阅读说明：本技术 一种电催化合成氘代布洛芬的方法 (Method for synthesizing deuterated ibuprofen through electrocatalysis ) 是由 苏陈良 欧伟 李瑛� 于 2020-07-29 设计创作，主要内容包括：本发明公开了一种电催化合成氘代布洛芬的方法,涉及药物合成技术领域。该方法包括步骤：S1、电解重水产生氘气；S2、将苯丙酮与S1得到的氘气进行氘代反应,并还原羰基,得到氘代化合物1；S3、将氘代化合物1进行傅克酰基化反应,使乙酰基进入对位,得到氘代的对异丁基苯乙酮；S4,将氘代的对异丁基苯乙酮与氯乙腈在碱的作用下进行羰基环氧化反应；S5,将S4的产物水解,即得到氘代布洛芬。本发明提供的电催化合成氘代布洛芬的方法,是以重水为氘源的电催化合成氘代布洛芬的温和高效方法,整个合成过程温和,合成的苄位氘代的布洛芬有望延长药物代谢周期,增强药效,减少给药量,从而降低毒副作用。(The invention discloses a method for synthesizing deuterated ibuprofen by electrocatalysis, and relates to the technical field of drug synthesis. The method comprises the following steps: s1, electrolyzing the heavy water to generate deuterium gas; s2, carrying out a deuteration reaction on propiophenone and deuterium gas obtained in the step S1, and reducing carbonyl to obtain a deuteration compound 1; s3, carrying out Friedel-crafts acylation reaction on the deuterated compound 1 to enable acetyl to enter para position to obtain deuterated p-isobutylacetophenone; s4, carrying out carbonyl epoxidation reaction on deuterated p-isobutylacetophenone and chloroacetonitrile under the action of alkali; and S5, hydrolyzing the product of S4 to obtain the deuterated ibuprofen. The method for synthesizing deuterated ibuprofen by electrocatalysis is a mild and efficient method for synthesizing deuterated ibuprofen by electrocatalysis with deuterium source as deuterium source, the whole synthesis process is mild, and the synthesized benzyl deuterated ibuprofen is expected to prolong the drug metabolism period, enhance the drug effect and reduce the dosage, thereby reducing the toxic and side effects.)

1. A method for synthesizing deuterated ibuprofen through electrocatalysis is characterized by comprising the following steps:

s1, electrolyzing the heavy water to generate deuterium gas;

s2, carrying out a deuteration reaction on propiophenone and deuterium gas obtained in the step S1, and reducing carbonyl to obtain a deuteration compound 1;

s3, carrying out Friedel-crafts acylation reaction on the deuterated compound 1 to enable acetyl to enter para position to obtain deuterated p-isobutylacetophenone;

s4, carrying out carbonyl epoxidation reaction on deuterated p-isobutylacetophenone and chloroacetonitrile under the action of alkali;

s5, hydrolyzing the product of S4 to obtain deuterated ibuprofen;

the structural formula of the propiophenone is shown as the following formula:

the structural formula of the deuterated ibuprofen is as follows:

2. the method for electrocatalytic synthesis of deuteroibuprofen as claimed in claim 1, wherein in said step S1, the specific operation of electrocatalytic heavy water is:

adding a heavy water salt solution into the electrolytic cell, and putting a conductive electrode;

the cathode cell and the anode cell are separated by a proton exchange membrane, and after the cathode cell and the anode cell are electrified, deuterium gas generated in the cathode cell is sent to step S2 by a gas guide tube.

3. The method for electrocatalytic synthesis of deuterated ibuprofen as recited in claim 2, wherein said conductive electrode is a platinum electrode and/or a graphite electrode.

4. The method for electrocatalytic synthesis of deuterated ibuprofen as recited in claim 3, wherein said step S2 is specifically performed by:

placing propiophenone, a palladium catalyst and potassium tert-butoxide in a reaction device according to a molar ratio of 8-12:0.8-2:1.5-3, wherein the reaction device is under negative pressure, introducing deuterium gas into the reaction device, and carrying out a deuteration reaction at room temperature;

and after the reaction is completed, filtering, and concentrating the filtrate under reduced pressure to obtain the deuterated compound 1.

5. The method for electrocatalytic synthesis of deuterated ibuprofen as recited in claim 4, wherein said reaction apparatus further comprises chlorobenzene; when chlorobenzene is used as a solvent, the amount of chlorobenzene is the amount of the solvent; when other solvents exist in the reaction device, the mass ratio of the propiophenone to the chlorobenzene in the system is more than or equal to 0.8.

6. The method for electrocatalytic synthesis of deuterated ibuprofen as recited in claim 5, wherein said step S3 is specifically performed by:

slowly adding the deuterated compound 1 into acetyl chloride in an ice-water bath, and reacting for 3-5 hours in the presence of a chloride catalyst and a chloride solvent;

after the reaction is finished, quenching the reaction by using a saturated sodium chloride aqueous solution, and extracting and purifying the product to obtain deuterated p-isobutylacetophenone;

the molar ratio of the deuterated compound 1 to the acetyl chloride is 0.8-1.2: 0.8-1.2.

7. The method of electrocatalytic synthesis of deuterated ibuprofen as recited in claim 6, wherein said chloride catalyst is anhydrous aluminum chloride and the chloride solvent is anhydrous dichloromethane.

8. The method for electrocatalytic synthesis of deuterated ibuprofen as recited in claim 7, wherein said step S4 is specifically performed by:

deuterated p-isobutylacetophenone, chloroacetonitrile and alkali are mixed according to a molar ratio of 0.8-1.2: 0.9 to 1.3, the solvent is anhydrous dichloromethane, and the reaction temperature is 5 to 8 ℃;

and quenching the reaction by using ice water after the reaction is finished, and extracting and purifying the product to obtain the epoxy product.

9. The method for electrocatalytic synthesis of deuteroibuprofen as recited in claim 8, wherein said base is slowly added dropwise into the reaction system, said base being a solution of potassium tert-butoxide in tert-butanol.

10. The method for electrocatalytic synthesis of deuterated ibuprofen as recited in claim 9, wherein said step S5 is specifically performed by:

and (2) reacting the product of S4, lithium bromide and water according to the molar ratio of 0.5-1:1-1.5:1.8-3, wherein the solvent is a mixture of DMF and MeCN, the reaction temperature is 80-95 ℃, cooling to room temperature after complete reaction, and extracting and purifying the product to obtain the deuterated ibuprofen.

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing deuterated ibuprofen by electrocatalysis.

Background

The chemical name of ibuprofen, 2- (4-isobutylphenyl) propionic acid, was 1968, and ibuprofen was first marketed in the uk by the british company for the treatment of mild to moderate pain and fever, with a history of use of more than 50 years to date. Ibuprofen, as a clinically widely used non-steroidal anti-inflammatory drug, has stronger antipyretic, anti-inflammatory and analgesic effects compared with aspirin, and has much smaller side effects than aspirin. Ibuprofen is the first choice of antipyretic and analgesic due to its stable and broad-spectrum excellent therapeutic effect. Ibuprofen is rapidly metabolized in the body, primarily in the omega-1 and omega-2 oxidations of isobutyl, first to alcohol and then to acid, with all metabolites inactivated.

Replacement of the hydrogen atom in the metabolic site of a drug with deuterium can alter the properties of the drug, such as half-life (reduced dosing times, reduced dose), absorption, distribution and toxicity, maintaining intrinsic activity and selectivity without altering the biological properties of the drug. In 4 months 2017, the first deuterated new drug, deutetrabenazine (abbreviated as SD809 in english), was approved by the Food and Drug Administration (FDA). According to clinical data, the tetrabenazine original drug has extremely serious toxic and side effects, 19 percent of patients show depression, and serious patients even have suicide tendency; and the deutetrabenazine is deuterated, so that the toxic and side effects of the obtained deutetrabenazine are obviously reduced, and only 2-4% of patients show depression. In view of the importance of deuterated drugs, a plurality of known famous drugs are developed into new drugs by taking deuterium as a core. However, most of the current medicine enterprises, especially the domestic medicine enterprises, still focus on the traditional medicine synthesis method due to the lack of advanced deuterated technology, rely on expensive and imported deuterated reagents, and become a major bottleneck which seriously restricts the research and development of novel deuterated medicines in China; in addition, precise deuteration to the site of drug metabolism is difficult to achieve.

Disclosure of Invention

The technical problem to be solved by the invention is the defects and shortcomings in the background technology, and the invention provides a method for synthesizing deuterated ibuprofen by electrocatalysis by taking heavy water as a deuterium source.

In order to solve the above problems, the present invention proposes the following technical solutions:

a method for synthesizing deuterated ibuprofen by electrocatalysis comprises the following steps:

s1, electrolyzing the heavy water to generate deuterium gas;

s2, carrying out a deuteration reaction on propiophenone and deuterium gas obtained in the step S1, and reducing carbonyl to obtain a deuteration compound 1;

s3, carrying out Friedel-crafts acylation reaction on the deuterated compound 1 to enable acetyl to enter para position to obtain deuterated p-isobutylacetophenone;

s4, carrying out carbonyl epoxidation reaction on deuterated p-isobutylacetophenone and chloroacetonitrile under the action of alkali;

s5, hydrolyzing the product of S4 to obtain deuterated ibuprofen;

the structural formula of the propiophenone is shown as the following formula:

the structural formula of the deuterated ibuprofen is as follows:

the further technical scheme is that in the method for synthesizing deuterated ibuprofen by electrocatalysis, in step S1, the specific operation of electrocatalysis heavy water is as follows:

adding a heavy water salt solution into the electrolytic cell, and putting a conductive electrode;

the cathode cell and the anode cell are separated by a proton exchange membrane, and after the cathode cell and the anode cell are electrified, deuterium gas generated in the cathode cell is sent to step S2 by a gas guide tube.

The further technical scheme is that the conductive electrode is a platinum electrode and/or a graphite electrode.

The further technical scheme is that the method for synthesizing deuterated ibuprofen by electrocatalysis comprises the following specific operations in step S2:

placing propiophenone, a palladium catalyst and potassium tert-butoxide in a reaction device according to a molar ratio of 8-12:0.8-2:1.5-3, wherein the reaction device is under negative pressure, introducing deuterium gas into the reaction device, and carrying out a deuteration reaction at room temperature;

after the reaction is completed, filtering, and concentrating the filtrate under reduced pressure to obtain a deuterated compound 1;

the structure of the deuterated compound 1 is as follows:

the further technical proposal is that chlorobenzene is also arranged in the reaction device; when chlorobenzene is used as a solvent, the amount of chlorobenzene is the amount of the solvent; when other solvents exist in the reaction device, the mass ratio of the propiophenone to the chlorobenzene in the system is more than or equal to 0.8.

The further technical scheme is that the method for synthesizing deuterated ibuprofen by electrocatalysis comprises the following specific operations in step S3:

slowly adding the deuterated compound 1 into acetyl chloride in an ice-water bath, and reacting for 3-5 hours in the presence of a chloride catalyst and a chloride solvent;

after the reaction is finished, quenching the reaction by using a saturated sodium chloride aqueous solution, and extracting and purifying the product to obtain deuterated p-isobutylacetophenone;

the molar ratio of the deuterated compound 1 to the acetyl chloride is 0.8-1.2: 0.8-1.2.

The technical scheme is that the chloride catalyst is anhydrous aluminum chloride, and the chloride solvent is anhydrous dichloromethane.

The further technical scheme is that the method for synthesizing deuterated ibuprofen by electrocatalysis comprises the following specific operations in step S4:

deuterated p-isobutylacetophenone, chloroacetonitrile and alkali are mixed according to a molar ratio of 0.8-1.2: 0.9 to 1.3, the solvent is anhydrous dichloromethane, and the reaction temperature is 5 to 8 ℃;

and quenching the reaction by using ice water after the reaction is finished, and extracting and purifying the product to obtain the epoxy product.

The further technical scheme is that the alkali is slowly dripped into a reaction system, and the alkali is tert-butyl alcohol solution of potassium tert-butoxide.

The further technical scheme is that the method for synthesizing deuterated ibuprofen by electrocatalysis comprises the following specific operations in step S5:

and (2) reacting the product of S4, lithium bromide and water according to the molar ratio of 0.5-1:1-1.5:1.8-3, wherein the solvent is a mixture of DMF and MeCN, the reaction temperature is 80-95 ℃, cooling to room temperature after complete reaction, and extracting and purifying the product to obtain the deuterated ibuprofen.

Compared with the prior art, the invention can achieve the following technical effects:

the method for synthesizing the deuterated ibuprofen by electrocatalysis is a mild and efficient method for synthesizing the deuterated ibuprofen by electrocatalysis with deuterium source, the cost is low, the whole synthesis process is mild, the deuterated sites are accurate, and the synthesized benzyl deuterated ibuprofen is expected to prolong the drug metabolism period, enhance the drug effect, reduce the dosage and further reduce the toxic and side effects.

The method for synthesizing the deuterated ibuprofen by electrocatalysis is based on the strategy of generating deuterium (gas) by electrocatalysis in situ, cheap heavy water is used as a deuterium source, so that the use of expensive and dangerous deuterium is avoided, and meanwhile, the device for electrochemically generating deuterium gas in situ, namely deuterium gas for chemical reaction can also be used for other chemical reactions involving hydrogen/deuterium gas, so that the synthesis of high-added-value deuterated chemicals with cheap heavy water as the deuterium source is realized.

Drawings

FIG. 1 is a schematic diagram of a reaction apparatus for electrocatalytic heavy water.

Detailed Description

The technical solutions in the examples will be described clearly and completely below

The term "room temperature" means 0 to 50 ℃; in some embodiments, room temperature represents 20-40 deg.C, and in some embodiments room temperature represents 25-35 deg.C.

The amount of the solvent required for the reaction used in the present invention is preferably such that the solvent completely dissolves the reactants, and may be varied depending on the reactants. In some embodiments, the amount of solvent required for the reaction may also be adapted to be more than just that required to dissolve the reactants.

The "inert reaction solvent" used in the present invention has the explanation generally described in the art, and specifically means a solvent which is not liable to react with the reactants and does not affect the progress of the reaction.

General synthetic procedure

In general, the compounds of the invention may be prepared by the methods described herein. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.

The solvents used in the present invention, such as chlorobenzene, dichlorobenzene, p-methyl chlorobenzene, anhydrous tetrahydrofuran, dioxane, toluene, diethyl ether, dichloromethane, chloroform, ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide, were previously dried by a drying method suitable in the art.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. Nuclear magnetic resonance spectroscopy with CDC1₃、d⁶-DMSO、CD₃OD or d⁶Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.25ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets), and dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).

Gas Chromatography (GC) is a chromatographic analysis method using a gas as a mobile phase. The vaporized sample is carried into the chromatographic column by carrier gas (mobile phase), the fixed phase in the column has different molecular forces from the components in the sample, the components flow out of the chromatographic column for different times, and the components are separated from each other. Using a suitable identification and recording system, a chromatogram is prepared which indicates the time and concentration at which the components flow out of the column. Qualitative analysis of the compounds was possible based on the time and sequence of the peaks indicated in the figures; according to the height and the area size of the peak, the compound can be quantitatively analyzed. The method has the characteristics of high efficiency, high sensitivity, strong selectivity, high analysis speed, wide application, simple and convenient operation and the like. The method is suitable for qualitative and quantitative analysis of volatile organic compounds. The analysis of the non-volatile liquid and solid substances can be carried out by pyrolysis and gasification.

GC-MS refers to a gas chromatograph-mass spectrometer, which is an analytical instrument for measuring the charge-to-mass ratio (charge-to-mass ratio) of ions.

Thin Layer Chromatography (TLC) is carried out by applying a suitable stationary phase to a glass plate, plastic or aluminum substrate in a thin, uniform layer. After spotting and developing, comparing the specific shift value (Rf) with that of chromatogram obtained by the same method based on the appropriate reference substance, and performing drug identification, impurity inspection or content determination. Thin layer chromatography is an important experimental technique for rapid separation and qualitative analysis of small amounts of substances, and is also used to follow the progress of the reaction.

The specific operation process comprises the following steps:

s1, electrolyzing the heavy water to generate deuterium gas;

referring to fig. 1, an apparatus for electrocatalytic heavy water is shown in fig. 1. Adding heavy water salt solution (sodium sulfate, sodium carbonate, etc.) into the electrolytic cell, and placing into a conductive electrode; the electrodes can be platinum electrodes, graphite electrodes and other conductive electrodes, the electrolytic cell is separated by a proton exchange membrane, and the cathode cell is connected with the chemical reaction device in the step S2 by an air duct. After the power is turned on, deuterium gas generated in the cathode cell is sent to step S2 by a gas-guiding tube.

It will be appreciated that the reduction potential of the anions ionized to salts cannot be lower than the reduction potential of hydroxide, otherwise the amount of salt will be consumed.

In one embodiment, the chemical reaction apparatus of step S2 is a flask.

S2, carrying out deuteration reaction on propiophenone and deuterium gas obtained from S1, and reducing carbonyl to obtain a deuteration compound 1, wherein the reaction process is as follows:

adding magnetons, compound 1(1480mg,10mmol,1.0equiv.), palladium acetate (224mg,1.0mmol,0.1equiv.), chlorobenzene (10mL), potassium tert-butoxide (224mg,2.0mmol,0.2equiv.), connecting the flask with a cathode pool of a heavy water electrolysis device through an air guide pipe, tying up a balloon, pumping out the air in the flask to enable the flask to be at a negative pressure, then setting the electrocatalysis to be in a 100mA constant current mode (enabling deuterium gas generated by heavy water electrocatalysis decomposed to be used for deuterium substitution reaction in the flask in situ), stirring the reaction at room temperature, monitoring the reaction by GC-MS, and completing the reaction after 12 hours. And (3) filtering the reaction solution, and concentrating the filtrate under reduced pressure to obtain a compound 2 (the compound 2 is the deuterated compound 1), wherein the compound 2 is directly used for the next Friedel-crafts acylation reaction.

It is understood that deuterium gas generated at the initial stage of the reaction is completely used for the reaction, and once deuterium gas is not required for the reaction at all, deuterium gas enters the balloon and is temporarily stored. In the whole process, the amount of deuterium generated by electrolyzing heavy water is slightly larger than that required by the reaction.

S3, carrying out Friedel-crafts acylation reaction on the deuterated compound 1 to enable acetyl to enter para position to obtain deuterated p-isobutylacetophenone, wherein the reaction process is as follows:

the product compound 2 of the previous step was slowly added to anhydrous dichloromethane (15mL) of acetyl chloride (785mg,10mmol,1.0equiv), anhydrous aluminum chloride (1330mg,10mmol,1.0equiv) under an ice-water bath, kept under ice bath for three hours, and the reaction was monitored by GC-MS for completion. The reaction was quenched with saturated aqueous sodium chloride (10mL), extracted three times with dichloromethane (3 × 6mL), the combined organic phases were concentrated under reduced pressure and further purified by column chromatography to give the pure deuterated compound 3(1655mg) as a colorless oil, the total yield of the two steps was 93%, and the deuteration rate was 80% as determined by nuclear magnetic resonance.

¹H NMR(600MHz,CDCl₃)0.91(d,J＝6.6Hz,6H),1.86-1.91(m,0.88H),2.51-2.54(m,0.4H),2.58(s,3H),7.23(d,J＝8.1Hz,2H),7.87(d,J＝8.1Hz,2H)ppm；¹³C NMR(150MHz,CDCl₃)22.2,26.5,30.0,44.9,128.3,129.2,134.9,147.5,197.9ppm；HRMS(ESI)m/zcalcd for[C₁₂H₁₅D₂O]⁺(M+H⁺):179.1399；found:179.1397.

S4, carrying out carbonyl epoxidation reaction on deuterated p-isobutylacetophenone and chloroacetonitrile under the action of alkali, wherein the reaction process is as follows:

magnetons, compound 3(178mg,1mmol,1.0equiv.), chloroacetonitrile (76mg,1.0mmol,1.0equiv.), and anhydrous dichloromethane (5mL) were added sequentially to a round-bottomed flask, and a solution of potassium tert-butoxide in tert-butanol (1M in t-BuOH,1.1mL,1.1mmol,1.1equiv.) was slowly added dropwise while maintaining the reaction temperature at 5-8 ℃. After one hour of reaction, the reaction was quenched by the addition of ice water (5mL), extracted three times with dichloromethane (3X 6mL), the combined organic phases concentrated under reduced pressure, and column chromatography (eluent 5% to 12% ethyl acetate in n-hexane) gave the product as the cis-trans isomer mixture 4, which was used directly in the next reaction.

S5, hydrolyzing the product of S4 to obtain deuterated ibuprofen, wherein the reaction process is as follows:

a round-bottomed flask was charged with magneton in this order, followed by column chromatography of the resulting epoxy compound 4 (cis-trans-isomer mixture 4) (150mg,0.74mmol,1.0equiv.), lithium bromide (116mg,1.33mmol,1.8equiv.), DMF (1.5mL), MeCN (1.5mL), H₂O (40mg,2.2mmol,3.0equiv.), reacting for 24 hours at 90 ℃, detecting whether the raw materials completely react by TLC, cooling the reaction to room temperature, adding ethyl acetate (10mL) and deionized water (5mL) into the product, extracting for three times by ethyl acetate (3 × 6mL), combining organic phases, concentrating under reduced pressure, and carrying out column chromatography (eluent is 40% ethyl acetate in n-hexane) to obtain deuterated ibuprofen 104mg as a white solid, wherein the total yield of the two steps S4 and S5 is 50%.

¹H NMR(600MHz,CDCl₃)0.90(d,J＝6.6Hz,6H),1.51(d,J＝7.2Hz,3H),1.83-1.86(m,1H),2.43-2.45(m,0.4H),3.72,(q,J＝7.2Hz,1H),7.10-7.13(m,2H),7.21-7.24(m,2H)；¹³C(150MHz,CDCl₃)18.1,22.4,30.1,44.9,45.1,127.3,129.4,137.0,140.9,180.3ppm；HRMS(ESI)m/z calcd for[C₁₃H₁₇D₂O₂]⁺(M+H⁺):209.1505；found:209.1501.

In conclusion, the method for synthesizing deuterated ibuprofen by electrocatalysis provided by the invention is a mild and efficient method for synthesizing deuterated ibuprofen by electrocatalysis with deuterium as a deuterium source, and has low cost; the whole synthesis process is mild, the deuterated sites are accurate, and the synthesized benzyl deuterated ibuprofen is expected to prolong the drug metabolism period, enhance the drug effect and reduce the dosage, thereby reducing the toxic and side effects.

The method for synthesizing the deuterated ibuprofen by electrocatalysis is based on the strategy of generating deuterium (gas) by electrocatalysis in situ, cheap heavy water is used as a deuterium source, so that the use of expensive and dangerous deuterium is avoided, and meanwhile, the device for electrochemically generating deuterium gas in situ, namely deuterium gas for chemical reaction can also be used for other chemical reactions involving hydrogen/deuterium gas, so that the synthesis of high-added-value deuterated chemicals with cheap heavy water as the deuterium source is realized.

In the above embodiments, the descriptions of the respective embodiments have respective emphasis, and for parts that are not described in detail in a certain embodiment, reference may be made to related descriptions of other embodiments.

While the invention has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.