JPH08301894A - New efficient production of 16-membered ring macrolide derivative - Google Patents

Abstract

PURPOSE: To efficiently obtain the subject antibiotic effective against gram-positive bacteria by directly methylating the 3"-hydroxyl group of a specific 16-membered ring macrolide derivative having the hydroxyl group at the 3" position as a starting raw material in mild conditions. CONSTITUTION: This new method for efficiently producing a 16-membered ring macrolide derivative comprises protecting the 2'-hydroxyl group of medemycin, a 16-membered ring antibiotic of the formula (R<1> is H, a 2-4C aliphatic acyl; R<2> is a 1-4C aliphatic alkyl), as a starting raw material with an acetyl group, methylating the 3"-tertiary hydroxyl group of the mycarose portion with a methylating agent such as methyl triflate, treating the 3'-quaternary ammonium salt group simultaneously methylated by the reaction with a peroxide, reducing the one oxygen-imparted compound of formula II (X is triflate) with lithium iodide to return into the tertiary amino group, and subsequently converting the 9-protecting group, thus efficiently obtaining the objective derivative of formula III (R<3> is H, a protecting group).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is effective against Gram-positive bacteria.
The present invention relates to a novel and efficient method for producing a 6-membered ring macrolide derivative.

[0002]

2. Description of the Related Art At present, groups in various countries are actively conducting derivative research on 16-membered macrolide antibiotics for the purpose of improving their clinical utility. Certain of these derivatives were synthesized in an attempt to improve in vitro antibacterial activity and / or pharmacokinetics by acylating a specific hydroxyl group. However, the mainstream of recent research on derivatives has been the introduction of substituted amino groups into 16-membered ring lactones (Journal of Antibiotics, 44 (4), 448 (1991)), or deoxylation of specific hydroxyl groups ( Journal of Antibiotics, 45
(1), 144 (1992)) or focused on alkylation.

On the other hand, the present inventors have conducted derivative research based on the idea of the chemical structure of L-cladinose, which is one of the constituent sugars of erythromycin, and found that the 9-position of the lactone ring was sp ³ carbon and the neutral sugar moiety. A 16-membered macrolide derivative in which the hydroxyl group at the 3 "position is methylated (the 4" position may be a free hydroxyl group or an acylated hydroxyl group),
It was clarified that they have excellent antibacterial activity (Japanese Patent Application No. 5-169418). Then, using a natural 16-membered ring macrolide antibiotic in which the hydroxyl group at the 3-position of the lactone ring is free or acylated as a starting material, a neutral sugar moiety is obtained via a methylthiomethyl ether synthetic intermediate at the 3-position. A patent application has been filed for a method for producing a 16-membered ring macrolide derivative in which the tertiary hydroxyl group at the 3 "position is methylated (Japanese Patent Application No. 6-105096, Japanese Patent Application No. 6-126654, Japanese Patent Application No. 6-145125). .

[0004]

The Raney nickel reduction, which is a key reaction for producing the above-mentioned derivative, is a heterogeneous reaction, and therefore its reproducibility is not always satisfactory. At the same time, in the scale-up, it is necessary to use Raney nickel in the reduction reaction in a large excess, and handling must be done with caution.

A method for producing a 16-membered macrolide derivative in which the hydroxyl group at the 3 "-position, which is a neutral sugar moiety, is methylated and the hydroxyl group at the 4" -position is acylated, without going through a heterogeneous reaction Nothing is known so far about. Therefore, an invention of a method for producing the compound with good reproducibility without going through a heterogeneous reaction is expected.

[0006]

[Means for Solving the Problems] Synthetic chemical studies were repeated to solve these problems, and any of the natural 16-membered macrolide antibiotics in which the hydroxyl group at the 3-position of the lactone ring was free or acylated was started. Even if used as a raw material, it is 3 "in 3"
We succeeded in direct methylation of the primary hydroxyl group and established a method for efficiently producing the desired 16-membered macrolide derivative.

The gist of the first aspect of the present invention lies in the following formula (I) as a novel compound.

Embedded image

[Wherein R ¹ is a hydrogen atom or a linear aliphatic acyl group having 2 to 4 carbon atoms, and R ² is a linear or branched aliphatic alkyl group having 1 to 4 carbon atoms] Using the compound represented by or a salt thereof as a starting material, the following formula (II)

[Chemical 4]

[Wherein R ¹ is a hydrogen atom or a linear aliphatic acyl group having 2 to 4 carbon atoms, and R ² is a linear or branched aliphatic alkyl group having 1 to 4 carbon atoms. R ³ is a substituent that modifies (or protects) a hydrogen atom or a hydroxyl group, or a salt thereof, and relates to a novel production method capable of efficiently chemically synthesizing a compound. The compound represented by the general formula (II) according to the present invention is produced by the method shown in the process chart 1 as follows (the compound represented by the general formula (II) is represented by the formula in the process chart 1). (VII) or formula (VIII)
Represented by).

[0010]

Embedded image

[0011]

[Chemical 6]

[0012] Regarding a promising antibacterial agent, a compound in which a methyl group is selectively introduced into a hydroxyl group at the 3 "-position, which is a neutral sugar moiety in a 16-membered macrolide derivative, is a prior application (Japanese Patent Application No. 169418), the present application uses any of the natural 16-membered macrolide antibiotics in which the hydroxyl group at the 3-position of the lactone ring is free or acylated as a starting material, and a special synthetic intermediate (Japanese Patent Application No. 6-194384), a new synthetic method has been described in which a methyl group is directly introduced into a neutral sugar moiety at the 3 "-position of the tertiary hydroxyl group under mild conditions. Will be described with reference to the process chart 1. Here, as an example of the production method, a natural 16-membered macrolide antibiotic in which the hydroxyl group at the 3-position of the lactone ring is propionylated is used as a starting material, but the hydroxyl group at the 3-position is free. It is also possible to directly introduce a methyl group into the tertiary hydroxyl group at the 3 "position efficiently by using the same methodology when using natural leucomycins as a starting material (Examples 4 to 7). .

First, in the general formula (I) (wherein, R ¹ is a hydrogen atom or a linear aliphatic acyl group having 2 to 4 carbon atoms, R ²
Is a linear or branched aliphatic alkyl group having 1 to 4 carbon atoms) of the free hydroxyl groups of the compound other than the 3 "position, that is, the 9th and 2'positions (and the starting material is leuco Mycin Fr
In the case of a group, a substituent is introduced into two (or three) hydroxyl groups at the 3rd position) to give a compound represented by the general formula (IV) (wherein R ² is a straight or branched chain having 1 to 4 carbon atoms). R ⁴ is a linear aliphatic acyl group having 2 to ⁴ carbon atoms or a substituent that modifies (or protects) a hydroxyl group, and R ⁵ is a substituent that modifies (or protects) a hydroxyl group. To obtain a compound represented by

First, the hydroxyl group at the 2'-position, which is the mycaminose portion of the compound represented by the formula (I), is selectively protected by an acetyl group to give a compound of the general formula (III) (wherein R ¹ is a hydrogen atom or A compound represented by a linear aliphatic acyl group having 2 to 4 carbon atoms and R ² is a linear or branched aliphatic alkyl group having 1 to 4 carbon atoms) is obtained. Next, the free hydroxyl group at the 9-position of the lactone ring (and at the 3-position when the starting material is the leucomycin Fr group) of the compound represented by the formula (III) is modified (or protected) with an appropriate substituent to give a compound of the formula ( The compound of formula IV) is obtained.

When R ¹ is a hydrogen atom in formula (II), the protecting group R ⁴ in formulas (IV), (V), (VI), and (VII) is an acetal-based substituent, for example, A 1-ethoxyethyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group and the like are convenient. Further, as the substituent R ⁵ , a lower aliphatic acyl group (Fermentation and Industry, 37 (12), 1171 (1
979)) may of course be a substituent which can be used for usual modification of a hydroxyl group, such as a methoxymethyl group and an ethoxyethyl group. Further, when the substituent R ⁵ is planned to be treated as a protective group for the hydroxyl group of the 16-membered macrolide derivative, an acetal-based substituent such as 1-ethoxyethyl group, tetrahydrofuranyl group or tetrahydropyranyl group is convenient. .

Among the compounds represented by the formula (IV), the compound in which R ⁵ is an acetyl group can be prepared from the compound represented by the formula (I) in one step. As an example,
Medemycin (in formula (I), R ¹ is a propionyl group and R ² is an ethyl group) is reacted with acetic anhydride in dry pyridine to give compound (1) (in formula (IV), R ² is A compound having an ethyl group, R ⁴ is a propionyl group, and R ⁵ is an acetyl group) was quantitatively obtained.

The types of substituents that can be used in the step and the reaction conditions for introducing the substituents are not limited to those described here, and general substituents used as protective groups for hydroxyl groups can be used. (Theodora W. Greene;
Peter GM Wuts. Protective Groups in Organic Syn
thesis , 2nd ed., Wiley: New York, 1991), and also regarding substituents that are difficult to use as a protecting group, they include all of their types and reaction conditions for introducing them.

An acetal-based protecting group having an asymmetric carbon atom,
For example, if a 1-ethoxyethyl group or the like is introduced into the hydroxyl group at the 9-position of the lactone ring (and the 3-position in the case of leucomycin Fr group), two types of derivatives (leucomycin Fr group while the substituent is introduced) are introduced. Exists as a mixture of four diastereoisomers. However, these isomers may or may not be separated. Also, when the substituent is regarded as a modifying group for the 9-position hydroxyl group of the lactone ring, these isomers may or may not be separated.

Secondly, the introduction of a methyl group into the tertiary hydroxyl group at the 3 "position of the mycarose moiety of the compound represented by the formula (IV) will be described. In the methylation of the present invention, dimethylamino at the 3'position is described. Since the group was also methylated at the same time to form a quaternary ammonium salt, it was also a problem to find a protecting group for this amino group, but this problem was solved by the method described below. The compound with an organic peroxide is used to donate one oxygen atom to protect the amino group. Then, a methyl group is introduced into the tertiary hydroxyl group at the 3 "position of the mycarose moiety to give a compound of the general formula (V) R ² has 1 carbon
~ 4 is a linear or branched aliphatic alkyl group, R ⁴ is a linear aliphatic acyl group having 2 to ⁴ carbon atoms or a substituent for modifying (or protecting) a hydroxyl group, and R ⁵ is A compound represented by a substituent that modifies (or protects) a hydroxyl group is obtained.

First, the oxygen atom donating reaction () with an organic peroxide will be described. One oxygen atom is endowed to the 3'-position dimethylamino group of mycaminose by this reaction, but since this compound is extremely unstable, it is used in the next reaction without isolation here. As the peroxide for carrying out the oxygen atom-donating reaction, other organic peroxides such as m-chloroperbenzoic acid, perbenzoic acid and peracetic acid, hydrogen peroxide may be used, and preferably m-chloroperbenzoic acid. It is an acid. As the reaction solvent, chloroform, methylene chloride,
Ether, t-butanol and the like may be used, and the reaction is completed in a short time at a temperature of -10 ° C to room temperature or higher.

Next, the direct alkylation of the hydroxyl group in the macrolide compound will be briefly described. The method for directly introducing an alkyl side chain into the free tertiary hydroxyl group at the 3 "position in the 16-membered ring macrolide of the leucomycin Fr group is described in the special synthetic intermediate described in the prior application (Japanese Patent Application No. 6-194384). It is achieved by way of
In the 14-membered macrolide compounds, the sites adjacent to the ester bond in the lactone ring are mainly C-methyl group (2-position) and C-
In contrast to the ethyl group (13th position), a 16-membered ring, such as leucomycins, has hydrogen atoms (2
Position) and a C-methyl group (15th position). Therefore, the ester bond in the 14-membered ring lactone under basic conditions is compared with the ester bond in the 16-membered ring lactone of leucomycin mainly because of their steric hindrance and electronic factors at the 2-position. And is superior and stable. As an example,
This is methylation of the secondary hydroxyl group of the neutral sugar moiety in the 14-membered ring macrolide compound, and it progresses easily by protecting other hydroxyl groups (Journal of Antibiotics, 43 (5), 566 ( 1990)). These alkylations are basically a modified method of the Williamson reaction using the classical and well-known strong bases.

However, in the 16-membered ring macrolide compound, in addition to the ester bond in the lactone ring described above, an acyl group at the 3-position of the lactone ring (or a free hydroxyl group) and an acyl group at the 4 "-position of the neutral sugar moiety Since there are many free aldehyde groups and unstable functional groups under isotonic base conditions, the usual Williamson reaction does not occur via the special synthetic intermediate of the previous application (Japanese Patent Application No. 6-194384). In consideration of these, the present inventors investigated the possibility of direct methylation under mild reaction conditions without going through a special synthetic intermediate. As a result, they found a method for efficiently introducing a methyl group.

By the way, in the methylation of the tertiary hydroxyl group at the 3 "-position in this step, the dimethylamino group moiety at the 3'-position to which an oxygen atom is endowed is also methylated at the same time as the formula (V).
To produce a methoxyammonium salt. Incidentally, X
^- for example, it is obvious that may exchange with other anions roots by known means such represents a case triflate anion with methyl triflate as a methylating agent using an anion exchange resin.

The base used in the methylation reaction is preferably a sterically bulky base with nucleophilicity suppressed as much as possible.
Other than di-tert-butylpyridine, 2,6-lutidine, collidine, 2,6-di-tert-butyl-4-methylpyridine, etc. may be used,
The reagent for introducing the methyl group may be methyl perfluoroalkanesulfonate having 1 to 4 carbon atoms such as methyl triflate, methyl iodide, trimethyloxonium tetrafluoroborate, or the like. The reaction solvent may be methylene chloride, chloroform or the like, and the reaction proceeds easily at 0 ° C to 100 ° C, preferably 20 ° C.
~ 30 ° C.

For example, compound (1) (in formula (IV)
R²Is represented by an ethyl group, R^FourIs represented by a propionyl group,
R^FiveIs a compound represented by an acetyl group)
Benzoic acid was used to donate one atom of oxygen. Then, chloride
In methylene, in the presence of 2,6-di-tert-butylpyridine,
It reacts with chill triflate and the tertiary hydroxyl group at the 3 "position and
Simultaneously with the 3'-position dimethylamino group moiety to which an oxygen atom is endowed
Compound (2) (in formula (V), R²But
Is an ethyl group, R^FourIs a propionyl group, R ^FiveIs
A compound which is a chill group) was obtained.

Thirdly, a simple method for converting the methoxyammonium group at the 3'-site of mycaminose into a reductive dimethylamino group will be described. In this derivative, the known amine oxide reduction method (Theodora W. Greene; Peter GM Wuts. Pr.
otective Groups in Organic Synthesis, 2nd ed., Wil
ey: New York, 1991), conversion to a dimethylamino group was extremely difficult. So A.Liguor
i et al. (A. Liguori et al., Chem. Ber., 121 , 105 (198
8)) is developed and applied to efficiently and reductively remove a methoxy group, and general formula (VI) (in the formula, R ² is a linear or branched aliphatic group having 1 to 4 carbon atoms). An alkyl group, R ⁴
To a compound represented by a linear aliphatic acyl group having 2 to 4 carbon atoms or a substituent for modifying (or protecting) a hydroxyl group, and R ⁵ is a substituent for modifying (or protecting) a hydroxyl group) Succeeded in converting. In the reaction, sodium iodide, potassium iodide or the like may be used in addition to lithium iodide. The reaction solvent may be dioxane, tetrahydrofuran, ether or the like, and the reaction proceeds easily at 0 ° C to 100 ° C, but is preferably 30 ° C to 80 ° C.

For example, the methoxy group is reductively deprotected by reacting the compound (2) with lithium iodide in dioxane, and the compound (3) (in the formula (VI), R ² is an ethyl group, R ^A compound in which ⁴ is a propionyl group and R ⁵ is an acetyl group) was obtained.

Fourthly, the substituent introduced into the hydroxyl group of the compound is selected under conditions suitable for the substituent (Theodora W. Gree.
ne; Peter GM Wuts. Protective Groups in Organic
Synthesis , 2nd ed., Wiley: New York, 1991) followed by sequential deprotection, and general formula (VII) (in the formula, R ² has 1 carbon atom).
~ 4 is a linear or branched aliphatic alkyl group, R ⁴ is a linear aliphatic acyl group having 2 to ⁴ carbon atoms or a substituent for modifying (or protecting) a hydroxyl group, and R ⁵ is A compound represented by a substituent that modifies (or protects) a hydroxyl group is obtained, and further, a compound represented by the general formula (VIII) (wherein R ² is a linear or branched aliphatic alkyl having 1 to 4 carbon atoms) a group, R ⁶ is an aliphatic acyl group of a straight-chain C2-4 hydrogen or C, R ⁷
Is a substituent that modifies (or protects) a hydrogen atom or a hydroxyl group). First, the acetyl group bonded to the 2'-position hydroxyl group of the compound represented by formula (VI) is deprotected to quantitatively obtain the compound represented by formula (VII). Next, in the case where a substituent is introduced as a protecting group on the 3- and / or 9-position hydroxyl groups, the substituents may be further deprotected to obtain the compound represented by formula (VIII).

For example, by reacting compound (3) in methanol, compound (4) (in formula (VII), R
^A compound in which ² is an ethyl group, R ⁴ is a propionyl group, and R ⁵ is an acetyl group).

In Process Diagram 1, as an example thereof, in the case of synthesizing a compound represented by the formula (VIII) from a compound represented by the formula (VI), a formula in which the acetyl group at the 2'-position is first deprotected The compound of formula (VIII) is derived via the compound of formula (VII). On the other hand, 3rd and 9th
After deprotecting the substituent at position 2, the acetyl group at position 2'can be deprotected to produce the compound represented by the formula (VIII) (Examples 6 to 7).

Finally, in the general formula (II) (wherein, R ¹ is a hydrogen atom or a linear aliphatic acyl group having 2 to 4 carbon atoms, R ²
Is a linear or branched aliphatic alkyl group having 1 to 4 carbon atoms, and R ³ is a substituent that modifies (or protects) a hydrogen atom or a hydroxyl group) For example, a known method of selectively acylating a hydroxyl group at the 9-position or 2'-position in the presence of a dilute acid (Fermentation and Industry, 37 (12), 1171
(1979)) or a known method of allylic rearrangement of the 9-position hydroxyl group to the 11-position or 13-position in the presence of a dilute acid (Chemical and Pharmaceutical Bretan, 18 (8), 1501 (19).
70), Annual Report of Meiji Seika, 12 , 85 (1972), Journal ・
Of Antibiotics, 35 (11), 1521 (1982)) or a known method of selectively oxidizing the 9-position hydroxyl group (Journal of Antibiotics, 24 (8), 526 (1971))
It is possible to produce a new useful substance based on the present invention by carrying out the above. Next, the present invention will be described in detail by reference examples and examples.

[0032]

【Example】

Reference Example 1 Compound (1) (in the formula (IV), R ² is represented by an ethyl group.
R ⁴ is a propionyl group and R ⁵ is an acetyl group.
Compounds) (Journal of Antibiotics
Scan, 24 (7), 452 (1971)) of the manufacturing method Medemaishin 10.0 g in dry pyridine 100 ml was added and dissolved, and stirred for 24 hours at room temperature was added acetic 4.6 ml anhydrous.
500 ml of saturated aqueous sodium hydrogen carbonate solution was gradually added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. This is methylene chloride 500
The mixture was extracted twice with ml, the organic layer was washed twice with 500 ml of saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, dried and then recrystallized (recrystallization solvent system: hexane-acetonitrile-isopropyl ether) to obtain 9.3 g of compound (1).

Example 1 Compound (2) (in the formula (V), R ² is represented by an ethyl group.
R ⁴ is a propionyl group and R ⁵ is an acetyl group.
And a compound in which X ^- is represented by a triflate anion)
In 20 g of methylene chloride was added to 2.0 g of the compound (1) to be prepared, and 579 mg of m-chloroperbenzoic acid was added, followed by stirring at room temperature for 30 minutes. The reaction mixture was diluted with 40 ml of chloroform, and the organic layer was washed with 20 ml of 5% sodium thiosulfite aqueous solution, 20 ml of saturated sodium hydrogen carbonate aqueous solution, and 20 ml of water, and then dried over anhydrous sodium sulfate. This was filtered, and the filtrate was concentrated under reduced pressure and dried to obtain a crude compound. This crude compound was extremely unstable and was used immediately in the next reaction. Add 10 ml of methylene chloride to the crude compound and dissolve it.4A molecular sieves 2.0 g, 2,6-di-tert-butylpyridine 501 μ
l, and methyl trifluoromethanesulfonate 757
After adding μl and stirring at room temperature for 14 hours, the mixture was heated under reflux for another hour to complete the reaction. The molecular sieves were removed by filtration, and the reaction solution was added with 40 ml of chloroform.
Diluted with. The organic layer was saturated aqueous sodium hydrogen carbonate 2
After washing with 0 ml and 20 ml of water, it was dried over anhydrous sodium sulfate. This was filtered, the filtrate was concentrated under reduced pressure and dried, and the residue was washed with 100 ml of hexane three times to obtain 2,6-di-tert-
At the same time as removing butylpyridine, crystallization was carried out to obtain 1.5 g of compound (2) as colorless needle crystals. Physicochemical properties of compound (2) (1) Color and shape: colorless needle crystal (2) Molecular formula: C ₄₈ H ₇₆ F ₃ NO ₂₁ S (3) Mass spectrum (SIMS): m / z 942 (M)
⁺ (C ₄₇ H ₇₆ NO ₁₈ ) (4) Specific rotation: [α] _D ²² -40 ° (c0.3, CHCl ₃ ) (5) Melting point: 115-119 ° C (6) ¹ H NMR spectrum (400MHz , CDCl ₃ ) δ
(ppm): 2.24 (br d, 2-H), 2.68 (dd, 2-H), 5.12 (br
d, 3-H), 3.19 (br d, 4-H), 3.37 (s, 4-OCH ₃ ), 3.96 (br
d, 5-H), 0.95 (br ddd, 7-H), 5.04 (dd, 9-H), 1.98
(m, 8-H), 2.00 (dd, 9-OCOCH ₃ ), 5.54 (dd, 10-H), 6.70
(dd, 11-H), 6.05 (br dd, 12-H), 5.84 (ddd, 13-H), 2.1
5 (dt, 14-H), 2.44 (br dt, 14-H), 4.94 (ddq, 15-H),
1.24 (d, 16-H ₃ ), 9.62 (br s, 18-H), 0.96 (d, 19-H ₃ ),
2.39 (q, 3-OCOC H ₂ CH ₃ ), 1.19 (t, 3-OCOCH ₂ C H ₃ ), 2.38
(q, 4 "-OCOC H ₂ CH ₃ ), 1.15 (t, 4" -OCOCH ₂ C H ₃ ), 4.95 (d,
1'-H), 5.42 (br s, 2'-H), 4.26 (br t, 3'-H), 4.21 (br
d, 4'-H), 3.59 (dq, 5'-H), 1.35 (d, 6'-H ₃ ), 2.14 (d
d, 2'-OCOCH ₃ ), 3.66 (s, 3'-N ⁺ (OCH ₃ ) ( CH ₃ ) ₂ ), 3.81 (s,
_{^{3'-N + (OCH 3)}} (CH 3) 2), 4.02 (s, 3'-N + (O CH 3) (CH 3) 2),
5.12 (d, 1 "-H), 1.65 (dd, 2" -H), 2.30 (d, 2 "-H), 1.07
(s, 3 "-CH ₃ ), 4.66 (d, 4" -H), 4.10 (dq, 5 "-H), 1.02
(d, 6 "-H ₃ ), 3.18 (s, 3" -OCH ₃ ) (7) ¹⁹ F NMR spectrum (235MHz, CDCl ₃ ) δ
(ppm): -78.8 (S) (8) ¹³ C NMR spectrum (100MHz, CDCl ₃ ) δ
(ppm): 200.7, 174.0, 173.7, 170.2, 169.6, 169.
4, 138.3, 134.1, 131.5, 125.4 (part of quartet), 12
2.2 (part of quartet), 122.1, 119.0 (part of quarte
t), 115.8 (part of quartet), 102.7, 98.3, 84.6, 80.
7, 79.0, 77.6, 77.2, 76.4, 75.9, 72.8, 70.2, 69.3,
69.0, 68.3, 63.6, 61.9, 56.3, 52.1, 51.1, 49.6, 4
2.1, 40.8, 37.3, 36.2, 31.2, 30.6, 28.5, 27.5 (2 ca
rbons), 21.3, 20.9, 20.7, 20.4, 18.6, 17.4, 15.1,
9.3, 8.8

Example 2 Compound (3) (in the formula (VI), R ² is represented by an ethyl group.
R ⁴ is a propionyl group and R ⁵ is an acetyl group.
Compounds) of Preparation compound (2) to 162 mg 1,4-dioxane 2.3 ml of lysis, lithium iodide 36.9 mg anhydrous addition, 3 at 80 ° C.
Heat for 0 minutes. The insoluble material was collected by filtration, and the filtrate was concentrated under reduced pressure. Dissolve the residue in 2 ml of chloroform and add 5% to the organic layer.
The extract was washed with 2 ml of an aqueous solution of sodium thiosulfite and 2 ml of saturated saline and then dried over anhydrous sodium sulfate. This was filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (10 g: chloroform-methanol-aqueous ammonia (800: 10: 1)) to obtain 101 mg of the compound (3). Obtained. Physicochemical properties of compound (3) (1) Color and shape: colorless glassy substance (2) Molecular formula: C ₄₆ H ₇₃ NO ₁₇ (3) Mass spectrum (SIMS): m / z 912 (M + H) ⁺ ( 4) Specific rotation: [α] _D ²¹ -83 ° (c0.12, CHC
l ₃ ) (5) Melting point: 118 to 119 ° C. (6) ¹ H NMR spectrum (400 MHz, CDCl ₃ ) δ
(ppm): 2.18 (br d, 2-H), 2.63 (dd, 2-H), 5.03 (br
d, 3-H), 1.14 (t, 3-OCOCH ₂ C H ₃ ), 3.42 (s, 4-OCH ₃ ), 3.
84 (br d, 5-H), 0.80 (br ddd, 7-H), 1.39 (br dt, 7-
H), 4.99 (dd, 9-H), 1.93 (s, 9-OCOCH ₃ ), 5.49 (dd, 10-
H), 6.65 (dd, 11-H), 5.98 (br dd, 12-H), 5.81 (ddd, 1
3-H), 2.09 (dt, 14-H), 4.89 (ddq, 15-H), 1.19 (d, 16-
H ₃ ), 2.73 (brdd, 17-H), 9.57 (br s, 18-H), 0.90 (d, 1
9-H ₃ ), 1.10 (t, 4 "-OCOCH ₂ C H ₃ ), 4.53 (d, 1'-H), 4.84
(dd, 2'-H), 1.93 (s, 2'-OCOCH ₃ ), 3.42 (t, 4'-H), 3.2
1 (dq, 5'-H ₃ ), 1.08 (d, 6'-H ₃ ), 2.35 (s, 3'-N (CH ₃ ) ₂ ),
4.74 (d, 1 "-H), 1.54 (dd, 2" -H), 2.21 (d, 2 "-H), 1.0
2 (s, 3 "-CH ₃ ), 3.19 (s, 3" -OCH ₃ ), 4.62 (d, 4 "-H), 4.4
7 (dq, 5 "-H), 0.98 (d, 6" -H ₃ )

Example 3 Compound (4) (in the formula (II), R ¹ is a propionyl group
, R ² is an ethyl group, and R ³ is an acetyl group.
The compound) (Japanese Patent Application No. 5-169418) of Preparation Compound (3) 62 mg was dissolved in methanol 1.0 ml,
The reaction was carried out at 40 ° C for 2 days. The reaction mixture was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (10 g:
Chloroform-methanol-ammonia water (800: 10: 1))
The compound (4) (51 mg) was obtained after purification. The various spectral data were in perfect agreement with those described in the literature.

Example 4Compound (5) (in formula (V), R ² represents a propyl group.
R ⁴ is represented by a 1-ethoxyethyl group, and R ⁵ is 1-ethoxy group.
Represented by a cyethyl group and X ⁻ represents a triflate anion.
Compound) 3,9-O-di (1-ethoxyethyl) -2'-O-acetylleucomy
Shin-A_Five(Japanese Patent Application No. 6-105096) 150 mg chloroform 4.5
ml to dissolve, add 44 mg of m-chloroperbenzoic acid, and
Stir for 15 minutes at warm temperature. Add 10 ml of chloroform to the reaction mixture.
Dilute the organic layer with 5% sodium thiosulfate aqueous solution 10 m
l, saturated aqueous sodium hydrogen carbonate solution 20 ml, and saturated food
After washing with 20 ml of brine, drying over anhydrous magnesium sulfate
did. This is filtered, the filtrate is concentrated under reduced pressure, dried and then roughened.
170 mg of the compound was obtained. This crude compound was extremely unstable.
It was immediately used for the next reaction. 150 mg of crude compound was added to
Add 1.5 ml of ethylene to dissolve and use 4A molecular sieves.
150 mg, 2,6-di-tert-butylpyridine 106 μl, and
Add 266 μl of chilled trifluoromethanesulfonate.
And stirred at room temperature for 17 hours. Molecular sieves
The organic layer was removed by filtration, and the organic layer was saturated with aqueous sodium hydrogen carbonate.
After washing with 15 ml of solution and 15 ml of saturated saline,
It was dried over sodium sulfate. Filter this and depressurize the filtrate
After concentrating and drying, the residue is purified by silica gel column chromatography.
Fee (15 g; chloroform-methanol-ammoni
A) Water (100: 10: 1)) to obtain 67 mg of compound (5)
Was. Physicochemical properties of compound (5) (1) Color and shape: colorless solid (2) molecular formula: C₅₂H₈₈F₃NO_{twenty one}S (3) Mass spectrum (SIMS): m / z 1002 (M)⁺
(C₅₁H₈₈NO₁₈) (4) Specific rotation: [α]_D ^{twenty one} -69 ° (c1.0, CH₃OH) (5) Melting point: No clear melting point at 110-115 ° C
Melting (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 3.37 (s, 4-OCH ₃), 3.47 (s, 4-OCH₃), 9.76 (b
r s, 18-H), 9.77 (br s, 18-H), 9.78 (br s, 18-H), 2.
16 (s, 2'-OCOCH₃), 3.65 (br s, 3'-N⁺(OCH₃) (CH ₃ )₂),
3.67 (br s, 3'-N⁺(OCH₃) (CH ₃ )₂), 3.83 (br s, 3'-N⁺(OC
H₃) (CH ₃ )₂), 3.85 (br s, 3'-N⁺(OCH₃) (CH ₃ )₂), 4.03 (s,
 3'-N⁺(OCH ₃ ) (CH₃)₂), 3.17 (br s, 3 "-OCH₃), 3.18 (s,
3 "-OCH₃)

Example 5Compound (6) (in formula (VI), R ² represents a propyl group.
R ⁴ is represented by a 1-ethoxyethyl group, and R ⁵ is 1-ethoxy group.
Method for producing compound represented by ciethyl group) To 50 mg of compound (5), add 500 μl of 1,4-dioxane and dissolve.
Then, add 13.3 mg of anhydrous lithium iodide, and add 60 at 80 ° C.
Heated for minutes. The reaction solution is returned to room temperature and then the insoluble matter is filtered off.
The filtrate was concentrated under reduced pressure. The residue is added to 5 ml of chloroform.
Dissolve the organic layer in a 5% aqueous solution of sodium thiosulfate 5 m
l, washed with saturated saline 5 ml, and then dried over anhydrous sodium sulfate
Dried in. This was filtered and the filtrate was concentrated under reduced pressure to obtain
TLC for preparative separation (developing system; hexane-ethyl acetate (1:
2)) refine | purified and the compound (6) 10 mg was obtained. Physicochemical properties of compound (6) (1) Color and shape: Colorless solid (2) Molecular formula: C₅₀H₈₅NO₁₇ (3) Mass spectrum (EIMS): m / z 971 (M)⁺ (4) Specific rotation: [α]_D ¹⁸ -85 ° (c1.0, CHCl₃) (5) Melting point: Melting at 67-70 ℃ without showing clear melting point.
Melt (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 3.86 (m, 3-H), 2.90 (br d, 4-H), 3.38 (s, 4-
OCH₃), 3.45 (s, 4-OCH₃), 4.16 (br d, 5-H), 4.19 (br
d, 5-H), 3.91 (br dd, 9-H), 4.01 (br dd, 9-H), 6.18
(br dd, 11-H), 6.19 (br dd, 11-H), 6.03 (br dd, 12-
H), 6.04 (br dd, 12-H), 5.17 (m, 15-H), 9.77 (br s, 1
8-H), 9.89 (br s, 18-H), 1.00 (br d, 19-H₃), 4.85 (q,
 3-OCH(OCH₂CH ₃) CH₃), 4.90 (q, 3-OCH(OCH₂CH₃) CH₃),
4.94 (br dd, 2'-H), 3.17 (br t, 4'-H), 3.18 (br t, 4'-
H), 2.03 (s, 2'-OCOCH₃), 2.39 (s, 3'-N (CH₃)₂), 4.81
(br d, 1 "-H), 4.82 (br d, 1" -H), 2.26 (br d, 2 "-He
q), 1.08 (s, 3 "-CH₃), 4.69 (d, 4 "-H), 5.54 (dq, 5"-
H), 5.55 (dq, 5 "-H), 1.05 (br d, 6" -H₃), 3.24 (s, 3 "-
OCH₃), 3.25 (s, 3 "-OCH₃), 1.69 (tq, 4 "-OCOCH₂CH ₂ CH₃),
 0.96 (tq, 4 "-OCOCH₂CH₂CH ₃ )

Example 6 Compound (7) (in formula (VI), R ² represents a propyl group.
And R ⁴ is represented by a hydrogen atom and R ⁵ is represented by a hydrogen atom.
Compound (45) (45 mg) was dissolved in a mixed solution of 5% acetic acid aqueous solution (3.3 ml) and acetonitrile (1.1 ml), and the mixture was reacted at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in chloroform (10 ml), and the mixture was washed successively with saturated aqueous sodium hydrogencarbonate solution (10 ml) three times and saturated brine (10 ml). The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue 26 mg.
Preparative TLC (Development system: chloroform-methanol (10:
1)) refine | purified and the compound (7) 1.0 mg was obtained. Physicochemical properties of compound (7) (1) Color and shape: Colorless solid (2) Molecular formula: C ₄₂ H ₆₉ NO ₁₅ (3) Mass spectrum (EIMS): m / z 827 (M) ⁺ (4) Specific rotation Degree: [α] _D ²³ -96 ° (c1.0, CHCl ₃ ) (5) Melting point: Melting at 105 to 108 ° C without showing a clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.00 (br d, 2-H), 2.67 (br dd, 2-H), 3.78
(br d, 3-H), 2.99 (br d, 4-H), 3.47 (s, 4-OCH ₃ ), 4.08
(br d, 5-H), 0.87 (ddd, 7-H), 1.47 (dt, 7-H), 1.88
(m, 8-H), 4.09 (dd, 9-H), 5.67 (dd, 10-H), 6.26 (dd, 1
1-H), 6.00 (br dd, 12-H), 5.60 (ddd, 13-H), 2.10 (dt,
14-H), 2.51 (br dt, 14-H), 5.28 (ddq, 15-H), 1.31
(d, 16-H ₃ ), 2.31 (br dd, 17-H), 2.87 (br dd, 17-H),
9.78 (s, 18-H), 0.99 (d, 19-H ₃ ), 4.66 (d, 1'-H), 4.93
(dd, 2'-H), 2.63 (t, 3'-H), 3.18 (t, 4'-H), 3.27 (dq,
5'-H), 1.18 (d, 6'-H ₃ ), 2.20 (s, 2'-OCOCH ₃ ), 2.43 (s,
3'-N (CH ₃ ) ₂ ), 4.82 (d, 1 "-H), 1.60 (dd, 2" -Hax), 2.27
(d, 2 "-Heq), 1.08 (s, 3" -CH ₃ ), 4.69 (d, 4 "-H), 4.54
(dq, 5 "-H), 1.05 (d, 6" -H ₃ ), 3.25 (s, 3 "-OCH ₃ ), 2.39
(m, 4 "-OCOC H ₂ CH ₂ CH ₃ ), 1.68 (tq, 4" -OCOCH ₂ C H ₂ CH ₃ ),
0.96 (t, 4 "-OCOCH ₂ CH ₂ C H ₃ ),

Example 7 Compound (8) (in formula (II), R ¹ represents a hydrogen atom)
R ² is represented by a propyl group and R ³ is represented by a hydrogen atom.
Method for producing compound (Japanese Patent Application No. 6-105096) 1.1 mg of compound (7) was dissolved in 1.2 ml of methanol and reacted at 40 ^° C. for 1 day. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by preparative TLC (developing system; chloroform-methanol-ammonia water (800: 10: 1)) to obtain 1.0 mg of compound (8). The various spectral data were in perfect agreement with those described in the literature.

[0040]

The effect of the present invention lies in that the compound represented by the general formula (II) is used as a starting material for a known naturally occurring 16-membered macrolide antibiotic represented by the general formula (I). Another object of the present invention is to provide a novel production method in which a methyl group is directly introduced into a tertiary hydroxyl group existing in a compound having poor chemical stability under mild reaction conditions.
For example, the present inventors have previously used midecamycin as a starting material, via a methylthiomethyl ether synthetic intermediate of the present invention at the 3 "position, and a compound (4 ), The total yield was 20%. However, according to the novel production method of the present invention, the total yield is 3 using medemycin as a starting material.
It became possible to synthesize the compound (4) at 3%.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Takayuki Usui 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Confectionery Co., Ltd.

Claims (1)

[Claims] 1. The following formula (I): [Wherein R ¹ is a hydrogen atom or a linear aliphatic acyl group having 2 to 4 carbon atoms, and R ² is a linear or branched aliphatic alkyl group having 1 to 4 carbon atoms] Or a salt thereof as a starting material, the compound represented by the following formula (II): [In the formula, R ¹ is a hydrogen atom or a linear aliphatic acyl group having 2 to 4 carbon atoms, R ² is a linear or branched aliphatic alkyl group having 1 to 4 carbon atoms, and R ² is ³ is a substituent that modifies (or protects) a hydrogen atom or a hydroxyl group, or a new efficient production method for obtaining a salt thereof.