21256-18-8 Usage
Description
Oxaprozin, also known as 4,5-diphenyl-2-oxazolepropionic acid (Daypro), is a non-steroidal anti-inflammatory drug (NSAID) that is structurally unique as a 3-substituted propionic acid derivative. It is characterized by its long half-life, which allows for once or twice daily dosing, and is used to relieve pain and inflammation associated with various forms of arthritis, including osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.
Uses
Used in Pharmaceutical Industry:
Oxaprozin is used as an anti-inflammatory agent for the shortand long-term management of osteoarthritis (OA) and rheumatoid arthritis (RA). It is administered as a once-daily dose of 600to 1,200-mg due to its long duration of action.
Used in Medical Treatment:
Oxaprozin is used to relieve the inflammation, swelling, stiffness, and joint pain associated with osteoarthritis and rheumatoid arthritis. It is comparable to Aspirin (A687780) in its anti-inflammatory effects.
Used in Antiparasitic Applications:
Oxaprozin is also used as an antiparasitic agent, although the specific application reason is not detailed in the provided materials.
Taboo
This drug has a Black Box Warning. This is the most serious warning from the Food and Drug Administration (FDA). A black box warning alerts doctors and patients to potentially dangerous effects.
Heart disease risk. Oxaprozin belongs to a drug class called nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs may increase your risk of heart-related diseases, such as heart attack, heart failure, and stroke. Your risk may be higher if you’re taking it long term, at high doses, or if you already have heart problems or risk factors for heart disease, such as high blood pressure.
May cause ulcers and stomach bleeding. Oxaprozin can cause ulcers and bleeding in your stomach and intestines. This can happen at any time during treatment and may not cause symptoms. Smoking cigarettes or drinking alcohol can make these conditions worse.
Coronary artery bypass graft surgery. Oxaprozin shouldn’t be used for pain after coronary artery bypass graft surgery. Taking it could increase your risk for a heart attack or stroke.
References
https://en.wikipedia.org/wiki/Oxaprozin
https://www.drugs.com/cdi/oxaprozin.html
http://www.healthline.com/health/oxaprozin/oral-tablet#Highlights1
References
1) Merck 14:6924
2) Ottonello et al. (2009), Delayed apoptosis of human monocytes exposed to immune complexes is reversed by oxaprozin: role of the Akt/IkappaB kinase/nuclear factor kappaB pathway; Br. .J. Pharmacol., 157 294
3) Dallegri et al. (2005), A review of the emerging profile of the anti-inflammatory drug oxaprozin; Expert Opin .Pharmacother., 6 777
Originator
Wyeth (United Kingdom)
Indications
Oxaprozin (Daypro) is approved for the treatment
of osteoarthritis and rheumatoid arthritis. Its long halflife
allows for once daily dosing.The most frequently reported
adverse effects of this drug are nausea, vomiting,
and dyspepsia.
Manufacturing Process
A clean dry reactor of 20 gallon (91 liters) capacity was charged with pyridine (9.25 kg), benzoin (16.5 kg) and succinic anhydride (11.7 kg.). The reactor was purged with nitrogen and a nitrogen atmosphere was maintain throughout the process. The mixture was heated without agitation until it became liquid at 85°C. Agitation was commenced and the mixture was heated at 90°-95°C for 1.5 hours. A solution of ammonium acetate (12.0 kg) in glacial acetic acid (35.0 kg) was charged to the header of the reactor and added to the reaction mixture over 15 minutes, maintaining the temperature between 90° and 95°C. The container for the solution and the header were washed with glacial acetic acid (4.0 kg) and the washing liquid was added to the reaction mixture. The reaction mixture was held at 90°-95°C for 2 hours. The reaction mixture was cooled to 50°C and transferred via a line filter to a reactor of 50 gallon (227 liters) capacity. The first reactor, lines and filter were washed with glacial acetic acid (4.0 kg.) which was combined with the reaction mixture. The reaction mixture was heated with agitation to 90°-95°C over 30 minutes and water (21.0 kg.) was added maintaining the temperature at 90°-95°C. The reaction mixture was then cooled to 20°-25°C over 55 minutes by means of water in the jacket of the reactor and then cooled to 10°-15°C by means of brine in the jacket and left overnight. The product was filtered on a ceramic filter and sucked well dry. The product on the filter was washed with a prefiltered mixture of glacial acetic acid (25.5 kg.) and water (12.5 kg) and
sucked well dry. Pre-filtered water (50.0 kg) and the filter cake were added to a reactor of 50 gallon (227 liters) capacity. The mixture was stirred at room temperature for 30 minutes and filtered on a ceramic filter and the product was sucked well dry. The product on the filter was washed twice with prefiltered water (10 kg each time) and sucked well dry. The product was then dried in a Mitchell oven at 80°C for 16-18 hours. The yield of crude β-(4,5diphenyloxazol-2-yl)propionic acid was 15.9 kg (69.8%). This material only just failed specification for acceptable purity because although TLC analysis showed only very faint trace impurities.
Recrystallisation of crude β-(4,5-Diphenyloxazol-2-yl)propionic acid
Methanol (62.0 kg) was added to a reactor of 50 gallon capacity (227 liters). 15.9 kg of the crude oxazole above prepared was added with agitation. The mixture was heated to reflux. All the solid dissolved. The mixture was then cooled to 50°C and transferred to a reactor of 20 gallon (91 liters) capacity. The larger reactor and transfer lines were washed through with methanol at about 40°C twice (3 kg each time). The mixture was cooled over 1 hour 50 minutes with agitation, gradually at first, to 15°-20°C by means of cooling water on the jacket of the reactor. The product was then filtered on a ceramic filter and sucked well dry. The product on the filter was washed twice with methanol (5 kg each time) and sucked well dry. The wash liquors were combined with the filtration liquors and retained. The product from the filter was dried in an air oven at 55°-60°C for 18 hours. The yield of β-(4,5diphenyloxazol-2-yl)propionic acid was 12.1 kg. TLC investigation showed the product to be pure. Melting point 160.5°-161.5°C.
Another crop of product was obtained from the methanol liquors as follows. The liquors were added to a reactor of 20 gallon (91 liters) capacity and the solvent was distilled off for 9 hours until solid appeared. The mixture was then cooled to 15° to 20°C over 1 3/4 hours using cooling water in the jacket of the reactor. The mixture was cooled to 10°C using brine in the jacket and stirred at this temperature for 30 minutes. The product was then filtered on a ceramic filter and sucked well dry. The product on the filter was washed twice with methanol (5 kg each time) and sucked well dry. The product was dried in an air oven at 55°-60°C for 18 hours. The yield was 2.14 kg. This product may also have been acceptably pure but its purity was not investigated. It was therefore retained as crude product to be resubjected to recrystallisation with methanol. The yield for the recrystallisation was thus 12.1 kg from a consumption of 13.76 kg of crude product, that is 88%. The overall yield of pure product is 69.8% times 88%, that is, 61.4%.
Therapeutic Function
Antiinflammatory
Pharmacokinetics
Oxaprozin is well absorbed (100%) following oral administration, but maximum plasma concentrations are not reached
until 3 to 5 hours following ingestion. Oxaprozin is an anti-inflammatory agent possessing a rapid onset of action and
a prolonged duration of action. In both the carrageenan raw paw edema assay and analgetic tests, it was equipotent
with aspirin. Oxaprozin has been associated with the appearance of rash and/or mild photosensitivity. Some patients
experience an increased incidence of rash on sun-exposed skin during clinical testing.
Safety Profile
Poison by ingestion, intravenous, and intraperitoneal routes. Moderately toxic by subcutaneous route. An experimental teratogen. Experimental reproductive effects. An anti-inflammatory agent. When heated to decomposition it emits toxic fumes of NOx.
Check Digit Verification of cas no
The CAS Registry Mumber 21256-18-8 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 2,1,2,5 and 6 respectively; the second part has 2 digits, 1 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 21256-18:
(7*2)+(6*1)+(5*2)+(4*5)+(3*6)+(2*1)+(1*8)=78
78 % 10 = 8
So 21256-18-8 is a valid CAS Registry Number.
InChI:InChI=1/C18H15NO3/c20-16(21)12-11-15-19-17(13-7-3-1-4-8-13)18(22-15)14-9-5-2-6-10-14/h1-10H,11-12H2,(H,20,21)
21256-18-8Relevant articles and documents
Metal-free syntheses of oxazoles and their analogues based on λ3-iodane-mediated cycloisomerization/functionalization reactions or [2+2+1] cycloaddition type reactions
Saito, Akio
, p. 84 - 98 (2017/04/17)
As a metal-free construction of oxazoles and furans concomitant with the introduction of oxygen functional groups or fluorine atoms into the side chains, we have developed λ3-iodane-mediated cycloisomerization/functionalization reactions of propargyl compounds. In these reactions, aryl- λ3-iodane ArI(X)Y works not only as a donor of heteroatomic functional groups but also as an activator of carbon-carbon triple bonds. Therefore, this methodology is not required any transition metal catalysts, which are frequently used in previous methods. Furthermore, this methodology can be extended to λ3-iodane-mediated [2+2+1] cycloaddition type reactions of alkynes, nitriles and heteroatoms for metal-free formation of oxazoles and imidazoles.
Synthesis of Extended Oxazoles III: Reactions of 2-(Phenylsulfonyl)methyl-4,5-diaryloxazoles
Patil, Pravin C.,Luzzio, Frederick A.
, p. 10521 - 10526 (2016/11/17)
2-((Phenylsulfonyl)methyl)-4,5-diphenyloxazole is a useful scaffold for synthetic elaboration at the 2-methylene position thereby affording extended oxazoles. The corresponding α-sulfonyl anion reacts smoothly with diverse alkyl halides giving monoalkylated (47-90%), dialkylated (50-97%), and cyclic (59-93%) products. The reductive desulfonylation of the monoalkylated and selected dialkylated products was optimized with a magnesium/mercuric chloride reagent system and afforded desulfonylated products in the range of 66-97%. The anti-inflammatory Oxaprozin was prepared using the α-sulfonyl carbanion strategy along with optimized desulfonylation.
One-pot preparation of 2,5-disubstituted and 2,4,5-trisubstituted oxazoles from aromatic ketones with molecular iodine, oxone, and trifluoromethanesulfonic acid in nitriles
Imai, Sho,Kikui, Hiroki,Moriyama, Katsuhiko,Togo, Hideo
, p. 5267 - 5274 (2015/07/15)
Alkyl aryl ketones were successfully converted into the corresponding 2,5-disubstituted and 2,4,5-trisubstituted oxazoles in good to moderate yields in a one-pot manner, utilizing iodine, Oxone, and trifluoromethanesulfonic acid in nitriles under transition-metal-free conditions. The present method could be used for the preparation of Oxaprozin from benzyl phenyl ketone and succinonitrile. A possible reaction mechanism was proposed in which the key intermediates were α-iodoalkyl aryl ketones and α-iodosylalkyl aryl ketones.
