JP5649170B2 - Tetrahydro-β-carboline derivative and method for producing the same - Google Patents

Description

  The present invention relates to a tetrahydro-β-carboline derivative and a method for producing the same.

  Unprecedented molecular supply technology is necessary for the search for compounds having specific biological activity, and new biologically active substances that have been successfully developed are expected to be used in pharmaceuticals and agricultural chemicals. Highly functionalized tetrahydro-β-carbolines often have high biological activity and are useful compounds present in various pharmaceuticals and natural products. Therefore, the development of an efficient method for synthesizing polysubstituted tetrahydro-β-carboline compounds is extremely important.

  At present, synthesis of tetrahydro-β-carboline derivatives has been achieved by various techniques. In particular, synthesis examples of β-carboline derivatives having a substituent at the 4-position carbon are described in the following documents.

C. A. Busacca, M .; C. Eriksson, Y.M. Dong, A.D. S. Prokopowicz, A.M. M.M. Salvagno, M .; A. Tschantz, J.A. Org. Chem. 1999, 64.4564-4568. M.M. Bandini, A.M. Meloni, F.M. Piccinelli, R.M. Sinisi, S .; Tommasi, A .; Umani-Ronchi, J.A. Am. Chem. Soc. 2006, 128.1424-1425. C. Rannoux, F.M. Roussi, P .; Retailleau, F.M. Guerrite, Org. Lett. 2010, 12, 1240-1243.

  However, in spite of its importance, there are still few synthesis examples of tetrahydro-β-carboline derivatives having a substituent at the 4-position carbon, and introduction of the substituent at the 4-position carbon requires a complicated multi-step reaction. In addition, only the β-carboline derivative having a specific stereochemistry is obtained by the synthesis method described in the above-mentioned literature, and development of a new β-carboline derivative synthesis method is desired in order to search for a novel bioactive substance.

  Then, in view of the said subject, this invention aims at providing the tetrahydro-beta-carboline derivative synthesis | combination using the indole derivative shown by (1).

  The inventors of the present invention have been diligently studying the above-mentioned problems, and by performing reduction of the nitro group and protection of the hydroxy group and subsequent octet-Spengler reaction with the aldehyde on the indole derivative represented by (1). The inventors discovered that a tetrahydro-β-carboline derivative represented by (2) can be obtained, and completed the present invention.

That is, the method for producing tetrahydro-β-carboline according to one means of the present invention comprises reducing the nitro group and protecting the hydroxy group with respect to the indole derivative represented by the following formula (1), followed by the Pictet-Spengler reaction with the aldehyde I do.

Here, R ¹ , R ² , and R ³ in the above formula are an aryl group, an alkyl group, or an acyl group. Moreover, you may have substituents, such as an alkyl group, an alkoxy group, a halogen group, and a nitro group, on the indole skeleton.

As a result, a tetrahydro-β-carboline derivative represented by the following formula (2) can be obtained.

Here, R ¹ , R ² , R ³ , and R ⁴ in the above formula are an aryl group, an alkyl group, or an acyl group. Moreover, you may have substituents, such as an alkyl group, an alkoxy group, a halogen group, and a nitro group, on the indole skeleton.

  As described above, according to the present invention, a novel tetrahydro-β-carboline compound that has not been reported so far can be effectively obtained in a short process, and various compounds can be synthesized and supplied.

  Embodiments of the present invention will be described below with reference to the drawings. However, the present invention can be implemented in many different modes and is not limited to the embodiments shown below.

(Embodiment 1)
In the method for producing tetrahydro-β-carboline according to the present embodiment, the indole derivative represented by the following formula (1) is subjected to reduction of the nitro group and protection of the hydroxy group, followed by a pitet-Spengler reaction with the aldehyde. The method for synthesizing the indole derivative (1) is not limited as long as it can be synthesized. For example, a method described in JP-A-2008-117919 can be used.

Here, R ¹ , R ² , and R ³ in the above formula are an aryl group, an alkyl group, or an acyl group. Moreover, you may have substituents, such as an alkyl group, an alkoxy group, a halogen group, and a nitro group, on the indole skeleton.

First, β-amino alcohol represented by the following formula (3) is added to the indole derivative represented by the above formula (1) by adding acetic acid and hydrochloric acid in a methanol solvent and reducing the nitro group using Zn powder under acidic conditions. Can be obtained.

Here, R ¹ , R ² , and R ³ in the above formula are an aryl group, an alkyl group, or an acyl group. Moreover, you may have substituents, such as an alkyl group, an alkoxy group, a halogen group, and a nitro group, on the indole skeleton.

In the above reaction, when R ¹ or R ² is an alkyl group, it is desirable to use Zn nanopowder with finer particles.

Next, the β-aminoalcohol represented by the above formula (3) can protect the hydroxyl group using a silicon halide reagent substituted with an alkyl group or an aryl group. For example, a compound represented by the following formula (4) can be obtained by reacting triethyl chloride in the presence of imidazole in dimethylformamide.

Here, R ¹ , R ² , and R ³ in the above formula are an aryl group, an alkyl group, or an acyl group. Moreover, you may have substituents, such as an alkyl group, an alkoxy group, a halogen group, and a nitro group, on the indole skeleton.

Next, by subjecting the compound represented by the above formula (4) to a Pictet-Spengler reaction with an aldehyde using trifluoroacetic acid as an acid catalyst in the presence of magnesium sulfate in chloroform, tetrahydro-β- represented by the following formula (2) A carboline derivative can be obtained.

Here, R ¹ , R ² , R ³ , and R ⁴ in the above formula are an aryl group, an alkyl group, or an acyl group. Moreover, you may have substituents, such as an alkyl group, an alkoxy group, a halogen group, and a nitro group, on the indole skeleton.

  In the above reaction, it is desirable to sufficiently form an imine by reacting an amine with an aldehyde before adding an acid catalyst.

In the above reaction, an aldehyde used as a reaction substrate is represented by the following formula (5). Here, R ⁴ can be an aryl group, an alkyl group, or an acyl group.

  As described above, according to the method according to the present embodiment, the tetrahydro-β-carboline derivative can be effectively obtained in a short process.

  Here, tetrahydro-β-carboline induction was actually synthesized by the method according to the above embodiment, and the result was confirmed. This will be specifically described below. Of course, the reaction according to the above embodiment can be carried out in many different ways and is not limited to the following examples.

  First, a reduction reaction of the nitro group of the indole derivative represented by (1) was performed.

Example 1
In this example, 0.104 g of an indole derivative represented by the following formula (1-1) was dissolved in 2.50 ml of methanol, and 0.834 ml of acetic acid, 1.67 ml of 1N hydrochloric acid and 0.364 g of Zn powder were added thereto. In addition, the reaction was performed at room temperature for 15 hours. As a result, 0.0942 g of the following compound (3-1) was obtained. The yield of (3-1) was 99%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (br, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.45 (m, 2H), 7.15-7.36 ( m, 11H), 7.11 (m, 1H), 4.69 (d, J = 1.4 Hz, 1H), 4.43 (d, J = 9.9 Hz, 1H), 3.90 (dd, J = 2.3, 10.0 Hz, 1H), 1.28 (br, 2H);
¹³ C NMR (125 MHz, CDCl 3) δ 144.0, 142.4, 136.3, 128.7, 128.6, 128.3, 127.0, 126.6, 125.6, 122.2, 121. 5, 119.6, 119.5, 117.8, 111.1, 71.8, 60.1, 46.0;
_{HRMS calcd for C 23 H 23 N} 2 O (M + H): 343.1805, found: m / z 343.1800;
[Α] _D ^25.0 = + 2.0 (c = 0.71, CHCl ₃ );
IR (neat) 3416, 3059, 3028, 1453, 908, 737, 701 cm ⁻¹ .

(Example 2)
In this Example 2, 0.0496 g of an indole derivative represented by the following formula (1-2) was dissolved in 1.18 ml of methanol, and 0.393 ml of acetic acid, 0.786 ml of 1N hydrochloric acid and 0. It was performed by adding 171 g and reacting at room temperature for 3 hours. As a result, 0.0452 g of the following compound (3-2) could be obtained. The yield of (3-2) was 99%.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.04 (br, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.42 (m, 2H), 7.25-7.33 (m, 3H), 7.12-7.19 (m, 2H), 7.10 (d, J = 2.3 Hz, 1H), 7.06, (m, 1H), 4.36 (d, J = 10 .3 Hz, 1H), 3.80 (dd, J = 1.1, 10.3 Hz, 1H), 3.23 (dd, J = 1.1, 8.0 Hz, 1H) 1.92 (br, 1H) ), 0.98-1.82 (m, 8H), 0.80-0.96 (m, 2H);
¹³ C NMR (125 MHz, CDCl ₃ ) δ 143.0, 136.2, 128.7, 128.6, 127.1, 126.5, 122.1, 121.0, 119.4, 117.9, 111.0 74.4, 54.0, 46.6, 41.5, 29.4, 29.3, 26.4, 26.2, 26.0;
_{HRMS calcd for C 23 H 29 N} 2 O (M + H): 349.2274, found: m / z 349.2264;
[Α] _D ^24.2 = −4.5 (c = 0.41, CHCl ₃ );
IR (neat) 3413, 3297, 3059, 2924, 2851, 1452, 741 cm ⁻¹ .

  The resulting compound (3) was protected with a hydroxy group.

Example 1
Example 1 was carried out by dissolving 0.0949 g of compound (3-1) in 1.39 ml of anhydrous dimethylformamide and reacting with 0.0930 ml of triethylsilyl chloride and 0.0943 g of imidazole at 0 ° C. for 1 hour. As a result, 0.104 g of the following compound (4-1) was obtained. The yield of (4-1) was 82%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (br, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.41 (m, 2H), 7.19-7.35 (m, 9H), 7.11-7.18 (m, 2H), 7.05 (m, 1H), 4.84 (d, J = 3.6 Hz, 1H), 4.22 (d, J = 8. 4 Hz, 1H), 3.65 (dd, J = 3.8, 8.6 Hz, 1H), 0.76 (t, J = 7.9 Hz, 9H), 0.30-0.42 (m, 6H) );
¹³ C NMR (100 MHz, CDCl ₃ ) δ 143.9, 142.8, 136.3, 129.1, 128.3, 128.0, 127.2, 126.9, 126.6, 126.2, 122.0 , 121.3, 119.4, 119.2, 118.3, 111.0, 75.3, 61.0, 46.6, 6.7, 4.8;
_{HRMS calcd for C 29 H 37 N} 2 OSi (M + H): 457.2670 found: m / z 457.2661;
[Α] _D ^24.6 = −2.0 (c = 0.33, CHCl ₃ );
IR (neat) 3421, 3166, 3060, 3027, 2953, 2911, 2875, 1454, 1060, 738, 700 cm ⁻¹ .

(Example 2)
In this example, 0.0477 g of compound (3-1) was dissolved in 0.685 ml of anhydrous dimethylformamide and reacted with 0.0460 ml of triethylsilyl chloride and 0.0466 g of imidazole at room temperature for 1 hour. As a result, 0.0507 g of the following compound (4-2) could be obtained. The yield of (4-2) was 80%.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.03 (br, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.29-7.35 (m, 3H), 7.22-7. 27 (m, 2H), 7.10-7.15 (m, 3H), 7.02 (m, 1H), 4.19 (d, J = 10.0 Hz, 1H), 3.70 (dd, J = 1.4, 7.2 Hz, 1H), 3.58 (dd, J = 1.5, 10.0 Hz, 1H), 1.88 (br, 1H), 1.62-1.84 (m) , 5H), 0.90-1.33 (m, 5H), 0.86 (t, J = 8.0 Hz, 9H), 0.51 (q, J = 8.0 Hz, 6H);
¹³ C NMR (125 MHz, CDCl ₃ ) δ 143.4, 136.1, 128.9, 128.4, 127.3, 126.2, 122.0, 120.4, 119.4, 119.2, 118.3 110.9, 54.9, 48.0, 42.3, 30.1, 30.0, 26.6, 26.5, 26.4, 7.0, 5.6;
HRMS calcd for C ₂₉ H ₄₃ N ₂ OSi (M + H): 463.3139, found: m / z 463.3127;
[Α] _D ^23.0 = −63.1 (c = 1.0, CHCl 3);
IR (neat) 3418, 3166, 3060, 2925, 2875, 2852, 1455, 1011, 738, 702 cm ⁻¹ .

  The resulting compound (4) was subjected to Pictet-Spengler reaction.

Example 1
In Example 1, 0.0388 g of Compound (4-1) was dissolved in 0.805 ml of anhydrous chloroform, and reacted with 0.0805 g of magnesium sulfate and 0.0245 ml of benzaldehyde at room temperature for 5 hours. Thereafter, 0.00658 ml of trifluoroacetic acid was added and reacted at room temperature for 19 hours. As a result, 0.0232 g of the following compound (2-1) was obtained. The yield of (2-1) was 67%.

¹ H _{NMR (400MHz, CDCl 3) δ7.53-7.62} (m, 3H), 7.35-7.50 (m, 6H), 7.18-7.30 (m, 7H), 7.06- 7.16 (m, 2H), 7.02 (m, 1H), 6.87 (m, 1H), 5.35 (d, J = 1.6 Hz, 1H), 4.02 (d, J = 9.7 Hz, 1H), 3.95 (dd, J = 1.8, 4.1 Hz, 1H), 3.83 (dd, J = 4.1, 9.7 Hz, 1H), 3.40 (br , 1H), 2.37 (br, 1H);
¹³ C NMR (100 MHz, CDCl ₃ ) δ 140.9, 140.4, 140.0, 136.2, 135.2, 129.9, 129.2, 128.7, 128.6, 128.5, 127 .9, 126.7, 126.5, 121.9, 119.5, 118.5, 114.4, 110.8, 74.5, 64.0, 59.5, 39.9;
_{HRMS calcd for C 30 H 26 N} 2 ONa (M + Na): 453.1937, found: m / z 453.1920;
[Α] _D ^25.7 = −6.4 (c = 1.0, CHCl ₃ );
IR (neat) 3412, 3332, 3060, 3030, 2919, 1493, 1454, 909, 737, 701 cm ⁻¹ .

(Example 2)
In Example 2, 0.0509 g of compound (4-2) was dissolved in 1.10 ml of anhydrous chloroform and reacted with 0.110 g of magnesium sulfate and 0.0499 g of 4-nitrobenzaldehyde at room temperature for 5 hours. Thereafter, 0.00899 ml of trifluoroacetic acid was added and reacted at room temperature for 24 hours. As a result, 0.0275 g of the following compound (2-2) could be obtained. The yield of (2-2) was 52%.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.32 (m, 2H), 7.74 (m, 2H), 7.44-7.52 (m, 3H), 7.19-7.33 (m, 5H) 7.11 (m, 1H), 6.99 (m, 1H), 5.39 (d, J = 1.5 Hz, 1H), 4.28 (dd, J = 1.7, 4.0 Hz, 1H), 3.50 (dd, J = 4.3, 9.1 Hz, 1H), 3.05 (d, J = 8.9 Hz, 1H), 2.25 (br, 2H), 1.66 1.92 (m, 5H), 1.10-1.40 (m, 6H);
¹³ C NMR (125 MHz, CDCl ₃ ) δ 148.4, 148.0, 140.5, 136.5, 133.8, 129.5, 129.4, 128.3, 126.9, 126.5, 124 3,122.4,119.9,118.6,114.7,110.9,75.0,60.2,58.8,40.4,38.7,30.8,26.9 , 26.5, 26.4, 25.3;
_{HRMS calcd for C 30 H 32 N} 3 O 3 (M + H): 482.2438, found: m / z 482.2429;
[Α] _D ^21.4 = −30.6 (c = 1.0, CHCl ₃ );
IR (neat) 3401, 3059, 2925, 2851, 1521, 1452, 1347, 744, 710 cm ⁻¹ .

  As described above, according to this example, it was confirmed that a polysubstituted tetrahydro-β-carboline compound could be synthesized.

  The present invention can supply a highly functionalized tetrahydro-β-carboline compound with high stereoselectivity, and thus is useful for the development and production of pharmaceuticals and agricultural chemicals, and has industrial applicability.

Claims (2)

A method of synthesizing a tetrahydro-β-carboline derivative represented by the following formula (2) using an indole derivative represented by the following formula (1).
(Wherein R ¹ is an aryl group, an alkyl group, an acyl group, or a hydrogen atom, and R ² and R ³ are an aryl group, an alkyl group, or an acyl group. And may have a substituent of an alkyl group, an alkoxy group, a halogen group, or a nitro group .

(Here, R ¹ is an aryl group, an alkyl group, an acyl group, or a hydrogen atom, and R ² , R ³ , and R ⁴ are an aryl group, an alkyl group, or an acyl group. (It may have an alkyl group, alkoxy group, halogen group, or nitro group substituent on the indole skeleton.) A tetrahydro-β-carboline derivative represented by the following formula (2).
(Here, R ¹ is an aryl group, an alkyl group, an acyl group, or a “hydrogen atom”, and R ² , R ³ , and R ⁴ are an aryl group, an alkyl group, or an acyl group. In addition, an alkyl group, an alkoxy group, a halogen group, or a nitro group substituent may be present on the indole skeleton.