Method of preparing alumina-supported catalyst and employment thereof

FIELD: catalyst preparation methods.

SUBSTANCE: invention relates to alumina-supported catalyst preparation method and employment thereof in reactions of nucleophilic substitution of aromatic halides containing electron-accepting group. In particular, alumina support impregnated with alkali selected from alkali metal hydroxides is prepared by treating alkali metal hydroxide aqueous solution with aluminum oxide in organic solvent followed by drying thus obtained catalyst mixture at temperature not lower than 150°C. Catalyst is, in particular, used to introduce electron-accepting protective groups into organic compounds comprising at least one of -OH, -SH, and -NH, as well as in reaction of substituting amino, thio, or ether group for halogen in a haloarene and in preparation of 2-puperidinobenzonitrile.

EFFECT: simplified preparation of catalyst and regeneration of spent catalyst, and avoided involvement of dangerous reactants.

11 cl, 20 ex

 

The technical field to which the invention relates.

The present invention relates to the preparation of the active catalyst based on alumina impregnated with metal hydroxide selected from alkali or alkaline earth metals. The thus obtained solid catalyst used for the introduction of protective groups in compounds that are used in many reactions chemical reactions and nucleophilic substitution of aromatic halides containing electron-withdrawing group.

The level of technology

Protection compounds containing active hydrogen, such as amines, phenols and thiols, is an integral part of chemical synthesis. Standard protective groups are tert-Boc group, which is injected in the interaction of di-tert-BUTYLCARBAMATE with amines with formation of carbamate. The introduction of the BOC-group is usually carried out in the interaction of amine with BOC-anhydride in the presence of a base. For the introduction of other common protective groups in the case of amines are usually used with Fmoc-chloride (to give permetrina group), Alloc-chloride (to give allylcarbamate group) and Cbz-chloride (to give benzyloxycarbonyl group).

For the introduction of specific protective groups use different reaction conditions, namely, a basic environment for the introduction of Boc - Alloc-groups and acid medium DL is the introduction of the Fmoc-group.

The present invention describes a simple and effective way of introducing different protective groups, namely with the use of aluminum oxide impregnated with a hydroxide under mild reaction conditions.

The reaction of aromatic nucleophilic substitution is carried out at a substitution group of a halogen in the presence of a strong nucleophile in harsh conditions, while in most cases the reaction is characterized by an extremely low yield. Developed improved ways of carrying out substitution reactions using catalysts based on metals such as copper, and a strong base such as tert-piperonyl potassium. Reaction conditions are quite specific, and outputs too low. For nucleophilic substitution of aromatic groups, halogen famous universal method using a mixture of reagents based on palladium, such as palladium acetate, palladium hydroxide or complex dibenzylidene-acetone, and a phosphine ligand in the presence of a base, such as tert-piperonyl sodium. In this reaction using phosphines, which in some cases are difficult and expensive reagents based on palladium, representing problems at their disposal, as a result, these reaction conditions are not suitable for use on an industrial scale.

The method according to the present image is meniu can be used for nucleophilic substitution of aromatic halides, containing electron-withdrawing groups, upon receipt of substituted aromatic compounds, which are widely used to produce fine chemical synthesis, which in turn are the source materials for production of the active pharmaceutical intermediate compounds.

In the literature there are many methods for nucleophilic substitution of aromatic halides, are included in this description as a reference. As metal choose palladium, which provides an efficient condensation of aromatic halides with a number of nucleophiles. In most cases, to conduct the reaction using trialkyl or triarylphosphine and palladium catalyst. In the article Stephen Buchwald et al. (J.Org.Chem., 2000, 65, 1158-1174 and other publications cited in this context), an efficient method is described amination of arylhalides, bromides and triflates using arylphosphine, palladium complex and grounds.

In article, Scott Sawyer et al. (J.Org.Chem., 1998, 63, 6338-6343) presents a synthesis dialling ethers, varietiesof and diarylamino using nucleophilic substitution of aryl halides in the presence of KF-alumina and crown ether 18-crown-6. The disadvantages of this method is used as a complexing agent 18-crown-6. This requires many who Ostanina processing of the reaction mixture until the distribution between the organic solvent and aqueous medium.

In standard ways using nucleophilic substitution in the presence of K2CO3-DMF) at high temperature, in this regard, such reaction conditions are difficult to reproduce on an industrial scale.

Disclosure of inventions

The main task of the present invention is to develop a solid catalyst that can be easily removed from the reaction mixture and thus can simplify the processing stage for the introduction of protective groups in the amines, alcohols and thiols, as well as for nucleophilic substitution.

Another important advantage of the present invention is the ease of processing and recycling of the catalyst.

Reaction conditions preclude the use of toxic and expensive solvents and thus meet the requirements of environmental protection.

Simple reaction conditions can be easily reproduced on an industrial scale.

The present invention is based on the discovery of the fact that the catalyst exhibits high activity when carrying out the reaction for introducing the protective group in amines, alcohols, phenols and thiols. A wide range of protective groups can be entered as an effective way to soft conditions at ambient temperature.

Another important achievement of the present invention are p Ostia and mild reaction conditions, which can be easily reproduced on an industrial scale.

The main advantages of the method according to the present invention in comparison with the methods described in the prior art for this type of reactions

1. The active catalyst can be obtained easily in large quantities and stored without appreciable loss of activity.

2. The catalyst may be used to enable a wide range of protective groups, as shown for almost any amines, alcohols, phenols or thiols.

3. Used heterogeneous catalyst is easily separated from the reaction products by simple filtration.

4. The reaction can be conducted in either polar or non-polar solvent, as shown using dioxane, dichloromethane, etc.

5. The catalyst is non-corroding cast and, therefore, is characterized by ease of processing in large volumes.

6. The catalyst is non-toxic and, therefore, its utilization, you can use simple methods that meet the requirements of environmental protection.

The implementation of the invention

The present invention primarily relates to the production of aluminum oxide impregnated with lithium hydroxide, and to use the thus obtained solid substance for introduction of a wide range of protective groups in the amines, alcohols, phenols is thiols.

The method according to the present invention can be used for the introduction of protective groups in the amines, alcohols, phenols, thiols, which are widely used to produce fine chemical synthesis, which in turn are the source materials for the production of active pharmaceutical intermediates.

N-Protected amino acids and other amines, ethers, and thioethers are used as intermediates in many reactions of organic synthesis. In the prior art known processes, which are used as homogeneous and heterogeneous catalysts for the introduction of protective groups mentioned in connection.

According to the invention, the catalyst comprises alumina impregnated base, which is selected from hydroxides of alkali or alkaline earth metal.

In one of the embodiments of the invention use a catalyst in which the base is lithium hydroxide.

The preferred catalyst, in which the content of the lithium hydroxide in the aluminum oxide is in the range from 0.3 to 3 wt.%.

The method of preparation of the catalyst include:

a) treatment of an aqueous solution of metal hydroxide, aluminum oxide in an organic solvent,

b) drying the mixture of the catalyst.

According to the invention, in the method of obtaining it is telesfora organic solvent is chosen from the series: dichloromethane, dioxane, toluene, acetonitrile or dimethylformamide (DMF).

In the method of producing catalyst preferably implementation drying in vacuum.

The invention includes a catalyst for the introduction of amines, which include both primary and secondary amines, and which is chosen from the series: aromatic, aliphatic, heterocyclic, cyclic amines, protective groups selected from the series: di-tert-BUTYLCARBAMATE (BOC-anhydride), 9-fluorenylmethoxycarbonyl (Fmoc-Cl), 9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide (Fmoc-OSu), allyloxycarbonyl (Alloc), benzylchloride (Cbz-Cl), acetic anhydride, triperoxonane anhydride, acid chloride, sulphonylchloride, to obtain the corresponding N-secure connections.

The invention is also directed to a catalyst for the introduction of alcohols, which include primary, secondary or tertiary alcohols and which is chosen from the series: aromatic, aliphatic, heterocyclic, cyclic alcohols, protective groups selected from the series: di-tert-BUTYLCARBAMATE (BOC-anhydride), 9-fluorenyl-methoxycarbonylethyl (Fmoc-Cl), 9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide (Fmoc-OSu), allyloxycarbonyl (Alloc), benzylchloride(Cbz-Cl), acetic anhydride, triperoxonane anhydride, acid chloride, sulphonylchloride, to obtain the corresponding O-protected question what's esters.

In addition, the invention relates to a catalyst for the introduction of thiols, which include primary, secondary, or tertiary thiols and which is chosen from the series: aromatic, aliphatic, heterocyclic, cyclic thiol protective groups selected from the series: di-tert-BUTYLCARBAMATE (BOC-anhydride), 9-fluorenyl-methoxycarbonylethyl (Fmoc-Cl), 9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide (Fmoc-OSu), allyloxycarbonyl (Alloc), benzylchloride(Cbz-Cl), acetic anhydride, triperoxonane anhydride, acid chloride, sulphonylchloride, to obtain the corresponding S-secure connections.

Preferably a catalyst for treatment of amines, alcohols and thiols of reactions of nucleophilic substitution.

A method of processing amines which are selected from range: primary, secondary, aromatic, aliphatic, heterocyclic or cyclic amines, aromatic halide, including electron-withdrawing group selected from the series: nitro, aldehyde, acid, ester, amide or nitrile, to obtain the corresponding substituted derivatives of aniline.

Also, a method of processing alcohols, which are selected from range: primary, secondary, tertiary, aromatic, aliphatic, heterocyclic or cyclic alcohols, aromatic halide, including the surrounding electron-withdrawing group, selected from the series: nitro, aldehyde, acid, ester, amide or nitrile, to obtain the corresponding substituted derivatives ethers.

Another embodiment of the invention is the processing method of thiols, which are selected from range: primary, secondary, or tertiary, aromatic, aliphatic, heterocyclic, cyclic thiols, aromatic halide, including electron-withdrawing group selected from the series: nitro, aldehyde, acid, ester, amide or nitrile, to obtain the corresponding substituted derivatives of simple thioethers.

In the present invention is disclosed a method of obtaining the active catalyst based on alumina impregnated with hydroxide of metal selected from alkaline or alkaline earth metals with the General formula

where n is 1 or 2, and M stands for Li or Mg or CA or Na

Spend the interaction of solid catalyst based on aluminum oxide-metal hydroxide with an amine of formula II with a protective group selected from the series: di-tert-BUTYLCARBAMATE (BOC-anhydride), 9-fluorenyl-methoxycarbonylethyl (Fmoc-Cl), 9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide (Fmoc-OSu), allyloxycarbonyl (Alloc), benzylchloride(Cbz-Cl), acetic anhydride, triperoxonane anhydride, acid chloride, sulphonylchloride, you get ACC is dtweedie N-secure connection.

where R1means hydrogen, alkyl, aryl, aralkyl, hetero, heteroalkyl, cyclo, a R2means hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, hetero, heteroalkyl, cyclo, provided that R1and R2both can mean hydrogen.

Interact solid catalyst based on aluminum oxide-metal hydroxide with an alcohol of the formula III and with a protective group selected from the series: di-tert-BUTYLCARBAMATE (BOC-anhydride), 9-fluorenyl-methoxycarbonylethyl (Fmoc-Cl), 9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide (Fmoc-OSu), allyloxycarbonyl (Alloc), benzylchloride(Cbz-Cl), acetic anhydride, triperoxonane anhydride, acid chloride, sulphonylchloride, you get a corresponding ethers.

where R3means alkyl, cycloalkyl, aryl, aralkyl, heterocycle, heteroalkyl, substituted aryl.

Spend the interaction of solid catalyst based on aluminum oxide-metal hydroxide with a thiol of formula IV with a protective group selected from the series: di-tert-BUTYLCARBAMATE (BOC-anhydride), 9-fluorenyl-methoxycarbonylethyl (Fmoc-Cl), 9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide (Fmoc-OSu), allyloxycarbonyl (Alloc), benzylchloride(Cbz-Cl), acetic anhydride, triperoxonane anhydride, acid chloride, Sul is familiarity, while getting the appropriate simple thioethers.

where R4means alkyl, cycloalkyl, aryl, aralkyl, heterocycle, heteroalkyl, substituted aryl.

The method includes the interaction of the substrate, namely the above-mentioned amines, alcohols or thiols with an active catalyst based on aluminum oxide containing the metal hydroxide in a solvent chosen from the group of dichloromethane, dioxane, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide, diisopropyl ether, methyl tributyl ether, cyclohexane, at a temperature of the environment and destruction of the active catalyst based on metal by simple filtration followed by removal of solvent, it required a secure connection.

Interact solid catalyst based on aluminum oxide-metal hydroxide with an aromatic halide of the formula V with a number of amines of the formula II, which are selected from primary and secondary amines, as well as on the choice of the number of: alkyl-, aryl-, aralkyl, cycloalkyl-, heterocycle and heteroelement will get substituted anilines.

Formula V

where X can mean fluorine, chlorine, bromine, located in ortho-, meta - or para-position relative to the nitro-group.

Spend interaction the solid catalyst based on aluminum oxide-metal hydroxide with an aromatic halide of the formula V with a number of alcohols of the formula III, chosen from primary, secondary and tertiary alcohols, as well as a number:

alkyl-, cycloalkyl, heterozygosity, phenol and substituted phenol will get substituted ethers.

Ensure the interaction of the solid catalyst based on aluminum oxide-metal hydroxide with an aromatic halide of the formula V with a number of thiols of the formula IV, which are selected from a number of: alkyl-, aryl-, aralkyl-, heterocycle-, cyclotomy will get replaced by a simple tiefer.

Interact solid catalyst based on aluminum oxide-metal hydroxide with an aromatic halide of the formula VI with a number of amines of the formula II, which are selected from primary and secondary amines, as well as on the choice of opting out of range:

alkyl-, aryl-, aralkyl, cycloalkyl-, heterocycle, heteroalkyl will get substituted anilines.

Formula VI

where X represents fluorine, chlorine, bromine, located in ortho-, meta - or para-position relative to the aldehyde group.

Spend the interaction of solid catalyst based on aluminum oxide-metal hydroxide with an aromatic halide of the formula VI with a number of alcohols of the formula III, which are selected from primary, secondary and tertiary alcohols, as well as on the choice of choosing from a number of: alkyl-, cycloalkyl-, g is eroticosspice, phenol and substituted phenol will get substituted ethers.

Interact solid catalyst based on aluminum oxide-metal hydroxide with an aromatic halide of the formula VI with a number of thiols of the formula IV, which are selected from a number of: alkyl-, aryl-, aralkyl-, heterocycle-, cyclotomy will get replaced by a simple tiefer.

Ensure the interaction of the solid catalyst based on aluminum oxide-metal hydroxide with an aromatic halide of the formula VII with a number of amines of the formula II, which are selected from primary and secondary amines, as well as on the choice of choosing from a number of: alkyl-, aryl-, aralkyl, cycloalkyl-, heterocycle, heteroalkyl will get substituted anilines.

Formula VII

where X represents fluorine, chlorine, bromine, located in ortho-, meta - or para-position with respect to the cyano.

Spend the interaction of solid catalyst based on aluminum oxide-metal hydroxide with an aromatic halide of the formula VII with a number of alcohols of the formula III, which are selected from primary, secondary and tertiary alcohols, and optionally choose from a number of: alkyl-, cycloalkyl, heterozygosity, phenol and substituted phenol will get substituted ethers.

Ensure the interaction of solid kata is Isadora on the basis of aluminum oxide-metal hydroxide with an aromatic halide of the formula VII with a number of thiols of the formula IV, choosing from a range of: alkyl-, aryl-, aralkyl-, heterocycle-, cyclotomy will get replaced by a simple tiefer.

The technique has been successfully used for the synthesis of 2-piperidinecarbonitrile (example 11), which is an important intermediate derivatives in the synthesis of substituted phenylacetamide - Repaglinide used to reduce blood sugar levels.

Spend the interaction of solid catalyst based on aluminum oxide-metal hydroxide with an aromatic halide of the formula VIII with a number of amines of the formula II, which are selected from primary and secondary amines, and optionally choose from a number of: alkyl-, aryl-, aralkyl, cycloalkyl-, heterocycle, heteroalkyl will get substituted anilines.

Interact solid catalyst based on aluminum oxide-metal hydroxide with an aromatic halide of the formula VIII with a number of alcohols of the formula III, which are selected from primary, secondary and tertiary alcohols, and optionally choose from a number of: alkyl-, cycloalkyl, heterozygosity, phenol and substituted phenol will get substituted ethers.

Ensure the interaction of the solid catalyst based on aluminum oxide-metal hydroxide with an aromatic halide of the formula VIII with a number of thiols of the formula IV, which is selected from the group: alkyl-, aryl-, alkyl-, heterocycle-, cyclotomy will get replaced by a simple tiefer.

Formula VIII

(where X is F, Cl or Br, a G means HE, OR1, NR2R3), where R1, R2, R3mean alkyl, cycloalkyl, aryl, aralkyl, heterocycle, heteroalkyl, substituted aryl, the substituents on the choice are located in the ortho-, meta-or para-position.

The method includes the interaction of the substrate, namely, amines, alcohols or thiols, with the above-mentioned aromatic halide with an active catalyst based on aluminum oxide containing the metal hydroxide in a solvent chosen from the group of dichloromethane, dioxane, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide, diisopropyl ether, methyl tert-butyl ether, cyclohexane, at a temperature of the environment and destruction of the active catalyst based on metal by simple filtration followed by removal of solvent, it required a secure connection.

In the interaction of amines, namely aniline with aryl halides, such as 2-chloronitrobenzene, in dioxane get nitroaniline. It is shown that the reaction is almost universal, as have been investigated by various amines which are selected from primary and secondary amines, as well as on the choice of the number of: aromatic, al is factual, cyclooctylamine etc., and the substitution reaction takes place smoothly with the formation of substituted nitroanilines.

In addition, the invention is illustrated by the following examples which are not intended to limit the scope of the claims.

Examples of preparation of the catalyst

Example 1. Obtaining aluminum oxide, saturated LiOH (the solvent is dichloromethane, the base is LiOH)

To a solution of LiOH (9.6 g, 0.4 mol) in water (100 ml) is added aluminum oxide (100 g) and stirred for 30 minutes To the mixture dobavlaut dichloromethane (250 ml) and evaporated. The residue is again treated with dichloromethane (250 ml) and evaporated. The obtained solid is dried at 100-120°C for 2 h, while having aluminum oxide impregnated with lithium hydroxide.

Yield: 115 g (9.6% LiOH aluminum oxide).

Example 2. Obtaining alumina impregnated with NaOH (solvent is acetonitrile, the base is NaOH)

To a solution of NaOH (30 g, 0.75 mol) in water (100 ml) is added aluminum oxide (100 g) and stirred for 45 minutes To the mixture dobavlaut acetonitrile (250 ml) and evaporated. The residue is again treated with acetonitrile (500 ml) and evaporated. The obtained solid is dried at 100-120°C for 5 h, while having alumina impregnated with sodium hydroxide.

Yield: 135 g (30% NaOH aluminum oxide)

Example 3. The floor is the group of aluminum oxide, saturated KOH (solvent - toluene, the base - END)

To a solution of KOH (30 g, of 0.53 mol) in water (150 ml) is added aluminum oxide (120 g) and stirred for 1 h To the resulting mixture are added toluene (500 ml) and evaporated. The residue is again treated with toluene (500 ml) and evaporated. The obtained solid is dried at 100-120°C for 4 h, while having alumina impregnated with potassium hydroxide.

Yield: 136 g (30% KOH aluminum oxide).

The use of such catalyst

Example 4. The use of aluminum oxide impregnated with NaOH

To a solution of aniline (5 g, 0,053 mol) in dichloromethane (50 ml) is added aluminum oxide impregnated with sodium hydroxide (5 g, obtained as described in example 2), the mixture is stirred for 5 min and slowly for 10 minutes at room temperature add benzylchloride (9 g, 0,053 mol). After 3 h the catalyst was filtered and the solid layer is washed thoroughly with dichloromethane. Transparent filtrate is concentrated and the product crystallized upon addition of petroleum ether.

Example 5. The use of aluminum oxide impregnated KON

To a solution of aniline (5 g, 0,053 mol) in dichloromethane (50 ml) is added aluminum oxide impregnated with sodium hydroxide (5 g, obtained as described in example 3), the mixture is stirred for 5 min and slowly for 10 minutes at room temperature on billaut a solution of BOC-anhydride (12 g, 0,054 mol) in dichloromethane (10 ml). After 5 hours the catalyst is filtered off and the solid layer is washed thoroughly with dichloromethane. Transparent filtrate is concentrated and the product crystallized upon addition of petroleum ether.

Example 6. The use of aluminum oxide impregnated LiOH

To 5 g of aniline in 50 ml of dichloromethane added 3 n solution of lithium hydroxide, adsorbed on aluminium oxide (1.3 g of lithium hydroxide 7.5 g of aluminum oxide), the mixture is stirred for 5 min at room temperature and slowly for 10 minutes add benzylchloride. After 3 h the catalyst was filtered and the solid layer is washed thoroughly with dichloromethane. After removal of the solvent and crystallization adding petroleum ether get the product with a yield of 95%.

Example 7. The use of aluminum oxide impregnated LiOH

To 5 g of aniline in 50 ml of dichloromethane added 3 n solution of lithium hydroxide, adsorbed on aluminium oxide (1.3 g of lithium hydroxide 7.5 g of aluminum oxide), the mixture is stirred for 5 min at room temperature and slowly for 10 minutes add allylchloroformate. After 3 h the catalyst was filtered and the solid layer is washed thoroughly with dichloromethane. After removal of the solvent and crystallization adding petroleum ether get the product with a yield of 7%.

Example 8. The use of aluminum oxide impregnated LiOH

To 5 g of aniline in 50 ml of dichloromethane added 3 n solution of lithium hydroxide, adsorbed on aluminium oxide (1.3 g of lithium hydroxide 7.5 g of aluminum oxide), the mixture is stirred for 5 min at room temperature and slowly for 10 minutes add the BOC-anhydride. After 12 h, the catalyst was filtered and the solid layer is washed thoroughly with dichloromethane. After removal of the solvent and crystallization adding petroleum ether get the product with a yield of 80%.

Example 9. The use of aluminum oxide impregnated LiOH

To 5 g of aniline in 50 ml of dichloromethane added 3 n solution of lithium hydroxide, adsorbed on aluminium oxide (1.3 g of lithium hydroxide 7.5 g of aluminum oxide), the mixture is stirred for 5 min at room temperature and slowly for 10 minutes add Fmoc-OSu. After 12 h, the catalyst was filtered and the solid layer is washed thoroughly with dichloromethane. After removal of the solvent and crystallization adding petroleum ether get the product with a yield of 95%.

Example 10. The use of aluminum oxide impregnated LiOH

To 5 g of 4-piperidone in 50 ml of dichloromethane added 3 n solution of lithium hydroxide absorbed on OK the ideal aluminum (1.3 g of lithium hydroxide 7.5 g of aluminum oxide), the mixture is stirred for 5 min at room temperature and slowly for 10 minutes add the BOC-anhydride. After 12 h, the catalyst was filtered and the solid layer is washed thoroughly with dichloromethane. After removal of the solvent and crystallization adding petroleum ether get the product with a yield of 80%.

Example 11. The use of aluminum oxide impregnated LiOH

To 5 g of 4-piperidone in 50 ml of dichloromethane added 3 n solution of lithium hydroxide, adsorbed on aluminium oxide (1.3 g of lithium hydroxide 7.5 g of aluminum oxide), the mixture is stirred for 5 min at room temperature and slowly for 10 minutes add allylchloroformate. After 12 h, the catalyst was filtered and the solid layer is washed thoroughly with dichloromethane. After removal of the solvent and crystallization adding petroleum ether get the product with a yield of 95%.

Example 12. The use of aluminum oxide impregnated LiOH

To 5 g of 4-piperidone in 50 ml of dichloromethane added 3 n solution of lithium hydroxide, adsorbed on aluminium oxide (1.3 g of lithium hydroxide 7.5 g of aluminum oxide), the mixture is stirred for 5 min at room temperature and slowly for 10 minutes add benzylchloride. After 3 h the catalyst was filtered and the solid layer is matalino washed with dichloromethane. After removal of the solvent and crystallization adding petroleum ether get the product with a yield of 95%.

Example 13. The use of aluminum oxide impregnated LiOH

To 5 g of 4-piperidone in 50 ml of dichloromethane added 3 n solution of lithium hydroxide, adsorbed on aluminium oxide (1.3 g of lithium hydroxide 7.5 g of aluminum oxide), the mixture is stirred for 5 min at room temperature and slowly for 10 minutes add Fmoc-OSu. After 12 h, the catalyst was filtered and the solid layer is washed thoroughly with dichloromethane. After removal of the solvent and crystallization adding petroleum ether get the product with a yield of 75%.

Example 14. The use of aluminum oxide impregnated LiOH

To 5 g of phenol in 50 ml of dichloromethane added 3 n solution of lithium hydroxide, adsorbed on aluminium oxide (1.3 g of lithium hydroxide 7.5 g of aluminum oxide), the mixture is stirred for 5 min at room temperature and slowly for 10 minutes add Alloc-Cl. After 12 h, the catalyst was filtered and the solid layer is washed thoroughly with dichloromethane. After removal of the solvent and crystallization adding petroleum ether get the product with a yield of 85%.

Example 15. Application of aluminum oxide, propeta the aqueous LiOH

To 5 g of thiophenol in 50 ml of dichloromethane added 3 n solution of lithium hydroxide, adsorbed on aluminium oxide (1.3 g of lithium hydroxide 7.5 g of aluminum oxide), the mixture is stirred for 5 min at room temperature and slowly for 10 minutes add Alloc-Cl. After 12 h, the catalyst was filtered and the solid layer is washed thoroughly with dichloromethane. After removal of the solvent and crystallization adding petroleum ether get the product with a yield of 70%.

Example 16. The use of aluminum oxide impregnated LiOH

To 5 g of 2-chlorobenzonitrile add 50 ml of DMF, and then 3 n solution of lithium hydroxide, adsorbed on aluminium oxide (2.7 g, to 0.108 M solution of lithium hydroxide 7.5 g of aluminum oxide), and stirred for 10 minutes Then slowly over 10 min add piperidine and refluxed at 120°C. After completion of the reaction reagent is filtered off and the DMF is removed under reduced pressure. The residue is washed with water and extracted with ethyl acetate. After removal of ethyl acetate to obtain 2-(1-piperidinyl)benzonitrile with the release of 50%.

Example 17. The use of aluminum oxide impregnated LiOH

To 5 g of 2-forventelige add 50 ml of DMF and 3 n solution of lithium hydroxide, adsorbed on aluminium oxide (2.7 g, to 0.108 M solution is hydroxide lithium 7.5 g of aluminum oxide), and stirred for 10 minutes Then slowly over 10 min add piperidine and refluxed at 120°C. After completion of the reaction reagent is filtered off and the DMF is removed under reduced pressure. The residue is washed with water and extracted with ethyl acetate. After removal of ethyl acetate to obtain 2-(1-piperidinyl)benzaldehyde with yields of 80%.

Example 18. The use of aluminum oxide impregnated LiOH

To 5 g of 2-forventelige add 50 ml of DMF and 3 n solution of lithium hydroxide, adsorbed on aluminium oxide (2.7 g, to 0.108 M solution of lithium hydroxide 7.5 g of aluminum oxide), and stirred for 10 minutes Then slowly over 10 min add cyclohexanol and refluxed at 120°C. After completion of the reaction reagent is filtered off and the DMF is removed under reduced pressure. The residue is washed with water and extracted with ethyl acetate. After removal of ethyl acetate to obtain 2-(1-cyclohexylthio)benzaldehyde with a yield of 85%.

Example 19.

To 5 g of 2-peritrabecular add 50 ml of DMF and 3 n solution of lithium hydroxide, adsorbed on aluminium oxide (2.7 g, to 0.108 M solution of lithium hydroxide 7.5 g of aluminum oxide), and stirred for 10 minutes Then slowly over 10 min add aniline and boil with the reverse was built in the ICOM at 120° C. After completion of the reaction reagent is filtered off and the DMF is removed under reduced pressure. The residue is washed with water and extracted with ethyl acetate. After removal of ethyl acetate to obtain 2-(N-phenylamino)nitrobenzene with the release of 90%.

Example 20. The use of aluminum oxide impregnated LiOH

To 5 g of 2-peritrabecular add 50 ml of DMF and 3 n solution of lithium hydroxide, adsorbed on aluminium oxide (2.7 g, to 0.108 M solution of lithium hydroxide 7.5 g of aluminum oxide), and stirred for 10 minutes Then slowly over 10 min add cyclohexanol and refluxed at 120°C. After completion of the reaction reagent is filtered off and the DMF is removed under reduced pressure. The residue is washed with water and extracted with ethyl acetate. After removal of ethyl acetate to obtain 2-(cyclohexylthio)nitrobenzene with the release of 90%.

1. A method of producing a catalyst comprising alumina impregnated base, which is selected from hydroxides of alkali metals, wherein spend processing an aqueous solution of alkali metal hydroxide, aluminum oxide in an organic solvent and the resulting mixture is dried catalyst at a temperature of less than 150°C.

2. The method according to claim 1, characterized in that the organic solvent SEL is given from the group including dichloromethane, dioxane, toluene, acetonitrile or dimethylformamide (DMF).

3. The catalyst obtained according to claim 1, for the introduction of electron-withdrawing protective groups in organic compounds containing at least one group selected from the range: -HE, SH, NH.

4. The use according to claim 3 for the introduction of protective groups in the amines, which represents a primary or secondary amines selected from a range, including aromatic, aliphatic, heterocyclic or cyclic amines.

5. The use according to claim 3 for the introduction of protective groups in the thiol, which represents a primary, secondary or tertiary thiol selected from a range, including aromatic, aliphatic, heterocyclic or cyclic thiols.

6. The use according to claim 3 for the introduction of protective groups selected from the series comprising di-tert-BUTYLCARBAMATE (BOC-anhydride), 9-fluorenylmethoxycarbonyl(Fmoc-C1), 9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide (Fmoc-OSu), allyloxycarbonyl (Alloc), benzylchloride(Cbz-Cl), acetic anhydride, triperoxonane anhydride, acid chloride, sulphonylchloride, to obtain compounds with appropriate protective groups.

7. The catalyst obtained according to claim 1, in substitution reactions of halogen in halogenate on the amino group, tigroup or ester group.

8. The use according to claim 7, in which for for the edenia halogen on the amino group of halogenated treated with an amine, chosen from a range that includes primary, secondary, aromatic, heterocyclic or cyclic amines.

9. The use according to claim 7, in which substitution of a halogen for tigroup halogenated is treated with a thiol, which is selected from a range that includes primary, secondary, or tertiary, aromatic, aliphatic, heterocyclic, cyclic thiols.

10. The use according to claim 7, in which halogenated contains electron-withdrawing group selected from the series comprising nitro, aldehyde, acid, ester, amide or nitrile.

11. The catalyst obtained according to claim 1, as a means to obtain 2-piperidinecarbonitrile by the reaction of 2-chlorobenzonitrile with piperidine.



 

Same patents:

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to biologically active compounds. Invention represents dipeptide nitrile inhibitors of cathepsin K, their pharmaceutically acceptable salts or their esters of the general formula:

wherein X means -CH or nitrogen atom (N); R means (C1-C7)-(lower)-alkyl, (C1-C7)-(lower)-alkoxy-(C1-C7)-(lower)-alkyl, (C5-C10)-aryl-(C1-C7)-(lower)-alkyl or (C3-C8)-cycloalkyl.

EFFECT: valuable biochemical properties of compounds.

6 cl, 12 ex

The invention relates to benzamide derivative of the formula I

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where R3represents (1-6C)alkyl or halogen; Q is aryl or heteroaryl, which optionally carries 1, 2, 3, or 4 substituent selected from hydroxy, halogen, cyano, nitro, amino, carboxy, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylamino and so on; R2- (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino or di-[(1-6C)alkyl]amino; p is 0, 1 or 2; q = 0, 1, 2, 3 or 4; R4- aryl, aryl-(1-6C)alkoxy, aryloxy, arylamino, cycloalkyl or heteroaryl and R4optionally carries 1, 2, 3, or 4 substituent selected from halogen, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino and so on, or its pharmaceutically acceptable salt, or cleaved in vivo ester

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

The invention relates to new compounds with strong anti-tumor activity that meets the General formula (I), where the values of R1- R7, A, Z, Y, X specified in paragraph 1 of the formula

The invention relates to organic chemistry and can find application in biochemistry and medicine

The invention relates to piperazine derivatives and methods for their preparation

The invention relates to compounds, compositions and methods suitable for the treatment of patients suffering from the blockade of receipt of calcium

The invention relates to new aralkylamines derivatives and their salts of interest as medicines, especially as a means of improving brain function, which can be shown senile dementia, Alzheimer's disease, etc

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention elates to the improved method for preparing (-)-cis-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidine. Method involves conversion of 1-methylpiperidine-4-one to hydrobromide followed by interaction with bromide to obtain 3-(R,S)-bromo-1-methyl-4-oxopiperidine hydrobromide and then with 1,3,5-trimethoxybenzene to obtain 3-(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropridine hydrobromide. Then by addition of the reaction solution with organic solvent 3-(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine hydrobromide is isolated firstly as a solid substance and then product is mixed with water and converted by stirring to 3-(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine. Prepared product is hydrogenated catalytically for preparing racemic 3,4-cis-alcohol and by cleavage of racemate by using chiral accessory reagents (-)-cis-3-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidine is prepared from racemic 3,4-cis-alcohol as a pure enantiomer. Proposed method provides simplifying a process for preparing abovementioned product and to reduce duration of process due to exclusion the hydroborating stage, oxidation by Swern, reduction with sodium boron hydride used in preparing the same product by the known method. Also, invention describes intermediates compounds: 3-(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine hydrobromide and 3-(R,S)-hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine.

EFFECT: improved preparing method.

3 cl, 10 ex

The invention relates to the production of carbonyl compounds, which are used as primary intermediates and fine organic synthesis

The invention relates to new chemical compounds with biological activity, in particular to new derivatives of phenylaniline, their tautomers and stereoisomers, including mixtures thereof, and their salts, pharmaceutical compositions with anti-thrombotic and anti antiaggregatory action

The invention relates to chemical technology and can be used in the processes of selection vinylcyclohexane and alkalinities compounds from mixtures and/or purification by distillation, as well as during storage and transportation

The invention relates to a method for inhibiting the polymerization of unsaturated hydrocarbons on the basis of 2,2',6,6'-tetramethyl-4-oxopiperidin-1-oxyl

The invention relates to the field of inhibitors of polymerization of unsaturated hydrocarbons, in particular inhibitor on the basis of stable iminoxyl radical 2,2',6,6'-tetramethyl-4-oxopiperidin-1-oxyl

The invention relates to organic chemistry, specifically to a method for producing alkyl substituted 4-piperidones. the General formula(1) where R, R', R" H, CH3that find use as intermediates in obtaining various biologically active substances, drugs and number of effective pesticides
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