Nedocromil Chemical Properties

Melting point:

298-300° (dec)

Boiling point:

645.5±55.0 °C(Predicted)

Density 

1.472±0.06 g/cm3(Predicted)

storage temp. 

Sealed in dry,2-8°C

solubility 

DMSO: soluble2mg/mL, clear (warmed)

pka

2.19±0.40(Predicted)

form 

Solid

color 

white to beige

Safety Information

Hazard Codes 

Xi

Risk Statements 

36

Safety Statements 

26

Nedocromil Usage And Synthesis

Description

Nedocromil sodium acts mainly by inhibiting the release of inflammatory mediators. It has a stabilizing action on mast cells similar to that of DSCG. Nedocromil is capable of inhibiting chloride ion flux in mast cells, epithelial cells, and neurons. This feature may explain why it can prevent responses such as mast cell degranulation and neuronal activation . Nedocromil is given by inhalation in the prophylactic control of asthma and rhinitis .

Originator

Alocril,Allergan,USA

Uses

Antiallergic (prophylactic).

Definition

ChEBI: Nedocromil is a dicarboxylic acid and an organic heterotricyclic compound. It has a role as a non-steroidal anti-inflammatory drug, an anti-asthmatic drug and an anti-allergic agent. It is a conjugate acid of a nedocromil(2-).

Manufacturing Process

4,6-Dioxo-10-propyl-4H,6H-pyrano[3,2-]quinoline-2,8-dicarbxylic acid disodium salt was prepared in 8 steps
1. 4-Acetamido-2-allylacetophenone
4-Acetamido-2-hydroxyacetophenone (19.3 g), allyl bromide (12.1 ml) and hydrous potassium carbonate (21.5 g) were stirred in dry dimethylformamide (250 ml) at room temperature for 24 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic solution was then washed well with water dried over magnesium sulphate and evaporated to dryness. The sub-title product was obtained as buff coloured solid (20.5 g). The structure of the product was confirmed by NMR and mass spectroscopy.
2. 4-Acetamido-3-allyl-2-hydroxyacetophenone
The above allyl ether (18.4 g) was heated at 200-210°C for 4 hours. 17.1 g of the thermally rearranged sub- title product was obtained as a brown solid. Again the structure was confirmed by NMR and mass spectroscopy.
3. 4-Acetamido-2-hydroxy-3-propyl acetophenone
The product of step 2 (17 g) was dissolved in glacial acetic acid and hydrogenated in the presence of Adams catalyst until hydrogen uptake had ceased. The catalyst was filtered off through a keiselguhr filter and the filtrate was evaporated to leave 13.0 g of almost colorless solid. The mass and NMR spectra confirmed the structure of product.
4. Ethyl-7-acetamido-4-oxo-8-propyl-4H-l-benzopyran-2-carboxylate
A mixture of diethyl oxalate (19.3 g; 17.9 ml) and the above product of step 3 (12.4 g) in dry ethanol (100 ml) was added to a stirred solution of sodium ethoxide in ethanol (prepared by dissolving sodium (6.1 g) in dry ethanol (200 ml)). The reaction mixture was refluxed for 3 hours and then poured into dilute hydrochloric acid and chloroform. The chloroform layer was separated, washed with water and dried. The solvent was evaporated to leave a brown solid which was dissolved in ethanol (300 ml) containing concentrated hydrochloric acid (3 ml) and the whole was refluxed for 1 hour. The reaction mixture was poured into water and the product was extracted into ethyl acetate which was washed with water and dried. The solvent was evaporated to leave 10 g of a sticky solid which had mass and NMR spectra consistent with the expected product.
5. Ethyl 7-amino-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate
A solution of the amide of step 4 (10 g) in ethanol (300 ml), containing concentrated hydrochloric acid (5 ml), was refluxed for 8 hours. The reaction mixture was diluted with water and extracted into ethyl acetate. The extract was washed with water, dried and the solvent was evaporated to leave a dark brown semi-solid. This was chromatographed on a silica gel column, using ether as eluant to give 4.8 g of the required product whose structure was confirmed by mass and NMR spectral evidence; mp 84-87°C.
6.8-Ethoxycarbonyl-2-methoxycarbonyl-4,6-dioxo-10-propyl-4H,6Hpyrano[3.2-g]quinoline
The amino benzopyran of step 5 (2.0 g) and dimethyl acetylene dicarboxylate (1.24 g; 1.01 ml) were refluxed in ethanol (30 ml) for 26 hours. The reaction mixture was cooled to 0°C and the insoluble yellow-brown solid was collected by filtration and washed with a little ethanol and dried to give 2.0 g of a product which was a mixture of maleic and fumaric esters obtained by Michael addition of the amine to the acetylene. This mixture of esters (2.0 g) was treated with polyphosphoric acid (30 ml) and heated on the steam bath with stirring for 20 minutes. The reaction mixture was then poured onto ice and stirred with ethyl acetate. The organic layer was separated, washed with water and dried. The solvent was evaporated to leave 1.6 g of a yellow orange solid. Recrystallisation of this solid from ethyl acetate gave the required product as fluffy orange needles, mp 187°-188°C.
7. 4,6-Dioxo-10-propyl-4H,6H-pyrano[3.2-g]quinoline-2,8-dicarboxylic acid
The above bis ester (2.5 g) was refluxed with sodium bicarbonate (1.64 g) in ethanol (100 ml) and water (50 ml) for 1.5 hours. The whole was poured into water and acidified to precipitate a gelatinous solid. This was collected by filtration, refluxed with ethanol and the product was separated by centrifugation (1.4 g), mp 303°-304°C dec. The structure of the product was confirmed by mass and NMR evidence.
8. Disodium 4,6-dioxo-10-propyl-4H,6H-pyrano[3,2-g]quinoline-2,8- dicarboxylate
The bis acid from step 6 (1.35 g) and sodium bicarbonate (0.661 g) in water (150 ml) were warmed and stirred until a clear solution was obtained. This solution was filtered and the filtrate was freeze dried to give 1.43 g of the required disodium salt.

Therapeutic Function

Antiallergic, Anti-asthmatic

Clinical Use

Nedocromil is a chromone analogue also used by inhalation as an aerosol, primarily in the prophylaxis of asthma and reversible obstructive airway disease. It inhibits release of allergic mediators, and it is effective in a broad range of patients. An ophthalmic solution is available for the treatment of seasonal and perennial allergic conjunctivitis. Other structurally related compounds are not currently available in the United States but are available in other markets.

Nedocromil(69049-73-6)Related Product Information

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• N,N-Diisopropylethylamine
• Ethylparaben
• Dihydromyrcenol
• Ethyl acetate
• Tetrahydropyran
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• Centchroman
• Propyl butyrate
• Tetrahydro-4H-pyran-4-one
• Ethyl acrylate
• 4-DIETHYLAMINO-2-METHOXY-BENZALDEHYDE
• 4-HYDROXY-2-METHYLQUINOLINE
• 3-(4-METHOXYBENZOYL)ACRYLIC ACID
• 4-HYDROXYBENZOYLACRYLIC ACID
• NEDOCROMIL DISODIUM SALT
• 4-(DIMETHYLAMINO)SALICYLALDEHYDE
• 6-ETHYLCHROMONE-2-CARBOXYLIC ACID