Hünig's base from BASF for more efficient pharmaceutical synthesis
Hünig's base from BASF for more efficient pharmaceutical synthesis
Hünig's base from BASF for more efficient pharmaceutical synthesis
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Hünig’s <strong>base</strong> <strong>from</strong> <strong>BASF</strong><br />
<strong>for</strong> <strong>more</strong> <strong>efficient</strong> <strong>pharmaceutical</strong> <strong>synthesis</strong><br />
By Dr. Thorsten Volk, <strong>BASF</strong><br />
Hünig’s <strong>base</strong> (N,N-diisopropylethylamine, DIPEA) – a colorless, slightly<br />
oily, flammable liquid – is a proton scavenger used mainly in the<br />
<strong>pharmaceutical</strong> industry <strong>for</strong> the <strong>synthesis</strong> of active <strong>pharmaceutical</strong><br />
ingredients (APIs). It is also employed in the manufacture of agricultural<br />
chemicals. Typical applications <strong>for</strong> Hünig’s <strong>base</strong> include chemical<br />
reactions such as acylation, elimination and alkylation of secondary<br />
amines with alkyl halogenides, where the respective halogen acid is<br />
generated in the course of the reaction. The halogen acid reacts with<br />
the nitrogen function of Hünig’s <strong>base</strong> and ammonium salts <strong>for</strong>m<br />
accordingly. Without Hünig’s <strong>base</strong>, some of the synthesized tertiary<br />
amine would take on the role of proton scavenger and hence reduce the<br />
yield. Although it must be strong, the auxiliary <strong>base</strong> must not be<br />
nucleophilic enough to act as an alkylating agent in its own right.<br />
Hünig’s <strong>base</strong> meets all the requirements <strong>for</strong> an auxiliary <strong>base</strong>. Its<br />
nucleophilicity is low due to steric hindrance, enabling its use in<br />
chemical reactions as a strong <strong>base</strong> and “proton sponge”. Unwanted<br />
secondary reactions do not occur because, unlike similar reagents such<br />
as di- and triethylamine which have both nucleophilic and basic<br />
properties, Hünig’s <strong>base</strong> is not capable of replacing the intended<br />
reaction partner due to its built-in steric hindrance.<br />
Prominent examples where Hünig’s <strong>base</strong> is used to great effect in the<br />
<strong>synthesis</strong> of complex precursors of active <strong>pharmaceutical</strong> ingredients<br />
include the drugs Valsartan and Pravastatin.<br />
Valsartan (Novartis) belongs a the class of drugs called non-peptide<br />
angiotensin II receptor antagonists. It is primarily used to treat high<br />
blood pressure. The drug is composed of a biphenyl structure<br />
substituted with a tetrazole group and another substituent containing an<br />
L-valine unit. The L-valine unit is converted to carbonic acid amide by<br />
aminolysis at room temperature whilst adding DIPEA. The hydrochloric<br />
acid generated during this reaction is bound by the Hünig’s <strong>base</strong> acting<br />
as a proton sponge [1].
Pravastatin (Pfizer) is a semisynthetic HMG-CoA reductase inhibitor<br />
(statin) with lipid-lowering properties. The enzyme which determines the<br />
pace of cholesterol <strong>synthesis</strong>, HMG-CoA reductase, is subject to<br />
competitive inhibition. Treatment with an HMG-CoA reductase inhibitor<br />
produces a dose-dependent reduction of plasma levels of total<br />
cholesterol and LDL cholesterol of up to 50 percent. Hünig’s <strong>base</strong> is<br />
successfully used as a proton scavenger in the <strong>synthesis</strong> of a precursor<br />
of the active <strong>pharmaceutical</strong> ingredient <strong>for</strong> nucleophilic substitution at<br />
the saturated carbon atom. Esterification with an alkyl halogenide takes<br />
place – <strong>base</strong>d on carbonic acid as an intermediate – and the hydrogen<br />
halogenide thus produced is bound by DIPEA [2].<br />
Another advantage of Hünig’s <strong>base</strong> <strong>for</strong> its application in chemical<br />
<strong>synthesis</strong> is that it is readily soluble in many organic solvents. At the<br />
same time, its hydrophilicity as a free <strong>base</strong> is so low that it is easy to<br />
recover in the process. One possible option is to extract Hünig’s <strong>base</strong><br />
into the aqueous phase as an ammonium salt <strong>from</strong> organic reaction<br />
mixtures that are not miscible with water.<br />
<strong>BASF</strong>, the world’s leading chemical company with its headquarters at<br />
Ludwigshafen, Germany has been a supplier of Hünig’s <strong>base</strong> and other<br />
proton scavengers since the mid-1990s. Other N-<strong>base</strong>s with protein<br />
scavenger properties similar to those of Hünig’s <strong>base</strong> include<br />
tritethylamine, tributylamine, 1,8-diazabicyclo-[5.4.0]undecen-7 (DBU),<br />
methylmorpholine and ethylmorpholine.<br />
However, the <strong>synthesis</strong> <strong>for</strong> the manufacture of DIPEA which was<br />
per<strong>for</strong>med in a continuous process at the Ludwigshafen site was<br />
unsatisfactory in terms of the product purity obtained. Moreover,<br />
manufacturing costs were high and yields low. Starting materials had to<br />
be discarded, resulting in high disposal costs.<br />
In response to these difficulties and in recognition of the market<br />
potential <strong>for</strong> high purity Hünig’s <strong>base</strong> in the <strong>pharmaceutical</strong> and<br />
agricultural chemicals industries, <strong>BASF</strong> Research and Development<br />
brought an improved technology to market readiness in record time<br />
which produced higher-purity Hünig’s <strong>base</strong> coupled with much higher<br />
yields. Although the starting date <strong>for</strong> modification of the manufacturing<br />
technology was not until the end of May 2005, production on a<br />
commercial scale was initialized as early as January 2006. Comparison<br />
of the <strong>for</strong>mer continuous process with the new batch process <strong>for</strong><br />
manufacture of Hünig’s <strong>base</strong> shows that – in addition to the higher<br />
purity – yields are higher and waste is lower. A guaranteed product<br />
purity of 99.5% or higher meets customer requirements, in particular<br />
those of the <strong>pharmaceutical</strong> industry. It enhances the process as a<br />
whole when the high purity of an auxiliary reagent such as Hünig’s <strong>base</strong><br />
results in fewer by-products during <strong>synthesis</strong> of an active<br />
<strong>pharmaceutical</strong> ingredient. It enhances the efficiency of the reaction<br />
process and lowers manufacturing costs, ultimately boosting overall<br />
cost-effectiveness.
The newly developed technology <strong>for</strong> the manufacture of Hünig’s <strong>base</strong><br />
constitutes a significant improvement in terms of sustainable<br />
development and environmental compatibility. Unlike the diethylsulfate<strong>base</strong>d<br />
processes used by a number of other suppliers, the <strong>BASF</strong><br />
process uses environmentally compatible starting materials like<br />
diisopropylamine and acetaldehyde. The high reaction yield produces<br />
less waste, and any waste produced is eliminated without any problems<br />
in a state of the art residue incineration plant.<br />
The <strong>BASF</strong> Intermediates Division is responsible <strong>for</strong> global development,<br />
production and marketing of Hünig’s <strong>base</strong> in addition to another 600<br />
products such as diols, amines, polyalcohols and acids. One of <strong>BASF</strong>’s<br />
major strengths is the high production capacities (<strong>more</strong> than 100 metric<br />
tons annually) in place at the Ludwigshafen site, the availability of single<br />
container solutions, and customized packaging and logistics solutions.<br />
Supplier reliability is excellent. <strong>BASF</strong> is also a reliable partner <strong>for</strong> users<br />
striving <strong>for</strong> <strong>more</strong> successful production processes on the basis of<br />
intelligent solutions and top quality products.<br />
[1] Eur. Pat. Appl. EP 443, 983 (1991), Priority CH Appl. 90/518,<br />
19 Feb 1990 (Ciba-Geigy)<br />
[2] Drugs Fut 1997, 22 (11), 1205<br />
Dr. Thorsten Volk<br />
Marketing Specialty Amines<br />
<strong>BASF</strong> Intermediates Division<br />
Phone +49 621 60-49662<br />
Fax +49 621 60-21033<br />
E-Mail: thorsten.volk@basf.com