Hünig's base from BASF for more efficient pharmaceutical synthesis

Hünig’s base from BASF
for more efficient pharmaceutical synthesis
By Dr. Thorsten Volk, BASF
Hünig’s base (N,N-diisopropylethylamine, DIPEA) – a colorless, slightly
oily, flammable liquid – is a proton scavenger used mainly in the
pharmaceutical industry for the synthesis of active pharmaceutical
ingredients (APIs). It is also employed in the manufacture of agricultural
chemicals. Typical applications for Hünig’s base include chemical
reactions such as acylation, elimination and alkylation of secondary
amines with alkyl halogenides, where the respective halogen acid is
generated in the course of the reaction. The halogen acid reacts with
the nitrogen function of Hünig’s base and ammonium salts form
accordingly. Without Hünig’s base, some of the synthesized tertiary
amine would take on the role of proton scavenger and hence reduce the
yield. Although it must be strong, the auxiliary base must not be
nucleophilic enough to act as an alkylating agent in its own right.
Hünig’s base meets all the requirements for an auxiliary base. Its
nucleophilicity is low due to steric hindrance, enabling its use in
chemical reactions as a strong base and “proton sponge”. Unwanted
secondary reactions do not occur because, unlike similar reagents such
as di- and triethylamine which have both nucleophilic and basic
properties, Hünig’s base is not capable of replacing the intended
reaction partner due to its built-in steric hindrance.
Prominent examples where Hünig’s base is used to great effect in the
synthesis of complex precursors of active pharmaceutical ingredients
include the drugs Valsartan and Pravastatin.
Valsartan (Novartis) belongs a the class of drugs called non-peptide
angiotensin II receptor antagonists. It is primarily used to treat high
blood pressure. The drug is composed of a biphenyl structure
substituted with a tetrazole group and another substituent containing an
L-valine unit. The L-valine unit is converted to carbonic acid amide by
aminolysis at room temperature whilst adding DIPEA. The hydrochloric
acid generated during this reaction is bound by the Hünig’s base acting
as a proton sponge [1].

Pravastatin (Pfizer) is a semisynthetic HMG-CoA reductase inhibitor
(statin) with lipid-lowering properties. The enzyme which determines the
pace of cholesterol synthesis, HMG-CoA reductase, is subject to
competitive inhibition. Treatment with an HMG-CoA reductase inhibitor
produces a dose-dependent reduction of plasma levels of total
cholesterol and LDL cholesterol of up to 50 percent. Hünig’s base is
successfully used as a proton scavenger in the synthesis of a precursor
of the active pharmaceutical ingredient for nucleophilic substitution at
the saturated carbon atom. Esterification with an alkyl halogenide takes
place – based on carbonic acid as an intermediate – and the hydrogen
halogenide thus produced is bound by DIPEA [2].
Another advantage of Hünig’s base for its application in chemical
synthesis is that it is readily soluble in many organic solvents. At the
same time, its hydrophilicity as a free base is so low that it is easy to
recover in the process. One possible option is to extract Hünig’s base
into the aqueous phase as an ammonium salt from organic reaction
mixtures that are not miscible with water.
BASF, the world’s leading chemical company with its headquarters at
Ludwigshafen, Germany has been a supplier of Hünig’s base and other
proton scavengers since the mid-1990s. Other N-bases with protein
scavenger properties similar to those of Hünig’s base include
tritethylamine, tributylamine, 1,8-diazabicyclo-[5.4.0]undecen-7 (DBU),
methylmorpholine and ethylmorpholine.
However, the synthesis for the manufacture of DIPEA which was
performed in a continuous process at the Ludwigshafen site was
unsatisfactory in terms of the product purity obtained. Moreover,
manufacturing costs were high and yields low. Starting materials had to
be discarded, resulting in high disposal costs.
In response to these difficulties and in recognition of the market
potential for high purity Hünig’s base in the pharmaceutical and
agricultural chemicals industries, BASF Research and Development
brought an improved technology to market readiness in record time
which produced higher-purity Hünig’s base coupled with much higher
yields. Although the starting date for modification of the manufacturing
technology was not until the end of May 2005, production on a
commercial scale was initialized as early as January 2006. Comparison
of the former continuous process with the new batch process for
manufacture of Hünig’s base shows that – in addition to the higher
purity – yields are higher and waste is lower. A guaranteed product
purity of 99.5% or higher meets customer requirements, in particular
those of the pharmaceutical industry. It enhances the process as a
whole when the high purity of an auxiliary reagent such as Hünig’s base
results in fewer by-products during synthesis of an active
pharmaceutical ingredient. It enhances the efficiency of the reaction
process and lowers manufacturing costs, ultimately boosting overall
cost-effectiveness.

The newly developed technology for the manufacture of Hünig’s base
constitutes a significant improvement in terms of sustainable
development and environmental compatibility. Unlike the diethylsulfatebased
processes used by a number of other suppliers, the BASF
process uses environmentally compatible starting materials like
diisopropylamine and acetaldehyde. The high reaction yield produces
less waste, and any waste produced is eliminated without any problems
in a state of the art residue incineration plant.
The BASF Intermediates Division is responsible for global development,
production and marketing of Hünig’s base in addition to another 600
products such as diols, amines, polyalcohols and acids. One of BASF’s
major strengths is the high production capacities (more than 100 metric
tons annually) in place at the Ludwigshafen site, the availability of single
container solutions, and customized packaging and logistics solutions.
Supplier reliability is excellent. BASF is also a reliable partner for users
striving for more successful production processes on the basis of
intelligent solutions and top quality products.
[1] Eur. Pat. Appl. EP 443, 983 (1991), Priority CH Appl. 90/518,
19 Feb 1990 (Ciba-Geigy)
[2] Drugs Fut 1997, 22 (11), 1205
Dr. Thorsten Volk
Marketing Specialty Amines
BASF Intermediates Division
Phone +49 621 60-49662
Fax +49 621 60-21033
E-Mail: thorsten.volk@basf.com