JPH07100689B2 - Mercaptoindoles - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention is represented by the general formula (I). (Wherein R is a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or an alkoxycarbonylmethyl group, and X is a substituted sulfonyl group). The novel compounds represented by the general formula (I) include, for example, 4-methylthiotryptamine [J.Med, Chem., 25 , 908 (1982)] and tunansynmycin [Hua Hsueh Hsueh Pao 34 , 129 (1976). Che
m, Abstr. 87 , 165948Z (1977)], which can be used as a synthetic intermediate for 4-mercaptoindole type physiologically active substances (see Reference Example below).

[Conventional technology]

Unstable 4-mercaptoindole itself is one of the versatile intermediates for the synthesis of useful 4-mecaptoindole compounds, but the previously known method for synthesizing 4-mercaptoindole [Can.J.Chem ., 40 , 511 (1962)] is a Reissert synthesis for 6-benzylthio-2-nitrotoluene and requires several steps, and the yield is not preferable.

In addition, 1-methoxycarbonyl-4- (ethoxythiocarbonylthio) indole, an analog of dithiocarbonate represented by the general formula (II) (described later), which is one of the starting materials for the synthesis of the compound of the present invention, was dissolved in a methanol solution. A method of obtaining 4-mercaptoindole by hydrolyzing with caustic soda is also known, but the yield of the starting material and the target material is poor (Somei,
Journal of Synthetic Organic Chemistry, 1982, 40 , 387.). Furthermore, there is also a method of synthesizing 4- (substituted mercapto) indole by subjecting 6- (substituted thio) -2-nitrotoluene to a Beimgruber-Batcho reaction (APKozikowski, MNGrsco, and JPSprin
Ger, J. Am. Chem. Soc., 1982, 104, 7622.) There are drawbacks such as difficulty in obtaining starting materials, use of expensive reagents, and not always easy operation.

[Problems to be solved by the invention]

As described above, the conventional methods for synthesizing 4-mercaptoindoles have the drawbacks that the raw materials are difficult to obtain, the operation is complicated, and the yield of the target product is low. .

The present invention overcomes these drawbacks and provides mercaptoindoles of the general formula (I) which can be easily synthesized in high yield and are raw materials for the synthesis of useful substances as described above.

[Means for solving problems]

The mercaptoindoles represented by the general formula (I) of the present invention have the general formula (II) (In the formula, R ¹ is a lower alkyl group and X is a substituted sulfonyl group.) The dithiocarbonic acid ester can be selectively produced.

The dithiocarbonic acid ester represented by the general formula (II) of the present invention has the general formula (In the formula, X is a substituted sulfonyl group.) The diazonium salt represented by the general formula (In the formula, R ¹ is a lower alkyl group and M is an alkali metal.) It can be produced by reacting with a dithiocarbonate.

The diazonium salt represented by the general formula (III) as a raw material is 4-aminoindole [Heterocycles 22 , 2313 (198
4); 23, 165 (1985) and is a compound which can be easily manufactured from the following Reference Examples refer to Fig.

The dithiocarbonate represented by the general formula (IV), which is one of the raw materials, can be easily obtained by a combination of alcohol, disulfide carbonic acid, and alkali, other than those inexpensively available as a commercial product such as potassium ethyl xanthate. It can be prepared.

When the diazonium salt represented by the general formula (III) is reacted with the compound represented by the general formula (IV), a solvent is usually used. Examples of the solvent include water, alcohol, acetone, dimethoxyethane, tetrahydrofuran and the like. Also, the reaction is -20 ℃ ~ 50
It proceeds at 0 ° C, but is preferably carried out at 0 ° C to room temperature.

In the general formula (II), R ¹ is methyl, ethyl, propyl, butyl, pentyl or the like, and X is
Examples include methanesulfonyl, ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl and the like.

In converting the compound represented by the general formula (II) into 4-mercaptoindoles represented by the general formula (I), use of a base is essential, and use of ethylenediamine is particularly preferable. In particular, when an electrophilic reagent does not coexist, a compound in which R is a hydrogen atom in the general formula (II) is provided. On the other hand, in the above reaction, together with a base such as ethylenediamine, the following general formula (V) RY- (V) (wherein, R is an alkyl group, an alkenyl group, or an alkoxycarbonylmethyl group, and Y is a halogen atom, a sulfonate group) When the electrophilic reagent represented by the formula (1) is present, a product in which R in the general formula (I) is other than a hydrogen atom can be obtained. Examples of the electrophilic agent of the general formula (V) include methyl iodide, methyl bromide, ethyl bromide, propyl bromide, isopropyl bromide, butyl bromide, allyl bromide, methallyl bromide, methallyl chloride, prenyl chloride,
Examples include propargyl bromide, benzyl chloride, benzyl bromide, chloromethylnaphthalene, bromoacetic acid methyl ester, chloroacetic acid ethyl ester, and sulfonic acid esters corresponding thereto. The amount used may be equivalent to about 4 equivalents to (II).

In the reaction, ethylenediamine or the like may be used in a large excess to serve also as a solvent, or 2 to 3 equivalents may be used with respect to the dithiocarbonate derivative (II). Examples of the reaction solvent include tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and the like. The reaction temperature around room temperature is sufficient. Further, the reaction is preferably carried out in an atmosphere of an inert gas such as nitrogen or argon.

In the mercaptoindoles represented by the general formula (I) obtained as described above, X is methanesulfonyl group, ethanesulfonyl group, benzenesulfonyl group, p-
R having a substituted sulfonyl group such as a toluenesulfonyl group,
Is a methyl group, an ethyl group, a propyl group, an isopropyl group,
Alkyl groups such as butyl, allyl, methallyl, prenyl, alkenyl such as propargyl, aralkyl such as benzyl, naphthylmethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, etc. Those having an alkoxycarbonylmethyl group can be exemplified.

Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples.

Reference example 1 5-chloro-4-oxo-1-p-toluenesulfonyl-4,5,6,
7.66 g (11.3 mmol) of 7-tetrahydroindole was dissolved in a mixed solvent of 20 ml of p-xylene and 0.4 ml of acetic acid, and then 8.71 g (113.0 mmol) of ammonium acetate was added, and the mixture was refluxed, stirred and reacted for 4 hours. The reaction mixture was cooled, poured into an aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane.
The dichloromethane layer was dried over sodium sulfate and then concentrated. The residue was subjected to silica gel column chromatography and developed with dichloromethane to give 4-amino-1-p-
Toluenesulfonyl indolol (2.32g, 71.8%) was obtained (conversion rate 92.6%) 4-amino-1-p-toluenesulfonylindole, melting point; 130-131 ° C (colorless needle crystals, recrystallized from ether) ¹ H NMR (CDCl ₃ , 100MHz); δ 2.30 (s, 3H), 3.68 (s, br
oad, 2H), 6.44 (d, 1H, J = 8.0Hz), 6.52 (d, 1H, J = 4.0)
Hz), 6.96 to 7.48 (m, 5H), 7.71 (d, 2H, J = 8.0Hz) ppm IR (KBr Disk); 3500, 3400, 1630, 1600, 1360, 1165cm ^-1 .

Mass (m / z,%); 286 (M ⁺ , 34), 132 (100).

Reference example 2 1-benzenesulfonyl-5-chloro-4-oxo-4,5,6,7-
Tetrahydroindole (75 mg, 0.24 mmol) was dissolved in a mixed solvent of p-xylene (5 ml) and acetic acid (0.1 ml), and then ammonium acetate (185 mg, 2.40 mmol) was added thereto.
The reaction was carried out for 30 minutes. After cooling the reaction solution, it was subjected to silica gel column chromatography and developed with dichloromethane to give 4-amino-1-benzenesulfonylindole (60 mg, 92.0%).

4-amino-1-benzenesulfonylindole melting point; 117-
118 ° C (colorless needle crystals, recrystallized from ether) ¹ H NMR (CDCl ₃ , 60NHz); δ3.73 (s, broad, 2H), 6.27
~ 6.54 (m, 2H), 6.82 ~ 7.48 (m, 6H), 7.63 ~ 7.97 (m,
2H) ppm IR (KBr Disk); 3480,3400,1635,1600,1370,1190,1130c
m ^-1 Mass (m / z,%); 272 (M ⁺ , 29), 131 (100).

Reference example 3 4-Amino-1-p-toluenesulfonylindole 149mg
(0.52 mmol) was suspended in water (4 ml) and 2N hydrochloric acid (1 ml), and an aqueous solution (2 ml) of 88.0 mg (1.27 mmol) of sodium nitrite was added dropwise under ice cooling. After stirring for 20 minutes under ice cooling,
A saturated aqueous solution of sodium borofluoride (1 ml) was added. After stirring for 20 minutes under ice cooling and 30 minutes at room temperature, the resulting precipitate was collected by filtration,
Wash with a little water and dichloromethane. Vacuum dried over phosphorus pentoxide, 1-p-toluenesulfonyl-4-indolediazonium tetrafluoroborate (176mg, 87.8
%)was gotten.

Melting point: 130-132 ° C (pale yellow needle crystals, recrystallized from methanol). _{^{1 H NMR (DMSO -d6, 100MHz}} ); δ2.36 (s, 3H), 7.50 (d,
2H, J = 8.2Hz), 7.56 (d, 1H, J = 3.8Hz), 7.90 (t, 1H, J
= 8.0Hz), 8.08 (d, 2H, J = 8.2Hz), 8.60 (d, 1H, J = 3.
8Hz), 8.74 (d, 1H, J = 8.0Hz), 8.88 (d, 1H, J = 8.0H)
z) ppm.

IR (KBr); 2260,1370,1170,1085,680 cm ^-1 .

Mass (m / z,%); 289 (M ⁺ ‐N ₂ · BF ₃ , 71), 155 (100), 9
1 (95), 28 (68).

Elemental analysis value; Calculated value as C ₁₅ H ₁₂ BF ₄ N ₃ O ₂ S (%); C, 46.78; H, 3.14; H, 10.91 Measured value (%); C, 46.65; H, 3.02; N, 10.78 Reference example 4 4-Amino-1-benzenesulfonylindole 142 mg (0.5
2 mmol) was used and the same reaction and post-treatment were carried out as in Reference Example 3 to obtain 1-benzenesulfonyl-4-indolediazonium tetrafluoroborate (180 mg, 93.3%).

Melting point: 119 to 121 ° C (pale yellow needle crystals, recrystallized from methanol). _{^{1 H NMR (DMSO -d6, 90MHz}} ); δ7.53 (d, 1H, J = 3.6Hz),
7.60 ~ 7.84 (m, 3H), 7.86 (t, 1H, J = 8.1Hz), 8.08 ~
8.27 (m, 2H), 8.57 (d, 1H, J = 3.6Hz), 8.71 (d, 1H, J
= 8.1Hz), 8.55 (d, 1H, J = 8.1Hz) ppm.

IR (KBr); 2260,1370,1150,1090,600 cm ^-1 .

Mass (m / z,%); 275 (M ⁺ ‐N ₂ · BF ₃ , 59), 141 (47), 134
(86), 107 (30), 77 (100), 28 (31).

Elemental analysis value; Calculated value as C ₁₄ H ₁₀ BF ₄ N ₃ O ₂ S (%); C, 45.31; H, 2.72; N, 11.32 Measured value (%); C, 45.11; H, 2.58; N, 11.28 Reference example 5 Potassium ethyl xanthate (160 mg, 1 mmol) was dissolved in 2 ml of acetone, and 1-
(P-Toluenesulfonyl) 4-indolediazonium ・
Tetrafluoroborate (120 mg, 0.31 mmol) was added and stirred. After the generation of nitrogen gas was completed, the mixture was stirred for about 10 minutes (total about 20 minutes), poured into saturated saline, and extracted with CH ₂ Cl ₂ . After drying over MgSO ₄ and concentrating, the residue was applied to a silica gel column and poured out with CH ₂ Cl ₂ / hexane (2: 1) to give 4- (ethoxythiocarbonylthio) -1- (p- Toluenesulfonyl) indole (10.5m
g, yield 86%) was obtained.

Light yellow columnar crystal (reconstituted from hexane-ethyl acetate) Melting point 93.0-94.9 ° C ¹ H NMR (in CDCl ₃ ); δ1.12 (t, J = 7.0Hz, 3H), 2.33
(S, 3H), 4.52 (q, J = 7.0Hz, 2H), 6.76 (d, J = 3.5Hz,
1H), 7.13 to 7.46 (m, 4H), 7.65 (d, J = 3.5Hz, 1H),
7.60〜8.18 (m, 3H) ppm IR (KBr); 1595,1368,1230,1165cm ^-1 Mass (m / z,%); 3.91 (M ⁺ , 17), 331 (20), 303 (31), 1
76 (48), 155 (35), 148 (57), 91 (100).

Elemental analysis value; Calculated value as C ₁₈ H ₁₇ NS ₃ O ₃ (%); C, 55.22; H, 4.38; N, 3.58; S, 24.57 Measured value (%); C, 55.02; H, 4.47; N, 3.52; S, 24.63 Reference example 6 The reaction was performed in the same manner as in Example 1 except that 1- (p-toluenesulfonyl) -4-indolediazonium tetrafluoroborate was replaced with equimolar 1-benzenesulfonyl-4-indolediazonium tetrafluoroborate, And by treatment, 1-benzenesulfonyl-
4- (Ethoxythiocarbonylthio) indole was obtained as colorless columnar crystals (106 mg).

Colorless columnar crystals (recrystallized from n-hexane-ethyl acetate) Melting point 71.0-73.0 ° C ¹ H NMR (in CDCl ₃ ); δ1.11 (t, J = 7.2Hz, 3H), 4.52
(Q, J = 7.2Hz, 2H), 6.78 (d, J = 3.8Hz, 1H), 7.24 to 7.
60 (m, 5H), 7.66 (d, J = 3.8Hz, 1H), 7.80 to 8.22 (m, 3
H) ppm IR (KBr); 1370,1167cm ^-1 Mass (m / z,%); 377 (M ⁺ , 24), 317 (26), 289 (41), 17
6 (57), 148 (76), 77 (100).

Elemental analysis value; Calculated value as C ₁₇ H ₁₅ NS ₃ O ₃ (%); C, 54.09; H, 4.01; N, 3.71; S, 25.48 Measured value (%); C, 53.87; H, 4.11; N, 3.67; S, 25.64 Example 1 Ethylenediamine (0.5 ml) was added to 4-ethoxythiocarbonylthio-1- (p-toluenesulfonyl) indole (203 mg, 0.52 mmol) at 30 ° C. under an argon atmosphere, and the mixture was stirred for 16 hours and 30 minutes. After completion of the reaction, the reaction mixture was poured into a 5% aqueous solution of sulfuric acid and extracted with dichloromethane. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column, dichloromethane and n-
When it was poured out with a 2: 1 mixed solvent of hexane, 4-mercapto-1-p-toluenesulfonylindole (148 mg, yield
94.0%) was obtained.

Colorless columnar crystals (reconstituted from n-hexane-ethyl acetate) melting point 104.0 to 106.0 ° C ¹ H NMR (in CDCl ₃ ); δ 2.30 (s, 3H), 3.48 (s, 1H),
6.70 (d, J = 3.8Hz, 1H), 7.10 to 7.30 (m, 4H), 7.61
(D, J = 3.8Hz), 7.68 to 7.94 (m, 3H) ppm IR (KBr); 2570,1595,1370,1165cm ^-1 .

Mass (m / z,%); 303 (M ⁺ , 59), 155 (19), 148 (100), 9
1 (54).

Elemental analysis value; Calculated value as C ₁₅ H ₁₃ NS ₂ O ₂ (%); C, 59.38; H, 4.32; N, 4.62; S, 21.13 Measured value (%); C, 59.25, H, 4.41; N, 4.58; S, 20.95 Example 2 4-ethoxythiocarbonylthio-1-benzenesulfonylindole (39 mg, 0.1 mmol) in an argon atmosphere at 30
Ethylenediamine (0.25 ml) was added at 0 ° C. and the mixture was stirred for 1 hr. After the reaction was completed, the reaction mixture was poured into a 5% sulfuric acid aqueous solution,
It was extracted with dichloromethane. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. This concentrate was applied to a silica gel column to remove dichloromethane and n-hexane.
When it was poured out with a 2: 1 mixed solvent, 4-mercapto-1-benzenesulfonylindole (26 mg, yield 87.0%) was obtained.

Light yellow columnar crystal (reconstituted from n-hexane-ethyl acetate) Melting point 89.0-91.0 ° C ¹ H NMR (in CDCl ₃ ); δ3.50 (s, 1H), 6.74 (d, J = 3.6
Hz, 1H), 7.12 to 7.60 (m, 5H), 7.62 (d, J = 3.6Hz, 1
H), 7.76 to 7.98 (m, 3H) ppm IR (KBr); 1575,1370,1167 cm ^-1 .

Mass (m / z,%); 289 (M ⁺ , 50), 148 (100), 77 (39) Elemental analysis value; Calculated value as C ₁₄ H ₁₁ NS ₂ O ₂ (%); C, 58.11; H , 3.83; N, 4.84; S, 22.16 Measured value (%); C, 58.21; H, 4.13; N, 4.73; S, 22.14 Example 3 4-Ethoxythiocarbonylthio-1- (p-toluenesulfonyl) indole (44 mg, 0.11 mmol) was dissolved in 1 ml of THF, ethylenediamine (0.1 ml) was added to this solution at room temperature under an argon atmosphere, and the mixture was stirred for 10 minutes. Then 3-chloro-2-methylpropene (45 μl, 0.46 mmol) was added at room temperature.
Stir for 40 minutes. After completion of the reaction, the reaction mixture was poured into a 5% aqueous solution of sulfuric acid and extracted with dichloromethane. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column, dichloromethane and n-
Elution with a 3: 2 mixed solvent of hexane gave 4- (2-methyl-2-propenylthio) -1- (p-toluenesulfonyl) indole (37 mg, yield 92.5%).

Colorless oil ¹ H NMR (in CDCl ₃ ); δ1.82 (broad s, 3H), 2.32 (s,
3H), 3.52 (s, 2H), 4.71 (broad s, 2H), 6.84 (d, J
= 3.8Hz, 1H), 7.13 to 7.36 (m, 4H), 7.59 (d, J = 3.8H
z, 1H), 7.68 to 7.94 (m, 3H) ppm.

IR (liquid film); 1600,1372,1170cm ^-1 .

Mass (m / z,%); 357 (M ⁺ , 62), 302 (15), 271 (44), 20
2 (47), 155 (52), 116 (28), 91 (100).

Example 4 4-Ethoxythiocarbonylthio-1- (p-toluenesulfonyl) indole (73 mg, 0.19 mmol) was dissolved in 1 ml of THF, and ethylenediamine (0.1 ml) was added to this solution at room temperature under argon atmosphere and stirred for 15 minutes. . Subsequently, ethyl chloroacetate (45 μl) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was poured into a 5% sulfuric acid aqueous solution,
It was extracted with dichloromethane. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. This concentrate was applied to a silica gel column to remove dichloromethane and n-hexane.
When it was poured out with a 2: 1 mixed solvent, 4-ethoxycarbonylmethylthio-1- (p-toluenesulfonyl) indole (70 mg, yield 96.4%) was obtained. Colorless columnar crystals (reconstituted from n-hexane-ethyl acetate) Melting point 61.5-62.5 ° C ¹ H NMR (in CDCl ₃ ); δ 1.10 (t, J = 7.1Hz, 3H), 2.33
(S, 3H), 3.62 (s, 2H), 4.08 (q, J = 7.1Hz, 2H), 6.8
6 (d, J = 3.8Hz, 1H), 7.14 to 7.42 (m, 4H), 7.62 (d, J
= 3.8Hz, 1H), 7.70 to 8.00 (m, 3H) ppm.

IR (KBr); 1725,1596,1367,1167cm ^-1 .

Mass (m / z,%); 389 (M ⁺ , 100), 234 (32), 162 (43), 9
1 (50).

Elemental analysis value; Calculated value as C ₁₉ H ₁₉ NS ₂ O ₄ (%); C, 58.59; H, 4.92; N, 3.60; S, 16.46 Measured value (%); C, 58.62; H, 5.01; N, 3.55; S, 16.34 Reference Example 7 4-Ethoxycarbonylmethylthio-1- (p-toluenesulfonyl) indole (60 mg, 0.13 mmol) was added to a solution of potassium hydroxide (30 mg, 85.5% purity 0.46 mmol) in 1.5 ml of methanol at room temperature under an argon atmosphere. Add 4
Stir for hours. Subsequently, potassium hydroxide (20 mg, 85.5% purity, 0.30 mmol) was further added, and the mixture was heated under reflux for 5 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was dissolved in methanol (0.2 ml) and ether (1 ml), and an ether solution of diazomethane was added to this solution at room temperature until generation of gas was not observed, and the mixture was stirred for 15 minutes. The reaction mixture was concentrated, and the concentrate was applied to a silica gel column and flushed with dichloromethane. 4-methoxycarbonylmethylthioindole (33 mg, yield 96.8%)
was gotten. This product is used as an intermediate for the synthesis of chuancinmycin [J. Am. Chem, Soc., 104, 7622 (198
2)].

Colorless columnar crystals (reconstituted from n-hexane-benzene) Melting point 82.5 ° C-83.0 ° C ¹ H NMR (in CDCl ₃ ); δ3.68 (s, 3H), 3.72 (s, 2H),
6.76 ~ 6.78 (m, 1H), 7.04 ~ 7.41 (m, 4H), 8.20 ~ 8.38
(M, 1H) ppm.

IR (KBr); 3335,1740,1725 cm ^-1 .

Mass (m / z,%); 221 (100, M ⁺ ), 162 (47), 148 (91), 1
18 (38), 117 (20), 104 (30).

Elemental analysis value; Calculated value as C ₁₁ H ₁₁ NSO ₂ (%); C, 59.71; H, 5.01; N, 6.33; S, 14.49 Measured value (%); C, 59.70; H, 4.90; N, 6.28; S, 14.63 Example 5 4-Ethoxythiocarbonylthio-1- (p-toluenesulfonyl) indole (24.5mg, 0.06mmol) was dissolved in 1.0ml THF, and ethylenediamine (50μl) was added to this solution at room temperature under argon atmosphere and stirred for 10 minutes. did. Subsequently, benzyl bromide (20 μl) was added, and the mixture was stirred at room temperature for 20 minutes. After the reaction was completed, the reaction mixture was poured into a 5% sulfuric acid aqueous solution,
It was extracted with dichloromethane. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. This concentrate was applied to a silica gel column to remove dichloromethane and n-hasan.
When it was run out with a mixed solvent of 3: 2, 4-benzylthio-1
-(P-Toluenesulfonyl) indole (20 mg, yield 81.2
%)was gotten.

Colorless columnar crystals (reconstituted from n-hexane-ethyl acetate) melting point 119.0-122.0 ° C ¹ H NMR (in CDCl ₃ ); δ2.35 (s, 3H), 4.11 (s, 2H),
6.77 (d, J = 3.7Hz, 1H), 7.12 to 7.36 (m, 9H), 7.57
(D, J = 3.7Hz, 1H), 7.68 to 7.96 (m, 3H) ppm.

IR (KBr); 1367,1170 cm ^-1 Mass (m / z,%); 393 (M ⁺ , 24), 238 (16), 91 (100).

Claims (1)

[Claims] 1. A general formula (In the formula, R is a hydrogen atom, an alkyl group, an alkenyl group, an aralkyl group or an alkoxycarbonylmethyl group, and X is a substituted sulfonyl group.) A mercaptoindole.