186826-86-8

Basic information

• Product Name: Moxifloxacin hydrochloride
• Synonyms: AVALOX;BAY-12-8039;(1's,6's)-1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride;1-CYCLOPROPYL-6-FLUORO-1,4-DIHYDRO- 8-METHOXY-7- [(4AS,7AS)-OCTAHYDRO-6H-PYRROLO[3,4-B]PYRIDIN-6-YL]-4-OXO-3-QUINOLINECARBOXYLIC ACID HYDROCHLORIDE;1-CYCLOPROPYL-7-[(S,S)-2,8-DIAZA-BICYCLO[4.3.0]NON-8-YL]-6-FLUORO-8-METHOXY-1,4-DIHYDRO-4-OXO-3-QUINOLINE CARBOXYLIC ACID HYDROCHLORIDE;ACTIRA;PROFLOX;MOXIFLOXACIN HCL
• CAS NO: 186826-86-8
• Molecular Formula: C₂₁H₂₄FN₃O₄*ClH
• Molecular Weight: 437.8923032
• EINECS: 1806241-263-5
• Product Categories: Active Pharmaceutical Ingredients;Moxifloxacin;API;ARICEPT
• Mol File: 186826-86-8.mol

Chemical Properties

• Melting Point: Slightly yellow to yellow crystalline powder, mp 324-325°
• Boiling Point: 636℃
• Flash Point: >110°(230°F)
• Appearance: white to beige/
• Vapor Pressure: 4.56E-17mmHg at 25°C
• Storage Temp.: 2-8°C
• Solubility: H2O: soluble5mg/mL, clear (warmed)
• Water Solubility: Sparingly soluble in water. Soluble in DMSO
• BRN: 8377447
• CAS DataBase Reference: Moxifloxacin hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Moxifloxacin hydrochloride(186826-86-8)
• EPA Substance Registry System: Moxifloxacin hydrochloride(186826-86-8)

Safety Data

• WGK Germany: 2
• RTECS: VB1983750
• HazardClass: IRRITANT
• Hazardous Substances Data: 186826-86-8(Hazardous Substances Data)

Usage

Uses

1. Used in Pharmaceutical Industry:
Moxifloxacin hydrochloride is used as an antibacterial agent for inhibiting the activities of Topo II (DNA gyrase) and topoisomerase IV, which are essential for bacterial DNA replication and repair.
2. Used in Respiratory Tract Infections Treatment:
Moxifloxacin hydrochloride is used as a treatment for respiratory tract infections such as community-acquired pneumonia, acute exacerbations of bronchitis, or acute sinusitis due to its broad-spectrum antibacterial activity and favorable pharmacokinetic profile.
3. Used in Ocular Infections Treatment:
Moxifloxacin hydrochloride is used as an ocular antibacterial agent for treating various eye infections, benefiting from its broad-spectrum activity and good tissue penetration.
4. Used in Cognitive Enhancement:
Moxifloxacin hydrochloride is used as an acetylcholinesterase inhibitor (reversible) and cognitive enhancer, potentially improving cognitive function by modulating the activity of acetylcholinesterase, an enzyme involved in the breakdown of the neurotransmitter acetylcholine.
5. Used in Antimicrobial Research:
Moxifloxacin hydrochloride serves as a subject of study for understanding the mechanisms of bacterial resistance and the development of new antimicrobial agents, given its broad-spectrum activity and the need for new treatments to combat antibiotic-resistant bacteria.
Brand names:
Avelox (Bayer)
Vigamox (Alcon)

Indications and Usage

Moxifloxacin Hydrochloride is a fluoroquinolone antibiotic developed by Bayer Pharmaceuticals (Germany.) It can be used to treat community-acquired pneumonia caused by Staphylococcus aureus, baccilus, pneumococcus, mucositis Moraxella, and Klebsiella pneumoniae, acute chronic bronchitis attacks, and acute sinusitis. For the treatment of adult bacterial lung infections, paranasal sinus, skin, and abdominal cavity. Also used to treat community-acquired pneumonia, chronic bronchitis, urogenital infection, and acute sinusitis.

Mechanisms of Action

Its active mechanisms and in vitro antibacterial spectrums are similar to those of other fluoroquinolones, but its profile towards gram-positive and anaerobic bacteria is similar to that of trovafloxacin, better than some older drugs. Compared with other fluoroquinolones, few gram-positive bacteria are resistant to Moxifloxacin Hydrochloride, or the spread of resistance is very slow. Gram-negative and enterococci strains with cross resistance to other fluoroquinolones have been found. It is effective at least against Staphylococcus aureus strains grlA, grlB, gyrA and gyrBcan, and 0.5-2 mg/L can inhibit Ciprofloxacin resistant Staphylococcus aureus, from large MIC to small Ciprofloxacin, Ofloxacin, Levofloxacin, Sparfloxacin, and Moxifloxacin.

Pharmacokinetics

After 45 healthy volunteers were orally administered single doses of 50-800 mg, their peak plasma concentration and area under the curve (AUC) increased linearly with dosage. Recommended oral dose is 400 mg, average Cmax is 2.5mg/L, peak time (tmax) is 1.5 hours, and AUC is 26.9 mg?h/L. For healthy volunteers who took 400 mg per day orally for 10 days, Cmax was 4.52 mg/L, 1.59 accumulated over 10 days. Oral bioavailability is 89%, apparent distribution volume 3.55 L/kg, plasma protein binding rate 48%. For 400 mg intravenously, Cmaxis 3.62 mg/L. AUC 34.6 mg?h/L. 24 hours after 13 healthy volunteers were given a single oral dose or intravenous injection of 400 mg, skin blister fluid concentration was twice that of serum, suggesting easier penetration of interstitial tissue. One hour after 18 patients ingested a single oral dose of 400 mg before undergoing bronchoscopy, bronchial epithelial cell fluid and bronchial biopsy tissue concentrations were 24.4 and 5.5 mg / L respectively, greater than the plasma concentration after 12 hours. An extremely high concentration (113.6 mg/L) was reached in macrophages. After 34 patients with chronic sinusitis received 5 oral doses of 400 mg, concentration in maxillary sinus mucosa exceeded blood plasma concentration. Three hours after the last dose, blood concentration peaked at 7.47 mg/kg; after 36 hours it was 1.25 mg/kg，suggesting a post-dosage effect. After healthy volunteers received an oral dose of 400 mg, total clearance rate and renal clearance rates were 14.9 and 3.03 L per hour respectively. The drug apparently does not undergo P450 metabolism. Metabolized in vitro into N-sulfate and acyl glucuronide, metabolites inactive. After healthy volunteers took 400 mg/d orally, the average elimination half-life (t1/2β) during the first day was 9.3 hours, 11.95 hours over 10 days. Another study showed that the average t1/2β is about 10-16 hours. After a single oral dose or intravenous infusion of 400 mg, the urine reabsorption rates were 19%-20% and 22% respectively.

Adverse Effects

The adverse effects of this product are mostly mild and transient, and 3.8% of patients discontinued treatment as a result of adverse effects. The most common effects were nausea (7.2%) and diarrhea (5.7%). The incidence of dizziness was 2.8%. Healthy volunteers experienced no changes in vital signs, hematology, blood biochemistry, and ECG. Studies show that it is different from lomefloxacin and did not show any phototoxicity.

Warnings and Precautions

Similar to other fluoroquinones, bioavailability of 400 mg of Moxifloxacin Hydrochloride declined significantly after combination with antacids. AUC and cmax decreased 45% and 40% compared with when used alone, but Moxifloxacin Hydrochloride absorption was not significantly affected when taken 2 hours before or 4 hours after taking antacids. When taken with iron, absorption decreased significantly, with AUC and cmax was 39% and 59% lower, respectively. No interaction with theophylline, probenecid, ranitidine, or warfarine.

Adverse reactions

Side effects of this product are mostly mild and transient , 3.8% of the patient discontinued treatment due to adverse events . The most common adverse reactions are nausea (7.2%) and diarrhea (5.7%). Dizziness is 2.8%. In healthy volunteers, no changes in vital signs, hematology, blood biochemistry and electrocardiogram. Studies have shown that the product is different from lomefloxacin , no drug-induced light toxicity.

Precautions

Similar to other fluoroquinolones , the product (400mg) in combination with antacids, bioavailability will fall significantly, AUC and cmax fall down 45% and 40% respectively when compared with alone, but using the moxifloxacin hydrochloride 2h before taking antacids or using antacids 4h after using this service, the absorption of the drug has no effect. If the product in combination with iron ,absorption rate decreases, AUC and cmax are reduced by 39% and 59%. The product has no interaction with theophylline, probenecid, ranitidine and warfarin .

Originator

Bayer (Germany)

Manufacturing Process

Manufacturing process for Moxifloxacin hydrochloride includes 3 steps: Synthesis of intermidate octahydropyrrolo[3,4-b]pyridine (2,8- diazabicyclo[4.3.0]nonane);Synthesis of intermidate 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4- oxo-3-quinolinecarboxylic acid;Syntesis of 1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4- dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid hydrochloride (moxifloxacin hydrochloride)

Therapeutic Function

Antibacterial

Biochem/physiol Actions

Moxifloxacin has proved to be effective in treating sinusitis, community-acquired respiratory tract infection, pneumonia and acute exacerbations of chronic bronchitis. It has improved anti-gram positive activity compared to other fluoroquinolone such as ciprofloxacin and ofloxacin. Moxifloxacin is useful in treating skin infections that is of bacterial origin. It is known to have proper penetration into peripheral tissues and inflammatory fluids. Fluoroquinolones stabilize DNA strand breaks created by DNA gyrase and topoisomerase IV by binding to the enzyme-DNA complex. Compared to mammalian DNA gyrase, moxifloxacin has 100 times higher affinity for bacterial DNA gyrase. Moxifloxacin is an antibiotic and works against both Gram-positive and Gram-negative bacteria. Moxifloxacin is being investigated for the treatment of multidrug-resistant tuberculosis.

references

[1]. cruz la, hall r: enantiomeric purity assay of moxifloxacin hydrochloride by capillary electrophoresis. j pharm biomed anal 2005, 38(1):8-13.[2]. kamruzzaman m, alam am, lee sh, ragupathy d, kim yh, park sr, kim sh: spectrofluorimetric study of the interaction between europium(iii) and moxifloxacin in micellar solution and its analytical application. spectrochim acta a mol biomol spectrosc 2012, 86:375-380.[3]. culley cm, lacy mk, klutman n, edwards b: moxifloxacin: clinical efficacy and safety. am j health syst pharm 2001, 58(5):379-388.[4]. turkes c, soyut h, beydemir s: human serum paraoxonase-1 (hpon1): in vitro inhibition effects of moxifloxacin hydrochloride, levofloxacin hemihidrate, cefepime hydrochloride, cefotaxime sodium and ceftizoxime sodium. j enzyme inhib med chem 2014:1-7.

InChI:InChI=1/C21H24FN3O4.ClH/c1-29-20-17-13(19(26)14(21(27)28)9-25(17)12-4-5-12)7-15(22)18(20)24-8-11-3-2-6-23-16(11)10-24;/h7,9,11-12,16,23H,2-6,8,10H2,1H3,(H,27,28);1H

Synthetic route

(4aS-cis)-1-cyclopropyl-7-(2,8-diazabicyclo-[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid-O3,O4(bis(acyloxy-O)) borate → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
With hydrogenchloride In methanol; water at 0 - 8℃; for 0.333333h; Temperature;	96.2%
With hydrogenchloride In methanol at -5 - 20℃; for 2h; pH=1; Temperature;	93.1%
With sodium hydroxide In acetone for 1h; Large scale;	89.8%

C27H33BFN3O8 → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
With hydrogenchloride In methanol at 20℃; for 2h; pH=3; pH-value;	92.9%

moxifloxacin ethyl ester tartrate → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
With hydrogenchloride In water at 60℃; for 6h; Solvent;	92.1%

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (112811-72-0) + (1S,6S)-2,8-diazabicyclo[4.3.0]nonane (151213-40-0) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Stage #1: 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid; (1S,6S)-2,8-diazabicyclo[4.3.0]nonane With titanium(IV) isopropylate; triethylamine In isopropyl alcohol at 100℃; Inert atmosphere; Stage #2: With hydrogenchloride In methanol at 20℃; for 1h; pH=1; Solvent; Reagent/catalyst;	90%
Multi-step reaction with 2 steps 1: Alkaline conditions 2: hydrogenchloride View Scheme
Stage #1: 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid; (1S,6S)-2,8-diazabicyclo[4.3.0]nonane With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20 - 85℃; for 36h; Inert atmosphere; Stage #2: With hydrogenchloride In water at 15℃; for 1h; pH=1.4 - 1.8; Inert atmosphere;	3.3 g

ethyl 8-methoxy-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (112811-71-9) + (1S,6S)-2,8-diazabicyclo[4.3.0]nonane (151213-40-0) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Stage #1: ethyl 8-methoxy-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate With boric acid; acetic anhydride at 90 - 100℃; for 3h; Stage #2: With triethylamine In acetonitrile at 20℃; for 0.5h; Stage #3: (1S,6S)-2,8-diazabicyclo[4.3.0]nonane Temperature; Solvent; Reagent/catalyst; Further stages;	89.78%

1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (O3,O4)bis(acyloxy-O)borate (139678-43-6) + (1S,6S)-2,8-diazabicyclo[4.3.0]nonane (151213-40-0) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Stage #1: 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (O3,O4)bis(acyloxy-O)borate; (1S,6S)-2,8-diazabicyclo[4.3.0]nonane With triethylamine In acetonitrile at 15℃; Stage #2: With hydrogenchloride In water pH=0.5; Temperature;	89.1%

magnesium hydroxide + 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acid + octahydro-1H-pyrrole[3,4-b]pyridine + magnesium methanolate (109-88-6, 16436-83-2, 16436-85-4) → Moxifloxacin HCl (I-HCl)-Exemplifying + moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
With tetrabutyl-ammonium chloride In N-methyl-acetamide; hydrogenchloride; ethanol; water	A n/a B 89%

L(+)-moxifloxacin tartrate (1082245-30-4) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
With hydrogenchloride In ethanol; water at 25 - 30℃; for 1h;	88.3%

C26H30BFN2O8 → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
With hydrogenchloride In water at 10℃; for 1h; Temperature;	81%

moxifloxacin (151096-09-2) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
With hydrogenchloride In methanol at 0 - 5℃; for 1h; pH=1.0 - 2.0; Product distribution / selectivity;	77%
With hydrogenchloride; edetate disodium In methanol; water at 0 - 38℃; for 2h;	54.84%
With hydrogenchloride In ethanol at 0 - 10℃; for 2h; Product distribution / selectivity;

C20H22BF2NO8 + (1S,6S)-2,8-diazabicyclo[4.3.0]nonane (151213-40-0) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Stage #1: C20H22BF2NO8; (1S,6S)-2,8-diazabicyclo[4.3.0]nonane With triethylamine In acetonitrile at 80 - 90℃; for 5h; Large scale; Stage #2: With hydrogenchloride In methanol at 0 - 20℃; for 3h; pH=Ca. 0.5; Large scale;	76.3%

1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-O3,O4-bis(propyloxy-O)borate (496919-99-4) + (1S,6S)-2,8-diazabicyclo[4.3.0]nonane (151213-40-0) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Stage #1: 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid O3,O4-bis(propyloxy-O)borate; (1S,6S)-2,8-diazabicyclo[4.3.0]nonane In butan-1-ol at 10 - 100℃; for 3h; Stage #2: With hydrogenchloride In methanol; butan-1-ol at 25 - 30℃; for 2h; pH=1.0 - 2.0; Stage #3: With hydrogenchloride; ammonia Product distribution / selectivity; more than 3 stages;	75%

C25H31FN4O3 → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
With hydrogenchloride In ethanol at 30 - 40℃; Temperature; Solvent; Inert atmosphere; Industrial scale;	75%

(1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4-(oxo-κO3)-3-quinolinecarboxylato-κO3)difluoroboron → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Stage #1: (1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4-(oxo-κO3)-3-quinolinecarboxylato-κO3)difluoroboron With triethylamine In methanol at 60 - 65℃; for 6 - 24h; Heating / reflux; Stage #2: With hydrogenchloride In methanol; water; acetonitrile at 0 - 25℃; for 1 - 2.5h; Product distribution / selectivity;	55%

(1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-(oxo-κO)-3-quinoline-carboxylato-κO3)difluoro-Boron + (1S,6S)-2,8-diazabicyclo[4.3.0]nonane (151213-40-0) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Stage #1: (1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-(oxo-κO)-3-quinoline-carboxylato-κO3)difluoro-Boron; (1S,6S)-2,8-diazabicyclo[4.3.0]nonane With triethylamine In methanol at 30℃; for 32h; Heating / reflux; Stage #2: With hydrogenchloride In methanol; water; acetonitrile at 0 - 25℃; for 3h; pH=~ 7; Product distribution / selectivity;

1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid monohydrochloride monohydrate (192927-63-2) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
In toluene Heating / reflux;

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid-O3,O4(bis(acyloxy-O)) borate (139693-52-0) + (1S,6S)-2,8-diazabicyclo[4.3.0]nonane (151213-40-0) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Stage #1: 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid-O3,O4(bis(acyloxy-O)) borate; (1S,6S)-2,8-diazabicyclo[4.3.0]nonane With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 75 - 80℃; for 1.5h; Stage #2: With hydrogenchloride; water In methanol at 25℃; pH=1.0 - 2.0;
Stage #1: 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid-O3,O4(bis(acyloxy-O)) borate; (1S,6S)-2,8-diazabicyclo[4.3.0]nonane With triethylamine In methanol Reflux; Stage #2: With hydrogenchloride In ethanol; water Acidic conditions;
Stage #1: 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid-O3,O4(bis(acyloxy-O)) borate; (1S,6S)-2,8-diazabicyclo[4.3.0]nonane With triethylamine In ethanol at 70℃; for 4h; Stage #2: With hydrogenchloride In water at 30℃; for 1h; pH=1; Solvent; Temperature; Heating;	45 g

(4aS-cis)-1-cyclopropyl-7-(2,8 diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic aid-O3,O4-bis(propyloxy-O)borate. → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
With hydrogenchloride In methanol at 25 - 30℃; for 2h; pH=1 - 2;

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (112811-72-0) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: magnesium hydroxide / acetonitrile / 1 h / 78 °C 1.2: 5 h / Reflux 2.1: hydrogenchloride / water; ethanol / 6 h / 20 - 60 °C View Scheme
Multi-step reaction with 2 steps 1.1: magnesium hydroxide / acetonitrile / 1 h / 78 °C 1.2: 5 h / Reflux 2.1: hydrogenchloride / water; ethanol / 10 h / 20 - 60 °C View Scheme
Multi-step reaction with 3 steps 1.1: boric acid / 80 - 90 °C 1.2: 1 h / 80 - 90 °C 2.1: triethylamine / water; acetonitrile / 10 - 20 °C 3.1: hydrogenchloride / water / 6 h / 10 - 15 °C / pH 1.0 - 2.0 View Scheme
Multi-step reaction with 3 steps 1.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 10 - 35 °C / Inert atmosphere 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 35 h / 20 - 85 °C / Inert atmosphere 3.1: sodium hydroxide; water / ethylene glycol / 115 °C / Inert atmosphere 3.2: 1 h / 15 °C / pH 1.4 - 1.8 / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: toluene / 105 - 115 °C / Inert atmosphere; Industrial scale 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 5 - 80 °C / Inert atmosphere; Industrial scale 3: hydrogenchloride / ethanol / 30 - 40 °C / Inert atmosphere; Industrial scale View Scheme

(1S,6S)-2,8-diazabicyclo[4.3.0]nonane (151213-40-0) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: magnesium hydroxide / acetonitrile / 1 h / 78 °C 1.2: 5 h / Reflux 2.1: hydrogenchloride / water; ethanol / 6 h / 20 - 60 °C View Scheme
Multi-step reaction with 2 steps 1.1: magnesium hydroxide / acetonitrile / 1 h / 78 °C 1.2: 5 h / Reflux 2.1: hydrogenchloride / water; ethanol / 10 h / 20 - 60 °C View Scheme
Multi-step reaction with 2 steps 1: diethylamine / acetonitrile / 80 °C 2: sodium hydroxide / 2.5 h / 80 °C View Scheme
Multi-step reaction with 3 steps 1: aluminum (III) chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 3 h / 60 °C 2: 2 h 3: hydrogenchloride / water / 6 h / 60 °C View Scheme

moxifloxacin p-toluenesulfonate → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; dichloromethane; isopropyl alcohol / 1 h / 30 - 35 °C 2: hydrogenchloride / water; ethanol / 10 h / 20 - 60 °C View Scheme

cis-6-benzyltetrahydro-1H-pyrrolo[3,4-b]pyridine-5,7(6H,7aH)-dione → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: lithium aluminium tetrahydride 2: Resolution of racemate 3: palladium on activated charcoal; hydrogen 4: Alkaline conditions 5: hydrogenchloride View Scheme

(S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane-D-tartrate (151213-39-7) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: palladium on activated charcoal; hydrogen 2: Alkaline conditions 3: hydrogenchloride View Scheme

ethyl 3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylate (112811-70-8) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium fluoride / N,N-dimethyl-formamide 2: Alkaline conditions 3: hydrogenchloride View Scheme

8-benzyl-2,8-diazabicyclo[4.3.0]nonane → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: Resolution of racemate 2: palladium on activated charcoal; hydrogen 3: Alkaline conditions 4: hydrogenchloride View Scheme

ethyl 8-methoxy-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (112811-71-9) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 2 h / 75 - 140 °C 1.2: 3 h / 55 - 120 °C 2.1: diethylamine / acetonitrile / 80 °C 3.1: sodium hydroxide / 2.5 h / 80 °C View Scheme
Multi-step reaction with 3 steps 1: glycine / 2.5 h / 80 - 98 °C / Inert atmosphere 2: 4-methyl-morpholine / acetonitrile / 2 h / 75 °C 3: hydrogenchloride / methanol / 2 h / 20 °C / pH 3 View Scheme
Multi-step reaction with 3 steps 1.1: 1 h / Reflux 1.2: 1 h / 70 - 105 °C 2.1: triethylamine / acetonitrile / 4 h / 50 °C 3.1: hydrogenchloride / ethanol; water / 1 h / 25 °C / pH 1 View Scheme

1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid-O3,O4(bis(acyloxy-O)) borate (139693-52-0) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: diethylamine / acetonitrile / 80 °C 2: sodium hydroxide / 2.5 h / 80 °C View Scheme

ethyl 1-cyclopropyl-6-fluoro-8-methoxy-7-((4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (1403836-23-6) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
With hydrogenchloride In water at -5℃; for 2h; pH=2; Temperature;
With hydrogenchloride In water at 25℃; for 3h; pH=2; Temperature;

C25H33FN4O3 (1028205-69-7) → moxifloxacin hydrochloride (186826-86-8)

Conditions	Yield
Stage #1: C25H33FN4O3 With water; sodium hydroxide In ethylene glycol at 115℃; Inert atmosphere; Stage #2: With hydrogenchloride In water at 15℃; for 1h; pH=1.4 - 1.8; Inert atmosphere;	6.4 g

2-iodoacetanilide (7212-28-4) + moxifloxacin hydrochloride (186826-86-8) → 1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-((4aS,7aS)-1-(2-oxo-2-(phenylamino)ethyl)hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)-1,4-dihydroquinoline-3-carboxylic acid

Conditions	Yield
With triethylamine In acetonitrile at 100℃; for 24h;	90%
With triethylamine In acetonitrile at 100℃; for 24h;	90%

[2,2]bipyridinyl (366-18-7) + yttrium(III) chloride hexahydrate + moxifloxacin hydrochloride (186826-86-8) → [Y(moxifloxacin hydrochloride)(2,2'-bipyridine)(H2O)2]Cl3.8H2O

Conditions	Yield
With sodium hydroxide In ethanol for 3h; Reflux;	88.71%

[2,2]bipyridinyl (366-18-7) + uranyl(VI) acetate dihydrate + moxifloxacin hydrochloride (186826-86-8) → [UO2(moxifloxacin hydrochloride)(2,2'-bipyridine)](CH3COO)2.H2O

Conditions	Yield
With sodium hydroxide In ethanol for 3h; Reflux;	85.57%

2-(bromomethyl)naphthalene (3163-27-7) + moxifloxacin hydrochloride (186826-86-8) → 1-cyclopropyl-6-fluoro-8-methoxy-7-((4aS,7aS)-1-(naphthalen-1-ylmethyl)octahydro-6H-pyrrolo[3,4-b]pyridine-6-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Conditions	Yield
Stage #1: moxifloxacin hydrochloride With potassium carbonate In water; acetonitrile at 20℃; for 0.0833333h; Stage #2: 2-(bromomethyl)naphthalene In water; acetonitrile at 20℃; for 25h;	84.6%

[2,2]bipyridinyl (366-18-7) + lanthanide(III)chloride heptahydrate + moxifloxacin hydrochloride (186826-86-8) → [La(moxifloxacin hydrochloride)(2,2'-bipyridine)(H2O)2]Cl3.8H2O

Conditions	Yield
With sodium hydroxide In ethanol for 3h; Reflux;	80.81%

[2,2]bipyridinyl (366-18-7) + cerium(IV) sulphate + moxifloxacin hydrochloride (186826-86-8) → [Ce(moxifloxacin hydrochloride)(2,2'-bipyridine)(H2O)2](SO4)2.6H2O

Conditions	Yield
With sodium hydroxide In ethanol for 3h; Reflux;	77.37%

[2,2]bipyridinyl (366-18-7) + zirconyl nitrate + moxifloxacin hydrochloride (186826-86-8) → [ZrO(moxifloxacin hydrochloride)(2,2'-bipyridine)(H2O)](NO3)2.H2O

Conditions	Yield
With sodium hydroxide In ethanol for 3h; Reflux;	75.6%

zirconium(IV) nitrate + water (7732-18-5) + moxifloxacin hydrochloride (186826-86-8) → C21H27FN3O6Zr(3+)*0.5H2O

Conditions	Yield
With triethylamine at 20℃; for 48h; pH=7.5 - 8; pH-value; Solvent;	65%

moxifloxacin hydrochloride (186826-86-8) → moxifloxacin (151096-09-2)

Conditions	Yield
With sodium hydroxide In water; acetone at 25 - 60℃; for 0.666667h; Product distribution / selectivity;
With sodium hydroxide In cyclohexane; water; acetone at 25 - 60℃; for 13.1667 - 15.1667h; Product distribution / selectivity; Heating / reflux;

Upstream product

• 151213-40-0 (1S,6S)-2,8-diazabicyclo[4.3.0]nonane 
• 192927-63-2 1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid monohydrochloride monohydrate 
• 139693-52-0 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid-O³,O⁴(bis(acyloxy-O)) borate 
• 112811-72-0 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid 
• 151213-39-7 (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane-D-tartrate 
• 112811-70-8 ethyl 3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylate 
• 128740-14-7 8-benzyl-2,8-diazabicyclo[4.3.0]nonane 
• 112811-71-9 ethyl 8-methoxy-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate 
• 1082245-30-4 moxifloxacin tartaric acid 
• 1403836-23-6 ethyl 1-cyclopropyl-6-fluoro-8-methoxy-7-((4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate 
• 1028205-69-7 C₂₅H₃₃FN₄O₃ 

Downstream Products

• 1253700-48-9 6-fluoro-8-methoxy-4-oxo-1-cyclopropyl-7-(2-(4-methylphenyl)sulfonyl-2,8-diazabicyclo[4.3.0]nonan-8-yl)-1,4-dihydroquinoline-3-carboxylic acid 

Relevant articles and documents

Preparation method of quinolone carboxylic acid derivative or phthalazinone carboxylic acid derivative

The invention belongs to the field of pharmaceutical chemicals, relates to a preparation method of a quinolone carboxylic acid derivative or a phthalazinone carboxylic acid derivative, and particularly relates to a preparation method of a 7-substituted-3-quinolone carboxylic acid derivative or a 7-substituted-1,5-phthalazinone carboxylic acid derivative. The preparation method comprises the following steps: (1) in an organic solvent, carrying out coupling reaction on a boron chelate II and organic amine III in the presence of an organosilicon compound to obtain a compound IV; and (2) mixing the compound IV with hydrochloric acid, and then filtering and separating the precipitated compound I. Compared with conventional methods, the preparation method provided by the invention has the advantages that the conditions are milder, the hydrolysis of the substrate quinoline carboxylic acid boric acid ester can be reduced, and meanwhile, the influence of a byproduct HF on the product purity is avoided. The method is high in yield and high in purity; compared with the traditional alkali, the organic silicon is more suitable for industrial preparation of the 7-substituted-3-quinolone carboxylic acid derivative or the 7-substituted-1,5-phthalazinone carboxylic acid derivative.

Preparation method of moxifloxacin hydrochloride (by machine translation)

The reaction: the reaction, is added into the reaction kettle, to heat, and then the,dihydro - 8 8-oxo- 3 3-dihydro-8-methoxy - 4 4-dioxanone introduced into the reaction kettle, is added to the reaction still 1 - for heating and reacting the, by the reaction; first and then, refluxing under, heating. 1st. The method comprises, condensation reaction; adding a protecting gas, to a reaction kettle.] and reacting, to obtain moxifloxacin hydrochloride; second by heating and reacting with a heating reaction of, by a heating reaction of a heating reaction unit of a reaction scheme of, second in a reaction still further, heating a reaction, solution in, a reaction still further to react with a, reaction gas, second and refluxing, the reaction. (S,S) - 2,8 - The method comprises the following steps of heating and separating [4.3 .0] out of a reaction; and refluxing the reaction gas . The reaction mixture; is introduced, into the reaction kettle. (by machine translation)

Preparation method of moxifloxacin hydrochloride

The invention discloses a preparation method of moxifloxacin hydrochloride, and the preparation method comprises the following steps: (1) preparing 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-O3,O4-boron diacetate, and (2) carrying out a reaction on the 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-O3,O4-boron diacetate; (2)adding the 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-O3,O4-boron diacetate and (S,S)-2,8-diazabicyclo[4.3.0]nonane in a solvent in the presence of an acid-binding agent to obtain a borane condensate, removing the solvent, dissolving the borane condensate in water, and adding hydrochloric acid to form salt and crystallize to obtain moxifloxacin hydrochloride. According to the preparation method, the borane condensate is dissolved in water, and hydrochloric acid is added for salifying and crystallizing, so that genotoxic impurities such as chloromethaneand chloroethane are not generated, and an impurity C is not generated; therefore, moxifloxacin hydrochloride prepared by means of the preparation method is high in purity and low in risk.

Preparation method of moxifloxacin hydrochloride (by machine translation)

The invention relates to a preparation method of moxifloxacin hydrochloride. , 1 - Cyclopropyl -7 - (S, S-2, diazabicyclo [4.3.0] nonane -8 - yl) -6 - fluoro -8 - methoxy -4 - oxo -1, 4 - dihydro -3 - quinoline carboxylic acid hydrochloride is prepared. The condensation reaction solvent acetonitrile is recovered after a certain technical means is recovered to form a condensation product borane chelating moxifloxacin, and the condensation reaction solvent acetonitrile can be reused for the condensation reaction step after the condensation reaction solvent acetonitrile is recovered by a certain technical means. The condensate is hydrolyzed with sodium hydroxide solution in acetone, and then pH is adjusted to acid by hydrochloric acid to form a moxifloxacin hydrochloride crude product, and the crude product is refined after refining in a mixture of ethanol and water to obtain refined moxifloxacin hydrochloride. To the method, the condensation reaction temperature is reduced, the product purity is improved, the emission of three wastes is reduced, the production cost is reduced, and the method is suitable for industrial production. (by machine translation)

Synthetic method of moxifloxacin hydrochloride

The invention discloses a synthetic method of moxifloxacin hydrochloride. The synthetic method comprises the following steps: under the protection of argon, taking gatifloxacin carboxylate and (S,S)-2,8-diazabicyclo[4.3.0]nonane as raw materials; taking an organic alkali or an inorganic alkali as an acid-binding agent and a Lewis acid as a catalyst; reacting in a certain solvent at a proper temperature; concentrating, processing by alkali liquor, separating out moxifloxacin monomers at an isoelectric point, reacting moxifloxacin monomers with an acid to form salt, concentrating to obtain a moxifloxacin hydrochloride crude product, re-crystallizing, filtering, washing and drying to obtain a refined moxifloxacin hydrochloride finished product. The preparation method is mild in reaction conditions, simple to operate, less in pollution, and high in yield and industrial production can be realized easily.

Preparation method of moxifloxacin hydrochloride and intermediate of moxifloxacin hydrochloride

The invention provides a preparation method of moxifloxacin hydrochloride and an intermediate of moxifloxacin hydrochloride, and belongs to the technical field of heterocyclic compound. The preparation method comprises following steps: gatifloxacin intermediate, (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane, a reaction solvent, an organic base, and a Lewis acid are mixed, are reacted fully at a preset temperature, and are subjected to cooling filtering, an obtained filtrate is heated, L-(+)-tartaric acid is added, thermal insulation crystallization is carried out, cooling is carried out, centrifugation filtration, washing, and drying are carried out so as to obtain moxifloxacin ethyl ester tartrate; moxifloxacin ethyl ester tartrate is added into a hydrogen chloride containing solution, heatingis carried out, thermal insulation full reaction is carried out, crystallization is carried out, after cooling, centrifugation filtration, beating, and baking are carried out so as to obtain finishedproducts. According to the preparation method, one-pot reaction is realized, the selectivity and conversion rate are higher than those of disclosed methods, energy is saved, post-treatment is convenient, the preparation method is suitable for industrialized production, and HPLC>99.9%.

Preparation process of moxifloxacin

The invention relates to the technical field of pharmaceutical engineering, specifically to a preparation process of moxifloxacin. The preparation process comprises the following steps: carrying out ahydrolysis reaction on a moxifloxacin chelate which is chelated with borate so as to form a crude moxifloxacin product containing boric acid; subjecting polyol and the crude moxifloxacin product containing boric acid to a chelation reaction; and then adding a poor solvent for crystallization. The preparation process of the invention can effectively remove elemental boron in the crude moxifloxacinproduct, and the yield and the purity of prepared moxifloxacin are excellent.

Preparation method of moxifloxacin hydrochloride

The invention discloses a preparation method of moxifloxacin hydrochloride. The method comprises the following steps: performing condensation by using 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-ethylquinolinecarboxylate as a central ring, and (S,S)-2,8-diazabicyclo[4,3,0]nonane as a side chain, after alkali hydrolysis is completed, adding a part of 6N hydrochloric acid, performing primary crystallization, adding the remaining 6N hydrochloric acid, performing secondary crystallization, and performing recrystallization on the crystallized product obtain by the secondary crystallization once by using ethanol to obtain the moxifloxacin hydrochloride with a high content and excellent quality. When the method provided by the invention is adopted to prepare the moxifloxacin hydrochloride, product loss caused by repeated crystallization is reduced, labor intensity is reduced, energy consumption is reduced, product stability is improved, product quality is greatly improved, and themethod is suitable for industrialized large-scale production; and the prepared moxifloxacin hydrochloride contains 99.6%-102.0% of C21H25ClFN3O4 calculated by an anhydrate, and has a low total impurity content.

Preparation method of moxifloxacin hydrochloride and intermediate thereof

The invention discloses a preparation method of moxifloxacin hydrochloride and an intermediate thereof. The preparation method of the intermediate III of the moxifloxacin hydrochloride includes the following steps: making an intermediate II of the moxifloxacin hydrochloride and (S,S)-2,8-diazabicyclo[4,3,0]nonane have condensation reaction in an organic solvent in the presence of alkali to obtainthe intermediate III of the moxifloxacin hydrochloride. The preparation method is simple and safe in operation, does not require special equipment and avoids use of highly toxic materials and mild inreaction conditions. The obtained the moxifloxacin hydrochloride I has high purity and low production cost, and is suitable for industrial production. (img file='DDA0001750656940000011.TIF' wi='700' he='192'/).

Moxifloxacin hydrochloride new preparation method

The invention provides a method for preparing a moxifloxacin intermediate and moxifloxacin hydrochloride, which comprises the following steps: carrying out condensation reaction on main ring chelate disclosed as Formula (I) and (S,S)-2,8-diazabicyclo-[4.3.0]nonane in the presence of an acid acceptor in a solvent, acidifying for salification, crystallizing, filtering, washing and drying to obtain the moxifloxacin hydrochloride. The method is characterized in that the solvent in the condensation reaction is alcohol. The condensation reaction is carried out in the alcohol solvent at the controlled temperature of 30-80 DEG C (preferably lower temperature), so the method has the advantage of mild reaction conditions, greatly reduces the generation of impurities, saves the energy; the alcohol solvent can be directly acidified after sufficient reaction, thereby saving the complex step of removing acetonitrile by evaporation and greatly simplifying the steps; and the method is suitable for industrial production.