80382-23-6

Basic information

• Product Name: Loxoprofen sodium
• Synonyms: alpha-methyl-4-((2-oxocyclopentyl)methyl)benzeneacetatesodiumsaltdihydrate;benzeneaceticacid,alpha-methyl-4-((2-oxocyclopentyl)methyl)-,sodiumsalt,di;cs-600;loxoprofensodium(patented-nosupply);loxoprofensodiumdihydrate;sodium2-(4-(2-oxocyclopentylmethyl)phenyl)propionatedihydrate;LOXOPROFEN SODIUM;sodium 2-[4-(2-oxocyclopentyl-1-methyl)phenyl]propionate dihydrate
• CAS NO: 80382-23-6
• Molecular Formula: C₁₅H₁₇O₃*Na
• Molecular Weight: 268.28
• EINECS: 1806241-263-5
• Product Categories: APIS;Aromatics;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Other APIs;Antipyretic analgesics;Analgesics
• Mol File: 80382-23-6.mol
• Article Data: 10

Chemical Properties

• Boiling Point: 417.9 °C at 760 mmHg
• Flash Point: 220.7 °C
• Appearance: /
• Vapor Pressure: 9.92E-08mmHg at 25°C
• Storage Temp.: Inert atmosphere,Room Temperature
• CAS DataBase Reference: Loxoprofen sodium(CAS DataBase Reference)
• NIST Chemistry Reference: Loxoprofen sodium(80382-23-6)
• EPA Substance Registry System: Loxoprofen sodium(80382-23-6)

Safety Data

• Hazardous Substances Data: 80382-23-6(Hazardous Substances Data)

Usage

Description

Loxoprofen sodium i s an antiinflammatory/analgesic agent useful in the management of rheumatoid arthritis and related disorders. It is converted in vivo to the corresponding trans-hydroxycyclopentane analog, through which it appears to exert its activity.

Originator

Sankyo (Japan)

Definition

ChEBI: A hydrate that is the dihydrate form of loxoprofen sodium. The parent acid, loxoprofen, is a prodrug that is rapidly converted to its active trans-alcohol metabolite following oral administration.

Brand name

LOXONIN

Mechanism of action

As most NSAIDs, loxoprofen is a non-selective cyclooxygenase inhibitor, and works by reducing the synthesis of prostaglandins from arachidonic acid.

Side effects

Adverse effects include anorexia, nausea, vomiting, bleeding, anemia, diarrhea, and constipation.

InChI:InChI=1/C15H18O3.Na/c1-10(15(17)18)12-7-5-11(6-8-12)9-13-3-2-4-14(13)16;/h5-8,10,13H,2-4,9H2,1H3,(H,17,18);/q;+1/p-1

Synthetic route

loxoprofen (68767-14-6, 83599-42-2, 87828-34-0, 87828-35-1, 89675-45-6, 89675-46-7, 90319-65-6, 90319-73-6, 90319-74-7, 90319-78-1, 90365-02-9) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
With sodium hydroxide In ethanol; water for 2h; Reflux;	96.6%
With methanol; sodium hydroxide for 1h;	95%
With sodium hydroxide In ethanol at 50℃; for 2h;	90.3%

2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2) + 2-ethoxycarbonyl-1-cyclopentanone (611-10-9) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
Stage #1: 2-[4-(bromomethyl)phenyl]propanoic acid; 2-ethoxycarbonyl-1-cyclopentanone With sodium hydroxide In N,N-dimethyl-formamide under 760.051 Torr; for 8h; Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide pH=5 - 6; Further stages;	92%

1-(1-chloroethyl)-4-methylbenzene (2362-36-9) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions

Yield

Multi-step reaction with 7 steps 1: magnesium / tetrahydrofuran / 1.5 h / 20 - 30 °C / Inert atmosphere 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / dichloromethane / Reflux 3: sulfuric acid / 16 h / 0 - 5 °C 4: sodium periodate / N,N-dimethyl-formamide / 150 °C 5: hydrogenchloride / water / 4.5 h / Reflux 6: 5%-palladium/activated carbon; hydrogen / methanol / 14 h / 10 - 15 °C / 1125.11 Torr / Autoclave 7: sodium hydroxide / ethanol / 1 h / Reflux View Scheme

(R,S)-2-(4'-methylphenyl) propionic acid (938-94-3) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions

Yield

Multi-step reaction with 6 steps 1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / dichloromethane / Reflux 2: sulfuric acid / 16 h / 0 - 5 °C 3: sodium periodate / N,N-dimethyl-formamide / 150 °C 4: hydrogenchloride / water / 4.5 h / Reflux 5: 5%-palladium/activated carbon; hydrogen / methanol / 14 h / 10 - 15 °C / 1125.11 Torr / Autoclave 6: sodium hydroxide / ethanol / 1 h / Reflux View Scheme

2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: sulfuric acid / 16 h / 0 - 5 °C 2: sodium periodate / N,N-dimethyl-formamide / 150 °C 3: hydrogenchloride / water / 4.5 h / Reflux 4: 5%-palladium/activated carbon; hydrogen / methanol / 14 h / 10 - 15 °C / 1125.11 Torr / Autoclave 5: sodium hydroxide / ethanol / 1 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: sulfuric acid / toluene / 35 °C 1.2: 5 h / 281 °C 2.1: sodium methylate / toluene; dimethyl sulfoxide; methanol / 1.5 h / 2 - 5 °C 2.2: 5 - 18 °C 3.1: acetic acid; sulfuric acid / water / 2 h / 110 °C 4.1: sodium hydroxide / acetone / 30 °C / pH 7.2 View Scheme
Multi-step reaction with 4 steps 1: sulfuric acid / 6 h / 0 - 5 °C 2: potassium carbonate / toluene / 12 h / Reflux 3: hydrogen bromide; acetic acid / 8 h / Reflux 4: sodium hydroxide / ethanol; water / 3 h / 20 °C / pH 7 - 8 View Scheme
Multi-step reaction with 4 steps 1: sulfuric acid / 6 h / Cooling with ice 2: toluene / 12 h / 110 °C 3: sodium hydroxide; water / toluene / 2 h / 80 °C 4: sodium hydroxide / ethanol / 2 h / 50 °C View Scheme

2-(4-bromomethylphenyl)propionic acid methyl ester (99807-54-2) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium periodate / N,N-dimethyl-formamide / 150 °C 2: hydrogenchloride / water / 4.5 h / Reflux 3: 5%-palladium/activated carbon; hydrogen / methanol / 14 h / 10 - 15 °C / 1125.11 Torr / Autoclave 4: sodium hydroxide / ethanol / 1 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: sodium methylate / toluene; dimethyl sulfoxide; methanol / 1.5 h / 2 - 5 °C 1.2: 5 - 18 °C 2.1: acetic acid; sulfuric acid / water / 2 h / 110 °C 3.1: sodium hydroxide / acetone / 30 °C / pH 7.2 View Scheme
Multi-step reaction with 2 steps 1.1: sodium carbonate / acetone 2.1: hydrogenchloride / acetic acid / Reflux 2.2: Reflux View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / toluene / 12 h / Reflux 2: hydrogen bromide; acetic acid / 8 h / Reflux 3: sodium hydroxide / ethanol; water / 3 h / 20 °C / pH 7 - 8 View Scheme
Multi-step reaction with 3 steps 1: toluene / 12 h / 110 °C 2: sodium hydroxide; water / toluene / 2 h / 80 °C 3: sodium hydroxide / ethanol / 2 h / 50 °C View Scheme

2-(4-formylphenyl)propionic acid methyl ester (63476-54-0) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / water / 4.5 h / Reflux 2: 5%-palladium/activated carbon; hydrogen / methanol / 14 h / 10 - 15 °C / 1125.11 Torr / Autoclave 3: sodium hydroxide / ethanol / 1 h / Reflux View Scheme

loxoprofen methyl ester (81762-92-7) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
With sodium hydroxide In ethanol for 1h; Reflux;	35.36 g

C14H19BrO2 → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: magnesium; iodine / tetrahydrofuran / 20 - 25 °C 1.2: 0 - 20 °C 2.1: hydrogenchloride / methanol; water / 0 °C / Reflux 2.2: 0 °C / Reflux 3.1: sodium hydroxide; methanol / 1 h View Scheme

1-bromomethyl-4-bromobenzene (589-15-1) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sodium methylate / methanol / Reflux 2.1: acetic acid; hydrogenchloride / water / Reflux 3.1: pyridinium p-toluenesulfonate / methanol / 45 - 50 °C 4.1: magnesium; iodine / tetrahydrofuran / 20 - 25 °C 4.2: 0 - 20 °C 5.1: hydrogenchloride / methanol; water / 0 °C / Reflux 5.2: 0 °C / Reflux 6.1: sodium hydroxide; methanol / 1 h View Scheme

methyl 2-oxocyclopentane-1-carboxylate (10472-24-9) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sodium methylate / methanol / Reflux 2.1: acetic acid; hydrogenchloride / water / Reflux 3.1: pyridinium p-toluenesulfonate / methanol / 45 - 50 °C 4.1: magnesium; iodine / tetrahydrofuran / 20 - 25 °C 4.2: 0 - 20 °C 5.1: hydrogenchloride / methanol; water / 0 °C / Reflux 5.2: 0 °C / Reflux 6.1: sodium hydroxide; methanol / 1 h View Scheme

methyl 1-(4-bromobenzyl)-2-oxocyclopentanonecarboxylate → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: acetic acid; hydrogenchloride / water / Reflux 2.1: pyridinium p-toluenesulfonate / methanol / 45 - 50 °C 3.1: magnesium; iodine / tetrahydrofuran / 20 - 25 °C 3.2: 0 - 20 °C 4.1: hydrogenchloride / methanol; water / 0 °C / Reflux 4.2: 0 °C / Reflux 5.1: sodium hydroxide; methanol / 1 h View Scheme

2-(4-bromobenzyl)cyclopentanone (500764-03-4) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: pyridinium p-toluenesulfonate / methanol / 45 - 50 °C 2.1: magnesium; iodine / tetrahydrofuran / 20 - 25 °C 2.2: 0 - 20 °C 3.1: hydrogenchloride / methanol; water / 0 °C / Reflux 3.2: 0 °C / Reflux 4.1: sodium hydroxide; methanol / 1 h View Scheme

methyl 2-(4-methylphenyl)propanoate (79443-97-3) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / Reflux 2.1: sodium carbonate / acetone 3.1: hydrogenchloride / acetic acid / Reflux 3.2: Reflux View Scheme

C18H22O5 → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
Stage #1: C18H22O5 With hydrogenchloride In acetic acid Reflux; Stage #2: With sodium hydroxide In ethanol Reflux;

cyclopentanone (120-92-3) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: toluene-4-sulfonic acid / toluene / 8 h / 110 °C 2: toluene / 12 h / 110 °C 3: sodium hydroxide; water / toluene / 2 h / 80 °C 4: sodium hydroxide / ethanol / 2 h / 50 °C View Scheme

1-(N-morpholino)cyclopent-1-ene (936-52-7) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: toluene / 12 h / 110 °C 2: sodium hydroxide; water / toluene / 2 h / 80 °C 3: sodium hydroxide / ethanol / 2 h / 50 °C View Scheme

sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6) → sodium 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoate sesquihydrate

Conditions	Yield
Stage #1: sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate With pyrographite In ethanol; water; acetone at 55 - 65℃; for 0.5h; Stage #2: In ethanol; water; acetone at 0 - 40℃; for 4h;	90.3%

sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6) + Tolperisone hydrochloride → loxoprofen tolperisone salt (1043449-71-3)

Conditions	Yield
In isopropyl alcohol at 20℃; for 0.5h;

sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6) → loxoprofen (68767-14-6, 83599-42-2, 87828-34-0, 87828-35-1, 89675-45-6, 89675-46-7, 90319-65-6, 90319-73-6, 90319-74-7, 90319-78-1, 90365-02-9)

Conditions	Yield
With hydrogenchloride In water; toluene

sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6) → loxoprofen methyl ester (81762-92-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / water; toluene 2: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / 0 - 20 °C View Scheme

sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6) → methyl (+/-)-2-<4-(trans-2-hydroxycyclopentylmethyl)phenyl>propionate (89631-57-2, 89675-48-9, 90319-84-9, 90319-85-0, 90319-86-1, 90319-87-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / water; toluene 2: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / 0 - 20 °C 3: sodium tetrahydroborate / ethanol / 2 h / 0 °C View Scheme

sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6) → C25H42O3Si

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogenchloride / water; toluene 2: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / 0 - 20 °C 3: sodium tetrahydroborate / ethanol / 2 h / 0 °C 4: 1H-imidazole / dichloromethane; N,N-dimethyl-formamide View Scheme

sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6) → C24H40O3Si

Conditions	Yield
Multi-step reaction with 5 steps 1: hydrogenchloride / water; toluene 2: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / 0 - 20 °C 3: sodium tetrahydroborate / ethanol / 2 h / 0 °C 4: 1H-imidazole / dichloromethane; N,N-dimethyl-formamide 5: lithium hydroxide monohydrate / water; tetrahydrofuran; ethanol View Scheme

sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6) → C32H53F2NO5Si

Conditions

Yield

Multi-step reaction with 6 steps 1: hydrogenchloride / water; toluene 2: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / 0 - 20 °C 3: sodium tetrahydroborate / ethanol / 2 h / 0 °C 4: 1H-imidazole / dichloromethane; N,N-dimethyl-formamide 5: lithium hydroxide monohydrate / water; tetrahydrofuran; ethanol 6: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C View Scheme

1-bromoethyl acetate + sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6) → C19H24O5

Conditions	Yield
With triethylamine In toluene

chloromethyl n-butyrate (33657-49-7) + sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6) → C20H26O5

Conditions	Yield
With triethylamine In toluene

Upstream product

• 2362-36-9 1-(1-chloroethyl)-4-methylbenzene 
• 938-94-3 (R,S)-2-(4'-methylphenyl) propionic acid 
• 111128-12-2 2-[4-(bromomethyl)phenyl]propanoic acid 
• 99807-54-2 2-(4-bromomethylphenyl)propionic acid methyl ester 
• 63476-54-0 2-(4-formylphenyl)propionic acid methyl ester 
• 81762-92-7 loxoprofen methyl ester 
• 120-92-3 cyclopentanone 
• 936-52-7 1-(N-morpholino)cyclopent-1-ene 
• 611-10-9 2-ethoxycarbonyl-1-cyclopentanone 
• 79443-97-3 methyl 2-(4-methylphenyl)propanoate 
• 500764-03-4 2-(4-bromobenzyl)cyclopentanone 
• 10472-24-9 methyl 2-oxocyclopentane-1-carboxylate 
• 589-15-1 1-bromomethyl-4-bromobenzene 
• 68767-14-6 loxoprofen 

Downstream Products

• 1043449-71-3 loxoprofen tolperisone salt 
• 68767-14-6 loxoprofen 
• 81762-92-7 loxoprofen methyl ester 
• 89631-57-2 methyl (+/-)-2-<4-(trans-2-hydroxycyclopentylmethyl)phenyl>propionate 

Relevant articles and documents

Loxoprofen derivative

The invention provides a Loxoprofen derivative shown in the following formula (I). R1 is hydrogen atoms or substituted or non-substituted alkyl, R2 is substituted or non-substituted alkyl, the Loxoprofen derivative has low gastrointestinal tract side effects, and the bioavailability can be improved. The formula (I) is shown in the specification.

New method for synthesizing loxoprofen sodium

The invention belongs to the field of synthesis of organic matters and specifically relates to a new method for synthesizing loxoprofen sodium. The synthesis method is characterized by taking 2-(4-bromomethyl) phenylpropionic acid as a raw material and performing a 4-step reaction to prepare the loxoprofen sodium. The new method for synthesizing the loxoprofen sodium adopted by the invention has the effects that the yield is increased and the industrial prospect is good.

Loxoprofen sodium preparation method

The invention discloses a loxoprofen sodium preparation method, which comprises: directly carrying out alkylation on 2-(p-bromomethyl)isophenylpropionic acid as a starting raw material under a NaOH and DMF system, carrying out hydrolysis decarboxylating to obtain a crude product, separating the by-product produced in the reaction through high-vacuum distillation to obtain loxoprofen acid, and carrying out salt forming to obtain the loxoprofen sodium. According to the present invention, the method has characteristics of less synthesis step, mild reaction condition, reasonable price and easy purchase of the raw material, low pollution and low production cost, and is suitable for industrial production, wherein the product content can reach more than 99.8%, and the single impurity is less than0.05%.