JPH05194576A - Production of 3,4'-dideoxymycaminosyl tylonolide derivative - Google Patents

Abstract

PURPOSE:To efficiently obtain in high yield the subject compound useful as e.g. an intermediate for antibacterial agents, etc., by reducing a specific compound in the presence of an alkali with shortened process. CONSTITUTION:The objective compound of formula II can be obtained by reducing a compound of formula I [A is protected carbonyl; B is protected aldehyde; R<1> is (protected) hydroxyl group; R<2> is H or lower alkanoyl group; R<3> is sulfonate residue; X is halogen] in the presence of an alkali such as potassium carbonate using a catalyst like platinum, palladium or Raney nickel in a solvent such as THF.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is a useful intermediate for producing 3,4'-dideoxymycaminosyl tylonolide or a salt thereof, which has an antibacterial action, particularly an excellent protective action against infection. The present invention relates to a novel method for synthesizing a 4'-dideoxymycaminosyl tylonolide derivative.

[0002]

2. Description of the Related Art 3,4'-Dideoxymycaminosyl tylonolide or a salt thereof exhibits antibacterial activity against microorganisms belonging to Gram positive and negative, and is particularly useful as an antibacterial agent because it is excellent in infection protection. That is,
-275894. 3,4'-dideoxymycaminosyl tylonolide or a salt thereof,
Starting from mycaminosyl tyronolide, which is an acid hydrolyzate of tylosin, and protecting the functional groups as appropriate,
It can be produced by deoxidizing the hydroxyl groups at the 3 and 4'positions and appropriately deprotecting.

When the conventional production method is applied, it is necessary to carry out the deoxidation of the hydroxyl groups at the 3 and 4'positions in separate steps. First, after sulfonylating the hydroxyl groups at the 3'and 4'positions, the 4'position is described in J. Antibiotics
34, pp. 1374-1376 or JP-A-2-19129.
A method is known in which halogenation is carried out by the method described in Japanese Patent No. 5 and further deoxidation is carried out by reduction with tributyltin hydride. JP-A-2-275894
Also in the publication, the hydroxyl group at the 4'position is deoxylated by the same method. Next, regarding the 3-position, a method in which sulfonic acid is eliminated under alkaline conditions to form a double bond and then deoxygenation is carried out by catalytically reducing the double bond can be considered. Therefore, according to the method to which the conventional method is applied, the deoxygenation at the 3-position and the 4'-position is performed by sulfonylating both hydroxyl groups and halogenating the 4'-position, followed by three steps (tributyltin hydride at the 4'-position). (Reduction, double bond formation at the 3-position and reduction), and the yield is at most 6
It was 5 to 70%. Further, tributyltin hydride used for deoxygenation at the 4'-position has problems in purification and odor, and has a problem in industrial implementation.

[0004]

SUMMARY OF THE INVENTION It is an object of the present invention to effectively solve the above-mentioned problems that the prior art has in producing 3,4'-dideoxymycaminosyl tylonolide or a salt thereof. The invention according to claim 1 provides a mycaminosyltylonolide derivative having a hydroxyl group protected by a sulfonyl group at the 3-position and a halogen atom at the 4'-position in one step, that is, at the 3-position. And 4 '
It is an object of the present invention to provide a method for producing a 3,4′-dideoxymycaminosyl tylonolide derivative which can efficiently replace hydrogen at positions at the same time with good yield. Moreover, it is a further object to provide a deoxidation method at the 4'-position which is effective for industrial use and does not use tributyltin hydride.

The invention according to claim 2 uses the method according to claim 1 to efficiently, efficiently and industrially apply the 3-position and 4-position from a mycaminosyl tylonolide derivative. The aim is to provide a method for simultaneous deoxygenation of the ′ -position.

[0006]

The present invention is for achieving the above-mentioned object, and as described in claim 1, the following general formula (II)

[0007]

[Chemical 5]

[In the formula (II), A represents a protected carbonyl group, B represents a protected aldehyde group, R ¹ represents an optionally protected hydroxyl group, and R ² represents a hydrogen atom or a lower group. Represents an alkanoyl group, R ³ represents a sulfonic acid residue, and X represents a halogen atom. ] The compound represented by the following general formula (I) characterized by reducing under alkaline conditions

[0009]

[Chemical 6]

[In the formula (I), each of A, B and R ¹ has the same meaning as described above. ] The manufacturing method of the 3,4'-dideoxy mycaminosyl tylonolide derivative shown by these.

Furthermore, the present invention provides the following general formula (IV) as described in claim 2.

[0012]

[Chemical 7]

[In the formula (IV), A, B, R ¹ and R ² have the same meanings as the above A, B, R ¹ and R ² , respectively. ] The mycaminosyl tylonolide derivative represented by the following formula is reacted with a sulfonylating agent to give a compound represented by the following general formula (III):

[0014]

[Chemical 8]

[In the formula (III), A, B, R ¹ , R ² and R ³
Have the same meanings as A, B, R ¹ , R ² and R ³ , respectively. ] The compound represented by the formula (III) is then produced by reacting the compound represented by the formula (III) with a halogenating agent, and the compound represented by the formula (II) is further prepared. It relates to a method for producing a 3,4′-dideoxymycaminosyl tylonolide derivative represented by the above general formula (I), which comprises reducing the compound represented by II) under alkaline conditions.

In the compounds represented by the formulas (I) to (IV) of the present invention, the protecting group for the carbonyl group or the aldehyde group represented by A or B includes acetal (or thioacetal), ketal (or thioketal) and the like. Examples of protected compounds include dimethyl acetal (dimethyl ketal), diethyl acetal (diethyl ketal), diethyl thioacetal (diethyl thioketal), ethylene acetal (ethylene thioketal), and propylene acetal (propylene ketal).

R ¹ represents an optionally protected hydroxyl group, and examples of the hydroxyl protecting group include a mycinosyl group,
Alkylsilyl group (t-butyldimethylsilyl, dimethylthexylsilyl, trimethylsilyl, triethylsilyl, tri (t-butyl) silyl, etc.), trityl group, tetrahydropyranyl group, tetrahydrofuranyl group, allyl group, acetyl group And lower alkanoyl groups, benzoyl groups, benzyl groups, methoxymethyl groups, benzyloxycarbonyl groups and the like. R ² represents a hydrogen atom or a lower alkanoyl group, and examples of the lower alkanoyl group include linear or branched alkanoyl groups having 1 to 6 carbon atoms, such as a formyl group, an acetyl group, a propionyl group, a butyryl group, Examples thereof include an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group and a hexanoyl group. R ³ represents a sulfonic acid residue, and examples thereof include a mesyl group, an ethanesulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a tosyl group, and a benzylsulfonyl group. X represents a halogen atom (eg, chlorine atom, bromine atom, iodine atom, etc.).

When the method of the present invention is used, 3,4'-dideoxymycaminosyl tylonolide, which is useful as an antibacterial agent, is compared to the conventional method by using tylosin, which is now commercially available and easily available, as a starting material. The number of steps can be shortened, and efficient and high-yield production can be achieved. That is, a hydroxyl group of mycaminosyl tylonolide obtained by acid hydrolysis of tylosin, an aldehyde group and a carbonyl group by a method usually used in this field, by appropriately protecting with a protecting group as described above, the formula (IV ) The mycaminosyl tylonolide derivative represented by

The mycaminosyl tylonolide derivative represented by the formula (IV) is reacted with a sulfonylating agent such as benzylsulfonic acid or its reactive derivative to sulfonylate the hydroxyl groups at the 3 and 4'positions. Thus, the compound of the above formula (III) can be obtained. Here, the benzyl sulfonic acid may have 1 to 3 substituents such as methyl group and ethyl group on the benzene ring. Examples of the reactive derivative of benzylsulfonic acid include halides such as chloride and bromide, and acid anhydrides. When R ² represents a hydrogen atom, the reaction with benzylsulfonyl chloride allows selective reaction at the 3 and 4 ′ positions. This sulfonylation reaction is usually
It is carried out in an organic solvent at 40 ° C to + 50 ° C. As the solvent, solvents such as acetonitrile, acetone, dimethyl sulfoxide, dioxane and the like can be used. Also, pyridine, 4-dimethylaminopyridine, triethylamine and the like can be used as a basic catalyst or as a solvent.

Then, the compound of formula (III) is treated with sodium iodide, potassium iodide, lithium bromide, tetrabutylammonium bromide, tetrabutylammonium in an inert solvent (eg acetone, 2-butanone, dimethylformamide etc.). By reacting with a halogenating agent such as chloride, the compound represented by the formula (II), which is selectively halogenated at the 4′-position, can be obtained.
Depending on the halogenation conditions, a compound having a double bond at the 2,3 position or the 3,4 position can be produced, and this compound can also be used as a raw material for the compound of the formula (I) in the next step. it can.

Then, the compound represented by the formula (II) is
Surprisingly, the hydrogen can be substituted at the 3 and 4'positions by blowing hydrogen into the reaction in the presence of an alkali and a catalyst in the reaction-inert to carry out reduction (catalytic reduction). .. This results in formula (II)
In one step and in high yield (about 80%),
The 3,4'-dideoxy derivative represented by the above formula (I) can be obtained.

Examples of the alkali that can be used here include sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and the like, and potassium carbonate is preferable among them. Examples of the catalyst that can be used for catalytic reduction include platinum, palladium, Raney nickel, and the like, with Raney nickel being preferred. As the inert solvent, benzene, toluene, ether, tetrahydrofuran, dimethylformamide,
Examples thereof include dimethyl sulfoxide. The reaction temperature will differ depending on the types of raw material compounds and reducing agents, but is preferably set between room temperature and cooling.

By using this method, it is possible to perform deoxidation of the 4'-position at the same time as deoxidation of the 3-position without using tributyltin hydride, which has problems in purification and odor, and therefore, industrial production. Is also extremely advantageous. The compound of formula (I) thus obtained has the 3,4'-dideoxy represented by the following general formula (V), which is useful as an antibacterial agent, by removing the protecting group according to the method usually used in this field. It is possible to obtain mycaminosyl tylonolide or a salt thereof.

[0024]

[Chemical 9]

Removal of the protecting group is usually carried out by adding hydrochloric acid in the presence of water,
By treatment with a mineral acid such as acetic acid or an organic acid such as trifluoroacetic acid or trichloroacetic acid, and in some cases, in a solvent such as dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, or an arylsulfonic acid such as p-toluenesulfonic acid. It can be carried out by treating with an alkylsulfonic acid such as methanesulfonic acid at room temperature or under heating.

The 3,4'-dideoxymycaminosyl tylonolide of the formula (V), which can be finally obtained by using the method of the present invention, has a gram content as described in JP-A-2-275894. It exhibits antibacterial activity against a wide range of positive and negative microorganisms. In particular, it is useful as an antibacterial agent because it is excellent in the protective action against infection.

[0027]

EXAMPLES The present invention will now be illustrated by examples. a) 23-0-t-butyldimethylsilyl-3,4'-
Di-0-benzylsulfonyl-mycaminosyl tylonolide 9,20-bis (ethylene acetal) (3)
Synthesis of

[0028]

[Chemical 10]

23-0-t-butyldimethylsilyl-mycaminosyl tylonolide 9,20-bis (ethylene acetanol) (4) 1.00 g (1.25 mmo)
1) was dissolved in 20 ml of anhydrous pyridine, cooled to -40 ° C, and stirred with benzylsulfonyl chloride 0.67 g (3.5
1 mmol) was added and the mixture was reacted at −20 ° C. for 3 hours. TL
The reaction was confirmed by C, 0.67 ml of water was added to stop the reaction, and the temperature was returned to room temperature. After 1 hour from the addition of water, the reaction solution was concentrated with a pump and extracted with chloroform. The chloroform layer was washed successively with saturated sodium bicarbonate water and saturated saline, dehydrated with magnesium sulfate, filtered, and the filtrate was concentrated. , Crude 23-0
-T-butyldimethylsilyl-3,4'-di-0-benzylsulfonyl-mycaminosyl tylonolide 9,
20-bis (ethylene acetal) (3) was obtained as a pale yellow foamy solid, 1.38 g (quantitative).

B) 3-0-benzylsulfonyl-23-
0-t-butyldimethylsilyl-4'-deoxy-4 '
-Iodo-Mycaminosil Tylonolide 9,20-
Synthesis of bis (ethylene acetanol) (2)

[0031]

[Chemical 11]

Unpurified compound (3) 41 obtained in the above a)
Dissolve 5 mg (0.375 mmol) in 6.2 ml of anhydrous methyl ethyl ketone, replace with nitrogen, add 84 mg (0.560 mmol) of sodium iodide, heat and stir at 80 ° C., return the reaction solution to room temperature after 30 minutes, and filter. Then, the filtered material was washed with acetone, and the filtrate and the washing liquid were combined and concentrated. The concentrated residue was extracted with chloroform and saturated sodium bicarbonate water, 10%
The extract was washed successively with sodium thiosulfate and saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give 410 mg of a pale yellow syrup. The obtained syrup was purified by silica gel column chromatography to give 3-0-benzylsulfonyl-23-0-t-butyldimethylsilyl-.
4'-deoxy-4'-iodo-mycaminosyl tylonolide 9,20-bis (ethylene acetanol)
300 mg (75% yield from the compound (4)) of (2) was obtained as a colorless solid. (Physicochemical properties) Specific optical rotation [α] ²⁷ _D −70 ° (c1, CHCl ₃ ) Elemental analysis C ₄₈ H ₇₈ NO ₁₃ ISSi as C H NI (%) Experimental value 54.09 7.27 1.08 11.95 Calculated value 54.17 7.39 1.32 11.92 Mass (FAB) m / z 1064 (M +
1) ⁺

C) Synthesis of 23-0-t-butyldimethylsilyl-3,4'-dideoxymycaminosyl tylonolide 9,20-bis (ethylene acetanol) (1)

[0034]

[Chemical 12]

296 mg of the compound (2) obtained in b) above
(0.278 mmol) is dissolved in 6 ml of methanol,
After adding 0.5 ml of Raney nickel and replacing with argon, 116 mg (0.835 mmol) of potassium carbonate was added,
Bubbling hydrogen for 3 hours. After completion of the reaction was confirmed by HPLC, the reaction solution was filtered, and then the filtrate was concentrated, extracted with chloroform, washed successively with 1M aqueous potassium carbonate solution and saturated brine, dried over magnesium sulfate, filtered, and filtered. Concentration gave 204 mg (95%) of crude compound as a colorless foamy solid. The obtained solid was purified by silica gel column chromatography, and 23-0-t-butyldimethylsilyl-
3,4'-dideoxymycaminosyl tylonolide
186 mg of 9,20-bis (ethylene acetanol) (1) was obtained as a colorless foamy solid (yield 87%). This product, ¹ H-nmr
Matched in Mass. (Physical and chemical properties) Mass (F.A.B.) m / z = 768 (M + 1)
_{^{+ 1 H-nmr (CDCl 3}} , TMS internal standard) δ0.88 (9H, s, of the t- butyldimethylsilyl t
- butyl), 1.02 (3H, d, CH 3 -21), 1.
_{24 (3H, d, CH 3} -6 '), 1.74 (3H, s,
_{CH 3 -22), 2.29 (6H} , s, N (CH 3) 2 -
3 '), 4.28 (1H, d, H-1'), 5.37 (1
H, d, H-13), 5.61 (1H, d, H-10),
6.39 (1H, d, H-11)

[0036]

INDUSTRIAL APPLICABILITY According to the present invention, 3,4'-dideoxymycaminosyltylonolide, which is useful as an antibacterial agent, is a useful intermediate for producing a salt thereof,
The 4'-dideoxymycaminosyl tylonolide derivative was prepared from a readily available tylosin analog (mycaminosyl tylonolide derivative, denomycyl tylonolide derivative, etc.) by shortening the process as compared with the conventional method. And can be manufactured with high yield. Further, according to the present invention, deoxygenation at the 4'-position can be carried out without using tributyltin hydride, which has been difficult in industrial production in the conventional method.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Shunji Kageyama 2-35-2 Kasuga, Tsukuba, Ibaraki Prefecture Etoile Kasuga 306 (72) Inventor, Toshiaki Miyake 3-5-1, Shimoda-cho, Kohoku-ku, Yokohama-shi, Kanagawa Hiyoshi Heights 207

Claims (2)

[Claims] 1. The following general formula (II): [In the formula (II), A represents a protected carbonyl group, and B
Represents a protected aldehyde group, R ¹ represents an optionally protected hydroxyl group, R ² represents a hydrogen atom or a lower alkanoyl group, R ³ represents a sulfonic acid residue, and X represents a halogen atom. .. ] The compound represented by the following general formula (I) is characterized by being reduced under alkaline conditions. [In the formula (I), A, B and R ¹ each have the same meaning as described above. ] The manufacturing method of the 3,4'-dideoxy mycaminosyl tylonolide derivative shown by these. 2. The following general formula (IV): [In the formula (IV), A, B, R ¹ and R ² have the same meanings as A, B, R ¹ and R ² respectively. ]
By reacting a mycaminosyl tylonolide derivative represented by the following with a sulfonylating agent, the following general formula (III): [In the formula (III), A, B, R ¹ , R ² and R ³ have the same meanings as A, B, R ¹ , R ² and R ³ described in claim 1. ] The compound represented by the formula (III) is then produced by reacting the compound represented by the formula (III) with a halogenating agent, and the compound represented by the formula (II) is further prepared. The compound of the general formula (I) according to claim 1, characterized in that the compound represented by II) is reduced under alkaline conditions.
A method for producing a 3,4′-dideoxymycaminosyl tylonolide derivative represented by: