CN104356135A - Pyrrolo[3,2-d] pyrimidine compound, and preparation method and purification method thereof - Google Patents

Pyrrolo[3,2-d] pyrimidine compound, and preparation method and purification method thereof Download PDF

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CN104356135A
CN104356135A CN201410521733.XA CN201410521733A CN104356135A CN 104356135 A CN104356135 A CN 104356135A CN 201410521733 A CN201410521733 A CN 201410521733A CN 104356135 A CN104356135 A CN 104356135A
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ethyl acetate
pyrrolo
adds
preparation
column chromatography
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张士磊
谢瑞
胡延维
陈韶华
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Suzhou University
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Suzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a pyrrolo[3,2-d] pyrimidine compound, and a preparation method and a purification method thereof. A condensed chemical structural formula of the pyrrolo[3,2-d] pyrimidine compound is shown in the description, wherein R1 represents halogen or methyl; R2 represents hydrogen, aryl, substituted aryl or alkyl. The prepared pyrrolo[3,2-d] pyrimidine compound is novel in structure; many active natural products and medicaments contain similar indole structures, so that the compound has high application value for the total synthesis of natural products and new medicament discovery, and has a broad application prospect.

Description

A kind of pyrrolo-[3,2-d] pyrimidine compound, preparation method and method of purification thereof
Technical field
The present invention relates to a kind of azolopyrimidines material, be specifically related to a kind of pyrrolo-[3,2-d] pyrimidines, preparation method and its method of purification, belong to technical field of organic synthesis.
Background technology
Benzazole compounds is the important framework structured compound that a class has special medicinal compound, and it is extensively present in natural product and medicine, has good biological activity.At a lot of natural product, as extensively there is indoles secondary metabolite in brassicaceous vegetable, a large amount of marine organisms and unwrapping wire bacterial classification.At present, Sutent, vinealeucoblastine(VLB), vincristine(VCR) etc. to have gone on the market input Clinical practice containing the medicine of indole structure.Because of its biological activity widely, Benzazole compounds receives much concern in the research of cancer therapy drug.In prior art, the document about pyrrolo-[3,2-d] miazines report is less, and particularly pyrrole ring 5 contains the synthesis rare report especially of the compound of substituting group and pyrimidine ring 6 aniline replacements.
Therefore, researching and developing new preparation method with more pyrrolo-[3, the 2-d] pyrimidine structure of preparing of simple, high yield is the compound of parent nucleus, has great importance to the discovery of medicine.
Summary of the invention
The object of this part is some aspects of general introduction embodiments of the invention and briefly introduces some preferred embodiments.May do in the specification digest and denomination of invention of this part and the application a little simplify or omit with avoid making this part, specification digest and denomination of invention object fuzzy, and this simplification or omit and can not be used for limiting the scope of the invention.
In view of Problems existing in above-mentioned and/or existing pyrrolo-[3,2-d] pyrimidine compound, propose the present invention.
Therefore, an object of the present invention is to provide a kind of pyrrolo-[3,2-d] pyrimidine compound, its be utilize the pyrimidines of alkynyl substituted to be raw material, silver compound be catalyst preparing pyrrolo-[3,2-d] pyrimidines.
For solving the problems of the technologies described above, according to an aspect of the present invention, the invention provides following technical scheme: a kind of pyrrolo-[3,2-d] pyrimidine compound, its chemical structure skeleton symbol is:
Wherein, R 1for halogen or methyl; R 2for hydrogen, aryl, substituted aryl or alkyl.
As a kind of preferred version of pyrrolo-of the present invention [3,2-d] pyrimidine compound, wherein: described substituted aryl is the aryl that 1 ~ 6 phenyl ring condenses, and its substituting group is selected from the one in the alkoxyl group of halogen, C1 ~ C3.
As a kind of preferred version of pyrrolo-of the present invention [3,2-d] pyrimidine compound, wherein: in described alkyl, carbon number is 1 ~ 13.。
Another object of the present invention is to provide the preparation method of a kind of pyrrolo-[3,2-d] pyrimidine compound, and the method reaction conditions is gentle, and product yield is high, is suitable for suitability for industrialized production.
For solving the problems of the technologies described above, according to another aspect of the present invention, the invention provides following technical scheme: the preparation method of a kind of pyrrolo-[3,2-d] pyrimidine compound, it comprises,
Chemical compounds I, Terminal Acetylenes, additive and the first catalyst mix are dissolved, under 0 ~ 50 DEG C of condition, react 10 ~ 30min obtain intermediate II, wherein, the skeleton symbol of described chemical compounds I is the skeleton symbol of described Terminal Acetylenes is described additive is triethylamine, and described first catalyzer is two (triphenylphosphine) palladium chloride and/or cuprous iodides; And,
The second catalyzer is added after described intermediate II being dissolved, under 70 ~ 90 DEG C of conditions, react 24 ~ 36h, obtain pyrrolo-[3,2-d] pyrimidines, wherein, described second catalyzer is one or more in Silver Nitrate, silver chloride, Silver monoacetate, silver suboxide.
As a kind of preferred version of preparation method of the present invention, wherein: described by chemical compounds I, Terminal Acetylenes, additive and the first catalyst mix dissolve, its in molar ratio, chemical compounds I: Terminal Acetylenes: additive: the first catalyzer=1:1.5:10:0.05.
As a kind of preferred version of preparation method of the present invention, wherein: described mixed dissolution, when it dissolves, the first solvent used is tetrahydrofuran (THF).
As a kind of preferred version of preparation method of the present invention, wherein: described described intermediate II is dissolved after add the second catalyzer, its in molar ratio, intermediate II: the second catalyzer=1:0.1 ~ 1.
As a kind of preferred version of preparation method of the present invention, wherein: described second catalyzer is Silver Nitrate.
As a kind of preferred version of preparation method of the present invention, wherein: described described intermediate II is dissolved after add the second catalyzer, its dissolve needed for the second solvent be one or more in DMF, acetonitrile, tetrahydrofuran (THF), toluene.
Another object of the present invention is to provide a kind of pyrrolo-[3,2-d] intermediate II that obtains of the preparation method of pyrimidine compound and pyrrolo-[3,2-d] method of purification of pyrimidines, this method of purification can effectively be purified intermediate II and pyrrolo-[3,2-d] pyrimidines.
For solving the problems of the technologies described above, according to a further aspect of the invention, the invention provides following technical scheme: a kind of pyrrolo-[3, 2-d] intermediate II that obtains of the preparation method of pyrimidine compound and pyrrolo-[3, 2-d] method of purification of pyrimidines, it comprises, the purification of intermediate II: after obtaining intermediate II, the cancellation that adds water in mixed solution is reacted, be extracted with ethyl acetate, merge organic layer, organic layer is through anhydrous sodium sulfate drying, revolve steaming and remove the first solvent, obtain residue and carry out the intermediate II that silica gel column chromatography obtains purification, wherein, the eluent of column chromatography is the mixed solution of ethyl acetate and sherwood oil, and the purification of pyrrolo-[3,2-d] pyrimidines: after obtaining pyrrolo-[3,2-d] pyrimidines, be cooled to room temperature, add ethyl acetate, then adds water washing and gets rid of the second solvent, separate organic layer, utilize anhydrous sodium sulfate drying organic layer, revolve and steam removing second solvent, obtain solid crude product, crude product carries out pyrrolo-[3, the 2-d] pyrimidines that silica gel column chromatography obtains purifying, wherein, the eluent of column chromatography is the mixed solution of ethyl acetate and sherwood oil.
Beneficial effect of the present invention:
(1) the present invention utilizes the pyrimidines of alkynyl substituted to be raw material first, the compound of silver successfully prepared pyrrolo-[3,2-d] pyrimidines for catalyzer, and product yield is up to 91%;
(2) pyrrolo-[3 prepared of the present invention, 2-d] pyrimidines novel structure, owing to all containing similar indoles structure in a lot of bioactive natural product and medicine, so compound disclosed by the invention can produce significant application value in the complete synthesis and new drug discovery of natural product, thus have a good application prospect;
(3) preparation method disclosed by the invention is simple, and reaction conditions is gentle, and reaction reagent is simple and easy to get, and product yield is high, is suitable for suitability for industrialized production.
Embodiment
For enabling above-mentioned purpose of the present invention, feature and advantage become apparent more, are described in detail below by the specific embodiment of the present invention.
Set forth a lot of detail in the following description so that fully understand the present invention, but the present invention can also adopt other to be different from alternate manner described here to implement, those skilled in the art can when without prejudice to doing similar popularization when intension of the present invention, therefore the present invention is by the restriction of following public specific embodiment.
Pyrrolo-[3,2-d] the miazines structure that the present invention relates to is a kind of structure being similar to indoles, is to the bioactive further exploration of Benzazole compounds.Reaction principle of the present invention is:
Embodiment 1
By 1mmol N 4-phenyl-4, the iodo-pyrimidine of 5-diamino-6-, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol trimethylsilyl acetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain white solid product, this product is dissolved in tetrahydrofuran (THF), slowly add 1mmol tetrabutyl ammonium fluoride at 0 DEG C in batches, finish, TLC detection reaction is complete, revolve steaming and remove solvent, obtain solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains brown solid 147mg and is final product.Overall yield reaches 70%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.20 (s, 1H), 9.24 (s, 1H), 8.35 (s, 1H), 7.88 (d, J=8.0Hz, 2H), 7.66 (s, 1H), 7.36 (t, J=7.4Hz, 2H), 7.02 (t, J=7.3Hz, 1H), 6.48 (s, 1H).
Embodiment 2
By 1mmol N 4-(3-chloro-phenyl-)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol trimethylsilyl acetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain faint yellow solid product, this product is dissolved in tetrahydrofuran (THF), slowly add 1mmol tetrabutyl ammonium fluoride at 0 DEG C in batches, finish, TLC detection reaction is complete, revolve steaming and remove solvent, obtain solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains brown solid 179mg and is final product.Overall yield reaches 73%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.76 (s, 1H), 10.01 (s, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 7.78 (d, J=7.9Hz, 1H), 7.70 (s, 1H), 7.37 (t, J=7.9Hz, 1H), 7.05 (d, J=7.6Hz, 1H), 6.50 (s, 1H).
Embodiment 3
By 1mmol N 4-(4-chloro-phenyl-)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol trimethylsilyl acetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain faint yellow solid product, this product is dissolved in tetrahydrofuran (THF), slowly add 1mmol tetrabutyl ammonium fluoride at 0 DEG C in batches, finish, TLC detection reaction is complete, revolve steaming and remove solvent, obtain solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains brown solid 172m gbe final product.Overall yield reaches 70%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.12 (s, 1H), 9.34 (s, 1H), 8.37 (s, 1H), 7.91 (d, J=5.6Hz, 2H), 7.68 (s, 1H), 7.41 (d, J=5.8Hz, 2H), 6.49 (s, 1H).
Embodiment 4
By 1mmol N 4-(3-bromophenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol trimethylsilyl acetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain white solid product, this product is dissolved in tetrahydrofuran (THF), slowly add 1mmol tetrabutyl ammonium fluoride at 0 DEG C in batches, finish, TLC detection reaction is complete, revolve steaming and remove solvent, obtain solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains brown solid 196mg and be final product.Overall yield reaches 68%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.15 (s, 1H), 9.42 (s, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 7.69 (s, 2H), 7.32 (t, J=8.0Hz, 1H), 7.20 (d, J=7.9Hz, 1H), 6.50 (s, 1H).
Embodiment 5
By 1mmol N 4-(4-bromophenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol trimethylsilyl acetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain white solid product, this product is dissolved in tetrahydrofuran (THF), slowly add 1mmol tetrabutyl ammonium fluoride at 0 DEG C in batches, finish, TLC detection reaction is complete, revolve steaming and remove solvent, obtain solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains brown solid 211mg and is final product.Overall yield reaches 73%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.12 (s, 1H), 9.33 (s, 1H), 8.36 (s, 1H), 7.85 (d, J=5.6Hz 2H), 7.68 (s, 1H), 7.54 (d, J=5.6Hz, 2H), 6.49 (s, 1H).
Embodiment 6
By 1mmol N 4-(3-aminomethyl phenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol trimethylsilyl acetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain brown solid, this product is dissolved in tetrahydrofuran (THF), slowly add 1mmol tetrabutyl ammonium fluoride at 0 DEG C in batches, finish, TLC detection reaction is complete, revolve steaming and remove solvent, obtain solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains yellow solid 157mg and is final product.Overall yield reaches 70%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.16 (s, 1H), 9.14 (s, 1H), 8.36 (s, 1H), 7.72-7.68 (m, 3H), 7.25 (t, J=8.1Hz, 1H), 6.80 (d, J=7.4Hz, 1H), 6.48 (s, 1H), 2.26 (s, 3H).
Embodiment 7
By 1mmol N 4-(4-aminomethyl phenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol trimethylsilyl acetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain yellow solid product, this product is dissolved in tetrahydrofuran (THF), slowly add 1mmol tetrabutyl ammonium fluoride at 0 DEG C in batches, finish, TLC detection reaction is complete, revolve steaming and remove solvent, obtain solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains brown solid 152mg and is final product.Overall yield reaches 68%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.12 (s, 1H), 9.11 (s, 1H), 8.33 (s, 1H), 7.73 (d, J=5.6Hz, 2H), 7.65 (s, 1H), 7.17 (d, J=5.5Hz, 2H), 6.47 (s, 1H), 2.29 (s, 3H).
Embodiment 8
By 1mmol N 4-(3-p-methoxy-phenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol trimethylsilyl acetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain white solid product, this product is dissolved in tetrahydrofuran (THF), slowly add 1mmol tetrabutyl ammonium fluoride at 0 DEG C in batches, finish, TLC detection reaction is complete, revolve steaming and remove solvent, obtain solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains brown solid 173mg and is final product.Overall yield reaches 72%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.16 (s, 1H), 9.21 (s, 1H), 8.37 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.37 (d, J=7.7Hz, 1H), 7.26 (t, J=8.1Hz, 1H), 6.62 (d, J=7.4Hz, 1H), 6.49 (s, 1H), 3.78 (s, 3H).
Embodiment 9
By 1mmol N 4-(4-p-methoxy-phenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol trimethylsilyl acetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain white solid product, this product is dissolved in tetrahydrofuran (THF), slowly add 1mmol tetrabutyl ammonium fluoride at 0 DEG C in batches, finish, TLC detection reaction is complete, revolve steaming and remove solvent, obtain solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains brown solid 171m gbe final product.Overall yield reaches 71%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.07 (s, 1H), 9.05 (s, 1H), 8.24 (s, 1H), 7.74 (d, J=7.7Hz, 2H), 7.63 (s, 1H), 6.96 (d, J=8.0Hz, 2H), 6.46 (s, 1H), 3.76 (s, 3H).
Embodiment 10
By 1mmol N 4-(3, 5-3,5-dimethylphenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol trimethylsilyl acetylene, 0 DEG C is kept to react 30min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain white solid product, this product is dissolved in tetrahydrofuran (THF), slowly add 1mmol tetrabutyl ammonium fluoride at 0 DEG C in batches, finish, TLC detection reaction is complete, revolve steaming and remove solvent, obtain solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains brown solid 161mg and is final product.Overall yield reaches 67%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.13 (s, 1H), 9.06 (s, 1H), 8.35 (s, 1H), 7.65 (s, 1H), 7.50 (s, 2H), 6.67 (s, 1H), 6.47 (s, 1H), 2.29 (s, 6H).
Embodiment 11
By 1mmol N 4-(3-bromophenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol phenylacetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain greenish yellow solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 24h at 70 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains brown solid 270mg and is final product.Overall yield reaches 74%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.67 (s, 1H), 9.35 (s, 1H), 8.43 (s, 1H), 8.38 (s, 1H), 7.89 (d, J=7.6Hz, 2H), 7.71 (d, J=7.9Hz, 1H), 7.57 (t, J=7.4Hz, 2H), 7.45 (t, J=7.2Hz, 1H), 7.35 (t, J=8.0Hz, 1H), 7.23 (d, J=7.7Hz, 1H), 7.03 (s, 1H).
Embodiment 12
By 1mmolN 4-(3-bromophenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol 3-butine-1 alcohol, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain white solid product.Above-mentioned gained solid product is dissolved in 5mlN, dinethylformamide, adds 0.1mmol Silver Nitrate, react and carry out 36h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains white solid 226mg and is final product.Overall yield reaches 68%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.05 (s, 1H), 9.39 (s, 1H), 8.34 (s, 2H), 7.69 (d, J=6.6Hz, 1H), 7.30 (t, J=8.0Hz, 1H), 7.17 (d, J=6.3Hz, 1H), 6.28 (s, 1H), 3.75 (t, J=7.6Hz, 2H), 2.94 (t, J=7.5Hz, 2H).
Embodiment 13
By 1mmolN 4-(3-bromophenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, the propargylamine of slow dropping 1.5mmol Boc protection, 0 DEG C is kept to react 30min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain white solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains yellow solid 284mg and is final product.Overall yield reaches 68%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.02 (s, 1H), 9.43 (s, 1H), 8.35 (d, J=10.4Hz, 2H), 7.68 (d, J=6.9Hz, 1H), 7.55 (s, 1H), 7.31 (t J=7.2Hz, 1H), 7.19 (d, J=6.5Hz, 1H), 6.31 (s, 1H), 4.34 (d, J=3.1Hz, 2H), 1.42 (s, 9H).
Embodiment 14
By 1mmolN 4-(3-bromophenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol ring third acetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain white solid product.Above-mentioned gained solid product is dissolved in 5mlN, dinethylformamide, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains white solid 231mg and is final product.Overall yield reaches 70%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (600MHz, dmso) δ 10.92 (s, 1H), 9.05 (s, 1H), 8.36 – 8.23 (m, 2H), 7.63 (dd, J=8.2,1.1Hz, 1H), 7.29 (t, J=8.0Hz, 1H), 7.16 (dd, J=7.9,0.8Hz, 1H), 6.20 (s, 1H), 2.48 (s, 1H), 2.18 – 2.08 (m, 1H), 1.10 – 1.03 (m, 2H), 0.86 – 0.79 (m, 2H).
Embodiment 15
By 1mmolN 4-(3-bromophenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol 1-hexin, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain white solid product.Above-mentioned gained solid product is dissolved in 5mlN, dinethylformamide, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains white solid 272mg and is final product.Overall yield reaches 79%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 10.98 (s, 1H), 9.13 (s, 1H), 8.34 (d, J=5.6Hz, 2H), 7.65 (d, J=8.0Hz, 1H), 7.31 (t, J=8.0Hz, 1H), 7.18 (d, J=7.7Hz, 1H), 6.26 (s, 1H), 2.81 (t, J=7.5Hz, 2H), 1.77 – 1.62 (m, 2H), 1.47 – 1.31 (m, 2H), 0.94 (t, J=7.3Hz, 3H).
Embodiment 16
By 1mmolN 4-(3-bromophenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol tridecyne, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain white solid product.Above-mentioned gained solid product is dissolved in 5mlN, dinethylformamide, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains white solid 332mg and is final product.Overall yield reaches 75%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.00 (s, 1H), 9.15 (s, 1H), 8.33 (s, 2H), 7.65 (d, J=8.0Hz, 1H), 7.30 (t, J=8.0Hz, 1H), 7.17 (d, J=7.7Hz, 1H), 6.24 (s, 1H), 2.78 (t, J=7.2Hz, 2H), 1.69 (t, J=6.3Hz, 2H), 1.31-1.21 (m, 18H), 0.82 (t, J=6.6Hz, 3H).
Embodiment 17
By 1mmolN 4-(3-bromophenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol 3, 3-dimethyl-ethyl acetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain white solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains white solid 276mg and is final product.Overall yield reaches 80%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 10.92 (s, 1H), 9.15 (s, 1H), 8.34 (s, 2H), 7.68 (d, J=8.0Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.19 (d, J=7.7Hz, 1H), 6.29 (s, 1H), 1.39 (s, 9H).
Embodiment 18
By 1mmolN 4-(3-bromophenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol is to chlorobenzene acetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain white solid product.Above-mentioned gained solid product is dissolved in 5mlN, dinethylformamide, adds 0.1mmol Silver Nitrate, react and carry out 24h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains white solid 312mg and is final product.Overall yield reaches 78%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.73 (s, 1H), 9.39 (s, 1H), 8.48 (s, 1H), 8.35 (s, 1H), 7.88 (d, J=8.3Hz, 2H), 7.69 (d, J=8.8Hz, 1H), 7.66 (d, J=8.4Hz, 2H), 7.37 (t, J=8.0Hz, 1H), 7.26 (d, J=7.7Hz, 1H), 7.08 (s, 1H).
Embodiment 19
By 1mmolN 4-(3-bromophenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol is to bromobenzene acetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain greenish yellow solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 24h at 70 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains white solid 360mg and is final product.Overall yield reaches 81%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.79 (s, 1H), 9.46 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 7.78 (s, 4H), 7.69 (d, J=8.0Hz, 1H), 7.37 (t, J=8.0Hz, 1H), 7.27 (d, J=7.8Hz, 1H), 7.10 (s, 1H).
Embodiment 20
By 1mmolN 4-(3-bromophenyl)-4, 5-diamino-6-iodine pyrimidine, 0.05mmol bis-(triphenylphosphine) palladium chloride, 0.05mmol cuprous iodide, 10mmol triethylamine, 5ml tetrahydrofuran (THF) adds in two-mouth bottle, under nitrogen protection and 0 DEG C of condition, slow dropping 1.5mmol meta-methoxy phenylacetylene, 0 DEG C is kept to react 10min, it is complete that TLC detects raw material reaction, the quencher that adds water in mixed solution is reacted, add extraction into ethyl acetate, merge organic layer, and with anhydrous sodium sulfate drying, revolve to steam and remove the residue that solvent obtains and carry out silica gel column chromatography, sherwood oil: ethyl acetate=5:1 wash-out, obtain greenish yellow solid product.Above-mentioned gained solid product is dissolved in 5ml DMF, adds 0.1mmol Silver Nitrate, react and carry out 36h at 90 DEG C, until raw material reaction is complete.Reaction solution is cooled to room temperature, adds ethyl acetate, and washes with water and remove DMF, and ethyl acetate layer is again with saturated common salt washing, and anhydrous sodium sulfate drying, revolves and steam removing organic solvent.The residue obtained carries out silica gel column chromatography, sherwood oil: ethyl acetate=1:1 wash-out, obtains white solid 308mg and is final product.Overall yield reaches 78%.Final product structural formula is as follows:
Hydrogen spectrum is split point: 1h NMR (400MHz, DMSO) δ 11.65 (s, 1H), 9.31 (s, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 7.72 (d, J=7.9Hz, 1H), 7.47 (t, J=8.2Hz, 3H), 7.35 (t, J=7.9Hz, 1H), 7.22 (d, J=7.5Hz, 1H), 7.04 (d, J=13.2Hz, 2H), 3.87 (s, 3H).
As can be seen here, pyrrolo-[3, the 2-d] pyrimidines that the present invention obtains, its skeleton symbol is:
Wherein, R 1for hydrogen, halogen, methyl; R 2for hydrogen, aryl, substituted aryl, alkyl.
R 1substituting group is selected from the one in halogen, methyl; R 2substituted aryl is the aryl that 1 ~ 6 phenyl ring condenses, and the substituting group in substituted aryl is selected from the one in the alkoxyl group of halogen, C1 ~ C3; Alkyl is the alkyl of C1 ~ C13.
The aryl that above-mentioned 1 ~ 6 phenyl ring condenses refers to the fused ring compound base condensed by 1 ~ 6 phenyl ring, such as naphthyl, anthryl, phenanthryl; The alkoxyl group of above-mentioned C1 ~ C3 refers to that carbonatoms is the straight or branched alkoxyl group of 1 ~ 3, such as methoxyl group, oxyethyl group, propoxy-or isopropoxy; The alkyl of above-mentioned C1 ~ C13 refers to that carbonatoms is straight chain, branched-chain alkyl or cycloalkyl, such as propyl group, cyclopropyl, butyl, isobutyl-, amyl group, hexyl, the tridecyl of 3 ~ 13.
R 1substituting group also can be selected from the one in chlorine, bromine, methoxyl group; R 2aryl is phenyl, naphthyl, anthryl, phenanthryl or pyrenyl; Substituting group in substituted aryl is selected from the one in chlorine, bromine, methoxyl group; Alkyl is the alkyl of C3 ~ C13.
It should be noted that, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to technical scheme of the present invention or equivalent replacement, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in the middle of right of the present invention.

Claims (10)

1. pyrrolo-[3, a 2-d] pyrimidine compound, is characterized in that: its chemical structure skeleton symbol is:
Wherein, R 1for halogen or methyl; R 2for hydrogen, aryl, substituted aryl or alkyl.
2. pyrrolo-[3,2-d] pyrimidine compound as claimed in claim 1, is characterized in that: described substituted aryl is the aryl that 1 ~ 6 phenyl ring condenses, and its substituting group is selected from the one in the alkoxyl group of halogen, C1 ~ C3.
3. pyrrolo-[3,2-d] pyrimidine compound as claimed in claim 2, is characterized in that: in described alkyl, carbon number is 1 ~ 13.
4. the preparation method of pyrrolo-as claimed in claim 1 [3, a 2-d] pyrimidine compound, is characterized in that: comprise,
Chemical compounds I, Terminal Acetylenes, additive and the first catalyst mix are dissolved, under 0 ~ 50 DEG C of condition, react 10 ~ 30min obtain intermediate II, wherein, the skeleton symbol of described chemical compounds I is the skeleton symbol of described Terminal Acetylenes is described additive is triethylamine, and described first catalyzer is two (triphenylphosphine) palladium chloride and/or cuprous iodides; And,
The second catalyzer is added after described intermediate II being dissolved, under 70 ~ 90 DEG C of conditions, react 24 ~ 36h, obtain pyrrolo-[3,2-d] pyrimidines, wherein, described second catalyzer is one or more in Silver Nitrate, silver chloride, Silver monoacetate, silver suboxide.
5. preparation method as claimed in claim 4, is characterized in that: describedly chemical compounds I, Terminal Acetylenes, additive and the first catalyst mix are dissolved, its in molar ratio, chemical compounds I: Terminal Acetylenes: additive: the first catalyzer=1:1.5:10:0.05.
6. preparation method as claimed in claim 4, is characterized in that: described mixed dissolution, and when it dissolves, the first solvent used is tetrahydrofuran (THF).
7. preparation method as claimed in claim 4, is characterized in that: described described intermediate II is dissolved after add the second catalyzer, its in molar ratio, intermediate II: the second catalyzer=1:0.1 ~ 1.
8. preparation method as claimed in claim 4, is characterized in that: described second catalyzer is Silver Nitrate.
9. preparation method as claimed in claim 4, is characterized in that: described described intermediate II is dissolved after add the second catalyzer, its dissolve needed for the second solvent be one or more in DMF, acetonitrile, tetrahydrofuran (THF), toluene.
10. the method for purification of the intermediate II that obtains of a preparation method as claimed in claim 4 and pyrrolo-[3,2-d] pyrimidines, is characterized in that: comprise,
The purification of intermediate II: after obtaining intermediate II, the cancellation that adds water in mixed solution is reacted, be extracted with ethyl acetate, merge organic layer, organic layer, through anhydrous sodium sulfate drying, revolves steaming and removes the first solvent, obtains residue and carries out the intermediate II that silica gel column chromatography obtains purification, wherein, the eluent of column chromatography is the mixed solution of ethyl acetate and sherwood oil; And,
The purification of pyrrolo-[3,2-d] pyrimidines: after obtaining pyrrolo-[3,2-d] pyrimidines, be cooled to room temperature, add ethyl acetate, then adds water washing and gets rid of the second solvent; Separate organic layer, utilize anhydrous sodium sulfate drying organic layer, revolve and steam removing second solvent, obtain solid crude product, crude product carries out pyrrolo-[3, the 2-d] pyrimidines that silica gel column chromatography obtains purifying, wherein, the eluent of column chromatography is the mixed solution of ethyl acetate and sherwood oil.
CN201410521733.XA 2014-09-30 2014-09-30 Pyrrolo[3,2-d] pyrimidine compound, and preparation method and purification method thereof Pending CN104356135A (en)

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