Indole C2-site methylation preparation method

Abstract

The invention discloses a preparation method of indole C2-position methylation, and belongs to the technical field of organic synthesis. According to the method, an indole derivative and a methylation reagent are used as initial raw materials and are stirred to react in an organic solvent at 70-100 DEG C under the action of a palladium catalyst, norbornene and alkali, and the C2-position methylated indole derivative can be obtained. The method is good in process, does not need anhydrous and anaerobic operation, does not involve organic strong alkali, does not need additional positioning groups, does not need to protect indole N-H in advance, is mild in reaction condition and good in substrate universality, and has relatively high practicability and industrial value.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation method for methylating indole C2. Background Art

[0002] As the simplest alkyl group in structure, methyl occupies a pivotal position in the field of drug synthesis. As the bioelectronic equivalent of hydrogen atoms, its exquisite introduction into drug active molecules can often optimize the bioavailability and pharmacological properties of these molecules, thereby greatly improving the efficacy and metabolic stability of drugs. This extraordinary transformation is vividly called the "magical methyl effect" by the industry. It is worth noting that according to statistics, among the 200 leading drugs in global sales in 2020, up to about 40% of the drug molecular structures contain C-methyl units. This proportion highlights the core value and wide application of methyl in modern drug design. Among them, in the optimization of drug active molecules containing indole skeletons, the introduction of methyl at the C2 position of indole is an important modification strategy. For example, the HDAC inhibitor panobinostat, the tyrosine kinase inhibitors brivanib and cediranib, and the non-steroidal anti-inflammatory drug indomethacin all have methyl at the C2 position of indole.

[0003] Currently, there are two main methods for introducing C2 methyl group by directly functionalizing the indole ring:

[0004] (1) The traditional method mainly involves deprotonation with a strong organic base such as n-butyl lithium and then adding an electrophilic reagent such as iodomethane to achieve methylation at the C2 position of indole (Org. Lett. 2015.664). This method usually requires strict anhydrous conditions, uses expensive anhydrous tetrahydrofuran, and has a limited substrate range, making it unsuitable for industrial production.

[0005] (2) The methods currently developed by researchers mainly focus on first introducing a directing group or other non-hydrogen atom substituents at the indole NH position and then achieving the methylation of the indole C2 position through a metal-mediated catalytic reaction, such as rhodium catalysis (ChemCatChem.2014.3069; Org.Lett.2015.2812; Angew.2021.6660; J.Org.Chem.2022.6161; Chem.Eur.J.2022.e202103837), palladium catalysis (Org.Biomol.Chem.2016.7443); ruthenium catalysis (Synthesi s.2017.127); iridium catalysis (RSCAdv.2023.11291). This type of method basically requires the introduction of additional directing groups and other functional groups at the indole NH position before methylating the C2 position. After the reaction, the directing groups need to be removed, which increases the reaction steps and does not have step economy or atom economy.

[0006] Therefore, it is very necessary to achieve C2 methylation of indole with a more convenient preparation method suitable for industrial production. Summary of the invention

[0007] In order to solve the problems existing in the prior art, the purpose of the present invention is to provide a preparation method of indole C2 methylation.

[0008] To achieve the above purpose, the technical solution provided by the present invention is as follows:

[0009] Indole derivative A and methylating agent B are used as starting materials, and under the action of palladium catalyst C, norbornene derivative D and base E, the mixture is stirred in organic solvent F at 70-100° C. until the reaction is completed. The reaction mixture is filtered, concentrated and purified by column chromatography to obtain C2 methylated indole derivative G as shown in the reaction formula. The reaction formula of the reaction is shown as follows:

[0010]

[0011] Wherein, R in the general formula A is a substituent on the indole benzene ring structure, n represents the number of R, 0≤n≤4; when n≥2, each R is the same or different.

[0012] Furthermore, R in the general formula A is selected from a hydrogen atom, a C1-C2 alkyl group, an alkoxy group, an ester group, an acyloxy group, a cyano group, an aldehyde group, a nitro group, and a halogen.

[0013] Furthermore, the molar ratio of the indole derivative A, the methylating agent B, the palladium catalyst C, the norbornene derivative D, and the base E is 1:(2-5):(0.05-0.5):(1-3):(3-6).

[0014] Further, the methylating agent B is One of the following, preferably

[0015] Further, the palladium catalyst C is one of: palladium acetate, bis(cyanobenzene)palladium dichloride, bis(acetylacetone)palladium, palladium chloride, tris(dibenzylideneacetone)dipalladium, palladium trifluoroacetate, bis(acetonitrile)palladium chloride, bistriphenylphosphinepalladium dichloride, tetrakis(triphenylphosphine)palladium, among which bis(cyanobenzene)palladium dichloride is preferred.

[0016] Furthermore, the norbornene derivative D is one of: 2-cyano-5-norbornene, 5-norbornene-2-carboxylic acid, 5-norbornene-2-ol, 5-norbornene-2-yl acetate, 5-norbornene-2-carboxylic acid methyl ester, and norbornene, among which norbornene is preferred.

[0017] Furthermore, the base E is one of cesium acetate, potassium acetate, sodium acetate, cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium bicarbonate, and sodium bicarbonate, among which sodium carbonate is preferred.

[0018] Furthermore, the solvent F is one of 1,4-dioxane, ethylene glycol dimethyl ether, acetonitrile, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, among which N,N-dimethylformamide is preferred.

[0019] Furthermore, in the preparation method, the heating process can use an oil bath, which can be silicone oil or paraffin oil; the filtration process uses a sand core funnel and filters under reduced pressure; the concentration process can use atmospheric distillation or reduced pressure distillation, preferably using a rotary evaporator to concentrate under reduced pressure; the purification process is to obtain a pure product through column chromatography.

[0020] The method of the present invention can efficiently prepare C2 methylated indole derivatives. Compared with the prior art, the present invention has the following advantages:

[0021] 1. The main raw materials involved in the present invention are indole and conventional methylating agents, which can be directly used as commercial reagents without special treatment and are low in price;

[0022] 2. The preparation method of the present invention does not require anhydrous and oxygen-free operation, does not involve strong organic bases, has better reaction conditions, is highly operable, and is easy for large-scale production;

[0023] 3. The preparation method of the present invention does not require the introduction of an additional directing group at the indole N1 position in advance, nor does it require the protection of the indole NH, which shortens the reaction steps, has good step economy and atom economy, and has lower industrial production costs.

[0024] 4. The preparation method involved in the present invention has good tolerance and universality to functional groups, and the substituents can be alkyl, alkoxy, acyloxy, cyano, ester, aldehyde, nitro, halogen atoms (F, Cl, Br), etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 For compound G-6 1 H-NMR (400MHz, CDCl3) chart;

[0026] Figure 2 For compound G-6 13 C-NMR (100 MHz, CDCl3) chart. DETAILED DESCRIPTION

[0027] The following are specific embodiments of the present invention, which further describe the technical solutions of the present invention, but the present invention is not limited to these embodiments.

[0028] Example 1: Preparation of Compound G-1

[0029]

[0030] Indole (0.20mmol, 23.4mg), trimethyl phosphate (0.80mmol, 112.0mg, 4eq.), norbornene (0.40mmol, 37.6mg, 2eq.), sodium carbonate (1.00mmol, 105.99mg, 5eq.), Pd(PhCN)2Cl2 (0.03mmol, 11.5mg, 0.15eq.), DMF (1mL) were added to a reaction tube (10mL) pre-equipped with a magnetic stirrer. After the addition of the above reagents, the reaction tube was transferred to an oil bath at 70°C and continued to stir for 12h. TLC detection (PE:EA=19:1, VAN color development) was performed. The reaction was terminated after the conversion of the raw materials was complete. The mixture was cooled to room temperature, saturated sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The target product G-1 (24.0 mg, yield 90%) was obtained as a light yellow solid by purification by column chromatography (ethyl acetate:petroleum ether=1:25, V:V). 1 H NMR (400MHz, CDCl3) δ7.69(s,1H),7.63–7.54(m,1H),7.28(dq,J=8.1,0.9Hz,1H),7.22–7.11(m,2H),6.28(dq,J=2.4,1.2Hz,1H),2.44(s,3H). 13 C NMR (101MHz, CDCl3) δ136.12,135.22,129.12,120.98,119.70,110.37,100.39,13.70.

[0031] Example 2: Preparation of Compound G-2

[0032]

[0033] The operation steps and conditions were the same as those in Example 1, except that the indole substrate used was 6-nitroindole (0.2 mmol, 32.4 mg), and compound G-2 (yellow solid, 10.0 mg, yield 28%) was obtained. 1H NMR (400MHz, CDCl3) δ8.35 (s, 1H), 8.25 (dd, J = 2.6, 0.7Hz, 1H), 7.99 (dd, J = 8.8, 2. 0Hz, 1H), 7.52 (d, J = 8.7Hz, 1H), 6.35 (dt, J = 2.0, 1.0Hz, 1H), 2.52 (d, J = 0.9Hz, 3H). 13 C NMR (101MHz, CDCl3) δ142.59,141.92,134.55,134.35,119.38,115.76,107.22,102.01,14.24.

[0034] Example 3: Preparation of Compound G-3

[0035]

[0036] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 5-methylindole (0.2 mmol, 26.2 mg), and compound G-3 (light yellow liquid, 26.1 mg, yield 90%) is obtained. 1 H NMR (400MHz, CDCl3) δ7.60 (s, 1H), 7.39–7.35 (m, 1H), 7.17 (d, J = 8.2Hz, 1H), 7.00 (dd ,J=8.1,1.7Hz,1H),6.19(dt,J=2.1,1.0Hz,1H),2.50(s,3H),2.42(d,J=1.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ135.29,134.43,129.42,128.81,122.46,119.49,110.00,99.96,21.55,13.75.

[0037] Example 4: Preparation of Compound G-4

[0038]

[0039] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 6-cyanoindole (0.2 mmol, 28.4 mg), and compound G-4 (yellow solid, 30.0 mg, yield 93%) is obtained. 1H NMR(400MHz, CDCl3)δ8.40(s,1H),7.61(d,J=1.2Hz,1H),7.54(d,J=8.2Hz,1H), 7.30(dd,J=8.2,1.4Hz,1H), 6.30(dt,J=2.2,1.1Hz,1H), 2.49(d,J=1.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ139.82,134.95,132.62,122.95,121.18,120.35,115.00,102.98,101.59,13.96.

[0040] Example 5: Preparation of Compound G-5

[0041]

[0042] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 5-methoxyindole (0.2 mmol, 29.4 mg), and compound G-5 (yellow liquid, 30.1 mg, yield 94%) is obtained. 1 H NMR (400MHz, CDCl3) δ7.75 (s, 1H), 7.15 (d, J = 8.7Hz, 1H), 7.04 (d, J = 2.3Hz, 1H), 6 .80(dt,J=8.7,2.1Hz,1H),6.20–6.14(m,1H),3.87(s,3H),2.41(d,J=1.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ154.16,136.07,131.28,129.62,110.97,110.72,102.04,100.35,56.00,13.82.

[0043] Example 6: Preparation of Compound G-6

[0044]

[0045] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is indole-4-carboxylic acid methyl ester (0.2 mmol, 35.0 mg), and compound G-6 (light yellow solid, 37.0 mg, yield 100%) is obtained. 1H NMR (400MHz, CDCl3) δ8.23 (s, 1H), 7.86 (d, J = 7.6Hz, 1H), 7.46 (dd, J = 8.0, 1.1Hz, 1H),7.14(t,J=7.8Hz,1H),6.87(dt,J=1.9,0.9Hz,1H),3.98(s,3H),2.48(s,3H). 13 C NMR (101MHz, CDCl3) δ168.49,137.90,137.07,128.98,123.22,120.45,120.17,115.10,102.10,51.78,13.91.

[0046] Example 7: Preparation of Compound G-7

[0047]

[0048] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 4-acetoxyindole (0.2 mmol, 35.0 mg), and compound G-7 (pink solid, 36.9 mg, yield 100%) is obtained. 1 H NMR (400MHz, CDCl3) δ8.00(s,1H),7.16–7.00(m,2H),6.80(dd,J=7.4,1.2Hz,1H),6.09(dt,J=2.1,1.0Hz,1H),2.38(s,3H),2.37(d,J=1.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ169.67,142.78,138.01,135.75,122.27,121.11,111.74,108.53,97.16,21.17,13.72.

[0049] Example 8: Preparation of Compound G-8

[0050]

[0051] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 6-methylindole (0.2 mmol, 26.2 mg), and compound G-8 (red solid, 28.0 mg, yield 96%) is obtained. 1H NMR (400MHz, CDCl3) δ7.70(s,1H),7.39(d,J=8.0Hz,1H),7.07(d,J=1.8Hz,1H ),6.90(dd,J=8.0,1.5Hz,1H),6.16(dt,J=2.1,1.0Hz,1H),2.47–2.37(m,6H). 13 C NMR (101MHz, CDCl3) δ136.64,134.42,130.70,126.94,121.37,119.36,110.41,100.23,21.79,13.81.

[0052] Example 9: Preparation of Compound G-9

[0053]

[0054] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 7-methylindole (0.2 mmol, 26.2 mg), and compound G-9 (yellow liquid, 14.5 mg, yield 45%) is obtained. 1 H NMR (400MHz, CDCl3) δ7.83(s,1H),7.45(dd,J=8.1,3.4Hz,1H),7.13–7.05(m,1H),7.02–6.91(m,1H),6.30(dq,J=2.2,1.1Hz,1H),2.58–2.44(m,6H). 13 C NMR (101MHz, CDCl3) δ135.68,134.80,128.66,121.66,119.87,119.44,117.47,100.96,16.72,13.80.

[0055] Example 10: Preparation of Compound G-10

[0056]

[0057] The operation steps and conditions were the same as those in Example 1, except that the indole substrate used was 5,6-dichloroindole (0.2 mmol, 37.2 mg), and compound G-10 (yellow solid, 40.0 mg, yield 100%) was obtained. 1 H NMR (400MHz, CDCl3) δ7.85 (s, 1H), 7.56 (s, 2H), 7.35 (s, 1H), 6.14 (d, J = 2.0Hz, 1H), 2.43 (s, 3H). 13C NMR (101MHz, CDCl3) δ137.48,135.03,129.06,124.67,123.71,120.66,111.76,100.37,13.86.

[0058] Example 11: Preparation of Compound G-11

[0059]

[0060] The operation steps and conditions were the same as those in Example 1, except that the indole substrate used was indole-6-carboxaldehyde (0.2 mmol, 29.2 mg), and compound G-11 (white solid, 32.0 mg, yield 99%) was obtained. 1 H NMR (400MHz, CDCl3) δ9.99 (d, J = 1.2Hz, 1H), 8.63 (s, 1H), 7.84 (s, 1H), 7.62–7.57 (m, 2H), 6.31 (s, 1H), 2.50 (s, 3H). 13 C NMR (101MHz, CDCl3) δ192.85,140.90,135.76,134.79,130.25,121.81,119.83,112.79,101.64,14.12.

[0061] Example 12: Preparation of Compound G-12

[0062]

[0063] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 5-iodoindole (0.2 mmol, 48.6 mg), and compound G-12 (white solid, 23.2 mg, yield 45%) is obtained. 1 H NMR (400MHz, CDCl3) δ7.87–7.79(m,2H),7.36(dd,J=8.5,1.7Hz,1H),7.02(d,J=8.5Hz,1H),6.15(dt,J=2.1,1.1Hz,1H),2.41(d,J=1.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ136.23,135.16,131.76,129.22,128.42,112.31,99.84,83.14,13.73.

[0064] Example 13: Preparation of Compound G-13

[0065]

[0066] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 6-fluoroindole (0.2 mmol, 27.2 mg), and compound G-13 (yellow solid, 28.5 mg, yield 93%) is obtained. 1 H NMR(400MHz, CDCl3) δ7.86(s,1H),7.39(dd,J=8.6,5.3Hz,1H),6.97(ddd,J=9.6,2.6,0.9Hz ,1H),6.82(ddd,J=9.8,8.6,2.3Hz,1H),6.18(dp,J=2.0,0.9Hz,1H),2.42(d,J=1.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ159.45 (d, J = 236.2Hz), 136.02 (d, J = 12.4Hz), 135.50 (d ,J=3.1Hz), 120.23(d,J=9.9Hz), 108.18(d,J=24.2Hz), 96.86(d,J=26.1Hz).

[0067] Example 14: Preparation of Compound G-14

[0068]

[0069] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 6-chloroindole (0.2 mmol, 33.2 mg), and compound G-14 (white solid, 29.3 mg, yield 80%) is obtained. 1 H NMR (400MHz, CDCl3) δ7.83 (s, 1H), 7.40 (d, J = 8.3Hz, 1H), 7.25 (d, J = 1.7Hz, 1H), 7.04(dd,J=8.4,1.9Hz,1H), 6.19(dt,J=2.2,1.1Hz,1H), 2.42(d,J=1.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ136.50,136.00,127.75,126.77,120.50,120.37,110.31,100.62,13.82.

[0070] Example 15: Preparation of Compound G-15

[0071]

[0072] The operation steps and conditions were the same as those in Example 1, except that the indole substrate used was 6-bromoindole (0.2 mmol, 39.2 mg), and compound G-15 (pink solid, 32.0 mg, yield 76%) was obtained.1 H NMR (400MHz, CDCl3) δ7.83 (s, 1H), 7.40 (dt, J = 1.6, 0.6Hz, 1H), 7.36 (d, J = 8.4 Hz,1H),7.16(dd,J=8.3,1.7Hz,1H),6.22–6.16(m,1H),2.42(d,J=1.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ136.95,135.97,128.07,122.96,120.92,114.33,113.26,100.69,13.82.

[0073] Example 16: Preparation of Compound G-16

[0074]

[0075] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 4-methylindole (0.2 mmol, 26.2 mg), and compound G-16 (yellow liquid, 28.8 mg, yield 99%) is obtained. 1 H NMR (400MHz, CDCl3) δ7.82 (s, 1H), 7.14 (d, J = 8.1Hz, 1H), 7.04 (dd, J = 8.1, 7.1Hz, 1H), 6.8 9(dt,J=7.2,0.9Hz,1H),6.25(dt,J=2.1,1.0Hz,1H),2.53(s,3H),2.45(d,J=1.0Hz,3H). 13 C NMR (101MHz, CDCl3) δ135.85,134.47,129.23,129.02,121.18,119.97,107.94,99.08,18.88,13.85.

[0076] The specific embodiments described herein are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the appended claims.

Claims

1. A method for preparing indole C2 methylation, characterized in that: The preparation method is as follows: using indole derivative A and methylating agent B as starting materials, stirring in organic solvent F under heating conditions of 70-100° C. until the reaction is completed, filtering the reaction mixture, concentrating, and purifying by column chromatography to obtain C2-methylated indole derivative G; the reaction expression of the reaction is as follows: Wherein, R in the general formula A is a substituent on the indole benzene ring structure, n represents the number of R, 0≤n≤4; when n≥2, each R is the same or different.

2. The method for preparing indole C2 methylation according to claim 1, characterized in that: R in the general formula A is selected from a hydrogen atom, a C1-C2 alkyl group, an alkoxy group, an ester group, an acyloxy group, a cyano group, an aldehyde group, a nitro group, and a halogen.

3. The method for preparing indole C2 methylation according to claim 1, characterized in that: The molar ratio of the indole derivative A, the methylating agent B, the palladium catalyst C, the norbornene derivative D, and the base E is 1:(2-5):(0.05-0.5):(1-3):(3-6).

4. The method for preparing indole C2 methylation according to claim 1, characterized in that: The methylating agent B is One of the following, preferably 5. The method for preparing indole C2 methylation according to claim 1, characterized in that: The methylating agent B is 6. The method for preparing indole C2 methylation according to claim 1, characterized in that: The palladium catalyst C is one of palladium acetate, di(cyanobenzene)palladium dichloride, di(acetylacetone)palladium, palladium chloride, tri(dibenzylideneacetone)dipalladium, palladium trifluoroacetate, bis(acetonitrile)palladium chloride, bistriphenylphosphinepalladium dichloride and tetrakis(triphenylphosphine)palladium.

7. The method for preparing indole C2 methylation according to claim 1, characterized in that: The norbornene derivative D is one of 2-cyano-5-norbornene, 5-norbornene-2-carboxylic acid, 5-norbornene-2-ol, 5-norbornene-2-yl acetate, 5-norbornene-2-carboxylic acid methyl ester and norbornene.

8. The method for preparing indole C2 methylation according to claim 1, characterized in that: The base E is one of cesium acetate, potassium acetate, sodium acetate, cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium bicarbonate, and sodium bicarbonate.

9. The method for preparing indole C2 methylation according to claim 1, characterized in that: The solvent F is one of 1,4-dioxane, ethylene glycol dimethyl ether, acetonitrile, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

10. The method for preparing indole C2 methylation according to claim 1, characterized in that: In the preparation method, an oil bath is used in the heating process, and the oil in the oil bath is silicone oil or paraffin oil; a sand core funnel is used in the filtration process, and the filtration is carried out under reduced pressure; atmospheric distillation or reduced pressure distillation is used in the concentration process; and a pure product is obtained through column chromatography in the purification process.

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