JPH11193285A - Production of bicyclic heterocyclic thiol compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing, industrially advantageously, the subject compound useful as a substituent for excellent antibiotics by converting an inexpensive stock compound without through an unstable intermediate. SOLUTION: This compound shown by formula VIII is obtained in high yield through steps of (1) reacting a compound shown by formula I (X<1> is a halogen) with a compound shown by the formula; R<1> -SH [R<1> is a (substituted) aralkyl, diphenylmethyl, triphenylmethyl or acyl] in the presence of a base, (2) treating the product of the above step (1) in the presence of a base to open its ring into a compound shown by formula II, (3) treating the compound shown by formula II with a reagent for producing a cyano compound into a compound shown by formula III, (4) reacting the compound shown by formula III with a hydroxylamine to form a compound shown by formula IV, (5) reducing the compound shown by formula IV and reacting the product with a compound shown by formula V (X<2> is a halogen) or its derivative to form a compound shown by formula VI, (6) halogenating the compound shown by formula VI and treating it close its ring into a compound shown by formula VII, and (7) eliminating the group R<1> from the compound shown by formula VII.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound of formula (11) useful as an antibiotic.

[0002]

Embedded image The present invention relates to a method for producing a bicyclic heterocyclic thiol compound which is a 3-position substituent of a β-methylcarbapenem derivative represented by the formula:

[0003]

2. Description of the Related Art A compound represented by the formula (11)
See -223587. Hereinafter, it is represented as compound (11). In addition, other compounds are similarly represented. )
Has a broad antibacterial spectrum, high antibacterial activity, and excellent safety, and is expected to be an excellent antibiotic. Its structural feature is that it has a bicyclic heterocyclic substituent as the 3-position substituent. The compound (10) required for the introduction of the substituent has been synthesized through the following production process using the compound (12) as a starting material (see JP-A-62-149683).

[0004]

Embedded image (In the formula, Ph represents a phenyl group, PMB represents a paramethoxybenzyl group, and Et represents an ethyl group.) The above-mentioned production method includes a step utilizing the Mitsunobu reaction, and in this step, the operation of isolating the product is extremely difficult. In addition, there is room for improvement as an industrial production method because the reaction materials and reagents are relatively expensive and mass acquisition is not easy.

The following production method using compound (13) as a starting material has also been developed (Japanese Patent Application Laid-Open No. 9-241260).
Japanese Patent Application Laid-Open No. H11-157, and the process of introducing a leaving group is low in yield, and many of the production intermediates are unstable and difficult to isolate and purify. .

[0006]

Embedded image (In the formula, Ms represents a methanesulfonyl group, and Ac represents an acetyl group.)

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide an industrially advantageous production method for obtaining a bicyclic heterocyclic thiol compound and an intermediate compound useful in this production method.

[0008]

Means for Solving the Problems As a result of intensive studies, the present inventor has conducted a conversion according to the following steps using a compound represented by the general formula (1) as a raw material to obtain a desired bicyclic compound. The present inventors have found that the heterocyclic thiol compound (10) can be produced industrially advantageously, and have completed the present invention.

[0009]

Embedded image

(Wherein X ¹ and X ³ each independently represent a halogen atom, R ¹ is an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, Represents a triphenylmethyl group which may have a group or an acyl group which may have a substituent.) That is, the present invention provides a compound represented by the general formula (1)

[0011]

Embedded image (Wherein X ¹ represents a halogen atom) in the presence of a base,

[0012]

Embedded image (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. Represents an acyl group which may be substituted with a compound represented by the general formula (2)

[0013]

Embedded image (Wherein R ¹ and X ¹ are the same as defined above), and the compound is subjected to ring closure in the presence of a base to obtain a compound represented by the general formula (3):

[0014]

Embedded image (Wherein R ¹ is the same as defined above), and then the compound is treated with a cyanating reagent to give a compound of the general formula (4)

[0015]

Embedded image (Wherein R ¹ is the same as defined above), and then reacted with hydroxylamines to obtain a compound of the general formula (5)

[0016]

Embedded image (Wherein R ¹ is the same as defined above), and the compound is reduced to obtain a compound represented by the general formula (6)

[0017]

Embedded image (Wherein R ¹ is the same as defined above) or a salt thereof, and then in the presence of a base,

[0018]

Embedded image (Wherein X ² represents a halogen atom), and a aldehyde compound represented by the general formula (7):

[0019]

Embedded image (Wherein R ¹ is the same as defined above), and the compound is halogenated to give a compound of the general formula (8a)

[0020]

Embedded image (Wherein X ³ represents a halogen atom and R ¹ is the same as defined above) and / or a compound of the general formula (8b)

[0021]

Embedded image (Wherein X ³ and R ¹ are the same as defined above), followed by ring closure to obtain a compound of the general formula (9)

[0022]

Embedded image (Wherein R ¹ is the same as defined above), and after removing a substituent R ¹ , a compound represented by the formula:

[0023]

Embedded image And a method for producing the compound represented by the formula:

Further, the compound represented by the general formula (1) is
General formula in the presence of a base

[0025]

Embedded image (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. With a compound represented by the general formula (2), and the compound is subjected to ring closure in the presence of a base to form a compound represented by the general formula (3):
Then, the compound is treated with a cyanating reagent to give a compound represented by the general formula (4), and then reacted with hydroxylamines to obtain a compound represented by the general formula (5)
And then reducing this compound,
After the compound represented by the general formula (6) or a salt thereof,
Formula in the presence of a base

[0026]

Embedded image (Wherein, X ² represents a halogen atom). The compound is reacted with an aldehyde compound or a derivative thereof to obtain a compound represented by the general formula (7), and then the compound is halogenated. And a method for producing a compound represented by the general formula (8a) and / or a compound represented by the general formula (8b).

Further, the compound represented by the general formula (1) is reacted with the compound represented by the general formula (1) in the presence of a base.

[0028]

Embedded image (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. And a compound represented by the general formula (2):

The present invention also relates to a method for producing a compound represented by the general formula (3), which comprises closing the compound represented by the general formula (2) in the presence of a base.

Alternatively, the present invention relates to a method for producing a compound represented by the general formula (4), comprising treating the compound represented by the general formula (3) with a cyanating reagent.

Further, the compound represented by the general formula (4) is
Characterized by reacting with hydroxylamines,
The present invention relates to a method for producing the compound represented by the general formula (5).

Further, the present invention relates to a method for producing a compound represented by the general formula (6) or a salt thereof, which comprises reducing the compound represented by the general formula (5).

Then, the compound represented by the general formula (6) or a salt thereof is converted to a compound represented by the formula

[0034]

Embedded image (Wherein X ² represents a halogen atom). A method for producing a compound represented by the general formula (7), characterized by reacting with an aldehyde compound represented by the following formula:

The general formula (2)

[0036]

Embedded image (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. And X ¹ represents a halogen atom.).

Further, the general formula (3)

[0038]

Embedded image (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. Represents an acyl group which may be substituted).

Then, the general formula (4)

[0040]

Embedded image (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. Represents an acyl group which may be substituted).

Alternatively, the general formula (5)

[0042]

Embedded image (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. Represents an acyl group which may be substituted).

Then, the general formula (6)

[0044]

Embedded image (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. And a salt thereof.

[0045]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described. First, the substituents of the compound used in the production method of the present application will be described.

The substituent R ¹ is not particularly limited as long as it can serve as a protecting group for the mercapto group. Examples of the protecting group for the mercapto group include an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, and a substituent. And an acyl group which may be present. Among these, preferred examples include an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, and a triphenylmethyl group which may have a substituent. .
Particularly preferred are aralkyl groups which may have a substituent, among which aralkyl groups which may have a substituent on a phenyl group are preferred. Examples of the aralkyl group include a benzyl group, a phenylethyl group, a methylbenzyl group, and a naphthylmethyl group, and a benzyl group is preferable. Examples of the substituent on the phenyl group include an alkyl group, an alkoxyl group, a nitro group, and a halogen atom. One or more of these may be substituted with one or more, such as a 4-methoxybenzyl group. , 4-chlorobenzyl group, 4-nitrobenzyl group,
2,4-dimethoxybenzyl group, 2,4-dichlorobenzyl group, 2,4-dinitrobenzyl group, 2,4,6-trimethylbenzyl group, 2,4,6-trimethoxybenzyl group, 2,4 6-trichlorobenzyl group and 2,
A 4,6-trinitrobenzyl group can be mentioned.

The substituent X ¹ is a halogen atom, the halogen atom is preferably a chlorine atom.

Next, the manufacturing method of the present invention will be described. The manufacturing method of the present invention includes the following steps. 1. An alkylthio group is introduced into compound (1) to obtain compound (2). 2. Compound (2) is closed to give compound (3). 3. Compound (3) is obtained by introducing a nitrile group into compound (4).
And 4. The nitrile group of the compound (4) is converted into an amidoxime group to obtain a compound (5). 5. Compound (5) is reduced to compound (6). 6. The compound (6) is reacted with an aldehyde compound or a derivative thereof to form an imidazole ring.
And 7. Compound (7) is treated with a halogenating reagent to give compound (8a) and / or compound (8b). 8. Compound (8a) and / or compound (8b) are closed to form compound (9). 9. The protecting group of compound (9) is removed to obtain compound (10).

Each step will be described in detail below.

Compound (2) is prepared from compound (1)
Step Compound (1) is reacted with a thiol compound (R ^1-
When reacted with SH), it can be converted to compound (2).

As the compound (1) as a reaction raw material, a commercially available compound may be used. When the optically active form of the compound (1) is used, the target compound (10) is obtained as an optically active form.

The thiol compound used in the reaction may be used in the range of 1 to 2 equivalents based on compound (1).

As the base to be used, organic bases such as pyridine, triethylamine and DBU, sodium hydroxide,
Inorganic bases such as potassium hydroxide, sodium carbonate and potassium carbonate can be mentioned, and preferred are sodium hydroxide and potassium carbonate. The base may be used in an amount of 1 to 2 equivalents.

This reaction may be carried out in a solvent, and any solvent may be used as long as it is inert to the reaction. For example, ethanol, hydrous ethanol, acetone, dichloromethane, Chloroform, dimethylformamide and the like can be mentioned. Among them, hydrous ethanol is preferred, and the water content of the hydrous ethanol may be in the range of 10% to 50%, preferably in the range of 30% to 40%. The solvent is 1 for compound (1).
5 to 25-fold amount (for example, 1 to 1 g of compound (1)
5 to 25 ml).

The reaction temperature may range from -50 ° C to 0 ° C, preferably from -20 ° C to -10 ° C. The reaction time may be generally from 0.5 hours to 2 hours.

The compound (2) can be isolated by column chromatography using silica gel or the like, but the reaction in the next step can be carried out continuously without isolating and purifying the compound (2).

Compound (3) is prepared from compound (2)
Step When the compound (2) is treated under basic conditions, a ring-closing reaction accompanied by a dehydrohalogenation reaction proceeds to produce a compound (3)
Is obtained.

As the base to be used, organic bases such as pyridine, triethylamine and DBU, sodium hydroxide,
Inorganic bases such as potassium hydroxide, sodium carbonate and potassium carbonate can be mentioned, and preferred are sodium hydroxide and potassium carbonate. The base may be used in an amount of 1 to 2 equivalents.

This reaction may be carried out in a solvent, and the solvent used may be the same as that used in the step of producing compound (2) from compound (1).

The reaction temperature may range from -10 ° C to 30 ° C, preferably from 0 ° C to 10 ° C. Reaction times may range from 2 hours to 15 hours.

The compound (3) can be isolated by column chromatography using silica gel or the like, but the reaction in the next step can be carried out continuously without isolating and purifying the compound (3).

When the compound (3) is produced continuously after the production of the compound (2) from the compound (1), the reaction system for producing the compound (2) is already basic, The compound (3) can be produced by raising the temperature of the reaction solution containing the compound (2).

Compound (4) is produced from compound (3)
Step Compound (3) can be converted to compound (4) by treating with a cyanating reagent.

Examples of the cyanating reagent used in this step include sodium cyanide, potassium cyanide, and trimethylsilyl cyanide. Preferably, potassium cyanide is used, and the amount used may be in the range of 1 to 2 equivalents.

The reaction temperature is preferably in the range of 20 ° C. to 50 ° C. Reaction times may range from 6 hours to 24 hours.

The compound (4) can be purified by column chromatography using silica gel or the like, but the compound (4) can be used in the next step without isolation and purification.

Compound (5) is produced from compound (4)
Step Compound (5) can be obtained by converting the nitrile group of compound (4) to an amidoxime group.

Examples of the reagent used for the conversion include an aqueous solution of hydroxylamine, hydroxylammonium sulfate, hydroxylammonium hydrochloride and the like, and an aqueous solution of hydroxylamine is preferred. The reagent may be used in the range of 3 to 10 equivalents to compound (4). When an ammonium salt is used, an equivalent amount of a neutralizing base is required. The neutralizing base may be either an organic base or an inorganic base, and examples thereof include pyridine, triethylamine, DBU, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide.

As the solvent used in this reaction, any solvent can be used as long as it is inert to the reaction, but ethanol is preferred. The reaction is usually carried out by heating under reflux. Reaction times may range from 2 hours to 15 hours.

The compound (5) can be purified by column chromatography using silica gel or the like, but the compound (5) can be used in the next step without isolation and purification.

Compound (6) is produced from compound (5)
Step Compound (5) can be converted to compound (6) by reduction.

For the reduction, a hydrogenolysis reaction may be performed in the presence of a catalyst and a hydrogen source.

As the catalyst, palladium-carbon is preferred. When 10% palladium-carbon is used, a catalyst having a weight of about 0.1 to 0.2 times the weight of the compound (5) may be used. Examples of the hydrogen source include hydrogen gas and formic acid, but hydrogen gas is preferable, and the pressure of the hydrogen gas may be about 1 atm. .

This reaction is usually carried out in a solvent, and any solvent can be used as long as it is inert to the reaction, but ethanol is preferred. The reaction temperature may be about room temperature. The reaction time may range from 3 hours to 15 hours, but usually the reaction is completed in about 3 hours to 4 hours.

In this reaction, if the oxime hydroxyl group of compound (5) is acetylated, the reaction proceeds rapidly. Acetic anhydride is preferred as the acetylating reagent,
It is used in the range of 1 to 2 equivalents based on compound (5).
After the compound (5) is acetylated, the reduction reaction may be performed, or the acetylation reagent may be coexisted in the reaction system at the start of the reduction reaction.

When the compound (6) is formed as a salt, the corresponding salt can be obtained by treating the compound with an organic acid such as acetic acid or formic acid or an inorganic acid such as hydrochloric acid. The resulting salt can be isolated and purified.

Compound (6) or a salt thereof to compound
Step of producing (7) Compound (7) can be obtained by reacting compound (6) or a salt thereof with halogenoacetaldehyde or a derivative thereof in the presence of a base.

The derivative of halogenoacetaldehyde is represented by the formula

[0079]

Embedded image (Wherein, X ⁴ represents a halogen atom, and M represents an alkali metal). An alkali metal salt of halogenoacetaldehyde bisulfite represented by the following formula:

In this step, halogenoacetaldehyde or a derivative thereof is used in an amount of 1 to 5 equivalents based on compound (6).

As the base to be used, pyridine, triethylamine, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, calcium hydride, sodium methoxide, sodium ethoxide, potassium-
Although t-butoxide, DBU, Dabco, etc. can be mentioned, it may be used in the range of 3 to 10 equivalents to compound (6).

As the solvent used in this reaction, any solvent can be used as long as it is inert to the reaction. Preferably, a chlorinated solvent such as dichloromethane, chloroform and 1,2-dichloroethane, and dimethylformamide are used. And amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide, and nitriles such as acetonitrile. The solvent is 3 for compound (6).
The amount may be 0 to 100 times (for example, 30 to 100 ml per 1 g of compound (6)).

The reaction may be carried out at a temperature in the range of about room temperature to 80 ° C., preferably in the range of 20 ° C. to 30 ° C.
Reaction times typically range from 15 hours to 72 hours.

Compound (7) can be isolated by column chromatography using silica gel or the like.

From compound (7) to compound (8a) and / or
Alternatively, a step of producing compound (8b) When compound (7) is treated with a halogenating reagent, compound (8a) and / or compound (8b) can be obtained.

As the halogenating reagent, thionyl chloride,
Thionyl bromide, sulfuryl chloride and the like can be used, but thionyl chloride is preferably used. The halogenating reagent is used in the range of 1 equivalent to 2 equivalents based on compound (7).

The reaction may be carried out in a solvent. As the solvent used, chloroform, methylene chloride, 1,1-
Dichloroethane, 1,2-dichloroethane and the like can be used, but it is preferable to carry out the reaction by adding diethyl ether to these single solvent systems.

The reaction can be carried out at a temperature in the range of 0 ° C. to 40 ° C., preferably at a temperature in the range of 20 ° C. to 30 ° C. The reaction is completed in 1 to 5 hours.

The main product obtained by the halogenation reaction of compound (7) is compound (8a), and in addition, compound (8b) may be obtained as an auxiliary product.
Both of the compound (8a) and the compound (8b) give a compound (9) which is a closed-ring compound. Therefore,
These may be used in the next step without separation and purification.

Compound (8a) and / or compound (8
Step of producing compound (9) from b) Compound (9) can be obtained by cyclizing compound (8a) and / or compound (8b).

The ring closure reaction may be carried out by heating compound (8a) and / or compound (8b) in the presence of sodium iodide or in the presence of a suitable base. Of these, ring closure is preferably performed in the presence of a base. As the base that can be used here, potassium carbonate, sodium hydride, potassium-t-butoxide, triethylamine, sodium hydroxide and the like can be used, and among these, sodium hydride, potassium-t-butoxide, and sodium hydroxide are preferable. . The base is the compound (8
It may be used in the range of 1 equivalent to 2 equivalents relative to a) and / or compound (8b).

This ring closure reaction may be carried out in a solvent,
As the solvent to be used, methylene chloride, 1,1-dichloroethane, 1,2-dichloroethane (when these do not use a base), acetonitrile, dimethylformamide, dimethylsulfoxide and the like can be used, and dimethylformamide and dimethylsulfoxide can be used. preferable. The amount of the solvent used is 10 to 20 times the amount of the compound (8a) and / or the compound (8b) (for example, 1 to 1 g of the compound (8a) and / or the compound (8b).
(From 0 ml to 20 ml). Compound (9) can be purified by column chromatography using silica gel.

Compound (10) is produced from compound (9)
That step Compound (9) Compound by leaving the protective group R ¹ from (10) can be obtained.

[0094] This step may be selected reaction conditions usually used depending on the protecting group R ^1. For example, a decomposition reaction by an acid and the like can be mentioned.

[0095]

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples. Example 1 4- (4-methoxybenzylthio) -3-hydroxy-
Butyronitrile epichlorohydrin (500 mg, 5.40 mmol)
And 4-methoxybenzylthiol (850 mg, 5.5
1 mmol) in ethanol (10 ml).
Cooled to 7 ° C. Sodium hydroxide (260 mg, 6.
50 mmol) in water (1.5 ml)
It was added dropwise over 5 minutes. At this time, the internal temperature was kept at -10 ° C or lower. Next, after stirring at an internal temperature of 0 ° C. for 3 hours, potassium cyanide (700 mg, 10.7 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours and further at 50 ° C. for 1.5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The residue obtained is chromatographed on silica gel (Merck Art 7734; 30).
g; chloroform), and the title compound (872 m
g, 68%).

IR (KBr-disk); 3460, 2
916, 2836, 2252, 1610, 1510, 1
300, 1246, 1176, 1028 cm ^-1 . MS (m / z); 237, 153, 121. ¹ H-NMR (CDCl ₃ ) δ; 7.23 (d, 2H, J
= 8.6Hz), 6.87 (d, 2H, J = 8.6H)
z), 3.88 (m, 1H), 3.81 (s, 3H),
3.71 (s, 2H), 2.70 (dd, 1H, J = 1
3.9 and 4.6 Hz), 2.61 (dd, 1H,
J = 16.5 and 5.6 Hz), 2.55 (d
d, 1H, J = 13.9 and 7.9 Hz), 2.
54 (dd, 1H, J = 16.5 and 5.9H
z).

Example 2 3- (4-methoxybenzylthio) -2-hydroxy-
1- [amino (hydroxyimino) methyl] propane 4- (4-methoxybenzylthio) -3-hydroxy-
Butyronitrile (356 mg, 1.5 mmol) was dissolved in ethanol (3.6 ml), and a 50% aqueous hydroxylamine solution (495 mg, 7.5 mmol) was added.
After heating under reflux for 2 hours, a 50% aqueous hydroxylamine solution (495 mg, 7.5 mmol) was added, and an additional 13% was added.
Heated to reflux for an hour. After the ethanol was distilled off, 1N hydrochloric acid and ethyl acetate were added, and the mixture was separated by shaking. The aqueous layer was made alkaline with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The residue obtained is chromatographed on silica gel (Merck Art 773).
4; 10 g; methanol / chloroform = 5/95) to give the title compound (338 mg, 83%).

IR (KBr-disk); 3354,2
912, 2841, 1658, 1608, 1512, 1
302, 1246, 1176, 1034 cm ^-1 . MS (m / z); 270, 215, 149, 121. _{^{1 H-NMR (CDCl 3)}} δ; 7.21 (d, 2H, J
= 8.6 Hz), 6.84 (d, 2H, J = 8.6H)
z), 3.89 (m, 1H), 3.79 (s, 3H),
3.68 (s, 2H), 2.60 (dd, 1H, J = 1
3.9 and 4.6 Hz), 2.49 (dd, 1H,
J = 13.9 and 7.9 Hz), 2.38 (d
d, 1H, J = 14.8 and 3.3 Hz), 2.
24 (dd, 1H, J = 14.8 and 7.9H
z).

Example 3 3- (4-methoxybenzylthio) -2-hydroxy-
1-amidinopropane monohydrochloride 3- (4-methoxybenzylthio) -2-hydroxy-
1- [amino (hydroxyimino) methyl] propane (1.35 g, 5.0 mmol) was added to ethanol (40 m
l) and dissolved in acetic anhydride (0.51 g, 5.0 mmol).
l) and 10% palladium-carbon were added, and the mixture was stirred at room temperature under a hydrogen stream for 4 hours. After removing the catalyst by filtration, a 1N hydrochloric acid ethanol solution (10 ml) was added to the filtrate while stirring at room temperature, and the solvent was distilled off. The obtained crystalline residue was recrystallized from ethanol and ethyl acetate to give the title compound (1.30 g, 89
%).

IR (KBr-disk); 3290,3
064,1676,1608,1512,1306,1
240, 1178, 1034 cm ^-1 . MS (m / z); 255, 224, 121. _{^{1 H-NMR (D 2 O}} ) δ; 6.95 (d, 2H, J =
8.6 Hz), 6.60 (d, 2H, J = 8.6H)
z), 3.62 (m, 1H), 3.44 (s, 3H),
3.40 (s, 2H), 2.35 (dd, 1H, J = 1
4.5 and 4.0 Hz), 2.25 (dd, 1
H, J = 16.5 and 5.6 Hz), 2.55
(D, 2H, J = 5.9 Hz), 2.15 (dd, 1
H, J = 14.5 and 9.0 Hz). Elemental analysis _{(C 12 H 19 N 2 O} 2 as SCl) theory; C: 49.56, H: 6.58 , N: 9.6
3, Cl: 12.19, S: 11.03 measured values; C: 49.41, H: 6.79, N: 9.6
7, Cl: 12.16, S: 11.52

Example 4 3- (4-methoxybenzylthio) -2-hydroxy-
1- (2-imidazoyl) propane 3- (4-methoxybenzylthio) -2-hydroxy-
1-amidinopropane monohydrochloride (145 mg, 0.5 m
mol) was dissolved in dimethyl sulfoxide (4.2 ml), 1,8-diazabicyclo [5,4,0] -7-undecene (228 mg, 1.5 mmol), and then sodium chloroacetaldehyde bisulfite (183 mg,
1.0 mmol) and stirred at room temperature for 8 hours. In addition, sodium chloroacetaldehyde bisulfite (183m
g, 1.0 mmol) and stirred at room temperature for 16 hours. The reaction solution was poured into ice water, an aqueous sodium hydroxide solution was added, and the mixture was extracted three times with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography (Merck Art 7734; 6 g; methanol / chloroform = 5/95) to give the title compound (86.2 mg, 52%).

¹ H-NMR (CDCl ₃ ) δ; 7.20
(D, 2H, J = 8.8 Hz), 6.95 (s, 2
H), 6.84 (d, 2H, J = 8.8 Hz), 3.9
9 (m, 1H), 3.80 (s, 3H), 3.68
(S, 2H), 3.03 (dd, 1H, J = 15.1)
and 2.9 Hz), 2.82 (dd, 1H, J = 1)
5.1 and 7.8 Hz), 2.60 (dd, 1H,
J = 13.7 and 4.9 Hz), 2.46 (d
d, 1H, J = 13.7 and 8.3 Hz).

Example 5 3- (4-methoxybenzylthio) -2-hydroxy-
1- (2-imidazoyl) propane 3- (4-methoxybenzylthio) -2-hydroxy-
1-amidinopropane monohydrochloride (581.6 mg, 2.
0 mmol) in 15% aqueous acetonitrile (20 ml)
And dissolved in potassium carbonate (829.2 mg, 6.0 mm
ol) followed by bromoacetaldehyde (737.7 m
g, 6.0 mmol) and stirred at room temperature for 36 hours. The reaction solution was poured into ice water, an aqueous sodium hydroxide solution was added, and the mixture was extracted three times with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography (Merck Art 7734; 6 g; methanol / chloroform = 5/95) to give the title compound (390.0 mg, 70%).

NMR was consistent with that of Example 4.

[0105]

The production method of the present invention is a production method in which the desired compound (10) can be obtained in good yield using an inexpensive reagent without passing through an unstable intermediate.

Claims (16)

[Claims] 1. A compound of the general formula (1) (Wherein X ¹ represents a halogen atom) in the presence of a base and a compound represented by the general formula: (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. And a compound represented by the general formula (2): (Wherein R ¹ and X ¹ are the same as defined above), and the compound is subjected to ring closure in the presence of a base to give a compound of the general formula (3) (Wherein R ¹ is the same as defined above), and then the compound is treated with a cyanating reagent to give a compound of the general formula (4): (Wherein R ¹ is the same as defined above) and then reacted with hydroxylamines to give a compound of the general formula (5) (Wherein R ¹ is the same as defined above), and the compound is reduced to give a compound of the general formula (6) (Wherein R ¹ is the same as defined above) or a salt thereof, and in the presence of a base, (Wherein X ² represents a halogen atom) or a derivative thereof, and reacted with a compound represented by the general formula (7). (Wherein R ¹ is the same as defined above), and the compound is halogenated to obtain a compound represented by the general formula (8a): (Wherein X ³ represents a halogen atom, and R ¹ is the same as defined above) and / or a compound represented by the general formula (8b): (Wherein X ³ and R ¹ are the same as defined above), and then the ring is closed to form a compound of the general formula (9). (Wherein R ¹ is the same as defined above), wherein a substituent R ¹ is eliminated. A method for producing a compound represented by the formula: 2. A compound of the general formula (1) (Wherein X ¹ represents a halogen atom) in the presence of a base and a compound represented by the general formula: (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. And a compound represented by the general formula (2): (Wherein R ¹ and X ¹ are the same as defined above), and the compound is subjected to ring closure in the presence of a base to obtain a compound represented by the general formula (3). (Wherein R ¹ is the same as defined above), and then the compound is treated with a cyanating reagent to give a compound of the general formula (4) (Wherein R ¹ is the same as defined above) and then reacted with hydroxylamines to give a compound of the general formula (5) (Wherein R ¹ is the same as defined above), and then this compound is reduced to give a compound of the general formula (6) (Wherein R ¹ is the same as defined above) or a salt thereof, and in the presence of a base, (Wherein X ² represents a halogen atom) or a derivative thereof, and reacted with a compound represented by the general formula (7). (Wherein R ¹ is the same as defined above), and then the compound is halogenated, wherein the compound is represented by the general formula (8a): (Wherein X ³ represents a halogen atom, R ¹ is the same as defined above) and / or a compound of the general formula (8b) (Wherein X ³ and R ¹ are the same as defined above). 3. A compound of the general formula (1) (Wherein X ¹ represents a halogen atom) in the presence of a base and a compound represented by the general formula: (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. Which represents an acyl group which may be reacted with a compound represented by the general formula (2): (Wherein, R ¹ and X ¹ are the same as defined above). 4. A compound of the general formula (2) (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. Wherein X ¹ represents a halogen atom, and the compound represented by the general formula (3) is ring-closed in the presence of a base. (Wherein, R ¹ is the same as defined above). 5. A compound of the general formula (3) (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. Wherein the compound represented by the general formula (4) is treated with a cyanating reagent. (Wherein, R ¹ is the same as defined above). 6. A compound of the general formula (4) (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. Wherein the compound represented by the general formula (5) is reacted with a hydroxylamine. (Wherein, R ¹ is the same as defined above). 7. A compound of the general formula (5) (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. Wherein the compound represented by the general formula (6) is reduced: (Wherein R ¹ is the same as defined above) or a method for producing the compound or a salt thereof. 8. General formula (6) (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. A salt of the compound represented by the formula: or a salt thereof, in the presence of a base. (Wherein, X ² represents a halogen atom), characterized by reacting with an aldehyde compound or a derivative thereof represented by the following general formula (7): (Wherein, R ¹ is the same as defined above). 9. The derivative of the aldehyde compound has the formula: (Wherein X ⁴ represents a halogen atom and M represents an alkali metal). 10. A compound of the general formula (2) (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. And X ¹ represents a halogen atom.). 11. A compound of the general formula (3) (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. Represents an optionally substituted acyl group.). 12. A compound of the general formula (4) (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. Represents an optionally substituted acyl group.). 13. A compound of the general formula (5) (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. Represents an optionally substituted acyl group.). 14. A compound of the general formula (6) (Wherein, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group which may have a substituent, or a group having a substituent. And a salt thereof. 15. The conditions of the ring-closure reaction for obtaining the compound represented by the general formula (9) are as follows: the compound represented by the general formula (8a) and / or the compound represented by the general formula (8b) The production method according to claim 1, wherein the reaction conditions are such that the treatment is carried out under the condition or heating in the presence of sodium iodide. 16. The method according to claim 1, wherein the hydroxylamine is an aqueous hydroxylamine solution, hydroxylammonium sulfate or hydroxylammonium hydrochloride.
Or the manufacturing method according to claim 6.