KR100203729B1 - 3'-alkyl or aryl silicaneoxybenzoxazinorifamycin - Google Patents

Abstract

The present invention relates to 3'-alkyl or arylsilyloxybenzoxazinolipamycins useful as intermediates in the synthesis of 3'-hydroxy-5'-substituted aminobenzoxazinolipamycin derivatives useful as antimicrobial agents and methods for their synthesis. . The present invention also relates to 3'-hydroxy-5'-substituted aminobenzoxazinolipamycin derivatives using 3'-alkyl or arylsilyloxybenzoxazinolipamycin as intermediates and methods for their synthesis.

Description

3'-alkyl or arylsilyloxybenzoxazinolipamycin derivatives

FIELD OF THE INVENTION The present invention relates to 3'-alkyl or arylsilyloxybenzoxazinolipamycins useful as intermediates for the preparation of 3'-hydroxy-5'-substituted aminobenzoxazinolipamycin derivatives useful as antimicrobials. .

The present invention further relates to 3'-hydroxy-5'-substituted aminobenzoxazinolipamycin derivatives using 3'-alkyl or arylsilyloxybenzoxazinolipamycin as intermediates and methods for their preparation.

It is known that 3'-hydroxy-5'-substituted benzoxazinolifamycin derivatives are useful as antibacterial agents, as disclosed in Japanese Patent Application Nos. 239676/1989 and 239677/1989. However, its synthetic intermediate 3'-hydroxybenzoxazinolipamycin, despite the use of a large amount of the secondary material 2-aminoresorcinol as disclosed in Japanese Patent Laid-Open No. 63-183587, However, the synthesis yield from rifamycin S was less than 10%, and the synthesis yield was poor.

Thus, as a result of earnest research to solve the above problems, by using 3'-alkyl or arylsilyloxybenzoxazinolipamycin instead of 3'-hydroxybenzoxazinolipamycin used as an intermediate, the therapeutic effect as an antimicrobial agent In spite of its superiority, it was found that 3'-hydroxy-5'-substituted aminobenzoxazinolipamycin, which has been difficult to synthesize so far, can be synthesized in high yield and efficiently, thereby completing the present invention.

Therefore, the present invention aims to use 3'-alkyl or arylsilyloxybenzoxazinolipamycin as an intermediate in the synthesis of 3'-hydroxy-5'-substituted aminobenzoxazinolipamycin.

The 3'-alkyl or arylsilyloxybenzoxazinolipamycins of the present invention are synthesized by reacting lipamycin S with 3-alkyl or arylsilyloxy-2-amino phenols of the general formula (I):

In the above formula, R ¹ , R ² and R ³ are the same or different and each independently represent an alkyl group, an aryl group or an aralkyl group having 1 to 6 carbon atoms.

In the present specification, examples of the alkyl group having 1 to 6 carbon atoms represented by R ¹ , R ² and R ³ include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, secondary-butyl group and tertiary group. -Butyl group, amyl group, isoamyl group, tertiary-amyl group, hexyl group, etc. are mentioned. Moreover, a phenyl group, a tolyl group, etc. are mentioned as an example of an aryl group. Moreover, a benzyl group, a phenethyl group, etc. are mentioned as an example of an aralkyl group.

The 3-alkyl or arylsilyloxy-2-amino phenols of the general formula (I) used for the synthesis of 3'-alkyl or arylsilyloxybenzoxazinolipamycins of the present invention can be synthesized as follows:

(1) 2-aminoresorcinol and general formula Wherein, R ¹ , R ² and R ³ are as described above and X represents a fluorine atom, chlorine atom, bromine atom, iodine atom, OClO ₃ and OSO ₂ -CF ₃ in the presence of a base or It can synthesize | combine by making it react in absence.

Examples of the base which can be used here include secondary or tertiary organic bases such as imidazole, pyridine, picoline, dimethylaniline, triethylamine, piperazine, morpholine and pyrrolidine. As an example of the inorganic base which can be used similarly, Alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide; Alkali earth metal hydroxides such as calcium hydroxide and barium hydroxide; Alkali metal or alkaline earth metal hydrides such as sodium hydride, potassium hydride and calcium hydride; Alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; And alkali metal carbonates such as sodium carbonate and potassium carbonate.

In addition, organic acid alkali metal salts such as sodium acetate and potassium acetate may also be used as the base, but organic bases such as piperazine and triethyl amine are preferably used. Best results are then obtained.

As an example of a reaction solvent, Ester, such as ethyl acetate and butyl acetate; Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylformamide, N, N-dimethylacetylamide, 1,1,3,3-tetramethylurea and dimethyl sulfoxide; Ethers such as dimethoxymethane and diethoxyethane; And acetonitrile may be used, but it is preferable to use an aprotic polar solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, and the best results are obtained.

The reaction temperature can be selected from the freezing point to the boiling point of the solvent, but is usually as low as possible, preferably below -10 ° C, with the best results obtained. Since the optimum reaction time depends on the reactants, solvents and the like used, the reaction should be determined by tracking the reaction by high performance liquid chromatography, thin layer chromatography, or the like. As a reactant used for reaction, the compound etc. which are represented by the following general formula besides the compound of the said general formula (IV) are mentioned, for example:

(Wherein R ¹ , R ² and R ³ are as defined above, and R ¹ , R ² , R ³ , Si are Is displayed.)

(2) 2-nitroresorcinol and the compound of the general formula (IV) are reacted to synthesize 3-alkyl or arylsilyloxy-2-nitrobenzene, and then nitro by a catalytic reduction reaction using palladium carbon or the like. It can synthesize | combine by reducing a group to an amino group.

The reaction between 2-nitroresorcinol and the compound of formula (IV) can be carried out under the same conditions as in the above method (1). In addition, other reactants other than the compound of the general formula (IV) used in the method (1) can be used in the same manner.

In the reduction reaction of the nitro group present in 3-alkyl or arylsilyloxy-2-nitrobenzene, various methods that can be used to reduce the aromatic nitro group to the amino group can be used. For example, although reduction with a nickel nickel, reduction with a metal zinc, etc. are mentioned, Reduction by the catalytic reduction method which uses palladium carbon, platinum oxide, strontium carbonate-palladium etc. as a catalyst is especially preferable.

Specific examples of the 3-alkyl or arylsilyloxy-2-aminophenol of the general formula (I) include

And the like.

Separation and purification of the reaction product of the 3-alkyl or arylsilyloxy-2-aminophenol of the present invention represented by the general formula (I) is relatively easy, and the reaction solvent is removed from the reaction product by distillation under reduced pressure, The crude product obtained can be purified by crystallization, column chromatography or the like to obtain the desired compound.

By reaction of 3-alkyl or arylsilyloxy-2-aminophenol of the general formula (I) with rifamycin S, 3-alkyl or arylsilyloxybenzoxazinolipamycin of the following general formula (II) is synthesized. Can:

In the above formula, R ¹ , R ² and R ³ are the same or different and each independently represent an alkyl group, an aryl group or an aralkyl group having 1 to 6 carbon atoms.

The 3'-alkyl or arylsilyloxybenzoxazinolipamycin of the present invention of general formula (II) is useful for the synthesis of 3'-hydroxy-5'-substituted aminobenzoxazinolipamycin useful as an antimicrobial agent as described below. Useful intermediates.

Synthesis of 3'-alkyl or arylsilyloxybenzoxazinolipamycin of the general formula (II) may be carried out as follows.

That is, lipamycin S and 3-alkyl or arylsilyloxy-2-aminophenol of the general formula (I) are dissolved in a solvent such as benzene and toluene, and reacted at room temperature to the boiling point of the solvent under stirring to synthesize them. Can be. Examples of the reaction solvent include aromatic hydrocarbons such as benzene and toluene, esters such as ethyl acetate and butyl acetate, acetic acid and acetonitrile, but aromatic hydrocarbons such as benzene and toluene are preferred, and the best results are obtained.

The reaction temperature can usually be selected from room temperature to the boiling point of the solvent, but it is most preferably carried out at about 60 ° C. in consideration of the reaction rate and the thermal stability of the raw materials and products. The optimal reaction time depends on the reactants, solvents, etc. to be used, so it should be determined by tracing the reaction by high-performance liquid chromatography or thin layer chromatography.

The 3'-alkyl or arylsilyloxybenzoxazinolipamycin of the general formula (II) is synthesized under the above conditions, but then rifamycin SV with reduced rifamycin S is obtained as a by-product. This rifamycin SV can be converted into rifamycin S by oxidation by adding an oxidizing agent such as manganese dioxide to the reaction system. Instead of isolating this rifamycin S, the desired 3'-alkyl or higher yields by reacting with addition of 3-alkyl or arylsilyloxy-2-amino phenol of the general formula (I). Arylsilyloxybenzoxazinolipamycin can be obtained. Examples of the oxidizing agent used for the oxidation of rifamycin SV include air, oxygen, persulfate, potassium ferricyanide, manganese dioxide, zinc dioxide, silver oxide, copper oxide, alkyl nitrite, hydrogen peroxide, and the like. Preferred, whereby the best results are obtained. Separation from the reaction product of 3'-alkyl or arylsilyloxybenzoxazinolipamycin of the present invention of general formula (II) is relatively easy, and solids such as oxidants are removed from the reaction product by filtration, and then reaction. The solvent is removed by distillation under reduced pressure or the like, and then the crude product obtained is purified by crystallization, column chromatography or the like to obtain the target compound.

The 3'-alkyl or arylsilyloxybenzoxazinolipamycin of the general formula (II) is treated with tetrabutylammonium fluoride or the like, and the 3'-hydroxybenz in which the alkyl or arylsilyloxy group at the 3 'position is substituted with a hydroxy group. Can be converted to oxazinolipamycin. Examples of the reaction solvent include alcohols such as methanol and ethanol, tetrahydrofuran, acetonitrile and the like.

Examples of reagents for decomposing silyloxy bonds include, in addition to the above-described tetrabutyl ammonium fluoride, a system in which tetrabutyl ammonium chloride and potassium fluoride coexist, acetic acid, hydrofluoric acid, and the like, and various methods for decomposing silyloxy bonds. You can use

It is known that the 3'-hydroxybenzoxazinolipamycin obtained is useful as an intermediate of 3'-hydroxy-5'-substituted aminobenzoxazinolipamycin synthesis which is useful as an antibacterial agent.

The 3'-alkyl or arylsilyloxybenzoxazinolipamycin of the present invention of general formula (II) is reacted with an amine of general formula (V) to give 3'-hydroxy-5 'of general formula (III) Substituted aminobenzoxazinolipamycins can be synthesized:

Where A is Or general formula , N is an integer of 3 to 7, R ⁴ and R ⁵ are the same or different, each independently represent a hydrogen atom or an alkyl group of 1 to 3 carbon atoms, R ⁶ represents an alkyl group of 1 to 6 carbon atoms . In other words, the 3'-alkyl or arylsilyloxybenzoxazinolipamycin of the general formula (II) is a useful intermediate for synthesizing 3'-hydroxy-5'-substituted aminobenzoxazinolipamycin.

The reaction of the 3'-alkyl or arylsilyloxybenzoxazinolipamycin of the general formula (II) with the amine of the general formula (V) dissolves both in a solvent, so that the presence of an oxidizing agent such as manganese dioxide, or It can be carried out in absence. Examples of the reaction solvent include halogenated hydrocarbons such as dichloromethane and chloroform, alcohols such as methanol and ethanol, pyridines such as pyridine and picoline, aromatic hydrocarbons such as acetonitrile, benzene and toluene, dimethyl formamide, dimethylacetamide, N, Aprotic polar solvents, such as N, N ', N'- tetramethylurea, and dimethyl sulfoxide, etc. are mentioned, The amine of general formula (V) used as a reactant can also be used. Among these solvents, aprotic polar solvents such as dimethylformamide, dimethyl acetamide, dimethyl sulfoxide and the like are preferred, and the best results are obtained.

The reaction temperature can be selected from the boiling point to the freezing point of the solvent, but considering the reaction rate and the stability of the 3'-hydroxy-5'-substituted aminobenzoxazinolipamycin of the general formula (III). It is preferable to carry out at room temperature vicinity.

General formula Specific examples of the group represented by (where n is an integer of 3 to 7)

Etc. can be mentioned. Also general formula

Specific examples of the group represented by (wherein R ⁴ , R ⁵ and R ⁶ are as described above).

And the like.

Examples of the oxidizing agent that can be used in the reaction in the presence of an oxidizing agent include air, oxygen, manganese dioxide, zinc dioxide, silver oxide, copper oxide, alkyl nitrite, and the like, but manganese dioxide, zinc dioxide, silver oxide, and the like are preferred. Good results are obtained.

The most preferable reaction time depends on the amine and the capacity of the formula (V) used in the reaction, the presence or absence of an oxidizing agent, the type of solvent, the reaction temperature, etc. do.

As described above, the novel 3'-alkyl or arylsilyloxybenzoxazinolipamycin of the general formula (II) according to the present invention may be substituted at the 5 'position with the reaction of replacing the 3'-alkyl or arylsilyloxy group with a hydroxy group. A useful intermediate for the synthesis of 3'-hydroxy-5'-substituted aminobenzoxazinolipamycins, in which the reaction of introducing a substituted amino group can be carried out in a one-step reaction.

EXAMPLE

Hereinafter, although an Example is given and demonstrated in order to make clear understanding of this invention, these are only illustrations and do not limit this invention.

Example 1

Synthesis of 2-amino-3-tert-butyldimethylsilyloxyphenol

161.6 g of 2-aminoresorcinol hydrochloride was dissolved in 1 L of dimethylacetamide (hereinafter referred to as DMA), and the reaction vessel was replaced with argon. Then, 94.8 g of anhydrous piperazine was added and stirred, and the mixture was cooled to -15 ° C. With good stirring, 180.9 g of tert-butyldimethylsilylchloride dissolved in 1 L of DMA was added dropwise over about 1 hour. Next, it stirred for 3.5 hours at -15 degreeC, and 3.6 ml of water were added, and it stirred for about 1 hour. The reaction mixture was analyzed by high performance liquid chromatography (column: Nacalitesk Cosmosil 5C18, 4.6 x 250 mm, mobile phase: methanol-water (95: 5), flow rate: 1.5 ml / min, detection: 254 nm). Formation was confirmed (reaction yield: 88%).

The precipitate produced from the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. 0.7 L of toluene was added to the concentrate, and the resulting precipitate was filtered off. The filtrate was washed four times with 0.5 L of 1N sodium carbonate buffer at pH 9.1 and then twice with 1 L of water. The toluene layer was concentrated to dryness under reduced pressure, and 0.5 liter of hexane was added to the residue, which was then heated to 60 ° C and dissolved. The solution was cooled, the resulting needle crystals were filtered and dried in vacuo to give 134.1 g of the target compound. The filtrate was concentrated to dryness and once again dissolved in 0.13 L of toluene and washed twice with 0.1 L of sodium carbonate buffer and then with 0.5 L of water. The toluene layer was separated, the toluene was distilled off under reduced pressure, and then 0.12 L of hexane was added to the residue, which was then dissolved by heating to 60 ° C. After cooling, the needle crystals formed were filtered and dried in vacuo to give 33.1 g of the target compound.

Elemental Analysis Value (C ₁₂ H ₂₁ NO ₂ Si)

Example 2

Synthesis of 2-amino-3-tert-butyldimethylsilyloxyphenol

The reaction was carried out under the same conditions as in Example 1, except that 0.35 L of triethylamine was used instead of the piperazine used in Example 1. As a result of analysis by high performance liquid chromatography, the production of the target compound was confirmed (reaction yield: 90%). In the same manner as in Example 1, a total of 172.3 g of the target compound were obtained.

Example 3

Synthesis of 2-amino-3-tert-butyldimethylsilyloxyphenol

The reaction was carried out under the same conditions as in Example 2 except that dimethylformamide was used instead of the reaction solvent DMA used in Example 2. As a result of analysis by high performance liquid chromatography, the production of the target compound was confirmed (reaction yield: 78%).

In the same manner as in Example 1, a total of 138.8 g of the target compound were obtained.

Example 4

Synthesis of 2-amino-3-tert-butyldimethylsilyloxyphenol

The reaction was carried out under the same conditions as in Example 1, except that 163.4 g of imidazole was used instead of the piperazine used in Example 1. As a result of analysis by high performance liquid chromatography, the production of the target compound was confirmed (reaction yield: 75%). In the same manner as in Example 1, a total of 131.7 g of the target compound were obtained.

Example 5

Synthesis of 3-tert-butyldimethylsilyloxybenzoxazinolipamycin

69.58 g of rifamycin S was dissolved in 508 ml of toluene and heated at 50 ° C. A solution of 19.51 g of 2-amino-3-tert-butyldimethylsilyloxyphenol in 192 ml of toluene was added to this solution for about 30 minutes. After the addition was completed, the mixture was stirred at 50 ° C for 6 hours. About 50 mL of toluene was removed by distillation under reduced pressure, 10.43 g of manganese dioxide was added, and it stirred at 40 degreeC for 40 minutes. The insoluble matter was filtered off and the residue was washed with toluene. The filtrate and the tax solution were combined to obtain about 700 ml by concentration under reduced pressure. Next, it heated at 50 degreeC, and added the solution of 7.18 g of 2-amino-3- tert- butyldimethyl silyloxyphenols in 72 ml of toluene for about 10 minutes. After the addition, the mixture was stirred at 50 ° C. for 14 hours. The insoluble matter was filtered off and the residue was washed with toluene. The filtrate and the tax solution were combined and analyzed by high-performance liquid chromatography (column: Nippon Spectroscopy Finepak SIL C18-10 4.6X250mm, mobile phase: acetonitrile-water (3: 1), flow rate: 2.0 ml / min, detection: 265 nm). The production of the target compound was confirmed (reaction yield: 90%).

The solution was concentrated under reduced pressure to about 300 mL, 300 mL of hexane was added thereto, and the mixture was left at room temperature to precipitate crystals. The resulting crystals were filtered off and dried in vacuo to afford 62.9 g of the target compound.

Elemental Analysis Value: C ₄₉ H ₆₂ N ₂ O ₁₃ Si

Example 6

Synthesis of 3'-hydroxy-5'-pyrrolidinobenzoxazinolipamycin

4.5 ml of DMA was placed in a 100 ml flask equipped with degassing with a vacuum pump and filled with argon. To this was added 1.83 g of 3'-tert-butyldimethylsilyloxybenzoxazinolipamycin and dissolved. In addition, 0.284 g of pyrrolidine and 0.522 g of manganese dioxide were added, followed by stirring at room temperature for 24 hours. Manganese dioxide was filtered out using a filter aid and washed with methanol. Combined filtrate and tax solution with high-performance liquid chromatography [column: Nacalitesk Cosmosil 5C 8, 4.6x150mm, mobile phase: methanol-water-trifluoroacetic acid (75: 25: 0.1), flow rate: 1.0 ml / min, detection: 290 nm ], The production of the target compound was confirmed (reaction yield: 90%).

The solution was concentrated to dryness and dissolved by adding 30 ml of ethyl acetate. Next, it was washed three times with water and then once with saturated brine and dried overnight with anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off, and the filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography [carrier: Wacogel C-200, developing solvent: chloroform-methanol (99: 1 to 98: 2)]. Fractions containing the target compound were collected, concentrated to dryness, 36 ml of ethanol was added to the residue, dissolved at 55 ° C, and left at room temperature to precipitate crystals. The resulting crystals were filtered off and dried in vacuo to yield 1.11 g of the target compound. The 1 H-nuclear magnetic resonance spectrum of the obtained target compound was consistent with that of the known compound, and its structure was confirmed.

[Examples 7 to 25]

Synthesis of 3'-hydroxy-5'-substituted aminobenzoxazinolipamycin

Instead of the pyrrolidine used in Example 6, the reaction was carried out and treated in the same manner as in Example 6 except that 2 equivalents of the amines listed in Table 1 were used for rifamycin S. The results obtained are shown in Table 1. The 1 H-nuclear magnetic resonance spectrum of each compound was consistent with that of the known one, and its structure was confirmed.

Example 26

Synthesis of 3'-hydroxy-5 '-(2,4,5-trimethylpiperazinyl) benzoxazinolipamycin

4.5 ml of DMA was put into a 100 ml flask with degassing and degassed with a vacuum pump, followed by argon. 1.373 g of 3'-tert-butyldimethylsilyloxybenzoxazinolipamycin was dissolved, 0.763 g of 1,2,5-trimethyl piperazine and 0.39 g of manganese dioxide were added thereto, and the mixture was stirred at room temperature for 96 hours. Manganese dioxide was filtered off using a filter aid, washed with methanol, and the filtrate and the tax solution were combined and analyzed by high-performance liquid chromatography (analysis conditions are the same as in Example 6). Yield: 90%).

Hereinafter, it post-treated and refine | purified similarly to Example 6. The fractions containing the target compound were collected, concentrated to dryness, 8 ml of ethyl acetate was added to the residue, dissolved at 55 ° C, and 12 ml of hexane was added thereto, and the mixture was left at room temperature to precipitate crystals. The resulting crystals were filtered off and dried in vacuo to afford 0.73 g of the target compound. The 1 H-nuclear magnetic resonance spectrum of the obtained target compound was the same as that of the known one, and the structure thereof was confirmed.

[Examples 27 to 29]

Synthesis of 3'-hydroxy-5'-substituted aminobenzoxazinolipamycin

Instead of the 1,2,5-trimethyl piperazage used in Example 26, the reaction was carried out and treated in the same manner as in Example 26, except that 4 equivalents of the amines listed in Table 2 were used for rifamycin S. The results obtained are shown in Table 2. The 1 H-nuclear magnetic resonance spectrum of each compound is consistent with that of a known one, and its structure was confirmed.

Claims (5)

3-alkyl or arylsilyloxy-2-aminophenol of the general formula (I) In the above formula, R ¹ , R ² and R ³ are the same or different and each independently represent an alkyl group, an aryl group or an aralkyl group having 1 to 6 carbon atoms. The 3-alkyl or arylsilyloxy-2-aminophenol of formula (I) according to claim 1, wherein R ¹ and R ² are methyl and R ³ is tert-butyl. A process for preparing 3-alkyl or arylsilyloxy-2-aminophenol according to claim 1, characterized by reacting 2-aminoresorcinol with a compound of formula (IV) Wherein R ¹ , R ² and R ³ are the same or different and each independently represent an alkyl, aryl or aralkyl group having 1 to 6 carbon atoms, and X represents a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or an OClO ₃ or OSO ₂ CF ₃ . The process for producing 3-alkyl or arylsilyloxy-2-aminophenol according to claim 3, wherein the reaction is carried out in the presence of a base. 5. The process of claim 4, wherein the base is selected from the group consisting of triethylamine, imidazole and piperazine. 6.