JPH0248596A - Tylosin derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R is acetyl, propionyl or Si(R')3 (R' is methyl, ethyl or propyl)]. EXAMPLE:2'-Acetyl-3,4-di-O-trimethylsilyltylosin. USE:A synthetic intermediate for tylosin intermediate contained in 16-membered ring macrolide antibiotic. PREPARATION:A tylosin shown by formula 11 (R'' is H, acetyl or propionyl) or 2'-O-acyltylosin is reacted with a boric acid compound (e.g., boric acid) and trialkylsilylated. Chlorotrimethylsilane may be cited as the silylating reagent. The amount of chlorotrimethylsilane used is preferably 4-5mols based on 1mol of 2'-O-acyltylosin in the case of 2'-O-acyltylosin.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides 2'-0-
The present invention relates to 3.4'"'-di-0-trialkylsilyl derivatives of acyltylosin and 3.2', 4" trirotrialkylsilyl derivatives of tylosin, and methods for producing them.

[Conventional technology]

16-membered ring macrolide antibiotics have excellent antibacterial activity and are widely used as pharmaceuticals, veterinary drugs, feed additives, and the like. In particular, tylosin is produced industrially in large quantities.

However, macrolide antibiotics generally have a low ability to be absorbed and excreted in the body, and due to the emergence of resistant bacteria, which is the fate of antibiotics, these antibiotics have to be treated chemically or
Much research is being conducted on tylosin derivatives, which have excellent absorption and excretion ability and are endowed with antibacterial activity against resistant bacteria through biological conversion methods.

Tylosin has the following formula It is a compound with

In particular, derivatives in which the 4''-position hydroxyl group of the 5-position disaccharide residue of tylosin is acylated, such as 4''-〇-(4-
methoxyphenylacetyl) tylosin, 4”-〇-(
4-acetylphenylacetyl) Taiguchi, Shin.

4''-0-(4-methylthiophenylacetyl)tylosin 4''-0-(3-pyridylacetyl)tylosin, 4''-0-(4-methylsulfonylphenylacetyl)tylosin, etc. are effective against macrolide-resistant bacteria. It has been found that it has excellent antibacterial activity and has improved absorption and excretion ability in the living body (Japanese Unexamined Patent Publication No. 1198-1988,
1-30596, 61-137895).

When these 4"-0-acyl derivatives of tylosin are chemically synthesized using tylosin as a raw material, the hydroxyl groups at the 2°, 4", and 4"' positions of tylosin are acylated, so the 2° After protecting the hydroxyl groups at the 4'' and 4'' positions, a desired acyl group is introduced at the 4'' position.
The method used was to remove the protective group at the position.

In the above synthesis method, when introducing a desired acyl group into the 4'' position, a compound acylated at the 3-position is produced as a by-product, reducing the yield of the target product.

For example, after tylosin is reacted with acetic anhydride to form 2'0-acetyltylosin, this 2'-0-acetyltylosin is reacted with halo-lower alkanoyl halide, lower alkoxycarbonyl halide, phenoxyacetyl halide in methylene chloride in the presence of pyridine. After separating the 2'',4'''-di〇-acylated tylosin by acylating with etc., and introducing the desired acyl group into the 4''' position,
It was produced by eliminating the acyl group at the 4''' position and/or the 2° position (JP-A-53-137982). However, the yield of the 4'''-di0 acyl derivative by this method was 10
~30%, and chromatography was essential for isolation.

[Problem to be solved by the invention]

In the above prior art, tylosin derivatives, especially 4”-
When chemically synthesizing 〇-acyltyrosine derivatives, 4”
To obtain an acyl protected form only at the ′ position,
It is necessary to separate the diacyl compound in which the hydroxyl groups at the ``position and 4'''' position are acylated and the diacyl compound in which only the hydroxyl group at the 4'' position is acylated by a separation means such as chromatography. However, the yield was low.

Furthermore, during the 4"-〇-acylation reaction of the protected product at the 4" position, 3,4"-di-low acyl-4 which was also acylated at the 3-position
″°-protector is sub-formed, desired 4”-〇-acyl-4”
- The yield of the protected product was reduced. In addition, there were also drawbacks such as the necessity of chromatography for their separation.

The present invention relates to the 3' and 4' positions of 2'-0-acyl tyrosine.
“Method for selectively protecting the hydroxyl group at position 3 and tylosin”
, 2° and 4° positions; and 3.
Useful new derivatives of 2'-0-acyltyrosine protected at the 4'' position and 3,2' and 4'°.

The object of the present invention is to provide novel derivatives of tylosin with protected positions.

[Means to solve the problem]

The present inventors have conducted repeated research in order to solve the drawbacks of the above-mentioned conventional techniques, and have found that
As a result of various studies on compounds in which the hydroxyl group at the ° position was selectively protected and compounds in which the hydroxyl groups at the 3, 2" and 4" positions of tylosin were protected, and the conditions for their protection, 2"
After adding a boric acid compound to a solution of -0-acyltylosin or tylosin, 2'-0-acyltylosin is selectively converted into 3. It was discovered that the hydroxyl group at the 2-position or the 3.2' and 4'-degree hydroxyl groups of tylosin can be selectively silylated, and the product is a new tylosin derivative and can be used as an intermediate for the production of 4'-position derivatives. They discovered that it is a useful substance and completed the present invention.

The present invention provides a compound of the formula (H [wherein R is an acetyl group, propionyl i or
)3 groups, and Ro represents a methyl group, ethyl group, or propyl group], and a tylosin derivative represented by the formula (n) [wherein, R represents a water atom, an acetyl group, or a propionyl group] ] This is a method for producing a tylosin derivative represented by formula (I) by treating tylosin or 2°-0-acyl tylosin with a boric acid compound and then subjecting it to trialkylsilylation.

Representative substances of the tylosin derivative represented by formula (1) of the present invention include the following.

2°-0-acetyl-3,4”°-di-0-trimethylsilyltyrosine, 2′-0-propionyl-3,4
”-di-0-trimethylsilyltyrosine, 2'-0-
Acetyl-3゜4'''°-di-lotriethylsilyltylosin, 2'-0-acetyl-3,4''-di-0-tripropylsilyltylosin, 2'-0-propionyl-3,4''-di 0-) ethylsilyltylosin, 3,2°, 4”-) ly-0-)lyntylsilyltylosin, 3.2”, 4””-tri0-triethylsilyltylosin, 3,2′,4 ``'-) Li-0-) Al with lifuropirsilyltylosin, etc.

The tylosin derivative represented by the formula (I) of the present invention is a compound of Streptomyces frasiae (Streptomyces frasiae).
fradiae) NRRL 2702 [a compound in which R1+ represents a hydrogen atom] and Japanese Patent Publication No. 54-22649, Antibiotics and Chemothe
2°-0-acetyltylosine and 2°-0-propionyltylosine [a compound in which R represents an acetyl group or a propionyl group in formula (II)] described in J. Rapy 11.3'28-554 (1961) as a starting material. It can be obtained by dissolving in a solvent, adding a boric acid compound, and then reacting with a silylation reagent such as trimethylsilane chloride, trimethylsilane bromide, triethylsilane chloride, tripropylsilane chloride, etc.

Here, the solvent is an aromatic hydrocarbon type.

Halogen hydrocarbon type, ether type, ester type.

Dimethylformamide, dimethylsulfoxide 4d.

Not only a single solvent such as acetonitrile, but also a mixed solvent such as toluene-dimethylsulfoxide, ethyl acetate-dimethylformamide, etc. can be used.

Examples of boric acid compounds include boric acid, boric anhydride, phenylboric acid, boric triester, and the like. Generally, the boric acid compound may be added in a dissolved state or in a solid state in the above-mentioned solvent. The amount of boric acid compound added is 0.5 per mole of tylosin or 2'-acetyl tylosin.
~1.2 mol, preferably 0.8~1.0 mol is used. Addition temperature and reaction temperature are 0 to 50°C, preferably at room temperature, with stirring, and reacted for 0.5 to 3 hours, preferably 1 hour. After protecting the hydroxyl groups at the 4" and 3" positions, directly Or, in some cases, add toluene, remove the resulting water, and then add the silylation reagent and organic base to 3.4.
Silylate the ``' position or the 3.2', 4'' position.

In the case of 2-0-acyl tyrosine, the silylation reagent used is 3 to 8 mol per mol of 2'-0-acyl tyrosine.
It is advisable to use moles, preferably 4 to 5 moles. In the case of tylosin, it is preferable to use 4 to 10 moles, preferably 5 to 7 moles, per mole of tylosin. These may be added in several parts. Further, triethylamine, isopropyl diethylamine, etc. can be used as an organic base as a reaction aid, but these can be added 1.0 to 2.0 times, preferably 1.1 to 1.2 times the amount of the silyl reagent used. In good condition.

To isolate the product from the reaction solution, the reaction solution was diluted with toluene,
After diluting with an organic solvent such as ethyl acetate or chloroform, saturated hydrogen carbonate solution), washing with IJum solution and brine, drying with Glauber's salt, and distilling off the solvent will yield the target compound represented by formula (I). can.

[Effect]

The tylosin derivative represented by formula (1) of the present invention includes 3.
The secondary hydroxyl groups at the 2' and 4'' positions are all protected compounds except for the hydroxyl group at the 4° position. Moreover, these protecting groups can be easily removed by known reactions. Therefore, the hydroxyl group at the 4° position By reacting reactive derivatives of various organic acids, various useful quilodine derivatives having the desired acyl group at the 4'' position can be selectively obtained! ! can be built.

Furthermore, since there is no by-product containing an anlu group at the 3-position, the desired product can be obtained without using chromatography.

〔Example〕

Hereinafter, the present invention will be explained in more detail with reference to Examples. However, the present invention is not limited thereto.

10.00 g of 2'-〇-acetyltylosin (1
0.44 mmof) and dimethylformamide 30
ml was added and dissolved, and the mixture was stirred at room temperature in the dark. To this, orthoboric acid [B (Kano), Ko 516 mg (8.35 m
mof) ノ'; 10rd solution of methylformamide was added little by little, and the mixture was stirred at room temperature for 2 hours. This was then added with 9.46 ml of triethylamine (67.84 mmo
f) was added dropwise, and after another 5 days, 7.9% of tritylene chloride was added.
Add 5 ml (62,62 mmof) dropwise and leave at room temperature for 2
Stirred for 6 hours. After the reaction was completed, excess toluene was added to the reaction solution to dilute it and washed once with saturated sodium bicarbonate solution. This aqueous layer was back-extracted once with toluene, and this was combined with the previous toluene layer. , and washed once with a saturated aqueous sodium chloride solution. After drying with anhydrous sulfuric acid, the solvent was distilled off under reduced pressure to obtain the title compound 10.92.
I got g.

Physical and chemical properties [α]” Knee 64.7° (C1,0, [:HCJ,
)IR(CHCJ2-): 2925,1?40,1
670.1590 cm-''H-NMR (CD (1
'+) δ[ppm Koni 0, 07 (9H
,s, -3i (C113) 3), 0.16 (
9) I, s, -3i (CH3) q).

1,75 (3H,s, 12-CJ), 2.02
(38,s, 2°-0COC83).

2,35 (6H,s, 3'-N (CH3) 2
), 3.45 (3H,s, 2'''-0CR,).

3, 56 (3Ls, 3”'-GCH3), 4.5
6 (11(,d, J=8.0Hz, Hl”).

5, 85 (IH, d, J=10.0Hz, H, 3
), 6.20 (IH, d, J=1'6.0Hz,
H, o).

7.25 (LH, d,, J'16.OHz, H++
), 9.70 (LH, s, -C) 10) 0, 972
g (0,882 mmol) of 2-0-acetyl-3,4"-di-0-trimethylsilyltylosine was dissolved in 3.0 ml of ethyl acetate, and 7.9 mg of dimethylaminopyridine (6,5Xl0-" mmol) was dissolved in 3.0 ml of ethyl acetate.
and triethylamine 0.25-(l, 79 mmo
A) was added, and 359 mg (1,43 mmo
42) dissolved in 3.0 ml of ethyl acetate was added dropwise over 4 minutes, stirred for 3 hours, and then cooled with water with 0.29 ml of methanol. (Add 7.15 mm and 3
Stirred for 0 minutes. 10ml of ice cubes in the reaction solution! After adding
Extracted with 10-ethyl acetate. The ethyl acetate layer was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2'-0
-acetyl-3, di-di-0-trimethylsilyl-4
”-〇-p-methoxyphenylacetyl-tylosin 1
．． 05g was obtained with a yield of 95%.

Furthermore, 1.05 g (0.84 mmoj) of 2'-loacetyl-3,4"-di-0-trimethylsilyl-4"
-〇-p-Methoxyphenylacetyl-tylosin was dissolved in 15.4rn1 of methanol/water (10:1) and 1
The mixture was heated under reflux at 4° for 5 hours.

Only methanol in the reaction solution was distilled off, and acetone 4 was added to the remaining solution.
- was added and dissolved, adjusted to pi (2.2) with 0.15N hydrochloric acid, and stirred at room temperature for 2 hours.The reaction solution was washed with toluene, and the pH was adjusted to 7.6 with 5N aqueous sodium hydroxide solution. After adjustment, extraction was performed with ethyl acetate.

The ethyl acetate layer was washed with pH 4.3 buffer, saturated sodium bicarbonate water, and then saturated saline, dried over anhydrous sodium sulfate, and further concentrated to give 4"-0-p-methoxyphenylacetyl-tylosin. 487 mg was obtained with a yield of 54.5%.

Melting point: 238-240℃ [α] 4°-43,6° (C1, O, C) 1301
1) UV:λ:W%”284 nm (ε19000
) 227 nm (E, 8700) IR: v base 2', 1725 cm -' (x
ster, aldehyde) 1675 C(n −' (both fQken)) 15
90 Cff1-' (double M combination) NMR (CDCf
, ) δ (ppm) : 9, 59 (18, s, -CI
O), 7.25 (IH, d, J=16Hz,
H,,).

6, 77 (2) 1. d, J・9Hz.

6, 18 (IN, d, J=16) 1z, Lo
).

2,46 (6H,s, 3°-N (CI(3) 2
), 1.77 (3H,9,12-C113)tylosin 1 g (1,09 mmoA) was converted into dimethyl acetate 6-
0.37 mal of triethylamine (2,
62 mmoβ), cooled on ice, and added 0.14 mj of trimethylchlorosilane! (2.29 mmoA) was added dropwise, the temperature was returned to room temperature, and the mixture was stirred for 16 hours.

67.5 mg of boric acid (1.09 mmoA) in the reaction solution
Slowly add 2 ml of dimethylformamide solution in which triethylamine is dissolved, stir for 30 minutes at room temperature, and add 0.0 ml of triethylamine.
．． 99 ml (7,01 mmo fl) and trimethylchlorosilane 0.83 iff (6,54 mmoj)
was added dropwise and stirred at the same temperature for 16 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

The residue was subjected to column chromatography using 30 g of silica gel and toluene-acetone (20:1), (10:1), (5
:1) and (3:1) to obtain 620 mg (yield 50%) of the title compound.

'H-NMR (C port C1s> δ (ppm): 0
．． 07 (9H, s, -5i (5a), 0.16 (98
, s, -3i (danL) 3).

0, 24 (9H, s, -3i (C11,) 3), 1
．． 78 (3)1. s, 12-Cf13).

2, bO(6)1. s, -N (CHz) 2)
, 3.45 (311,s, -0Cfl)3.6
0(3H,s, -OCH,), 4.58(LH,d
, J=8. OHz, H,”').

5,90 (L)l, d, J=10.0Hz, H
13).

6, 19 (IH, d, J=16. OHz, H, o
).

7, 30 (Itl, d, J=16.0Hz, H
11), 9.73 (E, s, -C) 10) The 3 and 4° positions of the rosin are silylated, and since the hydroxyl group at the 4° position is not silylated, the silyl form is extremely easily isolated from the reactants. This is a useful manufacturing method that allows for separation.

The 3,2'',4'''-)2-0-trimethylsilyltyrosine obtained in Example 3 was (p-methoxy)feracetylated in the same manner as in Example 2, and then treated with dilute hydrochloric acid to form 4''-0-
(p-methoxy)phenylacetyltylosin was obtained.

Its physicochemical properties were consistent with those obtained in Example 2.

〔Effect of the invention〕

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R is an acetyl group, a propionyl group, or Si(R
')_3 group, R' represents a methyl group, an ethyl group or a propyl group]. 2. Reacting tylosin or 2'-0-acyltyrosine represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R'' represents a hydrogen atom, an acetyl group, or a propionyl group] with a boric acid compound There are formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [wherein R is an acetyl group, a propiol group, or Si(R'
)_3 group, R' represents a methyl group, an ethyl group, or a propyl group] A method for producing a tylosin derivative.