Iloprost

From The Cure For The Needy

Contents 1 Iloprost (Ventavis) 1.1 Effective Against 1.2 Cost 1.3 Reported Routes of Synthesis 1.4 Submitted Syntheses

Iloprost (Ventavis)

Effective Against

Pulmonary hypertension, Scleroderma, Raynaud's phenomenon and Ischaemia

Iloprost is a form of prostacyclin. It is similar to a chemical in the body that widens (dilates) blood vessels, such as those in the arteries or lungs. Widening the blood vessels decreases high blood pressure.

The two diastereoisomers of iloprost differ in their potency in dilating blood vessels, with the 4S isomer substantially more potent than the 4R isomer.

Cost

From Tocris Bioscience: 181 USD (1mg)

Reported Routes of Synthesis

Reaction of the lactone (I) with lithium ethyl acetate followed by acid catalyzed dehydration and hydrolysis of the ester group with K2CO3 in methanol affords the hydroxy compound (II), which gives after Collins oxidation, treatment with 1,5-diazabicyclo [4.3. 0] non-5-ene (DBN) and reduction with NaBH4, the ketoester (III). Dealkoxy carbonylation with DABCO in toluene, benzoylation and removal of the silyl group with acetic acid in THF-water yield the ketone (IV). Ketalization of the ketone (IV) with ethylene glycol, Collins oxidation and condensation of the resulting aldehyde with the sodium salt of the phosphonate (V) afford the enone (VI). Reduction of (VI) with NaBH4 in methanol, cleavage of the ketal function with acetic acid-H2O and subsequent tetrahydropyranylation lead to the ketone (VII). Wittig condensation of the ketone (VII) with (VIII) and NaH in DMSO affords after chromatographic separation the acid (IX), which is finally deprotected to (X) (ZK-36374) by treatment with acetic acid in THF-water mixture.

Schillinger, E.; Vorbrueggen, H. Ciloprost. Drugs Fut 1981, 6(11): 676

Skuballa, W.; Raduechel, B.; Vorbrueggen, H.; Mannesmann, G.; Losert, W.; Casals, J. (Schering AG); Novel prostacyclin derivatives and a process for the preparation thereof. DE 2845770; ES 485199; US 4692464

Obtained from http://www.chemdrug.com/ Specific, translated page available here.

Cost of Starting Materials and Selected Reagents:
Starting Material [(4S,5R)-4-(hydroxymethyl)-2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-5-yl] benzoate
Possible Precursors:

• (−)-Corey lactone, 4-phenylbenzoate alcohol from Sigma-Aldrich: 195.5 USd (1g)
  
• (3aR,4S,5R,6aS)-(−)-Hexahydro-5-hydroxy-4-(hydroxymethyl)-2H-cyclopenta[b]furan-2-one from Sigma Aldrich: 438.5 USD (1 g)
  
• tert-Butyl(chloro)dimethylsilane from Sigma-Aldrich: 72.4 USD (25g)
  

Lithium Ethyl Acetate

• Ethyl Acetate from Sigma-Aldrich: 55.7 USD (1 L)
  
• Lithium from Sigma-Aldrich: 35.6 USD (10g)
  

Potassium Carbonate from Sigma-Aldrich: 35.6 USD (100g)
Sodium Borohydride from Sigma-Aldrich: 79.2 USD (100g)
Toluene from Sigma-Aldrich: 40.9 USD (1 L)
Methanol from Sigma-Aldrich: 42.3 USD (1 L)
p-Toluenesulfonic acid monohydrate from Sigma-Aldrich: 22.1 USD (100g)
1,5-diazabicyclo [4.3. 0] non-5-ene (DBN) from Sigma-Aldrich: 51.50 USD (25 mL, 1.005 g/mL)
Chromium(VI) oxide from Sigma-Aldrich: 227 USD (1 kg) (for Collins Reagent)
Pyridine from Sigma-Aldrich: 66.50 USD (100 mL, 0.978 g/mL)
1,4-diazabicyclo[2.2.2]octane (DABCO) from Sigma-Aldrich: 25.2 USD (25g)
Benzoyl Chloride from Sigma-Aldrich: 57.7 USD (250 mL, 1.211 g/mL)
Acetic Acid from Sigma-Aldrich: 28.8 USD (100g)
Ethylene glycol from Sigma-Aldrich: 30.6 USD (100mL,1.113 g/mL)
1-dimethoxyphosphoryl-3-methyl-hept-5-yn-2-one

•  ???

Sodium 5-triphenylphosphoranylidenepentanoate

• 5-Chlorovaleric Acid from Sigma-Aldrich: 68.8 USD (10 mL,1.17 g/mL)
  
• Triphenylphosphine from Sigma-Aldrich: 35.8 USD (100g)
  

3,4-Dihydro-2H-pyran (DHP) from Sigma-Aldrich: 20.7 USD (100 mL, 0.922 g/mL)
Sodium Hydride from Sigma-Aldrich: 147.5 USD (50g)

Submitted Syntheses