163133-43-5

Basic information

• Product Name: 4-(NITROOXY)BUTYL (2S)-2-(6-METHOXY-2-NAPHTHYL)PROPANOATE
• Synonyms: 4-(NITROOXY)BUTYL (2S)-2-(6-METHOXY-2-NAPHTHYL)PROPANOATE;NAPROXCINOD;(S)-2-(6-Methoxy-2-naphthyl)propanoic acid 4-nitrooxybutyl ester;Nitronaproxen;AZD 3582;HCT 3012;NAPROXCINOD INTERMEDIATES;AKFJWRDCWYYTIG-ZDUSSCGKSA-N
• CAS NO: 163133-43-5
• Molecular Formula: C₁₈H₂₁NO₆
• Molecular Weight: 347.36
• Mol File: 163133-43-5.mol
• Article Data: 7

Chemical Properties

• Boiling Point: 489.475 °C at 760 mmHg
• Flash Point: 193.208 °C
• Appearance: /
• Density: 1.213
• CAS DataBase Reference: 4-(NITROOXY)BUTYL (2S)-2-(6-METHOXY-2-NAPHTHYL)PROPANOATE(CAS DataBase Reference)
• NIST Chemistry Reference: 4-(NITROOXY)BUTYL (2S)-2-(6-METHOXY-2-NAPHTHYL)PROPANOATE(163133-43-5)
• EPA Substance Registry System: 4-(NITROOXY)BUTYL (2S)-2-(6-METHOXY-2-NAPHTHYL)PROPANOATE(163133-43-5)

Safety Data

• Hazardous Substances Data: 163133-43-5(Hazardous Substances Data)

Usage

Description

4-(NITROOXY)BUTYL (2S)-2-(6-METHOXY-2-NAPHTHYL)PROPANOATE, also known as a carboxylic ester derived from naproxen and 4-(nitrooxy)butanol, is a cyclooxygenase-inhibiting nitric oxide donator. It is metabolized to naproxen and a nitric oxide donating moiety, making it effective in the treatment of osteoarthritis.

Uses

Used in Pharmaceutical Industry:
4-(NITROOXY)BUTYL (2S)-2-(6-METHOXY-2-NAPHTHYL)PROPANOATE is used as a pharmaceutical agent for the treatment of osteoarthritis. It works by inhibiting cyclooxygenase and donating nitric oxide, which helps in reducing inflammation and pain associated with the condition.
Additionally, it can be used in the development of novel drug delivery systems to enhance its applications and efficacy in other medical conditions. Various organic and metallic nanoparticles can be employed as carriers for this compound, aiming to improve its delivery, bioavailability, and therapeutic outcomes.

Synthetic route

C21H18O4 (1395256-92-4) + 4-(nitrooxy)butan-1-ol (22911-39-3) → naproxcinod (163133-43-5)

Conditions	Yield
With dmap In dichloromethane; 1,2-dichloro-ethane at 0℃;	96.8%

C22H20O5 (1395256-94-6) + 4-(nitrooxy)butan-1-ol (22911-39-3) → naproxcinod (163133-43-5)

Conditions	Yield
With dmap In dichloromethane; 1,2-dichloro-ethane at 0℃;	92.8%

(S)-naproxenoyl chloride (51091-84-0) + 4-(nitrooxy)butan-1-ol (22911-39-3) → naproxcinod (163133-43-5)

Conditions	Yield
With calcium aluminosilicate In dichloromethane at 0 - 20℃; for 10h; Product distribution / selectivity;	90%
With calcium carbonate In dichloromethane at 0 - 20℃; for 10h; Product distribution / selectivity;	90%
In dichloromethane at 40℃; for 8.33333h; Heating / reflux;	88%

(2S)-2-(6-methoxy(2-naphthyl))propanoic acid (22204-53-1) + 4-(nitrooxy)butan-1-ol (22911-39-3) → naproxcinod (163133-43-5)

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 5℃; for 3h; Product distribution / selectivity;	85%

4-bromo-butyl (S)-2-(6-methoxy-2-naphthyl)-propanoate (1198786-35-4) → naproxcinod (163133-43-5)

Conditions	Yield
With silver nitrate In tetrahydrofuran; acetonitrile at 50℃; for 4h;	75%

1,4-butanediol dinitrate (3457-91-8) + Naprelan (26159-34-2) → naproxcinod (163133-43-5)

Conditions	Yield
In dimethyl sulfoxide for 120h;	75%

(2S)-2-(6-methoxy(2-naphthyl))propanoic acid (22204-53-1) + 4-(nitrooxy)butyl bromide (146563-40-8) → naproxcinod (163133-43-5)

Conditions	Yield
Stage #1: (2S)-2-(6-methoxy(2-naphthyl))propanoic acid With potassium hydrogencarbonate In DMF (N,N-dimethyl-formamide) at 50 - 60℃; for 1.5h; Stage #2: 4-(nitrooxy)butyl bromide With potassium iodide In DMF (N,N-dimethyl-formamide) at 20℃; for 25h;	73%

4-(nitrooxy)butyl p-toluensulfonate (669692-75-5) + (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (22204-53-1) → naproxcinod (163133-43-5)

Conditions	Yield
Stage #1: (2S)-2-(6-methoxy(2-naphthyl))propanoic acid With potassium hydrogencarbonate In DMF (N,N-dimethyl-formamide) at 50 - 60℃; for 1.5h; Stage #2: 4-(nitrooxy)butyl p-toluensulfonate In DMF (N,N-dimethyl-formamide) at 20℃; for 25h;	70%

(S)-4-hydroxybutyl-2-(6-methoxynaphtalen-2-yl) propanoate → naproxcinod (163133-43-5)

Conditions	Yield
With 2,6-di-tert-butyl-4-methylpyridine; trifluoromethylsulfonic anhydride; tetraethylammonium nitrate In dichloromethane at -70 - 20℃; for 4h;	65%

(S)-naproxenoyl chloride (51091-84-0) + 4-(nitrooxy)butan-1-ol (22911-39-3) → 2-(R)-(6-methoxy-2-naphthyl)-propanoic acid 4-nitroxybutyl ester (1262962-53-7) + naproxcinod (163133-43-5)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 10h; Product distribution / selectivity;
With 4-methyl-morpholine In dichloromethane at 0 - 20℃; for 10h; Product distribution / selectivity;

2-(S)-(4-chlorobutyl) 2-(6-methoxy-2-naphthyl)-propanoate (1198786-34-3) → naproxcinod (163133-43-5)

Conditions	Yield
With silver nitrate In acetonitrile at 25 - 85℃; Product distribution / selectivity; Industry scale;

2-(S)-(4-chlorobutyl) 2-(6-methoxy-2-naphthyl)-propanoate (1198786-34-3) → 1,4-butanediole bis-[2-(6-methoxy-2-naphthyl)]propionate + naproxcinod (163133-43-5)

Conditions	Yield
With silver nitrate In acetonitrile at 80 - 85℃;

(S)-2-(6-methoxy-2-naphthyl)propionyl acetate + 4-(nitrooxy)butan-1-ol (22911-39-3) → naproxcinod (163133-43-5)

Conditions	Yield
With dmap In dichloromethane for 2h;

(2S)-2-(6-methoxy(2-naphthyl))propanoic acid (22204-53-1) → naproxcinod (163133-43-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / diethyl ether / 18 h / 0 °C 2: diethyl ether / 18 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / 1,2-dichloro-ethane / 1 h / -25 °C 2: triethylamine / dichloromethane; 1,2-dichloro-ethane / 1 h View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 0 °C 2: dmap / dichloromethane; 1,2-dichloro-ethane / 0 °C View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 0 °C 2: dmap / dichloromethane; 1,2-dichloro-ethane / 0 °C View Scheme
Multi-step reaction with 2 steps 1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 2: trifluoromethylsulfonic anhydride; tetraethylammonium nitrate; 2,6-di-tert-butyl-4-methylpyridine / dichloromethane / 4 h / -70 - 20 °C View Scheme

C15H16O5S + 4-(nitrooxy)butan-1-ol (22911-39-3) → naproxcinod (163133-43-5)

Conditions	Yield
With triethylamine In dichloromethane; 1,2-dichloro-ethane for 1h;

naproxen + 4-(nitrooxy)butan-1-ol (22911-39-3) → naproxcinod (163133-43-5)

Conditions	Yield
In diethyl ether at 20℃; for 18h;

Upstream product

• 22911-39-3 4-(nitrooxy)butan-1-ol 
• 1395256-94-6 C₂₂H₂₀O₅ 
• 1395256-92-4 C₂₁H₁₈O₄ 
• 3457-91-8 1,4-butanediol dinitrate 
• 26159-34-2 Naprelan 
• 22204-53-1 (2S)-2-(6-methoxy(2-naphthyl))propanoic acid 
• 146563-40-8 4-(nitrooxy)butyl bromide 
• 669692-75-5 4-(nitrooxy)butyl p-toluensulfonate 
• 51091-84-0 (S)-naproxenoyl chloride 
• 1198786-34-3 2-(S)-(4-chlorobutyl) 2-(6-methoxy-2-naphthyl)-propanoate 
• 1198786-35-4 4-bromo-butyl (S)-2-(6-methoxy-2-naphthyl)-propanoate 

Relevant articles and documents

PROCESS FOR THE PREPARATION OF NITRATE ACID ESTER OF ORGANIC COMPOUNDS

The present invention relates to a one-step process for the synthesis of nitric acid esters or 15N isotopically labeled nitrate esters of organic compounds starting from the correspondent alcohols. Formula (I).

NAPTHYLENE INHIBITORS OF CYCLOOXYGENASE

The present invention relates to new napthylene inhibitors of cyclooxygenase activity, pharmaceutical compositions thereof, and methods of use thereof.

PROCESS FOR PREPARING 1,4-BUTANDIOL MONONITRATE

The present invention relates to a process for the preparation of 1,4-butanediol mononitrate as intermediate for large scale preparation of high purity nitrooxybutyl ester of pharmaceutically active compounds.