95-25-0

Usage

Skeletal muscle relaxants

Chlorzoxazone is an orally active central skeletal muscle relaxant with its chemical structure being completely different with all the other muscle relaxants. It, mainly through acting on the central cerebral cortex and the spinal cord, inhibits the multi-synaptic reflection related to muscle spasms and produces muscle relaxation, further relieves the spasm caused pain and increase the flexibility of the muscles involved. Acetaminophen belongs to non-steroidal anti-inflammatory drugs and may mainly exert the analgesic and antipyretic effects through the inhibition of prostaglandin synthesis. Muscle relaxation studies through mouse traction test have demonstrated that the compound Chlorzoxazone showed a dose-dependent muscle relaxant effect with excellent protective effect on the strychnine-induced seizures in mice. The existence of paracetamol in the compound chlorzoxazone tablets can further enhance the effect of chlorzoxazone. Hot plate analgesic tests have showed the compound chlorzoxazone has a significant analgesic effect in a dose-dependent manner. It also has antagonism effect on the painful writhing of mice caused by antimony potassium tartrate in a good dose-response relationship. Test results have showed that acetaminophen and chlorzoxazone analgesic synergy. This information is edited by Xiongfeng Dai from lookchem.

Pharmacokinetics

This product can be completely absorbed by the digestive tract with the plasma concentration reaching peak at 1.5-2 hours. It is distributed in muscle, kidney, liver, brain and fat. After 6 hours, the drug concentration decreases significantly. Almost all of the goods can subject to in vivo catabolism with the elimination half-life being about 1 hour. This information is edited by Xiongfeng Dai from lookchem.

Indications

Chlorzoxazone is suitable for the treatment of various kinds of acute and chronic soft tissue (muscles, ligaments and fascia) sprain, contusion, muscle pain after exercise, pain caused by muscle strain and the muscle spasms caused by the central nervous system lesions as well as chronic fasciitis.

Chlorzoxazone synthesis

Take 2, 5-dichloro-nitrobenzene as raw material; go through hydrolysis, reduction reaction to give 2-amino-4-chloro-phenol, followed by cyclization reaction in hydrochloric acid to obtain the finished product of Chlorzoxazone with the total yield being 84%.

Medicine interactions

When this product is used in combination with central inhibitory drugs such as phenothiazines and barbituric acid derivative and monoamine oxidase inhibition drugs, we should reduce the usage amount of this product.

Side effects

There may be occasionally mild drowsiness, dizziness, nausea, heart palpitations, weakness, abdominal pain and other reactions. This drug should be discontinued in case of allergic reactions. These adverse reactions are generally mild and may go away automatically or alleviated after stopping using this drug.

Uses

Different sources of media describe the Uses of 95-25-0 differently. You can refer to the following data:
1. It can be used as pharmaceutical intermediates. It can be used as central muscle relaxants, for being applied to a variety of soft tissue pain caused by chronic sprain, contusion and muscle strain as well as muscle spasms and pain caused by the central nervous system and so on.
2. Chlorzoxazone is a benzoxazolone derivative that causes skeletal muscle relaxation and blocks spasticity in clinical studies. Chlorzoxazone enhances small and intermediate conductance calcium-activated potassium channels (EC50s = 87 and 98 μM for KCa2.2 and KCa3.1, respectively). The cytochrome P450 isoform CYP2E1 converts chlorzoxazone to 6-hydroxy chlorzoxazone . The urinary excretion of this 6-hydroxy metabolite is often used as a probe of CYP2E1 activity in studies of hepatotoxicity.
3. For the relief of discomfort associated with acute painful musculoskeletal conditions.

Acute toxicity

Oral-rat LD50: 763 mg/kg; Oral-Mouse LD50: 440 mg/kg.

Flammability and hazard properties

Thermal decomposition can release nitrogen oxides and chlorides smoke.

Storage characteristics

Treasury: ventilated, low temperature and dry; store it separately from food raw materials.

Chemical Properties

White to Off-White Solid

Originator

Paraflex ,McNeil, US ,1958

Definition

ChEBI: A member of the class of 1,3-benzoxazoles that is 1,3-benzoxazol-2-ol in which the hydrogen atom at position 5 is substituted by chlorine. A centrally acting muscle relaxant with sedative properties, it is used for the symptomatic treatment of painful mus le spasm.

Manufacturing Process

A solution of 16.9 g (0.1 mol) of 2-amino-5-chlorobenzoxazole in 200 ml of 1 N HCl is refluxed until precipitation is complete. The resulting solid is collectedby filtration, dissolved in 200 ml of 1 N NaOH and the solution extracted with 50 ml of ether. Acidification of the alkaline solution gives a precipitate which is purified by crystallization from acetone to give 2-hydroxy-5-chlorobenzoxazole melting at 191° to 191.5°C.

Brand name

Paraflex (Ortho-McNeil).

General Description

Chlorzoxazone is a centrally active muscle relaxant used to treat painful muscle spasms linked to musculoskeletal disorders, such as fibrositis, bursitis, myositis, spondylitis, etc.Pharmaceutical secondary standard for application in quality control. Provides pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards.

Biochem/physiol Actions

Chlorzoxazone is a skeletal muscle relaxant.

Synthesis

Chlorzoxazone, 5-chloro-2-benzoxazolione (15.3.15), is synthesized by a hetercyclization reaction of 2-amino-4-chlorphenol with phosgene.

Environmental Fate

Chlorzoxazone ismetabolized by the CYP1A2 and CYP2E1 microsomal enzymes to a toxic metabolite 6-hydroxychlorzoxazone.

Toxicity evaluation

Chlorzoxazone is a white to off-white solid. It is soluble in organic solvents such as ethanol, methanol, and dimethyl sulfoxide (DMSO).

InChI:InChI=1/C7H4ClNO2/c8-4-1-2-6-5(3-4)9-7(10)11-6/h1-3H,(H,9,10)

Synthetic route

1-Phenylprop-1-yne (673-32-5) + chlorzoxazone (95-25-0) → 5-chloro-3-cinnamylbenzo[d]oxazol-2(3H)-one

Conditions	Yield
With triphenylphosphine; bis(dibenzylideneacetone)-palladium(0); 3-chlorobenzoate In 1,4-dioxane at 140℃; Sealed tube; Inert atmosphere;	88%

chlorzoxazone (95-25-0) → 6-Hydroxychlorzoxazone

Conditions	Yield
With human liver microsome at 37℃; for 0.333333h; pH=7.4; Enzyme kinetics; Oxidation; Enzymatic reaction;

chlorzoxazone (95-25-0) → 2-hydroxy-5-chloro-aniline (95-85-2)

Conditions	Yield
With sodium hydroxide at 60℃; Kinetics; Further Variations:; Temperatures;
With water for 2h; Heating;

1,4-dioxane (123-91-1) + 1-(4-trifluoromethylphenyl)ethanone (709-63-7) + chlorzoxazone (95-25-0) → 5-chloro-3-[2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl]-2-(3H)-benzoxazolone (202823-06-1)

Conditions	Yield
With bromine In diethyl ether; N,N-dimethyl-formamide	4.4 g (93%)

propargyl bromide (106-96-7) + chlorzoxazone (95-25-0) → 5-chloro-3-(prop-2-yn-1-yl)-1,3-benzoxazol-2(3H)-one (142429-03-6)

Conditions	Yield
With potassium carbonate In acetone; toluene	10.5 g (86%)

Upstream product

• 37551-43-2 N-(5-chlorosalicyl) hydroxamic acid 
• 61-80-3 zoxazolamine 
• 42953-11-7 (5-chloro-2-hydroxy-phenyl)-carbamic acid ethyl ester 
• 5471-76-1 2-amino-4-chlorophenol hydrochloride 
• 57-13-6 urea 
• 1659-31-0 2,2'-dipyridyl carbonate 
• 95-85-2 2-hydroxy-5-chloro-aniline 
• 74124-79-1 di(succinimido) carbonate 
• 32276-00-9 S,S-bis(1-phenyl-1H-tetrazol-5-yl) dithiocarbonate 
• 43112-61-4 (5-Chloro-2-hydroxy-phenyl)-carbamic acid phenyl ester 
• 7120-43-6 5-chlorosalicylamide 
• 34542-96-6 N',N'-dimethyl-N-(5-chloro-2-hydroxyphenyl)urea 
• 541-41-3 chloroformic acid ethyl ester 
• 24963-29-9 5-chloro-3-acetylbenz[d]oxazol-2(3H)-one 

Downstream Products

• 5790-90-9 5-chloro-3-methyl-1,3-benzoxazol-2(3H)-one 
• 6358-07-2 2-amino-4-chloro-5-nitrophenol 
• 17929-31-6 3-Pyrrolidinomethyl-5-chlor-2-benzoxazolinon 
• 16376-55-9 5-chloro-3-piperidin-1-ylmethyl-3H-benzooxazol-2-one 
• 16376-61-7 5-chloro-3-morpholin-4-ylmethyl-3H-benzooxazol-2-one 
• 5790-91-0 5-Chlor-2-oxo-3-aethyl-2.3-dihydro-benzoxazol 
• 17929-30-5 5-chloro-3-[4-(3-phenyl-propyl)-piperidin-1-ylmethyl]-3H-benzooxazol-2-one 
• 17929-34-9 5-chloro-3-(hydroxymethyl)benzo[d]oxazol-2(3H)-one 
• 62637-26-7 [3-(3,7-dichloro-benzo[b]pyridazino[4,3-e][1,4]oxazin-5-yl)-propyl]-dimethyl-amine 
• 16376-63-9 5-chloro-3-(4-phenyl-piperidin-1-ylmethyl)-3H-benzooxazol-2-one 
• 16376-53-7 5-chloro-3-((phenylamino)methyl)benzo[d]oxazol-2(3H)-one 
• 14733-75-6 5-chloro-3-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-3H-benzooxazol-2-one 
• 19231-16-4 5-Chlor-3-<1'-(2',3',4'-tri-O-benzoyl-β-D-ribopyranosyl)>-2-benzoxazolon 
• 27087-06-5 5-chloro-6-nitrobenzo[d]oxazol-2(3H)-one 

Relevant academic research and scientific papers

Continuous-Flow Hofmann Rearrangement Using Trichloroisocyanuric Acid for the Preparation of 2-Benzoxazolinone

A continuous-flow preparation of 2-benzoxazolinone via the Hofmann rearrangement of salicylamide has been implemented employing trichloroisocyanuric acid as the stable and atom-economic chlorinating agent. The system was optimized to avoid solid accumulation and allow the preparation of hundreds of grams of the pure desired material over a working day. Furthermore, a trichloroisocyanuric acid (TCCA)-based chlorination of 2-benzoxazolone to the corresponding 5-chloro derivative was also carried out under batch conditions.

Method for preparing carbonyl heterocyclic compound

The invention provides a method for preparing a carbonyl heterocyclic compound, wherein Lewis base and hydrosilane are used as accelerators and can efficiently enable an ortho-substituted aniline compound to react with normal-pressure CO2 to generate corresponding carbonyl heterocyclic compounds containing different functional groups under mild conditions (100 DEG C, digital). According to the method, normal-pressure CO2 is used as an environmentally-friendly non-toxic carbonylation reagent, and cheap Lewis base and PMHS (industrial silicon waste) are used as accelerators, so that the use of CO, high-pressure CO2 and noble metal catalysts is avoided, the intermediate isocyanate does not need to be purified and separated, the pure product can be obtained only through simple suction filtration and separation after the reaction is finished, and the synthetic method is efficient and universal, is suitable for preparing a series of benzimidazolone, benzoxazolone and benzothiazolone compounds and has high industrial application value.

Design, Synthesis, and In Silico Evaluation of Methyl 2-(2-(5-Bromo/chloro-2-oxobenzoxazol-3(2H)-yl)-acetamido)-3-phenylpropanoate for TSPO Targeting

The high expression of the translocator protein (TSPO) makes it an ideal target for imaging and therapy. The present study is aimed at optimizing acetamidobenzoxazolone-based TSPO ligands by structural modification to overcome the limitations of TSPO ligands of the first two generations such as nonspecificity and polymorphism. Three different TSPO proteins, 2MGY, 4RYQ, and 4UC1, in the native and mutated form were chosen. Acetamidobenzoxazolones modified with phenylalanine methyl ester (methyl 2-(2-(5-bromo/chloro-2-oxobenzooxazol-3(2H)-yl)acetamido)-3-phenylpropanoate, ABPO-Br, ABPO-Cl) through better or comparable docking scores than the known TSPO ligands such as MBMP, FEBMP, FPBMP, and PK11195 are identified as potential TSPO ligands. ABPO-Cl and ABPO-Br were synthesized using phenylalanine methyl ester as a moiety for incorporation of the desired pharmacophoric feature. All the intermediates and final compounds were purified using column chromatography and analytical HPLC (purity > 97%). The purified compounds were characterized by 1H, 13C NMR and mass spectroscopy. Drug likeliness and comparative bioactivity analysis were performed using QikProp through prediction of various properties. Both analogs follow all the five Lipinski rules and three Jogersen’s rules predicting their drug likeliness. The other important aspects related to TSPO ligands such as blood-brain barrier penetration and better contrast have been predicted through lipophilicity (QP log P = 2.76 and 2.74 for ABPO-Br and ABPO-Cl, respectively) and serum binding (QP log Khsa = ?0.18 and ?0.25 for ABPO-Br and ABPO-Cl, respectively). The selectivity and distribution of these TSPO ligands were confirmed by 99mTc-ABPO-Br dynamic image in New Zealand rabbit. These results have shown that the ABPO analogs have the potential to act as better ligands as compared to known acetamidobenzoxazolone derivatives and would be of interest as a promising starting point for designing compounds for TSPO targeting.

Concise and Additive-Free Click Reactions between Amines and CF3SO3CF3

Trifluoromethyl trifluoromethanesulfonate has proved to be an excellent reservoir of difluorophosgene and a promising click ligation for amines in the preparation of urea derivatives, heterocycles, and carbamoyl fluorides under metal- and additive-free conditions. The reactions are rapid, efficient, selective, and versatile, and can be performed in benign solvents, giving products in excellent yields with minimal efforts for purification. The characteristics of the reactions meet the requirements of a click reaction. The use of trifluoromethyl trifluoromethanesulfonate as a click reagent is advantageous over other “CO” sources (e.g., TsOCF3, PhCO2CF3, CsOCF3, AgOCF3, and triphosgene) because this reagent is readily accessible; easy to scale up; and highly reactive, even under metal- and additive-free conditions. It is anticipated that CF3SO3CF3 will be increasingly as important as SO2F2 as a click agent in future drug design and development.

Modified benzoxazolone (ABO-AA) based single photon emission computed tomography (SPECT) probes for 18 kDa translocator protein

Acetamidobenzoxazolone (ABO) has been modified to ABO-AA, 2-(2-(5-bromo/chloro benzoxazolone)acetamide)-3-(1H-indol-3-yl)propionate to improve pharmacokinetics and lipophilicity (log p = 2.04). The final compound was synthesized in better yield and in few

Comparative evaluation of 99mTc-MBIP-X/11[C] MBMP for visualization of 18 kDa translocator protein

An elevated translocator protein (18 kDa, TSPO) density is observed during inflammation in the brain and peripheral organs making it a viable target for imaging. Recently, our group has explored a pharmacophore skeleton acetamidobenzoxazolone for positron emission tomography (PET) and single photon emission computed tomography (SPECT) applications to target TSPO. 2-(2-(5-Bromo/chloro benzoxazolone)acetamide)-3-(1H-indol-3-yl)propionate (MBIP-Br/Cl) were synthesized by using tryptophan methyl ester and compared with 2-[5-(4-methoxyphenyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenyl acetamide (MBMP) through tracer techniques. Computational docking showed similar results for MBIP-Br/Cl in comparison to MBMP. Their ex vivo and in vivo biodistributions were assessed in TSPO-rich organs as well as their release kinetics 0-120 min post injection. The ex vivo biodistribution showed a 7 fold higher uptake (5.16%ID per g vs. 0.72%ID per g) in the heart and a 2.5 fold higher uptake (12.91%ID per g vs. 4.69%ID per g) in the lungs for 99mTc-MBIP-Cl compared to that of 99mTc-MBIP-Br at 15 min. These findings demonstrated that 99mTc-MBIP-Cl has improved pharmacokinetic properties compared to 99mTc-MBIP-Br for SPECT application and is comparable to [11C]MBMP.

Visible-Light-Induced Intramolecular C(sp2)-H Amination and Aziridination of Azidoformates via a Triplet Nitrene Pathway

Catalytic intramolecular C-H amination and aziridination reactions of o-allylphenyl azidoformates have been achieved under visible-light irradiation, providing a mild, clean, and efficient method for the synthesis of useful benzoxazolones and [5.1.0] bicyclic aziridines. Mechanistic studies suggest that a triplet nitrene acts as the reactive intermediate. The chemoselectivity of the reaction, with alkyl olefin aziridination ? electron deficient olefin aziridination ≈ C(sp2)-H amination ? C(sp3)-H amination was observed, which may be instructive in the development of an understanding of visible-light-induced triplet nitrene transformation reactions.

Synthesis, biological evaluation, and docking studies of some 5-chloro-2(3H)-benzoxazolone Mannich bases derivatives as cholinesterase inhibitors

A series of N-substituted-5-chloro-2(3H)-benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory, and antioxidant activities. The structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The free radical scavenging activity was also determined by in vitro ABTS (2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)) assay. The biological activity results revealed that all of the title compounds displayed higher AChE inhibitory activity than the reference compound, rivastigmine, and were selective for AChE. Among the tested compounds, compound 7 exhibited the highest inhibition against AChE (IC50 = 7.53 ± 0.17 μM), while compound 11 was found to be the most active compound against BuChE (IC50 = 17.50 ± 0.29 μM). The molecular docking study of compound 7 showed that this compound can interact with the catalytic active site (CAS) of AChE and also has potential metal chelating ability and a proper log P value. On the other hand, compound 2 bearing a methyl substituent at the ortho position on the phenyl ring showed better radical scavenging activity (IC50 = 1.04 ± 0.04 mM) than Trolox (IC50 = 1.50 ± 0.05 mM).

Iron-Catalyzed Arene C-H Amidation Using Functionalized Hydroxyl Amines at Room Temperature

Herein, we report Fe(III)(TPP)Cl as an effective catalyst for promoting arene C-H amidation through intramolecular cyclization of N-tosyloxyarylcarbamate substrates. The reaction proceeds via nitrene (outer sphere pathway) C(sp2)-H i

Application of Silicon-Initiated Water Splitting for the Reduction of Organic Substrates

The use of water as a donor for hydrogen suitable for the reduction of several important classes of organic compounds is described. It is found that the reductive water splitting can be promoted by several metalloids among which silicon shows the best efficiency. The developed methodologies were applied for the reduction of nitro compounds, N-oxides, sulfoxides, alkenes, alkynes, hydrodehalogenation as well as for the gram-scale synthesis of several substrates of industrial importance.