JP5192730B2 - Method for producing mercaptoheterocyclic compound - Google Patents

Description

  The present invention relates to a method for efficiently producing a mercapto heterocyclic compound.

  Conventionally, mercapto compounds have been widely used as synthetic raw materials for various drugs and agricultural chemicals. Among these, mercapto heterocyclic compounds are recognized as highly useful as pharmaceuticals (Patent Document 2), but their production has industrial problems in terms of yield and raw materials.

  Specifically, a mercapto heterocyclic compound is obtained by subjecting a heterocyclic compound having a detachable substituent (such as a halogen group, a mesyl group, or a tosyl group) and a thiocarboxylic acid alkali salt or thiourea to a substitution reaction in advance. After reacting after protecting substituents other than the substituent to be caused, it can be produced by performing the deprotection reaction (Non-patent Document 1, Patent Documents 1 to 3). However, the production method using thiourea has a low yield of the target product and is not practical as an industrial production method (Patent Document 1).

Moreover, in the manufacturing method using thiocarboxylic acid alkali salt, since the raw material thiocarboxylic acid alkali salt is expensive, it is inadequate in an industrial practical level (nonpatent literature 1, patent documents 1-3). Considering industrial practicality and economic efficiency, it is preferable to use a cheaper metal sulfide or metal hydrosulfide as a sulfidizing agent instead of an expensive sulfiding agent typified by alkali salts of thiocarboxylic acids. In the technology, when sodium hydrosulfide is used as a sulfiding agent, the yield was low (Non-patent Document 1).
U.S. Pat. No. 3,328,415 JP-T-2002-543069 JP-A-4-103584 GEORG FUCH, ARKIV FOR KEMI, 1966, 26 (P.111-116)

  The present invention provides a method for industrially producing a mercaptoheterocyclic compound useful as a synthetic raw material or intermediate for pharmaceuticals and agricultural chemicals, or a permanent wave drug, in a high yield and with high yield using readily available raw materials. This is the issue.

  As a result of intensive studies, the present inventors have found a method for easily producing a mercapto heterocyclic compound from inexpensive and readily available raw materials, and have completed the present invention. That is, the present invention relates to the following items [1] to [16].

  [1] The following formula (1)

(X represents a structure of any of —O—, —S—, —NH—, and —NR ¹ —. R ¹ represents an alkyl group, an alkoxy group, or an alkoxyalkyl group having 1 to 6 carbon atoms. Y Represents an oxygen atom, a sulfur atom or NR ² , R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and Z ¹ represents a divalent organic residue having at least one mercapto group.
A method for producing a mercaptoheterocyclic compound represented by:
Metal sulfide or metal hydrosulfide and the following formula (2)

(X and Y are as defined in the above formula (1), and Z ² represents a divalent organic residue having at least one halogen group.) In the presence of a solvent at pH 7. A method for producing a mercaptoheterocyclic compound, characterized by reacting under a condition of 0 to 11.0.

[2] Z ¹ in the formula (1) is a divalent organic residue having one mercapto group, and the mercapto group is directly bonded to the 2-position carbon atom of the mercapto heterocyclic compound. Z ² in the formula (2) is a divalent organic residue having one halogen group, and the halogen group is attached to the carbon atom at the 2-position of the compound represented by the formula (2). The method for producing a mercapto heterocyclic compound according to [1], wherein the mercapto heterocyclic compound is directly bonded.

  [3] The mercapto heterocyclic compound represented by the formula (1) is 2-mercapto-4-butyrolactone (also known as 2-mercapto-4-butanolide), 2-mercapto-4-methyl-4-butyrolactone, 2 -Mercapto-4-ethyl-4-butyrolactone, 2-mercapto-4-butyrothiolactone, 2-mercapto-4-butyrolactam, N-methoxy-2-mercapto-4-butyrolactam, N-ethoxy-2-mercapto- 4-butyrolactam, N-methyl-2-mercapto-4-butyrolactam, N-ethyl-2-mercapto-4-butyrolactam, N- (2-methoxy) ethyl-2-mercapto-4-butyrolactam, N- (2- Ethoxy) ethyl-2-mercapto-4-butyrolactam, 2-mercapto-5-valerolactone, 2- Lucapto-5-valerolactam, N-methyl-2-mercapto-5-valerolactam, N-ethyl-2-mercapto-5-valerolactam, N- (2-methoxy) ethyl-2-mercapto-5-valerolactam [1], which is a mercapto heterocyclic compound selected from the group consisting of N- (2-ethoxy) ethyl-2-mercapto-5-valerolactam and 2-mercapto-6-hexanolactam. A method for producing a mercaptoheterocyclic compound.

  [4] The method for producing a mercapto heterocyclic compound according to any one of [1] to [3], wherein the metal sulfide is an alkali metal sulfide, an alkaline earth metal sulfide, or a mixture thereof.

  [5] The mercaptoheterocycle according to any one of [1] to [3], wherein the metal sulfide is at least one selected from the group consisting of sodium sulfide, potassium sulfide, calcium sulfide and magnesium sulfide. Compound production method.

[6] The method for producing a mercapto heterocyclic compound according to any one of [1] to [3], wherein the metal hydrosulfide is sodium hydrosulfide or potassium hydrosulfide.
[7] The mercaptoheterocycle according to any one of [1] to [6], wherein a mixed solvent having a weight ratio of water to an organic solvent of 1: 0.1 to 10 is used as the solvent. Compound production method.

  [8] The organic solvent is one or more solvents selected from the group consisting of methanol, N-methylpyrrolidone, acetone, 1,4-dioxane, 1,2-dimethoxyethane, and N, N-dimethylformamide. The method for producing a mercapto heterocyclic compound as described in [7], wherein

  [9] Any one of [1] to [8], wherein the pH is adjusted within the above range by adding an inorganic acid or an inorganic alkali to the reaction solution between the start and the end of the reaction. A method for producing the mercaptoheterocyclic compound described in 1.

[10] The method for producing a mercaptoheterocyclic compound according to any one of [1] to [9], wherein the reaction is performed at 40 ° C. or lower.
[11] The metal sulfide or metal hydrosulfide is dissolved or dispersed in a solvent, and the temperature of the resulting solution or slurry is adjusted to −20 to 40 ° C., while the solution or slurry is represented by the formula (2). The method for producing a mercaptoheterocyclic compound according to any one of [1] to [10], wherein the reaction is performed by adding a compound to be produced.

  [12] The metal sulfide or metal hydrosulfide is dissolved or dispersed in a solvent, and the pH of the resulting solution or slurry is adjusted to 7.5 to 11.0. The method for producing a mercaptoheterocyclic compound according to any one of [1] to [11], wherein the reaction is performed by adding a compound represented by the formula:

  [13] Adjusting the pH of the solution or slurry within the above range by adding an inorganic acid to the solution or slurry while adjusting the temperature of the metal sulfide or metal hydrosulfide solution or slurry to 40 ° C. or lower. The method for producing a mercaptoheterocyclic compound according to [12], wherein

  [14] The equivalent ratio of the compound represented by formula (2) and the metal sulfide or metal hydrosulfide used for the reaction is 1: 0.8 to 5.0. [1] A method for producing a mercapto heterocyclic compound according to any one of [13].

[15] The method for producing a mercaptoheterocyclic compound according to any one of [1] to [14], wherein the pH of the reaction solution after the reaction is adjusted to 2.0 to 6.0.
[16] The production of a mercaptoheterocyclic compound according to [15], wherein the pH of the reaction solution after the reaction is adjusted within the above range by adding an inorganic acid to the reaction solution after the reaction. Method.

  According to the production method of the present invention, the mercapto heterocyclic compound represented by the formula (1) can be obtained with high yield and high productivity. In addition, since the production method of the present invention does not include a step of protection and deprotection by a protecting group, it can be produced in a shorter step compared to the conventional production method, and further, halogenoheterocyclic compounds having various substituents can be obtained. Since it is applicable, it is extremely useful as an industrial production method.

  Hereinafter, the present invention will be specifically described.

<Mercapto heterocyclic compound>
The mercapto heterocyclic compound obtained by the production method of the present invention has the following formula (1):

(However, X shows the structure in any one of -O-, -S-, -NH-, -NR < ¹ >-. R < ¹ > shows a C1-C6 alkyl group, an alkoxy group, or an alkoxyalkyl group. Y represents an oxygen atom, a sulfur atom or NR ² , R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and Z ¹ represents a divalent organic residue having at least one mercapto group. ).

In the above formula (1), X represents a structure of any of —O—, —S—, —NH—, and —NR ¹ —. R ¹ is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or 1 carbon atom.
-6 alkoxyalkyl groups are shown. Among these, as R ¹ , an alkyl group having 1 to 4 carbon atoms, an alkoxy group, and an alkoxyalkyl group are preferable, and among them, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a methoxyethyl group, and an ethoxyethyl group are preferable. It is more preferable in terms of obtaining industrial raw materials and handling.

In the above formula (1), Y represents an oxygen atom, a sulfur atom or NR ² . R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. Among these, as R ² , a hydrogen atom,
A methyl group and an ethyl group are preferable from the viewpoint of easy availability of industrial raw materials and handling. Among those listed above, as Y, oxygen atoms are more preferable from the viewpoint of industrial raw material availability and handling.

In the above formula (1), Z ¹ represents a divalent organic residue having at least one mercapto group (—SH). One or more mercapto groups may be used, but one is more preferable. The organic residue Z ¹ is preferably a hydrocarbon group having a mercapto group bonded thereto, and may have a branch or a side chain. Examples of the side chain include an alkyl group and an alkenyl group.

Preferred examples of such a divalent organic residue include those in which a mercapto group is bonded to an alkylene group. There is no restriction | limiting in particular in the position which a mercapto group couple | bonds with an alkylene group.
The mercapto group may be bonded directly to the alkylene group or may be bonded via another alkylene group (for example, the mercaptoethyl group is bonded to the carbon atom in the alkylene group).

  However, when the mercapto group is directly bonded to the alkylene group, the mercapto group is constrained by the ring. When the compound of the above formula (1) is used as a permanent wave agent, the reactivity of the mercapto group in the compound of the above formula (1) with respect to the cystine bond of hair is increased. Therefore, it is preferable that the mercapto group is directly bonded to the alkylene group.

  When the mercapto group is directly bonded to the alkylene group, the mercapto group is a compound 2 of the mercapto heterocyclic compound represented by the above formula (1) from the viewpoint of reactivity when replacing the halogen group in the raw material compound with the mercapto group. It is preferably bonded to the carbon atom at the position. The “second-position carbon atom” refers to the first carbon atom on the opposite side to —X— as viewed from the carbon atom to which Y is bonded in formula (1). The same applies to the position of “2-position carbon atom” in formula (2). The alkylene group is preferably an alkylene group having 2 to 8, preferably 3 to 7 carbon atoms in the main chain. When the alkylene group has a side chain, examples of the side chain include an alkyl group having 1 to 3 carbon atoms and an alkenyl group.

As the mercapto heterocyclic compound represented by the above formula (1) that can be produced by the production method of the present invention,
2-mercapto-3-propiolactone, 2-mercapto-2-methyl-3-propiolactone, 2-mercapto-3-methyl-3-propiolactone, 2-mercapto-3-ethyl-3-propio Lactone, 2-mercapto-2,3-dimethyl-3-propiolactone, 2-mercapto-3-propiolactam, 2-mercapto-2-methyl-3-propiolactam, 2-mercapto-3-methyl- 3-propiolactam, 2-mercapto-3-ethyl-3-propiolactam, 2-mercapto-2,3-dimethyl-3-propiolactam, 2-mercapto-3-propiothiolactone, 2-mercapto 2-methyl-3-propiothiolactone, 2-mercapto-3-methyl-3-propiothiolactone, 2-mercapto-3-ethyl- - propiolactone thiolactone, 2-mercapto-2,3-dimethyl-3-propiolactone thiolactone,
3-mercapto-4-butyrolactone, 2,3-dimercapto-4-butyrolactone, 2,4-dimercapto-4-butyrolactone, 3,4-dimercapto-4-butyrolactone, 3-mercapto-4-butyrothiolactone, 3 -Mercapto-4-butyrolactam, 2,3-dimercapto-4-butyrolactam, 2,4-dimercapto-4-butyrolactam, 3,4-dimercapto-4-butyrolactam,
2-mercapto-4-butyrolactone (alias: 2-mercapto-4-butanolide), 2-mercapto-2-methyl-4,4-dimethyl-4-butyrolactone, 2-mercapto-3- (2-propenyl) -4 -Butyrolactone, 2-mercapto-4-methyl-4-butyrolactone, 2-mercapto-2-methyl-4-butyrolactone, 2-mercapto-3-methyl-4-butyrolactone, 2-mercapto-4-methyl-4-butyrolactone 2-mercapto-3,4-dimethyl-4-butyrolactone, 2-mercapto-2-ethyl-4-butyrolactone, 2-mercapto-3-ethyl-4-butyrolactone, 2-mercapto-4-ethyl-4-butyrolactone 2-mercapto-4-butyrothiolactone, 2-mercapto-2-methyl-4-but Rothiolactone, 2-mercapto-3-methyl-4-butyrothiolactone, 2-mercapto-4-methyl-4-butyrothiolactone, 2-mercapto-3,4-dimethyl-4-butyrothiolactone, 2 -Mercapto-2-ethyl-4-butyrothiolactone, 2-mercapto-3-ethyl-4-butyrothiolactone, 2-mercapto-4-ethyl-4-butyrothiolactone, 2-mercapto-4- Butyrolactam, 2-mercapto-2-methyl-4-butyrolactam, 2-mercapto-3-methyl-4-butyrolactam, 2-mercapto-4-methyl-4-butyrolactam, 2-mercapto-
3,4-dimethyl-4-butyrolactam, 2-mercapto-2-ethyl-4-butyrolactam, 2-mercapto-3-ethyl-4-butyrolactam, 2-mercapto-4-ethyl-4-butyrolactam,

3-mercapto-5-valerolactone, 4-mercapto-5-valerolactone, 2,3-dimercapto-5-valerolactone, 2,4-dimercapto-5-valerolactone, 2,5-dimercapto-5-valerolactone 3,4-dimercapto-5-valerolactone, 3-mercapto-5-valerothiolactone, 3-mercapto-5-valerolactam, 4-mercapto-5-valerolactam, 2,3-dimercapto-5-valerolactam 2,4-dimercapto-5-valerolactam, 2,5-dimercapto-5-valerolactam,
2-mercapto-5-valerolactone, 2-mercapto-2-methyl-5-valerolactone, 2-mercapto-3-methyl-5-valerolactone, 2-mercapto-4-methyl-5-valerolactone, 2- Mercapto-5-methyl-5-valerolactone, 2-mercapto-2-ethyl-5-valerolactone, 2-mercapto-3-ethyl-5-valerolactone, 2-mercapto-4-ethyl-5-valerolactone, 2-mercapto-5-ethyl-5-valerolactone, 2-mercapto-5-valerolactam, 2-mercapto-2-methyl-5-valerolactam, 2-mercapto-3-methyl-5-valerolactam, 2- Mercapto-4-methyl-5-valerolactam, 2-mercapto-5-methyl-5-valerolactam, 2-mercapto-2 Ethyl-5-valerolactam, 2-mercapto-3-ethyl-5-valerolactam, 2-mercapto-4-ethyl-5-valerolactam, 2-mercapto-5-ethyl-5-valerolactam, 2-mercapto- 5-valerothiolactone, 2-mercapto-2-methyl-5-valerothiolactone, 2-mercapto-3-methyl-5-valerothiolactone, 2-mercapto-4-methyl-5-valerothiolactone, 2- Mercapto-5-methyl-5-valerothiolactone, 2-mercapto-2-ethyl-5-valerothiolactone, 2-mercapto-3-ethyl-5-valerothiolactone, 2-mercapto-4-ethyl-5 Valerothiolactone, 2-mercapto-5-ethyl-5-valerothiolactone,

3-mercapto-6-hexanolactone, 4-mercapto-6-hexanolactone, 5-mercapto-6-hexanolactone, 2,3-dimercapto-6-hexanolactone, 2,4-dimercapto-6 Hexanolactone, 2,5-dimercapto-6-hexanolactone, 3-mercapto-6-hexanolactam, 4-mercapto-6-hexanolactam, 5-mercapto-6-hexanolactam, 2,3- Dimercapto-6-hexanolactam, 2,4-dimercapto-6-hexanolactam, 2,5-dimercapto-6-hexanolactam,
2-mercapto-6-hexanolactone, 2-mercapto-2-methyl-6-hexanolactone, 2-mercapto-3-methyl-6-hexanolactone, 2-mercapto-4-methyl-6-hexanolactone Lactone, 2-mercapto-5-methyl-6-hexanolactone, 2-mercapto-6-methyl-6-hexanolactone, 2-mercapto-6-hexanolactam, 2-mercapto-2-methyl-6 Hexanolactam, 2-mercapto-3-methyl-6-hexanolactam, 2-mercapto-4-methyl-6-hexanolactam, 2-mercapto-5-methyl-6-hexanolactam, 2-mercapto- 6-methyl-6-hexanolactam, 2-mercapto-6-hexanothiolactone, 2-mercapto-2-methyl-6-hexanothiolac 2-mercapto-3-methyl-6-hexanothiolactone, 2-mercapto-4-methyl-6-hexanothiolactone, 2-mercapto-5-methyl-6-hexanothiolactone, 2-mercapto-6- Methyl-6-hexanothiolactone,
2-mercapto-7-heptanolactone, 2-mercapto-7-heptanothiolactone, 2-mercapto-7-heptanolactam,
2-mercapto-8-octanolactone, 2-mercapto-8-octanothiolactone, 2-mercapto-8-octanolactam,
2-mercapto-9-nonalactone, 2-mercapto-9-nonathiolactone, 2-mercapto-9-nonalactam, and N-alkyl derivatives of these lactams (for example, N-methyl or N-ethyl derivatives), N -Alkoxy derivatives (for example, N-methoxy or N-ethoxy derivatives), N-alkylalkoxy derivatives (for example, N- (2-methoxy) ethyl or N- (2-ethoxy) ethyl derivatives), and the like.

Among these, the production method of the present invention includes 3-mercapto-4-butyrolactone, 2,3-dimercapto-4-butyrolactone, 2,4-dimercapto-4-butyrolactone, 3-mercapto-4-butyrolactam, 2,3 -Dimercapto-4-butyrolactam, 2,4-dimercapto-4-butyrolactam, 2-mercapto-4-butyrolactone (2-mercapto-4-butanolide), 2-mercapto-4-methyl-4-butyrolactone, 2-mercapto- 4-ethyl-4-butyrolactone, 2-mercapto-4-butyrothiolactone, 2-mercapto-4-butyrolactam, N-methoxy-2-mercapto-4-butyrolactam, N-ethoxy-2-mercapto-4-butyrolactam N-methyl-2-mercapto-4-butyrolactam, - ethyl-2-mercapto-4-butyrolactam, N-(2-methoxy) ethyl-2-mercapto-4-butyrolactam, N-(2-ethoxy) ethyl-2-mercapto-4-butyrolactam,
2,3-dimercapto-5-valerolactone, 2,4-dimercapto-5-valerolactone, 2,5-dimercapto-5-valerolactone, 3-mercapto-5-valerolactam, 4-mercapto-5-valerolactam 2,3-dimercapto-5-valerolactam, 2,4-dimercapto-5-valerolactam, 2,5-dimercapto-5-valerolactam, 2-mercapto-5-valerolactone, 2-mercapto-5-valero Lactam, N-methyl-2-mercapto-5-valerolactam, N-ethyl-2-mercapto-5-valerolactam, N- (2-methoxy) ethyl-2-mercapto-5-valerolactam, N- (2 -Ethoxy) ethyl-2-mercapto-5-valerolactam and 2-mercapto-6-hexanolactam It can be suitably used for production.

  Among these, the production method of the present invention includes 2-mercapto-4-butyrolactone (2-mercapto-4-butanolide), 2-mercapto-4-methyl-4-butyrolactone, 2-mercapto-4-ethyl-4- Butyrolactone, 2-mercapto-4-butyrothiolactone, 2-mercapto-4-butyrolactam, N-methoxy-2-mercapto-4-butyrolactam, N-ethoxy-2-mercapto-4-butyrolactam, N-methyl-2 -Mercapto-4-butyrolactam, N-ethyl-2-mercapto-4-butyrolactam, N- (2-methoxy) ethyl-2-mercapto-4-butyrolactam, N- (2-ethoxy) ethyl-2-mercapto-4 -Butyrolactam, 2-mercapto-5-valerolactone, 2-mercapto-5-vale Lactam, N-methyl-2-mercapto-5-valerolactam, N-ethyl-2-mercapto-5-valerolactam, N- (2-methoxy) ethyl-2-mercapto-5-valerolactam, N- (2 -Ethoxy) ethyl-2-mercapto-5-valerolactam and 2-mercapto-6-hexanolactam can be suitably used for industrial production.

<Halogeno heterocyclic compounds>
In the production method of the present invention, the halogeno heterocyclic compound used as a raw material for producing the mercapto heterocyclic compound is represented by the following formula (2).

(Wherein, X and Y are as defined in the above formula (1), Z ² is. Showing a divalent organic residue having at least one halogen group) is a compound represented by the.
The halogeno heterocyclic compound of the above formula (2) reacts with a metal sulfide or a metal hydrosulfide to form a mercapto heterocyclic compound of the above formula (1). Therefore, X and Y in the above formula (2) are intended. X and Y of the compound of the above formula (1) are the same.

In the above formula (2), on the condition that Z ² is not the same as Z ¹ in the above formula (1), at least one halogen group (in the present invention, —F, —Cl, —Br, —I A divalent organic residue having any one of -At). Since the halogen group of Z ² is substituted with the mercapto group of the mercapto heterocyclic compound represented by the above formula (1) by the reaction of the halogeno heterocyclic compound with a metal sulfide or a metal hydrosulfide, the halogen group The number and position correspond to the number and position of the Z ¹ mercapto group in the above formula (1), and Z ² and Z ¹ each have a halogen group or a mercapto group. Only different. In other words, the site other than the halogen group of Z ² and the site other than the mercapto group of Z ¹ are the same.

  Therefore, as the compound represented by the above formula (2), a compound in which the mercapto group of the target compound represented by the above formula (1) is a halogen group may be selected. For example, when 2-mercapto-4-butyrolactone is the target product, examples of the compound represented by the formula (2) include 2-chloro-4-butyrolactone, 2-bromo-4-butyrolactone, and 2-iodo-4. -Any one of butyrolactone and the like may be selected. In addition, when 2,3-dimercapto-5-valerolactam is the target product, 2,3-dichloro-5-valerolactam, 2,3-dibromo-5-valero as the compound represented by the formula (2) Any of lactam, 2,3-diiodo-5-valerolactam and the like may be selected.

The halogen group is preferably —Br from the viewpoints of reactivity and availability.
The halogenoheterocyclic compound represented by the above formula (2) can be obtained as a commercial product, or can be produced according to a known method. For example, using commercially available lactone derivatives, thiolactone derivatives and cyclic ketone derivatives, US Pat. No. 4,247,468, J. MoI. Med. Chem. The halogenoheterocyclic compound represented by the above formula (2) is synthesized according to the method described in 1987.30.10.995-1998, Tetrahedron Asymmetry 2003.14.2587-2594, Tetrahedron Letters 2005.46.3041-3044, etc. it can.

<Metal sulfide or metal hydrosulfide>
The target mercapto heterocyclic compound (the above formula (1)) can be produced by the reaction of the corresponding halogeno heterocyclic compound (the above formula (2)) with a metal sulfide or a metal hydrosulfide.

Examples of the metal sulfide include alkali metal sulfides and alkaline earth metal sulfides, preferably sodium sulfide, potassium sulfide, magnesium sulfide and calcium sulfide. Of these, sodium sulfide and potassium sulfide are more preferable because they are inexpensive and easily available industrially.

  Examples of the metal hydrosulfide include alkali metal hydrosulfide, and sodium hydrosulfide and potassium hydrosulfide are preferable from the viewpoint of low cost and easy industrial availability.

<Solvent>
Solvents used for the reaction of the compound represented by the above formula (2) with metal sulfide or metal hydrosulfide include water; monoalcohols such as methanol, ethanol and isopropanol; polyhydric alcohols such as propylene glycol Ketones such as acetone and methyl ethyl ketone; ethers such as 1,4-dioxane, 1,2-dimethoxyethane, methyl-tert-butyl ether (MTBE), tetrahydrofuran (THF), and diethyl ether; ethyl acetate, butyl acetate and the like; Esters; N, N-dimethylformamide (DMF); N-methylpyrrolidone and the like can be mentioned, and these can be used alone or in combination of two or more. Among these, considering the reaction yield and the separation operation for the solvent-derived by-product, water, methanol, acetone, 1,4-dioxane, 1,2-dimethoxyethane, MTBE, THF, diethyl ether, DMF, N- It is more preferable to use one or two or more from the group consisting of methylpyrrolidone.

  The smaller the amount of the solvent used, the easier the side reaction proceeds. In that case, the yield of the mercapto heterocyclic compound represented by the above formula (1) may be reduced. On the other hand, when the amount of the solvent used is large, side reactions are suppressed and the yield of the mercaptoheterocyclic compound represented by the above formula (1) is improved, but the concentration of the reaction solution is diluted. May decrease. Therefore, the amount of solvent used is preferably determined in consideration of the reaction yield and productivity. Specifically, the aspect etc. which use a solvent by 100-2000 mass parts with respect to 100 mass parts of halogeno heterocyclic compounds represented by the said Formula (2) are mentioned, for example.

  Moreover, when using the mixed solvent which consists of 2 or more types of solvent as a solvent mentioned above, the mixed solvent which mixed water and the organic solvent mentioned above is preferable. In this case, from the viewpoint of improving the yield of the target product, as the organic solvent combined with water, among the organic solvents described above, methanol, N-methylpyrrolidone, acetone, 1,4-dioxane, 1,2-dimethoxyethane, One or more selected from the group consisting of THF and N, N-dimethylformamide are preferred, and 1,2-dimethoxyethane is more preferred.

  The mixing ratio of water and organic solvent is a weight ratio of water: organic solvent, preferably 1: 0.1 to 10, more preferably 1: 0.1 to 7.0, and still more preferably 1: 0.1 to 5.0.

<PH during reaction>
The reaction between the halogeno heterocyclic compound represented by the above formula (2) and the metal sulfide or metal hydrosulfide is preferably performed by bringing the halogeno heterocyclic compound and metal sulfide or metal hydrosulfide into contact with each other in the presence of a solvent. Is preferably performed by dissolving or dispersing the metal sulfide or metal hydrosulfide in the above-described solvent and bringing the resulting solution or slurry into contact with the halogeno heterocyclic compound.

The pH of the metal sulfide or metal hydrosulfide solution or slurry before pH adjustment is around 14, but during the reaction with the halogeno heterocyclic compound, the pH of the reaction solution is maintained at 7.0 to 11.0, It is important to react under this pH condition. The pH value of the reaction solution is preferably pH 7.0 to 10.0, and more preferably pH 7.0 to 9.5. When the pH value is less than 7.0, the conversion rate of the raw material does not increase and the yield tends to be low. When the pH value exceeds 11.0, the produced target product is decomposed by side reactions and collected. The rate tends to be low.

The pH value of the reaction solution may be measured using a commercially available pH meter. The temperature for measuring pH may be the temperature of the reaction solution at that time, and it is not necessary to change the temperature of the reaction solution in order to measure pH. That is, in the present invention, the pH value of the reaction solution is a value measured at the temperature during the reaction.

PH adjustment of the reaction solution
(I) In advance of the pH change of the reaction solution when the metal sulfide or metal hydrosulfide solution or slurry is reacted with the halogeno-heterocyclic compound, the pH of the solution or slurry is adjusted by adding an acid. You can do it before the reaction, such as adjusting it,
(ii) The reaction may be performed while adding an acid or alkali to the reaction solution,
Or
(iii) The above operations (i) and (ii) may be combined.

  When using a solution or slurry of a metal sulfide or metal hydrosulfide that has been previously adjusted in pH, the sulfurization is carried out so that the pH of the reaction solution during and after the addition of the halogeno-heterocyclic compound is within the predetermined pH range. It is preferable to adjust the pH of the metal or metal hydrosulfide solution or slurry.

  That is, it is desirable to adjust the pH in anticipation of a drop in the pH of the reaction solution during the reaction. Specifically, the pH of the metal sulfide or metal hydrosulfide solution or slurry is adjusted to 7.5 to 11. It may be adjusted to 0, preferably 8.0 to 10.0.

  By adjusting in this way, the pH of the reaction solution during the reaction can be maintained at 7.0 to 11.0, and the mercaptoheterocyclic compound represented by the above formula (1) can be produced with high yield. can do.

  Examples of the acid added for pH adjustment include inorganic acids and organic acids. Among these, an inorganic acid (mineral acid) is preferable from the viewpoint that no organic by-product is generated, and it is more preferable to use any one of hydrochloric acid, sulfuric acid, and nitric acid, which are industrially easily available. In this case, hydrochloric acid, sulfuric acid, and nitric acid may be used alone or in combination of two or more.

  When the pH is adjusted before the reaction, it is preferably carried out while keeping the temperature of the metal sulfide or metal hydrosulfide solution or slurry at 40 ° C or lower, more preferably 25 ° C or lower, and further preferably 15 ° C or lower. The lower limit of the temperature varies depending on the solvent to be used and is not particularly limited, but is generally preferably −20 ° C. or higher. In this case, the pH may be measured at the temperature.

  In addition, in order to adjust the pH of the reaction solution to pH 7.0 to 11.0 during the reaction, an acid or alkali is supplied according to the change in pH using a pH meter meter placed in the reaction solution. It is performed by maintaining the above pH range.

  As the acid, an inorganic acid or an organic acid can be used. Among these, an inorganic acid (mineral acid) is preferable from the viewpoint that no organic by-product is generated, and it is more preferable to use any one of hydrochloric acid, sulfuric acid, and nitric acid, which are industrially easily available. In this case, hydrochloric acid, sulfuric acid, and nitric acid may be used alone or in combination of two or more.

In addition, when alkali is used for pH adjustment, industrially general inorganic alkali is preferable, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydrosulfide, sodium sulfide, potassium sulfide, potassium hydrosulfide and the like. An aqueous solution is preferred.

  In addition, during these pH adjustments, hydrogen sulfide gas is generated by neutralization, thus preventing the release of hydrogen sulfide gas from the system, suppressing the total amount of acid required for pH adjustment, and improving the main reaction yield. From this point of view, it is preferable to use a closed reactor.

<Reaction operation>
Regarding the method of adding the halogenoheterocyclic compound represented by the above formula (2) to a metal sulfide or metal hydrosulfide solution or slurry, the halogenoheterocyclic compound is 2-halogeno-4-butyrolactone, 2-halogeno If it is a liquid compound at room temperature, such as -4-thiolactone, 2-halogeno-4-ethyl-4-butyrolactone, 2-halogeno-4-methyl-4-butyrolactone, add it after diluting in a solvent. It may be added as it is. However, in order to suppress a side reaction due to a local concentration gradient, a method of adding after diluting with a solvent is preferable. Similarly, a halogeno heterocyclic compound that is solid at room temperature is preferably diluted with a solvent before addition. As a solvent used for these dilution, any 1 or more types of organic solvents are mentioned preferably among the solvents used for the reaction mentioned above. The halogeno-heterocyclic compound may be dissolved using the organic solvent and added in the form of a solution to a metal sulfide or metal hydrosulfide solution or slurry.

  The temperature at which the halogeno heterocyclic compound represented by the above formula (2) is added to a metal sulfide or metal hydrosulfide solution or slurry greatly affects the yield of the target mercapto heterocyclic compound. It is preferable to cool a metal sulfide or metal hydrosulfide solution or slurry in advance, and the halogenoheterocyclic compound represented by the above formula (2) is added while cooling the reaction solution during the reaction as well. Is preferred. In this case, the set temperature is usually 40 ° C. or lower, preferably 25 ° C. or lower, more preferably 15 ° C. or lower, and further preferably 5 ° C. or lower. The lower limit of the set temperature is not particularly limited, but is preferably −20 ° C. or higher considering the productivity of the target product.

  In addition, the reaction system is maintained at a temperature of 40 ° C. or lower throughout the operation up to the completion of the reaction between the halogenoheterocyclic compound represented by the above formula (2) and the metal sulfide or metal hydrosulfide, including the above addition operation. Is desirable. The pressure during the reaction of the halogenoheterocyclic compound represented by the above formula (2) with a metal sulfide or metal hydrosulfide solution or slurry is preferably 0.09 to 0.50 MPa, and preferably 0.10 to 0.00. 30 MPa is more preferable. When the pressure is less than 0.09 MPa, the selectivity of the target product tends to decrease. On the other hand, when the pressure exceeds 0.50 MPa, a special reactor is required, which is not suitable for industrial production.

  The equivalent ratio of the halogenoheterocyclic compound represented by the above formula (2) to the metal sulfide or metal hydrosulfide used for the reaction (halogenoheterocycle compound: metal sulfide or metal hydrosulfide) is 1: 0. It is preferably 8 to 5.0, and more preferably 1: 1.0 to 5.0. If the equivalent ratio of the metal sulfide or metal hydrosulfide to the halogeno heterocyclic compound is less than the lower limit, the yield of the mercapto heterocyclic compound represented by the above formula (1) as the target product may be reduced. Moreover, when the equivalent ratio of the metal sulfide or metal hydrosulfide to the halogeno-heterocyclic compound exceeds 5.0, the reaction yield shows a high value, but the cost required for the treatment of the excess metal sulfide or metal hydrosulfide is high. As the pH increases, a large amount of acid is required to adjust the pH of the reaction solution. As a result, the concentration of the reaction solution decreases, the productivity deteriorates, and the industrial value tends to decrease.

The reaction solution after the reaction includes the mercapto heterocyclic compound represented by the above formula (1) and a thiolate anion of the mercapto heterocyclic compound. The reaction liquid after the reaction is neutral to alkaline, and the oxidation reaction of the target mercapto heterocyclic compound is likely to proceed. Of the mercaptoheterocyclic compounds represented by the above formula (1), a compound having a lactone skeleton is particularly susceptible to hydrolysis.

  Therefore, in order to suppress such a decrease in yield due to the oxidation reaction, the subsequent recovery and purification operations should be carried out with the pH being made more acidic by promptly adding acid to the reaction solution after the reaction. Is preferred. In this case, the preferable pH value range is 2.0 to 6.0.

  General-purpose inorganic acid and organic acid are mentioned as an acid added for pH adjustment of the reaction liquid after reaction. Among these, an inorganic acid (mineral acid) is preferable from the viewpoint that no organic by-product is generated, and one kind or a combination of two or more kinds is used from the group consisting of industrially easily available hydrochloric acid, sulfuric acid, and nitric acid. It is more preferable.

  Moreover, in order to suppress a hydrolysis reaction in a local low pH region during pH adjustment, it is preferable to add an acid while keeping the temperature of the solution at 25 ° C. or lower. Preferably it is 15 degrees C or less, More preferably, 5 degrees C or less is good. When the temperature exceeds 25 ° C., hydrolysis tends to proceed. There is no particular limitation on the lower limit of the temperature. It is sufficient that the pH can be adjusted without freezing the reaction solution.

Next, the recovery and purification operations of the target mercaptoheterocyclic compound will be described.
After adjusting the pH of the reaction solution after the reaction, an organic solvent incompatible with the reaction solution is added to the reaction solution after the pH adjustment, and the mercapto heterocyclic compound represented by the above formula (1) is included. Extract the organic phase.

  Examples of the organic solvent used for extraction include diethyl ether, MTBE, isopropyl ether, toluene, dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, butyl acetate, hexanol, and octanol. Two or more kinds can be used in combination. From the viewpoint of safety and industrial ease of handling, it is preferable to use one kind or a combination of two or more kinds from the group consisting of MTBE, chloroform, ethyl acetate, and butyl acetate.

  Further, depending on the type of solvent and the amount of solvent used in the reaction, the amount of metal sulfide or metal hydrosulfide used, etc., an inorganic salt may be precipitated in the reaction solution after the reaction. In this case, it is desirable to remove these by centrifugation or suction filtration before the extraction operation. The cake on the funnel in the centrifuge or by suction filtration may be washed with an organic solvent used for extraction.

  Next, the organic solvent of the extracted organic phase is distilled off. The liquid temperature of the distilled liquid when the organic solvent of the extracted organic phase is distilled off is preferably 100 ° C. or lower, and preferably 70 ° C. or lower. Further, the solvent may be distilled off under reduced pressure in consideration of the boiling point of the organic solvent used for extraction.

  The mercapto heterocyclic compound represented by the above formula (1) contained in the solution after the organic solvent used as the extraction solvent has been distilled off may be separated and purified by column chromatography as it is. When the compound of the above formula (1) is liquid, it may be purified by distillation purification. When performing distillation purification, in order to prevent thermal decomposition of the target mercaptoheterocyclic compound, it is preferable to carry out under reduced pressure conditions, and the degree of pressure reduction is adjusted so that the temperature of the liquid for distillation purification is maintained at 200 ° C. or lower. Good. In particular, it is preferable to adjust the degree of vacuum so that the temperature of the liquid is 150 ° C. or lower. In the case of a crystallizable compound, it may be purified by recrystallization.

EXAMPLES Hereinafter, although this invention is demonstrated further more concretely based on an Example, this invention is not limited to these Examples.
In the following examples, “%” is based on mass unless otherwise specified.

The conditions for high performance liquid chromatography analysis (hereinafter referred to as HPLC) in the following examples are as follows.
Column: Shodex NN-814 manufactured by Showa Denko KK (length 20 cm, inner diameter 0.5 cm)
Column temperature: 40 ° C
Eluent: 0.1% H ₃ PO ₄ , 8 mM-KH ₂ PO ₄
Flow rate: 1.5mL / min
Detection: RI, UV (detection wavelength 210 nm)
In the following examples, the pH value was measured using the following pH meter.

pH meter: Digital pH controller, manufactured by Tokyo Glass Instrument Co., Ltd. Model: FD-02
pH electrode: Tokyo Glass Instrument Co., Ltd., pH controller electrode Model: CE-108C

[Example 1]
Production of 2-mercapto-4-butyrolactone 70% sodium hydrosulfide (49 g, 0.6 mol, manufactured by Junsei Chemical Co., Ltd.), 1,2-dimethoxyethane (34 g, Junsei Chemical Co., Ltd., special grade) and purified water (distilled) Later, it was dissolved in a mixed solvent of 34 g) of water that passed through an ion exchange filter at room temperature. The solution was adjusted to pH 8.9 by adding hydrochloric acid (18 g, Junsei Chemical Co., Ltd., special grade 35% to 37%) with stirring under ice-cooling and normal pressure conditions (10 ° C. or less, about 0.10 MPa). . 2-Bromo-4-butyrolactone (34 g, 0.2 mol, manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise over about 20 minutes while cooling so that the temperature of the solution was maintained at 10 ° C. or lower. The reaction solution after completion of the dropwise addition was stirred for 2 minutes. The pH of the reaction solution from the start of dropping 2-bromo-4-butyrolactone to the stirring after completion of dropping was in the range of 7.5 to 8.9.

  Thereafter, hydrochloric acid (24 g) was added over about 5 minutes while cooling so that the temperature of the solution was 10 ° C. or lower, and the pH of the solution was adjusted to 4.0. After removing the inorganic salt precipitated in the solution by suction filtration, ethyl acetate (20 g, manufactured by Junsei Chemical Co., Ltd., special grade) was added to the filtrate side to extract the organic phase. The resulting aqueous phase was re-extracted with ethyl acetate (34 g). These extracted organic phases were combined, concentrated under reduced pressure, and purified by distillation to obtain 2-mercapto-4-butyrolactone (19 g, bp 94 ° C./0.3 kPa, yield 78%).

[Example 2]
Preparation of 2-mercapto-4-methyl-4-butyrolactone, except that 2-bromo-4-methyl-4-butyrolactone (36 g, 0.2 mol, manufactured by Aldrich) was used instead of 2-bromo-4-butyrolactone Prepared 2-mercapto-4-methyl-4-butyrolactone (20 g, bp 73 ° C./0.4 kPa, yield 77%) according to Example 1. The pH of the reaction solution from the start of dropping 2-bromo-4-methyl-4-butyrolactone to the stirring after the completion of dropping was in the range of 7.4 to 8.9.

[Example 3]
Production of 2-mercapto-4-ethyl-4-butyrolactone (1) Production of 2-bromo-4-ethyl-4-butyrolactone 90% in 4-ethyl-4-butyrolactone (46 g, 0.4 mol, manufactured by Aldrich) Add phosphorus tribromide (2 g, 0.07 mol, manufactured by Wako Pure Chemical Industries, Ltd.) at room temperature and add 10
Stir for minutes. The reaction solution was heated to 100 ° C., and bromine (64 g, 0.4 mol, manufactured by Junsei Chemical Co., Ltd.) was added dropwise from the dropping funnel over 1 hour. After completion of the dropwise addition, the reaction solution was stirred at 100 ° C. for 1 hour.

  After the reaction solution after the reaction was cooled to room temperature, water (100 g) was added little by little and stirred for 10 minutes. Furthermore, 200 g of ethyl acetate was added and extracted. The aqueous phase obtained by separation of the organic phase was re-extracted with ethyl acetate (90 g).

  These extracted organic phases are combined, dried over anhydrous sodium sulfate (manufactured by Junsei Co., Ltd.), and the organic phase from which sodium sulfate has been removed by filtration is concentrated and distilled under reduced pressure to give 2-bromo-4 -Ethyl-4-butyrolactone (50 g, bp. 104 ° C./0.4 kPa, yield 65%) was obtained.

(2) Production of 2-mercapto-4-ethyl-4-butyrolactone Instead of 2-bromo-4-butyrolactone, the above 2-bromo-4-ethyl-4-butyrolactone (39 g, 0.2 mol) was used. Then, the reaction was carried out according to Example 1, and the solution after the reaction was subjected to pH adjustment, suction filtration and extraction operation according to Example 1, and then purified by distillation to give 2-mercapto-4-ethyl-4-butyrolactone. (22 g, bp. 91 ° C./0.4 kPa, yield 75%) was obtained. The pH of the reaction solution from the start of dropping 2-bromo-4-ethyl-4-butyrolactone to the stirring after completion of dropping was in the range of 7.6 to 8.9.

[Example 4]
Production of 2-mercapto-4- butyrothiolactone (1) Production of 2-bromo-4-butyrothiolactone 4-Butyrothiolactone (100 g, 0.98 mol, manufactured by Aldrich) was dissolved in ethyl acetate (90 g, Dissolved in Junsei Chemical Co., Ltd.) and heated to 63 ° C. Bromine (180 g, 1.1 mol, manufactured by Junsei Chemical Co., Ltd.) was added dropwise over 15 minutes from the dropping funnel. After completion of dropping, the reaction solution was stirred at 63 ° C. for 24 hours.

The reaction solution after the reaction was cooled to room temperature, water (500 g) was added little by little, and the mixture was stirred for 10 minutes. Furthermore, 1000 g of ethyl acetate was added and extracted.
The aqueous phase obtained by separation of the organic phase was re-extracted with ethyl acetate (900 g). These extracted organic phases were combined, dried over anhydrous sodium sulfate (manufactured by Junsei Chemical Co., Ltd.), and the organic phase from which sodium sulfate was removed by filtration was concentrated and distilled under reduced pressure to give 2-bromo-4 -Butyrothiolactone (66 g, bp. 62 ° C./0.2 kPa, yield 37%) was obtained.

(2) Production of 2-mercapto-4-butyrothiolactone The 2-bromo-4-butyrothiolactone (36.2 g, 0.2 mol) was reacted according to Example 1 and reacted. The subsequent liquid was subjected to pH adjustment, suction filtration, and extraction operation according to Example 1, and then purified by distillation to give 2-mercapto-4-butyrothiolactone (21.4 g, bp. 62 ° C./0.00%). 2 kPa, yield 80%). The pH of the reaction solution from the start of dropping 2-bromo-4-butyrothiolactone to the stirring after completion of dropping was in the range of 7.5 to 8.9.

[Example 5]
Production of 2-mercapto-6-hexanolactam (1) Production of 2-bromo-6-hexanolactam Bromine (240 g, 1.5 mol, produced by Junsei Co., Ltd.) in benzene (50 g, produced by Junsei Chemical Co., Ltd.) Was cooled to 10 ° C. under ice cooling. 90% phosphorus tribromide (450 g, 1.6 mol, manufactured by Wako Pure Chemical Industries, Ltd.) was added to the cooled liquid while maintaining the reaction liquid temperature at 10 ° C. or lower, and the mixture was stirred for 60 minutes. A commercially available benzene (220 g) solution of 6-hexanolactam (85 g, 0.75 mol, Tokyo Chemical Industry Co., Ltd., product name ε-caprolactam) was added to the above reaction solution from the dropping funnel while maintaining the reaction solution temperature at 10 ° C. It was added dropwise over a period of minutes.

  After completion of the dropping, the reaction solution was heated to 45 ° C. and stirred for 5.5 hours. The reaction solution after the reaction was poured into 1000 g of ice, and the resulting benzene phase was separated and recovered. The recovered benzene phase was concentrated under reduced pressure to obtain 2-bromo-6-hexanolactam (53.5 g as crude crystals) as crude crystals.

(2) Production of 2-mercapto-6-hexanolactam Using the crude crystals of 2-bromo-6-hexanolactam (39 g), the reaction was carried out according to Example 1, and the solution after the reaction was carried out. According to Example 1, pH adjustment, suction filtration, and extraction operation were performed, and then the reaction solution was concentrated under reduced pressure to about half volume. To the concentrated liquid, ethyl acetate (330 g, manufactured by Junsei Chemical Co., Ltd., special grade) was added for extraction. The resulting aqueous phase was re-extracted with ethyl acetate (330 g). These extracted organic phases were combined and concentrated under reduced pressure to obtain 2-mercapto-6-hexanolactam as crude crystals. The crude crystals of 2-mercapto-6-hexanolactam were separated by silica gel column chromatography using hexane: ethyl acetate (volume ratio 2: 1) as a mobile phase to obtain crystals of 2-mercapto-6-hexanolactam. (26.1 g, 0.18 mol, 24% yield from 6-hexanolactam). The pH of the reaction solution from the start of 2-bromo-6-hexanolactam addition to the stirring after completion of the addition was in the range of 7.6 to 8.9.

[Example 6]
Synthesis of N-methyl-2-mercapto-4-butyrolactam (1) Production of 2,4-dibromobutyric acid bromide According to the method of Kamal et al. (Tetrahedron Asymmetry 2003, 14, 2587-2594), it was synthesized from 4-butyrolactone by the following method.

Phosphorus tribromide (12.5 g, 0.046 mol, manufactured by Tokyo Chemical Industry Co., Ltd.) was added to 4-butyrolactone (100 g, 1.15 mol, manufactured by Tokyo Chemical Industry Co., Ltd.).
Bromine (200 g, 1.25 mol, Wako Pure Chemical Industries, Ltd.) was added dropwise to the above solution over about 2 hours while stirring at a temperature of about 10 ° C. or lower. After dropping, the temperature was raised to 70 ° C., and bromine (200 g, 1.25 mol, Wako Pure Chemical Industries, Ltd.) was added dropwise over about 30 minutes. The solution after completion of the dropwise addition was heated to 80 ° C. and then stirred at 80 ° C. for 3 hours.

  After completion of the reaction, a glass tube was inserted into the lower part of the reaction solution, and nitrogen was blown from the glass tube to remove unreacted bromine and hydrogen bromide generated by the reaction. This reaction solution was distilled under reduced pressure to obtain 2,4-dibromobutyric acid bromide (190 g, 0.61 mol, bp. 87-88 ° C./0.7 kPa, yield 53%).

(2) Synthesis of N-methyl-2-bromo-4-butyrolactam N-methyl-2-bromo-4-butyrolactam According to the method of Kamal et al. (Tetrahedron Asymmetry 2003, 14, 2587-2594), it was synthesized from 2,4-dibromobutyric acid bromide by the following method.

2,4-dibromo so that a mixed solution of 40% methylamine aqueous solution (31.6 g, 0.4 mol, Junsei Chemical Co., Ltd.) and water 13.2 g was cooled to 10 ° C. or lower and kept at 10 ° C. or lower. Butyric acid bromide (148 g, 0.48 mol) was added dropwise over 15 minutes. After completion of dropping, the temperature was raised to 30 ° C. and stirred for 30 minutes. 200 g of chloroform was added to the reaction solution, and the organic phase was extracted. Magnesium sulfate was added to the separated organic phase and dried.

  The crude crystals obtained by concentrating the organic phase obtained by removing magnesium sulfate by filtration were washed with a 1: 1 solution of diethyl ether-hexane to give N-methyl-2,4-dibromobutyric acid amide (85. 6 g, 0.33 mol, mp 54 ° C., yield 69%). The obtained crystal was dissolved in THF (720 g, manufactured by Junsei Chemical Co., Ltd., special grade).

  The dissolved solution was cooled to 10 ° C. or lower under ice-cooling, and then 60% NaH in mineral oil (26.4 g, 0.66 mol, Junsei Chemical Co., Ltd.) was added little by little over about 15 minutes. After the addition, the mixture was warmed to room temperature and stirred for 2 hours. After the reaction solution after the reaction was concentrated to about 1/3 weight, the concentrated residue was put into ice water (400 g) and extracted with 400 g of chloroform. The concentrated residue obtained by concentrating the obtained chloroform phase was purified by silica gel column chromatography to obtain N-methyl-2-bromo-4-butyrolactam (45.6 g, 0.25 mol, yield 77%). It was.

(3) Synthesis of N-methyl-2-mercapto-4-butyrolactam 70% sodium hydrosulfide (19.1 g, 0.24 mol, manufactured by Junsei Chemical Co., Ltd.) and 1,2-dimethoxyethane (13.1 g, Junsei Chemical) It was dissolved at room temperature in a mixed solvent of purified water (made by Co., Ltd.) and purified water (water that passed through an ion exchange filter after distillation, 13.1 g). By adding hydrochloric acid (8.8 g, manufactured by Junsei Co., Ltd., special grade 35% to 37%) with stirring, the solution was ice-cooled under normal pressure conditions (10 ° C. or less, about 0.10 MPa), and pH 8. The temperature of the solution was cooled to 10 ° C. or lower under ice cooling. While cooling so that the temperature of the solution was maintained at 10 ° C. or lower, a mixed solution of N-methyl-2-bromo-4-butyrolactam (35.6 g, 0.2 mol) and DMF (156 g) was added to the cooled solution. It was added dropwise over about 30 minutes. The reaction solution after completion of the dropwise addition was stirred for 5 minutes. In addition, pH of the reaction liquid from the start of N-methyl-2-bromo-4-butyrolactam dropping to stirring after completion of dropping was within the range of 7.6 to 8.9.

  Then, hydrochloric acid (8.8g) was added over about 2 minutes, cooling so that the temperature of a solution might be 10 degrees C or less, and pH of the solution was adjusted to 6.0. After removing the inorganic salt precipitated in the solution by suction filtration, ethyl acetate (310 g, manufactured by Junsei Chemical Co., Ltd., special grade) was added to the filtrate side to extract the organic phase. The resulting aqueous phase was re-extracted with ethyl acetate (550 g). These extracted organic phases were combined and concentrated under reduced pressure. The residue obtained by concentration was purified by silica gel column chromatography to obtain N-methyl-2-mercapto-4-butyrolactam (20.6 g, 0.157 mol, yield 78%).

[Example 7]
Synthesis of 2-mercapto-4-butyrolactam (1) Synthesis of 2-bromo-4-butyrolactam 2,4-dibromobutyric acid bromide obtained by the method described in Example 6 was used instead of 40% aqueous methylamine solution. Except that ammonia water was used, 2,4-dibromobutyric acid amide (73.5 g, 0.30 mol, mp. 79 ° C., yield 63%) was obtained according to Example 6. The obtained crystal was dissolved in THF (650 g, Junsei Chemical Co., Ltd., special grade). The dissolved solution was adjusted to 10 ° C. or lower under ice cooling, and then 60% NaH in mineral oil (24 g, 0.60 mol, Junsei Chemical Co., Ltd.) was added little by little over about 15 minutes. After the addition, the mixture was warmed to room temperature and stirred for 2 hours. After the reaction solution was evaporated and concentrated to about 1/3 weight, the concentrated residue was put into ice water (360 g) and extracted with chloroform (360 g). The concentrated residue obtained by evaporating and concentrating the obtained chloroform phase was purified by silica gel column chromatography to obtain 2-bromo-4-butyrolactam (37.9 g, 0.23 mol, yield 27%).

(2) Synthesis of 2-mercapto-4-butyrolactam Examples were used except that 2-bromo-4-butyrolactam (32.8 g, 0.2 mol) was used instead of N-methyl-2-bromo-4-butyrolactam. 2-mercapto-4-butyrolactam (18.1 g, 0.15 mol, 77% yield) was synthesized according to 6. In addition, pH of the reaction liquid between the start of 2-bromo-4-butyrolactam dripping and the stirring after completion of the dripping was in the range of 7.6 to 8.9.

[Example 8]
Synthesis of N-ethyl-2-mercapto-4-butyrolactam (1) Synthesis of N-ethyl-2-bromo-4-butyrolactam 2,4-dibromobutyric acid bromide obtained by the method described in Example 6 was used. N-ethyl-2,4-dibromobutyric acid amide (91.7 g, 0.336 mol, yield 70%) was obtained according to Example 6 except that 70% ethylamine aqueous solution was used instead of 40% methylamine aqueous solution. Obtained. The obtained N-ethyl-2,4-dibromobutyric acid amide (81.9 g, 0.30 mol) was used for the reaction according to Example 7, and N-ethyl-2-bromo-4-butyrolactam (40 0.9 g, 0.21 mol, yield 71%).

(2) Synthesis of N-ethyl-2-mercapto-4-butyrolactam N-ethyl-2-bromo-4-butyrolactam (38.4 g, 0.2 mol) instead of N-methyl-2-bromo-4-butyrolactam N-ethyl-2-mercapto-4-butyrolactam (23.8 g, 0.16 mol, yield 82%) was synthesized according to Example 6 except that was used. The pH of the reaction solution from the start of dropping of N-ethyl-2-bromo-4-butyrolactam to the stirring after completion of dropping was in the range of 7.5 to 8.9.

[Example 9]
Synthesis of N-methoxy-2-mercapto-4-butyrolactam (1) Synthesis of N-methoxy-2-bromo-4-butyrolactam N-methoxy-2-bromo-4-butyrolactam was synthesized according to the method of Ikuta et al. (Journal of Medicinal Chemistry 1987, 30.1995-1998) was synthesized using 2,4-dibromobutyric acid bromide by the following method.

  O-methylhydroxyamine hydrochloride (52 g, 0.62 mol, manufactured by Junsei Chemical Co., Ltd.) and purified water (water passed through an ion exchange filter after distillation, 100 g) and chloroform (500 mL, Junsei Chemical Co., Ltd., special grade) The mixture was stirred under ice-cooling conditions, a mixed solution of 2,4-dibromobutyric acid bromide (169 g, 0.55 mol) and chloroform (100 mL) was added thereto, and then 100 mL of an aqueous solution in which NaOH (50 g) was dissolved was reacted. The solution was added dropwise while cooling so that the temperature was 10 ° C. or lower.

  After completion of the dropwise addition, the chloroform layer of the reaction solution was separated, and the layer was washed with 0.5 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and then dried over magnesium sulfate. The solution was concentrated under reduced pressure to obtain an oil (130 g) containing N-methoxy-2,4-dibromobutyric acid amide. This was used in the next reaction without any further purification.

After the obtained oil (130 g) containing N-methoxy-2,4-dibromobutyric acid amide was dissolved in benzene (500 mL), sodium hydride (12 g) was slowly added at 15 ° C. to 20 ° C. while cooling. Added. Ice was added to the reaction solution after the addition was completed to decompose excess sodium hydride, and the solution was washed with saturated brine and then dried over magnesium sulfate. The solution was concentrated under reduced pressure, then purified by silica gel-acetone / benzene column chromatography, and N-methoxy-2-bromo-4-butyrolactam (39 g, 0.2 mol, from 2,4-dibromobutyric acid bromide). Yield of 36%).

(2) Synthesis of N-methoxy-2-mercapto-4-butyrolactam N-methoxy-2-bromo-4-butyrolactam (39 g, 0.2 mol) was used instead of N-methyl-2-bromo-4-butyrolactam Except that, N-methoxy-2-mercapto-4-butyrolactam (23.8 g, 0.16 mol, yield 81%) was synthesized according to Example 6. In addition, pH of the reaction liquid from the start of N-methoxy-2-bromo-4-butyrolactam dropping to stirring after completion of dropping was in the range of 7.5 to 8.9.

[Example 10]
Synthesis of N-ethoxy-2-mercapto-4-butyrolactam (1) Synthesis of N-ethoxy-2-bromo-4-butyrolactam 2,4-dibromobutyric acid bromide (169 g, obtained by the method described in Example 6) 0.55 mol) and O-ethylhydroxyamine hydrochloride (61 g, 0.62 mol, manufactured by Wako Pure Chemical Industries, Ltd.) was used instead of O-methylhydroxyamine hydrochloride, according to Example 9. An oil (137 g) containing N-ethoxy-2,4-dibromobutyric acid amide was obtained. This was used in the next reaction without any further purification.

After the obtained oil (137 g) containing N-ethoxy-2,4-dibromobutyric acid amide was dissolved in benzene (500 mL), sodium hydride (12 g) was slowly added at 15 ° C. to 20 ° C. while cooling. Added. Ice was added to the reaction solution after the addition was completed to decompose excess sodium hydride, and the solution was washed with saturated brine and then dried over magnesium sulfate. The solution was concentrated under reduced pressure and then purified by silica gel-acetone / benzene column chromatography, and N-ethoxy-2-bromo-4-butyrolactam (42 g, 0.20 mol, 2,4-dibromobutyric acid bromide). Yield 37%).

(2) Synthesis of N-ethoxy-2-mercapto-4-butyrolactam N-ethoxy-2-bromo-4-butyrolactam (42 g, 0.2 mol) was used instead of N-methyl-2-bromo-4-butyrolactam Except that, N-ethoxy-2-mercapto-4-butyrolactam (24.8 g, 0.15 mol, yield 77%) was synthesized according to Example 6. In addition, pH of the reaction liquid between the start of N-ethoxy-2-mercapto-4-butyrolactam dripping and stirring after completion of the dripping was in the range of 7.6 to 8.9.

[Examples 11 to 15]
2-mercapto-4-butyrolactone was synthesized according to the method described in Example 1 except that the reaction was carried out by changing the pH value of the sodium hydrosulfide solution to be adjusted in advance according to Table 1. The results are shown in Table 1. The conversion, SH selectivity, MS selectivity, and DS selectivity in Table 1 were all calculated from HPLC measurement results.

[Comparative Examples 1-2]
2-mercapto-4-butyrolactone was prepared according to the method described in Example 1 except that the reaction was carried out by changing the pH value of the sodium hydrosulfide solution to be adjusted in advance to two points of pH 6.5 and 13.0. Was synthesized. The results are shown in Comparative Examples 1 and 2 in Table 1. The conversion, SH selectivity, MS selectivity, and DS selectivity in Table 1 were all calculated from HPLC measurement results.

[Comparative Example 3]
When a sodium hydrosulfide solution was prepared according to the method described in Example 1 without adjusting the pH with hydrochloric acid, the pH of this solution was 14.0. Using this solution, 2-mercapto-4-butyrolactone was synthesized according to the method described in Example 1. The results are shown in Comparative Example 3 in Table 1. The conversion, SH selectivity, MS selectivity, and DS selectivity in Table 1 were all calculated from HPLC measurement results.

[Examples 16 to 21]
Except that the pH of the sodium hydrosulfide solution before the reaction was adjusted to 8.5 and the equivalent ratio of the metal sulfide or metal hydrosulfide used to 2-bromo-4-butyrolactone was changed according to Table 2, the Examples Reaction was performed according to the method described in 1 to synthesize 2-mercapto-4-butyrolactone. The results are shown in Table 2. Note that the conversion, SH selectivity, MS selectivity, and DS selectivity in Table 2 were all calculated from HPLC measurement results. The pH of the reaction solution from the start of dropping 2-bromo-4-butyrolactone to the stirring after completion of dropping was in the range of 7.0 to 11.0 in all examples.

[Examples 22 to 32]
Examples 22-32 were performed for solvent screening. In these examples, in order to clarify the difference in effect between solvents, the equivalent ratio of sodium hydrosulfide to 2-bromo-4-butyrolactone was 1: 1, and the pH of the sodium hydrosulfide solution immediately before the reaction was 11. 0. Specifically, the procedure was as follows.

  70% sodium hydrosulfide (18 g, 0.22 mol, manufactured by Junsei Co., Ltd.), various organic solvents listed in Table 3 (68 g, Junsei Chemical Co., Ltd., special grade), or purified water (ion exchange filter after distillation) Passed through water, 68 g), or a mixed solvent of various organic solvents (34 g, manufactured by Junsei Chemical Co., Ltd.) and purified water (water passed through an ion exchange filter after distillation, 34 g) and added at room temperature to dissolve. I let you.

  The pH of the solution immediately before the reaction was adjusted to 11.0 by adding hydrochloric acid with stirring under ice-cooling and normal pressure conditions (10 ° C. or less, about 0.10 MPa) to the obtained solution. The temperature was cooled to 10 ° C. or lower under ice cooling.

  Subsequently, 2-bromo-4-butyrolactone (34 g, 0.2 mol, manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise over about 20 minutes while cooling the solution so as to maintain a temperature of 10 ° C. or lower. The pH of the reaction solution from the start of dropping 2-bromo-4-butyrolactone to the stirring after completion of dropping was in the range of 7.0 to 11.0 in all cases.

  The results of changing the solvent used are shown in Table 3. The SH selectivity and MS selectivity in Table 3 were both calculated from the HPLC measurement results.

[Examples 33 to 36]
2-mercapto-4-butyrolactone was synthesized by reacting according to the method described in Example 1, except that the temperature of the reaction solution during the reaction was changed according to Table 4. The results are shown in Table 4. However, the SH reaction yield in Table 4 is a value obtained by sampling the solution at the time when the pH is adjusted to 4.0 and calculating from the HPLC measurement result.

[Examples 37 to 41]
In the synthesis method of 2-mercapto-4-butyrolactone described in Example 1, a solution in which the pH value at the time of pH adjustment of the reaction solution after the reaction was changed according to Table 5 was allowed to stand at 25 ° C. or 50 ° C. for 3 hours. The storage stability of SH (2-mercapto-4-butyrolactone) was evaluated. The SH storage stability was measured by measuring the SH concentration immediately after pH adjustment of the reaction solution after reaction and the SH concentration after standing by HPLC, and the relative value (%) when the SH concentration immediately after pH adjustment was 100%. ).

  The results are shown in Table 5.

From Table 5, it can be seen that the decomposition reaction of SH is suppressed in the solution adjusted to pH 2.0 to 6.0 after the reaction.
[Example 42]
Production of 2-mercapto-4-butyrolactone (using Na ₂ S)
Sodium sulfide 9 hydrate (144 g, 0.6 mol, manufactured by Junsei Co., Ltd.) was passed through 1,2-dimethoxyethane (34 g, Junsei Chemical Co., Ltd., special grade) and purified water (after distillation through an ion exchange filter) It was dissolved in a mixed solvent of water and 34 g)) at room temperature. The solution was adjusted to pH 8.9 by adding hydrochloric acid (79 g, manufactured by Junsei Chemical Co., Ltd., special grade 35% to 37%) with stirring under ice-cooling and normal pressure conditions (10 ° C. or less, about 0.10 MPa). . 2-Bromo-4-butyrolactone (34 g, 0.2 mol, manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise over about 20 minutes while cooling so that the temperature of the solution was maintained at 10 ° C. or lower. The reaction solution after completion of the dropwise addition was stirred for 2 minutes. The pH of the reaction solution from the start of dropping 2-bromo-4-butyrolactone to the stirring after completion of dropping was in the range of 7.5 to 8.9.

  Thereafter, hydrochloric acid (24 g) was added over about 5 minutes while cooling so that the temperature of the solution was 10 ° C. or lower, and the pH of the solution was adjusted to 4.0. After removing the inorganic salt precipitated in the solution by suction filtration, ethyl acetate (20 g, manufactured by Junsei Chemical Co., Ltd., special grade) was added to the filtrate side to extract the organic phase. The resulting aqueous phase was re-extracted with ethyl acetate (34 g). These extracted organic phases were combined, concentrated under reduced pressure, and purified by distillation to obtain 2-mercapto-4-butyrolactone (17 g, bp. 94 ° C./0.3 kPa, yield 72%).

[Example 43]
Production of 2-mercapto-4-butyrolactone (using CaS)
Calcium sulfide (43.3 g, 0.6 mol, manufactured by Aldrich) is mixed with 1,2-dimethoxyethane (34 g, manufactured by Junsei Chemical Co., Ltd., special grade) and purified water (water passed through an ion exchange filter after distillation, 34 g). It dissolved in the mixed solvent at room temperature. This solution was adjusted to pH 8.9 by adding hydrochloric acid (78 g, Junsei Chemical Co., Ltd., special grade 35% to 37%) with stirring under ice-cooling and normal pressure conditions (10 ° C. or less, about 0.10 MPa). . 2-Bromo-4-butyrolactone (34 g, 0.2 mol, manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise over about 20 minutes while cooling so that the temperature of the solution was maintained at 10 ° C. or lower. The reaction solution after completion of the dropwise addition was stirred for 2 minutes. The pH of the reaction solution from the start of dropping 2-bromo-4-butyrolactone to the stirring after completion of dropping was in the range of 7.5 to 8.9.

  Thereafter, hydrochloric acid (24 g) was added over about 5 minutes while cooling so that the temperature of the solution was 10 ° C. or lower, and the pH of the solution was adjusted to 4.0. After removing the inorganic salt precipitated in the solution by suction filtration, ethyl acetate (20 g, manufactured by Junsei Chemical Co., Ltd., special grade) was added to the filtrate side to extract the organic phase. The resulting aqueous phase was re-extracted with ethyl acetate (34 g). These extracted organic phases were combined, concentrated under reduced pressure, and purified by distillation to obtain 2-mercapto-4-butyrolactone (15 g, bp 94 ° C./0.3 kPa, yield 63%).

Claims (16)

Following formula (1)

(X represents a structure of any of —O—, —S—, —NH—, and —NR ¹ —. R ¹ represents an alkyl group, an alkoxy group, or an alkoxyalkyl group having 1 to 6 carbon atoms. Y Represents an oxygen atom, a sulfur atom or NR ² , R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, Z ¹ represents an alkylene group to which at least one mercapto group is directly bonded, It may be branched and may have an alkyl group or an alkenyl group as a side chain .)
A method for producing a mercaptoheterocyclic compound represented by:
Metal sulfide or metal hydrosulfide and the following formula (2)

(X and Y are as defined in the above formula (1), Z ² is an alkylene group to which at least one halogen group is directly bonded, the alkylene group may be branched, and an alkyl group or alkenyl as a side chain. And a compound represented by formula (1) in the presence of a solvent under the conditions of pH 7.0 to 11.0. Z ¹ in the formula (1) is an alkylene group to which one mercapto group is directly bonded, and the alkylene group may be branched, and may have an alkyl group or an alkenyl group as a side chain. And the mercapto group is directly bonded to the carbon atom at the 2-position of the mercapto heterocyclic compound,
Z ² in the formula (2) is an alkylene group to which one halogen group is directly bonded, and the alkylene group may be branched, and may have an alkyl group or an alkenyl group as a side chain. The method for producing a mercapto heterocyclic compound according to claim 1, wherein the halogen group is directly bonded to the carbon atom at the 2-position of the compound represented by the formula (2).   The mercapto heterocyclic compound represented by the formula (1) is 2-mercapto-4-butyrolactone (also known as 2-mercapto-4-butanolide), 2-mercapto-4-methyl-4-butyrolactone, 2-mercapto- 4-ethyl-4-butyrolactone, 2-mercapto-4-butyrothiolactone, 2-mercapto-4-butyrolactam, N-methoxy-2-mercapto-4-butyrolactam, N-ethoxy-2-mercapto-4-butyrolactam N-methyl-2-mercapto-4-butyrolactam, N-ethyl-2-mercapto-4-butyrolactam, N- (2-methoxy) ethyl-2-mercapto-4-butyrolactam, N- (2-ethoxy) ethyl 2-mercapto-4-butyrolactam, 2-mercapto-5-valerolactone, 2-merca To-5-valerolactam, N-methyl-2-mercapto-5-valerolactam, N-ethyl-2-mercapto-5-valerolactam, N- (2-methoxy) ethyl-2-mercapto-5-valerolactam A mercaptoheterocyclic compound selected from the group consisting of N- (2-ethoxy) ethyl-2-mercapto-5-valerolactam and 2-mercapto-6-hexanolactam. A method for producing the mercaptoheterocyclic compound described in 1.   The method for producing a mercapto heterocyclic compound according to any one of claims 1 to 3, wherein the metal sulfide is an alkali metal sulfide, an alkaline earth metal sulfide, or a mixture thereof.   The method for producing a mercaptoheterocyclic compound according to any one of claims 1 to 3, wherein the metal sulfide is at least one selected from the group consisting of sodium sulfide, potassium sulfide, calcium sulfide and magnesium sulfide.   The method for producing a mercaptoheterocyclic compound according to any one of claims 1 to 3, wherein the metal hydrosulfide is sodium hydrosulfide or potassium hydrosulfide.   The method for producing a mercaptoheterocyclic compound according to any one of claims 1 to 6, wherein a mixed solvent having a weight ratio of water to an organic solvent of 1: 0.1 to 10 is used as the solvent.   The organic solvent is one or more solvents selected from the group consisting of methanol, N-methylpyrrolidone, acetone, 1,4-dioxane, 1,2-dimethoxyethane, and N, N-dimethylformamide. A method for producing a mercapto heterocyclic compound according to claim 7.   The mercapto complex according to any one of claims 1 to 8, wherein the pH is adjusted within the range by adding an inorganic acid or an inorganic alkali to the reaction solution between the start of the reaction and the completion of the reaction. A method for producing a ring compound.   The said reaction is performed at 40 degrees C or less, The manufacturing method of the mercapto heterocyclic compound in any one of Claims 1-9 characterized by the above-mentioned.   The compound represented by the formula (2) is dissolved or dispersed in the solvent, and the temperature of the resulting solution or slurry is adjusted to -20 to 40 ° C. The method for producing a mercaptoheterocyclic compound according to any one of claims 1 to 10, wherein the reaction is performed by adding.   After the metal sulfide or metal hydrosulfide is dissolved or dispersed in a solvent and the pH of the resulting solution or slurry is adjusted to 7.5 to 11.0, the solution or slurry is represented by the formula (2). The method for producing a mercaptoheterocyclic compound according to any one of claims 1 to 11, wherein the reaction is carried out by adding a compound.   Adjusting the pH of the solution or slurry within the above range by adding an inorganic acid to the solution or slurry while adjusting the temperature of the metal sulfide or metal hydrosulfide solution or slurry to 40 ° C. or lower. The method for producing a mercapto heterocyclic compound according to claim 12,   The equivalent ratio of the compound represented by the formula (2) used for the reaction and the metal sulfide or metal hydrosulfide is 1: 0.8 to 5.0. The manufacturing method of the mercapto heterocyclic compound in any one of -13.   The method for producing a mercaptoheterocyclic compound according to any one of claims 1 to 14, wherein the pH of the reaction solution after the reaction is adjusted to 2.0 to 6.0.   16. The method for producing a mercapto heterocyclic compound according to claim 15, wherein the pH of the reaction solution after the reaction is adjusted within the range by adding an inorganic acid to the reaction solution after the reaction.