42924-53-8

Basic information

• Product Name: Nabumetone
• Synonyms: relifex;RELAFEN;NABUMETONE;4-(6-methoxy-2-naphthalenyl)-2-butanon;4-(6-methoxy-2-naphthalenyl)-2-butanone;brl147777;4-(6-METHOXY-2-NAPHTHYL)BUTAN-2-ONE;4-[6-METHOXY-2-NAPHTHYL]-2-BUTANONE
• CAS NO: 42924-53-8
• Molecular Formula: C₁₅H₁₆O₂
• Molecular Weight: 228.29
• Product Categories: Active Pharmaceutical Ingredients;Anti-Inflammatory;Analgesic;Intermediates & Fine Chemicals;Pharmaceuticals;Steroids;Aromatics;API;BUTYN
• Mol File: 42924-53-8.mol

Chemical Properties

• Melting Point: 80-810C
• Boiling Point: 330.1°C (rough estimate)
• Flash Point: 165.4 °C
• Appearance: White powder
• Density: 1.0657 (rough estimate)
• Vapor Pressure: 9.69E-06mmHg at 25°C
• Refractive Index: 1.5542 (estimate)
• Storage Temp.: Refrigerator
• Solubility: Soluble in alcohol or chloroform
• Water Solubility: 6mg/L(22.5 oC)
• CAS DataBase Reference: Nabumetone(CAS DataBase Reference)
• NIST Chemistry Reference: Nabumetone(42924-53-8)
• EPA Substance Registry System: Nabumetone(42924-53-8)

Safety Data

• Hazard Codes: Xn
• Statements: 22-40
• Safety Statements: 36/37
• WGK Germany: 2
• RTECS: EL9085000
• Hazardous Substances Data: 42924-53-8(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Nabumetone is used as an anti-inflammatory agent for the treatment of inflammatory and degenerative rheumatic diseases, such as rheumatoid and osteoarthritis. Its long half-life and once-daily administration make it a convenient and effective option for managing these conditions.
Used in Medical Field:
Nabumetone is used as a local anesthetic to provide pain relief during minor surgical procedures or other medical interventions. Its anti-inflammatory properties also contribute to reducing inflammation and promoting healing at the site of application.
Used in Antimicrobial Applications:
Nabumetone is used as an antibacterial agent to combat bacterial infections. Its anti-inflammatory and antibacterial properties make it a valuable asset in treating and preventing infections in various medical settings.

Indications

Nabumetone (Relafen) is approved for rheumatoid arthritis, osteoarthritis, and pain management. Its long half-life allows for once-daily dosing. Although this drug is a weak inhibitor of COX, it is metabolized in the liver to 6-methoxy-2-naphthylacetic acid (6-MNA), a strong COX inhibitor that is chemically similar to naproxen. As with most NSAIDs, GI side effects are most commonly reported. The incidence of gastric ulceration is lower with nabumetone than with many other NSAIDs.This is due to its nature as a prodrug, not to COX-2 selectivity. Lower-bowel complaints, rashes, and CNS disturbances are common adverse effects.

Manufacturing Process

4-(5-Bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one50 grams (0.179 moles) of 2-acetyl-5-bromo-6-methoxynaphthalene and 200 ml of n-butyl acetate are placed in a flask equipped with refrigerator and stirrer and, under stirring and at the temperature of 15°C, 14.5 g (0.268 moles) of sodium methoxide are added. The temperature of the reaction mixture goes up to 25°C and is kept at this value for 30 minutes, then the mixture is warmed at 65°C for one hour, is added with 100 ml of water and is brought to pH 4 by adding a concentrated aqueous solution of hydrochloric acid. The reaction mixture is then cooled to 0°-5°C and kept at this temperature for one hour. The solid is filtered, abundantly washed with water on the filter, then washed with butyl acetate and dried in oven under vacuum obtaining 53 g of product with a yield equal to 92%.Example 1. 4-(6-Methoxy-2-naphthyl)butan-2-one48 grams (0.150 moles) of 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut- 3-en-2-one, 6.1 g of sodium acetate hydrate containing 32.4% of water, equivalent to 0.050 moles of sodium acetate, 4 g of a 50% suspension in water of 10% palladium on carbon, equivalent to 0.0019 moles of palladium, and 500 ml of methanol are put in a hydrogenator. The hydrogenator is washed with nitrogen in order to eliminate the oxygen and then hydrogen is introduced at the pressure of 2 atmospheres. The temperature of reaction is kept at 40°C for a period of time of 6 hours, then the hydrogen is let off, the hydrogenator is washed with nitrogen and the reaction mixture is filtered to eliminate the catalyst. The solution is brought to pH 6 with a 5% aqueous solution of sodium hydroxide and concentrated under vacuum. The oily residue is dissolved into 130 ml of isopropanol and 30 ml of N,Ndimethylformamide and the solution is added with 45 ml of water and 17.6 g of sodium bisulfite obtaining a suspension that is stirred for one hour at 60°C, then is cooled to 5°C and is filtered. The obtained solid is washed with 75 ml of methanol, suspended in 200 ml of a 5% aqueous solution of sodium hydroxide and kept under stirring at room temperature for three hours. The suspension is then filtered, the solid is washed with water until neutrality and dried in oven under vacuum obtaining 18 g of product with a yield equal to 52.8%.Example 2. 4-(6-Methoxy-2-naphthy)butan-2-oneThe reaction described above is repeated with the sole changes of doubling the amount of sodium acetate hydrate containing 32.4% of water, 12.22 g equivalent to 0.100 moles of sodium acetate, and of lowering the hydrogenation time to five hours. In this way 22.5 g of product are obtained with a yield equal to 66%.Example 3. 4-(6-Methoxy-2-naphthyl)butan-2-oneThe reaction described in example 3 is repeated with the sole changes of nearly triplicating the amount of sodium acetate hydrate containing 32.4% of water, 17.60 g equivalent to 0.145 moles of sodium acetate, and of lowering the hydrogenation time to five hours. The oil obtained by evaporating the solvent at the end of the reaction is treated with 300 ml of toluene and 100 ml of water and after 15 minutes of stirring the two layers are separated. The aqueous phase is discarded while the organic phase is evaporated under vacuum at 70°C obtaining an oil that is dissolved into 100 ml of methanol. The solution is kept at 0°C for two hours and the precipitated solid is filtered, washed with 15 ml of methanol cooled to 0°C and dried in oven under vacuum. In this way 21.7 g of product are obtained. The methanolic filtrates from crystallization and washing are concentrated under vacuum to half volume so obtaining, after cooling to 0°C, the crystallization of other 4 g of product with an overall yield equal to 75.3%.

Therapeutic Function

Antiinflammatory

Pharmacokinetics

Nabumetone is absorbed primarily from the duodenum. Milk and food increase the rate of absorption and the bioavailability of the active metabolite. Plasma concentrations of unchanged drug are too low to be detected in most subjects after oral administration, so most pharmacokinetic studies have involved the disposition of the active metabolite. Pharmacokinetic properties are altered in elderly patients, with higher plasma levels of the active metabolite being noted. Nabumetone undergoes rapid and extensive metabolism in the liver, with a mean absolute bioavailability of the active metabolite of 38%. The metabolism of nabumetone is illustrated in Figure 36.15. The major, most active metabolite is 6MNA, but the initial alcohol metabolite, a minor product, and its esters also possess significant anti-inflammatory properties.

Clinical Use

Nabumetone is indicated for the acute and chronic treatment of the signs and symptoms of osteoarthritis and rheumatoid arthritis. The recommended starting dosage is 1,000 mg as a single dose with or without food. More symptomatic relief of severe or persistent symp-toms may be obtained at doses of 1,500 or 2,000 mg/day

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 of 2 or more NSAIDs, including aspirin (increased side effects); avoid with ketorolac (increased risk of 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 and venlaflaxine. Antidiabetic agents: effects of sulphonylureas enhanced. Antiepileptics: possibly increased phenytoin concentration. Antivirals: increased risk of haematological toxicity with zidovudine; concentration possibly increased by ritonavir. 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 decreased. Pentoxifylline: increased risk of bleeding. Tacrolimus: increased risk of nephrotoxicity.

Metabolism

Nabumetone is rapidly metabolised in the liver to the main active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). The metabolite is a potent inhibitor of prostaglandin synthesis. Excretion of the metabolite is predominantly in the urine.

InChI:InChI=1/C15H16O3/c1-17-14-7-6-12-9-11(3-5-13(12)10-14)4-8-15(16)18-2/h3,5-7,9-10H,4,8H2,1-2H3

Synthetic route

4-(2-methoxynaphthalene-6-yl)but-3-en-2-one (127053-22-9, 56600-90-9) → nabumetone (42924-53-8)

Conditions	Yield
With hydrogen In toluene at 50℃; under 3750.38 Torr; for 1h; Catalytic behavior; Temperature; Pressure; Inert atmosphere; Schlenk technique; Autoclave;	99%
With 1% Pd on activated carbon; hydrogen In water at 45℃; under 760.051 Torr; for 15h; Reagent/catalyst; Green chemistry; chemoselective reaction;	95%
With hydrogen In N,N-dimethyl-formamide at 100℃;	90%

methyl vinyl ketone (78-94-4) + tris(6-methoxy-2-naphthyl)stibine → nabumetone (42924-53-8)

Conditions	Yield
With palladium diacetate; silver(I) acetate; acetic acid at 25℃; for 24h;	99%

4-(6-methoxy-2-naphthalenyl)-4-hydroxybut-3-en-2-one (73356-31-7) → nabumetone (42924-53-8)

Conditions	Yield
palladium on charcoal catalyst In acetic acid	93%
Multi-step reaction with 3 steps 1: acetic acid; hydrogen; palladium on activated charcoal / 20 °C 2: sulfuric acid 3: hydrogen / ethyl acetate / 4 h / 20 °C / 760.05 Torr View Scheme
Multi-step reaction with 3 steps 1: hydrogen; palladium 10% on activated carbon; sulfuric acid / ethyl acetate 2: sulfuric acid 3: hydrogen / ethyl acetate / 4 h / 20 °C / 760.05 Torr View Scheme

6-methoxynaphthalene-2-carbaldehyde (3453-33-6) + acetone (67-64-1) → C18H22O2 + nabumetone (42924-53-8)

Conditions	Yield
With hydrogen; Pd/Mg-Al hydrotalcite at 74.84℃; under 3750.38 Torr; for 1.25h;	A 11 % Chromat. B 89%

2-Bromo-6-methoxynaphthalene (5111-65-9) + methyl vinyl ketone (78-94-4) → nabumetone (42924-53-8)

Conditions	Yield
With tetrabutylammomium bromide; tetra-(n-butyl)ammonium iodide; nickel dibromide In pyridine; N,N-dimethyl-formamide at 70℃; Electrochemical reaction;	85%
Stage #1: methyl vinyl ketone With [2,2]bipyridinyl; water; cobalt(II) bromide In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 2-Bromo-6-methoxynaphthalene With pyridine; trifluoroacetic acid; lithium bromide; zinc In N,N-dimethyl-formamide at 80℃; for 0.333333h;	50%

2-hydroxy-3-butene (598-32-3) + 2-Bromo-6-methoxynaphthalene (5111-65-9) → nabumetone (42924-53-8) + 4-(6-methoxy-2-naphthyl)-3-butene-2-ol (127053-21-8)

Conditions	Yield
Stage #1: 2-hydroxy-3-butene With dicyclohexylmethylamine; tetrabutylammomium bromide In N,N-dimethyl acetamide; water at 20℃; for 0.25h; Heck reaction; Stage #2: 2-Bromo-6-methoxynaphthalene; 4'-hydroxyacetophenone oxime palladacycle catalyst In N,N-dimethyl acetamide; water at 120℃; for 9h; Heck reaction; Further stages.;	A 82% B n/a
With sodium hydrogencarbonate; bis-triphenylphosphine-palladium(II) chloride In various solvent(s) at 140℃; for 5h; Yield given;	A n/a B 9%

4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one → nabumetone (42924-53-8)

Conditions	Yield
With sodium hydroxide; sodium acetate; sodium acetate trihydrate; palladium In methanol; water; hydrogen; toluene	79.7%
With sodium hydroxide; sodium acetate; sodium acetate trihydrate; palladium In methanol; water; hydrogen; toluene	79.7%

sodium metabisulfite + 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one → nabumetone (42924-53-8)

Conditions	Yield
With sodium hydroxide; sodium acetate; palladium In water; hydrogen; isopropyl alcohol; toluene	78.5%
With sodium hydroxide; sodium acetate; palladium In water; hydrogen; isopropyl alcohol; toluene	78.5%
With sodium hydroxide; sodium acetate; palladium In water; hydrogen; isopropyl alcohol; toluene	74.8%
With sodium hydroxide; sodium acetate; palladium In water; hydrogen; isopropyl alcohol; toluene	74.8%

2-hydroxy-3-butene (598-32-3) + 2-Bromo-6-methoxynaphthalene (5111-65-9) → nabumetone (42924-53-8)

Conditions	Yield
With tetrabutylammomium bromide; sodium formate; sodium hydrogencarbonate; Pd-benzothiazole carbene at 130℃; for 3h; Heck reaction;	75%
With tetrabutylammomium bromide; sodium hydrogencarbonate; palladium dichloride at 120℃; for 6h; Heck coupling;	74%
Stage #1: 2-hydroxy-3-butene With dicyclohexylmethylamine; tetrabutylammomium bromide In N,N-dimethyl acetamide at 20℃; for 0.25h; Heck reaction; Stage #2: 2-Bromo-6-methoxynaphthalene; 4'-hydroxyacetophenone oxime palladacycle catalyst In N,N-dimethyl acetamide at 120℃; for 24h; Heck reaction; Further stages.;	90 % Spectr.
With Fe3O4@chitosan nanoparticles/Pd In ethanol at 140℃; for 24h;

6-methoxynaphthalene-2-carbaldehyde (3453-33-6) + acetone (67-64-1) → nabumetone (42924-53-8)

Conditions	Yield
With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; carbon monoxide In neat (no solvent) at 200℃; for 72h; Temperature; Autoclave;	75%
With hydrogen; magnesium oxide; palladium at 59.84℃; under 3750.38 Torr; for 1h;	98 % Chromat.

6-methoxynaphthalene-2-carbaldehyde (3453-33-6) → nabumetone (42924-53-8)

Conditions	Yield
	67%
Multi-step reaction with 2 steps 1: aq. NaOH 2: H2 / Pd-C / ethyl acetate View Scheme
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 210 °C / Continuous flow 2: hydrogen / N,N-dimethyl-formamide / 100 °C View Scheme
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 0.12 h / 70 °C / Microwave irradiation; Continuous flow 2: hydrogen / N,N-dimethyl-formamide / 100 °C View Scheme
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 4 h 2: hydrogen / ethyl acetate / 4 h / 20 °C / 760.05 Torr View Scheme

4-(6-methoxy-2-naphthalenyl)-4-hydroxybut-3-en-2-one (73356-31-7) → 4-(6-methoxynaphthalen-2-yl)butan-2-ol (65726-24-1) + nabumetone (42924-53-8) + (±)-4-hydroxy-4-(6-methoxy-2-naphthyl)-2-butanone (220786-56-1, 98386-83-5)

Conditions	Yield
With sulfuric acid; palladium 10% on activated carbon; hydrogen In ethyl acetate	A 5% B 65% C 5%

2-(2-iodoethyl)-6-methoxynaphthalene + chloroformic acid ethyl ester (541-41-3) + methyl iodide (74-88-4) → nabumetone (42924-53-8)

Conditions	Yield
With [2,2]bipyridinyl; chloro-trimethyl-silane; nickel(II) bromide 2-methoxyethyl ether complex; zinc In tetrahydrofuran; N,N-dimethyl acetamide at 40℃; for 1h; Sealed tube; Inert atmosphere;	54%

sodium acetate monohydrate + 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one → nabumetone (42924-53-8)

Conditions	Yield
With sodium hydroxide; sodium acetate; sodium hydrogensulfite; palladium In methanol; water; hydrogen; N,N-dimethyl-formamide; isopropyl alcohol	52.8%
With sodium hydroxide; sodium acetate; sodium hydrogensulfite; palladium In methanol; water; hydrogen; N,N-dimethyl-formamide; isopropyl alcohol	52.8%

methyl 3-(6-methoxynaphthalen-2-yl)propanoate (136579-95-8) + methyl magnesium iodide (917-64-6) → nabumetone (42924-53-8)

Conditions	Yield
In tetrahydrofuran at -55℃;	51%

methyl magnesium iodide (917-64-6) + 2-Methoxynaphthalen-6-propionitril (42924-52-7) → nabumetone (42924-53-8)

Conditions	Yield
In diethyl ether Heating;

ethyl 2-acetyl-3-(6-methoxy-2-naphthyl) propionate → nabumetone (42924-53-8)

Conditions	Yield
With potassium hydroxide In water for 6h; Heating;	4 g

2-(Bromomethyl)-6-methoxynaphthalene (73022-40-9) → nabumetone (42924-53-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: K2CO3 / acetone / 3 h / Heating 2: 4 g / KOH / H2O / 6 h / Heating View Scheme

2-(2-bromoethyl)-6-methoxynaphthalene (42924-51-6) → nabumetone (42924-53-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: aq. ethanol / Heating 2: diethyl ether / Heating View Scheme

2-<1-hydroxyethyl>-6-methoxynaphthalene (32725-05-6, 56523-40-1) → nabumetone (42924-53-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: PBr3 / benzene / Heating 2: aq. ethanol / Heating 3: diethyl ether / Heating View Scheme
Multi-step reaction with 2 steps 1: triphenylphosphine; 1H-imidazole; iodine / dichloromethane / 20 °C 2: [2,2]bipyridinyl; nickel(II) bromide 2-methoxyethyl ether complex; zinc; chloro-trimethyl-silane / N,N-dimethyl acetamide; tetrahydrofuran / 1 h / 40 °C / Sealed tube; Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: 1H-imidazole; triphenylphosphine; iodine / dichloromethane / 0 - 20 °C / Inert atmosphere 2: (2-(dimethylamino)-N-(quinolin-8-yl)acetamido)nickel(II) chloride; manganese / N,N-dimethyl-formamide / 16 h / 20 °C / Sealed tube View Scheme

methyl 6-methoxy-2-naphthylacetate (23981-48-8) → nabumetone (42924-53-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: LiAlH4 / diethyl ether / Heating 2: PBr3 / benzene / Heating 3: aq. ethanol / Heating 4: diethyl ether / Heating View Scheme

2-hydroxy-3-butene (598-32-3) + 2-Bromo-6-methoxynaphthalene (5111-65-9) → C15H16O2 + nabumetone (42924-53-8) + 3-(6-methoxy-2-naphthyl)-2-butanone (56600-77-2)

Conditions	Yield
Stage #1: 2-hydroxy-3-butene With dicyclohexylmethylamine; tetrabutylammomium bromide In N,N-dimethyl acetamide at 20℃; for 0.25h; Heck reaction; Stage #2: 2-Bromo-6-methoxynaphthalene; Kaiser oxime-derived complex on resin base In N,N-dimethyl acetamide at 120℃; for 24h; Heck reaction; Further stages. Title compound not separated from byproducts.;

2-hydroxy-3-butene (598-32-3) + 2-Bromo-6-methoxynaphthalene (5111-65-9) → nabumetone (42924-53-8) + 3-(6-methoxy-2-naphthyl)-2-butanone (56600-77-2)

Conditions	Yield
Stage #1: 2-hydroxy-3-butene With dicyclohexylmethylamine; tetrabutylammomium bromide In N,N-dimethyl acetamide at 20℃; for 0.25h; Heck reaction; Stage #2: 2-Bromo-6-methoxynaphthalene; Kaiser oxime-derived complex on resin base In N,N-dimethyl acetamide at 120℃; for 14h; Heck reaction; Further stages. Title compound not separated from byproducts.;

ethyl-5-(6-methoxy-2-naphthyl)-β-keto-pentanoate (1250259-21-2) → nabumetone (42924-53-8)

Conditions	Yield
With water; potassium hydroxide In ethanol Conversion of starting material;

β-naphthol (135-19-3) → nabumetone (42924-53-8)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: acetic acid; bromine / 0.5 h / 30 - 35 °C 2.1: acetic acid; tin / 3 h / 100 - 120 °C 3.1: potassium carbonate / acetone; water / 4 h / 10 - 50 °C / Cooling 4.1: magnesium; iodine / tetrahydrofuran / 5 h / Reflux 4.2: 1.75 h / 10 - 90 °C 4.3: 1 h / 20 °C 5.1: sodium hydroxide / water / 4 h 6.1: hydrogen / ethyl acetate / 4 h / 20 °C / 760.05 Torr View Scheme

1,6-dibromo-2-naphthol (16239-18-2) → nabumetone (42924-53-8)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: acetic acid; tin / 3 h / 100 - 120 °C 2.1: potassium carbonate / acetone; water / 4 h / 10 - 50 °C / Cooling 3.1: magnesium; iodine / tetrahydrofuran / 5 h / Reflux 3.2: 1.75 h / 10 - 90 °C 3.3: 1 h / 20 °C 4.1: sodium hydroxide / water / 4 h 5.1: hydrogen / ethyl acetate / 4 h / 20 °C / 760.05 Torr View Scheme

6-bromo-naphthalen-2-ol (15231-91-1) → nabumetone (42924-53-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetone; water / 4 h / 10 - 50 °C / Cooling 2.1: magnesium; iodine / tetrahydrofuran / 5 h / Reflux 2.2: 1.75 h / 10 - 90 °C 2.3: 1 h / 20 °C 3.1: sodium hydroxide / water / 4 h 4.1: hydrogen / ethyl acetate / 4 h / 20 °C / 760.05 Torr View Scheme

2-Bromo-6-methoxynaphthalene (5111-65-9) → nabumetone (42924-53-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: magnesium; iodine / tetrahydrofuran / 5 h / Reflux 1.2: 1.75 h / 10 - 90 °C 1.3: 1 h / 20 °C 2.1: sodium hydroxide / water / 4 h 3.1: hydrogen / ethyl acetate / 4 h / 20 °C / 760.05 Torr View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / diethyl ether / 0.5 h / 0 °C / Inert atmosphere 1.2: 1.42 h / Inert atmosphere 2.1: triphenylphosphine; 1H-imidazole; iodine / dichloromethane / 20 °C 3.1: [2,2]bipyridinyl; nickel(II) bromide 2-methoxyethyl ether complex; zinc; chloro-trimethyl-silane / N,N-dimethyl acetamide; tetrahydrofuran / 1 h / 40 °C / Sealed tube; Inert atmosphere View Scheme

nabumetone (42924-53-8) → C15H11(2)H5O2

Conditions	Yield
With tris(pentafluorophenyl)borate; water-d2 In tetrahydrofuran at 100℃; for 12h; Catalytic behavior; Reagent/catalyst; Solvent; Temperature; Inert atmosphere; regioselective reaction;	99%

nabumetone (42924-53-8) → 4-(5-iodo-6-methoxynaphthalen-2-yl)butan-2-one (1225055-49-1)

Conditions	Yield
With indium(III) triflate; N-iodo-succinimide In acetonitrile at 23℃; for 8h; Inert atmosphere; Darkness;	97%

4-trifluoromethylphenylamine (455-14-1) + nabumetone (42924-53-8) + p-butoxybenzaldehyde (5736-88-9) → 1-(4-butoxyphenyl)-5-(6-methoxynaphthalen-2-yl)-1-(4-(trifluoromethyl)phenylamino)pentan-3-one (1363178-37-3)

Conditions	Yield
Stage #1: 4-trifluoromethylphenylamine; p-butoxybenzaldehyde In ethanol at 25℃; for 0.333333h; Mannich reaction; Stage #2: nabumetone With hydrogenchloride In ethanol; chloroform; water at 25℃; for 22h; pH=4 - 5; Mannich reaction;	97%

nabumetone (42924-53-8) → 4-(6-methoxynaphthalen-2-yl)butan-2-ol (65726-24-1)

Conditions	Yield
With sodium tetrahydroborate In ethanol at -10 - 20℃; for 4h;	95%
With sodium tetrahydroborate In ethanol
With sodium tetrahydroborate In ethanol at -10℃; for 3h; Inert atmosphere;
With sodium tetrahydroborate In ethanol at 0 - 20℃; for 3h; Schlenk technique; Inert atmosphere;

4-trifluoromethylphenylamine (455-14-1) + nabumetone (42924-53-8) + 4-methyl-benzaldehyde (104-87-0) → 5-(6-methoxynaphthalen-2-yl)-1-p-tolyl-1-(4-(trifluoromethyl)phenylamino)pentan-3-one (1363178-36-2)

Conditions	Yield
Stage #1: 4-trifluoromethylphenylamine; 4-methyl-benzaldehyde In ethanol at 20℃; for 0.333333h; Mannich reaction; Stage #2: nabumetone With hydrogenchloride In ethanol; chloroform; water at 20℃; for 26h; pH=4 - 5; Mannich reaction;	95%

nabumetone (42924-53-8) → Nabumetone hydroxyimine (68427-21-4)

Conditions	Yield
With pyridine; hydroxylamine hydrochloride In ethanol Heating;	94%
With hydroxylamine hydrochloride

nabumetone (42924-53-8) → C15H19NO

Conditions	Yield
With nickel(II) tetrafluoroborate hexahydrate; ammonia; hydrogen; bis(2-diphenylphosphinoethyl)phenylphosphine In 2,2,2-trifluoroethanol at 120℃; for 24h; chemoselective reaction;	91%
With ammonia; hydrogen In tetrahydrofuran at 120℃; for 15h;	90%
With N,N'-bis(salicylidene)-1,2-phenylene-diaminocobalt(II); ammonia; hydrogen In tetrahydrofuran; water at 130℃; for 24h; Autoclave;	82%
With ammonium hydroxide; hydrogen at 140℃; under 48754.9 Torr; for 20h;

nabumetone (42924-53-8) + 4-Diazo-2,6-dibromo-2,5-cyclohexadienone (38676-25-4) → 4-(5-(3,5-dibromo-4-hydroxyphenyl)-6-methoxynaphthalen-2-yl)butan-2-one

Conditions	Yield
With bis{rhodium[3,3'-(1,3-phenylene)bis(2,2-dimethylpropanoic acid)]} at 20℃; for 16h; Inert atmosphere; Schlenk technique; Molecular sieve;	91%

nabumetone (42924-53-8) + 2,6-dichloro-4-diazocyclohexa-2,5-dien-1-one (31862-15-4) → 4-(5-(3,5-dichloro-4-hydroxyphenyl)-6-methoxynaphthalen-2-yl)butan-2-one

Conditions	Yield
With bis{rhodium[3,3'-(1,3-phenylene)bis(2,2-dimethylpropanoic acid)]} at 20℃; for 16h; Inert atmosphere; Schlenk technique; Molecular sieve;	90%

4-trifluoromethylphenylamine (455-14-1) + nabumetone (42924-53-8) + 4-bromo-benzaldehyde (1122-91-4) → 1-(4-bromophenyl)-5-(6-methoxynaphthalen-2-yl)-1-(4-(trifluoromethyl)phenylamino)pentan-3-one (1363178-35-1)

Conditions	Yield
Stage #1: 4-trifluoromethylphenylamine; 4-bromo-benzaldehyde In ethanol at 25℃; for 0.333333h; Mannich reaction; Stage #2: nabumetone With hydrogenchloride In ethanol; chloroform; water at 25℃; for 24h; pH=4 - 5; Mannich reaction;	89%

4-trifluoromethylphenylamine (455-14-1) + nabumetone (42924-53-8) + 3,4-dichlorobenzaldehyde (6287-38-3) → 1-(3,4-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1-(4-(trifluoromethyl)phenylamino)pentan-3-one (1206182-19-5)

Conditions	Yield
Stage #1: 4-trifluoromethylphenylamine; 3,4-dichlorobenzaldehyde In ethanol at 30℃; for 0.333333h; Mannich reaction; Stage #2: nabumetone With hydrogenchloride In ethanol; chloroform; water at 30℃; for 29h; pH=4 - 5; Mannich reaction;	89%

4-trifluoromethylphenylamine (455-14-1) + nabumetone (42924-53-8) + m-tolyl aldehyde (620-23-5) → 5-(6-methoxynaphthalen-2-yl)-1-m-tolyl-1-(4-(trifluoromethyl)phenylamino)pentan-3-one (1206182-16-2)

Conditions	Yield
Stage #1: 4-trifluoromethylphenylamine; m-tolyl aldehyde In ethanol at 31℃; for 0.333333h; Mannich reaction; Stage #2: nabumetone With hydrogenchloride In ethanol; chloroform; water at 31℃; for 23h; pH=4 - 5; Mannich reaction;	89%

nabumetone (42924-53-8) + methyl 3-diazo-6-oxocyclohexa-1,4-diene-1-carboxylate → methyl 2-hydroxy-5-(2-methoxy-6-(3-oxobutyl)naphthalen-1-yl)benzoate

Conditions	Yield
With bis{rhodium[3,3'-(1,3-phenylene)bis(2,2-dimethylpropanoic acid)]} In 1,2-dichloro-ethane at 50℃; for 16h; Inert atmosphere; Schlenk technique; Molecular sieve;	89%

4-trifluoromethylphenylamine (455-14-1) + nabumetone (42924-53-8) + 4-hydroxy-benzaldehyde (123-08-0) → 1-(4-hydroxyphenyl)-5-(6-methoxynaphthalen-2-yl)-1-(4-(trifluoromethyl)phenylamino)pentan-3-one (1363178-38-4)

Conditions	Yield
Stage #1: 4-trifluoromethylphenylamine; 4-hydroxy-benzaldehyde In ethanol at 20℃; for 0.333333h; Mannich reaction; Stage #2: nabumetone With hydrogenchloride In ethanol; chloroform; water at 20℃; for 25h; pH=3 - 4; Mannich reaction;	88%

4-trifluoromethylphenylamine (455-14-1) + nabumetone (42924-53-8) + 4-methoxy-benzaldehyde (123-11-5) → 5-(6-methoxynaphthalen-2-yl)-1-(4-methoxyphenyl)-1-(4-(trifluoromethyl)phenylamino)pentan-3-one (1206182-20-8)

Conditions	Yield
Stage #1: 4-trifluoromethylphenylamine; 4-methoxy-benzaldehyde In ethanol at 32℃; for 0.333333h; Mannich reaction; Stage #2: nabumetone With hydrogenchloride In ethanol; chloroform; water at 32℃; for 28h; pH=3 - 4; Mannich reaction;	87%

nabumetone (42924-53-8) → C15H19NO*(x)ClH

Conditions	Yield
Stage #1: nabumetone With ammonium hydroxide; hydrogen at 60℃; under 7500.75 Torr; for 20h; Autoclave; Stage #2: With hydrogenchloride In diethyl ether	87%

triphenylmethyl alcohol (76-84-6) + nabumetone (42924-53-8) → 4-(6-methoxynaphthalen-2-yl)-2-phenylbutan-2-ol

Conditions	Yield
Stage #1: triphenylmethyl alcohol; nabumetone With potassium phosphate; chloro(1,5-cyclooctadiene)rhodium(I) dimer; potassium tert-butylate; C69H57N2O2(1+)*BF4(1-)*H(1+) In toluene at 125℃; for 24h; Sealed tube; Stage #2: With sodium tetrahydroborate In methanol at 0 - 20℃; for 1h;	86%

nabumetone (42924-53-8) + sulfamethoxazole (723-46-6) + 4-nitrobenzaldehdye (555-16-8) → C32H30N4O7S

Conditions	Yield
With hydrogenchloride In ethanol; chloroform; water at 20 - 32℃; for 27h;	85%

nabumetone (42924-53-8) + benzaldehyde (100-52-7) → (E)-5-(2-methoxynaphthyl)-1-phenylpenta-1-en-3-one

Conditions	Yield
Stage #1: nabumetone With sodium hydroxide In methanol at 20℃; for 0.0833333h; Stage #2: benzaldehyde In methanol at 20℃; for 16h;	82%

2,4-thiazolidinedion (2295-31-0) + nabumetone (42924-53-8) → 5-[3-(6-Methoxy-naphthalen-2-yl)-1-methyl-prop-(E)-ylidene]-thiazolidine-2,4-dione

Conditions	Yield
With piperidine; benzoic acid In toluene Heating;	80%

4-trifluoromethylphenylamine (455-14-1) + nabumetone (42924-53-8) + 3-Fluorobenzaldehyde (456-48-4) → 1-(3-fluorophenyl)-5-(6-methoxynaphthalen-2-yl)-1-(4-(trifluoromethyl)phenylamino)pentan-3-one (1363178-31-7)

Conditions	Yield
Stage #1: 4-trifluoromethylphenylamine; 3-Fluorobenzaldehyde In ethanol at 13℃; for 0.333333h; Mannich reaction; Stage #2: nabumetone With hydrogenchloride In ethanol; chloroform; water at 13℃; for 23h; pH=4 - 5; Mannich reaction;	80%

4-trifluoromethylphenylamine (455-14-1) + nabumetone (42924-53-8) + benzaldehyde (100-52-7) → 5-(6-methoxynaphthalen-2-yl)-1-phenyl-1-(4-(trifluoromethyl)phenylamino)pentan-3-one (1236218-15-7)

Conditions	Yield
Stage #1: 4-trifluoromethylphenylamine; benzaldehyde In ethanol at 31℃; for 0.333333h; Mannich reaction; Stage #2: nabumetone With hydrogenchloride In ethanol; chloroform; water at 31℃; for 25h; pH=4 - 5; Mannich reaction;	79%

Upstream product

• 598-32-3 2-hydroxy-3-butene 
• 5111-65-9 2-Bromo-6-methoxynaphthalene 
• 3453-33-6 6-methoxynaphthalene-2-carbaldehyde 
• 67-64-1 acetone 
• 541-41-3 chloroformic acid ethyl ester 
• 74-88-4 methyl iodide 
• 78-94-4 methyl vinyl ketone 
• 127053-22-9 4-(2-methoxynaphthalene-6-yl)but-3-en-2-one 
• 917-64-6 methyl magnesium iodide 
• 42924-52-7 2-Methoxynaphthalen-6-propionitril 
• 127053-22-9 4-(6'-methoxy-2'-naphthyl)-3-buten-2-one 
• 73356-31-7 4-(6-methoxy-2-naphthalenyl)-4-hydroxybut-3-en-2-one 
• 3900-45-6 6-methoxy-2-acetylnaphthalene 
• 15231-91-1 6-bromo-naphthalen-2-ol 

Downstream Products

• 1206182-11-7 C₂₉H₂₆N₂O₆ 
• 1206182-12-8 C₂₉H₂₅Cl₂NO₄ 
• 1190945-00-6 4-(1-(3-fluorophenyl)-5-(6-methoxynaphthalen-2-yl)-3-oxopentylamino)benzoic acid 
• 1206182-10-6 C₂₉H₂₆ClNO₄ 
• 1206182-09-3 C₂₉H₂₆ClNO₄ 
• 1190945-05-1 4-(1-(4-bromophenyl)-5-(6-methoxynaphthalen-2-yl)-3-oxopentylamino)benzoic acid 
• 1190943-60-2 C₂₉H₂₇NO₄ 
• 1236218-09-9 C₃₀H₂₉NO₄ 
• 1190945-06-2 4-((5-(6-methoxynaphthalen-2-yl)-3-oxo-1-(p-tolyl)pentyl)amino)benzoic acid 
• 1190945-04-0 4-((5-(6-methoxynaphthalen-2-yl)-1-(3-methoxyphenyl)-3-oxopentyl)amino)benzoic acid 
• 1190945-07-3 4-(5-(6-methoxynaphthalen-2-yl)-1-(4-methoxyphenyl)-3-oxopentylamino)benzoic acid 
• 1190945-08-4 4-(1-(4-butoxyphenyl)-5-(6-methoxynaphthalen-2-yl)-3-oxopentylamino)benzoic acid 
• 1206182-08-2 C₃₀H₂₇NO₆ 
• 1206182-13-9 C₂₉H₂₇NO₅ 

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