Process for the manufacture of lysergic

acid
Abstract

Lysergic acid is formed in high yields and high quality by isomerizing paspalic acid in a
phase separated mixture formed by paspalic acid and a concentrated aqueous metal
hydroxide solution. ® KIPO & WIPO 2007

Classifications

C07D457/04 Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring

systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon
atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g.
ester or nitrile radicals, directly attached in position 8

KR20070024490A
South Korea

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Korean
Inventor
블라스티슬라브 모즈크제크
라디슬라브 크바크

Worldwide applications
2005 KR CA JP UA WO BR EP RU US CN

Application KR1020067018668A events

2004-02-20
Priority to US54655904P
2004-02-20
Priority to US60/546,559
2005-02-17
Application filed by 아이박스 파마슈티컬스 에스.알.오.
2007-03-02
Publication of KR20070024490A

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Description

translated from Korean

Lee Sergio geusan method {PROCESS FOR THE MANUFACTURE OF LYSERGIC

ACID} of

The invention relates to a method for producing and purifying Li Sergio geusan to
screen the isomers Pas palsan in a high yield.

Sergio Li is the mountain natural ergot (ergot) of the basic structural alkaloids. Which is
mass-produced as an intermediate to synthesize the various semi-synthetic ergot
alkaloids have utility as drugs been found as Ergo meth Lin, methyl Ergo meth Lin,
methicillin Sergio Zaid and needle Sergio golrin.

Paz palsan well as ergot alkaloids, which can be easily obtained by fermentation.
Transposition of the Li Sergio geusan palsan of fasteners are known in a variety of
ways. However, with the current conversion process is the epimer (epimer) of the acid
yisori Sergio undesirable impurities, such as are produced, the conversion method does
not provide a simple removal of impurities yisori Sergio geusan method.

Li is a natural compound having a chiral Sergio geusan, Paz palsan and yisori Sergio R
configuration on the central chiral acid (chiral) of one of these 5-position of the
skeleton. Lee Sergio geusan used herein, Sergio yisori geusan and Paz palsan implies a
d- Lee Sergio geusan, d- yisori Sergio geusan and d- palsan Pas. Their structures are
shown below:

Typically the Re Sergio acids prepared by decomposition of natural ergot alkaloids such
as ergotamine or Ergo toxin isolated from ergot singer. Another typical manufacturing
method is by fermentation, for example, Li Sergio geusan hydroxy- includes a portion
of the synthesis from a naturally occurring precursor that can be obtained by
isomerization of hydrolysis or fasteners palsan of ethylamine.
Paz isomerization of the palsan and its re Sergio geusan was first revealed by Kobel
[Helv. Chim. Acta 47: 1052 (1964)]. The isomerization is carried out by boiling the
fasteners palsan from a dilute aqueous solution of sodium hydroxide. However Pas case
of performing the isomerization of palsan In this way, the Li mothamyeo satisfactory,
the transition to Sergio geusan (as the reaction mixture is 5% or more fasteners palsan
the residue), because it uses the high temperature product decomposes significant
amounts. The other method [Helv described by Kobel. Chim. Acta 64: 478 (1981) and
JP 70013302], i.e. Similar results were obtained even when using the isomerization in
boiling aqueous solution of potassium hydroxide. In addition, (containing about 5% of
the release of Li Sergio the acid yisori Sergio geusan) the reaction mixture is to contain
a significant amount of yisori Sergio geusan (25%), which degrades both the yield and
quality of the resulting Li Sergio geusan. Thus there is a need to further purify the
product. Another drawback was the fact that a need for a reactor volume the
concentration of the parse palsan low in the reaction mixture.

Recently, the bar is disclosed a method of manufacturing the novel Li Sergio geusan
described the use of a tetraalkylammonium hydroxide aqueous solution in order to
screen the isomers palsan fasteners (U.S. Patent No. 6,242,603). The yield of the
isolated Lee Sergio geusan containing yisori Sergio geusan of about 3% has been
reported to be about 80%. The content of the fasteners palsan in the product is not
disclosed. The reference is, as well as the isomerization in which a dilute aqueous
sodium hydroxide or potassium hydroxide, boiling, it is described that for producing Li
Sergio geusan by the above-described method. These comparative examples are Li
Sergio the acid that is described that is formed to be less than 60% yield.

Therefore, high purity, as well as it would be desirable to find a method for the
production of Li to yield Sergio geusan.

Summary of the Invention

The present invention provides a novel production method for obtaining a high yield
and high purity by Lee Sergio geusan from palsan Pas.

The invention also provides a novel method for separating yisori Sergio geusan from Li
Sergio geusan.

An advantage of the present invention become apparent through the following detailed
description of invention are obtained by the discovery of the present invention that re
Sergio the acid phase (phase) can be formed from an aqueous solution of metal
hydroxide in the separation and Paz palsan mixture. It was also found that the present
inventors have found that the acids can be removed from the yisori Sergio Li Sergio
geusan via methanol washing. A further advantage of the present invention those skilled
in the art will be readily understood through the following detailed description of
invention.

In one embodiment, the present invention provides a novel method of producing, Li

Sergio geusan, comprising the isomerization Pas palsan in a separate mixture
comprising an aqueous solution of metal hydroxide and Paz palsan. Paz present in
palsan and amount sufficient to cause phase separation the reaction mixture The amount
of metal hydroxide. The method can be advantageously carried out at a relatively low
temperature within a few hours. Separation of essentially pure Li is Sergio geusan and
contains less than about 1% by weight and less than Pas palsan yisori Sergio geusan
about 1% by weight, can be achieved with greater than 70% yield. The method may
provide an epimerization (epimerization) of the undesired yisori Sergio preferred Li
Sergio geusan of geusan. Both the yield and quality of the isolated Lee Sergio geusan
was substantially better than with known to those skilled in the art as can be seen in
U.S. Patent No. 6,242,603 B1.

Sodium hydroxide and potassium hydroxide are all preferred metal hydroxide. Other
metal hydroxides (e.g., lithium, rubidium, cesium, magnesium, calcium, strontium and
barium) are also predicted would be useful in the present invention it will be considered
part of the present invention.

To form a phase-separated system, Paz palsan preferred that about 5%, 6%, 7%, 8%,
9% or 10% or more exists, and is about 5% by weight of a further desirable. In addition,
a metal hydroxide of about 12% by weight in water (e.g., sodium hydroxide and
potassium hydroxide), 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt% and 18 wt%, 19 wt%
or 20 wt% also preferable to use, and it is about 12% by weight and more preferably
from. Weight percentages are calculated by dividing the weight of a given component in
the total weight of the standard substance. For example, more than 12% aqueous
solution of potassium hydroxide or sodium hydroxide will require more than 12 g of
potassium hydroxide or sodium hydroxide, 100 g of an aqueous solution. To explain
also in a different manner, which means that there is 12 g of water and 88 g of
potassium hydroxide or sodium hydroxide. If not bound by theory, the phase separation
the reaction mixture is considered to provide an excellent medium for a Parse palsan
Chemistry isomers.

Paz palsan may be under relatively mild (mild) conditions, such as switching to Lee
Sergio geusan in the above-described phase separation medium and mixed at about
50 ℃ for about 4 hours. Conversion of fasteners palsan under these reaction conditions,
it is more preferably not less than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or
99% or more is preferable, and 98% . Therefore, the reaction mixture after
isomerization is preferably as measured by HPLC containing palsan Pas of less than
about 2.0%. In addition, isomerization of the yisori Pas palsan the amount Sergio
geusan (e. G., As determined by HPLC 18%) It should be noted that the containing not
a rare case.

In general, the present invention performs the combined Pas palsan, water and metal
hydroxide. For convenience Pas palsan is preferably added to an aqueous solution of
metal hydroxide. A time sufficient to achieve high conversion of the thus Lee Sergio
geusan if combined with component (e. G., About 1 hour, 2 hours, 3 hours, 4 hours, 5
hours, 6 hours, 7 hours, 8 hours or is agitated (agitate) for a time or more). The reaction
temperature is about 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃,
70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 preferably from ℃ to 100 ℃ and about 40 ℃, 41 ℃,
42 ℃, 43 ℃, 44 ℃, 45 ℃, 46 ℃, 47 ℃, 48 ℃, 49 ℃, 50 ℃, 51 ℃, 52 ℃, 53 ℃, 54 ℃,
and 55 ℃, the more preferable 56 ℃, 57 ℃, 58 ℃, 59 ℃, 60 ℃, this particular most
preferably 50 ℃.

After forming, it is desirable to separate from Li Sergio the acid reaction mixture. In yet
another embodiment, Sergio Li is separated from the reaction mixture by acidification
of the mountain to form the crystalline salt of Li Sergio geusan. Acidification it is
preferred to lower the pH of the reaction mixture to 4.0, 3.9, 3.8, 3.7, 3.6, 3.5 or less.
The acidification is preferably accomplished using sulfuric acid. The Li Sergio geusan
sulfate salt precipitated from the reaction mixture to the sulfuric acid the acidification is
formed. The precipitate is preferably separated from the reaction mixture by methods
known to those skilled in the art (e.g., filtration). In the experiment, the crude salt is Li
Sergio geusan turned out to contain Li Sergio geusan and yisori Sergio geusan formed
during the isomerization of the parse palsan substantially the same amount. Therefore,
the Li Sergio geusan formed preferably further separated from its epimer.

In yet another embodiment, the method of this invention is that in order to play a re
Sergio geusan from the salt of the Li Sergio geusan, alcohol extract of crude Li Sergio
geusan salt of a mixture of (e. G., Methanol, ethanol and isopropanol) and aqueous
ammonia to provide. Among the above alcohol is preferably methanol. Mixture of
alcohol and aqueous ammonia, 95: is preferably 5 (v / v). After extraction, the volume
of the extraction solution is preferably reduced. It is almost full removal of the ammonia
present in such reduction is preferred. In addition, it is preferable to further facilitate the
crystallization of Li Sergio geusan by reducing the volume of alcohol (e.g., methanol).

In yet another embodiment, the crystallization of the extracted Li Sergio geusan. The
crystallization may be advantageous to facilitate the addition of water. Then
crystallization Lee Sergio the acid is preferably separated leaving a mother liquor
(mother liquor). The mother liquor may be used repeatedly during the subsequent
isomerization step. A crystalline Li Sergio yield point that some acid yisori Sergio
geusan (e.g., less than about 10%) would contain have been found.

In still other embodiments, the content of yisori Sergio geusan can be further reduced by
washing the crystalline Li Sergio geusan with methanol. Surprisingly it appears to be
more soluble in methanol than the acid Lee Sergio geusan Sergio yisori. Therefore, it is
washed with methanol and the desired product is an easy way to further purification for
re Sergio geusan. In addition, it may be desirable to wash the crystalline material with
water prior to washing with methanol. After washing with methanol, the methanol wash
liquid remains. The wash liquid may be used at the time of repetition of the subsequent
isomerization step. Washing the crystalline Li Sergio geusan with methanol, it is
desirable to reduce the amount of yisori Sergio geusan impurity to less than about 3%
by weight. It is better to wash the Li Sergio geusan until it contains a yisori Sergio
geusan less than 1%.

The mother liquor obtained by filtering the crystalline Li Sergio geusan and methanol
scrubbing liquid mainly containing yisori Sergio geusan. In yet another embodiment,
the solution is Pas palsan the isomerization at the same time, re-recycling yisori Sergio
geusan a predetermined Li Sergio the epimer crystallized isomerization process geusan,
multiple is-full of the batch (multi-batch) or continuous process thereby increasing the
yield. This recirculation is preferred to achieve the combined second portion, water and
a metal hydroxide of the parse palsan (preferably sodium hydroxide or potassium
hydroxide) and a mother liquor and methanol wash liquid. Second iteration, or in order
to form a middle phase separation system for performing further iterations, it is
desirable to parse palsan is present from about 5%, 6%, 7%, 8%, 9% or 10% by weight
and, of which it is more preferably present in at least about 5% by weight, and is most
preferably present in an about 7% by weight or more. In addition, a metal hydroxide of
about 12% by weight in water (e.g., sodium hydroxide and potassium hydroxide), 13
wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt% and 18 wt%, 19 wt% or 20 wt% to use a
preferred, of which it is more preferred to use at least about 12% by weight, it is most
preferred to use about 15% by weight or more. A second temperature of the
isomerization or after the isomerization is preferably the same as those described for the
first isomerization. The above-mentioned process (for example, acidification,
separation, extraction, reduction, crystallization, separation and washing), each of which
carried out in the same manner as discussed above.

Recycling of the mother liquor can be repeated once, twice, three times, four times, five
times, six times, seven times, eight times, nine times, or ten times, and still obtain a
high-quality Li Sergio geusan. New parts of the parse palsan the mother liquor and
methanol wash liquid obtained from the previous isomerization every (new portion),
were combined with water and a metal hydroxide. The total yield of the multi-batch
process comprising a recycle of the mother liquor containing yisori Sergio geusan is
preferably in the range of about 70%, 75%, 80%, 85%, 90% to 95%, and more
preferably from about 90% . Quality of Li Sergio geusan obtained is very excellent. The
average content of the parse palsan is preferably lower than about 5%, 4.5%, 4%, 3.5%,
3%, 2.5%, 2%, 1.5%, 1% to 0.5%, and the lower is more preferably less than about 1%
Do. The average content of yisori Sergio geusan is preferably lower than about 5%,
4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1% to 0.5%, and the lower is more than about
1% desirable.

Another feature of the invention will become apparent from the following description of
exemplary embodiments provided to illustrate this invention and not intended to limit
the scope of the invention.

Example 1: Preparation of Li Sergio geusan do not use the mother liquor recycle

The palsan Pas (100.0 g) (titration analysis 98.5%) in which the rear of sodium
hydroxide (150 g) is dissolved in 5% aqueous sodium hydroxide solution (1,000 ㎖)
was added to the solution. The two phase mixture was observed was formed. Then the
resulting two-phase mixture was mixed at about 50 ℃ for about 4 hours under nitrogen.
The reaction mixture was diluted with water (1,000 ㎖), acidified to back cooling to
10 ℃, pH about 3.5 using 40% sulfuric acid. The suspension was formed of a crystalline
Li Sergio geusan sulfate, it was mixed at about 5 ℃ for about 2 hours. Crystalline Li
Sergio geusan sulfate is filtered off and, 95: 5 (v / v) was the extracted with a mixture (3
× 500 ㎖) of methanol and aqueous ammonia, the combined extracts are evaporated to
create approximately 200 g, water (200 ㎖) a rear, was crystallized at about 5 ℃ for 24
hours, diluted with. Then remove the crystalline Li Sergio geusan and washed with
water (100 ㎖) and methanol (3 × 100 ㎖). (For 60 ℃ and 30 mbar in 24 hours) and then
vacuum dried to give the Li Sergio geusan (73.4 g) (99.1% titration analysis, Paz palsan
content of 0.5%. 0.8% yisori Sergio geusan content).

Li a methanol solution obtained after washing the Sergio crystallization of geusan After
the obtained mother liquor, and the crystalline product was used in the embodiment was
made after the volume to about 200 ㎖, evaporated to Example 2.
Example 2: Preparation of re-using the mother liquor recycle Sergio geusan

Sodium (50 g) hydroxide was dissolved in water (800 ㎖) and the concentrated stock
solution of Example 1 (200 ㎖) obtained from. The palsan Pas (100.0 g) (titration
analysis 98.5%), and finally sodium hydroxide solution (150 g) was added to the
solution. Forming the rear two-phase reaction mixture, which was mixed at about 50 ℃
it for about 4 hours under nitrogen. The reaction mixture was diluted with water (1,000
㎖), acidified to pH 3.5 using a back which, 40% sulfuric acid cooled to 10 ℃. The
obtained suspension is mixed at about 5 ℃ for 2 hours, the crystalline Li Sergio geusan
sulfate and filtered. Lee Sergio geusan sulfate is 95: extracted with 5 (v / v) mixture (3 ×
500 ㎖) of methanol and aqueous ammonia. The combined extract is evaporated to
create about 200 g, it was crystallized for 24 hours at about 5 ℃ after diluted with water
(200 ㎖). Then remove the crystalline Li Sergio geusan and washed with water (100 ㎖)
and methanol (3 × 100 ㎖). Vacuum dried to give (60 ℃ and at 30 mbar for 24 h) was
later, Sergio geusan Li (90.8 g) (98.7% titration analysis, Paz palsan content 0.6%,
yisori Sergio geusan content 0.9%).

Li after the methanol solution obtained after washing after crystallizing of CERE
geusan the resulting mother liquor, and the crystalline product is evaporated to create a
volume of about 200 ㎖, placed ready for use in the next batch.

Herein it has been described with respect to preferred embodiments thereof and some
modification of the present invention. The present invention can be used in various
other combinations and atmosphere, it should be understood that any modifications or
alterations within the scope of the invention concept of the present invention shown
herein that it is also possible.