JP3209679B2 - Disulfide compound and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a disulfide compound, and more particularly, to a disulfide compound, an acid addition salt thereof, and a compound useful for deriving a thiol compound which is a synthetic intermediate of a carbapenem compound. Related to manufacturing method.

[0002]

2. Description of the Related Art Many compounds having a so-called carbapenem skeleton have been found so far, and some compounds having excellent antibacterial activity have been proposed. The present inventors have also studied the search for carbapenem compounds which exhibit strong antibacterial activity and also have a β-lactamase inhibitory action and excellent resistance to renal dehydropeptidase-I (DHP-I). 1-specific as a substituent at the 2-position of the skeleton
The following formula (A) in which a (1,3-thiazolin-2-yl) azetidin-3-ylthio group is introduced:

[0003]

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(1R, 5S, 6S) -2-
[1- (1,3-thiazolin-2-yl) azetidine-
3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapen-2-em-3-carboxylic acid has been newly found and proposed (JP-A-8-53).
453). The carbapenem compound represented by the above formula (A) not only exhibits a strong antibacterial activity by itself, but also a compound obtained by esterifying the carboxy group at the 3-position with a specific ester residue is digested by oral administration. It has good absorbability from the tube, and moreover, it is rapidly hydrolyzed in vivo in the ester to transfer to the active form,
It is a compound that has been widely expected as a carbapenem antibiotic that can be orally administered and that has never been seen before, and that has been desired to be developed. By the way, the production of the carbapenem compound represented by the above formula (A) has been performed by, for example, a method represented by the following reaction formula (a).

[0005]

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In the production of the conventional compound (A), the compound of the formula (II) reacted with the compound (B) is specifically converted to the compound of the formula (III) as shown in the following reaction formula (b). The compound of formula (II) produced by reacting the 2-substituted-1,3-thiazoline derivative of formula (IV) with the 3-mercaptoazetidine of formula (IV) is represented by the formula (B) Used for reaction with compounds.

[0007]

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(Wherein L represents a leaving group) However, the compound represented by the formula (II) produced according to the above reaction formula (b) can be obtained in a pure form by such a production method. However, it was inevitable that only a mixture containing contaminants was obtained, and its separation was also difficult. Therefore, the formula (II) produced by this method
The reaction yield in the step of using the compound represented by the formula (B) to react with the compound represented by the formula (B) to obtain the compound represented by the formula (C) is limited, and is still a problem as an industrial production method. In order to efficiently obtain a carbapenem compound of the formula (A), which has excellent antibacterial activity and is strongly desired for clinical development, it is necessary to use a compound of the formula (II) having a higher purity. It has been desired to establish a production method that enables development and industrial application thereof.

In view of the above circumstances, the present inventors have made intensive studies and found that the following formula (I):

[0010]

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When the disulfide compound of the formula (II) is reduced to the compound of the formula (II), the yield of the desired compound of the formula (II) is almost quantitative, and When the compound of the formula (II) thus produced is reacted with the compound (B) according to the reaction formula (a) to derive the compound represented by the formula (C), the compound (C) The reaction yield was found to be dramatically increased, and was newly found to be extremely useful as an industrial production method. Accordingly, the present invention provides a compound represented by the above formula (I), which is useful for deriving a thiol compound which is a synthetic intermediate of a carbapenem compound, and a method for producing the same.

[0012]

That is, the present invention provides the following formula (I):

[0013]

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And a disulfide compound and an acid addition salt thereof. The present invention also provides a method for producing the disulfide compound represented by the above formula (I). Specifically, the present invention provides the following formula (II):

[0015]

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3-mercapto-1- (1,3
A process for obtaining a compound of formula (I) by subjecting -thiazolin-2-yl) azetidine or an acid addition salt thereof to an oxidation reaction is provided. Further, the present invention provides another method for producing the disulfide compound of the formula (I), specifically, the following formula (III):

[0017]

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The 3-mercaptoazetidine represented by
The following formula (IV):

[0019]

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(Wherein L represents a leaving group)
Reacting a substituted-1,3-thiazoline derivative with the following formula (II):

[0021]

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3-mercapto-1- (1,3
(Thiazolin-2-yl) azetidine is obtained, and the resulting compound of the formula (II) is directly subjected to an oxidation reaction without isolation from the reaction solution to provide a process for obtaining the compound of the formula (I). . The present invention also provides still another method for producing the disulfide compound of the formula (I). Specifically, the present invention provides the following formula (V):

[0023]

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The compound represented by the following formula (IV):

[0025]

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(Wherein L represents a leaving group)
-To provide a process for the preparation of a compound of formula (I) by reacting a substituted-1,3-thiazoline derivative. Still another embodiment of the present invention relates to the provision of a compound as a raw material for deriving the disulfide compound of the formula (I), and specifically, the following formula (VI):

[0027]

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(Wherein R ¹ represents a hydrogen atom or an amino-protecting group). The disulfide compound represented by the formula (I) and the acid addition salt thereof provided by the present invention can be quantitatively derived to a thiol compound represented by the formula (II) with high purity by subjecting the compound to a reduction reaction. Using the thiol compound of formula (II), a carbapenem compound represented by the formula (A) having excellent antibacterial activity and capable of oral administration by esterification is produced on an industrial scale with high yield. be able to.

[0029]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. The disulfide compound represented by the formula (I) of the present invention can be produced by the method represented by the following reaction formula (c).

[0030]

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Wherein L represents a leaving group, R ² represents an amino-protecting group, and the numbers in brackets denote reaction steps for convenience of explanation. Examples of the "leaving group" represented include, for example, an azide group; a halogen atom such as chlorine, bromine and fluorine; a lower alkanoyloxy group such as acetoxy and propionyloxy group; benzenesulfonyloxy;
Sulfonyloxy groups such as tosyloxy and methanesulfonyloxy groups; lower alkoxy groups such as methoxy and ethoxy; lower alkylthio groups such as methylthio and ethylthio.

The "amino protecting group" represented by R ¹ or R ² is any protecting group known per se as a protecting group for an amino group in the field of peptide chemistry. Specifically, for example, (1) phthaloyl; benzoyl, or chlorobenzoyl, p-nitrobenzoyl,
benzoyl substituted with halogen, nitro or lower alkyl such as p-tert-butylbenzoyl and trioil; naphthoyl; phenylacetyl; phenoxyacetyl; lower alkylbenzenesulfonyl such as benzenesulfonyl, p-tert-butylbenzenesulfonyl and toluenesulfonyl; (2) aliphatic or halogenated aliphatic carboxylic acid acyl group: for example, camphorsulfonyl, methanesulfonyl, formyl, acetyl, valeryl, capryl, n-decanoyl, acryloyl, pivaloyl, halogenoacetyl (eg, monochloroacetyl, monobromoacetyl) , Dichloroacetyl, trichloroacetyl)
And (3) an esterified carboxy group: for example, ethoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, isobornyloxycarbonyl,
Phenyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and the like; (4) carbamoyl or thiocarbamoyl group: for example, methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl and the like or a corresponding thiocarbamoyl group; Is mentioned.

Formulas (I) and (II) provided by the present invention
Any of the compounds and the like shown can be isolated as an arbitrary acid addition salt. Organic acids among such acids that can be added include, for example, lower fatty acids such as acetic acid, propionic acid, butyric acid, trifluoroacetic acid, and trichloroacetic acid; and substituted or unsubstituted benzoic acids such as benzoic acid and p-nitrobenzoic acid. (Halo) lower alkylsulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid; benzenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, toluenesulfonic acid, 2,4,6-
Substituted or unsubstituted arylsulfonic acids such as triisopropylbenzenesulfonic acid; and organic phosphoric acids such as diphenylphosphoric acid. As the inorganic acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid,
Examples thereof include borofluoric acid, perchloric acid, and nitric acid.

The present invention will be described below by describing each step in the above reaction formula (c). Step [1] : In this step, 3-mercapto-1- (1,3-thiazolin-2-yl) azetidine represented by the formula (II) is subjected to an oxidation reaction to obtain a compound represented by the formula ( This is a step of deriving a disulfide compound represented by I). The reaction is carried out by using a compound of the formula (II) in an appropriate solvent using an oxidizing agent such as chromic acid, lead tetraacetate, organic peracid, H ₂ O ₂ , I ₂ , dimethylsulfoxide, or the like. This is achieved by performing air oxidation by passing air through the reaction solution in the presence of a catalyst. The solvent used may be any solvent that does not affect the oxidation reaction, that is, a solvent that is inert to the reaction, for example, alcoholic solvents such as methanol, ethanol, propanol, and n-butanol; diethyl ether, tetrahydrofuran, and the like. Ether solvents; hydrocarbon solvents such as n-heptane, n-hexane, cyclohexane, pentane and cyclopentane; ester solvents such as methyl acetate, ethyl acetate; halogen solvents such as dichloromethane, chloroform and carbon tetrachloride Solvent; acetonitrile,
Solvents such as dimethylformamide, dimethylacetamide and dimethylsulfoxide can be used, and among them, alcohol solvents are preferable, and methanol and ethanol are particularly preferable. In this case, as the compound of the formula (II), an acid addition salt thereof can also be used. In such a case, for example, an alkali metal hydrogencarbonate such as potassium hydrogencarbonate or sodium hydrogencarbonate; potassium carbonate An air oxidation is carried out by coexisting an alkali metal carbonate compound such as sodium carbonate, sodium carbonate or the like; an alkali metal hydroxide compound such as sodium hydroxide or potassium hydroxide; a tertiary organic amine such as triethylamine in the reaction system.
The amount of the catalyst such as iron trichloride to be added may be sufficient to end the desired oxidation reaction efficiently, and generally only needs to be a very small amount. Of these catalysts, iron trichloride is particularly preferred. The reaction temperature is not particularly limited.
By subjecting the compound of the formula (II) to air oxidation at 100 ° C., preferably at room temperature for several hours, the compound of the formula (II) is converted to the desired disulfide compound of the formula (I) with high purity and almost quantitatively.

Step [2] : This step is a step of obtaining 3-mercapto-1- (1,3-thiazolin-2-yl) azetidine represented by the formula (II) and subjected to the oxidation reaction in step [1]. And specifically, a 3-mercaptoazetidine of the formula (III) and a 2-substituted-of the formula (IV)
This is a step of reacting with a 1,3-thiazoline derivative.
In this step, a 3-mercaptoazetidine of the formula (III) and a 2-substituted-1,3-thiazoline derivative of the formula (IV) are reacted with a solvent inert to a reaction appropriately selected from the above, Preferably, in an alcoholic solvent such as methanol and ethanol, a suitable base, for example, potassium bicarbonate, alkali metal bicarbonate such as sodium bicarbonate, potassium carbonate, alkali metal carbonate such as sodium carbonate, sodium methoxide, The reaction is carried out in the presence or absence of a base such as an alkali metal alkoxide such as sodium ethoxide and potassium tert-butoxide.

The reaction temperature is not strictly limited, and can be appropriately changed depending on the solvent to be used, the type of the leaving group L in the compound of the formula (IV), and the amount of the leaving group. ° C, preferably from room temperature to about 8
The reaction can be carried out at a temperature in the range of 0 ° C., and under such conditions the reaction can be completed in about 1 to about 24 hours.
In addition, 3-
Mercapto-1- (1,3-thiazolin-2-yl) azetidine is a compound which can be directly reacted with the compound of the formula (B) in the above-mentioned reaction formula (a) to induce a carbapenem compound having antibacterial activity. The compound of the formula (II) obtained by this step [2] is not satisfactory in purity, and contains impurities and is difficult to separate. Accordingly, in view of this, the present invention provides a method of formula (I)
A method of oxidizing the compound of formula (I) to induce the compound of formula (I), and then reducing the compound of formula (I) to return the compound of formula (II) with good purity and almost quantitatively; In another aspect, the present invention provides a compound of formula (II)
Can be regarded as an industrial purification method for the compound of the formula (1).

Step [3] : This step is performed according to the formula (I) of the present invention.
Wherein the compound represented by the formula (V) is replaced with a 2-substituted compound represented by the formula (IV) also used in the step [2].
In this step, the desired compound of formula (I) is obtained by reacting the compound with a 1,3-thiazoline derivative. In such a process,
The reaction conditions and the like in the above step [2] are applied as they are.

Steps [4] and [5] : This step [4] and step [5] are performed according to the formula (V) used in step [3].
In order to obtain the compound represented by the formula (VII), 3-mercapto-1-amino protecting group-substituted azetidine represented by the formula (VII) is oxidized to obtain a disulfide compound represented by the formula (VI), This is a step obtained by removing an amino protecting group. In this case, the step [5] of oxidizing the 3-mercapto-1-amino protecting group-substituted azetidine represented by the formula (VII) to obtain a disulfide compound represented by the formula (VI) is performed in the above step [1]. The conditions of the oxidation reaction can be changed as appropriate and applied. The 3-mercapto-1-amino-protecting group-substituted azetidine represented by the formula (VII) used in this step is a compound in which the various amino-protecting groups exemplified above are substituted. As the group, those which are aliphatic acyl residues such as acetyl are particularly preferred. The present invention also provides a compound of the formula (VI) obtained by this step. Therefore, these compounds which are the object of the present invention are compounds having an amino protecting group exemplified above as R ² . It goes without saying that Further, in performing the deamination protecting group reaction in step [4], a deamination protecting group reaction widely used in peptide chemistry is applied. For example, decomposition in an appropriate solvent inert to the reaction exemplified above, for example, with an acid is preferable.

The disulfide compound of the formula (I) thus produced can be prepared, for example, by using triphenylphosphine in a suitable solvent inert to the reaction exemplified above, for example, a solvent such as tetrahydrofuran, acetonitrile, methanol, ethanol or the like. For example, a 3-mercapto-1- (1,3-thiazoline-2-) represented by the formula (II) can be obtained with good purity and almost quantitatively by a reduction reaction treated under acidic conditions using an aqueous 1N hydrochloric acid solution. Il) can be converted to azetidine. The compound of the formula (II) thus obtained with high purity is reacted with the compound of the formula (B) in the above-mentioned reaction formula (a), followed by deprotection to give the compound of the formula (A) To a carbapenem compound having the antibacterial activity shown by Although the compound of the formula (II) can be obtained by the step [2] of the present invention, the compound of the formula (II) obtained in such a step contains impurities and is satisfactory in purity. And its purification is also difficult. Therefore, in the present invention, the compound of the formula (II) obtained in the step [2] is once oxidized to be derived into the compound of the formula (I) and then further reduced, so that seemingly useless treatment is added. However, it is not inferior from the viewpoint of the yields of all the steps, but rather from the viewpoint that the reaction yield of the compound of the formula (II) and the compound of the formula (B) is remarkably improved. Is a better way. In particular, in view of the fact that the compound represented by the formula (B) is expensive, it can be said that the industrial merit of using a compound having high purity is extremely large.

[0040]

The present invention will be described in more detail with reference to the following Examples and Reference Examples, which should not be construed as limiting the scope of the present invention. The numbers in parentheses indicate compound numbers. Example 1 :

[0041]

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3-mercapto-1- (1,3-thiazolin-2-yl) azetidine hydrochloride (8.60 mmol
l) (1) In a solution of 1.81 g of methanol in 20 ml,
After adding 2.0 g of potassium hydrogen carbonate and ventilating air,
A catalytic amount of iron trichloride was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was filtered, and the filtrate was washed with 200 ml of water.
The resulting crystals were collected by filtration. The obtained crystals were washed with water and dried under reduced pressure at room temperature to quantitatively obtain the target disulfide compound (2) in a purity-converted yield. ¹ H-NMR (270 MHz) δ: 3.38 (t, 4
H, J = 7.6 Hz), 3.83 to 4.01 (m, 6
H), 4.03 (t, 4H, J = 7.6 Hz), 4.3
5 (t, 4H, J = 8.1 Hz) The purity of this compound was measured by HPLC under the following conditions, and as a result, the purity was almost quantitative. HPLC measurement conditions: Column: Ultran VX-octyl (4.6 × 2
50 mm) Moving layer: 0.01 M sodium dodecyl sulfate-acetonitrile aqueous solution 1: 1 v / v (pH adjusted to 2.2 with phosphoric acid) Flow rate: 1.4 ml / min Measurement wavelength: 216 nm Retention time: 4.1 minutes Injection volume: 20 μl Example 2 :

[0043]

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3-mercaptoazetidine hydrochloride (3)
2.39 g (19.04 mmol) of methanol 40m
To this solution, 2.41 ml of 2-methylthio-1,3-thiazoline (4) was added, and the mixture was refluxed for 4 hours. After completion of the reaction, the produced 3-mercapto-1- (1,3-thiazolin-2-yl) azetidine / hydrochloride (1) was used as it was without isolating it from the reaction solution. After adding 3.6 g of potassium hydrogen and passing air, a catalytic amount of iron trichloride was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was filtered, and the filtrate was 300 ml of water.
The resulting crystals were collected by filtration. The obtained crystals were washed with water, and dried under reduced pressure at room temperature to quantitatively obtain the target disulfide compound (2) in a yield in terms of purity. Its NMR data was identical to that obtained in Example 1. The purity was measured by HPLC in the same manner, and the content was almost quantitative. Example 3 :

[0045]

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1.86 g (10.75 mm) of compound (5)
ol) in 27 ml of methanol was added with 2.19 g of sodium methoxide, and the mixture was stirred at room temperature for 30 minutes. Then, 2.15 ml of 6N-hydrochloric acid aqueous solution was added, and the mixture was stirred for 15 minutes. Thus, compound (6) was obtained, and without isolation, 2.15 g of potassium hydrogen carbonate was added to the reaction solution, and a catalytic amount of iron trichloride was added thereto while passing air through, followed by stirring at room temperature for 2 hours. Was performed. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to obtain a compound (7). ¹ H-NMR (270 MHz) δ: 1.88 (s, 6
H), 3.79 to 3.99 (m, 4H), 4.01 to
4.15 (m, 2H), 4.25 to 4.36 (m, 2
H), 4.40 to 4.50 (m, 2H) To the obtained compound (7), 4.3 ml of a 3N aqueous hydrochloric acid solution was added, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the hydrochloric acid layer was washed by adding 3.61 ml of ethyl acetate and 3.61 ml of water, and the aqueous layer was concentrated under reduced pressure. The residue was dried at room temperature for 18 hours under reduced pressure to give the compound (as a solid). 8) to 1.2
g was obtained. Next, this compound (8) was added to 27 ml of methanol.
And 3-mercaptoazetidine 1.2 was added to this solution.
1 ml was added and the mixture was refluxed for 4 hours. After completion of the reaction, methanol was distilled off under reduced pressure, and the obtained residue was ethyl acetate (13.5).
ml and 54 ml of water were added and the aqueous layer was separated. 10 ml of methanol was added to the aqueous layer, and the mixture was stirred at room temperature.
When 1.3 ml of 0N-sodium hydroxide aqueous solution was added and stirred, crystals were precipitated. The obtained crystals were collected by filtration, washed with water, and dried under reduced pressure at room temperature for 18 hours to obtain 1.18 g of a disulfide compound (2) which was used as a metal. The NMR data of this product was the same as that of Example 1, and the purity was almost quantitative by a HPLC method. Reference Example 1 :

[0047]

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3-mercaptoazetidine hydrochloride (3)
To a solution of 720 mg in 10 ml of methanol was added 0.67 ml of 2-methylthio-1,3-thiazoline (4), and the mixture was refluxed for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 15 ml of water was added to the obtained residue, and the mixture was washed twice with 10 ml of ethyl acetate, and the aqueous layer was concentrated under reduced pressure. 1 ml of acetonitrile was added to the obtained residue and stirred, and 6 ml of tetrahydrofuran was stirred.
Was added dropwise over 20 minutes to precipitate crystals. The obtained crystals were collected by filtration and dried under reduced pressure at room temperature for 18 hours to obtain 1.05 g of the objective 3-mercapto-1- (1,3-thiazolin-2-yl) azetidine hydrochloride (1). Was. Its yield in terms of purity was 84.8%, and its purity was 86.0%.
7%. Reference Example 2 :

[0049]

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Method (a): A solution of 2.62 g of the disulfide compound (2) obtained in Example 1 in tetrahydrofuran was added.
An N-hydrochloric acid aqueous solution was added, and 1.89 g of triphenylphosphine was added thereto, followed by stirring at 50 to 60 ° C for 2 hours.
After completion of the reaction, 10 ml of ethyl acetate and 10 ml of water were added, and the aqueous layer was separated and concentrated under reduced pressure. 1.2 ml of methanol was added to the obtained residue, and the mixture was stirred.
ml was added dropwise over 15 minutes to precipitate crystals. The obtained crystals were collected by filtration and dried under reduced pressure at room temperature for 18 hours to give the desired 3-mercapto-1- (1,3-thiazoline-2).
2.62 g of -yl) azetidine hydrochloride (1) were obtained.
Its purity conversion yield was 94%, and its purity was 96.
7%. Method (b): disulfide compound (2) obtained in Example 1
To a solution of 693.1 mg of acetonitrile in 4 ml of water 0.0
43 ml and a solution of 14.6N hydrochloric acid in methanol 0.
34 ml of triphenylphosphine 62
9.5 mg was added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, 40 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 3 hours to precipitate crystals. The obtained crystals were collected by filtration and dried under reduced pressure at room temperature for 18 hours to obtain 837 mg of the desired 3-mercapto-1- (1,3-thiazolin-2-yl) azetidine hydrochloride (1). Its yield in terms of purity was 96.8%, and its purity was 97.5%.

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Claims (5)

(57) [Claims] (1) The following formula (I): And the acid addition salt thereof. 2. The following formula (II): 3. A disulfide represented by the formula (I) according to claim 1, wherein the 3-mercapto-1- (1,3-thiazolin-2-yl) azetidine or an acid addition salt thereof is subjected to an oxidation reaction. A method for producing a compound or an acid addition salt thereof. 3. The following formula (III): The 3-mercaptoazetidine represented by the following formula (I)
V): embedded image (Wherein L represents a leaving group)
Reaction of the 3-thiazoline derivative with the following formula (II): 3-mercapto-1- (1,3-thiazolin-2-yl) azetidine represented by the following formula:
The method for producing a disulfide compound represented by the formula (I) or an acid addition salt thereof according to claim 1, wherein the compound of the formula (I) is subjected to an oxidation reaction without isolation from the reaction solution. 4. The following formula (V): Has the following formula (IV): (Wherein L represents a leaving group)
Characterized by reacting a 3-thiazoline derivative,
A method for producing a disulfide compound represented by the formula (I) according to claim 1 or an acid addition salt thereof. 5. The following formula (VI): (Wherein, R ¹ represents a hydrogen atom or an amino-protecting group).