JP2847693B2 - Removal method of carboxyl group protecting group - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel method for removing a carboxyl-protecting group.

[0002]

2. Description of the Related Art A β-lactam compound having a carboxyl group in the molecule is a compound useful as an antibacterial agent having an excellent antibacterial action or an intermediate thereof. Examples of such antibacterial agents include penem antibacterial agents (Japanese Patent Publication No. 3-396).
JP-A-55-105686, JP-A-60-589
No. 87), a carbapenem antibacterial agent (JP-A-60-202)
886, JP-A-61-5081, JP-A-60-23
3077, JP-A-55-69586, EP-A-474243), oxapenem-based antibacterial agents (JP-A-5-1982)
8-103358), a cephem antibacterial agent (Japanese Unexamined Patent Publication No. Sho 62)
-277389) and carbacephem antibacterial agents (U.S. Pat. No. 4,174,316).

[0003] In the synthesis of these β-lactam antibacterial agents, the reaction is often advanced using an intermediate in which the carboxyl group is protected, and the carboxyl group protecting group used for such a purpose is allyl group. And substituted or unsubstituted allyl groups such as, 3-methylallyl group and 3-phenylallyl group.

A method for removing a substituted or unsubstituted allyl group is, for example, treatment with tetrakis (triphenylphosphine) palladium (0) in a mixed solvent of ethyl acetate and methylene chloride in the presence of potassium 2-ethylhexanoate. Method [Journal of Organic Chem.
mistry), 1982, vol. 47, 587-5
90] in an ethyl acetate-methylene chloride mixed solvent.
A method of treating with palladium diacetate and triethyl phosphite in the presence of sodium ethylhexanoate [Journal of Medicinal Chem.
Istry), 1990, Vol. 33, Nos. 77-86
Page] etc. are known.

[0005] However, when the above-mentioned substituted or unsubstituted allyl group is removed from a compound having an unstable structure such as a β-lactam compound, the target substance is decomposed or incompletely removed by the conventional method. For this reason, the yield is low, the catalyst cycle is poor, and a large amount of catalyst is required.

[0006]

SUMMARY OF THE INVENTION The present invention provides a novel method for removing a carboxyl-protecting group. More specifically, even when the compound having a carboxyl group protected by a substituted or unsubstituted allyl group is, for example, a compound having an unstable structure such as a β-lactam compound, without decomposing the target compound, It is an object of the present invention to provide a novel method for removing a carboxyl-protecting group, which can efficiently remove the protecting group.

[0007]

According to the present invention, the removal of a protecting group from a β-lactam compound having a carboxyl group protected by a substituted or unsubstituted allyl group can be carried out by using an allyl group scavenger in a water-containing organic solvent. In the presence of a palladium catalyst. As the organic solvent in the water-containing organic solvent used in this reaction, any organic solvent which is inert to the reaction and is mixed with water can be used, and a polar organic solvent is particularly preferable. As the polar solvent, for example, lower alkanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide,
Acetonitrile, acetone, hexamethylphosphoric triamide (HMPA) and the like can be mentioned, and among them, ethanol, tetrahydrofuran and dioxane are preferable.

The water content in these water-containing organic solvents is as follows:
It is preferably between 5% and 50%, especially between 10% and 20%.

As the palladium catalyst, any zero-valent palladium complex can be used. For example, tetrakis (triphenylphosphine) palladium (0), di [1,2-bis (diphenylphosphino) ethane] Palladium (0), bis (dibenzylideneacetone) palladium (0) and the like can be mentioned, and tetrakis (triphenylphosphine) palladium (0) is particularly preferable.

Further, a zero-valent palladium complex is formed from a divalent palladium compound and a phosphine in a reaction system,
This reaction can also be used. Examples of the divalent palladium compound include palladium di-lower alkanates such as palladium diacetate and palladium dihalides such as palladium dichloride. Examples of the phosphines include tri-lower alkyl such as trimethyl phosphite and triethyl phosphite. Examples thereof include phosphite and triphenylphosphine, and a combination of palladium di-lower alkanate and tri-lower alkyl phosphite is particularly preferable.

As an allyl group scavenger, JP-A-64-7
Any known allyl group scavenger described in No. 9180 and the like can be used, and examples thereof include alicyclic β-dicarbonyl compounds such as dimedone and 1,3-cyclohexadione; and fats such as acetylacetone and ethyl acetoacetate. Aromatic β-dicarbonyl compounds; aromatic amines such as N-lower alkylanilines and anilines; alkanoic acids having 2 to 9 carbon atoms such as acetic acid, propionic acid and 2-ethylhexanoic acid and alkali metal salts thereof; dimethylamine and diethylamine And the like, and particularly preferred are alicyclic β-dicarbonyl compounds, aliphatic β-dicarbonyl compounds and aromatic amines. The allyl group trapping agent can be used not only for unsubstituted allyl groups but also for substituted allyl groups.

In the reaction of the present invention, more preferably, a mixed solvent of ethanol and water, a mixed solvent of tetrahydrofuran and water, or a mixed solvent of dioxane and water is used as the water-containing organic solvent, and tetrakis (triethyl) is used as the palladium catalyst. (Phenylphosphine) palladium (0) or a zero-valent palladium complex generated in a reaction system from palladium diacetate and triethyl phosphite, and dimedone as an allyl group scavenger.

The reaction of the present invention is carried out under cooling to heating, for example,
It can be suitably carried out at 30C to 100C, especially at 20C to 40C.

This reaction is preferably carried out in the presence of an inorganic or organic base. Examples of such a base include alkali metals such as alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal hydroxide and alkali metal hydride. Examples include metal compounds and organic amines. These bases are usually used in an amount of 0.1 to 10 equivalents, preferably 1 to 4 equivalents, based on the starting compound. In addition, the amount of the base used is generally preferably such that the β-lactam ring is not cleaved, that is, an amount capable of maintaining the reaction system at pH 5 to 9, particularly pH 6 to 8.

In the present invention, the substituted or unsubstituted allyl group includes, for example, a compound represented by the formula: —CH ₂ —CH ＝ CHR
⁰ (wherein R ⁰ represents a hydrogen atom, a lower alkyl group or an aryl group), and more specifically, for example, allyl group, 3-methylallyl group, 3-phenylallyl group And the like.

As the β-lactam compound having a carboxyl group protected by a substituted or unsubstituted allyl group, any conventionally known β-lactam compound can be used.

[0017]

Embedded image

(Wherein R represents a substituted or unsubstituted allyl group), and a compound having a partial structure represented by the general formula [I]

[0019]

Embedded image

(Wherein R represents a substituted or unsubstituted allyl group, R ¹ and R ² each independently represent an organic group,
The _{formula: -CH 2 CH 2 -, -} S-CH 2 -, - O-CH
_{2 -, - CH 2 -,} - CH (R 3) -, - S- or -
Represents a group represented by O-, R ³ is a lower alkyl group, Y represents a sulfur atom, an oxygen atom or a single bond. )). Further preferred β-lactam compounds having a carboxyl group protected by a substituted or unsubstituted allyl group are those represented by the general formula [II]

[0021]

Embedded image

Wherein R is a substituted or unsubstituted allyl group, R ⁴ is a hydrogen atom or a hydroxyl-protecting group, and R ⁵ is a hydrogen atom or a lower alkyl group.

The β-lactam compound as described above is a compound useful as, for example, an antibacterial agent, a prodrug thereof, or a synthetic intermediate thereof.

In the general formula [I], as the organic group represented by R ¹ , any of the groups used in known β-lactam antibacterial agents can be used. Examples of such a group include, for example, a hydrogen atom, an amino group, an azido group, a mercapto group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an aryl group (for example, a phenyl group, a naphthyl group, etc.), a heterocyclic group (For example, pyrrolidinyl group, piperidyl group, furyl group, thienyl group, imidazolinyl group, pyridyl group, etc.) substituted carbonyl group, heterocyclic group (for example, pyrrolidinyl group, piperidyl group, furyl group,
Lower alkanoyl groups such as thienyl group, imidazolinyl group and pyridyl group). Further, these groups may have one or more substituents. Examples of such a substituent include an amino group, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a lower alkanoylamino group, Lower alkoxy lower alkanoyl group, mercapto group, lower alkylthio group, aralkyl group, aralkyloxycarbonyl group, heterocyclic group (eg, tetrahydropyranyl group, etc.), heterocyclic group (eg, thienyl group, etc.), substituted lower alkanoyl group And the like.

The organic group represented by R ² includes R ¹
Similarly to the above, any of the groups used in known β-lactam antibacterial agents can be used. Examples of such a group include, for example, a lower alkyl group, a cycloalkyl group, an aryl group (eg, a phenyl group), a heterocyclic group containing at least one nitrogen, oxygen or sulfur atom as a hetero atom (eg, Pyrrolidinyl, piperidyl, furyl, thienyl, imidazolinyl, pyridyl, etc.)
And the like. Further, these groups may have one or more substituents, such as a hydroxyl group, a lower alkyl group, an amino lower alkyl group,
Lower alkoxy group, amino group, lower alkylamino group,
Mercapto group, lower alkylthio group, amidino group, guanidino group, carbamoyl group, thiocarbamoyl group, sulfamoyl group, carbamoyloxy group, cyano group, carboxyl group, lower alkoxycarbonyl group, lower alkanoyloxy group, aralkyloxycarbonyl group, oxo group , A thioxo group, a halogeno group, a cycloalkyl group, an aryl group (for example, a phenyl group), a heterocyclic group (for example, a pyrrolidinyl group, a piperidyl group, a furyl group, a thienyl group, an imidazolinyl group, a pyridyl group, etc.). Can be

Further, the organic groups represented by R ¹ and R ² may be protected by a protecting group. As a protecting group,
Any of the conventional protecting groups can be suitably used.

As the protecting group for the hydroxyl group represented by R ⁴ ,
For example, a lower alkoxycarbonyl group, a halogeno lower alkoxycarbonyl group, a substituted or unsubstituted phenyl lower alkyl group (for example, a benzyl group optionally substituted with a nitro group or a lower alkoxy group), a tri-lower alkylsilyl group, a tri (substituted Or an unsubstituted phenyl) silyl group, a substituted or unsubstituted phenyl lower alkoxycarbonyl group (for example, a benzyloxycarbonyl group optionally substituted with a nitro group or a lower alkoxy group) and the like.

In the present invention, the lower alkyl group, lower alkoxy group and lower alkanol have 1 to 1 carbon atoms.
6, especially those having 1 to 4 carbon atoms. Examples of the lower alkanoyl group include 2 to 7 carbon atoms, especially 2 carbon atoms.
And cycloalkyl groups having 3 to 8 carbon atoms, especially those having 3 to 6 carbon atoms,
The lower alkanates include those having a lower alkanoyl group moiety of 2 to 7 carbon atoms, especially 2 to 5 carbon atoms.

[0029]

【Example】

Example 1 A mixture of 0.84 g of sodium bicarbonate in 10 ml of water, 0.84 g of dimedone and 80 ml of tetrahydrofuran was subjected to ultrasonic treatment for 5 minutes, and then the mixture was subjected to a nitrogen stream.
Add 0.11 g of palladium diacetate and 0.58 g of triethyl phosphite and stir for 3 minutes. Furthermore, (1R, 5S, 6S) -2-[(4R) -pyrrolidin-2-thion-4-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid allyl ester 3.83 g,
Stir at 35-37 ° C for 45 minutes. Thereafter, the mixture was stirred at 5 ° C. for 30 minutes, the precipitated crystals were collected by filtration, washed with tetrahydrofuran, dried under reduced pressure, and (1R, 5S, 6S)
-2-[(4R) -Pyrrolidin-2-thion-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1
3.28 g of -methylcarbapene-2-em-3-carboxylic acid sodium salt are obtained.

Yield: 90% NMR (D ₂ O) δ: 1.22 (3H, d, J = 7H)
z), 1.31 (3H, d, J = 6 Hz), 2.87-
3.07 (1H, m), 3.20-3.60 (3H,
m), 3.55-3.72 (1H, m), 4.05-
4.35 (4H, m).

Example 2 (1R, 5S, 6S) -2-[(4R) -pyrrolidine-
2-Thion-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-M-
400 mg of allyl 3-carboxylate was dissolved in 16 ml of tetrahydrofuran, and a mixture of 105 mg of potassium hydrogen carbonate in 4 ml of water and dimedone 660 m in the mixture.
g, 42 mg of tetrakis (triphenylphosphine) palladium (0) was added under a nitrogen stream, and the mixture was added at 25 ° C.
And stir in the dark for 30 minutes.

After the reaction, the solvent was distilled off under reduced pressure, and 15 ml of water was removed.
And wash with methylene chloride.

[0033] 40 mg of activated carbon was added to the aqueous layer and Celite 2 was added.
g, and then washed. The washing solution and the previously obtained aqueous layer are combined and washed twice with chloroform. The resulting aqueous solution was concentrated under reduced pressure to remove the dissolved organic solvent, and then lyophilized,
(1R, 5S, 6S) -2-[(4R) -pyrrolidine-
2-Thion-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-M-
328 mg of potassium 3-carboxylate are obtained.

Yield: 82% NMR (D ₂ O) δ: 1.20 (3H, d), 1.29
(3H, d), 2.94 (1H, dd), 3.28-
3.67 (4H, m), 4.06-4.27 (4H,
m).

Example 3 Dimedone (84 mg) was added to a solution of sodium bicarbonate (84 mg) in water (1 ml), and the mixture was sonicated to dissolve. Then, ethanol (8 ml) was added and the mixture was sonicated for 5 minutes.

Under a nitrogen stream, 11 mg of palladium diacetate and 0.06 ml of triethyl phosphite were introduced into the mixture.
And (1R, 5S, 6S) -2-[(4R) -pyrrolidin-2-thion-4-ylthio] -6-[(1R) -1
-Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylic acid allyl ester 383 mg,
Stir at 35-38 ° C for 1 hour. At 20 ° C
After stirring at 0 ° C for 5 minutes at 5 ° C, the precipitated crystals were collected by filtration.
(1R, 5S, 6S) -2-[(4R) -pyrrolidine-
2-Thion-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-methylcarbapen-2-M-
157 mg of sodium 3-carboxylate are obtained. After the mother liquor was concentrated under reduced pressure to remove ethanol, 20 ml of water was added, and the mixture was washed five times with 20 ml of chloroform. The aqueous layer is lyophilized to give a further 168 mg of the above sodium salt.

The NMR data of this product was consistent with that of Example 1.

Example 4 Dimedone (169 mg) was added to a solution of sodium hydrogencarbonate (169 mg) in water (2 ml), and the mixture was dissolved by ultrasonication. Under a nitrogen stream, dioxane (16 ml), palladium diacetate (23 mg) and triethyl phosphite (0.12 ml) were added. In addition, then (1R, 5S, 6S) -2-[(4R)-
Pyrrolidin-2-thione-4-ylthio] -6-[(1
R) -1-t-butyldimethylsilyloxyethyl]-
Add 1.03 g of allyl 1-methylcarbapene-2-m-3-carboxylate and stir at 30 ° C. for 30 minutes. After adding 32 ml of ether to the reaction solution and stirring at 25 ° C. for 15 minutes and 5 ° C. for 30 minutes, the precipitated crystals are collected by filtration, washed with ether, and dried under reduced pressure at 25 ° C. for 17 hours (1R, 5S, 6S). -2-[(4R) -pyrrolidine-
2-thion-4-ylthio] -6-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid sodium salt 88
Obtain 5 mg.

M. p. 133-136 ° C (decomposition).

Examples 5 to 8 By treating the compounds described in Table 1 in the same manner as in Examples 1 to 4, a substituted or unsubstituted allyl group (--CH ₂ CH ＝ C
The corresponding compound with HR ⁰ ) removed is obtained.

[0041]

[Table 1]

Examples 9 to 19 By treating the compounds shown in Tables 2 and 3 in the same manner as in Examples 1 to 4, the corresponding compounds from which allyl groups have been removed are obtained.

[0043]

[Table 2]

[0044]

[Table 3]

Reference Example (1) (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1
-Carboxyethyl] -2-azetidinone (10 g) and acetonitrile (50 ml) were mixed with 4-dimethylaminopyridine (400 mg) and t-butyl mercaptan (5.98).
g, 1,3-dicyclohexylcarbodiimide 8.22
g at -5 ° C. After stirring at room temperature for 17 hours, insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure. Ethyl acetate is added to the residue, washed, dried and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography to give (3S, 4S) -3-[(1
R) -1-t-butyldimethylsilyloxyethyl]-
11.7 g of 4-[(1R) -1-t-butylthiocarbonylethyl] -2-azetidinone are obtained.

(2) Compound 320m obtained in the above (1)
g, 169 mg of bromoacetic acid allyl ester and 1 ml of tetrahydrofuran, 0.94 ml of 1M sodium bis (trimethylsilyl) amide (tetrahydrofuran solution) was added dropwise at -65 ° C to -60 ° C, and the temperature was raised to -30 ° C. The reaction solution is poured into water, the product is extracted with diethyl ether, the organic layer is washed, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (3S, 4S) -3-[(1R) -1
-T-butyldimethylsilyloxyethyl] -4-
[(1R) -1-t-butylthiocarbonylethyl]-
538 mg of 1- (allyloxycarbonylmethyl) -2-azetidinone are obtained.

(3) To a mixture of 1 g of the compound obtained in the above (2) and 6 ml of tetrahydrofuran, 4.24 ml of 1M sodium bis (trimethylsilyl) amide (tetrahydrofuran solution) is added at -40 ° C to -30 ° C. -30
After stirring at 5 ° C. for 5 minutes, 230 mg of trimethylchlorosilane
At −60 ° C. After stirring for 5 minutes, 598 mg of diphenylphosphoryl chloride are added. After stirring for 1 hour at 0 ° C., the reaction is poured into phosphate buffer (pH 7.0) and the product is extracted with ethyl acetate. The obtained organic layer was washed, dried, concentrated under reduced pressure, and the residue was purified by a reverse-phase rover column (RP-8, manufactured by E. Merck) (solvent: acetonitrile: water = 3: 1), whereby: (1R, 5
R, 6S) -6-[(1R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-2-diphenylphosphoryloxy-carbapen-2-em-3-carboxylic acid allyl ester 1.1 g as oil Get as things.

(4) 100 mg of the compound obtained in the above (3)
And a mixture of 0.5 ml of acetonitrile with (4R)-
22 mg of 4-mercaptopyrrolidine-2-thione and 21 mg of diisopropylethylamine are added at 0 ° C. 0
After stirring at room temperature for 1 hour, the reaction solution was added to a phosphate buffer (pH
7.0) and the product is extracted with ethyl acetate.

The obtained organic layer was washed, dried, concentrated under reduced pressure, and then subjected to silica gel column chromatography (solvent: n-
Purification with hexane: chloroform: ethyl acetate = 5: 5: 4) gave (1R, 5S, 6S) -2-.
[(4R) -Pyrrolidin-2-thion-4-ylthio]
57 mg of -6-[(1R) -1-t-butyldimethylsilyloxyethyl] -1-methylcarbapen-2-em-3-carboxylic acid allyl ester are obtained.

(5) 50 mg of the compound obtained in the above (4),
To a mixture of 0.5 ml of tetrahydrofuran and 6.0 mg of acetic acid is added 0.35 ml of a 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran under ice-cooling, and the mixture is stirred at room temperature for 2 hours.

Ethyl acetate is added to the reaction solution, which is washed, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; chloroform: ethanol = 20:
By purifying in (1), (1R, 5S, 6S) -2
-[(4R) -pyrrolidin-2-thion-4-ylthio] -6-[(1R) -1-hydroxyethyl] -1-
13 mg of allyl methyl carbapene-2-m-3-carboxylate are obtained.

M. p. 139-141 ° C

[0054]

According to the present invention, a compound having a carboxyl group protected by a substituted or unsubstituted allyl group is
For example, even in the case of a compound having an unstable structure such as a β-lactam compound, a substituted or unsubstituted allyl group can be efficiently removed under mild conditions, so that a high yield of the target compound can be obtained without decomposing the compound. At a high rate and can be obtained easily. Therefore, the method of the present invention is an industrially advantageous method for removing a substituted or unsubstituted allyl group.

────────────────────────────────────────────────── ⁶ Continuation of the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 513/04 311 C07D 498/04 102A (56) References JP-A-3-130293 (JP, A) JP-A-62-61984 (JP, A) JP-A-2-290256 (JP, A) JP-A-61-286331 (JP, A) JP-A-55-94321 (JP, A) WO 92/2521 (WO, A) (58) ⁶ ) C07D 463/00 C07B 51/00 C07D 477/00 C07D 501/04 C07D 503/00 C07D 513/04 311 CA (STN) REGISTRY (STN)

Claims (13)

(57) [Claims] 1. A method for preparing a β-lactam compound having a carboxyl group protected by a substituted or unsubstituted allyl group in a water-containing organic solvent in the presence of an allyl group scavenger in the presence of divalent palladium
A method for removing a carboxyl group-protecting group, comprising treating a compound with a phosphine to remove a substituted or unsubstituted allyl group. 2. A β-lactam compound having a carboxyl group protected by a substituted or unsubstituted allyl group is represented by the formula: 2. The method according to claim 1, wherein the compound has a partial structure represented by the formula: wherein R represents a substituted or unsubstituted allyl group. 3. A β-lactam compound having a carboxyl group protected by a substituted or unsubstituted allyl group is represented by the general formula [I]: Wherein R is a substituted or unsubstituted allyl group, R ¹ and R ²
Each independently represents an organic group, and X represents a formula: —CH ₂ C
H _2- , -S-CH _2- , -O-CH _2- , -CH ₂ -,-
Represents a group represented by CH (R ³ ) —, —S— or —O—, R ³ represents a lower alkyl group, and Y represents a sulfur atom, an oxygen atom or a single bond. 2. The compound according to claim 1,
The described method. 4. A β-lactam compound having a carboxyl group protected by a substituted or unsubstituted allyl group is represented by the general formula [II]: The method according to claim 1, wherein R is a substituted or unsubstituted allyl group, R ⁴ is a hydrogen atom or a hydroxyl-protecting group, and R ⁵ is a hydrogen atom or a lower alkyl group. 5. The substituted or unsubstituted allyl group has the formula:
CH ₂ -CH = CHR ⁰ (wherein, R ⁰ is a hydrogen atom, a lower alkyl group or an aryl group.) Claim 1 any one process according 4 is a group represented by. 6. The method according to claim 5 , wherein the aqueous organic solvent is a mixed solvent of a polar organic solvent and water. 7. A palladium di-low palladium compound.
Grade alkanates or palladium dihalides, phosphites
Is tri-lower alkyl phosphite or triphenyl
7. The method according to claim 6, which is luphosphine. 8. A palladium compound having a low palladium divalent value.
Lower alkanates and phosphines are tri-lower alkyl phos
The method according to claim 7, which is a fight. 9. The water-containing organic solvent has a water content of 5 to 50%.
9. The method of claim 8, wherein 10. The method according to claim 9 , wherein the allyl group-capturing agent is an alicyclic or aliphatic β-dicarbonyl compound or an aromatic amine. 11. The method according to claim 11, wherein the divalent palladium compound is palladium diamine.
Acetate and phosphines are triethyl phosphite
The method according to claim 9 , wherein the allyl group-capturing agent is dimedone. 12. The method according to claim 11, wherein the water-containing organic solvent is a mixed solvent of ethanol and water, a mixed solvent of tetrahydrofuran and water, or a mixed solvent of dioxane and water. 13. The reaction according to claim 12, wherein the reaction is carried out in the presence of a base.
The described method.