CN100457736C - Using alkylmetal reagents for directed metalation of azaaromatics - Google Patents
Using alkylmetal reagents for directed metalation of azaaromatics Download PDFInfo
- Publication number
- CN100457736C CN100457736C CNB2004800088290A CN200480008829A CN100457736C CN 100457736 C CN100457736 C CN 100457736C CN B2004800088290 A CNB2004800088290 A CN B2004800088290A CN 200480008829 A CN200480008829 A CN 200480008829A CN 100457736 C CN100457736 C CN 100457736C
- Authority
- CN
- China
- Prior art keywords
- lithium
- trimethyl silyl
- azaaromatic
- replacement
- alkylmetal reagent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Abstract
Substituted alkylmetal reagents such as (trimethylsilylmethyl)lithium are reacted with azaaromatic compounds and/or nitrogen heterocycle compounds to produce functionalized azaaromatic compounds and functionalized nitrogen heterocycle compounds.
Description
The cross reference of related application
The application requires the rights and interests of following U.S. Patent application and they is incorporated herein by reference in full at this: the U.S. Provisional Patent Application No.60/460 that submitted on April 7th, 2003, submitted to but also do not have the U.S. Patent application " alkylmetal reagent is used for the direct metallized of azaaromatic compounds " of sequence number on April 6th, 994 and 2004.
Invention field
The present invention relates to the metallization of compound, more specifically relate to the metallization of azaaromatic compounds, and relate to the composition that is used for compound metalization.
Background of invention
Functionalized azaaromatic compounds for example pyridine, quinoline and pyrimidine can be as the foundation structure of biologically active cpds.For example functionalized azaaromatic compounds is applicable to pharmaceutical industry, for example is used for the treatment of central nervous system disorder.
Be used to produce the traditional method and the step employing metallization technology of functionalized azaaromatic compounds.Azaaromatic compounds can by with alkali for example lithium amide described deprotonation of azaaromatic is metallized.Though lithium amide commonly used for example diisopropylaminoethyl lithium (LDA) and tetramethyl-piperidide lithium (lithium tetramethylpiperidide) makes deprotonation of azaaromatic, the alkalescence of lithium amide is often by force to being enough to make the complete deprotonation of described azaaromatic compounds.And the productive rate of the functionalized azaaromatic compounds by utilizing lithium amide deprotonation preparation is general.The alkyl lithium reagents of not wishing to use other is n-Butyl Lithium for example because lithium alkylide for example n-Butyl Lithium or tert-butyl lithium trend towards the imine of the described azaaromatic compounds of nucleophillic attack.Sometimes, exist the lithium alkylide of the secondary amine that has catalytic amount can make deprotonation of azaaromatic effectively therein.This " catalytic metalization " technology often obtains general productive rate.Producing this general productive rate is because of the competitive addition of lithium alkylide to the two keys of carbon-nitrogen.As-kind of alternatives, proposed to use stronger alkali, and the functionalization of azaaromatic compounds has been tested.For example, highly basic and weak nucleophilic reagent be as 2,2,6,6-tetramethyl piperidine lithium (LiTMP) and
Base lithium (MesLi) has been used to functionalized azaaromatic compounds.Yet, using LiTMP and MesLi to prepare a large amount of functionalized azaaromatic compounds in industrial practice is restricted, because reactant is not easy to obtain, they often need extremely low temperature and/or form technology to be not easy to be used for large-scale commercial production technology.
Therefore wish to obtain to be used to promote the metallized method of azaaromatic compounds that it can amplify and the productive rate height in proportion.And wish that acquisition is used to promote method, technology and the compound of azaaromatic compounds and other compound metalization.
Summary of the invention
Embodiment of the present invention relate generally to the deprotonation of azaaromatic compounds such as nitrogenous six-ring, pyridine, quinoline, pyrimidine, pyridazine, pyrazine, pteridine, phthalazines, triazine, tetrazine etc.According to some embodiment, the reaction of the alkylmetal reagent that the direct deprotonation of azaaromatic compounds can be by azaaromatic compounds and replacement realizes.Described reaction can be carried out under the situation of the catalyzer that is with or without adding.In various embodiments, the alkylmetal reagent of described replacement for example (trimethyl silyl methyl) lithium (TMSMLi) is reacted with stoichiometry and azaaromatic compounds, prepare (lithiated) azaaromatic compounds of lithiumation, the azaaromatic compounds that it can be functionalized with the electrophilic reagent prepared in reaction.
In other embodiments of the present invention, by in the storage mixture, comprising solubleness and the storage stability that ether has improved the alkylmetal reagent that replaces.According to some embodiments, methyl tertiary butyl ether (MTBE) can be added (trimethyl silyl methyl) lithium composition, to improve the stability of (trimethyl silyl methyl) lithium composition.
Use the alkylmetal reagent that replaces so that deprotonation of azaaromatic has obtained the productive rate that improves, and provide scalable property to direct deprotonation technology, this amplification technique was not also realized in other deprotonation technology.
The accompanying drawing summary
Can more easily from the following description of this invention, understand the present invention in conjunction with the accompanying drawings, in the accompanying drawings:
Fig. 1 illustrates the reaction process of one embodiment of the invention.
Detailed Description Of The Invention
Now, describe more fully with reference to the accompanying drawings hereinafter the present invention, showed in the accompanying drawings Embodiments more of the present invention. Yet the present invention can be embodied in many different forms, The embodiment that invention is not to be considered as being limited to set forth here.
According to embodiment of the present invention, provide to be used for promoting azaaromatic compounds to take off proton Compound and/or the reagent changed. Provide in some embodiments alkylmetal reagent, with short Advance the direct deprotonation of azaaromatic compounds. In other embodiments of the present invention, can To promote the compound except azaaromatic compounds to take off proton with alkylmetal reagent Change.
In each embodiment of the present invention, can use with the alkylmetal reagent that replaces Direct deprotonation in azaaromatic compounds. Use the alkylmetal reagent that replaces as taking off Protonating agent is so that the nucleophillic attack minimum that is subjected on the imine of azaaromatic compounds Change. Directly deprotonation and on azaaromatic compounds minimized nucleophillic attack obtained changing Kind productive rate, and simplified the purification schemes of hydrogenation reaction.
Can comprise nitrogenous six-ring system with the example of the azaaromatic compounds of the alkylmetal reagent deprotonation that replaces according to embodiment of the present invention, as pyridine, quinoline, isoquinoline 99.9, acridine, phenanthridines, quinoxaline, oxazine, thiazine, purine, pyrimidine, pyridazine, pyrazine, pteridine, phthalazines, triazine, tetrazine etc.For example, can make 4-methoxypyridine, 2-fluorine pyridine, 2-methoxypyridine and 3-Methoxy Pyridine deprotonation according to embodiment of the present invention.Also can make other deprotonation of azaaromatic according to embodiment of the present invention with the alkylmetal reagent that replaces.
The alkylmetal reagent that embodiment of the present invention are used can comprise the methylmetal reagents of sterically hindered methylmetal reagents and/or replacement.For example, according to each embodiment of the present invention, (trimethyl silyl methyl) lithium is used as the alkylmetal reagent of replacement and reacts with azaaromatic compounds.Use (trimethyl silyl methyl) lithium to make the direct deprotonation of azaaromatic compounds make the nucleophillic attack that is subjected on the imine of azaaromatic compounds minimize.And, in reaction, only need (trimethyl silyl methyl) lithium of stoichiometry, thereby make productive rate improve and the purification schemes simplification.
The alkylmetal reagent of the replacement that embodiment of the present invention is used preferably demonstrates advantages of excellent stability.The methylmetal reagents of some replacements demonstrates advantages of excellent stability as (trimethyl silyl methyl) lithium, because can not 1 of metal hydride take place in composition, 2-eliminates reaction.The elimination of metal hydride reaction minimizing makes composition be produced, separate and stores the longer time in composition.
Fig. 1 for example understands the reaction process of embodiment of the present invention.As shown in Figure 1, use alkylmetal reagent (trimethyl silyl methyl) lithium to make the methoxypyridine deprotonation.According to embodiment of the present invention, 4-methoxypyridine can react with (trimethyl silyl methyl) lithium, reacts with the N-formyl piperidine then, and methoxyl group-3-pyridylaldehyde (pyridinecarboxaldehyde) (MPC) with preparation 4-.Be reflected at tetrahydrofuran (THF) (THF) and exist down, carrying out under-20 ℃ or the lower temperature approximately.Also with HCONR
2Add reaction mixture, wherein R is an alkyl, for example HCONR
2Be selected from dimethyl formamide and 1-formyl piperidine.The 4-methoxyl group that obtains-3-pyridylaldehyde direct crystallization from reaction mixture, productive rate is the MPC of about 60-about 100%, this depends on the temperature of use.For example, in the reaction process of Fig. 1, under-10 ℃, obtain 60% productive rate, and under-30 ℃, obtain 100% productive rate.Productive rate can be higher under the about temperature below-20 ℃, but the productive rate under higher temperature for example about-12 ℃ or higher temperature remains acceptable.The existence of direct ortho-metalated group produces the peculiar selectivity for the aromatic ring deprotonation.Equally, use these alkali that the side lithiumation may take place, wherein the side chain of aromatic ring is metallized.
Other embodiment of the present invention comprises that the substituted alkyl metal reagent that uses other and lithium methide such as neo-pentyl lithium make pyridine and nitrogen heterocyclic functionalized.Yet, use (trimethyl silyl methyl) lithium more more preferred, because it has higher solubleness (14% pair 5%) in hydrocarbon solvent than neo-pentyl lithium.The methylmetal reagents of the metal alkylide of other beta substitution, lithium alkylide and/or replacement also can be used together with embodiment of the present invention.For example, two-(trimethyl silyl) lithium methide, three-(trimethyl silyl) lithium methide and isobutyl-lithium can be used to make azaaromatic compounds functionalized.Embodiment of the present invention also comprise using to have general formula R
3W-CH
2The compound of-M makes deprotonation of azaaromatic, and wherein R is alkyl, aryl or Si; W is carbon, Si or Sn; And M is one or more metals that are selected from lithium, sodium, potassium, caesium, manganese, zinc and magnesium.
Do not detect the azaaromatic compounds of using with alkylmetal reagent of the present invention and be subjected to nucleophillic attack.And, only need the described alkylmetal reagent of stoichiometry.The method of embodiment of the present invention and technology provide the good productive rate of desired product.In addition, described technology and method are amplified easily, and this just makes embodiment of the present invention have commercial viability.
Other embodiment of the present invention relates to the formation of the alkylmetal reagent composition of replacement, particularly the formation of the alkylmetal reagent composition of the replacement of storage-stable.For example, according to embodiments more of the present invention, (trimethyl silyl methyl) lithium can be mixed solubleness with equimolar methyl tertiary butyl ether (MTBE), and improve the storage and the Treatment Stability of said composition with raising (trimethyl silyl methyl) lithium.
Usually, the alkylmetal reagent of replacement is mixed with storage as (trimethyl silyl methyl) lithium and is handled with hexane.Adding hexane in (trimethyl silyl methyl) lithium composition provides stability for (trimethyl silyl methyl) lithium composition, has (trimethyl silyl methyl) lithium that is up to about 8 weight % at about 5 ℃ in composition.At 5 ℃, wherein (trimethyl silyl methyl) lithium is spontaneous combustion above the mixture of (trimethyl silyl methyl) lithium in hexane of about 8 weight %, is easy to spontaneous combustion.Therefore, if at 5 ℃ or be lower than 5 ℃ and use down, trimethyl silyl lithium methide composition mixes with hexane can not surpass about 8 weight %.
According to other embodiments of the present invention, can make the alkyl methyl reagent mixture stable by in the alkyl methyl reagent mixture, adding ether with storage and processing.For example, make the alkylmetal reagent of replacement by the ether that in the alkylmetal reagent that replaces, adds about 3 molar equivalents of about 0.5-or about 1.5 molar equivalents of about 0.5-, stable as (trimethyl silyl methyl) lithium to store and processing.Embodiment of the present invention available ether includes, but are not limited to methyl tertiary butyl ether, diethyl ether, dme, dibutyl ether, cyclopentyl-methyl ether, diisopropyl ether, dipropyl ether, Methylal(dimethoxymethane), glycol dimethyl ether, diethoxyethane, diox, diglyme, triglyme, tetraethylene glycol dimethyl ether and methyltetrahydrofuran.
According to embodiment of the present invention, methyl tertiary butyl ether is added (trimethyl silyl methyl) lithium composition, to improve the stability of said composition.One molar equivalent or many molar equivalents methyl tertiary butyl ether are added the amount of (trimethyl silyl lithium methide) in the said composition mixture to be added that makes in (trimethyl silyl methyl) lithium composition can be increased.For example, can be equal to or less than the mixture for preparing, uses under about 5 ℃ and store hexane and (trimethyl silyl methyl) lithium by add methyl tertiary butyl ether in mixture, it has (trimethyl silyl methyl) lithium of about 25 weight %.The adding methyl tertiary butyl ether has also improved the solubleness of mixture.
According to embodiment of the present invention, methyl tertiary butyl ether is added (trimethyl silyl methyl) lithium composition, or the mixture of (trimethyl silyl methyl) lithium and hexane.Preferably after forming (trimethyl silyl methyl) lithium, the methyl tertiary butyl ether adding is somebody's turn to do in (trimethyl silyl methyl) lithium mixture, and preferably adds with a molar equivalent.Yet in other embodiments of the present invention, methyl tertiary butyl ether adds with the amount of about 0.5 molar equivalent (trimethyl silyl methyl) lithium to about 3 molar equivalents (trimethyl silyl methyl) lithium.
Various embodiments of the present invention can be used to produce and are used for reagent or the compound that drug manufacture is for example produced MPC.Functionalized azaaromatic compounds is through being commonly used for the foundation structure of biologically active cpds.For example the direct ortho lithiation by functionalized pyridine can form pyridyl pharmaceutical intermediate such as haloperidid and methoxypyridine.Yet the use of pyridyl intermediate is subjected to the restriction of production level in pharmaceutical industry.Up to now, some pyridyl medicine production levels only limit to the very low bench scale quantity of productive rate.Low-yield and make that the cost of this compound is very high amplifying this difficulty that is reacted on the commercial production levels.Use various embodiments of the present invention, productive rate can increase and production level can improve, because the technology of embodiment of the present invention and method are easy to amplify.
Improve productive rate and increase and produce and to illustrate by some embodiment.For example, use embodiment of the present invention to form 4-methoxyl group-3-pyridylaldehyde and under higher temperature, obtained better productive rate.Methoxyl group-3-pyridine boric acid has obtained 13% productive rate to use LDA and traditional method that azaaromatic compounds is carried out functionalized formation 2-, and embodiment of the present invention have obtained about 68% productive rate for this reaction.In addition, it is reported that the productive rate that uses PhLi and LDA to form 2-fluoro-3-pyridylaldehyde is 60%, and embodiment of the present invention reach about 90% productive rate.
Embodiment
Though following examples are not best, for example understand specific embodiments of the present invention:
Use (trimethyl silyl methyl) lithium to make deprotonation of azaaromatic
The solution (106mL, 12.8 weight % are in hexane) of (trimethyl silyl methyl) lithium is put into the three neck round-bottomed flasks of 250mL and is cooled to-40 ℃.Be lower than and in one hour, adding 4-methoxypyridine (10.0g) under-30 ℃ at the solution of tetrahydrofuran (THF) (THF) in (111mL).Finish lithiumation after about 1.5 hours.In 5 minutes, adding 1-formyl piperidine (10.6g) under-35 ℃.1.5 use acetate (15mL) and water (35mL) quencher reaction mixture after hour.Separate water layer and wash with 4x25mLEtOAc.Merge all organic layers, use MgSO
4Dry also vacuum concentration obtains the 16.0g yellow oil, its crystallisation by cooling.After the 30mL hexane/the 1mL Virahol ground, the GC area % purity of this material was 96.5% (13.02g, productive rate 99% is for test is proofreaied and correct).From IPA/ hexane (1: 3) recrystallization, obtain productive rate and be 83% desirable product, be pale yellow crystals.
Embodiment 2
Use (trimethyl silyl methyl) lithium to make deprotonation of azaaromatic
The solution (22mL, 13.8 weight % are in hexane) of (trimethyl silyl methyl) lithium is put into the three neck round-bottomed flasks of 100mL and is cooled to-50 ℃.Be lower than the solution that in 1 minute, adds 2-fluorine pyridine (2.0g), THF (25mL) and Diisopropylamine (0.13mL) under-50 ℃.After 3 hours, be lower than under-50 ℃ and in 1 minute, adding 1-formylpiperidine (2.4g).Mixture is warming up to room temperature and stirs a night.With acetate (3mL) and water (7mL) quencher reaction mixture.Separate water layer and wash with 3x25mLMTBE.Merge all organic layers, use MgSO
4Dry also vacuum concentration obtains the 3.79g brown oil.By silica gel this oil is carried out chromatographic separation, be used in the 15%EtOAc wash-out in the hexane, obtain 2.24g purity and be 92.4% 2-fluoro-3-pyridylaldehyde (productive rate 90% is for test is proofreaied and correct).
Embodiment 3
Use (trimethyl silyl methyl) lithium to make deprotonation of azaaromatic
Under-20 ℃ 2-methoxypyridine (23.2g) and Diisopropylamine (1.35mL) mixture in THF (223mL) added (trimethyl silyl methyl) lithium (218mL, in hexane, 13.8 weight %).Finish 84% lithiumation after 7 hours.In 40 minutes, adding tri-isopropylborate (40.8g) under-20 ℃.At room temperature stir the mixture a night.The NaOH of adding 5% (aqueous solution, 225mL).Taking out water layer and making the pH value by adding 10%HCl (aqueous solution) is 5.The white depositions that obtains is passed through filtering separation.After the drying, obtain 2-methoxypyridine-3-boric acid (productive rate 68%) of 22.23g.
Embodiment 4
Use (trimethyl silyl methyl) lithium to make deprotonation of azaaromatic
(trimethyl silyl methyl) lithium (20.9mL, 12.7 weight %) is put into the three neck round-bottomed flasks of exsiccant 50mL and is cooled to-20 ℃.In flask, add tetrahydrofuran (THF) (15mL), add 3-Methoxy Pyridine (2.0g) subsequently.After 1 hour, in flask, add trimethylchlorosilane (2.6mL).Mixture is warming up to ambient temperature overnight.Vacuum concentrated mixture, and use 5%NaHCO
3(10mL) and methyl tertiary butyl ether (15mL) distribute.Merge methyl tert-butyl ether layers, use MgSO
4Dry and concentrated, obtain 2.61 orange liquids that restrain.Product is purified by silica gel chromatographic column, obtains 1.76 gram 3-methoxyl group-4-trimethyl silyl pyridines (productive rate 53%).Product structure is by vapor-phase chromatography and mass spectroscopy, and (molecular weight equals 181),
1HNMR (0.3ppm, s, 9H); (3.9ppm, s, 3H); (7.2ppm, m, 1H) and (8.2ppm, m, 2H).
Embodiment 5
Use methyl tertiary butyl ether (MTBE) to come stable (trimethyl silyl methyl) lithium
At one night of Morton Cleve flask of a 3000mL of 125 ℃ of following oven-baked.Flask assembles dry-ice condenser, mechanical stirrer, thermopair and Claisen joint while hot.Device cools off under argon purge.The metallic lithium powder (/ 10.1 moles of 70.0 grams) that FMC Inc. is produced adds in the flask with the 900mL hexane.Then solution is heated to reflux temperature, about 68.0 ℃.Just reduce thermal source in case reflux, dropwise add chloro methyl trimethoxy base silane (/ 4.202 moles of 531.41 grams).During the feed step of technology, continue to reflux.When charging finishes, solution was stirred 0.5 hour under refluxing.Calm down in case reflux, just make solution be cooled to about 20 ℃.Methyl tertiary butyl ether (MTBE) with a molar equivalent (1.0 equivalents/4.20 mole) in 15 fens clock times dropwise adds in the solution.Can notice heat release during adding MTBE, solution temperature increases by 12.8 ℃.Finish in case MTBE adds, just make solution be cooled to about 25 ℃ gradually and filter then.
The product that obtains comprises that 1.50 grams have the sample of 8.8mL HCl, and the equivalent concentration of HCl (normality) is 0.4946=27.45%.After at room temperature storing 7 days, do not notice pressure difference in storage receptacle, sample is without any the sign that decomposes.Make sample stand 5 ℃ the some skies of cold environment then.During refrigerating, do not form crystal.Further the pyrophoricity of specimen is found its spontaneous combustion when 27.45 weight % (trimethyl silyl methyl) lithium.
Embodiment 6-comparative example
Attempt using tetrahydrofuran (THF) (THF) to come stable (trimethyl silyl methyl) lithium
At one night of Morton Cleve flask of a 1000mL of 125 ℃ of following oven-baked.Flask assembles dry-ice condenser, mechanical stirrer, thermopair and Claisen joint while hot.Device cools off under argon purge.The metallic lithium powder (/ 1.153 moles of 8.0 grams) that FMC Inc. is produced adds in the flask with the 145mL hexane.Then solution is heated to reflux temperature, about 68.0 ℃.Just reduce thermal source in case reflux, in flask, dropwise add chloro methyl trimethoxy base silane (/ 0.554 mole of 68 gram).During the feed step of technology, continue to reflux.When charging finishes, solution was stirred 1.5 hours under refluxing.Calm down in case reflux, just to make solution be cooled to about 20 ℃, in 15 fens clock times, the tetrahydrofuran (THF) (THF) of a molar equivalent (1.0 equivalents/1.153 mole) dropwise to be added in the solution subsequently.During adding THF, can notice heat release, notice that temperature increases by 25 ℃.Finish in case THF adds, just make solution be cooled to about 25 ℃ gradually and filter then.
The product that obtains comprises that 1.93 grams have the sample of 7.8mL HCl, and the equivalent concentration of HCl is 0.4946=18.91%.Sample at room temperature stores 7 days.The a large amount of pressure of sample produce also become muddy a little, form white solid.Notice the visible gas of from sample, emerging.Total for the second time alkalescence is calculated and is shown as 16.78%, and this calculates obviously than for the first time total alkalescence and reduces.After one month, sample solution becomes almost red, and sample has comprised extra throw out.
Embodiment 7-comparative example
In MTBE, form (trimethyl silyl methyl) lithium
At one night of Morton Cleve flask of a 500mL of 125 ℃ of following oven-baked.Flask assembles dry-ice condenser, mechanical stirrer, thermopair and Claisen joint while hot.Device cools off under argon purge.The metallic lithium powder (/ 0.764 mole of 5.30 gram) that FMC Inc. is produced adds flask with 115mL MTBE.Then solution is heated to reflux temperature, about 56.0 ℃.Just reduce thermal source in case reflux, in flask, dropwise add chloro methyl trimethoxy base silane (/ 0.367 mole of 44.97 gram).During the feed step of technology, continue to reflux.During feed step, notice, even use hexane bath MTBE also to cause some temperature control problems.When charging finished, solution remained the height heat release, arrives 89.5 ℃ of top temperatures on a point during the subsequent reactions.Cooling solution is to room temperature and filtered sample.Filtration treatment slowly and comprise washing.Sample is obviously soluble when 25 weight %.Notice and in sample, have white solid.During filtering, used filtration adjuvant.As if sample becomes muddy after storing a night, and become thickness.
Trial obtains total alkaline calculated value, and the result shows that the weight percentage of (trimethyl silyl methyl) lithium is less than 1.0%.Vapor-phase chromatography shows that sample mainly is 1,2-two (trimethyl silyl) ethane.
Certain embodiments of the present invention have been described, should understand, the present invention limits by appended claim, it is not that the details of setting forth by above-mentioned specification sheets limits, because many obvious variants of the present invention all are possible, and can not deviate from the spirit or scope of the present invention that claim limited hereinafter.
Claims (19)
1. method that is used to make deprotonation of azaaromatic, it comprises: make azaaromatic compounds and be selected from two-(trimethyl silyl) lithium methide, three-(trimethyl silyl) lithium methide or have formula R
3W-CH
2The alkylmetal reagent of the replacement of the compound of-M reacts, and wherein R is selected from alkyl, aryl and Si; W is selected from carbon, Si and Sn; Be selected from lithium, sodium, potassium, caesium, manganese, zinc and magnesium with M.
2. the process of claim 1 wherein that azaaromatic compounds is the compound of nitrogenous six-ring.
3. the process of claim 1 wherein that described azaaromatic compounds is to be selected from following compound: pyridine, quinoline, isoquinoline 99.9, acridine, phenanthridines, quinoxaline, oxazine, thiazine, purine, pyrimidine, pyridazine, pyrazine, pteridine, phthalazines, triazine, tetrazine, 4-methoxypyridine, 2-fluorine pyridine, 2-methoxypyridine and 3-Methoxy Pyridine.
4. the process of claim 1 wherein that the alkylmetal reagent of described replacement is (trimethyl silyl methyl) lithium.
5. the process of claim 1 wherein that the alkylmetal reagent of described replacement is selected from (trimethyl silyl methyl) lithium, neo-pentyl lithium and isobutyl-lithium.
6. the process of claim 1 wherein that M is a lithium.
7. the method for claim 1, it also comprises reacts the alkylmetal reagent of azaaromatic compounds and replacement in tetrahydrofuran (THF).
8. the method for claim 1, it comprises that also the alkylmetal reagent that makes azaaromatic compounds and replacement is at HCONR
2React under existing, wherein R is an alkyl.
9. the method for claim 8, wherein HCONR
2Be selected from N, dinethylformamide and 1-formyl piperidine.
10. method that is used to prepare 4-methoxyl group-3-pyridylaldehyde, it comprises: make 4-methoxypyridine and (trimethyl silyl methyl) lithium at tetrahydrofuran (THF) and HCONR
2React under existing, wherein R is an alkyl.
11. a mixture, it comprises: azaaromatic compounds and be selected from two-(trimethyl silyl) lithium methide, three-(trimethyl silyl) lithium methide or have formula R
3W-CH
2The alkylmetal reagent of the replacement of the compound of-M, wherein R is selected from alkyl, aryl and Si; W is selected from carbon, Si and Sn; Be selected from lithium, sodium, potassium, caesium, manganese, zinc and magnesium with M, the alkylmetal reagent of wherein said replacement makes described deprotonation of azaaromatic.
12. the reaction mixture of claim 11, wherein azaaromatic compounds is the compound of nitrogenous six-ring.
13. the reaction mixture of claim 11, wherein said azaaromatic compounds are to be selected from following compound: pyridine, quinoline, isoquinoline 99.9, acridine, phenanthridines, quinoxaline, oxazine, thiazine, purine, pyrimidine, pyridazine, pyrazine, pteridine, phthalazines, triazine, tetrazine, 4-methoxypyridine, 2-fluorine pyridine, 2-methoxypyridine and 3-Methoxy Pyridine.
14. the reaction mixture of claim 11, the alkylmetal reagent of wherein said replacement are (trimethyl silyl methyl) lithiums.
15. the reaction mixture of claim 11, the alkylmetal reagent of wherein said replacement are selected from (trimethyl silyl methyl) lithium, neo-pentyl lithium and isobutyl-lithium.
16. the reaction mixture of claim 11, wherein M is a lithium.
17. the reaction mixture of claim 11, it also comprises tetrahydrofuran (THF).
18. the reaction mixture of claim 11, it also comprises HCONR
2, wherein R is an alkyl.
19. the reaction mixture of claim 11, wherein said azaaromatic compounds is a 4-methoxypyridine, and the alkylmetal reagent of described replacement is (trimethyl silyl methyl) lithium.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US46099403P | 2003-04-07 | 2003-04-07 | |
| US60/460,994 | 2003-04-07 | ||
| US10/818,588 | 2004-04-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1768038A CN1768038A (en) | 2006-05-03 |
| CN100457736C true CN100457736C (en) | 2009-02-04 |
Family
ID=36743307
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800088290A Expired - Fee Related CN100457736C (en) | 2003-04-07 | 2004-04-07 | Using alkylmetal reagents for directed metalation of azaaromatics |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100457736C (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6657093B2 (en) * | 2001-06-20 | 2003-12-02 | Clariant Gmbh | Preparation of substituted aromatic compounds |
-
2004
- 2004-04-07 CN CNB2004800088290A patent/CN100457736C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6657093B2 (en) * | 2001-06-20 | 2003-12-02 | Clariant Gmbh | Preparation of substituted aromatic compounds |
Non-Patent Citations (2)
| Title |
|---|
| Lithiation of Methoxypyridines Directed by α-amino Alkoxides. Daniel L.Comins and Michael O.Killpack.J.Org.Chem.,,Vol.55 No.1. 1990 |
| Lithiation of Methoxypyridines Directed by α-amino Alkoxides. Daniel L.Comins and Michael O.Killpack.J.Org.Chem.,,Vol.55 No.1. 1990 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1768038A (en) | 2006-05-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2235001B1 (en) | Process for preparing pyridinone compounds | |
| JPS61287930A (en) | Production of polysilazane | |
| JP4573005B2 (en) | Method for producing perfluoroalkadiene | |
| WO2015074328A1 (en) | Method for preparing rosuvastatin sodium | |
| CN100457736C (en) | Using alkylmetal reagents for directed metalation of azaaromatics | |
| US7179940B2 (en) | (Aryl)(amino) borane compounds, method for preparing same | |
| CN114213424B (en) | Synthesis method of furan [3,2-b ] pyridine derivative | |
| JP4599169B2 (en) | Process for the synthesis of cycloorganylphosphane and di (alkali metal / alkaline earth metal) oligophosphanedides | |
| CN112851652B (en) | Catalytic oxidation synthesis method of 2- (substituted xanthyl) benzofuran compound | |
| CN112174909B (en) | Preparation method of aprepitant intermediate | |
| US7638635B2 (en) | Using alkylmetal reagents for directed metalation of azaaromatics | |
| JP6868890B2 (en) | Method for producing nitrogen-containing cyclic compound having a substituent on the ring | |
| JP3499595B2 (en) | Method for producing 2-cyanoimidazole compound | |
| CN109796372B (en) | Method for preparing polysubstituted alkenyl amidine | |
| CN108997252B (en) | Green synthesis method of oxadiazole derivative | |
| CN108503662A (en) | A kind of preparation method of ene-alkyne ylboronic acid ester | |
| CN113024464B (en) | Method for preparing [60] fullerene tetrahydroquinoline derivative based on triflic acid/p-toluenesulfonic acid catalysis | |
| EP0854135A2 (en) | Process for preparing 2-cyanobiphenyl compound | |
| CN117924343A (en) | New skeleton silicon heterocyclic benzo six-membered compound containing silicon chiral center, and preparation method and application thereof | |
| US5405960A (en) | Triarylborane derivatives, their preparation and their use as synthesis intermediates | |
| JP2773362B2 (en) | Quinoxaline-palladium complex and method for producing the same | |
| Khalafallah et al. | Heterocyclic fused rings with bridgehead nitrogen atoms: Single step synthesis of several polyfunctionally substituted fused pyridines | |
| JP2000503025A (en) | Method for producing 4-methyl-biphenyl derivative | |
| KR100795589B1 (en) | New Synthetic Method of 2-butyl-4-chloro-1-[[2'-1H-tetrazol-5-ylbiphenyl-4-yl]methyl]imidazole-5-carboxaldehyde | |
| KR100580940B1 (en) | Process for preparing 2-amino-4-chloro-5-nitro-61H-pyrimidinone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090204 Termination date: 20110407 |