the dashed line indicates either a single or double bond.
European Patent Application No. 13,762, published August 6, 1980 is concordant thereto and has a similar disclosure.
U.S. Patents 4,381,299 (issued April 26, 1983), 4,331,665 (issued May 25, 1982) and 45 4,332,798 (issued June 1, 1982) each issued on parent applications of U.S. 4,390,534, and have similar disclosures.
B) European Patent Application No. 62,321, published October 13, 1982, discloses cephem compounds of the formula N--i C S R1 t. -CONH - - N 11 S,,' N -N - \ 01 OR2 0 coo 9 CH2-K, _/ wherein RI is amino or protected amino; R2 is an optionally substituted lower aliphatic hydrocar60 bon group, or cycloalkenyl; and the group of the formula 2 GB2194789A 2 1 -N 1 k(D/ is an optionally substituted heterocyclic cation group containing more than one nitrogen atom; and pharmaceutically acceptable salts thereof. Also disclosed are intermediates of the formula 1 o R1 H -c -CONH S e X S CH2 -N OR2 R4 wherein R' and R2 are as defined above, R4 is a protected carboxyl group and X- is an acid residue.
C) European Patent Application No. 74,653, published March 23, 1983, discloses cephem 20 compounds of the formula N C S N 11 7 CONH 3 0 R2 U+ CH 2V "r 7" R 4 coo 0 7 wherein RI is amino or protected amino; R2 is an optionally substituted lower aliphatic hydrocarbon group, cyclo(lower)alkyl or cyclo- 30 (lower)alkenyl); R 3 is (lower)alkylamino, N-protected(lower)alkylamino, di(lower)alkylamino, sulfo(lower)alkylam ino, hydroxy(lower)alkylamino, N-protected hydroxy(lower)alkylamino, acyloxy(lower)alkyl, (lower) alkoxy(lower)alkoxy(lower)alkyl, di(lower)alkylamino(lower)alkyl, (lower)alkylthio (lower) alkyl, (lower)alkylthio, (lower)alkoxy, (lower)alkoxy(lower)alkoxy, hydroxy(lower)aikoxy, acyl(lower)alkyl, hydroxy(lower)alkylthio, di(lower)alkylamino(lower)alkylthio, N-containing unsaturated 5-membered heterocyclic group, N-containing unsaturated 5-membered heterocyclicthio, or N-containing unsaturated 5 or 6-membered heterocyclicthio(lower)alkyl which may be substituted with suitable substituent(s); and R4 is hydrogen or (lower)alkyl; or a salt thereof.
D) U.S. Patent 4,332,800, issued June 1, 1982 to Tsutomu Teraji et at., discloses inter alia compounds of the formula R1 N -CONH S N 11 11\ / m 5 OR2 1 Ut o- N)U X N CH2 e 0 n_ CO Oe wherein R' is amino or protected amino; R2 is (lower)aikyl and X is hydrogen or carbamoyl.
E) European Patent Application No. 47,977, published March 24, 1982, discloses cephem 55 compoundsof the formula (0)m f Am -T- C- CONH S 11 N 1 NJY)J-N tn- EH2R1 CO O(D 3 GB2194789A ZI wherein m is 0 or 1; Am is optionally substituted amino; T is a thiadiazolyl moiety (attached to the other groups by two of its carbon atoms); R. is hydrogen, optionally substituted alkyl, cycloalkyl or optionally substituted carbamoyl; and R, is optionally substituted thiazolio, optionally substituted pyrazolio, tri(lower)aikylammonio or a pyridinio group of the formula Ra (D 10 -H 11 Rcl. Rb in which Ra is substituted (lower)alkyl [the substituent being cycloalkyl, phenyl, hydroxy, alkoxy, halogen, cyano, carbamoy], carboxyl or sulfo], (lower)aikenyl or carboxy- substituted (lower)aike- 15 nyl, (lower)aikyithio or carboxy-substituted (lower)aikylthio, amino or monosubstituted amino [the substituent being (lower)aikyl, (lower)alkanoyl or aminobenzenesuifonyll, di(lower)aikylamino, sub stituted carbamoyl [the substituent being (lower)alkyl, hydroxy(lower)aikyi, (lower)alkoxy, hydroxy or cyanol, di(lower)aikylcarbamoy], thiocarbamoyl, cycloalky], phenyl, hydroxy, (lower)alkoxy, halo gen, (lower) alkoxycarbonyl, (lower)aikanoyloxy, (lower)alkanoyl, carboxyl, sulfo, cyano, nitro or 20 hydroxysuifo(lower)aikyi; Rb is hydrogen or carbamoy], or has the same meaning as Ra; and Rc is hydrogen or has the same meaning as Ra; and salts thereof.
Although not formally related, European Patent Application No. 25,017, published March 11, 1981, has a similar disclosure.
F) European Patent Application No. 30,630, published June 24, 1981, discloses 3-vinyl cephem compounds of the formula R' -A-CONH S -F, ^ 0 N R2 C"CH2 wherein RI is an optionally protected amino-substituted heterocyclic group which may also have halogen, or a group of the formula R3 S02HN CY in which R3 is (lower)alkyl; R2 is carboxy or protected carboxy; and A is lower alkylene which 45 may have a substituent selected from amino, protected amino, hydroxy, oxo and a group of the formula =N-OR4, wherein R4 is hydrogen, cyclo(lower)alkenyl, (lower)alkynyl, (lower)alkenyl [op tionally substituted by carboxy or protected carboxy], (lower)alkyl [optionally substituted by one or more of carboxy, protected carboxy, amino, proected amino, cyano, phosphono, protected phosphono and a heterocyclic group which itself may be substituted]; and salts thereof.
This application specifically discloses compounds of the formula N C-CONH S \\--- 11 H2 N -/\ S / N N \ ORI 01 EH CH2 in which OR 4 is methoxy, carboxymethoxy, tert-butoxycarbonyimethoxy or 1- tert-butoxycarbonyiethoxy.
G) U.K. Patent Specification No. 1,399,086 published June 25, 1975, contains a generic disclosure encompassing a vast number of cephalosporins of the formula
4 GB2194789A 4 R- C- CD-NH B 11 1 -5 N\oe PN p wherein R is hydrogen or an organic group, R.' is an etherifying monovalent organic group linked to the oxygen through a carbon atom, B is S or 1 S-0, and P is an organic group. In one embodiment, P may be inter alia a vinyl group of the formula -CH= C /R3 in which R-1 and RI independently may be hydrogen, nitrile, (lower)alkoxycarbonyl, or substituted or unsubstituted aliphatic, cycloaliphatic, araliphatic or aromatic. However, the 5-amino-1,2.4thiadiazol-3-yl group is not identified as a possible R substituent and there is no disclosure or suggestion that P may be a quaternary ammonio-substituted propenyl group. U.S. Patent 3,971,778 and its divisionals Nos. 4,024,133, 4,024,137, 4,064,346, 4,033, 950, 4,079,178, 4,091,209, 4,092,477 and 4,093,803 have similar disclosures.
H) European Patent Application No. 88,385, published September 14, 1983, discloses cornpounds of the formula R1 - C - CONH 5 I N W N R3 o- N ---T R4 in which R' is (unsubstituted) thiadiazoly]; R' is carboxy(lower)alkyl or protected carboxy(lower)alkyl; R3 is hydrogen, halogen or flower)aIkenyl; and R4 is carboxy or protected carboxy. Although 1-propenyl is listed as one of the possible meanings of R3, the application only exemplifies compounds where R3 is hydrogen, chloro or vinyl.
t,' 1 1) U.S. Patent No. 4,307,233 issued to Daniel Farge et al. on December 22, 1981, discloses inter alia, 3-vinylcephalosporin derivatives of the formula N C- CONH S I R3 H2 N-T' N TN S OR5 0 COOH CH=CH-N,, Rli in which R5 inter alia may be alkyl, vinyl, cyanomethyl or a protective group such as 2 methoxyprop-2-yl, and R3 and R 4 are alkyl groups (optionally substituted by hydroxy, alkoxy, amino, alkylamino or dialkylamino) or phenyl groups, or R 3 and R4, taken together with the nitrogen to which they are attached, may form a saturated heterocyclic ring of 5 or 6 members, 65 GB2194789A 5 optionally containing another hetero-atom selected from N, 0 and S, and optionally substituted by an alkyl group. The compounds are useful as intermediates in the preparation of 3-thiovinyl cephalosporin derivatives. There is no disclosure or suggestion of a 5-amino-1,2,4-thiadiazol-3-yi moiety in place of the 2-aminothiazol-4-yi substituent or of a quaternary ammonio-substituted propenyl moiety for the 3-substituent. Published United Kingdom Patent Application No. 2,051,062 is concordant thereto and has a similar disclosure.
J) European Patent Application No. 53,537, published June 9, 1982, discloses, inter afla, 3vinylcephalosporin derivatives of the formula N C -CONH S N 15 H2N S 0 CKHN R3 R4 COOR2 R a \ R b 5 5 in which Rg and Rb are the same or different and are hydrogen or alkyl, or taken together, form an alkylene group containing 2 or 3 carbon atoms, Rc, is an acid protecting group, R2 is an acid protecting group such as an ester, R3 and R4 are the same or different and are hydrogen, al kyl (optionally substituted by hydroxy, alkoxy, amino, alkylamino or dialkylamino) or phenyl groups, or R3 and R, taken together with the nitrogen to which they are attached, may form a saturated heterocyclic ring of 5 or 6 members, optionally containing another hetero-atom selected from N, 0 and S, and optionally substituted by an alkyl group. The compounds are useful as intermedi- ates in the preparation of 3-thiovinyl cephalosporin derivatives. There is no disclosure or suggestion of a 5-amino-1,2,4-thiadiazol-3-yl moiety in place of the 2-aminothiazol-4-yl substituent or of a quaternary ammonio-substituted propenyl group for the 3-substituent. U. S. 4,423,214 is concordant thereto and has a similar disclosure.
K) European Patent Application No. 53,074, published June 2, 1982, generically discloses a vast number of 3-vinylcephalosporin derivatives of the formula (0)n Rola NH R 3N CH=C-R3 COOR 7a wherein R', (in one of several embodiments) may be N c )s) H2H ORS in which R, inter alia may be hydrogen, alkyl, vinyl, cyanomethyl, an oxime-protecting group such as trityl, etc., or a group of the formula -C C -COOR5 Ra/ \Rb 5 in which Ra, and Rb, are the same or different, and may be hydrogen, alkyl or, taken together, 60 an alkylene radical of 2 or 3 carbon atoms, and R3, is hydrogen or an acid-protecting radical; R02, is hydrogen or an acid-protecting radical such as methoxymethyl; R (in one of several embodiment) may be a methyl group substituted by a 5- or 6-membered aromatic heterocyclic ring containing a single heteto atom, such as 2- or 3-pyridyl, 2- or 3- thienyl or 2- or 3-furyl; and R3 is a group of the formula 6 GB2194789A 6 R4S020- in which R4 may be alkyl, trihalomethyl or optionally substituted phenyl.
These compounds are stated to be intermediates in the preparation of compounds in which 5 the 3-substituent is a group of the formula R' 1 -CH = C-SR which are stated to have antibacterial activity.
Although this patent includes the possibility of R' being a methyl group substituted by an Ncontaining heterocyclic ring, in both the intermediates and final products (thus giving a heterocyclic-substituted propenyl moiety), it teaches only that the heterocyclic ring is attached via one of its carbon atoms. Thus, there is no suggestion of a quaternary ammoniosubstituted propenyl group. The reference exemplifies R' in the intermediates and final products only as methyl. Further, in both the intermediates and final product, the propenyl group must contain a second substituent (-03SR4 or -SR, respectively). Also there is no disclosure or suggestion of a amino- 1,2,4-thiadiazol-3-yl moiety in place of the 2aminothiazol-4-yi substituent.
5- L) European Patent Application No. 53,538, published June 9, 1982, discloses, inter alia, 3vinylcephalosporin intermediates of the formula N c- CON H ---3 N\ CH=CH- R3 1 H2 S OR5 in which n is 0 or 1, R5 is hydrogen, alky], vinyl, cyanomethyl or an oxime-protecting group, and R3 is halogen. There is no disclosure or suggestion of a 5-amino-1,2,4-thiadiazol-3-yi moiety in place of the 2- aminothiazol-4-yi substituent, and no disclosure or suggestion of a 3- halo-l35 propen-l-yl substituent in the 3-position.
Complete Disclosure
This application relates to novel cephalosporin derivatives which are potent antibacterial agents. More particularly, it relates to compounds of the formula S N--[Fc -CONN "k oo, N N R1HN S.\ OR2 G -N--?'nCHCH-CH2 N-=0 wherein R' is hydrogen or a conventional amino-protecting group, R2 is hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl 50 ring containing from 3 to 6 carbon atoms, or a group of the formula 1 R4 4 COON -C- CH=CH-0 -C-c=- C-0 or 'S 1 55 R 0 4 60 -C- COON 1 RS ' 1 7 GB2194789A 7 1 in which R3 is hydrogen, (lower)aikyl or carboxyl, X is halogen, hydroxy or (lower)aikoxy, and R4 and R5 are each independently hydrogen, methyl or ethyl, or R4 and R5, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, and -N=-Q is a quaternary ammonio group, and nontoxic pharmaceutically acceptable salts and physiologi- cally hydrolyzable esters thereof. Also included within the scope of the invention are the solvates (including hydrates) of the compounds of Formula 1, as well as the tautomeric forms of the compounds of Formula 1, e.g. the 2-iminothiazolin-4-yi form of the 2-aminothiazol-4-yl moiety.
In another aspect, this application relates to a process for the preparation of the compounds of Formula I and to certain intermediates in their preparation.
As shown in the structural formula, the compounds of Formula I have the "syn" or -Zconfiguration with respect to the alkoxyimino group. Because the compounds are geometric isomers, some of the "anti" isomer may also be present. This invention comprises compounds of Formula I containing at least 90% of the "syn" isomer. Preferably the compounds of Formula 1 are "syn" isomers which are essentially free of the corresponding "anti" isomers.
In addition to geometric isomers possible with respect to the alkoxyimino group, the compounds of Formula I (and the intermediates of Formulae Vill and IX) also form geometric (cis and trans) isomers about the double bond of the propenyl group. Both the cis ("Z") and trans ("E") isomers of these compounds are specifically included within the scope of this invention.
The nontoxic pharmaceutically acceptable salts of the compounds of Formula I include salts with mineral acids such as hydrochloric, hydrobromic, phosphoric and sulfuric, or with organic caboxylic acids or sulfonic acids such as acetic, trifluoroacetic, citric, formic, maleic, oxalic, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic, malic, methanesulfonic benzenesulfonic, ptoluenesulfonic and other acids known and used in the penicillin and cephalosporin arts. Prepara- tion of these acid addition salts is carried out by conventional techniques.
Examples of physiologically hydrolyzable esters of the compounds of Formula I include indanyl, phthalidyl, methoxymethyl, acetoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, 5-methyl-2-oxo1,3,-dioxolen-4-ylmethyI and other physiologically hydrolyzable esters known and used in the penicillin and cephalosporin arts. Such esters are prepared by conven- tional techniques known in the art.
The compounds of Formula I in which RI is hydrogen exhibit high antibacterial activity against various Gram-positive and Gram-negative bacteria, and are useful in the treatment of bacterial infections in animals, including man. The compounds of Formula I may be formulated for parenteral use in a conventional manner utilizing known pharmaceutical carriers and excipients, and may be presented in unit dosage form or in multi-dosage containers. The compositions may 40 be in the form of solutions, suspensions or emulsions in oily or aqueous vehicles, and may contain conventional dispersing, suspending or stabilizing agents. The compositions may also be in the form of a dry powder for reconstitution before use, e.g. with sterile, pyrogen-free water. The compounds of Formula I may also be formulated as suppositories utilizing conventional suppository bases such as cocoa butter or other glycerides. The compounds of this invention may, if desired, be administered in combination with other antibiotics such as panicillins or other cephalosporins.
is When provided in unit dosage forms the compositions will preferably contain from about 50 to about 1500 mg of the active ingredient of Formula 1. The dosage of the compounds of Formula I is dependent on such factors as the weight and age of the patient as well as the particular nature and severity of the disease, and is within the discretion of the physician.
However, the dosage for adult human treatment will usually be in the range of from about 500 to about 5000 mg per day, depending on the frequency and route of administration. When administered intramuscularly or intravenously to an adult human, a total dosage of from about 750 to about 3000 mg per day, in divided doses, normally will be sufficient, although higher 55 daily doses of some of the compounds may be desirable in the case of Pseudomonas infections.
The quaternary ammonio group of the formula 0 -N=-Q may be acyclic, cyclic, or a combination of the two, and may contain one or more additional hereto atoms selected from nitrogen, sulfur and oxygen.
An example of an acyclic quaternary ammonio group is a group of the formula 8 GB2194789A 8 R6 01 -N-R7 1 W' in which R6, R7 and R' may be the same or different and may, for example, be (lower)aikyl or substituted (lower)aikyl in which the substituents are, for example, halogen, amino with the provision that the amino group may not be on an a-carbon, hydroxy with the provision that the 10 hydroxy group may not be on an a-carbon, (lower)aikoxy with the provision that the alkoxy group may not be on an a-carbon, (lower)alkylthio, (lower)aikylamino, di(lower)aikylamino, carbamoVI, (lower)alkenyl, phenyl (lower)al kyl, phenyl or substituted phenyl (in which the substituents may be, for example, halogen, hydroxy, amino, (lower)aikylamino, di(lower)aikylamino, acylamino, (lower)alkyl, (lower)aikylthio, (lower)aikoxy or the like).
Examples of cyclic quaternary ammonio groups are fully unsaturated monocyclic heterocyclic ring systems, and bicyclic heterocyclic ring systems in which at least one N-containing ring is fully unsaturated. Suitable cyclic quaternary ammonio ring systems include, for example, those of the formulae 20 R9 G R9 2 - 9 N:YR10 Rio ==y' R' o 25 (D H (D H- (D R9 R9 R 9 30:ORlg 30 R10 S R1 0 (E) N-N R9 (D N R9 35 -R9 W-RIO 4-:]-Rlg 1 1 N N X ^It 0. R10 (9 "" S "" i 4 R9 40 R10 R9 R1 LO m - 'WNOm 1 (D 45 H R9 (D V, N -N "k 50 m- LXC,' N 5 R9 R10 10 R10 0 - H N lwno,,,JLR9 111 R10 and the like, in which R9 and R10 are the same or different and may be, for example, hydrogen, halogen, amino, (lower)aiky], (lower)aikenyl, (lower)alkylthio, carboxy, hydroxy, (lower)aikoxy, (lower)aikoxy(lower)aikyi, halo (lower)aikyi, hydroxy(lower)aikyi, amino(lower)aikyi, (lower) alkylami- no(lower)aikyl, di (lower) a 1 kylamino (lower)alky], (lower)aikylamino, di(lower)alkylamino, carboxy(low- 65 9 GB2194789A 9 er)aikyl, carboxy(lower)alkylamino, carboxy(lower)alkyithio, carbamoyl, N- (iower)alkylcarbamoyl, formylamino, acylamino, acyloxy, phenyl, pyridyl, amidino, guanidino and the like. Where the structure of the heterocyclic ring permits, R9 and R10, taken together, may be an alkylene group containing from 3 to 5 carbon atoms, e.g. propylene.
Examples of combined acyclic/cyclic quaternary ammonio groups include, for example, those 5 of the formulae E) A R12 10 0 / (D H 02 0 //'I R1 2 0 R12 R11 0 WY/H\,,5 15 R12 R12 /R12 20 H 5 N NH R11 \_J R11 RRI 1 (E) R12 (D / R12 25 - N 7 H R11 R11 30 R12 -N N R11 N\__,N-(lower)atkyl RP / H R11 OES)L0 35 and the like, in which R" may be, for example, (lower)alkyi, (lower)alkoxy(lower)aiky], hydroxy(lower)alkyl with the provision that the hydroxy may not be an a-carbon, carboxy(lower)alkyi, amino(lower)aikyl with the provision that the amino may not be on an a- carbon, (lower)aikenyl, halo(lower)aiky], allyl and the like, and R12 may be, for example, hydrogen, hydroxy, halogen, (lower)alkyl, hydroxy(lower)alky], (lower)aikoxy(lower)alky], halo(lower)alkyi, amino (lower)a 1 kyl, (lower)alkoxy, (lower) al kylthio, (lower)alkenyl, amino, (lower)alkylamino, di(lower)alkylamino, acylamino, acyloxy, carbamoyl, amidino(lower)aikyl, phenyl, pyridyi, amidino, quanidino and the like. Preferred quaternary-ammonio groups are those of the formulae R13 0 R16 45 (D 1 H G) N-C -R16/1 - R14 Y 1 R15 50 R17 1 -H G R18 08 R17 0 (D 1 N N 1 N-(CHAand - Y - z aA R20 5,1R21 wherein R 13, R 14 and R 15 are the same or different and are (lower)alkyl, (lower)aikeny], amino(low- 60 er)aikyl with the provision that the amino may not be on an a-carbon, or hydroxy(lower)aikyl with the provision that the hydroxy group may not be on an a-carbon; R16 is hydrogen, (lower)aikyi, (lower)aikoxy, (lower)aikyithio, amino, (lower)aikylamino, di(lower) alkylamino, formylamino, (lower)aikanoylamino, carboxy, hydroxy, carboxy(lower)aikyi, carboxy- (lower)aikyithio, hydroxy(lower)aikyl, halo(lower)alkyi, amino(lower)aikyi, (lower)aikoxy(lower)aikyi, 65 .i GB2194789A 10 carbamoyl or N-(iower)aikylcarbamoyi, or R16 may represent a divalent alkylene group having 3 to 5 carbon atoms; R17 is (lower)aikyi, (lower)alkoxy(lower)aikyi, halo(lower)alkyl, allyi, hydroxy(lower)aikyl with the provision that the hydroxy group is not on the a-carbon, amino(lower)aikyl with the provision 5 that the amino group is not on the a-carbon, or phenyl (lower)alkyl; W" is hydrogen, (lower)alkyl, (lower)aikoxy, (lower)aikoxy(lower)aikyi, (lower)aikyithio, amino, (lower)aikylamino, di(lower)alkylamino, carboxy, hydroxy, carboxy(lower)aikyi, hydroxy(lower)aikyi, amino(lower)aikyi, formy[amino, (lower)aikanoyiamino, carbamoyl or W(lower)alkylcarbamoyl; n is an integer of from 1 to 3, inclusive; Z is CH, or, when n is 2, Z also may be S, 0 or N-R19, in which R19 is hydrogen or (lower)aiky]; and R20 and R21 are the same or different and are hydrogen, (lower)alkyl, (lower)aikoxy, (lower)alkylthio, amino, (lower)aikylamino, di(lower)alkylamino, carboxy, hydroxy, hydroxy(lower)alkyl, amino(lower)aikyi, (lower)aikoxy(lower)alkyi, carboxy(lower)aikyl, carboxy(lower)aikylamino, (lower)aika- noylamino, carboxy(lower)aikanoylamino, carbamoyl or Nflower)alkylcarbarnoyl.
Particularly preferred quaternary ammonio groups are N(iower)aikylpyrrolidinio (and especially N-methylpyrrolidinio), tri(lower)aikylammonio (and especially trimethylammonio), pyridinio, aminopyridinio, formylaminopyridinio, carbamoylpyridinio, amino(lower)aikylpyridinio, carboxypyridinio, hydroxy(lower)alkylpyridinio, N-(iower)alkylcarbamoylpyridinio, (lower)alkylenepyridinio, 2-methylthi- azolio and 2-amino-5-thiazolo[4,5-clpyridinio.
In the compounds of Formula 1, particularly preferred values of R2 are (lower)alkyl (and especially methyl), cycloalkyl containing from 3 to 5 carbon atoms, 1-carboxycycloalk-l-yi containing from 3 to 5 carbon atoms, allyl, propargyl and carboxy(lower)aikyl (and especially 2-carboxyprop- 2) 3) 8) 2-yl). The most preferred compounds of the invention are 1) 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)-2-methoxyiminoacetamidol-3-[3(trimethy lammonio)-1 -pro pen- 1 -y11-3-cephem-4-carboxylate, 7-[2-(5-amino- 1,2,4-thiadiazol-3-yi)-2-methoxyiminoacetamido]-3-[3-(1 methylpyrrolidinio)- 1 - propen- 1 -yl]-3-cephem-4-carboxylate, 7-[2-(5-amino- 1,2,4-thiadiazol-3-yi)-2-methoxyiminoacetamidol-3-[3pyridinio- 1 -propen- 1 -y11-3- 30 cephem-4-carboxylate, 4) 7-[2-(5-amino1,2,4-thiadiazol-3-yi)-2-methoxyiminoacetamidol-3-[3-(3- aminopyridinio)1 -pro pen- 1 -yi]-3-cephem-4-carboxylate, 5) 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)-2-methoxyiminoacetamidol-3-[3-(3formyl aminopyridinio)-1- propen- 1 -yi]-3-cephem-4-carboxylate, 6) -7-[2-(5-amino-1,2,4-thiadiazol3-yl)-2-methoxyiminoacetamido]-3-[3-(3amino methylpyridinio)-1- propen- 1 -y11-3-cephem-4-carboxylate, 7) 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[3-(3carbam oyipyridinio)-1- propen- 1 -y]]-3-cephem-4-carboxylate, 7-[2-(5-amino- 1,2,4-thiadiazol-3-yi)-2-methoxyiminoacetamido]-3-[3-(4carbamoylpyridinio)- 1 - 40 propen- 1 -y11-3-cephem-4-carboxylate, 9) 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(2methyi thiazolio)-1 -pro pen- 1 -y11-3-cephem-4-carboxylate, 10) 7-[2-(5-amino- 1,2,4-thiadiazol-3-yi)-2-methoxyiminoacetamidol-3-[3(2-amino-5-thiazolo[4,5 -cl- pyridinio)- 1 -propen- 1 -y11-3-cephem-4-carboxylate, 11) 7-[2-(5-amino1,2,4-thiadiazol-3-y])-2-methoxyiminoacetamidol-3-[3(4-hydroxymethylpyridin io)- 1 -propen- 1 -y11-3-cephem-4-carboxylate, 12) 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)-2-methoxyiminoacetamidol-3-[3-(3hydrox ymethylpyridinio)- 1 -propen- 1 -y11-3-cephem-4-carboxylate, 13) 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)-2-methoxyiminoacetamidol-3-[3-(4IN-met hyicarbamoyllpyri- 50 dinio)- 1 -propen- 1 -y11-3-cephem-4-carboxylate, 14) 7-[2-(5-amino1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3(2,3-propylenepyridinio)- 1 - propen- 1 -y11-3-cephem-4-carboxylate, 15) 7-[2-(5-amino- 1,2,4-thiadiazol-3-yi)-2-ethoxyiminoacetamidol-3-[3-(4carbamoylpyridinio)- 1 -pro pen- 1 -y11-3-cephem-4-carboxylate, 16) 7-[2-(5-amino- 1,2,4-thiadiazol-3-yi)-2cyclopentyloxyiminoacetamidol3-[3-(4-carbamoylpyri di- nio)- 1 -propen- 1 -y11-3-cephem-4-carboxylate, 17) 7-[2-(5-amino1,2,4-thiadiazol-3-yi)-2-allyloxyiminoacetamidol-3-[3(4-carbamoylpyridinio) - 1 - propen- 1 -y11-3-cephem-4-carboxylate, 18) 7-[2-(5-amino- 1,2,4-thiadiazol-3-yi)-2-propargyloxyiminoacetamido]-3[3-(4-carbamoylpyridi nio)- 60 1 -propen- 1 -yi]-3-cephem-4-carboxylate, 19) 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)2-methoxyiminoacetamidol-3-[3-(4carbox ypyridinio)-1 -pro pen- 1 -y11-3-cephem-4-carboxylate, 20) 7-[2-( 1 5-amino- 1,2,4-thiadiazol-3-yi)-2-ethoxyiminoacetamidol-3[3(4-carboxypyridinio)-2-p ro- pen- 1 -VII-3-cephem-4-carboxylate, St 11 GB2194789A 11 21) 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)-2-methoxyiminoacetamido]-3-[3-(3carbox ymethylpyridinio)1-propen-l-yi]-3-cephem-4-carboxylate and 22) 7[2-(5-amino-1,2,4-thladiazol-3-yl)-2-methoxyiminoacetamido]-3-[3-(4carbox ymethylthiopyridinio)- 1 -propen- 1 -y11-3-cephem-4-carboxylate.
The numbering system utilized herein for the various reactants, intermediates and final products is as follows:
[Roman Numeral]- Arabic Numeral Letter (if appropriate)] [ (if appropriate) The Roman Numeral designates whether the compound is a final product [11 or an intermediate or other reactant [all other Roman Numerals]. The Arabic Numerals and Letters are not used in those instances where the overall class (genus) of compounds is meant.
The Arabic Numeral designates the particular meaning of substituent R2. If the particular R2 15 group contains a carboxyl group which is protected by a conventional carboxyl-protecting group, a---prime-(') is used after the Arabic Numeral to indicate this fact. No---prime-is used if the carboxyl group is unprotected. A---prime-also is used with the generic R2 substituent (i.e. RT) when generically referring to an R2 group containing a protected carboxyl group.
The Letter at the end of the compound number refers to the particular meaning of the quaternary ammonio group G) - N-Q.
For convenience, the Arabic Numerals and Letters assigned to some of the preferred R2 groups and quaternary ammonio groups are set forth below. Arabic Numeral R 2 1 2 3 4 methyl ethyl allyl propargyl cyclopentyl 12
GB2194789A 12 E) Letter A m 1-methylpyrrolidinio 5 0 pyridinio m 2-amino-5-thiaZO10[4t5-clpyridinio D m trimethylamonio E a 3-aminopyridinio 10 p m 3-formylaminopyridinio G m 3-carbamoylpyridinio E m 4-carbamoylpyridinio 15 1 m 3-aminame thylpyr i din io j m 2-methylthiazolio 9 m 3-hydr oxymethylpyri din io 20 L m 4-hydroxymethylpyridinio H m 4-(N-methylcarbamoyl)pyridinio N m 4-carboxypyridinio 25 0 a 2,31-propylenepyridinio p m 3-carboxymethylpyridinio 0 m 4-carboxymethylthiopyridinio 30 In the primary evaluation of the compounds of this invention, the Minimum Inhibitory Concen trations (MIC's) of the compounds were determined by the two-fold serial agar dilution method 35 in Mueller-Hinton agar against 32 strains of test orgaisms in six groups. The geometric means of the MIC's determined in these tests are shown in Table 1.
13 GB2194789A 13 Table 1 i Config. Geometric Mean of MIC (mcg/ml) at Cmpd. double (G+) Ia (G+)-Ib (G-)-Ia (G-)-Ib (G-)-II (G-)-III No. bond (5) (5) (5) (5) (5) (7) I-1A E/Z-1/1 0.26 0.70 0.05 0.15 0.23 2.4 I-1A E/Z-7/1 0.13 0.35 0.029 0.05 0.17 1.4 I-1B E 0.20 0.40 0.016 0.044 0.11 1.6 I-IB EIZ-1/4 0.35 0.80 0.05 0.11 0.35 3.5 I-1c E 0.10 0.20 0.0071 0.033 0.087 3.8 1-1D E/Z-1/1 0.61 1.4 0.10 0.26 0.46 2.4 I-1D E/za10/1 0.30 0.53 0.05 0.076 0.26 1.3 I-1E E 0.20 0.40 0.0094 0.029 0.10 1.4 1-1F E 0.15 0.40 0.0094 0.033 0.099 1.2 I-1G ú 0.20 0.35 0.0094 0.033 O.iO 1.4 I-1H E 0.20 0.40 0.013 0.043 0.10 0.97 1-11 E 0.80 1.6 0.10 0.20 0.69 3.1 I-ii E 0.17 0.35 0.025 0.076 0.15 1.6 1-19 ú 0.35 0.80 0.02 0.044 0.20 3.5 I-1L E 0.26 0.61 0.029 0.088 0.15 2.6 I-1m E 0.35 0.70 0.029 0.10 0.17 2.3 I-1N E/Zw7/1 1.2 1.6 0.013 0.066 0.30 5.7 I-10 E 0.17 0.35 0.029 0.033 0.11 14 I-2H E 0.20 0.40 0.014 0.057 0.15 1.4 1-2N 1.2 2.1 0.016 0.11 0.35 4.7 I-2N z 1.4 3.1 0.044 0.15 0.69 10 1-3H E 0.23 0.40 0.057 0.10 0.52 1.9 I-4H E 0.26 0.46 0.066 0.11 0.60 2.6 1-5 E 0.13 0.40 0.20 0.46 2.1 4.2 I-1p E 0.8 1.6 0.013 0.087 0.34 14 I-10 E 0.7 0.92 0.0095 0.044 0.23 14 14 GB2194789A 14 (G+)-1a Penicillin-sensitive S. aureus (5 strains) (G+)-Ib Penicillin- resistant S. aureus (5 strains) (G-)-]a Cephalothin-sensitive E. coli (2 strain), K1.
pneumoniae (1 strain) and Pr. mirabilis (2 strains) (G-)-Ib Cephalothinresistant E. cok (3 strains) and K1.
pneumoniae (2 strains) (G-)-11 M. morganii (1 strain), Ent. cloacae (2 strains) and Ser. marcescens (2 strains) (G-)-111 Ps. aeruginosa (7 strains) Table 2, below, gives the Protective Dose,, (PD,,) in mice for a number of the compounds of Formula 1 against selected microorganisms. Table 3 gives blood levels of various compounds of Formula 1 upon intramuscular administration of the test compounds to mice at a dosage of 20 15 mg/kg.
Table 2
PD so (znglkg) S. aureus E. Coli P. aeruginosa 25 Copd. No. smith JUhl A9843A I-1B 0.44 0 028 7.7 I-1B 0.65 0.072 NT 30. I-JC 0.22 0.013 NT 30 1-1G 0.96 0.021 5.92 1-1E 0.39 0.015 3.9 1-1j 0.35 0.029 NT 35 1-1K 0.53 NT NT I-1m 0.96 NT NT I-IN 2.0 NT NT 1-10 - 0.26 0.17 HT 40 1-2N 5.0 HT NT NT - Not Testeo 45 j; GB2194789A 15 Table 3
Q 6 Cmpd. No. Cmax T1/2 AUC 5 Imeg/Iftl) (min) (mc-q hr/ml) I-IB 17 21 11 1-1C 21 32 18 I-lD 20 19 11 10 23 16 14 19 16 9.7 I-1K 24 14 14 I-1m 20 23 14 15 1-1N 24 19 18 1-10 28 32 17 1-2N 22 20 12 - 20 1-3E 19 47 25 1-4E 27 22 16 -58 22 32 18 25 In another aspect, the invention relates to processes for the preparation of the compounds of Formula 1. The preferred procedures are shown below in Reaction Schemes la, lb and lc, while an alternative procedure is shown in Reaction Scheme 2. The abbreviation--Ph- represents the 30 phenyl group. Thus, the -CH(Ph)2 moiety is the benzhydry] group, which is a preferred carboxy] protecting group. When R2 contains a carboxyl group, it is desirable to protect the carboxyl group with a conventional carboxyl-protecting group such as the t-butyl moiety. Y represents chloro, bromo or iodo.
16 GB2194789A 16 Reaction Scheme la H2H "S PH-,, CH 2C' COOCHIPh)2 11 N C - COOH 10 Ill 1 N2N-/ S,-' N N', OR2 15 ,-S-,, H C-CONH \ 11 N, 1 H /N \. 0 \", %11 1v OR2 COO CH(Ph)q NaIorKI 25 N--\- C- CONH 1 ' -1, S/ N N 1.11 OR2N CH2I COOCH(PM2 v P(PM3 P(PM3 H C-UNH 5 VG --T- 11 - H2N'\ /N N ' OR2 N 0 v] S 0 [H 2 P(PM3 COOCH(PM2 1 base 45 N C-CONH vII _ S/ N N\ OR2 N CH =P(Ph)3 COOCH(M2 C1CH2CHO 55 N C-CONH 5 11 N N N2N OR2 0 CH=CHCH2C1 COO C H (PN2 il GB2194789A 17 Hal or KI N 'OR2 2 COOMPM2 IX .,, R HN "V (secondary arnine) H - C -CONH 5 / \ n HO ' S/ H N A "OR2 0 CH=CHCHZ-N ', R 111 ' r0OCH(PM2 0 X R 11 v H - - COHN S Y (D 1 1 \ 1 N 0 H, N ' / N H-, OR2 0 CH=CHCH-N=G) COUN(PM2 X11 debtock H C- ".". 5 \\ 11 l 0 \OR2 0 CO9G Q=-N Xl (tertiary amine) Reaction Scheme 'I a shows two alternate means of going from Compound IX to Compound X11. The direct route, utilizing a tertiary amine (Xl), is applicable for the preparation of all compounds of Formula 1. The indirect route, via Compound X, utilizes a secondary amine as reactant, and is quaternized in the following step. The secondary amine WNH may be acyclic (e.g. dimethylamine) or cyclic (e.g. pyrrolidine), and this indirect procedure therefore is suitable for the preparation of compounds of Formula 1 in which the quaternary ammonio group is acyclic or---mixed- acycliclcyclic. This indirect route is not suitable for the preparation of compounds of Formula 1 wherein the quaternary nitrogen is in a fully unsaturated heterocyclic ring (e.g. pyridinio, thiazolio, 2-amino-5- thiazolo[4,5-clpyridinio, and the like).
-1 18 GB2194789A 18 Reaction Scheme lb II C)-[NO 1 10 r"-CH = N 0 N CH2Ct CO0CH")2 Nal K I -CH=N S N 0 XIV DPN EH 21 CO0CH(PM2 P(PN3 CH = N v (E) N (D 0 M2P(Ph)3 CO0CH(N2 base r--CH= \=Y NT--ur-, X111 P(PN3 xv CW(PM3 M CO0CH(M2 19 GB2194789A 19 C1CH2CHO H XVII 0 CH:CH C H2 ú1 COOCH(PM2 or Net 6irard Reagent T H2H):: WCHCH2C1 COOCH (M2 XVIII C-COON 11 H2-'l\S."N N\MR2 V,,, asin scheme la Ill 1 Reaction Scheme lb is a variation of Reaction Scheme la in that the 7- amino group of the starting material (11) is protected as a Schiff base during most of the reaction steps, and the 30 desired 7-side chain acid is added later in the synthesis. Otherwise, the general procedure is similar.
GB2194789A 20 Reaction Scheme lc C H = N S CH=CH-CH2C1 XVI, CO0CH(M2 N a 1 or KI 10 CH = N S N CH=CH-CH21 xix OOCH(Ph S \===v R M N,,, R - "'R1 (secondary arnine) XX 0 CHCHCH2-N' 1 CO0CH(PN2 ' R V Y 35 r",CH = N 5 Y (D C==/):::NT 0 - xxl 0 CH=I"H2 N" CO0CH(M2 9 =- N xl (tertiary arnine) 5 45 H2N N (D - CM=CMCH2 - N= a n 0 coo E) 50 xxll N-acylation 1 with 111 55 N C -CONH S CH=CHCH2-N = a H2N /1, S,, \ OR2 0 coo e 21 GB2194789A 21 Reaction Scheme 1 c is a further variation of Reaction Scheme 1 b. In Reaction Schemes 1 a and 1 b, quaternization of the 3-side chain is the last step, but in Reaction Scheme 1 c the last step is acylation of the 7amino group. The relationship between Reaction Schemes 'I a, 'I b and 'I c is shown in the following flowchart.
22 GB2194789A 22 N2N ','S la N \b CH2C1 1 c CO0CH(PM2 1 N---Trc-CONH OCH A I H - H2N S.A OR2 0 CH2 C' XIII CH2CI 10 IV COOCH(Ph)2 COOCH(Ph)2 la Flb Ic 15 N--TrC-CONHT _7-N-AAtation H2NN lb 0 CPCHCHP 0 1PN b s A N OR2 N Vill la 1b Compound 1 CO0CH(P4) Duaternization Debtocking Z-N-Acylation lc =CHCH2C1 xVill CO0CH(M2 lc Guarternization Deblocking N N 5 (D A CH=CHCHiNZO OPH COOE) xxII 1 23 GB2194789A 23 In Reaction Schemes 1 a, lb and 1c, the benzhydryl group was shown as the preferred carboxyl-protecting group. It will be appreciated by those skilled in the art that other carboxylprotecting groups, well-known in the art, may be used. The acylating said III may be used in the form of a derivative such as its acid halide, activated ester, mixed acid anhydride, etc., all of which are well-known in the art. We prefer to utilize it in the form of its acid chloride. Acylating acid III also may have its amino group protected by any of the common amino-protecting groups, e.g. N- trityl, N-formyl, or the like. The base used to convert the phosphonium iodide (VI or XV) to give the phosphorylide (VII or XVI) may be NaOH, Na2CO31 IRA-410 (OH-) resin, IRA(CO,=) resin, or the like, or a mixture thereof. The chloroacetaldehyde used to convert the phosphorylide Vil to the 3-chloropropenyl-3-cephem compound Vill (or Compound XVI to Com- 10 pound XVII) may be the commercially available 40-50% aqueous solution, a distilled solution (e.g. 70%) or the anhydrous aldehyde.
We have found that Compound VIII prepared from Compound VII (Scheme 1a) typically had a Z:E ratio of about 2:1 at the propenyl double bond. Compound Vill prepared from Compound XVIII (Scheme lb), on the other hand, typically was almost exclusively the Z isomer. The difference may not be in the route used, but in the conditions utilized in the Wittig reaction (VII to Vill or XVI to XVII). We have also found that the use of an appropriate silyl reagent such as N,O-bis(trimethylsilyl)acetamide in the Wittig reaction (Vil to Vill in Scheme la and XVI to XVII in Scheme 1b) caused improvement of the yields and purity of Vill and XVIL The reaction is preferably carried out with 2-5 equivalents of the silyl reagent. When the chloropropenyl ce- 20 phem (VIII) was reacted with Nal in acetone to give the iodopropenyl cephem (IX), the double bond in the propenyl group was isomerized from Z to E during the iodination. A short reaction period retained the configuration of the parent Compound VIII to a large extent, while a long reaction period gave primarily the E isomer of Compound IX. However, an excessive reaction time at high temperature gives a lower purity compound IX. We find that about 10 minutes at 25 25'C and 2 hours at 5'C gives pure IX in good yield. When utilizing Reaction Scheme Ic, we have found that, when iodinating compound XIV with Nal, a purer compound is obtained if the acetone solution is diluted with CCI, when iodination is essentially completed, and the isomeriza tion portion of the reaction is conducted in the acetone-CC1, mixture. When iodination of the chloropropenyl cephem (XVII) to the iodopropenyl cephem (XIX) was performed with KI in DMF, 30 the isomerization of the double bond from Z to E proceeded as fast as the iodination did. The whole reaction completed within 45 minutes at room temperature to give pure XIX without dilution with CCI, in the coure of the reaction.
Compound XII normally was deblocked without purification, and the final product (1) was purified by reverse phase column chromatography utilizing a glass column containing the pacing 35 removed from a Waters' Associates PrepPAK-500/Cl, cartridge.
24 GB 2 194 789A 24 Reaction Scheme 2 N c - COHN 5 -HN J, S.-' H H \OR2 0 H CH=CH-CH21 Mill 11 _T( COOCH(M2 0 1 1 N. C -COHN s 11- 1 15 R14Nk s,'N H,, WCH-CH2I xxlv OR2 0 COOCH(Phh 20 0 1 e N C- CONH 1 IN -CH2N =Q xxv p H=CH Rl-H N 0 R2 0 ' COOCH"12 Reduction deblock H p S-CONW 1,,,S G) 1 G) N -N Rl -MN '-OR2 0 CH=CH-%N=_0 xw COOMPM2 H E- CONH,-S 11 11 1 S" H N,'OR2 -N G IKH2NaQ 1 H2N 0 cooe 50 GB2194789A 25 Reaction Scheme 2, shown in brief outline form above, is similar to Reaction Scheme 'I a except that Compound XXIII (equivalent to Compound W of Reaction Scheme la) is converted to its S-oxide prior to quaternization. Compound XXV is subsequently reduced, and the remainder of Reaction Scheme 2 is as Reaction Scheme la. In Reaction Scheme 2, it is preferred to protect the amino group of the 7-side chain with a known amino-protecting group such as the 5 trityl group.
The acylating acids of Formula Ill herein are either known compounds or are readily prepared by published procedures. European Patent Specification 7,470 published October 12, 1983 (application published February 6, 1980) exemplifies the preparation of compounds of Formula Ill wherein R2 is methyl, ethyl, propyl and isopropyl. U.S. Patent 4,390,534, referred to in the Prior 10 Art section, above, exemplifies the preparation of a wide variety of compounds of Formula Ill wherein R2 is, for example, cyclopentyl, 2-cyclopenten-l-yi, allyl, 2- propynyl, 1-tert. butyloxycar bonyl-l-methylethyi, 1-tert. butyloxycarbonyi-l-cyclopentyi, 1- ethoxycarbonyi-l-methylethyi, tert.
butyloxycarbonyl methyl, 1-tert. butyloxycarbonyi-2-methylpropy], trityl, and the like.
Compound 11 herein (7-amino-3-chloromethyi-3-cephem-4-carboxylate), used as a starting ma- 15 terial in Reaction Schemes la, 1b and lc, is a known compound.
The tertiary amines of Formula XI (and the secondary amines RR'NH) utilized in preparing the quaternary ammonio compounds of this invention are either known compounds or are readily prepared by those of ordinary skill in the art. Many of the amines are commercially available.
The present invention also provides a process for the preparation of compounds of the 20 formula H -IF-[ -CONH 5 A s,'N 11 --)-:N, G R1 HN N ' OR2,,e CH=CH-[92-N-=Q 1 wherein R' is hydrogen or a conventional amino-protecting group, R2 is hydrogen, a straight or 30 branched chain alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl or cycoalkenyl ring containing from 3 to 6 carbon atoms, or a group of the formula R4 C COON 35 C' C-s C-0 -E- CH=m-0 -C - S or R 0 C 40 1 R5 in which R3 is hydrogen, (lower)aikyl or carboxyl, X is halogen, hydroxy or (lower)alkoxy, and R 4 and R5 are each independently hydrogen, methyl or ethyl, or R4 and R5, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 50 carbon atoms, and 0 -N=-Q is a quaternary ammonio group, and nontoxic pharmaceutically acceptable salts and physiologi- 55 cally hydrolyzable esters thereof, which process comprises reacting a compound of the formula (0) m C - CONH 3 B2HN-S/ N H ', OR21 1 N CH21 COOB1 26 GB2194789A 26 wherein R 2' is the same as R2 or is a group of the formula COOBI 5 R4 'I or -C- coo B' 1 R5 in which X, R4 and R5 are as defined above, 131 is a conventional carboxyl-protecting group, B2 is hydrogen or a conventional amino- protecting group, Z is chloro, bromo or iodo, and m is zero or one, with a tertiary amine Q=-N (or sequentially with a secondary amine RR'NH and a compound of the formula R"Z), and, if m is 1, reducing the sulfoxide by conventional means, and subse15 quently removing all blocking groups by conventional means.
The present invention also provides a process for the preparation of compounds of the formula H c CONN - (D -H - - CKH CH2- H 0 11 11 H H OHN AS. \ OR2 1 coo wheren R' is hydrogen or a conventional amino-protecting group, R2 is hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring containing from 3 to 6 carbon atoms, or a group of the formula R4 1 R, 4 COON 30 -CCH=CH-RJ -C- c=c-0 or 1 R 5 AS 35 C 1 RS -C- COON 40, in which R3 is hydrogen, (lower)aikyl or carboxyl, X is halogen, hydroxy or (lower)aikoxy, and R4 and R5 are each independently hydrogen, methyl or ethyl, or R4 and R5, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 45 carbon atoms, and 0 - -Q N= is a quaternary ammonio group, and nontoxic pharmaceutically acceptable salts and physiologically hydrolyzable esters thereof, which process comprises acylating a compound of the formula H2H S H G) 0/Til 1H=CHCH2-M=Q 00 E) XX11 with an acid of the formula 27 GB2194789A 27 N - C-COON - -7N 82 HN 'N' , S/ N \9R2' or with an acylating derivative of said acid, wherein RT is the same as R2 or is a group of the formula Ill COOB 1 R4 10 1 or - c - coo B1 1 X R5 15 in which X, R4 and R5 are as defined above, B' is a conventional carboxyl- protecting group and B2 is hydrogen or a conventional amino-protecting group.
The reactions are carried out in a non-aqueous organic solvent such as dimethyl sulfoxide, hexamethylphosphoramide, methylene chloride, chloroform, ethyl ether, hexane, ethyl acetate, 20 tetrahydrofuran, acetonitrile and the like, or mixtures of such solvents. The reactions are conveni ently carried out at a temperature of from about - 1 O'C to about + 50'C; we normally prefer to conduct the reactions at room temperature. During the quaternization step, at least one mole of the tertiary amine should be used per mole of Compound IX, XlX, XXIII or XXIV; we normally prefer to utilize from about 25% to 100% excess of the tertiary amine.
Carboxyl-protecting groups suitable for use as B' in the above reactions are well-known to those skilled in the art and include aralkyl groups such as benzyi, p- methoxybenzyi, pnitrobenzyl and diphenyImethyl (benzhydryl); alkyl groups such as t-butyl; haloalkyl groups such as 2,2,2 trichloroethyl, and other carboxyl protecting groups described in the literature, e.g. in U.K. Patent 1,399,086. We prefer to utilize carboxylprotecting groups which are readily removed by treat- 30 ment with acid. Particularly preferred carboxyl-protecting groups are the benzhydry] and t-butyl moieties.
Amino-protecting groups suitable for use as B2 are also well-known in the art, and include the trityl group and acyl groups such as chloroacetyl, formyl and trichloroethoxycarbonyl. Amino- protecting groups which are readily removed by treatment with acid, e.g. the trityl group, are 35 preferred.
When the cephalosporin nucleus is utilized in the form of the 1 -oxide (m= 1), the 1 -oxide is prepared by known procedures such as oxidation with m-chloroperbenzoic acid, peracetic acid, sodium tungstate, etc. The 1-oxide subsequently may be reduced by known procedures, e.g.
reduction of the corresponding alkoxysulfonium salt with iodide ion in an aqueous medium. The 40 alkoxysulfonium salt itself is readily prepared by treatment of the 1- oxide with, for example, acetyl chloride.
In another aspect, this invention relates to novel intermediates of the formula H I-CONN 5 45 \\ H H K, MVIII M2H S/ 'OR1 OPCH:,-CHCH2Z wherein Z is chloro, bromo, or iodo, R2 is hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring containing from 3 to 6 carbon atoms, or a group of the formula 28 GB2194789A 28 R4 4 - COON -c- CH=CH-0 -c-c=c-o or s C -C- COON 1 0 0 in which R3 is hydrogen, (lower)aikyl or carboxyl, X is halogen, hydroxy or (lower)alkoxy, and R4 15 and R5 are each independently hydrogen, methyl or ethyl, or R4 and R5, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, and salts and esters thereof. Also included are compounds of Formula XXVIII in which the amino and/or carboxyl groups are protected by conventional amino- protecting or 20 carboxyl-protecting groups. In still another aspect, this invention relates to novel intermediates of the formula P23 R24 CH=N 5 25 MIX R25 0 rt ChCHCH2Z COOR22 30 wherein R22 is hydrogen or a conventional carboxyl-protecting group, and R23, R24 and R25 are the same or different and are hydrogen, hydroxy, (lower)alkyl or (lower)aikoxy, or a salt, solvate, hydrate or ester thereof.
In still another aspect, this invention relates to novel intermediates of the formula N2N H 5 - (D - 0 ', CH=CH- C- N = 0 00e XXII wherein -ON=-Q is a quaternary ammonio group; or a salt, ester, solvate or hydrate thereof.
As used herein, the terms acylamino and acyloxy refer to an acylated amino or acylated hydroxy group in which the acyl moiety is (lower)aikanoyl (e.g. formyi, acetyl, propionyl, butyryl, isobutyryl, isovalery], etc.), aroyl (e.g. benzoyl, etc.), (lower)aikaneshuifonyl (e.g. mesyl, ethane sulfonyl, etc.) or aryIsulfonyl (e.g. benzenesulfonyl, tosyl, etc.).
As used herein, the terms "(iower)aikyi", "(iower)aikoxy", "(iower)aikyithio" (or the like) mean straight or branched chain alkyl, alkoxy, alky[thio (or the like) groups containing from 1 to 6 50 carbon atoms, inclusive. Similarly, the terms (lower)aikenyl and (lower)aikynyl mean alkenyl or alkynyl groups containing from 2 to 6 carbon atoms.
Example 1
N C-CON H 5 55 N WCH-%-N H2H 0 n_ c] OCH3 cod,, 7 60 CH3 1AA Z/E=1/1 7-[2-(5-Amino- 1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(1methylpyrrolidino)- 1-propen l-yll-3-cephem-4-carboxylate (1-1A) 29 GB2194789A 29 To a solution of diphenyimethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)-2- methoxyiminoacetamidol3-(3-iodo-l-propen-l-yi)-3-cephem-4-carboxylate (]X-1) (Z/E=2/1, 150 mg, 0.21 mmole) in ethyl acetate (2 ml) was added a solution of 1-methylpyrrolidine (36 mg, 0.42 mmole) in ethyl acetate (1 ml) in one portion with stirring. The mixture was stirred for 15 minutes and diluted with isopropyl ether (10 mi) to form a precipitate, which was collected by filtration. A mixture of the 5 solid (130 mg), formic acid (1 mi) and concentrated HO (0.1 mi) was stirred at room tempera ture. After 1 hour, the reaction mixture was concentrated under reduced pressure, diluted with water (20 mi) and filtered. The aqueous solution was passed through a reverse phase column (the packing of PrepPAK-500/C1. cartridge, 100 m]), eluting with water and 10% CH30H. The desired fractions were collected, and concentrated in vacuo to a small volume and freeze-dried 10 to give 13 mg (12%) of the title compound (MA) (Z/E=1/1), melting at >2WC (dec.).
KBr V cm-1 3400, 1760, 1660, 1610.
max Phosphate buffer (pH 7) 1% UV: A rim (E 236 (372), 288 (322).
max 1 cm 20 NIVIR:.5 D20 2.31 (4H, m, 3.12 (3H, s, N-CH,), 3.6 (5H, ppm N 30 2-H & -'), 3.79 (1H, s, 2-H), 4.1 (2H, d, J8, C/4,N), 4.2 (3H, s, OCH3), 5.36 (1H, d, J=4.5, 6-H), 5.95 (3H, m, 7-H & 3-CH=C", 6.66 (1/2H, d, J=10, 3-CH cis), 7.0 (1/2H, d, J=16, 3-CH trans). 35 Example 2
40. N 11 E-CONH,'S N 71 - N17 M2N_Q',S,'N N\ 0.1 _ CH7-CH"CH2 OCH3 C00e \=7/ 1-113 E 7-[2-(5-Amino1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3- pyridinio- 1-propenl -y11-3ce phem-4-carboxylate (1- 18) A mixture of diphenyimethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)-2- methoxyiminoacetamido1-3- (3 iodo-l-propen-l-yi)-3-cephem-4-carboxylate (IM) (E, 716 mg, 1 mmole), pyridine (158 mg, 2 mmoles) in dimethyisulfoxide (DMSO) (1 m]) was stirred for 1 hour at room temperature. To the 50 mixture was added p-thy] acetate (20 mi) to precipitate a solid (620 mg), which was added to formic acid (6 mi) containing sodium bisulfite (60 mg). The mixture was stirred for 30 minutes at 4WC and concentrated to dryness. The residue was dissolved in H20 (40 mi) and some insolubles were removed. The aqueous solution was charged on a column of reverse phase (PrepPAK-500/C,, 100 ml) eluting with H20 (300 mi) and 5% aqueous CH,OH (800 mi), and the 55 eluate was monitored by uv (254 nm) and HPLC. The fractions (5% aqueous CH,,OH) containing the desired product were combined, concentrated to a small volume and lyophilized to yield 40 mg (8%) of the title compound (1-113), melting at >20WC (dec.).
KBr IR V cm-1 3350, 1760, 1660, 1600.
max GB2194789A 30 Phosphate buffer (pH 7) UV: A max D20+DMSO-cl, 1% nm (E 240 (352), 258 (366), 1 cm 267 (279), 290 (469).
NMR: (5 3.74 (2H, br-s, 2-11), 4.20 (3H, s, OCH3), ppm 5.92 (1H, d, J=4.5, 7-H), 6.15 (11-1, m, 3-CH=Cl-4, 7.04 (1H, cl, J=16, 3-CH trans), 10 8.2 (2H, m, Py-HU), 8.62 (11-1, m, Py-H4), 8.97 (2H, m, Py-H2,j.
Example 3
15 C CONH N N - OCH3 COOeCH=CH-CH2- NO 1-113 Z/E=4/1 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3pyridinio -l-propen-l-yll-3-ce- 25 phem-4-carboxylate (/- 1B) The chloropropenyl compound, diphenyimethyl 7-[2-(5-amino-1,2,4thiadiazol-3-yi)-2-methoxyiminoacetamidol-3-(3-chloro-1-propen-l-yi)-3-cephem-4-carboxylate (V111-1) (Z, 937 mg, 1.5 mmoles) was added to a stirred solution of pyridine (237 mg, 3 mmoles) in DMSO (3 mi) containing Nal (11 mg, 0.075 mmole). The mixture was allowed to stand overnight at room temperature in the dark. The mixture was diluted with ethyl acetate (30 mi) to separate the precipitate which was then collected by filtration, washed with ethyl acetate (10 mi) and dried to give 350 mg of the blocked product. The precipitate was treated with formic acid (3.4 mi) containing sodium bisulfite (34 mg) for 30 minutes at 4WC. After removal of the formic acid, the residue was purified by reverse phase column chromatography (packing of PrepPAK-500/C1, 35 cartridge, 100 mi) by eluting with 5% aqueous CH,OH. The fractions containing the desired product were combined on the basis of HPLC analysis, evaporated under reduced pressure and lyophilized to give 41 mg (5.5%) of the title compound (1-113) (Z/E=4/1). Mp.>20WC (dec.).
IR KBr V cm-1 3300, 1760, 1660, 1600.
max Phosphate buffer (pH 7) UV: A max 1% nm (E 237 (386), 250 (377), 1 cm 258 (369), 265 (347), 280 (311).
D20 NMR: (5 3.45 & 3.76 (each 1 H, d, J= 16, 2-H), 4.18 (3H, s, ppm OCH3), 5.34 (3H, m, CH=CH-CH, & 6-1-1), 5.92 (11-1, cl, J4.5, 7-H), 6. 58 (4/5H, cl, J=11, 3-CH cis), 7.03 (l/5H, d, J=16, 3-CH trans), 8.12 (21- 1, m, PY-H,,J, 8.56 (1H, m, Py-H4), 8.82 (2H, m, Py-H2,6).
Example 4 r-C-LONH 5 H ' it 49 (D ii,-IN N \ P pCH=CHCH27H - H N2N 5" U3 0 COOG) aS"O"NH2 1-1 C E "i 45 - GB2194789A 31 7-[2-(5-Amino1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(2amino-5-thiazolo[4,5 -clpyri- diniol-1-propen-l-yll-3-cephem-4-carboxylate (1-1Q A stirred solution of diphenyimethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)- 2-methoxyiminoacetamidol-3-(3-iodo-l-propen-l-yi)-3-cephem-4-carboxylate (IX-1) (E isomer, 714 mg, 1 mmole), 2 aminothiazolo[4,5-c]pyridine [prepared according to the procedure of T. Takashashi et al., Pharm.
Bull (Japan), 2, 34 (1954)] and dry DMSO (1 mi) was kept for 1 hour at room temperature. To the reaction mixture was added ethyl acetate (20 mi) to give a yellow powder (710 mg). Formic acid (7 mi) and sodium bisulfite (70 mg) were added to the powder (700 mg), and the mixture 10 was stirred for 30 minutes at 40-45'C. After evaporation, the residue was triturated with H,0 (40 m]). Insolubles were filtered off, and the filtrate was chromatographed over a reverse phase column (PrepPAK-500/C1,-, 100 m]), with H20 and 10% CH,OH as eluant. The fractions contain ing the desired product were combined, and the solvent was removed under reduced pressure.
Lyophilization gave the desired product (MC) as a colorless amorphous powder of the E isomer. 15 Yield 110 mg (19%). Mp. >200'C (dec.).
IR LIV:
KBr V cm-1 3300, 1760, 1660, 1630, 1600.
max Phosphate buffer (pH 7) A max DiVISO-c16+1D20 1% nm (E 245 (499), 285 (286).
1 cm NIVIR: (5 3.86 (3H, s, OCH3), 4.98 (11-1, cl, J=4.5, ppM 6H), 5.2 (2H, m, CH=CH-CH,), 5.57 (1H, m, 30 3-CH=CM, 5.96 (1H, m, 7-1-1), 7.16 (11-1, cl, J = 16, 3-CH trans), 8.36 & 8.45 (each 1 H, d, J=7, Py-H), 8.92 (11-1, s, Py-H).
Example 5 35
H I-CONH S 11 11 F 0, M2N',-5 'N H\ f., CH=CH-CH2-N'C3)3 OCH3 0 G 40 coo 1-11) Z/E=1/1 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidoj-3-(3trimethyl ammonio-l-propen-l- 45 yl)-3-cephem-4-carboxylate (/- 1D) To a solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2methoxyiminoacetamido]- 3-(3-iodo-l-propen-1-yi)-3-cephem-4-carboxylate (IX-1) (Z/E=2/1, 490 mg, 0.68 mmole) in ethyl acetate (14 ml) was added a 0. 1 M trimethylamine solution in ether (13.6 ml) in one portion.
The mixture was stirred for 10 minutes and evaporated to dryness, and the residue was triturated with ether (20 ml). The resulting solid (490 mg) was added to trifluoroacetic acid (0.2 ml) containing one drop of anisole. After 1.5 hours' stirring, the mixture was evaporated to dryness under reduced pressure and the residual oil was triturated with ether (20 ml). The resulting precipitate was collected by filtration and dissolved in H20 (20 ml). Some insolubles were removed, and the aqueous solution was eluted on a C,,, reverse phase column (the packing 55 of PrepPAK-500/C,, cartridge, Waters' 30 ml) using, water as eluant. Fractions containing the desired compound were combined and concentrated to a small volume and Iyophilized to afford 30 mg (9.2%) of the title compound (I-11D) (Z/E=1/1) as a colorless amorphous powder, melting at >150'C (dec.).
KBr IR V cm-1 3300, 1770, 1670, 1605.
max 32 GB2194789A 32 LIV: A E) mDle 6 Phosphate buffer (pH 7) - max 1% nm (E 236 (389), 287 (343).
1 cm D20 NMR: 3 3.45 & 3.7 (1 H, cl, J = 16, 2-1-1), 3.81 (1 H, s, 2M), pprn 0 4.1 (2H, cl, J=8, -CHN), 4.21 (3H, s, OCHJ, 5.39 (1H, cl, J=4.5,6-H), 5.95 (2H, m, 3-CH=CH & 7-H), 6.61 (l/2H, d, J = 11, 3-CH cis), 7.05 (l/2H, cl, J=16, 3-CH trans).
N C_ CONN - - 5 1 CKNIN2-H N2N \OCH3 ^0 IAE E M2 9 1 7-[2-(5-Amino1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(3- aminopyridinio)1-propen- 1 yll-3-cephem-4-carboxylate fl- 1E) Diphenyimethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)-2- methoxyiminoacetamido1-3-(3-iodo-1 -pro pen- 1 -yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) was added to a stirred solution of 3-aminopyridine (188 mg, 2 mmoles) in DIVISO (1 mi). The mixture was stirred for 1 hour and diluted with ethyl acetate (20 m]). The resulting precipitate was collected by filtration, washed with ethyl acetate and dried to give 520 mg of yellow powder. A mixture of the powder (500 mg), formic acid (5 m]) and sodium bisulfite (50 mg) was stirred for 30 minutes at 4WC. The 30 mixture was concentrated in vacuo, dissolved in H,0 (40 mi) and filtered to remove insolubles.
The aqueous solution was chromatographed on a column of reverse phase (packing of PrepPAK 500/C,, 100 m]), with 7.5% aqueous CH,OH elution. The fractions containing the desired compound were evaporated and lyophilized to give the title compound (IAE melting at >l8WC (dec.).
KBr IR V cm-1 3400, 1765, 1675, 1620, 1600 max UV: A Phosphate buffer (pH 7) 1% max nm (E) 246 (403), 290 (468).
1 em D20 NIVIR: (5 3.72 (21-1, m, 2-H), 4.14 (31-1, s, OCH3), 5.35 (3H, m, ppm 6-H & CH=CH-CH,), 5.9 (11-1, d, J=4.5, 7-H), 6.1 (1H, m, 3-CH=CM, 7.05 (1H, d, J16, 3-CH, trans), 8.1 (11-1, m, Py-HJ, 8.54 (11-1, br-s, Py-H6), 8.68 (1H, m, (Py-HJ, 9.4 (1H, m, Py-H2), (7 mg, 1.4%), Treatment of IX-1 (716 mg, 1 mmole) with 3-t-butoxycarbonylaminopyridine (324 mg, 2 55 mmoles) by a procedure similar to that described above gave 12 mg (2.3%) of 1-1E.
Example 7
1-1 E Z/E=1/1 -T- 1 (D 0 N CH=CHCH21 coo 0 NH2 33 GB2194789A 33 7-[2-(5-Amino- 1,2,4-thiadiazol-3-yi)-2-methoxyiminoacetamido]-3-[3-(3amino- 1-pyridinio)- 1-propen- 1-yl]-3-cephem-4-carboxylate (I-1E) A mixture of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)-2methoxyiminoacetamido]-35 (3-iodo-l-propen-1-yi)-3-cephem-4-carboxylate (IX-1) (Z/E=2/1, 500 mg, 0.7 mmole) and 3aminopyridine (66 mg, 0.7 mmole) in dimethylsulfoxide (1 ml) was stirred for 20 minutes at room temperature. The mixture was diluted with ethyl acetate (10 ml) and ether (10 ml), and the resulting precipitate was collected by filtration, washed with ether (10 ml) and dried. The quaternized salt was dissolved in formic acid (3 ml) containing concentrated HCI (0.3 ml) and stirred for 1.5 hours at room temperature. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in 2% HCI (10 ml) and filtered. The aqueous layer was chromatographed on a reverse phase column (PrepPAK-500/C,,, 100 ml). After washing with water (500 ml), the column was eluted with 5% aqueous CH30H. The fractions containing the title compound were combined, concentrated in vacuo and freeze-dried to give 15 mg (4.2%) of the title compound (I-1E) (Z/E=1/1) as a colorless amorphous powder. Mp. >160'C 15 (dec.).
KBr IR: V cm-1 3400, 1765, 1675, 1620, 1600.
max 20 Phosphate buffer (pH 7) 1% UV: A nm (E 244 (434), 287 (333).
max 1 cm 25 DIVISO-cl,+D20 NIVIR: 6 3.73 (2H, m), 4.14 (3H, s, OCH.), 5.35 (3H, 13pm m, 6-H & CH=CH-CH2), 6.0 (2H, m, 7-H & 30 3-CH=CM, 6.6 (l/2H, d, J= 11, 3-CH cis), 7.05 (l/2H, d, J=16, 3-CH trans), 8.08 (1H, m, Py-Hj, 8.6 (2H, m, Py-H4,6), 9.4 (1H, m, Py-H2).
35 Example 8
11 1- CONH N2Nk 5---HH 'GCH3 H n- 1-1F E 0 coo (9) Z 7-[2-(5-Amino1,2,4-thiadiazol-3-yl)-2methoxyiminoacetamidol-3-[3-(3formylaminopyridinio)- 1-propen-l-yll-3-cephem-4-carboxylate (P1F) A mixture of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)-2methoxyiminoacetamidol-3(3-iodo-l-propen-l-yi)-3-cephem-4-carboxylate (IM) (E, 716 mg, 1 mmole) and 3-formylamino- pyridine [prepared according to the procedure of N. Enomoto et al., Bull. Chem. Soc. Japan, 45, 50 2665 (1972)] (244 mg, 2 mmoles) in DMSO (2 mi) was stirred at room temperature for 1 hour, and poured into ethyl acetate (200 mi). The precipitate was collected by filtration, washed well with ethyl acetate and dried. A mixture of the quaternized salt (500 mg) and sodium bisulfite (50 mg) in HCOOH (5 m]) was stirred at 40-50'C for 80 minutes and evaporated to dryness in vacuo. The residue was dissolved in water (40 mi), neutralized with NaHC03 and then filtered to 55 remove insoluble material. The clear filtrate was chromatographed on a reverse phase column, PrepPAK-500/C,. (100 mi), with water and 5% CH30H, 10% CH30H, 20% CH30H and 30% CH,OH. The fractions containing the desired compound were combined, concentrated in vacuo and lyophilized to give 16 mg (2.9%) of the title compound (1AF) (E) as a tan powder. Mp.
>l7WC (dec.).
KBr V cm-1 3340(br), 1760, 1670, 1620(br), 1590.
max 34 GB2194789A 34 UV: A max Phosphate buffer (pH 7) D20+NaHCO, NIVIR: 3 ppm Example 9
1 % nm (E) 218 (428), 248 (362), 1 cm 290 (474).
3.68 (2H, br, 2-H), 4.15 (3H, s, OCH), 5.91 (1H,d,J=4.5,7-H), 6.25 (1H, m, CH=CH-CH,), 6.98 (1 H, d, J= 16, 3-CH trans), 8.8-7.9 (4H, m, Py-H), 9.38 (1H, br, NHCHO).
H C - CONH 5 + 2TN 11 H2M 5., N H 1.1. OCHIH ^ CH=CHCH2 i-1G E NH2 7-[2-(5-Amino- 1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(3carbamoylpyridinio)- 1-pro pen- l-yil-3-cephem-4-carboxylate (1-1G) To a solution of diphenyimethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-y])-2methoxyiminoacetamidol- 25 3-(3-iodo-l-propen-l-y])-3-cephem-4-carboxylate (IM) (E, 716 mg, 1 mmole), in DIVISO (2 mi) was added nicotrinamide (244 mg, 2 mmoles), and the mixture was stirred at ambient tempera ture for 1.5 hours and poured into ethyl acetate (200 m]) with stirring. The resulting precipitate was collected by filtration. The quaternized salt (500 mg) was dissolved in HCOOH (5 mi) in the presence of sodium bisulfite (50 mg), and the mixture was heated at 40- 50'C for 40 minutes, with stirring, and evaporated to dryness. The residue was dissolved in water (40 m]) and an insoluble solid was filtered off and washed with a small amount of water. The filtrate and wash were combined and chromatographed on a reverse phase column, PrepPAK- 500/C1, (100 mi).
After elution with water and 5%, 10% and 20% aqueous CH,OH, successively, the fractions containing the desired material were combined, concentrated in vacuo and freeze-dried to yield 21 mg (3.8%) of the title compound (1-1G) (E) as a yellow powder. Mp. >l7WC (dec.).
IR V KBr cm-1 3340(br), 1760, 1670, 1600.
max UV: A Phosphate buffer (pH 7) nm (El") 235 (326), 274 (sh, max 1 CM 405), 290 (446).
NMR: 6 D20+NaHCO3 3.68 (2H, br, 2-H), 4.15 (3H, s, OCH3), 5,32 PPM (1 H, d, J = 4.5, 6-H), 5.45 (1 H, d, J = 7, 45 CH=CH-CH2), 5.88 (1H, d, J=4.5, 7-H), 6.15 (1H, d-t, J=16 & 7, 3-CH=C", 7.00 (1H, d, J=16, 3-CH trans), 8.23 (1H, m, Py-H,), 9.03 (2H, m, Py-H4&6), 9.34 (1H, s, Py-Hj.
50 Example 10
CONN ) 11 1 E) 7 j -IN N N N S 0 CH=CHCH21 CON H Y_ 2 OCH5 00 1-11-1 E 7-[2-(5-Amino- 1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-(3-(4carbamoylpyridinio)- 1-pro pen- l-yll-3-cephem-4-carboxylate (/- M) To a stirred solution of diphenyimethyl 7-[2-(5-amino-1,2,4-thiadiazol-3yi)-2-methoxyiminoacetamidol-3-(3-iodo-l-propen-l-y])-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) in dry DIVISO (2 mi) was added isonicotinamide (244 mg, 2 mmoles). The mixture was stirred at room temperature for 1 hour and then poured into ethyl acetate (200 mi). The resulting precipitate was collected by filtration, washed well with ethyl acetate and dried. A stirred mixture of the 65 GB2194789A 35 quaternized material (400 mg) and sodium bisulfite (40 mg) in HCOOH (4 ml) was heated at 40-50'C for 1 hour, and evaporated to dryness under reduced pressure. The crude solid was dissolved in water (40 ml). After filtration of an insoluble material, the filtrate was chromato graphed on a reverse phase column (packing of PrepPAK/C,,,, 100 ml) using water and 5%, 10%, 20% and 30% aqueous CH,OH as eluant. The fractions containing the desired compound 5 were combined, evaporated and Iyophilized to give 21 mg (3.8%) of the title compound (I-1H) (E) as a pale yellow powder. Mp. >180C (dec.).
: V K13r cm-1 3340(br), 1760, 1670, 1600.
max 10 UV: A Phosphate buffer (pH 7) nm (El) 222 (362), 285 (452).
max 1 cm NMR: 6 D20+NaHCO3 3.68 (2H, br, 2-H), 4.15 (3H, s, OCHO, 5.33 15 PPM (11-1, d, J=4.5, 6-H), 5.46 (2H, d, J=7, CHCH-CH2), 5.90 (1H, d, J=4.5, 7-H), 6.17 (1H, d-t, J=16 & 7, 3-CH=C", 7.02 (1H, d, J = 16, 3-CH trans), 8.43 & 9.09 (each 2H, d, J = 7, Py-H). 20 Example 11
N N N k 5.00 1.1 1- CH CH CH2- C H2H OCH3 0 C00e 1-11 E CH2NH2 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(3aminom ethylpyridinio)-1- 30 propen-l-yl)-3-cephem-4-carboxylate (1-11) A mixture of the diphenyimethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2methoxyiminoacetamidol- 3-(3-iodo-l-propen-l-yi)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) and 3-(t-butyloxy carbonylaminomethyi)pyridine (516 mg, 2 mmoles) in DIVISO (2 m]) was stirred at ambient temperature for 30 minutes. The mixture was poured into ethyl acetate (200 m]), and the 35 precipitate was collected by filtration, washed well with ethyl acetate and dried. A mixture of the quaternized salt (500 mg), sodium bisulfite (50 mg) in HCOOH (5 mi) was stirred at 40-50"C for minutes and evaporated to dryness under reduced pressure. The residual solid was dissolved in water (40 M), and the mixture was neutralized with Nal---1C03. Insoluble material was filtered off, and the filtrate was chromatographed on a reverse phase column (packing of PrepPAK-500/C, cartridge, 100 m]), eluting with water, 5%, 10%, 20% and 30% aqueous CH30H, successively. The fractions containing the desired compound were combined, evaporated and Iyophilized to provide 10 mg (1.8%) of the title compound Q-11) (E) as a tan powder.
IR: V KBr em-' 3380(br), 1760, 1650(sh), 1620(sh).
max UV: A Phosphate buffer (PH 7) max NIVIR: (5 D20+NaHCO3 nm (E'%) 235 (sh, 260), 286 1 CM (370).
3.68 (2H, br, 2-H), 4.16 (3H, s, OCH,), 6.98 pPM (1 H, d, J = 16, 3-CH trans), 8.05 (1 H, m, Py-H,), 8.50 (1 H, m, Py-H4), 8.80 (2H, m, Py-H2.6).
Example 12
11 CONN F'NN N'JS"'N e., IN-CHCH2 NE ConH2 1-1H E OCH3 E 00 7-[2-(5-Amino1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(4carbamoylpyridinio)- 1-pro pen-l-yll-3-cephem-4-carboxylate (1-1H) A mixture of diphenyimethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2methoxyiminoacetamido]-3- 65 GB2194789A 36 (3-iodo-l-propen-1-yi)-3-cephem-4-carboxylate (IX-1) (E isomer, 4.1 g, 5. 7 mmoles) and isonicotinamide (1.4 g, 11 mmoles) is dry DMSO (6 ml) was stirred for 2 hours at room temperature while monitoring by TLC (silica gel plate, CHC[3:CH30h=3:1). The reaction mixture was diluted with ethyl acetate (100 ml) to separate a yellow gum, which was treated with formic acid (40 5 ml) and sodium bisulfite (390 mg) at 450C for 30 minutes. The resulting solution was concentrated to dryness. The residue was dissolved in H20 (100 ml) and insolubles were removed by filtration. The combined filtrate and water wash was applied to the top of a column containing reverse phase packing (PrepPAK-500/C,,, 120 ml). The column was eluted with H20. The eluate was collected in 300 ml fractions and monitored by uv (254 nm) and HPLC (Lichrosorb RP-18, 4 x 300 mm, 0.0 1 M ammonium phosphate buffer, pH 7.2 containing 20% CH30H). Fraction Nos. 4 and 5 were combined and concentrated to a small volume. Lyophilization gave 250 mg (8.1%) of the title compound I-1H, melting at >1800C (dec.).
The spectra indicated that the product was identical to that obtained in Example 10.
Preparation of the hydrochloride-To a suspension of Compound I-1H (98 mg, 0.18 mmole) in CH,OH (1 ml) was added 10% HCI (0.1 ml), and the mixture was stirred for 5 minutes. To the resulting yellow solution was added acetone (100 ml) to give a precipitate, which was collected by filtration, washed with acetone (2 x 10 ml) and dried in vacuo to give the hydrochloride salt of I-1H as a colorless powder. Yield 88 mg (79%). Mp. >190C (dec.).
IR V KBr cm-I 3300, 1770, 1680, 1620.
max uv: Z Phosphate buffer (pH 7) max nm (E'%) 227 (385), 286 1 cm (374).
25 NMR: 15 DO 2.32 (1H, s, acetone-H), 3.79 (2H, br-s, 2-H), 4.17 ppm 3H, s, OCH,), 5.34 (1H, d, J=4.5, 6-H), 5.49 (2H, d, J=7, CHCH-CH,), 5.93 (1H, cl, J=4.5, 7-H), 6.28 (1H, d-t, J=16 & 7, 3-CH=Ckn, 7.15 (1H, d, J=16, 3-CM, 8.43 & 9.1 (each 2H, cl, J=7, Py-H). 30 Example 13 - S H CONH (D lks,,'M H - H CM=CHICH H N2N OC3 0JIN 2- I-ii E COOG H3E-,53 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3(2methyi thiazolio)-1-propen-l- 40 yll-3-cephem-4-carboxylate (I- 1j) To a mixture of diphenyimethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)-2methoxyiminoacetamidol- 3-(3-iodo-l-propen-l-yi)-3-cephem-4-carboxylate (IX-1) (E, 714 mg, 1 mmole) and 2-methylthia zole [prepared according to the procedure of R. P. Kurkjy, E. V. Brown, J. Am. Chem. Soc., 74, 5778 (1952)] (198 mg, 2 mmoles) in dry CH2C12 (10 MO was added AgBF, (90% pure, 217 mg, 45 1 mmole) at -20'C. The mixture was stirred for 30 minutes at room temperature and filtered.
The precipitate was extracted with 10% CH,OH-CHC13 (3x20 mi). The combined extracts were washed with brine (2x5 mi), dried over M9SO, and evaporated to dryness to give a yellow residue, which was triturated with isopropyl ether and filtered to yield 350 mg of the quaternized product. A mixture of this solid, sodium bisulfite (35 mg) and formic acid (3.5 mi) was stirred at 50 4WC for 30 minutes. The mixture was concentrated to remove the formic acid, and the residue was diluted with H,0 (40 m]). Some insolubles were removed by filtration. The filtrate was placed on a reverse phase column (PrepPAK-500/C,, 100 mi). The column was eluted with H,0 (200 mi), 5% aqueous CH30H (400 m]) and 10% aqueous CH,OH (300 m]), successively.
The fractions containing the desired product were pooled on the basis of HPLC analysis (Lichro- 55 sorb RP- 18, 4 x 300 mm, 0.0 1 M ammonium phosphate buffer pH 7.2, containing 20% CH,OH). The combind solution was concentrated to a small volume and lyophilized to give 40 mg (7.7%) of the title compound (1-1J) (E). Mp. >l9WC (dec.).
IR: V KBr CM -1 3300, 1760, 1660, 1600. 60 max UV: A Phosphate buffer IpH 7) max nm (E'%) 238 (442), 292 (421).
1 CM 37 GB2194789A 37 NIVIR: 6 D20+DMSO-df; 3.06 (3H, s, thiazole-CH3), 3.74 (2H, br-s, PPM 2-H), 4.19 (3H, s, OCH.), 5.92 (1 H, d, J=4.5, 7-H), 6.1 (11-1, m, 3-CH=;:CM, 6.8 (1H, d, J=16, 3-CH trans), 8.04 & 8.23 (each 1H, d, J=4, thiazole-M.
Example 14 5
H H C_ CONH N ' % CHp WA'S"N H CHCHCH2- CY " 0 CH3 19 coo 1-11- E 7-[2-(5-Amino- 1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(4hydroxymethylpyridin io)- 1- 15 propen-l-yil-3-cephem-4-carboxylate fl-1Q A mixture of diphenyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)-2methoxyiminoacetamido]-3-(3-iodo- 1-propen-l-yl)-3-cephem-4-carboxylate (]X-1) (E isomer, 1.07 9, 1.5 mmole), 4-hydroxymethy] pyridine (818 mg, 7.5 mmole) in CH,Cl\1 (4.5 mi) and CH30H (3 mi) was stirred at room temperature under N2 atmosphere for one hour. After removal of the solvents by evaporation, 20 the residual oil was triturated with isopropyl ether, collected by filtration, and washed with a mixture of isopropyl ether and methanol (3A, 10 mi) to give 1.28 g of the quaternized cephem ester as a yellow powder. A solution of the quaternized ester (1.25 g) and sodium bisulfite (600 mg) in 85% HCOOH (10 m]) was stirred at room temperature under N2 atmosphere for one hour.
After the addition of 85% HCOOH (5 mi), the mixture was stirred under the same conditions for 25 an additional hour. Toluene was added and the reaction mixture was evaporated azeotropically under reduced pressure. The residue was triturated with acetone to yield 1.17 g of the crude formate of the title compound. A suspension of this compound (1.15 9) in water (100 mi) was filtered to remove insolubles, which were washed with water (10 mlx2). The filtrate and the washes were combined and subjected to reverse phase column chromatography. The column, 30 which was packed with the packing taken out of a prepPAK-500/C1, cartridge column (Waters) mi), was developed with water, 5% methanol and 10% methanol, successively. The fractions containing the desired compound were combined, concentrated under reduced pressure, and precipitated by the addition of acetone to give 100 mg of the title compound (1-1L) as a pale yellow powder. To a suspension of the powder (90 mg in methanol (9 m]) was added 1 M HO 35 in CH30H (0.5 mi) and the mixture was stirred at room temperature and concentrated in vacuo. To the concentrate was added isopropanol to precipitate 77 mg of the hydrochloride of the title compound. Pale yellow powder. M.p. >l90'C (dec.).
IR: V KBr CM -1 1775,1670,1635,1530. 40 max UV:.4 Phosphate buffer (pH 7) max nrn (c), 230 (22600), 264 (sh, 16300) NIVIR D20 3.83 (21-1, br. 2-CH), 4.17 (3H, s, pprn 91r OCI-IJI 5.06 (21-1, s, \===/), 5.36 (1 H, d, J=4.5 Hz, 6-1-1), 5.41 (21-1, cl, J=7 Hz, CH=CH-CH2), 5.94 (11-1, cl, J=4.5 Hz, 7-1-1), 6.36 (1H, d-t, 50 J=16 and 7 Hz, CH=CHCH2), 7.13 (1H, cl, J=16 Hz, CH=CH-CH,), 8.08 and 8.83 (each 2H, cl, J = 7 Hz, Py-H).
Example 15 55
H C-CONH S 11 A 0 N H IM\ o- NI, n N2N 51.1 0 N CH=CHCH2-',==-CONN2 0C2H5 COP 60 1-21-1 E 7-[2-(5-Amino1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamidol-3-[3-(4carbamoylpyridinio)- 1-propen l-y11-3-cephem-4-carboxylate (1-2H) To a solution of 200 mg of 7-amino-3-[3-(4-carbamoylpyridinio)-1-propen-lyil-3-cepham-4- 65 38 GB2194789A 38 carboxylate hydrochloride (E isomer) in 5 ml of 50% aqueous acetone was added portionwise mg of 2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyI chloride hydrochloride [prepared according to the procedure described in published Japan patent application (Kokai) 57-24389 (2/8/82)], and the mixture was adjusted to pH 6.5-7.0 with 2 N Na2CO3 (about 1 ml). The reaction mixture was stirred at 100C for an hour, acidified to pH 2 with 1 N HCl and evaporated 5 in vacuo. The residue was filtered and the filtrate was chromatographed on a column of HP-20, which was eluted with 500 ml of water and 25% aqueous isopropanol, successively. Fractions containing the desired product were combined and evaporated under reduced pressure. The oily residue was treated with isopropanol (20 ml) to give 263 mg (93%) of the title compound (1-2H). M.p. 170'C (dec.).
To a stirred suspension of 225 mg (0.40 mmole) of the above zwitterion in1O ml of methanol was added 1 ml of 1 N HCl in CH30H and the mixture was stirred at room temperature for 30 minutes. The solution was filtered and concentrated under reduced pressure. To the residue was added 15 ml of isopropyl alcohol, and the resulting precipitate was collected by filtration and dried in vacuo to give the title compound as its hydrochloride. Yield 146 mg (57%). M.p. 160'C 15 (dec.). Estimated purity 65%.
ppol V KBr CM -1 3300, 1780, 1680, 1620.
max UV: A Phosphate buffer (PH 7) nm (e), 227 max (22300), 288 (22800).
NIVIR: j D20 1.44 (3H, t, J=7 Hz, OCI-12-CH,), 3.74 (2H, br. s, 2-H) 4.45 (2H, q, J=7 Hz, OCH,-CHJ, 5.36 (1H, d, J=4.5 Hz, 6-H), 5.46 (2H, d, J=7 Hz, 3-CH=CH-CH2), 5.92 (11-1, d, J=4.5 Hz, 7-1-1), 6.20 (11-1, m, 3-CH=CM, 7.04 (1H, d, J=16 Hz, 3-CH=CH), 8.43 (2H, d, J=7 Hz, Py-H,), 9.10 (2H, cl, J=7 Hz, Py-HJ.
Example 16 7-[2-(5-Amino- 1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol3-[3-(4-carbamoylpyridinio)- 1-propen- 1 -y11-3-cephem-4-carboxylate (1- 1 H) (E isomer This Example shows the preparation of Compound I-IH via the last few steps of Reaction Scheme la or lb, wherein the intermediate benzhydryl 7[2-(5-amino-1,2,4-thiadiazol-3-yi)-2rnethoxyiminoacetamidol-3-[3-(4carbamoylpyridinio)-1-propen-l-yil-3-cephem-4 -carboxylate formate (XXVII1H) is isolated. A. Benzhydryl 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2methoxyiminoacetamidol-3-[3-(4-carbam oyl1-pyridinio)-1-propen-l-yll-3-cephem-4-carboxylate Formate (E isomer) (XXVII-M) A solution of X11-11-1 (Y0=10, E isomer) (34 g, 75% pure) in a mixture of acetone and CH,OH (l/1, 200 m[) was placed on a column of Amberlite IRA-410 (formate from 340 m[). The column was eluted with the same solvent system. The first fraction (1 L) was evaporated to about 100 m] of the volume and the brown residue was triturated with isopropyl ether (400 mi).
The resulting powder was collected by filtration and dried under vacuum to afford 29 9 (75% 45 pure by HPLC) of the title compound XXVII-11-1 (E isomer) as a brown powder melting at > 15WC (dec.).
V KBr cm-1 3300, 1780, 1680, 1630, 1600.
max IJV: A 11011 nm (E "r,) 282 (186).
max I CM NMR: (5 acelone-deICH3OH-c[4(111) 4.0 (3H, s, OCH3) 5.26, (1H, d, pp- J=4.5 Hz, 6-H), 5.43 (2H, d, J=7 Hz, CHW), 5.99 (1H, d, J=4.5 Hz, 7-H), 6.5 (1H, m, 3-CH=CM, 6.92 (1H, s, ChPh2), 7.1 (11-1, d, J=16 Hz, 3-CM, 7.35 (10H, m, Ph-M, 8.36 (1 H, s, F/C00), 8.46 & 9.12 (21-1 each, d, J=8, Hz, Py-H).
B. 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(4carbam oy1-1-pyridinio)1-propen-l-yll-3-cephem-4-carboxylate (1-1H) (E isomer) A mixture of XXV11-1 H (E isomer) from Step A (29 9, 75% pure) and 85% formic acid (290 mi) was stirred for 2 hours at room temperature. Evaporation of the mixture gave a brown oil 65 39 GB2194789A 39 which was triturated with acetone (500 mi). The powder was collected by filtration, washed with acetone (2 X 100 ml) and dried in vacuo to give 24 g (50% pure by HPLC) of the crude title compound. The brown solid was treated twice with 2 N HCI (1 L and 0.5 L). The aqueous extracts were combined and placed on a column packed with Diaion HP-20 (1. 5 L). The column was washed with water (8 L) and eluted with 30% CH:,OH (5 L). The fraction containing the 5 desired product was evaporated to about 30 m]. The concentrate was treated with acetone (200 mi) to give a precipitate, which was collected by filtration and dried in vacuo to give 10. 1 9 (85% pure) of the title compound (zwitterion form) as a yellow powder. To a suspension of this product in CH.01-1 (100 mi) was added N HCl in CH30H (55 mi) at room temperature and the mixture was stirred for 30 minutes. The resulting clear solution was filtered to remove insol- 10 ubles, concentrated to about 50 mi of the volume and precipitated with isopropanol (200 mi).
The resulting powder was collected, washed with isopropanol (50 mi) and dried in vacuo to give 10.5 g (85% pure) of the title compound 1-11-1 (E isomer) (HCI salt), melting at >1BO'C (dec.).
Pale yellow powder.
Example 17
7-[2-(5-Amino- 1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol3-(4carbamoylpyridinio)- 1-propen l-yll-3-cephem-4-carboxylate (1-1H) (E isomer) This example shows the preparation of Compound 1-11-1 via the last few steps of Reaction Scheme la or lb, wherein intermediate XXVII-11-1 (the formate) is not isolated.
A solution of IX-1 (E isomer) (27.6 9, 38.5 mmole) and isonicotinamide (22.8 9, 187 mmole) in a mixture of CH3M (120 m]) and CH30H (100 mi) was stirred at room temperature for 1 hour under a nitrogen atmosphere. After evaporation of the organic solvents, the oily residue was triturated with isopropyl ether to give 50.5 9 of a mixture of the quaternized salt and isonicoti namide. A solution of the mixture (50.3 9) and sodium bisuifite (16 9) in 85% HCOOH (160 mi) was stirred at room temperature for 40 minutes and subsequently at 4WC for 1 hour under N, The mixture was evaporated in vacuo. The residual oil was mixed with toluene (50 mi), evapo rated azeotropically and triturated with acetone (400 m]) to give 27.8 9 of the crude title compound. This material was treated twice with 2 N HCl (1 L and 0.5 L). The acid extracts were combined and placed on a column of HP-20 resin (1.5 L). The column was eluted with water (91---)and 30% methanol (101---). The fractions containing the desired compound were combined and concentrated to give a yellow oil, which was triturated with acetone (300 mi) to yield 9.35 9 of the zwitterion form of the title compound.
To a suspension of the product (9.3 9) in CH30H (180 mi) was added 1 N HCl in CH30H (55 mi) to obtain a clear solution. The solution was concentrated to about 100 mi and diluted with 35 isopropanol to precipitate 9.50 g (purity 75%) of the title compound 1-11- 1 (E isomer) as its hydrochloride. Pale yellow amorphous powder. M.p. >l9WC (dec.).
Example 18
7-[2-(5-Amino- 1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(4carbamoylpyridinio)- 1 -pro- 40 pen l-yll-3-cephem-4-carboxylate (l- M) (E isomer) This example shows the preparation of Compound 1-11-1 via the last step (7-Wacylation) of Reaction Scheme lc.
To an ice-chilled suspension of the 7-amino-cephem hydrochloride XXII-H (E isomer) (5.0 9, 12.6 mmole) in 50% aqueous acetone (100 m]) was added sodium bicarbonate if] small por- 45 tions. The pH of the mixture was monitored by a pH meter throughout the reaction. To the cold neutralized solution (pH about 7) was added 2-(5-amino-1,2,4-thiadiazol-3yi)-2-methoxyiminoace- tyl chloride hydrochloride (4.02 9, 15.6 mmole) in small portions over a period of an hour, and the pH of the reaction mixture was maintained in the range of 6.8-7.5 by occasional additions of sodium bicarbonate. The reaction was also monitored by tic. After all of Compound XXII-H 50 had been consumed, the mixture was acidified to pH 3 by the addition of 2 N hydrochloric acid.
The, mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with acetone (400 mi) to separate the precipitate, which was collected by filtration to afford 9.59 9 of the crude title compound as a light yellow powder. Estimated purity 40% by HPLC. A suspension of the crude product (9.5 g) in 2 N hydrochloric acid (150 m]) was filtered, 55 and the filtrate was adsorbed on a column of HP-20 resin (500 m]). After washing with water (1.5 L), the column was eluted with 25% aqueous isopropyl alcohol and the eluate was collected in 100-mi fractions. The desired fractions were pooled, acidified with 2 N hydrochloric acid (10 mi) and concentrated. The residual oil was triturated with isopropyl alcohol (200 mi), and the precipitate was collected by filtration. After drying over phosphorus pentoxide, 5.18 g of the 60 title compound 1-11-1 (E isomer) hydrochloride was obtained as a yellow amorphous powder.
M.p. >l9WC (dec.). Estimated purity 75%.
Example 19
Purification and crystallization of Compound 1-1H (E isomer) GB2194789A 40 Compound 1-11-1 hydrochloride obtained in Example 16 was a pale yellow amorphous powder of 85% purity.
Procedure 1 Six grams of the 85% purity hydrochloride was dissolved in 20 m[ of H20 and filtered through a celite pad. The ambercolored filtrate (pH 2) was passed through a reverse phase column (the packing of prepPAK-500/C, cartridge, Waters; 120 mi), which was eluted with water. The eluate was collected in 120-mi fractions with monitoring by HPLC. Fraction No. 3 through fraction No. 5 were combined and concentrated to about 10 m], and precipitated by acetone (100 mi) to give 3.3 9 of the zwitterion form of 1-1H (pale yellow amorphous powder; estimated 10 purity 95%).
To a suspension of the 95% purity powder (3.2 g) in CH,,OH (32 m]) was added N HCI in CH30H (18 mi), and the mixture was stirred at room temperature until a clear solution was obtained. The solution was filtered and the filtrate was concentrated to about 10 mi. To the concentrate was added isopropanol (100 mi) to separate a pale yellow precipitate, which was collected by filtration, washed with isopropanol (5 ml) and dried to yield 2.6 9 of the HCI salt (amorphous powder; estimated purity 95%).
A solution of the 95% purity hydrochloride (1 9) in water (4 mi) was adjusted to pH 6.5 with NaHC03 (200 mg) and stirred for 30 minutes. The crystals which separated during stirring were collected by filtration, washed with water (2 x 5 mi) and dried in vacuo to give 7 10 mg of 1- 1 H 20 (zwitterion form) as pale yellow prisms. M.p. > 185'C (dec.). Microanalysis showed it to be the trihydrate.
IR: V KBr CM -1 1780, 1695, 1660, 1630, 1610.
max 25 UV: X Phosphate buffer (PH 7) max nm (e) 227 (22000), 290 (23000). NMR: J DMSO-de,+D20 3.45 (21-1, br, s, 2-H), 3.9 (31-1, s, OCH3), ppm 4.99
(11-1, d, J=4.5 Hz, 6-H), 5.16 (21-1, d, 30 J7 Hz, CH2W), 5.61 (11-1, d, J=4.5 Hz, 7-H), 5.8 (11-1, d-t, J=16 & 17 Hz, 3-CH=CM, 6.93 (1 H, d, J = 16 Hz, 3-CM, 8.18 & 8.89 (each 2H, d, J=7 Hz, Py-H).
35 Anal. Calc'd for C211-12^06S2. 3H20: C, 42.14; H, 4.38; N, 18.72; S, 10. 71.
Found: C, 42.41;H, 4.35; N, 18.86; S, 11.00.
1-1K Column, Lichrosorb RP-18, 4x300 mm: Mobile phase, 0.01 M phosphate buffer (pH 7.2)/CH3OH=85/15: Detection, uv (254 rim).
Procedure 2 Once crystalline 1-11-1 had been obtained from Procedure 1, it was possible to obtain the crystalline zwitterion. form of 1-1H directly from the crude 1-11-1 hydrochloride by seeding with a 45 few crystals of the pure 1-1 H.
A solution of the 85% pure hydrochloride (250 mg) in water (1 mi) was treated with charcoal. The solution was adjusted to pH 6.5 with NaHCO, (60 mg) and decolorized with charcoal. The filtrate was seeded with a few pieces of the crystals obtained from Procedure 1 and stirred with overnight at room temperature. The separated crystals were collected by filtration, washed water (2x2 m]) and dried under reduced pressure to give 170 mg (80% recovery) of pale 50 yellow prisms of 1-11-1 (zwitterion form), melting at >185'C (dec.), which was identical with that obtained by Procedure 1, (as shown by]R, UV, NMR).
The crystalline zwitterion form of Compound 1-1H was slightly soluble in water (6 mg/mi in saline at 23"C).
Example 20 S
N C- CONN Ti: CH20H +1 H-CHi N:
8 2N OCH3 0 rnne"C 2 60 E 7-[2-(5-Amino1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol3-[-3-(3hydroxymethylpyridi nio)- 1propenyll-3-cephem-4-carboxylate (1-1K) (E isomer) A. Diphenylmethyl 7-[2-(5-Amino- 1,2,4-thiadiazol3-yl)-2methoxyiminoacetamidol-3-[3-(3-hydrox-65 41 GB2194789A 41 ymethylpyridinio)-1-propenyll-3-cephem-4-carboxylate iodide (E-isomer) (XII1K) To a solution of IX-1 (E-isomer, 1.79 9, 2.5 mmoles) in 2.5 mi of CH,30H and 7.5 mi of CH,Cl\1 was added 3-hydroxymethylpyridine (545 mg, 5 mmoles), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ethyl acetate (100 mi) with vigorous stirring. The resulting precipitate was collected by filtration, washed with a small 5 volume of ethyl acetate and dried to give 2.06 9 (100%) of the title compound X11-1K as a tan powder. Mp. 170-180'C (dec).
IR: v,,,,,, (KBr) in cm-1 1780, 1725, 1675, 1615, 1530, 1385, 1225, 1040, 750, 700.
UV: A (C2H501-1) in nm (E'%) 290 (196).
Max 1 CM NIVIR: 8 (DIVISO+D20) in ppm 3.7 (2H, br.s, 2-H), 3.91 (3H, s, OCH3), 4. 70 (2H, s, Py-CH2-OH), 5.28 (2H, m, CH2-N+), 5.23 (1 H, cl, J=5Hz, 6-H), 5.90 (1H, cl, J=51-1z, 7-H), 6.34 OH, rn, 3-CH=CM, 6.86 (1H, cl, J=16Hz, 3-CH), 6.89 (1H, 20 s, CHPh2) 7.35 (10H, m, Ph-H), 7.9-8.9 (4H, rn, Py-H).
B. 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(3hydrox ymethylpyridi- nio)-1-propenyll-3-cephem-4-carboxylate (1-1K) (E isomer) A mixture of X11-1 K (E isomer, 2.0 g, 2.4 mmoles) and sodium bisulfite (1 g) in 85% HCOOH (10 ml) was stirred for 2 hours at room temperature. The reaction mixture was concentrated to ca. 5 mi under reduced pressure. The oily residue was poured into acetone (100 mi) with vigorous stirring. The precipitate was collected by filtration, washed with a small amount of acetone and dried to give 1.1 g of a tan powder, which was purified by column chromatography 30 [using the packing of a PrepPAK-500/C1. cartridge (Waters)] to give 283 mg (22%) of 1-1K as an amorphous powder. The powder was crystallized from 4N H2S04 and acetone to give 144 mg of the title compound 1-1K as colorless needles. Mp. 185-188'C (dec.).
IR: 0,,, (KBr) in cm-1 1775, 1680sh, 1660, 1630, 1225, 1045, 850.
UV: A (Phosphate buffer, pH 7) in nm (E'% 1 CM) max NMR: 5 (D20) in ppm 3.75 (2H, s, 2-H), 4.18 (3H, s, OCH3), 4.97 (21A, s, Py-CHOH), 5.35 (1H, cl, J=4Hz, 6-H), 5.43 (2H, cl, J=6.51-1z, ) 236.5 (283), 275 sh (280), 292.5 (330).
CH,-N+), 5.92 (1H, cl, J=4Hz, 7-H), 6.18 (1H, d-t, J=161-1z, J=6.5Hz, 3-CH=CH-), 45 6.97 (1H, d, J=16Hz, 3-CH), 8.13 (1H, d-d, J=81-1z, J=6Hz, Py-H), 8.60 (1H, cl, J=81-1z, Py-H), 8.84 (1H, d, J=6Hz, Py-H), 8.90 (1 H, s, Py-H).
50 Example 21 5
H 11 C-CONH 11 k,' H G I H J 1-1, 0 C-" & N2N S UN3 G) 55 I-1m 7-[2-(5-Amino- 1,2,4-thiadiazol3-yl)-2-(Z)-methoxyiminoacetamidol-3-[3-(4N-methylcarbamoy lpyri60 dinio)- 1-propenyll-3-cephem-4-carboxylate (1110) (E isomer) A mixture of diphenyimethyl 7-[2-(5-amino1,2,4-thiadiazol3-yi)-2-methoxyiminoacetamido1-3 (3-iodo-l-propenyi)-3cephem-4carboxylate (IX-1) (E isomer, 450 mg, 0.62 mmole) and 4Nmethylcarbamoylpyridine [prepared according to the procedure of M. Samejima, YakugAu Zasshi, 80, 1706 (1960)] (215 mg, 1.58 mmoles) in acetonitrile (2 m]) was stirred under nitrogen 65 atmosphere for 5 hours at room temperature. The mixture was evaporated under reduced 42 GB 2 194 789A 42 pressure and the residue was triturated with ether to give 530 mg of the quaternary salt. A mixture of the solid and sodium bisulfite (150 mg) in 85% formic acid (2 mi) was stirred for 4 hours and then heated at 4WC: for 30 minutes. The mixture was evaporated under reduced pressure. The residue was triturated with acetone and the crude product was collected by filtration. The crude product was chromatographed on a column of HP-20 (1. 5 x 18 cm) and the 5 column was eluted with water and 30% aqueous methanol. The methanolic eluate was evapo rated under reduced pressure and the residue was freeze-dried to give 140 mg of an amorphous powder, which was further purified by HPLC (Column: Lichrosorb RP-18, Solvent: 15% CH,OH) and the eluate of HPLC was freeze-dried to give 60 mg (18%) of the title product 1-1M. Mp.
180-183'C (dec.). Estimated purity: 80%.
IR v (KBr) in cm-1 1760, 1660, 1600.
UV A (Phosphate buffer, pH 7) in nm (e) 230 (22100), 286 (22100).
NMR: J (D20) in ppm 3.08 (3H, s, COMCHJ, 3.72 (2H, s, 2-H), 15 4.16 (3H, s, OCH3), 5.35 (1H, d, J=4.51-1z, 6-H), 5.95 (1H, d, J=4.51-1z, 7-H), 7.00 (1 H, d, J = 16Hz, 3-CH), 8.35 (2H, d, J-6Hz, pyridine-H), 9.05 (2H, d, J=161-1z, pyridine-H). 20 Example 22
N- -CON H S -T Is G H N, N 97K H)s.-" CH=CH-CHN 2N.. -COOH OCH3 0 p 1-1N E/Z=7/1 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(4carbox ypyridinio)- 1-prope nyl]-3-cephem-4-carboxylatefl- IN) To a stirred suspension of isonicotinic acid (340 mg, 2.8 mmoles) in dry DMF (3.5 ml) was added N,O-bis(trimethylsilyi)acetamide (0.7 ml, 2.8 mmoles) under nitrogen atmosphere. To the resulting clear solution was added diphenylmethyl 7-[2-(5-amino-1,2,4- thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-l-propenyl)-3-cephem-4-carboxylate (IX-1) (E isomer, 720 mg, 1 mmole) in one portion, and the red solution was stirred for 1.5 hours at room temperature. The reaction mixture was added dropwise to a stirred saturated sodium chloride solution (50 ml) containing sodium thiosulfate (150 mg). The yellow precipitate was collected by filtration, washed with water, and dried to obtain 722 mg of a pale yellow powder. The powder (700 mg) 40 and sodium bisulfite (70 mg) were dissolved in 85% formic acid (5 ml), and the solution was allowed to stand at room temperature for 1.5 hours. The mixture was suspended in toluene (50 ml) and concentrated. The residue was triturated with acetone (70 ml), and the precipitate was isolated by filtration to afford 421 mg of a yellow powder. This crude powder (400 mg) was suspended in water (2 ml) and to the suspension was added sodium bicarbonate. The resulting 45 dark solution was adsorbed on a column of the packing (50 ml) of a PrepPAK/C, cartridge (Water's System 500), and the column was eluted by water (200 ml). The eluent was fraction ated into 10 fractions (20 ml of each), and the desired fractions (Fractions Nos. 4-7) were combined, acidified to pH 3 with 2N hydrochloric acid, and concentrated. The residue was triturated with acetone (30 ml) and the precipitate was collected by filtration to give 201 mg (37%) of the title compound I-1N as a yellow powder. E/Z=7/1; 80% pure. Mp. >1890C (dec.).
IR -: v. (KBr) in cm-1 1770, 1665, 1600.
UV: A,,, (Phosphate buffer, pH 7) in nm (e) 227 (22500), 290 (22100).
* NMR: J (D20+Nal-1COj in ppm 3.7 (2H, br.s), 4.15 (3H, s), 5.32 (1H, d, J=4Hz), 5.39 (2H, d, J=6Hz), 6.14 (1H, d-t, J= 15.5 and 6Hz), 7.03 (1 H, d, J=15.5Hz), 8.31 (2H, d, J=71-1z), 8.94 (2H, d,J7Hz).
43 Example 23
N C - CONN M2N S "0 C H3 1-10 E GB2194789A 43 - S + 0 -PN n_ 0 0 E) CHCH-CH2 t 7-[2-(5-Amino1,2,4-thiadiazol-3-yl)-2-(Z)methoxyiminoacetamidol-3-[3-(2, 3-cyclopentenopy ridi- nio)-1-propenyll-3-cephem-4-carboxylate (1-10) (E isomer) A mixture of diphenyimethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yi)-2methoxyiminoacetamido1-3(3-iodo-l-propenyl)-3-cephem-4-carboxylate (IX-1) (E isomer, 450 mg, 0.62 mmole) and 2,3cyclopentenopyridine (217 mg, 1.83 mmole) in acetonitrile (2 mi) was stirred under nitrogen atmosphere for 4 hours at room temperature. After evaporation under reduced pressure, the mixture was triturated with ether to give 560 mg of the quaternary salt. A mixture of the solid 15 and 85% formic acid (2 mi) was stirred under nitrogen for 3 hours at room temperature and then heated at 400C for 30 minutes. The mixture was evaporated under reduced pressure and trituration of the residue afforded 391 mg of the crude product, which was purified by chromatography on a column of HP-20 (1.5 X 18 cm). The column was eluted with water and 30% aqueous methanol. Evaporation of the methanolic eluate under reduced pressure, followed by freeze-drying afforded 160 mg of an amorphous powder, which was further purified by HPLC (Column: Lichrosorb, Solvent: 10% CH3OH). The eluate of HPLC was freeze-dried to give 50 mg (15%) of the title produce 1-10. Mp. >l9WC (dec.). Estimated purity: 75%.
IR 36 : V max (KBr) in cm-1 1765, 1670, 1600.
UV: A (Phosphate buffer, pH 7) in nm (e) 235 (20000), 283 (25000) NMR (D,0+Nal-IC0,) in ppm 2.2-2.6 (2H, m, -CH,-), 3.1-3.6 (4H, m, -CHA 3.72 (2H, s, 2-H), 4.17 (3H, OCH,), 5.33 (1H, d, J=4.5Hz, 6-H), 5.90 (1H, d, J=4.5Hz, 7-H), 6.75 (1H, d, J = 16Hz, 3-CH), 7.65-8.2 (3H, rn, pyridine-H).
H C-CONN H2N S, N H \ 0 0 H N COOH 1 [00e CH2CH-CH2 2 C2H5 12N 7-[2-(5-Amino- 1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamidol-3-[3-(4carboxypyridinio) - 1-prope nyll-3-cephem-4-carpoxylate (1-2N, E isomer) and 7-[2-(5-Amino 1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetamidol-3-[3(4carboxypyridinio) - 1-prope nyll-3-cephem-4-carboxylate (1-2N, Z isomer) To a chifled mixture of BSA (1.0 mi, 4.12 mmoles) and isonicotinic acid (506 mg, 4.12 mmoles) was added. IX-2 (from Preparation No. 21) (1.0 9, 1.37 mmoles), and the mixture was stirred under nitrogen at room temperature for 2 hours. The mixture was poured into 10% Na2S203 (20 mi) to precipitate 1.3 9 of the quaternary salt, which was collected by filtration, washed with water and dried. A mixture of the solid and sodium bisulfite (0.3 g) in formic acid 55 (98%, 5 mi) was heated at 4WC for 1 hour and evaporated under reduced pressure. The residue was triturated with acetone and filtered to give 900 mg of the crude product (E-propenyl isomer2-prpenyl isomer=2:1). Separation of the isomers was carried out by HPLC (Column:
Lichrosorb, Solvent: 15% CHOH). The faster moving fractions of HPLC were collected, evapo- rated under reduced pressure and freeze-dried to give the E-propenyl isomer of 1-2N (44 mg, 60 yield 6%). The slower moving fractions gave the Z-propenyl isomer of 1-2N (32 mg, yield 4%) in a similar procedure.
44 GB2194789A 44 1-2N, E isomer Mp.: >200'C (dec.).
IR: v,, (KBr) in cm-1 1765, 1660, 1620, 1380.
UV: A,,,. (Water) in rim (e) 228 (22200), 291 (23600).
NIVIR: (5 (D20) in ppm 1.45 (3H, t, J=61Hiz, CH2CH,), 3.72 (2H, s, 2-H), 4,45 (2H, q, CH2CH3), 5.40 (1H, cl, J=41Hiz, 6-H), 5.90 (11H, cl, J=41Hiz, 7-H), 7.05 (1H, cl, J=15Hz, 3-CH), 8.30 (2H, cl, J=61Hiz, Py-H), 8.95 (2H, d, J=61Hiz, Py-H).
1-2N, Z isomer Mp.:>200'C (dec.).
IR: v,,,,, (KBr) in cm-1 1760, 1660(sh), 1620, 1370.
UV: (Phosphate buffer, pH 7) in rim (e) 225 (22400), 275 (sh, 16000).
NMR: 3 (D20) in ppm 1.45 (3H, t, J=7Hz, CH2CH3), 3.50 (11H, cl, J=171Hiz, 2-H), 3.75 (11H, cl, J=1171HIz, 2-H), 5.38 (1H, d, J=41Hz, 6-H), 5.95 (11H, cl, J=4Fiz, 7-H), 6.62 (11H, cl, J=11111Az, 3-CH), 8.35 (2H, d, J=61HIz, Py-H), 8.92 (2H, cl, J=61Hiz, Py-H).
Example 25
N - C-CONH 7 (D -- W 11 N N N 22 N J S- '\O 0 G CHCH-EH27N' CONH2 W= 00 G IC=7 MI-CH=17M CH2 1-31A E 7-[2-(Amino1,2,4-thiadiazol-3-yl)-2-(propen-3-yloxyimino)acetamidol-3[3-(4-carbamoylpy ridinio)- 1- propenyll-3-cephem-4-carboxylate (1-3H) (E isomer) To a solution of 35 mg (0.08 mole) of 7-amino-3-[3-(4-carbamoylpyridinio)- 1-(E)-propenyll-3cephem-4-carboxylate hydrochloride in 2 m] of 50% aqueous acetone was added 52 mg of 2-[5 amino1,2,4-thiadiazol-3-yi)1-2-(propen-3yloxyimino)acetyl chloride hydrochloride (from Preparation 40 No. 25) and the mixture was adjusted to pH 6.5-7.0 with 2N Na2C03, The mixture was stirred at room temperature for 1 hour, acidified to pH 2 with 1 HCI and concentrated under reduced pressure. The residue was chromatographed on a column of HP-20 resin which was eluted with 300 mi of water and 30% CH,01HI-1H.O. Fractions containing the product were combined and evaporated under reduced pressure. The residue, 73 mg, was purified by a column of reverse phase carrier which was taken out of a PrepPAK-500/C1, cartridge (Waters, 30 mi). The column was eluted with water, 5% CH,OH, 10% CH,OH and 20% CH,OH, successively. Fractions containing the product were combined and lyophilized to afford 26 mg (62%) of the title product 1-3H. Mp. 160C (dec.).
M: V max (KBr) in cm-1 3400, 1765, 1680, 1605, 1400.
UV: A,,., (Phosphate buffer, pH 7) in rim (e) 226 (24600), 288 (22800) NMR (D,O) in ppm 3.75 (2H, s, 2-H), 5.41 (1H, cl, J=51Hiz, 6-H), 5.50 (411, m, CH2N+ & CH=CH2), 5,98 (1H, cl, J=51Az, 7-H), 6.20 (11A, m, 3-CH=CM, 7.09 (111, cl, J=17Fiz, 3-CH), 8.50 (2H, d, J=7Hz, Py-H), 9.16 (2H, cl, J=7Hz, Py-H).
1 GB2194789A 45 Example 26
N n C-CONN 'S 11 91 - - (D TH H N S \n 0 1-4H E 1 - Code CH2C=CH 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-propargyloxyiminoacetamidol-3-[3(4-c arbamoylpyridinio)-1- 10 propenyll-3-cephem-4-carboxylate (1-4H) (E isomer) To a solution of 86 mg (0.19 mole) of 7-amino-3-[3-(4-carbamoylpyridinio)- 1-(E)-propenyll-3cephem-4-carboxylate hydrochloride (XXII-H) in 2 mi of 50% aqueous acetone was added 63 mg of 2-propargyloxyimino-2-[5-amino-1,2, 4-thiadiazol-3-yi)acetyl chloride hydrochloride (from Preparation No, 26). The suspension was maintained at pH 6.5-7.0 with 2N Na2C03 and then 15 stirred at room temperature for 1 hour. The reaction mixture was acidified to pH 2 with 1 N HCI and concentrated in vacuo. The residue was diluted with 30 mi of water, neutralized with NaHC03 and filtered. The filtrate was transferred on the top of a column which was packed with reverse phase carrier (30 ml) taken from a PrepPAK-500/C,8 cartridge (Waters). The column was eluted with water, 5% CH30H, 10% CH30H and 20% CH30H, successively. Fractions containing the product were combined and lyophilized to afford 13 mg (12%) of the title product 1-4H. Estimated purity 70%. Mp. 160'C.
IR: v m,,,, (KBr) in cm-1 3400, 2120, 1765, 1680, 1610.
UV: A niax (Phosphate buffer, pH 7) in nm (e) 229 (24000), 288 (21200).
NIVIR: 8 (D20) in ppm 3.78 (2H, s, 2H), 5.15 (2H, cl, J= 1 Hz, -CH2-C=CH), 5.40 (1H, d, J=51-1z, 6-H), 5.50 (2H, m, CH-N+), 5.98 (1H, d, J=511z, 7-H), 6.20 (1H, m, 3-CH=CM, 7.05 (1H, cl, J=17HZ, 3-CM, 8.50 (2H, d, J=71-1z, Py-H), 9.16 (2H, cl, J=71-1z, Py-H).
Example 27 C-CONH 3 1-H- - 11 4 (D s','N H\ CHCH-CH2-bl CONN2 H2H 0 (D 1-51-1 Ef.
7-[2-(5-Amino- 1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetamidol-3[3-(4-carbamoylpyri dinio)- 145 propenyll-3-cephem-4-carboxylate (1-5H) (E isomer) To a stirred solution of 139 mg (0.31 mmole) of 7-amino-3-[3-(4carbamoylpyridinio)-1-propenyl]-3-cephem-4-carboxylate hydrochloride in 3. 5 m] of 50% aqueous acetone in an ice-cooling bath was added portionwise 120 mg (0.44 mmole) of 2-(5-amino-1,2,4-thiadiazol-3-yi)-2cyclopentyloxyiminoacetyl chloride hydrochloride (from Preparation No. 27). The mixture was adjusted to pH 6.5-7.0 with 2N Na2CO, (0.9 ml) and stirred for 1 hour at 10'C. The reaction mixture was acidified to pH 2 with 1N HCI and evaporated under reduced pressure. The residue was chromatographed on a column of HP-20 resin (20 mi) and was eluted with 300 m] of water and 30% CH,OH-H20, successively. Fractions containing the product were combined and concentrated in vacuo. The residue was treated with 60 mi of acetone to give 111 mg (83%) of the title compound 1-5H. Mp. 160'C (dec.). Estimated purity 70%.
IR: v m (KBr) in cm-1 3400, 1770, 1680, 1605, 1530.
UV: A (Phosphate buffer, pH 7) in nm (e) 224 (23300), 286 (24600).
46 GB2194789A 46 NIVIR: (DMSO-de,) in ppm 1.70 (8H, br.s, E br.s, X] 5.05 (1H, cl, J=5Hz, 6-H), 5.30 (2H, m, CH2W), 5.67 (1H, d-d, J=5Hz & 7Hz, 7-H), 6.20 (1H, m, 3-CH=CM, 7.08 (11-1, cl, J=17Hz, 3-CH), 8.34 (2H, cl, J = 7Hz, Py-H), 9. 11 (2H, d, J=7Hz, Py-H), 9.38 (1H, d, J=7Hz, 7-NH).
8-(] 1-), 4.68 (1 H, Example 28 S
N C-CONN ---IT- ji - A,S,A No OF-7N 0 CH=CH-CH21' N CH3 U COOE) 1-1p E ChCOON 7-[2-(5-Amino 1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(3carboxymethylpyridin io)- 1propenyll-3-cephem-4-carboxylate (1-1P) (E isomer) A. Diphenyimethyl 7-[2-(5-Amino-1,2,4-thiadiazol-3-yi)-2methoxyiminoacetamido1-3-[3-(3-carbox ymethylpyridinio)-1-propenyl]-3cephem-4-carboxylate (X11-1P, iodide, E isomer) 25 To a suspension of 3carboxymethylpyridine hydrochloride (0.89 g, 5 mmoles) in 10 mi of CH,Cl, was added N,O-bis(trimethyisiiyi)acetamide (4.97 mi, 18 mmoles), and the mixture was stirred at room temperature until a clear solution was obtained. To the solution was added IX-1 (1.79 9, 2.5 mmoles), and the mixture was allowed to stand at room temperature. After 3 hours, 3 m] of CH30H was added to the cooled mixture and the solution was evaporated in vacuo to give an oil which was triturated with ethyl acetate to afford 2. 28 g of the title compound X11-1 P as a tan powder. Mp. 16VC (dec.).
IR v.. (KBr) in cm-1 1780, 1720, 1675, 1630, 1530, 1385, 1225, 1045, 755, 700.
UV: A (C2H,OH) in nm (E'%) 295 (188).
max 1 em NIVIR: 5 (DIVISO+D,0) in ppm 3.70 (2H, br.s, 2-H), 3.90 (5H, s, OCH, & Py-CH,CO), 5.25 (31-1, m, -CH2W & 6-H), 5.92 (1H, d, J=4.51-1z, 7-1-1), 6.35 (1H, m, 3-CH=CH-), 6.90 (1H, cl, J=16Hz, 3-CH), 6.92 (1H, s, Cl-lPh2), 7.35 (10H, m, Ph-H), 8.8-9.0 (41-1, m, Py-H).
4.0 B. 7-[2-(5-Amino1,2,4-thiadiazol-3-yl)-2methoxyiminoacetamidol-3-[3-(3carboxymethylpyridin io)1-propenyll-3-cephem-4-carboxylate (1-1P) (E isomer) 50 A mixture of X111-1P (iodide) (2.28 9) and sodium bisulfite (1. 1 9) in 85% HCOOH (10 mi) was 50 stirred at room temperature for 2 hours. The reaction mixture was concentrated to ca. 5 mi under reduced pressure. The oily residue was triturated with acetone (100 mi) to give 1.22 g of the crude product, which was purified by column chromatography (HP-20, 420 mi) to afford 533 mg of the title compound 1-1P (38%, from IX-1) as a pale yellow amorphous powder. Mp 16WC (dec.).
IR: v m (KBr) in cm-1 1770, 1670, 1600, 1530, 1385, 1140, 1040.
UV:Am,,. (Phosphate buffer, pH 6.2) in rim (E 1%) 234 (374), 277sh (390), 290 (402).
1 em NIVIR: 3 (D,O+NaHCOa) in ppm 3.78 (2H, s, 2-H), 3.92 (211, s, Py-CH2CO), 4.22 (3H, s, OCHJ, 5.40 (1H, cl, J=4Hz, 6-H), 5.44 (2H, cl, J=6.5Hz, -CH2-N+), 5.97 (1H, cl, J=4Hz, 7-H), 6.20 (11-1, d-t, J=16 & 6.5Hz, 3-CH=CM, 7.08 OFI, d, J=16Fiz, 3-CH), 8.11 (1H, d-d, J=8 & 7Hz, Py-H5), 8.53 (1H, d, J=81-1z, Py-H4), 8.82 (1H, d, J=7Hz, Py-HJ, 8.86 (1H, s, Py-H2), C-CONH 5 11 11 y y N N 7N e 1 CH=CH-CHA S-CHOOH OCH3 coo & & 1-11G E 4 GB2194789A 47 7-[2-(5-Amino-1,2,4-thiadiazol3-yl)-2-methoxyiminoacetamidol-3-[3-(4carbox ymethylthiopyridinio)- 20 1-propenyll-3-cephem-4-carboxylate (1-1Q) (E isomer) A. Diphenyimethyl 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2methoxyiminoacetamido1-3-[3-(4-carbox - ymethylthiopyridinio)1-propenyll-3-cephem-4-carboxylate (X11- 1Q, iodide, E isomer) To a suspension of 4-carboxymethylthiopyridine (0.88 g, 5 mmoles) in 10 mi of CH2C1, was added N,O-bis(trimethyisilyl)acetamide (5 mI, 18 mmoles), and the mixture was stirred at room temperature until a clear solution was obtained. To the solution was added IX-1 (E isomer 1.79 9, 2.5 mmoles) and the mixture was allowed to stand at room temperature. After 3 hours, 3 mI of CH,OH was added to the cold mixture and the solution was evaporated in vacuo to give oily residue which was triturated with ethyl acetate to give 2.43 g of the title compound X11-1Q (iodide) as a tan powder. Mp. 15WC (dec.).
IR v (KBr) in cm-1 1780, 1720, 1670, 1625, 1525, 1385, 1225, 1115, 1040, 755, 700.
LIV: A (C2H,OH) in nm (E'%) 312 (299). 35 max 1 CM NIVIR: & (DMSO-d,+D20) in ppm 3.70 (2H, br.s, 2-H), 3.93 (31-1, s, OCH3), 5.07 (21-1, m, CH2-W) 5.23 (1H, cl, J=5Hz, 6-H), 510 (11-1, d, J=5Hz, 7-H), 6.29 (11H, m, 3-CHCM, 6.87 (1H, d, J=16Hz, 3-CH), 6.91 (1H, s, CHPh,), 7.35 (10H, m, Ph-H), 7.88 & 8.58 (each 2H, cl, J=61-1z, Py-H).
B. 7-[2-(5-Amino- 1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(4carboxymethylthiopyr idinio)- 1 -propenyll-3-cephem-4-carboxylate (/- 1 Q) (E isomer) A mixture of X11-1Q (iodide, 2.43 9) and sodium bisulfite (1.1 9) in 85% HCOOH (10 m]) was 50 stirred at room temperature for 2 hours. The reaction mixture was concentrated to ca. 5 m] under reduced pressure. The oily residue was triturated with acetone (100 m]), filtered and dried to give a crude product (1.39 g), which was purified by column chromatography (HP-20, 20 m]) to afford 577 mg of the title compound 1-1Q (39% from IX-1) as a pale yellow amorphous powder. Mp. 18WC (dec.).
IR v.ax (KBr) in cm-1 1765, 1670, 1625, 1530, 1380, 1110, 1035.
UV: A (phosphate buffer, pH 6.2) in nm (E'%) 234 (459), 310 (678).
max 1 CM 48 GB2194789A 48 NMR: J (D2C)+NaHCO3) in ppm 3.79 (2H, br.s, 2-H), 4.10 (2H, s, S-CH2), 4.23 (3H, s, OCH.), 5.25 (2H, d, J=6.5Hz, CH2-W), 5.39 (1H, d, J=4.0Hz, 6-H), 5.97 (1H, cl, J=4Hz, 7-H), 6.18 (1H, d-t, J=15.5Hz & 6.5Hz, 3-CH=CM, 7.05 (111, cl, J=15.5Hz, 3-CH), 7.84 & 8.55 (each 2H, d, J=7Hz, Py-H).
Example 30 5
H C, CONH 11. H3 C H N N JL CH=CH-CH21 N2N 5.-' 'OCH3 0 9 - coo 1-1A E/Z=711 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(lmethyl pyrrolidinio)-l-prope- 20 nyll-3-cephem-4-carboxylate sulfate (11A, sulfate) A. Dipheny1methyl 7-[2-(5-Amino-1,2,4-thiadiazol-3-yi)-2methoxyiminoacetamidoJ-3-[3-(l-methyl pyrrolidinio)-l-propenyll-3-cephem-4-carboxylate (XII-1A, iodide) To a cold solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)2-methoxyiminoace- tamidoj-3-(3-iodopropenyl)-3-cephem-4-carboxylate (IX-1) (from Preparation No. 14) (21.5 g, 30 25 mmoles) in ethyl acetate (300 ml) was added dropwise a solution of 1- methylpyrrolidine (2.55 g, mmoles) in ethyl acetate (30 ml) over a period of 1 hour at -5 to O'C, with stirring. After stirring for an additional 10 minutes, the resulting precipitate was collected by filtration and washed with chloroform (200 ml) to give 23.0 g (95.8%) of the title compound (IX-1A, iodide), melting at >175C (dec.).
T IR: v (KBr) in em-' 3300, 1780, 1730, 1685, 1615.
UV: A (C2H,OH) in nm (E'%) 218 (435), 295 (188) max 1 CM 35 B. Diphenylmethyl 7-[2-(5-Amino- 1,2,4-thiadiazoi-3-yl)-2methoxyiminoacetamidol-3-[3-(1 -methylpyrrolidinio)-1-propenyll-3-cephem4-carboxylate (X11-1A, chloride) The compound (X11-1A, iodide) (23 9, 28. 7 mmoles) was dissolved in a mixture of acetone and methanol (1A, 230 mi) and applied on an Amberlite IRA-410 (chloride form, 230 mi) column which was pretreated with the same mixed solvent. The column was developed with the solvent and the fractions containing the desired compound were combined and concentrated to an oily residue, which was triturated with ethyl acetate (300 mi) to yield 17.9 g (87.7%) of the title compound (X11-1A, chloride), melting at 190C (dec.).
IR: V max (KBr) in cm-1 3380, 1780, 1680, 1620.
UV: Amax (C?H,,OH) in rim (E'%) 220 (369), 290 (232).
1CM C. 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(1methyi pyrrolidinio)-1- propenyll-3-cephem-4-carboxylate sulfate fl- 1A, sulfate) A mixture of the compound (X11-1A), chloride), (17.8'9, 25 mmoles) in 85% formic acid (178 m[) was stirred at room temperature for 2 hours under a nitrogen atmosphere. The mixture was evaporated in vacuo and the oily residue was triturated with acetone to give 9.80 9 of crude 55 1-1A. Concentration of the filtrate and the acetone washings yielded additional 2.95 9 of crude 1-1 A. Two crops of the crude material were combined and extracted with 2N HO (1 L and 0.5 L). The combined extracts were adsorbed on a Diaion HP-20 resin (1.5 L column), which was eluted with water and 30% aqueous methanol. The desired fractions were collected and evapo rated in vacuo to an oily residue, which was triturated with isopropanol (200 mi) and acetone 60 (200 m]), successively, to yield 7.09 g of a light yellow powder. This material (6.80 9) was dissolved in water (20 mi) and then subjected to column chromatography over the packing of PrepPAK-500/C, cartridge (90 mi), using water and 10% aqueous methanol as an eluent. The eluate was collected in 20-mI fractions with monitoring by HPLC. [Column, Nucleocil SSC-OlDS-262, 8x100 mm; Mobile phase, 0.01M phosphate buffer (pH 7.2)/CH, OH=90:10; 65 49 GB2194789A 49 Detection, IJIV (254 nm)]. Fraction No. 4 through Fraction No. 10 were combined, evaporated under reduced pressure and lyophilized to give 2.28 9 of a yellow powder (IE/Z=7/1, 70% pure) [Crop 1]. Fraction No. 11 through Fraction No. 85 were worked up in the same manner as described above to give 3.27 9 of yellow powder (IE/Z=5/1, 70% pure) [Crop 21. A portion of Crop 1 (1.0 9) was purified by rechromatography on the packing of PrepPAK500/C, cartridge (90 mi). The column was eluted with water and 5% aqueous methanol, successively. The eluate containing the desired compound was concentrated and lyophilized to yield 638 mg (IE/Z=7/1, 80% pure) of yellow powder. Another portion of Crop 1 (1.14 g) was worked up the same way to give 880 mg (IEIZ=7/1, 80% pure) of yellow powder. The two purified samples were combined and a portion (1.45 g) dissolved in 1 N sulfuric acid (5 mi). The solution was diluted 10 with acetone (315mi), with stirring. The creamy precipitate was collected by filtration to obtain 1.48 g of the title compound (1-1A, sulfate) (IE/Z=7/1, 80% pure), melting at >l8WC (dec.).
IR UV: 2, v (KBr) in cm 3380, 3000, 1765, 1675, 1630, 1535, 1390, 1115 m,, (Phosphate buffer, pH 7) in nm (e) 236 (19900), 291.5 (22500).
1 NMR: 6 (D20+NaHC03) in ppm 2.36 (4H, br., H), 3.15 20 (3H, s, CH3 + 3.62 (5H, br., 2-H and I), 3.83 (1 H, 25 br., 2-H), 4.13 (2H, d, J=8Hz, CH2N+), 4.22 (3H, s, OCHO, 5'39 (11-1, d, J=4.5Hz, 6-H), 5.96 (11-1, d, J=4.5Hz, 7-H), 6.00 (11-1, m, 30 3-CH=CH, 6.67 (1/8H, d, J=lOHz, 3-CH, cis), 7.04 (7/8H, d, J=16Hz, 3-CH, trans).
35 N C-CONH- S 11 1 H2N ISooN N P?e A Oh \OCH3 0 C00- CH"CH-CH2 G 7-12-Amino- 1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3trimethylammonip- 1-propenyll-3 cephem-4-carboxylate fl- W) A. Diphenyimethyl 7-[2-(5-amino- 1,2,4-thiadiazol-3-yl)-2methoxyiminoacetamidol-3-(3-trimethylammonio-1-propenyl)-3-cephem-4-carboxylate (XII-1D, iodide) To a solution of 13.0 9 (19 mmoles) of diphenyimethyl 7-[2-(5-amino-1,2,4thiadiazol-3-yi)-2methoxyiminoacetamidol-3-(3-iodopropenyi)-3-cephem-4-carboxylate (IM, from Preparation No.
10) in 38 mi of dry ethyl acetate was added 1.75 mi (19.1 mmoles) of 1. 1 N trimethylamine in ethyl acetate at -WC, and the mixture was stirred for 1 hour at -WC. The resulting precipitate 50 was filtered off, washed well with CHCI, and dried to give 12.5 g (88%) of the title compound (XII-1D) as the iodide.
IR vm,, (KBr) in cm-1 3300, 1765, 1720, 1665.
UV 1n, (C,HrOH) in nm (e) 300 (18400).
40--- B. Diphenylethyl 7-[2-(5-Amino-1,2,4-thiadiazol-3-yi)-2methoxyiminoacetamidol-3-(3-trimethyl am-monio-l-propenyl)-3-cephem-4-carboxylate (X11-1D, chloride) The iodide (X11AD, 12.5 g) was dissolved in 60 m] of CH,OH-acetone (1:1) and passed through a column 6f ion-exchange resin [IRA-410 (Cl-), 125 mi]. The column was eluted with 60 300 m] of CH,OH-acetone (M), and the eluate was evaporated in vacuo and triturated with 300 mi of isopropyl-ether to afford 10.4 g (91%) of the quaternary salt (XII- 1D, chloride).
GB2194789A 50 IR v,,,,,, (KBr) in cm-1 3300, 1765, 1710, 1665. UV Ar,, (C,H,OH) in nm (e) 298 (15100).
C. 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[3trimethyl ammonio-l-propenyl]-3-cephem-4-carboxylate (I-M, sulfate, E isomer) A solution of 10.4 g (16.0 mmoles) of Xll-1D (chloride) in 20.8 ml of 85% formic acid was allowed to stand for 3 hours at room temperature and concentrated in vacuo. The residue was treated with 210 ml of isopropanol and the precipitate was filtered off. The solid (10.1 g) was triturated with 210 ml of water and neutralized with sodium bicarbonate. The suspension was 10 filtered off and the filtrate was chromatographed on a column of HP-20 (300 ml) which was eluted with water (1000 ml), 10% CH30H (200 ml) and 30% CH30H (150 ml), successively. Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was purified by reverse phase chromatography. The column was packed with a packing obtained from a PrepPAK-500/Cl, cartridge (Waters, 200 ml). Elution with water (600 15 ml) and 30% CH30H (200 ml), successively, followed by concentration of fractions containing the desired product gave 2.52 g (18%) of the title compound. A solution of the zwitterionic product (1.5 g) in 1N H,SO, (5 ml) was added portionwise to 300 ml of acetone and the resulting precipitate was filtered and dried. Yield of I-11D sulfate was 1.42 g (80%). The ratio of E/Z was approximately 10/1 based on HPLC.
IR v,,,, (KBr) in cm-1 3380, 1765, 1665. UV A... (Phosphate buffer, pH 7) in rim (e) 237 (19500), 293 (22400).
NMR: 3 (D20) in ppm 3.25 (9H, s, N±CH3), 3.94 (2H, s, 2-H), 4.14 (2H, d, J=7Hz, C1-12N-1), 4.23 (3H, s, O-CH.), 5.42 (1H, cl, J=4.5Hz, 6-H), 6.00 (1H, d, J=4.5Hz, 7-H), 6.23 (1H, d-t, J=7 & 16Hz, 3-CH=CM, 7.23 (IH, d, J=16Hz, 3-CH).
Example 32
N S J 35 k N H2H 5, CH=CH-CHI-IC-1- CON H? 0C43 0.0 ==Y - coo 1-1 H E 7-[2-(5-Amino- 1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol-3-[3-(4carbamoylpyridinio)- 1-propenyll-3-cephem-4-carboxylate (/- 1H, E isomer) To a mixture of 7-amino-3-[3-(4-carbamoylpyridinio)-1-(E)-propenyll-3cephem-4-carboxylic acid 45 hydrochloride (XXII-H, 397 mg, 1 mmole) and NaHC03 (168 mg, 2 mmoles) in aqueous DMF (water, 3.5 mi and DMF, 7.5 mi) was added benzotriazol-l-yi-2-(5-amino-1, 2,4-thiadiazol-3-yi)-2methoxyiminoacetate (479 mg, 1.5 mmoles) (from Preparation No. 28). The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was adjusted to pH 3-4 with 3N H0 and diluted with 200 m] of acetone to give a precipitate, which was collected by filtration. The crude product was dissolved in a small volume of aqueous THF and the solution was adjusted 50 to pH 6.8 with NaHCO, treated with decolorizing carbon, concentrated to ca. 1 m] and seeded with a few pieces of crystalline 1-1H. After stirring overnight, the crystalline precipitate was collected by filtration to afford the title compound 1AH (zwitterion form). Yield 83 mg (16%).
Mp. >185'C (dec.). Physico-chemical data of this product were identical to those of the compound in Example 10.
Preparation No. 1 Diphenylmethyl 7-[2-(5-Amino- 1,2,4-thiadiazol-3-yo-2methoxyiminoacetamidol-3-chloromethyl-3- cephem-4-carboxylate (IV- 1) To a stirred suspension of 2-(5-amino-1,2,4-thiadiazol-3-yi)-2methoxyiminoacetic acid (111-1) 60 (2.1 9, 10 mmole) in dry CH2C12 (50 mi) was added PC1, (2.09 g, (10 mmole) at -30'C, and the mixture was stirred for 20 minutes at -15 to -20 OC. To the above acid chloride solution was added a solution of diphenyimethyl 7-amino-3-chloromethyi-3-cephem-4carboxylate hydrochloride (11) (4.5 9, 10 mmole) in CH2C1. (50 M1) containing N,O-bis- (trimethyisiiyi)acetamide (10 9, 50 mmole) at -30'C. After stirring at -MC for 1 hour, the mixture was concentrated to remove 65 51 GB2194789A 51 the CH2C12 and diluted with ethyl acetate (200 mi). The mixture was washed with 10% aqueous Nal-IC03 (2x40 m]), H20 (2x20 mi) and brine (10 mi), successively, and dried overM ' 9S04. The solvent was evaporated in vacuo and the resulting oily residue (10 g) was dissolved in CHCI, (20 m[) and chromatographed on a silica gel (Wako gel C-200, 100 9 containing 10 mi of 1/1.5 M pH 7 phosphate buffer (using 1-3% CH301-1-CHC13, Fractions containing the title compound were 5 evaporated to give 5.7 9 (95%) of IV-1 as a yellow amorphous powder. M. p. >140 'C (dec.).
KBr IR V cm-1 3300, 1780, 1720, 1680, 1620.
max 10 EtOH UV A nrn (6) 245 (1800), 280 (9900).
max 15 WSO-d,, NIVIR: 8 3.53 (21-1, A8q, 2-H), 3.94 (31-1, s, OCHJ, 4.42 ppm (21-1, s, 3-CH2), 5.22 (11-1, d, J=4.5, 6-H), 5.92 20 (11-1, d-d, J=4.5 & 6, 7-H), 6.93 (11-1, s, CHPh2), 7.36 (10H, m, Ph-H), 8.1 (21-1, br-s NH2), 9.58 (11-1, d, J=6, 7-NH).
Preparation No. 2 25 Diphenyimethyl 7-[2-(5-Amino1,2,4-thiadiazol-3-yl)-2- methoxyiminoacetamidol-3-iodomethyl-3-cephem-4-carboxylate (V- 1) A mixture of IV-1 from Preparation No. 1 (5.7 9, 9.5 mmole) and Nal (4.3 9 29 mmole) in dry acetone (50 mi) was stirred for 5 minutes at room temperature. The mixture was concentrated under reduced pressure and the resulting oil was shaken with a mixture of ethyl acetate (100 m]) 30 and H20 (10 mi). The organic layer was separated and washed with 10% w/v sodium thiosulfate and brine, successively. After drying, the ethyl acetate was removed in vacuo to give 6.1 9 (93%) of the title compound (VA) as a yellow amorphous powder melting at >120 OC (dec.).
KBr 35 IR V cm-1 3300, 1780, 1725, 1680, 1620.
max ROH 40 UV: A nm (e) 245 (17000), 282 (12000).
max DMSO-d, 45 NIVIR: 3 3.72 (21-1, ABq, 2-H), 3.94 (3H, s, OCH.), 4.23 ppM (21-1, s, 3-CH,), 5.21 (1H, d, J=4.5, 6-H), 5.89 (1H, d-d, J=4.5 & 6, 7-H), 6.94 OH, d, ChPh2), 7.35 (10H, m, Ph-H), 8.12 (21-1, br-s, NH2), 9.65 (11-1, d, J=6, 7-NH)). 50 Preparation No. 3 Diphenyimethyl 7-[2-(5-Amino- 1,2,4-thiadiazol-3-yl)-2methoxyiminoacetamidol-3-triphenylphosphoniomethyl-3-cephem-4-carboxylate iodide (0-1) A mixture of V-1 from Preparation No. 2 (690 mg, 1 mmole) and triphenylphosphine (786 mg, 55 3 mmole) in ethyl acetate (20 mi) was stirred overnight at room temperature. The solid which separated was collected, washed with ethyl acetate (2 x 10 mi) and dried to give 950 mg (100%) of the phosphonium iodide V1-1. M. p. 186 'C (dec.).
52 GB2194789A 52 IR KBr: v cm-1 3300, 1780, 1710, 1680, 1610. max COH UV: A nm (e) 268 (15000), 275 (13000), 300 (7300).
max DIVISOA6 NIVIR: & 3.52 (2H, br-s, 2H), 3.94 (3H, s, OCH,), 5.34 ppm (1H, d, J=4.5, 6-H), 5.9 (1H, m, 7-H), 6.3 (1H, s), 7.3 (10H, m, Ph-H), 7.8 (15H, m, Ph-H).
Preparation No. 4 Diphenyimethyl 7-[2-(5-Amino- 1,2,4-thiadiazol-3-yl)-2methoxyiminoacetamidol-3-[(triphenylphosphoranylidene)methyll-3-cephem-4-carboxylate (VII- 1) A mixture of V1-1 from Preparation No. 3 (952 mg, 1 mmole), Amberlite IRA- 410 (OH- form, 20 500 mg) and N NaOH (4 mi) in CH2C12 (10 m[) was stirred for 1 hour at room temperature. The mixture was filtered and the separated organic layer was dried over M9S04 and concentrated under diminished pressure. The resulting oil was triturated with ethyl acetate and the resulting yellow precipitate was collected by filtration to give 740 mg (90%) of the title compound V11A.
M.p. >l8WC (dec.).
KBr IR V cm-1 3400, 1750, 1630.
max EtOH LIV: A nm (8) 268 (12000), 276 (10000), 384 (23000).
max Preparation No. 5 Diphenylmethyl 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2methoxyiminoacetamido1-3-(3-chloro-1-p ropen-1-yl)-3-cephem-4-carboxylate (Vill-1) To a solution of VII-1 from Preparation No. 4 (6.9 g, 8.4 mmole) were added MgS04 (3 g) 40 and 40% choroacetaldehyde (810 mg, 8.4 mmole). The mixture was stirred for 1.5 hours at room temperature and then filtered. The filtrate was eluted on silica gel (Wakogel C-200, 100 g containing 10 ml of 1/1.5 M phosphate buffer) column by using CHC13, and CHCI, containing CH30H. Fractions containing the desired product (0.5-1% CH30H-CHC13) were evaporated in vacuo to give 1.6 g (30%) of the title compound VIII-1 as a yellow amorphous powder, which was a mixture of the Z and E isomers with respect to the chloropropenyl moiety (Z/E=2/1, by 45 nmr). M.p. >130'C (dec.).
KBr IR V cm-1 3300, 1780, 1725, 1680, 1620.
max ROH UV: A nm (e) 240 (20000), 286 (12000).
max 53 GB2194789A 53 DMSO-d6+D,0 NIVIR: (5 3.56 & 3.8 (m, 2-H), 3.94 (3H, s, OCH,), PPM 4.16 (cl, J=7.5, CHCl), 5.26 (1H, cl, J=4.5, 6-H), 5.87 (1H, cl, J=4.5, 7-H), 5 6.28 (2/3H, cl, J= 11, 3-CH cis-H), 6.72 (1 /3H, cl, J = 16, 3-CH trans-H), 6.81 (2/3H, s, ChPh2), 6.92 (l/3H, s, ChPh2), 7.4 (10H, m, Ph-H).
10 Preparation No. 6 Diphenylmethyl 7-Benzylideneamino-3[(triphenylphosphoranylidene)methyll-3-cephem-4-carboxy late (XVI) To a solution of diphenyimethyl 7-benzylideneamino-3[(triphenylphosphonio)methyll-3-cephem- 4-carboxylate iodide (XV) [prepared according to the procedure of Japan published patent application (Kokai) 56-86187 (7/31/81)l (60 9, 70 mmole) in CH2C12 (350 mi) were added N NaOH (140 m]) and Amberlite IRA-410 (OH- form, 35 9) at WC. The mixture was stirred for 1 hour at WC and filtered. The organic layer was separated, dried over M9S04, concentrated to ca. 100 mi of volume and precipitated with ethyl acetate (500 mi). The resulting yellow solid was collected by filtration and dried in vacuo to afford 48 g (94%) of the title compound XVI, 20 melting at 195-WC (dec.).
KBr IR: V cm-1 1770, 1620.
max Preparation No. 7 Diphenyimethyl 7-Benzylideneamino3-(3-chlorol-propen-l-yl)-3-cephem-4- carboxylate (XVII) To a stirred solution of M from Preparation No. 6 (2.9 g, 4 mmole) in a mixture of CH2C12 (40 mi) and H20 (10 mi), was added anhydrous chloroacetaidehyde (800 mg) at room tempera- 30 ture. To the mixture was added additional 800 mg of chloroacetaldehyde in three portions over a period of 1 hour, while the pH of the mixture was kept between 6 to 9 by addition of N NaOH. After 15 minutes, the aqueous layer was removed and the organic layer was dried over Mgso,. Evaporation of the solvent gave a red oil which was dissolved in a mixture of ethyl acetate and isopropyl ether (l/2, 80 mi). The solution was washed with saturated aqueous Nal-IC03 (10 mi) and HP (10 mi), successively. After drying over M9SO, removal of the solvent afforded 3.3 g of yellow oil. A solution of the oil in CH2C12 (50 mi) was filtered with aid of silica gel (12 9, Wakogel C-200) containing 1/1.5 M phosphate buffer (1.2 mi, pH 6. 4) and the silica gel was washed with CH2C12 (50 m]). The filtrate and washing were combined and evaporated to dryness. The residue was triturated with n-hexane to give 1.7 9 (80%) of the title compound (XVII) as a yellow powder. The nmr spectrum indicated that the chloropropenyl moiety had the Z configuration. M.p. >WC (dec.).
KBr IR V cm-1 3400, 1775, 1720, 1630.
max ROH UV: A nm (E) 253 (11000), 258 (11000), 265 (10000), 273 max (8300), 281 (7000), 290 (6300).
NIVIR: (5 DIVISO-d, 3.63 (2H, br-s, 2-H), 4.0 (2H, m, CH2-CI), 5.42 ppM (2H, m, 6-H & 3-CH=CM, 5.72 (1H, d, J=4.5, 7-h), 6.27 (1H, d, J=11, 3-CH), 6.85 (1H, s, CHPhj, 7.33 (10H, m, Ph-H).
Preparation of anhyclrous chloroacetaidehyde Anhydrous calcium chloride was added to a chilled solution of 50% aqueous chloroacetaldehyde (50 mi), with stirring, to separate it into two layers. The chloroacetaidehyde hydrate layerM (the upper layer) was separated and diluted with CI-IC13 (100 M1), mixed with M9SO, (20 g), heated to reflux for 5 minutes, and filtered. The solvent and water were removed azeotropi- cally (b.p. 56-64'Q2), and the residue was distilled to give anhydrous chloroacetaldehyde(3), b.p.
54 GB2194789A 54 70-82T/760 mm.
Ir film V cm-1 1720.
max (1) R.P. Kurkjy, E. V. Brown, J. Amer. Chem. Soc., 74, 5778 (1952).
(2) S. Trippett, D. M. Walker, J. Chem. Soc., 1961 1266. 10 (3) H. 0. House, V. K. Jones, G. A. Frank, J. Org. Chem., - 29, 3327 (1964).
Preparation No. 8 Diphenyimethyl 7-Amino-3-(3-chloro-l-propen-l-yl)-3-cephem-4-carboxylate (XVIII) A solution of XVII from Preparation No. 7 (180 mg, 0.34 mmole) in ethyl acetate (10 mi) was added to a solution of Girard Reagent T [(carboxymethyl)trimethylammonium chloride hydrazidel (251 mg, 1.5 mmole) in CH30H (10 mi) containing acetic acid (0.25 m]), at YC. After stirring for minutes at 5'C, the mixture was concentrated to remove the CH,OH and then ethyl acetate (20 mi) was added. The ethyl acetate solution was washed with H20 (2x5 mi), saturated aqueous NaHCO, (5 m[) and brine (5 mi), successively and dried over M9SO, Evaporation of the 20 solvent gave 145 mg (97%) of the title compound XVIII (Z isomer) as a yellow powder. M.p.
> 1 00'C (dec.).
KBr IR V cm-1 3400, 1770, 1720.
max EtOH UV: A nrn (s) 252 (3700)1 258 (3800), 260 (4000), 274 max (4000), 285 (4000).
Preparation No. 9 Diphenyimethyl 7-[2(5-Amino- 1,2,4-thiadiazol-3-yl)-2methoxyiminoacetamidol-3-(3-chloro- 1 -pro- penl-yl)-3-cephem-4-carboxylate (V111-1) A mixture of 2-(5-amino-1,2,4-thiadiazol-3-yi)-2-methoxyiminoacetic acid (111-1) (10.1 g, 50 mmole) and PC1, (10.4 g, 50 mmole) in dry CH,Cl, (100 mi) was stirred at - 7 to - 15C for 2 hours. The clear solution was poured into n-hexane (500 mi) to give a precipitate. The organic la er was discarded bv decantation and the re ainina solid as triturated ith n- hexane 1100 Y mi). The yellow precipitate was collected by filtration and dried in vacuo to give 12.5 9 (99%) of 40 the acid chloride, melting at 80'C (dec.).
nujol IR: V cm-1 1770.
max The acid chloride.(25 mg, 0.1 mmole) was added to a solution of XVIII (Z isomer) from Preparation No. 8 (44 mg, 0.1 mmole) in dry CH2C12 (5 mi) at room temperature, with stirring. After 30 minutes, the mixture was concentrated under reduced pressure and diluted with ethyl 50 acetate (20 mi) and saturated aqueous NaHCO, (5 mi). The organic layer was washed with saturated aqueous NaHCO, (5 ml), brine (5 mi), 10% HCI (5 mi) and brine (5 mi). The solvent was dried over M9SO, and then evaporated to dryness to give the product as a yellow foam.
The foam was purified by silica gel (Wakogel C-200, 1 g, containing 0.1 mi of 1/1.5 M phosphate buffer p 6.4) column chromatography by elution with CH2C12- CH30H (100: 1), to give 31 mg (50%) of the title compound V111-1 (Z isomer) as a yellow powder. M.p. >l5OT 55 (dec.).
KBr IR V cm-1 3400, 1775, 1720, 1675, 1630.
max GB2194789A 55 EtOH UV: A nm (.s) 240 (17000), 280 (10000).
max DIVISO-cl, NIVIR: (5 3.6 (2H, m, 2-H), 3.92 (3H, s, O-CH3), 4.0 (2H, ppm m, CHCl), 5.27 (2H, m, 6-H & 3-CH=CM, 5.83 (1H, d-d, J = 4.5 & 10, 7-H), 6.25 (1 H, d, J = 11, 3-CM, 10 6.83 (1H,s, CHPh2), 7.33 (10H, m, Ph-H), 8.0 (2H, br-s, NI-12), 9.57 (1 H, cl, J = 10, 7-NH).
Preparation No. 10 Diphenylmethyl 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2methoxyiminoacetamido1-3-(3-iodo-l-pr openl-yl)-3-cephem-4-carboxylate (IX- 1) A solution of V111-1 from Preparation No. 5 (Z/E=211, 480 rng, 0.77 mmole) in dry acetone (10 m]) containing Nal (346 mg, 2.3 mmole) was stirred for 30 minutes at ambient temperature.
The reaction mixture was evaporated under reduced pressure. The resulting oil was partitioned between ethyl acetate (50 m]) and water (10 mi). The upper layer was washed with 10% w/v 20 aqueous sodium thiosulfate solution (10 mi) and brine (10 mi) successively, and dried over M9S04. Evaporation of the solvent gave 540 mg (98%) of the title compound W-1 (Z/E=1/1) as a reddish amorphous solid, melting at >l2WC (dec.).
IR KBr V cm-1 3300, 1780, 1720, 1680, 1620.
max EtOH UV: A nm (e) 240 (21000), 290 (12000).
max DMSO+D20 35 NIVIR: J 3.67 (2H, m, 2-H), 5.29 (11-1, d, J=4.5, 6-H, PPM 5.95 (11-1, d, J=4.5, 7-H), 6.27 (1/2H, d, J = 11, 3-CH cis), 6.7 2 (1/21-1, d, J = 16, 3-CH trans), 6.87 & 6.96 (each 1/2H, s, ChPh2), 7.4 (10H, m, Ph-H). 40 Preparation No. 11 Diphenyimethyl 7-[2-(5-Amino-1,2,4-thiadiazol-3yl)-2methoxyiminoacetamido1-3-(3-iodo-1-pr open- l-yl)-3-cephem-4-carboxylate (IX-1) A mixture of V111-1 (Z isomer) from Preparation No. 9 (5.6 g, 9 mmole) and Nal (4 9, 27 45 mmole) in dry acetope (100 mi) was stirred for 1.5 hours at room temperature. The mixture was evaporated and the resulting oil was diluted with ethyl acetate (90 mi). The ethyl acetate layer was washed with 10% w/v aqueous sodium thiosulfate solution (10 mi) and 1- 1,0 (10 mi).
Removal of the dried (M9S04) solvent gave a yellow oil, which was solidified by trituration with isopropyl ether. Filtration of the precipitate gave 4.3 g (67%) of the title compound IX-1 as the 50 E isomer. M.p. >l6WC (dec.).
KBr IR V cm-1 3400, 1780, 1725, 1680, 1610.
max EtOH UV: A nm (8) 240 (18000), 297 (11000).
max 56 GB2194789A 56 DIVISO-dr,+D,0 NIVIR: 8 3.90 (31-1, s, OCH3), 5.25 (1 H, rn, 6-H), 5.95 13pm (1 lI, rn, 7-11), 6.72 (d, J=16, 3-CH trans), 6.96 (1 H, s, CH-Ph2), 7.4 (101-1, m, Ph-H). 5 Preparation No. 12 Benzhydryl 7-Amino-3-[3-chforo-1-propen-l-yll-3-cephem-4-carboxylate (Z- isomer) (XVIII) Compound XVIII is the common intermediate utilized in Reaction Schemes 'I b and 'I c.
A. Benzhydryl 7-Benzylideneamino-3-triphenylphosphoniamethyl-3-cephem-4carboxylate chloride (XW To a suspension of benzhydry] 7-amino-3-chloromethyl-3-cephem-4- carboxylate hydrochloride (11 hydrochloride) (200 9, 0.44 mole) in CH2C12 (940 mi) was added 1 N NaOH (440 mi) at room temperature. The mixture was shaken for 10 minutes and the organic layer was separated. To the organic layer were added M9S04 (75 9) and benzaldehyde (51 9, 0.48 mole) and the mixture was allowed to stand for 3 hours. The reaction mixture was filtered and the insolubles were washed with C1-1,02 (200 mi). To the combined filtrate and washings was added triphenylphos phine (126 9, 0.48 mole). The mixture was concentrated to about 400 mi and allowed to stand for 4 days. The resulting viscous oil was diluted with ethyl acetate (1 1) and triturated to 20 separate the title compound XV a pale yellow crystalline powder which was collected by filtration and dried in vacuo. Yield 322 9 (96%). M.p. 185-190'C (dec.).
KBr IR V cm-1 1780, 1720, 1630.
max CH2C12 UV: A nm (c) 260 (24100). 30 max B. Benzhydryl 7-Benzylideneamino-3-[(triphenylphosphoranylidene)methyll-3cephem-4-carboxy late (XVI) A mixture of XV (322 9, 0.42 mole) and 5 N Na,CO, (252 mi) in CH,CI, (1.6 L) was stirred 35 vigorously for 15 minutes at room temperature. The organic layer was separated, dried over MgSO, and concentrated to about 500 mi of volume. The concentrate was added to acetone (1 L), with stirring, to give a light yellow crystalline powder which was collected by filtration to yield 237 9 (78%) of XVI, melting at 195-198'C (dec.).
KBr IR V cm-1 1770, 1620.
max CH2CI2 I UV: A nm (8) 254 (23000), 389 (22000).
max CDC13 NIVIR: (5 2.56 & 3.16 (21-1, A13q), 5.00 (!H, d, J=4 Hz), 5.23 ppm (11-1, d, J=4 Hz), 5.47 (11-1, d, J=22 Hz), 6.95 (11-1, s), 7.2-7.8 (301-1, m), 8.55 (11-1, s).
C. Benzhydryl 7-Amino-3-[chloro- 1-propen- l-y11-3-cephem-4-carboxylate hydrochloride (Z isomer) (XVIII Hydrochloride) To a refluxing solution of M (214 g, 0.294 mole) and N,O-bis- (trimethyisilyl)acetamide (40 mi, 0.15 mole) in dry CH2C12 (2.9 L) was added dropwise, with stirring, a 50% solution of chloroacetaidehyde (93 9, 0.59 mole) in Ci-IC13 over a period of 15 minutes. After standing for 60 minutes, the mixture was concentrated to dryness. To the residual oil were added CH2C12 (1.5 L), Girard Reagent T (99 g, 0.59 mole) and 10% aqueous HCl (300 mi), and the mixture was stirred for 1 hour at room temperature. The organic layer was washed with water (200 mi) and a saturated NaCI solution layer was washed with water (200 mi) and a saturated NaCI solution (200 mi), dried over MgSO,, treated with charcoal (5 9) and filtered. The filtrate was 65 57 GB2194789A 57 cooled to - 1 O'C and treated with 1 N HCI in CH30H (300 ml). The mixture was stirred for 30 minutes at room temperature and concentrated to about 300 ml. The concentrate was diluted with ethyl acetate (400 ml) and seeded with a few crystals of XVIII hydrochloride. After 2 hours the separated crystals were collected by filtration, washed with ethyl acetate (200 ml) and dried in vacuo to give 74 9 (53%) of the title compound XVIII as its hydrochloride, melting at > 1 85"C 5 (dec.). Pale yellow needles.
KBr IR V cm-1 2830, 1780, 1720.
max ROH UV: X nm (a) 286 (8800).
max DIVISO-cl, NIVIR: 3 3.73 (2H, br, -s, 2-1-1), 3.97 (21-1, m, CH20), 5.22 13pm (11-1, cl, J=4.5 Hz, 6-H), 5.37 (11-1, cl, J=4.5 Hz, 20 7-1-1), 5.77 (1 H, m, 3-CH = C", 6.45 (1 H, cl, J = 11 Hz, 3-CH, 6.88 (1H, s, ChPh,), 7.33 (10H, br, s, Ph-M.
25 Anal. Cale'd for C2,1-1,N203SCIMC1:C, 57.87; H, 4.65; N, 5.87; S, 6.72; Cl, 14.85.
Found: C, 57.62; H, 4.53; N, 5.70; S, 8.64; 30 Cl, 14.89.
Preparation No. 13 Benzhydryl 7-[2-(5-Amino-1.2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol3-[3chloro-1-p ropen-1- yll3'cephem-4-carboxylate (Z isomer) (V111-1) To a stirred solution of XVIII (Z isomer) (20 9, 42 mmole) in CH2C12 (420 mi) containing N,O bis(trimethyisilyi)acetamide (34 mi, 125 mmole) was added 2-(5-amino-1,2, 4-thiadiazol-3-yl)-2- methoxyiminoacetyl chloride hydrochloride (15.2 9, 59 mmol) in three portions over a period of minutes at -10 to O'C. The mixture was stirred for 30 minutes at O-WC and concentrated under reduced pressure. The residual brown oil was dissolved in ethyl acetate (420 mi) and the 40 solution was washed successively with saturated aqueous NaHCO, (3x 15 mi), saturated aque ous NaCI (15 mi), 10% HCI (15 mi) and saturated aqueous NaCI (15 mi), and concentrated to about 50 m[ of the volume. To the concentrate was added n-heptane (200 mi) to give 28.5 9 (90% pure) of the title compound V111-1 (Z-isomer) as a colorless powder. M.p.>l5WC (dec.).
KBr IR V cm-1 3400, 1780, 1720, 1680, 1620.
max EtOH UV: A nm (r) 240 (20000), 283 (12000).
max acetone-d, NMR: (5 3.6 (21-1, m, 2-H), 3.95 (3H, s, OCH,), 4.0 P13m (2H, m, CHCl), 5.32 (11-1, d, J=4.5 Hz, 6-H), 5.62 (11-1, m, 3-CH=CM, 6.03 (11-1, cl, J=4.5 Hz, 7-H), 6.32 (1 H, cl, J= 11 Hz, 3-CH), 60 6.87 (11-1, s, ChPh2), 7.33 (10H, br, s, Ph-H).
Preparation No. 14 Benzhydryl 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2methoxyiminoacetamidol-3-[3-iodo-l-'p ropen-165 yll-3-cephem-4carboxylate (E isomer) (IX- 1) 58 GB2194789A A mixture of V111-1 (Z isomer) (28.5 9, 90% pure) and sodium iodide (19 9) in dry acetone (420 m]) was stirred for 10 minutes at room temperature and allowed to stand at WC for 2 hours. The mixture was concentrated under reduced pressure. To the residue were added ethyl acetate (420 mi) and 10% w/v aqueous sodium thiosulfate solution (30 m]), and the mixture was shaken. The organic layer was washed with water (30 mi), dried over MgSO, and evaporated to about 50 mi of volume. The concentrate was diluted with n-heptane (200 mi) to yield 30.6 g (95% pure) of the title compound.IX-1 (E isomer) as a yellow powder, melting at > 1 2WC (dec.).
KBr 10 IR V cm-1 3400, 1780, 1725, 1680, 1620.
max EtOH 15 UV A nm (6) 306b (15000).
max acetone-dr, 20 NMR: 8 3.71 (2H, m, 2-H), 3.97 (3H, s, OCH,), 4.0 PPM (2H, cl, J-8 Hz, CH21), 5.26 (1H, d, J=4.5 Hz, 6-H), 6.03 (1 H, d-d, J=4.5 & 8 Hz, changed to doublet J=4.5 Hz by D,O, 7-H), 6.32 (1H, d-t, J=15 & 8 Hz, 3-CH=CM, 6.79 (1H, d, J=15 Hz, 25 3-Ckn, 6.98 (1H, s, ChPh2), 7.35 (10H, m, Ph-H), 7.63 (2H, br, s, disappeared by D,O, N14,), 8.52 (1H, d, J=8 Hz, disappeared by D20, 7-NM.
30 Preparation No. 15 Benzhydryl 7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidol3-[3-(4-carbam oyl-l-py- ridinio)-1-propen-l-yll-3-cephem-4-carboxylate Iodide (E isomer) (X11- 114) To a suspension of IX-1 (E isoer) (30.5 9) and isonicotinamide (26 9, 212 mmole) in CH,M (120 m]) was added CH30H (100 mi) until the mixture became clear. The solution was stirred for 35 2 hours under nitrogen atmosphere at room temperature and concentrated to about 100 mi under reduced pressure. The residual semi-solid was triturated with isopropyl ether (200 mi).
The solvent was removed by decantation and the residual yellow powder was washed with a mixture of isopropyl ether and CH,OH (3/1, 120 mi). The powder was collected by filtration and dried in vacuo to give 36 9 (75% pure estimated by HPLC) of the title compound X11-1 H (E 40 isomer) as a light yellow powder melting at >l5WC (dec.).
KBr IR V cm-1 3300, 1780, 1720, 1680, 1620.
max 45 EtOH 1%H UV: A nm (E) 282 (170).
max 1 cm 50- DMSO-d, NMR: ú5 3.72 (2H, m, 2-H), 3.90 (3H, s, OCH3), 5.25 (3H, ppm m, 6-H & CH2W), 5.9 (1H, d-d, J=4.5 & 8 Hz, 55 changed to a doublet J=4.5 Hz by D20 addition, 7-H), 6.35 (1H, m, 3-CH=CF4, 6.89 (1H, s, ChPh2), 6.9 (1H, cl, J=16 Hz, 3-CM, 7.35 (10H, m, Ph-H), 8.06 (2H, br, s, disappeared by D,O, N142), 8.21 (2H, br, s, disappeared by D20 60 addition, NH2), 8.36 & 9.07 (each 2H, cl, J=6 Hz, Py-M, 9.57 (1H, d, J=8 Hz, disappeared by D,0 addition, 7-NH).
Preparation No. 16 65 11 59 GB2194789A 59 Benzhydryl 7-Benzylideneamino-3-[3-chloro-1-propen-1-yl]-3-cephem-4- carboxylate (XV11) (Z isomer) To an ice-cooled mixture of the crystalline 7-amino-cephem intermediate XVIll (Z isomer) (13.4 g, 28 mmole) and benzaldehyde (3.3 g, 31 mmole) in ethyl acetate (150 ml) was added dropwise 0.5 N sodium hydroxide (56 ml, 28 mmole) over a period of 20 minutes, to maintain the temperature of the reaction mixture below 10"C. The mixture was stirred with cooling for another 15 minutes, and the organic layer was separated, washed with saturated aqueous sodium bicarbonate (100 m1x2) and dried over magnesium sulfate. To the dried solution was added a small amount of charcoal and the mixture was filtered. The filtrate was concentrated to dryness. The residual oil was dissolved in carbon tetrachloride (50 ml), and concentrated again. 10 This procedure was repeated 3 times, and the mixture was monitored by reverse phase tlc to confirm that all of the starting 7- aminocephalosporin was converted to the Schiff's base. Removing the solvent in vacuo gave 16.45 g of the title compound XVII (Z isomer) as a pale yellow powder (estimated purity 85%; M.p. 74'C (dec.), which was used for the next step without purification.
IR LIV:), max MC13 KBr V cm-1 1780, 1725, 1635. max CH,Cl, 1% nm (a) (E 257 (400).
1 cm NMR: (5 6.18 (1 H, d, J = 11 Hz).
ppm Preparation No. 17 Benzhydryl 7-Benzyiideneamino-3-[3-(4-carbamoyl-l-pyridinio)1-propen-lyll-3-cephem-4-c arboxyl- 30 ate Iodide (XXM) (E isomer) To a chilled mixture of the 3-chloropropenyleephem XVII (Z isomer) (16.4 9) in acetone (5 mi), was added dropwise a solution of sodium iodide (6.3 9, 42 mmole) in acetone (30 mi) over 10 minutes under nitrogen atmosphere, and the mixture was stirred at room temperature. The reaction was monitored by the ratio of uv absorption 1% 1 cm 1% (255 nm)/E (320 nm)l.
1 cm When the ratio reached below 1.30 (after 45 minutes), the mixture was diluted with carbon tetrachloride (400 mi), and allowed to stand at room temperature. When the ratio came to below 1.10 (after 3 hours), the mixture was concentrated to a half its volume. The concentrate was treated with a small amount of charcoal and diatomaceous earth, and filtered. The filter cake was washed with a 1:1 mixture (100 mi) of methylene chloride and carbon tetrachloride. 45 To the combined solution of the filtrate and washings, was added a solution of isonicotinamide (3.5 9, 28.7 mmole) in dimethylformamide (20 mi) and the mixture was concentrated under reduced pressure. The concentrate was afflowed to stand at room temperature for 1.5 hours and washed with isopropyl ether (100 m]x3). The residual brown semi-solid was dissolved in methylene chloride (50 mi) and the solution was added dropwise, with stirring, to ethyl acetate 50 (1.5 L). The resulting precipitate was collected by filtration and washed with ethyl acetate (200 mi). After drying over phosphorous pentoxide in vacuo, 17 gof the title compound M-H (E isomer) was obtained. Yellow amorphous powder. Mp. 150-155'C (dec.). Estimated purity 80% by nmr.
KBr IR V cm-1 1775, 1725, 1690, 1635.
max CH2C12 UV: A nm (E max 1 cm ) 258 (335), 298 (255).
GB2194789A 60 NIVIR: (5 DMSO-d6 ppm 3.4-3.8 (2H, br.), 5.35 (2H, br.), 5.41 (1H, d, J=4 Hz), 5.73 (1H, cl, J=4 Hz), 6.93 (1H, s), 6.97 (1H, cl, J=16 Hz), 7.3-7.5 (15H, br. s), 8.40 (2H, d, J=6.5 Hz), 9.15 (2H, cl, J=6.5 Hz).
Preparation No. 18 7-Amino-3-[3-(4-carbamoyl- 1-pyridinio)- 1-propenl-yll-3-cephem-4- carboxylate (XXIM) (E isomer) 10 To a suspension of the quaternized cephem XXI-H (17 9) in 85% formic acid (25 m]) was added dropwise concentrated hydrochloric acid (5 mi), and the mixture was stirred at room temperature for 1.5 hours and treated with a small amount of charcoal. The mixture was filtered and washed with 85% formic acid (5 mi). The filtrate was combined with the wash and poured into acetone (1 L), with stirring. The resulting precipitate was collected by filtration to give 9.52 9 of yellow-colored crude product. To a suspension of the crude material (9.5 9) in water (50 m]) was added a small amount of charcoal, and the mixture was filtered. The filtrate was added dropwise, with stirring, to isopropyl alcohol (700 mi). The resulting precipitate was collected by filtration, washed with a small amount of methanol (30 mi), and dried to give 7.58 9 of the title compound XXII-H (E isomer) as the hydrochloride. Light yellow powder. Estimated purity 85% by UV. M.p. (173-188'C (dec.).
KBr IR V cm-1 1795, 1680, 1620, 1575, 1540.
max UV: A max NIVIR: 5 13pm Phosphate buffer (pH 7) 1% D20+Xl nm (E) 294 (457).
1 cm 3.82 (2H, s), 5.17 (11-1, cl, J=5 Hz), 5.33 (2H, d, J=7 Hz), 5.43 (11-1, d, J=5 Hz), 6.37 (1H, d-t, J=16 & 7 Hz), 7.23 (1 H, d, J=16 Hz), 8.34 (2H, cl, J=7 Hz), 9.00 (2H, d, J7 Hz).
Preparation No. 19 2-(5-Amino-1,2,4thiadiazol-3-yl)-2-methoxyiminoacetyl Chloride Hydrochloride (111-1 as its acid chloride hydrochloride) A. 2-Cyano-2-methpxyiminocetamide To a stirred mixture of a-cyanoacetamide (252 9, 3 mole) and sodium nitrite (414 9, 6 mole) in water (600 mi) was added acetic acid (371 mI, 10 mole) at 5-MC over 1. 5 hours. The 45 mixture was allowed to stir for another 1.5 hours and adjusted to pH 8.5 with 6 N NaOH. To the mixture was added dimethyl sulfate (568 m], 6 mole) at 15-20'C and the mixture was stirred at 4WC for 1.5 hours. The reaction mixture was adjusted to pH 8.5 with 6 N NaOH and allowed to stand at WC overnight to separate the precipitate, which was collected by filtration, washed with cold water and air-dried to give 292 g (77%) of the title compound as brown 50 needles melting at 170-1720C.
KBr V cm-1 3400, 3180, 1720(sh), 1715, 1690, max 1615, 1570.
H,O UV: A nm (8) 238.5 (8290), 268 (sh, 3870).
max 61 GB2194789A 61 DIVISO-d6 NMR: (5 4.20 (3H, s, OCH.), 7.85 (2H, br. NH2).
PPM Anal. CaWd. for C,H.)N302: C, 37.80; H, 3.97; N, 33.06 Found: C, 37.43; H, 3.75; N, 32.51.
B. 2-Methoxyiminopropanedinitrile A stirred mixture of 2-cyano-2-methoxyiminoacetamide (88.9 g, 0.7 mole), sodium chloride (70 g) and phosphorus oxychloride (97 ml, 1.05 mole) in dry 1,2-dichloroethane (350 ml) was refluxed for 16 hours. The insolubles were filtered off through a dicalite pad and washed with dichloroethane. The filtrate and the wash were combined, and poured into stirred ice- water (1.5 15 Q to decompose the excess of phosphorus oxychloride. The organic phase was washed with 10% NaHCQ, (500 ml), water (500 mlx3) and a saturated NaCl solution (500 ml), and dried over MgS04. The filtrate was distilled under diminished pressure to give 61.5 g (81%) of the title compound boiling at 620C/24 mm Hg. (Lit., b.p. 47-48'C/12 mm Hg).
CDC13 NMR: (5 Liquid Film IR: v cm-1 3020, 2960, 2245, 2020, 1530, 1455, max 1080.
ppm 4.35 (3H, s, OCHJ.
C. 2-Cyano-2-methoxyiminoacetamidinium Acetate To a solution of ammonium chloride (28.4 g 0.53 mole) in 28% aqueous ammonia (355 ml) 30 and ethanol (180 ml) was added dropwise a solution of 2- methoxyiminopropanedinitrile (58.0 g, 0.53 mole) in ethanol (120 ml) at -15 to -10'C over a period of 30 minutes, with stirring.
The mixture was stirred at -10'C overnight and then at ambient temperature (20-250C) for one day. The reaction mixture was partitioned between water (350 ml) and CH2C12 (350 ml), and the aqueous phase was saturated with sodium chloride, and extracted again with CH2CI2 (300 ml). 35 The organic extracts were combined, dried over MgSO, and evaporated in vacuo. A solution of the residue in ethyl acetate (1.6 Q was adjusted to pH 3-4 with acetic acid to precipitate the title compound as crystals, which were collected by filtration and washed with ethyl acetate.
Yield 67.6 g (69%). M.p. 152-4C (dec.). [Lit., m.p. 150-155'C (dec.)].
KBr IR V cm-1 3160, 2900, 2360, 2235, 2000, 1665, 1555, max 1495, 1415.
ROH LIV: Z nm (r) 243 (8500), 265 (sh, 5380), 305 (sh, 1400).
max DIVISO-d6 NIVIR: 3 ppm 1.88 (3H, s, CH3COOH), 4.15 (3H, s, OCH,), 7.60 (4H, br,).
Anal. Calc'd for C41-1,NP.CH3COOH: C, 38.71; H, 5.41; N, 30.09 Found:C, 38.71; H, 5.59; N, 29.51.
D. 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2methoxyiminoacetonitrile To a suspension of 2-cyano-2-methoxyiminoacetamidinium acetate (125 9, 0. 672 mole) in CH,OH (1.25 L) were added dropwise triethylamine (234 m], 1. 68 mole) at -10'C, and subsequently Br, (41.6 m[, 0.806 mole) over 20 minutes at -15 to -10'C, and the mixture was stirred for 20 minutes. To the mixture was added dropwise a solution of KSM (78.3 g, 0.806 mole) in CH,OH (550 mi) over 1 hour at - 15 to - 1 O'C. After stirring at O-WC for 1 hour, the 65 62 GB2194789A 62 mixture was poured into ice-water (12 L) to form a crystalline precipitate, which was collected by filtration, washed with water and air- dried to give 120 9 (98%) of the title compound. M.p. 263-WC (dec.). The m.p. of the compound prepared by us is higher by about WC than that given in the literature [m.p. 210-150C (dec.)], but our spectral and microanalytical data are 5 consistent for the structure.
KBr IR V cm-1 3435, 3260, 3120, 2960, 2245, 2020, 1630, max 1545, 1455, 1415.
10 ROH UV: A nm (8) 248 (13300), 310 (3470).
max 15 DMSO-d, NMR: J ppm 4.21 (3H, s, OCH3), 8.30 (21-1, br. W2).
Anal. CalcA for C,H^OS: C, 32.78; H, 2.75; N, 38.23; S, 17.50 Found: C, 32.76; H, 2.51; N, 38.02;. S, 17.50.
E. 2-(5-Arnino- 1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic Acid (1//- 1) A mixture of 2-(5-amino-1,2,4-thiadiazol-3-V1-2-methoxyiminoacetonitrile (18.3 g, 0.1 mole) in 4 N NaOH (250 mi) was heated at 50-55'C with stirring for 3 hours. The reaction mixture was adjusted to pH 1 with HP0, and washed with ethyl acetate (100 mi), saturated with NaCI, and extracted three times with a mixture of ethyl acetate and tetrahydrofuran (3: 1, 300 m]x2, and 30 mix 1). The extracts were combined, dried over M9SO, and concentrated under reduced pressure. The residue was triturated with isopropyl ether to afford pale yellow crystals of the title acid. Yield 16.8 9 (83%). M.p. 184-WC (dec.). [Lit., m.p. 180-182'C (dec.)].
KBr 35 IR V cm-1 3460, 3260, 3140, 1725, 1620, 1605, 1545.
max H20 40 IJV A nm (8) 234 (13200), 288 (sh, 3620).
max F. 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetyl Chloride Hydrochloride To a suspension of 2-(5-amino-1,2,4-thiadiazol-3-yi)-2-methoxyiminoacetic acid (111-1) (40.4 9, 45 0.2 mole) in dry CH2C1. (400 mi) was added PC1, (41.6 g, 0.2 mole) in one portion at -50'C.
The mixture was stirred for 4 hours at -20 to -5'C, and poured into a mixture of n-heptane and isopropyl ether (2: 1, 2 L). The yellow precipitate was collected by filtration, washed with the same solvent mixture, and dried with KOH under reduced pressure to give 46.0 9 (90%) of the title acid chloride.
IR Nujol V cm-1 1775.
max Japan Kokai 57-158769 published September 30, 1982, to Fujisawa (Brit. appl., 3/6/81) Preparation No. 20 GB2194789A 63 H C-CONH 5 -TCQCHCH-CH2-Cl N2N j Ls.,,' N 9\ 0 0 Vill Z A C2N5 COOCH(PM2 Diphenyimethyl 7-[2-(5-Amino- 1,2,4-thiadiazol-3-yl)-2-(Z)ethoxyiminoacetamidol-3-[3-chloro- 1-pro- 10 penyll-3-cephem-4-carboxylate (V111-2, Z isomer) To a mixture of N,O-bis(trimethyisiiyi)acetamide (2.3 m], 9 mmoles) and crystalline diphenyimethy[ 7-amino-3-[3-chloro-l-(Z)-propen-l-yi]-3- cephem-4-carboxylate hydrochloride (XVIII) (1.338 g, 2.8 mmoles) (from Preparation No. 12) in methylene chloride (10 m]) was added 2-(5-amino1,2,4-thiadiazol-3-yi)-2-(Z)-ethoxyiminoacetyl chloride hydrochloride (800 mg, 2.95 mmoles) portionwise, with stirring, at - 1 O'C and the mixture was allowed to stand at O'C for 2 hours. The mixture was diluted with ethyl acetate (200 mi), washed with water and evaporated under reduced pressure. Trituration of the residue with isopropyl ether afforded the title product V111-2 as an amorphous powder. Yield 1.70 g (95%). Mp. >150C (dec.).
: v,,,,,, (KBr) in cm-1 3300, 1780, 1720, 1690, 1380, 1220.
UV: Amax (C21-1501-1) in nm (c) 285 (11000).
NMR: (5 (DMS0A6) in ppm 1.26 (31-1, t, J7Hz, CH2CH3), 4.25 (21-1, q, J=711z, CH2CH3), 5.90 (11-1, d-d, J=4 & 8Hz, 7-H), 6.26 (11-1, d, J=111-tz, 3CH), 6.85 (11-1, s, Cl-lPh2), 9.53 (11-1, d, J=81-1z, 7-NH).
Preparation No. 2 1 CONH N\ N 0 CH=CH- CH2 1 1 L2H5 COO C H (P W2 IX-2 A mixture of E and Z isomers Diphenyimethyl 7-[2-(5-Amino1,2,4-thiadiazol-3-yl)-2-(Z)- ethoxyiminoacetamidol-3-[3-iodo- 1 -propenyll-3-cephem-4-carboxylate (IX-2) A mixture of V111-2 (1.90 g, 3 mmoles) (from Preparation No. 20) and sodium iodide (1.4 g, 9 mmoles) in acetone (20 mi) was stirred for 10 minutes at room temperature and then allowed to.
stand at WC for 3 hours. The mixture was evaporated under reduced pressure, diluted with ethyl acetate (100 mi), washed with 10% sodium thiosulfate and water, and evaporated under re duced pressure. Trituration of the residue with isopropyl ether gave 1.82 9 (84%) of the title product IX-2 as a light brown amorphous powder.
IR vm. (KBr) in cm-1 3290 1770, 1720, 1670, 1530, 1370, 1220.
uv: A Preparation No. 22 1% (C,H50H) in nm (E 304 (199).
1 CM 64 GB2194789A 64 1 IG (D CR=CH-CH N,CON 0TiN 2 - H 2 COO CH (PM2 M-H iodide E Diphenyimethyl 7-Benzylideneamino-3-[(E)-3-(4-carbamoylpyridinio)-1propeny11-3-cephem-4-ca r- 10 boxylate (XXl-H iodide) (E isomer) To a chilled solution of the 3-chloropropenylcephem (XVII, Z isomer, 42.8 g, 90 mmoles) (from Preparation No. 16) in dry DIVIF (80 m[), was added KI (20 9, 120 mmoles) in one portion, and the mixture was stirred at room temperature. The reaction was monitored by the ratio of 15 UV absorption 1 % 1 % [E (255 nm)/E (320 nm)l.
1 em 1 em When the ratio became below 1.10 (after 45 minutes), the mixture was diluted with 800 mi of methylene chloride, treated with active carbon (4 g), and filtered. The filter cake was washed with 100 mi of CH,Cl, To the combined filtrate and washings was added isonicotinamide (14.64 g), and the mixture was concentrated under reduced pressure. The concentrate was kept at room temperature for 1.5 hours and washed with a mixture of toluene and n-heptane (1A, 600 m]). The residual brown semi-solid was dissolved in CH2C12 (100 mi) and the solution was added dropwise to ethyl acetate (3 Q with vigorous stirring. After drying over P20. in vacuo, 57.37 9 (88%) of the quaternized title product XXI-H was obtained as the iodide. Yellow amorphous powder. Mp. 150-155'C (dec.). This product was identical to that obtained by iodination with Nal (Preparation No. 17).
Preparation No. 23 MCH2N- 4l _N 0 COCH-CH2-Cl COO C H(Ph h XVIII Z I Diphenylmethyl 7-Amino-3-(3-chloro-1-propenyl)-3-cephem-4-carboxylate hydrochloride (Z isomer) 40 (XVIII, Hydrochloride) A 25% solution of chloroacetaldehyde (69 9, 0.22 mmoles) in CK13 was added to a solution of XVI (80 9, 0.11 mole) in CH2C12 (1,1 L) containing N,Obis(trimethyisiiyi)acetamide (16.2 mi, 0.06 mole) at -10'C in one portion, and the mixture was allowed to stand overnight at 5'C.
The mixture was concentrated to ca. 0.3 L, diluted with a mixed solvent of ethyl acetate and 45 isopropyl ether (l/2, 0.6 L), treated with silica gel (Wakogel C-100, 60 9) and filtered through a dicalite pad. The filter cake was washed with the same solvent system (0. 2 L). The combined filtrate and washing were concentrated to ca. 0.2 L, treated with Girard Reagent T (60 g, 0.26 mole) and 4N HCl (220 mi), and seeded with a few crystals of XVIII hydrochloride. After stirring for 3 hours, the resulting crystals were collected by filtration, washed with water (0.5 L) and 50 ethyl acetate (0.5 L) and dried in vacuo to give 37 9 (70%) of the title compound XVIII hydrochloride, melting at >185'C (dec.). Pale yellow needles. This product was identical to that obtained in Preparation No. 12.
Preparation No. 24 MCIH2N 5 xVill z N At.
CH=CH- CH2- Cl COO C H(Ph h Diphenylmethyl 7-Amino-3-(3-chloro-1-propenyl)-3-cephem-4-carboxylate hydrochloride (Z isomer) 65 (XVIII, Hydrochloride) GB2194789A To a solution of chloroacetaidehyde (25% solution in CHC13, 628 mg, 2 mmoles) in CH2C12 (10 mi) were added N,O-bis(trimethyisiiyi)acetamide (0. 135 mi, 0.5 mmole) and W (728 mg, 1 mmole), successively, at 5'C. The mixture was allowed to stand overnight at WC. The mixture was evaporated and diluted with a mixture of ethyl acetate and isopropyl ether (l/2, 10 mi).
Insolubles were removed by filtration and the filtrate was concentrated to ca. 5 mi. The concentrate was treated with 4N HQ (2 mi), seeded with XVIII hydrochloride and stirred for 1 hour at room temperature. The crystals were collected by filtration, washed with ethyl acetate (10 mi) and water (10 mi) and dried in vacuo to give 384 mg (80%) of the title compound XVIII hydrochloride, melting at >l8WC (dec.). Pale yellow needles. This product was identical to that 10 obtained by Preparation No. 12.
Preparation No. 25 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(propen-3-yloxyimino)-acetyl chloride hydrochloride (111-3 as its acid chloride hydrochloride A. Methyl 2-(5-t-butoxycarbonylammonio-1,2,4-thiadiazol-3-yl)-2-(propen-3yloxyimino)a cetate 15 A mixture of 685 mg (3.37 mmoles) of W(propen-3-yloxy)phthalimide [prepared according to the procedure of E. Grochosaki & J. Jurczak, Synthesis 1976 6821 and 175 mg (3.35 mmoles) of hydrazine hydrate in 5 mi of C,H,OH was stirred for 1 hour at room temperature. The resulting precipitate was filtered off and the filtrate and washings were combined. To the solution was added 967 mg (3.37 mmoles) of methyl 2-(5-t- butoxycarbonylamino-1,2,4-thiadiazol-3-yi)-2-oxoacetate, and the mixture was allowed to stand for 1 hour at room temperature and concentrated by a rotary evaporator. The residue was purified by silica gel chromatography.
The column was eluted with n-hexane/ethyl acetate (4:11) and fractions containing the major product were combined and evaporated under reduced pressure. Yield 514 mg (46%). Mp.
83-86'C.
IR: v,,,. (KBr) in cm-1 3100, 1745, 1710, 1610.
UV: Amax (C2H,OH) in rim (a) 223 (9700), 242 (10000).
NMR: & (CDCI,) in ppm 1.55 (9H, s, BOC-H), 4.40 (2H, cl, J=5Hz, O-CH2), 5. 21 (21-1, m, C112=CH), 5.90 (1H, m, -CH=CH2), 9.50 (1H, br.s, NH).
B. 2-(5-t-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-(propen-3yloxyimino)ace tic acid') A solution of 770 mg (2.3 mmoles) of methyl 2-(5-t-butoxycarbonylamino-1, 2,4-thiadiazol-3yi)-2-(propen-3-yioxyimino) acetate and 3.5 m] of 2N NaOH solution (7.0 mmoles) in 15 m] of CH30H was refluxed for 30 minutes. The reaction mixture was concentrated in vacuo and diluted with 10 mi of ethyl acetate-H20 (1:1). The water layer was separated, acidified to pH 2 with 6N 40 HCI and extracted with ethyl acetate (10 mix2). The ethyl acetate solution was dried over M9SO, and concentrated by a rotary evaporator to afford 596 mg (81%) of the title compound.
Mp. 134-135'C (lit": mp. 135-136'C.
IR: v zx (Nujol) in cm-1 3150, 1745, 1710, 1550.
UV: Amax (C2H,OH) in nm (c) 223 (11000), 242 (11300).
NIVIR: 3 (DMSO-d6) in ppm 1.55 (9H, s, BOC-H), 4.77 (21-1, d, J=5Hz, OCH2), 5.22 (2H, m, C142=CH), 6.0 (1H, m, CH=CH2).
1) 1. Csendes, et al., J. Antibiotics, 36, 1020 (1983).
C. 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(propen-3-yloxyimino)acetic acid (111-3)1) A solution of 570 mg (1.74 mmoles) of 2-(5-t-butoxycarbonylamino-1,2,4- thiadiazol-3-yi)2(propen-3-yloxyimino)acetic acid in 6 mi of trifluoroacetic acid was allowed to stand for 1 hour at ambient temperature. Evaporation followed by trituration with 30 mi of isopropyl ether gave 376 mg (95%) of the title compound. Mp. 1OWC (dec.).
66 GB2194789A 66 IR: v (Nujol) in cm-1 3180, 1710, 1545, 1460 UV: 4 (C,.H,,OH) in nm (c) 245 (13500).
NIVIR: 8 (DIVISO-d6) in ppm 4.77 (21-1, d, J=5Hz, O-CH,), 5.20 (2H, m, CH=CH), 6.0 (1H, m, CH=CH2).
1) Japan Kokai 57-112396 (7/13/82, Fujisawa) Brit. appl. 7935538 (10/12/79).
D. 2-(5-Amino-1,2,4-thiadiazol3-yl)-2-(propen-3-Yloxyimino)acetyl chloride hydrochloride A solution of 350 mg (1.54 mmoles) of 111-3 and 410 mg (1.97 mmoles) of phosphorous pentachloride in dichloromethane (5 m]) was stirred for 1 hour at 2WC. The reaction mixture was 15 poured into 60 mi of n-hexane and the precipitate was filtered off. Yield 323 mg.
IR: v,,,. (Nujol) in cm-1 1765.
Preparation No. 26 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-propargyloxyiminoacetyl chloride hydrochloride (111-4 as its acid 20 chloride hydrochloride) A. Methyl 2-(5-t-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2propargyloxyiminoacetate A suspension of 870 mg (4.32 mmoles) of N-propargyloxyphthalimidel) and 200 mg (4.0 mmoles) of hydrazine hydrate in 5 mi of ethanol was stirred at 2WC for 1 hour and filtered. To the combined filtrate and washings was added 1.0 g (3.86 mmoles) of methyl 2(5-t-butoxycar bonylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetate2). The solution was allowed to stand for 1 hour and concentrated under reduced pressure. Purification by silica gel chromatography followed by evaporation afforded 319 mg (27%) of the title product. Mp. 72-75C.
IR: v,,,, (KBr) in cm-1 3200, 2380, 1745, 1710, 1610.
UV: Amax (C2H,OH) in nm (e) 235 (12200).
NMR: 3 (DIVISO-dj in ppm 1.56 (9H, s, BOC-1-1), 3.55 (1H, t, J=2Hz, C=CH), 4.85 (21-1, d, J=2Hz, -CH2-C=-CH), 8.9 (11-1, br.s, NH).
1) Commercially available, Aldrich. 2) 1. Csendes et al., J. Antibiotics 36, 1020 (1983).
B. 2-(5-t-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2propargyloxyiminoacetic acid A solution of 490 mg (1.4 mmoles) of methyl 2-(5-t-butoxycarbonylamino-1, 2,4-thiadiazol-3yl)-2-propargyloxyiminoacetate and 2.2 m[ of 2N aqueous NaOH solution (4.4 mmoles) in 14. mI of CH,OH was refluxed for 30 minutes. The reaction mixture was concentrated under reduced pressure and 10 mi of ethyl acetate-1-120 (1:1) was added to the solution. The separated water layer was acidified to pH 2 with 6N HCI and extracted with ethyl acetate (2 x 10 m]). Drying over M9S04 followed by evaporation of the organic layer gave 149 mg (89%) of the title product. Mp. 1350C (dec.).
IR: v,,,,, (Nujol) in cm-1 3350, 1720, 1670, 1550, UV: max (C2H,OH) in nrn (.-) 233 (11500).
NIVIR: 6 (DIViSO-dj in ppm 1.55 (9H, s, BOC-1-1), 3.55 (1 H, t, J=2Hz, C=CH), 4.89 (2H, d, J=21-1z, CH2_C-CH), 9.0 (1H, s, NH).
C. 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-propargyloxyiminoacetic acid (1114)3) A solution of 410 mg (1.26 mmoles) of 2-(5-t-butoxycarbonylamino-1,2,4- thiadiazol-3-yi)-2propargyloxyiminoacetic acid in 5 mi of trifluoroacetic acid was allowed to stand for 1 hour at 60 2WC. Evaporation followed by trituration of the residue with 25 mi of isopropyl ether gave 204 mg (72%) of the title compound. Mp. 156-158'C (dec.).
Zll 67 GB2194789A 67 IR: v,,,,, (Nujol) in cm-1 3300, 2480, 1730, 1610.
UV Amax (C2H5OH) in nm (e) 234 (12000).
NIVIR (5 (DIVISO-d6) in ppm 3.52 (1H, t, J2Hz, C-CH), 4.86 (2H, cl, J=2Hz, CH2-C=-CH), 8.10 (2H, br.s, NH2).
3) Japan Kokai 57-112396 (7/13/82, Fujisawa) Brit. appl. 7935538 (10/12/79).
* D. 2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-propargyloxyiminoacetyl chloride hydrochloride A mixture of 175 mg (0.07 mmol) of 111-4 and 182 mg (0.88 mmole) of phosphorous pentachloride in dichloromethane (2 mi) was stirred for 1 hour at -WC. The reaction mixture was poured into 30 m] of n-hexane and the precipitate was filtered off. Yield 65 mg (34%).
IR: v,,,, (Nujol) in em-' 1770.
Preparation No. 2 7 2-(5-Amino1,2,4-thiadiazol-3-yl)-2-cyclopentyloximinoacetyl chloride hydrochloride (111-5 as its acid chloride hydrochloride) A. Methyl 2-(5-tbutoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoaceta te A suspension of 860 mg (3.7 mmoles) of N-(cyclopentyloxy)phthalimidel) and 185 mg (3.7 mmoles) of hydrazine hydrate in 5 MI Of C21---1,0H was stirred for 1 hour at ambient temperature and filtered. The filtrate and washings were combined and added to 1.06 9 (3.7 mmoles) of methyl 2-(5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yi)- 2-oxoacetate2). The solution was allowed to stand for 1 hour at room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography. Elution with n-hexane-ethyl acetate (4:1) followed by evaporation gave the title product. Yield 906 mg (81%). Mp. 115-118'C.
IR: v,,,,, (KBr) in em-' 3200, 1745, 1710, 1550.
UV Arriax (C2H5OH) in nm (e) 217 (1800), 252 (7600).
NIVIR (5 (CIDC13) in ppm 1.51 (9H, s, BOC-H), 1.60 (8H, br.s, H-C), 3.88 (3H, s, OCH3), 4.90 (1H, br.s, X]), 8.70 (1H, br.s, NH).
0 / 1) U.S. Patent 3,971,778 (7/27/76; Glaxo), Brit. appl. 49255 (10/25/72). 2) 1. Csendes et al., J. Antibiotics 36, 1020 (1983).
B. 2-(5-t-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2cyclopentyloxyiminoaceti c acid A solution of 500 mg (1.34 mmoles) of methyl 2-(5-t-butoxycarbonylamino-1,2,4-thiadiazol-3Vi)-2cyclopentyloxyiminoacetate and 2N NaOH solution (2 mi, 4 mmoles) in 15 mi of CH30H was refluxed for 30 minutes. The reaction mixture was evaporated and 10 m] of ethyl acetateH20 (1:1) was added to the solution. The water layer was separated, acidified to pH 2 with 6N HCI and extracted with ethyl acetate (10 mix2). The organic layer was washed with brine, dried over M9S04 and concentrated under reduced pressure to give 377 mg (78%) of the title compound. Mp. 18WC (dec.), IR Vmax (KBr) in em-' 3160, 1710, 1550.
UV Amax (C2H5OH) in nm (e) 238 (13300).
60NIVIR (DIVIS0) in ppm 1.51 (9H, s, BOC-H), 1.70 (SH, br.s., H H]), 4.8 2 (1 H, m, /X]) - C. 2-(5-Amino1,2,4-thiadiazol-3-yl)2-cyclopentyloxyiminoacetic acid (111-5, Z isorneffl) 68 GB2194789A 68 A solution of 348 mg (0.97 mmoles) of 2-(5-t-butoxycarbonylamino-1,2,4thiadiazol-3-yi)-2cyclopentyloxyiminoacefic acid in 2 mi of trifluoroacetic acid was allowed to stand for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was triturated with 5 mi of isopropyl ether and 10 mi of hexane to give 215 mg (86%) of the 5 title compound. Mp. 162-165C (dec.) [iit3): Mp. 160- 165'C (dec.)].
IR: v..... (Nujol) in cm-1 3290, 3200, 1710, 1615, 1600.
LIV: Amax (CAOH) in nm (e) 238 (13300).
NIVIR: 3 (DIVISO-dj in ppm 1.17-2.10 (8H, m), 4.60-4.98 (1H, m), 8.22 (2H, s).
3) Japan Kokai 57-158769 (9/30/82, Fujisawa) Brit. appl. 8107134 (3/6/81).
D. 2-(5-Amino- 1,2,4-thiadiazol-3-yi)-2-cyclopentyloxyiminoacetyl chloride hydrochloride A solution of 190 mg (0.74 mmole) of 111-5 and 219 mg (1.0 mmole) of phosphorous pentachloride in dichloromethane (5 mi) was stirred for 1 hour at room temperature. The reaction mixture was poured into 50 mi of n-hexane. The resulting precipitate was collected by filtration. 20 Yield 122 mg (60%).
IR: %,,,. (Nujol) in cm-1 1760.
Preparation No. 28 Benzotriazol- l -yl-2-(5-amino1,2,4-thiadiazol-3-yl)-2- methoxyiminoacetate A mixture of 1-hydroxybenzotriazole (2.7 9, 20 mmoles) and dicyclohexylcarbodiimide (4.12 g, mmoles) in 65 m] of DMF was stirred at room temperature. After 15 minutes, 111-1 (4.04 9, mmoles) was added to the stirring mixture at O'C, and stirring was continued for 3 hours.
The reaction mixture was filtered to remove the insoluble urea, and the filter cake was washed 30 with a small volume of 13MF The filtrate and washings were combined and poured into 800 mi of ice water. The precipitate was collected by filtration to give 5.24 9 (82%) of the title compound as a light grey powder. Mp. 189-192'C (dec.).
iR: v.,,, (KBr) in cm-1 1815, 1620, 1540, 1415, 1090, 1060, 1005, 945, 865, 740.
1% LIV: Amax (CAOH) in nm (IE 246 (580), 283sh (228).
1 cm

Claims (25)

1. A compound of the formula S 45 N N 11 -ii R1 HH '' S OR2 0 -CHCH-CH2Z C0081 50 wherein R' is hydrogen or a conventional amino-protecting group, R2 is hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl 55 ring containing from 3 to 6 carbon atoms, or a group of the formula 69 GB2194789A 69 R4 4 COON 1 -c- CH=CH-0 -C-C=ú4 or R'5 b 5 C -C- COON 10 1 R5 in which R3 is hydrogen, (lower)alkyl or carboxyl, X is halogen, hydroxy or (lower)alkoxy, and R4 15 and R5 are each independently hydrogen, methyl or ethyl, or R4 and R5, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, B' is hydrogen or a conventional carboxyl-protecting group and Z is chloro, bromo or iodo; or a salt, hydrate, solvate or ester thereof.
2. A compound of Claim 1 wherein Z is chloro or iodo, and R 2 is (lower)alkyl, cycloalkyl of 3 20 to 5 carbon atoms, 1-carboxycycloalk-l-yi of 3 to 5 carbon atoms, ally], propargyl or carboxy( lower)alkyl; or a salt, hydrate, solvate or ester thereof.
3. The compound of claim 1 or 2 wherein R 2 is methyl, ethyl, cyclopenty], allyl or propargy].
4. The compound of claim 1,2 or 3 wherein B' is hydrogen or a benzhydryl group and R' is hydrogen or a trityl group.
5. The compound of Claim 4 which is diphenyimethyl 7-[2-(5-amino-1,2,4thiadiazol-3-yi)-2methoxyiminoacetamidol-3-(3-iodo-l-propen-l-y])-3-cephem-4-carboxylate, or a salt, hydrate, so] vate or ester thereof.
6. The compound of Claim 4 which is diphenyimethyl 7-[2-(5-amino-1,2,4thiadiazol-3-yi)-2ethoxyiminoacetamidol-3-(3-iodo-l-propen-l-yi)-3-cephem-4-carboxylate, or a salt, hydrate, sol- 30 vate or ester thereof.
7. The compound of Claim 4 which is diphenyimethyl 7-[2-(5-amino-1,2,4thiadiazol-3-yl)-2cyclopentyloxyiminoacetamidol-3-(3-iodo-l-propen-l-yi)-3-cephem-4carboxylat e, or a salt, hy drate, solvate or ester thereof.
8. The compound of Claim 4 which is diphenyimethyl 7-[2-(5-amino-1,2,4thiadiazol-3-yi)-2- 35 allyloxyiminoacetamidol-3-(3-iodo-l-propen-l-yi)-3-cephem-4-carboxylate, or a salt, hydrate, sol vate or ester thereof.
9. The compound of Claim 4 which is diphenyimethyl 7-[2-(5-amino-1,2,4thiadiazol-3-yi)-2propargyloxyiminoacetamido]-3-(3-iodo-l-propen-l-yi)-3-cephem-4carboxylate, or a salt, hydrate, solvate or ester thereof.
10. The compound of Claim 4 which is diphenyimethyl 7-[2-(5-amino-1,2,4thiadiazol-3-yi)-2methoxyiminoacetamidol-3-(3-chloro-l-propen-l-yl)-3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof.
11. The compoupd of Claim 4 which is diphenyimethyl 7-[2-(5-amino-1,2,4thiadiazol-3-yi)-2ethoxyiminoacetamido]-3-(3-chloro-l-propen-l-yi)-3-cephem-4-carboxylate, or a salt, hydrate, sol- 45 vate or ester thereof.
12. The compound of Claim 4 which is diphenyimethyl 7-[2-(5-amino-1,2,4thiadiazol-3-yi)-2cyclopentyloxyiminoacetamidol-3-(3-chioro-l-propen-l-yl)-3-cephem-4carboxyl ate, or a salt, hy drate, solvate or ester thereof.
13. The compound of Claim 4 which is diphenyimethyl 7-[2-(5-amino-1,2,4thiadiazol-3-yi)-2- 50 allyloxyiminoacetamidol-3-(3-chloro-l-propen-l-yi)-3-cephem-4-carboxylate, or a salt, hydrate, sol vate or ester thereof.
14. The compound of Claim 4 which is diphenyimethyl 7-[2-(5-amino-1,2,4thiadiazol-3-yi)-2propargyloxyiminoacetamido]-3-(3-chloro-l-propen-l-yl)-3-cephem-4carboxylat e, or a salt, hy- drate, solvate or ester thereof.
15. A compound of the formula GB2194789A 70 R23 R24 5 R25 1CH= CHCH2Z MIX wherein R22 is hydrogen or a conventional carboxyl-protecting group, and R23, R24 and R25 are the same or different and are hydrogen, hydroxy, (lower)alkyl or (lower)alkoxy and Z is chloro, bromo or iodo; or a salt, solvate, hydrate, or ester thereof.
16. A compound of Claim 15 wherein R22 is the benzhydryl group and Z is chloro or iodo.
17. A compound of claim 15 or 16 wherein R23, R24 and R 25 are hydrogen.
18. The compound of Claim 17 which is benzhydryl 7-benzylideneamino-3-[3chloro-l-propen1 -yi]-3-cephem-4-carboxylate.
19. The compound of Claim 17 which is benzhydryl 7-benzylideneamino-3-[3iodo-l-propen-lyi]-3-cephem-4-carboxylate.
20. A process for the preparation of compounds of the formula VIII R23 R24 CH= N R25 CH2 CHCH22 wherein R22 is hydrogen or a conventional carboxyl-protecting group, and R23, R24 and R25 are the same or different and are hydrogen, hydroxy, (lower)aikyl or (lower)alkoxy and Z is chloro, bromo or iodo; or a salt, solvate, hydrate, or ester thereof, which comprises, reacting a compound of formula 11, R23 24 R -c CHO R25 wherein R23, R24 ano R25 are as defined above, with a compound of formula Ill, Y /PN 5 CH2C1 0 CO OR22.
wherein R22 is a conventional carboxyl-protecting group, to give a compound of formula IV, n71 R&.
R24 WN R25 CH2C1 11 Ill lz then reacting compound of formula IV with sodium iodide or potassium iodide to give a compound of formula V, IV z VIII 25 71 GB2194789A 71 R24 CE A - 5 FN R25 0 - CH21 COOR22 P23 v 5 then reacting compound of formula V with triphenylphosphine to give a compound of formula VI, R23 S R24 -0-, CH=N FQ (D R25 n ' CHPph)3 Y V1 CO R22 or reacting a compound of formula IV with triphenylphosphine to give a compound of formula VI, then reacting a compound of formula V1 with a base to give a compound of formula V11, R23 R14 WN N R2 5 OP = P (Ph)3 COOR q V11 then reacting a compound of formula VII, with ZCH2CHO, wherein Z is chlorine, bromine or iodine, to give a compound of formula Vill, R.2 3 R24 -on CH=N 5 R25 CH=CH-CH22 0 - COOR22 Vill 40 and finally if desired removing by conventional means the carboxyl- protecting group R22 to give the corresponding free acid and converting said free acid to its salt or ester thereof.
21. A process for the preparation of compounds of the formula N II I-CONH S 11 R1 HH) 5---N N -OR2 g-'--1'CH=CH-CH2Z c 0 0 81 wherein R' is hydrogen or a conventional amino-protecting group, R2 is hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring containing from 3 to 6 carbon atoms, or a group of the formula 72 GB2194789A 72 R4 - -c- CH=CH-0 -c- c= C-0 4 COON A R 5 b or C -c- CODH 1 R5 in which R3 is hydrogen, (lower)alkyl or carboxyl, X is halogen, hydroxy or (lower)alkoxy, and R4 and R5 are each independently hydrogen, methyl or ethyl, or R4 and R5, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, B' is hydrogen or a conventional carboxyl-protecting group and Z is chloro, bromo or iodo, or a salt, hydrate, solvate or ester thereof, which comprises reacting a corn20 pound of formula 1, Q H2 N 5 0 N CH2C1 /)iN COOB1 1 with a compound of formula 11 c - COOH RIHN- K, OR2 11 wherein R', R 2 and B' are as defined above, to give a compound of formula Ill, N-\7- C - CONN A\/ / N N\ FN R1HN 5 OR2 0 CH2C1 COOB1 Ill 40 then reacting compqund of formula III with sodium iodide or potassium iodide to give a com- 45 pound of formula IV, Z' N C CONN -TN N\ S OR2 0 CH21 R1 HN COOB1 IV 50 then reacting compound of formula IV with triphenylphosphine to give a compound of formula V, 55 S R1HN. /M H\ N 0 OR2 0 CH2 P Ph)3 ^ --coo B' V or reacting a compound of formula Ill with triphenylphosphine to give a compound of formula V, 65 then reacting compound of formula V with a base to give a compound of formula VI, 73 GB2194789A 73 C - CONH S Y G) R1 HN N \OR2 0 CH2P I Ph)3 S __Fl - - -.
coo B1 V1 then reacting compound of formula V1 with CICH,CHO to give compound of formula V11, % C_ CONH 5 ONN/4S/ OR2 0 CHCHCH2C1 ú00B1 V11 then reacting compound of formula V11 with sodium iodide or potassium iodide to give compound of formula Vill, or reacting compound of formula V11 with sodium bromide or potassium 20 bromide to give compound of formula IX S N C - CONH 11 RNN-\S/ N N \OR2 0 N WCHCH2I COOB1 All 25 E CONH S R1HN.,S/ N N \ WEM29r IX coo B' and finally removing all blocking groups by conventional means and if desired converting the free acid compound to its salt or ester thereof.
22. A process as claimed in claim 20 substantially as described in respect of any of the foregoing Examples.
23. A process as claimed in claim 21 substantially as described in respect of any of the 40 foregoing Examples.
24. A compound as claimed in claim 15 prepared by a process as claimed in claim 20 or 22.
25. A compound as claimed in claim 1 prepared by a process as claimed in claim 21 or 23.
Published 1988 at The Patent Office, State House, 66/71 High Holborn, London WC1R 4TP. Further copies may be obtained from The Patent Office, Sales Branch, St Mary Cray, Orpington, Kent BR5 3RD. Printed by Burgess & Son (Abingdon) Ltd. Con. 1/87.
GB08721346A 1984-04-09 1987-09-10 Antibacterial agent intermediates Expired GB2194789B (en)

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JPH085897B2 (en) * 1986-11-06 1996-01-24 エーザイ株式会社 3-propenyl cephem derivative
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JPH0699449B2 (en) * 1988-03-16 1994-12-07 エーザイ株式会社 Synthetic intermediate of cephem derivative
EP0612751A3 (en) * 1988-03-16 1994-09-21 Eisai Co Ltd Compounds for the preparation of cephem derivatives.
FR2655042B1 (en) * 1989-11-29 1994-01-21 Adir Cie NOVEL SUBSTITUTED BENZOTHIAZOLINONES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
FR2663332B1 (en) * 1990-06-15 1997-11-07 Roussel Uclaf NOVEL CEPHALOSPORINS COMPRISING IN POSITION 3 A RADICAL PROPENYL SUBSTITUTED BY A QUATERNARY AMMONIUM, THEIR PREPARATION PROCESS, THEIR APPLICATION AS MEDICAMENTS, THE COMPOSITIONS CONTAINING THEM AND THE NEW INTERMEDIATES OBTAINED.
US5126336A (en) * 1990-08-23 1992-06-30 Bristol-Myers Squibb Company Antibiotic c-3 catechol-substituted cephalosporin compounds, compositions and method of use thereof
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