CN103254194A - Preparation method of 8-thiaxanthine compound - Google Patents
Preparation method of 8-thiaxanthine compound Download PDFInfo
- Publication number
- CN103254194A CN103254194A CN201310186179XA CN201310186179A CN103254194A CN 103254194 A CN103254194 A CN 103254194A CN 201310186179X A CN201310186179X A CN 201310186179XA CN 201310186179 A CN201310186179 A CN 201310186179A CN 103254194 A CN103254194 A CN 103254194A
- Authority
- CN
- China
- Prior art keywords
- formula
- preparation
- thia
- xanthine
- xanthine compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CC*[n]1c(N(*)C(N(*)C2=O)=O)c2nc1 Chemical compound CC*[n]1c(N(*)C(N(*)C2=O)=O)c2nc1 0.000 description 4
- XKCMTRRZQAPFIB-UHFFFAOYSA-N CCBc(cc1)ccc1Sc([n]1C)nc(C(N2C)=O)c1N(C)C2=O Chemical compound CCBc(cc1)ccc1Sc([n]1C)nc(C(N2C)=O)c1N(C)C2=O XKCMTRRZQAPFIB-UHFFFAOYSA-N 0.000 description 1
- ACDRXCSZAAKDAP-UHFFFAOYSA-N CCC(C(C(CC)C(N)=C1)=O)C1=O Chemical compound CCC(C(C(CC)C(N)=C1)=O)C1=O ACDRXCSZAAKDAP-UHFFFAOYSA-N 0.000 description 1
- PKIXKWWGILUFAW-UHFFFAOYSA-N CCC(C(C(CC)C(N)=C1C=O)=O)C1=O Chemical compound CCC(C(C(CC)C(N)=C1C=O)=O)C1=O PKIXKWWGILUFAW-UHFFFAOYSA-N 0.000 description 1
- FNIQYOUSUJTZII-CSKARUKUSA-N CCN(C(C(NC(/C=C/c(cc1OC)ccc1OC)=O)=C(N)N1CC)=O)C1=O Chemical compound CCN(C(C(NC(/C=C/c(cc1OC)ccc1OC)=O)=C(N)N1CC)=O)C1=O FNIQYOUSUJTZII-CSKARUKUSA-N 0.000 description 1
- LUWBSLKMUMZQPP-UHFFFAOYSA-N CCN(C(N)=C(C(N1C)=O)N)C1=O Chemical compound CCN(C(N)=C(C(N1C)=O)N)C1=O LUWBSLKMUMZQPP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of an 8-thiaxanthine compound. The method comprises the following steps of: in the presence of a copper salt catalyst, carrying out a reaction on an xanthine compound having a structure shown in a formula II and sulfur compound having a structure shown in a formula III to generate the 8-thiaxanthine compound having a structure shown in a formula I, wherein R1, R2 and R3 are methyl, ethyl, benzyl, normal-butyl, isobutyl, allyl or 2-pyrimidyl, R1, R2 and R3 are same or different; and R4 is ethyl, n-propyl, phenyl, benzyl, cyclohexyl, p-methylphenyl, 2-naphthyl, p-chlorphenyl, p-bromophenyl or 3-nitrobenzophenone. According to the preparation method, by using low-cost copper salt as a catalyst, a product can be successfully prepared in one step, and the preparation method is simple and efficient, high in yield and has wide application prospect.
Description
Technical field
The present invention relates to the field of chemical synthesis, be specifically related to a kind of preparation method of 8-thia Xanthine compounds.
Background technology
Xanthine (xanthine) is a kind of organ and interior purine bases of body fluid that extensively is present in human body and the other biological body, is commonly used for gentle stimulant and bronchodilator, is particularly suitable for treating symptoms of asthma.Common Xanthine compounds has caffeine (caffeine), theophylline (theophylline) and Theobromine etc.Caffeine and the natural adenosine antagonist of theophylline Chang Zuowei have effects such as pain relieving or inhibition asthma.Because caffeine and theophylline all contain a common mother nucleus structure-xanthine, people begin the synthetic xanthine derivative of a large amount of research as adenosine receptor antagonists, wherein especially gain great popularity with the 8-Xanthine compounds that replaces.On the research basis of the 8-Xanthine compounds that replaces, the chemist has developed a series of clinical effective drug molecules.
For example, KW-3902 is as a kind of A
1The AR adenosine receptor antagonists has been used for cardiopathic clinical treatment, is carrying out clinical three phases tests (P.G.Baraldi, M.A.Tabrizi, S.Gessi and P.A.Borea, Chem.Rev., 2008,108,238) at present.
Simultaneously, the Xanthine compounds that the 8-aryl replaces often has tangible fluorescence property, adds that xanthine structure itself just extensively exists in organism, therefore, organism is not had toxicity substantially, can be used as a kind of fluorescent tag molecule nontoxic or low toxicity and be used for the molecular fluorescence imaging technique, the early detection and judgement (D.Zhao, W.Wang, the F.Yang that are used for the cancer molecule, J.Lan, L.Yang, G.Gao and J.You, Angew.Chem., Int.Ed., 2009,48,3296).
In addition, studies show that 8-thia Xanthine compounds has certain antitumour activity, it can suppress the activity of the central nervous system of rat and rabbit.For example, bibliographical information (H.P.Booysen, C.Moraal, G.Terre ' Blanche, A.Petzer, J.J.Bergh and J.P.Petzer, Bioorg.Med.Chem., 2011,19,7507), following 8-thia Xanthine compounds has very high activity to human body monoamine oxidase MAO-B, its IC
50=0.167 μ M.
The Xanthine compounds of 8-thia makes it can be used as the treatment that lead compound is used for parkinsonism to the highly selective restraining effect of monoamine oxidase B (MAO-B).Therefore, the Xanthine compounds of 8-thia is synthetic extremely important.The synthetic method of traditional 8-thia Xanthine compounds generally is to introduce halogen by Xanthine compounds II through halogenating reaction, obtains the xanthine derivative VI of halo, and then VI reacts synthetic with mercaptan again under alkaline condition, and concrete synthetic route is as follows:
Yet at first, halogenating reaction need be used the halogen of excessive severe corrosive, bromine etc. for example, difficult be used for extensive synthetic; Secondly, the mercaptan compound volatility is very strong, usually has special odor, operates to have very big difficulty, and is also very big to the influence of environment; At last, because the easy oxidation of mercaptan obtains disulfide, cause the generation of more by product, so this method often needs to add excessive mercaptan, cause the reaction of atomic economy lower, be unfavorable for large-scale production.Therefore, it is extremely urgent to seek 8-thia Xanthine compounds synthetic method economic, safe and simple to operate.
Recently, the strategy based on the c h bond activation begins to develop and obtained more application at organic chemistry.C h bond is the simplest in the organic compound, modal functional group, if can directly realize its reaction, can simplify synthetic route greatly, shorten reaction process, be most economical, succinct, cleaning and one of route of synthesis efficiently, meets the development trend of modern green synthetic chemistry.
Summary of the invention
The invention provides a kind of preparation method of 8-thia Xanthine compounds, mantoquita with cheapness is the reaction that catalyzer is realized Xanthine compounds 8-position C-H key and disulfide, can successfully prepare 8-thia Xanthine compounds once going on foot, preparation is simple, the productive rate height.
A kind of preparation method of 8-thia Xanthine compounds may further comprise the steps:
Under the effect of copper salt catalyst, the disulfide of the Xanthine compounds of formula II structure and formula III structure reacts the 8-thia Xanthine compounds of production I structure in organic solvent;
Formula II; Formula III; Formula I;
Among the formula I, R
1, R
2, R
3Be methyl, ethyl, benzyl, normal-butyl, isobutyl-, allyl group or 2-pyrimidyl, R
1, R
2And R
3Identical or inequality, R
4For ethyl, n-propyl, phenyl, benzyl, cyclohexyl, p-methylphenyl, 2-naphthyl, rubigan, to bromophenyl or 3-nitrophenyl; R among the formula II
1, R
2, R
3With the R among the formula I
1, R
2, R
3Has identical meanings; R in the formula III
4With the R among the formula I
4Has identical meanings.
Certainly, R
1, R
2, R
3Also can select other alkyl, R for use
4Also can select the aromatic substituent of other replacement for use.
The concrete synthetic route of above-mentioned reaction is as follows:
Xanthine compounds from formula II structure, directly pass through its C-H priming reaction, next step directly obtains the 8-thia Xanthine compounds of formula I structure in the existence of copper salt catalyst with the disulfide of air-stable, easy to operate formula III structure, and this preparation method has realized 8-thia Xanthine compounds synthetic of formula I structure simply, effectively.
By research, the present invention has realized 8-thia Xanthine compounds synthetic of formula I structure, by conditional filtering, has chosen optimal conditions:
Add Silver monoacetate in reaction, when copper salt catalyst adds fast response, can improve productive rate by adding Silver monoacetate, make preparation method of the present invention, speed of response is very fast, and the productive rate height.
The Xanthine compounds of described formula II structure and the mol ratio of Silver monoacetate are 1:0.02～0.05, and Silver monoacetate plays the carrying out that promotes reaction, the Xanthine compounds of relative formula II structure, and addition is a small amount of.
Described copper salt catalyst is venus crystals, and venus crystals can be brought into play katalysis preferably in organic solvent, add the carrying out of fast response.When copper salt catalyst is selected venus crystals for use, and in reaction, add Silver monoacetate, can have certain synergy, can improve speed of response, can improve productive rate again.
Described organic solvent is N, dinethylformamide (DMF), and this organic solvent provides good reaction environment, is conducive to the carrying out that reacts.Organic solvent does not have strict restriction as the solvent of reaction, and the constant that can adopt those skilled in the art to know is generally being as the criterion by the solubilizing reaction thing.
Described neutralized verdigris, Silver monoacetate, organic solvent DMF(N, dinethylformamide) is the commercially available prod.
The disulfide of the Xanthine compounds of described formula II structure, formula III structure and the mol ratio of copper salt catalyst are 1:0.5～0.6:0.2～1, above-mentioned mol ratio raw material is conducive to the carrying out that react, and obtains the 8-thia Xanthine compounds of formula I structure smoothly.
The temperature of described reaction is 110 ℃～130 ℃, is conducive to the carrying out that react, and further preferred, the temperature of described reaction is 120 ℃.
The time of described reaction does not have strict restriction, by timing sampling, carries out trace analysis with existing analytical procedure such as tlc (TLC), all reacts when wherein a kind of raw material or plurality of raw materials to finish, and the terminal point that is considered as reacting gets final product.Through overtesting, to carry out fully in order to make reaction, the time of described reaction is 8～16 hours, more preferably 10～14 hours, further is preferably 12 hours.
Described being reflected at adopts technology such as extraction, washing, drying and column chromatography for separation to carry out aftertreatment after reacting completely successively, to obtain the high product of purity.Described extraction can adopt methylene dichloride as extraction agent.Described washing can be adopted the saturated common salt washing.The condition of described column chromatography for separation is: silica gel 300～400 orders, and elutriant adopts methylene dichloride-acetone system, and the volume ratio of methylene dichloride and acetone is 15～25:1, more preferably 20:1 in methylene dichloride-acetone system.
The 8-thia Xanthine compounds of the formula I structure of preparation method's preparation of the present invention can carry out the Liebeskind-Srogl linked reaction with boric acid well, preparation high yield, the 8-aryl that fluorescence activity or physiologically active are arranged or the xanthine derivative of alkenyl substituted.
The present invention also provides the preparation method of the Xanthine compounds of a kind of 8-aryl or alkenyl substituted, and preparation is simple, the productive rate height.
The preparation method of the Xanthine compounds of a kind of 8-aryl or alkenyl substituted may further comprise the steps:
Under three (dibenzalacetones), two palladiums and the cuprous effect of thiophene-2-carboxylic acid, the compound of the 8-thia Xanthine compounds of formula I structure and formula IV structure reacts the 8-aryl of production V structure or the Xanthine compounds of alkenyl substituted in organic solvent;
Among the formula V, R
1, R
2, R
3Be methyl, ethyl, benzyl, normal-butyl, isobutyl-, allyl group or 2-pyrimidyl, R
1, R
2And R
3Identical or inequality, R
5Be the phenyl of phenyl, 2-furyl, styryl, replacement, the 2-furyl of replacement or the styryl of replacement; R among the formula I
1, R
2, R
3With the R among the formula V
1, R
2, R
3Has identical meanings, R
4For ethyl, n-propyl, phenyl, benzyl, cyclohexyl, p-methylphenyl, 2-naphthyl, rubigan, to bromophenyl or 3-nitrophenyl; R among the formula IV
5With the R among the formula V
5Has identical meanings.
The concrete synthetic route of above-mentioned reaction is as follows:
At three (dibenzalacetone) two palladium (Pd
2(dba)
3) and thiophene-2-carboxylic acid cuprous (CuTC) effect down, can have certain synergy to reaction, can improve speed of response, can improve productive rate again.
Among the formula I, R
4Be preferably phenyl, the compound of formula IV structure is boric acid compound.
As preferably, described organic solvent is tetrahydrofuran (THF) (THF), and this organic solvent provides good reaction environment, is conducive to the carrying out that reacts.Organic solvent does not have strict restriction as the solvent of reaction, and the constant that can adopt those skilled in the art to know is generally being as the criterion by the solubilizing reaction thing.
As preferably, the cuprous mol ratio of the 8-thia Xanthine compounds of described formula I structure, compound, three (dibenzalacetone) two palladiums of formula IV structure and thiophene-2-carboxylic acid is 1:0.8～1.2:0.03～0.08:1～2, above-mentioned mol ratio raw material is conducive to the carrying out that react, and obtains the 8-aryl of formula V structure or the Xanthine compounds of alkenyl substituted smoothly.Further preferred, be 1:1:0.05:1.5.
Three (dibenzalacetone) two palladium (Pd
2(dba)
3), tetrahydrofuran (THF) (THF), thiophene-2-carboxylic acid cuprous (CuTC), the three is the commercially available prod.
As preferably, the temperature of described reaction is 50 ℃～70 ℃, is conducive to the carrying out that react, and further preferred, the temperature of described reaction is 60 ℃.
The time of described reaction does not have strict restriction, by timing sampling, carries out trace analysis with existing analytical procedure such as tlc (TLC), all reacts when wherein a kind of raw material or plurality of raw materials to finish, and the terminal point that is considered as reacting gets final product.Through overtesting, to carry out fully in order to make reaction, the time of described reaction is preferably 8～16 hours, more preferably 10～14 hours, further is preferably 12 hours.
Described being reflected at adopts technology such as extraction, washing, drying and column chromatography for separation to carry out aftertreatment after reacting completely successively, to obtain the high product of purity.Described extraction can adopt methylene dichloride as extraction agent.Described washing can be adopted the saturated common salt washing.The condition of described column chromatography for separation is: silica gel 300～400 orders, and elutriant adopts methylene dichloride-acetone system, and the volume ratio of methylene dichloride and acetone is 15～25:1, more preferably 20:1 in methylene dichloride-acetone system.
As preferably, among the formula V, R
1Be methyl, R
2Be ethyl, R
3Be ethyl, R
5It is 3,4-dimethoxy-styryl; R among the formula I
1, R
2, R
3With the R among the formula V
1, R
2, R
3Has identical meanings, R
4Be phenyl; R among the formula IV
5With the R among the formula V
5Has identical meanings.Concrete synthetic route is as follows:
Above-mentioned reaction is the synthetic of a kind of anti-Parkinson disease clinical medicine KW-6002, and productive rate is 83%.
Compared with prior art, the present invention has following advantage:
The preparation method of 8-thia Xanthine compounds of the present invention, be the reaction that catalyzer is realized the disulfide of the Xanthine compounds 8-position C-H key of formula II structure and formula III structure with the mantoquita of cheapness first, can successfully prepare 8-thia Xanthine compounds once going on foot, preparation is simple, the productive rate height, functional group's compatibility is good.The use of the disagreeableness halogenating reaction of traditional environment has been avoided in the application of c h bond functionalization strategy, and making originally needed the synthetic process of multistep realizing once going on foot, and improves atom utilization greatly, has reduced waste discharge, has significantly reduced Financial cost.This seems increasingly serious current at the energy, material growing tension and environmental protection problem, has great importance.
Simultaneously, the 8-thia Xanthine compounds of the present invention's preparation can successfully carry out the Liebeskind-Srogl linked reaction, the especially synthetic Xanthine compounds with 8-aryl, heteroaryl or alkenyl substituted of fluorescence activity and physiologically active of Xanthine compounds that replaces for synthetic various 8-provides simple, an effective synthetic method, preparation is simple, the productive rate height.And on this basis, be that 8-thia Xanthine compounds sets out, realized the synthetic method of anti-Parkinson disease clinical medicine KW-6002, productive rate is up to 83%, need 5 step chemical reactions with original bibliographical information, 33% overall yield is compared, and very large raising and progress have been arranged, and has a good application prospect.
Embodiment
Embodiment 1:
In the round-bottomed flask of 25mL, add Silver monoacetate (7mg 0.05mmol) and venus crystals (100mg 0.5mmol), adds 2mL DMF(N, dinethylformamide) dissolving, then adds caffeine 1a(385mg, 2.5mmol, namely among the formula II, R
1, R
2, R
3Be methyl) and diphenyl disulfide 2a(325mg, 1.5mmol, namely in the formula III, R
4Be phenyl) the formation reaction system.Reaction system adds the 5mL shrend at 120 ℃ after following 12 hours goes out methylene dichloride (10mL) extraction three times.The organic layer that organic phase merging back obtains after washing with saturated common salt is through anhydrous sodium sulfate drying, rotary evaporation desolventizing again, (elutriant: the volume ratio of methylene dichloride and acetone=20:1) obtains 1 of 717.5mg to use silica gel (300～400 order) column chromatography for separation then, 3,7-trimethylammonium-8-thiophenyl xanthine (productive rate: 95%), be white solid.135～137 ℃ of the fusing points of product;
1H NMR (CDCl
3, 600MHz): δ 7.29-7.37 (m, 5H), 3.93 (s, 3H), 3.57 (s, 3H), 3.40 (s, 3H);
13C NMR (150MHz, CDCl
3) δ 155.0,151.4,148.1,146.4,130.9,130.5,129.6,128.3,109.6,33.2,29.9,28.0.Show that white solid is 1,3 shown in the structural formula 3aa, 7-trimethylammonium-8-thiophenyl xanthine.
Embodiment 2:
Make the catalyzer except the venus crystals of 2.5mmol replaces the venus crystals of 0.5mmol among the embodiment 1, all the other operation stepss obtain 1,3,7-trimethylammonium-8-thiophenyl xanthine 3aa with embodiment 1, productive rate 85%, and the product characterization data is with embodiment 1.
Embodiment 3:
Make the additive except the Silver monoacetate of 0.125mmol replaces the Silver monoacetate of 0.05mmol among the embodiment 1, all the other operation stepss obtain 1,3,7-trimethylammonium-8-thiophenyl xanthine 3aa with embodiment 1, productive rate 91%, and the product characterization data is with embodiment 1.
Embodiment 4:
Except the diphenyl disulfide 2a with 1.25mmol replaces the diphenyl disulfide 2a of 1.5mmol among the embodiment 1, all the other operation stepss obtain 1,3,7-trimethylammonium-8-thiophenyl xanthine 3aa with embodiment 1, productive rate 84%, and the product characterization data is with embodiment 1.
Embodiment 5:
Except with 7-benzyl-1,3-dimethyl xanthine 1b(2.5mmol, namely among the formula II, R
1Be benzyl, R
2And R
3Be methyl) replace among the embodiment 1 outside the caffeine 1a, all the other operation stepss get white solid with embodiment 1, productive rate 95%.The fusing point of product: 122～124 ℃;
1H NMR (CDCl
3, 400MHz): δ 7.38-7.28 (m, 10H), 5.63 (s, 2H), 3.54 (s, 3H), 3.41 (s, 3H);
13C NMR (100MHz, CDCl
3): δ 154.7,151.4, and 148.5,147.0,135.7,131.0,130.7,129.4,128.8,128.4,128.2,127.8,108.8,49.4,29.9,28.1; HRMS:calcd for C
20H
19N
4O
2S (M+H)
+379.1229, Found379.1231.Show that white solid is the 7-benzyl-1 shown in the structural formula 3ba, 3-dimethyl-8-thiophenyl xanthine.
Embodiment 6:
Except with 7-butyl-1,3-dimethyl xanthine 1c(2.5mmol, namely among the formula II, R
1Be normal-butyl, R
2And R
3Be methyl) replace among the embodiment 1 outside the caffeine 1a, all the other operation stepss get white solid with embodiment 1, productive rate 87%.The fusing point of product: 78～80 ℃;
1H NMR (CDCl
3, 400MHz): δ 7.42-7.31 (m, 5H), 4.37 (t, J=7.3Hz, 2H), 3.56 (s, 3H), 3.41 (s, 3H), 1.71-1.67 (m, 2H), 1.37-1.31 (m, 2H), 0.92 (t, J=7.3Hz, 3H);
13C NMR (100MHz, CDCl
3) δ 154.6,151.5,148.4,146.1,131.3,130.7,129.5,128.3,108.9,46.6,32.8,29.9,28.0,19.7,13.6; HRMS:calcd for C
17H
21N
4O
2S (M+H)
+345.1385 Found 345.1381.Show that white solid is the 7-normal-butyl-1 shown in the structural formula 3ca, 3-dimethyl-8-thiophenyl xanthine.
Embodiment 7:
Except with 7-isobutyl--1,3-dimethyl xanthine 1d(2.5mmol, namely among the formula II, R
1Be isobutyl-, R
2And R
3Be methyl) replace among the embodiment 1 outside the caffeine 1a, all the other operation stepss get white solid with embodiment 1, productive rate 70%.The fusing point of product: 87-88 ° C;
1H NMR (CDCl
3, 600MHz): δ 7.44-7.29 (m, 5H), 4.21 (d, J=7.8Hz, 2H), 3.56 (s, 3H), 3.42 (s, 3H), 2.30-2.25 (m, 1H), 0.95 (d, J=6.6Hz, 6H);
13C NMR (150MHz, CDCl
3): δ 154.6,151.4, and 148.4,146.9,131.0,130.9,129.5,128.3,109.1,53.4,29.9,29.9,28.0,19.6; HRMS:calcd for C
17H
21N
4O
2S (M+H)
+345.1385, Found345.1380.Show that white solid is the 7-isobutyl--1 shown in the structural formula 3da, 3-dimethyl-8-thiophenyl xanthine.
Embodiment 8:
Except with 7-allyl group-1,3-dimethyl xanthine 1e(2.5mmol, namely among the formula II, R
1Be allyl group, R
2And R
3Be methyl) replace among the embodiment 1 outside the caffeine 1a, all the other operation stepss get white solid with embodiment 1, productive rate 83%, the fusing point of product: 78～80 ℃;
1H NMR (CDCl
3, 600MHz): δ 7.45-7.40 (m, 2H), 7.38-7.31 (m, 3H), 5.87-5.94 (m, 1H), 5.20 (d, J=10.2Hz, 1H), 5.11 (dd, J=17.4,0.6Hz, 1H), 5.05 (d, J=5.4Hz, 2H), 3.57 (s, 3H), 3.41 (s, 3H);
13C NMR (150MHz, CDCl
3): δ 154.5,151.4, and 148.3,146.5,131.8,131.0,130.9,129.5,128.4,118.6,108.7,48.4,29.9,28.0; HRMS:calcd for C
16H
17N
4O
2S (M+H)
+329.1072, Found329.1077.Show that white solid is the 7-allyl group-1 shown in the structural formula 3ea, 3-dimethyl-8-thiophenyl xanthine.
Embodiment 9:
Except using the 7-(2-pyrimidyl)-1,3-dimethyl xanthine 1f(2.5mmol, namely among the formula II, R
1Be 2-pyrimidyl, R
2And R
3Be methyl) replace among the embodiment 1 outside the caffeine 1a, all the other operation stepss get white solid with embodiment 1, productive rate 75%.The nuclear-magnetism of product characterizes:
1H NMR (CDCl
3, 600MHz): δ 8.94 (d, J=4.9Hz, 2H), 7.60-7.52 (m, 2H), 7.46 (t, J=4.9Hz, 1H), 7.43-7.38 (m, 3H), 3.50 (s, 3H), 3.41 (s, 3H);
13C NMR (150MHz, CDCl
3): δ 158.6,154.3, and 153.4,152.3,151.5,149.5,134.0,139.4,129.3,129.0,120.5,108.5,30.1,28.3; HRMS:calcd for C
17H
15N
6O
2S (M+H)
+367.0977, Found367.0974.Show that white solid is the 7-shown in the structural formula 3fa (2-pyrimidyl)-1,3-dimethyl-8-thiophenyl xanthine.
Embodiment 10:
Except with 1-benzyl-3,7-dimethyl xanthine 1g(2.5mmol, namely among the formula II, R
2Be benzyl, R
1And R
3Be methyl) replace among the embodiment 1 outside the caffeine 1a, all the other operation stepss are with embodiment 1, and productive rate 81% gets white solid.The fusing point of product: 114-116 ° C;
1H NMR (CDCl
3, 600MHz): δ 7.52-7.27 (m, 10H), 5.21 (s, 2H), 3.95 (s, 3H), 3.58 (s, 3H);
13C NMR (150MHz, CDCl
3) δ 154.8,151.3,148.2,146.6,137.3,130.9,130.5,129.6,128.9,128.4,128.3,127.6,109.6,44.5,33.2,29.9; HRMS:calcd for C
20H
19N
4O
2S (M+H)
+379.1229, Found379.1222.Show that white solid is the 1-benzyl-3 shown in the structural formula 3ga, 7-dimethyl-8-thiophenyl xanthine.
Embodiment 11:
Except with 1-normal-butyl-3,7-dimethyl xanthine 2h(2.5mmol, namely among the formula II, R
2Be normal-butyl, R
1And R
3Be methyl) replace among the embodiment 1 outside the caffeine 1a, all the other operation stepss get white solid with embodiment 1, productive rate 73%.The fusing point of product: 102～104 ℃;
1H NMR (CDCl
3, 400MHz): δ 7.36-7.31 (m, 5H), 4.00 (t, J=7.6Hz, 2H), 3.92 (s, 3H), 3.55 (s, 3H), 1.68-1.60 (m, 2H), 1.42-1.36 (m, 2H), 0.95 (t, J=7.6Hz, 3H);
13C NMR (150MHz, CDCl
3): δ 154.9,151.2, and 148.1,146.2,131.5,130.4,129.6,128.2,109.7,41.3,33.1,30.1,29.8,20.2,13.8; HRMS:calcd for C
17H
21N
4O
2S (M+H)
+345.1385, Found345.1380.Show that white solid is the 1-normal-butyl-3 shown in the structural formula 3ha, 7-dimethyl-8-thiophenyl xanthine.
Embodiment 12:
Except with 1-isobutyl--3,7-dimethyl xanthine 2i(2.5mmol, namely among the formula II, R
2Be isobutyl-, R
1And R
3Be methyl) replace among the embodiment 1 outside the caffeine 1a, all the other operation stepss get white solid with embodiment 1, productive rate 65%.The fusing point of product: 82～84 ℃;
1H NMR (CDCl
3, 400MHz): δ 7.39-7.30 (m, 5H), 3.92 (s, 3H), 3.83 (d, J=7.6Hz, 2H), 3.55 (s, 3H), 2.19-2.12 (m, 1H), 0.92 (d, J=6.8Hz, 6H);
13C NMR (150MHz, CDCl
3): δ 155.1,151.5, and 148.1,146.3,130.9,130.5,129.6,128.3,109.6,48.2,33.2,29.9,27.2,20.2; HRMS:calcd for C
17H
21N
4O
2S (M+H)
+345.1385, Found345.1386.Show that white solid is the 1-isobutyl--3 shown in the structural formula 3ia, 7-dimethyl-8-thiophenyl xanthine.
Embodiment 13:
Except with 1-allyl group-3,7-dimethyl xanthine 2j(2.5mmol, namely among the formula II, R
2Be allyl group, R
1And R
3Be methyl) replace among the embodiment 1 outside the caffeine 1a, all the other operation stepss get white solid with embodiment 1, productive rate 68%.The fusing point of product: 123～124 ℃;
1H NMR (CDCl
3, 400MHz): δ 7.37-7.30 (m, 5H), 5.96-5.86 (m, 1H), 5.29-5.17 (m, 2H), 4.64-4.61 (m, 2H), 3.92 (s, 3H), 3.56 (s, 3H);
13C NMR (100MHz, CDCl
3) δ 154.5,151.0,148.2,146.6,132.2,130.8,130.6,129.6,128.3,117.7,109.6,43.4,33.2,29.8; HRMS:calcd for C
16H
17N
4O
2S (M+H)
+329.1072, Found329.1067.Show that white solid is the 1-allyl group-3 shown in the structural formula 3ja, 7-dimethyl-8-thiophenyl xanthine.
Embodiment 14:
Except with 4,4'-dimethyl diphenyl disulfide 2b(1.5mmol, namely in the formula III, R
4Be p-methylphenyl) replace among the embodiment 1 outside the diphenyl disulfide 2a, all the other operation stepss get white solid with embodiment 1, productive rate 95%.136～138 ℃ of the fusing points of product;
1H NMR (CDCl
3, 400MHz): δ 7.28-7.13 (m, 4H), 3.90 (s, 3H), 3.54 (s, 3H), 3.38 (s, 3H), 2.33 (s, 3H);
13C NMR (100MHz, CDCl
3): δ 154.9,151.4, and 148.0,147.2,138.7,131.2,130.4,126.9,109.4,33.1,29.8,27.9,21.1; HRMS:calcd for C
15H
17N
4O
2S (M+H)
+317.1072, Found317.1077.Show that white solid is 1,3 shown in the structural formula 3ab, the toluene sulfenyl of 7-trimethylammonium-8-xanthine.
Embodiment 15:
Except with two (2-naphthyl) disulfide 2c(1.5mmol, namely in the formula III, R
4Be the 2-naphthyl) replace among the embodiment 1 outside the diphenyl disulfide 2a, all the other operation stepss get white solid with embodiment 1, productive rate 70%.The fusing point of product: 172～174 ℃;
1H NMR (CDCl
3, 400MHz): δ 7.88 (d, J=1.5Hz, 1H), 7.83-7.76 (m, 3H), 7.54-7.49 (m, 2H), 7.39 (dd, J=8.8,2.0Hz, 1H), 3.95 (s, 3H), 3.57 (s, 3H), 3.41 (s, 3H);
13C NMR (100MHz, CDCl
3): δ 155.0,151.4, and 148.1,146.5,133.6,132.6,129.8,129.5,127.9,127.8,127.6,127.5,127.1,127.0,109.6,33.2,29.9,28.0; HRMS:calcd for C
18H
17N
4O
2S (M+H)
+353.1072, Found353.1075.Show that white solid is 1,3 shown in the structural formula 3ac, 7-trimethylammonium-8-(2-naphthalene sulfenyl) xanthine.
Embodiment 16:
Except with 4,4'-dichloro diphenyl disulfide 2d(1.5mmol, namely in the formula III, R
4Be rubigan) replace among the embodiment 1 outside the diphenyl disulfide 2a, all the other operation stepss get white solid with embodiment 1, productive rate 75%.The fusing point of product: 165～168 ℃;
1H NMR (CDCl
3, 600MHz): δ 7.29-7.35 (m, 4H), 3.94 (s, 3H), 3.54 (s, 3H), 3.40 (s, 3H);
13C NMR (150MHz, CDCl
3): δ 154.9,151.4, and 148.1,146.0,134.7,132.1,129.8,129.1,109.6,33.1,29.9,28.0; HRMS:calcd for C
14H
14ClN
4O
2S (M+H)
+337.0526, Found337.0529.Show that white solid is 1,3 shown in the structural formula 3ad, the chlorobenzene sulfenyl of 7-trimethylammonium-8-xanthine.
Embodiment 17:
Except with 4,4'-dibromo diphenyl disulfide 2e(1.5mmol, namely in the formula III, R
4For to bromophenyl) replace among the embodiment 1 outside the diphenyl disulfide 2a, all the other operation stepss get white solid with embodiment 1, productive rate 92%.The fusing point of product: 151-154 ° C;
1H NMR (CDCl
3, 600MHz): δ 7.50-7.26 (m, 4H), 3.96 (s, 3H), 3.57 (s, 3H), 3.42 (s, 3H);
13C NMR (150MHz, CDCl
3): δ 154.9,151.4, and 148.1,145.8,132.7,132.2,129.8,122.7,109.6,33.1,29.9,28.0; HRMS:calcd for C
14H
14BrN
4O
2S (M+H)
+381.0021, Found381.0015.Show that white solid is 1,3 shown in the structural formula 3ae, the bromobenzene sulfenyl of 7-trimethylammonium-8-xanthine.
Embodiment 18:
Except with 3,3'-dinitrobenzene diphenyl disulfide 2f(1.5mmol, namely in the formula III, R
4Be the 3-nitrophenyl) replace among the embodiment 1 outside the diphenyl disulfide 2a, all the other operation stepss get white solid with embodiment 1, productive rate 75%.The fusing point of product: 223-226 ℃;
1H NMR (CDCl
3, 400MHz): δ 8.31 (t, J=2.0Hz, 1H), 8.18 (dd, J=8.2,1.2Hz, 1H), 7.69 (d, J=7.9Hz, 1H), 7.55 (t, J=8.0Hz, 1H), 4.01 (s, 3H), 3.56 (s, 3H), 3.42 (s, 3H);
13C NMR (100MHz, CDCl
3): δ 154.9,151.3, and 148.2,144.3,135.8,133.6,130.3,125.0,123.1,122.5,109.8,33.2,29.9,28.1; HRMS:calcd for C
14H
14N
5O
4S (M+H)
+348.0766, Found348.0758.Show that white solid is 1,3 shown in the structural formula 3af, 7-trimethylammonium-8-m-nitro sulfenyl xanthine.
Embodiment 19:
Except using benzyldithio toluene 2g(1.5mmol, namely in the formula III, R
4Be benzyl) replace among the embodiment 1 outside the diphenyl disulfide 2a, all the other operation stepss get white solid with embodiment 1, productive rate 65%.147～149 ℃ of the fusing points of product;
1H NMR (CDCl
3, 400MHz): δ 7.37-7.28 (m, 5H), 4.47 (s, 2H), 3.74 (s, 3H), 3.62 (s, 3H), 3.40 (s, 3H);
13C NMR (100MHz, CDCl
3): δ 154.6,151.5, and 150.0,148.4,136.6,128.9,128.7,127.9,108.7,37.5,32.2,29.8,27.9.Show that white solid is 1,3 shown in the structural formula 3ag, 7-trimethylammonium-8-benzylthio-xanthine.
Embodiment 20:
Except with diethyl disulfide 2h(1.5mmol, namely in the formula III, R
4Be ethyl) replace among the embodiment 1 outside the diphenyl disulfide 2a, all the other operation stepss get white solid with embodiment 1, productive rate 78%.The fusing point of product: 132～134 ℃;
1H NMR (CDCl
3, 400MHz): δ 3.84 (s, 3H), 3.56 (s, 3H), 3.39 (s, 3H), 3.28 (q, J=7.4Hz, 2H), 1.43 (t, J=7.4Hz, 3H);
13C NMR (150MHz, CDCl
3) δ 154.6,151.5,151.1,148.5,108.5,32.1,29.7,27.8,27.2,15.0; HRMS:calcd for C
10H
15N
4O
2S (M+H)
+255.0916, Found255.0910.Show that white solid is 1,3 shown in the structural formula 3ah, 7-trimethylammonium-8-ethylmercapto group xanthine.
Embodiment 21:
Except using dipropyl disulfide 2i(1.5mmol, namely in the formula III, R
4Be n-propyl) replace among the embodiment 1 outside the diphenyl disulfide 2a, all the other operation stepss get white solid with embodiment 1, productive rate 70%.The fusing point of product: 124～127 ° of C;
1H NMR (CDCl
3, 600MHz): δ 3.86 (s, 3H), 3.57 (s, 3H), 3.40 (s, 3H), 3.26 (t, J=7.2Hz, 2H), 1.84-1.75 (m, 2H), 1.06 (t, J=7.4Hz, 3H);
13C NMR (150MHz, CDCl
3): δ 154.6,151.6, and 151.4,148.5,108.5,34.7,32.1,29.7,27.8,23.0,13.2; HRMS:calcd for C
11H
17N
4O
2S (M+H)
+269.1072, Found269.1077.Show that white solid is 1,3 shown in the structural formula 3ai, 7-trimethylammonium-8-rosickyite base xanthine.
Embodiment 22:
Except using dicyclohexyldisulfide 2j(1.5mmol, namely in the formula III, R
4Be cyclohexyl) replace among the embodiment 1 outside the diphenyl disulfide 2a, all the other operation stepss get white solid with embodiment 1, productive rate 65%.The fusing point of product: 132～134 ℃;
1H NMR (CDCl
3, 600MHz): δ 3.87 (s, 3H), 3.79-3.74 (m, 1H), 3.57 (s, 3H), 3.40 (s, 3H), 2.10-2.05 (m, 2H), 1.82-1.70 (m, 2H), 1.68-1.62 (m, 1H), and 1.58-1.49 (m, 2H), 1.45-1.39 (m, 2H), 1.34-1.28 (m, 1H);
13C NMR (150MHz, CDCl
3): δ 154.4,151.3, and 150.2,148.3,108.2,47.1,33.2,32.2,29.6,27.7,25.7,25.3.Show that white solid is 1,3 shown in the structural formula 3aj, 7-trimethylammonium-8-cyclohexyl xanthine.
Embodiment 23:
In the round-bottomed flask of 10mL, add 1,3,7-trimethylammonium-8-thiophenyl xanthine 3aa (120.9mg, 0.4mmol, namely among the formula I, R
1, R
2And R
3Be methyl, R
4Be phenyl), phenylo boric acid 4a(48.8mg, 0.4mmol, namely among the formula IV, R
5Be phenyl), Pd
2(dba)
3(20.6mg 0.02mmol), CuTC(114.4mg, 0.6mmol) adds the dissolving of 2mL tetrahydrofuran (THF) and forms reaction system.Reaction system adds the 5mL shrend in reaction under 60 ℃ after 12 hours goes out methylene dichloride (10mL) extraction three times.The organic layer that organic phase merging back obtains after washing with saturated common salt is through anhydrous sodium sulfate drying, rotary evaporation desolventizing again, (elutriant: the volume ratio of methylene dichloride and acetone=20:1) obtains 143.5mg1 to use silica gel (300～400 order) column chromatography for separation then, 3,7-trimethylammonium-8-phenyl yanthine (productive rate: 90%), be white solid.
The fusing point of this white solid is 180～181 ℃;
1H NMR (CDCl
3, 600MHz): δ 7.70-7.68 (m, 2H), 7.54-7.53 (m, 3H), 4.07 (s, 3H), 3.65 (s, 3H), 3.45 (s, 3H);
13C NMR (150MHz, CDCl
3): δ 155.4,152.0, and 151.5,148.0,130.3,129.1,128.8,128.1,108.4,33.8,29.7,27.9.Show that white solid is 1,3 shown in the structural formula 5aa, 7-trimethylammonium-8-phenyl yanthine.
In addition, document discloses this compound 5aa(D.Zhao, W.Wang, F.Yang, J.Lan, L.Yang, G.Gao and J.You, Angew.Chem., Int.Ed., 2009,48,3296) have fluorescence activity preferably, the fluorescent tag molecule that can be used as a kind of low toxicity is used for the molecular fluorescence imaging technique, be used for early detection and the judgement of cancer molecule, have a good application prospect.
Embodiment 24:
Except with 2-furyl boric acid 4b(0.4mmol, namely among the formula IV, R
5Be the 2-furyl) replace among the embodiment 23 outside the phenylo boric acid 4a, all the other operation stepss get white solid with embodiment 23, productive rate 75%.
1H?NMR(CDCl
3,600MHz):δ7.68-7.64(m,1H),7.11-7.09(m,1H),6.63-6.61(m,1H),4.25(s,3H),3.62(s,3H),3.43(s,3H);
13C?NMR(150MHz,CDCl
3):δ155.4,151.6,148.3,144.7,144.1,142.9,113.5,112.1,107.9,33.6,29.8,28.0；HRMS:calcd?for?C
12H
13N
4O
3(M+H)
+261.0988,Found261.0979。Show that white solid is 1,3 shown in the structural formula 5ab, 7-trimethylammonium-8-(2-furyl) xanthine.
Embodiment 25:
Except with styryl boric acid 4c(0.4mmol, namely among the formula IV, R
5Be styryl) replace among the embodiment 23 outside the phenylo boric acid 4a, all the other operation stepss get white solid with embodiment 23, productive rate 70%.
1H?NMR(CDCl
3,600MHz):δ7.82(d,J=15.7Hz,1H),7.59-7.58(m,2H),7.43-7.36(m,3H),6.93(d,J=15.7Hz,1H),4.07(s,3H),3.64(s,3H),3.42(s,3H);
13C?NMR(150MHz,CDCl
3):δ155.2,151.7,149.9,148.5,138.3,135.4,129.5,128.9,127.3,111.2,107.9,31.5,29.8,27.9。Show that white solid is 1,3 shown in the structural formula 5ac, 7-trimethylammonium-8-styryl xanthine.
The novel synthesis of embodiment 26(anti-Parkinson disease clinical medicine KW-6002):
Except with 3,4-dimethoxy-styryl boric acid (0.4mmol, namely among the formula IV, R
5Be 3,4-dimethoxy-styryl) replace phenylo boric acid and 1,3-diethyl-8-thiophenyl 9-methyl xanthine among the embodiment 23 (0.4mmol, namely among the formula I, R
1Be methyl, R
2And R
3Be ethyl, R
4Be phenyl) replace 1,3 among the embodiment 23, outside 9-trimethylammonium-8-thiophenyl xanthine, all the other operation stepss get white solid with embodiment 23, productive rate 83%, mp=101～103 ℃;
1H NMR (CDCl
3, 600MHz): δ 7.71 (d, J=15.6Hz, 1H), 7.17 (dd, J=8.2,1.9Hz, 1H), 7.07 (d, J=1.9Hz, 1H), 6.88 (d, J=8.2Hz, 1H), 6.74 (d, J=15.8Hz, 1H), 4.19 (q, J=7Hz, 2H), 4.07 (q, J=7Hz, 2H), 4.03 (s, 3H), 3.93 (s, 3H), 3.90 (s, 3H), 1.36 (t, J=7Hz, 3H), 1.23 (t, J=7Hz, 3H);
13C NMR (150MHz, CDCl
3): 155.1,150.8,150.4,150.2,149.2,148.2,138.2,128.6,121.2,111.2,109.5,109.3,108.0,56.0,55.9,38.4,36.3,31.5,13.4,13.4; HRMS:calcd for C
20H
25N
4O
4(M+H)
+385.1876, Found385.1879.Show that this white solid is (the E)-8-shown in the structural formula KW-6002 (3,4-dimethoxy-styryl)-1,3-diethyl-heteroxanthine.
As a comparison, KW-6002 is the new drug of a treatment parkinsonism of Japanese Kyowa Hakko company exploitation, and Japan and the U.S. carry out the test of clinical second phase at present.It synthesizes bibliographical information (J.Hockemeyer, J.C.Burbiel and C.E.M ü ller, J.Org.Chem., 2004,69,3308) by following synthetic route:
This synthetic route needed for 5 steps, overall yield 33%, and exist the disagreeableness halogenated solvent methylene dichloride of environment for use, need high pressure-temperature reaction shortcomings such as (170～180 ℃).Under comparing, the present invention is from 8-thiophenyl xanthine, and by the linked reaction of simple palladium catalysis, the productive rate with 83% has synthesized KW6002, is the present the most effectively synthetic route of KW-6002.Particularly this synthetic route has been avoided the complex operations of polystep reaction, and carries out under gentle relatively condition (60 ℃), and is simple to operate, and it is synthetic to be fit to scale.
Claims (10)
1. the preparation method of a 8-thia Xanthine compounds is characterized in that, may further comprise the steps:
Under the effect of copper salt catalyst, the disulfide of the Xanthine compounds of formula II structure and formula III structure reacts the 8-thia Xanthine compounds of production I structure in organic solvent;
Formula II; Formula III; Formula I;
Among the formula I, R
1, R
2, R
3Be methyl, ethyl, benzyl, normal-butyl, isobutyl-, allyl group or 2-pyrimidyl, R
1, R
2And R
3Identical or inequality, R
4For ethyl, n-propyl, phenyl, benzyl, cyclohexyl, p-methylphenyl, 2-naphthyl, rubigan, to bromophenyl or 3-nitrophenyl; R among the formula II
1, R
2, R
3With the R among the formula I
1, R
2, R
3Has identical meanings; R in the formula III
4With the R among the formula I
4Has identical meanings.
2. the preparation method of 8-thia Xanthine compounds according to claim 1 is characterized in that, adds Silver monoacetate in reaction.
3. the preparation method of 8-thia Xanthine compounds according to claim 2 is characterized in that, the Xanthine compounds of described formula II structure and the mol ratio of Silver monoacetate are 1:0.02～0.05.
4. the preparation method of 8-thia Xanthine compounds according to claim 1 is characterized in that, described copper salt catalyst is venus crystals.
5. the preparation method of 8-thia Xanthine compounds according to claim 1 is characterized in that, described organic solvent is N, dinethylformamide.
6. the preparation method of 8-thia Xanthine compounds according to claim 1 is characterized in that, the disulfide of the Xanthine compounds of described formula II structure, formula III structure and the mol ratio of copper salt catalyst are 1:0.5～0.6:0.2～1.
7. the preparation method of 8-thia Xanthine compounds according to claim 1 is characterized in that, the temperature of described reaction is 110 ℃～130 ℃.
8. the preparation method of 8-thia Xanthine compounds according to claim 1 is characterized in that, the time of described reaction is 8～16 hours.
9. the preparation method of 8-thia Xanthine compounds according to claim 1 is characterized in that, described being reflected at adopts extraction, washing, drying and column chromatography for separation to carry out aftertreatment after reacting completely successively.
10. the preparation method of 8-thia Xanthine compounds according to claim 9, it is characterized in that, described extraction adopts methylene dichloride as extraction agent, the saturated common salt washing is adopted in described washing, the condition of described column chromatography for separation is: silica gel 300～400 orders, elutriant adopts methylene dichloride-acetone system, and the volume ratio of methylene dichloride and acetone is 15～25:1 in methylene dichloride-acetone system.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310186179.XA CN103254194B (en) | 2013-05-17 | 2013-05-17 | Preparation method of 8-thiaxanthine compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310186179.XA CN103254194B (en) | 2013-05-17 | 2013-05-17 | Preparation method of 8-thiaxanthine compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103254194A true CN103254194A (en) | 2013-08-21 |
| CN103254194B CN103254194B (en) | 2015-07-08 |
Family
ID=48958457
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310186179.XA Expired - Fee Related CN103254194B (en) | 2013-05-17 | 2013-05-17 | Preparation method of 8-thiaxanthine compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103254194B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744464A (en) * | 2013-11-15 | 2015-07-01 | 南京华威医药科技开发有限公司 | Istradefylline crystal forms |
| CN105884776A (en) * | 2014-11-05 | 2016-08-24 | 南京瑞天医药科技有限公司 | New crystal form of istradefylline and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1331676A (en) * | 1998-12-23 | 2002-01-16 | 罗狄亚化学公司 | Method for preparing aromatic diphenyl thioethers |
| WO2002085838A1 (en) * | 2001-04-24 | 2002-10-31 | Massachusetts Institute Of Technology | Copper-catalyzed formation of carbon-heteroatom and carbon-carbon bonds |
| US20030207900A1 (en) * | 2002-03-07 | 2003-11-06 | Chen Jian Jeffrey | Bicyclic pyridine and pyrimidine p38 kinase inhibitors |
-
2013
- 2013-05-17 CN CN201310186179.XA patent/CN103254194B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1331676A (en) * | 1998-12-23 | 2002-01-16 | 罗狄亚化学公司 | Method for preparing aromatic diphenyl thioethers |
| WO2002085838A1 (en) * | 2001-04-24 | 2002-10-31 | Massachusetts Institute Of Technology | Copper-catalyzed formation of carbon-heteroatom and carbon-carbon bonds |
| US20030207900A1 (en) * | 2002-03-07 | 2003-11-06 | Chen Jian Jeffrey | Bicyclic pyridine and pyrimidine p38 kinase inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| HERMANUS P. BOOYSEN等: "Thio- and aminocaffeine analogues as inhibitors of human monoamine oxidase", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| SHOUHUI ZHANG等: "Copper-Catalyzed Thiolation of the Di- or Trimethoxybenzene AreneC-HBond with Disulfides", 《J. ORG. CHEM.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744464A (en) * | 2013-11-15 | 2015-07-01 | 南京华威医药科技开发有限公司 | Istradefylline crystal forms |
| CN104744464B (en) * | 2013-11-15 | 2016-09-21 | 南京华威医药科技开发有限公司 | Istradefylline crystal formation |
| CN105884776A (en) * | 2014-11-05 | 2016-08-24 | 南京瑞天医药科技有限公司 | New crystal form of istradefylline and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103254194B (en) | 2015-07-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112851646A (en) | Preparation method of Tegolrazan | |
| CN103254194B (en) | Preparation method of 8-thiaxanthine compound | |
| KR100704009B1 (en) | 6-Alkylamino-2-methyl-2'-N-methyl substituted sulfonamidomethyl-2H-1-benzopyran derivatives as anti-inflammatory inhibitors | |
| CN102993205A (en) | High-yield purification method for preparation of high-purity sildenafil freebases | |
| CN102659494A (en) | Method for asymmetric synthesis of 3,3-disubstituted-2-oxindole compound | |
| CN103275079B (en) | Preparation method for 8-aryl or vinyl-substituted xanthine compound | |
| CN107602559A (en) | A kind of method of the asymmetric ciprofloxacin eye drops synthesis of chiral ternary carbocyclic nucleoside triggered by Michael's addition | |
| CN114195818B (en) | 4-arylthio coumarin compound and preparation method thereof | |
| CN111233666A (en) | Method for efficiently synthesizing trifluoromethyl compound, trifluoromethyl compound and application | |
| WO2016125845A1 (en) | Cross-coupling method, and method for producing organic compound using said cross-coupling method | |
| Stefanachi et al. | Fast and highly efficient one-pot synthesis of 9-deazaxanthines | |
| CN111362962B (en) | Tetrafluorobenzyl norcantharidin carboxylate and synthesis method thereof | |
| CN1298403A (en) | Process for making 1,3-disubstituted-4-oxocyclic ureas | |
| CN113105459A (en) | Triazolopyrimidine derivative and preparation method and application thereof | |
| CN117362273B (en) | Preparation method of indole morphinan derivative | |
| CN1298402A (en) | Process for making 1,3-disubstituted-4-oxocyclic ureas | |
| CN101066956A (en) | Polysubstituted aurone derivative and its prepn and use | |
| CN112745314B (en) | Preparation and synthesis method of aromatic amine compound with specific HIF-2 alpha inhibition effect | |
| US6734313B2 (en) | Synthesis of spiro esters, spiro ortho carbonates, and intermediates | |
| CN103408520B (en) | 3-[(2-fluoro-6-methoxyl) phenyl]-5-tetrachlorophthalide, as well as preparation method thereof | |
| CN104684921B (en) | Linker molecules for the light cleavable with diaryl sulfide skeleton that temporary bioconjugates synthesizes | |
| CN110590760B (en) | 2, 1-benzisoxazole derivative and synthetic method and application thereof | |
| WO2023053054A1 (en) | Process for the preparation of taxane derivatives | |
| CN112898297B (en) | Polysubstituted biquinoline compound and preparation method and application thereof | |
| US6613918B1 (en) | Synthesis of spiro ortho esters, spiro ortho carbonates, and intermediates |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150708 Termination date: 20170517 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |