166983-58-0

Basic information

• Product Name: 5,7-dihydroxy-8-propanoyl-4-propyl-2H-chromen-2-one
• Synonyms: 5,7-Dihydroxy-8-propionyl-4-propyl-2H-chromen-2-one
• CAS NO: 166983-58-0
• Molecular Formula: C₁₅H₁₆O₅
• Molecular Weight: 276.2845
• Mol File: 166983-58-0.mol

Chemical Properties

• Boiling Point: 523.2°C at 760 mmHg
• Flash Point: 198.8°C
• Density: 1.29g/cm³
• Vapor Pressure: 1.45E-11mmHg at 25°C
• Refractive Index: 1.589
• CAS DataBase Reference: 5,7-dihydroxy-8-propanoyl-4-propyl-2H-chromen-2-one(CAS DataBase Reference)
• NIST Chemistry Reference: 5,7-dihydroxy-8-propanoyl-4-propyl-2H-chromen-2-one(166983-58-0)
• EPA Substance Registry System: 5,7-dihydroxy-8-propanoyl-4-propyl-2H-chromen-2-one(166983-58-0)

Safety Data

• Hazardous Substances Data: 166983-58-0(Hazardous Substances Data)

Upstream product

• 66346-59-6 5,7-dihydroxy-4-propylcoumarin 
• 79-03-8 propionyl chloride 
• 123-62-6 propionic acid anhydride 
• 3249-68-1 ethyl butyroyl acetate 
• 108-73-6 3,5-dihydroxyphenol 

Downstream Products

• 161753-49-7 (+/-)-Calanolide D 
• 161753-49-7 (+/-)-12-oxocalanolide A 
• 142632-32-4 (+)-calanolide A 

Relevant articles and documents

Automated process research. An example of accelerated optimization of the Friedel-Crafts acylation reaction, a key step for the synthesis of anti-HIV (+)-calanolide A

An automated process research approach to reaction optimization was developed. Chemical process research can be greatly accelerated by coupling automated synthesis equipment with statistical design of experiments (DoE). With the use of an automated process approach, multiple experiments can be performed in parallel on an automated platform, and multiple parameters that may influence process performance can be examined within one set of experiments generated from statistical design. We have successfully applied an automated process research approach to optimize the Friedel-Crafts acylation reaction that was used in our total synthesis of (+)-calanolide A, a potential anti-HIV agent currently in clinical trials. The in situ yield for a coumarin product was successfully optimized, increasing from 70% to 97% by HPLC analysis.

PROCESSES FOR PREPARING CALANOLIDE A AND INTERMEDIATES THEREOF

The present invention provides a production method of Calanolide A according to the following method wherein each symbol is as defined in the specification, as a more convenient and industrially practical method for the synthesis of Calanolide A from an easily available starting material.

Method for treating and preventing mycobacterium infections

Calanolides and analogues thereof that demonstrate potent mycobacterium activity are provided. Also provided is a method of using calanolides and analogues thereof for treating or preventing mycobacterium infections. The calanolides and analogues thereof provided are obtained via syntheses employing chromene 4 and chromanone 7 as key intermediates.

Calanolide analogues and methods of their use

Calanolide analogues that demonstrate potent antiviral activity against many viruses are provided. Also provided is a method of using calanolide analogues for treating or preventing viral infections. The calanolide analogues provided are obtained via syntheses employing chromene 4 and chromanone 7 as key intermediates.

Method for the preparation of (+/-)-calanolide A and intermediates thereof

A method of preparing (+/-)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. Useful intermediates for preparing (+/-)-calanolide A and its derivatives are also provided. According to the disclosed method, chromene 4 intermediate was reacted with acetaldehyde diethyl acetal or paraldehyde in the presence of an acid catalyst with heating, or a two-step reaction including an aldol reaction with acetaldehyde and cyclization either under acidic conditions or neutral Mitsunobu conditions, to produce chromanone 7. Reduction of chromanone 7 with sodium borohydride, in the presence of cerium trichloride, produced (+/-)-calanolide A. A method for resolving (+/-)-calanolide A into its optically active forms by a chiral HPLC system or by enzymatic acylation and hydrolysis is also disclosed. Finally, a method for treating or preventing a viral infections using (+/-)-calanolide or (-)-calanolide is provided.

Method for the preparation of (+)-calanolide a and analogues thereof

A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (±)-8a. Separation and enzyme-mediated resolution of (±)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (+)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.

Method for the preparation of (+)-calanolide A and analogues thereof

A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (±)-8a. Separation and enzyme-mediated resolution of (±)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (+)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.

Method for the preparation of (+)-calanolide A and intermediates thereof

A method for preparing (±)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. Useful intermediates for preparing (±)-calanolide A and its derivatives are also provided. According to the disclosed method, chromene 4 intermediate was reacted with acetaldehyde diethyl acetal in the presence of an acid catalyst with heating to produce chromanone 7. Reduction of chromene 7 with sodium borohydride, in the presence of cerium trichloride, produced (±)-calanolide A, which was purified chromatographically.

Synthesis, chromatographic resolution, and anti-human immunodeficiency virus activity of (±)-calanolide A and its enantiomers

The anti-HIV agent (±)-calanolide A (1) has been synthesized in a five- step approach starting with phloroglucinol [→ 5 → 6 → 11 → 18 → (±)- 1], which includes Pechmann reaction, Friedel-Crafts acylation, chromenylation with 4,4-dimethoxy-2-methylbutan-2-ol, cyclization, and Luche reduction. Cyclization of chromene 11 to chromanone 18 was achieved by employing either acetaldehyde diethyl acetal or paraldehyde in the presence of trifluoroacetic acid and pyridine or PPTS. Luche reduction of chromanone 18 at lower temperature preferably yielded (±)-1. Reduction of chromone 12, synthesized by Kostanecki-Robinson reaction from chromene 11, failed to afford (±)-1. The synthetic (±)-1 has been chromatographically resolved into its optically active forms, (+)- and (-)-1. The anti-HIV activities for synthetic (±)-1, as well as resultant (+)- and (-)-1, have been determined. Only (+)-1 accounted for anti-HIV activity, which was similar to the data reported for the natural product, and (-)-1 was inactive.

Novel Approach for Synthesis of (+/-)-Calanolide A and Its Anti-HIV Activity

Anti-HIV agent (+/-)-calanolide A (1) has been synthesized.The key intermediate, chromone 5, was synthesized by the sequence of Pechmann reaction, acylation and chromenylation by 4,4-dimethoxy-2-methylbutan-2-ol.The anti-HIV activity for synthetic (+/-)-1 has been determined and compared with the natural product.