阅读说明：本技术 一种富电子四苯乙烯基催化剂及其制备方法与应用 (Electron-rich tetraphenyl ethylene catalyst and preparation method and application thereof ) 是由 唐波 丁彤 张广录 陈蓁蓁 于 2020-05-12 设计创作，主要内容包括：本发明涉及超分子催化剂技术领域,具体涉及一种富电子四苯乙烯基催化剂及其制备方法与应用。所述催化剂包括金属离子和含有四苯乙烯基团的配体,所述金属离子作为结点,与所述配体的类席夫碱结构通过配位键连接在一起形成具有空腔的笼式结构,所述类席夫碱结构是由氨基和醛基吡啶的缩合反应实现。与溶液反应相比,本发明合成的具有笼式结构的催化剂在催化过程消耗量小,而且显示出更高的催化活性和更快的反应速率。此外,由于纳米配位笼的柔性和疏水空腔的存在,可以有效地包封平面型的反应底物,当产物为非平面型时可以很容易地从笼腔中排出,减小产物抑制作用,提高反应效率。(The invention relates to the technical field of supramolecular catalysts, in particular to an electron-rich tetraphenyl ethylene catalyst and a preparation method and application thereof. The catalyst comprises metal ions and a ligand containing tetraphenylethylene groups, wherein the metal ions are used as nodes and are connected with a Schiff-like base structure of the ligand through coordination bonds to form a cage-type structure with a cavity, and the Schiff-like base structure is realized by condensation reaction of amino and aldehyde pyridine. Compared with solution reaction, the catalyst synthesized by the invention has a cage structure, is low in consumption in the catalytic process, and shows higher catalytic activity and faster reaction rate. In addition, due to the flexibility of the nanometer coordination cage and the existence of the hydrophobic cavity, a planar reaction substrate can be effectively encapsulated, and when a product is a non-planar product, the product can be easily discharged from the cage cavity, so that the product inhibition effect is reduced, and the reaction efficiency is improved.)

1. The electron-rich tetraphenyl ethylene catalyst is characterized by comprising metal ions and ligands containing tetraphenyl ethylene groups, wherein the metal ions are used as nodes and are connected with Schiff-like base structures of the ligands through coordination bonds to form cage structures with cavities, and the Schiff-like base structures are realized by condensation reaction of amino and aldehyde pyridine.

2. The electron-rich tetraphenylvinyl catalyst of claim 1 wherein said metal junction comprises any of ferrous ions, cuprous ions, zinc ions.

3. The electron-rich tetraphenylethylene catalyst of claim 1 or 2, characterized in that the tetraphenylethylene group-containing ligand comprises any one of tetraphenylethylene group-containing ligands having an amino group.

4. The preparation method of the electron-rich tetraphenyl vinyl catalyst is characterized by comprising the following steps:

(1) adding a ligand containing a tetraphenylethylene group, pyridine-2-formaldehyde or 4-fluoropyridine-2-formaldehyde and a metal ion source into a solvent, and then degassing to obtain a reaction solution;

(2) and (2) heating the reaction solution obtained in the step (1) to react under a protective atmosphere, adding the obtained reaction solution into anhydrous ether after the reaction is finished, and washing the obtained precipitate to obtain the catalyst.

5. The method for preparing the electron-rich tetraphenylvinyl catalyst according to claim 4, wherein in step (1), the solvent is any one of acetonitrile, toluene, methanol, and N, N-dimethylformamide.

6. The method for preparing an electron-rich tetraphenylvinyl catalyst of claim 4 wherein in step (1), the source of metal ions comprises a source of iron ions or a source of copper ions;

preferably, the source of iron ions comprises Fe (OTf)₂、Fe(BF₄)₂Preferably, the ligand is reacted with Fe (OTf)₂Or Fe (BF)₄)₂The molar ratio of (A) is 0.55-0.80;

preferably, the copper ionsThe sub-source comprising Cu (CH)₃CN)₄BF₄And CuOTf, preferably, the ligand is reacted with Cu (CH)₃CN)₄BF₄Or the molar ratio of CuOTf is 0.90-1.10.

7. The method for preparing the electron-rich tetraphenylvinyl catalyst of claim 4, wherein in step (1), the molar ratio of the ligand to pyridine-2-carbaldehyde or 4-fluoropyridine-2-carbaldehyde is 0.45 to 0.60;

or, in the step (2), the heating temperature is 0-55 ℃, and the reaction time is 8-14 h.

8. The method for preparing the electron-rich tetraphenylvinyl catalyst according to claim 4, wherein in step (2), the protective atmosphere is nitrogen or inert gas; or, in the step (2), the detergent adopted for washing is anhydrous diethyl ether.

9. Use of the electron-rich tetraphenylvinyl catalyst according to any one of claims 1 to 3 or the electron-rich tetraphenylvinyl catalyst prepared by the process according to any one of claims 4 to 8 for the synthesis of 2, 3-dihydroquinazolinones.

10. The use of claim 9, wherein in the synthesis process, 2-aminobenzamide and 4-fluorobenzaldehyde are used as reaction substrates, and acetonitrile and tetrahydrofuran are used as solvents; preferably, the volume ratio of acetonitrile to tetrahydrofuran is 2: 1.

Technical Field

The invention relates to the technical field of supramolecular catalysts, in particular to an electron-rich tetraphenyl ethylene catalyst and a preparation method and application thereof.

Background

The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.

The 2, 3-dihydro quinazolinone compound is an important condensed heterocycle, and has good pharmacological activity in the aspects of tumor resistance, pain relief, fibrosis resistance, antibiotics and the like. The synthesis of this compound, which has been reported to date, requires a Lewis acid (e.g. Sc (OTf))₃、Ga(OTf)₃) OrAcids (such as phosphoric acid and sulfonic acid) are used as catalysts, the chemical reaction process is complex (condensation is performed first and then cyclization is performed), the consumption of the catalysts is high, the catalytic efficiency is low, and a large number of byproducts are generated, so that the production of the catalysts in actual life is seriously influenced.

The potential applications of self-assembled supramolecular coordination cages in molecular recognition and storage, sensing, catalysis, and drug transport proteins are attracting increasing attention. Notably, coordination cages are discrete supramolecules composed of metal junctions and organically linked ligands, the intrinsic cavities of which can serve as tunable microenvironments. Thus, certain specific chemical reactions can be carried out within the coordination cage cavity, enabling regioselective and stereoselective reactions of substrates. Since the chemical reaction is carried out in a limited space, this is completely different from the homogeneous reaction in a solution. The good adjustable structure of the coordination cage provides an ideal platform for designing the supermolecule catalyst for chemical conversion. Fujita and Raymond have made pioneering work, representative reactions of which include Diels-Alde reaction, epoxidation, aza-Cope rearrangement, Knoevenagel reaction, Nazarov cyclization, and the like. Although there are many examples of effective bimolecular reactions that can be carried out in vessels that do not have catalytically active sites, there is a need to design new supramolecular capsules to facilitate more complex reactions. Moreover, the narrow range of reaction types limits their use in practical organic synthesis. The complex cascade or continuous catalytic reaction in nature has great application value, because the process can lead the reaction intermediate to generate the target product through continuous reaction.

Disclosure of Invention

Rational design of catalytic cages for tandem reactions is an urgent problem to be solved, and product inhibition is another challenge of catalytic cycling processes. In order to solve the problems, the invention provides an electron-rich tetraphenyl vinyl catalyst, and a preparation method and application thereof. The invention adds the electron-rich tetraphenyl ethylene group (TPE) into the catalyst with cage structure to induce the cascade reaction of two components and reduce the product inhibition. In order to achieve the above object, the technical solution of the present invention is as follows.

In a first aspect of the present invention, there is provided an electron-rich tetraphenylethylene-based catalyst comprising a metal ion and a ligand containing a tetraphenylethylene group, said metal ion serving as a junction, being connected to a schiff-base-like structure of said ligand by a coordination bond to form a cage structure having a cavity. The Schiff base structure is realized by condensation reaction of amino and aldehyde pyridine.

Further, the metal junction includes ferrous ions (Fe)²⁺) Cuprous ion (Cu)⁺) Zinc ion (Zn)²⁺) And the like.

Further, the ligand containing a tetraphenylethylene group includes any one of ligands containing a tetraphenylethylene group having an amino group.

For the electron-rich tetraphenylvinyl catalyst (abbreviated as "nanocage") of the present invention, the metal ion junctions, the inherent cavities of tetraphenylvinyl groups, enable the catalyst to perform certain specific chemical reactions different from those in solution, provide the possibility for substrate selection, regio-selective and stereoselective organic reactions, and provide an ideal platform for designing supramolecular catalysts for chemical transformations.

In a second aspect of the present invention, there is provided a process for preparing an electron-rich tetraphenylvinyl catalyst, comprising the steps of:

(1) adding a ligand containing a tetraphenylethylene group, pyridine-2-formaldehyde or 4-fluoropyridine-2-formaldehyde and a metal ion source into a solvent, and then degassing to obtain a reaction solution.

(2) And (2) heating the reaction solution obtained in the step (1) to react under a protective atmosphere, adding the obtained reaction solution into anhydrous ether after the reaction is finished, and washing the obtained precipitate to obtain the catalyst.

Further, in the step (1), the solvent includes any one of acetonitrile, toluene, methanol, N-dimethylformamide, and the like.

Further, in the step (1), the metal ion source comprises an iron ion source or a copper ion source; optionally, the source of iron ions comprises Fe (OTf)₂、Fe(BF₄)₂(ii) a The copper ion source comprises Cu (CH)₃CN)₄BF₄And CuOTf.

Further, in the step (1), the ligand is reacted with Fe (OTf)₂Or Fe (BF)₄)₂Is 0.55 to 0.80.

Further, in the step (1), the ligand is reacted with Cu (CH)₃CN)₄BF₄Or the molar ratio of CuOTf is 0.90-1.10.

Further, in the step (1), the molar ratio of the ligand to pyridine-2-formaldehyde or 4-fluoropyridine-2-formaldehyde is 0.45-0.60. It should be noted that the pyridine-2-carbaldehyde and the 4-fluoropyridine-2-carbaldehyde are in an alternative relationship.

Further, in the step (2), the protective atmosphere is nitrogen or inert gas.

Further, in the step (2), the heating temperature is 0-55 ℃, and the reaction time is 8-14 h.

Further, in the step (2), the detergent used for washing is anhydrous diethyl ether.

In a third aspect of the invention, the application of the electron-rich tetraphenyl vinyl catalyst in the synthesis of 2, 3-dihydro quinazolinone compounds is provided. Preferably, 2-aminobenzamide and 4-fluorobenzaldehyde are taken as reaction substrates, acetonitrile and tetrahydrofuran are taken as solvents, and optionally the volume ratio of the acetonitrile to the tetrahydrofuran is 2: 1.

Compared with solution reaction, the catalyst synthesized by the invention has a cage structure, is low in consumption in the catalytic process, and shows higher catalytic activity and faster reaction rate. In addition, due to the flexibility of the nanometer coordination cage and the existence of the hydrophobic cavity, a planar reaction substrate can be effectively encapsulated, and when a product is a non-planar product, the product can be easily discharged from the cage cavity, so that the product inhibition effect is reduced, and the reaction efficiency is improved.

Compared with the prior art, the invention has the following beneficial effects:

(1) the ligand of the tetraphenylethylene group with rich electrons, which is designed and synthesized in the invention, can promote deprotonation of a reaction intermediate, so that the reaction intermediate has stronger nucleophilicity in cyclization, the generation of a reaction product is promoted, and the reaction efficiency is improved.

(2) The planar reaction substrate is favorable for entering the cavity of the electron-rich tetraphenyl vinyl catalyst, and is easy to form pi-pi accumulation with an electron-rich tetraphenyl vinyl group ligand, and meanwhile, non-planar reaction products are easier to separate from the cavity, so that the product inhibition effect is weakened.

(3) The present invention is achieved by varying the substituent groups (e.g., -H, -CH₃、-OCH₃and-F, -Cl, etc.), can realize selective regulation and control of absorption and release of the reaction substrate, achieve the aim of improving activity and selectivity, and contribute to promoting the research on supermolecule catalytic application of novel molecular cages.

(4) The electron-rich tetraphenyl vinyl catalyst prepared by the invention has the advantages that the limit function of a hydrophobic cavity can improve the reaction activity and selectivity, and a new thought is provided for the design of the catalyst for supermolecular synthesis.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description, serve to explain the invention without unduly limiting the invention.

FIG. 1 shows a second embodiment of the present invention for synthesizing Fe-TPE catalyst¹H NMR spectrum.

FIG. 2 shows the synthesis of a second embodiment of the catalyst Fe-TPE¹³C NMR spectrum.

FIG. 3 shows the Cu-TPE synthesized as the catalyst in the second embodiment of the invention¹H NMR spectrum.

FIG. 4 shows the Cu-TPE synthesized by the second embodiment of the present invention¹³C NMR spectrum.

FIG. 5 shows a third embodiment of the present invention in which Fe-TPE and Cu-TPE are interconverted¹H NMR spectrum.

FIG. 6 shows the reaction of Fe-TPE with a substrate 1a according to a fourth embodiment of the present invention¹H NMR spectrum.

FIG. 7 shows the reaction of Fe-TPE with a substrate 2b according to a fourth embodiment of the present invention¹H NMR spectrum.

FIG. 8 is a graph showing the change in the yield of 2, 3-dihydroquinazolinone synthesized in the fifth example of the present invention.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or starting materials used in the present invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described in this invention are exemplary only.

As mentioned above, rational design of catalytic cages for tandem reactions is an urgent problem to be solved, and product inhibition is another challenge in the catalytic cycling process. Therefore, the invention provides an electron-rich tetraphenyl vinyl catalyst, a preparation method and an application thereof, and the invention is further explained according to the drawings and the detailed description of the specification.

First embodiment

The synthesis of 4- (4- {1- [4- (4-aminophenyl) phenyl ] -2, 2-diphenylvinyl) aniline (ligand containing tetraphenylethylene group) whose reaction process is referred to formula (1), comprising the steps of:

(1) synthesis of ligand precursor 2 Br-TPE: A1.6M solution of n-butyllithium in hexane (7.0mL, 11.2mmol) was added to a solution of diphenylmethane (1.81g, 18.0mmol) in anhydrous tetrahydrofuran (27mL) at 0 ℃ under a nitrogen atmosphere. After stirring at this temperature for 2 hours, bis (4-bromophenyl) methanone (2.90g, 8.6mmol) was added and allowed to continue to react, after 10 hours, it was gradually warmed to room temperature and the reaction was quenched with aqueous ammonium chloride solution, and then the reaction solution was extracted three times with dichloromethane. After anhydrous sodium sulfate was added to remove a small amount of water in the organic phase and dichloromethane was removed using a rotary evaporator, the obtained intermediate was dissolved in 45mL of toluene, p-toluenesulfonic acid (0.37g, 1.94mmol) was added thereto, and the reaction was refluxed for 12 hours and cooled to room temperature after the reaction was completed. The solvent was removed from the reaction solution using a rotary evaporator and the crude product was purified over a silica gel column (eluent n-hexane) to give 2Br-TPE as a white solid (2.6g, 62% yield).

(2) And (3) synthesis of a ligand: 2Br-TPE (2.5065g, 5.14mmol), 4-aminophenylboronic acid pinacol ester (4.5g, 20.5mmol), K₂CO₃(4.2607g，30mmol)，Pd(PPh₃)₄(597.2mg, 0.52mmol) and TBAB (165.7mg, 0.53mmol) were added to a solution of toluene/water (5.5:1, V/V, 165mL) and degassed three times. Then, in N₂The reaction mixture was reacted at 90 ℃ for 12 hours under an atmosphere. After the reaction, the reaction mixture was cooled to room temperature, the solvent in the reaction mixture was removed, and the crude product was purified with a silica gel column (eluent dichloromethane: ethyl acetate, V: V, 60:1) to obtain 4- (4- {1- [4- (4-aminophenyl) phenyl ] white solid]2, 2-diphenylvinyl) aniline (L in formula (1) in a yield of about 45%.

Second embodiment

1. The synthesis of an electron-rich tetraphenyl vinyl catalyst (Fe-TPE) with the reaction process being referred to formula (2) comprises the following steps: coupling ligand (477.8mg, 0.93mmol), pyridine-2-carbaldehyde (198.9mg, 1.86mmol), Fe (OTf)₂(219.2mg, 0.62mmol) was added to 40mL of acetonitrile and degassed three times. Then, in N₂The reaction mixture was reacted at 50 ℃ for 12 hours under an atmosphere. After the reaction is finished, the reaction solution is cooled to room temperature, the reaction solution is poured into anhydrous ether, and the generated precipitate is centrifuged and washed with the anhydrous ether for three times to obtain purple solid, namely Fe-TPE, wherein the yield is 76.5%. FIGS. 1 and 2 are Fe-TPE respectively¹HNMR、¹³C NMR spectrum.

2. The synthesis of the electron-rich tetraphenyl vinyl catalyst (Cu-TPE) has a reaction process with reference to formula (2), and comprises the following steps: ligand (453.2mg, 0.88mmol), pyridine-2-carbaldehyde (188.7mg, 1.76mmol), Cu (CH)₃CN)₄BF₄(277.4mg, 0.88mmol) was added to 40mL acetonitrile and degassed three times. Then, in N₂The reaction mixture was reacted at 50 ℃ for 12 hours under an atmosphere. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was poured into anhydrous ether, and the resulting precipitate was centrifuged and washed with anhydrous ether three times to obtain a brown solid, i.e., Cu-TPE, with a yield of 80.5%. FIGS. 3 and 4 are Cu-TPE respectively¹H NMR、¹³C NMR spectrum.

Third embodiment

This embodiment is at N₂Catalysis of the second example synthesis by relative conversion of Fe-TPE and Cu-TPE under protectionThe stability of the agents Fe-TPE and Cu-TPE is tested, and the method comprises the following steps:

(1) converting Fe-TPE into Cu-TPE: Fe-TPE (17.2mg, 6.17. mu. mol), Cu (CH)₃CN)₄BF₄(5.9mg, 18.8. mu. mol) was added to the acetonitrile (6ml) solution and degassed three times. Then, in N₂The reaction solution was refluxed for 12 hours under an atmosphere. After the reaction was completed, it was cooled to room temperature, the reaction solution was poured into anhydrous ether, and the resultant precipitate was centrifuged and washed with anhydrous ether three times to obtain a violet solid.

(2) Conversion of Cu-TPE to Fe-TPE: mixing Cu-TPE (20.2mg, 12. mu. mol), Fe (OTf)₂(5.7mg, 16. mu. mol) was added to the acetonitrile (6ml) solution and degassed three times. Then, in N₂The reaction solution was refluxed for 12 hours under an atmosphere. After the reaction was completed, it was cooled to room temperature, the reaction solution was poured into anhydrous ether, and the resultant precipitate was centrifuged and washed with anhydrous ether three times to obtain a violet solid.

As shown in FIG. 5¹And H NMR spectrum analysis shows that the Fe-TPE has higher stability. In addition, it can be seen that the final product was a purple solid, and Fe-TPE had higher stability.

Fourth embodiment

Considering the influence of a catalytic substrate on the stability of the nano coordination cage, the method takes the synthesis of 2, 3-dihydro quinazolinone compounds as an example to verify the stability of the catalyst Fe-TPE synthesized in the second embodiment in the reaction process, and comprises the following steps:

(1) respectively preparing Fe-TPE, a substrate 1a (2-aminobenzamide) and 2b (4-fluorobenzaldehyde) into 100 mmol.L^-1CH (A) of₃CN-d₃The solution of (1).

(2) The solution volume ratio of Fe-TPE and the substrate 1a (2-aminobenzamide) or 2b (4-fluorobenzaldehyde) is respectively 1:1, 1:2, 1:3, 1:4 and 1:5, and the solution volume ratio is 100 mmol.L^-1CH (A) of₃CN-d₃The solution was added to a reaction flask and reacted at 40 ℃ for 8 hours. After the reaction is finished, the 1H NMR charts shown in fig. 6 and 7 show that: the Fe-TPE does not change with the increase of the substrate 1a or 2b, and the Fe-TPE has good stabilityAnd (4) sex.

Fifth embodiment

In this example, the Fe-TPE synthesized in the second example is used as a catalyst, and the reaction solvent is screened in the synthesis of 2, 3-dihydroquinazolinone compounds, wherein the reaction process is as shown in formula (3), and specifically comprises the steps of reacting 1a (2-aminobenzamide, 6.8mg, 0.05mmol), 2b (4-fluorobenzaldehyde, 6.8mg, 0.055mmol) and Fe-TPE (0.14mg, 5 × 10 mmol)^-5mmol) was added to 3ml of a reaction solvent (acetonitrile: tetrahydrofuran ═ 2:1, V/V), and the resulting solution was stirred at 40 ℃ for 8 hours. After completion of the reaction, 600. mu.L of the reaction mixture was taken out, spun-dried, and then charged with a solution containing 20 mmol. multidot.L^-1500 μ LDMSO-d of internal standard (2,4, 5-trichloropyrimidine)₆Dissolving it in water, using¹The H NMR spectrum was subjected to yield calculation, and the results are shown in Table 1. By spectrogram analysis, when the solvent is acetonitrile/tetrahydrofuran with the volume ratio of 2:1, the yield is highest, and the solvent is the best reaction solvent.

TABLE 1

Sixth embodiment

Taking 1a (2-aminobenzamide) and 2b (4-fluorobenzaldehyde) as substrates and taking the synthesis of 2, 3-dihydroquinazolinone compounds as an example, the catalytic capacities of the two catalysts (Fe-TPE and Cu-TPE) prepared in the second example are respectively researched within 0.25-6h, and the specific method is that 1a (13.6mg and 0.1mmol), 2b (13.6mg and 0.11mmol), Fe-TPE (0.27mg and 1 × 10 mmol) and Fe-TPE are respectively added^-4mmol) or Cu-TPE (0.17mg, 1 × 10)^-4mmol) was added to 6ml of a solvent (acetonitrile: tetrahydrofuran ═ 2:1, V/V), and the resulting mixed solution was reacted at 40 ℃. At different reaction times 600. mu.L of solution was taken out, spun dry and then diluted with a solution containing 20 mmol. multidot.L^-1500 μ LDMSO-d of internal standard (2,4, 5-trichloropyrimidine)₆Dissolving it in water, using¹The H NMR spectrum was used for the yield calculation, and the results are shown in FIG. 8. The knotThe result shows that the Fe-TPE has faster reaction rate and higher reaction yield when being used as a catalyst.

Seventh embodiment

Synthesizing different 2, 3-dihydro quinazolinone compounds by using reaction substrates with different functional groups, wherein the reaction process refers to formula (4), and the specific method comprises the steps of preparing substrate 1(0.05mmol), substrate 2(0.055mmol), Fe-TPE (5 × 10 mmol)^-5mmol) or Cu-TPE (5 × 10-5mmol) was added to 3ml of a solvent (acetonitrile: tetrahydrofuran ═ 2:1, V/V), the resulting solution was stirred at 40 ℃ for 8 hours, after the reaction was completed, 600. mu.L of the reaction solution was taken out, spun dry, and then the solution was treated with a solvent containing 20 mmol. multidot.L^-1500 μ L DMSO-d of internal standard (2,4, 5-trichloropyrimidine)₆Dissolving it in water, using¹And calculating the yield of the H NMR spectrum. The results are shown in Table 1. The result shows that the two catalysts have good catalytic action, and compared with Cu-TPE, Fe-TPE has more remarkable catalytic activity when being used as a catalyst.

TABLE 2

Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.