181695-72-7

Basic information

• Product Name: VALDECOXIB
• Synonyms: 4-(5-METHYL-3-PHENYL-4-ISOXAZOLYL)BENZENESULFONAMIDE;AKOS 92130;BEXTRA;VALDECOXIB;BEXTRA(VALDECOXIB);Bextra, 4-(5-Methyl-3-phenyl-4-isoxazolyl)benzenefulfonamide;4-(5-methyl-3-phenyl-oxazol-4-yl)benzenesulfonamide;Bextra, 4-(5-Methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide
• CAS NO: 181695-72-7
• Molecular Formula: C₁₆H₁₄N₂O₃S
• Molecular Weight: 314.36
• EINECS: 448-010-8
• Product Categories: Active Pharmaceutical Ingredients;Osteoarthritis and Rheumatoid Arthritis;Intermediates & Fine Chemicals;Pharmaceuticals;Amines;Aromatics;Heterocycles;Sulfur & Selenium Compounds;SC-65872, YM-974
• Mol File: 181695-72-7.mol

Chemical Properties

• Melting Point: 162-164°C
• Boiling Point: 481.191 °C at 760 mmHg
• Flash Point: 244.815 °C
• Appearance: white to off-white/
• Density: 1.303 g/cm³
• Vapor Pressure: 2.03E-09mmHg at 25°C
• Refractive Index: 1.608
• Storage Temp.: Store at RT
• Solubility: DMSO: >25mg/mL
• PKA: 9.83±0.10(Predicted)
• CAS DataBase Reference: VALDECOXIB(CAS DataBase Reference)
• NIST Chemistry Reference: VALDECOXIB(181695-72-7)
• EPA Substance Registry System: VALDECOXIB(181695-72-7)

Safety Data

• Hazard Codes: Xn,N
• Statements: 63-48/22-51/53
• Safety Statements: 36/37-61
• RIDADR: UN 3077 9 / PGIII
• WGK Germany: 3
• Hazardous Substances Data: 181695-72-7(Hazardous Substances Data)

Usage

Originator

Pharmacia (Searle) (USA)

Preparation

The step for the synthesis of valdecoxib: Deoxybenzoin is converted to the corresponding oxime by treatment with hydroxylamine under basic conditions with sodium acetate in aqueous ethanol or in toluene in presence of potassium hydroxide in absolute ethanol. The treatment of the oxime under nitrogen with two equivalents of butyllithium in tetrahydrofuran is followed by cyclization in ethyl acetate or acetic anhydride to the isoxazoline derivative. Finally, treatment of the isoxazoline with cold chlorosulfuric acid followed by reaction of the intermediate with aqueous ammonia afforded valdecoxib.

Biochem/physiol Actions

Valdecoxib is reported to elicit anti-inflammatory, analgesic and antipyretic functionality. It acts as a substrate for the liver enzyme cytochrome P450 2C9(CYP2C9) and cytochrome P450 3A4 (CYP3A4).

Pharmacokinetics

Valdecoxib is freely soluble in alkaline aqueous solutions. At recommended doses, the mean oral bioavailability for valdecoxib is 83%, and the time to peak concentration is approximately 3 hours. Time to peak plasma concentration was delayed by 1 to 2 hours when administered with a high-fat meal. Protein binding is very high at 98%. Valdecoxib exhibits linear pharmacokinetics over the usual clinical dose range. Valdecoxib is extensively metabolized in humans. The primary metabolite for valdecoxib involved CYP2C9 hydroxylation of the 5-Me group, which was further metabolized to the inactive carboxylate, and N-hydroxylation at the sulfonamide moiety. Oxidative breakdown of the N-hydroxy sulfonamide function group led to the formation of the corresponding sulfinic acid and sulfonic acid metabolites. The O-and N-glucuronides were the major urinary metabolites. Only 3% of the administered dose was recovered in urine as unchanged valdecoxib.

Clinical Use

Valdecoxib is approved for the relief of the signs and symptoms of osteoarthritis and adult rheumatoid arthritis and for the treatment of primary dysmenorrhea. Valdecoxib is contraindicated for the treatment of postoperative pain immediately following coronary artery bypass graft surgery.

Clinical claims and research

Valdecoxib is a substrate of CYP3A4 but no metabolism interference was seen with commonly used synthetic narcotics, alfentanil and fentanyl. Clinical studies have shown that valdecoxib is as effective as naproxen in treating osteoarthritis, rheumatoid arthritis and dysmenornhoea. The efficacy of valdecoxib was also demonstrated in managing postoperative pain (oral and orthopedic surgery) with effective analgesia and time to rescue medication superior to those obtained with rofecoxib. Several clinical trials showed that valdecoxib has a better upper gastrointestinal safety profile compared to naproxen, ibuprofen or diclofenac and does not affect platelet function. Less abdominal pain, dyspepsia and constipation were observed with valdecoxib than with naproxen. Valdecoxib is contraindicated in patients with a history of allergic reactions to sulfonamides due to reported anaphylactic and skin reactions.

Mode of action

Valdecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic properties in animal models. The mechanism of action is believed to be due to inhibition of prostaglandin synthesis primarily through inhibition of cyclooxygenase-2 (COX-2). At therapeutic plasma concentrations in humans valdecoxib does not inhibit cyclooxygenase-1 (COX-1).

references

[1] talley j j, brown d l, carter j s, et al. 4-[5-methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide, valdecoxib: a potent and selective inhibitor of cox-2. journal of medicinal chemistry, 2000, 43(5): 775-777.[2] nussmeier n a, whelton a a, brown m t, et al. complications of the cox-2 inhibitors parecoxib and valdecoxib after cardiac surgery. new england journal of medicine, 2005, 352(11): 1081-1091.

InChI:InChI=1/C16H14N2O3S/c1-11-15(12-7-9-14(10-8-12)22(17,19)20)16(18-21-11)13-5-3-2-4-6-13/h2-10H,1H3,(H2,17,19,20)

Upstream product

• 701-34-8 4-bromo-benzenesulfonic acid amide 
• 491876-01-8 C₁₀H₁₀BNO₃ 
• 37928-17-9 5-methyl-3,4-diphenyl isoxazole 
• 181696-73-1 3,4-diphenyl-4-hydrido-5-hydroxy-5-methylisoxazole 
• 374715-24-9 5-methyl-3-phenyl-4-(4,4,5,5-tetramethyl[1.3.2]dioxaborolan-2-yl)-isoxazole 
• 31295-66-6 5-methyl-4-iodo-3-phenylisoxazole 
• 214360-51-7 benzenesulfonamide-4-boronic acid pinacol ester 
• 934-16-7 phenylhydroxamoyl chloride 
• 1027564-45-9 5-hydroxy-5-methyl-3-phenyl-4,5-dihydro-2-isoxazole 
• 1008-74-8 5-methyl-3-phenylisoxazole 
• 1336-21-6 ammonium hydroxide 
• 952-06-7 deoxybenzoin oxime 
• 108-24-7 acetic anhydride 
• 857259-65-5 5-methyl-3,4-diphenyl-5-(pyrrolidin-1-yl)-4,5-dihydroisoxazole 

Downstream Products

• 198471-06-6 N-[[4-[5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide 
• 198470-84-7 parecoxib 
• 181697-32-5 [[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]-carbamic acid, 1,1-dimethylethylester 
• 181695-81-8 4-(5-hydroxymethyl-3-phenylisoxazol-4-yl)benzenesulfonamide 
• 473465-01-9 N,N-bis(4-methoxybenzyl)-4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide 
• 198471-65-7 methyl N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]carbamate 
• 198471-70-4 1,1-dimethylethyl-N-[2-[[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]-2-oxoethyl]carbamate 
• 181695-80-7 [4-[4-(aminosulfonyl)phenyl]-3-phenyl-isoxazol-5-yl]acetic acid 
• 1373038-60-8 C₃₂H₂₅N₃O₆S₂ 
• 181697-33-6 [[4-[3-phenyl-5-(3,3,3-trifluoro-2-oxopropyl)isoxazol-4-yl]phenyl]sulfonyl]-carbamic acid, 1,1-dimethylethylester 
• 181696-23-1 4-[3-phenyl-5-(3,3,3-trifluoro-2-oxopropyl)isoxazol-4-yl]benzenesulfonamide 

Relevant articles and documents

NHC-palladium-catalyzed ionic liquid-accelerated regioselective oxyarylation of alkynes with diaryl ethers?

The first NHC-palladium-catalyzed regioselective oxyarylation of oxime ether in a task-specific ionic liquid via C(sp3)-O and C(sp2)-O bond cleavage of two different types of ethers for the assembly of structurally diverse 4-arylisoxazoles is described. Both the basic ionic liquid [C3NH2mim]Br and NHC-Pd catalyst IPr-Pd-Im-Cl2 played an important role in this transformation. Notably, this new approach provides a practical and straightforward route to access a broad range of privileged 4-arylisoxazole structures with good yields and excellent regioselectivities. Significantly, this catalytic system can be recycled up to eight times without significant loss of catalytic activity.

Preparation method of parecoxib sodium

The invention belongs to the technical field of parecoxib sodium production and provides a preparation method of parecoxib sodium, which comprises the following steps: (1) carrying out sulfonation reaction on acetophenone and chlorosulfonic acid to obtain an intermediate (I) 1-phenyl-2-(4-sulfonyl chloride phenyl)acetophenone; (2) carrying out acetylation reaction on the intermediate I and acetyl chloride to obtain an intermediate (II) 1-phenyl-2-(4-sulfonyl chloride phenyl)-2-acetyl ethanone; (3) refining the intermediate II; (4) carrying out cyclization reaction on the refined intermediate II and hydroxylamine hydrochloride to obtain an intermediate III 4-(5-methyl-3-phenyl-4-isoxazole)benzenesulfonyl chloride; (5) carrying out ammoniation reaction on the intermediate III and ammonia water to obtain an intermediate IV 4-(5-methyl-3-phenyl-4-isoxazole)benzenesulfonamide; (6) carrying out propionylation reaction on the intermediate IV and propionic anhydride to obtain parecoxib; and (7) carrying out salt forming reaction on the intermediate V and sodium hydroxide to obtain the parecoxib sodium. The technical problems that an existing parecoxib sodium synthesis method is complex in reaction process and high in production cost are solved.

Parecoxib sodium, injection preparation and preparation method

The invention discloses parecoxib sodium, an injection preparation and a preparation method. The preparation method of the parecoxib sodium is as follows: 5-methyl-3,4-diphenylisoxazole is used as theraw material; sulfonation and amination are carried out in sequence, so that a valdecoxib intermediate is obtained; then, the valdecoxib intermediate is subjected to acylation reaction and salt forming reaction, so that crude parecoxib sodium is obtained; the crude parecoxib sodium is dissolved and decolourized, so that the finished parecoxib sodium is obtained; the finished parecoxib sodium is the parecoxib sodium A crystal form; and the parecoxib sodium preparation for injection is prepared by adding accessories into the parecoxib sodium A crystal form. The preparation method of the parecoxib sodium in the invention is simple in synthetic route and moderate in reaction condition; raw materials are available at low prices; and furthermore, the impurity content of the prepared parecoxib sodium is low.

Preparation method of parecoxib sodium

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of parecoxib sodium. 5-methyl-3, 4-diphenyl isoxazole is used as a raw material, and the parecoxib sodium is obtained through sulfonation reaction, ammoniation reaction, propionylation reaction and salification. The method has the advantages of mild reaction, easy operation, great reductionof the generation of HCl gas, short reaction time, high product yield, and suitableness for industrial production.

Preparation method of parecoxib sodium

The invention belongs to the technical field of drug preparation, and specifically relates to a preparation method of parecoxib sodium. The preparation method comprises sulfonation reactions, amination reactions, propionylation reactions, and salt forming reactions. In sulfonation reactions, 5-methyl-3,4-diphenyl isoxazole is taken as the primary raw material and directly carries out reactions with chlorosulfonic acid, after reactions, and the reaction system is poured into water to carry out quenching to obtain suspension of reaction products. All used reagents are common reagents; the preparation method only uses third kind solvents, which are regulated by International Council for Harmonization (ICH) and are harmless for human body; the operation of the preparation method and post treatment is simple, the repeatability is good, the yield is high, and the cost is low. The purity of prepared parecoxib sodium can reach 99.9% or more. The quality of prepared parecoxib sodium is higher than the standards made by a plant that develops parecoxib sodium. The preparation method is suitable for industrial production of pharmaceutical enterprises.

A handkerchief auspicious past cloth sodium freeze-dried powder, its preparation method and its powder products

The invention discloses a parecoxib sodium freeze-dried powder, a preparation method and a powder product thereof. The freeze-dried powder comprises 95-100 wt% of the parecoxib sodium and 0-5 wt% of a pH regulator; or 40-100 wt% of the parecoxib sodium and 0-60 wt% of L-malate. The freeze-dried powder has simple preparation method, is free of auxiliary materials or employs few auxiliary materials, is reduced in cost, and satisfies national medicine standards in storage stability, clinical application stability and safety.

Valdecoxib and synthesis method thereof

The invention belongs to the technical field of medicine, and particularly relates to vardicoxib and a synthesis method thereof. The synthesis method includes the steps that: taking acetone and pyrrolidine as initial raw materials for sequential multiple reactions; and carrying out washing, drying, filtering and evaporating to obtain vadicoxib. According to the synthesis method of vardicoxib, acetone and pyrrolidine are selected as the initial raw materials; a plurality of reactions with subsequently added reaction products are carried out to obtain to obtain vardicoxib through synthesis at last; reaction conditions (such as the reaction conditions, reactant adding time, reaction temperature, heating reflux time and the like) of each reaction are controlled, so that the reaction rate can be effectively increased, and the reaction time is shortened; by reasonably setting the component content ratio of each raw material, the purity and yield of the product can be effectively improved; and in conclusion, the synthesis method of the vadicoxib is short in reaction time, the raw materials are easy to obtain and low in price, the purity of the final product reaches up to 99.538%, the yield reaches up to 95.7%, and industrial production is facilitated.

Bone-targeted parecoxib sodium nanocapsule freeze-dried injection and preparation method thereof

The invention discloses a bone-targeted nanocapsule freeze-dried injection containing parecoxib sodium and a preparation method of the injection. By virtue of a preparation, namely the injection, the concentration of parecoxib sodium in a bone tissue can be increased, so that the effects of parecoxib sodium in orthopedic surgeries and bone cancer analgesia are improved. By utilizing a capsule material and a carrier material which have good biodegradability and biocompatibility, a drug can be tightly combined with soft and hard tissues in a human body in a short time after entering the human body so as to rapidly play a role of treatment. By utilizing a nanocapsule packaging manner, the content of degradation products of the preparation is extremely low.

Oxyboration with and without a Catalyst: Borylated Isoxazoles via B-O-Bond Addition

Herein we report an oxyboration reaction with activated substrates that employs B-O σ bond additions to C-C π bonds to form borylated isoxazoles, which are potential building blocks for drug discovery. Although this reaction can be effectively catalyzed by gold, it is the first example of uncatalyzed oxyboration of C-C π bonds by B-O σ bonds-and only the second example that is catalyzed. This oxyboration reaction is tolerant of groups incompatible with alternative lithiation/borylation and palladium-catalyzed C-H activation/borylation technologies for the synthesis of borylated isoxazoles.

A method of preparing intermediates handkerchief auspicious past cloth sodium

The invention discloses a novel method for preparing a parecoxib sodium intermediate 5-methyl-3, 4-diphenyl isoxazole. The method comprises the following steps: performing rearrangement reaction on a compound in the formula I (referring to the Specification)under the action of a catalyst to prepare a compound in the formula II(referring to the Specification); and under the condition of a catalyst, reacting hydroxylammonium chloride with the compound in the formula II to prepare 5-methyl-3,4-diphenyl isoxazole. The method disclosed by the invention has the advantages of mild reaction condition, good simplicity and convenience for operation, low cost, environmental-friendliness and the like.