CN108912121A - Preparation method, the preparation method of intermediate and intermediate of three kinds of methyl-uric acid class compounds - Google Patents

Preparation method, the preparation method of intermediate and intermediate of three kinds of methyl-uric acid class compounds Download PDF

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CN108912121A
CN108912121A CN201810897027.3A CN201810897027A CN108912121A CN 108912121 A CN108912121 A CN 108912121A CN 201810897027 A CN201810897027 A CN 201810897027A CN 108912121 A CN108912121 A CN 108912121A
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compound
dimethyl
reagent
tert
ether
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张健
廖琪林
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Nanjing Newport Biotechnology Co Ltd
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Nanjing Newport Biotechnology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals

Abstract

The preparation method of compound obtaining, with antidepression, tranquilizing soporific, anti-inflammatory and antalgic, the irritability damage for mitigating liver cell and raising locomitivity and other effects and its preparation method of intermediate and intermediate can be extracted from the plants such as tea tree the present invention provides three kinds.Operation of the present invention is easy, highly-safe, Atom economy is high, the three wastes are few；Supplementary material is cheap and easy to get, toxicity is low, safety and stability；Reaction condition is mild, and impurity is few, high income；The present invention avoids column from chromatographing by crystallization purifying product, and operation is simple, process stabilizing, easily controllable, post-reaction treatment is convenient, can economy be advantageously used in industrialized production.

Description

The preparation of the preparation method, intermediate and intermediate of three kinds of methyl-uric acid class compounds Method
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to the preparation method of three kinds of methyl-uric acid class compounds, in The preparation method of mesosome and intermediate.
Background technique
Methyl-uric acid Alkaloid is found from tea tree earliest, is primarily present in card type coffee, A Biou in Libiee In the Coffeas and cocoa platymiscium such as auspicious kind of library tower kind coffee, Devi coffee.This kind of compound molecule mother nucleus structure is identical, in people It can mutually convert in vivo or in plant.Research in recent years finds tetramethyluric acid (Theacrine), big fruit caffeine (Liberine), big fruit caffeine (Methylliberine) of methyl etc. has antidepression, tranquilizing soporific, anti-inflammatory and antalgic, mitigation The irritability damage of liver cell and raising locomitivity and other effects are one of the hot spots of current purine alkaloid research.
The chemical structure of tetramethyluric acid, methyl big fruit caffeine and big fruit caffeine
Content is few in the plants such as tea tree and extraction process is complicated for this Alkaloid.There is document report will by bioconversion The natural materials such as caffeine are transformed into urine acid compounds, but its low efficiency, it is at high cost, be difficult to industrialize.In CN104086550 Report a kind of with the synthetic method for preparing tetramethyluric acid under uric acid and methylating reagent high pressure, this method condition is harsh, if It is standby to require height, and have some potential safety problems.It reports in CN103755705 and is passed through by 1,3- dimethyl pyrimidine -2,4,6- triketone Chloro, methylamine solution, bromo, methylamine solution and cyclization prepare tetramethyluric acid.The route raw material is easy to get, it is easier to operate, but needs to use To a large amount of phosphorus oxychloride, there is security risk and generate a large amount of acid waste water, reaction route is as follows：
It is reported in CN106046004 by 6- amino -1,3- dimethyl pyrimidine -2,4- diketone through nitrosation, reduction, cyclization Tetramethyluric acid is prepared with methylation.The route raw material is easy to get, yield is good, but nitrosation has a security risk, and when reduction is used To sodium hydrosulfite, a large amount of high-salt wastewaters are generated, and methylation need to carry out at high temperature, the high requirements on the equipment, reaction route is as follows：
About the synthesis of methyl big fruit caffeine (Methylliberine) and big fruit caffeine (Liberine), on document It there is no synthesis report, only report O (2)-methyl-uric acid methyl in Phytochemistry 1975,14,747-750 The method of change, but there is no industrial value.
Therefore, green, safe and simple, efficient tetramethyluric acid, the big fruit caffeine of methyl and big fruit caffeine are developed Chemical synthesis process seems very urgent.
Summary of the invention
The object of the present invention is to provide three kinds can be extracted from the plants such as tea tree it is obtaining, have antidepression, tranquilizing soporific, The preparation method of the compound of anti-inflammatory and antalgic, the irritability damage for mitigating liver cell and raising locomitivity and other effects, and wherein The preparation method of mesosome and intermediate.
To realize the above-mentioned technical purpose, the present invention uses following technical scheme：
A method of preparation of compounds of formula (1) compound represented (I), compound (II) as shown in formula (2),
Wherein, compound (I)：R=H；Compound (II)：R=CH3；R1=H or R1=CH3；
It is characterized in that, working as R1When=H, the method is comprised the steps of：
Step a：Under the conditions of alkali presence or alkali-free, with carbon acylating reagent ring occurs for compound (III) in certain solvent Reaction is closed, compound (IV) is obtained；
Step b：Under alkaline condition, compound (IV) reacts to obtain compound (I) or compound with methylating reagent (II), reaction route is as follows：
Work as R1=CH3When, the method comprises the steps of：
Step a：Under the conditions of alkali presence or alkali-free, compound (XII) reacts hair with carbon acylating reagent in certain solvent Raw cyclization reaction, obtains compound (XIII)；
Step b：Under alkaline condition, compound (XIII) reacts in certain solvent with methylating reagent, obtains chemical combination Object (II), reaction route is as follows：
Wherein, work as R1=H or CH3When, in step a, carbon acylating reagent is phosgene, triphosgene, carbonyl dimidazoles, carbonic acid two One of methyl esters, diphenyl carbonate, methylchloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate or urea are more Kind, preferably one of triphosgene, carbonyl dimidazoles, dimethyl carbonate, methylchloroformate, ethyl chloroformate or urea or more Kind；The alkali is sodium bicarbonate, sodium carbonate, saleratus, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, potassium phosphate, hydroxide Sodium, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, tert-butyl alcohol magnesium, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, ethyl alcohol Sodium, triethylamine, diethylamine, dimethylamine, trimethylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0], 1,5- diazabicyclo [4.3.0] nonyl- 5- alkene or 1,4- diazabicylo One of [2.2.2] octane is a variety of, preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, tertiary fourth One of potassium alcoholate, triethylamine, diisopropyl ethyl amine or 4-dimethylaminopyridine are a variety of；The solvent be selected from benzene, toluene, Chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, isopropyl acetate, 2- butanone, acetone, 1,2- dimethyl -2- miaow Oxazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyridine, methanol, ethyl alcohol, isopropanol, n-butanol, ethylene glycol, the tert-butyl alcohol, uncle Amylalcohol, polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, 1,2- propylene glycol, diethoxy first Alkane, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, n-hexane, hexamethylene, dichloromethane One of alkane, 1,2- dichloroethanes, chloroform or water are a variety of；Preferably toluene, acetonitrile, methanol, ethyl alcohol, glycol dinitrate Ether, diethoxymethane, dioxane, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, One of N-Methyl pyrrolidone, tetrahydrofuran, 2- methyltetrahydrofuran or water are a variety of.
Wherein, work as R1=H or CH3When, in step a, when carbon acylating reagent is triphosgene, the carbon acylating reagent and change The molar feed ratio for closing object (III) and carbon acylating reagent and compound (XII) is 0.25-2:1, preferably 0.3-1:1；Work as carbon When acylating reagent is other reagents in addition to triphosgene, the carbon acylating reagent and compound (III) and carbon acylating reagent and change Close mole the feeding intake than for 0.8-5 of object (XII):1, preferably 1-3:1；The alkali and compound (III) and carbon acylating reagent Molar ratio with compound (XII) is 0.9-5:1, preferably 1-3:1；Reaction temperature is selected from -78-150 DEG C, preferably It is -10-80 DEG C；Reaction time is 0.5-36 hours, preferably 1-24 hours.
Wherein, work as R1=H or CH3When, in step b, the methylating reagent is dimethyl suflfate, iodomethane, bromine first One of alkane, chloromethanes, dimethyl carbonate or trimethyl phosphate are a variety of；The alkali is sodium bicarbonate, sodium carbonate, bicarbonate Potassium, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, hydrogen Calcium oxide, tert-butyl alcohol magnesium, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, triethylamine, diethylamine, dimethylamine, trimethylamine, Diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 11 carbon -7- of 1,8- diazabicyclo [5.4.0] One of alkene, 1,5- diazabicyclo [4.3.0] nonyl- 5- alkene or Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane are a variety of, preferably For sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, two or 1,8- diazabicyclo One of [5.4.0] 11 carbon -7- alkene is a variety of；The solvent be selected from benzene, toluene, chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, Cyanophenyl, ethyl acetate, isopropyl acetate, 2- butanone, acetone, 1,2- dimethyl -2- imidazolone, dimethyl sulfoxide, dimethyl sulfone, ring Fourth sulfone, hexamethyl phosphamide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N- methyl pyrrole Pyrrolidone, pyridine, methanol, ethyl alcohol, isopropanol, n-butanol, ethylene glycol, the tert-butyl alcohol, tert-pentyl alcohol, polyethylene glycol, ethylene glycol list first Ether, glycol dimethyl ether, diethylene glycol dimethyl ether, 1,2- propylene glycol, diethoxymethane, dioxane, methyl tertiary butyl ether(MTBE), In isopropyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, chloroform or water It is one or more；Preferably toluene, acetonitrile, methanol, ethyl alcohol, glycol dimethyl ether, diethoxymethane, dioxane, N, Dinethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, tetrahydrofuran, 2- first One of base tetrahydrofuran or water are a variety of.
Wherein, as R=H and R1When=H, in step b, the molar ratio of the methylating reagent and compound (IV) are 0.6- 5:1, preferably 0.8-1.2:1；The molar ratio of the alkali and compound (IV) are 0.6-5:1, preferably 0.8-3:1；Instead Temperature is answered to be selected from 0-150 DEG C, preferably 0-80 DEG C；Reaction time 0.5-36 hour, preferably 1-24 hour；
Wherein, work as R=CH3And R1When=H, in step b, the molar ratio of the methylating reagent and compound (IV) is 1.5-10:1, preferably 1.8-5:1；The molar ratio of the alkali and compound (IV) are 1.5-10:1, preferably 1.8-5:1；Instead Temperature is answered to be selected from 0-150 DEG C, preferably 0-80 DEG C；Reaction time 0.5-36 hour, preferably 1-24 hour；
Wherein, work as R=CH3And R1=CH3When, in step b, the molar ratio of the methylating reagent and compound (XIII) For 0.6-5:1, preferably 0.8-3:1；The molar ratio of the alkali and compound (XIII) are 0.6-5:1, preferably 0.8- 3:1；Reaction temperature is selected from 0-150 DEG C, preferably 0-80 DEG C；Reaction time 0.5-36 hour, preferably 1-24 hour.
A kind of compound (IV), has following structure formula：
A kind of formula (2) compound represented (III), compound (XII) preparation method,
Wherein, compound (III)：R1=H；Compound (XII)：R1=CH3；It is characterized in that, working as R1When=H, the side Method includes the following steps：
Step 1：Compound (V) reacts in certain solvent with halide reagent, obtains compound (VI)；
Step 2：Under conditions of with/without catalyst, compound (VI) reacts in certain solvent with aminating agent, obtains Compound (III)；
Reaction route is as follows：
Wherein, X is chlorine, bromine or iodine；
Work as R1=CH3, the described method comprises the following steps：
Step a：Compound (V) reacts in certain solvent with halide reagent, obtains compound (VI)；
Step b：Under conditions of with/without catalyst, compound (VI) reacts in certain solvent with methylamine reagent, obtains To compound (XII)；
Reaction route is as follows：
Wherein, in step 1 and step a, the halide reagent is N- chlorosuccinimide, trichloroisocyanuric acid, dichloro Glycolylurea, N- bromo-succinimide, C5H6Br2N2O2 or N- iodo succinic acid imines；The solvent is selected from benzene, toluene, chlorobenzene, two Toluene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, isopropyl acetate, 2- butanone, acetone, 1,2- dimethyl -2- imidazolone, two First sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- bis- Ethyl-formamide, N-Methyl pyrrolidone, pyridine, methanol, ethyl alcohol, isopropanol, n-butanol, ethylene glycol, the tert-butyl alcohol, tert-pentyl alcohol, Polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, 1,2- propylene glycol, diethoxymethane, two Six ring of oxygen, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, n-hexane, hexamethylene, methylene chloride, 1, One of 2- dichloroethanes, chloroform or water are a variety of；Preferably toluene, methanol, acetonitrile, methanol, ethyl alcohol, glycol dinitrate One of ether, diethoxymethane, dioxane, tetrahydrofuran, 2- methyltetrahydrofuran or water are a variety of.
Wherein, when halide reagent is N- chlorosuccinimide, N- bromo-succinimide or N- N-iodosuccinimide When, the molar ratio of the reagent and compound (V) are 0.6-5:1, preferably 0.8-3:1；When halide reagent be two chlordantoins or When diiodo- glycolylurea, the molar ratio of the reagent and compound (V) are 0.3-2.5:1, preferably 0.4-1.5:1；Work as halide reagent When for trichloroisocyanuric acid, the molar ratio of the reagent and compound (V) are 0.15-2:1, preferably 0.3-1:1；Reaction temperature Selected from 0-150 DEG C, preferably 0-80 DEG C；Reaction time 0.5-36 hour, preferably 1-24 hour.
Wherein, in step 2, the aminating agent ammonia, ammonium hydroxide, methanol ammonia or ethyl alcohol ammonia it is one or more；The step b In, the methylamine reagent is the one or more of methylamine, methylamine water, methylamine methanol or methylethylolamine；The catalyst is copper One of powder, cuprous oxide, stannous chloride, cuprous bromide or cuprous iodide are a variety of；The solvent is selected from benzene, toluene, chlorine Benzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, isopropyl acetate, 2- butanone, acetone, 1,2- dimethyl -2- imidazoles Ketone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyridine, methanol, ethyl alcohol, isopropanol, n-butanol, ethylene glycol, the tert-butyl alcohol, uncle penta Alcohol, polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, 1,2- propylene glycol, diethoxymethane, Dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, n-hexane, hexamethylene, methylene chloride, One of 1,2- dichloroethanes, chloroform or water are a variety of；Preferably toluene, methanol, ethyl alcohol, glycol dimethyl ether, diethoxy One of methylmethane, dioxane, tetrahydrofuran, 2- methyltetrahydrofuran or water are a variety of.
Wherein, in step 2 and step b, the molar ratio and the methylamine reagent of the aminating agent and compound (VI) Molar ratio with compound (VI) is 1-40:1, preferably 1-20:1；The molar ratio of the catalyst and compound (VI) is 0.01-1:1, preferably 0.05-0.5:1；Reaction temperature is selected from 0-150oC, preferably 20-120oC；Reaction time, 0.5-36 was small When, preferably 1-24 hours.
A kind of preparation method of formula (3) compound represented (VII), comprises the steps of：
Step a：Compound (VIII) reacts in certain solvent with halide reagent, obtains compound (IX)；
Step b：Under conditions of with/without catalyst, compound (IX) in certain solvent with the methylamine reagent system of reacting Standby compound (X)；
Step c：Under alkali presence or alkali-free existence condition, compound (X) reacts in certain solvent with carbon acylating reagent Cyclization reaction occurs, obtains compound (XI)；
Step d：Under alkaline condition, compound (XI) reacts in certain solvent with methylating reagent, obtains compound (VII)；
Reaction route is as follows：
Wherein, X is chlorine, bromine or iodine.
Wherein, in step a, the halide reagent be N- chlorosuccinimide, trichloroisocyanuric acid, two chlordantoins, N- bromo-succinimide, C5H6Br2N2O2 or N- iodo succinic acid imines；The solvent be selected from benzene, toluene, chlorobenzene, dimethylbenzene, Isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, isopropyl acetate, 2- butanone, acetone, 1,2- dimethyl -2- imidazolone, diformazan are sub- Sulfone, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethyl Formamide, N-Methyl pyrrolidone, pyridine, methanol, ethyl alcohol, isopropanol, n-butanol, ethylene glycol, the tert-butyl alcohol, tert-pentyl alcohol, poly- second Glycol, glycol monoethyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, 1,2- propylene glycol, diethoxymethane, dioxy six Ring, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, n-hexane, hexamethylene, methylene chloride, 1,2- bis- One of chloroethanes, chloroform or water are a variety of；Preferably toluene, methanol, acetonitrile, methanol, ethyl alcohol, glycol dimethyl ether, two One of ethoxy methane, dioxane, tetrahydrofuran, 2- methyltetrahydrofuran or water are a variety of.
Wherein, in step a, when halide reagent is N- chlorosuccinimide, N- bromo-succinimide or N- iodo fourth When imidodicarbonic diamide, the molar ratio of the halide reagent and compound (VIII) are 0.6-5:1, preferably 0.8-3:1；When halogenation tries When agent is two chlordantoins or diiodo- glycolylurea, the molar ratio of the halide reagent and compound (VIII) are 0.3-2.5:1, preferably 0.4-1.5:1；When halide reagent is trichloroisocyanuric acid, the molar ratio of the reagent and compound (VIII) are 0.15-2: 1, preferably 0.3-1:1；0-150 DEG C of reaction temperature, preferably 0-80 DEG C；In reaction time 0.5-36 hour, preferably 1-24 is small When.
Wherein, in step b, the methylamine reagent is one kind or more of methylamine, methylamine water, first ammonia methanol or methylethylolamine Kind；The catalyst is one of copper powder, cuprous oxide, stannous chloride, cuprous bromide or cuprous iodide or a variety of；It is described molten Agent is selected from benzene, toluene, chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, isopropyl acetate, 2- butanone, acetone, 1, 2- dimethyl -2- imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N,N-dimethylformamide, N, N- Dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyridine, methanol, ethyl alcohol, isopropanol, n-butanol, second Glycol, the tert-butyl alcohol, tert-pentyl alcohol, polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, 1,2- the third two Alcohol, diethoxymethane, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, n-hexane, One of hexamethylene, methylene chloride, 1,2- dichloroethanes, chloroform or water are a variety of；Preferably toluene, methanol, ethyl alcohol, second two One of diethylene glycol dimethyl ether, diethoxymethane, dioxane, tetrahydrofuran, 2- methyltetrahydrofuran or water are a variety of.
Wherein, in step b, the molar ratio of the methylamine reagent and compound (IX) are 1-40:1, preferably 1-20:1； The molar ratio of the catalyst and compound (IX) are 0.01-1:1, preferably 0.05-0.5:1；Reaction at moderate temperatures into Row, it is described to be selected from 0-150 DEG C, preferably 20-120 DEG C；Reaction time 0.5-36 hour, preferably 1-24 hour.
Wherein, in step c, the carbon acylating reagent is phosgene, triphosgene, carbonyl dimidazoles, dimethyl carbonate, carbonic acid One of diphenyl ester, methylchloroformate, ethyl chloroformate, benzyl chloroformate, phenyl chloroformate or urea are a variety of, preferably One of triphosgene, carbonyl dimidazoles, dimethyl carbonate, methylchloroformate, ethyl chloroformate or urea are a variety of；The alkali For sodium bicarbonate, sodium carbonate, saleratus, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, potassium phosphate, sodium hydroxide, hydroxide Potassium, lithium hydroxide, magnesium hydroxide, calcium hydroxide, tert-butyl alcohol magnesium, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, three second Amine, diethylamine, dimethylamine, trimethylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1,8- bis- 11 carbon -7- alkene of azabicyclo [5.4.0], 1,5- diazabicyclo [4.3.0] nonyl- 5- alkene or 1,4- diazabicylo One of [2.2.2] octane is a variety of, preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, tertiary fourth One of potassium alcoholate, triethylamine, diisopropyl ethyl amine or 4-dimethylaminopyridine are a variety of；The solvent be selected from benzene, toluene, Chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, isopropyl acetate, 2- butanone, acetone, 1,2- dimethyl -2- miaow Oxazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyridine, methanol, ethyl alcohol, isopropanol, n-butanol, ethylene glycol, the tert-butyl alcohol, uncle Amylalcohol, polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, 1,2- propylene glycol, diethoxy first Alkane, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, n-hexane, hexamethylene, dichloromethane One of alkane, 1,2- dichloroethanes, chloroform or water are a variety of；Preferably toluene, acetonitrile, methanol, ethyl alcohol, glycol dinitrate Ether, diethoxymethane, dioxane, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, One of N-Methyl pyrrolidone, tetrahydrofuran, 2- methyltetrahydrofuran or water are a variety of.
Wherein, in step c, when carbon acylating reagent is triphosgene, mole throwing of the carbon acylating reagent and compound (X) Material is than being 0.25-2:1, preferably 0.3-1:1；When carbon acylating reagent is other reagents in addition to triphosgene, the phosphinylidyne The molar feed ratio of reagent and compound (X) are 0.8-5:1, preferably 1-3:1；The alkali and compound (X's) feeds intake mole Than for 0.9-5:1, preferably 1-3:1；Reaction carries out at moderate temperatures, described to be selected from -78-150 DEG C, preferably -10-80 ℃；Reaction time 0.5-36 hour, preferably 1-24 hour.
Wherein, in step d, the methylating reagent is dimethyl suflfate, iodomethane, bromomethane, chloromethanes, carbonic acid two One of methyl esters or trimethyl phosphate are a variety of；The alkali is sodium bicarbonate, sodium carbonate, saleratus, potassium carbonate, carbonic acid Caesium, calcium carbonate, lithium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, the tert-butyl alcohol Magnesium, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, triethylamine, diethylamine, dimethylamine, trimethylamine, diisopropyl ethyl Amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0], 1,5- diaza One of bicyclic [4.3.0] nonyl- 5- alkene or Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane are a variety of, preferably sodium carbonate, carbonic acid Potassium, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, two or 1,8- diazabicyclo [5.4.0] 11 One of carbon -7- alkene is a variety of；The solvent is selected from benzene, toluene, chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, acetic acid second Ester, isopropyl acetate, 2- butanone, acetone, 1,2- dimethyl -2- imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl Phosphamide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyrrole Pyridine, methanol, ethyl alcohol, isopropanol, n-butanol, ethylene glycol, the tert-butyl alcohol, tert-pentyl alcohol, polyethylene glycol, glycol monoethyl ether, ethylene glycol Dimethyl ether, diethylene glycol dimethyl ether, 1,2- propylene glycol, diethoxymethane, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, four One of hydrogen furans, 2- methyltetrahydrofuran, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, chloroform or water or It is a variety of；Preferably toluene, acetonitrile, methanol, ethyl alcohol, glycol dimethyl ether, diethoxymethane, dioxane, N, N- dimethyl Formamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, tetrahydrofuran, 2- methyl tetrahydro furan It mutters or one of water or a variety of.
Wherein, in step d, the molar ratio of the methylating reagent and compound (XI) are 0.6-5:1, preferably 0.8-3: 1；The molar ratio of the alkali and compound (XI) are 0.6-5:1, preferably 0.8-3:1；Reaction temperature is selected from 0-150 DEG C, Preferably 0-80 DEG C；Reaction time 0.5-36 hour, preferably 1-24 hour.
Compared with prior art, the invention has the advantages that：Operation of the present invention is easy, highly-safe, atom passes through Ji property is high, the three wastes are few；This supplementary material is cheap and easy to get, toxicity is low, safety and stability；Reaction condition is mild, and impurity lacks, high income； The present invention by crystallize or mashing purified product, avoid column from chromatographing, operation is simple, process stabilizing, it is easily controllable, reaction after Processing is convenient, can economy be advantageously used in industrialized production.
Specific embodiment
The present invention is further illustrated below with reference to embodiment, following implementation only describes this by way of example Invention.These embodiments are not meant to be limited the present invention.It is obvious that those of ordinary skill in the art can be In the scope of the present invention and essence, various flexible and modification is carried out to the present invention.It is to be understood that this invention is intended to cover The accommodation and modification for including in the appended claims.
Raw material 6- amino -2- methoxyl group -3- methylpyrimidine base -4- ketone and 5,6- diamino -2- first used in the present invention Oxygroup -3- methylpyrimidine base -4- ketone can easily be prepared with bibliography Synthetic Commun.1989,19,843-850. Wherein, 5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone can also be prepared according to the method for this patent.
The preparation of the big fruit caffeine of embodiment 1
(1) preparation of 5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone
6- amino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 64.5mmol) is dissolved in tetrahydrofuran, 20-30 DEG C N- chlorosuccinimide (12.9g, 96.8mmol) is added portionwise, finishes latter 20-30 DEG C and react 6 hours, react substantially complete Entirely.Add water, methylene chloride after concentration, hypo solution, sodium bicarbonate aqueous solution, washing are successively used in liquid separation, and organic phase is dense It is recrystallized after contracting, the chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone 10.4g of off-white powder 6- amino -5-, yield is obtained after drying 85%.
The chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone (10.4g, 54.8mmol) of 6- amino -5- is suspended in methanol, adds Enter ammonium hydroxide (35.8g, 548mmol), 50-60 DEG C is reacted 12 hours, and reaction is substantially completely.Methylene chloride, moisture is added in concentration Liquid is recrystallized with water after organic phase concentration, off-white powder 5,6- diamino -2- methoxyl group -3- methylpyrimidine base-is obtained after drying 4- ketone 8.4g, yield 90%.
(2) preparation of big fruit caffeine
5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 58.8mmol) are suspended in methanol, are added Potassium carbonate (17.9g, 129.4mmol), 0-10 DEG C is added portionwise triphosgene (8.7g, 29.4mmol).20-30 DEG C is maintained after finishing Reaction 2 hours.After concentration plus water is beaten.Off-white powder 10.4g, yield 90% are dried to obtain after filtering.
The cyclocomplex (10.4g, 53mmol) that upper step obtains is suspended in acetone, is added potassium carbonate (7.3g, 53mmol), 20-30 DEG C of addition dimethyl suflfate (6.7g, 53mmol), 50-60 DEG C is reacted 6 hours, and raw material fundamental reaction finishes；Concentration, according to It is secondary to be beaten with water and methanol；The big fruit caffeine 7.2g of off-white color, yield 65%, purity 98% are obtained after drying.1H NMR (400MHz,CDCl3)δ4.08(s,3H),3.49(s,3H),3.36(s,3H)。
The preparation of the big fruit caffeine of embodiment 2
(1) preparation of 5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone
6- amino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 64.5mmol) is dissolved in tetrahydrofuran, 20-30 DEG C C5H6Br2N2O2 (13.8g, 48.4mmol) is added portionwise.It finishes latter 20-30 DEG C to react 6 hours, reaction is substantially completely.After concentration Add water, methylene chloride, liquid separation is successively used hypo solution, sodium bicarbonate aqueous solution, washing, tied again after organic phase concentration Crystalline substance obtains the bromo- 2- methoxyl group -3- methylpyrimidine base -4- ketone 12.1g of off-white powder 6- amino -5-, yield 80% after drying.
The bromo- 2- methoxyl group -3- methylpyrimidine base -4- ketone (12.1g, 51.6mmol) of 6- amino -5- is suspended in tetrahydrofuran In, be added ammonium hydroxide (16.9g, 258mmol), 110-120 DEG C confined reaction 1 hour, reaction substantially completely.Dichloro is added in concentration Methane, moisture liquid are recrystallized with water after organic phase concentration, off-white powder 5,6- diamino -2- methoxyl group -3- first are obtained after drying Yl pyrimidines base -4- ketone 7.8g, yield 89%.
(2) preparation of big fruit caffeine
5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 58.8mmol) are suspended in toluene, are added Sodium hydroxide (58.8mmol), 0-10 DEG C is added portionwise triphosgene (17.6mmol).Maintain 50-60 DEG C of reaction 12 small after finishing When.After concentration plus water is beaten.Off-white powder 10.4g, yield 90% are dried to obtain after filtering.
The cyclocomplex (10.4g, 53mmol) that upper step obtains is suspended in acetonitrile, addition sodium hydroxide (7.3g, 42.4mmol), 20-30 DEG C of addition bromomethane (6.7g, 42.4mmol), 70-80 DEG C confined reaction 2 hours, raw material fundamental reaction It finishes.Concentration is successively beaten with water and methanol.The big fruit caffeine 7.2g of off-white color, yield 65% are obtained after drying.Purity 98%.1H NMR(400MHz,CDCl3)δ4.08(s,3H),3.49(s,3H),3.36(s,3H)。
The preparation of the big fruit caffeine of embodiment 3
(1) preparation of 5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone
6- amino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 64.5mmol) is dissolved in toluene, and 20-30 DEG C point It criticizes and N- bromo-succinimide (51.6mmol) is added, finish latter 70-80 DEG C and react 1 hour, reaction is substantially completely.Add after concentration Water, methylene chloride, liquid separation are successively used hypo solution, sodium bicarbonate aqueous solution, washing, are recrystallized after organic phase concentration, The chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone 10.6g of off-white powder 6- amino -5-, yield 87% are obtained after drying.
The bromo- 2- methoxyl group -3- methylpyrimidine base -4- ketone (10.4g, 54.8mmol) of 6- amino -5- is suspended in toluene, adds Enter ammonia (54.8mmol), 20-30 DEG C is reacted 24 hours, and reaction is substantially completely.Methylene chloride, moisture liquid, organic phase is added in concentration Recrystallized after concentration with water, after drying off-white powder 5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone 8.4g, Yield 90%.
(2) preparation of big fruit caffeine
5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 58.8mmol) are suspended in N, N- dimethyl methyl In amide, it is added sodium tert-butoxide (176.4mmol), 0-10 DEG C is added portionwise triphosgene (58.8mmol).50-60 is maintained after finishing DEG C reaction 12 hours.After concentration plus water is beaten.Off-white powder 10.4g, yield 90% are dried to obtain after filtering.
The cyclocomplex (10.4g, 53mmol) that upper step obtains is suspended in N-Methyl pyrrolidone, and potassium tert-butoxide is added (159mmol), 20-30 DEG C of addition dimethyl carbonate (63.6mmol), 70-80 DEG C is reacted 2 hours, and raw material fundamental reaction finishes； Concentration is successively beaten with water and methanol；The big fruit caffeine 7.3g of off-white color, yield 66% are obtained after drying.Purity 98%.1H NMR (400MHz,CDCl3)δ4.08(s,3H),3.49(s,3H),3.36(s,3H)。
The preparation of the big fruit caffeine of embodiment 4
(1) preparation of 5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone
6- amino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 64.5mmol) is dissolved in tetrahydrofuran, 20-30 DEG C N- chlorosuccinimide (12.9g, 96.8mmol) is added portionwise.It finishes latter 20-30 DEG C to react 6 hours, react substantially complete Entirely.Add water, methylene chloride after concentration, hypo solution, sodium bicarbonate aqueous solution, washing are successively used in liquid separation, and organic phase is dense It is recrystallized after contracting, the chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone 10.4g of off-white powder 6- amino -5-, yield is obtained after drying 85%.
In chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone (10.4g, 54.8mmol) the suspension dioxane of 6- amino -5-, It is added ammonium hydroxide (548mmol), is added catalyst cuprous bromide (27.4mmol), 50-60 DEG C is reacted 12 hours, is reacted substantially complete Entirely.Concentration is added methylene chloride, moisture liquid, is recrystallized after organic phase concentration with water, off-white powder 5,6- diamino are obtained after drying Base -2- methoxyl group -3- methylpyrimidine base -4- ketone 8.4g, yield 90%.
(2) preparation of big fruit caffeine
5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 58.8mmol) are suspended in methanol, are added Potassium carbonate (17.9g, 129.4mmol), 0-10 DEG C is added portionwise triphosgene (8.7g, 29.4mmol).20-30 DEG C is maintained after finishing Reaction 2 hours.After concentration plus water is beaten.Off-white powder 10.4g, yield 90% are dried to obtain after filtering.
The cyclocomplex (10.4g, 53mmol) that upper step obtains is suspended in acetone, is added potassium carbonate (53mmol).20-30℃ It is added dimethyl suflfate (53mmol).50-60 DEG C is reacted 6 hours, and raw material fundamental reaction finishes.Water and methanol are successively used in concentration Mashing.The big fruit caffeine 7.2g of off-white color, yield 65%, purity 98% are obtained after drying.1H NMR(400MHz,CDCl3)δ4.08 (s,3H),3.49(s,3H),3.36(s,3H)。
The preparation of the big fruit caffeine of 5 methyl of embodiment
(1) preparation of 5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone
6- amino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 64.5mmol) is dissolved in methanol, and 0-10 DEG C point It criticizes and N- N-iodosuccinimide (193.5mmol) is added, finish latter 0-10 DEG C and react 24 hours, reaction is substantially completely.After concentration Add water, methylene chloride, liquid separation is successively used hypo solution, sodium bicarbonate aqueous solution, washing, tied again after organic phase concentration Crystalline substance obtains the chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone 10.4g of off-white powder 6- amino -5-, yield 85% after drying.
The bromo- 2- methoxyl group -3- methylpyrimidine base -4- ketone (10.4g, 54.8mmol) of 6- amino -5- is suspended in ethylene glycol two It in methyl ether, is added methanol ammonia (1096mmol), 50-60 DEG C is reacted 12 hours, and reaction is substantially completely.Concentration, addition methylene chloride, Moisture liquid is recrystallized with water after organic phase concentration, off-white powder 5 is obtained after drying, and 6- diamino -2- methoxyl group -3- methyl is phonetic Piperidinyl -4- ketone 8.4g, yield 90%.
(2) preparation of the big fruit caffeine of methyl
5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 58.8mmol) are suspended in methanol, are added Potassium carbonate (12.2g, 88.2mmol), 0-10 DEG C is added portionwise methylchloroformate (6.1g, 64.7mmol).20- is maintained after finishing 30 DEG C are warming up to 50-60 DEG C the reaction was continued 5 hours after reaction 2 hours.After concentration plus water is beaten.Dried after filtering off-white color is solid Body 10.4g, yield 90%.
The cyclocomplex (10.4g, 53mmol) that upper step obtains is suspended in DMF, is added DBU (24.2g, 159mmol).20- 30 DEG C of addition iodomethane (18.9g, 133mmol).80-90 DEG C is reacted 12 hours, and raw material fundamental reaction finishes.It is filtered after adding water, Filter cake successively uses water and methanol to be beaten.The big fruit caffeine 9.5g of off-white color methyl, yield 80% are obtained after drying.Purity 98%.1H NMR(400MHz,CDCl3)δ4.04(s,3H),3.58(s,3H),3.43(s,3H),3.34(s,3H)。
The preparation of the big fruit caffeine of 6 methyl of embodiment
(1) preparation of 5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone
6- amino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 64.5mmol) is dissolved in tetrahydrofuran, 20-30 DEG C two chlordantoins (25.8mmol) is added portionwise, finishes latter 20-30 DEG C and react 6 hours, reaction is substantially completely.After concentration plus water, Methylene chloride, liquid separation successively use hypo solution, sodium bicarbonate aqueous solution, washing, recrystallize, dry after organic phase concentration The chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone 10.6g of off-white powder 6- amino -5-, yield 84% are obtained after dry.
The chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone (10.4g, 54.8mmol) of 6- amino -5- is suspended in methanol, adds Enter ethyl alcohol ammonia (548mmol), 50-60 DEG C is reacted 12 hours, and reaction is substantially completely.Concentration is added methylene chloride, moisture liquid, has Machine is recrystallized after being mutually concentrated with water, and off-white powder 5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone are obtained after drying 8.5g, yield 91%.
(2) preparation of the big fruit caffeine of methyl
5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 58.8mmol) are suspended in tetrahydrofuran, It is added diisopropyl ethyl (58.8mmol), 0-10 DEG C is added portionwise carbonyl dimidazoles (117.6mmol).20- is maintained after finishing 30 DEG C are warming up to 50-60 DEG C the reaction was continued 5 hours after reaction 2 hours.After concentration plus water is beaten.Dried after filtering off-white color is solid Body 10.4g, yield 90%.
The cyclocomplex (10.4g, 53mmol) that upper step obtains is suspended in ethyl alcohol, is added potassium tert-butoxide (104.4mmol). 20-30 DEG C of addition trimethyl phosphate (95.4mmol).70-80 DEG C is reacted 12 hours, and raw material fundamental reaction finishes.Add mistake after water Filter, filter cake successively use water and methanol to be beaten.The big fruit caffeine 9.5g of off-white color methyl, yield 80% are obtained after drying.Purity 98% 。1H NMR(400MHz,CDCl3)δ4.04(s,3H),3.58(s,3H),3.43(s,3H),3.34(s,3H)。
The preparation of the big fruit caffeine of 7 methyl of embodiment
(1) preparation of 5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone
6- amino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 64.5mmol) is dissolved in tetrahydrofuran, 20-30 DEG C C5H6Br2N2O2 (96.8mmol) is added portionwise, finishes latter 20-30 DEG C and react 6 hours, reaction is substantially completely.After concentration plus water, Methylene chloride, liquid separation successively use hypo solution, sodium bicarbonate aqueous solution, washing, recrystallize, dry after organic phase concentration The chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone 10.4g of off-white powder 6- amino -5-, yield 85% are obtained after dry.
The chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone (10.4g, 54.8mmol) of 6- amino -5- is suspended in diethoxy It in methane, is added ammonium hydroxide (548mmol), is added catalyst cuprous oxide (13.7mmol), 50-60 DEG C is reacted 12 hours, reaction Substantially completely.Concentration is added methylene chloride, moisture liquid, is recrystallized after organic phase concentration with water, off-white powder 5 is obtained after drying, 6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone 8.4g, yield 90%.
(2) preparation of the big fruit caffeine of methyl
5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 58.8mmol) are suspended in diethoxymethane In, it is added 4-dimethylaminopyridine (176.4mmol), 0-10 DEG C is added portionwise dimethyl carbonate (176.4mmol).It is tieed up after finishing Being warming up to 50-60 DEG C after holding 20-30 DEG C of reaction 2 hours, the reaction was continued 5 hours.After concentration plus water is beaten.Class is dried to obtain after filtering White solid 10.4g, yield 90%.
The cyclocomplex (10.4g, 53mmol) that upper step obtains is suspended in ethyl alcohol, is added sodium carbonate (265mmol).20-30 DEG C be added bromomethane (265mmol).80-90 DEG C is reacted 12 hours, and raw material fundamental reaction finishes.It is filtered after adding water, filter cake is successively It is beaten with water and methanol.The big fruit caffeine 9.5g of off-white color methyl, yield 80% are obtained after drying.Purity 98%.
The preparation of the big fruit caffeine of 8 methyl of embodiment
(1) preparation of 5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone
6- amino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 64.5mmol) is dissolved in ethyl alcohol, and 20-30 DEG C point It criticizes and trichloroisocyanuric acid (64.5mmol) is added, finish latter 20-30 DEG C and react 6 hours, reaction is substantially completely.After concentration plus water, Methylene chloride, liquid separation successively use hypo solution, sodium bicarbonate aqueous solution, washing, recrystallize, dry after organic phase concentration The chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone 10.4g of off-white powder 6- amino -5-, yield 85% are obtained after dry.
The chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone (10.4g, 54.8mmol) of 6- amino -5- is suspended in diethoxy It in methane, is added ammonium hydroxide (548mmol), is added catalyst copper powder (2.74mmol), 50-60 DEG C is reacted 12 hours, and reaction is basic Completely.Concentration is added methylene chloride, moisture liquid, is recrystallized after organic phase concentration with water, off-white powder 5,6- bis- are obtained after drying Amino -2- methoxyl group -3- methylpyrimidine base -4- ketone 8.4g, yield 90%.
(2) preparation of the big fruit caffeine of methyl
5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 58.8mmol) are suspended in methanol, are added Potassium carbonate (88.2mmol), 0-10 DEG C is added portionwise ethyl chloroformate (64.7mmol).Maintain 20-30 DEG C of reaction 2 small after finishing When after be warming up to 50-60 DEG C the reaction was continued 5 hours.After concentration plus water is beaten.Off-white powder 10.4g is dried to obtain after filtering, is received Rate 90%.
The cyclocomplex (10.4g, 53mmol) that upper step obtains is suspended in DMF, is added DBU (24.2g, 159mmol).20- 30 DEG C of addition iodomethane (133mmol).80-90 DEG C is reacted 12 hours, and raw material fundamental reaction finishes.Filtered after adding water, filter cake according to It is secondary to be beaten with water and methanol.The big fruit caffeine 9.5g of off-white color methyl, yield 80% are obtained after drying.Purity 98%.
The preparation of the big fruit caffeine of 9 methyl of embodiment
(1) preparation of 5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone
6- amino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 64.5mmol) is dissolved in diethoxymethane, 20-30 DEG C is added portionwise trichloroisocyanuric acid (19.4mmol), finishes latter 20-30 DEG C and reacts 6 hours, reaction is substantially completely.It is dense Add after contracting, methylene chloride, liquid separation, hypo solution, sodium bicarbonate aqueous solution, washing is successively used, after organic phase concentration Recrystallization obtains the chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone 10.5g of off-white powder 6- amino -5-, yield after drying 86%.
In chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone (10.4g, 54.8mmol) the suspension dioxane of 6- amino -5-, It is added ammonium hydroxide (548mmol), is added catalyst stannous chloride (27.4mmol), 50-60 DEG C is reacted 12 hours, is reacted substantially complete Entirely.Concentration is added methylene chloride, moisture liquid, is recrystallized after organic phase concentration with water, off-white powder 5,6- diamino are obtained after drying Base -2- methoxyl group -3- methylpyrimidine base -4- ketone 8.3g, yield 89%.
(2) preparation of the big fruit caffeine of methyl
5,6- diamino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 58.8mmol) are suspended in methanol, are added Potassium carbonate (88.2mmol), 0-10 DEG C is added portionwise urea (64.7mmol).It is risen after maintaining 20-30 DEG C of reaction after finishing 2 hours The reaction was continued 5 hours to 50-60 DEG C for temperature.After concentration plus water is beaten.Off-white powder 10.4g, yield 90% are dried to obtain after filtering.
The cyclocomplex (10.4g, 53mmol) that upper step obtains is suspended in DMF, is added DBU (24.2g, 159mmol).20- 30 DEG C of addition iodomethane (133mmol).80-90 DEG C is reacted 12 hours, and raw material fundamental reaction finishes.Filtered after adding water, filter cake according to It is secondary to be beaten with water and methanol.The big fruit caffeine 9.5g of off-white color methyl, yield 80% are obtained after drying.Purity 98%.
The preparation of the big fruit caffeine of 10 methyl of embodiment
(1) 6- amino -2- methoxyl group -3- methyl -5- (methylamino) pyrimidine radicals -4- ketone
6- amino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 64.5mmol) is dissolved in tetrahydrofuran, 20-30 DEG C N- chlorosuccinimide (96.8mmol) is added portionwise, finishes latter 20-30 DEG C and react 6 hours, reaction is substantially completely.Concentration Afterwards plus water, methylene chloride, liquid separation are heavy after successively using hypo solution, sodium bicarbonate aqueous solution, washing, organic phase to be concentrated Crystallization obtains the chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone 10.8g of off-white powder 6- amino -5-, yield 88% after drying.
In chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone (10.4g, 54.8mmol) the suspension tetrahydrofuran of 6- amino -5-, The methylamine solution (274mmol) of 30% concentration is added, 20-30 DEG C is reacted 12 hours, and reaction is substantially completely.Concentration is added Methylene chloride, moisture liquid are recrystallized with water after organic phase concentration, off-white powder 8.4g, yield 90% are obtained after drying.
(2) preparation of the big fruit caffeine of methyl
6- amino -2- methoxyl group -3- methyl -5- (methylamino) pyrimidine radicals -4- ketone (10g, 54.2mmol) is suspended in methanol In, 0-10 DEG C is added portionwise carbonyl dimidazoles (10.5g, 65.0mmol).50-60 DEG C is warming up to after finishing to react 5 hours.Concentration Afterwards plus water is beaten.Off-white powder 8.89g, yield 89% are dried to obtain after filtering.
The cyclocomplex (8.89g, 48mmol) that upper step obtains is suspended in acetonitrile, is added triethylamine (72mmol), 20-30 DEG C It is added bromomethane (6.84g, 72mmol), 80-90 DEG C of vexed tank is reacted 12 hours, and raw material fundamental reaction finishes；It filters, filters after adding water Cake successively uses water and methanol to be beaten；Off-white color tetramethyluric acid 9.1g, yield 85%, purity 98% are obtained after drying.
The preparation of the big fruit caffeine of 11 methyl of embodiment
(1) 6- amino -2- methoxyl group -3- methyl -5- (methylamino) pyrimidine radicals -4- ketone
6- amino -2- methoxyl group -3- methylpyrimidine base -4- ketone (10g, 64.5mmol) is dissolved in tetrahydrofuran, 20-30 DEG C N- chlorosuccinimide (96.8mmol) is added portionwise.It finishes latter 20-30 DEG C to react 6 hours, reaction is substantially completely.Concentration Afterwards plus water, methylene chloride, liquid separation are heavy after successively using hypo solution, sodium bicarbonate aqueous solution, washing, organic phase to be concentrated Crystallization obtains the chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone 10.4g of off-white powder 6- amino -5-, yield 85% after drying.
In chloro- 2- methoxyl group -3- methylpyrimidine base -4- ketone (10.4g, 54.8mmol) the suspension tetrahydrofuran of 6- amino -5-, The methylethylolamine solution (274mmol) of 30% concentration is added, 20-30 DEG C is reacted 12 hours, and reaction is substantially completely.Concentration, Methylene chloride, moisture liquid is added, is recrystallized after organic phase concentration with water, off-white powder 8.4g, yield 90% is obtained after drying.
(2) preparation of the big fruit caffeine of methyl
6- amino -2- methoxyl group -3- methyl -5- (methylamino) pyrimidine radicals -4- ketone is dissolved in DMF, 0-10 DEG C of addition carbonic acid Dimethyl ester (65.0mmol).100-110 DEG C is warming up to after finishing to react 12 hours.Water is added to filter, filter cake adds water to be beaten.After filtering Dry to obtain off-white powder 9.11g, yield 80%.
The cyclocomplex (9.11g, 43mmol) that upper step obtains is suspended in acetonitrile, is added potassium tert-butoxide (52mmol).20-30 DEG C be added iodomethane (52mmol).80-90 DEG C is reacted 12 hours, and raw material fundamental reaction finishes.Concentration is successively beaten with water and methanol Slurry.Off-white color tetramethyluric acid 8.7g, yield 90% are obtained after drying.Purity 98%.
The preparation of 12 tetramethyluric acid of embodiment
6- amino -1,3- dimethyl pyrimidine base -2,4- diketone (10g, 64.5mmol) is dissolved in acetonitrile, and 20-30 DEG C point It criticizes and N- chlorosuccinimide (12.9g, 96.8mmol) is added.It finishes latter 20-30 DEG C to react 6 hours, reaction is substantially completely.It is dense Add after contracting, methylene chloride, liquid separation, hypo solution, sodium bicarbonate aqueous solution, washing is successively used, after organic phase concentration Recrystallization obtains chloro- 1,3- dimethyl pyrimidine base -2, the 4- diketone 10.4g of off-white powder 6- amino -5-, yield 85% after drying.
Chloro- 1,3- dimethyl pyrimidine base -2, the 4- diketone (10.4g, 54.8mmol) of 6- amino -5- is suspended in ethyl alcohol, adds Enter the methylethylolamine solution (28.3g, 274mmol) of 30% concentration, 20-30 DEG C is reacted 12 hours, and reaction is substantially completely.Concentration, Methylene chloride, moisture liquid is added, is recrystallized after organic phase concentration with water, off-white powder 6- amino -1,3- diformazan is obtained after drying Base -5- (methylamino) pyrimidine radicals -2,4- diketone 8.4g, yield 90%.
6- amino -1,3- dimethyl -5- (methylamino) pyrimidine radicals -2,4- diketone (10g, 54.2mmol) is suspended in methanol In, 0-10 DEG C is added portionwise carbonyl dimidazoles (10.5g, 65.0mmol).50-60 DEG C is warming up to after finishing to react 5 hours.Concentration Afterwards plus water is beaten.Off-white powder 8.89g, yield 89% are dried to obtain after filtering.
The cyclocomplex (8.89g, 48mmol) that upper step obtains is suspended in acetonitrile, is added triethylamine (72mmol), 20-30 DEG C It is added bromomethane (6.84g, 72mmol), 80-90 DEG C of vexed tank is reacted 12 hours, and raw material fundamental reaction finishes；It filters, filters after adding water Cake successively uses water and methanol to be beaten, and obtains off-white color tetramethyluric acid 9.1g, yield 85%, purity 98% after dry.
The preparation of 13 tetramethyluric acid of embodiment
6- amino -1,3- dimethyl pyrimidine base -2,4- diketone (10g, 64.5mmol) is dissolved in acetonitrile, and 20-30 DEG C point It criticizes and C5H6Br2N2O2 (13.8g, 48.4mmol) is added.It finishes latter 20-30 DEG C to react 6 hours, reaction is substantially completely.Add after concentration Water, methylene chloride, liquid separation are successively used hypo solution, sodium bicarbonate aqueous solution, washing, are recrystallized after organic phase concentration, Bromo- 1,3- dimethyl pyrimidine base -2, the 4- diketone 12.9g of off-white powder 6- amino -5-, yield 85% are obtained after drying.
Bromo- 1,3- dimethyl pyrimidine base -2, the 4- diketone (12.9g, 55.1mmol) of 6- amino -5- is suspended in methyl tetrahydro furan In muttering, the methylamine methanol solution (165mmol) of 30% concentration is added, 20-30 DEG C is reacted 12 hours, and reaction is substantially completely.Concentration, Methylene chloride, moisture liquid is added, is recrystallized after organic phase concentration with water, off-white powder 6- amino -1,3- diformazan is obtained after drying Base -5- (methylamino) pyrimidine radicals -2,4- diketone 11.1g, yield 90%.
6- amino -1,3- dimethyl -5- (methylamino) pyrimidine radicals -2,4- diketone (10g, 54.2mmol) is dissolved in DMF, 0- 10 DEG C of addition dimethyl carbonates (65.0mmol).100-110 DEG C is warming up to after finishing to react 12 hours.Water is added to filter, filter cake adds Water mashing.Off-white powder 9.11g, yield 80% are dried to obtain after filtering.
The cyclocomplex (9.11g, 43mmol) that upper step obtains is suspended in acetonitrile, is added potassium tert-butoxide (52mmol).20-30 DEG C be added iodomethane (52mmol).80-90 DEG C is reacted 12 hours, and raw material fundamental reaction finishes.Concentration is successively beaten with water and methanol Slurry.Off-white color tetramethyluric acid 8.7g, yield 90% are obtained after drying.Purity 98%.
The preparation of 14 tetramethyluric acid of embodiment
6- amino -1,3- dimethyl pyrimidine base -2,4- diketone (10g, 64.5mmol) is dissolved in acetonitrile, and 20-30 DEG C point It criticizes and trichloroisocyanuric acid (32mmol) is added.It finishes latter 20-30 DEG C to react 6 hours, reaction is substantially completely.Hou Jiashui, two is concentrated Chloromethanes, liquid separation successively use hypo solution, sodium bicarbonate aqueous solution, washing, recrystallize, dry after organic phase concentration Chloro- 1,3- dimethyl pyrimidine base -2, the 4- diketone 10.4g of off-white powder 6- amino -5-, yield 85% are obtained afterwards.
Chloro- 1,3- dimethyl pyrimidine base -2, the 4- diketone (10.4g, 54.8mmol) of 6- amino -5- is suspended in ethyl alcohol, adds Enter the methylamine solution (54.8mmol) of 30% concentration, 20-30 DEG C is reacted 12 hours, and reaction is substantially completely.Dichloromethane is added in concentration Alkane, moisture liquid are recrystallized with water after organic phase concentration, off-white powder 6- amino -1,3- dimethyl -5- (methylamine are obtained after drying Base) pyrimidine radicals -2,4- diketone 8.4g, yield 90%.
6- amino -1,3- dimethyl -5- (methylamino) pyrimidine radicals -2,4- diketone (10g, 54.2mmol) is suspended in methanol In, 0-10 DEG C is added portionwise carbonyl dimidazoles (65.0mmol).50-60 DEG C is warming up to after finishing to react 5 hours.Add water after concentration Mashing.Off-white powder 8.89g, yield 89% are dried to obtain after filtering.
The cyclocomplex (8.89g, 48mmol) that upper step obtains is suspended in acetonitrile, is added triethylamine (72mmol), 20-30 DEG C It is added bromomethane (6.84g, 72mmol), 80-90 DEG C of vexed tank is reacted 12 hours, and raw material fundamental reaction finishes；It filters, filters after adding water Cake successively uses water and methanol to be beaten, and obtains off-white color tetramethyluric acid 9.1g, yield 85%, purity 98% after dry.
The preparation of 15 tetramethyluric acid of embodiment
6- amino -1,3- dimethyl pyrimidine base -2,4- diketone (10g, 64.5mmol) is dissolved in acetonitrile, and 20-30 DEG C point It criticizes and trichloroisocyanuric acid (32mmol) is added.It finishes latter 20-30 DEG C to react 6 hours, reaction is substantially completely.Hou Jiashui, two is concentrated Chloromethanes, liquid separation successively use hypo solution, sodium bicarbonate aqueous solution, washing, recrystallize, dry after organic phase concentration Chloro- 1,3- dimethyl pyrimidine base -2, the 4- diketone 10.6g of off-white powder 6- amino -5-, yield 87% are obtained afterwards.
Chloro- 1,3- dimethyl pyrimidine base -2, the 4- diketone (10.4g, 54.8mmol) of 6- amino -5- is suspended in ethyl alcohol, adds Enter the methylamine water solution (1096mmol) of 30% concentration, 20-30 DEG C is reacted 12 hours, and reaction is substantially completely.Dichloro is added in concentration Methane, moisture liquid are recrystallized with water after organic phase concentration, off-white powder 6- amino -1,3- dimethyl -5- (first are obtained after drying Amido) pyrimidine radicals -2,4- diketone 8.4g, yield 90%.
6- amino -1,3- dimethyl -5- (methylamino) pyrimidine radicals -2,4- diketone (10g, 54.2mmol) is suspended in methanol In, 0-10 DEG C is added portionwise carbonyl dimidazoles (65.0mmol).50-60 DEG C is warming up to after finishing to react 5 hours.Add water after concentration Mashing.Off-white powder 8.89g, yield 89% are dried to obtain after filtering.
The cyclocomplex (8.89g, 48mmol) that upper step obtains is suspended in acetonitrile, is added triethylamine (72mmol), 20-30 DEG C It is added bromomethane (6.84g, 72mmol), 80-90 DEG C of vexed tank is reacted 12 hours, and raw material fundamental reaction finishes；It filters, filters after adding water Cake successively uses water and methanol to be beaten, and obtains off-white color tetramethyluric acid 9.1g, yield 85%, purity 98% after dry.
The preparation of 16 tetramethyluric acid of embodiment
6- amino -1,3- dimethyl pyrimidine base -2,4- diketone (10g, 64.5mmol) is dissolved in acetonitrile, and 20-30 DEG C point It criticizes and trichloroisocyanuric acid (32mmol) is added.It finishes latter 20-30 DEG C to react 6 hours, reaction is substantially completely.Hou Jiashui, two is concentrated Chloromethanes, liquid separation successively use hypo solution, sodium bicarbonate aqueous solution, washing, recrystallize, dry after organic phase concentration Chloro- 1,3- dimethyl pyrimidine base -2, the 4- diketone 10.6g of off-white powder 6- amino -5-, yield 87% are obtained afterwards.
Chloro- 1,3- dimethyl pyrimidine base -2, the 4- diketone (10.4g, 54.8mmol) of 6- amino -5- is suspended in ethyl alcohol, adds Enter the methylamine water solution (1096mmol) of 30% concentration, 20-30 DEG C is reacted 12 hours, and reaction is substantially completely.Dichloro is added in concentration Methane, moisture liquid are recrystallized with water after organic phase concentration, off-white powder 6- amino -1,3- dimethyl -5- (first are obtained after drying Amido) pyrimidine radicals -2,4- diketone 8.4g, yield 90%.
6- amino -1,3- dimethyl -5- (methylamino) pyrimidine radicals -2,4- diketone (10g, 54.2mmol) is suspended in methanol In, it is added saleratus (88.2mmol), 0-10 DEG C is added portionwise carbonyl dimidazoles (65.0mmol).50- is warming up to after finishing 60 DEG C are reacted 5 hours, and after concentration plus water is beaten, and off-white powder 8.89g, yield 89% are dried to obtain after filtering.
The cyclocomplex (8.89g, 48mmol) that upper step obtains is suspended in acetonitrile, is added triethylamine (72mmol), 20-30 DEG C It is added bromomethane (6.84g, 72mmol), 80-90 DEG C of vexed tank is reacted 12 hours, and raw material fundamental reaction finishes；It filters, filters after adding water Cake successively uses water and methanol to be beaten, and obtains off-white color tetramethyluric acid 9.1g, yield 85%, purity 98% after dry.

Claims (20)

1. a kind of preparation of compounds of formula (1) compound represented (I), the method for compound (II) as shown in formula (2),
Wherein, compound (I)：R=H；Compound (II)：R=CH3；R1=H or R1=CH3；
It is characterized in that, working as R1When=H, the method is comprised the steps of：
Step a：Under the conditions of alkali presence or alkali-free, it is anti-that with carbon acylating reagent cyclization occurs for compound (III) in certain solvent It answers, obtains compound (IV)；
Step b：Under alkaline condition, compound (IV) reacts to obtain compound (I) or compound (II) with methylating reagent, instead Answer route as follows：
Work as R1=CH3When, the method comprises the steps of：
Step a：Under the conditions of alkali presence or alkali-free, compound (XII), which reacts in certain solvent with carbon acylating reagent, occurs ring Reaction is closed, compound (XIII) is obtained；
Step b：Under alkaline condition, compound (XIII) reacts in certain solvent with methylating reagent, obtains compound (II), reaction route is as follows：
2. preparation method according to claim 1, which is characterized in that work as R1=H or CH3When, in step a, carbon acylating reagent For phosgene, triphosgene, carbonyl dimidazoles, dimethyl carbonate, diphenyl carbonate, methylchloroformate, ethyl chloroformate, chloro-carbonic acid benzyl One of ester, phenyl chloroformate or urea are a variety of, preferably triphosgene, carbonyl dimidazoles, dimethyl carbonate, chloro-carbonic acid first One of ester, ethyl chloroformate or urea are a variety of；The alkali is sodium bicarbonate, sodium carbonate, saleratus, potassium carbonate, carbon Sour caesium, calcium carbonate, lithium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, the tert-butyl alcohol Magnesium, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, triethylamine, diethylamine, dimethylamine, trimethylamine, diisopropyl ethyl Amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0], 1,5- diaza One of bicyclic [4.3.0] nonyl- 5- alkene or Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane are a variety of, preferably sodium carbonate, carbonic acid Potassium, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropyl ethyl amine or 4-dimethylaminopyridine One of or it is a variety of；The solvent is selected from benzene, toluene, chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, acetic acid Isopropyl ester, 2- butanone, acetone, 1,2- dimethyl -2- imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyridine, methanol, Ethyl alcohol, isopropanol, n-butanol, ethylene glycol, the tert-butyl alcohol, tert-pentyl alcohol, polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, two Glycol dimethyl ether, 1,2- propylene glycol, diethoxymethane, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- One of methyltetrahydrofuran, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, chloroform or water are a variety of；It is preferred that For toluene, acetonitrile, methanol, ethyl alcohol, glycol dimethyl ether, diethoxymethane, dioxane, N,N-dimethylformamide, N, N- dimethyl acetamide, N, in N- diethylformamide, N-Methyl pyrrolidone, tetrahydrofuran, 2- methyltetrahydrofuran or water It is one or more.
3. preparation method according to claim 1, which is characterized in that work as R1=H or CH3When, in step a, when phosphinylidyneization is tried When agent is triphosgene, the molar feed ratio of the carbon acylating reagent and compound (III) and carbon acylating reagent and compound (XII) It is 0.25-2:1, preferably 0.3-1:1；When carbon acylating reagent is other reagents in addition to triphosgene, the phosphinylidyneization examination Agent and compound (III) and carbon acylating reagent and compound (XII's) mole feeds intake than for 0.8-5:1, preferably 1-3:1； The molar ratio of the alkali and compound (III) and carbon acylating reagent and compound (XII) are 0.9-5:1, preferably 1- 3:1；Reaction temperature is selected from -78-150 DEG C, preferably -10-80 DEG C；Reaction time is 0.5-36 hours, preferably 1-24 hours.
4. preparation method according to claim 1, which is characterized in that work as R1=H or CH3When, in step b, the methyl Change reagent is one of dimethyl suflfate, iodomethane, bromomethane, chloromethanes, dimethyl carbonate or trimethyl phosphate or a variety of； The alkali be sodium bicarbonate, sodium carbonate, saleratus, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, potassium phosphate, sodium hydroxide, Potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, tert-butyl alcohol magnesium, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, Triethylamine, diethylamine, dimethylamine, trimethylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 11 carbon -7- alkene of 8- diazabicyclo [5.4.0], 1,5- diazabicyclo [4.3.0] nonyl- 5- alkene or 1,4- diazabicylo One of [2.2.2] octane is a variety of, preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, tertiary fourth Potassium alcoholate, triethylamine, two or one of 11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0] are a variety of；The solvent is selected from Benzene, toluene, chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, isopropyl acetate, 2- butanone, acetone, 1,2- diformazan Base -2- imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N,N-dimethylformamide, N, N- dimethyl Acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyridine, methanol, ethyl alcohol, isopropanol, n-butanol, ethylene glycol, uncle Butanol, tert-pentyl alcohol, polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, 1,2- propylene glycol, diethyl Oxygroup methane, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, n-hexane, hexamethylene, One of methylene chloride, 1,2- dichloroethanes, chloroform or water are a variety of；Preferably toluene, acetonitrile, methanol, ethyl alcohol, ethylene glycol Dimethyl ether, diethoxymethane, dioxane, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethyl formyl One of amine, N-Methyl pyrrolidone, tetrahydrofuran, 2- methyltetrahydrofuran or water are a variety of.
5. the preparation method according to claim 4, which is characterized in that as R=H and R1When=H, in step b, the methyl The molar ratio for changing reagent and compound (IV) is 0.6-5:1, preferably 0.8-1.2:1；The alkali feeds intake with compound (IV's) Molar ratio is 0.6-5:1, preferably 0.8-3:1；Reaction temperature is selected from 0-150 DEG C, preferably 0-80 DEG C；Reaction time 0.5-36 Hour, preferably 1-24 hours；
Work as R=CH3And R1When=H, in step b, the molar ratio of the methylating reagent and IV are 1.5-10:1, preferably 1.8- 5:1；The molar ratio of the alkali and compound (IV) are 1.5-10:1, preferably 1.8-5:1；Reaction temperature is excellent selected from 0-150 DEG C It is selected as 0-80 DEG C；Reaction time 0.5-36 hour, preferably 1-24 hour；Work as R=CH3And R1=CH3When, it is described in step b The molar ratio of methylating reagent and compound (XIII) are 0.6-5:1, preferably 0.8-3:1；The alkali and compound (XIII) Molar ratio be 0.6-5:1, preferably 0.8-3:1；Reaction temperature is selected from 0-150 DEG C, preferably 0-80 DEG C；Reaction time 0.5-36 hours, preferably 1-24 hours.
6. a kind of compound (IV), it is characterised in that：Have following structure formula：
7. the preparation method of a kind of formula (2) compound represented (III), compound (XII),
Wherein, compound (III)：R1=H；Compound (XII)：R1=CH3；It is characterized in that, working as R1When=H, the method packet Include following steps：
Step 1：Compound (V) reacts in certain solvent with halide reagent, obtains compound (VI)；
Step 2：Under conditions of with/without catalyst, compound (VI) reacts in certain solvent with aminating agent, obtains chemical combination Object (III)；
Reaction route is as follows：
Wherein, X is chlorine, bromine or iodine；
Work as R1=CH3, the described method comprises the following steps：
Step a：Compound (V) reacts in certain solvent with halide reagent, obtains compound (VI)；
Step b：Under conditions of with/without catalyst, compound (VI) reacts in certain solvent with methylamine reagent, is changed It closes object (XII)；
Reaction route is as follows：
8. preparation method according to claim 7, which is characterized in that in step 1 and step a, the halide reagent is N- Chlorosuccinimide, trichloroisocyanuric acid, two chlordantoins, N- bromo-succinimide, C5H6Br2N2O2 or N- iodo succinic acid Imines；The solvent is selected from benzene, toluene, chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, isopropyl acetate, 2- Butanone, acetone, 1,2- dimethyl -2- imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N, N- diformazan Base formamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyridine, methanol, ethyl alcohol, isopropyl Alcohol, n-butanol, ethylene glycol, the tert-butyl alcohol, tert-pentyl alcohol, polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, diethylene glycol two Methyl ether, 1,2- propylene glycol, diethoxymethane, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- methyl tetrahydro One of furans, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, chloroform or water are a variety of；Preferably toluene, first Alcohol, acetonitrile, methanol, ethyl alcohol, glycol dimethyl ether, diethoxymethane, dioxane, tetrahydrofuran, 2- methyltetrahydrofuran Or one of water or a variety of.
9. preparation method according to claim 8, which is characterized in that when halide reagent is N- chlorosuccinimide, N- When bromo-succinimide or N- N-iodosuccinimide, the molar ratio of the halide reagent and compound (V) are 0.6-5:1, Preferably 0.8-3:1；When halide reagent is two chlordantoins or diiodo- glycolylurea, mole of the halide reagent and compound (V) Than for 0.3-2.5:1, preferably 0.4-1.5:1；When halide reagent is trichloroisocyanuric acid, the halide reagent and compound (V) molar ratio is 0.15-2:1, preferably 0.3-1:1；Reaction temperature is selected from 0-150 DEG C, preferably 0-80 DEG C；Reaction time 0.5-36 hours, preferably 1-24 hours.
10. preparation method according to claim 7, which is characterized in that in step 2, the aminating agent be ammonia, ammonium hydroxide, Methanol ammonia or ethyl alcohol ammonia it is one or more；In the step b, the methylamine reagent be methylamine, methylamine water, methylamine methanol or Methylethylolamine it is one or more；The catalyst is in copper powder, cuprous oxide, stannous chloride, cuprous bromide or cuprous iodide It is one or more；It is different that the solvent is selected from benzene, toluene, chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, acetic acid Propyl ester, 2- butanone, acetone, 1,2- dimethyl -2- imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N, Dinethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyridine, methanol, second Alcohol, isopropanol, n-butanol, ethylene glycol, the tert-butyl alcohol, tert-pentyl alcohol, polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, diethyl Glycol dimethyl ether, 1,2- propylene glycol, diethoxymethane, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- first One of base tetrahydrofuran, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, chloroform or water are a variety of；Preferably Toluene, methanol, ethyl alcohol, glycol dimethyl ether, diethoxymethane, dioxane, tetrahydrofuran, 2- methyltetrahydrofuran or water One of or it is a variety of.
11. preparation method according to claim 7, which is characterized in that in step 2 and step b, the aminating agent and change The molar ratio of the molar ratio and the methylamine reagent and compound (VI) of closing object (VI) is 1-40:1, preferably 1-20:1； The molar ratio of the catalyst and compound (VI) are 0.01-1:1, preferably 0.05-0.5:1；Reaction temperature is selected from 0-150 DEG C, preferably 20-120 DEG C；Reaction time 0.5-36 hour, preferably 1-24 hour.
12. a kind of preparation method of formula (3) compound represented (VII),
It is characterized in that, comprising the steps of：
Step a：Compound (VIII) reacts in certain solvent with halide reagent, obtains compound (IX)；
Step b：Under conditions of with/without catalyst, compound (IX) reacts preparationization with methylamine reagent in certain solvent It closes object (X)；
Step c：Under the conditions of alkali presence or alkali-free, compound (X), which reacts in certain solvent with carbon acylating reagent, occurs cyclization Reaction, obtains compound (XI)；
Step d：Under alkaline condition, compound (XI) reacts in certain solvent with methylating reagent, obtains compound (VII)；
Reaction route is as follows：
Wherein, X is chlorine, bromine or iodine.
13. preparation method according to claim 12, which is characterized in that in step a, the halide reagent is N- chloro Succimide, trichloroisocyanuric acid, two chlordantoins, N- bromo-succinimide, C5H6Br2N2O2 or N- iodo succinic acid imines； The solvent be selected from benzene, toluene, chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, isopropyl acetate, 2- butanone, Acetone, 1,2- dimethyl -2- imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N, N- dimethyl formyl Amine, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyridine, methanol, ethyl alcohol, isopropanol, just Butanol, ethylene glycol, the tert-butyl alcohol, tert-pentyl alcohol, polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, 1,2- propylene glycol, diethoxymethane, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, One of n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, chloroform or water are a variety of；Preferably toluene, methanol, second In nitrile, methanol, ethyl alcohol, glycol dimethyl ether, diethoxymethane, dioxane, tetrahydrofuran, 2- methyltetrahydrofuran or water It is one or more.
14. preparation method according to claim 13, which is characterized in that in step a, when halide reagent is N- chloro fourth two When acid imide, N- bromo-succinimide or N- N-iodosuccinimide, the molar ratio of the reagent and compound (VIII) is 0.6-5:1, preferably 0.8-3:1；When halide reagent is two chlordantoins or diiodo- glycolylurea, the reagent and compound (VIII) Molar ratio be 0.3-2.5:1, preferably 0.4-1.5:1；When halide reagent is trichloroisocyanuric acid, the reagent and chemical combination The molar ratio of object (VIII) is 0.15-2:1, preferably 0.3-1:1；0-150 DEG C of reaction temperature, preferably 0-80 DEG C；When reaction Between 0.5-36 hours, preferably 1-24 hours.
15. preparation method according to claim 12, which is characterized in that in step b, the methylamine reagent be methylamine, Methylamine water, first ammonia methanol or methylethylolamine it is one or more；The catalyst is copper powder, cuprous oxide, stannous chloride, bromination One of cuprous or cuprous iodide is a variety of；The solvent is selected from benzene, toluene, chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, benzene Nitrile, ethyl acetate, isopropyl acetate, 2- butanone, acetone, 1,2- dimethyl -2- imidazolone, dimethyl sulfoxide, dimethyl sulfone, ring fourth Sulfone, hexamethyl phosphamide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N- methylpyrrole Alkanone, pyridine, methanol, ethyl alcohol, isopropanol, n-butanol, ethylene glycol, the tert-butyl alcohol, tert-pentyl alcohol, polyethylene glycol, glycol monoethyl ether, It is glycol dimethyl ether, diethylene glycol dimethyl ether, 1,2- propylene glycol, diethoxymethane, dioxane, methyl tertiary butyl ether(MTBE), different In propyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, chloroform or water It is one or more；Preferably toluene, methanol, ethyl alcohol, glycol dimethyl ether, diethoxymethane, dioxane, tetrahydrofuran, One of 2- methyltetrahydrofuran or water are a variety of.
16. preparation method according to claim 12, which is characterized in that in step b, the methylamine reagent and compound (IX) molar ratio is 1-40:1, preferably 1-20:1；The molar ratio of the catalyst and compound (IX) are 0.01-1:1, it is excellent It is selected as 0.05-0.5:1；Reaction carries out at moderate temperatures, described to be selected from 0-150 DEG C, preferably 20-120 DEG C；Reaction time 0.5-36 hours, preferably 1-24 hours.
17. preparation method according to claim 12, which is characterized in that in step c, the carbon acylating reagent is light Gas, triphosgene, carbonyl dimidazoles, dimethyl carbonate, diphenyl carbonate, methylchloroformate, ethyl chloroformate, benzyl chloroformate, One of phenyl chloroformate or urea are a variety of, preferably triphosgene, carbonyl dimidazoles, dimethyl carbonate, methylchloroformate, One of ethyl chloroformate or urea are a variety of；The alkali is sodium bicarbonate, sodium carbonate, saleratus, potassium carbonate, carbonic acid Caesium, calcium carbonate, lithium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, the tert-butyl alcohol Magnesium, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, triethylamine, diethylamine, dimethylamine, trimethylamine, diisopropyl ethyl Amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0], 1,5- diaza One of bicyclic [4.3.0] nonyl- 5- alkene or Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane are a variety of, preferably sodium carbonate, carbonic acid Potassium, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropyl ethyl amine or 4-dimethylaminopyridine One of or it is a variety of；The solvent is selected from benzene, toluene, chlorobenzene, dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, acetic acid Isopropyl ester, 2- butanone, acetone, 1,2- dimethyl -2- imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, pyridine, methanol, Ethyl alcohol, isopropanol, n-butanol, ethylene glycol, the tert-butyl alcohol, tert-pentyl alcohol, polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, two Glycol dimethyl ether, 1,2- propylene glycol, diethoxymethane, dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- One of methyltetrahydrofuran, n-hexane, hexamethylene, methylene chloride, 1,2- dichloroethanes, chloroform or water are a variety of；It is preferred that For toluene, acetonitrile, methanol, ethyl alcohol, glycol dimethyl ether, diethoxymethane, dioxane, N,N-dimethylformamide, N, N- dimethyl acetamide, N, in N- diethylformamide, N-Methyl pyrrolidone, tetrahydrofuran, 2- methyltetrahydrofuran or water It is one or more.
18. preparation method according to claim 17, which is characterized in that in step c, when carbon acylating reagent is triphosgene When, the molar feed ratio of the carbon acylating reagent and compound (X) are 0.25-2:1, preferably 0.3-1:1；When carbon acylating reagent When for other reagents in addition to triphosgene, the molar feed ratio of the carbon acylating reagent and compound (X) are 0.8-5:1, preferably For 1-3:1；The molar ratio of the alkali and compound (X) are 0.9-5:1, preferably 1-3:1；Reaction at moderate temperatures into Row, it is described to be selected from -78-150 DEG C, preferably -10-80 DEG C；Reaction time 0.5-36 hour, preferably 1-24 hour.
19. preparation method according to claim 12, which is characterized in that in step d, the methylating reagent is sulfuric acid One of dimethyl ester, iodomethane, bromomethane, chloromethanes, dimethyl carbonate or trimethyl phosphate are a variety of；The alkali is carbonic acid Hydrogen sodium, sodium carbonate, saleratus, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, hydrogen Lithia, magnesium hydroxide, calcium hydroxide, tert-butyl alcohol magnesium, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, triethylamine, diethyl Amine, dimethylamine, trimethylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1,8- diazabicyclo In [5.4.0] 11 carbon -7- alkene, 1,5- diazabicyclo [4.3.0] nonyl- 5- alkene or 1,4- diazabicylo [2.2.2] octane It is one or more, preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, One of two or 1,8- diazabicyclo [5.4.0], 11 carbon -7- alkene is a variety of；The solvent be selected from benzene, toluene, chlorobenzene, Dimethylbenzene, isopropylbenzene, acetonitrile, cyanophenyl, ethyl acetate, isopropyl acetate, 2- butanone, acetone, 1,2- dimethyl -2- imidazolone, Dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl phosphamide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- Diethylformamide, N-Methyl pyrrolidone, pyridine, methanol, ethyl alcohol, isopropanol, n-butanol, ethylene glycol, the tert-butyl alcohol, uncle penta Alcohol, polyethylene glycol, glycol monoethyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, 1,2- propylene glycol, diethoxymethane, Dioxane, methyl tertiary butyl ether(MTBE), isopropyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, n-hexane, hexamethylene, methylene chloride, One of 1,2- dichloroethanes, chloroform or water are a variety of；Preferably toluene, acetonitrile, methanol, ethyl alcohol, glycol dimethyl ether, two Ethoxy methane, dioxane, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N- methyl One of pyrrolidones, tetrahydrofuran, 2- methyltetrahydrofuran or water are a variety of.
20. preparation method according to claim 12, which is characterized in that in step d, the methylating reagent and compound (XI) molar ratio is 0.6-5:1, preferably 0.8-3:1；The molar ratio of the alkali and compound (XI) are 0.6-5:1, Preferably 0.8-3:1；Reaction temperature is selected from 0-150 DEG C, preferably 0-80 DEG C；Reaction time 0.5-36 hour, preferably 1-24 Hour.
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CN110204547A (en) * 2019-07-04 2019-09-06 绍兴市精益生物化工有限公司 A kind of synthetic method of 1,3- dimethyl uric acid
CN110256435A (en) * 2019-07-04 2019-09-20 绍兴市精益生物化工有限公司 A kind of one-step synthesis method method of 1,3- dimethyl uric acid
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