Preparation method of indole C2-site trideuterium methylation

Abstract

The invention discloses a preparation method of indole C2-site trideuterium methylation, and belongs to the field of organic synthesis. According to the method, an indole derivative and a trideuterium methylation reagent are used as initial raw materials and are stirred to react in an organic solvent at 60-80 DEG C under the action of a palladium catalyst, norbornene and alkali, and the C2-site trideuterium methylated indole derivative can be obtained. The method is good in process, free of water-free and oxygen-free operation, free of organic strong base, free of additional positioning groups, mild in reaction condition and high in operability. The method solves the problem that deuteration in indole C2-site trideuterium methylation in the prior art is incomplete or needs to be assisted by a positioning group, and has relatively high practicability and industrial value.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis and relates to a preparation method of trideuterium methylation at the C2 position of indole. Background Art

[0002] Deuterium (D), as a stable and non-radioactive isotope of hydrogen (H), is also called heavy hydrogen. In view of its non-toxic and non-radioactive characteristics, coupled with the increasingly abundant safety data support, the application of deuterium atoms in the field of drug research and development is gradually gaining widespread attention and favor. Specifically, deuterated drugs refer to a new type of drug obtained by chemically replacing specific hydrogen atoms in the molecular structure of the original drug with deuterium atoms. At the molecular level, due to the minimal difference in shape between hydrogen (H) and deuterium (D), this replacement usually does not interfere with the "lock and key" binding mode between the drug molecule and its target, thereby ensuring that the deuterated drug can maintain the same pharmacological activity as the original drug. However, it is worth noting that the mass of deuterium atoms is twice that of hydrogen atoms. This change in physical properties leads to significantly higher stability of carbon-deuterium bonds (CD) in compounds compared to carbon-hydrogen bonds (CH), usually 6 to 9 times higher. This enhanced bond stability means that more energy is required for the dissociation of CD bonds during metabolism. Therefore, deuterated drug molecules can often show optimized pharmacokinetic (PK) characteristics and / or metabolic profiles while maintaining their original pharmacological activity. This feature not only improves the metabolic stability of the drug, but also improves its pharmacokinetic properties, making it possible to achieve goals such as reducing the dosage and frequency of administration (Nat. Rev. Drug Dis scov. 2023.562).

[0003] Among the numerous deuterated drugs studied, trideuterated methyl (three hydrogen atoms on the methyl group are all deuterated) occupies the most important position. As shown below, two deuterated drug molecules (deutetrabenazine and deuterated colexitinib) approved by the U.S. Food and Drug Administration (FDA) and one deuterated drug molecule (donafenib) approved by the National Medical Products Administration were successfully marketed by replacing the original methyl group with trideuterated methyl.

[0004]

[0005] In the optimization of active pharmaceutical molecules containing indole skeletons, the introduction of a methyl group at the C2 position of indole is an important modification strategy. As shown below, the HDAC inhibitor panobinostat, the tyrosine kinase inhibitor brivanib, and the nonsteroidal anti-inflammatory drug indomethacin all have a methyl group at the C2 position of indole.

[0006]

[0007] It can be expected that during the construction and optimization of drug molecule libraries, the introduction of trideuterated methyl at the C2 position of indole may lead to the emergence of some active molecules with higher stability, longer half-life, and better metabolic kinetics than the original molecules. At present, there are two main methods for introducing trideuterated methyl at the C2 position by directly functionalizing the indole ring, as shown below: (1) Deuterated water exchange strategy under weak acid catalysis. This strategy requires the introduction of a methyl group at the C2 position of indole in advance, and then the trideuterated methylation at the C2 position of indole is achieved through an exchange strategy with deuterated water under the catalysis of a weak acid such as benzoic acid (Org. Biomol. Chem. 2017.2507; Chem. Commun. 2021.77). This strategy has the following problems: an excess of deuterated water is required, and the deuteration ratio does not reach 100%, generally hovering around 90%. Such results are not suitable for drugability studies (mixtures, not single molecules). (2) Metal catalysis strategy assisted by a positioning group. This strategy requires the introduction of a directing group at the indole NH position in advance, and then, under the catalysis of metal rhodium or copper, deuterated acetic acid (CD3COOD) or deuterated dimethyl sulfoxide is used as a deuterium source to achieve deuterium methylation at the C2 position of indole (Org. Biomol. Chem. 2022.7645; CN202311190958). Although this strategy solves the problems of excessive use of deuterium source and incomplete deuteration, the method involves the introduction and removal of directing groups. The entire strategy requires three steps of reaction, which obviously does not have step economy.

[0008]

[0009] Therefore, it is very necessary to develop a more convenient preparation method to achieve trideuterium methylation at the C2 position of indole for industrial production. Summary of the invention

[0010] The purpose of the present invention is to provide a preparation method for trideuterium methylation of indole C2 position in view of the above problems existing in the prior art. The technical problem to be solved by the present invention is to provide a low-cost preparation method for trideuterium methylation of indole C2 position.

[0011] The purpose of the present invention can be achieved by the following technical solutions:

[0012] Indole derivative A and trideuterium methylation 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 60-80° C. until the reaction is completed. The reaction mixture is filtered, concentrated and purified by column chromatography to obtain C2 trideuterium methylated indole derivative G as shown in the reaction formula. The reaction formula of the reaction is shown as follows:

[0013]

[0014] Wherein, R in the general formula A is a substituent on the indole benzene ring structure.

[0015] Furthermore, R in the general formula A is selected from one of a hydrogen atom, a methyl group, an ester group, chlorine and bromine.

[0016] Furthermore, the molar ratio of the indole derivative A, the trideuterated methylation agent B, the palladium catalyst C, the norbornene derivative D, and the base E is 1:(3-6):(0.05-0.5):(1-5):(3-6), wherein the preferred molar ratio is A:B:C:D:E=1:4:0.15:2:5.

[0017] Further, the trideuterated methylation reagent B is One of the following, preferably

[0018] Furthermore, the palladium catalyst C is one of palladium acetate, palladium chloride, palladium trifluoroacetate, bis(acetonitrile)palladium chloride, di(cyanobenzene)palladium dichloride, and tetrakis(triphenylphosphine)palladium, among which palladium chloride is preferred.

[0019] Furthermore, the norbornene derivative D is: One of the following, preferably

[0020] Furthermore, the base E is one of cesium acetate, sodium acetate, cesium carbonate, potassium carbonate and sodium carbonate, wherein sodium carbonate is preferred.

[0021] Furthermore, the solvent F is one of 1,4-dioxane, ethylene glycol dimethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, among which N,N-dimethylformamide is preferred.

[0022] 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.

[0023] The method of the present invention can efficiently prepare C2 trideuterated methylated indole derivatives. Compared with the prior art, the present invention has the following advantages:

[0024] 1. The main raw materials involved in the present invention are indole and conventional trideuterium methylation reagents, which can be directly used as commercial reagents without special treatment and are low in price;

[0025] 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;

[0026] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 For compound G-2 1 H-NMR (400MHz, CDCl3) chart;

[0028] Figure 2 For compound G-2 13 C-NMR (100 MHz, CDCl3) chart. DETAILED DESCRIPTION

[0029] The following are specific embodiments of the present invention and the accompanying drawings to further describe the technical solution of the present invention, but the present invention is not limited to these embodiments.

[0030] Example 1: Preparation of Compound G-1

[0031]

[0032] Indole (0.20mmol, 23.4mg), trimethyl trideuterated phosphate (0.80mmol, 112.0mg, 4eq.), norbornene (0.40mmol, 37.6mg, 2eq.), sodium carbonate (1.00mmol, 105.99mg, 5eq.), PdCl2 (0.03mmol, 5.3mg, 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 (22.8 mg, yield 85%) was obtained as a light yellow solid by purification by column chromatography (ethyl acetate:petroleum ether=1:25, V:V). 1H NMR (400MHz, CDCl3) δ7.90 (s, 1H), 7.72 (dd, J = 7.4, 1.4Hz, 1H), 7.44 (dd, J = 7.6, 6.2Hz, 1H), 7.36-7.27 (m, 2H), 6.42 (d, J = 2.1Hz, 1H). 13 C NMR (101MHz, CDCl3) δ136.1,135.0,129.1,120.9,120.8,119.6,110.2,100.4,13.0(h).

[0033] Example 2: Preparation of Compound G-2

[0034]

[0035] The operation steps and conditions were the same as those in Example 1, except that the indole substrate used was indole-6-carboxylic acid methyl ester (0.2 mmol, 35.2 mg), and compound G-2 (yellow solid, 33.8 mg, yield 88%) was obtained. 1 H NMR (400MHz, CDCl3) δ8.57(s,1H),8.09(s,1H),7.79(dd,J=8.3,1.5Hz,1H),7.53(d,J=8.3Hz,1H),6.27(d,J=2.0Hz,1H),3.94(s,3H). 13 C NMR (101MHz, CDCl3) δ168.74,139.34,135.49,133.13,122.34,120.88,119.12,112.75,101.02,51.99,13.19(t).

[0036] Example 3: Preparation of Compound G-3

[0037]

[0038] 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 solid, 23.1 mg, yield 78%) is obtained. 1 H NMR(400MHz, CDCl3) δ7.95(s,1H),7.24(dd,J=7.0,0.7Hz,1H),7.11(dd,J=2.6,1 .7Hz,1H),7.05(ddq,J=7.0,2.0,0.6Hz,1H),6.20(d,J=2.3Hz,1H),2.49(s,3H). 13C NMR (101MHz, CDCl3) δ135.1,134.4,1294,1288,122.4,119.4,109.9,100.0,21.5,13.8(t).

[0039] Example 4: Preparation of Compound G-4

[0040]

[0041] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 6-methoxyindole (0.2 mmol, 29.4 mg), and compound G-4 (light yellow solid, 28.2 mg, yield 86%) is obtained. 1 H NMR (400MHz, CDCl3) δ8.05 (s, 1H), 7.41 (d, J = 8.3Hz, 1H), 6.87–6.73 (m, 2H), 6.17 (s, 1H), 3.86 (s, 3H) 13 C NMR (101MHz, CDCl3) δ155.7,136.8,133.9,123.3,120.1,109.0,100.0,94.5,55.8,13.7(t).

[0042] Example 5: Preparation of Compound G-5

[0043]

[0044] 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, 27.6 mg, yield 84%) is obtained. 1 H NMR (400MHz, CDCl3) δ8.03(s,1H),7.06(d,J=8.8Hz,1H),6.91(d,J=1.2Hz,1H),6.68(dd,J=8.8Hz,1.2Hz,1H),6.05(s,1H),3.75(s,3H). 13 C NMR (101MHz, CDCl3) δ154.1,136.0,131.2,129.6,112.4,110.9,110.7,102.0,100.3,55.9,13.8(t).

[0045] Example 6: Preparation of Compound G-6

[0046]

[0047] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 5-bromoindole (0.2 mmol, 39.2 mg), and compound G-6 (light yellow solid, 33.9 mg, yield 80%) is obtained. 1 H NMR (400MHz, CDCl3) δ8.09 (s, 1H), 7.55 (d, J = 2.0Hz, 1H), 7.12-7.06 (m, 2H), 6.06 (s, 1H). 13 C NMR (101MHz, CDCl3) δ135.6,131.2,130.1,124.6,121.2,115.0,113.2,101.6,13.6(t).

[0048] Example 7: Preparation of Compound G-7

[0049]

[0050] The operation steps and conditions are the same as those in Example 1, except that the indole substrate used is 5-chloroindole (0.2 mmol, 30.2 mg), and compound G-7 (yellow liquid, 30.1 mg, yield 91%) is obtained. 1 H NMR (400MHz, CDCl3) δ8.14(s,1H),7.36(d,J=2.0Hz,1H),7.03(d,J=8.8Hz,1H),6.93(dd,J=8.4Hz,2.0Hz,1H),6.04(s,1H). 13 C NMR (101MHz, CDCl3) δ134.4,130.2,129.8,125.1,121.0,119.0,111.2,100.0,13.7(t).

[0051] 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 preparation method for trideuterated methylation of indole C2, characterized in that: The preparation method is as follows: using indole derivative A and trideuterium methylation agent B as starting materials, under the action of palladium catalyst C, norbornene derivative D, and base E, stirring in organic solvent F under heating conditions of 60-80° C. until the reaction is completed, and the reaction mixture is filtered, concentrated, and purified by column chromatography to obtain C2 trideuterium methylated indole derivative G as shown in the reaction formula. The reaction formula of the reaction is shown as follows: Wherein, R in the general formula A is a substituent on the indole benzene ring structure.

2. The method for preparing indole C2 trideuterium methylation according to claim 1, characterized in that: R in the general formula A is selected from one of a hydrogen atom, a methyl group, an ester group, chlorine and bromine.

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

4. The preparation method of trideuterium methylation of indole C2 according to claim 3, characterized in that: The molar ratio of the indole derivative A, the trideuterated methylation agent B, the palladium catalyst C, the norbornene derivative D, and the base E is A:B:C:D:E=1:4:0.15:2:

5.

5. The preparation method of trideuterium methylation of indole C2 according to claim 1, characterized in that: The trideuterated methylation reagent B is One of them.

6. The preparation method of trideuterium methylation of indole C2 according to claim 1, characterized in that: The palladium catalyst C is one of palladium acetate, palladium chloride, palladium trifluoroacetate, bis(acetonitrile)palladium chloride, di(cyanobenzene)palladium dichloride and tetrakis(triphenylphosphine)palladium.

7. The method for preparing indole C2 trideuterium methylation according to claim 1, characterized in that: The norbornene derivative D is: One of them.

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

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

10. The preparation method of trideuterium methylation of indole C2 position according to claim 1, characterized in that: In the preparation method, the heating process is an oil bath, and the oil used in the oil bath is silicone oil or paraffin oil; the filtration process uses a sand core funnel and is filtered under reduced pressure; the concentration process is atmospheric distillation or rotary evaporator reduced pressure concentration; The purification process is to obtain pure products by column chromatography.

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