CN109021010B - Preparation method of L- α -choline alfoscerate - Google Patents

Preparation method of L- α -choline alfoscerate Download PDF

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CN109021010B
CN109021010B CN201810662151.1A CN201810662151A CN109021010B CN 109021010 B CN109021010 B CN 109021010B CN 201810662151 A CN201810662151 A CN 201810662151A CN 109021010 B CN109021010 B CN 109021010B
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dioxaphospholane
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姜鹏飞
于景喜
李翠
王伟
于凯
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Shenyang Gold Jyouki Technology Co ltd
Jinjiuqi Fushun Pharmaceutical Co ltd
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Abstract

The invention relates to the field of L- α -choline glycerophosphate, in particular to a preparation method of high-purity L- α -choline glycerophosphate, which adopts glycidol as a raw material to prepare L- α -choline glycerophosphate, firstly, phosphorus trichloride and ethylene glycol are utilized to prepare 2-chloro-1, 3, 2-dioxolane, then, the 2-dioxolane is oxidized, trimethylamine and dioxolane are added for reaction, then, acid is added for ring opening and oxidation to obtain L- α -choline glycerophosphate chloride, and finally, resin is added for removing chloride ions to obtain a final product.

Description

Preparation method of L- α -choline alfoscerate
The technical field is as follows:
the invention relates to the field of L- α -choline alfoscerate, in particular to a preparation method of L- α -choline alfoscerate with high purity.
Background
Senile dementia also known as Alzheimer's Disease (AD) is a primary degenerative encephalopathy occurring in the elderly and pre-senile stages, and is a persistent higher nerve functional activity disorder, namely, disorders in memory, thinking, analytical judgment, visual space recognition, emotion and the like without disturbance of consciousness, and the characteristic pathological changes of the senile dementia are cerebral cortex atrophy accompanied by β -amyloid deposition, neurofibrillary tangles, reduction of a large number of memory neurons and formation of senile plaques, so that no specific treatment or treatment medicine for reversing disease progression is available at present.
L- α -choline alfoscerate has chemical structure (containing 40.5% choline) and physical and chemical properties which are mutually connected, so that the choline alfoscerate is a substance which is very beneficial to brain tissues and can protect the metabolism of the brain tissues at any time, is one of phospholipid metabolism products in organisms and is an important biosynthetic precursor of a nerve transmission medium Acetylcholine (Acetylcholine).
At present, L- α -choline alfoscerate is mainly from two known sources, one is natural product separation and extraction (GB 2058792; US 2864848; US 5100787; US 53115023; JP61158990), the purity of the separated product is low, the impurities are more, the cost of raw materials is high, the operation is complex, the industrialization degree is not high, the other is chemical synthesis, the sources of the raw materials for chemical synthesis are wide, the price is low, and the impurities are less than the main sources of the current L- α -choline alfoscerate.
European patent publication (EP 0486100) utilizes 2-chloro-2-oxo-1, 3, 2-dioxaphospholane to react with R-glycerol acetonide, then depropanethione is removed in diluted hydrochloric acid to obtain L- α -choline glycerophosphate crude product, and the pure product is obtained after ion exchange resin, wherein the reaction formula is as follows:
Figure BDA0001707011640000021
the method has the defects that two raw materials are not easily obtained, the 2-chloro-2-oxo-1, 3, 2-dioxolane has very active property and is unstable in air, R-glycerinol acetonide has high price, the cost of the raw materials is equivalent to the price of the commercialized L- α -choline glycerophosphate, and the route is not practical in industrialization.
Chinese patent (publication No. CN101544667A) utilizes the reaction of glycidol and p-toluenesulfonyl chloride to obtain p-toluenesulfonic acid glycidyl ester, then the p-toluenesulfonic acid glycidyl ester reacts with phosphorylcholine tetraalkylammonium hydroxide, and then the reaction product is hydrolyzed and ring-opened to obtain L- α -choline glycerophosphate chloride, and the final product is obtained after resin treatment, the yield is 53%. the reaction formula is as follows:
Figure BDA0001707011640000022
the method improves the ee value of the product by refining in one step when preparing the p-toluenesulfonic acid glycidyl ester, but the raw material phosphorylcholine tetraalkyl ammonium hydroxide needs to be synthesized by phosphorylcholine calcium salt, and the production of the phosphorylcholine calcium salt generates a large amount of three wastes, so that the three wastes cannot be treated, and the bottleneck of industrialization is formed.
Korean patent publication No. KR200939132 utilizes benzyl glycidyl ether to react with phosphorylcholine, and then removes the benzyl group by hydrogenation using palladium on carbon to obtain L- α -phosphorylcholine chloride.
Figure BDA0001707011640000031
The use of benzyl glycidyl ether in this route requires deprotection of the upper protection, increases costs, uses noble metal catalysts for deprotection, requires hydrogenation, and also limits industrial scale-up. In addition, the synthesis of the phosphorylcholine generates a large amount of solid waste, and the environmental protection pressure is great.
Chinese patent (publication No. CN101967160A) replaces calcium phosphorylcholine chloride with sodium salt by sodium carbonate, then reacts with R-3-chloro-1, 2-propylene glycol in ethanol to obtain L- α -choline glycerophosphate chloride, and gets L- α -choline glycerophosphate by recrystallization, the reaction formula is as follows:
Figure BDA0001707011640000032
the method has simple process steps and high yield, is an ideal route at present, but the synthesis of the phosphoryl chloride calcium salt needs excessive phosphoric acid, and the industrialization of the phosphoryl chloride calcium salt is greatly limited by the generated waste acid, solid waste and waste gas.
The invention content is as follows:
in order to overcome the defects in the prior art, the invention provides the preparation method of L- α -choline alfoscerate, which has the advantages of more reasonable process design, simple operation, high product yield and purity and less byproduct.
In order to achieve the purpose of the invention, the invention adopts the technical scheme that:
a process for preparing L- α -choline glycerophosphate includes such steps as preparing 2-chloro-1, 3, 2-dioxolane from phosphorus trichloride and ethanediol, oxidizing, adding trimethylamine and dioxolane, reacting, adding acid to hydrolyze for ring opening to obtain L- α -choline glycerophosphate chloride, and adding resin to remove chloride ions.
The preparation method of L- α -choline alfoscerate comprises the following synthetic route:
Figure BDA0001707011640000041
the preparation method of L- α -choline alfoscerate comprises the steps of preparing (R) -2- (ethylene oxide-2-methoxyl) -1,3, 2-dioxolane, dropwise adding 2-chlorine-1, 3, 2-dioxolane into a solution of glycidol and an acid-binding agent, monitoring the reaction to be complete, filtering, and distilling under reduced pressure to obtain a product, wherein the acid-binding agent is Triethylamine (TEA), N-Diisopropylethylamine (DIPEA) or pyridine, and the solvent is dichloromethane, diethyl ether or tetrahydrofuran.
The preparation method of L- α -choline glycerophosphate is (R) -2- (ethylene oxide-2-methoxyl) -1,3, 2-dioxaphospholane 2-oxide, wherein (R) -2- (ethylene oxide-2-methoxyl) -1,3, 2-dioxaphospholane is dissolved in a dichloromethane solvent, a catalyst salen Mn is added, the reaction is finished, and the solvent is evaporated to obtain a product.
The preparation method of L- α -choline glycerophosphate comprises the steps of dissolving (R) -2- (ethylene oxide-2-methoxyl) -1,3, 2-dioxaphospholane 2-oxide in a solvent, adding trimethylamine gas, adding acid after the reaction is finished, heating and refluxing, and completely evaporating the solvent to obtain L- α -choline glycerophosphate chloride, wherein the acid is hydrochloric acid, sulfuric acid or phosphoric acid with the concentration of 0.01-1 wt%, and the solvent is methanol, ethanol, acetone, acetonitrile or tetrahydrofuran.
The preparation method of L- α -choline alfoscerate comprises the steps of dissolving L- α -choline alfoscerate chloride in deionized water, adding quantitative anion resin, stirring, measuring no chloride ions by using silver nitrate, filtering, and evaporating the solvent to dryness to obtain the final product L- α -choline alfoscerate.
The design idea of the invention is as follows:
the method takes 2-chloro-1, 3, 2-dioxaphospholane and chiral glycidol as starting materials, the reaction is finished, the raw materials are simply distilled and purified, Salen Mn is used for oxidation, the catalyst is removed by filtration, the reaction product is reacted with trimethylamine, acid is used for catalysis, hydrolysis and ring opening are carried out, L- α -choline glycerophosphate is obtained, and chloride ions are removed by resin, so that pure L- α -choline glycerophosphate is obtained.
The invention has the advantages and beneficial effects that:
the synthesis route of L- α -choline alfoscerate is green and environment-friendly, no solid waste is generated, raw materials are easy to obtain, unit reaction operation is simple, yield is considerable, and product purity is high.
Drawings
FIG. 1 is a drawing of compound c from example 11H NMR chart.
FIG. 2 is a drawing showing the preparation of compound d in example 11H NMR chart.
FIG. 3 shows GPC of the compound in example 11H NMR chart.
FIG. 4 is a GPC L C map of the compound in example 1.
The specific implementation mode is as follows:
the present invention will be explained in further detail below by way of examples and figures.
Example 1
The synthetic route of L- α -choline alfoscerate of this example is as follows:
Figure BDA0001707011640000051
(1) the synthesis of (R) -2- (oxiraneyl-2-methoxy) -1,3, 2-dioxaphospholane (compound c) is as follows:
slowly adding 2-chloro-1, 3, 2-dioxaphospholane (100g, 790mmol) to a diethyl ether (200ml) solution of R-glycidol (58g, 790mmol) and triethylamine (88g, 869.73mmol) at zero temperature, heating to room temperature for reaction for 3h after dripping, detecting that the reaction is complete by thin layer chromatography (T L C) (n-hexane/ethyl acetate ═ 5/1 according to the volume ratio), filtering, washing a filter cake with diethyl ether, recovering the diethyl ether from the filtrate, and distilling the residue under reduced pressure to obtain 123g of (R) -2- (ethylene oxide-2-methoxy) -1,3, 2-dioxaphospholane with the yield of 94.8%.
As shown in fig. 1, from1The H NMR spectrum showed that 1H NMR (400MHz, CDCl3) was 4.09-4.14(m,2H),3.86-3.93(m,3H),3.64-3.71(m,1H), 3.01-3.02(m,1H), 2.69-2.71(m,1H), 2.69-2.71(m,1H), 2.53-2.55(m,1H), and these data indicate that the structure of compound c prepared in this example is correct.
(2) The synthesis of (R) -2- (oxirane2-methoxy) -1,3, 2-dioxaphospholane 2-oxide (compound d) is as follows:
compound C (100g, 609mmol) was dissolved in 200ml of dichloromethane, Salen Mn catalyst (1g) was added, oxygen was bubbled through, the reaction was allowed to proceed overnight at room temperature, the reaction was complete by thin layer chromatography (T L C) (n-hexane/ethyl acetate 5/1 by volume ratio), the catalyst was filtered off, and the solvent was evaporated to dryness to give 108g of (R) -2- (oxirane-2-methoxy) -1,3, 2-dioxaphospholane 2-oxide in 98.41% yield.
As shown in fig. 2, from1The H NMR spectrum showed that 1H NMR (400MHz, CDCl3) was 4.37-4.57(m,5H),3.98-4.05(m,1H),2.86-3.26(m,1H), 2.84-2.86(m,1H), 2.67-2.69(m,1H), 2.69-2.71(m,1H), 2.53-2.55(m,1H), and these data indicate that the structure of compound d prepared in this example is correct.
(3) L- α -Choline Glycophosphate chloride (Compound e) was synthesized as follows:
dissolving (R) -2- (ethylene oxide-2-methoxy) -1,3, 2-dioxaphospholane 2-oxide (100g, 555mmol) (compound d) in 300ml ethanol, introducing trimethylamine (32g, 555mmol) at zero temperature, detecting (n-hexane/ethyl acetate 1/10 in terms of volume ratio) by thin layer chromatography (T L C) to completely react, adding 100g diluted hydrochloric acid (concentration is 1 wt%), heating and refluxing for 8h, and evaporating the solvent to dryness to obtain 180g of L- α -crude choline glycerophosphate chloride (compound e).
(4) L- α -choline alfoscerate was synthesized as follows:
l- α -choline alfoscerate (compound e) (180g) is dissolved in 1kg deionized water, the deionized water is filtered through 717 type ion exchange resin, water is distilled off under reduced pressure to obtain 140g of residue, the residue is dissolved in 280g of ethanol, the temperature is kept at zero temperature for 4h, crystals are separated out and filtered, a filter cake is washed and filtered by 20g of cold ethanol, and then the filter cake is dried to obtain 110g of product, wherein the yield is 77%.
As shown in fig. 3, from1The 1H NMR spectrum showed that 4.26(s,1H),3.79-3.88(m,3H),3.60-3.63(D,2H),3.55-3.56(dd,1H),3.16(s,9H) were confirmed by 1H NMR (400MHz, D2O), and these data indicate that the GPC structure of the compound prepared in this example was correct.
As shown in fig. 4, from the L C pattern of compound GPC in example 1, RT 23.47min and purity 100% were observed.
Example 2
The difference from example 1 is that the synthesis of the friedel-crafts agent using N, N-diisopropylethylamine, (R) -2- (oxirane-2-methoxy) -1,3, 2-dioxaphospholane (compound c) is as follows:
slowly adding 2-chloro-1, 3, 2-dioxaphospholane (100g, 790mmol) to a tetrahydrofuran (200ml) solution of R-glycidol (58g, 790mmol) and N, N-diisopropylethylamine (112.41g, 869.73mmol) at zero temperature, heating to room temperature for reaction for 3h after dropwise addition, detecting complete reaction (N-hexane/ethyl acetate 5/1 in terms of volume ratio) by thin layer chromatography (T L C), filtering, washing a filter cake with tetrahydrofuran, recovering tetrahydrofuran from the filtrate, and distilling the residue under reduced pressure to obtain 121g of (R) -2- (ethylene oxide-2-methoxy) -1,3, 2-dioxaphospholane with the yield of 93.26%.
Example 3
In contrast to example 1, the synthesis of (R) -2- (oxirane2-methoxy) -1,3, 2-dioxaphospholane 2-oxide (compound d) by oxidation of phosphorus with the organic acid oxidant m-chloroperoxybenzoic acid was as follows:
on the basis of example 1, compound C (100g, 609mmol) was dissolved in 200ml of dichloromethane, m-chloroperoxybenzoic acid (85 wt% purity, 131g, 609mmol) was added in portions, reaction was carried out for 4 hours, detection by thin layer chromatography (T L C) (n-hexane/ethyl acetate 5/1 by volume ratio) led to completion of the reaction, m-chloroperoxybenzoic acid as a reaction by-product was filtered off, dichloromethane as a solvent was evaporated, and reduced pressure distillation was carried out to obtain 90g of (R) -2- (oxirane-2-methoxy) -1,3, 2-dioxaphospholane 2-oxide, with a yield of 82%.
Example 4
The difference from example 1 is that trimethylamine is replaced by a trimethylamine ethanol solution, and L- α -choline glycerophosphate (compound GPC) is synthesized as follows:
based on example 3, (R) -2- (ethylene oxide-2-methoxy) -1,3, 2-dioxaphospholane 2-oxide (100g, 555mmol) (compound d) was dissolved in 300ml ethanol, trimethylamine ethanol solution (20 wt% concentration, 160g, 555mmol) was added dropwise at zero degree, thin layer chromatography (T L C) was performed to detect that the reaction (n-hexane/ethyl acetate ═ 1/10 by volume ratio) was complete, 100g dilute sulfuric acid (1 wt%) was added, the reaction was performed at reflux temperature for 8h, the solvent was evaporated to dryness to obtain 180g of crude L- α -choline glycerophosphate chloride (compound e), L- α -choline phosphate chloride (compound e) was dissolved in 1kg deionized water, ion exchange resin type 717 was passed, water was distilled off under reduced pressure to obtain 140g of residue, the residue was dissolved in 280g ethanol, the temperature was maintained at zero degree for 4h, a cake was precipitated, filtered and washed with 20g of cold ethanol, and then dried to obtain 105g of product with 73.94% yield.
It should be noted that the above-mentioned embodiments are only for illustrating the technical concept and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims (1)

1. A preparation method of L- α -choline alfoscerate is characterized in that the synthetic route is as follows:
Figure FDA0002470540880000011
(1) preparation of (R) -2- (Oxirane-2-methoxy) -1,3, 2-dioxaphospholane: dripping 2-chloro-1, 3, 2-dioxaphospholane into a solution of R-glycidol and an acid-binding agent, monitoring the reaction to be complete, and filtering and distilling under reduced pressure to obtain a product; wherein the acid-binding agent is Triethylamine (TEA), N-Diisopropylethylamine (DIPEA) or pyridine, and the solvent is dichloromethane, diethyl ether or tetrahydrofuran;
(2) preparation of (R) -2- (Oxirane-2-methoxy) -1,3, 2-dioxaphospholane 2-oxide: dissolving (R) -2- (ethylene oxide-2-methoxyl) -1,3, 2-dioxaphospholane into a dichloromethane solvent, adding a catalyst salenMn, introducing oxygen through a bubbler, filtering the catalyst after the reaction is finished, and evaporating the solvent to obtain a product;
(3) dissolving (R) -2- (ethylene oxide-2-methoxyl) -1,3, 2-dioxaphospholane 2-oxide in a solvent, adding trimethylamine gas, adding acid after the reaction is finished, heating and refluxing, and completely evaporating the solvent to obtain L- α -choline glycerophosphate chloride, wherein the acid is hydrochloric acid with the concentration of 0.01-1 wt%, and the solvent is methanol, ethanol, acetone, acetonitrile or tetrahydrofuran;
(4) dissolving L- α -choline alfoscerate chloride in deionized water, adding quantitative anion resin, stirring, measuring no chloride ion by using silver nitrate, filtering, and evaporating the solvent to dryness to obtain a final product L- α -choline alfoscerate.
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