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Method For Preparing Racemic Or Optically Active ??Glycerophosphoryl Choline

Abstract: The present invention relates to a method for preparing racemic or optically active a?glycerophosphoryl choline and more specifically to a method for mass producing racemic or optically active D or L a?glycerophosphoryl choline through a substitution reaction of choline phosphate or a salt thereof and racemic or optically pure (S) and (R) 3 halo 1 2 propandiols in the presence of a medium using an inorganic base which increases activity of the reaction at a high temperature. The method for preparing racemic or optically active D or L a?glycerophosphoryl choline according to the present invention is economical by using a low priced starting material compared with the conventional method provides a convenient preparation procedure by performing a one pot reaction without a separate purification procedure and can quantitatively mass produce racemic or optically active D or L a?glycerophosphoryl choline and a salt thereof in the presence of a medium without a side reaction by using an inorganic base which increases activity of the reaction.

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Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
28 July 2016
Publication Number
36/2016
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

ENZYTECH LTD.
57 Sinilseo ro 86beon gil Daedeok gu Daejeon 306 230

Inventors

1. HWANG Soon Ook
109 1402 Expo Apt. 448 Expo ro Yuseong gu Daejeon 305 761
2. YUN Dae Myoung
304 Pureumvill 84 Sintanjin ro 778beon gil Daedeok gu Daejeon 306 816

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