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123447-62-1 Usage

Abstract

Prulifloxacin, a prodrug of Ulifloxacin inhibits replication of bacterial DNA (nuclear material) by inhibition of DNA-gyrase in microbes, is a newer class of fluoroquinolone exerts broad-spectrum anti-bacterial activity against several Gram-positive and Gram-negative organisms. Prulifloxacin is generally prescribed for the treatment of uncomplicated lower urinary tract infections, acute exacerbations of chronic bronchitis and complicated lower urinary tract infections.

Quinolone antibiotics

Prulifloxacin is a quinolone antibiotic, a fluoroquinolone antibiotics prodrug NM394 by the Japan Pharmaceutical Co. and Meiji Seika Kaisha, Ltd. joint research and development in the late eighties, and it was first approved for marketing in December 2002 in Japan. the dosage form is 100mg tablets, by inhibiting bacterial DNA topoisomerase ⅱ and ⅳ activity and bacterial DNA synthesis, completing sterilization, which is different from the traditional model, without drug resistance to other classes of antibiotics. It is used for the treatment of respiratory gram-positive bacteria and negative bacteria clinically, which is caused by infections, urogenital infections, otolaryngology infection, biliary tract infections, enteritis, skin and soft tissue infections and surgical infections. Notable features are as follows: Anti-gram-positive bacteria are similar with ciprofloxacin. The anti-Gram-negative bacteria, led by pseudomonas aeruginosa, is better than the similar products, such as ciprofloxacin, ofloxacin, levofloxacin, resistance to green pus bacillus particularly high sensitivity, and the antibacterial abilitu is better than the gatifloxacin class and other antibiotics currently listed. The oral absorption is good without savings and cerebrospinal fluid distribution,? and the side effects is little. The half-life is as long as 8-9 hours, and the number of eating medication is few. Rapid onset, time to peak within 0.5 to 1 hour, the effet is stronger (due to bacterial accumulation in good).

Indication

It is used for the treatment of prulifloxacin sensitive staphylococcus, streptococcus, Neisseria gonorrhoeae, (except typhoid, paratyphoid) pneumoniae, Enterococcus, Moraxella Alex Salmonella, E. coli, Shigella, Salmonella, lemon acid bacteria, Klebsiella pneumoniae, Serratia, Proteus, Vibrio cholerae, Pseudomonas aeruginosa, Streptococcus digestion, they can cause the following infections: Superficial skin infections (acute superficial folliculitis, infectious impetigo), deep skin infections (cellulitis, erysipelas, boils, boils swollen disease, appendicitis, suppurative paronychia), chronic pyoderma (sebaceous cyst infection, purulent, etc.). Superficial secondary infections, such as abscess, trauma, burns, and surgical trauma. Acute respiratory infections (pharyngitis, tonsillitis, acute bronchitis), chronic respiratory disease secondary infection (chronic bronchitis, diffuse bronchiolitis, bronchiectasis, emphysema, pulmonary fibrosis, bronchial asthma, etc.) and pneumonia. Cystitis, pyelonephritis, prostatitis. Cholecystitis, cholangitis. Infectious enteritis, bacillary dysentery, salmonellosis, cholera. The uterine infection, adnexitis. Blepharitis, stye. Otitis media, sinusitis.

Pharmacokinetics

After oral administration, Prulifloxacin is rapidly metabolized as an active form of drug, Ulifloxacin. The drug exerts good penetration into the target tissue with prolonged elimination half-life with once-daily administration. After absorption, Cmax is generally achieved within one hour, and apparent Vss is 1231 L. About 45% of the administered drug is bound to plasma proteins. The drug is extensively metabolized by first-pass metabolism into active metabolites. The terminal half-life of Ulifloxacin is 10.6-12.1 hours. The drug is mainly excreted via the urine as unmetabolized drug.

Prulifloxacin Intermediate

Prulifloxacin Intermediate PL-7 Appearance: white to light yellow powder Chemical name: 6,7-difluoro-2-mercapto-ethyl-4-hydroxy-quinoline-3-carboxylic acid ethyl ester CAS: 154330-68-4 ?Molecular Formula: C14H13F2NO3S Prulifloxacin intermediate PL-9 Appearance: white to light yellow powder Chemical name: 6,7-difluoro-1-methyl-4-oxo--4H-(1,3) thiazine (3,2a) and quinoline-3-carboxylate CAS: 113046-72- Molecular Formula:C14H11F2NO3S Prulifloxacin Intermediate PL-10 Appearance: white to light yellow powder Chemical Name: 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl) 4H-(1,3) thiazine (3,2a) and quinoline-3-carboxylate CAS: 113028-17-4 ?Molecular Formula:C18H20FN3O3S Prulifloxacin Intermediate PL-11 Appearance: white to light yellow powder Chemical Name: 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-(1,3) thiazine (3,2a) and quinoline-3-carboxylic acid CAS : 112984-60-8 Molecular Formula:C16H16FN3O3S Application:For the total synthesis of gatifloxacin antibacterials

Side effects

Abdominal cramp, Confusion, Diarrhoea, Drowsiness, Altered taste, Epigastric pain, Gastritis, Headache, Hot flashes, Increased bilirubin in the blood, Itching, Loss of appetite, Sedation, Skin rash, Sleep disorder, Vomiting, Nausea.

References

https://www.ncbi.nlm.nih.gov/pubmed/15456336 http://www.drugsupdate.com/generic/view/1110/Prulifloxacin

Description

Prulifloxacin was launched as the third fluoroquinone. It was introduced in Japan as an oral treatment for urinary tract infections (UTls), respiratory tract infections (RTls) and bacterial pneumoniae. It can be synthesized in 10 steps from commercially available 3,4-difluoroaniline. Key steps involve the cyclization of 6,7-difluoro-rl-hydroxy-2- thioquinoline-3carboxylic acid ethyl ester with 1 ,I-dibromomethane to give the corresponding thiazeto-[3,2a]quinoline. Aromatic nucleophilic substitution of the 7-fluoro atom with piperazine followed by hydrolysis of the ethyl ester and finally alkylation of the piperazinyl moiety with 4-(bromomethyl)-5-methyl-l ,bdioxol-Bone complete the synthesis. Prulifloxacin is a lipophilic prodrug, which is rapidly hydrolyzed to the corresponding Ndealkylated piperazine, NM 394, by paraoxonase type enzymes in blood and liver following intestinal absorption. The DNA gyrase inhibitor NM 394 accounts for all antimicrobial activity: it shows a similar or greater activity against gram-positive bacteria compared to ciprofloxacin, and a greater activity in the case of gram-negative bacteria. In clinical studies, prulifloxacin has shown good efficacy against UTls and RTls. The drug is mainly excreted in the urine and in the feces as unchanged NM 394, which has a plasma half-life of approximately 8 h. Phototoxicity in animal models is less severe than with other quinolones. Prulifloxacin is well tolerated with an adverse effect profile similar to that of other fluoroquinolones.

Chemical Properties

Off-White Solid

Originator

Nippon Shinyaku (Japan)

Uses

Different sources of media describe the Uses of 123447-62-1 differently. You can refer to the following data:
1. Fluoroquinoline antibacterial; prodrug for active metabolite, Ulifloxacin. Antibacterial.
2. Prulifloxacin Polymorph I is a crystallization form of a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class. Prulifloxacin is a prodrug for active metabolite, Ulifloxacin. Antibacterial.
3. Prulifloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class. Prulifloxacin is a prodrug for active metabolite, Ulifloxacin. Antibacterial.

Brand name

Sword

Pharmaceutical Applications

A lipophilic prodrug which is very rapidly metabolized by esterase into ulifloxacin, a 6-fluoro, 7-piperazinyl thiazetoquinoline.Ulifloxacin is moderately active against Staph. aureus (MIC 0.4–0.8 mg/L) and inactive against Str. pneumoniae (MIC 2–8 mg/L) as well as against Enterococcus spp. Against Enterobacteriaceae (MIC 0.05–0.8 mg/L) and Ps. aeruginosa (MIC 0.2–0.8 mg/L) activity is similar to that of ciprofloxacin. It is active against fastidious Gram-negative bacilli, but not against anaerobes and non-fermentative Gram-negative bacilli. Activity against Acinetobacter spp. is modest.Prulifloxacin is rapidly converted into ulifloxacin and after 3 h is no longer detected in blood. In volunteers receiving a single oral dose, peak plasma concentrations of 0.68 mg/L (300 mg dose) to 1.88 mg/L (for 400 mg dose) were attained between 0.67 and 1.25 h. The mean apparent elimination half-life was 8 h and the mean cumulative elimination rate in urine within 48 h was 31–46%. Other inactive metabolites account for 7% of the dose. Half the administered dose is eliminated in feces within 72 h as ulifloxacin and 4% as prulifloxacin. Protein binding is 45%.

Synthesis

The synthesis of prulifloxacin (22)started with the treatment of 3,4- difluoroaniline (183) with carbon disulfide in the presence of TEA to give the triethylammonium dithiocarbamate, which by reaction with ethyl chloroformate and TEA in chloroform, was converted into isothiocyanate 184 in 74% yield. Reaction of 184 with diethyl malonate in the presence of KOH in dioxane yielded methylenemalonate 185 potassium salt, which was ethylated with ethyl sulfate in ethanol to give compound 186 in excellent yield. 6,7- Difluoroquinoline 187 was obtained with the highest yield and regioselectivity when precursor 186 was heated in refluxing xylene. To suppress the side reaction in the subsequent chlorination, quinoline 187 was acylated to give 188 with acetyl chloride in chloroform. Chlorination of 188 with sulfuryl chloride gave compound 189 in 79% yield. Compound 189 was treated with sodium acetate in THF to afford cyclized compound 190, which was condensed with piperazine in DMF to give compound 191. The hydrolysis of ester 191 with KOH in hot t-butanol gave free acid 192, which was finally condensed with 4-(bromomethyl)-5- methyl-1, 3-dioxol-2-one (163) by treatment of potassium bicarbonate in DMF to give prulifloxacin (22).

Check Digit Verification of cas no

The CAS Registry Mumber 123447-62-1 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,2,3,4,4 and 7 respectively; the second part has 2 digits, 6 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 123447-62:
(8*1)+(7*2)+(6*3)+(5*4)+(4*4)+(3*7)+(2*6)+(1*2)=111
111 % 10 = 1
So 123447-62-1 is a valid CAS Registry Number.
InChI:InChI=1/C21H22FN3O6S/c1-10-16(31-21(29)30-10)9-23-3-5-24(6-4-23)15-8-14-12(7-13(15)22)18(26)17(20(27)28)19-25(14)11(2)32-19/h7-8,11,17,19H,3-6,9H2,1-2H3,(H,27,28)

123447-62-1 Well-known Company Product Price

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  • TCI America

  • (P2058)  Prulifloxacin  >98.0%(HPLC)(T)

  • 123447-62-1

  • 1g

  • 950.00CNY

  • Detail
  • TCI America

  • (P2058)  Prulifloxacin  >98.0%(HPLC)(T)

  • 123447-62-1

  • 5g

  • 3,300.00CNY

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123447-62-1SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 10, 2017

Revision Date: Aug 10, 2017

1.Identification

1.1 GHS Product identifier

Product name Prulifloxacin

1.2 Other means of identification

Product number -
Other names nm441

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:123447-62-1 SDS

123447-62-1Synthetic route

4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one
80715-22-6

4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one

ulifloxacin
112984-60-8

ulifloxacin

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
With potassium hydrogencarbonate In N,N-dimethyl-formamide at 0℃; for 5h; Large scale;95.4%
With potassium hydrogencarbonate In N,N-dimethyl-formamide for 5h; Ambient temperature;62%
Stage #1: ulifloxacin With potassium hydrogencarbonate In acetonitrile at 25 - 30℃;
Stage #2: 4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one at 15 - 30℃; for 27 - 28.25h;
Stage #1: 4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one; ulifloxacin With potassium hydrogencarbonate In N,N-dimethyl-formamide at 0 - 28℃; for 3 - 4h;
Stage #2: With hydrogenchloride In chloroform; water for 0.25h; pH=0.8 - 1.0;
Stage #1: ulifloxacin With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 0.166667h;
Stage #2: 4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one In acetonitrile at 10 - 30℃; for 21h; Product distribution / selectivity;
4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one
80715-22-6

4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one

ulifloxacin
112984-60-8

ulifloxacin

A

prulifloxacin
123447-62-1

prulifloxacin

B

6-fluoro-1-methyl-4-oxo-7-<4-<(2-oxo-1-methylenepropyl)oxycarbonyl>-1-piperazinyl>-4H-<1,3>thiazeto<3,2-a>quinoline-3-carboxylic acid
156834-57-0

6-fluoro-1-methyl-4-oxo-7-<4-<(2-oxo-1-methylenepropyl)oxycarbonyl>-1-piperazinyl>-4H-<1,3>thiazeto<3,2-a>quinoline-3-carboxylic acid

C

7-<4-<1-<4-(3-carboxy-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinolin-7-yl)>-1-piperazinylmethyl>-2-oxopropoxycarbonyl>-1-piperazinyl>-6-fluoro-1-methyl-4-oxo-4H-<1,3>thazeto<3,2-a>quinoline-3-carboxylic acid

7-<4-<1-<4-(3-carboxy-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinolin-7-yl)>-1-piperazinylmethyl>-2-oxopropoxycarbonyl>-1-piperazinyl>-6-fluoro-1-methyl-4-oxo-4H-<1,3>thazeto<3,2-a>quinoline-3-carboxylic acid

D

1,1-bis<(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl>-4-(3-carboxy-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinoline-7-yl)-1-piperazinium bromide

1,1-bis<(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl>-4-(3-carboxy-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinoline-7-yl)-1-piperazinium bromide

Conditions
ConditionsYield
With potassium hydrogencarbonate In N,N-dimethyl-formamide at 30℃; for 2h; Product distribution; Rate constant; various periods of time (3 h); activation energy 29.1 kJ mol-1;A 93.6 % Spectr.
B 2.0 % Spectr.
C 0.5 % Spectr.
D 1.1 % Spectr.
4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one
80715-22-6

4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one

ulifloxacin
112984-60-8

ulifloxacin

A

prulifloxacin
123447-62-1

prulifloxacin

B

6-Fluoro-1-methyl-7-[4-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-piperazin-1-yl]-4-oxo-4H-2-thia-8b-aza-cyclobuta[a]naphthalene-3-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester

6-Fluoro-1-methyl-7-[4-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-piperazin-1-yl]-4-oxo-4H-2-thia-8b-aza-cyclobuta[a]naphthalene-3-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester

Conditions
ConditionsYield
With potassium hydrogencarbonate for 3h; Product distribution; also in presence of DIPEA, car. concn. of substrates;
4-chloromethyl-5-methyl-1,3-dioxol-2-one
80841-78-7

4-chloromethyl-5-methyl-1,3-dioxol-2-one

ulifloxacin
112984-60-8

ulifloxacin

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
With N-ethyl-N,N-diisopropylamine; sodium bromide 1.) DMF, 303 K, 2 h, 2.) DMF, 304 K, 1 h; Yield given. Multistep reaction;
3,4-difluorophenyl isothiocyanate
113028-75-4

3,4-difluorophenyl isothiocyanate

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
Multi-step reaction with 6 steps
1: 1.) KOH / 1.) dioxane, RT, 30 min., 2.) 4 deg C, 15 h
2: 2.22 g / K2CO3 / dimethylformamide / 1 h / 70 °C
3: 0.350 g / PPE / 1.5 h / 80 °C
4: 84 percent / dimethylformamide / Ambient temperature
5: 88 percent / KOH / 2-methyl-propan-2-ol; H2O / 1 h / 50 - 60 °C
6: 62 percent / KHCO3 / dimethylformamide / 5 h / Ambient temperature
View Scheme
Multi-step reaction with 8 steps
1: 1.) KOH / 1.) dioxane, RT, 30 min., 2.) 4 deg C, 15 h
2: dimethylformamide / 1.) 0 deg C, 1.5 h, 2.) RT, 2 h
3: 58 percent / diphenyl ether / 5 h / 240 °C
4: 99 percent / 35percent HCl / ethanol / 2 h / Ambient temperature
5: 47 percent / K2CO3, KI / dimethylformamide / 0.5 h / 105 - 110 °C
6: 84 percent / dimethylformamide / Ambient temperature
7: 88 percent / KOH / 2-methyl-propan-2-ol; H2O / 1 h / 50 - 60 °C
8: 62 percent / KHCO3 / dimethylformamide / 5 h / Ambient temperature
View Scheme
ethyl 7,6-difluoro-4-hydroxy-2-mercaptoquinoline-3-carboxylate
84339-06-0

ethyl 7,6-difluoro-4-hydroxy-2-mercaptoquinoline-3-carboxylate

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: 47 percent / K2CO3, KI / dimethylformamide / 0.5 h / 105 - 110 °C
2: 84 percent / dimethylformamide / Ambient temperature
3: 88 percent / KOH / 2-methyl-propan-2-ol; H2O / 1 h / 50 - 60 °C
4: 62 percent / KHCO3 / dimethylformamide / 5 h / Ambient temperature
View Scheme
3,4-difluorophenyl dithiocarbamic acid triethylammonium
144514-15-8

3,4-difluorophenyl dithiocarbamic acid triethylammonium

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
Multi-step reaction with 7 steps
1: ethyl chloroformate, triethylamine / CHCl3 / 3.5 h / Ambient temperature
2: 1.) KOH / 1.) dioxane, RT, 30 min., 2.) 4 deg C, 15 h
3: 2.22 g / K2CO3 / dimethylformamide / 1 h / 70 °C
4: 0.350 g / PPE / 1.5 h / 80 °C
5: 84 percent / dimethylformamide / Ambient temperature
6: 88 percent / KOH / 2-methyl-propan-2-ol; H2O / 1 h / 50 - 60 °C
7: 62 percent / KHCO3 / dimethylformamide / 5 h / Ambient temperature
View Scheme
Multi-step reaction with 9 steps
1: ethyl chloroformate, triethylamine / CHCl3 / 3.5 h / Ambient temperature
2: 1.) KOH / 1.) dioxane, RT, 30 min., 2.) 4 deg C, 15 h
3: dimethylformamide / 1.) 0 deg C, 1.5 h, 2.) RT, 2 h
4: 58 percent / diphenyl ether / 5 h / 240 °C
5: 99 percent / 35percent HCl / ethanol / 2 h / Ambient temperature
6: 47 percent / K2CO3, KI / dimethylformamide / 0.5 h / 105 - 110 °C
7: 84 percent / dimethylformamide / Ambient temperature
8: 88 percent / KOH / 2-methyl-propan-2-ol; H2O / 1 h / 50 - 60 °C
9: 62 percent / KHCO3 / dimethylformamide / 5 h / Ambient temperature
View Scheme
ethyl 6,7-difluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate
113046-72-3

ethyl 6,7-difluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: 84 percent / dimethylformamide / Ambient temperature
2: 88 percent / KOH / 2-methyl-propan-2-ol; H2O / 1 h / 50 - 60 °C
3: 62 percent / KHCO3 / dimethylformamide / 5 h / Ambient temperature
View Scheme
ethyl 6,7-difluoro-4-hydroxy-2-<(methoxymethyl)thio>-quinoline-3-carboxylate
113028-77-6

ethyl 6,7-difluoro-4-hydroxy-2-<(methoxymethyl)thio>-quinoline-3-carboxylate

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: 99 percent / 35percent HCl / ethanol / 2 h / Ambient temperature
2: 47 percent / K2CO3, KI / dimethylformamide / 0.5 h / 105 - 110 °C
3: 84 percent / dimethylformamide / Ambient temperature
4: 88 percent / KOH / 2-methyl-propan-2-ol; H2O / 1 h / 50 - 60 °C
5: 62 percent / KHCO3 / dimethylformamide / 5 h / Ambient temperature
View Scheme
3-(3,4-difluorophenyl)-4-methyl<1,3>thiazetidin-2-ylidenemalonate
144514-35-2

3-(3,4-difluorophenyl)-4-methyl<1,3>thiazetidin-2-ylidenemalonate

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: 0.350 g / PPE / 1.5 h / 80 °C
2: 84 percent / dimethylformamide / Ambient temperature
3: 88 percent / KOH / 2-methyl-propan-2-ol; H2O / 1 h / 50 - 60 °C
4: 62 percent / KHCO3 / dimethylformamide / 5 h / Ambient temperature
View Scheme
diethyl<<(3,4-difluorophenyl)amino><(methoxymethyl)-thio>methylene>malonate
113028-76-5

diethyl<<(3,4-difluorophenyl)amino><(methoxymethyl)-thio>methylene>malonate

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
Multi-step reaction with 6 steps
1: 58 percent / diphenyl ether / 5 h / 240 °C
2: 99 percent / 35percent HCl / ethanol / 2 h / Ambient temperature
3: 47 percent / K2CO3, KI / dimethylformamide / 0.5 h / 105 - 110 °C
4: 84 percent / dimethylformamide / Ambient temperature
5: 88 percent / KOH / 2-methyl-propan-2-ol; H2O / 1 h / 50 - 60 °C
6: 62 percent / KHCO3 / dimethylformamide / 5 h / Ambient temperature
View Scheme
ethyl 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate
113028-17-4

ethyl 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 88 percent / KOH / 2-methyl-propan-2-ol; H2O / 1 h / 50 - 60 °C
2: 62 percent / KHCO3 / dimethylformamide / 5 h / Ambient temperature
View Scheme
Multi-step reaction with 2 steps
1.1: potassium hydroxide; water / 1 h / 80 - 85 °C
1.2: 1 h / 20 °C / pH 6.5 - 7
2.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 0.17 h / 20 °C
2.2: 21 h / 10 - 30 °C
View Scheme
[[(3,4-difluorophenyl)amino]-mercaptomethylene]-malonic acid diethyl ester potassium salt

[[(3,4-difluorophenyl)amino]-mercaptomethylene]-malonic acid diethyl ester potassium salt

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: 2.22 g / K2CO3 / dimethylformamide / 1 h / 70 °C
2: 0.350 g / PPE / 1.5 h / 80 °C
3: 84 percent / dimethylformamide / Ambient temperature
4: 88 percent / KOH / 2-methyl-propan-2-ol; H2O / 1 h / 50 - 60 °C
5: 62 percent / KHCO3 / dimethylformamide / 5 h / Ambient temperature
View Scheme
Multi-step reaction with 7 steps
1: dimethylformamide / 1.) 0 deg C, 1.5 h, 2.) RT, 2 h
2: 58 percent / diphenyl ether / 5 h / 240 °C
3: 99 percent / 35percent HCl / ethanol / 2 h / Ambient temperature
4: 47 percent / K2CO3, KI / dimethylformamide / 0.5 h / 105 - 110 °C
5: 84 percent / dimethylformamide / Ambient temperature
6: 88 percent / KOH / 2-methyl-propan-2-ol; H2O / 1 h / 50 - 60 °C
7: 62 percent / KHCO3 / dimethylformamide / 5 h / Ambient temperature
View Scheme
3,4-difluoroaniline
3863-11-4

3,4-difluoroaniline

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
Multi-step reaction with 8 steps
1: 0 °C
2: ethyl chloroformate, triethylamine / CHCl3 / 3.5 h / Ambient temperature
3: 1.) KOH / 1.) dioxane, RT, 30 min., 2.) 4 deg C, 15 h
4: 2.22 g / K2CO3 / dimethylformamide / 1 h / 70 °C
5: 0.350 g / PPE / 1.5 h / 80 °C
6: 84 percent / dimethylformamide / Ambient temperature
7: 88 percent / KOH / 2-methyl-propan-2-ol; H2O / 1 h / 50 - 60 °C
8: 62 percent / KHCO3 / dimethylformamide / 5 h / Ambient temperature
View Scheme
Multi-step reaction with 10 steps
1: 0 °C
2: ethyl chloroformate, triethylamine / CHCl3 / 3.5 h / Ambient temperature
3: 1.) KOH / 1.) dioxane, RT, 30 min., 2.) 4 deg C, 15 h
4: dimethylformamide / 1.) 0 deg C, 1.5 h, 2.) RT, 2 h
5: 58 percent / diphenyl ether / 5 h / 240 °C
6: 99 percent / 35percent HCl / ethanol / 2 h / Ambient temperature
7: 47 percent / K2CO3, KI / dimethylformamide / 0.5 h / 105 - 110 °C
8: 84 percent / dimethylformamide / Ambient temperature
9: 88 percent / KOH / 2-methyl-propan-2-ol; H2O / 1 h / 50 - 60 °C
10: 62 percent / KHCO3 / dimethylformamide / 5 h / Ambient temperature
View Scheme
6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid acetonitrile solvate
791105-27-6

6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid acetonitrile solvate

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
at 50 - 80℃; under 20 Torr; for 24h; Product distribution / selectivity; Neat (no solvent);
In acetonitrile at 80℃; Purification / work up;
6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid hydrochloride

6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid hydrochloride

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
With triethylamine In methanol; dichloromethane at 0 - 5℃; for 1.5h; Product distribution / selectivity;
ethyl 5,6-difluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinoline carboxylate

ethyl 5,6-difluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinoline carboxylate

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1.1: N,N-dimethyl-formamide / 9.17 h / 10 - 55 °C
2.1: potassium hydroxide; water / 1 h / 80 - 85 °C
2.2: 1 h / 20 °C / pH 6.5 - 7
3.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 0.17 h / 20 °C
3.2: 21 h / 10 - 30 °C
View Scheme
4,5-Dimethyl-1,3-dioxole-2-one
37830-90-3

4,5-Dimethyl-1,3-dioxole-2-one

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: N-Bromosuccinimide / chloroform / Reflux; Large scale
2: potassium hydrogencarbonate / N,N-dimethyl-formamide / 5 h / 0 °C / Large scale
View Scheme
prulifloxacin
123447-62-1

prulifloxacin

6-fluoro-1-methyl-7-<4-<(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl>-1-piperazinyl>-4-oxo-4H-<1,3>thiazeto<3,2-a>quinoline-3-carboxylic acid hydrochloride

6-fluoro-1-methyl-7-<4-<(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl>-1-piperazinyl>-4-oxo-4H-<1,3>thiazeto<3,2-a>quinoline-3-carboxylic acid hydrochloride

Conditions
ConditionsYield
With hydrogenchloride for 6h; Ambient temperature;82%
4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one
80715-22-6

4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one

prulifloxacin
123447-62-1

prulifloxacin

6-Fluoro-1-methyl-7-[4-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-piperazin-1-yl]-4-oxo-4H-2-thia-8b-aza-cyclobuta[a]naphthalene-3-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester

6-Fluoro-1-methyl-7-[4-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)-piperazin-1-yl]-4-oxo-4H-2-thia-8b-aza-cyclobuta[a]naphthalene-3-carboxylic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester

Conditions
ConditionsYield
With potassium carbonate In N,N-dimethyl-formamide at 39.9℃; for 3h;72%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 24.9℃; Rate constant; also in presence of DIPA and TNBA, var concn. of DMDO-Br and amines;
prulifloxacin
123447-62-1

prulifloxacin

ornidazole
16773-42-5

ornidazole

6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)piperazin-1-yl]-4-oxo-4H-2-thia-8b-aza-cycobuta[a]naphthalene-3-carboxylic acid 1-chloromethyl-2-(2-methyl-5-nitro-imidazol-1-yl)ethyl ester

6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl)piperazin-1-yl]-4-oxo-4H-2-thia-8b-aza-cycobuta[a]naphthalene-3-carboxylic acid 1-chloromethyl-2-(2-methyl-5-nitro-imidazol-1-yl)ethyl ester

Conditions
ConditionsYield
With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 16h;65%
C21H27N3O8S2

C21H27N3O8S2

prulifloxacin
123447-62-1

prulifloxacin

Conditions
ConditionsYield
Stage #1: prulifloxacin With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide at 20℃; for 3h;
Stage #2: C21H27N3O8S2 With dmap In dichloromethane; N,N-dimethyl-formamide at 20℃; for 16h;
60%
4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one
80715-22-6

4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one

prulifloxacin
123447-62-1

prulifloxacin

1,1-bis<(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl>-4-(3-carboxy-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinoline-7-yl)-1-piperazinium bromide

1,1-bis<(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl>-4-(3-carboxy-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinoline-7-yl)-1-piperazinium bromide

Conditions
ConditionsYield
In N,N-dimethyl-formamide for 34h; Ambient temperature;27%
In N,N-dimethyl-formamide at 30.9℃; Rate constant;
ulifloxacin
112984-60-8

ulifloxacin

prulifloxacin
123447-62-1

prulifloxacin

7-<4-<1-<4-(3-carboxy-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinolin-7-yl)>-1-piperazinylmethyl>-2-oxopropoxycarbonyl>-1-piperazinyl>-6-fluoro-1-methyl-4-oxo-4H-<1,3>thazeto<3,2-a>quinoline-3-carboxylic acid

7-<4-<1-<4-(3-carboxy-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinolin-7-yl)>-1-piperazinylmethyl>-2-oxopropoxycarbonyl>-1-piperazinyl>-6-fluoro-1-methyl-4-oxo-4H-<1,3>thazeto<3,2-a>quinoline-3-carboxylic acid

Conditions
ConditionsYield
In N,N-dimethyl-formamide at 30.9℃; Rate constant;
prulifloxacin
123447-62-1

prulifloxacin

acetonitrile
75-05-8

acetonitrile

6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid acetonitrile solvate
791105-27-6

6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid acetonitrile solvate

Conditions
ConditionsYield
at 14.3 - 65℃; Product distribution / selectivity;

123447-62-1Downstream Products

123447-62-1Relevant articles and documents

Studies on synthesis of the antibacterial agent NM441. II. Selection of a suitable base for alkylation of 1-substituted piperazine with 4- (bromomethyl)-5-methyl-1,3-dioxol-2-one

Fujii,Nishida,Abiru,Yamamoto,Kise

, p. 1872 - 1877 (1995)

Diisopropylamine (DIPA), N,N-diisopropylethylamine (DIPEA), tributylamine (TNBA) and 7-(1-piperazinyl)-4-quinolone-3-carboxylic acid (2) were titrated in water-dimethylformamide (DMF) mixtures containing 45-98% DMF. Apparent pK(a) values in anhydrous DMF (pK(DMF)) were calculated by extrapolation from the variation in the half-neutralization pH values in aqueous DMF. The validity of the relative basicity derived from the pK(DMF)S was confirmed by examination of the kinetics of esterification of a derivative of 2 with 4- (bromomethyl)-5-methyl-1,3-dioxol-2-one (DMDO-Br). Relative basicities in DMF were: the carboxylate anion of 2 >> DIPA > DIPEA > TNBA > the amino group in the piperazinyl part of 2. This order is clearly different from that observed in water. We concluded that DIPEA is a suitable agent to suppress the undesired esterification during the reaction to mask the amino group of 2 with a DMDO group, because it does not remove a proton from the carboxyl group, but only from the protonated amino group.

CRYSTALLINE FORM OF PRULIFLOXACIN AND PROCESSES FOR ITS PREPARATION

-

, (2012/01/14)

The present invention relates to a crystalline polymorphic form of 6-fluoro-1-methyl-7- {4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-4H-[1,3]-thiazeto-[3,2- a]-quinoline-3-carboxylic acid (prulifloxacin). More specifically, the invention relates to a crystalline form of prulifloxacin (herein referred to as Form A), and a method for preparing the crystalline Form A. The present invention further provides a pharmaceutical formulation comprising the novel form of prulifloxacin.

PROCESS FOR PREPARATION OF PRULIFLOXACIN USING NOVEL INTERMEDIATES

-

Page/Page column 8, (2008/12/05)

The present invention provides a novel process for the preparation of prulifloxacin intermediate, 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid, thereby producing prulifloxacin and its pharmaceutical acceptable acid addition salts thereof in high purity and in high yield using novel intermediates in lesser reaction time. Thus, for example, ethyl 6,7-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate is reacted with boric acid in presence of acetic anhydride and acetic acid to give borane compound, which is then condensed with piperazine in presence of acetonitrile and dimethylsulfoxide, followed by treatment with potassium hydroxide solution to give 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid.

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