KR101247079B1 - An adhesive polymer comprising catechol group, a preparation method thereof and an adhesive nanoparticle formed by self-assembling of the polymer - Google Patents

Abstract

The present invention relates to an adhesive polymer compound comprising a catechol group, a method for preparing the same, and an adhesive nanoparticle formed by self-assembling the adhesive polymer compound, and more particularly, contains a catechol having excellent adhesion to a metal implant surface. The present invention relates to an adhesive polymer compound, a method for preparing the adhesive polymer compound, and a nanoparticle designed to be self-assembled and to support and sustain release of an ionic growth factor.

Description

Adhesive polymer compound comprising a catechol group, a method for preparing the same, and an adhesive nanoparticle formed by self-assembly of the adhesive polymer compound of the polymer}

The present invention relates to an adhesive polymer compound comprising a catechol group, a method for preparing the same, and an adhesive nanoparticle formed by self-assembling the adhesive polymer compound, and more particularly, contains a catechol having excellent adhesion to a metal implant surface. The present invention relates to an adhesive polymer compound, a method for preparing the adhesive polymer compound, and a nanoparticle designed to be self-assembled and to support and sustain release of an ionic growth factor.

For dental implants with osteogenic capacity, various surface treatment approaches have been used to induce sustained growth factor release [34-37]. Most systems are based on coating of biodegradable polymers (poly (glycolide-co-lactide) (PLGA), poly (D, L-lactide) (PDLLA)) for loading and release of growth factors. Although various growth factors, including BMP-2, TGF-β and IGF-1, can be incorporated into the polymer coating, there are many disadvantages. First, these coating processes require organic solvents that can adversely affect protein stability. Second, a simple solvent coating that drips the coating solution onto the implant surface and dries cannot produce a uniform coating layer of constant thickness. Thus, it is difficult to obtain planned controlled release of growth factors. Third, low interfacial adhesion between the polymer coating and the implant surface is another major limitation. This is because coatings with low interfacial affinity can be peeled off from the implant surface. For this reason, there is a need to develop new coating techniques that can stably and uniformly hold growth factors and release them in a controlled manner.

Among the various delivery systems, nanoparticle type carriers are ideal for medical equipment. This is because their clear and uniform nanostructures can load and release drugs or growth factors in a planned manner. Several nanoparticle systems have been reported for surface immobilization on medical equipment [38,39]. They are based on PLGA nanoparticles for the controlled release of low molecular weight drugs, which are adhered to the metal surface through ionic interactions. However, these systems could not be used for growth factor delivery and ionic interactions could not ensure stable immobilization of nanoparticles to the surface of medical devices. Therefore, there is a need to develop a nanoparticle-type adhesive carrier that can safely support growth factors and be stably immobilized on the surface of medical equipment.

Under this background, the present inventors coated the implant surface with nanoparticles containing catechol with excellent metal adhesive surface adhesion and designed to support the ionic growth factor, and then safely supported the growth factor without using an organic solvent. The present invention has been completed by confirming that it can provide an implant surface coating method capable of inducing sustained release of growth factors.

It is an object of the present invention to provide an adhesive polymer compound comprising a catechol group.

Another object of the present invention is to provide an adhesive nanoparticle formed by self-assembly of the adhesive polymer compound.

Still another object of the present invention is to provide a coated adhesive composition comprising the adhesive nanoparticles.

Still another object of the present invention is to provide a method of preparing the adhesive polymer compound.

It is still another object of the present invention to provide adhesive nanoparticles which can be introduced on the surface of dental, orthopedic or angioplasty implants to induce the sustaining and sustained release of growth factors for bone regeneration.

In order to solve the above problems, the present invention provides an adhesive polymer compound represented by the following formula (1).

Where

n is an integer from 10 to 100,

m is an integer of 10-100.

Preferably, in the above formula,

n is an integer from 20 to 70,

m is an integer of 10-30.

In addition, the present invention provides an adhesive nanoparticle formed by self-assembling the adhesive polymer compound represented by the formula (1).

In the present invention, the term 'self-assembling' refers to a phenomenon in which molecules form an orderly structure in which individual components spontaneously without artificial manipulation. In order for the molecules to self-assemble, the structural shape of the components must form a regular structure and there must be weak non-covalent forces between the molecules.

Adhesive nanoparticles self-assembled adhesive polymer compound represented by Formula 1 has a catechol group on the surface, poly (L- aspartate) portion is located in the shell, poly (L-phenylalanine) portion is located in the core To form spherical core-shell structured nanoparticles.

The adhesive nanoparticles may be loaded with drugs, growth factors or combinations thereof in the core or shell. The adhesive nanoparticles having the drug and / or growth factor mounted on the core or shell may be applied to a dental or orthopedic implant and used as a coating, and at the same time, the drug and / or growth factor may serve as a carrier of the drug and / or growth factor. Can be done.

In the present invention, the drug is bisphosphonate-based etidronate, clodronate, palmidronate, alendronate, alvanronate, ibandronate, risedronate Zoledronate, Tiludronate, [1-hydroxy-2- (imidazo [1,2-a] pyridin-3-yl) ethylidene] -bisphosphonic acid monohydrate ([1-hydroxy-2- (imidazo [1,2-a] pyridin-3-yl) ethylidene] -bisphosphonic acid monohydrate (YH529), icadronate, olpadronate, neridro Neridronate and disodium-1-hydroxy-3- (1-pyrrolidinyl) -propylidene-1,1-bisphosphonate (disodium-1-hydroxy-3- (1-pyrrolidinyl) -propylidene-1, 1-bisphosphonate, EB-1053). In addition, in addition to the bisphosphonate-based drugs, there may be mentioned paclitaxel, docetaxel, sirolimus, dexamethasone, and dexamethasone, but are not limited thereto. The drug may be used alone or in combination of two or more thereof.

In the present invention, the growth factor is bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), platelet-derived growth factor (PDGF), conversion growth factor- transforming growth factor-β, TGF-β, insulin-like growth factors (IGFs), parathyroid hormone (PTH), and combinations thereof, but are not limited thereto. It is not.

The present invention also provides a coated adhesive composition comprising the adhesive nanoparticles.

The adhesive composition may be adhered to a substrate selected from the group consisting of plastics, glass, metals, ceramics, and polymer synthetic resins.

In addition, the present invention provides a method for producing an adhesive polymer compound represented by the formula (1) shown in Scheme 1.

[Reaction Scheme 1]

Specifically, the present invention provides a method for preparing an adhesive polymer compound represented by Chemical Formula 1, including the following steps as in Scheme 1.

1) preparing a compound represented by the following Chemical Formula 4 by polymerizing the compound represented by the following Chemical Formula 3 in the presence of the compound represented by the following Chemical Formula 2;

2) preparing a compound represented by Chemical Formula 6 by polymerizing a compound represented by Chemical Formula 5 to a compound represented by Chemical Formula 4;

3) preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 6 with boron halide; And

4) debenzylating the compound represented by Chemical Formula 7 to prepare a compound represented by Chemical Formula 1 below:

[Formula 1]

[Formula 2]

(3)

[Formula 4]

[Chemical Formula 5]

[Formula 6]

[Formula 7]

Step 1 is a step of preparing a compound represented by the formula (4) by polymerizing the compound represented by the formula (3) in the presence of the compound represented by the formula (2), using the compound represented by the formula (2) as an initiator It is a step of forming the poly (benzyl asperate) compound by which the compound represented by General formula (3) is superposed | polymerized and the 3, 4- dimethoxybenzylamine which is a precursor of a catechol group couple | bonded with the terminal represented by General formula (4).

In the present invention, the molar ratio of the compound represented by the formula (2) of the step 1) and the compound represented by the formula (3) is preferably from 1:10 to 1: 100. If the molar ratio of the compound represented by Formula 2 and the compound represented by Formula 3 is outside the above range, there is a disadvantage in that the reaction is not completed or a side reaction occurs.

Step 1) may be carried out using dimethylformamide, chloroform or a combination thereof as a solvent.

The reaction temperature of step 1) is preferably 20 to 45 ℃. If the reaction temperature is outside the above range there is a disadvantage that a side reaction occurs.

Step 2 is a step of preparing a compound represented by the formula (6) by polymerizing the compound represented by the formula (5) to the compound represented by the formula (4), the compound represented by the formula (5) Forming a poly (phenylalanine) moiety by polymerizing the compound.

In the present invention, the molar ratio of the compound represented by the formula (4) and the compound represented by the formula (5) of step 2) is preferably 1:10 to 1: 100. If the molar ratio of the compound represented by Formula 4 and the compound represented by Formula 5 is outside the above range, there is a disadvantage in that the reaction is not completed or a side reaction occurs.

Step 2) may be carried out using dimethylformamide, chloroform or a combination thereof as a solvent.

The reaction temperature of step 2) is preferably 20 to 45 ℃. If the reaction temperature is outside the above range there is a disadvantage that a side reaction occurs.

Step 3 is a step of preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 6 with boron halide, and reacting the compound represented by Chemical Formula 6 with boron halide by 3,4-dimethoxybenzyl Removing the methyl group of the amine to form a catechol group.

In the present invention, the molar ratio of the compound represented by the formula (6) of the step 3) and boron halide is 1:10 to 1: 100. If the molar ratio of the compound represented by Formula 6 and the boron halide is outside the above range, there is a disadvantage in that the reaction is not completed or a side reaction occurs.

Step 3) may be carried out using methylene chloride, chloroform or a combination thereof as a solvent.

The boron halide compound of step 3) may be boron tribromide, boron trichloride, or a combination thereof, but is not limited thereto.

Step 4 is a step of preparing the compound represented by the following formula 1 by debenzylating the compound represented by the formula (7), the poly (benzyl aspartate) portion by debenzylating the compound represented by the formula (7) Conversion to poly (aspartate).

Step 4) may be performed using a sodium hydroxide (NaOH), potassium hydroxide (KOH), a Pd / C catalyst or a combination thereof as a debenzylating agent, but is not limited thereto.

In the present invention, the molar ratio of the compound represented by the formula (6) of step 4) and the debenzylating agent is 1:10 to 1: 200 is preferred. If the molar ratio of the compound represented by Formula 6 and the debenzylating agent is outside the above range, there is a disadvantage in that the reaction is not completed or a side reaction occurs.

Hereinafter, the configuration of the present invention will be described in detail.

For successful use of nanoparticles on dental implants, the nanoparticles must satisfy the following two preceding conditions. First, they must be free from risk of firm adhesion or loss to the Ti surface. Second, the nanoparticles should be designed to bind BMP-2 and IGF-1 simultaneously. The isoelectric points of BMP-2 and IGF-1 are 8.5 and 8.6, respectively. Accordingly, their charge is positive at physiological pH. Therefore, nanoparticles must carry an anionic charge for effective binding.

For the first requirement for such strong adhesion, the present invention utilizes a catechol group of 3,4-dihydroxy-L-phenylalanine (DOPA), which is a major component derived from mussel adhesive proteins. DOPA and other catechol compounds act as strong binders for coating metals and inorganic surfaces because they form strong covalent and non-covalent interactions with metal or metal oxide substrates.

For this second requirement, the present invention utilizes a combination of natural anionic polymers such as poly (L-aspartic acid). For this design, we used a catechol- and anionic poly (amino acid) -based Ti-bonded nanoparticle system. This system induces rapid osteoadhesion by releasing BMP-2 and IGF-1 in a controlled manner and maintaining their transport intact on the Ti surface of the fine grooves.

Synthesis of self-assembled Ti-adhesive polymer is carried out as follows.

To prepare Ti-adhesive nanocarriers for controlled release of BMP-2, catechol-poly (L-aspartic acid) -b-poly (L-phenylalanine) (catechol-b-PAsp-b-PPhe) A process for the synthesis of self-assembly biblock copolymers was designed. Because poly (amino acids) (PAsp and PPhe) have low toxicity and immunogenicity, they were chosen as block components.

Catechol-b-PAsp-b-PPhe is b-benzyl L-aspartate N-carboxylhydride (BAsp-NCA) and L- in the presence of a 3,4-dimethoxybenzylamine initiator as shown in Scheme 2 below. It is prepared via a one-pot synthesis of deprotection followed by two-step polymerization of phenylalanine N-carboxyhydride (Phe-NCA).

[Reaction Scheme 2]

The molar ratio of Asp to Phe can be controlled and can be preliminarily determined as 48:16 ([Asp]: [PPhe]). Block copolymers have a narrow size distribution (polydispersity index = 1.44).

Preparation of Ti-adhesive nanoparticles is carried out as follows.

The polymer micelle-type nanoparticles can be prepared through the polymer designed in the present invention. As shown in FIG. 2, the catechol-PAsp-b-PPhe self-assemble is a core-shell polymeric nanoparticle with three distinct, distinct domains consisting of a Ti-adhesive catechol moiety, an anionic PAsp shell and a hydrophobic PPhe core To form.

Transmission electron microscopy (TEM) showed spherical uniform nanoparticle formation. The zeta potential of the nanoparticles was significant negative (-44.32) due to the PAsp shell (FIG. 3). These anionic PAsp domains can be used as binding regions for BMP-2 and IGF-1 (the isoelectric points of BMP-2 and IGF-1 are 8.5 and 8.6, respectively), which are positively charged at physiological pH.

The Ti-adhesive nanoparticles formed as above, ie catechol-functionalized nanoparticles, are immobilized on the Ti substrate.

The nanoparticles have hundreds of catechol groups on the surface. Therefore, the bonding strength of the nanoparticles to the Ti surface is extremely enhanced through cooperative adhesion of terminal catechol groups.

As a next step, the present invention confirmed whether BMP-2 can bind (or mount) onto immobilized nanoparticles.

As a result, it was confirmed that BMP-2 was not effectively bound on the unmodified Ti surface, while BMP-2 could be effectively mounted on the nanoparticle-immobilized surface (FIG. 7).

The present invention is coated on the surface of the implant using nanoparticles containing catechol with excellent adhesion to the metal implant surface and designed to support the ionic growth factor, can be safely supported growth factors without the use of organic solvents There is an effect that can provide an implant surface coating method that can induce sustained release of the factor.

1 is a ¹ H NMR spectrum for confirming the structure of a catechol-containing block copolymer.
Figure 2 schematically shows the appearance of catechol-PAsp-b-PPhe self-assembled to form Ti-adhesive nanoparticles for BMP-2 loading / release.
3 shows the average diameter, zeta potential and morphology of Ti-adhesive nanoparticles.
4 is a Fe-SEM image showing the appearance of surface-immobilized nanoparticles on a Ti substrate.
5 is an XPS survey spectrum of unmodified Ti and nanoparticle-immobilized Ti surfaces. Inset shows high resolution spectra for the C 1s region of nanoparticle-immobilized Ti (0.5 g / l).
6 shows water contact angles on Ti and nanoparticle-immobilized Ti substrates inherently.
FIG. 7 shows confocal laser scanning microscopy (CLSM) images of unmodified Ti surface (a) and catechol-nanoparticle immobilized Ti surface (b) after incubation with FITC-labeled BMP-2, and surface -BMP-2 sustained release release (c) from Ti surface coated with adhesive nanoparticles.

Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for describing the present invention more specifically, and the scope of the present invention is not limited by these examples.

Example  1: self-assembly Ti Synthesis of Adhesive Polymers

To 3,4-dimethoxybenzylamine (0.06 g, 0.4 mmol) in DMF (15 ml) add b-benzyl L-aspartate N-carboxyhydride (BAsp-NCA) (5.03 g, 20 mmol) To 35 ° C. for 24 hours. L-phenylalanine N-carboxylhydride (Phe-NCA) (1.55 g, 8 mmol) was added to the reaction mixture and polymerized at 35 ° C for 24 hours. The reaction product was precipitated and separated, and then dried under reduced pressure at 25 ° C. for 24 hours (yield: 74.3%). To the reaction product (2 g, 0.16 mmol) was added boron tribromide (0.15 ml, 1.6 mmol) in methylene chloride (20 ml) and reacted at 25 ° C. for 18 hours. The reaction product was separated and lyophilized for 72 hours (yield: 48%). The reaction product (0.85 g, 0.06 mmol) was dissolved in 50 ml of dimethyl sulfoxide, and 200 ml of 0.1 N sodium hydroxide was added to carry out debenzylation at 25 ° C. for 3 hours. The reaction product was separated and lyophilized for 72 hours to prepare a block copolymer (yield: 76%).

Experimental Example  1: self-assembly Ti -Check the structure of the adhesive polymer

The structure of the self-assembled Ti-adhesive polymer prepared in Example 1 was confirmed by ¹ H NMR spectrum.

The results are shown in Fig.

1, it could be confirmed that catechol-terminated PAsp-b-PPhe was synthesized.

Example  2: Ti Preparation of Adhesive Nanoparticles

0.001 g of the self-assembled Ti-adhesive polymer prepared in Example 1 was suspended in 1 ml of physiological saline to obtain Ti-adhesive nanoparticles by self-assembly (FIG. 2).

Experimental Example  2: Ti -Physical Properties of Adhesive Nanoparticles

The average particle size (hydrodynamic diameter) of the Ti-adhesive nanoparticles obtained as in Example 2 was calculated by dynamic light scattering.

As a result, the average particle size of the Ti-adhesive nanoparticles was found to be 41.4 nm (Fig. 3).

On the other hand, when the Ti-adhesive nanoparticles obtained in Example 2 were examined by a transmission electron microscope (TEM), it was confirmed that spherical uniform nanoparticles were formed. The zeta potential of the nanoparticles was significant negative (-44.32) due to the PAsp shell (FIG. 3). This anionic PAsp domain was expected to be used as a binding region for positively charged BMP-2 and IGF-1 at Bphysiological pH (BMP-2 and IGF-1 are 8.5 and 8.6, respectively). (FIG. 2).

Example  3: Ti Of adhesive nanoparticles Ti On board  Immobilization

The Ti-adhesive nanoparticles formed as above, ie catechol-functionalized nanoparticles, were immobilized on the Ti substrate.

For surface immobilization, 0.1 g / l and 0.5 g / L aqueous nanoparticle solutions were equilibrated with the Ti substrate.

As shown in FIG. 4, it can be confirmed that the adhesive nanoparticles are stably fixed on the Ti surface through a field emission scanning electron microscope (Fe-SEM). By controlling the concentration of nanoparticles, the immobilization density can be controlled. Specifically, as the concentration of nanoparticles was increased from 0.1 g / l to 0.5 g / l, the density of the immobilized nanoparticles increased from 1.72 × 10 ⁻⁸ / mm ² to 4.09 × 10 ⁻⁸ / mm ² .

Experimental Example  3: Ti Of adhesive nanoparticles Ti On board  Immobilization investigation

Immobilization of nanoparticles on the Ti surface was investigated through X-ray photoelectron spectroscopy (XPS) and contact angle measurements.

5 shows XPS survey spectra of unmodified Ti substrates and nanoparticle-immobilized Ti substrates. The original Ti surface consists mainly of Ti and O originating from the oxide of the original surface and contains a small amount of C from hydrocarbon contaminants. Settling of the catechol-PAsp-b-PPhe nanoparticles was confirmed through a significant increase in the C molar ratio. As the concentration of nanoparticles used for immobilization increased, the Ti atomic ratio decreased while the surface C atomic ratio increased from 24.8% to 32.8%. In addition, the presence of undetectable N was observed on the unmodified Ti substrate, and the N atomic ratio also increased in proportion to the nanoparticle concentration, similar to the increasing tendency of the C signal. High resolution XPS spectral analysis also showed good agreement with the chemical structure of the immobilized nanoparticles. As shown in the inset of FIG. 5, C 1s high-resolution scan results of nanoparticle-immobilized Ti (0.5 g / L) showed aliphatic ( C- C / C- H corresponding to binding energies of 284.5, 286.4 and 288.4 eV, respectively). ), Ether ( C- O) and ester (O- C = O) carbon.

As shown in Figure 6, the change in contact angle also confirmed the nanoparticle immobilization on the Ti substrate. Prior to nanoparticle immobilization, the static water contact angle of the Ti substrate was 75.3 °. After immobilization of the nanoparticles (0.1 g / l), the contact angle decreased to 36.4 ° and further decreased to 27.0 ° as the concentration of nanoparticles increased. This indicates that the surface hydrophilicity of the Ti substrate is increased due to the immobilized nanoparticles. Anionic PAsp shells are the main factor for the reduction of the contact angle.

Example  4: BMP Combination of -2 and Ti  Control emission from surface

In this example, it was confirmed whether BMP-2 can be bound (or mounted) onto the immobilized nanoparticles.

The nanoparticles have an anionic, dense PAsp shell and are able to bind positively charged BMP-2 through electrostatic interaction. FITC-labeled BMP-2 was used to visualize BMP-2 binding onto nanoparticles.

7 shows that BMP-2 does not bind effectively on unmodified Ti surface. However, strong FITC fluorescence was observed on the nanoparticle-immobilized surface, indicating effective loading of BMP-2 on the nanoparticles. The amount of BMP-2 loaded can be controlled by adjusting the BMP-2 feed amount. 7 (c) shows that BMP-2 is released over 40 days without noticeable burst release. Regardless of the amount of BMP loaded, the rate of release was similar, indicating that the amount of BMP-2 released could be controlled.

Claims (16)

Adhesive polymer compound represented by the following formula (1):
[Formula 1]

In this formula,
n is an integer from 10 to 100,
m is an integer of 10-100.
Adhesive nanoparticles formed by self-assembly of the adhesive polymer compound of claim 1.
According to claim 2, wherein the adhesive nanoparticles catechol group is located on the surface of the poly (L- aspartate) portion is located in the shell and the poly (L-phenylalanine) portion is located in the core, the adhesive nano particle.
The adhesive nanoparticle of claim 2, wherein the adhesive nanoparticle is provided with a drug, a growth factor, or a combination thereof in a core or a shell.
The drug according to claim 4, wherein the drug is ethidronate, clathronate, palmidronate, alendronate, ibandronate, risedronate, zoleronate, tiludronate, [1-hydroxy-2- (Imidazo [1,2-a] pyridin-3-yl) ethylidene] -bisphosphonic acid monohydrate, icadronate, olpadronate, neridronate, disodium-1-hydroxy-3- ( Adhesive nanoparticles which are any one of 1-pyrrolidinyl) -propylidene-1,1-bisphosphonate, paclitaxel, docetaxel, sirolimus, dexamethasone and combinations thereof.
The method of claim 4, wherein the growth factor is any one of bone growth factor, fibroblast growth factor, platelet-induced growth factor, transforming growth factor-β, insulin-like growth factor, paratyroid hormone, and a combination thereof. Nanoparticles.
Adhesive composition containing the adhesive nanoparticle in any one of Claims 2-6.
8. The adhesive composition of claim 7, wherein the adhesive composition is adhered to a substrate selected from the group consisting of plastics, glass, ceramic metals, and polymeric synthetic resins.
Method for producing an adhesive polymer compound represented by the formula (1) comprising the following steps:
Preparing a compound represented by the following Chemical Formula 4 by polymerizing the compound represented by the following Chemical Formula 3 in the presence of the compound represented by the following Chemical Formula 2 (step 1);
Preparing a compound represented by Chemical Formula 6 by polymerizing a compound represented by Chemical Formula 5 with a compound represented by Chemical Formula 4 (step 2);
Preparing a compound represented by Chemical Formula 7 by reacting the compound represented by Chemical Formula 6 with boron halide (step 3); And
Debenzylating the compound represented by Chemical Formula 7 to prepare a compound represented by Chemical Formula 1 (step 4):
[Formula 1]

In this formula,
n is an integer from 10 to 100,
m is an integer from 10 to 100,
(2)

(3)

[Chemical Formula 4]

In this formula,
n is an integer from 10 to 100,
[Chemical Formula 5]

[Chemical Formula 6]

In this formula,
n is an integer from 10 to 100,
m is an integer from 10 to 100,
(7)

In this formula,
n is an integer from 10 to 100,
m is an integer of 10-100.
The method of claim 9, wherein step 1) is performed using dimethylformamide, chloroform, or a combination thereof as a solvent.
The method of claim 9, wherein the reaction temperature of step 1) is 20 to 45 ° C. 11.
The method of claim 9, wherein step 2) is performed using dimethylformamide, chloroform, or a combination thereof as a solvent.
The method of claim 9, wherein the reaction temperature of step 2) is 20 to 45 ° C. 11.
The method of claim 9, wherein step 3) is performed using methylene chloride, chloroform, or a combination thereof as a solvent.
The method of claim 9, wherein the boron halide compound of step 3) is boron tribromide, boron trichloride, or a combination thereof.
The method of claim 9, wherein step 4) is performed using sodium hydroxide, potassium hydroxide, a Pd / C catalyst, or a combination thereof as a debenzylating agent.

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