JPH05331174A - 7-acyl-3-substituted carbamoyloxycephem compound and its production - Google Patents

Abstract

PURPOSE:To provide a new compound having a broad antibacterial spectrum, giving powerful antibacterial activity on esp. influenza virus, useful for antibacterial agents to be used in the form of injection or through oral route. CONSTITUTION:The compound of formula I [R<1> is lower alkyl, lower alkoxy- substituted lower alkyl or halogen-substituted lower alkyl; R<2> is (protected) carboxyl], e.g. 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-N- methylcarbamoyloxymethyl-3-cephem-carboxylic acid sodium salt. The compound of the formula I can be obtained by eliminating the protecting group in a compound which is obtained by reaction of a compound of formula II with a compound of formula III [R<3> is (protected) hydroxyl group; R<4> is (protected) amino] in the presence of a condensation agent such as N,N'-dicyclohexylcarbodiimide in a solvent such as THF.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel antibacterial agent 3-substituted carbamoyloxymethyl-3-cephem derivative having excellent action as a medicine and a method for producing the same.

[0002]

2. Description of the Related Art At present, several kinds of semi-synthetic cephalosporins are commercially available and used as therapeutic agents for various infectious diseases. Up to now, the general formula has been disclosed in JP-A-53-34794.

[Chemical 4] (In the formula, Y represents hydrogen or a nucleophilic compound functional group.), And a 7-acylaminocephem derivative is disclosed. In addition, Japanese Patent Publication No. 1-47141 discloses a compound represented by the following general formula.

[Chemical 5] (Here, R ⁶ is an amino group or an acylamino group, R ⁷
Is a carboxyl group or a protected carboxyl group, Amino (lower) alkylamino group, saturated 5 containing 1 to 4 nitrogen atoms optionally substituted by lower alkyl
Or a 6-membered heterocyclic (lower) alkylamino group or a saturated 5- or 6-membered heterocyclic group containing 2 to 4 nitrogen atoms which may be substituted with lower alkyl or hydroxy (lower) alkyl, X is -S- However, none of them have obtained sufficient antibacterial activity, and development of a cephem compound having a stronger antibacterial activity is desired.

[0003]

As described above, antibiotics are effective for the treatment of infectious diseases, but the object of the present invention is to provide a cephem compound having a stronger antibacterial activity, especially a strong activity against Haemophilus influenzae. To provide.

[0004]

Means for Solving the Problems As a result of earnest research aimed at developing a cephalosporin compound having a useful antibacterial activity, the present inventors have found that 2- (2-aminothiazole-2) at the 7-position.
The inventors have found that a novel cephem derivative having a (hydroxyimino) acetic acid group and a mono-substituted carbamoyloxy group at the 3-position exhibits a strong antibacterial activity, and completed the present invention.

That is, the present invention has the general formula (I)

[Chemical 6] (Wherein R ¹ represents a lower alkyl group, a lower alkoxy group-substituted lower alkyl group or a halogen atom-substituted lower alkyl group, and R ² represents a carboxy group or a protected carboxy group) and a pharmaceutically acceptable compound. And a salt thereof, and a method for producing the same.

In the above general formula (I), the lower alkyl group found in the definition of R ¹ is a linear or branched alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl or n-.
Propyl, isopropyl, n-butyl, isobutyl, s
Examples thereof include ec-butyl and tert-butyl, preferably methyl, ethyl and the like.

The lower alkoxy group in the definition of R ¹ includes an alkoxy group derived from the above lower alkyl group, and preferable examples of the lower alkoxy-substituted lower alkyl group include 2-methoxyethyl and 2-ethoxy. Examples thereof include ethyl. Examples of the halogen atom that can be substituted on the alkyl group include fluorine, chlorine, iodine, etc., preferably a fluorine atom, and the number of which may be substituted is 1 to 3.

The protecting group for the carboxyl group of R ² is
Lower alkyl group such as methyl, ethyl, t-butyl; p
-Methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl, phenethyl and the like, a lower alkyl group substituted by a phenyl group which may have a substituent; 2,2,2-trichloro Halogenated lower alkyl groups such as ethyl and 2-iodoethyl; pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 1-pivalo Lower alkanoyloxy lower alkyl groups such as yloxyethyl and 2-pivaloyloxyethyl; higher alkanoyloxy lower alkyl groups such as palmitoyloxyethyl, heptabecanoyloxymethyl, 1-palmitoyloxyethyl; methoxycarbonyloxymethyl, -Lower alkoxycarbonyloxy lower alkyl groups such as butoxycarbonyloxyethyl, 1-t-butoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl; carboxylower such as carboxymethyl and 2-carboxyethyl Alkyl group; Heterocyclic group such as 3-phthalidyl; 4-glycyloxybenzoyloxymethyl, 4- [N- (t-butoxycarbonyl)
A benzoyloxy lower alkyl group which may have a substituent such as glycyloxy] benzoyloxymethyl;
(5-methyl-2-oxo-1,3-dioxolen-4
(Substituted dioxolene) lower alkyl group such as -yl) methyl; cycloalkyl-substituted lower alkanoyloxy lower alkyl group such as 1- (cyclohexylacetyloxy) ethyl, cycloalkyloxycarbonyloxy such as 1- (cyclohexyloxycarbonyloxy) ethyl Examples include lower alkyl groups. In short, any group may be used as long as it is a protective group that can be decomposed into a carboxylic acid by some means.

The pharmaceutically acceptable salt is
For example, alkali metal salts such as sodium salts and potassium salts; ammonium salts; quaternary ammonium salts such as tetraethylammonium salts and betaine salts; alkaline earth metal salts such as calcium salts and magnesium salts; hydrochlorides, hydrobromides, Inorganic acid salts such as hydroiodide, sulfate, carbonate, bicarbonate; organic carboxylates such as acetate, maleate, lactate, tartrate; methanesulfonate, hydroxymethanesulfonate Organic sulfonates such as hydroxyethane sulfonate, taurine salt, benzene sulfonate and toluene sulfonate; amino acid salts such as arginine salt, lysine salt, serine salt, aspartate salt, glutamate salt and glycine salt; trimethylamine Salt, triethylamine salt, pyridine salt, procaine salt,
Picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt,
Examples include amine salts such as tris (hydroxymethylamino) methane salt and phenethylbenzylamine salt.

The compound of the present invention can be produced by the following method. General formula (IV)

[Chemical 7] (In the formula, R ⁵ is hydrogen, a lower alkyl group, a halogen-substituted lower alkyl group, a lower alkoxy group, a halogen-substituted lower alkoxy group, a phenyl lower alkyl group, a thienyl lower alkyl group, a phenyl lower alkoxy group, and R ² is a carboxy group or (Which means a protected carboxy group) or a salt thereof with N, N'-carbonyldiimidazole to give an active derivative.

[Chemical 8] (In the formula, R ¹ represents a lower alkyl group, a lower alkoxy group-substituted lower alkyl group or a halogen atom-substituted lower alkyl group.) Or a salt thereof, and if necessary, sulfoxidation or sulfoxide reduction is carried out. Then, the acyl group or alkoxycarbonyl group of R ⁵ is removed to give the compound of the general formula (II)

[Chemical 9] (Wherein R ¹ and R ² are the same as defined above) or a salt thereof, and a compound of the general formula (III)

[Chemical 10] (In the formula, R ³ represents a hydroxyl group or a protected hydroxyl group, and R ⁴ represents an amino group or a protected amino group.) The compound is reacted in the presence of a condensing agent for acylation.
Examples of the condensing agent include carbodiimide (N, N'-dicyclohexylcarbodiimide, etc.), carboxy compound (carbonyldiimidazole, etc.), isoxazolyu salt, acylamino compound (2-ethoxy-1-ethoxycarbonyl 1,2-dihydroxyquinoline, etc.), etc. It can be used as appropriate.

When a reactive acid derivative of the compound (III) is used, the reactive acid derivative is an acid anhydride,
Examples include acid halides and active ester forms. The acid anhydrides include symmetrical acid anhydrides and mixed acid anhydrides, and the mixed acid anhydrides include mineral acids (phosphoric acid, sulfuric acid, carbonic acid, etc.),
Organic acids (alkanoic acid, aralkanic acid, sulfonic acid, etc.)
A mixed acid anhydride with and may be used. As the active ester form, N-hydroxysuccinimide, N-hydroxyphthalimide and other N-humanroxy compound esters, thiol esters (aralkyl thiol ester,
Heterocyclic thiol ester, etc.) and aryl ester (phenyl ester, halophenyl ester, nitrophenyl ester, etc.) can be appropriately used. The reaction is dichloromethane, chloroform, tetrahydrofuran, acetone, ethyl acetate, methanol,
The reaction can be performed in an inert solvent such as ethanol, dimethyl sulfoxide, N, N-dimethylformamide, benzene, toluene, hexane at a reaction temperature of -50 to + 50 ° C.

Examples of the amino group-protecting group include formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, phenylacetyl group, thienylacetyl group, t-butoxycarbonyl group, benzyloxycarbonyl group, trityl group, Examples thereof include p-methoxybenzyl group, diphenylmethyl group, benzylidene group, p-nitrobenzylidene group, m-nitrobenzylidene group, 3,4-methylenedioxybenzylidene group and m-chlorobenzylidene group. Examples of the protecting group for the hydroxyimino group include a trityl group and a tetrahydropyranyl group.

The reaction product is subjected to deprotection of amino group, hydroxyl group and carboxy group depending on the type of protective group used, and then the compound of the general formula (I)

[Chemical 11] (In the formula, R ¹ and R ² are the same as defined above.) And a pharmaceutically acceptable salt thereof can be obtained. When R ⁴ is a carboxy group or a salt thereof, an alkali metal salt is added, if necessary, and esterified by an alcohol-reactive derivative thereof by a known method to give a compound represented by the formula [I] and a pharmaceutically acceptable salt thereof. The salt can be obtained.

The compounds of the present invention have excellent antibacterial activity and R ²
A compound having a protected carboxy group is particularly useful as an oral antibacterial agent. When the compound of the present invention is used as an antibacterial agent, it is usually 100 mg to 5 g per day
It can be administered orally or parenterally in divided doses. The dose may be adjusted depending on age and symptoms. The preparation includes tablets, granules, powders, capsules, syrups, liquids and the like. These can be produced by a conventional method by adding a known pharmaceutical carrier.

[0015]

In order to show the usefulness of the compound of the present invention, Table 1 shows the results of measurement of the minimum inhibitory concentration (MIC) of various representative compounds of the present invention obtained in the following Examples against various bacteria. ..

[Table 1] As shown in Table 1, the compound of the present invention is a useful compound having an excellent antibacterial activity, particularly a strong antibacterial activity against Haemophilus influenzae.

[0016]

EXAMPLES The present invention will now be described in more detail by way of examples, which should not be construed as limiting the invention thereto. The starting materials for producing the compound of the present invention are listed as Production Examples. In the formula, Tr represents a trityl group BH
Represents a benzhydryl group.

Production Example 1 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2-trityloxyiminoacetamide]
-3-N-Methylcarbamoyloxymethyl-3-cephem-4-carboxylic acid benzhydryl

[Chemical formula 12] Tetrahydrofuran (40 ml) and methanol (40 ml) are added to benzhydryl 7-formamido-3-monomethylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (3.54 g). Then, concentrated hydrochloric acid (3.6 ml) is added at room temperature, and the mixture is stirred at the same temperature for 3 hours. The reaction solution was evaporated under reduced pressure, the resulting residue was diluted with ethyl acetate,
The extract is washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated. Separately add 2 to the obtained residue.
-Trityloxyimino-2- (2-tritylaminothiazol-4-yl) acetic acid (4.9 g), dicyclohexylcarbodiimide (1.52 g) and 1-hydroxybenzotriazole (1.0 g) were added to tetrahydrofuran (30 ml). The solution stirred for 30 minutes is added at room temperature. After stirring overnight at the same temperature, the reaction solution is filtered and the filtrate is diluted with ethyl acetate water. Further, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate,
The solvent is distilled off. The obtained residue was purified by column chromatography (SiO ₂ , benzene: ethyl acetate = 6: 1) to give the title compound (5.39 g, yield 66%).

NMR (CDCl ₃ .δ) 2.75 (3H, d, J = 5 Hz), 3.25, 3.5
2 (2H, ABq, J = 18Hz), 4.40 (1H,
d, J = 5 Hz), 4.77, 5.07 (2H, AB
q, J = 14Hz), 5.05 (1H, d, J = 5H
z), 6.10 (1H, dd, J = 5Hz, 9Hz),
6.43 (1H, s), 6.97 (1H, s), 7.2
1 to 7.39 (40H, m)

Production Example 2 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2-trityloxyiminoacetamide]
-3-N- (2-methoxyethyl) carbamoyloxymethyl-3-cephem-4-carboxylic acid benzhydryl

[Chemical 13] The above compound was obtained in the same manner as in Production Example 1. (Yield 53
%)

NMR (CDCl ₃ .δ) 3.32 to 3.38 (5H, m) 3.42 (2H,
t, J = 5 Hz), 3.25, 3.49 (2H, AB
q, J = 18Hz), 4.78, 5.05 (2H, AB
q, J = 12Hz), 5.08 (1H, d, J = 5H
z), 6.1 (1H, dd, J = 5Hz, 9Hz),
6.42 (1H, s), 6.94 (1H, s), 7.3
~ 7.4 (40H, m)

Production Example 3 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2-trityloxyacetamide] -3-
N- (2-monofluoroethyl) carbamoyloxymethyl-3-cephem-4-carboxylic acid benzhydryl

[Chemical 14] The above compound was obtained in the same manner as in Production Example 1.

NMR (CDCl ₃ .δ) 3.1-3.4 (4H, m), 4.2-4.4 (2H,
m), 4.85 (2H, ABq, J = 14Hz), 4.
92 (1H, d, J = 4.9 Hz), 6.04 (1H,
dd, J = 4.9 Hz, 8.9 Hz), 6.44 (1
H, s), 6.95 (1H, s), 7.1 to 7.5 (4
0H, m)

Production Example 4 7-[(Z) -2- (2-tritylaminothiazole-
4-yl) -2-trityloxyacetamide] -3-
Benzhydryl N- (2,2,2-trifluoroethyl) carbamoyloxymethyl-3-cephem-4-carboxylic acid The above compound was obtained in the same manner as in Production Example 1.

[Chemical 15]

NMR (CDCl ₃ ) 3.21 (2H, ABq, J = 19 Hz), 3.52
~ 3.58 (2H, m), 4.88 (2H, ABq, J
= 14 Hz), 4.91 (1H, d, J = 4.9H)
z), 6.03 (1H, dd, J = 4.9 Hz, 8.8)
Hz), 6.45 (1H, s), 6.95 (1H,
s), 7.13 to 7.47 (40H, m)

Example 1 7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-N
-Methylcarbamoyloxymethyl-3-cephem-carboxylic acid sodium salt

[Chemical 16] A solution of the compound (5.35 g) obtained in Production Example 1 in anisole (25 ml) was added to trifluoroacetic acid (20 m) under ice cooling.
1) is added and then stirred at the same temperature for 1 hour. Isopropyl ether is added to the reaction solution and the precipitate is collected by filtration. Formic acid (35 ml) is added to the obtained powdery solid, and the mixture is stirred at room temperature for 1 hr. The reaction solution is evaporated under reduced pressure, and the residue is diluted with methanol. Sodium acetate (1.0 g) is added to this solution, and methanol is distilled off. The residue obtained is diluted with ethyl acetate and triturated with isopropyl ether. When purified by liquid chromatography, the title compound (326m
g, yield 14%) was obtained.

NMR (D ₂ O.δ) 2.54 (3H, s), 3.21, 3.51 (2H, A)
Bq, J = 18 Hz) 4.60, 4.70 (2H, AB
q, J = 18 Hz), 5.06 (1H, d, J = 4.8)
Hz), 5.69 (1H, d, J = 4.8Hz), 6.
83 (1H, s)

Example 2 7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-N
-(2-Methoxyethyl) carbamoyloxymethyl-
3-Cephem-4-carboxylic acid sodium salt

[Chemical 17] The above compound was obtained in the same manner as in Example 1 except that the compound of Production Example 2 was used. (Yield 46%)

NMR (D ₂ O.δ) 3.17 (2H, t, J = 5 Hz), 3.20 (3H,
s), 3.26, 3.53 (2H, ABq, J = 18H)
z), 3.40 (2H, t, J = 5Hz), 4.55,
4.76 (2H, ABq, J = 12Hz), 5.09
(1H, d, J = 5Hz), 5.71 (1H, d, J =
5Hz), 6.85 (1H, s)

Example 3 7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-N
-(2-Monofluoroethyl) carbamoyloxymethyl-3-cephem-4-carboxylic acid sodium salt

[Chemical 18] The compound of Preparation Example 3 was used and treated in the same manner as in Example 1 to obtain the above compound.

NMR (D ₂ O.δ) 3.2-3.5 (4H, m) 4.2-4.4 (2H,
m), 4.65 (2H, ABq, J = 12Hz), 5.
05 (1H, d, J = 4.8Hz), 5.68 (1H,
d, J = 4.8 Hz), 6.80 (1H, s)

Example 4 7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-N
-(2,2,2-Trifluoroethyl) carbamoyloxymethyl-3-cephem-4-carboxylic acid sodium salt

[Chemical 19] The above compound was obtained in the same manner as in Example 1 using the compound of Production Example 4.

NMR (D ₂ O.δ) 3.39 (2H, ABq, J = 18 Hz), 3.66-
3.73 (2H, m), 4.71 (2H, ABq, J =
13 Hz), 5.08 (1H, d, J = 4.8 Hz),
5.70 (1H, d, J = 4.8Hz), 6.81 (1
H, s)

Example 5 7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-N
-Methylcarbamoyloxymethyl-3-cephem-4
-Carboxylic acid pivaloyloxymethyl

[Chemical 20] Iodomethyl pivalate (51 mg) was added to a solution of the compound (106 mg) obtained in Example 1 in N, N-dimethylacetamide (2 ml) under ice-cooling, and then the mixture was stirred at the same temperature for 1 hour. Ethyl acetate and water are added to the reaction solution, the ethyl acetate layer is separated, washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate, isopropyl ether was added, and the precipitate was collected by filtration,
After washing with isopropyl ether, the title compound (44m
g, yield 35%) was obtained.

NMR (CDCl ₃ .δ) 1.13 to 1.15 (9H, m), 2.70 (3H,
s), 3.42 to 3.59 (2H, m), 4.72 to
4.76 (1H, m), 4.95 to 5.05 (2H,
m), 5.78 to 5.81 (1H, m), 5.81
5.89 (2H, m), 6.93 (1H, s)

Example 6 7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-N
-Methylcarbamoyloxymethyl-3-cephem-4
-Carboxylic acid 1- (isopropoxycarbonyloxy) ethyl

[Chemical 21] The above compound was obtained in the same manner as in Example 5. (Yield 55
%)

NMR (CD ₃ OD.δ) 1.25 to 1.35 (9H, m), 1.51 to 1.57
(3H, m), 2.70 (3H, s), 3.48-3.
70 (2H, m), 4.75 to 4.90 (1H, m),
5.02 to 5.09 (1H, ABq, J = 14Hz),
5.16-5.21 (1H, m), 5.90-5.95
(1H, m), 6.75 (1H, s), 6.84-6.
95 (1H, m)

Example 7 7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-N
-(2-Methoxyethyl) carbamoyloxymethyl-
3-Cephem-4-carboxylic acid pivaloyloxymethyl

[Chemical formula 22] The above compound was obtained in the same manner as in Example 5 except that the compound obtained in Example 2 was used.

NMR (CDCl ₃ .δ) 1.26 to 1.28 (9H, m), 3.36 to 3.40
(5H, m), 3.47 to 3.50 (3H, m), 3.
62 (1H, d, J = 18Hz), 4.84, 5.10
(2H, ABq, J = 13Hz), 5.04 (1H,
d, J = 3.5 Hz), 5.86, 5.96 (2H, A
Bq, J = 5 Hz), 5.91 to 5.94 (1H,
m), 7.05 (1H, s)

Example 8 7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-N
-(2-Monofluoroethyl) carbamoyloxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl

[Chemical formula 23] The above compound was obtained in the same manner as in Example 5 except that the compound obtained in Example 3 was used.

NMR (CD ₃ OD.δ) 1.22 (9H, s), 3.3 to 3.4 (2H, m),
3.63 (2H, ABq, J = 18Hz), 4.35
4.50 (2H, m), 4.96 (2H, ABq, J =
13 Hz), 5.20 (1 H, d, J = 4.8 Hz),
5.83-5.94 (3H, m), 6.76 (1H,
s)

Example 9 7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-N
-(2,2,2-Trifluoroethyl) carbamoyloxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl

[Chemical formula 24] The above compound was obtained in the same manner as in Example 5 except that the compound obtained in Example 4 was used.

NMR (CD ₃ OD.δ) 1.21 (9H, s), 3.61 (2H, ABq, J =
18Hz), 3.74 to 3.81 (2H, m), 5.0
0 (2H, ABq, J = 14Hz), 5.19 (1H,
d, J = 4.9 Hz), 5.83 to 5.94 (3H,
m), 6.76 (1H, s)

Front Page Continuation (72) Inventor Atsushi Kamata 4-19-13 Kasuga, Tsukuba, Ibaraki Prefecture (72) Inventor Akihiko Tsuruoka 2-23-5, Amakubo, Tsukuba, Ibaraki Prefecture (72) Yoshimasa Machida Tsukuba, Ibaraki Prefecture Shimohirooka 500-81

Claims (2)

[Claims] 1. A compound represented by the general formula (I): (Wherein R ¹ represents a lower alkyl group, a lower alkoxy group-substituted lower alkyl group or a halogen atom-substituted lower alkyl group, and R ² represents a carboxy group or a protected carboxy group) and a pharmaceutically acceptable compound. That salt that will be. 2. A compound represented by the general formula (II): (Wherein R ¹ represents a lower alkyl group, a lower alkoxy group or a lower alkyl group substituted with a halogen atom, and R ² represents a carboxy group or a protected carboxy group) or a salt thereof. General formula (III): (Wherein R ³ represents a hydroxyl group or a protected hydroxyl group, R ⁴ represents an amino group or a protected amino group), or a reaction derivative thereof, or a salt thereof. The method for producing a compound according to claim 1, wherein when the compound has a protecting group, the protecting group is optionally removed.