JPS6154037B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula (In the formula, R ₁ is a hydrogen atom or an alkanoyl group having 2 to 3 carbon atoms, R ₃ is an alkanoyl group having 2 to 5 carbon atoms, and R ₄ is an alkanoyl group having 2 to 6 carbon atoms.) The present invention relates to a new method for producing compounds that can be used. The above compound [5] was discovered by the present inventor, and is a compound of known 16-membered ring macrolide antibiotics, such as leucomycins, diyosamicin, antibiotic YL-704 class, antibiotic SF- It has stronger antibacterial activity against susceptible bacteria than the 837 class espinomycins, and is effective against bacteria resistant to other macrolide antibiotics, such as oleandomycin, erythromycin, carbomycin, and spiramycin. Moreover, it is difficult to undergo deacylation at the 4″ position, which is one of the causes of inactivation of 16-membered ring macrolide antibiotics, and the persistence of blood concentration increases significantly.Furthermore, the general properties of macrolide antibiotics The strong, persistent bitter taste is alleviated, making it useful as a syrup for children who cannot take tablets or capsules, and it is an antibiotic that is clinically expected to be extremely effective in treating infections.The above compound [5] In particular, in order to produce the compound [5] in which R ₁ is a hydrogen atom, leucomycins in which R ₁ is a hydrogen atom, that is, leucomycin
A ₁ , leucomycin A ₅ , leucomycin A ₇ , leucomycin A ₉ or its 2′-acyl derivative (Tokukosho
9-chlorinated acetyl compound (JP-A-Sho No. 53-7434)
No. 50-96584) is reacted with an aliphatic carboxylic acid anhydride, such as acetic anhydride, in the presence of an inorganic base such as an alkali carbonate, and the ring is closed via the carbon atom at the 18th position and the oxygen atom at the 3rd position to form a hydroxyl group at the 3rd position. At the same time, the hydroxyl group at the 2′ position is acylated if no acyl group has been introduced, and then 3″-acylated with an aliphatic carboxylic acid halide under heating in the presence of a tertiary organic amine in an inert organic solvent. , and then treated with ammonia-containing methanol to remove the protecting groups at the 9-, 3-, and 18-positions, followed by heat treatment in methanol to remove the 2'-position acyl group (especially 148793)) It is necessary to protect the hydroxyl groups at the 9- and 3-positions with separate protecting groups, and it is not necessary to introduce a protecting group for the hydroxyl group at the 3-position due to ring closure with the 18-position. However, there was a drawback that it was not possible to obtain the target compound [5] in a good yield because it was not carried out efficiently. As a result of various studies, we found that when a silyl group is used, the 3- and 9-position hydroxyl groups can be quantitatively protected in one step, and it is stable in water and will not be eliminated, and that it can be used in an aqueous acid solution or with a hydrous lower alkanol under heating. I learned that it can be efficiently eliminated.The use of silyl groups as protective groups for hydroxyl groups has been reported many times, but from the common knowledge of chemistry that they are easily hydrolyzed and eliminated with water, the above findings do not work. This is an extremely unexpected fact, and the present invention was completed based on this knowledge. (In the formula, R ₁ is a hydrogen atom or R ₁₁ group, R ₁₁ is an alkanoyl group having 2 to 3 carbon atoms, and R ₄ is a C 2 to 6 alkanoyl group.
6 alkanoyl groups, R ₆ represents a hydrogen atom or a lower alkanoyl group) is silylated with a silylating agent to form a compound with the formula (In the formula, R ₁₂ is a hydrogen atom, R ₁₁ group or R ₅ group, and R ₅ is a silyl group. R ₁₁ , R ₄ and R ₆ mean the same groups as above). The compound [2] is heated in an inert organic solvent and has a carbon number of 2 to 5.
Acylated with aliphatic carboxylic acid halide,
formula (In the formula, R ₃ is an alkanoyl group having 2 to 5 carbon atoms.
R ₁₃ is an R ₁₁ group or an R ₅ group, R ₈ is an alkanoyl group having 2 to 5 carbon atoms, and R ₁₁ , R ₄ and R ₅ are the same groups as above) and the formula (In the formula, R ₁₃ , R ₃ , R ₄ , R ₅ and R ₈ mean the same groups as above). (B) a step of removing the silyl group and the 18- and 2'-position acyl groups by heat treatment in aqueous lower alkanol; (B) removing the silyl group and the 18-position by treating in aqueous lower alkanol in the presence of a base without heating; (C) a step of removing the acyl group at the 2'-position by heat treatment in methanol which may contain water; (C) a step of removing the acyl group at the 18-position by treatment in methanol containing ammonia After removing the group, heat treatment is performed in a water-containing lower alcohol to remove the silyl group and the 2'-position acyl group, or (D) treatment is performed in ammonia-containing methanol to remove the 18-position acyl group. After that, the silyl group and the 18- and 2'-position acyl groups are removed by heat treatment in methanol to remove the 2'-position acyl group and acid aqueous solution to remove the silyl group. This is a method for producing the target compound [5], which is characterized by eliminating the target compound [5], which is obtained in a better yield than the method of the earlier application, JP-A-54-148793. The purpose of this invention is to provide a new manufacturing method. The starting material [1] in the present invention includes known 16-membered ring macrolide antibiotics, such as the leucomycin group, diyosamycin, and the antibiotic YL-704.
group, the antibiotic SF-837 group, the espinomycin group or their 2'-acyl derivatives. this
2'-acyl derivatives can be produced by the method disclosed in Japanese Patent Publication No. 7434/1983. Examples of the silylating agent for silylating the starting material [1] include tri-substituted halogenosilanes and hexa-substituted disilazane. Examples of tri-substituted halogenosilanes include tri-lower alkylhalogenosilanes, and for example, trimethylchlorosilane is preferred. Examples of the hexa-substituted disilazane include hexa-lower alkylsilazane, and for example, hexamethyldisilazane is preferred. In addition to the above, any silylating agent may be used as long as it can introduce a silyl group that is not eliminated by water. The above silylation is usually carried out in an inert organic solvent such as methylene chloride, chloroform, dichloroethane, methyl isobutyl ketone at room temperature or below. The proportion of the silylating agent used varies depending on whether R ₁ of the starting material [1] is a hydrogen atom or an R ₁₁ group (an alkanoyl group having 2 to 3 carbon atoms). Approximately 2 to 5 when R ₁ is a hydrogen atom
If R ₁ is an R ₁₁ group, it may be used in an amount of about 1 to 1.8 times in mole. In the above silylation, when a trisubstituted halogenosilane is used as the silylating agent, it is preferable to use a suitable tertiary organic amine as the dehydrohalogenating agent. For example, pyridine compounds such as pyridine, quinoline compounds such as quinoline, N-methylmorpholine, dimethylaniline,
Examples include diethylaniline and tribenzylamine. As a result of the above silylation, when R ₁ is a hydrogen atom, the hydroxyl groups at the 3- and 9-positions are silylated,
When R ₁ is an R ₁₁ group, only the hydroxyl group at the 9-position is silylated. The product [2] obtained by the above silylation is
It is obtained by pouring the reaction solution into water and extracting with a suitable non-hydrophilic organic solvent. This extract is washed with a dilute aqueous acid solution and a dilute aqueous alkali solution as necessary, concentrated, and used for the next reaction. The silyl group of this compound [2] is stable even in the presence of water and is not eliminated. Next, compound [2] was added to an aliphatic carboxylic acid halide having 2 to 5 carbon atoms under heating in an inert organic solvent.
Perform 3″-acylation. Inert organic solvents include tetrahydrofuran,
Examples include dioxane, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, butyl acetate, benzene, toluene, chloroform, dichloroethane, and particularly preferred are dioxane, methyl ethyl ketone, methyl isobutyl ketone, and dichloroethane. Examples of aliphatic carboxylic acid halides include acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride, valeryl chloride, isovaleryl chloride, and the like. The above 3''-acylation reaction is preferably carried out in the presence of a known tertiary organic amine.
Examples of such tertiary organic amines include dimethylaniline, tribenzylamine, pyridine,
Picoline, collidine, N-methylpiperidine, N
-Methylmorpholine, quinoline, isoquinoline, etc., and tribenzylamine is particularly preferred. The heating temperature for the above reaction is usually in the range of 50 to 120°C. The reaction time mainly depends on the type of acylating agent and the reaction temperature, but since the progress of the reaction can be tracked using thin layer chromatography such as silica gel, the end point of the reaction can be determined by waiting for the disappearance of compound [2]. Bye. As a result of the above reaction, when the 2'-position is a hydroxyl group, not only the 3'-position hydroxyl group but also this hydroxyl group is acylated to produce compound [3] and compound [4]. These products Pour the reaction solution into water,
By adjusting the pH of the aqueous system to 8 to 10 and extracting with a suitable non-hydrophilic organic solvent, compound [3]
and compound [4] in the form of a mixture. These can be used in the next reaction without any particular purification. The above mixture,

From [Formula] - Conversion of CH ₂ CHO, elimination of the silyl group at the 3-position and/or 9-position, and elimination of the acyl group at the 2'-position are:
This can be done by the following various methods. [A] Method of heat treatment in aqueous lower alkanol, [B] Non-heat treatment in aqueous lower alkanol in the presence of a base to remove the silyl group and the acyl group at position 18, followed by treatment in methanol which may contain water. [C] After treatment with ammonia-containing methanol to eliminate the acyl group at the 18-position, heat treatment is performed in a water-containing lower alkanol to remove the silyl group and the 2'-position acyl group. A method of eliminating the acyl group at position ′ or [D] A step of removing the acyl group at position 18 by treatment with ammonia-containing methanol, and then heating in methanol to eliminate the acyl group at position 2′ and a step of removing the silyl group by treatment with an acid aqueous solution is carried out beforehand. The lower alkanol in each of the above methods is preferably methanol or ethanol. Method [A]
Examples of the base in [B] include alkali carbonate, triethylamine, and basic resins. Heating in each of the above methods is carried out under reflux of a commonly used organic solvent. Method [B]
Reactions that are not specified as non-heating or heating usually mean that they are carried out at room temperature or lower. Since the above-mentioned elimination reaction can be tracked by thin layer chromatography using silica gel or the like, the end point of the reaction can be appropriately determined. In order to collect the target compound [5] thus obtained from the reaction solution, known methods for separating and purifying macrolide antibiotics, such as concentration, extraction, washing, dissolution, recrystallization, etc. , chromatography using an adsorbent such as silica gel, activated alumina, or adsorption resin. Next, the present invention will be specifically explained with reference to Examples. Unless otherwise specified, Rf values in the examples were measured by thin layer chromatography (TLC) using the following carrier and developing solvent. Support: Merck Silica Gel 60 (Art.5721) Developing solvent: A: n-hexane-benzene-acetone-ethyl acetate-methanol (90:80:25:60:30) B: benzene-acetone (3:1) Example 1 3″-O-acetylleucomycin A ₅ 65 g of 2′-O-acetylleucomycin A ₅ is dissolved in 300 ml of dry dichloromethane, 44 ml of dry pyridine and 39 ml of trimethylchlorosilane are added thereto, and the mixture is stirred at room temperature for 1 hour. Pour the reaction solution into water 2 and extract with 500ml of chloroform.
Washed in the order of 0.1N hydrochloric acid, water, and 3% ammonia water, dried over anhydrous magnesium sulfate, and dried under reduced pressure to obtain 2'-O-acetyl-3,9-di-O-(trimethylsilyl)leucomycin A ₅ 69 g of crude product was obtained. The above crude product was dissolved in 200 ml of dry methyl ethyl ketone, 227 g of tribenzylamine was added thereto, and then 51 ml of acetyl chloride was added under ice cooling, and the mixture was heated and stirred at 70° C. for 15 hours. Add the reaction solution to 2 parts water.
After pouring it inside and adjusting the pH to 9.5 with ammonia water,
Extract with chloroform 1. Wash the extract with water,
After drying with anhydrous magnesium sulfate, concentrate under reduced pressure.
2′,3″-di-O-acetyl-3,9-di-O-
(Trimethylsilyl)leucomycin A ₅ , 17, 18
-Enol-18,2′,3″-tri-O-acetyl-
A product containing 3,9-di-O-(trimethylsilyl)-leucomycin A ₅ and a large amount of tribenzylamine is obtained. Add 250 ml of ammonia-saturated methanol to this under ice-cooling, and stir at room temperature for 1.5 hours. Pour the reaction solution into 2 parts of water, and add 1 part of chloroform.
Extract with The extract is washed with water, dried over anhydrous magnesium sulfate, and then dried under reduced pressure. The residue is dissolved in 600 ml of cold methanol and the undissolved tribenzylamine is separated and recovered. After heating the liquid under reflux for 20 hours,
Dry under reduced pressure to give 3″-O-acetyl-3,9-di-O
- Obtain 69 g of crude product of (trimethylsilyl)leucomycin A ₅ . This was mixed with acetic acid-tetrahydrofuran-water (3:
1:1) Dissolve in 250ml and stir at room temperature for 1 hour. Add 1 chloroform to the reaction solution and wash with 3% aqueous ammonia. The chloroform layer was dried over anhydrous magnesium sulfate and then dried under reduced pressure to obtain 64 g of a crude product of 3''-O-acetylleucomycin _A5 .
Dissolve this in as little benzene as possible and charge it to a silica gel column. Elute with benzene-acetone (10:1-8:1-6:1). Each fraction is tracked by silica gel thin layer chromatography, and fractions around Rf _A 0.45 are collected and dried under reduced pressure to obtain 45.5 g of purified product (yield 70.0%). TLC: Rf _A = 0.45, Rf _B = 0.10 Mass (m/e); 813 (M ⁺ ), 754 (M ⁺ −59), 726
(M ⁺ -87) Titer: 2850γ/mg (converted to standard leucomycin) Example 2 Dissolve 65 g of 3″-O-propionyl leucomycin A ₅ 2′-O-acetyl leucomycin A ₅ in 300 ml of dry dichloromethane, and dissolve this Add 44 ml of dry pyridine and 39 ml of trimethylchlorosilane to the solution and stir at room temperature for 1 hour. Pour the reaction solution into 2 ml of water and extract with 500 ml of chloroform.
Washed in the order of 0.1N hydrochloric acid, water and 3% ammonia water, dried over anhydrous magnesium sulfate, and dried under reduced pressure to obtain 2'-O-acetyl-3,9-di-O-(trimethylsilyl)leucomycin A ₅ 70g of crude product was obtained. Dissolve the above crude product in 250ml of dry dioxane,
Add 230 g of tribenzylamine to this, add 65 ml of propionyl chloride under ice cooling, and stir at 90°C for 24 hours. The reaction solution was poured into 2 parts of water, adjusted to pH 9.5 with aqueous ammonia, and then extracted with 1 part of chloroform. The extract was dried over anhydrous magnesium sulfate and dried under reduced pressure to give 2'-O-acetyl-3''-O-propionyl-3,9-di-O-(trimethylsilyl)leucomycin A ₅ and a small amount of 2'- A product containing O-acetyl-17,18-enol-18,3''-di-O-propionyl-3,9-di-O-(trimethylsilyl)leucomycin A ₅ and a large amount of tribenzylamine is obtained. Add 250 ml of ammonia-saturated methanol to this under ice-cooling, and stir at room temperature for 1.5 hours. The reaction solution was poured into 2 parts of water and extracted with 1 part of chloroform. The extract is washed with water, dried over anhydrous magnesium sulfate, and then dried under reduced pressure. The residue is dissolved in cold methanol and the undissolved tribenzylamine is separated and recovered. After heating the liquid under reflux for 20 hours, it was dried under reduced pressure to give 3″-O-propionyl-3,9-di-
A crude product of O-(trimethylsilyl)leucomycin _A5 is obtained. This was mixed with acetic acid-tetrahydrofuran-water (3:
1:1) Dissolve in 250ml and stir at room temperature for 1 hour. Add 1 chloroform to the reaction solution and wash with 3% aqueous ammonia. The chloroform layer was dried over anhydrous magnesium sulfate and dried under reduced pressure to obtain 60 g of crude 3″-O-propionylleucomycin _A5 . Dissolve this in as little benzene as possible,
Charge the silica gel column. benzene-
Elute with acetone (15:1-10:1-8:1-6:1). Each fraction was tracked by silica gel thin layer chromatography, and fractions around R _A =0.57 were collected and dried under reduced pressure to obtain 48.2 g of purified product (yield 73.0%). TLC: Rf _A = 0.57, Rf _B = 0.14 Mass (m/e); 827 (M ⁺ ), 754 (M ⁺ −73), 740
(M ⁺ -87) Titer: 2850γ/mg (converted to standard leucomycin) Example 3 3″-O-acetylleucomycin A ₄ (3,
3″-di-O-acetylleucomycin A ₅ ) Dissolve 30 g of 2′-O-acetyl leucomycin A ₅ in 150 ml of dry dichloromethane, and add 6 ml of dry pyridine and trimethylchlorosilane under ice-cooling.
Add 5.69 ml and stir at room temperature for 1 hour. reaction solution
Washed in the order of 0.1N hydrochloric acid, water, and 3% ammonia water, dried over anhydrous magnesium sulfate, and dried under reduced pressure to obtain 30.2 g of crude product of 2'-O-acetyl-9-O-trimethylsilylleucomycin A ₅ . get. Dissolve the above crude product in 150ml of dry dioxane,
Tribenzylamine 113g, acetyl chloride
Add 26 ml and stir at 80°C for 40 hours. Pour the reaction solution into water 1 and adjust the pH with aqueous ammonia.
After adjusting to 9.5, extract with 500 ml of chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ammonia-saturated methanol to the residue
Add 150 ml and stir at room temperature for 2 hours. Pour the reaction solution into 1.5 ml of water and extract with 500 ml of chloroform. The chloroform layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Pour the residue into 200ml of cold methanol.
and separate the insoluble tribenzylamine. After heating the liquid under reflux for 20 hours, it was dried under reduced pressure.
A crude product of 3″-di-O-acetyl-9-O-trimethylsilylleucomycin A ₅ is obtained. This is mixed with acetic acid-tetrahydrofuran-water (3:1:1) 125
ml and stir at room temperature for 2 hours. Add 500 ml of chloroform to the reaction solution and wash with 3% aqueous ammonia. The chloroform layer was dried over anhydrous magnesium sulfate and then dried under reduced pressure to obtain 29.8 g of crude 3,3''-di-O-acetylleucomycin _A5 . This was dissolved in as little benzene as possible and applied to a silica gel column. Charge. Elute with benzene-acetone (10:1 to 8:1 to 6:1). Follow each fraction by silica gel thin layer chromatography, collect fractions around Rf _A = 0.58, and dry under reduced pressure. to obtain 21.2 g (yield 67.2%) of purified product. TLC: Rf _A = 0.58, Rf _B = 0.15 Mass (m/e): 855 (M ⁺ ), 796 (M ⁺ -59), 768
(M ⁺ −87)

Claims (1)

[Claims] 1 formula (In the formula, R ₁ is a hydrogen atom or R ₁₁ group, R ₁₁ is an alkanoyl group having 2 to 3 carbon atoms, and R ₄ is a C 2 to 6 alkanoyl group.
6 alkanoyl groups, R ₆ represents a hydrogen atom or a lower alkanoyl group) is silylated with a silylating agent to form the formula (In the formula, R ₁₂ is a hydrogen atom, R ₁₁ group or R ₅ group, and R ₅ is a silyl group. R ₁₁ , R ₄ and R ₆ mean the same groups as above). The compound [2] is heated in an inert organic solvent and has a carbon number of 2 to 5.
Acylated with aliphatic carboxylic acid halide,
formula (In the formula, R ₃ is an alkanoyl group having 2 to 5 carbon atoms.
R ₁₃ is an R ₁₁ group or an R ₅ group, R ₈ is an alkanoyl group having 2 to 5 carbon atoms, and R ₁₁ , R ₄ and R ₅ are the same groups as above) and the formula (In the formula, R ₁₃ , R ₃ , R ₄ , R ₅ and R ₈ mean the same groups as above) is obtained. Silyl group and 18 by heat treatment in lower alkanol
(B) treatment in the presence of a base in a hydrous lower alkanol without heating to remove the silyl group and the acyl group at the 18th position, and remove the acyl group at the 18th position. The acyl group at position 2' is removed by heat treatment in methanol, or (C) the acyl group at position 18 is removed by treatment in methanol containing ammonia, followed by heat treatment in aqueous lower alcohol. or (D) treatment in ammonia-containing methanol to eliminate the 18-position acyl group, followed by heat treatment in methanol.
A formula characterized by elimination of the acyl group at the 2' position and treatment with an acid aqueous solution to eliminate the silyl group. A method for producing a compound represented by the formula (wherein R ₁ , R ₃ and R ₄ mean the same groups as above). 2. The manufacturing method according to claim 1, which is a compound [] in which R ₁ is a hydrogen atom. 3. The method according to claim 2, wherein R ₄ is an acetyl, propionyl, butyryl or isovaleryl group. 4. The production method according to claim 2, wherein R ₆ is a lower alkanoyl group. 5. The production method according to claim 4, wherein the lower alkanoyl group is an acetyl group. 6 Claim 1 in which the silylating agent is a tri-substituted halogenosilane or a hexa-substituted disilazane
Manufacturing method described in section. 7. The manufacturing method according to claim 6, wherein the tri-substituted halogenosilane is a tri-lower alkyl halogenosilane. 8. The manufacturing method according to claim 7, wherein the tri-lower alkylhalogenosilane is trimethylchlorosilane. 9 When silylating only the hydroxyl group at the 9-position of compound [1] with tri-substituted halogenosilane, approximately
8. The production method according to claim 7, wherein 1.0 to 1.8 times the mole is used, and when silylating the hydroxyl groups at the 3- and 9-positions, the amount is about 2 to 5 times the mole. 10. The production method according to claim 6, wherein the hexa-substituted disilazane is hexa-lower alkyldisilazane. 11. The production method according to claim 10, wherein the hexa-lower alkyldisilazane is hexamethyldisilazane. 12. The method according to claim 1, wherein the silylation is carried out in an inert organic solvent. 13. The production method according to claim 12, which is carried out in the presence of a tertiary organic amine when the silylating agent is a trisubstituted halogenosilane. 14. The method according to claim 1, wherein the aliphatic carboxylic acid halide is acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride, valeryl chloride or isovaleryl chloride. 15. The production method according to claim 1, wherein the acylation is carried out at a temperature in the range of 50 to 120°C. 16. The production method according to claim 1, wherein the acylation is carried out in the presence of a tertiary organic amine. 17. The method according to claim 16, wherein the tertiary organic amine is dimethylaniline, diethylaniline, tribenzylamine, pyridine, picoline, collidine, quinoline, isoquinoline, N-methylpiperidine or N-methylmorpholine. 18. The method according to claim 1, wherein the inert organic solvent is dioxane, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, butyl acetate, benzene, dichloroethane or toluene. 19. The production method according to claim 1, wherein the silyl group and the acyl groups at the 18th and 2' positions are removed by heat treatment in a hydrous lower alkanol. 20. The production method according to claim 19, wherein the lower alkanol is methanol or ethanol. 21. The production method according to claim 19, wherein the hydrous lower alkanol may contain a base. 22. The production method according to claim 21, wherein the base is a tertiary organic amine, a basic resin, or an alkali carbonate. 23. The production method according to claim 19, wherein the heat treatment is carried out under reflux of lower alkanol. 24 A patent in which the silyl group and the acyl groups at the 18- and 2'-positions are eliminated by a step of treatment in a water-containing lower alkanol in the presence of a base without heating and a step of heat treatment in methanol which may contain water. The manufacturing method according to claim 1. 25. The production method according to claim 24, wherein the lower alkanol is methanol or ethanol. 26. The manufacturing method according to claim 24, wherein non-heating means room temperature or lower temperature. 27. The production method according to claim 26, wherein the base is a tertiary organic amine, a basic resin, or an alkali carbonate. 28. The production method according to claim 24, wherein the heat treatment is performed under reflux of methanol. 29. The process according to claim 1, wherein the elimination of the silyl group and the acyl groups at the 18- and 2'-positions is carried out in the order of the steps of treatment in methanol containing ammonia and heat treatment in aqueous lower alkanol. 30. The production method according to claim 29, wherein the lower alkanol is methanol or ethanol. 31. The manufacturing method according to claim 30, wherein the heat treatment is performed under reflux of lower alkanol. 32 The silyl group and the 18-position and 2'-position acyl groups are removed by a step of treatment in methanol containing ammonia, a step of heat treatment in methanol, and a step of treatment with an acid aqueous solution, as described in claim 1. manufacturing method. 33. The manufacturing method according to claim 32, wherein the heat treatment is performed under reflux of methanol. 34. The production method according to claim 32, wherein the acid aqueous solution is hydrous acetic acid which may contain a hydrophilic organic solvent. 35. The production method according to claim 1, which is a compound [5] in which R ₁ is a hydrogen atom. 36 Claim 3 in which R ₃ is an acetyl, propionyl, butyryl or isovaleryl group
The manufacturing method described in Section 5. 37. The method according to claim 36, wherein R ₄ is a propionyl, butyryl or isovaleryl group. 38. The production method according to claim 1, which is a compound [5] in which R ₁ is an alkanoyl group having 2 to 3 carbon atoms. 39. The production method according to claim 38, wherein the alkanoyl group is an acetyl group. 40 Claim 3 in which R ₃ is an acetyl, propionyl, butyryl or isovaleryl group
The manufacturing method described in Section 9. 41 Claim 4 in which R ₄ is an acetyl, propionyl, butyryl or isovaleryl group
The manufacturing method described in item 0.