JP2008189589A - Phosphorylcholine group-containing cyclic ketal compound, method for producing the same, and method for producing phosphatidylcholine group-containing diol compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new phosphorylcholine group-containing cyclic ketal compound enabling a polymer surface or a polymer to be introduced with phosphatidylcholine groups excellent in biosafety, water-holding ability and water-absorbing capacity and also developable to the medical sector because of having intramolecular phosphorylcholine group, to provide a method for producing the above cyclic ketal compound, and to provide a method for efficiently producing a phosphatidylcholine group-containing diol compound using the above cyclic ketal compound. <P>SOLUTION: The cyclic ketal compound of 1,3-propanediol having on its 2-position a phosphorylcholine-substituted methyl group is provided. A hydro-ring-opening reaction of this compound is also provided. The above compound is usable as a raw material for pharmaceuticals or as an intermediate for organic syntheses. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a phosphorylcholine group-containing cyclic ketal compound that can be used as a pharmaceutical raw material or an organic synthetic intermediate, a method for producing the same, and a method for producing a phosphatidylcholine group-containing diol compound.

Conventionally, cyclic ketal compounds have been used as organic synthesis intermediates useful for protecting hydroxyl groups from reacting during organic synthesis. As such a cyclic ketal compound, for example, in Patent Document 1, a substituted 1,3-dioxane derivative that can be used as a pharmaceutical intermediate or an industrial high-performance solvent is disclosed in Patent Document 2, in which trimethylolalkane monoalkyl ether is used. Patent Document 3 proposes a 1,3-dioxane derivative as a solvent for dispersing a recording agent for ink jetting.
In addition, as cyclic ketal compounds that are commercially available industrial synthetic raw materials, isopropylidenetrimethylolethane, isopropylidenetrimethylolpropane, isopropylidenetrimethylolbutane, isopropylidenetrimethylolmethylcyclohexane, sec-butylidenetrimethylolethane, sec -Butylidenetrimethylolpropane, sec-butylidenetrimethylolbutane, sec-butylidenetrimethylolmethylcyclohexane and the like are known.

By the way, phosphatidylcholine having a phosphorylcholine group is known as a main component of a biological membrane, and is used as a model system for biological function analysis, a drug delivery system (DDS) carrier utilizing characteristics of forming liposomes in water, etc. It has been attracting attention in the fields of cosmetics, medicine, pharmacy, biochemistry, etc. due to its excellent biocompatibility, water retention and water absorption.
For example, Patent Document 4 proposes a diol compound having a phosphatidylcholine group. The diol compound having a phosphatidylcholine group described in this document is a useful compound capable of introducing a phosphatidylcholine group excellent in biological safety, water retention and water absorption into a polymer surface or a polymer.
However, the method for producing a phosphatidylcholine group-containing diol described in Patent Document 4 has a problem that impurities are easily generated because the reaction is performed in a state where the hydroxyl group is not protected. Therefore, it can be used for the development of a new method for producing a phosphatidylcholine group-containing diol compound with little generation of impurities, as well as for such a production method, and can also be used as a pharmaceutical raw material or an organic synthetic intermediate for industrial use. Therefore, development of a cyclic ketal compound having a new molecular structure has been demanded.
Patent Document 5 proposes a method for producing a phosphatidylcholine group-containing diol using a compound having a hydroxyl group protected with a t-butyldimethylsiloxymethyl protecting group or the like. However, there is no known method for producing a phosphatidylcholine group-containing diol using a compound having a hydroxyl group protected by a ketal protecting group.
JP-A-62-53984 JP 2001-72635 A JP-A-62-177079 Japanese Patent Laid-Open No. 10-287687 Japanese National Patent Publication No. 8-507293

An object of the present invention is to introduce a phosphatidylcholine group excellent in biosafety, water retention and water absorption into a polymer surface or polymer, and can be used for efficient production of a phosphatidylcholine group-containing diol compound. An object of the present invention is to provide a novel phosphorylcholine group-containing cyclic ketal compound that can be used as a synthetic intermediate and that can be developed in the medical field by having a phosphorylcholine group in the molecule, and a method for producing the same.
Another object of the present invention is to efficiently produce a phosphatidylcholine group-containing diol compound capable of introducing a phosphatidylcholine group excellent in biosafety, water retention and water absorption into a polymer surface or polymer. It is to provide a manufacturing method.

(式(１)中、Ｒ₁は水素原子、炭素数１〜２０のアルキル基又は炭素数６〜２０のアリール基を表す。Ｒ₂及びＲ₃は同一であっても異なっても良く、水素原子、メチル基又はエチル基を表す。) According to the present invention, there is provided a phosphorylcholine group-containing cyclic ketal compound represented by the formula (1).

(In the formula (1), R ₁ represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms or an aryl group having 6 to 20 carbon atoms. R ₂ and R ₃ may be the same or different, and Represents an atom, a methyl group or an ethyl group.)

(式(２)及び式(４)中、Ｒ₁、Ｒ₂及びＲ₃は式(１)のものと同様である。)
また本発明によれば、上記工程(a)の反応を、４０〜６０℃で行う上記式(１)で表されるホスホリルコリン基含有環状ケタール化合物の製造方法が提供される。 According to the invention, in order to obtain a compound represented by the formula (4), a cyclic ketal represented by the formula (2) and a 2-chloro-2-oxo-1, represented by the formula (3) Phosphorylcholine represented by the above formula (1), comprising a step (a) of reacting 3,2-dioxaphosphorane and a step (b) of reacting a compound represented by the formula (4) with trimethylamine. A method for producing a group-containing cyclic ketal compound is provided.

(In Formula (2) and Formula (4), R ₁ , R ₂ and R ₃ are the same as those in Formula (1).)
Moreover, according to this invention, the manufacturing method of the phosphorylcholine group containing cyclic ketal compound represented by the said Formula (1) which performs reaction of the said process (a) at 40-60 degreeC is provided.

(式(５)中、Ｒ₁は式(１)のものと同様である。) Furthermore, according to the present invention, the phosphorylcholine group-containing cyclic ketal compound represented by the above formula (1) is represented by the formula (5) including a step of hydrolytic ring-opening reaction with a water-containing solvent in the presence of an acid catalyst. A method for producing a phosphatidylcholine group-containing diol compound is provided.

(In formula (5), R ₁ is the same as that in formula (1).)

The phosphorylcholine group-containing cyclic ketal compound represented by the formula (1) of the present invention has a hydrophilic phosphorylcholine group in the molecular structure, and also has a cyclic ketal, and therefore has two primary hydroxyl groups exhibiting high reactivity. It is useful as a synthetic intermediate for producing a compound represented by the formula (5) having a phosphatidylcholine group having excellent biological safety, water retention and water absorption. In addition, having a phosphorylcholine group in the molecule can be expected to expand into the medical field.
The production method of the present invention can efficiently obtain the target product. In particular, the production method of the phosphatidylcholine group-containing diol compound uses the above-mentioned phosphorylcholine group-containing cyclic ketal compound of the present invention to produce water in the presence of an acid catalyst. Since two primary hydroxyl groups exhibiting high reactivity can be generated by hydrolytic ring opening due to, the formation of impurities can be suppressed and the target product can be obtained efficiently.
The obtained phosphatidylcholine group-containing diol compound is excellent in polycondensation and surface modification, and can be expected to be used as a raw material and material in a wide range of fields including the medical field.

Hereinafter, the present invention will be described in more detail.
The phosphorylcholine group-containing cyclic ketal compound of the present invention is a compound represented by the formula (1). In the formula (1), R ₁ represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms or an aryl group having 6 to 20 carbon atoms, and an alkyl group having 1 to 20 carbon atoms is preferable from the viewpoint of production, and in particular, methyl Group and ethyl group are preferred. R ₂ and R ₃ may be the same or different and each represents a hydrogen atom, a methyl group, or an ethyl group, and is a methyl group from the viewpoint of ease of removal of the residue during the cyclic ketal removal reaction. Is preferred.

  The compound represented by the formula (1) is a compound that can be used as a precursor of the phosphatidylcholine group-containing diol compound represented by the formula (5). For example, isopropylidenetrimethylolethanephosphorylcholine, isopropylidenetrimethylolpropanephosphorylcholine Isopropylidenetrimethylolbutanephosphorylcholine, isopropylidenetrimethylolmethylcyclohexanephosphorylcholine, sec-butylidenetrimethylolethanephosphorylcholine, sec-butylidenetrimethylolpropanephosphorylcholine, sec-butylidenetrimethylolbutanephosphorylcholine, sec-butylidenetrimethylolmethyl Cyclohexanephosphorylcholine is mentioned, and it is isopropyl from the viewpoint of ease of reaction and availability of raw materials. Dentrimethylol ethane phosphorylcholine is preferred.

The compound represented by the formula (1) of the present invention is represented by, for example, the cyclic ketal represented by the formula (2) and the formula (3) in order to obtain the compound represented by the formula (4). A step (a) of reacting 2-chloro-2-oxo-1,3,2-dioxaphosphorane, and a step of reacting the resulting compound represented by the formula (4) with trimethylamine (b) And a method for producing a compound represented by the above formula (1) of the present invention.
In Formula (2) and Formula (4), R ₁ represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, or an aryl group having 6 to 20 carbon atoms, and an alkyl group having 1 to 20 carbon atoms from the viewpoint of production. Among them, a methyl group and an ethyl group are preferable. R ₂ and R ₃ may be the same or different and each represents a hydrogen atom, a methyl group, or an ethyl group, and is a methyl group from the viewpoint of ease of removal of the residue during the cyclic ketal removal reaction. Is preferred.

Examples of the cyclic ketal represented by the formula (2) used in the step (a) include isopropylidenetrimethylolethane, isopropylidenetrimethylolpropane, isopropylidenetrimethylolbutane, isopropylidenetrimethylolmethylcyclohexane, sec-butylidene. Examples include trimethylolethane, sec-butylidenetrimethylolpropane, sec-butylidenetrimethylolbutane, sec-butylidenetrimethylolmethylcyclohexane, and isopropylidenetrimethylol from the viewpoint of ease of reaction and availability. Ethane is preferred.
Such a cyclic ketal includes, for example, trimethylolethane, trimethylolpropane, trimethylolbutane, etc. and a carbonyl compound represented by the formula (6) in the presence of a catalyst such as hydrochloric acid, sulfuric acid, paratoluenesulfonic acid, etc. It can be synthesized by a cyclization reaction in a solvent such as petroleum ether, benzene, toluene, hexane.

式(６)中、Ｒ₂及びＲ₃は式(２)のものと同一である。式(６)で表されるカルボニル化合物としては、例えば、ホルムアルデヒド、アセトアルデヒド、アセトン、メチルエチルケトン、３−ペンタノンが挙げられ、反応後の除去の容易さからアセトンが好ましく挙げられる。

In the formula (6), R ₂ and R ₃ are the same as those in the formula (2). Examples of the carbonyl compound represented by the formula (6) include formaldehyde, acetaldehyde, acetone, methyl ethyl ketone, and 3-pentanone, and acetone is preferable because of easy removal after the reaction.

In the reaction in step (a), the amount of 2-chloro-2-oxo-1,3,2-dioxaphosphorane represented by formula (3) is used in the cyclic ketal represented by formula (2). On the other hand, the molar ratio is preferably 1.0 to 2.0 times.
The reaction in step (a) can be carried out in the presence of a catalyst. Examples of the catalyst include triethylamine, diisopropylamine, pyridine, dimethylaminopyridine, tetramethyl-1,3-butanediamine, tetramethyl-1,3-propanediamine, dimethyldiethyl-1,3-propanediamine, and pentamethyl. Examples include diethylenediamine, tetraethylmethanediamine, dimethylcyclohexylamine, diethylcyclohexylamine, methyloctylcyclohexylamine, and methyldodecylcyclohexylamine. From the viewpoint of product purity, use of diisopropylamine is preferred.
The amount of the catalyst used is preferably 1.0 to 2.0 times the molar ratio relative to the cyclic ketal represented by the formula (2).

The reaction in the step (a) can be performed in the presence of a solvent that is not reactive with 2-chloro-2-oxo-1,3,2-dioxaphosphorane represented by the formula (3). . Preferred examples of such solvents include acetone, methyl ethyl ketone, acetonitrile, chloroform, carbon tetrachloride, dichloromethane, benzene, toluene, hexane, pyridine, and tetrahydrofuran (THF). Most preferably mentioned.
The usage-amount in the case of using the said solvent is about 0.1-1000 mass parts normally with respect to 100 mass parts of cyclic ketal represented by Formula (2).

The reaction conditions in the step (a) can be appropriately selected in order to obtain the target compound represented by the formula (4), but the reaction temperature is usually in the range of 25-60 ° C, preferably 40-60 ° C. When the reaction temperature is lower than 40 ° C., the reaction may take a long time, and the purity may be lowered. When the reaction temperature exceeds 60 ° C., the decomposition reaction with 2-chloro-2-oxo-1,3,2-dioxaphospholane tends to occur, and the purity of the product may be lowered.
Although reaction time changes with conditions, such as reaction temperature and the kind and quantity of a catalyst, about 1 to 10 hours are preferable normally.

  The compound represented by the above formula (4) obtained by the above-mentioned reaction in the step (a) is not purified as it is, or is isolated and purified by treatment such as salt filtration and drying under reduced pressure, and then the next step ( Can be used for b).

In the reaction in the step (b), the amount of trimethylamine used is preferably 1.0 to 3.0 times the molar ratio of the compound represented by the formula (4).
The reaction in step (b) can be carried out in the presence of a solvent that is not reactive with the compound represented by formula (4). Examples of such solvents are preferably acetone, methyl ethyl ketone, acetonitrile, chloroform, carbon tetrachloride, dichloromethane, benzene, toluene, hexane, pyridine, and THF. These solvents may be used alone, but a plurality of solvents can be selected and mixed, and a mixed solvent of acetonitrile and THF is most preferable from the viewpoint of trimethylamine solubility.
The usage-amount in the case of using the said solvent is about 0.1-1000 mass parts normally with respect to 100 mass parts of compounds represented by Formula (4).

The reaction conditions in the step (b) can be appropriately selected in order to obtain the desired phosphorylcholine group-containing cyclic ketal compound represented by the formula (1), but the reaction temperature is preferably 10 to 90 ° C.
The obtained phosphorylcholine group-containing cyclic ketal compound represented by the formula (1) can be purified by recrystallization, drying under reduced pressure or the like as it is.
The obtained phosphatidylcholine group-containing cyclic ketal compound can be used as it is as a polymer additive or a pharmaceutical raw material.

In the method for producing a phosphatidylcholine group-containing diol compound represented by the above formula (5) of the present invention, the phosphorylcholine group-containing cyclic ketal compound represented by the above formula (1) is hydrolyzed with a water-containing solvent in the presence of an acid catalyst. A step of ring-opening reaction. In formula (5), R ₁ is the same as R ₁ of formula (1).
Preferred examples of the acid catalyst include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; and organic acids such as paratoluenesulfonic acid. Hydrochloric acid is particularly preferred from the viewpoint of ease of catalyst removal after the reaction. The amount of the acid catalyst used is preferably such that the proportion of the total amount in the reaction system is usually 0.1 to 10.0% by mass.

  Examples of the water-containing solvent include water alone or a mixed solvent of water and a water-soluble solvent such as methanol, ethanol, isopropanol, THF, acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, and dimethylacetamide. A mixed solvent of methanol and water is most preferable because of easy removal after the reaction.

The reaction temperature of the hydrolytic ring-opening reaction is preferably in the range of 0 to 50 ° C. When the reaction temperature exceeds 50 ° C., side reactions such as ester hydrolysis or transesterification may occur. In addition, when the reaction temperature is lower than 0 ° C., there is a possibility that moisture is solidified. On the other hand, although reaction time changes with conditions, such as reaction temperature and the kind and quantity of a catalyst, about 1 to 6 hours are preferable normally.
As the hydrocyclization reaction proceeds, a carbonyl compound may be by-produced in the reaction system. For the purpose of shortening the reaction time, the by-product carbonyl compound is removed by means such as distillation under reduced pressure. It is preferable to remove from the inside.
In the production method of the present invention, the target phosphatidylcholine group-containing diol compound can be obtained with very high purity by using a phosphorylcholine group-containing cyclic ketal compound as a precursor.

EXAMPLES Hereinafter, although an Example demonstrates this invention still in detail, this invention is not limited to these.
Production Example 1
(Synthesis of the compound represented by the formula (2))
Isopropylidenetrimethylolethane was produced by the following synthesis method according to M. Renoll, MS Newman, Org. Syn. Coll. 3, 502 (1955).
To a eggplant-shaped flask equipped with a calcium tube, a condenser tube and a Dean-stark trap, 100 g of trimethylolethane, 300 ml of acetone, 3 g of p-toluenesulfonic acid monohydrate and 300 ml of petroleum ether were added, The mixture was heated to reflux in an oil bath set to. After 12 hours, the reaction mixture was cooled to room temperature after confirming that no more water was produced at a water content of about 15 ml. Next, 3 g of sodium acetate was added and the mixture was further stirred for 30 minutes, and then petroleum ether and acetone were distilled off by an evaporator.
The crude product thus obtained was distilled under reduced pressure under conditions of a bath temperature of 75 ° C., a fraction temperature of 65 ° C., and a degree of vacuum of 5 mmHg, yielding 130.6 g, yield 91%, and isopropylidene trimethylol as a colorless and transparent liquid. I got ethane. The measurement result of ¹ H-NMR is shown below.
_{^{1 H-NMR (CDCl 3)}} 0.8ppm, s, C H 3 (3H) 1.3-1.5ppm, d, C H 3 (6H) 2.2ppm, s, O H (1H) 3.5 -3.7 ppm, m, C H ₂ (6H)

Production Example 2
(Synthesis of the compound represented by the formula (2))
The same operation as in Production Example 1 was carried out except that methyl ethyl ketone was used in place of acetone to obtain a colorless transparent liquid sec-butylidenetrimethylolethane in a yield of 139.6 g and a yield of 88%. The measurement result of ¹ H-NMR is shown below.
_{^{1 H-NMR (CDCl 3)}} 0.8ppm, s, C H 3 (3H) 0.8-1.0ppm, t, CH 2 C H 3 (3H) 1.2-1.4ppm, d, C H ₃ (3H) 1.6-1.8 ppm, q, C H ₂ CH ₃ (2H) 2.2 ppm, s, O H (1H) 3.5-3.7 ppm, m, C H (6H)

Example 1
(Synthesis of compound represented by formula (1), reaction temperature 45 ° C.)
To the eggplant-shaped flask, 20.0 g of isopropylidenetrimethylolethane synthesized in Production Example 1, 200 ml of THF and 15.9 ml of diisopropylamine were added and cooled to 0 ° C. A dropping funnel was attached, and 16.4 g of 2-chloro-2-oxo-1,3,2-dioxaphospholane was added dropwise over 15 minutes. After completion of the dropping, the reaction system was heated to 45 ° C. and reacted for 2 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, and the precipitated hydrochloride was removed by filtration, and the residue was concentrated under reduced pressure to obtain a cyclic ketal having a 2-oxo-1,3,2-dioxaphosphoranyl group. .
200 ml of acetonitrile and 25 ml of trimethylamine were added to the obtained cyclic ketal and reacted at 70 ° C. for 15 hours. After completion of the reaction, recrystallization was performed to obtain isopropylidenetrimethylolethane monophosphorylcholine as a white solid in a yield of 17.7 g and a yield of 44%. The measurement result of ¹ H-NMR and the purity based on the integral value of ³¹ P-NMR are shown below.
¹ H-NMR (CD ₃ OD) 0.9 ppm, s, C H ₃ (3H) 1.3-1.5 ppm, d, C H ₃ (6H) 3.2 ppm, s, N ⁺ -(C H _{3 ) 3 (9H) 3.5-3.7ppm, m} , C-C H 2 (6H) 3.9ppm, d, N + -C H 2 (2H) 4.3ppm, m, O-C H 2 - C (2H)
³¹ P-NMR (CD ₃ OD) -10.7 ppm (8%), 0.5 ppm (92%)
The ³¹ P-NMR peak of isopropylidenetrimethylolethane monophosphorylcholine was observed at 0.5 ppm. Therefore, the purity was 92%.

Example 2
(Synthesis of compound represented by formula (1), reaction temperature 25 ° C.)
To the eggplant-shaped flask, 20.0 g of isopropylidenetrimethylolethane synthesized in Production Example 1, 200 ml of THF and 15.9 ml of diisopropylamine were added and cooled to 0 ° C. A dropping funnel was attached, and 16.4 g of 2-chloro-2-oxo-1,3,2-dioxaphospholane was added dropwise over 15 minutes. After completion of dropping, the reaction system was kept at 25 ° C. and stirred for 2 hours. The precipitated hydrochloride was removed by filtration, and the residue was concentrated under reduced pressure to obtain a cyclic ketal having a 2-oxo-1,3,2-dioxaphosphoranyl group.
200 ml of acetonitrile and 25 ml of trimethylamine were added to the obtained cyclic ketal and reacted at 70 ° C. for 15 hours. After completion of the reaction, recrystallization was performed to obtain a white solid isopropylidenetrimethylolethane monophosphorylcholine in a yield of 4.5 g and a yield of 11%. The measurement result of ¹ H-NMR and the purity based on the integral value of ³¹ P-NMR are shown below.
¹ H-NMR (CD ₃ OD) 0.9 ppm, s, C H ₃ (3H) 1.3-1.5 ppm, s × 2, C H ₃ (6H) 3.2 ppm, s, N ⁺ -(C H ₃ ) ₃ (9H) 3.5-3.7 ppm, m, C—C H ₂ (6H) 3.9 ppm, d, N ⁺ —C H ₂ (2H) 4.3 ppm, m, O—C H _2- C (2H)
³¹ P-NMR (CD ₃ OD) -10.7 ppm (8%), 0.5 ppm (68%), 1.3 ppm (8%), 18.5 ppm (13%), 19.2 ppm (3%)
The ³¹ P-NMR peak of isopropylidenetrimethylolethane monophosphorylcholine was observed at 0.5 ppm. The purity was 68%.

Example 3
(Synthesis of compound represented by formula (1), reaction temperature 45 ° C.)
The same operation as in Example 1 was carried out except that sec-butylidenetrimethylolethane synthesized in Production Example 2 was used instead of isopropylidenetrimethylolethane, and the yield was 15.8 g and the yield was 41%. sec-Isobutylidenetrimethylolethane monophosphorylcholine was obtained. The measurement result of ¹ H-NMR is shown below.
_{^{1 H-NMR (CD 3 OD}} ) 0.9ppm, s, C H 3 (3H) 0.8-1.0ppm, t, CH 2 C H 3 (3H) 1.2-1.4ppm, d, C H ₃ (3H) 1.6-1.8 ppm, q, C H ₂ CH ₃ (2H) 3.2 ppm, s, N ⁺ -(C H ₃ ) ₃ (9H) 3.5-3.7 ppm, m , C—C H ₂ (6H) 3.9 ppm, d, N ⁺ —C H ₂ (2H) 4.3 ppm, m, O—C H ₂ —C (2H)
³¹ P-NMR (CD ₃ OD) -10.7 ppm (9%), 0.5 ppm (91%)
The purity of the sec-isobutylidenetrimethylolethane monophosphorylcholine as measured by ³¹ P-NMR integration was 91%.

Example 4
(Synthesis of compound represented by formula (1), reaction temperature 25 ° C.)
The same operation as in Example 2 was carried out except that sec-butylidenetrimethylolethane synthesized in Production Example 2 was used instead of isopropylidenetrimethylolethane, and a yield of 3.9 g, a yield of 10% was obtained. sec-Isobutylidenetrimethylolethane monophosphorylcholine was obtained. The measurement result of ¹ H-NMR is shown below.
_{^{1 H-NMR (CD 3 OD}} ) 0.9ppm, s, C H 3 (3H) 0.8-1.0ppm, t, CH 2 C H 3 (3H) 1.2-1.4ppm, d, C H ₃ (3H) 1.6-1.8 ppm, q, C H ₂ CH ₃ (2H) 3.2 ppm, s, N ⁺ -(C H ₃ ) ₃ (9H) 3.5-3.7 ppm, m , C—C H ₂ (6H) 3.9 ppm, d, N ⁺ —C H ₂ (2H) 4.3 ppm, m, O—C H ₂ —C (2H)
³¹ P-NMR (CD ₃ OD) -10.7 ppm (7%), 0.5 ppm (71%), 1.3 ppm (8%), 18.5 ppm (12%), 19.2 ppm (2%)
The purity of the sec-isobutylidene trimethylolethane monophosphorylcholine as determined by ³¹ P-NMR integration was 71%.

Example 5
(Synthesis of the compound represented by the formula (5))
A magnetic stirrer, 7.8 g of isopropylidenetrimethylolethane monophosphorylcholine synthesized in Example 1, 10 ml of methanol and 600 μl of 4N hydrochloric acid were added to the screw tube, and the mixture was stirred at room temperature for 3 hours. After stirring, white solid trimethylolethane monophosphatidylcholine was obtained in a yield of 6.3 g and a yield of 83% by drying under reduced pressure.
The measurement result of ¹ H-NMR and the purity based on the integral value of ³¹ P-NMR are shown below.
¹ H-NMR (CD ₃ OD) 0.9 ppm, s, C H ₃ (3H) 3.2 ppm, s, N ⁺ -(C H ₃ ) ₃ (9H) 3.4-3.8 ppm, m, C _{-C H 2 (6H) 3.8ppm,} d, N + -C H 2 (2H) 4.3ppm, m, O-C H 2 -C (2H)
³¹ P-NMR (CD ₃ OD) -10.8 ppm (1%), 1.3 ppm (99%)
The purity of the resulting trimethylolethane monophosphatidylcholine was 99% according to the integral value of ³¹ P-NMR.

Example 6
(Synthesis of the compound represented by the formula (5))
A magnetic stirrer, 7.8 g of sec-isobutylidenetrimethylolethane monophosphatidylcholine synthesized in Example 3, 10 ml of methanol and 600 μl of 4N hydrochloric acid were added to the screw tube, and the mixture was stirred at room temperature for 3 hours. After stirring, white solid trimethylolethane monophosphatidylcholine was obtained by drying under reduced pressure at a yield of 5.5 g and a yield of 84%. The measurement result of ¹ H-NMR and the purity based on the integral value of ³¹ P-NMR are shown below.
¹ H-NMR (CD ₃ OD) 0.9 ppm, s, C H ₃ (3H) 3.2 ppm, s, N ⁺ -(C H ₃ ) ₃ (9H) 3.4-3.8 ppm, m, C _{-C H 2 (6H) 3.8ppm,} d, N + -C H 2 (2H) 4.3ppm, m, O-C H 2 -C (2H)
³¹ P-NMR (CD ₃ OD) -10.8 ppm (1%), 1.3 ppm (99%)
The purity of the resulting trimethylolethane monophosphatidylcholine was 99% according to the integral value of ³¹ P-NMR.

Claims (4)

A phosphorylcholine group-containing cyclic ketal compound represented by the formula (1):

(In the formula (1), R ₁ represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms or an aryl group having 6 to 20 carbon atoms. R ₂ and R ₃ may be the same or different, and Represents an atom, a methyl group or an ethyl group.) In order to obtain a compound represented by the formula (4), a cyclic ketal represented by the formula (2) and a 2-chloro-2-oxo-1,3,2-dioxaphospho represented by the formula (3) The method for producing a phosphorylcholine-containing cyclic ketal compound according to claim 1, comprising a step (a) of reacting with orchid and a step (b) of reacting trimethylamine with the compound represented by formula (4).

(In Formula (2) and Formula (4), R ₁ represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, or an aryl group having 6 to 20 carbon atoms. R ₂ and R ₃ may be the same or different. And may represent a hydrogen atom, a methyl group or an ethyl group.)   The manufacturing method of Claim 2 which performs reaction of a process (a) on 40-60 degreeC conditions. A process for producing a phosphatidylcholine group-containing diol compound represented by formula (5), comprising a step of subjecting the phosphorylcholine group-containing cyclic ketal compound of claim 1 to a hydrolytic ring-opening reaction with a water-containing solvent in the presence of an acid catalyst.

(In Formula (5), R ₁ represents a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, or an aryl group having 6 to 20 carbon atoms.)