CA1146165A - Process for the manufacture of acyl derivatives - Google Patents
Process for the manufacture of acyl derivativesInfo
- Publication number
- CA1146165A CA1146165A CA000364648A CA364648A CA1146165A CA 1146165 A CA1146165 A CA 1146165A CA 000364648 A CA000364648 A CA 000364648A CA 364648 A CA364648 A CA 364648A CA 1146165 A CA1146165 A CA 1146165A
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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
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- 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
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- 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
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Table Devices Or Equipment (AREA)
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Abstract
ABSTRACT OF THE DISCLOSURE
A process for the manufacture of novel antibiotics of the general formula I
wherein X represents the group or (a) (b) as well as of salts of these compounds and hydrates of these compounds and salts, which process comprises reacting a halide of the general formula II
wherein X has the significance given earlier and Y represents a halogen atom, or a salt thereof with thiourea and, if desired, converting a compound of for mula I obtained into a salt or hydrate or into a hydrate of sald salt.
A process for the manufacture of novel antibiotics of the general formula I
wherein X represents the group or (a) (b) as well as of salts of these compounds and hydrates of these compounds and salts, which process comprises reacting a halide of the general formula II
wherein X has the significance given earlier and Y represents a halogen atom, or a salt thereof with thiourea and, if desired, converting a compound of for mula I obtained into a salt or hydrate or into a hydrate of sald salt.
Description
The present invention relates to a process for the manufacture of novel acyl derivatives. More particularly, tne invention is concerned with a process for the manufacture of cephalosporin derivatives.
The cephalosporin derivatives manufactured in accordance with the present inven~ion are compounds of the general formula H H
C~30N - - C - CONH ~ S ~ I
N ~ o ~ ~ C~l2 - ~ - X
H2N ~ COOH
~' :~`
wherein X represents the group H
H3C \ N O N ~ OH
N ~ ~ N ~ o (a) ~b) as well as salts of these compounds and hydrates o these compounds and salts.
Group ~b) is present in tautomeric equilibrium ~ith group ~a).
Examples of salts of compounds of formula I are alkali metal salts such as the sodium and potassium salt, the ammonium salt, alkaline earth metal salts SUch as the calcium 5alt, salts with organic bases such as salts with ~6~6~
amines (e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, N7N'-dibenzylethylethylenediamines7 alkylamines or dialkylamines) and salts with amino acids ~e.g. salts with arginine or lysine). The salts can be mono-salts or di-salts. The ~ ~ .
:
.~
:
'
The cephalosporin derivatives manufactured in accordance with the present inven~ion are compounds of the general formula H H
C~30N - - C - CONH ~ S ~ I
N ~ o ~ ~ C~l2 - ~ - X
H2N ~ COOH
~' :~`
wherein X represents the group H
H3C \ N O N ~ OH
N ~ ~ N ~ o (a) ~b) as well as salts of these compounds and hydrates o these compounds and salts.
Group ~b) is present in tautomeric equilibrium ~ith group ~a).
Examples of salts of compounds of formula I are alkali metal salts such as the sodium and potassium salt, the ammonium salt, alkaline earth metal salts SUch as the calcium 5alt, salts with organic bases such as salts with ~6~6~
amines (e.g. salts with N-ethyl-piperidine, procaine, dibenzylamine, N7N'-dibenzylethylethylenediamines7 alkylamines or dialkylamines) and salts with amino acids ~e.g. salts with arginine or lysine). The salts can be mono-salts or di-salts. The ~ ~ .
:
.~
:
'
- 2 -.
.- .
~ ~6~L65 ,, ,~
second salt formation can occur in compounds with the hydroxy moiety of the 2,5~dihydro-6-hydroxY 2~methyl-5-oxo-as--triazin-3-yl group.
:~.
~ The compounds of formula I also form addition salts ; `:
with organic or inorganic acids. Examples of such salts are hydrohalides ~e.g. hydrochlorides, hydrobromides and hydroiodides), other mineral acid salts such as sulphates, nitrates, phosphates and the Iike, alkylsulphonates and monoarylsulphonates such as ethanesulphonates, toluene-10 sulphonates, benzenesulphonates and the like and otherorganic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.
, The compound~ of formula I and their salts can be ` hydrated. The hydration can be effected in the course of the manu~acturing proaeas or aan occur gradually as .. ~ :
a~ result af the hygrosaopic praperties of an inltially `anhydrous product.
~: : :
The cephalosporin derivatives manuactured in accordance wlth the present invention can be present in the syn-isomeric form (Z form) S
C O N H~
~2~
. CCH3 .; `
.
s or in the anti-isomeric form (E form) ox as mixtures of these two forms. The syn-isomeric form is preferred, as are mixtures in which the syn-isomeric fonm predominates.
Preferred cephalosporin derivatives manufactured in accordance with the present invention are:
(6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-(Z-methoxy-imino acetamido]-3-/ [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-y~ lO -triazin-3~yl)thio]~ethyl /-8-oxo-5-thia-l-azabicyclo[4.2.0~-oct~2-ene-2-carboxylic acid and its salts as ~ell as the ~ corresponding hydrates.
:~ :
The aforementioned cephalosporin derivatives are manufactured in accordance with the present invention by reacting a ha~ide of the general formula .:
~`
~, . . . . -.
H H
C~130N= F CON~I~ ~ 11 CO ~J~CH2--S--X
wherein X has the significance given earlier and Y represents a halogen atom, or a salt thereof wikh thiourea and, if desired, converting a compound of formula I obtained into a salt or hydrate or into a hydrate of said salt.
l~e halide starting materials of formula II can be prepared, for example, by reacting a primary amine of the general formula H
~ 2 :~ A ~ C112 - S - X III
COOH
~herein:X has the significance given earlier, ,~, ~, , .:
~' .
,'~
. . . . - . :
,~
with a halogenated carboxylic acid of the general formula CH30N==~C - C~0~
' wherein Y represents a halogen atom, `~ or with a reactive derivative thereof. The halogenated carbo~ylic acid of formula IV is used either in free form in the presen~e of a condensing agent (e.g. a N,~-disubstituted ~ .
carbodiirnide such as N~N'-dicyclohexyl~arbodiimide or an azolide compound such as N,N'- carbonyldiimidazole or N,N'-~.~
-thionyldiimidazole~ ox in the form of an acid halide such as the acid chloride or bromide, in the form of an acid anhydride such as an acid anhydride with a carbonic acid monoester (e.g.with monomethyl carbonate or monoisopropyl carbonate) or ln the form of an activated ester such as the p-nitrophenyl ester, 2,4-dinitrophenyl ester, N-hydroxy-succinimide ester of N-hydroxyphthalimide ester. The reaction is generally carried out in an inert organic solvent, for example, a halogenated hydrocarbon such as~chloroform, -~
dichlorometha~e, carbon tetrachloride, an ether such as tetrahydrouran, dioxan, dlmethylformamide~ dimethylacetamide, r,~ater or mixtures thereof. The reaction is preferably carried out at a temperature in the range of from about -50C to +40C, especially at about -10C to -~10C.
:, :
~.. .
S
The halide starting materials of formula II can also be prepared by halogenating a compound of the general formula H H
C~30N F - CO~H ~ ~ V
CO o ~CII-- S--X
CH COOH
wherein X has the significance given earlier.
The compounds of formula V can be obtained by reacting a primary amine of formula III hereinbefore with 3-oxo-2-methoxyiminobutyric acid or with a reactl~e derivative thereof. This reaction is carried out in essentially the same manner as described earlier in connection with the reaction of a primary smine of formula III with a halogenated carboxylic acid o~ formula IV or with a reactive derivative thereof. The halogenation of the reaction product ~i.e.
a compound of fo~mula V) leads to a halide of formula IT and is preferably carried out by treatment with the corresponding halogen or thionyl halide ~e.g.
,i with chlorine, bromine or sulphuryl chloride), preferably in an inert solvent such as a halogena~ed hydrocarbon (e.g. dichloro-:
~ ~ _ 7 _ .
s methane, dichloroethane, chloroform, dichloroethylene or carbon tetrachloride), a lower alkanecarboxylic acid (e.g.
acetic acid) or an aromatic hydrocarbon (e.g. benzene or toluene). The halogenation is generaLly carried out at a S temperature between about 0C and 60C.
The halides of formula II and their preparation from primary amines of formula III or from compounds of formula V
as well as the compounds of formula V and their preparation from primary amlnes of formula III also form part of the ` 10 present in~en~ion.
: .
The reaction of a halide of formula II or a salt thereof with thiourea in accordance with the present invention is preerably carr~ed out in an inert solven~ such as, for example, a lower alkanol (e.g. ethanol), a lower ketone (e.g acetone), an ether (e.g. tetrahydrofuran or dioxan), dimethylformamide, dimethylacetamide, water or mixtures thereof. The reaction is generally carried out at a temperature in the range of from about 0C to 60C, preferably at room temperature. The chloride, bromide, ; 20 fluoride or iodide can be used as the halide or formllla II, the chloride or the bromide being preferred. ~he free acid of formula II or a salt thereof can be used in the present process. As salts of the acids of formula II there come into consideration the same salts as mentioned earlier in connection with the salts or the compounds of rormula I.
' :~
~, ,.~ . . - . , . .
.. . . . ... : ~ ~ , s ,~
o~
The manufacture of the salts and hydrates of the compounds of formula I or the hydrates of such salts can be carried out in a manner known per se; fox example, by reacting a carboxylic acid of formula I with an equivalent amount of the desired base, conveniently in a solvent such as water or an organic solvent (e.g. ethanol, methanol, acetone or the like~. When a second equivalent of base is used, salt formation aLso takes place on tautomeri.c enol form which may be present (2,5-dihydro-6 hydroxy-2-methyl--5-oxo-as-triazin-3-yl group X), a di-salt being formed.
The temperature at whlch the salt formation is carried out is not critical. The salt ~ormation is generally carried out at roo~ temperature, but it ca~ also be carried out at a temperature slightly above or below room ~emperature, lS or example in the range of ~rom about 0C to +50C.
:, :` :
The manufacture of the hydrates usually takes place automatlcally in the course of the manufacturing process or as a result of the hygroscopic properties of an initially ~:, ~ anhydrous product. For the controlled manufacture of a ; 20 hydrate, a completely or partially anhydrous product (compound of formula I or salt thereof) can be exposed to a moist atmosphere (e.g. at about +10C to ~40C).
..
A syn/anti mixture o~ a compound of formula I which may be obtained can be separated intc, the corresponding syn and ,. . . . ~ , , ~ ~
Jo ~ a ~
r~r anti forms in the customary manner; for example, by re-crystallisation or by chromatographical methods using a suitable solvent or solvent mixture.
The compounds of formula I and their salts as well as the hydrates of these compounds and salts possess antibiotic, especially bactericidal, activitY. They have a broad spectrwm of activity ~gainst gram-positive and gram-negative microorgani~ms, including ~-lactamas ~ form~r~ Staphylococci and ; various ~-lactamase-forming gram-n~gative ~acteria such as, for example, Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Serratia marcescens and Pro~eus and Klebsiella species.
:
The compounds of formula I and their salts as well as the hydrates o these compounds ~nd salts can be used for the ~reatment and prophylaxis of infectious diseases. A
daily dosage of about 0.1 g to about 2 g is envlsaged for adults. The administration is preferably carried out by the parenteral route.
In order to demonstrate the antimicrobial activity of the compounds of formula I, the activity in vitro (minimum inhibitory concentratlon in ~g/ml) was ascertained for (6R,7R)-7-E2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino~ac~tamido]-~3~ r [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]methyl /-8-oxo-S-thia-l-azabicyclo~4.2.0]oct-2-ene-2-ll s~ l t -caxboxylic acid ~denoted as A hereinafter. The results are compiled in the following Table:
Test organisms _ _ . ._ _ __ _ ~ .
Haemophilus influenzae Stxain 1 0.08 S Strain 2 0.005 Strain 3 0.005 Strain 4 0.005 Strain 5 0.0025 Strain 6 0.0025 S~rain 7 0.0025 _ _ ~
:: KlebsieLla pneumoniae 1.2 ~: ; Escherichia coli Strain 1 0.02 ; Strain 2 0.5 ~' _ . . . .. _ , .
,~ :, `~ : Proteus mirabllisStrain 1 '0.01 ` 15 Strain 2 <0 01 : Proteus vulgaris '0.01 " __ ___ __ .
Rroteus rettgeri '0.01 _. . .
Staphylococcus aureus 5train ATCC
653~ 2.5 Penicillin-:, -resistant straln 2.5 :
. ~ , ~ .
s 1~-~ ,s ,3 Test organisms A
. Pseudomonas aeruginosa Strain 1 0.3 : . Strain 2 10 ~- Strain 3 2.5 S Strain 4 S
Strain 5 S
Strain 6 10 Strain 7 5 ~ . _ _ : Serratia marcescens0.08 ~he antibacteriaL activity in vivo was ascertained ~: as ~ollows: :
, Groups of five mice are infected intraperitoneally "
; with an aqueous suspension of Escherichia coli. The test : substance is administered subcutaneously in physiological : lS sodium chloride solution ~hree times (i.e. I hour, 2.5 hours and 4 hours) after the infection. The number of surviving animals is determined on the fourth day. Various dosages are administered and the dosage at which 50% of the experimental animals survive (CD50, mg/kg) is determined by interpolation.
;~, : ~ . .... .
- ~ , ~ - :. .
... ~ . , ., .. ~ ,. . - , .t Test substance I A
~_ ~ __ CD50, mg/kg 0.005 Toxicity :.~
Test substance ¦ A
. .
LD50, mg/kg l.v. 250~500 s.c. >4000 p.o. >5000 _ _ __ . _ T __ _ _ 1 : The compounds of formula I and their salts as well , : :
as the:hydrates of said compounds and salts can be used as : 10~: medlcaments; for example, in the form of pharmaceutical preparations whlch contain them~in association with a ~ compatible pharmaceutical carrier material. This carrier :~ material can be an organic or inorganic inert carrier materiaL suitable for enteral ox parenteral administration ., such as, for exam~le, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, poly-alkyleneglycols, petroleum jelly etc. The pharmaceutical ~ preparations can be made up in a solid form (e.g. as tablets, .
~;
: I k:
~1 .r 6~
dragees, suppositories or capsules) or in a liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations can be sterilised and/ox can contain adjuvants such as preserving, stabilising, wetting : 5 or emulsifying agents r salts for varyin~ the osmotic pressure, anaesthetics or buffers. They can also contain other therapeu~ically valuable substances. The co~pounds of formula I and their salts as well as the hydrates of such compounds and salts are preferably administered parenterally and for this purpose are preferably formulated as ;: ~ lyophilisates or dry powders for dilution with customary agents such as water or isotonic sodium chloride solution~
-:~ The readily hydrolysable esters or ethers of fo.rmula I and ., .
:~ their salts as well as hydrates of such salts can aLso be administered enterally.
~ '~
;~ :
: ~' .
': "
.. ,. ~ :
~:- - ~ . . : .
The folLowing Examples illustrate the present invention:
28.8 g of (6R,7R)-7-/ 4-bromo-2-[(~)-methoxyimino]-acetoacetamido /-3-/ [(2,5-dihydro-6-hydroxy-2-methyl-5--oxo-as-triazin-3-yl)thio~methyl /-~ oxo-S-thia-l-aza-bicyclo~4.2.0loct-2-ene-2-carboxylic acid are dissolved in 400 ml of ahsolute ethan~l. The solution is treated with 7.6 g of thiourea. After stirring for 15-20 minutes at 25C, the product begins to crystallise from the orange solution as the hydrobromide. After stirring for 1.5 hours, the hydrobromide is filtered off under suction, washed successively with 200 ml of alcohol and 200 ml of low--boillng petroleum ether and dried at 35-40C overnight in a high vacuum. 22g of almost colourless hydrobromide are obtained. This is dissolved, together with 15.7 g of sodium acetate trihydrate, in a mixture of 110 ml of water ; and 110 ml of acetone. 140 ml of acetone are added to the resulting solution until it is slightly turbid. Shortly thereafter the product begins to crystalllse. The mixture ls stlrred for 30 minutes and 180 ml of acetone are added dropwise during a further 30 minutes t the crysta~lisation ,then being complete. The product is filtered off under suction, washed successively wi.th 250 ml of 85% aqueous I; ~.,1 :
' ~
.
~lD
acetone, 250 ml of acetone and 250 ml of low-boiling petroleum ether and finally dried at 25C in ~acuo.
There are obtained 19.6 g (59~3~ oi theory) of the almost colourless disodi~n salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl) ; S -2-(Z-methoxyimino)acetamido~-3-/ [2,5-dihydro-6-hydroxy-2--methyl-5-oxo-as-triazin-3-yl)thio]methyl /-8-oxo-5-thia-azabicycloC4.2.0]oct-2-ene 2-carboxylic acid which is recrystallised from water/acetone. There are obtained 17.3 g (52.3~ of theory~ of pure substance with []25 =
-150.8 (c = 1 in wat2r). lH-NMR spectrum in DMSO-d6 value~ in ppm, s = singlet, d = doublet, q = quartet, b - broad; J = coupling constant in Hz; number o~ pxoton~
in parentheses): 3.47 (N--CH3) (s~ (3), 3.49 (2-C~) (AB-q/centering value; Jgem = ~ 18 Hz) (2), 3.85 [=N'0CH3, (Z)] (s~ ~3j, 4.37 (3-CH2-S)~AB-q/centerlng value; Jgern =
.5 H~) (2), 5.04 (E-6) (d'JE-6~H-7 = 4-5 Hz) (l)~ 5-59 ;~ q' h-7~NH 8 H~JH_7 H-6 = 4.5 Hz (1), 6.75 - ~; (thiazolyl-H) (s) (l), 7~.29 (-NH2) (b) (2), 9,52 (-C0-NH-) NH,H-7 The (6R,7R)-7-/ 4-bromo-2-[(Z)-methoxyimino]aceto-acet~nido /~3~ r [(2,5-dihydro~6-hydroxy-2-methyl-5-oxo--as-triazin-3-yl)thio}methyl 7-8-oxo-5-thia-l-azabicyclo[4.2.0~-oct-2-ene-2-carbo~ylic acid used as the starting rnaterial can be prepared as follows:
~1 . ., I! :
, 11 592.1 g o acetoacetic acid tert.butyl ester are dissolved in 560 ml of glacial acetic acid. A solution of 290.6 g of sodium nitrite in 655 ml of water is added dropwise to this solution at 5-10C during 2.5 hours. The resulting yellow suspension is stirred at 20C for 30 minutes, treated with 940 ml of water and stirxed for a further 2 hours~
The mixture is treated with 900 ml of water and 900 g of ice and extracted three times in a stirxing vessel with 1 litre of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 litre o water each time, then treated with 5 litxes o~ water and the pH is adjusted to 6.8 with sodi~ hydrogen carbonate. After separating the aqueous phase, it is washed once with water.
Thereafter, the ethyl acetate solution is dried over sodium - 15 sulphate and evaporated at 40C ln vacuo. There is obtained .~
(Z)-2-hydroxyimino-3-oxobutyric acid tert.butyl ester in the ~, form of a yellow oil which is dried at 40C in a high ~1 vacuum for a further 9 hours. The yield amounts to 626.65 g ~. ,, (89.2~ of theory).
626.65 g of (Z)-2 hydroxyimino 3-oxobutyric acid tert.butyl ester are dissolved in 2.86 litres of acetone.
The solution is cooled to 5~C and treated portionwise with 703.5 g of potassium carbonate. 322 ml of dimethyl sulphate are then added dropwise to the yellow suspension without cooling during 1 hourl where~y the temperature of the mi~ture should not rise above 25C. The light beige ., ~ f , I :
, ~ . .:
.: , . : . . : .
s Ig suspension is stirred at 20-25C for ca ~L hours until starting material can no longer be detected by thin-layer chromatography. The mixture is then poured into 7 litres of water and extracted three times with 1 litre of ethyl ; 5 acetate each time. The combined ethyl acetate extracts are washed three times with 1 litre of water each time, dried over sodium sulphate and evaporated at 40C in vacuo. The residual yellow oil is dried at 40C in a hign vacuum for a further 6 hours and subsequently di~tilled. Thexe are obtained 577 g (85.6% of theory) of (Z)~2~methoxyimino-3--oxobutyric acid tert.butyl ester in the form of a yellow oil of boiling point 57C/0.02 mm Hg. lE-NMR spectrum in CDC13 (~-values in ppm, s = singlet, number of protons ; ~ in parentheses)~ 1.55 [-C(CH3)3] (s) (9), 2.36 (CH3-CO) (s~
~ 15 (3) 4 01 [= N~OCH3 (Z)] (s) (3) .":
86 g of (Z)-2-methoxyimino-3-oxobutyric acid tert.-butyl ester are dissolved in 400 ml of trifluoroacetic acid.
The $olution is left to stand at 25C for 1 hour and then evaporated at 35C in vacuo. The oily residue is crystallised from ether/petroleum ether. There are obtained 50 g (80.6~ o~ theory) of yellowish water-soluble (Z)-2-~' methoxyimino-3-oxobutyric acid of melting point 80-85c.
H-NMR spectrum in CDC13 (~-values in ppm, s = singlet, humber of protons in parentheses): 2.43 (C~3-CO) (3), 4.14 ~ 25 [= N CH3, (z)~ (s) (3), 10.47 (OH) (s) (l).
:. ' ' ~ ", ., L6~
~o~
;~ .
145 g of tZ)-2-methoxyimino-3-oxobutyric acid are dissolved in 1000 ml of alcohol-free and water-free dichloromethane. 10 ml of 30~ hydxobromic acid in glacial acetic acid axe added to the resulting solution. Then, a solution of 37~5 ml of bromine in 112.S ml of dichloro-; methane is added dropwlse during ca 2 hours, the temperature of the mixture being held at 20~25C by slight cooling.
Nitrogen is now blown through the mixture vigorously to remove hydrogen bromide. Subsequently, 250 g of ice, 250 ml of water and 2 litres of ether are added successi~ely. The ar~ueous phase is separate-d and discarded. The organic phase is washed with 250 ml of water and Z50 ml of saturated sodium chloride solution, dried over sodium sulphate and ~!
evaporated in vacuo. There are obtained 170 g of a brown oil which is crystallised from carbon tetrachloride. There are o~tained 100 g (44.6% of theoryj of al~ost colourless (Z)-4-bromo-2-methoxyimino-3-oxobutyric acid. lH-NMR
~, :
spec~rum in CDC13 (~-values in ppm, s = singlet, number of protons in parentheses): 4.24 [= N CH3, (z) (5) (3), 4.41 (-C~2-) (s) (2), 11.00 (OH) (s) (1).
.
37.1 g of (7R)-7-amino-3-desacetoxy-3-[(2,5 dihydro--6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-cephalosporanic acid are suspended ln 800 ml of ethyl acetate and treated with 100 ml of N,O-bis-(trimethylsilyl)-acetamide. The mixture is stirred at ~5C for 30 minutes with the exclusion of moisture, a light yellow solut'on resulting. This . !
.
~o , -,~r -.i~
solution, cooled to -10C, is added dropwise at -10C to 0C during 30 mintues to a solution of (Z)~4-bromo-2--methoxyimino~3-oxobutyric acid chloride, prepared from 22.4 g of (Z)-4-bromo-2-methoxyi~ino-3-oxobutyric acid in 300 ml of alcohol-free and water-free dichloromethane and 20.8 g of phosphorus pentachloride at 8-10C. The mixture is stirred at 0-5C for 30 minutes and at 25C for 1 hour.
1 litre of ethyl acetate and 500 ml o~ water are added while stirring. The aqueous phase and the resinous intermediate layer are discarded. The organic phase is washed six times with 500 ml of water each time, dried over sodium sulphate and concentrated at 40C in vacuo to a voLume of 200 ml. ThP orange ~oloured concentrate is added drop-wise while stirring to 1.8 litres of ethex, the product separating in amorphous form. This product is filtexed off under suction, washed successively with 1 litre of ethex and 1 litre o low-boiling petroleum ether and dried at 35C in vacuo overnight. There are obtained 37.~ g (64.4% of theory) of (6R,7R)-7- f 4-bromo-2-C(Z)-methoxyimino]acetoacetamido ~ -20 -3-_ ~(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]methyl~ -8-oxo-5-thia-1-azabicyclo~4.2.0~oct-2-ene-2--carboxylic acid in the form of a beige amorphous product with ~]25 = -223.1 (c = 1 in methanol. lH-N~R spectrum in DMS0-d6 (~ alues in ppm, s = singlet, d = doublet, q =
quartet, b = broad; ~ = coupling constant in Hz; number of ~;I protons in parentheses): 3.60 (N-CH3) (s) (3), 3.63 (2-CH2) (AB-q/centerirg value; J = 18 Hz) (2)j 4.07 [= N'OCH3, '' :, s (Z)] (s) (3), 4.25 (3-CH2-S)(AB-q/centering value; Jgem ~
13 Hz) (2), 4.62 (Br-CH2 ) (s) (2), 5.15 (H 6) (d~H 6 ~-7 =
5 Hz) (1), 5.78 (H-7) (q/JH-7 N~ ~ 8 H2~ JH-7~H-6 (1), 9.47 (NH) d,JNH H-7 = 8 Hz) (1), 11.1~ (-COOH and ~GH) (b) (2).
~ .
Manufacture of dry ampoules for intramuscular administration:
A lyophilisate of 1 g of the disodium salt of ~` 10 ~6R~7Rj-7-E2-(2-amino-4 thiozolyl)~2~(Z-methoxyimino)-acetamido]-3-/ [(2,5 dihydro 6-hydroxy-2-~iethyl-5-oxo--as-:: -triazln-3-yl)t~io]methyl /-8-oxo-5-thia 1-azabicyclo~4.2.0]-oct-2-ene-2-carboxylic acid is manufactured in the customary manner and ~illed into an ampoule. Prior to the administratio~
the lyophilisate is treated with 2.5 ml of a 2~ aqueous lidocaine hydrochloride solution.
.:
, :
~: ~ : : .
.- .
~ ~6~L65 ,, ,~
second salt formation can occur in compounds with the hydroxy moiety of the 2,5~dihydro-6-hydroxY 2~methyl-5-oxo-as--triazin-3-yl group.
:~.
~ The compounds of formula I also form addition salts ; `:
with organic or inorganic acids. Examples of such salts are hydrohalides ~e.g. hydrochlorides, hydrobromides and hydroiodides), other mineral acid salts such as sulphates, nitrates, phosphates and the Iike, alkylsulphonates and monoarylsulphonates such as ethanesulphonates, toluene-10 sulphonates, benzenesulphonates and the like and otherorganic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.
, The compound~ of formula I and their salts can be ` hydrated. The hydration can be effected in the course of the manu~acturing proaeas or aan occur gradually as .. ~ :
a~ result af the hygrosaopic praperties of an inltially `anhydrous product.
~: : :
The cephalosporin derivatives manuactured in accordance wlth the present invention can be present in the syn-isomeric form (Z form) S
C O N H~
~2~
. CCH3 .; `
.
s or in the anti-isomeric form (E form) ox as mixtures of these two forms. The syn-isomeric form is preferred, as are mixtures in which the syn-isomeric fonm predominates.
Preferred cephalosporin derivatives manufactured in accordance with the present invention are:
(6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-(Z-methoxy-imino acetamido]-3-/ [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-y~ lO -triazin-3~yl)thio]~ethyl /-8-oxo-5-thia-l-azabicyclo[4.2.0~-oct~2-ene-2-carboxylic acid and its salts as ~ell as the ~ corresponding hydrates.
:~ :
The aforementioned cephalosporin derivatives are manufactured in accordance with the present invention by reacting a ha~ide of the general formula .:
~`
~, . . . . -.
H H
C~130N= F CON~I~ ~ 11 CO ~J~CH2--S--X
wherein X has the significance given earlier and Y represents a halogen atom, or a salt thereof wikh thiourea and, if desired, converting a compound of formula I obtained into a salt or hydrate or into a hydrate of said salt.
l~e halide starting materials of formula II can be prepared, for example, by reacting a primary amine of the general formula H
~ 2 :~ A ~ C112 - S - X III
COOH
~herein:X has the significance given earlier, ,~, ~, , .:
~' .
,'~
. . . . - . :
,~
with a halogenated carboxylic acid of the general formula CH30N==~C - C~0~
' wherein Y represents a halogen atom, `~ or with a reactive derivative thereof. The halogenated carbo~ylic acid of formula IV is used either in free form in the presen~e of a condensing agent (e.g. a N,~-disubstituted ~ .
carbodiirnide such as N~N'-dicyclohexyl~arbodiimide or an azolide compound such as N,N'- carbonyldiimidazole or N,N'-~.~
-thionyldiimidazole~ ox in the form of an acid halide such as the acid chloride or bromide, in the form of an acid anhydride such as an acid anhydride with a carbonic acid monoester (e.g.with monomethyl carbonate or monoisopropyl carbonate) or ln the form of an activated ester such as the p-nitrophenyl ester, 2,4-dinitrophenyl ester, N-hydroxy-succinimide ester of N-hydroxyphthalimide ester. The reaction is generally carried out in an inert organic solvent, for example, a halogenated hydrocarbon such as~chloroform, -~
dichlorometha~e, carbon tetrachloride, an ether such as tetrahydrouran, dioxan, dlmethylformamide~ dimethylacetamide, r,~ater or mixtures thereof. The reaction is preferably carried out at a temperature in the range of from about -50C to +40C, especially at about -10C to -~10C.
:, :
~.. .
S
The halide starting materials of formula II can also be prepared by halogenating a compound of the general formula H H
C~30N F - CO~H ~ ~ V
CO o ~CII-- S--X
CH COOH
wherein X has the significance given earlier.
The compounds of formula V can be obtained by reacting a primary amine of formula III hereinbefore with 3-oxo-2-methoxyiminobutyric acid or with a reactl~e derivative thereof. This reaction is carried out in essentially the same manner as described earlier in connection with the reaction of a primary smine of formula III with a halogenated carboxylic acid o~ formula IV or with a reactive derivative thereof. The halogenation of the reaction product ~i.e.
a compound of fo~mula V) leads to a halide of formula IT and is preferably carried out by treatment with the corresponding halogen or thionyl halide ~e.g.
,i with chlorine, bromine or sulphuryl chloride), preferably in an inert solvent such as a halogena~ed hydrocarbon (e.g. dichloro-:
~ ~ _ 7 _ .
s methane, dichloroethane, chloroform, dichloroethylene or carbon tetrachloride), a lower alkanecarboxylic acid (e.g.
acetic acid) or an aromatic hydrocarbon (e.g. benzene or toluene). The halogenation is generaLly carried out at a S temperature between about 0C and 60C.
The halides of formula II and their preparation from primary amines of formula III or from compounds of formula V
as well as the compounds of formula V and their preparation from primary amlnes of formula III also form part of the ` 10 present in~en~ion.
: .
The reaction of a halide of formula II or a salt thereof with thiourea in accordance with the present invention is preerably carr~ed out in an inert solven~ such as, for example, a lower alkanol (e.g. ethanol), a lower ketone (e.g acetone), an ether (e.g. tetrahydrofuran or dioxan), dimethylformamide, dimethylacetamide, water or mixtures thereof. The reaction is generally carried out at a temperature in the range of from about 0C to 60C, preferably at room temperature. The chloride, bromide, ; 20 fluoride or iodide can be used as the halide or formllla II, the chloride or the bromide being preferred. ~he free acid of formula II or a salt thereof can be used in the present process. As salts of the acids of formula II there come into consideration the same salts as mentioned earlier in connection with the salts or the compounds of rormula I.
' :~
~, ,.~ . . - . , . .
.. . . . ... : ~ ~ , s ,~
o~
The manufacture of the salts and hydrates of the compounds of formula I or the hydrates of such salts can be carried out in a manner known per se; fox example, by reacting a carboxylic acid of formula I with an equivalent amount of the desired base, conveniently in a solvent such as water or an organic solvent (e.g. ethanol, methanol, acetone or the like~. When a second equivalent of base is used, salt formation aLso takes place on tautomeri.c enol form which may be present (2,5-dihydro-6 hydroxy-2-methyl--5-oxo-as-triazin-3-yl group X), a di-salt being formed.
The temperature at whlch the salt formation is carried out is not critical. The salt ~ormation is generally carried out at roo~ temperature, but it ca~ also be carried out at a temperature slightly above or below room ~emperature, lS or example in the range of ~rom about 0C to +50C.
:, :` :
The manufacture of the hydrates usually takes place automatlcally in the course of the manufacturing process or as a result of the hygroscopic properties of an initially ~:, ~ anhydrous product. For the controlled manufacture of a ; 20 hydrate, a completely or partially anhydrous product (compound of formula I or salt thereof) can be exposed to a moist atmosphere (e.g. at about +10C to ~40C).
..
A syn/anti mixture o~ a compound of formula I which may be obtained can be separated intc, the corresponding syn and ,. . . . ~ , , ~ ~
Jo ~ a ~
r~r anti forms in the customary manner; for example, by re-crystallisation or by chromatographical methods using a suitable solvent or solvent mixture.
The compounds of formula I and their salts as well as the hydrates of these compounds and salts possess antibiotic, especially bactericidal, activitY. They have a broad spectrwm of activity ~gainst gram-positive and gram-negative microorgani~ms, including ~-lactamas ~ form~r~ Staphylococci and ; various ~-lactamase-forming gram-n~gative ~acteria such as, for example, Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Serratia marcescens and Pro~eus and Klebsiella species.
:
The compounds of formula I and their salts as well as the hydrates o these compounds ~nd salts can be used for the ~reatment and prophylaxis of infectious diseases. A
daily dosage of about 0.1 g to about 2 g is envlsaged for adults. The administration is preferably carried out by the parenteral route.
In order to demonstrate the antimicrobial activity of the compounds of formula I, the activity in vitro (minimum inhibitory concentratlon in ~g/ml) was ascertained for (6R,7R)-7-E2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino~ac~tamido]-~3~ r [(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]methyl /-8-oxo-S-thia-l-azabicyclo~4.2.0]oct-2-ene-2-ll s~ l t -caxboxylic acid ~denoted as A hereinafter. The results are compiled in the following Table:
Test organisms _ _ . ._ _ __ _ ~ .
Haemophilus influenzae Stxain 1 0.08 S Strain 2 0.005 Strain 3 0.005 Strain 4 0.005 Strain 5 0.0025 Strain 6 0.0025 S~rain 7 0.0025 _ _ ~
:: KlebsieLla pneumoniae 1.2 ~: ; Escherichia coli Strain 1 0.02 ; Strain 2 0.5 ~' _ . . . .. _ , .
,~ :, `~ : Proteus mirabllisStrain 1 '0.01 ` 15 Strain 2 <0 01 : Proteus vulgaris '0.01 " __ ___ __ .
Rroteus rettgeri '0.01 _. . .
Staphylococcus aureus 5train ATCC
653~ 2.5 Penicillin-:, -resistant straln 2.5 :
. ~ , ~ .
s 1~-~ ,s ,3 Test organisms A
. Pseudomonas aeruginosa Strain 1 0.3 : . Strain 2 10 ~- Strain 3 2.5 S Strain 4 S
Strain 5 S
Strain 6 10 Strain 7 5 ~ . _ _ : Serratia marcescens0.08 ~he antibacteriaL activity in vivo was ascertained ~: as ~ollows: :
, Groups of five mice are infected intraperitoneally "
; with an aqueous suspension of Escherichia coli. The test : substance is administered subcutaneously in physiological : lS sodium chloride solution ~hree times (i.e. I hour, 2.5 hours and 4 hours) after the infection. The number of surviving animals is determined on the fourth day. Various dosages are administered and the dosage at which 50% of the experimental animals survive (CD50, mg/kg) is determined by interpolation.
;~, : ~ . .... .
- ~ , ~ - :. .
... ~ . , ., .. ~ ,. . - , .t Test substance I A
~_ ~ __ CD50, mg/kg 0.005 Toxicity :.~
Test substance ¦ A
. .
LD50, mg/kg l.v. 250~500 s.c. >4000 p.o. >5000 _ _ __ . _ T __ _ _ 1 : The compounds of formula I and their salts as well , : :
as the:hydrates of said compounds and salts can be used as : 10~: medlcaments; for example, in the form of pharmaceutical preparations whlch contain them~in association with a ~ compatible pharmaceutical carrier material. This carrier :~ material can be an organic or inorganic inert carrier materiaL suitable for enteral ox parenteral administration ., such as, for exam~le, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, poly-alkyleneglycols, petroleum jelly etc. The pharmaceutical ~ preparations can be made up in a solid form (e.g. as tablets, .
~;
: I k:
~1 .r 6~
dragees, suppositories or capsules) or in a liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations can be sterilised and/ox can contain adjuvants such as preserving, stabilising, wetting : 5 or emulsifying agents r salts for varyin~ the osmotic pressure, anaesthetics or buffers. They can also contain other therapeu~ically valuable substances. The co~pounds of formula I and their salts as well as the hydrates of such compounds and salts are preferably administered parenterally and for this purpose are preferably formulated as ;: ~ lyophilisates or dry powders for dilution with customary agents such as water or isotonic sodium chloride solution~
-:~ The readily hydrolysable esters or ethers of fo.rmula I and ., .
:~ their salts as well as hydrates of such salts can aLso be administered enterally.
~ '~
;~ :
: ~' .
': "
.. ,. ~ :
~:- - ~ . . : .
The folLowing Examples illustrate the present invention:
28.8 g of (6R,7R)-7-/ 4-bromo-2-[(~)-methoxyimino]-acetoacetamido /-3-/ [(2,5-dihydro-6-hydroxy-2-methyl-5--oxo-as-triazin-3-yl)thio~methyl /-~ oxo-S-thia-l-aza-bicyclo~4.2.0loct-2-ene-2-carboxylic acid are dissolved in 400 ml of ahsolute ethan~l. The solution is treated with 7.6 g of thiourea. After stirring for 15-20 minutes at 25C, the product begins to crystallise from the orange solution as the hydrobromide. After stirring for 1.5 hours, the hydrobromide is filtered off under suction, washed successively with 200 ml of alcohol and 200 ml of low--boillng petroleum ether and dried at 35-40C overnight in a high vacuum. 22g of almost colourless hydrobromide are obtained. This is dissolved, together with 15.7 g of sodium acetate trihydrate, in a mixture of 110 ml of water ; and 110 ml of acetone. 140 ml of acetone are added to the resulting solution until it is slightly turbid. Shortly thereafter the product begins to crystalllse. The mixture ls stlrred for 30 minutes and 180 ml of acetone are added dropwise during a further 30 minutes t the crysta~lisation ,then being complete. The product is filtered off under suction, washed successively wi.th 250 ml of 85% aqueous I; ~.,1 :
' ~
.
~lD
acetone, 250 ml of acetone and 250 ml of low-boiling petroleum ether and finally dried at 25C in ~acuo.
There are obtained 19.6 g (59~3~ oi theory) of the almost colourless disodi~n salt of (6R,7R)-7-[2-(2-amino-4-thiazolyl) ; S -2-(Z-methoxyimino)acetamido~-3-/ [2,5-dihydro-6-hydroxy-2--methyl-5-oxo-as-triazin-3-yl)thio]methyl /-8-oxo-5-thia-azabicycloC4.2.0]oct-2-ene 2-carboxylic acid which is recrystallised from water/acetone. There are obtained 17.3 g (52.3~ of theory~ of pure substance with []25 =
-150.8 (c = 1 in wat2r). lH-NMR spectrum in DMSO-d6 value~ in ppm, s = singlet, d = doublet, q = quartet, b - broad; J = coupling constant in Hz; number o~ pxoton~
in parentheses): 3.47 (N--CH3) (s~ (3), 3.49 (2-C~) (AB-q/centering value; Jgem = ~ 18 Hz) (2), 3.85 [=N'0CH3, (Z)] (s~ ~3j, 4.37 (3-CH2-S)~AB-q/centerlng value; Jgern =
.5 H~) (2), 5.04 (E-6) (d'JE-6~H-7 = 4-5 Hz) (l)~ 5-59 ;~ q' h-7~NH 8 H~JH_7 H-6 = 4.5 Hz (1), 6.75 - ~; (thiazolyl-H) (s) (l), 7~.29 (-NH2) (b) (2), 9,52 (-C0-NH-) NH,H-7 The (6R,7R)-7-/ 4-bromo-2-[(Z)-methoxyimino]aceto-acet~nido /~3~ r [(2,5-dihydro~6-hydroxy-2-methyl-5-oxo--as-triazin-3-yl)thio}methyl 7-8-oxo-5-thia-l-azabicyclo[4.2.0~-oct-2-ene-2-carbo~ylic acid used as the starting rnaterial can be prepared as follows:
~1 . ., I! :
, 11 592.1 g o acetoacetic acid tert.butyl ester are dissolved in 560 ml of glacial acetic acid. A solution of 290.6 g of sodium nitrite in 655 ml of water is added dropwise to this solution at 5-10C during 2.5 hours. The resulting yellow suspension is stirred at 20C for 30 minutes, treated with 940 ml of water and stirxed for a further 2 hours~
The mixture is treated with 900 ml of water and 900 g of ice and extracted three times in a stirxing vessel with 1 litre of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 litre o water each time, then treated with 5 litxes o~ water and the pH is adjusted to 6.8 with sodi~ hydrogen carbonate. After separating the aqueous phase, it is washed once with water.
Thereafter, the ethyl acetate solution is dried over sodium - 15 sulphate and evaporated at 40C ln vacuo. There is obtained .~
(Z)-2-hydroxyimino-3-oxobutyric acid tert.butyl ester in the ~, form of a yellow oil which is dried at 40C in a high ~1 vacuum for a further 9 hours. The yield amounts to 626.65 g ~. ,, (89.2~ of theory).
626.65 g of (Z)-2 hydroxyimino 3-oxobutyric acid tert.butyl ester are dissolved in 2.86 litres of acetone.
The solution is cooled to 5~C and treated portionwise with 703.5 g of potassium carbonate. 322 ml of dimethyl sulphate are then added dropwise to the yellow suspension without cooling during 1 hourl where~y the temperature of the mi~ture should not rise above 25C. The light beige ., ~ f , I :
, ~ . .:
.: , . : . . : .
s Ig suspension is stirred at 20-25C for ca ~L hours until starting material can no longer be detected by thin-layer chromatography. The mixture is then poured into 7 litres of water and extracted three times with 1 litre of ethyl ; 5 acetate each time. The combined ethyl acetate extracts are washed three times with 1 litre of water each time, dried over sodium sulphate and evaporated at 40C in vacuo. The residual yellow oil is dried at 40C in a hign vacuum for a further 6 hours and subsequently di~tilled. Thexe are obtained 577 g (85.6% of theory) of (Z)~2~methoxyimino-3--oxobutyric acid tert.butyl ester in the form of a yellow oil of boiling point 57C/0.02 mm Hg. lE-NMR spectrum in CDC13 (~-values in ppm, s = singlet, number of protons ; ~ in parentheses)~ 1.55 [-C(CH3)3] (s) (9), 2.36 (CH3-CO) (s~
~ 15 (3) 4 01 [= N~OCH3 (Z)] (s) (3) .":
86 g of (Z)-2-methoxyimino-3-oxobutyric acid tert.-butyl ester are dissolved in 400 ml of trifluoroacetic acid.
The $olution is left to stand at 25C for 1 hour and then evaporated at 35C in vacuo. The oily residue is crystallised from ether/petroleum ether. There are obtained 50 g (80.6~ o~ theory) of yellowish water-soluble (Z)-2-~' methoxyimino-3-oxobutyric acid of melting point 80-85c.
H-NMR spectrum in CDC13 (~-values in ppm, s = singlet, humber of protons in parentheses): 2.43 (C~3-CO) (3), 4.14 ~ 25 [= N CH3, (z)~ (s) (3), 10.47 (OH) (s) (l).
:. ' ' ~ ", ., L6~
~o~
;~ .
145 g of tZ)-2-methoxyimino-3-oxobutyric acid are dissolved in 1000 ml of alcohol-free and water-free dichloromethane. 10 ml of 30~ hydxobromic acid in glacial acetic acid axe added to the resulting solution. Then, a solution of 37~5 ml of bromine in 112.S ml of dichloro-; methane is added dropwlse during ca 2 hours, the temperature of the mixture being held at 20~25C by slight cooling.
Nitrogen is now blown through the mixture vigorously to remove hydrogen bromide. Subsequently, 250 g of ice, 250 ml of water and 2 litres of ether are added successi~ely. The ar~ueous phase is separate-d and discarded. The organic phase is washed with 250 ml of water and Z50 ml of saturated sodium chloride solution, dried over sodium sulphate and ~!
evaporated in vacuo. There are obtained 170 g of a brown oil which is crystallised from carbon tetrachloride. There are o~tained 100 g (44.6% of theoryj of al~ost colourless (Z)-4-bromo-2-methoxyimino-3-oxobutyric acid. lH-NMR
~, :
spec~rum in CDC13 (~-values in ppm, s = singlet, number of protons in parentheses): 4.24 [= N CH3, (z) (5) (3), 4.41 (-C~2-) (s) (2), 11.00 (OH) (s) (1).
.
37.1 g of (7R)-7-amino-3-desacetoxy-3-[(2,5 dihydro--6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]-cephalosporanic acid are suspended ln 800 ml of ethyl acetate and treated with 100 ml of N,O-bis-(trimethylsilyl)-acetamide. The mixture is stirred at ~5C for 30 minutes with the exclusion of moisture, a light yellow solut'on resulting. This . !
.
~o , -,~r -.i~
solution, cooled to -10C, is added dropwise at -10C to 0C during 30 mintues to a solution of (Z)~4-bromo-2--methoxyimino~3-oxobutyric acid chloride, prepared from 22.4 g of (Z)-4-bromo-2-methoxyi~ino-3-oxobutyric acid in 300 ml of alcohol-free and water-free dichloromethane and 20.8 g of phosphorus pentachloride at 8-10C. The mixture is stirred at 0-5C for 30 minutes and at 25C for 1 hour.
1 litre of ethyl acetate and 500 ml o~ water are added while stirring. The aqueous phase and the resinous intermediate layer are discarded. The organic phase is washed six times with 500 ml of water each time, dried over sodium sulphate and concentrated at 40C in vacuo to a voLume of 200 ml. ThP orange ~oloured concentrate is added drop-wise while stirring to 1.8 litres of ethex, the product separating in amorphous form. This product is filtexed off under suction, washed successively with 1 litre of ethex and 1 litre o low-boiling petroleum ether and dried at 35C in vacuo overnight. There are obtained 37.~ g (64.4% of theory) of (6R,7R)-7- f 4-bromo-2-C(Z)-methoxyimino]acetoacetamido ~ -20 -3-_ ~(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]methyl~ -8-oxo-5-thia-1-azabicyclo~4.2.0~oct-2-ene-2--carboxylic acid in the form of a beige amorphous product with ~]25 = -223.1 (c = 1 in methanol. lH-N~R spectrum in DMS0-d6 (~ alues in ppm, s = singlet, d = doublet, q =
quartet, b = broad; ~ = coupling constant in Hz; number of ~;I protons in parentheses): 3.60 (N-CH3) (s) (3), 3.63 (2-CH2) (AB-q/centerirg value; J = 18 Hz) (2)j 4.07 [= N'OCH3, '' :, s (Z)] (s) (3), 4.25 (3-CH2-S)(AB-q/centering value; Jgem ~
13 Hz) (2), 4.62 (Br-CH2 ) (s) (2), 5.15 (H 6) (d~H 6 ~-7 =
5 Hz) (1), 5.78 (H-7) (q/JH-7 N~ ~ 8 H2~ JH-7~H-6 (1), 9.47 (NH) d,JNH H-7 = 8 Hz) (1), 11.1~ (-COOH and ~GH) (b) (2).
~ .
Manufacture of dry ampoules for intramuscular administration:
A lyophilisate of 1 g of the disodium salt of ~` 10 ~6R~7Rj-7-E2-(2-amino-4 thiozolyl)~2~(Z-methoxyimino)-acetamido]-3-/ [(2,5 dihydro 6-hydroxy-2-~iethyl-5-oxo--as-:: -triazln-3-yl)t~io]methyl /-8-oxo-5-thia 1-azabicyclo~4.2.0]-oct-2-ene-2-carboxylic acid is manufactured in the customary manner and ~illed into an ampoule. Prior to the administratio~
the lyophilisate is treated with 2.5 ml of a 2~ aqueous lidocaine hydrochloride solution.
.:
, :
~: ~ : : .
Claims (15)
1. A process for the manufacture of compounds of the general formula I
wherein X represents the group or (a) (b) as well as of salts of these compounds and hydrates of these compounds and salts, which process comprises reacting a halide of the general formula II
wherein X has the significance given earlier in this claim and Y
represents a halogen atom, or a salt thereof with thiourea and, if desired, converting compound of formula I obtained into a salt or hydrate or into a hydrate of said salt.
wherein X represents the group or (a) (b) as well as of salts of these compounds and hydrates of these compounds and salts, which process comprises reacting a halide of the general formula II
wherein X has the significance given earlier in this claim and Y
represents a halogen atom, or a salt thereof with thiourea and, if desired, converting compound of formula I obtained into a salt or hydrate or into a hydrate of said salt.
2. A process according to claim 1 wherein a starting material of formula II in which Y represents a bromine atom is used.
3. A process according to claim 1 or claim 2, wherein the halide starting material of formula II is used in the syn form (Z form).
4. A process according to claim 1 wherein the halide starting material of formula II is, prepared by reacting a primary amine of the general formula III
wherein X has the significance given in claim 1, with a halogenated carboxylic acid of the general formula IV
wherein Y represents a halogen atom, or with a reactive derivative thereof.
wherein X has the significance given in claim 1, with a halogenated carboxylic acid of the general formula IV
wherein Y represents a halogen atom, or with a reactive derivative thereof.
5. A process according to claim 4 wherein a halogenated carboxylic acid of formula IV in which Y
represents a bromine atom or a reactive derivative thereof is used.
represents a bromine atom or a reactive derivative thereof is used.
6. A process according to claim 4 wherein the starting material of formula IV or a reactive derivative thereof is used in the syn form (Z form).
7. A process according to any one of claims 4 to 6 wherein the acid chloride of a halogenated carboxylic acid of formula IV is used.
8. A process according to claim 1 wherein the halide starting material of formula II is prepared by halogenating a compound of the general formula V
wherein X has the significance given in claim 1.
wherein X has the significance given in claim 1.
9 . A process according to claim 8 wherein the compound of formula V is used in the syn form (Z form).
10. A process according to claim 8 wherein the compound of formula V is prepared by reacting a primary amine of the general formula III
wherein X has the significance given in claim 1, with 3-oxo-2 methoxyiminobutyric acid or with a reactive derivative thereof.
wherein X has the significance given in claim 1, with 3-oxo-2 methoxyiminobutyric acid or with a reactive derivative thereof.
11. A process according to claim 10 wherein 3-oxo-2-methoxy-iminobutyric acid chloride is used.
12. A process according to claim 10 or claim 11, in which the 3-oxo-2-methoxyiminobutyric acid or reactive derivative thereof is used in the syn form (Z form).
13. A process for the manufacture of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido)-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and salts of this compound as well as hydrates of this compound and salts which process comprises reacting a (6R,7R)-7-[4-halogen-2-[(Z)-methoxy-imino]-acetoacetamido ] -3-[ [(2,5-dihydro-6-hydroxy-2-methyl-5--oxo-as-triazin-3-yl)thio]methyl ]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid with thiourea and if desired converting the product otained into a salt or hydrate or into a hydrate of said salt.
14. Compounds of the general formula I
wherein X represents the group or (a) (b) as well as salts of these compounds and hydrates of these compounds and salts, whenever prepared according to the process claimed in Claim 1 or by an obvious chemical equivalent thereof.
wherein X represents the group or (a) (b) as well as salts of these compounds and hydrates of these compounds and salts, whenever prepared according to the process claimed in Claim 1 or by an obvious chemical equivalent thereof.
15. (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and salts of this compound as well as hydrates of this compound and salts whenever prepared according to the process claimed in Claim 13 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH10384/79 | 1979-11-21 | ||
| CH1038479 | 1979-11-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1146165A true CA1146165A (en) | 1983-05-10 |
Family
ID=4362652
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000364648A Expired CA1146165A (en) | 1979-11-21 | 1980-11-14 | Process for the manufacture of acyl derivatives |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0030294B1 (en) |
| JP (2) | JPS5692894A (en) |
| KR (1) | KR860000852B1 (en) |
| AT (1) | ATE8896T1 (en) |
| AU (1) | AU533088B2 (en) |
| CA (1) | CA1146165A (en) |
| DE (1) | DE3068905D1 (en) |
| DK (1) | DK166728B1 (en) |
| ES (2) | ES496994A0 (en) |
| FI (2) | FI67385C (en) |
| GR (1) | GR71879B (en) |
| HU (1) | HU184941B (en) |
| IE (1) | IE50516B1 (en) |
| IL (1) | IL61486A (en) |
| NO (2) | NO166229C (en) |
| NZ (1) | NZ195547A (en) |
| PH (2) | PH17359A (en) |
| PT (1) | PT72084B (en) |
| SI (1) | SI8012952A8 (en) |
| YU (1) | YU42364B (en) |
| ZA (1) | ZA807099B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5574155A (en) * | 1992-02-20 | 1996-11-12 | Biochemie Gesellschaft M.B.H. | Process for the synthesis of the disodium salt hemiheptahydrate of ceftriaxone |
| US6800756B2 (en) | 2002-05-03 | 2004-10-05 | Orchid Chemicals And Pharmaceuticals, Ltd. | Method for the preparation of ceftiofur sodium and its intermediates |
| US7339055B2 (en) | 2003-08-22 | 2008-03-04 | Orchid Chemicals & Pharmaceuticals Ltd. | Process for the preparation of cephalosporin antibiotic |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0830051B2 (en) * | 1986-05-21 | 1996-03-27 | 武田薬品工業株式会社 | Process for producing 4-halogeno-2-substituted oxyimino-3-oxobutyric acid ester or amide |
| JP2595605B2 (en) * | 1988-01-18 | 1997-04-02 | 武田薬品工業株式会社 | Method for producing 2-substituted oxyimino-3-oxobutyric acid |
| AT398764B (en) * | 1992-01-28 | 1995-01-25 | Lek Tovarna Farmacevtskih | METHOD FOR PRODUCING CEFTRIAXONDINATRIUM SALZHEMIHEPTAHYDRATE |
| AT411598B (en) * | 1999-04-29 | 2004-03-25 | Biochemie Gmbh | Preparation of beta-lactam derivatives used as antibacterial agents by reacting cephalosporanic acid derivative with imine compound, then thiourea compound |
| AT408225B (en) * | 1999-04-29 | 2001-09-25 | Biochemie Gmbh | Process for the preparation of cephalosporins |
| EP1399429A1 (en) * | 2001-06-14 | 2004-03-24 | Orchid Chemicals and Pharmaceuticals Ltd | 1,3,4-oxadiazol-2-yl thioesters and their use for acylating 7-aminocephalosporins |
| IN192139B (en) | 2001-11-26 | 2004-02-21 | Lupin Ltd | |
| WO2003089406A1 (en) * | 2002-04-19 | 2003-10-30 | Orchid Chemicals And Pharmaceuticals Limited | A process for the preparation of cephalosporin intermediate and its use for the manufacture of cephalosporin compounds |
| US6919449B2 (en) | 2002-04-19 | 2005-07-19 | Orchid Chemicals And Pharmaceuticals Limited | Process for the preparation of cephalosporin intermediate and its use for the manufacture of cephalosporin compounds |
| WO2004083216A1 (en) * | 2003-03-20 | 2004-09-30 | Orchid Chemicals & Pharmaceuticals Ltd | A process for the preparation of cephalosporins |
| ES2348299T3 (en) | 2003-04-16 | 2010-12-02 | Sandoz Ag | PROCEDURES FOR THE PREPARATION OF CEFEPIME. |
| US7847093B2 (en) | 2003-04-16 | 2010-12-07 | Sandoz Ag | Processes for the preparations of cefepime |
| US7098329B2 (en) * | 2003-06-19 | 2006-08-29 | Orchid Chemicals & Pharmaceuticals Ltd. | Process for the preparation of a cephalosporin antibiotic |
| US20050059820A1 (en) * | 2003-09-17 | 2005-03-17 | Debashish Datta | Method for manufacture of ceftriaxone sodium |
| WO2005040175A2 (en) * | 2003-10-22 | 2005-05-06 | Ranbaxy Laboratories Limited | Process for the preparation of cephem carboxylic acids |
| US20050119244A1 (en) | 2003-12-02 | 2005-06-02 | Acs Dobfar S.P.A. | Process for preparing cephalosporins with salified intermediate |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4200745A (en) * | 1977-12-20 | 1980-04-29 | Eli Lilly And Company | 7[2-(2-Aminothiazol-4-yl)-2-alkoxyimino]acetamido 3[4-alkyl-5-oxo-6-hydroxy-3,4 dihydro 1,2,4-triazin 3-yl]thio methyl cephalosporins |
| JPS5498795A (en) * | 1978-01-13 | 1979-08-03 | Takeda Chem Ind Ltd | Cephalosporin derivative and its preparation |
| MC1259A1 (en) * | 1978-05-30 | 1980-01-14 | Hoffmann La Roche | ACYL DERIVATIVES |
-
1979
- 1979-11-30 FI FI793768A patent/FI67385C/en not_active IP Right Cessation
-
1980
- 1980-11-07 PH PH24818A patent/PH17359A/en unknown
- 1980-11-14 CA CA000364648A patent/CA1146165A/en not_active Expired
- 1980-11-14 IL IL61486A patent/IL61486A/en not_active IP Right Cessation
- 1980-11-14 ZA ZA00807099A patent/ZA807099B/en unknown
- 1980-11-14 NZ NZ195547A patent/NZ195547A/en unknown
- 1980-11-17 HU HU802744A patent/HU184941B/en unknown
- 1980-11-17 AU AU64438/80A patent/AU533088B2/en not_active Expired
- 1980-11-18 GR GR63382A patent/GR71879B/el unknown
- 1980-11-18 AT AT80107160T patent/ATE8896T1/en not_active IP Right Cessation
- 1980-11-18 DE DE8080107160T patent/DE3068905D1/en not_active Expired
- 1980-11-18 EP EP80107160A patent/EP0030294B1/en not_active Expired
- 1980-11-18 JP JP16148780A patent/JPS5692894A/en active Granted
- 1980-11-20 SI SI8012952A patent/SI8012952A8/en unknown
- 1980-11-20 YU YU2952/80A patent/YU42364B/en unknown
- 1980-11-20 NO NO803516A patent/NO166229C/en unknown
- 1980-11-20 IE IE2408/80A patent/IE50516B1/en not_active IP Right Cessation
- 1980-11-20 PT PT72084A patent/PT72084B/en unknown
- 1980-11-20 ES ES496994A patent/ES496994A0/en active Granted
- 1980-11-20 KR KR1019800004446A patent/KR860000852B1/en active
- 1980-11-20 DK DK496380A patent/DK166728B1/en not_active IP Right Cessation
-
1981
- 1981-06-18 NO NO81812083A patent/NO166228C/en unknown
- 1981-07-01 ES ES503583A patent/ES8204997A1/en not_active Expired
- 1981-12-16 PH PH26633A patent/PH18468A/en unknown
-
1984
- 1984-06-28 FI FI842614A patent/FI71563C/en not_active IP Right Cessation
-
1985
- 1985-12-20 JP JP60285859A patent/JPS61143392A/en active Granted
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5574155A (en) * | 1992-02-20 | 1996-11-12 | Biochemie Gesellschaft M.B.H. | Process for the synthesis of the disodium salt hemiheptahydrate of ceftriaxone |
| US6800756B2 (en) | 2002-05-03 | 2004-10-05 | Orchid Chemicals And Pharmaceuticals, Ltd. | Method for the preparation of ceftiofur sodium and its intermediates |
| US7339055B2 (en) | 2003-08-22 | 2008-03-04 | Orchid Chemicals & Pharmaceuticals Ltd. | Process for the preparation of cephalosporin antibiotic |
| US7345169B2 (en) | 2003-08-22 | 2008-03-18 | Orchid Chemicals & Pharmaceuticals Ltd. | Process for the preparation of cephalosporin antibiotic |
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