KR100451414B1 - Indol derivatives and a preparation method thereof - Google Patents

Abstract

Heterocyclic compounds of formula (6) and methods for their preparation.

Formula 6

Wherein R is H or a halogen element selected from Cl, F, Br and I, and Y is -Ts (tosyl), -Ms (mesyl) or -Ac (acetyl).

Description

Indole derivatives and preparation method thereof

The present invention relates to a novel indole derivative and a method for preparing the same, and more specifically, homoallyl by simultaneously performing allylation of aldehyde (-CHO) and reduction of nitro group (-NO ₂ ) using indium metal and acid. The present invention relates to a process for preparing an indole derivative by obtaining a linoallylic alcohol, and then performing a cyclization reaction in the presence of an organic base through a protection reaction of a primary amine and an oxidation reaction of a secondary alcohol. .

Generally, indole compounds are widely used as major intermediates of many medicines and pesticides. Existing methods for synthesizing indole derivatives include Fischer indole synthesis method ( Chem. Rev. , 1942, 30 , 69, Heterocyclic Compounds , Vol 3). , Wily, New York, 1952, Chapter 1), Madeleine indole synthesis ( Chem. Ber ., 1912 , 45 , 1128) and Reissert indole synthesis ( J. Chem. Soc ., 1921 , 119 , 1602). As the compound having a structure similar to that of the compound of the present invention, the compound having the following structure will be unique ( Chem. Ber ., 1961, 94, 2960).

However, the present inventors have intensively studied a novel method for preparing an indole derivative through a short reaction process using a starting material which can be easily obtained without using a difficult reaction process or an expensive raw material. Therefore, it has been found that various indole derivatives can be synthesized in high yield under mild reaction conditions such as organic base at room temperature, unlike the existing violent reaction conditions.

Accordingly, an object of the present invention is to use a compound of formula (3) obtained by a method of simultaneously performing allylation of aldehyde (-CHO) and reduction reaction of nitro group (-NO ₂ ) using an indium metal and an acid as a starting material. To provide a process for preparing an indole derivative comprising the protection of a nuclear primary amine, an oxidation of a nucleophilic secondary alcohol and a cyclization reaction in the presence of an organic base at room temperature, and a novel indole compound thus prepared.

Hereinafter, the present invention will be described in detail.

The compound of formula 1 is reacted with the compound of formula 2 in the presence of an indium metal and an acid to simultaneously achieve an allylation of aldehyde and a reduction reaction of nitro group (Korean Patent Application No. 37558/2000). To obtain a compound of formula (4) by protecting the amine (-NH ₂ ) group in the compound of formula (3), and the compound of formula (5) obtained by oxidation of a secondary alcohol to a compound of formula (6) in the presence of an organic base It relates to a production method for cyclization.

In Formula 1 to Formula 6 and Scheme 1, R is H or a halogen element selected from Cl, F, Br and I; X is a halogen element selected from the group consisting of Cl, Br and I and Y is -Ts (tosyl), -Ms (mesyl) or -Ac (acetyl).

The production method of the present invention will be described in more detail as follows.

Compounds of formula (1), 2-3 equivalents of indium metal and 1-3 equivalents, preferably 1.1-2 equivalents of compound of formula (2) to a suitable organic solvent are added to a suitable organic solvent and the mixture is slowly The reaction was advanced by adding. In this case, the acid is a strong acid including HCl, HBr, sulfuric acid, nitric acid and trifluoroacetic acid, and is used in 1-2 equivalents with respect to indium. After addition of the acid at 20-100 ° C., the mixture was further stirred for about 10 minutes to 1 hour, and then the reaction was terminated by TLC. This reaction is carried out under polar solvents such as tetrahydrofuran, acetonitrile, N, N'-dimethylacetamide, N, N'-dimethylformaldehyde, methanol, ethanol, isopropyl alcohol and a mixed solution of these and water and the like. NaHCO ₃ was added to the reaction mixture, which was then extracted using an organic solvent. And then through conventional work-up including drying the organic layer (e.g., MgSO ₄ , Na ₂ SO _4, etc.) and filtration, purifying by reduced pressure of the filtrate, chromatography and recrystallization, etc. Compounds were synthesized (Korean Patent Application No. 37558/2000 by the inventors).

The compound of formula 3 is added to 3 mL of pyridine and then slowly add about 1-3 equivalents of TsCl (para-toluenesulfonyl chloride) at 0 ° C. Compounds for protecting primary amines may be tosyl (-Ts) groups, mesyl (-Ms) groups or acetyl (-Ac) groups. The reaction is carried out for about 3 to 24 hours. After the reaction proceeds, the mixture is extracted twice using 20 mL of water and 10 mL of methylene chloride. The organic solvent and excess pyridine were dried over MgSO ₄ (or Na ₂ SO ₄ ), the filtrate was concentrated under reduced pressure and purified by chromatography to give the compound of formula 4 in 62-78% yield. Alternatively, it is also possible to dissolve Formula 3 in methylene chloride and then carry out the same process as above using about 1-1.5 equivalents of TsCl and the like.

The compound of formula 4 thus obtained is dissolved in 2 mL of methylene chloride, and then 1-3 equivalents of PCC (pyridinium chlorochromate) or PDC (pyridinium dichromate) is slowly added at room temperature. At this time, the preferred amount of PCC or PDC is about 2 equivalents. Alternatively, secondary alcohols can be oxidized using Swern's oxidation or Dess-Martin periodinan oxidation. This mixture is allowed to react for about 4 to 12 hours. After the reaction proceeded, 3 mL of diethyl ether was added and filtered using celite. The organic solvent was concentrated and purified by chromatography to give the compound of formula 5 in a yield of 65-84%.

The compound of formula 5 thus obtained is dissolved in 2 mL of methylene chloride and then reacted at room temperature in the presence of an organic base. Organic bases that can be used include DBU (1,8-diazabicyclo [5.4.0] undec-7-ene), DBN (1,5-diazabicyclo [4.3.0] non-5ene), pyridine or tri Ethylamine. Preference is given to using 2 equivalents of diisopropylethylamine ( i- Pr ₂ NEt) as the organic base. After reacting for about 10 minutes to 5 hours, the reaction mixture is extracted twice with 10 mL of methylene chloride. The organic layer was dried over magnesium sulfate, concentrated and purified by chromatography to give the compound of formula 6 in a yield of 67-88%. The reaction temperature is in the range of -78 to 50 ° C, preferably room temperature to 40 ° C.

Isomers may be produced in the process of preparing the compound of Formula 6, which may be separated by physical methods or the use of chiral auxiliaries. And the present invention includes individual isomers or racemates thereof.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to these examples.

Example

Example 1. 2-2-hydroxy-2- [2- (para-toluenesulfonylamino) phenyl] ethylacrylic acid methyl ester

Dissolve starting material 2- [2- (2-aminophenyl) -2-hydroxyethyl] acrylic acid methyl ester (51.4 mg, 0.23 mmol) in 3 mL of pyridine, and then slowly para-toluenesulfate at 0 ° C. under nitrogen atmosphere. Ponylchloride (88.6 mg, 0.46 mmol) was added and reacted at room temperature for about 12 hours. 10 mL of water was added to the reaction mixture and extracted using methylene chloride. The organic layer was dried using MgSO ₄ (or Na ₂ CO ₃ ) and the solvent was removed under reduced pressure. Chromatography gave 87.4 mg (78%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.33 (3H, s), 2.47 (2H, d, J = 6.48 Hz), 3.35 (1H, d, J = 3.18 Hz), 3.76 (3H, s), 4.78 (1H, m), 5.44 (1H, s), 6.15 (1H, d, J = 1.2 Hz), 6.98-7.17 (3H, overlap H), 7.18 (2H, d, J = 8.01 Hz), 7.42 (1H , d, J = 7.95 Hz), 7.67 (2H, d, J = 8.25 Hz), 8.58 (1 H, s); ¹³ C NMR (CDCl ₃ , 75 MHz) δ 21.9, 41.2, 52.7, 60.8, 122.2, 124.9, 127.5, 127.6, 128.7, 129.4, 130.0, 133.3, 135.5, 136.6, 137.4, 144.1; IR (neat, cm ^-1 ) 3482, 3238, 1718, 1710, 1340, 1158, 928.

Example 2. 2-2- [2-chloro-6- (para-toluenesulfonylamino) phenyl] -2-hydroxyethylacrylic acid methyl ester

Dissolve starting material 2- [2- (2-amino-6-chlorophenyl) -2-hydroxyethyl] acrylic acid methyl ester (38.5 mg, 0.15 mmol) in 3 mL of pyridine, and then slowly at 0 ° C. under nitrogen atmosphere. Para-toluenesulfonylchloride (43.1 mg, 0.23 mmol) was added and reacted at room temperature for about 12 hours. 10 mL of water was added to the reaction mixture, and the mixture was extracted using methylene chloride. The organic layer was dried using MgSO ₄ (or Na ₂ CO ₃ ) and the solvent was removed under reduced pressure. Chromatography gave 46.6 mg (76%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 2.35 (3H, s), 2.47 (2H, m), 3.79 (3H, s), 4.09 (1H, s), 5.47 (1H, s), 5.49 (1H, m ), 6.17 (1H, s), 6.98 (1H, d, J = 8.1 Hz), 7.07 (1H, t, J = 8.1 Hz), 7.23 (2H, d, J = 8.25 Hz), 7.45 (1H, d , J = 8.1 Hz), 7.75 (2H, d, J = 8.22 Hz), 9.70 (1H, s, -NH-).

Example 3. 2-2- [5-chloro-2- (para-toluenesulfonylamino) phenyl] -2-hydroxyethylacrylic acid methyl ester

Dissolve starting material 2- [2- (2-amino-5-chlorophenyl) -2-hydroxyethyl] acrylic acid methyl ester (81.3 mg, 0.32 mmol) in 3 mL of pyridine, and then slowly at 0 ° C. under nitrogen atmosphere. Para-toluenesulfonylchloride (121.3 mg, 0.63 mmol) was added and reacted at room temperature for about 12 hours. 10 mL of water was added to the reaction mixture, and the mixture was extracted using methylene chloride. The organic layer was dried using MgSO ₄ (or Na ₂ CO ₃ ) and the solvent was removed under reduced pressure. Chromatography gave 80 mg (62%) of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz) δ 2.36 (3H, s), 2.42 (2H, m, overlap), 3.18 (1H, d, J = 2.94 Hz), 3.82 (3H, s), 4.69 (1H, m ), 5.54 (1H, s), 6.21 (1H, s), 7.13 (1H, s), 7.15 (1H, overlap), 7.21 (2H, d, J = 8.25 Hz), 7.23 (1H, overlap), 7.39 (1H, d, J = 9.33 Hz), 7.65 (2H, d, J = 8.25 Hz), 8.45 (1H, s, -NH-)

Example 4. 2-2-oxo-2- [2- (para-toluenesulfonylamino) phenyl] ethylacrylic acid methyl ester

2-2-hydroxy-2- [2- (para-toluenesulfonyl) phenyl] ethylacrylic acid methyl ester (33.6 mg, 0.0895 mmol) was dissolved in 3 mL of methylene chloride, and then 20 mg of silica gel at room temperature under nitrogen atmosphere. And PCC (38.6 mg, 0.179 mmol) were added. After the reaction for about 16 hours, the mixture was filtered using Celite. The solvent was removed under reduced pressure and purified by chromatography to give 28 mg (84%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.19 (3H, s), 3.87 (3H, s), 3.98 (2H, s), 5.63 (1H, s), 6.4 (1H, s), 7.0-7.88 ( 8H, overlap H), 11.25 (1 H, s); ¹³ C NMR (CDCl ₃ , 75 MHz) δ 14.6, 43.1, 52.6, 119.3, 123.0, 124.9, 127.6, 129.3, 130.0, 131.6, 133.2, 134.4, 136.6, 140.6, 140.3, 167.1; IR (neat, cm ⁻¹ ) 3124, 1726, 1650, 1334, 1160.

Example 5. 2-2- [2-chloro-6- (para-toluenesulfonylamino) phenyl] -2-oxoethylacrylic acid methyl ester

2-2- [2-Chloro-6- (para-toluenesulfonyl) phenyl] -2-hydroxyethylacrylic acid methyl ester (46.6 mg, 0.11 mmol) was dissolved in 3 mL of methylene chloride, followed by room temperature under nitrogen atmosphere. 20 mg silica gel and PCC (49 mg, 0.23 mmol) were added. After the reaction for about 16 hours, the mixture was filtered using Celite. The solvent was removed under reduced pressure and purified by chromatography. 30 mg (65%) of the title compound were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.37 (3H, s), 3.67 (2H, s, -CH _2- ), 3.87 (3H, s), 5.77 (1H, s), 6.42 (1H, s) , 7.07 (1H, d, J = 7.02 Hz), 7.24 (3H, dt, overlap of proton), 7.61 (1H, d, J = 8.31 Hz), 7.71 (2H, d, J = 8.28 Hz), 8.31 ( 1H, br s, -NH-)

Example 6. 2-2- [5-chloro-2- (para-toluenesulfonylamino) phenyl] -2-oxoethylacrylic acid methyl ester

2-2- [5-chloro-2- (para-toluenesulfonyl) phenyl] -2-hydroxyethylacrylic acid methyl ester (80 mg, 0.19 mmol) was dissolved in 3 mL of methylene chloride and then at room temperature under nitrogen atmosphere. 20 mg of silica gel and PCC (84 mg, 0.39 mmol) were added. After the reaction for about 16 hours, the mixture was filtered using Celite. The solvent was removed under reduced pressure and the residue was purified by chromatography to give 67 mg (85%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.36 (3H, s), 3.76 (3H, s), 3.90 (2H, s), 5.64 (1H, s), 6.39 (1H, s), 7.22 (2H, d, J = 8.22 Hz), 7.37 (1H, d, J = 2.37 Hz), 7.64 (1H, overlap), 7.68 (2H, d, J = 8.22 Hz), 7.80 (1H, s), 11.0 (1H, br s, -NH-)

Example 7. 2- [3-oxo-1- (para-toluenesulfonyl) -2,3-dihydro- 1H -Indol-2-yl] propionic acid methyl ester

Dissolve 2-2-oxo-2- [2- (para-toluenesulfonyl) phenyl] ethylacrylic acid methyl ester (63.6 mg, 0.14 mmol) in 3 mL of methylene chloride, and then diisopropylethyl at room temperature under nitrogen atmosphere. Amine (60 μl, 0.34 mmol) was added. After about 4 hours, when the starting material disappeared, 3 mL of H ₂ O was added to terminate the reaction and extracted twice with methylene chloride. The organic layer was dried over magnesium sulfate, the solvent was removed, and then chromatographed to give 47 mg (88%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.26 (3H, d, J = 9.03 Hz), 2.35 (3H, s), 3.67 (1H, m), 3.73 (3H, s), 4.22 (1H, d, J = 2.46 Hz), 7.20-8.1 (8H, overlap H of another isomer); ¹³ C NMR (CDCl ₃ , 75 MHz) δ 11.6, 21.9, 43.4, 52.6, 68.1, 117.6, 124.6, 125.2, 125.7, 127.8, 130.4, 130.5, 137.5, 145.6, 153.7, 173.7, 197.3 .; IR (neat, cm-1) 1724, 1602, 1364, 1174; Analytical Calcd for HRMS (EI) C ₁₉ H ₁₉ NO ₅ S: 373.0984. Found: 373.0991.

Example 8. 2- [4-Chloro-3-oxo-1- (para-toluenesulfonyl) -2,3-dihydro-1 H Indole-2-yl] propionic acid Methyl ester

2-2- [2-chloro-6- (para-toluenesulfonyl) phenyl] -2-oxoethylacrylic acid methyl ester (29.1 mg, 0.07 mmol) was dissolved in 3 mL of methylene chloride and then at room temperature under nitrogen atmosphere. Diisopropylethylamine (25 μl, 0.14 mmol) was added. After about 10 minutes, when the starting material disappeared, 3 mL of H ₂ O was added to terminate the reaction and extracted twice with methylene chloride. The organic layer was dried over magnesium sulfate, the solvent was removed, and then 24.3 mg (84%) of the title compound were obtained by chromatography.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.32 (3H, d, J = 7.26 Hz), 2.37 (3H, s), 3.50 (1H, m), 3.72 (3H, s), 4.22 (1H, d, J = 2.49 Hz), 7.13 (1H, d, J = 8.19 Hz), 7.23 (3H, overlap of protons), 7.52-7.62 (4H, overlap of protons); ¹³ C NMR (CDCl ₃ , 75 MHz) δ 11.4, 21.5, 43.3, 52.2, 67.8, 115.2, 126.1, 127.4, 130.1, 132.1, 132.4, 136.9, 145.5, 154.6, 173.1, 194.0; IR (neat, cm ⁻¹ ) 1730, 1590, 1366, 1174; Analytical Calcd for HRMS (EI) C ₁₉ H ₁₈ ClNO ₅ S: 409.0565. Found: 409.0560.

Example 9. 2- [5-chloro-3-oxo-1- (para-toluenesulfonyl) -2,3-dihydro-1 H -Indol-2-yl] propionic acid methyl ester

2-2- [5-chloro-2- (para-toluenesulfonyl) phenyl] -2-oxoethylacrylic acid methyl ester (67.1 mg, 0.16 mmol) was dissolved in 3 mL of methylene chloride and then at room temperature under nitrogen atmosphere. Diisopropylethylamine (57.3 μl, 0.33 mmol) was added. After about 40 minutes, when the starting material disappeared, 3 mL of H ₂ O was added to terminate the reaction and extracted twice with methylene chloride. The organic layer was dried over magnesium sulfate, the solvent was removed, and then chromatographed to give 45 mg (67%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.30 (3H, d, J = 6.48 Hz), 2.37 (3H, s), 3.52 (1H, m), 3.71 (3H, s), 4.15 (1H, d, J = 2.64 Hz), 7.23-8.06 (7H, overlap with isomer respectively); ¹³ C NMR (CDCl ₃ , 75 MHz) δ 12.1, 21.9, 43.8, 52.7, 68.5, 118.9, 124.1, 127.8, 130.5, 131.2, 132.8, 137.6, 145.9, 151.9, 173.6, 196.1 .; IR (neat, cm ⁻¹ ) 1728, 1602, 1366, 1174, 1130 .; Analytical Calcd for HRMS (EI) C ₁₉ H ₁₈ ClNO ₅ S: 407.0594. Found: 407.0591.

The manufacturing method of the present invention has the following characteristics as compared to the conventional method.

1) It can be prepared through a short reaction process from o -nitrobenzaldehyde.

2) The yield is high in most cases.

3) Synthesis of various indole derivatives is possible.

The production process of the invention can be used to prepare indole derivatives, which are the major intermediates of pharmaceuticals and pesticides, in a relatively short time under mild reaction conditions such as organic bases.

Claims (4)

Indole derivatives of the formula (6) or isomers thereof. Formula 6 Wherein R is H or a halogen element selected from Cl, F, Br and I and Y is -Ts (tosyl) or -Ms (mesyl) A compound of formula 1 is reacted with a compound of formula 2 in the presence of an indium metal and an acid to simultaneously perform allylation of aldehydes and reduction of nitro groups to obtain a compound of formula 3, and an amine (-NH ₂ ) Protecting the group to obtain a compound of formula 4, oxidizing the secondary alcohol of the compound of formula 4 to obtain a compound of formula 5, and cyclizing the compound of formula 5 in the presence of an organic base to prepare a heterocyclic compound of formula How to. Formula 1 Formula 2 Formula 3 Formula 4 Formula 5 Formula 6 Scheme 1 In Formulas 1 to 6 and Scheme 1, R is H or a halogen element selected from Cl, F, Br and I, X is a halogen element selected from the group consisting of Cl, Br, I and Y is -Ts (Tosyl) or -Ms (mesyl). The reaction of claim 2, wherein the oxidation of the secondary alcohol is performed using PCC (pyridinium chlorochromate) or PDC (pyridinium dichromate), Swern's oxidation or Dess-Martin periodinan oxidation reaction. Method characterized by using the method. The organic base of claim 2, wherein the organic base is diisopropylethylamine, DBU (1,8-diazabicyclo [5.4.0] undec-7-ene), DBN (1,5-diazabicyclo [4.3.0] Non-5-ene), triethylamine or pyridine.