WO1999033830A1

WO1999033830A1 - Process for the preparation of heterobicyclic thiol compound

Info

Publication number: WO1999033830A1
Application number: PCT/JP1998/005782
Authority: WO
Inventors: Toshifumi Akiba; Tatsuru Saito; Kazuaki Kanai
Original assignee: Daiichi Pharmaceutical Co., Ltd.
Priority date: 1997-12-26
Filing date: 1998-12-21
Publication date: 1999-07-08
Also published as: JPH11193285A; AU1684899A

Abstract

A process for the preparation of the compound represented by chemical formulae (1, 2, 3, 4, 5, 6, 7, 8a, 8b, 9, 10) which is useful as a raw material for the preparation of antibiotics; and intermediates used for the preparation of the compound: wherein X?1 and X3¿ are each halogeno; and R1 is (substituted) aralkyl, (substituted) diphenylmethyl, (substituted) triphenylmethyl or (substituted) acyl.

Description

Specification

For producing cyclic-heterocyclic thiol compounds

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

The present invention relates to a method for producing a bicyclic heterocyclic thiol compound which is a 3-position substituent of a 3-methylcarbapanem derivative represented by the formula: and a production intermediate thereof. Background art

The compound represented by the formula (11) (see Japanese Patent Application Laid-Open No. 2-235887. Hereinafter, the compound is represented by the compound (11). Other compounds are similarly represented.) Has a broad antibacterial spectrum, high antibacterial activity, and excellent safety, and is expected to be an excellent antibacterial substance. 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 was synthesized through the following production process using the compound (12) as a starting material (Japanese Patent Application Laid-Open No. Sho 62-1496983). See).

(In the formula, Ph represents a phenyl group, PMB represents a paramethoxybenzyl group, and Et represents an ethyl group.)

The above-mentioned production method has a step of utilizing the Mitsunobu reaction, and in this step, the operation of isolating the product is extremely complicated, and the reaction raw materials and reagents are relatively expensive, so that it is not easy to obtain a large amount. Therefore, there is room for improvement as an industrial manufacturing method.o

Further, the following production method using compound (13) as a starting material has also been developed (see Japanese Patent Application Laid-Open No. 9-241260), but the step of introducing a leaving group has a low yield. In addition, many of the production intermediates are unstable and difficult to isolate and purify.

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

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 for this production method. Disclosure of the invention

As a result of intensive studies, the inventor of the present invention obtained the desired bicyclic heterocyclic thiol compound (1) by converting the compound represented by the general formula (1) as a raw material according to the following steps. 0) can be industrially advantageously produced, and the present invention has been completed.

(In the formula, X ′ and X ³ each independently represent a halogen atom, and R ′ has an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, and a substituent. Represents an optionally substituted triphenylmethyl group or an optionally substituted phenyl group.)

That is, the present invention provides a compound represented by the general formula (1):

(In the formula, X ¹ represents a halogen atom.)

In the presence of a base, a compound represented by the general formula

R ¹ — SH

(Wherein, R ¹ has 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 which has a substituent. Represents an optionally substituted acyl group.) With the compound represented by the general formula (2)

FTS

X ¹ (2)

(In the formula, R 'and X' are the same as defined above.)

A compound represented by the general formula (3)

o (3)

(In the formula, R 'is the same as defined above.)

And then treating the compound with a cyanating reagent to obtain a compound represented by the general formula (4)

R, S

CN (4)

(Wherein R ¹ is as defined above.)

After reacting with a hydroxylamine, the compound represented by the general formula (5)

(Five)

(Wherein R ¹ is as defined above.) And then reducing this compound to obtain a compound represented by the general formula (6)

(Wherein R ¹ is as defined above.)

Or a salt thereof, and then in the presence of a base,

HO

(In the formula, X ² represents a halogen atom.)

With an aldehyde compound or a derivative thereof represented by the following formula:

(In the formula, R 'is the same as defined above.)

Then, the compound is halogenated to obtain a compound represented by the general formula (8a)

(In the formula, X ^{: 1} represents a halogen atom, and R ¹ is the same as defined above.) And a compound represented by the general formula (8): R, S

(Wherein X ³ and R ¹ are as defined above.)

The compound represented by the general formula (9)

(Wherein R ¹ is as defined above.)

A compound represented by the formula: wherein the substituent R ′ is eliminated.

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

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

R ¹ — SH

(Wherein, R ′ is 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 Represents an optionally substituted acyl group. )

Reacting with the compound represented by the general formula (2) to form a compound represented by the general formula (2), and ring-closing this compound in the presence of a base to obtain a compound represented by the general formula (3). After treating with a reagent to form a compound represented by the general formula (4), the compound is reacted with hydroxylamines to form a compound represented by the general formula (5), and then the compound is reduced, After converting the compound represented by the general formula (6) or a salt thereof into a compound represented by the formula

(In the formula, X ² represents a halogen atom.)

And a derivative thereof. The present invention relates to a method for producing a compound represented by the general formula (7).

R ¹ — SH

(In the formula, R ′ 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 substituent. Represents an optionally substituted acyl group.)

A method for producing a compound represented by the general formula (2), characterized by reacting with a compound represented by the following formula:

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

Alternatively, the compound represented by the general formula (3) is treated with a cyanating reagent. And a method for producing the compound represented by the general formula (4).

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

Further, the present invention relates to a method for producing a compound represented by the general formula (6) or a salt thereof, comprising 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

(In the formula, X ² represents a halogen atom.)

The general formula (2)

(Wherein, R ¹ has 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 which has a substituent. X ¹ represents a halogen atom, and X ¹ represents a halogen atom.

Furthermore, the general formula (3)

(Wherein, R ¹ is an aralkyl group which may have a substituent, It represents a good diphenylmethyl group, a triphenylmethyl group which may have a substituent or an acyl group which may have a substituent. )

With respect to the compound represented by

And the general formula (4)

(Wherein, R ¹ has 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 which has a substituent. Represents an optionally substituted acyl group.)

With respect to the compound represented by

Or 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 substituent. Represents an optionally substituted acyl group.)

With respect to the compound represented by

And the general formula (6)

(In the formula, R ′ is an aralkyl group which may have a substituent, It represents a good diphenylmethyl group, a triphenylmethyl group which may have a substituent or an acyl group which may have a substituent. )

And a salt thereof.

(Embodiment of the invention)

The present invention will be described.

First, the substituents of the compound used in the production method of the present invention 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 protective group for the mercapto group include an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenyloxynyl group which may have a substituent, and a substituent. And an optionally substituted acyl group. 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 an aralkyl group which may have a substituent, and among them, an aralkyl group which may have a substituent in a phenyl group portion is preferable. 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, for example, 4- Methoxybenzyl group, 4-cyclobutenyl group, 412 trobenzyl 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 2,4,6-trinitrobenzyl group.

The substituent X ′ represents a halogen atom, and a chlorine atom is preferred as the halogen atom.

Next, the manufacturing method of the present invention will be described.

The manufacturing method of the present invention comprises 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. A nitrile group is introduced into compound (3) to give compound (4).

4. Convert the nitrile group of compound (4) to an amide oxime group to obtain 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, thereby obtaining a compound (7).

7. Treat compound (7) with a halogenating reagent to give compound (8a) and Z or compound (8b).

8. Compound (8a) and Z or compound (8b) are closed to give compound (9).

9. The protecting group of compound (9) is removed to obtain compound (10).

Each step will be described in detail below.

Step of producing compound (2) from compound (1)

When the compound (1) is reacted with a thiol compound (R'-SH) in the presence of a base, the compound (1) can be converted to the 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 desired compound (10) can be obtained as an optically active form.

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

Examples of the base used include organic bases such as pyridine, triethylamine and DBU, and inorganic bases such as sodium hydroxide, sodium hydroxide, sodium carbonate and potassium carbonate. Preferably, water is used. Sodium oxide and potassium carbonate. The amount of the base used may be 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, aqueous ethanol, acetone, dichloromethane, chloroform Examples include form and dimethylformamide. Of these, hydrous ethanol is preferable, and hydrous ethanol The percentage can range from 10% to 50%, and preferably ranges from 30% to 40%. The solvent may be used in an amount of 15 to 25 times the amount of the compound (1) (for example, 15 ml to 25 ml per 1 g of the compound (1)).

Reaction temperatures may range from 150 to 0 ° C, preferably from 120 ° C to 110 ° C. The reaction time may be generally 0.5 to 2 hours.

Compound (2) can be isolated by column chromatography using silica gel or the like, and the reaction of the next step can be performed continuously without isolating and purifying compound (2).

Step of producing compound (3) from compound (2)

When the compound (2) is treated under basic conditions, a ring closure reaction involving a dehydrohalogenation reaction proceeds to obtain a compound (3).

Examples of the base used include organic bases such as pyridine, triethylamine and DBU, and inorganic bases such as sodium hydroxide, hydroxide hydroxide, sodium carbonate, carbonate carbonate, and the like. Preferably, sodium hydroxide. And potassium carbonate. The amount of the base used may be 1 to 2 equivalents.

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

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

Compound (3) can be isolated by column chromatography using silica gel, etc. The reaction in the next step can be performed continuously without isolating and purifying Compound (3).

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

Step of producing compound (4) from compound (3)

Compound (3) can be converted to compound (4) by treating with a cyanating reagent. As the cyanating reagent used in this step, sodium cyanide, lithium cyanide, trimethylsilyl cyanide and the like are strong, preferably lithium cyanide, and the amount used is 1 to 2 equivalents. Range is fine.

The reaction temperature is preferably in the range of 10 ° C to 50 ° C. Reaction times may range from 6 hours to 24 hours.

The compound (4) can be used for the reaction of the next step without isolating and purifying the compound (4) without the need to isolate and purify the compound (4) by column chromatography using silica gel.

Step of producing compound (5) from compound (4)

Compound (5) can be obtained by converting the nitrile group of compound (4) to an amide oxime group.

As the reagent used for the conversion, an aqueous solution of hydroxylamine, hydroxyammonium sulfate, hydroxyammonium hydrochloride and the like are strong, 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 base is required. The base may be either an organic base or an inorganic base, and examples thereof include pyridine, triethylamine, DBU, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like.

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, etc. The compound (5) can be used in the next step reaction without isolation and purification o

Step of producing compound (6) from compound (5)

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.

Palladium-carbon is preferred as the catalyst. When using 10% palladium on carbon, use a catalyst about 0.1 to 0.2 times the weight of compound (5). Just use it. Examples of the hydrogen source include hydrogen gas and formic acid.

Hydrogen gas is preferable, and the pressure of 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, and preferably ethanol can be used. The reaction temperature may be about room temperature. The reaction time may be in the range of 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. As the acetylating reagent, acetic anhydride is preferable, and it is used in the range of 1 to 2 equivalents to the compound (5). After the compound (5) is acetylated, the reduction reaction may be performed, but 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 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.

Step of producing compound (7) from compound (6) or a salt thereof

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

Derivatives of halogenoacetoaldehyde include those of the formula

(In the formula, X ′ represents a halogen atom, and M represents an alkali metal.)

And a halogenoacetyl aldehyde bisulfite metal salt represented by the following formula:

In this step, compound (6) is reacted with halogenoacetoaldehyde or its derivative. Use the body in the range of 1 to 5 equivalents.

As the base to be used, pyridine, triethylamine, potassium carbonate, sodium hydroxide, hydroxide hydroxide, sodium hydride, calcium hydride, sodium methoxide, sodium ethoxide, potassium butoxide, DBU, Dabco, etc. The force that can be used 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, 1,2-dichloroethane, or the like, Examples thereof include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfokinde, and nitriles such as acetonitrile. The solvent may be used in an amount of 30 to 100 times the amount of the compound (6) (for example, 30 to 100 ml of 1 g of the compound (6)).

The reaction temperature may be 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.

Step of producing compound (8a) and / or compound (8b) from compound (7) When compound (7) is treated with a halogenating reagent, compound (8a) and Z or compound (8b) are obtained. Can be.

As the halogenating reagent, thionyl chloride, thionyl bromide, sulfuryl chloride and the like can be used, but it is preferable to use thionyl chloride. The halogenating reagent is a compound (

Use in the range of 1 to 2 equivalents to 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. It is preferable to carry out the reaction by adding one ter.

The reaction can be carried out in the range of 0 ° C to 40 ° C, but is preferably carried out 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. Each of these compounds (8a) and (8b) gives compound (9) which is a closed-ring compound. Therefore, they can be used in the next step without separation and purification.

Step of producing compound (9) from compound (8a) and / or compound (8b) By closing the ring of compound (8a) and / or compound (8b), compound (9) can be obtained .

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. Bases that can be used here include potassium carbonate, sodium hydride, potassium monobutoxide, triethylamine, sodium hydroxide, etc. Among these, sodium hydride, potassium-t-butoxide, hydroxide Sodium is preferred. The base may be used in the range of 1 equivalent to 2 equivalents based on compound (8a) and / or compound (8b).

This ring closure reaction may be carried out in a solvent. Examples of the solvent used include methylene chloride, 1,1-dichloroethane, 1,2-dichloroethane (when these do not use a base), acetonitrile, and dimethyl. Formamide, dimethyl sulfoxide and the like can be used, but dimethyl formamide and dimethyl sulfoxide are preferred. The amount of solvent used is 10 to 20 times the amount of compound (8a) and Z or compound (8b) (for example, 1 g of compound (8a) and / or 1 g of compound (8b). (At a rate of 10 m 1 to 20 m 1). Compound (9) can be purified by column chromatography using silica gel.

Step of producing compound (10) from compound (9)

Compound (9) Compound by leaving the protective group R ¹ from (1 0) can be obtained.

In this step, reaction conditions usually used may be selected according to the protecting group R ¹ . For example, a decomposition reaction by an acid and the like can be mentioned. BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto. For specific examples of the production of the compound (7) to the compound (10), see JP-A-9-329394.

[Example 1]

4- (4-methoxybenzylthio) 1-3-hydroxy-butyronitrile

Dissolve Epichlorohydrin (500 mg, 5.40 mmo 1) and 4-Methoxybenzylthiol (850 mg, 5.51 mm 01) in ethanol (10 m 1) And — cooled to 17 ° C. A solution of sodium hydroxide (26 mg, 6.50 mmo 1) dissolved in water (1.5 ml) was added dropwise over 15 minutes. At this time, the internal temperature was kept at 110 ° C or lower. Then, after stirring at an internal temperature of 0 ° C for 3 hours, potassium cyanide (

700 mg, 10.7 mmo 1), add 1.5 hours at room temperature, and then add 1.

Stir for 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 resulting residue was subjected to gel chromatography on a silica gel (Merck Art 734; 30 g; black form) to give the title compound (872 mg, yield 68%). Obtained. IR (KB r—disk); 3 4 6 0, 2 9 16, 2 8 3 6, 2 2 5 2 7 6, 1 0 2 8 cm " ¹ .

MS (m / z); 2 3 7, 1 5 3, 1 2 1.

Ή-NMR (CD C 13) δ; 7.23 (d, 2 H, J = 8.6 H z), 6.

8 7 (d, 2 H, J = 8.6 Hz), 3.88 (m, 1 H), 3.81 (s, 3 H), 3.71 (s, 2 H), 2.70 (dd, 1H, J = 13.9 and 4.6Hz), 2.61 (dd, 1H, J = 16.5 and 5.6Hz), 2. 5 5 (dd, 1 H, J = 13.9 and 7.9 Hz), 2.54 (dd, 1 H, J = 16.5 and 5, 9 Hz).

[Example 2]

3- (4-Methoxybenzylthio) 1 2—Hydroxy 1-11 [Amino (hydroximino) methyl propane 4-(4-Methoxybenzylthio) 1-3-hydroxy-butyronitrile (356 mg, 1.5 mmo 1) was dissolved in ethanol (3.6 ml), and 50% hydroxyxylamine was dissolved. An aqueous solution (495 mg, 7.5 mmo 1) was added. After heating under reflux for 2 hours, a 50% aqueous solution of hydroxylamine (495 mg, 7.5 mmol) was added, and the mixture was further heated under reflux for 13 hours. After the ethanol was distilled off, 1N hydrochloric acid and ethyl acetate were added, and the mixture was shaken and separated. 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 obtained residue was subjected to silica gel chromatography (Mercck Art 7334; 10 g; methanol / chloroform / form = 5/95) to give the title compound (338 mg, yield 8). 3%).

IR (KB r-disk); 3 3 5 4, 2 9 1 2, 2 8 4 1, 1 6 5 8, 1 6 0 8, 1 5 1 2, 1 3 0 2, 1 2 4 6, 1 1 7 6, 1 0 3 4 cm ¹ .

MS (mZz); 27 0, 2 15, 1 49, 1 2 1.

_{Ή-NMR (CDC 1 3)} δ; 7. 2 1 (d, 2 H, J = 8. 6 H z), 6. 8 4 (d, 2 H, J = 8. 6 H z), 3. 8 9 (m, 1 H), 3.79 (s, 3 H), 3.68 (s, 2 H), 2.60 (dd, 1 H, J = 13.9 and 4. 6 Hz), 2.49 (dd, 1 H, J = 13.9 and 7.9 Hz), 2.38 (dd, 1 H, J = 14.8 and 3.3 H) z), 2.24 (dd, 1H, J = 14.8 and 7.9Hz).

[Example 3]

3- (4-Methoxybenzylthio) 1 2-hydroxy 1 1-Amidinopropane

• ¾a acid

3- (4-Methoxybenzylthio) 1-2-hydroxy-1-1- [amino (hydroxymino) methyl] propane (1.35 g, 5.0 mm 01) in ethanol (

Acetic anhydride (0.51 g, 5.0 mmo 1) and 10% paradigm carbon were added, and the mixture was stirred at room temperature under a hydrogen stream for 4 hours. After removing the catalyst by filtration, 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% yield). IR CKB r- disk); 3290, 3 06 4, 16 7 6, 16 08, 15 15 12, 13, 06, 12 04, 11, 78, 10 03 4 cm— '.

MS (m / z); 2 5, 5, 2 4, 1 2 1.

Ή-NMR (D ₂ 0) 5; 6.95 (d, 2 H, J-8.6 Hz), 6.60 (d, 2 H, J = 8.6 Hz), 3. 6 2 (m, 1 H), 3.44 (s, 3 H), 3.40 (s, 2 H), 2.35 (dd, 1 H, J = 14.5 and 4. 0 Hz), 2.25 (dd, 1 H, J = 16.5 and 5.6 Hz), 2.55 (d, 2 H, J = 5.9 Hz), 2. 1 5 (dd, 1 H, J = 14.5 and 9.0 Hz).

Elemental analysis (as _{_{_{C 12 H I 9 N 2 0}}} 2 SC 1)

Theoretical value; C: 49.56, H: 6.58, N: 9.63, C1: 12.19, S: 11.03

Measured value; C: 49.41, H: 6.79, N: 9.67, C1: 12.16, S: 1.1.52

[Example 4]

3- (4-Methoxybenzylthio) 1-2-Hydroxy-1-1 (2-I-midazolyl) propane

3- (4-Methoxybenzylthio) -l-hydroxyl-l-amidinopropane monohydrochloride (145 mg, 0.5 mmol) was dissolved in dimethylsulfoxide (4.2 ml). 1,8-diazabicyclo [5,4,0] —7-ndecene (2 28 mg, 1.5 mmo 1) followed by sodium chloroacetoaldehyde bisulfite (183 mg, 1.0 mmo 1) The mixture was stirred at room temperature for 8 hours. Further, sodium chloroacetaldehyde sodium bisulfite (183 mg, 1.0 mmo 1) was added, and the mixture was 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 734; 6 g; methanol Z-cloth form = 5/95) to give the title compound (86.2 mg, yield Rate of 52%).

_{Ή-NMR (CDC 1 3)} 5; 7. 2 0 (d, 2 H, J = 8. 8 H z), 6. 9 5 (s, 2 H), 6.84 (d, 2 H, J = 8.8 Hz), 3.99 (m, 1 H), 3.80 (s, 3 H), 3.68 (s, 2H), 3.03 (dd, 1H, J = 15.1 and 2.9Hz), 2.82 (dd, 1H, J = 15. 1 and 7.8 Hz), 2.60 (dd, 1 H, J = 1 3.7 and 4.9 Hz), 2.46 (dd, 1 H, J = 1 3.7 and 8.3 Hz).

[Example 5]

3- (4-Methoxybenzylthio) 1-2-Hydrox1-1-1 (2-imidazolyl) propane

3- (4-Methoxybenzylthio) 1-2-hydroxy_1-amidinopropane monohydrochloride (581.6 mg, 2.0 mmo1) in 15% aqueous acetonitrile (58%)

20 ml), add potassium carbonate (829.2 mg, 6.0 mmol), and then add bromoacetoaldehyde (737.7 mg, 6.0 mmol). At room temperature

The mixture was stirred 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-(Merc Art 773 4; 6 g; methanol / chloroform = 5/95) to give the title compound (390.0 mg, yield). 70%).

NMR was consistent with that of Example 4. Industrial applicability

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

Claims

l. General formula (i)

0,

X ¹ (1)

Mouth-blue

(In the formula, X ¹ represents a halogen atom.)

In the presence of a base, a compound represented by the general formula

R ¹ -SH

With the compound represented by the general formula (2)

(Where R 'and X ¹ are the same as defined above.)

A compound represented by the general formula (3)

(Wherein R ¹ is as defined above.) And then treating the compound with a cyanating reagent to obtain a compound represented by the general formula (

Four)

(In the formula, R 'is the same as defined above.)

After reacting with a compound represented by the general formula (5)

(Wherein R ¹ is as defined above.)

And then reducing this compound to obtain a compound represented by the general formula (6)

(Wherein R ¹ is as defined above.)

Or a salt thereof, and then in the presence of a base,

X 2

No Cho

(In the formula, X ² represents a halogen atom.)

Reacting with a compound represented by the formula or a derivative thereof;

(In the formula, R 'is the same as defined above.)

(Wherein X ³ represents a halogen atom, and R ′ is the same as defined above.) And / or a general formula (8b)

(Wherein X ³ and R ′ are the same as defined above.)

The compound represented by the general formula (9)

(Wherein R ¹ is as defined above.)

A method for producing a compound represented by the formula:

2. General formula (1)

0, "1 (1)

(In the formula, X ′ represents a halogen atom.)

In the presence of a base, a compound represented by the general formula

R ¹ — SH

With the compound represented by the general formula (2)

(In the formula, R 'and X' are the same as defined above.)

A compound represented by the general formula (3)

R ¹ S, Z? (3) (Wherein R ¹ is as defined above.)

(Wherein R ¹ is as defined above.)

After reacting with a compound represented by the general formula (5)

(Wherein, R ¹ is the same as defined above.)

(Wherein R ¹ is as defined above.)

Or a salt thereof, and then in the presence of a base,

X 2 CHO

(In the formula, X ² represents a halogen atom.)

A compound represented by the general formula (7): (7)

R, S

(Where R 'is the same as defined above.)

A method for producing a compound represented by the formula:

3. General formula (1)

0

X, (1)

(In the formula, X ′ represents a halogen atom.)

In the presence of a base, a compound represented by the general formula

R ¹ — SH

(In the formula, R ′ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group or a substituent which may have a substituent. Represents an optionally substituted acyl group.)

A compound represented by the general formula (2):

A method for producing a compound represented by the formula:

4. 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 substituent. Wherein X ¹ represents a halogen atom, and X ¹ represents a halogen atom.) The compound represented by the formula:

O

(3)

(Where R 'is the same as defined above.)

A method for producing a compound represented by the formula:

5. General formula (3)

0

R'S, I (3)

(In the formula, R ′ 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 which has a substituent. Represents an optionally substituted acyl group.)

Wherein the compound represented by the formula is treated with a cyanating reagent;

(Where R 'is the same as defined above.)

A method for producing a compound represented by the formula:

6. General formula (4)

Wherein the compound represented by the general formula (5) is reacted with a hydroxyamine.

R, S

(Wherein R ¹ is as defined above.)

A method for producing a compound represented by the formula:

7. General formula (5)

(In the formula, R ¹ represents an aralkyl group which may have a substituent, a diphenylmethyl group which may have a substituent, a triphenylmethyl group or a substituent which may have a substituent. Represents an optionally substituted acyl group.)

A compound represented by the general formula (6):

(Where R 'is the same as defined above.)

A method for producing a compound represented by the formula: or a salt thereof.

8. General formula (6)

In the presence of a base, a compound represented by the formula

(In the formula, χ ² represents a halogen atom.)

Characterized by reacting with an aldehyde compound represented by or a derivative thereof. General formula (7)

(7)

(In the formula, R 'is the same as defined above.)

A method for producing a compound represented by the formula:

9. Derivatives of aldehyde compounds have the formula

(In the formula, X ⁴ represents a halogen atom, and M represents an alkali metal.)

9. The production method according to claim 8, which is a compound represented by the formula:

1 0. General formula (2)

(In the formula, R ′ 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 substituent. X ′ represents a halogen atom, and X ′ represents a halogen atom.

1 1. General formula (3)

, /. (3)

(Wherein, R ¹ has 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 which has a substituent. Represents an optionally substituted acyl group.)

A compound represented by the formula:

1 2. General formula (4)

A compound represented by the formula:

1 3. General formula (5)

A compound represented by the formula:

1 4. General formula (6)

(In the formula, R ¹ has 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 which has a substituent. Represents an optionally substituted acyl group.)

And a salt thereof.

15. The conditions for the ring closure reaction to obtain the compound represented by the general formula (9) are as follows: 2. The method according to claim 1, wherein the reaction is carried out in the presence or heating conditions in the presence of sodium iodide.

16. The method according to claim 1, 2 or 6, wherein the hydroxylamine is an aqueous hydroxylamine solution, hydroxylammonium sulfate or hydroxylammonium hydrochloride.