Precursors of D-luciferin and D-luciferin derivatives and methods for producing the same

Abstract

While methods involving the cyclization of diaminodithioether-substituted compounds have been proposed for the production of D-luciferin and D-luciferin derivatives, the yields have been insufficient for industrialization. [Solution] Instead of directly cyclizing the diaminodithioether-substituted product, a diketone-substituted product obtained by diketonizing the diaminodithioether-substituted product was used as an intermediate, allowing for the production of D-luciferin and D-luciferin derivatives in higher yield. Specifically, this involves a step of reacting the diaminodithioether-substituted product with sodium periodate in the presence of dichloromethane.

Description

[Technical Field]

[0001] This invention provides precursors for firefly luciferin and firefly luciferin derivatives. [Background technology]

[0002] Conventionally, the production of firefly luciferin and firefly luciferin derivatives used 2-cyano-6-hydroxybenzothiazole as a raw material. However, this method was expensive and complicated due to the use of various chemicals such as oxidizing agents, reducing agents, acids, bases, and organometallic compounds.

[0003] To solve this problem, Patent Document 1 proposes a method using diaminodithioether substituted compounds, which are relatively easy to obtain. Patent Document 1 states that, as shown in Figure 4 of the present application, D-luciferin and D-luciferin derivatives represented by formula (14) are produced by cyclizing the diaminodithioether substituted compound represented by formula (11) in the presence of a base.

[0004] [ka]

[0005] [ka]

[0006] In both formulas (11) and (14), X is H, OCH3, or OH, and Y, Z, and W are one organic group selected from the group consisting of alkyl groups, N,N-2 substituted amino groups, alkoxy groups, aryl groups, and aryloxy groups.

[0007] Furthermore, the diaminodithioether-substituted compound represented by formula (11) can be produced by reacting the D-cysteine-substituted compound represented by formula (12) with the o-aminobenzenethiol derivative represented by formula (13), as shown in Figure 5.

[0008] [ka]

[0009] [ka]

[0010] In both formulas, X is H, OCH3, or OH, and Y, Z, and W are one organic group selected from the group consisting of alkyl groups, N,N-2 substituted amino groups, alkoxy groups, aryl groups, and aryloxy groups.

[0011] Furthermore, the D-cysteine-substituted compound represented by equation (12) can be obtained by reacting tetrachloroethylene and D-cysteine ​​in the presence of a base, as shown in Figure 6. [Prior art documents] [Patent Documents]

[0012] [Patent Document 1] Patent No. 7194404 [Overview of the project] [Problems that the invention aims to solve]

[0013] The method described in Patent Document 1 is a groundbreaking method that can reduce the manufacturing costs of firefly luciferin and firefly luciferin derivatives (Formula (14)), and the yield has also improved compared to conventional methods. However, there was still a challenge in that the yield was not satisfactory for industrialization. [Means for solving the problem]

[0014] To solve the above problems, the present invention provides a method for producing firefly luciferin and firefly luciferin derivatives (formula (14)) that improves upon the method of Patent Document 1 and has the potential to yield higher yields.

[0015] More specifically, the method for producing firefly luciferin and firefly luciferin derivatives according to the present invention is characterized by passing through the diketone substituent of formula (1) from the diamino dithioether substituent shown in formula (11). This is because it is considered that the cyclization reaction is likely to be promoted by passing through the diketone substituent. Therefore, the present invention provides a diketone substituent of formula (1) and a method for producing firefly luciferin and firefly luciferin derivatives using the same. That is, the diketone substituent according to the present invention has the structure of formula (1).

[0016] [Chemical formula]

[0017] Here, X is H, OCH3 or OH, and Y, Z and W are one organic group selected from the group consisting of an alkyl group, N,N-2 substituted amino group, alkoxy group, aryl group and aryloxy group.

[0018] In addition, the method for producing the diketone substituent according to the present invention is characterized by having a step of reacting the diamino dithioether substituent of formula (11) with sodium periodate.

[0019] In addition, the method for producing firefly luciferin and firefly luciferin derivatives according to the present invention includes a step of reacting the diamino dithioether substituent of formula (11) with sodium periodate to obtain a diketone substituent, and a step of cyclizing the diketone substituent. [Advantages of the Invention]

[0020] By passing through the diketone substituent (formula (1)) according to the present invention, it is highly likely that firefly luciferin and firefly luciferin derivatives (formula (14)) can be produced more efficiently than when directly cyclizing the diamino dithioether substituent shown in formula (11). [Brief Description of the Drawings]

[0021] [Figure 1] This figure shows the production reaction for the diketone-substituted compound according to the present invention. [Figure 2] This figure shows the reaction in Example 1. [Figure 3] This figure shows the reaction in Example 2. [Figure 4] This figure shows the reaction to obtain D-luciferin and D-luciferin derivatives from the diaminodithioether substituted product shown in Patent Document 1. [Figure 5] The diagram shows the reaction between the diaminodithioether substituted product and the D-cysteine ​​substituted product and the o-aminobenzenethiol derivative. [Figure 6] The diagram shows the reaction between tetrachloroethylene and D-cysteine ​​to obtain the D-cysteine-substituted product. [Figure 7] The diagram shows the reaction in which diaminodithioether-substituted compounds can also be obtained from aminothioether derivatives and D-cysteine. [Figure 8] The diagram shows the reaction between an o-aminobenzenethiol derivative and tetrachloroethylene to obtain an aminothioether derivative. [Modes for carrying out the invention]

[0022] The diketone-substituted compound according to the present invention and a method for producing D-luciferin and D-luciferin derivatives using the same will be described below with reference to drawings and examples. The following description illustrates one embodiment of the present invention and one example, and the present invention is not limited to the following description. The following description may be modified without departing from the spirit of the present invention. All references cited herein are incorporated herein by reference. In this specification, when a numerical range is described as "A to B", it means "A or more and B or less". In this specification, "Me" is an abbreviation for methyl group (CH3-).

[0023] The diketone-substituted product according to the present invention has the structure represented by formula (1).

[0024] [ka]

[0025] Here, X is H, OCH3, or OH, and Y, Z, and W are one organic group selected from the group consisting of alkyl groups, N,N-2 substituted amino groups, alkoxy groups, aryl groups, and aryloxy groups.

[0026] Figure 1 shows the reaction for the formation of this diketone-substituted compound (formula (1)). The diketone-substituted compound (formula (1)) can be obtained by oxidizing the diaminodithioether-substituted compound represented by formula (11) in the presence of sodium periodate (NaIO4). At this time, D-luciferin and D-luciferin derivatives represented by formula (14) are also produced simultaneously.

[0027] In this invention, the diaminodithioether-substituted product represented by formula (11), which serves as the starting material, can be obtained by the method described in Patent Document 1. This method is shown in Figure 5 in this specification.

[0028] Furthermore, the method shown in Figure 7 is also possible for producing the diaminodithioether substituted product (formula (11)). This method involves adding D-cysteine ​​to the aminothioether derivative represented by formula (15) and reacting it in the presence of a base. The base can be any one of the following: NaOH, DBN, or triethylamine.

[0029] [ka]

[0030] Here, X is H, OCH3, or OH, and Y, Z, and W are one organic group selected from the group consisting of alkyl groups, N,N-2 substituted amino groups, alkoxy groups, aryl groups, and aryloxy groups.

[0031] Furthermore, as shown in Figure 8, an aminothioether derivative represented by formula (15) can be obtained by reacting an o-aminobenzenethiol derivative represented by formula (13) with tetrachloroethylene in the presence of a base.

[0032] Furthermore, the o-aminobenzenethiol derivative represented by formula (13) can be obtained by hydrolyzing the benzothiazole derivative represented by formula (16), which is relatively easy to obtain.

[0033] [ka]

[0034] Here, X is H, OCH3, or OH, and Y, Z, and W are one organic group selected from the group consisting of alkyl groups, N,N-2 substituted amino groups, alkoxy groups, aryl groups, and aryloxy groups. [Examples]

[0035] Examples of the diketone-substituted compound (formula (1)) and the method for producing D-luciferin and D-luciferin derivatives (formula (14)) using the present invention are shown below.

[0036] <Example 1: Production of Diketone Body 1A> Figure 2 shows the reaction diagram for the production method of diketone 1A. In equation (1), W, Y, and Z are hydrogen (H), and Y is OCH3. In a glass flask, 1.5 mL of dichloromethane (CH2Cl2: labeled "MeCN" in Figure 2), 1.5 mL of acetonitrile (CH3CN), and 183.0 mg and 0.5 mmol of dichloromethane (11A) were added. Then, 473.9 mg and 2.2 mmol of sodium periodate (NaIO4) dissolved in 1 mL of water were added dropwise, and the mixture was stirred for 3 hours.

[0037] Subsequently, several drops of the reaction solution were taken and the presence of a diketone body (novel compound 1A) was confirmed by HRMS (High-Resolution Mass Spectrum) analysis. At the same time, the presence of D-luciferin derivative 14A was also confirmed.

[0038] The results for diketone body 1A and D-luciferin derivative 14A are shown. Diketone bodies (novel compound 1A) HRMS (ESI, positive) calcd for C 12 H 15 O5N2S2 "M+H" + 329.0417; found 329.0279. D-luciferin derivative 14A HRMS (ESI, negative) calcd for C 12 H9O3N2S2 "MH" - 293.0060; found 293.0065.

[0039] <Example 2: Production of Diketone Body 1B> Figure 3 shows the reaction diagram for the production method of diketone 1B. In equation (1), W, Y, and Z are hydrogen (H), and Y is OH. In a glass flask, 176.9 mg and 1.01 mmol of D-cysteine ​​(labeled "D-Cys" in Figure 3), 3 mL of dichloromethane (CH2Cl2), 3 mL of acetonitrile (CH3CN), 621.0 mg and 5.0 mmol of DBN (1,5-diazabicyolo[4.3.0]non-5-ene), and 273.9 mg and 1.01 mmol of 2-amino-5-hydroxybenzenethiol substituted compound (15B) were added and the mixture was stirred for 1 hour. After that, the pH was adjusted to 3 with 1 M aqueous HCl, and 942.6 mg and 4.41 mmol of sodium periodate (NaIO4) dissolved in 2 mL of water were added dropwise and the mixture was stirred for 3 hours.

[0040] Subsequently, several drops of the reaction solution were taken and the presence of a diketone body (novel compound 1B) was confirmed by HRMS analysis. At the same time, the presence of D-luciferin derivative 14B was also confirmed.

[0041] Results of diketone 1B and D - luciferin derivative 14B are shown. Diketone (novel compound 1B) HRMS (ESI, positive) calcd for C 11 H 13 O5N2S2 “M + H” + 317.0206; found 317.0259. D - luciferin derivative 14B HRMS (ESI, positive) calcd for C 11 H8O3N2S2Na “M + Na” + 302.9869; found 302.9864.

Industrial Applicability

[0042] By passing through the diketone substituent from the diamino dithioether substituent according to the present invention, D - luciferin and D - luciferin derivatives can be obtained in high yields. That is, it can be said that the diketone substituent according to the present invention is a precursor for obtaining D - luciferin and D - luciferin derivatives in high yields.

Claims

1. (1) The compound of formula (1). 【Chemistry 101】 Here, X is H, OCH ３ or OH, Y, Z, and W are alkyl groups, N,N-2 substituted amino groups, and alkoxy groups. It is one organic group selected from the group consisting of aryl groups and aryloxy groups.

2. A method for producing D-luciferin and D-luciferin derivatives represented by formula (14), comprising the step of oxidizing a diaminodithioether substituted product represented by formula (11) in the presence of sodium periodate to produce a diketone substituted product represented by formula (1) and D-luciferin and D-luciferin derivatives represented by formula (14). 【Chemical Engineering 102】 【Chemistry 103】 【Chemical 104】 Here, X is common to all equations, and OCH is H. ３ or OH, Y, Z, and W are alkyl groups, N,N-2 substituted amino groups, and alkoxy groups. It is one organic group selected from the group consisting of aryl groups and aryloxy groups.

3. The method for producing D-luciferin and D-luciferin derivatives according to claim 2, comprising the step of reacting a D-cysteine ​​substituted compound represented by formula (12) with an o-aminobenzenethiol derivative represented by formula (13) in the presence of a base. 【Chemistry 105】 【Chemistry 106】 Here, X is common to all equations, and OCH is H. ３ or OH, Y, Z, and W are alkyl groups, N,N-2 substituted amino groups, and alkoxy groups. It is one organic group selected from the group consisting of aryl groups and aryloxy groups.

4. The method for producing D-luciferin and D-luciferin derivatives according to claim 3, wherein the compound represented by formula (12) is reacted with tetrachloroethylene and D-cysteine ​​under a base.

5. The compound of formula (13) is obtained by hydrolyzing the compound represented by formula (16). A method for producing D-luciferin and D-luciferin derivatives according to claim 3. 【Chemistry 107】 Here, X is H, OCH ３ or OH, Y, Z, and W are alkyl groups, N,N-2 substituted amino groups, and alkoxy groups. It is one organic group selected from the group consisting of aryl groups and aryloxy groups.

6. The compound of formula (11) is obtained by reacting an aminothioether derivative represented by formula (15) with D-cysteine ​​under a base, as described in claim 2, for the method of producing D-luciferin and D-luciferin derivatives. 【Chemistry 108】 Here, X is H, OCH ３ or OH, Y, Z, and W are alkyl groups, N,N-2 substituted amino groups, and alkoxy groups. It is one organic group selected from the group consisting of aryl groups and aryloxy groups.

7. The method for producing D-luciferin and D-luciferin derivatives according to claim 6, wherein the compound of formula (15) is reacted with the compound represented by formula (13) and tetrachloroethylene under a base. 【Chemistry 109】 Here, X is H, OCH ３ or OH, Y, Z, and W are alkyl groups, N,N-2 substituted amino groups, and alkoxy groups. It is one organic group selected from the group consisting of aryl groups and aryloxy groups.

8. The method for producing D-luciferin and D-luciferin derivatives according to claim 7, wherein the compound of formula (13) is obtained by hydrolyzing the compound represented by formula (16). 【Chemical 110】 Here, X is H, OCH ３ or OH, Y, Z, and W are alkyl groups, N,N-2 substituted amino groups, and alkoxy groups. It is one organic group selected from the group consisting of aryl groups and aryloxy groups.

9. A method for producing D-luciferin and D-luciferin derivatives according to any one of claims 2 to 8, wherein the base is one of NaOH, DBN, or triethylamine.

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