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5104-49-4

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5104-49-4 Usage

Anti-inflammatory analgesics

Flibanserin , also known as flurbiprofen, flurbiprofen, is a potent Phenylalanine anti-inflammatory and antipyretic analgesics,it can inhibit prostaglandin synthesizing cyclooxygenase to have analgesic, anti-inflammatory and antipyretic effects. Its anti-inflammatory and analgesic effects are 250 times and 50 times of aspirin (also known as acetylsalicylic acid) . The oral absorption is rapid , peak plasma concentration achieves after 1.5 hours , half-life is 3.5 hours, it has wide tissue distribution, PPB is 99.4%, it can compete with drugs having a high plasma protein binding rate to bind plasma protein .it Metabolizes in the liver and becomes flurbiprofen hydroxy and its aldehyde acid conjugates. T1/2 is 3.5 h. Urine and fecal excretion,account for approximately 60% and 40% respectively . Age has no effect on drug metabolism. It is Mainly used for rheumatoid arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis. It is also used in preventing aphakic cystoid patchy edema After surgical removal of the lens, inhibiting pupillary constrictionsurgery, treatment of inflammation after cataract and trabeculoplasty argon laser eye surgery. It Also applies to pain caused by some other reasons such as trauma, sprains, surgery.

Toxicity

Non-steroidal anti-inflammatory drug (NSAID) has anti-inflammatory, analgesic and antipyretic effects, toxicity ascending ranking is nabumetone, salsalate, sulindac, diclofenac, ibuprofen, one fabric ibuprofen, aspirin, naproxen, tolmetin, flurbiprofen, piroxicam, a phenoxy ibuprofen, indomethacin, mefenamic acid chlorine. Traditional NSAID medications may be the preferred aspirin, if children in the course of treatment can not tolerate its adverse reactions, use of other non-steroidal anti-inflammatory drugs is taken. a selective COX-2 inhibitor Has been developed, which will replace all traditional NSAID. Selective COX-2 inhibitors which has been listed are nimesulide (Nimeng Shu), rofecoxib (Vioxx), celecoxib (Celebrex), etodolac (Rodin), meloxicam. A recent large-scale, international, multi-center, randomized, double-blind technology, prospective study has shown that selective COX-2 inhibitors have few side effects on the gastrointestinal tract, kidneys, having no significant effect on platelet function,it can be used as drug of choice for early combination therapy of JRA children replacing aspirin . The above information is edited by the lookchem of Tian Ye.

Adverse reactions

The most common adverse reactions are indigestion, stomach discomfort, occasional headache, skin rash. Peptic ulcer, bronchial asthma patients and pregnant women, lactating women should not take. Other adverse reactions are nausea, diarrhea, abdominal pain, blurred vision, urinary tract infection symptoms, dermatitis. Few have elevated liver transaminases, continuing medication, may develop, or remain unchanged or disappear. Mild tingling and burning sensations and (or) visual disturbances when it is dropped into the eye.because it leads to platelet aggregation and prolongs bleeding time, it is reported that the application of the drug in the eye surgery increases intraocular hemorrhage tendency.in Animal experiments, Flibanserin 50~100 mg/kg, medication for three months, can cause renal papillary necrosis. For Humans,it also has this effect.

Chemical Properties

Different sources of media describe the Chemical Properties of 5104-49-4 differently. You can refer to the following data:
1. White fine crystalline powder. Melting point 110111 ℃. Soluble in alcohol, ether, acetone, chlorine protection, chloroform and other organic solvents, almost insoluble in water, with a pungent odor.
2. White to Off-White Crystalline Solid

Uses

Different sources of media describe the Uses of 5104-49-4 differently. You can refer to the following data:
1. This product is anti-inflammatory drug for chronic arthritis and pain, inflammation of Deformation joint disease , and pain after surgery and tooth extraction. Mouse oral LD50 of 140mg/kg, rats 640-800mg/kg.
2. A cyclooxygenase inhibitor
3. An anti-inflammatory used as an analgesic.
4. antiinflammatory, analgesic

production method

It is obtained by 2-fluoro-linked acetophenone through oxidation, esterification, transesterification, hydrolysis, decarboxylation reaction.

Description

Flurbiprofen synthesis was originally reported in 1974. During a study of the pharmacological properties of a large number of substituted phenylalkanoic acids, including ibuprofen and ibufenac, the most potent were found to be substituted 2-(4-biphenyl)propionic acids. Further toxicological and pharmacological studies indicated that flurbiprofen possessed the most favorable therapeutic profile, so it was selected for further clinical development. It was not marketed until 1987, when it was introduced as the sodium salt as Ocufen, the first topical NSAID indicated for ophthalmic use in the United States. The indication for Ocufen is the same as that for Profenal—that is, to inhibit intraoperative miosis induced by prostaglandins in cataract surgery.

Originator

Froben, Boots,UK ,1977

Indications

Flurbiprofen (Ansaid) is indicated for the treatment of rheumatoid arthritis and osteoarthritis. Its half-life, longer than that of many of the NSAIDs, allows for twice daily dosing.The most common adverse effects of flurbiprofen are similar to those of the other acidic NSAIDs. Flurbiprofen inhibits both COX isoforms about equally.

Manufacturing Process

A mixture of 3-acetyl-2-fluorobiphenyl, MP 95°C to 96°C, (73.5 g) [prepared from 4.bromo-3-nitroacetophenone (Oelschlage, Ann., 1961, 641, 81) via-4acetyl-2-nitrobiphenyl, MP 106°C to 108°C (Ullman reaction), 4-acetyl-2aminobiphenyl, MP 124°C to 125°C (reduction), and finally the Schiemann reaction], sulfur (17.4 g) and morpholine (87 ml) was refluxed for 16.5 hr, and then the resulting thiomorpholide was hydrolyzed by refluxing with glacial acetic acid (340 ml) concentrated sulfuric acid (54 ml) and water (78 ml) for 24 hr. The cooled solution was diluted with water, and the precipitated crude 2-fluoro-4-biphenylylacetic acid was collected. (A sample was purified by recrystallization to give MP 143°C to 144.5°C; Found (%): C, 73.2; H, 4.8. C14H11FO2 requires C, 73.1; H, 4.8.)A sodium carbonate solution of the crude acetic acid was washed with ether and then acidified with hydrochloric acid; the required acid was isolated via an ether extraction and was esterified by refluxing for 6 hr with ethanol (370 ml) and concentrated sulfuric acid (15 ml). Excess alcohol was distilled, the residue diluted with water and the required ester isolated in ether. Distillation finally gave ethyl 2-fluoro-4-biphenylacetate, BP 134°C to 136°C/0.25 mm.This ester (70g) and diethyl carbonate (250 mg) were stirred at 90°C to 100°C while a solution of sodium ethoxide [from sodium (7.8 g) and ethanol (154 ml)] was added over 1 hr. During addition, ethanol was allowed to distill and after addition distillation was continued until the column heat temperature reached 124°C. After cooling the solution to 90°C, dimethyl sulfate (33 ml) was followed by a further 85 ml of diethyl carbonate. This solution was stirred and refluxed for 1 hr and then, when ice cool, was diluted with water and acetic acid (10 ml). The malonate was isolated in ether and fractionally distilled to yield a fraction boiling at 148°C to 153°C/0.075 mm, identified as the alpha-methyl malonate. This was hydrolyzed by refluxing for 1 hr at 2.5 N sodium hydroxide (350 ml) and alcohol (175 ml), excess alcohol was distilled and the residual suspension of sodium salt was acidified with hydrochloric acidto give a precipitate of the alpha-methyl malonic acid. This was decarboxylated by heating at 180°C to 200°C for 30 minutes and recrystallized from petroleum ether (BP 80°C to 100°C) to give 2-(2-fluoro-4biphenylyl)propionic acid, MP 110°C to 111°C

Brand name

Ansaid (Pharmacia & Upjohn).

Therapeutic Function

Antiinflammatory

General Description

Flurbiprofen (Ansaid, Ocufen, Froben), is another drug inthis class indicated for both acute and long-term managementof RA and OA but with a more complex mechanism ofaction. Unlike the other drugs in this class, it does not undergochiral inversion (i.e., the conversion of the “inactive”[R]-enantiomer to the active, [S]-enantiomer). Similar to aspirinand other salicylates, both flurbiprofen enantiomersblock COX-2 induction as well as inhibiting the nuclearfactor-κB-mediated polymorphonuclear leukocyte apoptosissignaling; therefore, both enantiomers are believed to contributeequally to its overall anti-inflammatory action.(R)-flurbiprofen is actually a strong clinical candidate forthe treatment of Alzheimer disease, because it has beenshown to reduce Aβ42 production by human cells.

Biological Activity

Potent inhibitor of cyclooxygenase (IC 50 values are 0.1 and 0.4 μ M for inhibition of human COX-1 and COX-2 respectively). Analgesic, anti-inflammatory and antipyretic in vivo . Inhibits tumor cell growth in vitro and in vivo . Also inhibits fibroblast proliferation in vitro .

Pharmacokinetics

Flurbiprofen is well absorbed after oral administration, with peak plasma levels being attained within 1.5 hours. Food alters the rate of absorption but not the extent of its bioavailability. It is extensively bound to plasma proteins (99%).and has a plasma half-life of 2 to 4 hours. Metabolism is extensive, with 60 to 70% of flurbiprofen and its metabolites being excreted as sulfate and glucuronide conjugates. Flurbiprofen shows some interesting metabolic patterns, with 40 to 47% as the 4′-hydroxy metabolite, 5% as the 3′,4′-dihydroxy metabolite, 20 to 30% as the 3′-hydroxy- 4′-methoxy metabolite, and the remaining 20 to 25% of the drug being excreted unchanged. None of these metabolites demonstrates significant anti-inflammatory activity.

Clinical Use

Flurbiprofen is indicated as an oral formulation for the acute or long-term treatment of rheumatoid arthritis and osteoarthritis and as an ophthalmic solution for the inhibition of intraoperative miosis.

Drug interactions

Potentially hazardous interactions with other drugs ACE inhibitors and angiotensin-II antagonists: antagonism of hypotensive effect; increased risk of nephrotoxicity and hyperkalaemia. Analgesics: avoid concomitant use with other NSAIDs or aspirin; avoid concomitant use with ketorolac (increased side effects and haemorrhage). Antibacterials: possibly increased risk of convulsions with quinolones. Anticoagulants: effects of coumarins and phenindione enhanced; possibly increased risk of bleeding with heparin, dabigatran and edoxaban - avoid long term use with edoxaban. Antidepressants: increased risk of bleeding with SSRIs or venlafaxine. Antidiabetics: effects of sulphonylureas enhanced. Antiepileptics: possibly enhanced effect of phenytoin. Antivirals: concentration possibly increased by ritonavir; increased risk of haematological toxicity with zidovudine. Ciclosporin: may potentiate nephrotoxicity. Cytotoxics: reduced excretion of methotrexate; increased risk of bleeding with erlotinib. Diuretics: increased risk of nephrotoxicity; antagonism of diuretic effect; hyperkalaemia with potassium-sparing diuretics. Lithium: excretion reduced (risk of lithium toxicity). Pentoxifylline: increased risk of bleeding. Tacrolimus: increased risk of nephrotoxicity

Metabolism

Flurbiprofen is metabolised mainly by hydroxylation (via the cytochrome P450 isoenzyme CYP2C9) and conjugation in the liver and excreted in the urine. The rate of urinary excretion of flurbiprofen and its two major metabolites ([2-(2-fluoro-4′-hydroxy-4-biphenylyl) propionic acid] and [2-(2-fluoro-3′-hydroxy-4′-methoxy-4-biphenylyl) propionic acid]) in both free and conjugated states is similar for both the oral and rectal routes of administration.

Check Digit Verification of cas no

The CAS Registry Mumber 5104-49-4 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 5,1,0 and 4 respectively; the second part has 2 digits, 4 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 5104-49:
(6*5)+(5*1)+(4*0)+(3*4)+(2*4)+(1*9)=64
64 % 10 = 4
So 5104-49-4 is a valid CAS Registry Number.
InChI:InChI=1/C12H4F14/c13-7(9(15,16)17,10(18,19)20)5-1-2-6(4-3-5)8(14,11(21,22)23)12(24,25)26/h1-4H

5104-49-4 Well-known Company Product Price

  • Brand
  • (Code)Product description
  • CAS number
  • Packaging
  • Price
  • Detail
  • TCI America

  • (F0371)  Flurbiprofen  >98.0%(T)(HPLC)

  • 5104-49-4

  • 5g

  • 890.00CNY

  • Detail
  • TCI America

  • (F0371)  Flurbiprofen  >98.0%(T)(HPLC)

  • 5104-49-4

  • 25g

  • 2,750.00CNY

  • Detail
  • Alfa Aesar

  • (B22603)  2-Fluoro-alpha-methyl-4-biphenylacetic acid, 99%   

  • 5104-49-4

  • 1g

  • 608.0CNY

  • Detail
  • Alfa Aesar

  • (B22603)  2-Fluoro-alpha-methyl-4-biphenylacetic acid, 99%   

  • 5104-49-4

  • 5g

  • 2260.0CNY

  • Detail
  • Alfa Aesar

  • (B22603)  2-Fluoro-alpha-methyl-4-biphenylacetic acid, 99%   

  • 5104-49-4

  • 25g

  • 8311.0CNY

  • Detail
  • Sigma-Aldrich

  • (PHR1499)  Flurbiprofen  pharmaceutical secondary standard; traceable to USP, PhEur

  • 5104-49-4

  • PHR1499-500MG

  • 934.95CNY

  • Detail
  • Sigma-Aldrich

  • (F0285200)  Flurbiprofen  European Pharmacopoeia (EP) Reference Standard

  • 5104-49-4

  • F0285200

  • 1,880.19CNY

  • Detail
  • USP

  • (1285750)  Flurbiprofen  United States Pharmacopeia (USP) Reference Standard

  • 5104-49-4

  • 1285750-200MG

  • 4,326.66CNY

  • Detail

5104-49-4Synthetic route

methyl 2-(2-fluoro-4-biphenylyl)propionate
113544-38-0, 113544-39-1, 114376-61-3, 66202-86-6

methyl 2-(2-fluoro-4-biphenylyl)propionate

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
With sulfuric acid; water In 1,4-dioxane at 120℃; for 4h; Inert atmosphere;99%
With potassium hydroxide In ethanol75%
With sodium hydroxide
C12H16FNO5S
1201594-47-9

C12H16FNO5S

phenylboronic acid
98-80-6

phenylboronic acid

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
Stage #1: C12H16FNO5S; phenylboronic acid With potassium phosphate; bis(tricyclohexylphosphine)nickel(II) dichloride In toluene at 130℃; for 24h; Suzuki-Miyaura coupling reaction; Inert atmosphere;
Stage #2: With sulfuric acid In 1,4-dioxane; water at 100℃; for 6h;
99%
α-methyl-(2-fluoro-4-biphenylyl)acetonitrile
74648-00-3

α-methyl-(2-fluoro-4-biphenylyl)acetonitrile

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
With sodium hydroxide In ethanol; water at 110℃; for 5h;99%
With sodium hydroxide In ethanol; water at 110℃; for 7h; Inert atmosphere;84%
Stage #1: α-methyl-(2-fluoro-4-biphenylyl)acetonitrile With sodium hydroxide In ethanol; water for 5h; Inert atmosphere; Reflux;
Stage #2: With sulfuric acid In ethanol; water at 20℃; Inert atmosphere;
82%
With sulfuric acid In water at 100℃; for 3h;
3-(2-fluorobiphenyl-4-yl)butan-2-one
72625-13-9

3-(2-fluorobiphenyl-4-yl)butan-2-one

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
With sodium hypochlorite at 70℃; for 0.25h;95%
4-bromo-3-fluoro α-methylphenylacetic acid

4-bromo-3-fluoro α-methylphenylacetic acid

phenylboronic acid
98-80-6

phenylboronic acid

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
With palladium on activated charcoal; sodium carbonate In water for 6h; Reflux;94.98%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In ethanol; water; toluene for 6h; Concentration; Reagent/catalyst; Suzuki Coupling; Inert atmosphere; Reflux;81.7 g
2-(2-fluoro-[1,1'-biphenyl]-4-yl)acetic acid
5001-96-7

2-(2-fluoro-[1,1'-biphenyl]-4-yl)acetic acid

methyl iodide
74-88-4

methyl iodide

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
Stage #1: 2-(2-fluoro-[1,1'-biphenyl]-4-yl)acetic acid With lithium hexamethyldisilazane In tetrahydrofuran at 20℃; for 0.333333h; Inert atmosphere;
Stage #2: methyl iodide In tetrahydrofuran at 20℃; for 0.333333h; Inert atmosphere;
77%
With potassium tert-butylate; lithium diisopropyl amide 1.) THF, hexane, -25 deg C, 2 h; Yield given; Multistep reaction;
Stage #1: 2-(2-fluoro-[1,1'-biphenyl]-4-yl)acetic acid With n-butyllithium In tetrahydrofuran; hexanes at 0℃; for 0.166667h; Inert atmosphere;
Stage #2: methyl iodide In tetrahydrofuran; hexanes Inert atmosphere;
carbon dioxide
124-38-9

carbon dioxide

1-ethyl-3-fluoro-4-phenylbenzene
55258-76-9

1-ethyl-3-fluoro-4-phenylbenzene

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; triisopropylsilanethiol In N,N-dimethyl-formamide at 0℃; under 3040.2 Torr; for 24h; Irradiation; Sealed tube;76%
2-Fluoro-4-((E)-1-methyl-but-2-enyl)-biphenyl

2-Fluoro-4-((E)-1-methyl-but-2-enyl)-biphenyl

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
With ozone In acetone at -78℃;75%
ethyl 2-(2-fluoro-4-biphenylyl)-propionate
64858-90-8

ethyl 2-(2-fluoro-4-biphenylyl)-propionate

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
Stage #1: ethyl 2-(2-fluoro-4-biphenylyl)-propionate With water; sodium hydroxide at 95℃; for 3h;
Stage #2: In ethyl acetate; Petroleum ether at 65℃;
72.2%
With sodium hydroxide Reflux;
With lithium hydroxide In tetrahydrofuran; water at 20℃;93.9 mg
trimethylborane
593-90-8

trimethylborane

1-bromo-3-fluoro-4-phenylbenzene
41604-19-7

1-bromo-3-fluoro-4-phenylbenzene

Ethyl oxalyl chloride
4755-77-5

Ethyl oxalyl chloride

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
Stage #1: 1-bromo-3-fluoro-4-phenylbenzene With magnesium
Stage #2: Ethyl oxalyl chloride
Stage #3: trimethylborane Further stages;
67%
C12H16FNO5S
1201594-47-9

C12H16FNO5S

phenylboronic acid
98-80-6

phenylboronic acid

A

fluorobiprofen
5104-49-4

fluorobiprofen

B

methyl 2-(2-fluoro-4-biphenylyl)propionate
113544-38-0, 113544-39-1, 114376-61-3, 66202-86-6

methyl 2-(2-fluoro-4-biphenylyl)propionate

Conditions
ConditionsYield
With potassium phosphate; bis(tricyclohexylphosphine)nickel(II) dichloride In toluene at 130℃; for 24h; Suzuki-Miyaura coupling reaction; Inert atmosphere;A 29%
B 56%
carbon dioxide
124-38-9

carbon dioxide

4-ethenyl-2-fluorobiphenyl
63444-55-3

4-ethenyl-2-fluorobiphenyl

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
Stage #1: carbon dioxide; 4-ethenyl-2-fluorobiphenyl With diethylzinc In N,N-dimethyl acetamide; toluene at 20 - 80℃; for 24h; Inert atmosphere; Sealed tube;
Stage #2: diazomethane
55%
carbon dioxide
124-38-9

carbon dioxide

C20H24BFO2

C20H24BFO2

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
With copper(l) iodide; cesium fluoride; sodium t-butanolate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride In 2-methyltetrahydrofuran at 120℃; for 24h; Sealed tube;53%
Stage #1: carbon dioxide; C20H24BFO2 With potassium tert-butylate In tetrahydrofuran; toluene at -78 - 20℃; under 760.051 Torr; for 3h;
Stage #2: With hydrogenchloride In tetrahydrofuran; water; toluene
diester of flurbiprofen

diester of flurbiprofen

pentaethylene glycol
2615-15-8

pentaethylene glycol

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
In acetone; benzene38.5%
diethyl 2-(2-fluorobiphenyl-4-yl)-2-methylmalonate
42771-81-3

diethyl 2-(2-fluorobiphenyl-4-yl)-2-methylmalonate

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
With sodium hydroxide In ethanol; water for 6h; Reflux;34%
Multi-step reaction with 2 steps
1.1: sodium hydroxide / ethanol / 6 h / 20 °C / Inert atmosphere; Schlenk technique
1.2: Inert atmosphere; Schlenk technique
2.1: Escherichia coli arylmalonate decarboxylase; tris hydrochloride / 1 h / 30 °C / pH 8.5 / Inert atmosphere; Schlenk technique
View Scheme
diphenyl N-<2-(2-fluoro-4-biphenylyl)-1-pyrrolidinopropylidene>phosphoramidate
71574-83-9

diphenyl N-<2-(2-fluoro-4-biphenylyl)-1-pyrrolidinopropylidene>phosphoramidate

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
With potassium hydroxide In ethylene glycol for 8h; Heating;30%
diester of flurbiprofen

diester of flurbiprofen

Tetraethylene glycol
112-60-7

Tetraethylene glycol

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
In acetone; benzene30%
Sodium; 2-(2-fluoro-biphenyl-4-yl)-1-oxo-propane-1-sulfonate

Sodium; 2-(2-fluoro-biphenyl-4-yl)-1-oxo-propane-1-sulfonate

fluorobiprofen
5104-49-4

fluorobiprofen

Conditions
ConditionsYield
With potassium carbonate In water Yield given;
complex of flurbiprofen with β-cyclodextrin (1:1)

complex of flurbiprofen with β-cyclodextrin (1:1)

A

fluorobiprofen
5104-49-4

fluorobiprofen

B

β‐cyclodextrin
7585-39-9

β‐cyclodextrin

Conditions
ConditionsYield
at 15℃; Thermodynamic data; Equilibrium constant; ΔG298, ΔH, ΔS298; stability constant; dissolution rate; other temperatures;
Conditions
ConditionsYield
Stage #1: fluorobiprofen With (S)-1-phenyl-ethylamine In methanol; toluene at 20 - 60℃; for 0.166667h;
Stage #2: In methanol; toluene at 0 - 5℃; for 1h;
85.2%
Stage #1: fluorobiprofen With (S)-1-phenyl-ethylamine In toluene at 60℃; for 0.5h;
Stage #2: With ammonium hydroxide In ethyl acetate for 0.166667h;
66%
Multi-step reaction with 4 steps
1.1: 99 percent / H2SO4 / 3 h / Heating
2.1: diisopropylamine; n-BuLi / tetrahydrofuran; hexane / 0.83 h / -78 °C
2.2: 90 percent / hexane; tetrahydrofuran / 2 h / 0 °C
3.1: 85 percent / KOH / H2O; ethanol / 1 h / 0 °C
4.1: Tris-HCl buffer; arylmalonate decarboxylaze EC 4.1.1.76 / H2O; ethanol / 0.67 h / 30 °C / pH 8.0
View Scheme
fluorobiprofen
5104-49-4

fluorobiprofen

2-(2-fluoro-biphenyl-4-yl)-propan-1-ol
64858-91-9

2-(2-fluoro-biphenyl-4-yl)-propan-1-ol

Conditions
ConditionsYield
Stage #1: fluorobiprofen With triethanolamine; isobutyl chloroformate In tetrahydrofuran for 1h;
Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at -20 - 0℃; for 2.25h;
95%
Multi-step reaction with 2 steps
1: 94 percent / SOCl2 / 6 h / Heating
2: 78 percent / LAH / diethyl ether / 8 h / Heating
View Scheme
With dimethylsulfide borane complex
fluorobiprofen
5104-49-4

fluorobiprofen

α-Methyl-3-fluoro-4-phenylbenzeneacetyl chloride
137361-33-2, 56430-63-8

α-Methyl-3-fluoro-4-phenylbenzeneacetyl chloride

Conditions
ConditionsYield
With thionyl chloride In DMF (N,N-dimethyl-formamide); 1,2-dichloro-ethane Heating / reflux;100%
With oxalyl dichloride In benzene for 3h; Heating;
With phosphorus pentachloride In tetrachloromethane at 40℃; for 0.5h;
fluorobiprofen
5104-49-4

fluorobiprofen

2-(2-fluoro-[1,1′-biphenyl]-4-yl)propanehydrazide
190124-72-2

2-(2-fluoro-[1,1′-biphenyl]-4-yl)propanehydrazide

Conditions
ConditionsYield
Stage #1: fluorobiprofen With hydrazine hydrate; 1,1'-carbonyldiimidazole In tetrahydrofuran for 0.166667h;
Stage #2: With hydrazine hydrate In tetrahydrofuran for 4h; Reflux;
89%
Multi-step reaction with 2 steps
1: sulfuric acid / 3 h / Reflux
2: hydrazine hydrate / ethanol / 2 h / Reflux
View Scheme
Multi-step reaction with 2 steps
1: sulfuric acid / 0.25 h / Reflux; Microwave irradiation
2: hydrazine hydrate / ethanol / Reflux; Microwave irradiation
View Scheme
Multi-step reaction with 2 steps
1: sulfuric acid / 6 h / Reflux
2: hydrazine hydrate / ethanol / 8 h / Reflux
View Scheme
Multi-step reaction with 2 steps
1: sulfuric acid / 3 h / Reflux
2: hydrazine hydrate / 2 h / Reflux
View Scheme
methanol
67-56-1

methanol

fluorobiprofen
5104-49-4

fluorobiprofen

methyl 2-(2-fluoro-4-biphenylyl)propionate
113544-38-0, 113544-39-1, 114376-61-3, 66202-86-6

methyl 2-(2-fluoro-4-biphenylyl)propionate

Conditions
ConditionsYield
With sulfuric acid for 3h; Heating;99%
With sulfuric acid for 0.25h; Reflux; Microwave irradiation;98.8%
With sulfuric acid for 3h; Reflux;95%
fluorobiprofen
5104-49-4

fluorobiprofen

1,2:3,4-di-O-isopropylidene-α-D-galactopyranose
4064-06-6

1,2:3,4-di-O-isopropylidene-α-D-galactopyranose

diacetone 6'-O-flurbiprofen-D-galactopyranoside
1207167-00-7

diacetone 6'-O-flurbiprofen-D-galactopyranoside

Conditions
ConditionsYield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap In dichloromethane at 20℃; for 12h;61%
fluorobiprofen
5104-49-4

fluorobiprofen

2-selenocyanatopropanamine hydrobromide

2-selenocyanatopropanamine hydrobromide

2-(2-fluorobiphenyl-4-yl)-N-(3-selenocyanatopropyl)propanamide

2-(2-fluorobiphenyl-4-yl)-N-(3-selenocyanatopropyl)propanamide

Conditions
ConditionsYield
Stage #1: fluorobiprofen With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane; N,N-dimethyl-formamide at 25℃; for 0.5h;
Stage #2: 2-selenocyanatopropanamine hydrobromide In dichloromethane; N,N-dimethyl-formamide at 25℃; for 16h;
65%
Stage #1: fluorobiprofen With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane; N,N-dimethyl-formamide at 25℃; for 0.5h; Inert atmosphere;
Stage #2: 2-selenocyanatopropanamine hydrobromide In dichloromethane; N,N-dimethyl-formamide at 25℃; for 16h; Inert atmosphere;
62%
Stage #1: fluorobiprofen With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane; N,N-dimethyl-formamide at 25℃; for 0.5h;
Stage #2: 2-selenocyanatopropanamine hydrobromide In dichloromethane; N,N-dimethyl-formamide at 25℃; for 16h;
fluorobiprofen
5104-49-4

fluorobiprofen

sodium 2-(2-fluoro-4-biphenylyl)propionate dihydrate

sodium 2-(2-fluoro-4-biphenylyl)propionate dihydrate

Conditions
ConditionsYield
Stage #1: fluorobiprofen With ascorbic acid In ethanol; water at 70 - 75℃; Large scale;
Stage #2: With sodium hydroxide In ethanol; water for 1.5h; Large scale;
95.7%
fluorobiprofen
5104-49-4

fluorobiprofen

flurbiprofen sodium

flurbiprofen sodium

Conditions
ConditionsYield
With sodium methylate In methanol at 65℃; for 1.5h; Large scale;94.8%
3-methylpyridin-2-ylamine
1603-40-3

3-methylpyridin-2-ylamine

fluorobiprofen
5104-49-4

fluorobiprofen

2-(2-fluoro-(1,1'-biphenyl)-4-yl)-N-(3-methylpyridin-2-yl)propanamide

2-(2-fluoro-(1,1'-biphenyl)-4-yl)-N-(3-methylpyridin-2-yl)propanamide

Conditions
ConditionsYield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 20℃; for 24h;91%
fluorobiprofen
5104-49-4

fluorobiprofen

tert-butyl (2,2-difluoro-3-hydroxypropyl)carbamate

tert-butyl (2,2-difluoro-3-hydroxypropyl)carbamate

C23H26F3NO4

C23H26F3NO4

Conditions
ConditionsYield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 5h;100%
Phenylselenyl chloride
5707-04-0

Phenylselenyl chloride

fluorobiprofen
5104-49-4

fluorobiprofen

C21H17FOSe

C21H17FOSe

Conditions
ConditionsYield
With tributylphosphine In dichloromethane at -15℃; for 3h; Inert atmosphere;73%
With tributylphosphine In dichloromethane at -15℃; for 3h; Inert atmosphere;73%
fluorobiprofen

fluorobiprofen

(S)-4-(3-aminoazepan-1-yl)coumarin

(S)-4-(3-aminoazepan-1-yl)coumarin

C30H29FN2O3

C30H29FN2O3

fluorobiprofen
5104-49-4

fluorobiprofen

dichlorodihydroxydiamineplatinum

dichlorodihydroxydiamineplatinum

cisplatin flurbiprofen

cisplatin flurbiprofen

Conditions
ConditionsYield
Stage #1: fluorobiprofen With oxalyl dichloride at 70℃; for 1h; Inert atmosphere;
Stage #2: dichlorodihydroxydiamineplatinum In tetrahydrofuran at 70℃; for 2h; Temperature; Darkness;
92.3%
N-tert-butoxycarbonyl-3-aminopropanol
58885-58-8

N-tert-butoxycarbonyl-3-aminopropanol

fluorobiprofen
5104-49-4

fluorobiprofen

Boc-aminopropanol-flurbiprofen

Boc-aminopropanol-flurbiprofen

Conditions
ConditionsYield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Cooling with ice;94%
fluorobiprofen
5104-49-4

fluorobiprofen

acetyl chloride
75-36-5

acetyl chloride

2-(4′-acetyl-2-fluoro-[1,1′-biphenyl]-4-yl)propanoic acid

2-(4′-acetyl-2-fluoro-[1,1′-biphenyl]-4-yl)propanoic acid

Conditions
ConditionsYield
Stage #1: acetyl chloride With aluminum (III) chloride In dichloromethane at 0℃; for 0.5h; Friedel-Crafts Acylation;
Stage #2: fluorobiprofen In dichloromethane at 20℃; for 3h; Friedel-Crafts Acylation;
64.1%
Conditions
ConditionsYield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;55%
fluorobiprofen
5104-49-4

fluorobiprofen

methyl 2-(4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl)acetate

methyl 2-(4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl)acetate

methyl 2-(4-(3-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propanamido)phenyl)-1H-1,2,3-triazol-1-yl)acetate

methyl 2-(4-(3-(2-(2-fluoro-[1,1'-biphenyl]-4-yl)propanamido)phenyl)-1H-1,2,3-triazol-1-yl)acetate

Conditions
ConditionsYield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 40℃; Inert atmosphere; Sealed tube;84%
4-hydroxybenzenesulphonamide
1576-43-8

4-hydroxybenzenesulphonamide

fluorobiprofen
5104-49-4

fluorobiprofen

2-(2-fluorobiphen-4-yl)-N-(4-hydroxyphenylsulfonyl)propionamide

2-(2-fluorobiphen-4-yl)-N-(4-hydroxyphenylsulfonyl)propionamide

Conditions
ConditionsYield
Stage #1: fluorobiprofen With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 5℃; for 2h;
Stage #2: 4-hydroxybenzenesulphonamide With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 20℃; for 6h;
79%
2-Methanesulfonyl-ethylamine
49773-20-8

2-Methanesulfonyl-ethylamine

fluorobiprofen
5104-49-4

fluorobiprofen

2-(2-fluorobiphen-4-yl)-N-(2-methylsulfonylethyl)propanamide

2-(2-fluorobiphen-4-yl)-N-(2-methylsulfonylethyl)propanamide

Conditions
ConditionsYield
Stage #1: fluorobiprofen With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 5℃; for 2h;
Stage #2: 2-Methanesulfonyl-ethylamine In dichloromethane
77%
benzenesulfonamide
98-10-2

benzenesulfonamide

fluorobiprofen
5104-49-4

fluorobiprofen

2-(2-fluorobiphen-4-yl)-N-(phenylsulfonyl)propionamide

2-(2-fluorobiphen-4-yl)-N-(phenylsulfonyl)propionamide

Conditions
ConditionsYield
Stage #1: fluorobiprofen With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 5℃; for 2h;
Stage #2: benzenesulfonamide With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 20℃; for 6h;
79%
fluorobiprofen
5104-49-4

fluorobiprofen

(S)-4-(3-aminopyrrolidin-1-yl)coumarin

(S)-4-(3-aminopyrrolidin-1-yl)coumarin

C28H25FN2O3

C28H25FN2O3

Conditions
ConditionsYield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.5h;83%
fluorobiprofen
5104-49-4

fluorobiprofen

2-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)-3H-benzocoumarin-3-one

2-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)-3H-benzocoumarin-3-one

2-methoxy-4-(3-oxo-3-(3-oxo-3H-benzocoumarin-2-yl)prop-1-en-1-yl)phenyl 2-(2-fluoro[1,1′-biphenyl]-4-yl)propanoate

2-methoxy-4-(3-oxo-3-(3-oxo-3H-benzocoumarin-2-yl)prop-1-en-1-yl)phenyl 2-(2-fluoro[1,1′-biphenyl]-4-yl)propanoate

Conditions
ConditionsYield
With dmap; triethylamine; trichlorophosphate In dichloromethane at 20℃;80%
fluorobiprofen
5104-49-4

fluorobiprofen

(S)-4-(3-minopiperidin-1-yl)coumarin

(S)-4-(3-minopiperidin-1-yl)coumarin

C29H27FN2O3

C29H27FN2O3

Conditions
ConditionsYield
With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.5h;72%

5104-49-4Relevant articles and documents

Biotransformation with whole microbial systems in a continuous flow reactor: Resolution of (RS)-flurbiprofen using Aspergillus oryzae by direct esterification with ethanol in organic solvent

Tamborini, Lucia,Romano, Diego,Pinto, Andrea,Contente, Martina,Iannuzzi, Maria C.,Conti, Paola,Molinari, Francesco

, p. 6090 - 6093 (2013)

Cell-bound lipases of dry mycelium of Aspergillus oryzae were used in organic solvent for the resolution of racemic flurbiprofen by direct esterification with ethanol in a flow-chemistry reactor. Under flow conditions a significant reduction of the reaction time and an increase of the enantioselectivity were achieved compared to the batch mode. Moreover, the process was implemented by adding an in-line purification step integrated with the racemization of the unreacted flurbiprofen directly into a polymer-supported resin.

Method for determination of optical purity of 2-arylpropanoic acids using urea derivatives based on a 1,1′-binaphthalene skeleton as chiral NMR solvating agents: Advantages and limitations thereof

Cu?ínová, Petra,Hájek, Peter,Jank?, Kristyna,Holakovsky, Roman

, p. 410 - 417 (2019)

Five optically active urea derivatives (1-5) were used as NMR solvating agents for analysis of the optical purity of different 2-arylpropanoic acids commonly used as nonsteroidal anti-inflammatory drugs. These novel chiral solvating agents were more efficient at discriminating the respective enantiomers of targets than the chiral solvating agents known so far, without the need to add a base for achieving the signal splitting. The advantages and limits of the use of these novel chiral solvating agents were studied.

Direct enantioselective HPLC monitoring of lipase-catalyzed kinetic resolution of flurbiprofen

Ghanem, Ashraf

, p. 597 - 603 (2010)

The solvent versatility of Chiralpak IB, a 3,5-dimethylphenylcarbamate derivative of cellulose-based chiral stationary phase, is demonstrated in the direct enantioselective HPLC monitoring of lipase-catalyzed kinetic resolution of flurbiprofen in nonstandard HPLC organic solvents. Nonstandard HPLC organic solvents were used as the reaction media for the lipase-catalysis and in mean time as diluent to dissolve the difficult to dissolve enzyme substrate (the acid) and as eluent for the simultaneous enantioselective HPLC baseline separation of both substrate and product in one run without any further derivatization.

A Highly Enantioselective Alkene Methoxycarbonylation Enables a Concise Synthesis of (S)-Flurbiprofen

Harkness, Gavin J.,Clarke, Matthew L.

, p. 4859 - 4863 (2017)

A highly enantioselective synthesis of (S)-flurbiprofen methyl ester in two steps from commercially available 4-bromo-2-fluoro-1,1′-biphenyl is shown. [PdCl2((S)-xylyl-phanephos)] catalyst is used to accomplish both Grignard cross-coupling and the highly enantioselective intermolecular methoxycarbonylation reaction.

Different in vitro activity of flurbiprofen and its enantiomers on human articular cartilage

Panico,Cardile,Vittorio,Ronsisvalle,Scoto,Parenti,Gentile,Morrone,Nicolosi

, p. 1339 - 1344 (2003)

The 2-arylpropionic acid derivatives or 'profens' are an important group of non-steroidal anti-inflammatory drugs that have been used for the symptomatic treatment of various forms of arthritis. These compounds are chiral and the majority of them are stil

An efficient method for the synthesis of (S)-flurbiprofen by 1,2-rearrangement of the aryl group

Chen, Hua,Dai, Yuhao,Liu, Yu,Luo, Kaihong,Zhang, Yi

, (2022/03/15)

(S)-Flurbiprofen (1) is a nonsteroidal anti-inflammatory drug (NSAID) used to relieve pain and inflammation associated with osteoarthritis. Herein a new and practical method for the preparation of 1 from 4-bromo-2-fluorobiphenyl (2) is reported, which achieves a good overall yield (20%) and high enantioselectivity (96%). This method avoids the use of expensive catalysts and affords the possibility of large-scale manufacturing with simple operations.

Enantioselective Synthesis of Chiral Carboxylic Acids from Alkynes and Formic Acid by Nickel-Catalyzed Cascade Reactions: Facile Synthesis of Profens

Fu, Kaiyue,Ma, Yu,Sun, Yaxin,Tang, Bo,Yang, Guang,Yang, Peng,Yue, Jieyu,Zhang, Li,Zhou, Jianrong Steve

supporting information, (2021/11/22)

We report a stereoselective conversion of terminal alkynes to α-chiral carboxylic acids using a nickel-catalyzed domino hydrocarboxylation-transfer hydrogenation reaction. A simple nickel/BenzP* catalyst displayed high activity in both steps of regioselective hydrocarboxylation of alkynes and subsequent asymmetric transfer hydrogenation. The reaction was successfully applied in enantioselective preparation of three nonsteroidal anti-inflammatory profens (>90 % ees) and the chiral fragment of AZD2716.

Preparation method of flurbiprofen

-

Paragraph 0064; 0076-0077, (2021/05/12)

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of flurbiprofen, which comprises the following steps: carrying out Sonogashira coupling reaction on 4-bromo-2-fluorobiphenyl and trimethylsilylacetylene under the catalysis of palladium to obtain 4-trimethylsilylethynyl-2-fluorobiphenyl, removing trimethylsilyl from the product in an alkaline solution without separation, so as to obtain 4-ethynyl-2-fluorobiphenyl; and then taking a complex formed by nickel and a phosphine ligand in situ as a catalyst, taking formic acid as a carboxylation and hydrogenation reagent, carrying out hydrocarboxylation-hydrogenation cascade reaction on the 4-ethynyl-2-fluorobiphenyl, and conducting purifying to obtain flurbiprofen. The method has the advantages of easily available raw material sources, short route, simple operation, mild reaction conditions and high yield. According to the present invention, ethynyl is directly converted into a propionic acid group through the efficient one-pot cascade reaction, and the racemic flurbiprofen, the levorotatory flurbiprofen and the dextrorotatory flurbiprofen can be synthesized only by changing the phosphine ligand type, such that the preparation of the optical pure flurbiprofen through the tedious and low-efficiency splitting of the racemic flurbiprofen is avoided.

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