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Allessan®CAP
A Highly Efficient Coupling and Water Removal Reagent
Dr. Peter Talbiersky
WeylChem International GmbH
May 2016
Allessan® CAP
Chemical Name: Propane Phosphonic Acid Anhydride (PPA)
Empirical Formula: [C3H7O2P]3
CAS-No: 68957-94-8
Molecular Weight: 318.18 g/mol
H3C
O
O
O
P
O
O
P
Clear colourless liquid
O
Bp 200 °C/0.4 bar
Density 1.069 g/mL at 25 °C
P
H3C
CH3
Benefits
Allessan®CAP is an outstanding peptide coupling and water removal reagent, offering several
advantages over many other traditional but hazardous coupling reagents such as DCC (toxic),
HOBt (explosive), HBTU and PyBOP.
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Safe handling – no CMR properties, non-toxic, non-allergenic, non-sensitizing
Excellent safety profile: high thermal stability, no decomposition
Broad functional group tolerance, mild reaction conditions (0-25°C)
Well established at large scale for challenging liquid phase amide/peptide coupling reactions
Low epimerization, no additives required
Excellent selectivity, high chemical and optical purity, high product purities and excellent yields
Easy purification/work up due to water soluble ionic by-products, no need of chromatographic columns
Simple product isolation by liquid/liquid extraction and phase separation
Reduced overall process costs
Long shelf life (> 36 months)
No special storage required
Comparision of degree of racemization of different coupling reagents
Coupling Reagent
Racemization [%]
Yield [%]
PPA
1.8
86.6
HOBt/DCC
5.9
60.5
HOBt/EDC
11.1
67.3
HOAt/DCC
11.6
n.a.
PyBOP
14.2
63.4
HBTU
16.1
65.6
HATU
21.1
n.a.
* Supplement to Chimica Oggi/CHEMISTRY TODAY Vol 26 nr 4 • Focus on Peptides
PPA, DMF
DIPEA
Benefits of PPA versus common coupling reagents
Applications
Thanks to its less toxic nature, broad spectrum of applications, high selectivity and mild operating
conditions, Allessan®CAP offers several benefits in both medicinal chemistry and process
chemistry.
Allessan®CAP can be used for:
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Peptide couplings (linear and cyclic peptides)
Amidations
Esterifications
Functional Group Transformation (nitrile formation, olefine formation, aclohol oxidation,
reduction of carboxylic acids, Lossen rearrangement, Beckmann rearrangement)
• Synthesis of heterocyclic compounds (pyrazolone, indole, quinolines, coumarins)
• Swern-type oxidations as a substitute of oxalyl dichloride and triethylamine
• Aza-Diels-Alder reactions as a catalyst
Applications
General Mechanism for peptide/amide synthesis:
1st step: Formation of a mixed anhydride via ring opening of Allessan®CAP
2nd step: Formation of the corresponding peptide with formation of easily removable, nonhazardous, water-miscible propane phosphonic acid as a by-product
** ISSN 20799780, Review Journal of Chemistry, 2014, Vol. 4, No. 2, pp. 53–131. © Pleiades Publishing, Ltd., 2014.
Applications
Allessan®CAP as a coupling agent:
The pharmaceutical industry uses Allessan®CAP mainly in the synthesis of peptides as active
pharmaceutical ingredients or advanced building blocks.
• Synthesis of amides and linear peptides (especially suited for connecting sterically hindered
amino acids)
• Synthesis of cyclic peptides (head-to-tail peptide macrocyclization)
• Coupling of racemization-prone substrates, using pyridine as a base
• Coupling of deactivated amino acids
Benefits of Allessan®CAP vs traditional coupling agents:
Low susceptibility towards racemization
** ISSN 20799780, Review Journal of Chemistry, 2014, Vol. 4, No. 2, pp. 53–131. © Pleiades Publishing, Ltd., 2014.
Applications
Allessan®CAP as a coupling agent:
The pharmaceutical industry uses Allessan®CAP mainly in the synthesis of peptides as active
pharmaceutical ingredients or advanced building blocks.
• Synthesis of amides and linear peptides (especially suited for connecting sterically hindered
amino acids)
• Synthesis of cyclic peptides (head-to-tail peptide macrocyclization)
• Coupling of racemization-prone substrates, using pyridine as a base
• Coupling of deactivated amino acids
Benefits of Allessan®CAP vs traditional coupling agents:
Faster reactions with higher yield
CH2Cl2, NMM
48h, 62%
CH2Cl2, DMAP
16h, 65%
PPA
(1 equiv.)
BOP
(1 equiv.)
Cyclosporine
** ISSN 20799780, Review Journal of Chemistry, 2014, Vol. 4, No. 2, pp. 53–131. © Pleiades Publishing, Ltd., 2014.
Applications
Allessan®CAP as a coupling agent:
The pharmaceutical industry uses Allessan®CAP mainly in the synthesis of peptides as active
pharmaceutical ingredients or advanced building blocks.
• Synthesis of amides and linear peptides (especially suited for connecting sterically hindered
amino acids)
• Synthesis of cyclic peptides (head-to-tail peptide macrocyclization)
• Coupling of racemization-prone substrates, using pyridine as a base
• Coupling of deactivated amino acids
Benefits of Allessan®CAP vs traditional coupling agents:
Effective coupling of deactivated amino acids
** ISSN 20799780, Review Journal of Chemistry, 2014, Vol. 4, No. 2, pp. 53–131. © Pleiades Publishing, Ltd., 2014.
Allessan®CAP as a water scavenger agent:
Allessan®CAP is a pH neutral dehydration reagent, similar in strenghth to the highly reactive and
hazardous phosphorous pentoxid and polyphosphoric acid, alternative to molecular sieves for
water removal from organic solvents and providing Lewis acid catalysis potential for reactions.
Allessan®CAP is a condensation reagent for the synthesis of:
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Carboxamides from carboxylic acids and amines
Peptides from protected amino acids
Esters from carboxylic acids and alcohols
Hydroxamic acids from carboxylic acids and hydroxylamines
Weinreb amides from carboxylic acids and N,O-Dialkylhydroxylamindes
Barton anhydrides from thiohydroxamic acids and carboxylic acids
Nitriles from aldoximes or carboxylic acids and tert-amines
Easy access to Weinreb amides
Allessan®CAP allows mild reaction conditions and easy work up
The Weinreb amides can be converted into aldehydes in high yield, while the chiral information is
fully maintained.
** ISSN 20799780, Review Journal of Chemistry, 2014, Vol. 4, No. 2, pp. 53–131. © Pleiades Publishing, Ltd., 2014.
Further synthetic applications of Allessan®CAP:
Functional group transformations using Allessan®CAP
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Conversion of aldoximes and ketoximes into nitriles and amides
Transformation of aromatic, heteroaromatic and aliphatic aldehydes to respective nitriles
Direct conversion of carboxylic acids and carboxamides into nitriles
Direct conversion of formamides into isonitriles
Oxidation of primary and secondary alcohols to corresponding carbonyl compounds
Synthesis of olefines from primary and secondary alcohols
Reduction of carboxylic acids into alcohols
Chemoselective acetalization and thioacetalization of aldehydes
Conversion of Nα-protected amino/peptide acids into thioacids
Conversion of Amino-substitued carboxamides into imidazolidines
Conversion of N-acylhydrazides into oxadiazoles
Conversion of hydroxamic acid to an isocyanate (Lossen rearrangement)
Easy access to nitriles and amides in excellent yields:
Allessan®CAP allows mild reaction conditions and reduction of toxic by-products at the same time
** ISSN 20799780, Review Journal of Chemistry, 2014, Vol. 4, No. 2, pp. 53–131. © Pleiades Publishing, Ltd., 2014.
Further synthetic applications of Allessan®CAP:
Functional group transformations using Allessan®CAP
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Conversion of aldoximes and ketoximes into nitriles and amides
Transformation of aromatic, heteroaromatic and aliphatic aldehydes to respective nitriles
Direct conversion of carboxylic acids and carboxamides into nitriles
Direct conversion of formamides into isonitriles
Oxidation of primary and secondary alcohols to corresponding carbonyl compounds
Synthesis of olefines from primary and secondary alcohols
Reduction of carboxylic acids into alcohols
Chemoselective acetalization and thioacetalization of aldehydes
Conversion of Nα-protected amino/peptide acids into thioacids
Conversion of Amino-substitued carboxamides into imidazolidines
Conversion of N-acylhydrazides into oxadiazoles
Conversion of hydroxamic acid to an isocyanate (Lossen rearrangement)
Additional Information
Conversion of carboxylic acid derivatives into
nitriles:
Conversion of formamides into isonitriles:
** ISSN 20799780, Review Journal of Chemistry, 2014, Vol. 4, No. 2, pp. 53–131. © Pleiades Publishing, Ltd., 2014.
Further synthetic applications of Allessan®CAP:
Functional group transformations using Allessan®CAP
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Conversion of aldoximes and ketoximes into nitriles and amides
Transformation of aromatic, heteroaromatic and aliphatic aldehydes to respective nitriles
Direct conversion of carboxylic acids and carboxamides into nitriles
Direct conversion of formamides into isonitriles
Oxidation of primary and secondary alcohols to corresponding carbonyl compounds
Synthesis of olefines from primary and secondary alcohols
Reduction of carboxylic acids into alcohols
Chemoselective acetalization and thioacetalization of aldehydes
Conversion of Nα-protected amino/peptide acids into thioacids
Conversion of Amino-substitued carboxamides into imidazolidines
Conversion of N-acylhydrazides into oxadiazoles
Conversion of hydroxamic acid to an isocyanate (Lossen rearrangement)
Allessan®CAP – Additional Information
Oxidation of alcohols to the corresponding
carbonyl compounds:
Reduction of carboxylic acids into alcohols:
Synthesis of olefines:
** ISSN 20799780, Review Journal of Chemistry, 2014, Vol. 4, No. 2, pp. 53–131. © Pleiades Publishing, Ltd., 2014.
Further synthetic applications of Allessan®CAP
Functional group transformations using Allessan®CAP
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Conversion of aldoximes and ketoximes into nitriles and amides
Transformation of aromatic, heteroaromatic and aliphatic aldehydes to respective nitriles
Direct conversion of carboxylic acids and carboxamides into nitriles
Direct conversion of formamides into isonitriles
Oxidation of primary and secondary alcohols to corresponding carbonyl compounds
Synthesis of olefines from primary and secondary alcohols
Reduction of carboxylic acids into alcohols
Chemoselective acetalization and thioacetalization of aldehydes
Conversion of Nα-protected amino/peptide acids into thioacids
Conversion of Amino-substitued carboxamides into imidazolidines
Conversion of N-acylhydrazides into oxadiazoles
Conversion of hydroxamic acid to an isocyanate (Lossen rearrangement)
Allessan®CAP catalyzed acetalization
Access to acetals and thioacetals with high chemoselectivity and high yields
** ISSN 20799780, Review Journal of Chemistry, 2014, Vol. 4, No. 2, pp. 53–131. © Pleiades Publishing, Ltd., 2014.
Further synthetic applications of Allessan®CAP
Synthesis of heterocyclic compounds using Allessan®CAP
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Synthesis
Synthesis
Synthesis
Synthesis
Synthesis
Synthesis
Synthesis
Synthesis
Synthesis
Synthesis
Synthesis
of β-lactams and β-sultams
of pyrazolones
of carbamates
of imidazoles
of 1,2,4-triazoles
of 1,2,4-oxadiazoles
of 1,3,4-thiadiazoles
of indoles
of quinolines
of hydroxamates
of coumarins via Perkin condensation
Allessan®CAP mediated synthesis of various heterocycles:
** ISSN 20799780, Review Journal of Chemistry, 2014, Vol. 4, No. 2, pp. 53–131. © Pleiades Publishing, Ltd., 2014.
Further synthetic applications of Allessan®CAP
Allessan®CAP is a reagent for the synthesis of
Ureas, urethanes and thiocarbamates from hydroxamic acids and an appropriate N-,O-, or S- nucleophile
Allessan®CAP is a substitute for :
Oxalyl dichloride and triethylamine in Swern-type oxidations of primary or secondary alcohols
Allassan®CAP as an efficient catalyst/promoter
• Synthesis of pyrano – and furo [3,2-c] quinolines by Aza-Diels-Alder reactions of aldamines with
dihydropyran or dihydrofuran
• Beckmann rearrangement of ketoximes to amides and of aldoximes to nitriles
• Quick access to Bi(indolyl)methanes
• Synthesis of 2-azetidinones by [2+2] ketene-imine cycloaddition (Staudinger)
• Synthesis of novel γ–carboline derivatives
Allessan®CAP as an acid activating agent
Synthesis of acyl azides and ureidopeptides
Facility, Packaging, Solvents
Facility:
• Allessan®CAP is being produced in an ISO9001 certified facility for more than one decade now
• Capacity: several hundreds of tons per year
Variety of Solvents:
• Allessan®CAP is typically offered as a concentrated 50% (w/w) solution in various kinds of
solvents
• The most common solvents are EtOAc and THF, but we are highly flexible regarding our
customer needs (DMF, 2-Me-THF, ACN, BuOAc, toluene, …)
Packaging:
• 5 L, 50 L, 200 L steel drums with PE inliners or twinlock drums (DMF)
• Only 5 L drums are allowed to be shipped by air freight
General CoA of Allessan®CAP
* Content of solvent free Allessan®CAP = 100 - solvent content
Dr. Peter Talbiersky
Marketing & Sales Manager
WeylChem International GmbH
Alt-Fechenheim 34
60386 Frankfurt am Main
Germany
Tel. +49 69 506 820 2386
[email protected]
www.weylchem.com
01.03.2016
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