73384-59-5 Usage
Uses
Used in Pharmaceutical Industry:
(6R,7R)-7-[[(2E)-2-(2-Amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-5,6-dioxo-1H-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is used as an antibacterial agent for the treatment of various infections caused by clinically significant microorganisms, including Gram-positive, Gram-negative, aerobic, anaerobic, and blue-pus bacillus. It is particularly effective against infections such as peritonitis, sepsis, meningitis, cholangitis, empyema of the gall bladder, pneumonia, lung abscesses, pyelonephritis, infections of the bones, joints, skin, soft tissues, abdominal and gynecological infections, and infected wounds and burns.
Used in Research and Development:
(6R,7R)-7-[[(2E)-2-(2-Amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-5,6-dioxo-1H-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is also used in research and development for the discovery and development of new antimicrobial agents. Its unique structure and broad-spectrum activity make it a valuable tool for studying the mechanisms of action and resistance of various microorganisms, as well as for designing new drugs to combat antibiotic-resistant infections.
Originator
Rocephin,Roche,Switz.,1982
Manufacturing Process
19 g of (6R,7R)-7-[2-[2-(2-chloroacetamido)-4-thiazolyl]-2-(methoxyimino)
acetamido]-8-oxo-3-[[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-
yl)thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are
suspended in 150 ml of water together with 9.5 g of thiourea. The pH is
adjusted to 6.8 with 5% sodium hydrogen carbonate solution while gassing
with nitrogen and stirring, there being obtained a yellow-orange solution. The
pH of the solution is held constant at 6.8-7.0 for 6 hours by adding sodium
hydrogen carbonate solution by means of an autotitrator. 100% formic acid is
added to the orange colored solution until the pH is 3.5. The precipitated
material is filtered off under suction and washed with 100 ml of 10% formic
acid. This material is denoted as (1). The filtrate is adjusted to pH 2.5 by
adding 100% formic acid, whereby additional substance precipitates out. The
mixture is held in an ice-bath for 1 hour, the precipitated substance is then
filtered off and washed with a small amount of ice-water. This material is
denoted as fraction I. The aforementioned orange-brown material (1) is
suspended in 250 ml of water. The suspension is adjusted to pH 7 with 2 N
sodium hydroxide, there being obtained an orange-brown solution. Additional
100% formic acid is added to this solution until the pH is 3.5. The material which thereby precipitates out is filtered off under suction and discarded. The
filtrate is adjusted to pH 2.5 with 100% formic acid, whereby additional
substance precipitates out. The mixture is held in an ice-bath for 1 hour, the
precipitated substance is then filtered off under suction and washed with a
small amount of ice-water. This material is denoted as fraction II. Fractions I
and II are suspended together in 500 ml of ethanol and evaporated in a
rotary evaporator in order to remove water. After adding ether, the mixture is
filtered under suction and the precipitate is washed successively with ether
and low-boiling petroleum ether. There is thus obtained the title substance in
the form of a yellowish solid material which is denoted as A.
The mother liquors and washings of fractions I and II are concentrated from a
volume of about 1.7 liters to 250 ml, the pH is adjusted to 2.5 with 100%
formic acid and the solution is stored overnight in a refrigerator, whereby
further substance crystallizes. This is filtered off under suction and washed
with a small amount of water. The residue on the suction filter is
azeotropically distilled with ethanol. There is obtained solid, almost colorless
title substance which is denoted as B. B is purer than A according to thin-layer
chromatography.
In order to obtain pure title substance, the acid B is suspended in 150 ml of
methanol and treated while stirring with 10 ml of a 2 N solution of the sodium
salt of 2-ethylcaproic acid in ethyl acetate. After about 10 minutes, there
results a solution which is treated with 100 ml of ethanol. The mixture is
extensively concentrated at 40°C in vacuo. The sodium salt precipitates out in
amorphous form after adding ethanol. This salt is filtered off under suction,
washed successively with ethanol and low-boiling petroleum ether and dried at
40°C in a high vacuum. There is obtained the title substance in the form of an
almost colorless amorphous powder.
Therapeutic Function
Antibacterial
Antimicrobial activity
Most β-lactamase-producing enterobacteria are highly susceptible,
as are streptococci (but not enterococci) and fastidious
Gram-negative bacilli, although brucellae are less sensitive
(MIC 0.25–2 mg/L). Treatment failure has been reported in
tularemia. Ps. aeruginosa, mycoplasmas, mycobacteria and L.
monocytogenes are resistant.
Acquired resistance
Ceftriaxone is hydrolyzed by some chromosomal enzymes, including those of Enterobacter spp. and B. fragilis. Derepression of chromosomal β-lactamase production can cause resistance in some species of Gram-negative bacilli in vitro and has been observed in patients.
Pharmacokinetics
Cmax 500 mg/L intramuscular: c. 40 mg/L after 2 h
1 g intravenous (15–30-min infusion): c. 120–150 mg/L end infusion
Plasma half-life: 6–9 h
Volume of distribution: 0.15 L/kg
Plasma protein binding: 95%
Distribution
Ceftriaxone penetrates well into normal body fluids and natural and experimental exudates. In children treated for meningitis with 50 or 75 mg/kg intravenously over 10–15 min, mean peak CSF concentrations ranged from 3.2 to 10.4 mg/L, with lower values later in the disease. In patients receiving 2 g before surgery, concentrations in cerebral tissue reached 0.3–12 mg/L. In patients with pleural effusions of variable etiology given a 1 g intravenous bolus, concentrations of 7–8.7 mg/L were found at 4–6 h. In patients with exacerbations of rheumatoid arthritis receiving the same dose, joint fluid contained concentrations close to those in the serum, but with wide individual variation. Tissue fluid:serum ratios have varied from around 0.05 in bone and muscle to 0.39 in cantharides blister fluid. The apparent volume of distribution is increased in patients with cirrhosis where the drug rapidly enters the ascitic fluid, but its elimination kinetics are unaffected.
Ceftriaxone rapidly crosses the placenta, maternal doses of 2 g intravenously over 2–5 min producing mean concentrations in cord blood of 19.5 mg/L, a mean cord:maternal serum ratio of 0.18; and in amniotic fluid 3.8 mg/L, a fluid:maternal serum ratio of 0.04. The plasma elimination half-life appears to be somewhat shortened in pregnancy (5–6 h). Some appear in the breast milk, the milk:serum ratio being about 0.03–0.04, secretion persisting over a long period with a half-life of 12–17 h.
Metabolism and excretion
Ceftriaxone is not metabolized. Biliary excretion is unusually high, 10–20% of the drug appearing in the bile in unchanged form, with concentrations up to 130 mg/g in biopsied liver tissue from patients receiving 1 g intravenously over 30 min. The insoluble calcium salt may precipitate in the bile leading to pseudolithiasis. About half the dose appears in the urine over the first 48 h, somewhat more (c. 70%) in neonates. Excretion is almost entirely by glomerular filtration, since there is only a small effect of probenecid on the excretion of the drug. The half-life is not linearly correlated with creatinine clearance in renal failure and, in keeping with the low free plasma fraction, it is not significantly removed by hemodialysis. The volume of distribution is not affected by renal failure.
Clinical Use
Uses of Ceftriaxone are similar to those of cefotaxime, the long half-life offering the advantage of once-daily administration. It is used in the treatment of acute bacterial meningitis and as an alternative to rifampicin (rifampin) in the prophylaxis of meningococcal disease.
Side effects
Reactions are those common to other cephalosporins. Mention has been made of thrombocytopenia, thrombocytosis, leukopenia, eosinophilia abdominal pain, phlebitis, rash, fever and increased values in liver function tests. Diarrhea is common and suppression of the aerobic and anaerobic fecal flora has been associated with the appearance of resistant bacteria and yeasts.
Biliary pseudolithiasis due to concretions of insoluble calcium salt has been described in adults but principally in children. The precipitates can be detected in a high proportion of patients by ultrasonography and can occasionally cause pain, but resolve on cessation of treatment. Ceftriaxone is better avoided in patients with pre-existing biliary disease, but the principal hazard appears to be misdiagnosis of gallbladder disease and unnecessary surgery.
Synthesis
Ceftriaxone, 7-[[(2-amino-4-thiazolyl)-2-(Z)-(methyoximino)acetyl]amino]-8-
oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl)thio]methyl]-5-thia-1-
azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (32.1.2.72), is synthesized by acylating
7-amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl-1,2,4-triazin-5-on-3-yl)thio]methyl]3-cefem-
4-carboxylic acid (32.1.2.70), by the 2-(4-thiazolyl)-2-methoxyiminoacetic acid chloride,
which is protected at the amino group by a chloroacetyl group, namely with 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetylchloride (32.1.2.67). The last is synthesized from
ethyl ester of 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid (32.1.2.52), the amino
group of which is protected by the acylation with chloracetic acid chloride in dimethylacetamide, giving ethyl ester of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetic acid
(32.1.2.65). Hydrolysis of the ester group of this compound by potassium hydroxide to an acid
(32.1.2.66), and its subsequent reaction with phosphorous pentachloride in the presence of
trimethylamine gives 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetylchloride
(32.1.2.67). The synthesis of 7-amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl-1,2,4-triazin-5-
on-3-yl)thio]methyl]-3-cefem-4-carboxylic acid (32.1.2.70) is done in parallel. In order to do
this, methylhydrazine is reacted with potassium thiocyanate to give 1-amino-1-methylthiourea
(32.1.2.68), which is reacted with dimethyloxalate in the presence of sodium methoxide to
form a heterocyclization product, 2,5-dihydro-6-hydroxy-2-methyl-3-mercapto-1,2,4-triazin-
5-on (32.1.2.69). Reacting this with 7-aminocephalosporanic acid replaces the acetoxy group giving 7-amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl-1,2,4-triazin-5-on-3-yl)thio]methyl]-3-
cefem-4-carboxylic acid (32.1.2.70). Acylating this with the acid chloride synthesized earlier
(32.1.2.67) in tetrahydrofuran in the presence of sodium hydroxide gives the desired product
(32.1.2.71). Removal of the chloroacetyl protection in this molecule is accomplished in the
following manner. Subsequent reaction of the product (32.1.2.71) with thiourea in the presence of sodium bicarbonate results in the formation of a new thiazole derivative. Subsequent
cleaving of the resulting secondary heteroaromatic amine with formic acid gives ceftriaxone
(32.1.2.72).
Metabolism
About 40-65% of a dose of ceftriaxone is excreted
unchanged in the urine, principally by glomerular
filtration; the remainder is excreted in the bile and is
ultimately found in the faeces as unchanged drug and
microbiologically inactive compounds.
Check Digit Verification of cas no
The CAS Registry Mumber 73384-59-5 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 7,3,3,8 and 4 respectively; the second part has 2 digits, 5 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 73384-59:
(7*7)+(6*3)+(5*3)+(4*8)+(3*4)+(2*5)+(1*9)=145
145 % 10 = 5
So 73384-59-5 is a valid CAS Registry Number.
InChI:InChI=1/C18H18N8O7S3/c1-25-18(22-12(28)13(29)23-25)36-4-6-3-34-15-9(14(30)26(15)10(6)16(31)32)21-11(27)8(24-33-2)7-5-35-17(19)20-7/h5,9,15H,3-4H2,1-2H3,(H2,19,20)(H,21,27)(H,23,29)(H,31,32)/b24-8-
73384-59-5Relevant articles and documents
Design and synthesis of novel active phosphonate esters and their application in preparation of ceftriaxone
Ren, Hui-Xue,Sun, You-Min,Wu, Dao-Ji,Ma, Yong-Shan,Ying, Han-Jie,Ma, Yan
, p. 155 - 159 (2014/07/07)
For a series of active phosphonate esters, the anhydride abbreviated as ANPTA (6a) exhibits the highest reactivity in the preparation of ceftriaxone. The synthesis of ceftriaxone was optimized with the pilot-scale yield reaching 95.7%. The results were explained from the structural viewpoint and supported by analysis of the calculated Mulliken atomic charge distribution.
IMPROVED PROCESS FOR THE PREPARATION OF CEPHALOSPORIN ANTIBIOTICS
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Page/Page column 11-12, (2008/06/13)
Abstract The present invention more particularly relates to a process for the preparation of cephalosporin antibiotics of the Formula (I) wherein R1 represents hydrogen, trityl, alkyl like CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6) alkyl; R2 is carboxylate ion or COORd, where Rd represents hydrogen, ester or a counter ion which forms a salt; R3 represents hydrogen, CH3, CH2OCH3, CH2OCOCH3, CH=CH2, Formula (II).
PROCESS FOR THE PREPARATION OF CEPHALOSPORIN ANTIBIOTIC
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Page/Page column 10, (2010/02/11)
A process for the preparation of cephalosporin antibiotic of the formula (I) wherein R1 represents hydrogen, trityl, etc,; R3 is carboxylate ion or COORd, where Rd represents hydrogen, ester or a counter ion which forms a salt; R4 represents H, OCH3, OCOCH3, =CH2, OCONH2, etc, which comprises: (i) condensing the activated derivative of the formula (III) where X represents halogen atom, with 7-amino cephalosporin derivative of the formula (XV) wherein R represents hydrogen, lower alkyl, etc, in the presence of a solvent at a temperature in the range of -50 °C to +50 °C to produce a compound of formula (XVI) ii) maintaining the pH in the range 5.0-10.0 using an inorganic base, iii) cyclizing the compound of formula (XVI) with thiourea to produce compound of formula (I).
Method for manufacture of ceftriaxone sodium
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Page/Page column 20-21, (2008/06/13)
An improved process for preparation of ceftriaxone sodium of formula (II), is disclosed.
Method for manufacture of ceftriaxone sodium
-
, (2008/06/13)
An improved process for preparation of ceftriaxone sodium of formula (II), is disclosed.
Process for preparing cephalosporins with salified intermediate
-
Page/Page column 6, (2010/02/11)
Cephalosporins may be conveniently prepared by a process in which 7-ACA is silylated, acylated, desilylated and then salified to give an intermediate which is eventually cyclized with thiourea.
IMPROVED PROCESS FOR THE MANUFACTURE OF CEFTRIAXONE SODIUM
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Page/Page column 8, (2010/02/14)
A process for the production of (6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-syn-methoxyimino)acetamido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid (Ceftriaxone acid) in water is discussed. The synthesis is effected by condensing (7R)-7-Amino-3-deacetoxy-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]cephalosporanic acid (7-ACT) with 2-(2-chloroacetamido-4-thiazolyl)-2-syn-methoxyiminoacetyl chloride followed be deblocking amino function. Finally, (6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-syn-methoxyimino)acetamido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid (Ceftriaxone acid) is converted into Ceftriaxone disodium hemiheptahydrate in aqueous acetone using sodium-2-ethylhexanoate as sodium source. Isolation steps at every stage are quite short. The purity of the final product is obtained in more than 99 % by HPLC profile.
NOVEL INTERMEDIATES FOR SYNTHESIS OF CEPHALOSPORINS AND PROCESS FOR PREPARATION OF SUCH INTERMEDIATES
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Page 29, (2008/06/13)
A novel 4-halo-2-oxyimino-3-oxo butyric acid-N, N-dimethyl formiminium chloride chlorosulfate of formula (I) useful in the preparation of cephalosporin antibiotics, wherein X is chlorine or bromine; R is hydrogen, C1-4 alkyl group, an easily removable hydroxyl protective group, -CH2COOR5, or -C(CH3)2COOR5, wherein R5 is hydrogen or an easily hydrolysable ester group. The compound of formula (I) is prepared by reacting 4-halo-2-oxyimino-3-oxobutyric acid of formula (IV1), wherein X, R and R5 are as defined above, with N, N-dimethylformiminium chloride chlorosulphate of formula (VII), in an organic solvent at a temperature ranging from -30 °C to -15 °C. The cephalosporins that may be prepared from the intermediate include cefdinir, cefditoren pivoxil, cefepime, cefetamet pivoxil, cefixime, cefmenoxime, cefodizime, cefoselis, cefotaxime, cefpirome, cefpodoxime proxetil, cefquinome, ceftazidime, cefteram pivoxil, ceftiofur, ceftizoxime, ceftriaxone and cefuzonam.
A PROCESS FOR THE PREPARATION OF A CEPHALOSPORIN ANTIBIOTIC
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Page/Page column 6-8, (2010/02/10)
An improved process for the preparation of ceftriaxone sodium comprising the steps of : i) reacting the 3-cephem derivative of formula (II) with halo acid derivative of formula (III) wherein X represents halogen and Y represent halogen in the presence of silylating agent and methylene chloride at -25 to 10 °C, to produce (IV), ii) quenching the reaction by pouring the reaction mixture into water or in a aqueous solution of sodium carbonate, iii) preparing sodium salt solution of (IV) by adding sodium carbonate and separating the organic layer, iv) cyclizing the sodium salt of (IV) in the aqueous solution with thiourea at a temperature in the range of 0 to 30 °C, v) adjusting the pH to 1.5 to 2.5 to precipitate the ceftriaxone free acid, vi) converting the ceftriaxone free acid to sodium salt using sodium-2-ethyl hexanoate in water and vii) precipitating and isolating the ceftriaxone sodium.
Beta-lactam production
-
, (2008/06/13)
The present invention provides processes for the production of a compound of formula I wherein X, R1 and R2 are substituents conventional in cephalosporin chemistry; especially a compound of formula I is ceftrixone, cefotaxime; e.g., in the form of a salt.
