KR930003491B1 - Process for preparation of amino glycosides - Google Patents

Abstract

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Description

Method for preparing amino glycosides

The present invention is of general formula (II)

Wherein R ₁ represents a hydrogen atom, a hydroxyl group or a methoxy group from the compound represented by the general formula (I)

It is related with the manufacturing method of the amino glycoside represented by (wherein, R <_1> has the meaning of the former).

Compounds of general formula (I) are useful as pharmaceuticals because they have antimicrobial properties (Japanese Patent Publication Nos. 53-127401 55-40605, 55-55198, 55-164695, 56-2997, 56-164197 See each specification).

The compound of general formula (I) has a glycyl group in the 4-amino methylamino group, and this is a big factor of antimicrobial potency enhancement.

However, since the glycyl group is easily hydrolyzed under basic conditions in the synthesis process, it is not preferable to use a protecting group that desorbs under basic conditions for the synthesis of these compounds. Therefore, the benzyloxy carbonyl group which can be released by contact reduction under weak acidic conditions is widely used. Since the catalytic reduction catalyst is expensive and the apparatus is not suitable for industrial production, Development was desired.

It is therefore an object of the present invention to provide an industrially advantageous method of preparing amino glycosides of general formula (I) which is inexpensive and uses safe materials and devices to produce the desired compound (I) in high yield.

As a result of various studies, the present inventors have applied O-hydroxy aromatic aldehydes to the compound of formula II to protect amino groups at the 1, 2, and 6 positions as the seed base, and then, by using a β-dicarbonyl compound, When the glycine or its reactive derivative protecting the amino group is acted on, the glycyl group is easily introduced to obtain a compound of formula I in which four amino groups are protected. The present invention has been completed by finding that the compound is obtained in high yield.

The method of the present invention is represented by the following scheme.

(Wherein, R ₁ is an electric meaning, R ₂ is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and R ₃ and R ₄ are the same or different, and thus a lower alkyl group, a lower alkoxy group or a substituent) It may represent a phenyl group which may have, or R ₃ and R ₄ may combine to form a lower alkylene group.)

The raw material compound (II) of this method is all well-known compounds, and the compound whose R <_1> is a methoxy group is a compound of cis coordination with respect to the sporalysin B (KA-6606II, the sugar residue of 2-position aminopropyl group) ) And sporarizine E (KA-6606VI; amino group at position 1 is known as a trans coordination compound for sugar residues at position 2) and are available as metabolites of microorganisms of the genus Saccharopolyspora. (See Japanese Patent Laid-Open Nos. 53-127401 and 55-111497). Compound (II) wherein R ₁ is a hydroxyl group is 5-di-O-methylsporaricin B (5-di-O-methyl-KA-6606II) and 5-di-O-methylsporaricin E (5-di -O-methyl-KA-6606VI), obtained by cleaving a methyl ether group by reacting an acid, preferably an inorganic acid, to compound (II) wherein R ₁ is a methoxy group (Japanese Patent Laid-Open No. 55-55198). And specifications 56-2998). Compound (II), wherein R ₁ is a hydrogen atom, is known as dimethoxysporaricin B (5-dimethoxy-KA-6606II) and dimethoxysporaricin E (5-dimethoxy-KA-6606VI), and R _It can manufacture by leaving the 5-position hydroxyl group of compound (II) which ₁ is a hydroxyl group (refer Unexamined-Japanese-Patent No. 56-164197 specification).

As a lower alkyl group represented by R <_2> , R <_3> and R <_4> in the said general formula, the C1-C6 linear or branched thing is preferable.

As an alkyl group in a lower alkoxy group, said alkyl group is preferable.

As a halogen atom which R <_2> represents, fluorine, a chlorine, a bromine atom, etc. are preferable. The phenyl group represented by R ₃ and R ₄ may be substituted with a lower alkyl group, a lower alkoxy group, a halogen atom, or the like such as electricity. As a lower alkylene group which R <_3> and R <_4> combine and form, C2-C8 linear or branched thing is preferable.

Next, the implementation of the method of the present invention will be described in detail.

① Preparation of compound (IV) from compound (II):

When compound (III) is made to react with compound (II), compound (IV) is obtained. When compound (III) is used in the amount of 3 equivalents or more with respect to compound (II), the desired product is obtained, but it is preferable to use 3 equivalents to avoid reaction with the methyl amino group at the 4-position. The reaction is preferably carried out in a solvent, and solvents such as methanol, ethanol, dimethylformamide and a mixture of these and water can be used. The reaction is completed in a few minutes to 0 to 100 ° C., preferably around room temperature. Separation and purification of compound (IV) can be carried out by a conventional method, but can be used for the following reaction as prepared.

② Preparation of Compound (IV) from Compound (IV):

When compound (IV) or a reactive derivative thereof is applied to compound (IV), compound (VI) is obtained. Compound (V) is for example a general formula

The compounds represented by (wherein R ₃ and R ₄ have the meaning of the foregoing) and glycine can be produced by reacting in the presence of a base.

Examples of reactive derivatives include acid halides, acid anhydrides, mixed acid anhydrides, and the like, such as acid halogenides, active esters such as phenyl esters, cyanomethyl esters, N-hydroxysuccinimide esters and N-hydroxyphthalimide esters. What is used in the field of peptide synthesis, etc. can be used.

The reaction is completed by contacting compound (IV) with 1-3 equivalents of compound (V) at 0-200 ° C. for several minutes in the presence of a base, preferably in a solvent. At this time, examples of the solvent used may include cyclic ethers such as tetrahydrofuran and dioxane, methylene chloride, acetonitrile and dimethylformamide. Examples of the base include inorganic bases such as sodium hydroxide and calcium hydroxide, and organic bases such as triethylamine, pyridine and dimethylaminopyridine.

③ Preparation of Compound (I) from Compound (VI):

When an acid is made to react with compound (VI), the target compound (I) is obtained. As the acid, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, p-trienesulfonic acid and the like are used. This reaction is completed by adding 4-10 equivalents of the above acid to the reaction solution after the completion of the reaction of the above ② and stirring at 0-50 ° C. for 1-10 hours.

Isolation and purification of the target compound (I) is carried out by conventional methods, and column chromatography is particularly preferred. As an adsorbent, it is preferable to use cation exchange resins, such as CM- Sephadex, Amberlite IRC-50, IRC-84, CG-50, carboxymethylcellulose, for example. The development can be carried out by a concentration gradient method or a concentration step method, using an alkaline solution such as aqueous ammonia solution, aqueous ammonium formic acid solution, and the like as a developing solvent. By collecting the active fractions from the eluate and freezing them, a pure product of the target compound can be obtained.

Compound (I) can be induced with acid addition salts according to conventional methods. As the acid, inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, carbonic acid, acids and the like, and organic acids such as acetic acid, fumaric acid, malic acid, citric acid, mandelic acid and succinic acid are used.

EXAMPLE

5-di-O-methylsporaricin A [5-di-O-methyl-KA-6606I; Preparation of Compound (I)] wherein R ₁ is hydroxyl group:

(a) 100 mg of 5-di-O-methylsporaricin B is dissolved in 2 ml of methanol, and then 1.2 ml of a methanol solution of salicylic aldehyde (10v / v%) is added and allowed to stand at room temperature for 30 minutes.

The reaction solution was concentrated to give pale yellow 1,2 ', 6'-tris-N-salicylidene-5-di-O-methylsporaricin B [Compound (IV) wherein R ₁ is a hydroxyl group and R ₂ is a hydrogen atom. ] Preparations are obtained. This is used for the next reaction without purification again.

(b) The N-protective compound obtained in (a) is dissolved in 2.5 ml of dioxane, 125 mg of benzoyl isopropenyl glycanomethyl ester and 0.1 ml of triethylamine are added and warmed at 60 ° C for 2 hours.

2.5 ml of dioxane and 0.3 ml of 6N hydrochloric acid are added to the reaction solution, and the mixture is stirred at room temperature for 2 hours.

15 ml of water is added, concentrated to about 15 ml below 30 ° C and washed with chloroform. The aqueous layer was diluted with water, neutralized with ammonia water, and then adsorbed onto a column packed with 10 ml of CM-Sephadex C-25 (NH ₄ type), and 100 ml each of 0.05 and 0.5 ammonia water was used for the concentration gradient method. To purify.

The fractions containing the desired product were collected and lyophilized to yield 5-89 mg of di-O-methylsporaricin A89 as a colorless solid.

Its physicochemical and biological properties are consistent with that of the package.

Claims (1)

General formula

(Wherein R ₁ represents a methoxy group, a hydroxyl group or a hydrogen atom)

Wherein R ₂ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom

Wherein R ₁ and R ₂ have the meaning of electricity.

(Wherein, R ₃ and R ₄ are the same or different and may represent a lower alkyl group, a lower alkoxy group or a phenyl group which may have a substituent, or R ₃ and R ₄ may combine to form a lower alkylene group. By reacting a carboxylic acid represented by.) Or a reactive derivative thereof

(Each symbol in the formula has the meaning of electricity.) A general formula characterized by reacting an acid with a compound of formula (VI).

A method for producing amino glycosides or acid addition salts thereof, wherein R ₁ has the meaning of electricity.