TW200808681A - A series of deuterium labelled compounds as drug testing standards and their preparations - Google Patents

Abstract

The present invention provides a series of compounds wherein part of hydrogens are substituted by deuteriums and a method of synthesis therefor. The compounds of the present invention conotaining deuteriums are used as constrast standards in a quantification of a similar compound with unknown concentration by GC-MS.

Description

IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a method for preparing a compound, a comparative test product of a medicinal medicinal standard and a preparation thereof, and a preparation thereof as a target drug. 】 ί / . With the advancement of society, the abuse of drugs has become a serious social problem in order to solve the paralysis. The amount of the species: oligo =; = = take = :: Γ 2: ί analysis costs and other factors. For thorough: check: have high _ do not need to live % ^. Sexual additions are enough to be confirmed, and can = ί; ? Analysis of the positive ^ also 1 consumption-sex (spedfldty), and the recording is at least the same as the initial screening 'To enable the results of drug confirmation. The choice of this method will be the key to the entire drug abuse test, and the results will have a decisive impact on the judgment. At present, in the urine U, in the method of monitoring the use of music, gas chromatography mass spectrometry (GC-MS) technology is generally recognized as a reliable technology, and is currently used analytical technology. Generally, there are four methods for quantification by gas chromatography mass spectrometry: 1. External standard method 2. Area normalization 3. Standard addition 4. Internal standard method (Internal standard) ) 200808681 ^, the above-mentioned parent financial and financial error, its error value and the contents of the specimen, the position of the wood π, the tongue and the tongue, and more, due to the processing of the W and the error of the instrument itself, etc. Related, so the same sample may also detect different content. , the standard method is _-mathematics_, the signal intensity of the known wave of music is contained in the volume, and the condition of the drug in the object to be tested is calculated, and only the same volume is hidden, ie = The signal of the test drug is calculated. The main reason is that the signal and concentration = 4 relationship, and when the drug is not contained, the signal intensity should be zero, only for the same injection volume, then the drug concentration can be measured in this way. Therefore, the use of external standard methods usually causes large errors. - Method · Quantify the peak area of a substance in an unknown sample directly compared with the peak area of the object 彳 彳 彳 σ. It is usually required that the concentration of the standard is close to the concentration of the _ component, and a small quantitative error is called. The area ί - method is to multiply the area of all the scales by the _ pair correction, the sum after the child, the so-called "normal". The premise of the sampling method using the area normalization method is that the sample t is washed away from the column at all ages, and the low content is required to be detected by the instrument. The quasi-curve method is adopted: the standard substance of the component to be tested is formulated into a standard solution of different concentrations, and after chromatography, a standard curve is prepared, that is, a relationship between the concentration of the substance and its area (or peak height). According to the color ♦ area (or +*) of the component to be tested in the sample, the corresponding concentration is found from the standard curve. The slope of the standard curve is related to the nature of the material and the characteristics of the instrument, and is equivalent to the correction factor of the component to be tested. Therefore, when using different instruments, the standard curve must be re-measured and the conditions at each test must be consistent with the conditions of the standard curve. The quantitative determination of the quasi-method in 200808681 is similar to the drug to be tested in order to make the chemical composition of the compound and the substance with higher stability, ^, mouth. The peaks of the internal standard products are as close as possible, but the test (4) is heterogeneous one: === object j and the standard products within the two major categories should meet the following requirements: ° ΐ::= ί spectrum conditions have - The chemical stability of the test; the elution of the sputum material during the retention time, · the two adjacent peaks of the soldiers reach the baseline separation; the substance-specific correction factor should be known or measurable; "Being profitable" has similar concentration and similar retention behavior; has higher purity. When the substance|=°^' standard and analyte are simultaneously carried out, the signal of the standard or reference substance can be compared to calculate the content. This is a kind of green. 111 is the loss caused by the sample processing, or ==, into the error generated by the analysis of the mass spectrometer, 14 is the same product, the same loss is lost. The value of the whole analysis process remains No change. When the analysis starts, the known amount ασ ' is added, then the ratio of the internal standard to the drug content in the sample is the loss and error of the solid two analysis process, which can be ignored. In order to obtain the degree (prcdskm) Fresher than the entire analysis step, the better the better, and when the instrument parameters and elution conditions occur non-human changes: 'internal standard and sample components will be affected by the service, thus eliminating the mistakes. When the sample The situation is not understood, the matrix of the sample is very complicated or 200808681

Hi! The method of collecting seeds is more suitable when using the product. It is considered to be a combination of the internal standard method and the external standard method. The amount of the sample is taken, and the concentration of the sample to be tested is added to the chromatographic analysis, and the concentration of the added standard solution is the horizontal coordinate ordinate. The concentration of the component to be tested in the sample is the distance from the origin of the intersection point of the /, '", k-coordinate extension line. The standard test of the test is added to the same sample matrix, the mouth L sub = The 4^ method can eliminate the matrix interference. However, since each sample=matching 4 _ on the mixture solution containing the sample solution and the standard solution, this method is not suitable for the analysis of a large number of samples. The gas chromatography-linked f-spectrum technique has a 1^ point and _ condition. The case of #际上的杂检测 usually has = metabolic timeliness and accompanying a large number of sample samples.

Isotope dilution method in Meth d/ί method (IS〇t〇piC dirty plus is the standard used in 22 and the drug to be detected has _ structure, only 稃: η 素: 凡素. Current drug testing experiment Most of the chambers use the position: Γΐ structure as the internal standard. Use the same material in the same structure, the fresh material in the structure, the analysis and retention time =:, the isotope content is fixed, you can not The amount of drug in the H concentration is very consistent with the timeliness of the unit and the complexity of the bulk of the sample. 氘 is a stable form of hydrogen, a symbol of the same position, generally D〇h. Its * is also touched, Read in. The content of nature is about the name and the neutron group... one of the seven thousandths of 1虱, so it is replaced by the 200808681 atmosphere; ^ part of the hydrogen in the drug, most of the physicochemical properties are the same There is only a slight difference in quality. Gas chromatography mass spectrometry (GC-MS) has three characteristics: high sensitivity, high forensic ability and compatibility with chromatographic instruments, and is used by all analyzers. The most extensive analytical instrument for a wide range of applications Qualitative and quantitative analysis of complexes and complex mixtures of compounds. If a compound is to be quantified, the concentration of the GC of the known compounds at different concentrations must be first plotted, and then the sample of unknown concentration should be analyzed by GC. The integrated area is known, and the integrated area is plotted against the concentration. After comparison, the concentration of the product can be pushed. m Q and 'If you use a compound containing bismuth, you only need to know the amount == Sample mixing 'by containing 氖 氖 不含 : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : The spirit of the present invention conceives the method of the standard test substance standard of the present invention. The following is a brief description of the invention. [Summary of the invention] = The current cumbersome process encountered in testing the drug, cup, and Gas compound, its structure is shown in Formula 1: "

Wherein R 1 is methyl oxygen, and R 2 is chlorine, bromine, hard, ethyl sulfur, 200,808,681 thiol, aldehyde, nitrovinyl, chlorosulfonate, dimethylvinylamine, or hydrogen, R3 is methyl oxygen, isopropylamine, a base or a hydrogen thereof, R4 ethylamine, isopropylamine, aldehyde group, nitrovinyl group, chlorosulfonate group, monomethylethyleneamine or hydrogen One of them, in which R1 or above to J gas is replaced by gas. The invention further provides a method for synthesizing a compound containing & compound, comprising the steps of: (1-1) taking a hydrogen peroxide and mixing with hydroquinone and tetrabutylammonium bromide to form a first reaction liquid; -2) adding hydrazine iodide (cdj) to the first reaction liquid to carry out the reaction to form a second reaction liquid; (1-3) extracting the second reaction liquid to obtain a first extract; (1-4) The first extract is subjected to column chromatography purification to obtain a 1,4-bis (trideuteriomethoxy) benzene. According to the above invention, the following steps are further included: (2-1) reacting the bis-indenyl oxy-oxide with titanium tetrachloride and dichloromethyl decyl ether (ChCHOCH3) to form a third reaction liquid; 2 2) For the color gradation analysis of the δ haidi two reaction solution, one race, one separation liquid; (2-3) the first separation liquid is purified by column chromatography to obtain a 2,5_double ( (2,5-bis(tridecyloxy)benzoic acid and nitro oxime reaction 10 200808681 Reflowing to obtain a first collection; (2-5) performing a film chromatography on the first collection to obtain a bis(dimethoxymethyloxy)-2-(2-nitrovinyl)benzene (1) , 4_bis(trideuteriummethoxy)-2_(2_nitr〇vinyl)benzene); (2_6) reacting the bismuth-bis(trimethyleneoxy)>2_(2-nitrovinyl)benzene with deuterated IS lithium for reflux, Obtaining a second collection; (2-7) adjusting the second collection to be acidic; (2-8) drawing the second collection adjusted to be acidic to obtain a second extract; and (2 9) Collecting the aqueous layer of the second extract to adjust the solution Extracting an alkaline solution to obtain 2-[2,5-bis(trideterimmnethoxyphenyl)ethylamine). According to the above invention, the following Step: (3-1) reacting 2-[2,5-bis(trimethyloloxy)phenyl]ethylamine with bromine to form a fourth reaction solution; (3-2) the fourth reaction After the pH of the liquid is adjusted to η or more, the fourth reaction solution is extracted to obtain 2-[4-bromo-2,5-bis(trimethyleneoxy)phenyl]ethylamine (2-[4-bromo -255-bis(trideuteriummethoxy)phenyl]ethylamine) According to the above invention, the following steps are further included: (4-1) Salinization of 2-[2,5-bis(trimethyleneoxy)phenyl]ethylamine Thereafter, recrystallization is carried out to obtain 2-[2,5-bis(trimethyleneoxy)phenyl]ethylamine hydrochloride; (4-2) 2-[2,5-bis(tridecyloxy) Phenyl]ethylamine hydrochloride reacts with 11 200808681 gasified sulfuric acid (SO2CI2) to form a fifth reaction solution; (4-3) after the fifth color reaction layer is subjected to thin film chromatography, diethyl ether is added to produce a precipitate. And (4-4) recrystallize the precipitate to give 2-[4-chloro-2,5-bis(trimethyleneoxy)phenyl]ethylamine hydrochloride (2-[4-chloro- 295 -bis(trideuteriummethoxy)phenyl]ethylamine hydrochloride) 0 According to the above invention, the following steps are further included: (5-1) 2·[2,5-bis(trimethyloloxy)phenyl]ethylamine and dimethyl anhydride Mixing and heating to obtain a sixth reaction liquid; (5-2) purifying the sixth reaction liquid by column chromatography to obtain a 2-{2_[2,5-bis(tridecyloxy)phenyl]B }},3_dione (2- {2-[2?5-bis(trideuteriummethoxy)phenyl]ethyl} isoindole-1 ? 3- dione); (5-3) the 2-{ 2-[2,5-bis(trimethyloloxy)phenyl]ethyl}isoprol-1,3-one ketone reacts with murine moth (IQ) to obtain a seventh reaction solution; 5_4) extracting the seventh reaction solution to obtain a third extract; (5-5) collecting the organic layer of the third extract, and performing column chromatography purification to obtain a 2-{2_[4- moth_2 ,5-bis(trimethyleneoxy)phenyl]ethyl}isoindole-1 3_ — , one ketone (2- {244-I〇do-2?5-bis(trideuteriummethoxy)phenyl]ethyl} isoin Dole-l,3-dione); (5-6) 2-{2H2,5-bis(trimethyleneoxy)phenyl]ethyl}isoindole-1,3-dione with hydrazine Heating the reaction to obtain a solid; 12 200808681 (5-7) filtering the solid a filtrate, and the solid is washed with ethanol to obtain a washing liquid; and (5-8) the filtrate and the washing liquid are collected and concentrated together to obtain a 2·[4_hard-2,5-double (two gas enthalpy According to the above invention, the following steps are further included: (6-1) the 2,5-di (three)氘Methyloxy)benzaldehyde is reacted with nitroethane to reflux to obtain a third collection; (6-2) Thin layer chromatography is performed on the δHaidi collection to obtain a second separation solution; -3) extracting the second separation liquid to obtain a fourth extract; (6-4) collecting the organic layer of the fourth stroke liquid, and performing column chromatography purification to obtain a 1,4-double (triterpene) Methyloxy)_2-(2-aminopropenyl)benzene (1,4_biS(frideUteriUmmeth〇xy)_2-(2-nitopropenyl)benzene); (6_5) the 1,4-double (three-infrared oxime oxygen) > 2_(2•Aminopropenyl)benzene is reacted with lithium aluminum hydride to reflux to obtain a fourth collection; (6-6) the pH of the fourth collection is at least greater than 9; and (6-7) Extracting the fourth collection to obtain a fifth extract; (6-8) collecting the fifth extract The organic layer can be obtained as a 2-[2,5-bis(trimethyleneoxy)phenyl]methylethylamine (2 [2,5 bis(frideuteriummethoxyphenyl) small methylethylamine). The following steps: (7-1) The 2-[2,5-bis(trimethyleneoxy)phenyl] benzhydrylethylamine salt 13 200808681 is formed, and then recrystallized to obtain a 2-[2,5- Bis(trimethyloloxy)phenyl]-l-methylethylamine hydrochloride; (7-2) 2_[2,5-bis(trimethyleneoxy)phenyl]-1-methyl The ethylamine hydrochloride reacts with bromine to obtain an eighth reaction solution; (7-3) makes the eighth reaction solution alkaline;

(7-4) extracting the alkaline reaction solution to obtain a sixth extract; (7-5) collecting the organic layer of the sixth extract, and performing tube chromatography purification to obtain a 2_[4 _Bromo-2,5_bis(tridecyloxy)phenyl] cyanoethylamine (2-[4-Bromo-2?5-bis(trideuteriummethoxy)phenyl]^ 1 -methylet hylamine) ° according to the above The invention further comprises the following steps: (8-1) reacting the 1,4-bis(trimethyleneoxy)benzene with chlorosulfonic acid to obtain a ninth reaction liquid; (8-2) adding ice water to the a ninth reaction solution to produce stratification; (8-3) extracting the aqueous layer in the layer to obtain a seventh extract; (8-4) collecting the organic layer of the seventh extract for column chromatography Purification, a pair of (3,5-bis(trideuteriummethoxy)benzenesulfonyl chloride); (8-4) 2,5-bis(tridecyloxy)belite The ruthenium chloride is dissolved in the solution containing 25% sulfuric acid; (8-5) the zinc reaction is added to obtain a tenth reaction liquid; (8-6) the tenth reaction liquid is extracted to obtain an eighth extract liquid; 8-7) Collect the organic layer of the eighth stroke liquid, and perform column chromatography purification to obtain a 2,5-double (three Yue gas-yl) benzenethiol 14 200808681 (2,5-bis (trideuteriummethoxy) benzenetlii〇l). According to the above invention, the following steps are further included: (9-1) reacting the 2,5-bis(trimethylenethio)benzenethiol with ethaneethane and refluxing to obtain a fifth collection; (9- 2) performing a fine layer analysis on the collection of the quince five, obtaining a third separation liquid, (9-3) acidifying the third separation liquid with hydrochloric acid, and extracting the acidified third separation liquid to obtain a ninth extraction liquid. (9-4) Collecting the organic layer of the ninth stroke liquid, and purifying it by column chromatography to obtain 2-ethyl-p-aminobenzenesulfonyl q+bis(trimethyleneoxy) stupid (2-Ethylsulfanyl) -l^bis(trideute^^^ ; (9-5) force the 2-ethyl-plycosyl yellow-based ''double (three-infrared oxime oxygen) to dichlorogen and monomethyl hydrazine In the brewing amine reflux solution, heating to obtain a solid; (9-6) dissolving the solid to obtain a solution; (9-7) purifying the solution by column chromatography to obtain a 4-ethyl-p-aminobenzene Sulfo-2,5-bis(tridecyloxy)benzofural (4-Ethylsulfanyl·2?5-bis(trideuteriummeώ^^; (9-8) 4-ethyl-p-aminophenylsulfonyl _ 2,5_bis(trimethyloloxy)phenylfurfural and nitrodecane are reacted to obtain an eleventh reaction liquid; (9-9) for the eleventh The solution was subjected to film chromatography to obtain one μethyl p-aminophenylsulfo-2,5-bis(trimethyleneoxy)4-(2-nitrovinyl)benzene (l-Ethylsulfanyl-2?5). -bis(trideuteriummethoxy)-4-(2-nitrovinyl) benzene); (9-10) 1-ethyl-p-plylite-based 2,5-bis(trimethylidene 15 200808681 oxy)-4 - (2-nitrovinyl)benzene is reacted with lithium aluminum hydride to obtain a twelfth reaction liquid; (9-11) to draw the twelfth reaction liquid to obtain a tenth extract; (9-12) The organic layer of the tenth extract is collected to obtain a 2-[4-ethyl-p-amino-p-c-c-yl-2,5-bis(tridecyloxy)phenyl]ethylamine (244-Ethylsulfanyl-2, 5-bis(trideuteriummethoxy)phenyl]ethyl amine) ° According to the above invention, the following steps are further included: (10-1) The 2,5-bis(trimethyloloxy)benzenethiol is reacted with bromopropane to reflux. Obtaining a sixth collection; (10-2) performing a film chromatography on the sixth collection to obtain a fourth separation liquid; (10_3) acidifying the fourth separation liquid with hydrochloric acid, and extracting the fourth separation of the acidification Liquid, an eleventh extract; (10-4) collecting the organic layer of the eleventh extract, into Purification by column chromatography to obtain 1,4-bis(trioxeriummethoxy-2-propylsulfanylbenzene) ί (10-5) phosphorus oxychloride and The dimethylformamide is heated to reflux, and the 1,4-bis(> sulphuryloxy)-2-propyl sulphate benzene is added and heated to obtain a solid; (10-6) the solid is dissolved. Obtain a solution; (10-7) Purify the solution by column chromatography to obtain a 2,5-bis(trimethyleneoxy)-4-propylsulfonamide aldehyde (2,5 VII iS) (trideUterimnmeth〇xy) bucket propylsulfanylbenzaldehyde) 16 200808681 (10-8) The 2,5-bis(di-j-l-yloxy)-4-propyl-tallowamine betidine and nitromethane are reacted to obtain a tenth Three reaction liquid; (1〇4) performing a film chromatography on the thirteenth reaction liquid to obtain a 1,4-bis(trimethyloloxy)-2-(2-nitrovinyl)_5_propyl 1,4-bis(trideuteriummethoxy)-2-(2-nitrovinyl)-5-propylsulfan ylbenzene; (ΚΜ0) 1,4_bis(trimethyleneoxy)>2_(2_ Nitrovinyl) _5_ propyl amine is stupid with lithium hydrazine and refluxed to obtain a seventh collection; (10-11) extraction The seventh collection obtains a twelfth extract; (KM2) collects the organic layer of the twelfth extract to obtain a 2-[25_bis(trimethyloloxy-M-propylsulfonylphenyl)ethylamine ( 2-[2,5-bis(Mdeuteriummethoxy)-4-propylsulfanyipheny1]ethy lamine) The present invention further provides a method for synthesizing a ruthenium-containing compound, comprising the steps of: (1) taking potassium hydroxide and 4-hydroxybenzaldehyde And tetrabutylammonium bromide is mixed to form a first reaction liquid; (2) adding nitrogen moth to the first reaction liquid to form a second reaction liquid; (3) extracting the second reaction liquid, a first extract; (4) purifying the first extract by column chromatography to obtain a 4-trideuterium methoxybei^ddehyde>; (5) the 4-trisyl group Oxybenzaldehyde is reacted with nitroethane to reflux to obtain a first collection; 17 200808681 (6) extracting the first collection to obtain a second extract; (7) performing a column on the extract of the younger brother Purification by chromatography to obtain 1 -trideuteriummethoxy «4-(2-nitropropenyl)benzene (8) adding θ hai 1* 曱 曱 氧 氧 氧 -4-(2-Shisyl propyl propyl) and reacting with an aluminum hydride clock to reflux, to obtain a second collection; (9) making the second collection The pH is at least greater than 9; (10) extracting the pH-adjusted second collection to obtain a third extract; and (11) collecting the organic layer of the third extract to obtain a 2-(4-three) 2-(4-trideuteriummethoxyphenyl)-1 -methylethylamine. The present invention further provides a nitrogen-containing compound having the structure shown in Formula 2: n(ch3)2

Wherein R 1 is a decyloxy group, R 2 is a nitrogen, oxygen or sulfur, and at least one hydrogen on R 1 is substituted by hydrazine. The invention further provides a method for synthesizing a ruthenium-containing compound, comprising the steps of: (1) taking potassium hydroxide, adding 3-mercapto-4-nitrophenol and tetrabutylammonium bromide to obtain a first reaction liquid; 200808681 (2) Adding a moth to the first reaction solution to obtain a second reaction solution, (3) drawing the reaction solution to obtain a first extract; (4) the first The extract is purified by column chromatography to obtain 4-trideuteriummethoxy-2-methyl-1 -nitrobenzene; (5) the 4-trimole The base oxy-2-indenyl nitrobenzene is condensed with n,N-dimercaptocarbamamine dihydrazide and heated under reflux to obtain a [2-(5-tridecyloxy-2-stone) ) vinyl] dimethylamine ([2-(5-trideuteriummetlioxy-2-nitr〇phenyl)vinyl]dimethylamin e); (6) The [>(5_tridecyloxy 1nitrophenyl)ethylene Hydrogenation of diamine to obtain a third reaction solution; (7) Purifying the third reaction solution by column chromatography to obtain 5-trideuteriummethoxy-lH-indole (8) The 5-trione methyloxy-ΐΗ-, σ Reacting with grass chloroform to obtain a fourth reaction solution; (9) adding didecylamine to the fourth reaction solution to obtain a solid; (10) dissolving the solid and recrystallizing to obtain a 2-(5- Trimethyl sulfhydryl-oxo-, °-3-3-yl)-N,N-didecyl-2-oxo-acetamide (2-(5-trideuteriummethoxy-1 H-indol-3 -yl)- N?N-dimethyl-2-〇x oacetamide) ·' (11) The 2-(5-tridecyloxy-1H-indole-3-yl)-N,N-dimercapto-2- The oxetamine is reacted with lithium aluminum hydride to reflux to obtain a first collection 19 200808681; (12) extracting the first collection to obtain a second extract; (13) collecting the organic of the second extract a layer of [2<5-trideuteriumethoxy-lH-indol-3-yl)ethyl]dimethylamine) The present invention is fully understood by the following description of the preferred embodiments and the accompanying drawings, and in. [Embodiment] '

OR 2 : R = CH3 2d; R = cd3 In the glove box, take potassium hydroxide (4.30g, 77.0mm〇1) and grind it with a sister, then add Hydroquinone (code 1 above). Structural formula, 3.40 g, 30.〇mm〇1) and tetrabutylammonium bromide (0.34 g, 12 curry 1) are ground together together. Institute (4), 56 mL, 93.0 mmol), 3 days at 40 t, the reaction was terminated by adding water. After dichloromethane was removed, the organic layer extract was dried with anhydrous sulfur, filtered, and concentrated to a Siliea gel column. Purification and purification, acetic acid ethyl acetate / hexane 'Ac: Η一! : 19) as the axial phase, the production of white crystal 曰: Μ-bis (trimethyl oxy) benzene, the structural code of the above code 2d 4, 29.0 melon, yield 95%. (When a moth scale is added, the product 20 200808681 1, 'Dimethoxybenzene, the structural formula of the above code 2, yield 98%) can be obtained. The physical property of the cerium-containing compound "1,4-bis(trimethylenethio)benzene," is abbreviated as m/p·: 56-57 °C; hydrogen nuclear magnetic resonance spectroscopy, hereinafter abbreviated as ιΗ ( 3〇〇MHz, CDC13, δ) : 6·90 (s, 6H); Carbon nuclear magnetic resonance spectroscopy, the following abbreviation is 13C NMR (75 MHz, CDC13, δ): 153·7, 114·6, 55·2- 54·6(ιη); Infrared absorption spectrum, hereinafter abbreviated as IR (KBr): 3164, 3106, 3061, 3044, 2505, 2217, 2065, 1943, 1867 cm4.

Conventional 1,4-dimethoxybenzene, physical properties mp: 55-56 °CJ 4 NMR (300 MHz, CDC13, δ): 6·88 (s, 4H), 3.76 (s , 6H); 13CNMR (125.7MHz, CDC13, δ) : 153·7,114.6,55·6 ; IR (KBr): 3111,3071,3012,2832,2056,1967,1872, 1643 cm"1 ° Comparing the physical properties of 2 with 2d, it can be known that 2d and 2, which only replace six bismuth, have similar physical properties.

1,4_bis(trimethyloloxy)benzene (3.50 g, 25.0 mmol) was dissolved in anhydrous dichlorinated broth (478 mL), and injected at 0 ° C under argon, 21 200808681 four gas Titanium (5.00 mL, 46.0 mmol), followed by injection of dichloromethoxymethane (4.20 mL, 46.5 mmol), the solution was dark red, stirred at room temperature for 15 minutes, and then analyzed by thin layer chromatography Thin Layer Chromatography (hereinafter referred to as TLC) tracking, until the disappearance of the raw materials, adding 185 mL of water, 'collecting the organic layer, washing the organic layer with 140 mL of water, drying the water sulfuric acid', filtering, and concentrating immediately to the Silica gel column Purification of the product as a mobile phase with ethyl acetate / hexane (EtOAc························································ 3.15 g, 18.3 mmol, yield 73%. (If the starting material is 2, the product 2,5-dioxabenzoquinone can be obtained, as shown in the above formula 3, yield 64%). Physical properties of the cerium-containing compound "2,5-bis(trimethyleneoxy)benzaldehyde, mp: 50-51 ° C; 4 NMR (300 MHz, CDC13, δ): 10·48 (s, 1 Η) ,7·33 (d, J = 3.2Hz, 1H), 7.15 (dd, J=9.1, 3.3 Hz, 1H), 6.95 (d, J = 9.1Hz, 1H); 13C NMR (75 MHz, CDC13 , δ) : 189·5,156.7,153·5, 124.9,123·4,113·3,110.4,55.6-54.7 (iv); IR (KBr): 3098,3052,2873,2231,2070,1674,1616, 1495, 1432, 1401, 1293, 1221 cnf1 ; Fast atomic impact mass spectrometry, hereinafter abbreviated as MS-FAB (m/z): 173 (Μ+ + 1,100); high resolution fast atomic impact mass spectrometry, abbreviated as hrms- Fab (πι/ζ): (:9Η4)6〇3 The calculated value of [M+] is 172.1004; the measured value is 22 200808681 172.1002. The conventional "2,5-dimethoxybenzaldehyde" which has not been replaced by hydrazine Physical properties mp··· 49-50 〇C ; 4 NMR (300 MHz, CDC13, δ): 10.48 (s, 1Η), 7·33 (d, J = 3.3 Hz, 1H), 7.15 (dd, J= 9.1,3·3Ηζ,1H),6.96 (d, J = 9.1 Hz, 1H), 3·89 (s, 3H), 3.80 (s, 3H); 13C NMR (125.7 MHz, CDC13, δ) 189.4, 156.6 ,15 3.4, 124.8, 123·3, 113.2, 110.3, 56·0, 55·7; IR (KBr): 3098, 3061, 2985, 2967, 2878, 2846, 2770, 1674, 1499, 1428, 1289, 1189, 1159 Cm-1 ; MS-FAB (m/z) : 167 (M++ 1,47), 165 (28), 105 (54), 75 (100); HRMS-FAB (m/z) : [M+] of C9H1G03 The calculated value is 166.0629; the measured value is 166.0632. From the physical properties of 3 and 3d above, it can be known that 3d and 3, which only replace six ruthenium, have similar physical properties.

3 :R = CH3 4 : R DiCH3 3d: R = CD3 4d: R = CD3 2,5_bis(trimethyloxy)benzaldehyde (2.90g, 17.〇mm〇l) and nitro Hydrane (5.77 mL, 1〇5·〇mmol) was placed in a round bottom flask, anhydrous ammonium acetate (catalytic amount) was added, refluxed at l ° ° C for 2.5 hours, followed by TLC until the end of the reaction, concentrated, yielding yellow The crystal of 1,4_bis(tritylmethyloxy)-2-(2-shidocylvinyl)benzene, as described above under the designation 4d, 3.50 23 200808681 g, 16·0 mmd, yield 94%. (If the starting material is 3, the product 1,4-Dimethoxy-2-predopylidene vinyl)benzene can be obtained, as shown in the above formula 4, yield 94%). Physical properties of the rabbit compound "1,4-bis(di-decyloxy)-2-(2-nitrovinyl)benzene, mp: 12M22 °C; 4 NMR (300 MHz, CDC13, 5): 8·14 (d, Bu 13.6 Hz, 1Η), 7·88 (d, J = 13.7 Hz, 1H), 7·03-6·99 (dd, J = 9·0, 3·〇Hz, 1H) , 6.96 (d, J = 2·9 Hz, 1Η), 6.91 (d, J = 8·9 Hz, 1H); 13CNMR (75MHz, CDC13, (5): 153.9, 153.5, 138.4, 135.3 , 119.4, 119.1, 116.3, 112·4; IR (KBr): 3104, 2221, 2075, 1616, 1496, 1346, 1253, 1234 cm'1 ; MS-FAB (m/z): 216 (M++1 , 10), 170 (19), 75 (100); HRMS-FAB (m/z): The calculated value of [M+H]+ of C1()H6D6N04 is 216.1136; the measured value is 216.1145. Physical properties of substituted "1,4-dioxan-2-(2-nitrovinyl)benzene, mp: 119-120 °C ϊ 4 NMR (300 MHz, CDC13, δ): 8·14 ( d, J = 13.6 Hz, 1H), 7·87 (d, J 2·13 Hz, 1H), 7.03-6.99 (dd, J = 9·0, 10 Hz, 1H), 6.97 (d, J = 3.0 Hz, 1H), 6·84 (d, J = 1〇·6 Hz, 1H), 3.90 (s, 3H), 3.80 (s, 3H); 24 200808681 13C NMR (75 MHz, CDC13, δ) ·· 153.9,153.5,138·4, 135.2,119.4,119.1,116·3,112.4,56·0,55·8; IR (KBr): 3106,2963,2954,2922 , 2837,1616,1495, 1419,1351,1252,1221,1176 cm·1 ; MS-FAB (m/z): 210 (Μ++1,3),194 (4),164 (5),75 (100); HRMS-FAB (m/z): The calculated value of [M+] of C^HnNC^ is 209.0688; the measured value is 209.0685. It can be known from the comparison of the physical properties of 4 and 4d above that only six hydrogens are substituted. 4d has similar physical properties to 4. RO,

OR

_2_)

OR 4 : R = CH.3 4d: R = 〇D3 δ (2C-H); R = CH3 δ·Η€Ι (2C-H:-HCi); R = CH3 ύ (2C-H-dg), R = CD3 6d-HCl |2C-H-ci€«HCi): R = CD^ M-bis(triazomethyloxy)_2♦yrylvinyl)benzene (3 5〇g, l6.0mmol) Dissolved in anhydrous tetrahydrofuran (15. 〇mL), slowly added lithium aluminum hydride (L1AIH4 '2.70 g, 7〇.〇mm〇i) in anhydrous tetrahydrofuran (68 〇mL) suspension, reflux 24 hours After cooling to room temperature, the reaction was quenched with tetrahydrofuran and water (1:1) and aqueous sodium hydroxide solution under ice-cold, and the solution was filtered with celite, using (10) and tetrahydro-d-propane. The solid is washed to fluffy, and the filtrate is concentrated. The aqueous solution is made acidic with dilute hydrochloric acid. After the extraction with dichloromethane, the water is added twice; the liquid is adjusted to be inspective and extracted with trichloromethane for three times. After the organic layer is concentrated, the product 2_(2,5•bis(decyloxy)phenyl)ethylamine' has the structural formula of 5d as above, and the product 5 salt is re-knotted, and the wire 5d; _(four) is called Into $200808681 acid gas, at this time the reaction bottle has a solid precipitate, stir for a few minutes, then let stand for a few minutes, the solid is filtered, Recrystallization from methanol/diethyl ether gives the crystal of the product 2-(2,5-bis(di-mercaptooxy)phenyl)ethylamine hydrochloride as the above formula 5d · HC1. 55 g, 6.9 mmol, yield 43%. (If the starting material is 4, the product 2-(2,5-bis(trimethyleneoxy)phenyl)ethylamine, the above formula No. 5, yield 70%) can be obtained. Physical properties of the cerium-containing compound "2-(2,5-bis(tridecyloxy)phenyl)ethylamine hydrochloride, H NMR (300 MHz ^ D20 5 δ) : 6.92 (άΊ = 8.9 Ηζ) ^ 1Η) ^ 6·84-6·80 (dd, J = 8·9, 3·0 Hz, 1Η), 6.78 (d, J = 3·0 Hz, 1H), 3.13 (t, J = 6·8 Hz, 2H), 2.86 (t, J = 6.9 Hz, 2H); 13CNMR (75 MHz, CD3OD, δ): 153.7, 151.7, 125.4, 116.5, 112.4, 111·2, 39·4, 28· 6 ; IR (KBr): 2965, 2908, 2832, 2753, 2653, 2564, 2464, 2217, 2063, 1500, 12389 cm4 ; MS face FAB (m/z): 188 (M+-C1,100), 185 ( 8), 171 (42), 158 (10), 75 (8); HRMS-FAB (m/z): The calculated value of [M+-C1] of CioHioDsNO is 188.1551; the measured value is 188.1553. Physical properties of hydrazine-substituted "2-(2,5-dimethoxyphenyl)ethylamine hydrochloride" 4 NMR (300 MHz, D20, ά): 6.80-6.68 (m, 3H), 3.78 (s, 3H), 3·77 (s, 3H), 2·93 (t, 6.9 Hz, 2H), 2·75 (t, J = 6.9 Hz, 2H); (due to 2-(2,5-diopter) The shape of oxyphenyl)ethylamine hydrochloride 26 200808681 is not easy to measure 1H NMR, so the data is changed to 2-(2,5-dioxane) Formal detection of ethylamine) 13CNMR (75MHz, CD3OD, 5): 153·7,151·7,125·5, 116·5,112·5,111·3,54·9,54.7,39· 4,28·5 ; IR (KBr) ·· 3413,2965,2904,2830,2757,2653,2055 ' 1612,1504,1226,1041 cnf1 ; MS-FAB (m/z) ·· 182 (Μ+- α,100),165 (76),152 (19), 150 (25); HRMS-FAB (m/z): The calculated value of [M+_C1] for C10H16NO2 is 182.1181; the measured value is 182.1177. Comparing with the physical properties of 5d, it can be known that 5d and 5, which only replace six hydrogens, have similar physical properties.

δ (2C-H); R = CH3 5ci {2C-H-de); R = CD3 R0rv^_ h_ ROyv^_3+cr !i^B): R = CH3 6*HC1 (2C.B.HCI} :R^CH3 6d {2C-B-de): R C03 6d*HCI i2C-B-d6-HCI): R = CD3

2_(2,5-Bis(tridecyloxy)phenyl)ethylamine (15 g, 8 〇mm〇1) was dissolved in glacial acetic acid (2.5 mL), and bromine was added (a43 mL, 84 mm 〇1) a solution of acetic acid (2.5 mL). After a few minutes, a solid is generated and exothermed, the reaction is returned to room temperature, filtered and washed with a cool acid, the solid is dissolved in hot water, and the aqueous sodium hydroxide solution is added to make the system alkaline. (At least 1) 11 丨)), extracted with dichlorohydrazine, and concentrated to obtain the product, the secret product of the product, genus phenyl] ethylamine, the structural formula of the above code & For the 2C-B-d6 'subsequent oxidative column chromatography minus, the product obtained 27 is 200808681 2_[4'-2,5-bis(trimethyleneoxy)phenyl]ethylamine hydrochloride, as the above code It is a structural formula of 6d HC1, 〇50 g, 1.9 mmol), and the yield is 24%. (If the starting material is 5, the product 厶(4-bromo-2,5-dimethoxyphenyl)ethylamine hydrochloride can be obtained as the above formula 6 · HC1, yield 40%). Physical properties of the compound containing 2-(4-[2-, 2-bis(trimethyloxy)phenyl]ethylamine, 4 NMR (300 MHz, CD3Q, δ) : 7.02 (s, 1H) , 6.74 (s, 1Η), 2.93 (t, J = 6.9 Hz, 2Η), 2·74 (t, J = 7·2 Hz, 2Η); 13 CNMR(75 MHz, CD3C1, 5): 151.9 , 149.6, 1128.3, 115.7, 10 115.0, 1108.7, 56.3-54.8 (m), 42·0, 31.9; IR (KBr): 3367, 2938, 2854, 2217, 2129, 2071, 1581, 1492, 1488, 1392, 1106 cm-1 ; Electron Impact Mass Spectrometry, hereinafter abbreviated as MS-EI (m/z) ·· 267 (16, 81Br), 265 (17,79Br), 250 (12), 248 (12), 238 (91) , 236 (100), 157(3); HRMS-EI (m/z): The calculated value of [M+] for C1()H8D679BrN02 is 265·0578; the measured value is 265.0580. Physical properties of -(4-bromo-2,5-dioxaxyphenyl)ethylamine hydrochloride" NMR (300 MHz, D20, δ): 7.16 (s, 1 Η), 6.87 (s, Η), 3.69 (s, 3Η), 3.66 (s, 3Η), 3·10 (t, J = 6·9 Hz, 2Η), 2.85 (t, J = 6.9Hz, 2H); IR (KBr): 2938, 2900 , 2842, 2692, 2040, 1604, 1500, 1388, 1207 cm -1 ; 28 200808681 M S-FAB (m/z) ·· 262 (M+-C1,43),260 (48),245 (92), 243 (100),230 (70),228 (65),215 (28),213 (25), 165 (52), 164 (58); HRMS-FAB (m/z): calculated value of [M'Cl] of C1()H1579BrN02 is 260.0286; measured value is 260.0282. From the above 6 · HC1 and A comparison of physical properties of 6d reveals that 6d, which replaces only six hydrogens, has similar physical properties to 6·HC1.

Cr'J,, 〇R 5 HC! (2C-H*HCi): R = CH3 7.HCI (2C heart HCI): R = CH3 5d HCI {2C-H-drHCJ}; R ^ 〇D3 7d*HCi {2C*C-drH€i): R-CD3 Dissolve 2-(2,5-bis(trimethyleneoxy)phenyl)ethylamine hydrochloride (0.90 g, 4.0 mmol) in an ice bath In glacial acetic acid (8. 〇mi), it is intensely disturbed and slow

f Ai drops plus chlorinated sulfuric acid (SUlf\jjyl chl〇ride, §Q2C12, 〇5, 6 Q _〇1) ' - It is necessary to make the whole (four) system lower than the thief's reaction, initially there will be sediment production, and later After being clarified, the mixture is scrambled at room temperature and then tlc Ok for about 3 hours. After the reaction is completed, the reaction mixture is added with an equal amount of diethyl ether, and then precipitated, and the mixture is further stirred at room temperature for 30 minutes. The solid is filtered, the solid is used, and /(10) is recrystallized to obtain the product 2-[4-chloro-2,5-bis(--methylmethyloxy)phenyl]ethylamine hydrochloride, as described above. Zhuang 2C-C-d6, 030g,, 2mm〇1^i29%: = the starting material is 5 ', then the product m5_dioxaxyphenyl] can be obtained. The human & female, as described above, has a structural formula of 7 The rate is 47%). Physicochemical substance 2_[4_chloro-2,5_bis(trimethyloloxy)phenyl]ethylamine hydrochloride 29 200808681 Physical properties of salt "HNMRP (8) MHz, D20, 5): 6.96 (s, 1 Π) , 6.85(s, 1Η), 3.08(t, J = 6.7Hz, 2H), 2.87(t, J = 6.8Hz, 2H); 13CNMR(75MHz, CD3OD, δ) : 151·6,149·1,124.1 , 121.1, 115·2, 112.8, 39·2, 28·2; IR (KBr): 3422, 2935, 2900, 2225, 2071, 1496, 1454, 11 1400, 1222, 1095 cnf1 ; MS-EI (m/ z) : 223 (5,37C1),221 (15,35C1),194 (34), 192 (100),176 (10),174 (31),75 (17); HRMS-EI (m/z) : The calculated value of [M+] for C1()H8D635C1N02 is 221.1083; the measured value is 221.1081. "2-[4-Chloro-2,5-dimethoxyphenyl]ethylamine hydrochloride not conventionally substituted by hydrazine Physical Properties iHNMRpOOMHz, D20,5): 6.96 (s,1H),6·85 (s,1Η),3·69 (s,3Η), 3.65 (s,3Η),3.11 (t,J = 7.0 Hz, 2Η), 2.83 (t, J = 6.9Hz, 2H); 13CNMR (75MHz, CD3OD, δ) ·· 151·7,149.1,124·1, 121.1,115.2,112·8,55·9,55 · 2,39·2,28·2 ; IR (KBr): 3004,2935,2900,2846,2032 1604,1500, 1392,1211,1033 cnf1 ; MS-FAB (m/z) : 218 (M+-C1,36),216 (100),201 (29), 199 (85),185 (25),163 (5), 75(17); HRMS-FAB(m/z): The calculated value of [M+-C1] for C1()H1535ClN02 is 216.0791; the measured value is 216.0792. 30 200808681 From the above 7 · HC1 and 7d · HC1 The physical properties of the 7d · HC1 and 7 · Ηα have similar physical properties.

δ {2C m R = CH3 5d {2C-H-cie); R =: cd3

:R = CH: Sad: R = CD- Mix 2_(2,5-bis(trimethyloloxy)phenyl)ethylamine (tetra) with a coffee and phthalic anhydride (0.58 g, 3·9 mmol) To 13 (rc, dissolved in a clear liquid, solidified after several minutes of heating, purified by Siliegd column chromatography, ethyl acetate / hexane (EtOAc: Hexane = 1: 9) as mobile phase, yellow The product of the solid 2-{2-[2,5-bis(tridecyloxy)phenyl]ethyl}isoindole-1,3-dione, the structural formula of the above code 5ad, 〇59g, 1.86 Mmmol, yield 71%. (If the starting material is 5, the product 2_[2_(2,5-dioxaphenyl)ethyl]isoindole 4,3-dione can be obtained, as the above code 5a The structural formula, the yield is 50%). The physical properties of the ruthenium-containing compound ":^^^^ 氘 氘 氘 氘 氘 氘 氘 ^ ^ ^] mp : 109-110 °C ; NMR (300 MHz, CDC13, δ): 7.82-7.79 (m, 2H), 7.70-7.67 (m, 2H) ' 6.71-6.68 (m, 3H), 3·96 (t, J:=: 6 9

Hz, 2H), 2.99 (t, J = 7·1 Hz, 2H); 13C NMR (75 MHz, CDC13, δ): 168·2,153 3, 152.0,133·7,132·2,127.6,123.0 , 116.6, 112 6, 112.2, 111·1, 37·8, 29·7; • ' 31 200808681 IR (KBr): 3073, 2938, 2217, 2063, 1774, 1708, 1504, 1392, 1295 cm-1; MS-EI (m/z) : 317 (100), 170.2 (96), 160 (63), 157 (38), 77 (25), 75 (6); HRMS-EI (m/z) : C18HnD6N〇 The calculated value of [M+] of 4 is 317.1528; the measured value is 317.1533. Physical properties of "2-[2-(2,5-dimethoxyphenyl)ethyl]isoindole-1,3-dione" which are not substituted by deuterium mp : 110-111 〇C ; NMR (300 MHz, CDC13, δ): 7.82-7.79 (m, 2H), 7·70 face 7.67 (m, 2H), 6.71-6.68 (m, 3H), 3.96 (t, J = 6·9 Hz, 2H), 3.71 (s, 3H), 3·67 (s, 3H), 3.00-2.95 (t, J 27.0 Hz, 2H); 13C NMR (75 MHz, CDC13, δ): 168.2, 153.3, 152.0, 133.7, 132", 127.7, 123·0, 116.6, 112·3, 111.1, 55·7, 55·6, 37·9, 29·7; IR (KBr): 2989, 2935, 2830, 1770, 1708, 1612, 1392, 1357, 1226 cnT1 ; MS-FAB (m/z) : 312 (Μ+ + 1,96),311 (61),165 (100),151 (74),75 (65); HRMS- FAB (m/z): The calculated value of [M+] for C18H17N04 is 311.1153; the measured value is 311.1158. It can be seen from the comparison of the physical properties of 5a and 5ad described above that 5ad and 5a which replace only six hydrogens have similar physical properties.

513 : R = CH3 5b d: R = cq^ 5a : R = CH3 5ad: R = CD3 32 200808681 /itr 一· a '(dimethyloxy)phenyl]ethyl}isoindole-1,3 - Diketone (_ g ' 1.5 mmGl) is dissolved in glacial acetic acid (5 〇) in the pit, adding chlorine dissolved in acetic acid (10) 眺), 1 ,mmol), disturbing at 3〇c After an hour, pour the mixture into water (milk site). At this point, the solution is turbid in color, extracted 4 times with dichlorohydrazine, and washed with water sulfite _ (_g, Μ mmd). After concentration, it was purified by Silica gd column chromatography with ethyl acetate/hexane (5) 〇Ac:

HeXane=l: 1〇) is the mobile phase, which gives the product of yellow solid 2_{2_[4_iodo 2'5_bis(mono-indolyloxy)phenyl]ethyl}individually) The structural formula of the above code 5bd is '0.65 g' 1.5 mm and the yield is 95%. (If the starting material is 5a, the product 2_[2_(4_Moth-2,5-dioxaxyphenyl)ethyl]isoindole H3-dione can be obtained, the structural formula of the above code 5b, yield 91%). Physical properties of the compound "2-{2-丨4-硖-2,5-bis(trimethyleneoxy)phenyl]ethyl}isoindole-1,3·dione" mp : 154- 155 °C ; NMR (300 MHz, CDC13, δ): 7.82-7.79 (m, 2H), 7.72-7.68 (m, 2H), 7.15 (s, 1Η), 6·60 (s, 1H), 3 · 96 (t, J = 6·8 Hz, 2H), 2·99 (t, J = 7.0 Hz, 2H); 13C NMR (75 MHz, CDC13, δ) ················· , 127.8, 123·1, 121.4, 113.6, 83.6, 37.5, 29.6; IR (KBr): 3459, 3058, 2931, 2857, 2225, 2129, 2071, 1770, 1712, 1484, 1392 cm]. Physical properties of "2-[2-(4-iodo-2,5-dimethoxyphenyl)ethyl]isoindole-1,3-dione" which are not substituted by deuterium mp : 154-155 °C ; 33 200808681 4 NMR (300 MHz, CDC13, δ) ··············································· 58 (s,1H),3·93 (t,J = 6·9 Hz, 2H), 3.68 (s,3H), 3.67 (s,3H),2·97 (t,J = 6.9 Hz, 2H) 13CNMR (75MHz, CDC13,3): 168.1,152.5, 133.8, 132.0,127.8,123·8,121.4,113·6,83·3,57·0,56.0, 37.5^29.6 ; IR (KBr) : 2935 , 2846, 1770, 1712, 1496, 1392, 1349 ^ 1211 cm-1;

MS-FAB (m/z) ·· 438 (M+ + 1,14),311 (28),167 (17),75 (100); HRMS_FAB (m/z) : C18H16N04I [calculated value of M scoop 437.0124; measured value is 437.0123. From the comparison of the physical properties of the above 5b and 5bd, it can be known that 5bd which replaces only six hydrogens has similar physical properties to 5b.

HC!(g)

ΝΗ3"〇Γ 8.HCI (2C.|, HCi): R = CH3 Βύ Η〇\ (2C-l-drHCI): R = CD3 will be 2 to know 4-moth_2,5_dimethoxyphenyl) Ethyl]iso-H 3-3-dione (0.65 g, i.5 mmol) was dissolved in hot isopropanol and added to hydrazine (〇2, 53.9 mm· produced a clear liquid and heated at 1 〇〇t for several minutes) After that, a soft white milk solid will be produced. After stirring for 15 hours, the reaction = ^, : _ to solid, _ ethanol wash, the filtrate and the washing liquid are collected: -: shrink: to obtain yellow sticky The product of the liquid 2-[4 Lu A double emulsion) phenyl]ethylamine' has the structural formula of the above code 8d, the following 34 200808681 is abbreviated as 2C-I-d6, 0·45 g, 1.4 mmol, yield 98%. (If the starting material is 5b, the product 2-(4-iodo-2,5-dimethoxyphenyl)ethylamine hydrochloride can be obtained, as shown in the above formula 8 · HC1, hereinafter abbreviated as 2C4 , yield 91%). Physical properties of the cerium-containing compound "2-[4-iodo-2,5-bis(trimethyleneoxy)phenyl]ethylamine" NMR (300 MHz, CD3C1, δ): 7·20 (s, 1H) ), 6.66 (s, 1Η), 2.93 (t, J = 6·6 Hz, 2Η), 2.74 (t, J = 6·8 Hz, , 2H); 13C NMR (75 MHz, CD3C1/small CD3OD, δ ): 151.9, 151.8, 128.2, 120.9, 113·2, 82·0, 40.6, 33.19; IR (KBr): 2927, 2861, 2221, 2067, 1631, 1577, 1484, 1388, 1303, 1226 cm-1; HRMS-EI (m/z): Calculated for [M+] of C1()H8D6N02I: 313.0439; Physical properties of "2-(4-iodo-2,5-dimethoxyphenyl)ethylamine hydrochloride" which is not substituted by hydrazine 咕 NMR (300 MHz, D20, δ): 7.35 (s, 1H ),6·82 (s,Η),3·75 (s,3Η),3·72 (s,3Η),3·139 (t,J=7.0 Hz,2H),2·86 (t,J = 6·9 Hz, 2H); (Since NMR is not easily detected in the form of 2-(4-moth-2,5-dioxaxyphenyl)ethylamine hydrochloride, the data is changed to 2-( Form detection of 4-iodo-2,5-dioxaxyphenyl)ethylamine) 13C NMR (75 MHz, CD3OD, δ): 152.6, 152.3, 128/7, 121.3, 113·6, 82.1, 56· 0,55.2,40·9,32·8 ; IR (KBr) : 2954,2900,2753,2657,2553,2460, 2044,1662,1604,1492,1384,1211 cm-1 ; MS-FAB (m/ z) : 308 (Μ+-α,100),291 (91),276 (27),261 (19),218 (3); 35 200808681 HRMS-FAB (m/z) ·· C1()H15N02I The calculated value for [M+-C1] was 308.0147; the measured value was 308.0144. ... From the above physical properties of 8 · HC1 and 8d, it can be known that 8d which replaces only six hydrogens has similar physical properties to 8 · HC1.

CISO3H 2 : R = CH3 2d: R = CD3 ro\^^so2ci I! 1

x^'〇R 9 :R = CH3 9d: R = CD3

Under the open system, l, 4-bis(di-JTL methyloxy)benzene (6.00 g, 42 〇mmol) was dissolved in methylene chloride (37·8 mL), and chlorhexate was slowly added dropwise. CISO3H ' 22·33 mL ' 336.0 mmol) ' When half of the acid is added, a solid will be formed. If the solid is added continuously, the color of the solution is dark green liquid. When the total acid is added, the color of the solution becomes Dark red, stirring for 20 minutes, the mixture was slowly added dropwise to ice water, and after stratification, the gas extraction was carried out with two gas sulphur, and the sulphur extraction was carried out with a blue extract. After filtration and concentration, the Silicagel column chromatography was used to purify the acetic acid. g|/hexane (Εί〇Α^ : hexane = 1 : 9) is the mobile phase, which gives the product 2 of light yellow solid, bismuth (three said methyloxy) benzene stone yellow brewed chlorine, the structure of the above code is % Formula, 5 〇化, daughter-in-law mmd 'yield 50 〇 / 〇. (If the starting material is 2, the product 2,5-dioxabenzoquinone chloride, as shown in the above formula 9, yield 51%) can be obtained. Containing the compound ‘‘2,5-bis(tridecyloxy)benzene), 〇 m.p. : 119-120〇C ;

Hz, = 9.1 H NMR (300 MHz, CDC13, δ): 7·46 (d, j : 1H) ’ 7.25 (dd ′ J = 9·1 Hz, 3·1, 1H), 7 〇7 〆

Hz,1H) ; U 36 200808681 13C NMR (75 MHz, CDC13, δ) : 152·6,151·5, 131·8,123.8,114.7,113.4,56·5-54·7 (m); IR ( KBr): 3120, 3061, 2236, 2078, 1571, 1495, 1414, 1365, 1230, 1172, 1100 cnT1. Physical properties of "2,5-dioxabenzene chlorohydrazine" which has not been replaced by hydrazine mp: 120-121〇C; 咕NMR (300 MHz, CDC13, δ) ·················· 3·6 Hz, 1H), 7·25 (dd, J 2·9 Hz, 3.2, 1H), 7·08 (d, J = 9·2 Hz, 1H), 4.01 (s, 3H), 3 · 77 (s, 3H); 13C NMR (125·7 MHz, CDC13, δ): 152.6, 151.5, 131.8, 123.8, 123.8, 114.8, 113.3, 56·9, 56.13; IR (KBr): 3120, 3106, 3074, 3017, 2971, 2944, 2841, 1405, 1365, 1230, 15 1167 cm·1. It can be seen from the comparison of the physical properties of 9 and 9d described above that 9d and 9 which only replace six hydrogens have similar physical properties.

Age 丫~Zn, HCI CLor — 9 :R = CH3 MR = CD3 In the open system, 25% sulfuric acid (22·4 rnL) is placed in a beaker, 2'5 bis (two mouse methyl oxy) benzite yellow The brewing gas (5·〇〇g, 20.0 mmol) was added to heat at 100 ° C, and zinc powder (6 74 g, 103 Ommol) was slowly added, and all the zinc powder was added, 1 (8). After heating at C for 1 hour, it was cooled to room temperature, and the solution was filtered over celite, and the solid was washed with diethyl ether. The aqueous layer was extracted with diethyl ether. The extract of the organic layer was dried over anhydrous magnesium sulfate. Purification by column chromatography 'Acetyl acetate / hexane (EtOAc : Hexane = 1 : 19) as mobile phase to give the product as a yellow liquid 2,5-bis(tridecyloxy)benzenethiol, 37 200808681 It is a structural formula of 10d, 2.53 g, 14.4 mmol, and a yield of 72%. (If the starting material is 9, the product 2,5-dioxaxybenzenethiol, the structural formula of the above code 10, yield 71%) can be obtained. Physicochemical properties of 2,5-bis(trimethyloloxy)benzenethiol containing 4 ° NMR (300 MHz, CDC13, δ): 6.84 (d, 2.9 Hz, 1H), 6 ·78 (d, J two 8.9 Hz, 1 Η), 6.65 (dd, Bu 8·9, 2·9 Hz, 1H), 3·88 (s, 1H); 1 o C NMR (75 MHz, CDC13 , δ) : 153·2, 148.5, 121.2, 114.4, 111·1, 11〇·8, 52.2-53.9 (m); IR (KBr): 3160,3066,3034,2572,2249,2222, 2128,2070 , 1598, 1585, 1485 cnT1 ; MS-FAB (m/z) : 177 (M++1, 35), 176 (100), 144 (73), 115 (22); HRMS_FAB (m/z) : C8H4D602S The calculated value of [M+] is 176.0772; the measured value is 170.0775. The physical properties of "2,5-dimethoxybenzenethiol, which is not substituted by deuterium, NMR (300 MHz, CDCI3, δ): 6.84 ( d, J = 3.0 Hz, 1H), 6·79 (d, J = 8.9 Hz, 1H), 6.66 (dd, J = 8·9, 3·0 Hz, 1H), 3·90 (s, 1H) , 3.84 (s, 3H); 13C NMR (75 MHz, CDC13, δ): 153.7, 149.0, 121.8, 114.9, 111·6, 110·9, 56.2, 55·5; IR (KBr): 3061,3003, 2949, 2832, 2567, 2487, 1598, 1593, 1585, 1495, 1463, 1446 cm]; M S-FAB (m/z) : 171 (M++1,32),170 (100),138 (76),109 (76); HRMS-FAB (m/z): Calculation of [M+] of C8H10O2S The value is 170.0402; the measured value is 170.0396. It can be known from the comparison of the physical properties of 10 and 10d above that only 38 200808681 six hydrogens of l〇d have similar physical properties to ι〇.

忉: R = CH3 10d: R rr CD3

RO 11 :R di CH3 11d; R = CD3 Potassium hydroxide (〇·89 g, 15·8 mm〇1) was dissolved in ethanol (21 mL) and 2,5-bis(di-methyloxy)benzene was added. A solution of mercaptan (2 53 §, 14 41 ^ Fu) in ethanol (14.5 mL), followed by the addition of ethyl bromide (215 mp, 8 mmol), then a white precipitate, which was refluxed for 15 hours at 1 〇〇〇c. The reaction was followed by TLC, water was added to 45 mL, acidified with hydrochloric acid, and the mixture was extracted with dichloromethane, and then washed with 5% NaOH. The extract was dried over anhydrous magnesium sulfate, filtered, and purified by silica gel column chromatography. Ethyl acetate / hexane (EtOAc : Hexane = 1 : 49) is the mobile phase, the product of the yellow liquid is 2-ethyl-p-aminophenylsulfonyl-indole, 4-bis(trimethyleneoxy)benzene, as the code is The structural formula of lid, 2.81 g, 13·7 mmd, yield 95%. (If the starting material is 10', the product 2-ethyl-plycosyl-1,4-dioxobenzene, as shown in the above formula 11, yield 79% can be obtained. Physical properties of the cerium-containing compound "2-ethyl-p-aminophenyl hydrazine_1, winter bis(trimethyloloxy)benzene, A NMR (300 MHz, CDC13, δ): 6·82 (d, J = 2.9 Hz, 1H), 6·77 (d, J = 8·8 Hz, 1H), 6.68 (dd, J = 8.8, 2.9 Hz, 1H), 2·95 (q, J = 7·4 Hz , 2H), 1·35 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDC13, δ): 153.8, 151.2, 126.3, 114.9, 111·1,110·5, 56.0-54.3 (m ),25·8,13·9 ; IR (KBr) : 3072,3034,2965,2968,2872,2212, 39 200808681 1481,1477 cm]; MS-FAB (m/z) ·· 205 (M++ 1,43), 204 (100), 175 (6.5), 75 (11); HRMS-FAB (m/z): The calculated value of [M+] for C1()H8D602S is 204.1085; the measured value is 204.1085. Physical properties of "2-ethyl-p-aminophenylsulfomethoxybenzene" which was not substituted by deuterium 4 NMR (300 MHz, CDC13, δ): 6.83 (d, J = 2.9 Hz, 1H), 6.78 ( d, J = 8·8 Hz, 1H), 6·69 (dd, J = 8·8, 2.9 Hz, 1H), 3.88 (s, 3H), 3·77 (s, 3H), 2·90 ( q, J = 7.4 Hz, 2H), 1.35 (t, J = 7.4 Hz, 3H); 13C NMR (125.7 MHz, CDC13, δ): 153·8, 151.2, 126.3 , 114·9, 111.1, 11〇·2, 56·2, 55·7, 25·7, 13·8; IR (KBr): 3056, 2958, 2937, 2834, 1490, 1463, 1405 cm·1 ; MS-FAB (m/z) : 199 (Μ++1,23),198 (33),169 (19) ^ 75.3 (100); HRMS-FAB(m/z): Calculated for [M+] of C10H14O2S It is 198.0714; the measured value is 198. 〇 714. It can be known from the comparison of the physical properties of 11 and lid above that lids which replace only six hydrogens have similar physical properties to 11 . r 〇 TVSC2H5 (10) F ~ ρ 〇〇ζ 11 : r = c:h3 11d: R = cd3

12d: R = CD3 Phosphorus oxychloride (P0C13, 3.08 mL, 39·8 mmol) and dimercaptocarboxamide &amine (DMF'3.1 mL, 33 3 mm 〇1) were placed at 1 Torr. The hydrazine is heated to reflux, and then 2-ethyl-p-amine albendamine is added from bis(tris-decyloxy)benzene (:heart, 40 200808681 13·3 mmol), and then heated for 2 minutes, and the solution is poured. Preheated to 55 C stirred water, stirring was continued for 15 hours, at which time the oil became solid, filtered and washed with water. The solid was dissolved in ethyl acetate and dried with anhydrous squash. Purification by Silicagel column chromatography eluting with ethyl acetate / hexane (EtOAc: Hexane 2: 19) as the mobile phase to give the product as a white solid. 4-ethyl-amine acesulfonyl-2,5-bis (triterpene) Benzoyloxy)benzaldehyde, as described above under the designation 12d, 2.90 g, 12.5 mmol, yield 94 0/〇. (If the starting material is 11 ', the product 4-ethyl-plycosyl-yl-2,5-dioxaxybenzaldehyde, as shown in the above formula 12, yield 79%) can be obtained. Physical properties of the cerium-containing compound "4-ethyl-p-aminophenyl- 2,5-bis(trimethyloxy)benzaldehyde, mp: 85-86 °C; 4 NMR (300 MHz, CDC13, δ) : 10.35 (s,1Η), 7.24 (s,1H),6·76 (s,1H),3.03 (q,J = 7·4 Hz, 2H), 1.44 (t, 7.4 Hz, 3H) 13C NMR (75 MHz, CDC13, δ): 188.8, 156.9, 150.0, 137.6, 121.2, 109.0, 107.2, 55·9_54·8 (m), 25.0 ^ 13.3 ; IR (KBr) : 3120,3066,3039, 2967,2927,2869, 2231,2208,2123,2069,1660,1594,1477 cirf1 ; MS_FAB (m/z) : 233 (M++1,100),232 (44),204 (2),203 ( 3) ' 75 (15); HRMS-FAB (m/z) : The calculated value of [M+] of CnH8D603S is 232.1034; the measured value is 232.1040. "4-ethyl-p-aminobenzenesulfonyl which is not substituted by deuterium" -2,5-Dimethoxybenzaldehyde'' physical properties mp· : 87-88〇C ; 41 200808681 4 NMR (300 MHz, CDC13, δ) : 10.35 (s,1H), 7·24 (s, 1H),6·76 (s,1H),3·91 (s,3H),3.88 (s, 3H),3.03 (q,J = 7.4 Hz, 2H), 1.44 (t, J 7.4 Hz, 3H ); 13C NMR (125 MHz, CDC13, δ) 188.5, 156.8, 150.0, 137.5, 121.3, 109·1, 107.3, 56·1, 25.0, 13.2; IR (KBr): 3074, 3052, 3030, 2971, 2936, 2873, 2756, 1656, 1589, 1482, 1396 Cnf1 ;

MS-FAB (m/z) : 227 (M++1,100),226 (23),198 (3),197 (6),166 (2),165 (2),75 (11); HRMS The calculated value of [M+] for -FABCm/zV.CuHHOsS is 226.0663; the measured value is 226.0674. From the comparison of the physical properties of the above 12 and 12d, it can be known that 12d and 12, which only replace six hydrogens, have similar physical properties.

RO OHC

)D

.SC2H5 "OR CH3N02 RO 丫〆, /Ί / N02 C2H5S

4-Ethyl p-aminobenzenesulfonyl 2,5-dioxabenzoquinone (28 g, 12 mmol) and nitrodecane (22 9 g, 420.0 mmol) were placed in a round bottom flask. Anhydrous ammonium acetate (catalytic amount), (10). After refluxing for a few minutes, tlc chased I until the reaction was over, and the filtrate was concentrated to give an orange-red crystal = 1 - ethyl p-Amphetamine - 2, 5 - bis (three decyl oxy-M) (2_ Lin-based vinyl) benzene, as described above, has a structural formula of 13d, 3.15 g, 11.4 mmol, yield 95%. (If the contact is 12, it can be obtained as an anthracene [ethyl-p-propylamine-based 2'5 Methyloxy_4_(2-nitrovinyl)benzene, the structural formula of the above code D, 97%). 42 200808681 The ruthenium containing compound "1-ethyl-p-aminophenylsulfonyl-2,5· Physical properties of bis(trimethyleneoxy)-4-(2-nitrovinyl)benzene mp : 153-154 ° C ; 4 NMR (300 MHz, CDC13, δ) : 8.14 (d, J 2 13 · 5 Hz, 1 Η), 7·86 (d, J 2:13 Hz, 1 Η), 6.82 (s, 1 Η), 6.76 (s, 1H), 3.03 (q, J 7.4 Hz, 2H) , 1.42 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDC13, δ) ··· 154.3,150.2, 137.1,135.2,134.3,115.4,112.1,109.5,56·1-55·0 (m ),25·3,13·5; IR (KBr): 3097,2975,2931,2227,2069,1612,1594,1490,1413,1342,1247,1226 cm·1 ; MS-FAB (m/z ) : 276 (M++1,3),257 (2),247 (2), 217 (7),215 (3),75 (100),74 (17); HRMS-FAB (m/z) : The calculated value of [M+] for C12H9D6N04S is 275.0109; the measured value is 275.1104. "1-ethyl-p-aminophenyl-transyl-2,5-dimethyloxy-4-2-nitro" Physical properties of ethylene benzene" mp: 152-153 〇C; 咕 NMR (300 MHz, CDC13, δ) ·· 8.14 (d, Bu 13·5 Hz, 1 Η), 7.85 (d, J = 13·5 Hz, 1Η),6·83 (s,1Η), 6.78 (s,Η),4·32 (s,1H),3·93 (s,3H),3.88 (s, 3H), 3.00 (q,J = 7·4 Hz, 2H), 1.42 (t, J 7.4 Hz, 3H); 13C NMR (125·7 MHz, CDC13, δ): 154.3, 150.3, 137.1, 135.2, 134.2, 115.5, 112·2, 109 · 5,56·4, 56],25·3,13·5; IR (KBr): 3097,2975,2937,2832,1616,1594, 1494,1440,1400,970 cm·1 ; 43 200808681 MS- FAB (m/z): 270 (M++1,13),254 (11),241 (9), 197 (5),133 (29),75 (100); HRMS-FAB (m/z) : The calculated value of [M+] for C12H15N04S is 269.0721; the measured value is 269.0728. From the comparison of the physical properties of the above 13 and 13d, it can be known that 13d and 13 which only replace six hydrogens have similar physical properties. Α〇γ^^Ν02Α|Η3 R0 c2h5sJ, ^Sdr c2h5s

NHo R〇, ‘HC_ c2h5s"

OR 焉+cr 13 : R =: CH3 13d: R = CD3;

G. 54 mL of fuming sulfuric acid was slowly added to the anhydrous tetrahydroanthracene (2·20 g, 58·0 mmol) containing gasified I(R) under argon at 〇 °C (thf, 934)

mL) Suspended in the ocean solution (note! At this time, the container may spark, need to carefully add fuming sulfuric acid). Stir for about 丨min, then slowly add 1 in tetrahydrofuran (44.8 mL). -ethyl-p-aminophenylsulfonyl-2,5-bis(trimethyleneoxy(4)2-shidocylvinyl)benzene (3.15 g, H.4 m_, _ chick for about 5 minutes, New at room temperature for 丨 hours After that, the temperature was raised to Xian C and stirred for another 30 minutes. The water was slowly added dropwise (2 4 and tetrachlorine (11.6 mL), and the reaction was stopped with aqueous solution of water and aqueous solution. Soil filtration, wash with THF to fluffy, concentrate the filtrate, dilute with sulfur-water, take care of the water, and then dilute the water, after the second gas layer is concentrated, The product obtained 2 pieces of ethyl methyloxyguanamine, the structure i of the above code (4), the following = 2C-T_2-d6, the product 14d acid salt was recrystallized and purified, and the product 44 200808681 was dissolved in ether ( In 50眺), the hydrochloric acid gas is blown. At this time, the reaction bottle has been solidified and settled for several minutes. After a few minutes, it is left to stand for a few minutes. The mixture is _transformed and recrystallized with I alcohol/ice to obtain the product 2_[4_B The crystal of bis(dimethyloxy)phenyl]ethylamine hydrochloride is exemplified by the above formula. The structural formula of HC1 is hereinafter referred to as 2_Cnd6 · Hci, 2 i7 g, 7 k. 67%. (If the starting material is 13, the product 2_(4_ethyl to the private stone?, yl 2,5-monooxyphenyl) ethylamine hydrochloride can be obtained, as the above code is 14·Ηα The structural formula, hereinafter abbreviated as 2-C-T_2.HCl, yield 79%). The ruthenium-containing compound "2-丨4-ethyl-p-aminobenzene cyclinyl-2,5-bis(trimethyleneoxy) Physical properties of phenylethylamine hydrochloride H NMR (300 MHz, D20, δ) ····································· , Bu 7·1 Hz, 2Η), 2·88-2·81 (m, 4Η), 1·16 (t, J = 7.3 Hz, 3Η); 13 C NMR (75 MHz, D20, δ): 151.7 , 151·0, 124.0, 122.8, 114·3, 113.4, 55.9-55.4 (m), 39.6, 27.8, 26·2, 13.3 ; IR (KBr): 2956, 2904, 2751, 2657, 2555, 2061, 2048 , 1608, 1486, 1400, 1226, 1059 cm·1 ; MS_FAB (m/z): 248 (M+-a, 95), 233 (8), 231 (100), 218 (32), 217 (14), 75 (6); HRMS-FAB (m/z) : calculated value of [M+-C1] of C12H14D6N02S 248.1585; measured value is 248.1597. Physical properties of "2-(4-ethyl-p-aminophenylsulfo-2,5-dioxaxyphenyl)ethylamine hydrochloride" which is not substituted by deuterium 4 NMR (300 MHz, D20, δ) : 6·90 (s, 1H), 6.83 (s, 1H), 3.72 (s, 6H), 3.13 (t, J = 7·2 Ηζ, 2Η), 2·88·2·80 (m, 4H) , 1.15 (t, J = 7·4 Hz, 3H); 45 200808681 13C NMR (125·7 MHz, D20, δ): 151·8, 151.1, 124.1, 122·8, 114.4, 113·6, 56· 4,56·1,39·6,27.7, 26.2 ^ 13.3 ; IR (KBr) : 3214,2958,2900,2751,2657,2042, 1608,1500,1463,1386,1207 cm]; MS-FAB (m /z) : 278 (Μ++1,1),244 (6),242 (100), 212 (15),211 (8),75 (36); HRMS-FAB(m/z):C12H2〇 The calculated value of [M'Cl] for N02S is 242.1214; the measured value is 242.1218. From the physical properties of the above 14 · HC1 and 14d · HC1, it can be seen that 14d.HCl, which only replaces six hydrogens, has similar physical properties to 14.HC1.

RO

C3H7Br 10 :R-CHa 10d: R ^ CD3 RO. .^^SC3H7L^or 15:R:CH3 15d:R = CD3 sodium hydroxide (0.42 g, 7.4 mmol) is dissolved in ethanol (9.2 (7) butyl), Add 2,5-bis(trimethyleneoxy)benzenethiol (U9g, 6.8mm〇i) in ethanol (6.92 mL), then add bromopropane (1.23 mL, 13.5, white precipitate, 100 After refluxing for 1.5 hours at °c, the solution layer was subjected to TLC to trace the reaction. Water was added to 30 mL, acidified with hydrochloric acid, extracted with dichlorohydrazine, and the organic layer was washed with 5% sodium hydroxide. The extract was dried over anhydrous sulfuric acid and filtered. After concentration, it was purified by silica gel column chromatography eluting with ethyl acetate / hexane (EtOAc: Hexane = 1 : 19) as the mobile phase to give the product 1,4-bis(trimethyleneoxy) propylene as a yellow liquid. Sulfonamide, as described above under the symbol i5d, has the structural formula '1.43§'6.6111111〇1, yield 97%. (If the starting material is 1〇, 46 200808681, the product 1,4-dimethoxy-2-propyl stone can be obtained. Xylamine benzene, the structural formula of the above code a, yield 84%). Physical properties of the cerium-containing compound "1,4-bis(trimethylenemethyloxy)-2-propylsulfonamide, 4 NMR (300 MHz, CDC13, δ): 6.82 (d J = 2·9 Hz, 1Η), 6·77 (d, J = 8·8 Hz, 1Η), 6.67 (dd, J = 8.8 Hz, 3·0, 1H), 2·88 (t, J 2 7·2 Hz, 2H), 1·73]·66 (m, 2H), 1·〇6 (t, Bu 7·4 Hz, 3H); 13C NMR (75 MHz, CDC13, δ): 153.8, 151.3 , 126·6, 114.9, 111·b 110.4, 55·7-54·5 (m), 33·7, 22.2 ^ 13.6; IR (KBr): 3070, 3033, 2958, 2927, 2869, 2246, 2215, 2069,1589,1481,1280,1222,1106 cnT1 ; MS_FAB (m/z) : 219 (M++1,56),218 (100),204 (6),191 (14),176 (15), 144 (44); HRMS-FAB (m/z): calculated value of [M+] for CuHkjDWA 218.1242; measured value 218.1257. "1,4-Dimethoxy-2-propylsulfonamide not known by hydrazine" Physical properties of benzene" NMR (300 MHz, CDC13, δ): 6·82 (d, 2.9 Hz, 1 Η), 6.77 (d, J = 8·8, 1H), 6, 68 (dd, J = 8·8,2·9 Hz, 1H),3·77 (s,3H),3·70 (s,3H),2·88 (t,J = 7.4 Hz, 2H),1.75-1.63 (m, 2H), 1.06 (t, 7.4 Hz, 3H); 13C NMR (125.7 MHz, CDC13, δ): 153·8, 151.2, 126·6, 114·9, 111.1, 110·1, 56·3, 55 .7,33.7,22·2 ' 13.5 ; IR (KBr) : 2994,2958,2937,2873,2832,1589, I486 , 1463 , 1405 , 1274 , 1220 , 1047 cnf1 ; MS-FAB (m/z) : 213 (Μ++1,100),212 (37),197 (19),183 (20),169 (33), 138 (86); 47 200808681 HRMS-FAB(m/z): CuH1602S [M+ The calculated value was 212.0871; the measured value was 212.0869. From the physical properties of 15 and 15d above, it can be known that 15d and 15 which replace only six hydrogens have similar physical properties.

DfvlF POCl3 15 : R = CH3 15d: R = CD3

RO OHC

/ W, OR 16 :R=CH3 16d: R = CD3 oxalate (POCl3 ' 1.39 mL, 14.9 mmol) and dimercaptoamine (U9 mL, 18.0 mmol) in l〇〇t : heating under reflux, and then adding 1 '4-bis(dihydromethyloxy)-2-propyl schaffaamine benzene (1·3 g, 6·〇mmol), and then heating for 20 minutes, the solution is poured into Preheat to 55 stirring water, continue to stir for 1.5 hours, at which time the oil becomes solid, filter and wash the solid with water, dissolve the solid with ethyl acetate, dry over anhydrous magnesium sulfate, filtered and concentrated to Silica gel Purification by column chromatography, ethyl acetate / hexane (EtOAc: Hexane = 1 : 19) as mobile phase to give the product as a pale yellow solid 2,5-bis(trimethyleneoxy) propyl sulfonamide Formaldehyde, as the code name for the ship's structural formula, Hg, u mm 产率 yield Hong%. (If the starting material is 15, the product 2,5-dimercaptooxypropyl sulfonamide benzaldehyde, the structural formula of the above code 16 is obtained, the yield is 84%). Antimony-containing compound "2,5-bis(trimethyleneoxypropylsulfonamide benzaldehyde, physical property W mp: 82-83〇C; 4 NMR (300 MHz, CDC13, δ): 1〇·35 ( s,, 7·24 (s,1H),6·76 (s,1H),2·96 (t,J = 7·2 Hz, 1.82-1.75 (m,2H), 1.12 (t, J = 7.4 Hz,3H); 48 200808681 13C NMR (75 MHz, CDC13, δ) ·· 188·6,156.9, 150.1,137·8,121·3,110.4,107.3,56·0-55·2(ιη), 32·9,21·7,13·6; IR (KBr): 3037,3035,2964,2927,2859,2221, 2069,1670,1589,1481,1405,1267,1226 cm·1 ; MS-FAB ( m/z) : 247 (Μ++1,100),246 (38),133 (10),75 (6),43 (4); HRMS-FAB ·· C12H1()D6 02S of [M+] The calculated value is 246.1190; the measured value is 246.1195. The physical properties of "2,5-dimethyloxy-4-propylsulfonamide benzaldehyde" which has not been replaced by deuterium mp· : 78-79〇C ; 屮 NMR (300 MHz, CDC13, δ) ·· 10.39 (s,1H), 7·24 (s,1Η), 6.90 (s,1Η),3·89 (s,3Η),3·88 (s, 3H), 2.96 (t, J = 7·3 Hz, 2H), 1.85-1·72 (m, 2H), 1.12 (q, J = 7.3 Hz, 3H); 13C NMR (125 MHz, CDC13, δ) ·· 188.6,156.9, 150.1,137.8,121.3,109.1,1〇7·3,56·2,32.9,21.7, 13.6; IR (KBr): 3071,3047,3017, 2963, 2927, 2855, 1670, 1593, 1485, 1472, 1396, 1212 cnf1 ; MS-FAB (m/z): 241 (M++1, 54), 240 (7), 225 (2), 133 ( 48), 75 (100), 43 (2), 29 (31); HRMS-FAB ·· C12H16〇2S The calculated value of [M+] is 240.0820; the measured value is 240.0822. From the physical properties of 16 and 16d above, it can be seen that 16d and 16 which only replace six hydrogens have similar physical properties. 49 200808681

RCX

OHC

Sc3h7 CH3fsj〇, C3H7S,

RD

17 : R = CH3 17d: R : CD3 16 :R=CH3 16d: R = CD3 2,5_bis(trimethyleneoxy)+propylsulfonamide benzaldehyde (126g, 51 mmol) and nitropyr (9.7 mL, 180.0 mmol) was placed in a round bottom flask, anhydrous ammonium acetate (catalytic amount) was added, and refluxed for 1 hour at 100 t: the solution layer was traced by TLC until the end of the reaction, and the reaction mixture was concentrated to give a yellow crystal. , 4-bis(trimethyleneoxy)_2_(2-nitrovinyl)_5-propylsulfonyl female, the above formula is 17d, 1.41 g, 4.9 mmol, yield 95%. (If the starting material is 16, the product 丨, 4• dimercaptooxy-2-(2-nitrovinyl)-5-propyl schaffaamine benzene, the structural formula with the above code π, yield 99 %). Physical properties of the cerium-containing compound "1,4-bis(trimethyloloxy)-2-(2-nitrovinyl)-5-propyl- propylamine" mp : 12M22〇C ; 4 NMR (300 MHz , CDC13, δ) : 8.14 (d, J = 13.5 Hz, 1H), 7.85 (d, Bu 13.6 Hz, 1H), 6·82 (s, 1H), 6·76 (s, 1H), 2.96 (t, J = 7·2 Hz, 1H), 1.83-1.71 (m, 2H), 1.11 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDC13, δ): 154.3, 150·2 , 136·9, 135.2, 134·6, 115.3, 112·0, 109.3, 56.1-54.7 (m), 33”, 21·9, 13·6; IR (KBr): 3142, 2967, 2940, 2070, 1616,1602, 1553,1490,1387,1342,1275,1239,1100 cnf1 ; MS-FAB (m/z) : 290 (MM,46),289 (12),274 (46),260 (8), 246 (19), 244 (100), 218 (12), 43 (46); 50 200808681 HRMS-FAB (m/z): The calculated value of [M+] for C13HnD6N04S is 289.1248; the measured value is 289.1250. Physical properties of "1,4-didecyloxy-2_(2_thyl vinyl)-5-propylsulfonamide" which is not replaced by hatred mp: 120-121; 咕 NMR ( 300 MHz, CDC13, δ): 8.14 (d, J 23.5 Hz, 1H), 7·86 (d, J 23.5 Hz, 1H), 6·82 (s, 1H), 6·76 (s, 1H ), 3.88 (s, 3H), 3·85 (s, 3H), 2.96 (t, J 2 7.3 Hz, 2H), 1.81-1.69 (m, 2H), 1.11 (q, J 27.4 Hz, 3H); 13C NMR (125.7 MHz, CDC13, δ): 154.3, 150.2, 137.0, 135.2, 134.5, 115.3, 112·1, 109.4, 56·3, 56·0, 33·1, 21·8, 13· 6 ; IR (KBr) : 3142,3012,2971,2936,1620,1602, 1553,1495,1382,1338,1221 cm-1 ; MS-FAB (m/z) : MS_FAB (m/z) : 284 ( Μ++1,21),268 (25),239 (29),238 (100),225 (50),43 (54); HRMS-FAB (m/z) : Calculated value of [M+] of C13H17N04S It is 283.0878; the measured value is 283.0889. It can be known from the physical properties of 17 and 17d described above that 17d and 17 which only replace six ruthenium have similar physical properties.

17 :R = CH3 17d: R = CD3

Nh2 HCi(g) NH3+Cr

18 {2C«T-7): R = CH3 18«HC1 (2C-T-7-HCI): R = CHs 18d {2C-T-7〇: R = CDs 18d-HCI {2C-T-7- drHCi): R = 〇〇3 Slowly dilute sulfuric acid (〇.5〇mL) into anhydrous tetrahydrofuran containing hydrogenated lithium (0.77 g, 20.0 mmol) under argon at 〇C (2〇·ΐ5 mL) ) Suspension 51 200808681 In the floatation solution, slowly add Μ-bis(trimethyleneoxy)_2 valent vinyl group in the tetrahydrofuran (7·5〇) at room temperature. Sulfonamide benzene G · 3 〇 g ' 4 · 5 mmol), followed by 8 (reflow under rc for 10 hours, the reaction was terminated with sodium hydroxide water / gluten solution and isopropanol (3 · 32 mL), the solution was stone The mixture was filtered with celite, and the solid was washed with tetrahydrofuran, isopropanol and diethyl ether until fluffy. After the filtrate was concentrated, the aqueous solution was acidified with dilute sulfuric acid, and extracted twice with dichloromethane, and then the aqueous solution was made alkaline. After extracting three times with dichloromethane and concentrating the organic layer, the product 2-[2,5-bis(tridecyloxy)- 4-propylsulfonylphenyl]ethylamine, as shown above, 18d, was obtained. Formula, hereinafter abbreviated as 2CHd6, the product 18d is made into the hydrochloride salt and recrystallized and purified, and the product 18d is dissolved. In the ether (5〇mL), the hydrochloric acid gas is blown. At this time, the reaction bottle has been solidified, and the mixture is stirred for several minutes, and then left to stand for several minutes. The solid is filtered and recrystallized with methanol/diethyl ether to obtain the product 2_[ Crystal of 2,5_bis(trimethyleneoxy)_4-propylsulfonylphenyl]ethylamine hydrochloride, as shown in the above formula 18d.HC1, hereinafter abbreviated as 2md6 · HC1, 0.47g, L8 mm 〇1), yield 40%. (If the starting material is 18, the product 2_(2,5-didecyloxy- ice-propyl-featheramine phenyl)ethylamine hydrochloride can be obtained, as the above code is 18 • The structural formula of the brain, hereinafter abbreviated as 2-C_T-7 · HC1, yield 47%). ί (Physical properties of bis(three-infrared thiol)·4·propyl propyl phenyl] ethylamine hydrochloride H NMR (300 MHz, D2 〇, δ): 6.92 (s, 1H), 6.85 (s, Η), 3.16 (t ' J = η Ηζ, 2 Η), 2 9 〇 2 82 ADD, 4 Η), 1.57- 1.49 (in ' 2Η), 0.92 (t, J = 7.3 Ηζ, 3Η); 13C NMR (75 MHz, CD3〇D, δ) : 151 8,(5) 7, 124.4, 122.9, U3.8, 112.5,551_54 〇 (10), 39 4, 52 200808681 33·7,28·3,22·1,12·3 ; IR (KBr) : 2958,2923,2904,2819,2753,265 7, 2460, 2213, 2048, 1484, 1400, 1222 cnf1 ; MS_FAB (m/z) : 262 (M+-CBu 96), 247 (5), 245 (100), 232 (22), 203 (7) , 189 (7); HRMS-FAB (m/z): Calculated for [M+-C1] of C13H16D6N04S: 262.1741; "2-(2,5-Dimethyloxy-4-propylsulfonylamino)ethylamine hydrochloride" which is not substituted by deuterium" Physical Properties 4 NMR (300 MHz, D20, δ): 6·89 (s, 1H ), 6.82 (s, 1Η), 3·71 (s, 6Η), 3·12 (t, J = 7.01 Hz, 2Η), 2·86-2·78 (m, 4H), 1 · 55-1·43 (m, 2H), 0·87 (t, J = 7.4 Hz, 3H); 13CNMR (125MHz, D2〇, 3): 151.8, 151.1, 124.0, 123.1, 114.4, 113.5, 56· 4,56·2,39·6,34.0,27.7, 21.8^12.5; IR (KBr): 3214,2958,2904,2751,2657,2559, 2460,2043,1602,1495,1387,1208,1037 cnf1 ; MS-FAB (m/z) ·· 256 (M+_a,90),241 (5),239 (100),226 (24),212 (7),197 (11),183 (16); HRMS -FAB(m/z): The calculated value of [M'Cl] for C13H22N04S is 256.1371; the measured value is 256.1366. From the physical properties of the above 18 · HC1 and 18d · HC1, it can be known that 18d · HC1 which only replaces six hydrogens has similar physical properties to 18 · HC1.

20 : R Di CH3 20d: R = CD3 53 200808681 In the glove phase towel, take the sutured potassium (2 53 g, 伽面冲用研:J after the 'addition...methyl...min (3-methyl-4-nitro_phenol 'Formula code 19 (4) g, 4L0 mmol) and tetrabutyl bromide (2〇7 _, 〇6, ground, stir at room temperature for 15 minutes, add people with MK (27 mL ' 42.5mm〇l) 'Stirring at 4 (TC for 3 days, adding water to stop the reaction, taking the dichlorohydrazine material to take 'the organic layer extract is dried with anhydrous brittle magnesium, concentrated and concentrated by Silica gel column chromatography to Ethyl acetate/hexane (EtOAC: Hexane=l:19) is the mobile phase, which is a solid color: dimercaptooxy-2-mercapto-1-nitrobenzene, as shown in the above code 2〇d structure Formula, 6.14 g, 36.0 mmol), yield 88%. (When iodomethane is added, the product 4-mercaptooxy-2-methyl-1-nitrobenzene can be obtained, the above formula is 2 〇. , yield 81%). The physical property of the ruthenium-containing compound "4·trimethylol-2-methyl-1-nitrobenzene, mp: 54-55〇C; iH NMR (300 MHz, CDC13, 5) : 8·10 (d, 8.8

Hz, 1H), 6·81-6·76 (m, 2H), 2·63 (s, 3H); 13C NMR (75 MHz, CDC13, d): 163.0, 142.1, 137", 127.5, 117.4, 111.8 , 21.7 ; IR (KBr) : 3120,3054,2985,2931,2075,1608, 1581,1496,1334,1292,1265 cm-1 ; MS-FAB (m/z): 170 (M++1,6 ), 167 (10), 75 (100); HRMS-FAB (m/z): The calculated value of [M+] for C8H6D3N03 is 170.0767; the measured value is Π0.0765. The physical properties of "winter methyloxy-2-mercapto-1-nitrobenzene" which has not been replaced by deuterium mp· : 54-55〇C; 54 200808681 4 NMR (300 MHz, CDC13, δ): 8.10 ( d, J = 8·7 Hz, 1H), 6·82 (d, J = 2·7 Hz, 1H), 6.78 (s, 1H), 3·87 (s, 3H), 2.63 (s, 3H) 13C NMR (125.7 MHz, CDC13, δ): 162.9, 142.0, 136·9,27·4,117.3,111.7,55·6,21·5; IR (KBr): 3125,3012,2981,2936,2837 , 1607, 1580, 1495, 1324, 1284, 1257, 1078 cm·1 ; MS-FAB (m/z): 168.2 (M++1, 45), 152 (32), 137 (11), 105 (100 HRMS-FAB (m/z): Calculated for [M++H] of C8H10NO3: 168.0660; From the above physical properties of 20 and 20d, it can be known that 20d and 20 which replace only six hydrogens have similar physical properties.

21d: R = CD3 4·3氘Methoxyoxanyl succinylbenzene (6〇7g, 35 7mm〇1) was dissolved in anhydrous dimethyl decylamine (36mL), then n, n _ dimethylformamide dinonyl acetal (N? N-dimethylf〇nnamide-dimethylacetal 5 14.2 mL ^ 107.1 mmol), heated to 13 ° C reflux for 7 hours, (color changes from yellow to orange to red , and finally it will turn into a deep red color, and then use the vacuum distillation to obtain the product of dark red solid [2_(5_tridecyloxy-2-nitrophenyl)vinyl]dimethylamine, code 21d above. The structural formula directly proceeds to the next reaction. (If the starting material is 20, the product [2_(5_mercaptooxy-2_nitrobenzene)vinyl]diguanamine) can be obtained. 55 200808681

RO

21 : R = CH3 21 d: R = CD3 H2; Pd

Dissolve [2_(5_trimethyloloxy-2-nitrophenyl)vinyl]dimethylamine in Yishui Benzene (125 mL) and add Pd/C (0.80 g) at a hydrogen pressure of 5 psi The hydrogenation reaction was carried out, and after 1.5 hours, the catalyst was removed by filtration through diatomaceous earth, concentrated, and purified by Silica gel column chromatography, with acetic acid (g EtOAc / Hexane = 1 : 19) For the mobile phase, the product of the yellow solid was obtained from the product: tris-methyl methoxy-1H-indole (the above formula 22d, 3 g, 25 mmol), yield 70% in two consecutive steps. (If the starting material is, the product 5-methyloxy-1H-indole can be obtained in a yield of 41% in two consecutive steps). Physical properties of the cerium-containing compound "5-trimethylsulfonium-1 ugly-吲哚" mp· : 58-59〇C; towel NMR (300 MHz, CDC13, δ): 8·04 (br, 1H), 7.30 (d, J = 8·6 Hz, 1H), 7·19 (t, J = 2.8 Hz, 1H), 7·11 (d, J = 2.4 Hz, 1H), 6.88- (dd, J = 8.8 , 2.4 Hz, 1H), 6·49-6·48 (m, 1H); 13C NMR (75 MHz, CDC13, δ): 154.2,131,0, 128.5,125.0,112.3,111.8,102·3,55 ·9-54·8 (m); IR (KBr): 3401,3100,2221,2063,1612,1577,1477,1322,1284,1230,1164 cnT1 ; MS-FAB (m/z) : 151 (M ++1,100), i50 (74), 132 (35), 117 (9), 116 (3); HRMS-FAB (m/z) ·· C9H6D3NO The calculated value of [M++H] is 150.0869 The measured value is 150.0865. 56 200808681 "5-Mercapto-oxy-1open-oxime" which is not replaced by hydrazine. Physical properties ιη·ρ· : 54-55 C, 4 NMR (300 MHz, CDC13, δ) : 8·05 (br ,1Η), 7.30 (d, J 2·8 Hz, 1Η), 7·11 (d, J 2·4 Hz, 1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 6.49- 6.48 (m,1H), 3·85 (s,3H); 13C NMR (75 MHz, CDC13, δ) ·· 154.2,131.0, 128.3,124.9,112.3,111.8,102.3,55·9 ; IR (KBr) : 3402,3106,2994,2954,2936,2832,1616,1576,1485,1450 cm-1 ; MS-FAB (m/z) ·· 148 (M++1,100),147 (82),133 (89), 75 (47); HRMS-FAB (m/z): The calculated value of [M+] of C9H9NO is 147.0684; the measured value is 147.068. It can be known from the comparison of the physical properties of 22 and 22d above that only six are replaced. 22d and 22 have similar physical properties.

1 (COCl}2 2· (CH3)2NH.HCl (aq)

Reward@2 23 : R = CH3 23d: R = C〇3 Under 〇C, the grass ^& rat (2.28 mL, 26.1 mmol) is dissolved in anhydrous ether (35 mL), slowly dissolved in anhydrous B.趟 (2〇 _ 孓 曱 曱 氧 氧 ( 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 1.9 , the upper layer B _ out, for the new Esaki to go, continue to see, '1 77 hours, then remove the upper layer of the squad, so act three times, that is, 57 200808681 can get (5-tridecyloxy-1H- 5 each yl) 5-(5-trideuteriummethoxy-lH-indol-3-yl)ox〇acetyl chloride) ^ Next, prepare 40% aqueous solution of dimethylamine, and take water under ice bath ( 54.0 mL) and sodium hydroxide (22.4 g, 560 mmol) were placed in a beaker. After complete dissolution, a solution of dimethylamine hydrogen chloride (45.8 g, 561.6 mmol) was added to give a milky white solution, then 〇°c, borrowed Add a few (5-tridecyloxy-1H, 哚!yl) side oxyethyl hydrazine chloride from a small amount of diethyl ether, a large amount of solids were produced, and the mixture was stirred for 30 minutes at 〇 ° C to solidify Filtration, washing with water and diethyl ether, the solid was dissolved with hot THF, and then recrystallized from diethyl ether to give the product 2-(5-tris-methyloxy-1H-indole-3_yl) as a white solid. _N,N-dimercapto-2-oxoacetamide, the structural formula of the above code 23d, 1.76 g, 7.1 mmol, yield 55%. (If the starting material is 22, the product 2_(5 can be obtained) _Methyloxy-1H-indole-3-yl)-N,N-dimethyl-2-oxoacetamide, yield 46% in two consecutive steps. Paper-containing compound "2-(5_ Physical properties of tris-n-methoxy-LiT_吲哚-3_yl)_iV,7V·dimethyl-2-oxoacetamide mp : 226-227〇C ; 4 NMR (300 MHz, CDC13 / a little CD3OD , δ) : 7·68 (d, J = 3.3 Hz, 1H), 7.61 (s, 1H), 7·20 (d, J 2·8 Hz, 1H), 6.78-6.74 (dd, J = 8 ·8,2.5 Hz,1H), 2.96 (s, 3H), 2.90 (s,3H); 13C NMR (75 MHz, CDC13 / a little CD3OD, δ) ·· 186.0,168.2,156.4,136.5,131·8, 126.0, 114·1, 113·5, 112.8, 103.0, 37.3, 34.0; IR (KBr): 3131, 3100, 3046, 2896, 2248, 2217, 2071, 1631, 1469, 1442, 1276 cnT1; 58 20080868 1 MS-FAB (m/z): 250 (M++1,34), 207 (42), 149 (37), 75 (100); HRMS-FAB (m/z): C13H12D3N203 [M++ The calculated value for H] is 250.1267; the measured value is 250.1272. "2-(5-Methyloxy-LfiT-吲哚-3-ylHV, 7V-dimethyl-2. oxoacetamide) physical properties mp: 229-230〇C; 4 NMR (300 MHz, CDC13 / a little CD3OD, δ): 7.69 (s, 1 Η), 7·63 (s, 1H), 7.21 (d, 8.8 Hz, 1H), 6·79 (d, J 8.9 Hz, 1H), 3.96 (s, 3H), 3·75 (s, 3H), 2·95 (s, 3H), 2.91 (s, 3H); 13C NMR (75 MHz, CDC13 / a little CD3OD, δ) : 186.0,168.2,156.4,136.5,131·9,126·0,114.0,113·4,112·8,103.0,37·3,34·0; IR (KBr): 3129,3102,3048,2937, 2900,1629, 1440,1270,1214,1170,1081,811,665 cm-1 ; MS-FAB (m/z) : 247 (Μ++1,52),148 (15),133 (13), 75 (100); HRMS_FAB (m/z): The calculated value of [M+] is 246·1004; the measured value is 246.1005. From the physical properties of 23 and 23d above, it can be known that only 23d of the six hydrogens are replaced. 23 has similar physical properties.

23 : R = CH' 23d: R II CD 24 (5-_o-DMT): R = CH3 R = CD: 2-(5-tridecyloxy-1H-吲哚-3-yl)_N, N-dimercapto-2-side 59 200808681 Oxy acetamidine &amine (1 46 〇·“η ι\ ,· 0 g,5·9 mmol) dissolved in anhydrous tetrahydrofuran (2〇眺) (0.89 g, 2.3 mmol) in a suspension of anhydrous four gas (0 mL), gently reflux for 2 hours, cooled to room service 'stop the reaction with aqueous sodium hydroxide under ice cooling, the solution was diatomaceous earth Filtration, wash the solid with ether to fluffy, extract with diethyl ether, and then condense the organic layer to give the product [2-(5-tridecyloxy-1H-indole-3-yl)ethyl] Dimethylamine (the above formula is 24d, hereinafter referred to as 5-Meo-DMT-d3, ΐ·26 g, 5 7 〇1), and the yield is 97%. (If the starting material is 23 ', the product|>(5_decyloxy-1H-吲哚-3_yl)ethyl]diamine can be obtained as the structural formula of the above code 24, hereinafter referred to as 5-Meo. -DMT, yield 93%). Physical properties of the ruthenium containing compound "[2-(5-trimethyloxy-anthracepin-3-y1)ethyl]dimethylamine, 4 NMR (300 MHz, CDC13, δ) : 7·94 (br,1Η), 7·25 (d, J = 8·8 Hz, 1Η), 7·04 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 2.3 Hz, 1H), 6.86 ( Dd, J = 8·8, 2·4 Hz, 1H), 2.93 (t, 2.7 Hz, 2H), 2.65 (t, Bu 2.3 Hz, 2H), 2.34 (s, 6H); 13C NMR (75 MHz , CDC13, <5) : 153.8, 131.5, 127.8, 122.4, 113.9, 112.0, 111.9, 100.6, 60·2, 45.4 ^ 23.8 ; IR (KBr): 3131, 3104, 3035, 2946, 2857, 2819, 2784 , 2240, 2210, 2059, 1473 cmf1 ; MS-FAB (m/z) : 222 (M+ +1,100), 220 (18), 177 (64), 132 (19), 130 (8), 75 ( 4); HRMS-FAB(m/z): The calculated value of [M++H] for C13H16D3N20 is 222.1682; the measured value is 222.1687. 60 200808681 Conventional [2-(5-methyloxy) Physical properties of -1-indole-3-yl)ethyl]dimethylamine" NMR (300 MHz, CDC13, δ): 7.87 (br, 1H), 7.25 (d, J = 8·8 Hz, 1H ), 7·05 (d, J = 2·3 Hz, 1H), 7·01 (d, J = 2·2 Hz, 1H), 6.87 (dd, J 8.8, 2.2 Hz, 1H), 3.86 (s, 3H), 2.91 (t, J = 2·2 Hz, 2H), 2.64 (t, J = 2.2 Hz, 2H), 2.34 ( s,6H); 13C NMR (75 MHz, CDC13,5): 153.8,131.5, 127·8,122·4,112.0,111.8,100.7,60·2,56.0,45.4, 23.8; IR (KBr) : 3127 , 3100,3039,2938,2865,2863, 2754,1585,1473,1442,1218,1064 cm-1 ; MS-FAB (m/z) : 219 (M+ +1,100),174 (49),132 (7), 130 (6), 75 (4); HRMS-FAB (m/z): The calculated value of [M++H] for C13H19N20 is 219.1497; the measured value is 219.1495. From the physical properties of 24 and 24d above, it can be seen that 24d and 24, which only replace six hydrogens, have similar physical properties.

Ch3ch2no2 ro,, /, ^y^〇2 25 : R = CH3 25d; R = CD3 2,5-bis(trimethyloloxy)benzaldehyde (3.00 g, 18,0 mmol) was dissolved in glacial acetic acid ( In 15.5 mL), add nitroethyl bromide (2.17 g, 29.0 mmol) and anhydrous ammonium acetate (〇9 g, 18.0 mmol), 10 (reflow at TC for 3 hours' TLC tracking until the disappearance of the raw materials to reduce the reaction flask to the chamber After being concentrated under reduced pressure, the mixture was suspended in water and extracted with dichloromethane. The organic layer extract was concentrated to 61 200808681, and then ethyl acetate/hexane (EtOAc: HeXane = 丨: 39) was used as the water. Purification by column chromatography gave the product as a yellow solid, 4-bis(-(methyloxy)-2-(2-aminopropylpropyl)benzene, as shown in the above formula 25d, 3.53 g, 15.4 mmd ' The yield is 86%. (If the starting material is 3, the product 1,4-dimethyloxy-2_(2-aminopropenyl)benzene can be obtained, the above formula is 25, the yield is 65%) Physical properties of the Jil-containing compound "1,4-bis(tris-methyloxy)-2-(2-aminopropenyl)benzene, mp: 77-78〇C; 咕NMR (300 MHz, CDC13) , δ) : 8·23 (s, 1H), 6·69 (q, J = 3.0 Hz, 1Η), 6.87 ( s,1Η),6·85 (d,J = 2.9 Hz, 1H), 2.39 (s,3H); 13C NMR (75 MHz, CDC13, δ): 153.1,152.7, 147.7,130.1,122.5,115.7,115.4 , 111.7, 55.4-54.6 (m), 14.11; IR (KBr): 3070, 2923, 2854, 2356, 2248, 2225, 2071, 1646, 1496, 1427, 1295, 1268, 1238 cm·1; MS-FAB ( m/z) ·· 230 (M++1,3),214 (9),184 (100), V, 115 (1); HRMS-FAB (m/z) : CnH7D6N04 [calculated value of Mf 229.1251; measured value is 229.1221. The physical properties of "1,4-didecyloxy-2-(2-aminopropenyl)benzene" are not substituted by hydrazine mp : 77-78〇C ; 咕 NMR (300 MHz, CDC13, δ): 6·92 (d, J = 9·0 Hz, 1H), 6.84 (dd, 9.0 Hz, 3·0, 1H), 6·75 (d, J = 3· 〇Hz,1H),3.66 (s,3H),3·62 (s,3H),3·55 (q,J = 6.6 33 Hz,1H), 2·80-2·72 (m,2H), 1.12 (d, J = 3.8 Hz, 62 200808681 3H); 13C NMR (125.7 MHz, CDC13, δ) ·· 153·1, 152.4, 147.7, 129.6, 122.0, 116·0, 115.7, 111.2, 56.0, 55.8; IR (KBr) ·· 3037,3007,2971,2936,2923,2838 1645, 1508, 1494, 1455, 1329, 1298, 1227 cm]; MS-FAB (m/z): 224 (M++1, 10), 223 (18), 208 (3), 177 (7), 136 (100), 107 (28); The calculated value of [M+] for HRMS-FABCm/z^CuHnNCU was 223.0844; the measured value was 223.0843. It can be seen from the comparison of the physical properties of 25 and 25d described above that 25d and 25, which only replace six hydrogens, have similar physical properties.

25 : R = CH3 26 (DMA): R = CH3 26-HCI (DMA HCI) R = CH3 2Sd: R = CD3 2SCMDMA is): R = CD3 2&ΦΗα (DMA-drHCI): R Two CD3 will M- Bis(tridecyloxy)_2_(2-aminopropenyl)benzene (175 g, 7.8 mmol) was dissolved in dry diethyl ether (53 mL) and slowly added to an aluminum halide (1.19 g, 31.4 mmol) The suspension of anhydrous diethyl ether (10.8 mL) was refluxed for 20 hours. The reaction was stopped by adding water to an ice bath. The solution was filtered over celite, and the solid was washed with ether to fluffy, and finally water was added to bring the filtrate to a volume of 54 and then added. Sodium potassium tartrate (3·30 g, 113.0 mmol), followed by the addition of aqueous sodium hydroxide solution, the pH of the solution is greater than 9, after concentration, the aqueous solution is extracted with dichloromethane, the organic layer is dried over sodium sulphate, and the organic layer is concentrated. The product of the product 2-[2,5-bis(trimethyleneoxy)phenyl]indenyl-ethyl as the above code 26d is obtained, and the product 26d is made into hydrochloric acid 63 200808681 salt recrystallized and purified, the product is obtained. 26d (hereinafter referred to as DMA_d6) is dissolved in ethylene crystal, and the product 2_[2,5_double (three) human hydrochloric acid gas can be obtained. At this time, the reaction bottle has a solid sink, stirring. After a few minutes, let stand for a few more minutes, filter the solids, and then use ethanol/B_

It is called DMA-d6 · HC1, 2,5_bis (trimethylsulfonyloxy)phenyl] small methyl ethylamine C is 26d · HC1 structural formula, the following is simple 1.27 g '5·48 mmol) The yield is 70%. (If the starting material is 25, the product 2_(2,5-dimethyloxyphenyl)methylethylamine' has the structural formula of the above 26, yield 70%). For the nature of the ruthenium containing compound "2-[2,5-bis(trimethyleneoxy)phenylmethylethylamine, 4 NMR (300 MHz, CDC13, δ): 6.79-6.69 (m, 3 Η) , 3·22-3·15 (m, 1H), 2·74_2·46 (m, 2H), 1.11 (d, J = 3·6 Hz, 3H); 13C NMR (75 MHz, CDC13, δ): 153.1,151.7, 129·1,117.1,111.1,ιιι·〇,55·〇_54·;[ ,46 9, 43.2,41.1,23.4 ; IR (KBr) : 3359,3289,3066,3043,2962,2923 , 2869, 2248, 2213, 2129, 2067, 1589, 1496, 1234, 1110, 686 cnT1 ; MS-EI (m/z): 201 (6), 194 (15), 192 (50), 174 (33) , 158 (100), 140 (26); HRMS_EI (m/z) : The calculated value of [M+] of CnHuDeO is 201.1629; the measured value is 201.1637. Conventional is not replaced by "2-(2,5-two) Physical properties of decyloxyphenyl)-1 -mercaptoethylamine NMR (300 MHz, D20, δ): 6.92 (d, J = 9.0 Hz, 1H), 6.84 (dd, J = 9·0) , 3.0 Hz, 1Η), 6.75 (d, J = 3.0 64 200808681

Hz, 1H), 3.66 (s, 3H), 3.62 (s, 3H), 3.55 (q, J 2.6 Hz, 1H), 2·80-2·72 (m, 2H), 1·12 ( d, J ii 3·8 Hz, 3H); 13C NMR (125.7 MHz, D20, δ): 152·7, 151.8, 125.3, 117·5, 113·4, 112.6, 84.1, 55·8, 34·8 , 17.5; IR (KBr) ·· 2939, 2832, 2572, 2513, 2491, 1997, 1975, 1607, 1606, 1509, 1505, 1463, 1225, 1044 cm·1 ; MS-FAB (m/z): 196 (M+-C1,100), 179 (56), 164 (9), 151 (15), 75 (20); The calculated value of [M'Cl] of HRMS-FABCm/z^CuHuNCU is 96.1337; 196.1342. From the physical properties of 26 · HC1 and 26d above, it can be known that 26d which replaces only six hydrogens has similar physical properties to 26 · HC1.

26*HCi R = CH3 2Sd.HCI (D off A-drHCI): R =^CD3

NH3+Cr R〇 Βί2 AcOH

OR 27 ; R ^ CH3 27d: R two CD3 circumference 丨

Br^^^OR 27.HCI (DOB-HCI): R di CH3 27d-HGI {OOB.drHCl): R = CD3 2-[2,5-bis(trimethyloloxy)phenyl]fluorenyl Ethylamine hydrochloride (0·38 g '1.9 mmol) was dissolved in glacial acetic acid (3 mT), and bromine (〇·06 mL '1.2 mmol) in acetic acid (0.5 mL) was added dropwise and stirred. 5 hours, pour the mixture into a water towel (20 mL), turbid solution with acetaminophen twice, then add sodium hydroxide water> gluten solution to make it detectable, extract with dichloromethane, concentrate, testability The oxidized shoe is purified by chromatography, and the product can be _product 2_[4_淳 双 bis(tri-methyloxy)phenyl H-methylethylamine, as the above code is another structural formula, hereinafter referred to as D0B_d6, _ g , 14 with 〇), yield 74%. (If the starting material is 26. HC1, then the product ice desert _2 & 65 200808681 dimethoxyphenyl) small methyl ethylamine, the structural formula of the above code 27.HC1, hereinafter referred to as DOB · HC1 , yield 55%). Physical properties of the ruthenium containing compound "2_[4_bromo-2,5-bis(trimethyleneoxy)phenyl] dimethylethylamine, 4 NMR (300 MHz, CDC13, δ): 7·02 ( 1H),6·72 (s, 1Η), 3.21 (t, J = 6·9 Hz, 1Η), 2.71-2.44 (m, 2Η), 1·11 (d, 6.3 Hz, 3H); 13C NMR (75 MHz, CDC13, δ): 152.1, 149.7, 128.3, 115.8, 115·3, 108.9, 46·9, 41·0, 23·6; IR (KBr): 3336, 3239, 3154, 2954, 2919, 2873, 2213, 2071, 1488, 1392, 1230 cm-1; MS-EI (m/z): 281 (M+-HC1,8,81Br), 279 (M+-HQ,6,79Br),265 (4) ,263 (5),238 (99),236 (100),220 (13), 218 (11),205 (10),203 (11),143 (10),78 (38); HRMS-EI( m/z) · · The calculated value of [M+] of CnHioDWO/hr is 279.0734; the measured value is 279.0733. It is conventionally not replaced by hydrazine "2-(4-)-2,5-dimethyloxyphenyl)- Physical properties of 1-methylethylamine hydrochloride NMR (300 MHz, D20, δ): 7·18 (1H), 6.8 (s, 1 Η), 3.72 (s, 3 Η), 3.67 (s, 3 Η) ), 3·54 (t, J = 6·8 Hz, 1H), 2.97 (d, J = 3·7 Hz, 2H), 1.16 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDC13, δ): 152.1, 149.7, 128.2, 115·8, 115·4, 109·0, 56·6, 56·0, 46·9, 40·8, 23·3 ·· IR ( KBr): 2992, 2904, 2830, 2738, 2028, 1592, 1496, 1465, 1388, 1211 cm-1; MS-FAB (m/z): 276 (Μ+-Π,91),274 (85), 196 (100), 179 (39), 75 (18); calculated value of [M+-C1] of HRMS-FABCm/z^CnHnNC^Br 66 200808681 is 274.0442; measured value is 274 〇 452. From the above physical properties of 27 · HC1 and 27d, it can be known that 27d which replaces only six hydrogens has similar physical properties to 27 · HC1.

28 29 : R = CH3 29d: R = CD3 In a glove box, take potassium hydroxide (0.92g, 16〇mm〇1) and grind it with a mortar, then add 4-hydroxybenzaldehyde (4-hydroxybenzaldehyde, as above The structural formula code 28, 2·〇〇g, 16.0 mm〇i) and the desertified tetrabutylammonium (83 mg '〇·3 mmol) were ground and stirred at room temperature for 15 minutes. Methyl iodide (0.52 mL, 819 mm 〇1), stirred at 4 ° C for 3 days, the reaction was quenched with water, extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. Ester/hexane OEtOAUHexane: 1:39'1:19) Purification by Siicacarel column chromatography for the mobile phase gave the product 4_triterpene oxymethylfurfural as a yellow liquid, as described above under the designation 29 <1 , 1.〇2 8,7.3111111〇1, yield 89°/. . (When the mothane is added, the product 4-mercaptooxybenzaldehyde is obtained, and the above formula 7 is a structural formula of 29, and the yield is 61%). Physical properties of the ruthenium-containing compound "4-trimethyl benzyl benzene aldehyde, 4 NMR (300 MHz, CDC13, δ): 9.88 (s, 1H), 7.85 (d, J = 8 · 8 Hz, 2 Η ), 7.01 (d, J = 8·7 Hz, 2Η) 13C NMR (75 MHz, CDC13, δ): 190.8, 164.6, 132.1, 131.9, 114.7, 114·3, 55.3-54.1 (m); IR (KBr ) : 3358,3066,2922,2743,2258,2222, 2070,1693,1598,1504,1316 cnT1 ; 67 200808681 MS-FAB (m/z) : 140 (M++1,17),138 (45) , 124 (100), 105 (62), 75 (45); HRMS-FAB (m/z) · · C8H6D302 The calculated value of [M+H]+ is 140.0787; the measured value is 140.0790. Substituting "4-mercaptooxybenzaldehyde" for physical properties 4 NMR (300 MHz, CDC13, δ): 9·87 (s, 1H), 7.84 (d, J = 8·8 Hz, 2 Η), 7.01 (d, J 2.8 Hz, 2 Η), 3·88 (s, 3H); 13C NMR (125 MHz, CDC13, δ): 190.8, 164.5, 131.9, 129.9, 114.2, 55.6; IR (KBr): 3357,3070,3008,2967,2937,2836, 2738,1687,1602,1513,1459 cm-1; MS-FAB (m/z): 137 (M++1,28),135 (100),121 (69), 105 (66), 77 (62); HRMS-FAB (m/ z) : The calculated value of [M++H] of C8H902 is 137.0602; the measured value is 137.0603. It can be seen from the physical properties of 29 and 29d described above that 29d and 29 which only replace three hydrogens have similar physical properties. Ch3ch2no2 r〇

30 : R = CH3 30d : R = CD3

29 :R:CH3 29d: R = CD3 Φ tris-decyloxybenzoic acid (〇.94g, 6.8 mmol) was dissolved in anhydrous acetic acid (3.8 mL), and nitroethane (0.97 mL, 14.0 mmol) was added. And anhydrous acetic acid (〇·78 g, 10.1 mmol), refluxed at 120 ° C for 60 minutes. After cooling, it was concentrated with a reduced pressure concentrator, extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. After concentration, purification was carried out by smcagd column chromatography eluting with ethyl acetate/hexane 68 200808681 (EtOAc Hexaned: 39) as the mobile phase to give the product as a yellow solid, 1-trimethyleneoxy-4-(2-nitropropene) Base) The above formula is 3〇d, 〇·87 g, 4.4 mmol, yield 66%. (If the starting material is 29, the product ^methyloxy_4_(2_nitropropenyl)benzene can be obtained in a yield of 62%). Physical properties of the murine compound '1-diazamethyloxybutyr (2-propenylpropyl)benzene, mp: 46-47〇C; 咕NMR (300 MHz, CDC13, δ): 8.07 (s, 1Η), 7.41 (d, J = 2·9 Hz, 2H), 6·99 (d, J = 3·0 Hz, 2H), 2·47 (s, 3H); 13C NMR (75 MHz, CDC13, δ) : 161·1,145.6, 133·6,131·7,125.7,114·8,55·2·55·3 (m),14·0 ; IR (KBr) ·· 2221,2069,1643, 1598,1513,1494, 1307,1267,1176 cnf1 ; MS-FAB (m/z) ·· 197 (Μ++1,48),181 (59),150 (27),149 (100),132 ( 50); HRMS-FAB (m/z): Calculated for [M]+ of CiqH8D3N03: 196.0924; The physical properties of "1-mercaptooxy-4-(2-shiosylpropyl) benzene" which is not substituted by gas are mp: 45-46 ° C; 4 NMR (300 MHz, CDC13, δ): 8.07 (s ,1H),7·41 (d,J = 2.9 Hz, 2Η), 7·00 (d, J = 2·9 Hz, 2Η), 3·81 (s, 3H), 2·47 (s, 3H) 13C NMR (125 MHz, CDC13, δ): 161·0, 145.6, 133.5, 132·0, 124·6, 114.4, 55·3, 14·0; IR (KBr): 3030, 2963, 2937, 2832 ' 1643,1607, 69 200808681 1509,1499,1306,1252,1172 cnT1 ; MS-FAB (m/z) ·· 194 (M++1,49),193 (13),178 (22),147 (16), 132 (100); HRMS-FAB (m/z) · · C10H12NO3 The calculated value of [M+H]+ is 194.07817; the measured value is 194.816. From the above physical properties of 30 and 30d, it can be known that 30d and 30, which only replace three hydrogens, have similar physical properties.

30d: R = CD3 31d {PMA-d5v R = CEh 31*HC1 {PMA*HC!}; R ~ CH3 '· (just A-cirHCI): R = CD3 1-tri-decyl oxygen hopper (2- The nitropropenyl)benzene (087 g, 44 mmol) was dissolved in anhydrous diethyl ether (30 mL) and placed in a liquid addition funnel, and anhydrous diethyl ether containing <RTI ID=0.0> 3 〇mL) in the suspension solution, at this time the lithium aluminum hydride in the reaction bottle is sticky, after the addition, reflux for 48 hours, cooled to room temperature, the reaction was terminated with dilute sulfuric acid, the solution was filtered with diatomaceous earth, Dilute sulfuric acid extraction, after the aqueous solution is combined, add potassium tartrate potassium (21.00 g, 74·4 mm〇1) aqueous solution, adjust the pH of the reaction solution to more than 9 with aqueous sodium hydroxide solution, and extract the aqueous solution with methylene chloride. Organic After the layer is concentrated, the product 2 and tris-methoxyphenyl) small methyl ethylamine are obtained, as shown in the above formula 31d, and the product (hereinafter abbreviated as PMA_d3) is made into a salt. Recrystallization purification, product 31d Dissolve in isopropanol, blow hydrochloric acid gas, at this time the reaction bottle will have a solid sinking hall, take out the stirrer, add (10) (9.7 chaos), let stand overnight, solid The product can be obtained by filtration, and the product 2_(crystal of 4-methylethylamine hydrochloride, as the above coded 31d.Ha (4) 70 200808681 hereinafter referred to as PMA_d3 · HC1 〇·57 g, 2·8 mmol, can be obtained. The yield was 63%. (If the starting material is 30, the crystal of the product 孓(4-methoxyphenyl)-1_methylethylamine hydrochloride can be obtained, and the above formula is 31 · Ηα, Abbreviated as PMA · HOI, yield 85%). Physical properties of the compound "2-(4-trimethylmethoxyphenyl)-indole methyl ethylamine hydrochloride, 4 NMR (300 MHz, D2) 〇,δ) : 7·15 (d, J 2·6 Hz, 2Η), 6.90 (d, J = 8·7 Hz, 2Η), 3·52-3·41 (m, 1Η), 2.83-2.70 (m, 2H), 1·18 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, D2 〇, δ): 157.9, 130.6, 130.3, 128·5, 114·3, 55 · 1-53·9 (m), 49·3, 49.2, 39·2, 17·4; IR (KBr): 2942, 2802, 2748, 2603, 2213, 2190, 2065, 1513, 1261, 1114, 993 Cm·1 ; MS-FAB (m/z) : 169 (M'Cn, 100), 152 (92), 151 (8), 150 (4); HRMS-FAB(m/z) : C10H13D3NO [M+ The calculated value of -C1] is 169.1416; the measured value is 169.1417. It is not known that "2-(4-methoxyphenyl) small methyl ethylamine hydrochloride" is replaced by hydrazine. Physical properties 4 NMR (300 MHz, D20, δ): 7.15 (d, J = 4.8 Hz, 2H) , 6.90 (d, J = 4.6 Hz, 2H), 3.72 (s, 3H), 3.52-3.42 (m, 1H), 2.84 (d, 6.9 Hz, 2H), 1.19 (d, 6.6 Hz, 3H) 13C NMR (125 MHz, D20, δ) ·· 157.9,130.6,128.5, 114.3,55·3,49,1,39],17·3; IR (KBr): 2911,2811,2707,2603,2522 ,1612, 1511,1253,1033 cm-1 ; MS-FAB (m/z) : 166 (M+_C1,100),164 (19),150 71 200808681 (36),149 (100),148 (25 ), 133 (29); HRMS-FAB (m/z) · C10H16NO [JVf^Cl] has an ancient ten tube value of 166.1231; the measured value is 166.1235. # From the comparison of the physical properties of 31 and 3Id above, it can be known that only 31 d and 31 of the wind have similar physical properties. As described above, the ruthenium-containing compound which replaces a part of hydrogen atoms in the present invention has similar physical properties to the compound which is not originally substituted by ruthenium. In addition, most of the hydrochlorides are crystals. Therefore, experiments with hydrochloride crystals are relatively stable and easy to store, and the balance is convenient. However, some salted compounds cannot be prepared, so the spectral data are collected in an unsalted state. The Hewlett-Packard HP-6890 Gas Chromatograph was used to connect the _5973 Mass Selective Detector mass spectrometer in series to a gas chromatography mass spectrometer (GC-MS). The separation column of the gas chromatograph is Hp_5MS (length ΐ2·5 m film thickness 0·33μπι, inner (four)·2 mm). The temperature rise plan is maintained at 0 (5 minutes for rc as the starting temperature, and is maintained at 每·5 ^ liters per minute. The carrier gas is high purity helium (99.999%), and the gas flow rate is controlled to be every minute. 0.6 ml. The temperature of the injection part is set to 2 thieves, the transfer line of the mass spectrometer and the temperature of the ion source are set to be fine. 〇 and 23 (). 〇, the electron impact is free, the free voltage is 7〇eV, and the ion scan range is 4〇~45〇_. In the above-mentioned compound containing the chaotic compound and the non-ambient compound, the following compounds were selected for GC-MS analysis, as shown in Table 1. From the results of Table 1, the two substituted six or After the H compound of Sanqian is analyzed by gas chromatography, the residence time and the relative intensity of the detected ions are very similar, so the ruthenium-containing compound of the present invention can be used as a GC_MS analysis ratio 72 200808681 The retention time of each compound after GC-MS analysis of the standard product table is determined by the compound retention (min) 2C-C-d6 5.88 2C-C 5.90 2C-B-d6 6.19 2C-B 6.21 2C-I- D6 6.56 2C-I 6.57 2C-T-2-d6 6.62 2C-T-2 6.63 2C-T-7-d6 6.90 2C-T-7 6·9 1 DMA- d6 5.19 DMA 5.20 DOB-d6 6.12 DOB 6.13 PMA-d3 4.60 PMA 4.61 Relatively strong detection of ions between 0 inches ^'^' Legs, 191 (69.4), 31 escape, 185 (78·7), 31 · Mi, 361 (76.3), 23 · Μ 1,355 (75·6), 229 · Withdrawal, 296 (80.9), 2δ3 · 4Μ, 290 (85.6), 277 · 217^343 (82.6)^230 · ancestors, Zero.1), ~3: δ 231^ 357 (78.1), 24 m, 351 (89.6), 23δ 1M'297 (93.2), 1S7 · Escape '291 (95.4), l5 . 2M, 262 (86.8), 37 : Plastic, 256 (85.5), 369 (5 Ι24Ί51 (40.3)^264 (1132 * bottomed, 148 (4 New Zealand uses ruthenium-containing compounds as GC_MS quantitative analysis, only need to add a known amount of gas-containing compounds The root of the unknown concentration can be compared with the ion integral of the sand-unspecified ion, and the concentration of the sample of 2 waves is determined. Therefore, the traditional operation is required, and the standard of the sample without the claw must be firstly plotted. The integral φ product is plotted as a figure. The present invention has been modified by those skilled in the art for the purpose of repairing 73 200808681, but it is not intended to be protected by the scope of the patent application. [Simple description of the diagram] None [Key component symbol description] None 74

Claims (1)

200808681 X. Scope of application for patents·· 1. A bismuth-containing compound whose structure is as shown in formula 1: Wherein R1 is methyl oxygen and R2 is chlorine, bromine, iodine, ethylsulfide, propylsulfide, acid group, nitrovinyl, chlorosulfonate, dimercaptovinylamine, or hydrogen, one of which is R3 Is one of methyl oxygen, isopropylamine, nitro or hydrogen, and R4 is ethylamine, isopropylamine, aldehyde, nitrovinyl, chlorosulfonate, dimethylvinylamine or hydrogen. One of them, wherein at least one hydrogen on R1 or R3 is substituted by deuterium. 2. A method for synthesizing a gas-containing compound, comprising the steps of: (1) mixing potassium hydroxide with hydroquinone and tetrabutylammonium bromide to form a first reaction solution; (2) adding hydrazine methyl iodide (cdj) to the first reaction liquid to carry out a reaction to form a di-reaction liquid; (3) extracting the second reaction liquid to obtain a first extract; and (4) performing the first extract Purification by column chromatography gave one oxime, 4-bis(tridecyloxy)benzene. 3. The method of claim 2, wherein step (3) is extracted with a gas-fired gas. 4. The method of claim 2, wherein the column chromatography of step (4) is carried out with ethyl acetate/hexane as the mobile phase. 5. For example, the method of Shen Qiao's patent scope is 帛4 j, in which the ratio of ethyl acetate/hexane is 75/2008. 6. The method of claim 2, wherein the gel system of the column chromatography of step (4) is silicone. 7. The method of claim 2, further comprising the steps of: (5) reacting the ruthenium containing 1 dimethyl oxybenzene with titanium tetrachloride and methylene chloride to form a third reaction liquid. (6) performing a film chromatography on the third reaction solution to obtain a first separation liquid; (7) performing a column chromatography purification on the first separation liquid to obtain a 2 r' T-based oxygen benzene Formaldehyde; (8) refluxing the 2,5-bis(trioxomethyloxy)benzyl-methyl group to obtain a first collection; (=)· and crystallization of the first collection to obtain _ 2, 5_ double (three atmospheres of decyloxy) benzaldehyde; (11) adjusting the collection of the second brother to be acidic; &quot;&quot;i'' 1,4_双(三氘曱基8·If the patent application scope is the seventh item, #丄,;^ 9. If the method of claim 7 is applied, the acetaminophen/hexane is burned to the mobile phase. Wherein the column chromatography is acetic acid. 10. The method of claim 7 wherein the ratio of step ester to hexane is 1/39. The method of the present invention is the method of claim 7, wherein the gel system of the column chromatography is tannin. 12. The method of claim 7, wherein 4d of the step (1) is first dissolved in anhydrous tetrahydrofuran, and then the step (1) is carried out. 13. The method of claim 7, wherein the step (12) is extracted with methylene chloride. 14. The method of claim 7, further comprising the step of: (14) reacting the 2-[2,5-bis(trimethyloloxy)phenyl]ethylamine with bromine to form a fourth (15) After adjusting the pH of the fourth reaction solution to above 丨丨, extracting the fourth reaction solution to obtain 2-[4-bromo-2,5-bis(tridecyloxy) Phenyl]ethylamine. 15. The method of claim 5, wherein 5d of the step is first dissolved in glacial acetic acid, and then step (14) is carried out. 16. The method of claim 14, wherein the step (15) is extracted with dichlorohydrazine. 17. The method of claim 7, further comprising the steps of: (14) salting the 2-[2,5-bis(tridecyloxy)phenyl]ethylamine, and recrystallizing 2 -[2,5-bis(tridecyloxy)phenyl]ethylamine hydrochloride; (15) 2-[2,5-bis(trimethyleneoxy)phenyl]ethylamine hydrochloride The salt reacts with chlorinated sulfuric acid (S〇2Cl2) to form a fifth reaction solution; 〇6) after the fifth reaction layer is analyzed by the color layer of the film, the sputum is introduced into the precipitate; and (17) recrystallized The sinking thing, obtained - [4 'chloro 2,5_bis (trimethylol) phenyl] ethylamine hydrochloride. 18. The method of claim 17, wherein the step (4) of the 200,808,681, and the ethylamine is first dissolved in the ethyl bond, and then the method of the invention is as described in claim 17, for example. , wherein the method is the method of the seventh aspect of the patent, wherein the step (10) of the hydrazine diacetate) phenyl] ethylamine hydrochloride is first dissolved in glacial acetic acid, Then proceed to step (15). For example, the method of claim 7 of the patent scope further comprises heating the mixture of 2-[2,5-bis(trimethylol)phenyl]ethylamine and lysine to deliver a sixth reaction solution; (^) The sixth reaction solution is purified by recording chromatography to obtain -2. That is, 5_bis(di-methyloxy)phenyl]ethyl}isophene-1,3-dione; 06) The 2_{2_[2,5_bis(tri-indolyloxy)'phenyl]ethyl}isodecyl-1,3-dione is reacted with vaporized iodine (IC1) to obtain a seventh reaction solution; (17) extracting the seventh reaction solution to obtain a third extract; (18) collecting the organic layer of the third extract, and performing column chromatography purification to obtain a 2-{2_[4-substituting 2,5· Bis(trimethyloloxy)phenyl]ethyl}iso-_u_di-class; (10) 2-{2-[4-Moth-2,5-bis(trimethyleneoxy)phenyl] Ethyl}iso-p-1,3-dione is heated with hydrazine to obtain a solid; and /' (2〇) is filtered to obtain a filtrate, and the solid is washed with ethanol to obtain a washing solution. (21) The filtrate and the washing liquid were collected and concentrated to obtain a 2-[[iota][iota]methyloxy)phenylamine. The method of claim 21, wherein the column chromatography is carried out with acetic acid/hexane as the mobile phase. 78 200808681. The method of claim 21, wherein the ratio of ethyl acetate/hexane in the step (15) is 1/9. 24. The method of claim 21, wherein the column chromatography gel system is a gel. 25. The method of claim 21, wherein the step (16) is 2] 20 bis(trimethyloloxy)phenyl]ethyl}isoindole, and the oxadione is first dissolved in glacial acetic acid. Then proceed to step (16). 26. The method of claim 21, wherein the step (17) is extracted with methylene chloride. 27. The method of claim 21, wherein the ratio of ethyl acetate/hexane in the step (18) is 1/10. 28. The method of claim 22, wherein the 2_d of the step (19) is 2,5-bis(tris-methyloxy)phenyl]ethyl}iso. Xie Budu], 3_dione is first dissolved in isopropanol, and then step (19). 29. The method of claim 7, wherein the method further comprises the following steps: (14) reacting the 2,5-bis(trimethyleneoxy)benzaldehyde with nitroethane to reflux, obtaining a third (15) performing a film chromatography on the third collection to obtain a second separation solution, (16) extracting the second separation liquid to obtain a fourth extraction liquid; (17) collecting the fourth extraction liquid The organic layer of the stroke liquid is purified by column chromatography to obtain a 1,4_bis(dimurinoyloxy)_2_(2-aminopropenyl)benzene; (18) the 1,4-double ( Trimethyl oxo) 2 yl propyl propyl benzene is reacted with lithium aluminum hydride to reflux to obtain a fourth collection; (19) the pH of the fourth collection is at least greater than 9; The fourth extract is extracted to obtain a fifth extract; 79 200808681 (21) The methyl extract of the fifth extract is collected as a phenyl] small methyl ethylamine. , can be obtained - 2 like - double (three 氘 30. If the application of the scope of the 29th item of oxygen) benzoquinone disk is first dissolved in glacial acetic acid, which is ° Hai 2,5 _ double (two gas 曱 3!. Patent application No. 29 ^^^f (4). Arobine extraction. The middle step (16) is dichloro 32. For example, the vinegar/hexane is the mobile phase. The column chromatography is the ratio of ethyl acetate/hexane which is acetic acid 33·as in the scope of claim 29 of the patent application. The method, wherein the acetic acid of the step (9) is as described in claim 29 of the patent scope. , wherein the column chromatography gel system 35 · as claimed in the scope of the 29th article of the Shide / a pound of mu&quot; to go to the step (18) of 1 4-bis (didecyloxy)_2_ ( 2_Aminopropylamine, ^^, step (10). ~Base) is first dissolved in anhydrous ether, then into 36. According to the scope of claim 29, the method of spoon extraction, _ (10) is two Chlorine 37. The method of claim 29, further comprising the steps of: / (21) salting the 2-[2,5-bis(tricarbenyloxy)phenyl]methylethylamine ,re-crystallize - 2_[2,5_bis(trimethyloloxy)phenyl]*mercaptoethylamine hydrochloride; (22) 2-[2,5-bis(diazamethyloxy)phenyl] The hydrazine ethylamine hydrochloride reacts with bromine to obtain an eighth reaction solution; (23) makes the eighth reaction solution alkaline, and (24) extracts the experimental eighth reaction solution to obtain a sixth Extract; 80 200808681 (2)) The organic layer of the (6) sixth extract was collected and purified by tube riding to obtain 2-[4-bromo-2,5-bis(trimethyleneoxy)phenyl]_丨_ Methyl ethylamine. I, as in the patent application No. 37, the step (21) is recrystallized from /ethyl ether. 39. The method of claim 37, wherein the step (?) is again ("monomethyloxy)phenyl]-1-methylethylamine in glacial acetic acid, and then (22). 4. The method of claim 37, wherein step (23) is extracted by a hospital. The method of claim 37, wherein the column chromatography of the step (25) is alkaline alumina column chromatography. 曰 42 · The method of claim 2, further includes the following Step: reacting M_bis(trimethyloloxy)benzene with chlorolithic acid at night to obtain a ninth (6) adding ice water to the ninth reaction solution to produce stratification; The water layer in the layer obtains a seventh extract; (8) collecting the organic layer of the seventh extract, and purifying the bis(tridecyloxy)benzenesulfonium chloride by f-column chromatography; $2,5_bis(trioxomethyloxy)benzene copper chloride dissolved in 25% thioindole) is added to zinc to obtain a tenth reaction solution; αι) extracts the tenth reaction solution, and obtains an eighth An extract, and (12) collecting the organic layer of the eighth extract, and purifying by column chromatography to obtain a 2,5-bis(tri-indolyloxy)benzenethiol. The method according to the item, wherein the step (5) of α 81 200808681 bis (dimethylmethyl oxy) phenyl thiol first &gt; valley is gas-fired, and then step (5) is carried out. 44. The method of the present invention, wherein the step (7) is extracted by diterpene. ^ 45. The method of claim 42, wherein the column chromatography is carried out with ethyl acetate/hexanol as the mobile phase. 46. The method of claim 42, wherein the ethyl acetate/hexane ratio of the step (8) is 1/9. The method of claim 42, wherein the column chromatography is矽胶. /版丁, 48. For example, please refer to the method of the 42nd patent range, wherein the step (9) is taken by the ^^^^^. 49. The method of claim 42 of the patent scope, wherein the step (10) is B The ratio of ester to hexane is 1/19. 5〇· The method of claim 42 of the patent scope further includes ^ ^ 3 m oxygen) stupid sulfur __ reflux, to obtain a fifth collection; ~ = the fifth collection is subjected to film chromatography, and the third separation liquid is obtained; (15) the second separation liquid is acidified with hydrochloric acid, and the ninth extraction liquid is taken to take the third separation after acidification. The core layer of Jiu Cui Mi, the recording layer is reduced, and the ethyl-p-amine-based Shihuang-based '4-bis(trimethyleneoxy)benzene; (17) is added to the 2_B. For the amine benzene sulfo group: and the second, _ stream, heating: solid in two (18) each solution of the solid, to obtain - solution, 〇 9) the solution was purified by column chromatography, An 'ethyl p-phthalate yellow base 82 200808681 _2,5_ bis (tridecyloxy) benzyl; (20) the 4-ethyl p-amino sulfonyl 2 5 nitro group Reaction, get - tenth - reaction) night; and "&quot; A soil milk) clumsy disk and (21) the tenth-reaction solution for the thin benzotrisyl 2,5-bis (trimethylmethyl) Oxygen) ♦ 曰 曰 ) ) ) ; _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Twelfth reaction solution; milk) (2 stone margin (23) extracting the Xuan Er reaction solution to obtain a tenth extract; and ^242 5 stone κ- 2,5-bis(di-methyloxy)phenyl]ethylamine. 51. The method of claim 50, wherein the step of the bis(trimethyloloxy)benzenethiol is first dissolved in ethanol, and then the step is performed. 52. The method of claim 50, wherein Methyl chloride extraction. ^ ^ 53. The method of claim 50, wherein the column chromatography is performed by using ethyl acetate/hexane as the mobile phase. 54. The method of claim 50, wherein the ethyl acetate/hexane ratio of the step (10) is 1/9. 55. As in the method of applying for the patent item 5, the grade of the cap f-column is hair spray. 56. The method of claim 5, wherein the step (10) is dissolved in ethyl acetate. 57. The method of claim 5, wherein the ratio of ethyl acetate to hexane of the step (19) is 1/19. 58. The method of claim 50, wherein the step (10) of the application 83 200808681 is first dissolved in the tetrahydrofuran, and then the step of: the method of applying the dry 5° term, wherein the step (23) is In the second method, the method further comprises the steps of: flowing, obtaining a sixth-receiving thiol) and reacting with the propyl group to carry out the reaction (14), damaging the sixth collection (15), acidifying the first portion with hydrochloric acid. Four points ', a fourth separation solution; get an eleventh extract; / night, draw the acidified fourth separation solution, (16) collect the tenth - one of the extracts M-double (three atmospheres Methyl oxy (tetra) sulphate is purified and purified by a solution of methyl ketone-2-propyl sulphate and heated to obtain a solid; (18) dissolving the solid to obtain a solution; (19) The solution was purified by column chromatography to obtain -2 &amp; oxon-propyl-featheramine benzene light; 'JILT aldehyde and nitro-methyl (20) 2,5-bis (tri-methyl) Oxygen) propyl sulfonamide benzene fluorene reaction 'to obtain a thirteenth reaction liquid; (21) the thirteenth reaction liquid was subjected to thin film chromatography to obtain a 1 'biguanide methyloxy)_2_(2-; 5 肖基乙基基)_5_propylglycosylamine benzene; ^22) The 1A bis(trimethyloloxy), although the schiffyl propyl propyl acetamide is reacted with lithium aluminum hydride, is refluxed to obtain a first Seven collections; (23) extracting the seventh collection to obtain a twelfth extract; (24) collecting the organic layer of the twelfth extract to obtain a 2_[2,5_double (three-methyl) Oxygen)_xypropylsulfonylphenyl]ethylamine. Another claw 84 200808681 The method of claim 60, wherein the step is 2,5-62 ^ phenylsulfurate (four), riding step (13). The armor of the method of item 60, wherein the step (15) is a method of the second step wherein the column chromatography is acetic acid, wherein the acetic acid of the step (16) 63 is as claimed in claim 6 Ethyl acetate/hexane is the mobile phase. 64. The method of claim 6 of the patent scope The ratio of ethyl ester to hexane is 1/19. A column chromatography chromatography gel system. The method of claim 6, wherein the method is a dream gel. 66. The method of claim 6, wherein the step (15) is dissolved in ethyl acetate. 67. The method of claim 60, wherein the ethyl acetate/hexane ratio of the step (10) is 1/19. 68. The method of claim 60, wherein the step (5) (7) is first dissolved in tetrahydrofuran and then the step (22) is carried out. 69. The method of claim 6, wherein the step (23) is extracted with dichloromethane. 70. A method for synthesizing a ruthenium-containing compound, comprising the steps of: (1) mixing potassium hydroxide with 4-hydroxybenzaldehyde and tetrabutylammonium bromide to form a first reaction solution; (2) adding ruthenium Methyl iodide reacts with the first reaction liquid to form a second reaction liquid; (3) Strokes a Haidi-reaction liquid 'to obtain a ^1' extract; (4) pipe the first extract Purification by column chromatography to obtain _4_tri-m-methyl oxymethane aldehyde; 85 200808681 Reacting with nitro-ethyl (5) to carry out the 4-trimethyl methaldehyde-formaldehyde stream to obtain a first collection (6) extracting the first-collection to obtain a second extract; (7) purifying the n-th british f-column chromatography - 1 - oxy-4-(2-nitropropenyl)benzene; · '(tetra)ylpropenyl)benzene is reacted with an aluminum halide clock to reflux, to obtain a second collection; (9) to make the pH of the second collection at least greater than 9; and (1) to extract the pH adjustment After the second collection, a third extract (11) is obtained to collect the organic layer of the second stroke liquid to obtain monotriphenyl)-1-methylethylamine. A method of claim 7G, wherein the step (3) is extracted with methylene chloride. 72. If the method of replenishing the 7G supplement is applied, the chromatographic system is prepared by using acetic acid acetonitrile/hexane as the mobile phase. 73. The method of claim 70, wherein the ethyl acetate/hexane ratio of the step (4) is 1/19. 74. The method of claim 70, wherein the column chromatography gel system is tannin. 75. The method of claim 70, wherein the step (5) of 4_trimethyl methacrylate is first dissolved in anhydrous acetic acid, and then step (5) is carried out. 76. The method of claim 70, wherein the step (6) is extracted with methylene chloride. 77. The method of claim 70, wherein the ethyl acetate/hexane ratio of the step (7) is 1/39. 86 200808681 78. The method of claim 70, wherein the step = methyl oxygen _ 4 propyl propyl) benzene is first dissolved in anhydrous sulphur, and then step ς as in the scope of claim 70 A method in which a chloroform is extracted. { } 80. — A compound containing ruthenium, the structure of which is shown in Equation 2: Composition, R1 up to where R1 is methoxy, and R2 is one of nitrogen, oxygen or sulfur. One hydrogen is replaced by deuterium. 81. A method for synthesizing a compound containing jTl, comprising the steps of: tetrabutylammonium (1), dehydration, addition of 3-methyl-4-nitrophenol and bromination to obtain a first reaction solution; (2) Adding hydrazine iodine to the first reaction solution to obtain a second reaction solution; (3) extracting the second reaction solution to obtain a first extract; (4) performing column chromatography on the first extract Purification, to obtain a 'triterpene methyloxy 1 methyl + nitrobenzene; (5) the 4_ triterpene methyloxy 2 - fluorenyl small nitro stupid with n, N-dimercaptomethyl hydrazine &amp; The amine-mercaptoacetal is heated and refluxed to obtain a [2_(5-tridecyloxy-2-nitro)vinyl]dimethylamine; (6) the quinone (5-trimethylmethyl) Oxygen 2_nitrophenyl)vinyl]diamine is hydrogenated to obtain a third reaction solution; 87 200808681 (7) The third reaction solution is purified by column chromatography to obtain a trimethyl group.革•m-吲哚: 】 (8) reacting the 5-dimethyl sulfonium with grass-brewed chlorine to obtain a fourth reaction solution, (9) adding dimethylamine to the fourth reaction solution To obtain a solid; (10) dissolve the solid and recrystallize, - 2 points of tri- &amp; methyl oxo 〇 嗓 -2- -2- -2- ; ; ;; (11) the 2-(5- 氖 氖 氧 氧 ^ ^ 侧 与 与The lithium aluminum hydride reaction is carried out to reflux to obtain a first collection; (12) taking the first collection to obtain a second extraction liquid; (13) collecting the organic layer of the diastolic liquid to obtain a [2_ (5_三气曱美$-lif-吲哚!yl)ethyl]dimethylamine. Earth-milk 82. The method of claim 81, wherein the step (3) is extracted with dichloromethane. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The ratio of ethyl acetate/hexane is 1/19. 85. The method of claim 81, wherein the column chromatography gel system is a gel. 86. The method of claim 81 , wherein the step (the triterpene oxy-2-indenyl-μnitrobenzene is dissolved in anhydrous dimethyl decylamine. 87. The method of claim 81, wherein Step (6) The method of the method of claim 81, wherein the hydrogen pressure of the step (6) is the same as the method of the invention. The method of claim 81, wherein the ethyl acetate/hexane ratio of the step (7) is 1/19. 90. The method of claim 81, wherein the step (8) The 5-trimethyloxy-1-lean is first dissolved in anhydrous ether, and then the step (8) is carried out. 91. The method of claim 81, wherein the step (10) is to dissolve the solid in tetrahydrofuran. 92. The method of claim 81, wherein the step (10) is crystallization with diethyl ether. 93. The method of claim 81, wherein 23d of the step (11) is first dissolved in anhydrous tetrahydrofuran, and then step (11) is carried out. 94. The method of claim 81, wherein the step (13) is extracted with diethyl ether. 89 200808681 VII. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 4 200808681 Invention patent specification (Do not change the format, order and bold text of this manual, please do not fill in the ※ part) ※Application number ※Application deadline: XIPC classification I, invention name: (Chinese / English) A quinone-containing compound as a standard for drug testing and a preparation method thereof A SERIES OF DEUTERIUM LABELLED COMPOUNDS AS DRUG TESTING STANDARDS AND THEIR PREPARATIONS I. Applicant: (1 person in total) Name: (Chinese/English) Control of the Department of Health of the Executive Yuan Representative of the National Bureau of Controlled Drugs, Department of Health: (Chinese / English) Jian Junsheng / Chien, Chun-Sheng Residence or Business Office Address: (Chinese / English) σ North Linsen South Road No. 6 / No 6. Lin-Sheng South Road, Taipei, Taiwan, ROC Nationality: (Chinese/English) Republic of China/TW II, Inventor: (Total 2 persons) Name··(Chinese/English) 1 ·Chen Qinghuan/Chinpiao Chen 2 ·The ultimate Yazhu / Ya-ZhuXu country: (Chinese / English) h Republic of China / TW 2 · Republic of China / Τ λ ¥