KR101735349B1 - Preparation method for sulfur-bridged alkoxysilanated phosphorylcholine - Google Patents

Abstract

상기 화학식 1에서, R₁, R₂ 및 R₃는 각각 수소, (C₁-C₆) 알콕시, 비치환된 (C₁-C₆) 직쇄 또는 분지쇄 알킬, 치환된 (C₁-C₆) 직쇄 또는 분지쇄 알킬, 할로겐, 하이드록실, 페닐 및 벤질로 이루어진 그룹으로부터 선택되고, R₁, R₂ 및 R₃ 중 적어도 하나는 (C₁-C₆) 알콕시이고, m은 1 내지 7로부터 선택되는 정수이며, 본 발명에서는 구리(I)-촉매 및 티올-렌(thiol-ene) “클릭” 반응이 알콕시실란화 PC 모이어티를 합성하는 매우 간편하고 효율적인 방법을 제공한다는 점을 규명하였고, 총 12종의 알콕시실란화 PC를 매우 고수율로 수득할 수 있었으며, 본 발명에 따른 방법으로 수득된 알콕시실란화 PC가 표면 개질제로 사용될 수 있다는 점을 실험을 통해 규명하였으며, 또한 본 발명에서, 알콕시실란화 PC는 실리카 비드 표면에 임플란트되었고, 로딩율을 정량함으로써 알콕시실란화 PC가 실리카 비드 표면에 성공적으로 임플란트되었다는 점을 규명하였다.The present invention relates to a process for preparing alkoxy phosphorylcholine by reacting an alkenyl phosphorylcholine with a thiol compound represented by the following formula (1) by a thiol-ene click reaction to form a sulfur-bridged alkoxy The present invention relates to a method for preparing alkoxysilanated phosphorylcholine
[Chemical Formula 1]

In Formula 1, R _1, R ₂ and R ₃ are each hydrogen, (C ₁ -C ₆₎ alkoxy, unsubstituted (C ₁ -C ₆₎ linear or branched alkyl, substituted (C ₁ -C ₆ ring ) At least one of R ₁ , R ₂ and R ₃ is (C ₁ -C ₆ ) alkoxy and m is from 1 to 7; and R ₁ is selected from the group consisting of halogen, hydroxyl, phenyl and benzyl, And that the present invention provides a very simple and efficient way to synthesize an alkoxysilylated PC moiety with a copper (I) -catalyst and a thiol-ene "click" reaction, A total of 12 types of alkoxysilylated PCs were obtained at a very high yield and that the alkoxysilanated PCs obtained by the process according to the present invention could be used as surface modifiers, Alkoxy silanized PCs were implanted on the silica bead surface and quantified the loading rate , Indicating that alkoxy silanized PCs were successfully implanted into the silica bead surface.

Description

Preparation of sulfur-bridged alkoxysilanated phosphorylcholine < RTI ID = 0.0 >

The present invention relates to a process for preparing alkoxy phosphorylcholine by reacting an alkenyl phosphorylcholine with a thiol compound represented by the following formula (1) by a thiol-ene click reaction to form a sulfur-bridged alkoxy The present invention relates to a method for preparing alkoxysilanated phosphorylcholine,

[Chemical Formula 1]

In Formula 1,

R ₁ , R ₂ and R ₃ are each independently selected from hydrogen, (C ₁ -C ₆ ) alkoxy, unsubstituted (C ₁ -C ₆ ) linear or branched alkyl, substituted (C ₁ -C ₆ ) Alkyl, halogen, hydroxyl, phenyl and benzyl,

At least one of R ₁ , R ₂ and R ₃ is (C ₁ -C ₆ ) alkoxy,

m is an integer selected from 1 to 7;

Phosphorylchloine (PC) derivatives are widely used as surface modifiers due to their excellent biocompatibility, hemocompatibility and hydrophilicity. The alkoxysilane is an efficient coupling agent for modifying the surface properties and can be used to connect the desired substrate with the PC moiety. Phosphorylcholine (PC) has a structure defined by a flow mosaic model, a biomembrane model proposed by Singer and Nicolson. The phospholipid containing the head group PC is a major component of all eukaryotic membranes and constitutes at least 10% of all bacterial membranes. Therefore, PC derivatives have been widely used as biomembrane structures with high affinity for living organs and tissues, and have been shown to inhibit blood-contact devices, bio-mimic membranes and cell adhesion, or undesirable protein interactions It is an excellent anti-fouling surface modifier for use in various medical purposes such as surface treatment to reduce the surface area.

Applied Materials In the scientific field, it is very important to modify the physical and chemical properties of a specific surface. One of the common methods for surface modification is to implant alkoxy- or halo-silyl functionalized modifiers on hydroxylated surfaces such as metal oxides, nanoparticles and medical devices.

The formation of strong Si-O bonds without catalyst is particularly useful for connecting functional groups to substrates. Efforts have been made to synthesize PC-containing macromolecules for the modification of medical devices having methoxysilyl groups. For example, copolymers of 2-methacryloyloxyethylphosphorylcholine (MPC) and 3-trimethoxysilylpropyl methacrylate (MPS) are synthesized via radical polymerisation. The trimethoxysilyl group of MPS acts as a coupling agent to enhance the adhesion force on the contact lens.

3-mercaptopropyltrimethoxysilane is used to initiate thiol-ene radical photopolymerization of MPC, where the trimethoxysilyl group acts as an end-blocker And the coupling agent is coupled so that poly (MPC) is coated on the Mg-Al-Zn alloy. For application purposes, PC-containing micro-molecules have been useful not only for large devices due to their excellent modifying properties, but also for nano-sized particles. Chloro-silanized PCs were first made to construct biofilms on the hydroxylated surfaces. However, it had to go through more than five steps and the total yield was very limited and limited. Recently, MPC and trimethoxysilane were used in the synthesis of trimethoxysilanized MPC for the modification of medical alloys by Pt / C-catalyzed hydrosilylation reaction of methanol. However, when MPC was hydrosilylated analogously to trialkoxysilane, the desired product was not obtained because the trialkoxysilane reacted with the alkyl alcohol in the presence of a Pt / C or Karstedt catalyst. Thus, it can be seen that the Pt-catalyzed hydrosilylation reaction is not suitable for the production of alkoxy silanized PC.

The present inventors have identified that methallylsilinated PCs can be synthesized through copper (I) -catalyst-click reactions and can be applied to the modification of silica beads. However, when compared to methoxy- and chloro-silanized PCs, the methylallylsilyl group needs activation to act as a modifier in the presence of triflic acid. Therefore, it is necessary to develop a method for bonding an alkoxysilyl group to a PC moiety.

U.S. Patent No. 8,183,355 U.S. Patent No. 8,623,928

The present invention provides a method for efficiently and easily synthesizing a sulfur-crosslinked alkoxysilanated phosphorylcholine by copper (I) -catalyst and thiol-enantiomer reaction.

The present invention also provides a method for preparing a sulfur-crosslinked alkoxysilanated phosphorylcholine in a very high yield under unfavorable conditions, and a method for easily scaling up the reaction.

The present invention also aims to provide a highly active surface modifier prepared by the above process.

The present invention relates to a process for preparing alkoxy phosphorylcholine by reacting an alkenyl phosphorylcholine with a thiol compound represented by the following formula (1) by a thiol-ene click reaction to form a sulfur-bridged alkoxy The present invention relates to a process for preparing alkoxysilanated phosphorylcholine:

[Chemical Formula 1]

In Formula 1,

R ₁ , R ₂ and R ₃ are each independently selected from hydrogen, (C ₁ -C ₆ ) alkoxy, unsubstituted (C ₁ -C ₆ ) linear or branched alkyl, substituted (C ₁ -C ₆ ) Alkyl, halogen, hydroxyl, phenyl and benzyl,

At least one of R ₁ , R ₂ and R ₃ is (C ₁ -C ₆ ) alkoxy,

m is an integer selected from 1 to 7;

The present invention has demonstrated that copper (I) -catalyst and thiol-ene "click" reactions provide a very simple and efficient way to synthesize alkoxy silanized PC moieties.

Further, by using the method according to the present invention, it was possible to obtain a total of 12 kinds of alkoxy silanated PCs at a very high yield, and it was confirmed that the alkoxy silanized PC obtained by the method according to the present invention can be used as a surface modifier .

In addition, in the present invention, alkoxy silanized PCs were implanted on the surface of silica beads, and by quantifying the loading rate, it was found that alkoxy silanized PCs were successfully implanted on the silica bead surface.

Figure 1 shows a method for synthesizing triazole-crosslinked alkoxysilanated phosphorylcholine.
Figure 2 shows a method for synthesizing sulfur-crosslinked alkoxysilanated phosphorylcholine (2e-2l).
Fig. 3 shows an example of modification of the silica surface using alkoxysilane phosphorylcholine.

The present invention relates to a process for preparing alkoxy phosphorylcholine by reacting an alkenyl phosphorylcholine with a thiol compound represented by the following formula (1) by a thiol-ene click reaction to form a sulfur-bridged alkoxy The present invention relates to a process for preparing alkoxysilanated phosphorylcholine:

[Chemical Formula 1]

In Formula 1,

R ₁ , R ₂ and R ₃ are each independently selected from hydrogen, (C ₁ -C ₆ ) alkoxy, unsubstituted (C ₁ -C ₆ ) linear or branched alkyl, substituted (C ₁ -C ₆ ) Alkyl, halogen, hydroxyl, phenyl and benzyl,

At least one of R ₁ , R ₂ and R ₃ is (C ₁ -C ₆ ) alkoxy,

m is an integer selected from 1 to 7;

In one aspect of the present invention, the alkenylphosphorylcholine is selected from the group consisting of allylphosphorylcholine or 2-methacryloyloxyethyl phosphorylcholine. The sulfur-bridged ) ≪ / RTI > alkoxysilanated phosphorylcholine is provided.

In one embodiment of the present invention, the sulfur-bridged alkoxysilanated phosphorylcholine is characterized in that the sulfur-bridged alkoxysilanated phosphorylcholine is represented by the following formula (2) or A method of making is provided:

(2)

(3)

In the general formula (2) or (3)

R ₁ , R ₂ and R ₃ are each independently selected from hydrogen, (C ₁ -C ₆ ) alkoxy, unsubstituted (C ₁ -C ₆ ) linear or branched alkyl, substituted (C ₁ -C ₆ ) Alkyl, halogen, hydroxyl, phenyl and benzyl,

At least one of R ₁ , R ₂ and R ₃ is (C ₁ -C ₆ ) alkoxy,

m is an integer selected from 1 to 7;

In one aspect of the present invention, at least one of R ₁ , R ₂ and R ₃ is selected from the group consisting of methyl, ethyl, methoxy and ethoxy. The sulfur-bridged ) ≪ / RTI > alkoxysilanated phosphorylcholine is provided.

In one aspect of the present invention, at least two of R ₁ , R ₂ and R ₃ are selected from the group consisting of methyl, ethyl, methoxy and ethoxy. The sulfur- -bridged alkoxysilanated phosphorylcholine is provided.

In one aspect of the present invention, there is provided a process for preparing a sulfur-bridged alkoxysilanated phosphorylcholine, wherein n is 3.

In one aspect of the present invention, there is provided a process for preparing a sulfur-bridged alkoxysilanated phosphorylcholine, wherein m is 3.

The present invention also relates to a process for preparing a modified silica by reacting a sulfur-crosslinked alkoxysilanated phosphorylcholine prepared by the process with a compound of the formula:

[Chemical Formula 4]

.

.

The present invention also provides a sulfur-bridged alkoxysilanated phosphorylcholine compound prepared by the above process.

The present invention also provides prepared modified silica compounds prepared by the above process.

As is known, the coupling of the terminal alkyne with the terminal alkyne using a copper (I) -catalyst can be used to elaborately and selectively select 1,2,3-triazole in a very wide range.

Figure 1 shows how a copper (I) -catalyst click reaction can be used to synthesize triazole-crosslinked alkoxy silanated PCs (2a-2d).

Hereinafter, the present invention will be described in more detail with reference to Examples. It should be understood, however, that the following examples are for the purpose of promoting understanding of the present invention and are not intended to limit the scope of the present invention.

Example  One. Triazole - Crosslinked Alkoxy silanization Of phosphorylcholine  synthesis

First, 3-azidopropyl alkoxysilane (1a-1d, Table 1) was synthesized from commercially available 3-chloropropylalkoxysilane to synthesize propargylphosphorylcholine (PPC). Equimolar 3-azidopropyl alkoxysilane and PPC (1 mmol) were mixed in the presence of CuI / DIPEA (2 mmol / 4 mmol). The reaction was then dissolved in ethanol in the presence of argon. Ethanol (5 mL) and allowed to react at 60 ° C for 12 hours.

From Table 1, it can be seen that azide (1a-1d) is coupled with PPC to produce alkoxy silanated PC. The copper (I) catalyst was filtered under nitrogen conditions to purify the final product. After removing the solvent under reduced pressure, the residue was washed several times with anhydrous hexane. Finally, the target product (2a-2d) was obtained in the form of a pale yellow powder, with a yield of 90-92%.

(The following Table 1 shows the triazole-crosslinked alkoxysilanated phosphorylcholine (2a-2d)

While the radical-base thiol-ene reaction is another approach to alkoxy silanized PCs. Such reactions have been used extensively in the synthesis of new polymeric materials for applications ranging from dendrimers, functionalized biomolecules, biomacromolecules, and lithography to porous microparticles. The reaction involves the addition of a thiol to an alkene, as another member of the click response family. The thiol-ene reaction is carried out under mild conditions at room temperature, is regioselective, is resistant to multiple functional groups, the reaction proceeds neatly, is conveniently obtained in quantitative or near quantitative yield, There is an advantage that a purification process is not necessary. In the field of organic-silicon chemistry, the method has proven to be a useful method for synthesizing functionalized silanes, silicon elastomeric materials and oxide-free silicon surfaces. Thus, the thiol-ene reaction may be suitable for the synthesis of alkoxy silanated PCs.

Example  2. Yellow- Crosslinked Alkoxy silanization PC Synthesis of

Alkenylphosphorylcholine, such as 2-methacryloyloxyethylphosphorylcholine (MPC) and allylphosphorylcholine (APC), were prepared. The sulfur-crosslinked alkoxysilanated PC (2e-2l) was then synthesized via a thiol-enantiomeric reaction to initiate benzophenone under a 300-nm UV lamp as shown in FIG. A slight excess of 3-mercaptopropyl alkoxysilane (1e-11, 1.10 mmol) and alkenyl PC (1 mmol) were dissolved in 2 mL of ethanol (EtOH) in the presence of 2 mol% of benzophenone, The reaction was carried out under gas for 15 minutes.

Table 2 shows that the mercapto-silane is selectively positioned by the thiol-ene reaction. After removal of the solvent under reduced pressure, the product (2e-2l) residue was washed with hexane to remove unreacted 3-mercaptopropylalkoxysilane and benzophenone. The final product was obtained in quantitative yield in the form of a pale yellow powder. This seems to be due to the higher reactivity of the acryloyl groups on the MPC than the vinyl groups on the APC, with shorter reaction times being used for the thiol-ene reaction of MPC. (Table 2 below shows the sulfur-crosslinked alkoxy silanated PC (2e-2l)

Manufacturing example  1. Silica Bead  Prize Alkoxy silanization PC Loading

To demonstrate that all alkoxy silanated PCs are useful as surface modifiers, they were implanted onto silica beads, as shown in Fig. Alkoxysilane PC (1 mmol) and silica beads (400 mmg) were dispersed in a mixed solution of 20 mL IPA / toluene (10 mL / 10 mL). After heating for 24 hours at 90 DEG C under nitrogen, the modified silica was filtered, washed with ethanol and toluene, and dried in a vacuum oven for 24 hours. The loading rates of alkoxy silanized PCs on silica beads were measured as shown in Table 3 below. (The loading rate of the alkoxy silanized PC was determined based on the N value of the modified silica analyzed by elemental analysis. [For example, the loading rate of 2j modified silica 2j-silica is (C (%) 9.0929, N (%) 0.8921) = (0.8921 × 10 ^-2 g of N / 1 g of compound PC-modified silica 2j-silica ) × 10 ³ mmol of N / 14 g of N × 1 mmol of 2j / of N) = 0.63 mmol 2j / 1 g of compound PC-modified 2j- silica .) (Table 3 below shows the loading rate of alkoxysilylated PC (2a-2l) on silica beads)

The resulting modified silica was analyzed by elemental analysis. As shown in Table 3, the loading rate of alkoxy silylated PCs analyzed by nitrogen element analysis was 0.31 ~ 0.63 mmol / g. The methoxy-silanization modifier was more active than the ethoxy-silanization modifier, the trimethoxy group produced a higher reaction point and the loading rate was higher.

Also, the loading rate was affected by the steric hindrance of the silane tail. The alkoxysilylpropyltriazolyl PC tail (2a-2d) had the greatest steric hindrance, and the effect of the steric hindrance of the alkoxysilylpropyl thiolated methyl isobutyrate PC tail (2i-2l) on the alkoxysilylpropyl thiolated ethylene (2i-2l) stellar obstructions. However, in the case of silanized PCs with the same &quot; crosslinking &quot;, the mono-alkoxy silanated PC is slightly smaller than the PC of the di-alkoxy silanated PC, for example, 2c (0.31 mmol / g) <2d High loading rate. This seems to be due to the fact that the di-alkoxy group exhibits a stronger steric hindrance effect than the mono-alkoxy group. To further confirm the surface modification of the silica, the surface element composition of some modified silica beads was analyzed by XPS. For example, in Table 4, the elemental surface composition ratio was analyzed to be 0.62 / 2.85 / 13.36, and the modified silica phase P / N / C ratio was analyzed to be 1.0 / 4.5 / 21.5, 20). The results show that the PC moiety was successfully immobilized on silica.

Surface Element Composition of Alkoxy Silylated PC-Modified Silica Modified silica O (%) Si (%) C (%) N (%) P (%) S (%) 2b-silica 53.32 29.85 13.36 2.85 0.62 2e-silica 52.20 29.75 18.35 0.82 0.90 0.86 2f-silica 51.96 29.50 17.95 1.32 1.46 1.44 2g-silica 50.79 28.78 17.65 1.15 1.32 1.12 2h-silica 53.36 30.76 19.68 0.68 0.69 0.64 2j-silica 54.69 28.60 16.90 1.26 1.36 1.31

[ conclusion ]

It can be seen that the triazole- or sulfur-crosslinked alkoxysilanated phosphorylcholine can be synthesized very efficiently and easily through copper (I) -catalyst and thiol-enantiomeric reaction. The use of the process according to the invention can be obtained in very high yields under unfavorable conditions and the reaction can be easily scaled up. Experimental results show that the synthesized alkoxy silanized PC is immobilized on silica beads and is a highly active surface modifier. The method according to the present invention is a suitable technique for developing PC-containing silicone materials for application to blood-contact conditions and biomimetic systems.

Claims (10)

(a) reacting an alkenyl phosphorylcholine with a thiol compound represented by the following formula (1) by a thiol-ene click reaction to obtain a sulfur-crosslinked preparing a sulfur-bridged alkoxysilanated phosphorylcholine; And
[Chemical Formula 1]

(2)

(Wherein R _1, R ₂ and R ₃ are methoxy, and m is an integer selected from 1 to 3.)
(b) a process for producing a modified silica by reacting the sulfur-crosslinked alkoxysilanated phosphorylcholine prepared in the step (a) with a compound represented by the following formula
(3)

.

delete delete delete delete delete A process according to claim 1, wherein m is 3. delete delete delete

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