Specification
Technical Field
The present invention relates to a method for
preparing racemic or optically active aglycerophosphorylcholine,
and more particularly to a method
5 of preparing racemic or optically active D or L-ctglycerophosphorylcholine
in large amounts by subletting
choline phosphate or a salt thereof and racemic or optically
highly pure (S) or (R) -3-halo-l,2-propanediol to a
substitution reaction in a medium at high temperature In the
10 presence of an inorganic base which increases the actlvlty of
the reaction.
Background Art
Racemic or optically active D or L-ctglycerophosphorylcholine,
a compound represented by the
15 following Formula 1, is known to have excellent effects on
the treatment of secondary spptoms caused by cerebrovascular
defects, senlle cognitive disorders (memory impairment,
distraction, loss of sense of direction, loss of motivation
and spontaneity, concentration decline) such as degenerative
20 brain organic psycho-syndrome, and senile pseudo-depression
such as emotional and behavioral changes (emotional
instability, irritability, lack of attention). In addltlon,
this compound is known as an excellent drug that promotes the
production of the brain neurotransnutter acetylcholine to
25 thereby normalize abnormal choline neurotransmission caused
by lack of acetylcholine and normalize the function of
damaged neurons.
Formula 1
wherein * is a chiral center and refers to a racemic or
optically active D or L-a-optical isomer.
The racemic or optically active D or L-aglycerophosphorylcholine
having excellent pharmacological
effects as described above can be prepared by organic
synthetic methods or can be prepared by deacylating the acyl
phospholipids of plants (soy lecithin) or animals (egg yolk
10 or bovine brain), and representative methods for preparation
of this compound are as follows.
As shown in Reaction Scheme 1 below, Korean Patent No.
0262281 discloses a method of preparing
glycerophosphorylcholine by deacylating a natural or
15 synthetic phospholipid mixture by alcoholysis, followed by
treatment with basic ion exchange resin. However, this
method is a method of purifying phospholipids from a
starting material containing a large amount of impurities by
deacylation, and has disadvantages in that it has a low
20 recovery of glycerophosphorylchoLine in the preparation of
glycerophosphorylcholine and is not suitable for the
production of a large amount of glycerophosphorylcholine,
due to the use of basic ion exchange resln in the
purification process.
Reaction Scheme 1
wherein W a ~ ~RI dma y ba the same or differeat and am Bach
independently o e13-C~ alkyl or a CIS-6~5 msna- or polyunsubstituted
aa2keyl.
US Patent No. 5250719 di~closesa p r m s s 6f preparing
0 or L-a-glycempho~mylchoLitle according to a methad
similar to that s h m in Reaatian $*erne 1 abve. Hewevex,
this process Pias disaclvantaqes in that the purification
process is cemplez due to the use of ion axehange resin and
10 in that the recovery of L-~q1yce-r~hosphorylCholii~ee low.
Ia European Patent Eo. 217,765 Bl, @wleated soy or
egg lecithin is deacylatM, BRQ then L-aglyoero@
h&sphory1choline and L-a-gly~er~phosph0xylt:Raline
ethanolainitle are complezed with zinc saltb to remove ethas
15 h p u r i t i ~ s ~T he c ~is dleampo~s& wi th pyridine and
saparmtad by ion exchange resin, and the mixture of L-aglycarophosphoryhh03.
ine and La-glprophospho~y1choline
ekhanolamine i s also separated by iw ezchmp resin,
thereby preparing L-cc-glycerophosphoryl&o1ine. This
20 ijseparatian methad hets disddntages in that, h a u s e the
process of preplafig L-w-glycerophosphorylGfnoline i s
c m p ~ e d of several steps, the preparatim r is
co~nplt3lh, and because the purifimkian pracess cmiprises the
use of im ex&ange resin twiee, it is inefficiest, and alao
25 the yield is very low.
In aeldition, a n\etKad of prepaxing
gl~e1~sphory1Chel-ine by deacylating lecithin eztracted
from vegetable materials or animal organs is known (Biochim.
Biophys. Acta, 488:36, 1977; Biochim. Biophys. Acta,
1003:277, 1989). However, this method has disadvantages in
that, because various by-products such as D-1,2-
5 glycerophosphate are produced depending on deacylation
reaction conditions (reaction time, reaction temperature,
the kind of base and the kind of solvent), the purification
process is complex and the yield is low.
As seen in the above-described known examples, the
10 methods of preparing L-a-glycerophosphorylcholine from
materials such as lecithin extracted from plants or animals
have an advantage in that materials required for preparation
of L-a-glycerophosphorylcholine are readily available in
nature. However, because the extracted material contains a
15 large amount of impurities, it is necessary to purify the
extracted material using ion exchange resin or the like, and
for this reason, the purification process is complex and it
is difficult to prepare L-a-glycerophosphorylcholine with
high purity. In addition, because the recovery of L-a-
20 glycerophosphorylcholine is low, the methods are
uneconomical and are also unsuitable for the production of a
large amount of L-a-glycerophosphorylcholine.
Meanwhile, regarding conventional methods of preparing
glycerophosphorylcholine by organic synthetic methods, a
25 method of preparing D,L-a-glycerophosphorylcholine using
D,L-acetone glycerol as a starting material as shown in
Reaction Scheme 2 below is known (J. Qrg. Chem., 26:608,
1961). However, this method has disadvantages in that,
because a total of four reaction steps are carried out, the
reaction process is complicated, and because the reactions
are carried out under an anhydrous condition, the reaction
process is complicated. In particular, there is a
disadvantage in that this method is difficult to apply
5 industrially, because the starting material D,L-acetone
glycerol is very expensive and because expensive compounds
such as palladium and silver carbonate are used to remove a
phenyl group and a chlorine ion, which act as protecting
groups in the reactions.
Reaction Scheme 2
Furthemore, J. Am. Chem. Soc. Vol. 70. pp 1394 (1948)
discloses a method of preparing L-a-glycerophosphory1choline
via a method similar to the above-described method.
As shown in Reaction Scheme 3 below, European Patent
Publication No. 468100 discloses a method of preparing
racemic or L-a-glycerophosphorylcholine from the
substitution reaction of isopropylidene glycerol with 2-
chloro-2-oxy-3,3,2-dioxaphospholane. However, this method
20 also problems in that expensive isopropylidene glycerol and
2-chloro-2-oxy-3,3,2-dioxaphospholane are used as the
starting materials and ln that the reaction is carried out
under an anhydrous condition, and thus the reaction
conditions are strict. In addition, there is a problem in
that racgmic or L-er-&ycerophwsphorylcholine lrmst be finally
purified & ion aschange resin after hydrolysis.
Reaction Scheme 3
5 wherein is a chiral center and refers to a racmic or Lform
optical isomer.
Korean Patent Application Publication No. 2011-0066004
discloses a method comprising a step of reacting a
phosphorylcholine chloride calcium salt with an alkali metal
10 base in an aqueous solution to produce an alkali metalsubstituted
salt, followed by a reaction with glycldal
without separating the alkali metal-substituted salt.
Reaction Scheme 4
CI' ,I .A "...I*.a 1S.k q- 4 - [:Fj-,,
Documents
Application Documents
| # |
Name |
Date |
| 1 |
201617025888-AbandonedLetter.pdf |
2019-09-30 |
| 1 |
Priority Document [28-07-2016(online)].pdf |
2016-07-28 |
| 2 |
Form 5 [28-07-2016(online)].pdf |
2016-07-28 |
| 2 |
201617025888-Correspondence-111018.pdf |
2018-10-13 |
| 3 |
Form 3 [28-07-2016(online)].pdf |
2016-07-28 |
| 3 |
201617025888-OTHERS-111018.pdf |
2018-10-13 |
| 4 |
Form 18 [28-07-2016(online)].pdf_126.pdf |
2016-07-28 |
| 4 |
201617025888-Proof of Right (MANDATORY) [11-10-2018(online)].pdf |
2018-10-11 |
| 5 |
Form 18 [28-07-2016(online)].pdf |
2016-07-28 |
| 5 |
201617025888-FER.pdf |
2018-09-14 |
| 6 |
Description(Complete) [28-07-2016(online)].pdf |
2016-07-28 |
| 6 |
201617025888-Correspondence-210916.pdf |
2016-09-24 |
| 7 |
Form 26 [20-09-2016(online)].pdf_15.pdf |
2016-09-20 |
| 7 |
201617025888-Power of Attorney-210916.pdf |
2016-09-24 |
| 8 |
Form 26 [20-09-2016(online)].pdf |
2016-09-20 |
| 8 |
201617025888.pdf |
2016-09-20 |
| 9 |
Form 26 [20-09-2016(online)].pdf |
2016-09-20 |
| 9 |
201617025888.pdf |
2016-09-20 |
| 10 |
201617025888-Power of Attorney-210916.pdf |
2016-09-24 |
| 10 |
Form 26 [20-09-2016(online)].pdf_15.pdf |
2016-09-20 |
| 11 |
Description(Complete) [28-07-2016(online)].pdf |
2016-07-28 |
| 11 |
201617025888-Correspondence-210916.pdf |
2016-09-24 |
| 12 |
Form 18 [28-07-2016(online)].pdf |
2016-07-28 |
| 12 |
201617025888-FER.pdf |
2018-09-14 |
| 13 |
Form 18 [28-07-2016(online)].pdf_126.pdf |
2016-07-28 |
| 13 |
201617025888-Proof of Right (MANDATORY) [11-10-2018(online)].pdf |
2018-10-11 |
| 14 |
Form 3 [28-07-2016(online)].pdf |
2016-07-28 |
| 14 |
201617025888-OTHERS-111018.pdf |
2018-10-13 |
| 15 |
Form 5 [28-07-2016(online)].pdf |
2016-07-28 |
| 15 |
201617025888-Correspondence-111018.pdf |
2018-10-13 |
| 16 |
Priority Document [28-07-2016(online)].pdf |
2016-07-28 |
| 16 |
201617025888-AbandonedLetter.pdf |
2019-09-30 |
Search Strategy
| 1 |
201617025888SearchStrategypdf_13-09-2018.pdf |