Note: Descriptions are shown in the official language in which they were submitted.
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The present invention relates to a process for the
production of 5~-[2-(p-chlorophenoxy)-isobutyryl]-~ -
nicotinoyl glycol ester.
~ -[2-(p-chlorophenoxy-isobutyryl]-~ -nicotinoyl
glycol ester is a known chemical compound which melts at
47C. As a component of pharmaceutical preparations, ~-[2-
(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester has
a liquid-lowering effect in the case of hyperlipoidemia and
in the case of increased triglyceride and cholesterol
values. Clinical tests have shown that with an intake of
300 mg of ~-[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl
glycol ester per patient per day, there is significant
decrease in the content of cholesterol, triglyceride,
phosphatides and free fatty acids in the blood of the
patients.
A process for the production of ~ -[2-(p-chloro-
phenoxy)-isobutyryl]-~ -nicotinoyl glycol ester is already
known. According to German Patent No. 941 217, 2-(p-chloro-
phenoxy)-isobutyric acid is reacted with an ethylene glycol
excess in the presence of catalytic quantities of phosphoric
acid and p-toluolsulphonic acid to give a semi-ester. This
semi-ester is reacted with an excess of nicotinic acid
chloride in tetrahydrofuran under cooling with ice. After
re-crystallization from acetic acid, a 70% yield of ~-[2-
(p-chlorophenoxy)-isobutyryl]- ~-nicotinoyl glycol ester
hydrochloride having a melting point of 100C is obtained.
Although this known process leads to useful
yields of the desired compound, it does have certain dis-
advantages. The nicotinic acid chloride reacted with the
semi-ester is a compound sensitive to hydrolysis. For
this reason the reaction must be carried out in moisture-
free conditions. Moreover, during the reaction free hydro-
chloric acid is produced, which demands corrosion-resistant
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apparatus.
The present invention seeks to provide an improved
process for the production of ~-[2-~p-chlorophenoxy-isobutyryl]-
~-nicotinoyl glycol ester, which substantially precludes
the above-mentioned disadvantages and leads to an improved
yield of the desired product.
According to the present invention there is
provided a process for the production of ~ -[2-~p-chloro-
phenoxy)-isobutyryl]- ~-nicotinoyl glycol ester in which
~ -[2-(p-chlorophenoxy)-isobutyryl]- ~-ethyl chloride ester
is reacted with an alkali metal salt of nicotinic acid.
Under the reaction conditions which are provided in accordance
with the invention, the desired ester is produced in yields
Of 90 to 95%-
To the expert it must be considered amazing
that practically no quaternisation of the pyridine nitrogen
occurs during the reaction of the higher alkyl chloride.with
the nicotinic acid salt which is a pyridine derivative.
It is known from the Handbook of Synthetic Medicines
(SYNTHETISCHE ARZNEIMITTEL), edited by Dr. W. Knoblock,
Akademie-Verlag, Berlin 1961, page 531, that during the
reaction of pyridine with cetyl chloride or other higher
alkyl chloride, it is N-cetylpyridium-chloride which
is chiefly obtained. Therefore, it is surprising that
practically no alkylation of the pyridine nitrogen occurs ;
during the reaction provided in accordance with the inven-
tion but that the desired ~ -[2-(p-chlorophenoxy)-isobutyryl)-
~ -nicotinoyl glycol ester is obtained in yields of 90 to
95~.
In the process according to the invention the sodium
salt of nicotinic acid is preferably used although other
alkali metal salts, such as lithium and potassium nicotinates
10541S3
are also suitable.
The reaction is preferably carried out in a polar
solvent having quite a high boiling point; solvents which
can be used for this purpose are tetra-hydrofuran, dimethyl-
5 formamide and dimethylsulphoxide. Dimethylformamide isespecially preferred because the best yields of ~ -[2-(p-
chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester are-
obtained. The process according to the invention is carried
out at quite a high temperature. Temperatures of 120 to
180C are suitable. At these temperatures, approximately
20 to 200 minutes reaction duration is needed for a virtually
complete reaction. However, even shorter times lead to
; a satisfactory reaction when the reactiontemperatures are
higher.
The process of the invention for the production
of ~ -[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol
ester leads to particularly good yields when ~ -[2-(p-chloro-
phenoxy)-isobutyryl]-~ -ethyl chloride ester is reacted
with sodium nicotinate for 30 to 120 minutes in boiling
dimethylformamide. At the same time approximately 5% of
dimethylformamide is advantageously removed by distillation
from the boiling dimethylformamide, so as to rid the reaction
mixture of volatile impurities that have formed. When the
reaction has ended, the reaction mixture is cooled to room
temperature. The sodium chloride that has formed is filtered
off and washed several times with small quantities of dimethyl-
formamide. The washing dimethylformamide is combined with
the reaction solution and the dimethylformamide is then
completely removed by distillation at a moderately high
temperature in vacuum. The raw ~ -[2-(p-clorophenoxy)-
isobutyryl]-~ -nicotinoyl glycol ester which then remains,
and which is virtually free of dimethylformamide, is absorbed
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in isopropanol and stirred in boiling isopropanol for
about 40 to 120 minutes together with a bleaching agent.
The bleaching agent is subsequently filtered from the hot
solution. An example of a suitable bleaching agent is
Tonsil 70 CC (Trade ~ark). The warm filtered solution
containing the desired product is then mixed in a ratio
of about 1:1 with cold isopropanol and the crystallization
of the desired ester commences. After about 6 to 10 hours
at 6 to 8C the desired product has largely crystallized
out and the crystalline pulp is spun off, comminuted and
dried. A 70 to 75% yield of ~ -[2-(p-chlorophenoxy)-isobut-
yryl]-~ -nicotinoyl glycol ester is obtained. It is a white
to pale yellow product. During re-processing of the mother
liquor, a further approximately 20% of ester is isolated
so that using the process of the invention a total yield
of about 90 to 95% is achieved.
The reactants, solvents and adjuvants used in the
process according to the invention are, on the whole, easily
accessible starting materials and are commercially obtainable.
If ~ -[2-(p-chlorophenoxy)-isobutyryl]-~ - ethyl chloride
ester should not be available in the required quantity and/or
purity, then this ester may, for example, be obtained quite
easily from ethyl chloride and p-chlorophenoxy-isobutyric
acid. For example, 4 moles of ethyl chloride may be heated
to about 100C with 1 mole of p-chlorophenoxy-butyric acid
in the presence of catalytic quantities of boron trifluoride
(approx. 5%, referred to the acid), and caused to react at -
this temperature within 50 to 60 minutes. The excess ethyl - -
chloride is then removed by distillation, the residue is
absorbed into chloroform and washed several times with 10%
NaHCO3 solution. Fractional distillation is then carried out.
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It is possible for the d - [2-(p-chlorophenoxy)-isobutyryl]-
-ethyl chloride ester to be distilled in water jet vacuum
without decomposing. Boiling point 181C/13 torr.
The invention will now be further described with
reference to the following example.
Example:
,
8,310 kg of ~ -[2-(p-chlorophenoxy)-isobutyryl]-
-ethyl chloride ester, 4,350 kg of sodium nicotinate
and 60,000 litres of dimethylformamide are placed in a
reaction flask provided with stirring means and a column.
They are reacted while being stirred and heated to 150 to
155C, for 60 minutes. During the course of the reaction
3 litres of dimethylformamide are removed under normal pressure
by way of the distillation column. When the reaction has
ended, the deposit is cooled to room temperature and the
sodium chloride that has separated out is removed by filtra-
tion. Subsequent washing of the filter cake is effected
with approx. 8 litres of dimethylformamide.
The filtrate is sub~ected to vacuum distillation at
15 to 20 torr, approximately 60 litres of dimethylformamide
being removed during this process. The distillation residue
is stirred under reflux with 5 litres of isopropanol and 0.5
kg of active carbon for a period of 60 minutes, and is then
filtered in a pressure filter. The filter cake is sub-
sequently washed with approximately 2 litres of isopropanol.
Finally, the filtrate is mixed with 3 litres of cold
isopropanol and crystallized at 10C.
After standing overnight, the reaction product
is centrifuged and is dried in a vacuum drying cabinet at
30C. In the next batch the mother lye is used instead of
the isopropanol.
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Approximately 10 kg of ~ -[2-(p-chlorophenoxy)-
isobutyryl]-~ -nicotinoyl glycol ester having a melting
point of 46 to 48 is obtained (91% of theory).
The product has the following analysis: -
C: calculated: 59.40%, found: 59.22%
H: " 4.95%, " 4.98~
Cl: " 9.80% " 9.59%
N: " 3.85% " 3.88%
- The ~ -[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl
glycol ester produced in accordance with the invention is
a pale yellow, crystalline powder, which can be used as
the active agent in pharmaceutical preparations. Both -
in human beings and in animals, oral administration, e.g. in
the form of tablets, lozenges, soft gelatin capsules and
hard gelatin capsules leads to a significant reduction
in the content of cholesterol, triglyceride phosphatides
and free fatty acids in the blood. ~-[2-(p-chlorophenoxy)-
isobutyryl]-~ -nicotinoyl glycol ester can also be worked
into tablets, lozenges and capsules that release the active
agent after a time-lag. A suitable medicine to be used
orally may for example consist of gelatin capsules each of
which contains 300 mg of ~ -[2-(p-chlorophenoxy)-isobutyryl]- ;
~-nicotinoyl glycol ester in 245 mg of wax mixture.
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