阅读说明：本技术 一种吲哚类化合物的氘代合成方法 (Deuterated synthesis method of indole compound ) 是由 邹宏斌 张金泉 张帅众 于 2020-05-06 设计创作，主要内容包括：本发明提供一种吲哚类化合物的氘代合成方法,将吲哚类化合物通过重水、催化剂、碱及溶剂混合反应在合适的反应温度和时间条件下,通过导向基团DG导向的碳氢键活化反应进行氢氘交换生成氘代吲哚类产物。本发明提供的方法反应条件温和,工艺简单,成本低,氘代位置选择性好,产率及氘代率高；并且,通过采用相对廉价的重水作为氘源,有效避免了氘代化合物制备过程中昂贵氘源的使用,能进一步降低氘代化合物的制备成本。(The invention provides a deuterated synthesis method of indole compounds, which comprises the step of carrying out deuterium exchange on the indole compounds through a carbon-hydrogen bond activation reaction guided by a guide group DG under the conditions of proper reaction temperature and time through a mixed reaction of heavy water, a catalyst, alkali and a solvent to generate deuterated indole products. The method provided by the invention has the advantages of mild reaction conditions, simple process, low cost, good selectivity of deuterated positions, high yield and deuterated rate; in addition, by adopting relatively cheap heavy water as a deuterium source, the use of an expensive deuterium source in the preparation process of the deuterated compound is effectively avoided, and the preparation cost of the deuterated compound can be further reduced.)

1. a deuterated synthesis method of indole compounds is characterized by comprising the following steps: the indole compound shown in the formula (1) is subjected to mixed reaction of a catalyst, a base and a solvent in the presence of heavy water, and a deuterated indole product shown in the formula (2) is obtained under the conditions of proper reaction temperature and time, wherein the reaction formula is as follows:

wherein:

the position of a guide group DG is one of N1, C2, C3, C4, C5, C6 or C7 on an indole ring;

r is selected from one of hydrogen, methyl, methoxy, benzyloxy, ester group, cyano, nitro, fluorine, chlorine or bromine, and is positioned at one of N1, C2, C3, C4, C5, C6 or C7 on the indole ring;

the catalyst is selected from dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer [ Cp RhCl₂]₂Or pentamethylcyclopentadienylcarbonyldiiodocobalt CpCo (CO) I₂One or two of them;

the alkali is selected from one of sodium acetate, potassium acetate or cesium acetate;

the solvent is selected from one or two of 1, 2-dichloroethane, acetonitrile or tetrahydrofuran;

the temperature range is 25-130 ℃;

the time range is 12-36 h.

2. The synthesis method of claim 1, wherein when the position of the guiding group is at position N1 of the indole ring, the indole compound represented by formula (3) under the participation of heavy water, and under the control of a catalyst, a base, a solvent, a temperature and reaction time, selective deuterated indole products, such as 2-deuterated indole products represented by formula (3-1), 2-and 7-deuterated indole products represented by formula (3-2), and 2-, 3-and 7-deuterated indole products represented by formula (3-3), are obtained under different reaction conditions; the reaction equation for the reaction is as follows:

wherein R is selected from one of hydrogen, methyl, methoxy, benzyloxy, ester group, cyano, nitro, fluorine, chlorine or bromine, and is at one of C2, C3, C4, C5, C6 or C7 on the indole ring;

the catalyst is selected from dichloro(pentamethylcyclopentadienyl) rhodium (III) dimer [ Cp RhCl₂]₂Or pentamethylcyclopentadienylcarbonyldiiodocobalt CpCo (CO) I_{In 2 (2)}One or two of (a);

the alkali is selected from one of sodium acetate, potassium acetate and cesium acetate;

the solvent is one or two selected from 1, 2-dichloroethane, acetonitrile and tetrahydrofuran;

the temperature range is 25-130 ℃;

the time range is 12-36 h.

3. The synthesis method of claim 1, wherein when the position of the guiding group is at the position of N1 of the indole ring and the position of C2 is an aromatic amide group, the indole compound shown in the formula (4) is subjected to catalyst, alkali, solvent, temperature and reaction time control in the presence of heavy water to obtain a selective 4-position deuterated indole product shown in the formula (4-1), and the reaction equation of the reaction is as follows:

wherein R is selected from one of hydrogen, methyl, methoxy, fluorine, chlorine or bromine, and is positioned at one of C5, C6 and C7 on the indole ring;

ar is selected from one of substituted or unsubstituted benzene ring or thiophene ring;

the catalyst is selected from dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer [ Cp RhCl₂]₂；

The alkali is selected from one of sodium acetate, potassium acetate or cesium acetate;

the solvent is selected from one or two of 1, 2-dichloroethane, acetonitrile or tetrahydrofuran;

the temperature range is 90-130 ℃;

the time range is 12-24 h.

4. The synthetic method of claim 1, wherein when the position of the directing group is not at the N1 position of the indole ring, the indole compounds represented by the formulas (5) to (11) are obtained by the participation of heavy water through the control of catalysts, bases, solvents, and temperature and reaction time to obtain deuterated indole compounds represented by the formulas (5-1) to (11-1), respectively, wherein the formula (5) is used for preparing the compound of the formula (5-1), the formula (6) is used for preparing the compound of the formula (6-1), the formula (7) is used for preparing the compound of the formula (7-1), the formula (8) is used for preparing the compound of the formula (8-1), the formula (9) is used for preparing the compound of the formula (9-1), the formula (10) is used for preparing the compound of the formula (10-1), and the formula (11) is used for preparing the compound of the formula (11-1), the reaction equation for the reaction is as follows:

wherein R is one of H, methyl, tert-butyloxycarbonyl, methoxy and halogen, and the position of R is one of N1, 5-position or 6-position.

The catalyst is selected from dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer [ Cp RhCl₂]₂；

The alkali is selected from one of sodium acetate, potassium acetate and cesium acetate;

the solvent is 1, 2-dichloroethane;

the temperature is 90 ℃;

the time is 36 h.

5. The synthesis method according to claim 1 or 2, wherein when the position of the guide group is at position N1 of the indole ring, the indole compound represented by formula (3) is prepared by: (1) catalyst pentamethylcyclopentadienylcarbonyldiiodocobalt Cp Co (Co) I₂Reacting sodium acetate in acetonitrile at 90 ℃ for 12 hours to obtain a selective 2-position deuterated indole product shown in a formula (3-1); (2) catalyst pentamethylcyclopentadienylcarbonyldiiodocobalt Cp Co (Co) I₂And dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer [ Cp RhCl₂]₂Reacting potassium acetate in 1, 2-dichloroethane at 25 ℃ for 36 hours to obtain selective 2-and 7-deuterated indoles as shown in formula (3-2); (3) catalyst and process for preparing sameDichloro (pentamethylcyclopentadienyl) rhodium (III) dimer [ Cp RhCl₂]₂Reacting cesium acetate in tetrahydrofuran at 130 ℃ for 36 hours to obtain selective 2, 3 and 7-position deuterated indole products shown in a formula (3-3); the reaction equation for the reaction is as follows:

wherein R is selected from one of hydrogen, methyl, methoxy, benzyloxy, ester group, cyano, nitro, fluorine, chlorine or bromine, and is at one of C2, C3, C4, C5, C6 or C7 position on the indole ring.

6. A synthesis method according to claims 1 and 3, characterized in that: when the position of the guide group is at the N1 position of the indole ring and the C2 position is the aromatic amide group, the indole compound shown as the formula (4) is prepared by a catalyst dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer [ Cp RhCl ] in the presence of heavy water₂]₂Reacting sodium acetate in acetonitrile and 1, 2-dichloroethane at 130 ℃ for 12 hours, and then reacting at 90 ℃ for 12 hours to obtain a selective 4-deuterated indole product shown in the formula (4-1); the reaction equation for the reaction is as follows:

wherein R is selected from one of methyl, methoxy, fluorine, chlorine or bromine, and is positioned at one of C5, C6 or C7 on the indole ring;

ar is selected from one of benzene ring, 4-position halogen or methoxy substituted benzene ring or thiophene ring.

7. The synthesis method according to claims 1 and 4, characterized in that: when the position of the guide group is not at the N1 position of the indole ring, the indole compounds shown in the formulas (5) to (11) are prepared by the catalyst dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer [ Cp & RhCl ] in the presence of heavy water₂]₂Sodium acetate in 1, 2-dichloroAfter reacting in ethane at 90 ℃ for 36 hours, obtaining deuterated indole compounds shown in formulas (5-1) to (11-1), wherein formula (5) is used for preparing the compound shown in formula (5-1), formula (6) is used for preparing the compound shown in formula (6-1), formula (7) is used for preparing the compound shown in formula (7-1), formula (8) is used for preparing the compound shown in formula (8-1), formula (9) is used for preparing the compound shown in formula (9-1), formula (10) is used for preparing the compound shown in formula (10-1), and formula (11) is used for preparing the compound shown in formula (11-1), wherein the reaction formula is as follows:

wherein R is one of H, methyl at N1, N1 tert-butyloxycarbonyl, methoxy at 5, bromine at 5 or chlorine at 6.

Technical Field

The invention belongs to the field of organic matter synthesis, and particularly relates to a deuterated synthesis method of an indole compound.

Background

Deuterium (1)²H or D) has the characteristics of stability and no radioactivity, and has wide application in a plurality of research fields, including labeling in microanalysis, improvement of the pharmacokinetic properties of chemical substances in drug discovery, and reaction research in kinetic isotope effect research. Indole is the most common heterocycle in nature and is important to our life. They are found in nucleic acids, vitamins, antibiotics, hormones, alkaloids and pigments. Indole derivativesAre widely used to produce a large number of industrial products ranging from pharmaceuticals, pesticides, to herbicides. The multifunctionality of deuterium and indole means that deuterated indole may have good development potential, and the preparation of deuterated indole compounds is particularly important. Currently, the synthesis of deuterated indoles (Yau, W.; etc., J.Labelled Compound. radiopharm.1999,42,709; Murray, A.T.; etc. org.Biomol. chem.2016,14,3787; Kerr, W.J.; etc. ACS Catal.2017,7,7182.) is mainly directed to deuteration at the 2 or 3 position of the indole, or to non-selective deuteration at different positions of the indole with low deuteration rate, and these methods also involve expensive deuterium sources (such as deuterium gas) and harsh reaction conditions (high pressure, high temperature), so that the applicability and substrate applicability of these methods are limited to a large extent.

Disclosure of Invention

In view of the above defects or improvement needs of the prior art, the present invention aims to provide a method for synthesizing an indole compound by deuteration, wherein the reaction process of the deuterium-hydrogen exchange reaction, the types and proportions of the raw materials used, the corresponding reaction conditions, and the like are studied and improved, so that compared with the prior art, the problems of poor selectivity of the deuteration position and low deuteration rate of the deuterated indole compound, and the problems of severe reaction conditions and expensive deuterium source used in the preparation process can be effectively solved. The invention utilizes the catalyst, the solvent and the alkali to carry out hydrogen-deuterium exchange on the indole compound through the carbon-hydrogen bond activation reaction under the condition of containing the deuterium source to generate the deuterated indole product, and has the advantages of mild reaction conditions, simple process, low cost, good deuterated position selectivity, high yield and deuterated rate; in addition, by adopting relatively cheap heavy water as a deuterium source, the use of an expensive deuterium source in the preparation process of the deuterated compound is effectively avoided, and the preparation cost of the deuterated compound can be further reduced.

In order to achieve the purpose, the invention provides a deuterated synthesis method of an indole compound, which is realized by the following steps: taking indole compounds shown as formula (1) and heavy water (D)₂O), a catalyst, alkali and a solvent are mixed and reacted, and a deuterated indole product shown in the formula (2) is obtained under the conditions of proper reaction temperature and time; said counterThe reaction equation should be as follows:

wherein:

the position of the guiding group (DG) is one or two of N1, C2, C3, C4, C5, C6 or C7 on the indole ring.

R is selected from one of methyl, methoxy, benzyloxy, ester group, cyano, nitro, fluorine, chlorine or bromine, and is at one of N1, C2, C3, C4, C5, C6 or C7 on the indole ring.

The catalyst comprises (pentamethylcyclopentadienyl) rhodium (III) dichloride dimer ([ Cp RhCl)₂]₂) Or pentamethylcyclopentadienylcarbonyldiiodocobalt (CpCo (CO) I₂) One or two of them;

the base comprises one of sodium acetate (NaOAc), potassium acetate (KOAc), or cesium acetate (CsOAc);

the solvent comprises 1, 2-Dichloroethane (DCE), acetonitrile (CH)₃CN) or Tetrahydrofuran (THF);

the temperature range is 25-130 ℃;

the time range is 12-36 h.

When the position of the directing group is at the position of N1 of the indole ring, as shown in formula (1), the method is characterized by comprising the following steps: under the participation of heavy water, the indole compound shown in the formula (3) is controlled by a catalyst, alkali, a solvent, temperature and reaction time to respectively obtain selective deuterated indole products under different reaction conditions, such as a 2-position deuterated indole product shown in the formula (3-1), 2-position and 7-position deuterated indole products shown in the formula (3-2) and 2-, 3-and 7-position deuterated indole products shown in the formula (3-3);

the reaction equation is as follows:

wherein R is selected from one of hydrogen, methyl, methoxy, benzyloxy, ester group, cyano, nitro, fluorine, chlorine and bromine, and is at one of C2, C3, C4, C5, C6 and C7 on the indole ring;

the catalyst is selected from dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer [ Cp RhCl₂]₂Or pentamethylcyclopentadienylcarbonyldiiodocobalt CpCo (CO) I₂One or two of them;

the base comprises one of sodium acetate, potassium acetate and cesium acetate;

the solvent comprises one or two of 1, 2-dichloroethane, acetonitrile and tetrahydrofuran;

the temperature range is 25 to 130 ℃;

the time range is 12 to 36 h.

When the position of the guide group is at the N1 position of the indole ring and the C2 position is an aromatic amide group, the method is characterized by comprising the following steps: the indole compound shown in the formula (4) can be used for obtaining a selective 4-deuterated indole product shown in the formula (4-1) in the presence of heavy water through the control of a catalyst, alkali, a solvent, temperature and reaction time; the reaction equation for the reaction is as follows:

wherein R is selected from one of hydrogen, methyl, methoxy, fluorine, chlorine and bromine, and is at one of C5, C6 and C7 on the indole ring;

ar is selected from one of benzene ring and thiophene ring.

The catalyst is selected from dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer [ Cp RhCl₂]₂；

The alkali is selected from one of sodium acetate, potassium acetate and cesium acetate;

the solvent is selected from 1, 2-dichloroethane and acetonitrile;

the temperature range is 90 to 130 ℃;

the time range is 12 to 24 h.

When the position of the directing group is not at the position of N1 of the indole ring, as shown in formula (1), the method is characterized by comprising the following steps: the indole compounds shown in formulas (5) to (11) are respectively obtained through controlling a catalyst, a base, a solvent and temperature and reaction time in the presence of heavy water to obtain deuterated indole compounds shown in formulas (5-1) to (11-1), wherein formula (5) is used for preparing a compound shown in formula (5-1), formula (6) is used for preparing a compound shown in formula (6-1), formula (7) is used for preparing a compound shown in formula (7-1), formula (8) is used for preparing a compound shown in formula (8-1), formula (9) is used for preparing a compound shown in formula (9-1), formula (10) is used for preparing a compound shown in formula (10-1), and formula (11) is used for preparing a compound shown in formula (11-1), and the reaction formulas are as follows:

the catalyst is selected from dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer [ Cp RhCl₂]₂；

The alkali is selected from one of sodium acetate, potassium acetate and cesium acetate;

the solvent is selected from 1, 2-dichloroethane;

the temperature is 90 ℃;

the time is 36 h.

In general, compared with the prior art, the above technical solution contemplated by the present invention can achieve the following beneficial effects: (1) the synthesis method of the deuterated indole compound provided by the invention has the advantages of good deuterated position selectivity and high deuterated rate. (2) The synthesis method of the deuterated indole compound provided by the invention has the advantages of mild reaction conditions, simple process, good substrate applicability and high yield. (3) The deuterated solvent used in the invention is from heavy water, and has low cost and easy obtainment. (4) The catalysts used in the present invention are mostly common, readily available (directly commercially available) catalysts.

In conclusion, the invention realizes the deuterium marking of the indole compound by utilizing the low-cost deuterium source and carrying out hydrogen and deuterium exchange through the carbon-hydrogen bond activation reaction, and compared with the prior art, the invention does not need to adopt the expensive deuterium source and harsh reaction conditions.

Detailed Description

The invention is further illustrated by the following examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.