112344-52-2

Usage

InChI:InChI=1/C17H14F2O3/c1-10(17(21)22)8-16(20)12-4-2-11(3-5-12)14-7-6-13(18)9-15(14)19/h2-7,9-10H,8H2,1H3,(H,21,22)

Synthetic route

4-(2',4'-difluorobiphenyl-4-yl)-2-methylene-4-oxobutanoic acid (161692-81-5) → 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2)

Conditions	Yield
With hydrogen; palladium on activated charcoal In 1,4-dioxane at 20℃; under 3750.3 Torr;	74%

2,4-difluorobiphenyl (37847-52-2) + 2-methylsuccinic anhydride (4100-80-5) → 4-(2',4'-difluorobiphenyl-4-yl)-3-methyl-4-oxobutanoic acid + 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2)

Conditions	Yield
With aluminium trichloride In 1,2-dichloro-ethane 1) 10 degC, 4 h, 2) 20 degC, 16 h;	A n/a B 40.2%

2-methylenesuccinic acid (97-65-4) + potassium bromide → 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 92 percent / Ac2O / 4 h / 80 °C 2: 63 percent / AlCl3 / CH2Cl2 / 1.) 10 deg C, 4 h, 2.) 20 deg C, 2 h 3: 74 percent / H2 / Pd/C / dioxane / 20 °C / 3750.3 Torr View Scheme

itaconic acid anhydride (2170-03-8) → 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 63 percent / AlCl3 / CH2Cl2 / 1.) 10 deg C, 4 h, 2.) 20 deg C, 2 h 2: 74 percent / H2 / Pd/C / dioxane / 20 °C / 3750.3 Torr View Scheme

(R)-1-phenyl-ethyl-amine (3886-69-9) + 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) → 4-(2',4'-Difluoro-biphenyl-4-yl)-2-methyl-4-oxo-butyric acid; compound with (R)-1-phenyl-ethylamine

Conditions	Yield
In diethyl ether; acetone for 1h;	97%

L-lysine (56-87-1) + 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) → (+/-)-4-(2',4'-fifluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid L-(+)-lysine salt

Conditions	Yield
In water; dimethyl sulfoxide	95%

2-methyl-propan-1-ol (78-83-1) + 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) → 4-(2',4'-Difluoro-biphenyl-4-yl)-2-methyl-4-oxo-butyric acid isobutyl ester

Conditions	Yield
With thionyl chloride 1.) -15 deg C, 30 min, 2.) 40-45 deg C, 2 h;	91%

4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) → 4-(2',4'-difluorobipenyl-4-yl)-2-methylbutyric acid (847475-35-8)

Conditions	Yield
With hydrogen; palladium on activated charcoal In water; acetic acid at 60℃; for 5h;	87%

4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) + cyclohexylamine (108-91-8) → 4-(2',4'-Difluoro-biphenyl-4-yl)-2-methyl-4-oxo-butyric acid; compound with cyclohexylamine

Conditions	Yield
In diethyl ether; acetone for 1h;	86%

4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) + benzylamine (100-46-9) → 4-(2',4'-Difluoro-biphenyl-4-yl)-2-methyl-4-oxo-butyric acid; compound with benzylamine

Conditions	Yield
In water; dimethyl sulfoxide	72%

ethanol (64-17-5) + 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) → 4-(2',4'-Difluoro-biphenyl-4-yl)-2-methyl-4-oxo-butyric acid ethyl ester

Conditions	Yield
With thionyl chloride 1.) -15 deg C, 30 min, 2.) 40-45 deg C, 2 h;	69%

4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) → (+/-)-4-(2',4'-difluorobiphenyl-4-yl)-4-hydroxy-2-methylbutanoic lactone

Conditions	Yield
With potassium hydroxide; sodium tetrahydroborate In water 1) 34-40 deg C, 3 h; 2) 20 deg C, 20 h;	58%

(R)-1-phenyl-ethyl-amine (3886-69-9) + 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) → (R)-(+)-flobufen (R)-(+)-1-phenylethylammonium salt

Conditions	Yield
In diethyl ether at 20℃;	56%

(S)-1-phenyl-ethylamine (2627-86-3) + 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) → (S)-(-)-flobufen (S)-(-)-1-phenylethylammonium salt

Conditions	Yield
In diethyl ether at 20℃;	55%

morpholine (110-91-8) + 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) → 4-(2',4'-Difluoro-biphenyl-4-yl)-2-methyl-1-morpholin-4-yl-butane-1,4-dione

Conditions	Yield
With 1-ethyl-piperidine; chloroformic acid ethyl ester 1.) DMF, CH2Cl2, 30 min, 2.) 20 deh C, 2 h; Yield given. Multistep reaction;

(R)-1-phenyl-ethyl-amine (3886-69-9) + 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) → 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid R-(+)-1-phenylethylamide

Conditions	Yield
With 1-ethyl-piperidine; chloroformic acid ethyl ester 1.) DMF, CH2Cl2, 30 min, 2.) 20 deh C, 2 h; Yield given. Multistep reaction;

4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) + ethylamine (75-04-7) → 4-(2',4'-Difluoro-biphenyl-4-yl)-N-ethyl-2-methyl-4-oxo-butyramide

Conditions	Yield
With 1-ethyl-piperidine; chloroformic acid ethyl ester 1.) DMF, CH2Cl2, 30 min, 2.) 20 deh C, 2 h; Yield given. Multistep reaction;

4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) + N-butylamine (109-73-9) → N-Butyl-4-(2',4'-difluoro-biphenyl-4-yl)-2-methyl-4-oxo-butyramide

Conditions	Yield
With 1-ethyl-piperidine; chloroformic acid ethyl ester 1.) DMF, CH2Cl2, 30 min, 2.) 20 deh C, 2 h; Yield given. Multistep reaction;

4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) + GlyOEt*HCl (459-73-4) → [4-(2',4'-Difluoro-biphenyl-4-yl)-2-methyl-4-oxo-butyrylamino]-acetic acid ethyl ester

Conditions	Yield
With 1-ethyl-piperidine; chloroformic acid ethyl ester 1.) DMF, CH2Cl2, 30 min, 2.) 20 deh C, 2 h; Yield given. Multistep reaction;

4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (112344-52-2) + benzylamine (100-46-9) → N-Benzyl-4-(2',4'-difluoro-biphenyl-4-yl)-2-methyl-4-oxo-butyramide

Conditions	Yield
With 1-ethyl-piperidine; chloroformic acid ethyl ester 1.) DMF, CH2Cl2, 30 min, 2.) 20 deh C, 2 h; Yield given. Multistep reaction;

Upstream product

• 2170-03-8 itaconic acid anhydride 
• 97-65-4 2-methylenesuccinic acid 
• 161692-81-5 4-(2',4'-difluorobiphenyl-4-yl)-2-methylene-4-oxobutanoic acid 
• 37847-52-2 2,4-difluorobiphenyl 
• 4100-80-5 2-methylsuccinic anhydride 

Related news

Metabolic pathways of flobufen (cas 112344-52-2) — a new antirheumatic and antiarthritic drug. Interspecies comparison07/22/2019

SummaryMetabolic transformations of flobufen, [4-(2′,4′-difluorobiphenyl-4-yl)-4-oxo-2-methylbutanoic acid], a non-steroid antiinflammatory agent, were studied in vitro using the following biological models and species: rat and mouse liver homogenates and liver subcellular fractions (5 000 g a...detailed

Structural study of flobufen (cas 112344-52-2) II. An unexpected role of packing effects on the dihedral angle of phenyl rings in crystal structures of 2,4-difluorobiphenyls07/20/2019

The absolute structure of the (R)-(+)-1-phenylethylammonium salt of (R)-(+)-flobufen (4-(2′,4′-difluorobiphenyl-4-yl)-2-methyl-4oxobutanoic acid) was determined by a single-crystal X-ray study. Comparison of the structure of this flobufen salt with those of flobufen and dehydroflobufen (4-(2′...detailed

Liquid chromatographic–electrospray mass spectrometric determination (LC–ESI-MS) of phase II metabolites of flobufen (cas 112344-52-2) in rat liver microsomes—Chiral discrimination07/19/2019

Glucuronidation of the non-steroidal anti-inflammatory chiral drug flobufen and its major metabolite M17203 has been implicated as an important mechanism of flobufen elimination. To characterize flobufen metabolism by O-glucuronidation, new liquid chromatographic method (LC) coupled with ESI-MS ...detailed

Relevant academic research and scientific papers

4-(2',4'-DIFLUOROBIPHENYL-4-YL)-2-METHYL-4-OXOBUTANOIC ACID AND ITS DERIVATIVES

Friedel-Crafts reaction of itaconic anhydride (III) with 2,4-difluorobiphenyl (II) afforded unsaturated acid IV which was hydrogenated to give 4-(2',4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acod (I).A series of functional derivatives and salts of the acid I has been prepared.The antiinflammatory effect of these compounds was compared with that of acid I using selected experimental inflammation models.The analgesic activity in the intraperitoneal iritation test was also evaluated.In the case of (R)-(+)-1-phenylethylamide Vf the ratio of the diastereisomers was determined by HPLC.

QUANTITATIVE RELATIONS BETWEEN STRUCTURE AND ANTIINFLAMMATORY ACTIVITY OF ARYLOXOALKANOIC ACIDS

The antiinflammatory effect of a series of aryloxoalkanoic acids II and of their biphenyl derivatives III was examined by measuring the inhibition of the development of carageenan- and adjuvant-induced edemas.The quantitative relations between the antiinflammatory effect and physicochemical and structural parameters of the compounds tested were evaluated.The equations obtained by the method of regression analysis showed a significant linear dependence of both inhibitory activities on the lipophilicity of the compounds and a considerable effect of some structural changes as expressed by indicator variables.The antiinflammatory effect is especially enhanced in both tests by the presence of a cyclic substituent at the aromatic ring.The high antiinflammatory effect of biphenylyl derivatives III is paralleled by their prolonged action.The prolongation of the effect is most likely a result of a suitable biotransformation of acid III to an efficient metabolite.The structural requirements which resulted from both the regression analysis and from the hypothesis of biotransformation of acids III were utilized in the synthesis of suitably substituted biphenylyloxoalkanoic acids.By this approach derivatives IIIe-i were obtained some of which showed a high antiinflammatory and also protracted effect. 4-(2',4'-Difluorobiphenylyl)-4-oxo-2-methylbutanoic acid (VUFB 16066, Flobufen) was chosen for further preclinical development.