阅读说明：本技术 一种依帕司他的制备方法 (Preparation method of epalrestat ) 是由 颜世强 杨杰 何淑旺 曹焕英 郭伟 解春文 胡醒 于 2021-08-19 设计创作，主要内容包括：本发明涉及医药技术领域,尤其涉及一种依帕司他的制备方法。本发明提供的制备方法,包括以下步骤：将3-羧甲基绕丹宁、α-甲基肉桂醛、催化剂和水混合,依次进行缩合反应和加酸中和,得到依帕司他粗品；所述催化剂包括碱性催化剂和相转移催化剂；将所述依帕司他粗品和醇类有机溶剂混合进行重结晶,得到所述依帕司他。本发明所述制备方法采用水作为反应溶剂,安全环保；本发明将现有的“粗品制备-酸化游离-重结晶”三道工序简化为“粗品制备-重结晶”两道工序,将粗品制备和酸化游离两道工序合二为一,简化了工序；重结晶采用醇类有机溶剂有利于回收再利用。(The invention relates to the technical field of medicines, in particular to a preparation method of epalrestat. The preparation method provided by the invention comprises the following steps: mixing 3-carboxymethyl rhodanine, alpha-methyl cinnamaldehyde, a catalyst and water, and sequentially carrying out condensation reaction and acid addition neutralization to obtain an epalrestat crude product; the catalyst comprises a basic catalyst and a phase transfer catalyst; and mixing the crude epalrestat product with an alcohol organic solvent for recrystallization to obtain the epalrestat. The preparation method adopts water as a reaction solvent, and is safe and environment-friendly; the invention simplifies the three existing procedures of 'crude product preparation-acidification dissociation-recrystallization' into two procedures of 'crude product preparation-recrystallization', integrates the two procedures of crude product preparation and acidification dissociation into one, and simplifies the procedures; the alcohol organic solvent is adopted for recrystallization, so that the recovery and the reutilization are facilitated.)

1. A preparation method of epalrestat is characterized by comprising the following steps:

mixing 3-carboxymethyl rhodanine, alpha-methyl cinnamaldehyde, a catalyst and water, and sequentially carrying out condensation reaction and acid addition neutralization to obtain an epalrestat crude product; the catalyst comprises a basic catalyst and a phase transfer catalyst;

and mixing the crude epalrestat product with an alcohol organic solvent, and recrystallizing to obtain the epalrestat.

2. The method of claim 1, wherein the basic catalyst comprises an amine catalyst.

3. The method of claim 2, wherein the amine catalyst comprises one or more of ethylenediamine, dimethylethylenediamine, tetramethylethylenediamine, methylamine, ethylamine, isopropylamine, pyridine, piperidine, piperazine, imidazole, morpholine, tetrahydropyrrole, tetramethylguanidine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylenediamine, triethylamine, N-diisopropylethylamine, 1, 6-hexamethylenediamine, 2-dimethylaminoethylamine, and 3-dimethylaminopropylamine.

4. The method of claim 1, wherein the phase transfer catalyst is polyethylene glycol.

5. The method according to any one of claims 1 to 4, wherein the molar ratio of the 3-carboxymethylrhodanine to the α -methylcinnamaldehyde to the basic catalyst is (0.8 to 1.2): (0.8-1.2): (0.1 to 1);

the volume ratio of the mass of the 3-carboxymethyl rhodanine to the water is 1 g: (5-100) mL;

the volume ratio of the water to the phase transfer catalyst is (1-100): 1.

6. the method according to claim 1, wherein the condensation reaction is carried out at a temperature of 0 to 100 ℃ for 1 to 10 hours.

7. The method of claim 1, wherein the acid comprises an inorganic acid and/or an organic acid.

8. The method according to claim 7, wherein the inorganic acid comprises one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and hydrobromic acid;

the organic acid comprises one or more of formic acid, acetic acid, trifluoroacetic acid, lactic acid, benzoic acid, succinic acid, fumaric acid, maleic acid, citric acid, tartaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

9. The method according to claim 1, wherein the alcoholic organic solvent comprises one or more of methanol, ethanol, isopropanol and n-butanol.

10. The method according to claim 1 or 9, wherein the recrystallization temperature is 0 to 100 ℃.

Technical Field

The invention relates to the technical field of medicines, in particular to a preparation method of epalrestat.

Background

Epalrestat, chemical name is 5- [ (1Z,2E) -2-methyl-3-phenylpropylidene ] -2-sulfo-2, 4-thiazolidinedione-3-acetic acid, and chemical structure is as follows:

epalrestat, a novel aldose reductase inhibitor developed by japanese national ministry, was first marketed in japan in 1992 for the treatment of diabetic complications such as neuropathy, corneal epithelial disorders, retinopathy, and microvascular lesions.

There are many reports on the synthesis of epalrestat at home and abroad, and most of the epalrestat is prepared by condensation reaction of 3-carboxymethyl rhodanine and alpha-methyl cinnamaldehyde. For example: li Du Xin (journal of the university of Shanxi (Nature science edition) 1995,18, 413-415), Shanghai (journal of Chinese medicine industry) 1996,27,5-6) and Li Yuezhen (journal of Chinese medicine chemistry 2001,11,165-167) all report that 3-carboxymethyl rhodanine and alpha-methyl cinnamaldehyde take condensation reaction to synthesize epalrestat by taking glacial acetic acid as a reaction solvent and sodium acetate as a catalyst. In the synthesis method, glacial acetic acid is used as a reaction solvent, the glacial acetic acid has irritation and strong corrosivity, and the industrial large-scale use of glacial acetic acid is very inconvenient and is easy to cause safety accidents; in addition, the use of a large amount of glacial acetic acid can cause the increase of the difficulty of dangerous waste treatment, and is not beneficial to environmental protection. In a word, the method has great hidden danger in the aspects of safety and environmental protection, so that the process is not suitable for industrial scale-up production.

Disclosure of Invention

The invention aims to provide a preparation method of epalrestat, which adopts water as a reaction solvent and is environment-friendly and safe.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides a preparation method of epalrestat, which comprises the following steps:

mixing 3-carboxymethyl rhodanine, alpha-methyl cinnamaldehyde, a catalyst and water, and sequentially carrying out condensation reaction and acid addition neutralization to obtain an epalrestat crude product; the catalyst comprises a basic catalyst and a phase transfer catalyst;

and mixing the crude epalrestat product with an alcohol organic solvent for recrystallization to obtain the epalrestat.

Preferably, the basic catalyst comprises an amine catalyst.

Preferably, the amine catalyst comprises one or more of ethylenediamine, dimethylethylenediamine, tetramethylethylenediamine, methylamine, ethylamine, isopropylamine, pyridine, piperidine, piperazine, imidazole, morpholine, tetrahydropyrrole, tetramethylguanidine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylenediamine, triethylamine, N-diisopropylethylamine, 1, 6-hexamethylenediamine, 2-dimethylaminoethylamine and 3-dimethylaminopropylamine.

Preferably, the phase transfer catalyst is polyethylene glycol.

Preferably, the molar ratio of the 3-carboxymethyl rhodanine to the alpha-methyl cinnamaldehyde to the basic catalyst is (0.8-1.2): (0.8-1.2): (0.1 to 1);

the volume ratio of the mass of the 3-carboxymethyl rhodanine to the water is 1 g: (5-100) mL;

the volume ratio of the water to the phase transfer catalyst is (1-100): 1.

preferably, the condensation reaction is carried out at the temperature of 0-100 ℃ for 1-10 h.

Preferably, the acid comprises an inorganic acid and/or an organic acid.

Preferably, the inorganic acid comprises one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and hydrobromic acid;

the organic acid comprises one or more of formic acid, acetic acid, trifluoroacetic acid, lactic acid, benzoic acid, succinic acid, fumaric acid, maleic acid, citric acid, tartaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

Preferably, the alcohol organic solvent comprises one or more of methanol, ethanol, isopropanol and n-butanol.

Preferably, the temperature of recrystallization is 0-100 ℃.

The invention provides a preparation method of epalrestat, which comprises the following steps: mixing 3-carboxymethyl rhodanine, alpha-methyl cinnamaldehyde, a catalyst and water, and sequentially carrying out condensation reaction and acid addition neutralization to obtain an epalrestat crude product; the catalyst comprises a basic catalyst and a phase transfer catalyst; and mixing the crude epalrestat product with an alcohol organic solvent for recrystallization to obtain the epalrestat. The preparation method adopts water as a reaction solvent, and is safe and environment-friendly; the invention simplifies the three existing procedures of 'crude product preparation-acidification dissociation-recrystallization' into two procedures of 'crude product preparation-recrystallization', integrates the two procedures of crude product preparation and acidification dissociation into one, and simplifies the procedures; the alcohol organic solvent is adopted for recrystallization, so that the recovery and the reutilization are facilitated.

Detailed Description

The invention provides a preparation method of epalrestat, which comprises the following steps:

mixing 3-carboxymethyl rhodanine, alpha-methyl cinnamaldehyde, a catalyst and water, and sequentially carrying out condensation reaction and acid addition neutralization to obtain an epalrestat crude product; the catalyst comprises a basic catalyst and a phase transfer catalyst;

and mixing the crude epalrestat product with an alcohol organic solvent for recrystallization to obtain the epalrestat.

In the present invention, all the starting materials for the preparation are commercially available products known to those skilled in the art unless otherwise specified.

Mixing 3-carboxymethyl rhodanine, alpha-methyl cinnamaldehyde, a catalyst and water, and sequentially carrying out condensation reaction and acid addition neutralization to obtain an epalrestat crude product; the catalyst includes a basic catalyst and a phase transfer catalyst.

In the present invention, the basic catalyst preferably includes an amine-based catalyst; the amine catalyst preferably comprises one or more of ethylenediamine, dimethylethylenediamine, tetramethylethylenediamine, methylamine, ethylamine, isopropylamine, pyridine, piperidine, piperazine, imidazole, morpholine, tetrahydropyrrole, tetramethylguanidine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylenediamine, triethylamine, N-diisopropylethylamine, 1, 6-hexamethylenediamine, 2-dimethylaminoethylamine and 3-dimethylaminopropylamine, more preferably one or more of tetrahydropyrrole, dimethylethylenediamine, 2-dimethylaminoethylamine and 3-dimethylaminopropylamine, and most preferably 2-dimethylaminoethylamine and/or 3-dimethylaminopropylamine; when the alkaline catalyst is more than two of the specific choices, the proportion of the specific substances is not limited in any way, and the specific substances can be mixed according to any proportion.

In the invention, the phase transfer catalyst is preferably polyethylene glycol, the polyethylene glycol is preferably one or more of polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000 and polyethylene glycol 2000, and more preferably polyethylene glycol 400; when the polyethylene glycol is more than two of the specific choices, the proportion of the specific substances is not limited in any way, and the specific substances can be mixed according to any proportion.

In the present invention, the water is preferably purified water.

In the invention, the molar ratio of the 3-carboxymethyl rhodanine to the alpha-methyl cinnamaldehyde is preferably (0.8-1.2): (0.8 to 1.2), and more preferably 1: 1.

In the invention, the molar ratio of the 3-carboxymethyl rhodanine to the basic catalyst is preferably (0.8-1.2): (0.1 to 1), more preferably 1: (0.3 to 0.8), most preferably 1: (0.6-0.8).

In the present invention, the ratio of the mass of the 3-carboxymethyl rhodanine to the volume of the water is preferably 1 g: (5-100) mL, more preferably 1 g: (10-50) mL, most preferably 1 g: 20 mL.

In the invention, the volume ratio of the water to the phase transfer catalyst is preferably (1-100): 1, more preferably (2 to 50): 1, most preferably (8-10): 1.

in the present invention, the mixing is preferably performed by mixing water and a phase transfer catalyst, and then adding 3-carboxymethylrhodanine, alpha-methylcinnamaldehyde and an alkaline catalyst in this order under stirring. In the present invention, the stirring conditions are not particularly limited, and the stirring may be carried out by using conditions known to those skilled in the art. The present invention does not have any particular limitation on the manner of adding the 3-carboxymethyl rhodanine and the alpha-methyl cinnamaldehyde, and can be carried out in a manner well known to those skilled in the art. In the invention, the 3-dimethylaminopropylamine is preferably added dropwise; the dropping process is not particularly limited, and may be carried out by a process known to those skilled in the art.

In the invention, the condensation reaction temperature is preferably 0-100 ℃, more preferably 40-80 ℃, and most preferably 50-60 ℃; the time is preferably 1 to 10 hours, and more preferably 2 to 4 hours.

In the present invention, the acid preferably includes an inorganic acid and/or an organic acid; the inorganic acid preferably comprises one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and hydrobromic acid, and more preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or hydrobromic acid; when the inorganic acid is more than two of the specific choices, the proportion of the specific substances is not limited in any way, and the inorganic acid can be mixed according to any proportion. The present invention does not require any concentration of the above-mentioned inorganic acid, and a commercially available inorganic acid (i.e., a conventional commercially available product) known to those skilled in the art may be used. The organic acid preferably comprises one or more of formic acid, acetic acid, trifluoroacetic acid, lactic acid, benzoic acid, succinic acid, fumaric acid, maleic acid, citric acid, tartaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and more preferably formic acid, acetic acid, trifluoroacetic acid, lactic acid, benzoic acid, succinic acid, fumaric acid, maleic acid, citric acid, tartaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; when the organic acid is more than two of the specific choices, the proportion of the specific substances is not limited in any way, and the organic acid can be mixed according to any proportion.

In the present invention, the process of neutralization by addition of an acid is preferably accompanied by a process of naturally returning to room temperature. The acid adding amount in the acid adding and neutralizing process is not limited at all, and the aim of completely dissociating the crude epalrestat product can be fulfilled.

After the neutralization by adding acid is finished, the method also preferably comprises the steps of filtering, leaching and drying in sequence; the filtration is not particularly limited in the present invention and may be carried out by a process known to those skilled in the art. In the present invention, the rinsing is preferably performed using purified water, and the object of the rinsing is preferably a filter cake obtained by filtration. In the present invention, the drying is preferably vacuum drying; the temperature of the vacuum drying is preferably 40 ℃, and the time is preferably 2.0 h.

After the epalrestat crude product is obtained, the epalrestat crude product and an alcohol organic solvent are mixed and recrystallized to obtain the epalrestat.

In the present invention, the alcohol organic solvent preferably includes one or more of methanol, ethanol, isopropanol and n-butanol; when the alcohol organic solvent is more than two of the specific choices, the invention does not have any special limitation on the proportion of the specific substances, and the specific substances can be mixed according to any proportion.

The amount of the alcohol organic solvent is not limited in any way, and the crude epalrestat can be fully suspended in the alcohol organic solvent by adopting the amount well known by the technical personnel in the field.

In the invention, the recrystallization process is preferably to mix the crude epalrestat product and an alcohol organic solvent under the condition of stirring, adjust the temperature to 0-100 ℃, preserve the temperature for 1-10 h, and recover the temperature to room temperature; more preferably, the epalrestat crude product and an alcohol organic solvent are mixed, the temperature is adjusted to 20-80 ℃, and then the temperature is kept for 2-6 hours, and then the room temperature is recovered; most preferably, the epalrestat crude product and an alcohol organic solvent are mixed, the temperature is adjusted to 40-60 ℃, and then the temperature is kept for 2-4 hours, and then the temperature is recovered to the room temperature. The stirring process is not particularly limited, and may be performed by a method known to those skilled in the art. In the present invention, the room temperature is preferably naturally recovered.

After the recrystallization is finished, the method also preferably comprises the steps of filtering, leaching and drying which are sequentially carried out; the filtration is not particularly limited in the present invention and may be carried out by a process known to those skilled in the art. In the present invention, the leaching is preferably performed by using the alcohol organic solvent described in the above technical scheme, and the leaching object is preferably a filter cake obtained by filtration. In the present invention, the drying is preferably vacuum drying; the temperature of the vacuum drying is preferably 40 ℃, and the time is preferably 2.0 h.

The following examples are provided to illustrate the preparation of epalrestat according to the present invention in detail, but they should not be construed as limiting the scope of the present invention.

Example 1

Mixing 3.2L of purified water and 0.8L of polyethylene glycol 400, adding 3-carboxymethyl rhodanine (152.8g, 0.80mol) and alpha-methyl cinnamaldehyde (140.0g, 0.96mol) at room temperature under stirring, then finally dropwise adding 3-dimethylaminopropylamine (80.0mL, 0.64mol), stirring at 60 ℃ for 2h under heat preservation, adding 200mL of concentrated hydrochloric acid (mass concentration is 37%) while naturally cooling, filtering after naturally cooling, leaching the obtained filter cake with 1.0L of purified water, and performing vacuum drying at 40 ℃ for 2.0h to obtain a crude epalrestat product (yellow solid, 245.0g, 96%);

mixing the crude epalrestat (160.0g, 0.5mol) with 1000mL of methanol, stirring at 60 ℃ for 2.0h under heat preservation, naturally cooling, filtering, leaching the obtained filter cake with 200mL of methanol, and drying at 40 ℃ for 2.0h under vacuum to obtain epalrestat (139.2g, yield 87%, purity 99.76%).

The nuclear magnetic data of the epalrestat are as follows:¹H NMR(400MHz,CDCl₃)δ13.46(br,1H),7.63(s,1H),7.49-7.38(m,6H),4.73(s,2H),2.23(s,3H)。

example 2

Mixing 3.6L of purified water and 0.4L of polyethylene glycol 400, adding 3-carboxymethyl rhodanine (152.8g, 0.80mol) and alpha-methyl cinnamaldehyde (140.0g, 0.96mol) at room temperature under stirring, then finally dropwise adding 3-dimethylaminopropylamine (78.0mL, 0.64mol), stirring at 60 ℃ for 2h under heat preservation, adding 200mL of concentrated hydrochloric acid (mass concentration is 37%) while naturally cooling, filtering after naturally cooling, leaching the obtained filter cake with 1.0L of purified water, and performing vacuum drying at 40 ℃ for 2.0h to obtain a crude epalrestat product (yellow solid, 211.8g, 83%);

mixing the crude epalrestat (160.0g, 0.5mol) with 1000mL of methanol, stirring at 60 ℃ for 2.0h under heat preservation, naturally cooling, filtering, leaching the obtained filter cake with 200mL of methanol, and drying at 40 ℃ for 2.0h under vacuum to obtain epalrestat (136g, yield 85%, purity 99.68%).

The nuclear magnetic data of the epalrestat are as follows:¹H NMR(400MHz,CDCl₃)δ13.46(br,1H),7.63(s,1H),7.49-7.38(m,6H),4.73(s,2H),2.23(s,3H)。

example 3

Mixing 3.6L of purified water and 0.4L of polyethylene glycol 200, adding 3-carboxymethyl rhodanine (152.8g, 0.80mol) and alpha-methyl cinnamaldehyde (140.0g, 0.96mol) at room temperature under stirring, then finally dropwise adding 3-dimethylaminopropylamine (80.0mL, 0.64mol), stirring at 80 ℃ for 2h under heat preservation, adding 200mL of concentrated hydrochloric acid (mass concentration is 37%) while naturally cooling, filtering after naturally cooling, leaching the obtained filter cake with 1.0L of purified water, and performing vacuum drying at 40 ℃ for 2.0h to obtain a crude epalrestat product (yellow solid, 194.0g, 76%);

mixing the crude epalrestat (160.0g, 0.5mol) with 1000mL of methanol, stirring at 60 ℃ for 3.0h under heat preservation, naturally cooling, filtering, leaching the obtained filter cake with 200mL of methanol, and drying at 40 ℃ for 2.0h under vacuum to obtain epalrestat (136.0g, yield 85%, purity 99.71%).

The nuclear magnetic data of the epalrestat are as follows:¹H NMR(400MHz,CDCl₃)δ13.46(br,1H),7.63(s,1H),7.49-7.38(m,6H),4.73(s,2H),2.23(s,3H)。

example 4

Mixing 3.8L of purified water and 0.2L of polyethylene glycol 400, adding 3-carboxymethyl rhodanine (152.8g, 0.80mol) and alpha-methyl cinnamaldehyde (140.0g, 0.96mol) at room temperature under stirring, then finally dropwise adding 3-dimethylaminopropylamine (70.2mL, 0.64mol), stirring at 60 ℃ for 2h under heat preservation, adding 100mL of concentrated sulfuric acid (the mass concentration is 98%) while naturally cooling, filtering after naturally cooling, leaching the obtained filter cake with 1.0L of purified water, and performing vacuum drying at 40 ℃ for 2.0h to obtain a crude epalrestat (yellow solid, 137.8g, 54%);

mixing the crude epalrestat (160.0g, 0.5mol) with 1000mL of methanol, stirring at 80 ℃ for 3.0h under heat preservation, naturally cooling, filtering, leaching the obtained filter cake with 200mL of methanol, and drying at 40 ℃ for 2.0h under vacuum to obtain epalrestat (129.6g, yield 81%, purity 99.67%).

The nuclear magnetic data of the epalrestat are as follows:¹H NMR(400MHz,CDCl₃)δ13.46(br,1H),7.63(s,1H),7.49-7.38(m,6H),4.73(s,2H),2.23(s,3H)。

example 5

Mixing 3.2L of purified water and 0.8L of polyethylene glycol 400, adding 3-carboxymethyl rhodanine (152.8g, 0.80mol) and alpha-methyl cinnamaldehyde (140.0g, 0.96mol) at room temperature under stirring, then dropwise adding tetrahydropyrrole (53.5mL, 0.64mol), stirring at 60 ℃ for 2h under heat preservation, adding 200mL of concentrated hydrochloric acid (mass concentration is 37%) while naturally cooling, filtering after naturally cooling, leaching the obtained filter cake with 1.0L of purified water, and drying at 40 ℃ for 2.0h in vacuum to obtain crude epalrestat (yellow solid, 199.1g, 78%);

mixing the crude epalrestat (160.0g, 0.5mol) with 1000mL of methanol, stirring at 80 ℃ for 3.0h under heat preservation, naturally cooling, filtering, leaching the obtained filter cake with 200mL of methanol, and drying at 40 ℃ for 2.0h under vacuum to obtain epalrestat (129.6g, yield 81%, purity 99.68%).

The nuclear magnetic data of the epalrestat are as follows:¹H NMR(400MHz,CDCl₃)δ13.46(br,1H),7.63(s,1H),7.49-7.38(m,6H),4.73(s,2H),2.23(s,3H)。

example 6

Mixing 3.2L of purified water and 0.8L of polyethylene glycol 400, adding 3-carboxymethyl rhodanine (152.8g, 0.80mol) and alpha-methyl cinnamaldehyde (140.0g, 0.96mol) at room temperature under stirring, then finally dropwise adding 3-dimethylaminopropylamine (1000.0mL, 0.80mol), stirring at 60 ℃ for 2.0h under heat preservation, adding 200mL of concentrated hydrochloric acid (mass concentration is 37%) while naturally cooling, filtering after naturally cooling, leaching the obtained filter cake with 1.0L of purified water, and performing vacuum drying at 40 ℃ for 2.0h to obtain a crude epalrestat (yellow solid, 237.3g, 93%);

mixing the crude epalrestat (160.0g, 0.5mol) with 1000mL of methanol, stirring at 60 ℃ for 2.0h under heat preservation, naturally cooling, filtering, leaching the obtained filter cake with 200mL of methanol, and drying at 40 ℃ for 2.0h under vacuum to obtain epalrestat (132.8g, yield 83%, purity 99.70%).

The nuclear magnetic data of the epalrestat are as follows:¹H NMR(400MHz,CDCl₃)δ13.46(br,1H),7.63(s,1H),7.49-7.38(m,6H),4.73(s,2H),2.23(s,3H)。

the foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.