152-72-7

Usage

Uses

Used in Pharmaceutical Industry:
ACENOCOUMAROL is used as an anticoagulant agent for preventing and treating blood clots. It acts as a Vitamin K antagonist, which inhibits the synthesis of clotting factors in the liver, thus reducing the risk of clot formation.
Used in Antimicrobial Applications:
ACENOCOUMAROL is also used as an antimicrobial agent, leveraging its properties to combat various types of infections.

Originator

Sintrom ,Geigy ,US ,1957

Manufacturing Process

16 parts of 4-hydroxycoumarin and 19 parts of 4-nitrobenzalacetoneare thoroughly mixed and heated for 12-14 hours in an oil bath, the temperature of which is between 135°C and 140°C. After cooling, the melt is dissolved in a little acetone. The solution is slowly added to a lye made up from 6 parts of sodium hydroxide in 400 parts of water while stirring and then the mixture is stirred for 30 minutes. A little animal charcoal is then added, the mixture is stirred for a further 15 minutes, 400 parts of water are added and the charcoal and undissolved components are separated by filtration under suction. The clear solution is made acid to Congo red paper with hydrochloric acid and the product which is precipitated is filtered off under suction. 3-[α- (4'-Nitrophenyl)-β-acetylethyl]-4-hydroxycoumarin is obtained. MP 196-199°C. It should be noted that the process is akin to that for Warfarin except that 4- nitrobenzalacetone replaces benzalacetone as a raw material.

Therapeutic Function

Anticoagulant, Vitamin

Clinical Use

Anticoagulant

Safety Profile

Poison by intraperitoneal route.Moderately toxic by ingestion. A human teratogen by anunspecified route. When heated to decomposition it emitstoxic fumes such as NOx.

Synthesis

Acenocoumarin, 3-(α-acetonyl-p-nitrobenzyl)-4-hydroxycoumarin (24.1.11), is synthesized by a scheme completely analogous to making warfarin, but using p-nitrobenzalacetone.

Drug interactions

Potentially hazardous interactions with other drugs There are many significant interactions with coumarins. Prescribe with care with regard to the following: Anticoagulant effect enhanced by: alcohol, amiodarone, anabolic steroids, aspirin, aztreonam, bicalutamide, cephalosporins, chloramphenicol, cimetidine, ciprofloxacin, fibrates, clopidogrel, cranberry juice, danazol, dipyridamole, disulfiram, dronedarone, esomeprazole, ezetimibe, fibrates, fluconazole, flutamide, fluvastatin, grapefruit juice, itraconazole, ketoconazole, levamisole, levofloxacin, macrolides, methylphenidate, metronidazole, miconazole, nalidixic acid, neomycin, norfloxacin, NSAIDs, ofloxacin, omeprazole, pantoprazole, paracetamol, penicillins, propafenone, ritonavir, rosuvastatin, SSRIs, simvastatin, sulfinpyrazone, sulphonamides, tamoxifen, testosterone, tetracyclines, thyroid hormones, tigecycline, toremifene, tramadol, trimethoprim, valproate, vitamin E, voriconazole. Anticoagulant effect decreased by: acitretin, azathioprine, carbamazepine, enteral feeds, enzalutamide, fosphenytoin, griseofulvin, oral contraceptives, phenobarbital, phenytoin, primidone, rifamycins, St John’s wort (avoid), sucralfate, vitamin K. Anticoagulant effects enhanced / reduced by: anion exchange resins, corticosteroids, dietary changes, efavirenz, fosamprenavir, tricyclics. Analgesics: increased risk of bleeding with IV diclofenac and ketorolac - avoid concomitant use. Anticoagulants: increased risk of haemorrhage with apixaban, dabigatran, edoxaban and rivaroxaban - avoid. Antidiabetic agents: enhanced hypoglycaemic effect with sulphonylureas also possible changes to anticoagulant effect. Ciclosporin: there have been a few reports of altered anticoagulant effect; decreased ciclosporin levels have been seen rarely. Cytotoxics: increased risk of bleeding with erlotinib; enhanced anticoagulant effect with capecitabine, etoposide, fluorouracil, ifosfamide, sorafenib and tegafur; reduced effect with mercaptopurine and mitotane.

Metabolism

Acenocoumarol is extensively metabolised, although the metabolites appear to be pharmacologically inactive in man. 29% is excreted in the faeces and 60% in the urine, with less than 0.2% of the dose being renally excreted unchanged.

InChI:InChI=1/C19H15NO6/c1-11(21)10-15(12-6-8-13(9-7-12)20(24)25)17-18(22)14-4-2-3-5-16(14)26-19(17)23/h2-9,15,22H,10H2,1H3

Synthetic route

4-hydroxy[1]benzopyran-2-one (1076-38-6) + (E)-4-(4-nitrophenyl)-3-buten-2-one (946-49-6, 3490-37-7, 30625-98-0) → acenocoumarol (152-72-7)

Conditions	Yield
With polystyrene-divinylbenzene support prepared with 2-ethylhexanoic acid as porogen with immobilized 1,5,7-triazabicyclo[4.4.0]dec-5-ene at 100℃; for 72h; Reagent/catalyst; Michael Addition; Green chemistry;	96%
With N-ethyl-N,N-diisopropylamine In water for 18h; Michael Addition; Reflux;	96%

4-(p-nitrophenyl)-3-butene-2-one (946-49-6, 3490-37-7, 30625-98-0) + 4-hydroxy[1]benzopyran-2-one (1076-38-6) → acenocoumarol (152-72-7)

Conditions	Yield
potassium fluoride; N-benzyl-N,N,N-triethylammonium chloride In water for 2h; Product distribution; Heating; var. catalysts;	92%
potassium fluoride; N-benzyl-N,N,N-triethylammonium chloride In water for 2h; Heating;	92%

4-hydroxy[1]benzopyran-2-one (1076-38-6) + 2-Methoxypropene (116-11-0) + 4-nitrobenzaldehdye (555-16-8) → acenocoumarol (152-72-7)

Conditions	Yield
Stage #1: 4-hydroxy[1]benzopyran-2-one; 2-Methoxypropene; 4-nitrobenzaldehdye With ethylenediamine diacetic acid In 1,4-dioxane at 90℃; tandem Knoevenagel-hetero-Diels-Alder reaction; Stage #2: With hydrogenchloride; silica gel In water; trifluoroacetic acid at 20℃;

acenocoumarol (152-72-7) + (1R,2S,5R)-menthyl chloroformate (14602-86-9) → Carbonic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester 3-[1-(4-nitro-phenyl)-3-oxo-butyl]-2-oxo-2H-chromen-4-yl ester

Conditions	Yield
With TEA In 1,2-dichloro-ethane for 0.5h; Ambient temperature;	100%

acenocoumarol (152-72-7) → 4-Hydroxy-3-[3-[(E)-hydroxyimino]-1-(4-nitro-phenyl)-butyl]-chromen-2-one

Conditions	Yield
With pyridine; sodium hydroxide; hydroxylamine hydrochloride In ethanol 1) 12 h, 2) reflux, 6 h;	70%

methanol (67-56-1) + acenocoumarol (152-72-7) → 2-methoxy-2-methyl-4-(4-nitro-phenyl)-3,4-dihydro-2H-pyrano[3,2-c]chromen-5-one + 2-methoxy-2-methyl-4-(4-nitro-phenyl)-3,4-dihydro-2H-pyrano[3,2-c]chromen-5-one

Conditions	Yield
With hydrogenchloride for 22h; Reflux;	A 12% B 64%

acenocoumarol (152-72-7) + acetic anhydride (108-24-7) → 4-acetoxy-3-<1-(4-nitrophenyl)-3-oxobutyl>-2H-1-benzopyran-2-one

Conditions	Yield
for 1h; Heating;	49.4%

acenocoumarol (152-72-7) → 4'-Amino-warfarin

Conditions	Yield
With hydrogen; nickel

acenocoumarol (152-72-7) → 4-[1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-3-oxo-butyl]-benzenediazonium; chloride

Conditions	Yield
Multi-step reaction with 2 steps 1: H2 / Raney Ni 2: 1.) ice-bath, 1 h, 2.) 0 deg C, overnight View Scheme

Upstream product

• 946-49-6 4-(p-nitrophenyl)-3-butene-2-one 
• 1076-38-6 4-hydroxy[1]benzopyran-2-one 
• 116-11-0 2-Methoxypropene 
• 555-16-8 4-nitrobenzaldehdye 
• 946-49-6 (E)-4-(4-nitrophenyl)-3-buten-2-one 

Related news

Proton pump inhibitors and the risk of overanticoagulation during ACENOCOUMAROL (cas 152-72-7) maintenance treatment09/29/2019

In the Netherlands, several reports have described a potentiation of acenocoumarol‐induced anticoagulation by co‐medication of omeprazole or esomeprazole and competitive inhibition of CYP2C19 has been suggested as a possible mechanism for this interaction. We conducted an observational cohort ...detailed

Relevant academic research and scientific papers

New selective cyclooxygenase-2 inhibitors from cyclocoumarol: Synthesis, characterization, biological evaluation and molecular modeling

In this work, a serie of cyclocoumarol derivatives was designed, synthesized, characterized and studied for their potentialities as selective inhibitors of COX-2. All target compounds have been screened for their anti-inflammatory activity by the assay of PGE2 production. Among them, compound 5d exhibited the most potent inhibitory activity with a PGE2 inhibition compared to NS-398 (79% and 88% respectively) and showed non-inhibitory activity towards the COX-1 enzyme. Docking studies revealed the capacity of this compound to occupy the selective COX-2 cavity establishing additional hydrogen bonds between the oxygen of the methoxy group and the His90 and Arg513 of the binding site of the enzyme.

A bis-Lewis basic 2-aminoDMAP/prolinamide organocatalyst for application to the enantioselective synthesis of Warfarin and derivatives

A new chiral sec-amine/amidine-base hybrid catalyst, 2-aminoDMAP/prolinamide, is reported, which is able to catalyze conjugate addition of 4-hydroxycoumarin and various benzylideneacetones, a reaction that directly gives anticoagulant Warfarin and its analogues, with good yields (70-87%) and enantioselectivities (58-72%).

Helical-Peptide-Catalyzed Enantioselective Michael Addition Reactions and Their Mechanistic Insights

Helical peptide foldamer catalyzed Michael addition reactions of nitroalkane or dialkyl malonate to α,β-unsaturated ketones are reported along with the mechanistic considerations of the enantio-induction. A wide variety of α,β-unsaturated ketones, including β-aryl, β-alkyl enones, and cyclic enones, were found to be catalyzed by the helical peptide to give Michael adducts with high enantioselectivities (up to 99%). On the basis of X-ray crystallographic analysis and depsipeptide study, the amide protons, N(2)-H and N(3)-H, at the N terminus in the α-helical peptide catalyst were crucial for activating Michael donors, while the N-terminal primary amine activated Michael acceptors through the formation of iminium ion intermediates.

Asymmetric synthesis of warfarin and its analogues on water

The asymmetric Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones on water without organic co-solvents is reported to be catalysed by organic primary amines. The application of enantiomerically pure (S,S)-diphenylethylenediamine affords a series of important pharmaceutically active compounds in good to excellent yields (73-98%) and with good enantioselectivities (up to 76% ee) via reactions accelerated by ultrasound. In particular, our developments led to an efficient protocol for the 'solids on water' formation of the anticoagulant warfarin in both enantiomeric forms. The presented scalable and environmentally friendly organocatalytic approach affords the target drug in enantiomerically pure form.

Synthesis and characterization of novel polystyrene-supported TBD catalysts and their use in the Michael addition for the synthesis of Warfarin and its analogues

In the search for efficient and polymeric supports for organic bases to be used in environmentally friendly media and conditions, novel polystyrene-bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) has been prepared and characterized. Their catalytic properties have been tested in the Michael additions of 4-hydroxycoumarin to α,β-unsaturated ketones as a representative useful process for the syntheses of 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H- chromen-2-one (Warfarin), 4-hydroxy-3-(1-(4-nitrophenyl)-3-oxobutyl)-2H- chromen-2-one (Acenocumarol), 4-hydroxy-3-(1-(4-chlorophenyl)-3-oxobutyl) -2H-chromen-2-one (Coumachlor), and 4-hydroxy-3-(1-(4-methoxyphenyl)-3- oxobutyl)-2H-chromen-2-one. Products were obtained in high to quantitative conversion yields. The novel catalytic systems showed promising catalytic properties, and they could be all easily recovered by filtration and have been reused for three representative consecutive runs without any significant lowering of their activity.

Highly enantioselective synthesis of Warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalysts

An efficient enantioselective Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones catalysed by primary amine-phosphinamide bifunctional catalysts has been developed. This reaction afforded Warfarin and its analogs in moderate to excellent yie

Organocatalytic Asymmetric Michael Reaction of Cyclic 1,3-Dicarbonyl Compounds and α,β-Unsaturated Ketones - A Highly Atom-Economic Catalytic One-Step Formation of Optically Active Warfarin Anticoagulant

A broad range of Michael adducts 3 were obtained by the organocatalytic asymmetric Michael addition of cyclic 1,3-dicarbonyl compounds 1 to α,β-unsaturated ketones 2. The reaction allows a one-step synthesis of the optically active anti-coagulant warfarin and several analogues 3 on a kilogram scale in up to 99% yield with 88% ee (>99.9% ee after a single recrystallization).

An asymmetric approach to coumarin anticoagulants via hetero-Diels-Alder cycloaddition

We have developed a general, two-step protocol for the synthesis of chiral non-racemic coumarin anticoagulants (e.g. warfarin, coumachlor and acenocoumarol). This approach features a one-pot three-component tandem Knoevenagel-hetero-Diels-Alder reaction between in situ generated 3-arylidene-2,4-chromanediones and iso-propenyl ether derived from (-)-menthol.