CN109608462A - A kind of 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds and its synthetic method and the application in drug - Google Patents

A kind of 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds and its synthetic method and the application in drug Download PDF

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CN109608462A
CN109608462A CN201811537904.2A CN201811537904A CN109608462A CN 109608462 A CN109608462 A CN 109608462A CN 201811537904 A CN201811537904 A CN 201811537904A CN 109608462 A CN109608462 A CN 109608462A
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alcoxyl
mercaptopurine
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CN109608462B (en
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林东恩
江子炀
张逸伟
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South China University of Technology SCUT
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    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract

The invention discloses a kind of 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds and its synthetic method and the applications in drug.The synthetic method is using purine compound and ether compound or thio-ether type compounds as raw material, and ethers or thio-ether type compounds are excessive, non-metallic catalyst is added into raw material, it adds oxidant and inorganic base obtains reaction mixture, it heats the reaction mixture and continuously stirs and reacted, it is cooling after reaction and remove solvent and obtain the 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds.Raw material of the present invention is cheap and easily-available, reaction condition is mild, reaction step is few, easy to operate, solve expensive starting materials, process complexity, severe reaction conditions, it is cumbersome the problems such as, effective ways are provided for the synthesis and application of acyclonucleosides class drug, raw material is provided for the research of new antianxiety, antidepressant, and there is extensive prospects for commercial application.

Description

A kind of 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds and its synthetic method With the application in drug
Technical field
The present invention relates to chemistry and pharmaceutical technology fields, and in particular to 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone Close object and its synthetic method and the application in drug.
Background technique
Purine -8- ketone compounds are many natural nucleus glycosides compounds, Advanced Drug intermediate and biological active matter The chief component of matter.They are usually applied to potential anxiolytic drugs and antidepressant, efficient interferon inducer, The antioxidant of small molecule immune stimulant and physiology.In view of above-mentioned property, the conjunction of purine -8- ketone compounds At technique study be very it is necessary to.
The synthesis main method for the purine -8- ketone compounds being currently known has: 1, using purine N7- quaternary ammonium salt chemical combination Object carries out photocatalysis oxidation reaction purine biosynthesis -8- ketone compounds (referring to bibliography [1]: K Kameyama, M Sako, K Hirota,et al.,A New Method for the preparation of7,9-Disubstituted 8- Oxoadenines[J].Synthesis,1983,10:849-850.)；2, copper catalysis N9- alkylated purines compound and halogenated Oxidative coupling purine biosynthesis -8- the ketone compounds of hydrocarbon are (referring to bibliography [2]: Li J P, Huang Y, Xie M S, et al.,One-Pot Synthesis of 7,9-Dialkylpurin-8-one Analogues:Broad Substrate Scope[J].J.Org.Chem,2013,78:12629-12636).First method substrate tolerance is not strong, and step is various, and Purine N7- quaternary ammonium salt can not be directly obtained as raw material.Second method needs transition metal as catalyst, easy and purine It is chelated or is coordinated, lead to transition-metal catalyst Poisoning Effect yield.
So far, purine -8- ketone compounds are conducted extensive research both at home and abroad, by being repaired to purine ring There are the active purine -8- ketone compounds of good biological to be of great significance currently for decorations and transformation, synthesis.
Summary of the invention
To solve the deficiencies in the prior art, that the present invention provides a kind of raw materials is cheap and easily-available, reaction condition is mild, reaction step Suddenly less, it is easy to operate, efficiently synthesize 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds approach, it is former based on solving The problems such as material is expensive, process is complicated, severe reaction conditions, the research for antiviral, antianxiety, antidepressant provides raw material, And there is extensive prospects for commercial application.
Of the invention is achieved through the following technical solutions.
7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds, such compound have the feature that
Wherein: R1For halogen or alkoxy；R2For H or halogen；R3For alkyl；X is O or S.
Another object of the present invention additionally provides a kind of synthesis side of 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds Method.This method using purine compound and ring/alkyl ether or ring/alkyl sulfide ether compound as raw material, ether compound or Thio-ether type compounds are excessive, and non-metallic catalyst and oxidant is added into raw material under air conditions and inorganic base obtains instead Mixed liquor is answered, the reaction mixture is heated and is stirred, cool down after reaction and removes solvent, obtains the 7- alkyl -9- Alcoxyl/mercaptopurine -8- ketone compounds.
Further, the catalyst is containing iodine catalyst.
Further, the amount of the substance based on purine compound, the dosage containing iodine catalyst are 20~30%, oxidant Dosage be 3~5 equivalents, the dosage of inorganic base is 2~3 equivalents, the dosage of ether compound or thio-ether type compounds is 40~ 60 equivalents.
Further, the iodine catalyst that contains is elemental iodine, sodium iodide, potassium iodide or tetrabutylammonium iodide.
Further, the oxidant is tert-butyl hydroperoxide (TBHP).
Further, the inorganic base is sodium carbonate, potassium carbonate, cesium carbonate.
Further, the ether compound is naphthenic base ethers or alkyl ether compound, and thio-ether type compounds are ring Alkyl sulfide ethers or alkyl sulfide ether compound.
Further, reaction mixture is heated to 70~90 DEG C, reacts 8-24h.
Further, it is tracked and is reacted with TLC, after terminating reaction, is cooled to room temperature, be concentrated in vacuo solvent, chromatographed through column pure Change obtains the 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds.7- alkyl -9- alcoxyl/mercaptopurine -8- the ketone Class compound can be applied to new anti-virus drug.
The present invention is added using cheap and easily-available (ring) alkyl ether or (ring) alkyl sulfide ether compound as raw material and solvent It is opened containing iodine catalyst by oxidative dehydrogenation coupling reaction for the synthesis of 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds A variation route is sent out.
Purine N9- alkylation-C8- carbonylation formula provided by the invention is as follows:
Wherein: R1For halogen or alkoxy；R2For H or halogen；R3For alkyl；X is O or S.
Compared with prior art, the present invention has following usefulness compared with prior art:
(1) reaction step is few: synthetic route provided by the invention is not necessarily to carry out pre-activate processing to raw material, avoids reaction Process it is cumbersome.
(2) reaction condition is mild: synthetic route provided by the invention only needs to be added alkali carbonate, non-in the feed Metallic catalyst and oxidant are placed at 70~90 DEG C and react, also avoid the harshness of anhydrous and oxygen-free under air conditions Condition.
(3) catalyst cheaply easily obtains: catalyst provided by the invention is to avoid expensive transition gold containing iodine catalyst The use of category, and work well, while avoiding the nitrogen-atoms on purine ring makes transition-metal catalyst be poisoned.
(4) heterocycle reagent easily obtains: (ring) alkyl ether or (ring) alkyl sulfide ether compound in raw material of the present invention, just It preferably and easily obtains, was both used as reactant, also used as solvent, and recoverable.
Specific embodiment
Specific implementation of the invention is described in detail below with reference to example, but implementation and protection of the invention is not limited to This.
Embodiment one
Dry 35 milliliters of tube sealings for having added magneton are taken, the chloro- 7- benzyl purine (0.1mmol, 0.0244g) of 6-, I is added2 (0.02mmol, 0.0051g), K2CO3(4mmol had not only made raw material but also had made molten by (0.2mmol, 0.0276g) and 0.36mL THF Agent), TBHP (0.3mmol, 0.0274g) is slowly added in mixed liquor.Reaction tube is placed in 90 DEG C of oil baths under air conditions Agitating and heating 8h in pot.It is tracked and is reacted with TLC, after terminating reaction, is cooled to room temperature to reaction solution, solvent is concentrated in vacuo, through column Chromatographic purifying obtains target product 6- chloro- 7- benzyl -9- (2- tetrahydrofuran) purine -8- ketone (labeled as 3a), yield 87%.1H NMR (400MHz, CDCl3) δ 8.47 (s, 1H), 7.51-7.16 (m, 5H), 6.36 (dd, J=7.7,4.8Hz, 1H), 5.34 (s, 2H), 4.33 (dd, J=14.8,7.7Hz, 1H), 4.03 (dd, J=10.1,5.4Hz, 1H), 2.84-2.72 (m, 1H), 2.47- 2.53(m,1H),2.44–2.33(m,1H),2.15–2.03(m,1H)；13C NMR(100MHz,CDCl3)δ152.43, 150.51,149.87,136.21,128.85,128.02,127.33,119.35,83.60,70.27,45.20,29.23, 25.91.HR-MS(ESI)calcd for[M+Na]+:C16H15ClN4NaO2:353.0776,found:353.0779.
Embodiment two
Take dry 35 milliliters of tube sealings for having added magneton, be added the chloro- 7- benzyl purine of 2,6- bis- (0.1mmol, 0.0278g), KI (0.02mmol, 0.0033g), Na2CO3(5mmol both made by (0.2mmol, 0.0212g) and 0.45mL THF Raw material makees solvent again), TBHP (0.4mmol, 0.0365g) is slowly added in mixed liquor.Reaction tube is set under air conditions The agitating and heating 16h in 80 DEG C of oil bath pans.It is tracked and is reacted with TLC, after terminating reaction, is cooled to room temperature to reaction solution, vacuum is dense Contracting solvent obtains target product 2 through column chromatographic purifying, and chloro- 7- benzyl -9- (2- tetrahydrofuran) purine -8- ketone of 6- bis- (is labeled as 3b), yield 80%.1H NMR (400MHz, CDCl3) δ 7.33-7.26 (m, 5H), 6.30 (dd, J=7.6,4.7Hz, 1H), 5.29 (s, 2H), 4.31 (q, J=7.4Hz, 1H), 4.01 (dd, J=12.5,7.7Hz, 1H), 2.66 (dt, J=13.0, 6.5Hz, 1H), 2.49 (dd, J=12.3,7.0Hz, 1H), 2.43-2.31 (m, 1H), 2.12-2.00 (m, 1H)；13C NMR (100MHz,CDCl3)δ152.29,151.32,151.02,136.39,135.85,128.92,128.16,127.27, 118.35,83.88,70.43,45.30,29.48,25.82.HR-MS(ESI)calcd for[M+Na]+:C16H14Cl2N4NaO2: 387.0386,found:387.0390.
Embodiment three
Dry 35 milliliters of tube sealings for having added magneton are taken, the chloro- 7- ethyl purine (0.1mmol, 0.0183g) of 6- is added, TBAI (0.02mmol, 0.0074g), Cs2CO3(6mmol had not only made raw material but also had made by (0.2mmol, 0.0652g) and 0.54mL THF Solvent), TBHP (0.5mmol, 0.0457g) is slowly added in mixed liquor.Reaction tube is placed in 90 DEG C of oil under air conditions Agitating and heating is for 24 hours in bath.It is tracked and is reacted with TLC, after terminating reaction, is cooled to room temperature to reaction solution, be concentrated in vacuo solvent, warp Column chromatographic purifying obtains target product 6- chloro- 7- ethyl -9- (2- tetrahydrofuran) purine -8- ketone (labeled as 3c), yield 82%.1H NMR (400MHz, CDCl3) δ 8.45 (s, 1H), 6.31 (dd, J=7.8,4.8Hz, 1H), 4.30 (dd, J=14.8, 7.6Hz, 1H), 4.19 (q, J=7.1Hz, 2H), 4.00 (dt, J=12.5,6.2Hz, 1H), 2.81-2.64 (m, 1H), 2.54- 2.41 (m, 1H), 2.42-2.29 (m, 1H), 2.16-1.98 (m, 1H), 1.38 (t, J=7.1Hz, 1H)；13C NMR(100MHz, CDCl3)δ151.87,150.21,149.81,135.79,119.33,83.42,70.17,37.14,29.15,25.88, 15.46.HR-MS(ESI)calcd for[M+Na]+:C11H13ClN4NaO2:291.0619,found:291.0622.
Example IV
Take dry 35 milliliters of tube sealings for having added magneton, be added 6- methoxyl group -7- benzyl purine (0.1mmol, 0.0240g), NaI (0.02mmol, 0.0031g), K2CO3(5mmol both made by (0.25mmol, 0.0345g) and 0.45mL THF Raw material makees solvent again), TBHP (0.3mmol, 0.0274g) is slowly added in mixed liquor.Reaction tube is set under air conditions The agitating and heating 8h in 80 DEG C of oil bath pans.It is tracked and is reacted with TLC, after terminating reaction, is cooled to room temperature to reaction solution, is concentrated in vacuo Solvent obtains target product 6- methoxyl group -7- benzyl -9- (2- tetrahydrofuran) purine -8- ketone through column chromatographic purifying and (is labeled as 3d), yield 80%.1H NMR(400MHz,CDCl3) δ 8.29 (s, 1H), 7.51-7.17 (m, 5H), 6.29 (dd, J=7.7, 5.0Hz, 1H), 5.14 (s, 2H), 4.29 (q, J=7.6Hz, 1H), 4.05 (s, 3H), 3.98 (dd, J=12.4,7.7Hz, 1H), 2.76 (dt, J=13.0,6.5Hz, 1H), 2.51-2.41 (m, 1H), 2.37-2.26 (m, 1H), 2.10-1.97 (m, 1H)；13C NMR(100MHz,CDCl3)δ152.53,152.28,150.10,148.66,137.11,128.61,128.09, 127.81,107.73,83.21,69.88,53.82,46.11,29.06,25.96.HR-MS(ESI)calcd for[M+Na]+: C17H18N4NaO3:349.1271,found:349.1275.
Embodiment five
Dry 35 milliliters of tube sealings for having added magneton are taken, the chloro- 7- benzyl purine (0.1mmol, 0.0244g) of 6-, I is added2 (0.025mmol, 0.0064g), K2CO3(4mmol had not only made raw material but also had made for (0.3mmol, 0.0414g) and 0.44mL dioxane Solvent), TBHP (0.4mmol, 0.0365g) is slowly added in mixed liquor.Reaction tube is placed in 90 DEG C of oil under air conditions Agitating and heating 8h in bath.It is tracked and is reacted with TLC, after terminating reaction, is cooled to room temperature to reaction solution, be concentrated in vacuo solvent, warp Column chromatographic purifying obtains target product 6- chloro- 7- benzyl -9- (2- dioxane) purine -8- ketone (labeled as 3e), yield 75%.1H NMR(400MHz,CDCl3) δ 8.41 (s, 1H), 7.30-7.16 (m, 5H), 5.75 (dd, J=10.1,2.8Hz, 1H), 5.26 (s, 2H), 4.75-4.66 (m, 1H), 3.97-3.92 (m, 2H), 3.79 (dd, J=7.4,3.9Hz, 1H), 3.78-3.71 (m, 2H)；13C NMR(100MHz,CDCl3)δ151.96,150.73,149.69,136.78,135.90,128.90,128.15, 127.38,119.44,78.08,67.70,66.20,65.69,45.51.HR-MS(ESI)calcd for[M+Na]+: C16H15ClN4NaO3:369.0725,found:369.0729.
Embodiment six
Dry 35 milliliters of tube sealings for having added magneton are taken, the chloro- 7- benzyl purine (0.1mmol, 0.0244g) of 6-, I is added2 (0.03mmol, 0.0077g), K2CO3(5mmol had not only made raw material but also had made for (0.2mmol, 0.0276g) and 0.55mL thiophane Solvent), TBHP (0.3mmol, 0.0274g) is slowly added in mixed liquor.Reaction tube is placed in 90 DEG C of oil under air conditions Agitating and heating 20h in bath.It is tracked and is reacted with TLC, after terminating reaction, is cooled to room temperature to reaction solution, be concentrated in vacuo solvent, warp Column chromatographic purifying obtains target product 6- chloro- 7- benzyl -9- (2- thiophane) purine -8- ketone (labeled as 3f), yield 72%.1H NMR(400MHz,CDCl3) δ 8.47 (s, 1H), 7.41-7.21 (m, 5H), 6.35 (dd, J=8.1,5.8Hz, 1H), 5.33 (s, 2H), 3.52-3.44 (m, 1H), 3.03-2.95 (m, 1H), 2.74-2.67 (m, 1H), 2.62 (dt, J=10.5,5.1Hz, 1H),2.48–2.38(m,1H),2.13–2.02(m,1H)；13C NMR(100MHz,CDCl3)δ152.14,150.39, 149.50,136.24,136.20,128.86,128.03,127.31,119.44,60.62,45.34,34.62,34.22, 31.83.HR-MS(ESI)calcd for[M+Na]+:C16H15ClN4NaOS:369.0547,found:369.0550.
Embodiment seven
Dry 35 milliliters of tube sealings for having added magneton are taken, the chloro- 7- benzyl purine (0.1mmol, 0.0244g) of 6-, I is added2 (0.02mmol, 0.0051g), K2CO3(6mmol had not only made raw material but also had made molten for (0.2mmol, 0.0276g) and 0.46mL methyl sulfide Agent), TBHP (0.3mmol, 0.0274g) is slowly added in mixed liquor.Reaction tube is placed in 70 DEG C of oil baths under air conditions Pot in agitating and heating for 24 hours.It is tracked and is reacted with TLC, after terminating reaction, is cooled to room temperature to reaction solution, solvent is concentrated in vacuo, through column Chromatographic purifying obtains chloro- 7- benzyl -9- (methylthiomethyl) purine -8- ketone of target product 6- (labeled as 3g), yield 70%.1H NMR(400MHz,CDCl3)δ8.48(s,1H),7.57–7.06(m,5H),5.35(s,2H),5.07(s,2H),2.31(s, 3H)；13CNMR(100MHz,CDCl3)δ152.76,150.90,149.74,136.34,136.13,128.89,128.12, 127.33,119.47,45.46,44.17,16.10.HR-MS(ESI)calcd for[M+Na]+:C14H13ClN4NaOS: 343.0391,found:343.0393.
Embodiment eight
Dry 35 milliliters of tube sealings for having added magneton are taken, the chloro- 7- benzyl purine (0.1mmol, 0.0244g) of 6-, I is added2 (0.02mmol, 0.0051g), K2CO3(6mmol had not only made raw material but also had made molten for (0.2mmol, 0.0276g) and 0.35mL ether Agent), TBHP (0.3mmol, 0.0274g) is slowly added in mixed liquor.Reaction tube is placed in 70 DEG C of oil baths under air conditions Agitating and heating 8h in pot.It is tracked and is reacted with TLC, after terminating reaction, is cooled to room temperature to reaction solution, solvent is concentrated in vacuo, through column Chromatographic purifying obtains target product 6- chloro- 7- benzyl -9- (1- ethoxyethyl group) purine -8- ketone (labeled as 3h), yield 69%.1H NMR(400MHz,CDCl3) δ 8.49 (s, 1H), 7.44-7.18 (m, 5H), 5.86 (q, J=6.3Hz, 1H), 5.35 (s, 2H), 3.65-3.50 (m, 1H), 3.50-3.36 (m, 1H), 1.91 (d, J=6.3Hz, 3H), 1.19 (t, J=7.0Hz, 3H) .13C NMR(100MHz,CDCl3)δ152.71,150.77,149.93,136.46,136.31,128.88,128.06, 127.23,119.22,81.02,64.71,45.29,19.41,14.83.HR-MS(ESI)calcd for[M+Na]+: C16H17ClN4NaO2:355.0932,found:355.0935。
The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention.The technology of the industry Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this The principle of invention, under conditions of not departing from spirit and scope of the invention, various changes and improvements may be made to the invention, these changes Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by have appended claims and Its equivalent thereof.

Claims (10)

1. a kind of 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds, which is characterized in that the 7- alkyl -9- alcoxyl/sulphur Base purine -8- ketone compounds structural formula is as follows:
Wherein: R1For halogen or alkoxy；R2For H or halogen；R3For alkyl；X is O or S.
2. 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds synthetic method described in claim 1, which is characterized in that The synthetic method is using purine compound and ether compound or thio-ether type compounds as raw material, and ethers or thioether class chemical combination Object is excessive, and non-metallic catalyst is added into raw material, adds oxidant and inorganic base obtains reaction mixture, heats described anti- It answers mixed liquor and continuously stirs and reacted, it is cooling after reaction and remove solvent and obtain the 7- alkyl -9- alcoxyl/sulfenyl Purine -8- ketone compounds.
3. 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds synthetic method, feature exist according to claim 2 In the non-metallic catalyst is containing iodine catalyst.
4. 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds synthetic method, feature exist according to claim 3 In the amount of the substance based on purine compound, the dosage containing iodine catalyst is 20~30%, and the dosage of oxidant is worked as 3~5 Amount, the dosage of inorganic base are 2~3 equivalents, and the dosage of ether compound or thio-ether type compounds is 40~60 equivalents.
5. 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds synthetic method, feature exist according to claim 3 In the catalyst is elemental iodine, sodium iodide, potassium iodide or tetrabutylammonium iodide.
6. special according to the 7- alkyl -9- alcoxyl of claim 2 or 4/mercaptopurine -8- ketone compounds synthetic method Sign is that the oxidant is tert-butyl hydroperoxide, and the inorganic base is sodium carbonate, potassium carbonate or cesium carbonate.
7. 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds synthetic method, feature exist according to claim 2 In the ether compound is naphthenic base ethers or alkyl ether compound, and thio-ether type compounds are naphthenic base thioether class or alkane Base thio-ether type compounds.
8. 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds synthetic method, feature exist according to claim 2 In reaction mixture is heated to 70~90 DEG C, reacts 8-24h.
9. 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds synthetic method, feature exist according to claim 2 In, with TLC track react, terminate reaction after, be cooled to room temperature, be concentrated in vacuo solvent, obtain the 7- hydrocarbon through column chromatographic purifying Base -9- alcoxyl/mercaptopurine -8- ketone compounds.
10. 7- alkyl -9- alcoxyl/mercaptopurine -8- ketone compounds are in antiviral, antianxiety and anti-suppression described in claim 1 Application in strongly fragrant drug.
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