CN111675708A - Preparation method of 6-cyano-7-azaindole and derivatives thereof - Google Patents
Preparation method of 6-cyano-7-azaindole and derivatives thereof Download PDFInfo
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- CN111675708A CN111675708A CN202010521180.3A CN202010521180A CN111675708A CN 111675708 A CN111675708 A CN 111675708A CN 202010521180 A CN202010521180 A CN 202010521180A CN 111675708 A CN111675708 A CN 111675708A
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Abstract
The invention discloses a preparation method of 6-cyano-7-azaindole and derivatives thereof, which comprises the following steps: dissolving a compound shown in a formula (1) in a solvent, and reacting with an organic base and a cyaniding reagent under the action of a catalyst to obtain a final product shown in a formula (2); the process uses safe and nontoxic potassium ferrocyanide as a cyano source, has simple and convenient reaction operation, high yield and small influence on the environment, and is suitable for large-scale preparation of 6-cyano-7-azaindole and 1-benzoyl-6-cyano-7-azaindole derivatives thereof.
Description
Technical Field
The invention relates to a preparation method of 6-cyano-7-azaindole and derivatives thereof, belonging to the field of synthesis of medical intermediates.
Background
The 7-azaindole is used as a bioisostere of indole or purine and has wide application in drug development. Among them, 6-cyano-7-azaindole (I) is a key intermediate for the synthesis of a selective cyclin-dependent kinase (CDK) 7 inhibitor (WO 2019143719a 1). Among mammalian CDKs, CDK7 has a unique integrated kinase activity that contributes to the regulation of the cell cycle and gene transcription. The selective CDK7 inhibitor is expected to play an important role in treating cancers (e.g., leukemia, breast cancer, melanoma, multiple myeloma, ovarian cancer, etc.), fibrotic diseases (e.g., non-alcoholic steatohepatitis, rheumatoid arthritis, systemic lupus erythematosus), infectious diseases (e.g., viral infections caused by influenza virus, Human Immunodeficiency Virus (HIV), herpes virus or Human Papilloma Virus (HPV)), and the like. Thus, 6-cyano-7-azaindole (I) and its derivatives: the 1-benzoyl-6-cyano-7-azaindole (II) has wide market prospect.
The existing synthesis process of 6-cyano-7-azaindole (I) is as follows:
patent WO2007048070 reports a process for the preparation of 6-cyano-7-azaindole (I) from 7-azaindole-7-oxide (III). In the process, the used potassium cyanide is extremely toxic, and the generated cyanide ion-containing wastewater has great influence on the environment and is not suitable for large-scale preparation of I.
Reagents and conditions: a)i-PrI，CH3CN，45 ℃；b) aq. NH4Cl, KCN, 45 ℃
the literature Synthesis, 2008, (2),201-214 reports a process for preparing 6-cyano-7-azaindole (I) from the 7-azaindole-7-oxide/m-chlorobenzoic acid complex (IV). In the process, the extremely toxic potassium cyanide is also needed, and the process is not suitable for large-scale preparation of I.
Reagents and conditions: a) me2SO4，BuOAc，75-80 ℃；b) aq. NH4Cl, KCN, 50 ℃, and the yield of 2 steps is 76%.
The literature Synthesis, 2008, (13), 2049-2054 reports that 6-cyano-7-azaindole (I) can be prepared from 7-azaindole-7-oxide (III) by reaction with 6 equivalents of Trimethylsilylcyanide (TMSCN). The reaction time is long, 6 days are needed, and a large amount of trimethylsilyl cyanide is needed in the reaction. Trimethylsilyl cyanide has high toxicity and high cost. Therefore, the process is also not suitable for the large-scale preparation of I.
Reagents and conditions: a) TMSCN, Et3N,MeCN,reflux,6days，88%。
Patents WO2012095463 and WO2018013867 report the preparation of I from 6-bromo-7-azaindole (V) under palladium catalysis with zinc powder and zinc cyanide:
reagents and conditions: a) zn (CN)2, Zn powder, 5 mol% PdCl2(dppf)∙CH2Cl2, DMF, 140℃,4h, 44%
In the process, zinc cyanide is high in toxicity, zinc powder is an explosive chemical and a strong reducing agent, and a final product needs to be purified by column chromatography, so that the process is not suitable for large-scale preparation of I.
A process for preparing 1-benzoyl-6-cyano-7-azaindole (II) is described in the literature Synthesis, 1992, (7), 661-663. In the process, 7-azaindole-7-oxide (III) reacts with 3 equivalents of trimethylsilyl cyanide and 2 equivalents of benzoyl chloride (BzCl) to obtain 1-benzoyl-6-cyano-7-azaindole (II). The process requires the use of more toxic trimethylsilylcyanide and the yield of the product 1-benzoyl-6-cyano-7-azaindole is only 39%, the reaction requires column chromatography to remove the 1-benzoyl-6-chloro-7-azaindole by-product, and therefore, the process is not suitable for large-scale preparation of II.
Reagents and conditions: a) TMSCN, BzCl, THF, r.t.
The 6-cyano-7-azaindole (I) and the derivative 1-benzoyl-6-cyano-7-azaindole (II) thereof have wide market prospect in the field of pharmaceutical chemistry, potassium cyanide or sodium cyanide used in the prior art is a highly toxic substance, and the potassium cyanide or sodium cyanide has large influence on the environment when being used in large quantities. Other sources of cyano groups such as zinc cyanide or trimethylsilyl cyanide are also more toxic. Therefore, the development of a synthetic method which has safe process and environmental protection, does not use dangerous or toxic reagents and is suitable for large-scale production of the 6-cyano-7-azaindole and the derivative 1-benzoyl-6-cyano-7-azaindole thereof has important significance.
Disclosure of Invention
The invention aims to provide a new process for preparing 6-cyano-7-azaindole and derivatives thereof, namely 1-benzoyl-6-cyano-7-azaindole, and solves the problems that the existing method uses toxic and dangerous reagents and is not suitable for large-scale preparation.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of 6-cyano-7-azaindole and derivatives thereof comprises the following synthetic process route:
wherein, in formula (1), R is a hydrogen atom or a benzoyl group;
in formula (2), R is a hydrogen atom or a benzoyl group.
Further, the compound shown in the formula (1) is dissolved in a solvent, and reacts with an organic base and a cyaniding reagent under the action of a catalyst to obtain a final product shown in the formula (2).
Further, the molar ratio of the compound represented by the formula (1) to the catalyst is 1: 0.001-1, preferably 1: 0.01-0.1.
Further, the catalyst is palladium acetate.
Further, the molar ratio of the catalyst to the organic base is 1: 0.1 to 10, preferably 1: 2-4.
Further, the organic base is triethylene diamine.
Further, the molar ratio of the compound shown in the formula (1) to the cyaniding reagent is 1: 0.01 to 10, preferably 1: 0.2-1.
Further, the cyaniding reagent is potassium ferrocyanide or potassium ferrocyanide trihydrate.
Further, the solvent is any one or more of N, N-dimethylformamide and N, N-dimethylacetamide.
Further, the reaction temperature is 78-180 ℃, preferably 80-140 ℃.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the invention discloses a preparation method of 6-cyano-7-azaindole and derivatives thereof, the process of the invention uses safe and nontoxic potassium ferrocyanide as a cyano source, has simple and convenient reaction operation, high yield and small influence on environment, and is suitable for large-scale preparation of 6-cyano-7-azaindole and derivatives thereof, namely 1-benzoyl-6-cyano-7-azaindole.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound prepared in example 1;
FIG. 2 is a NMR spectrum of the compound prepared in example 3.
Detailed Description
The technical solutions provided by the present invention will be described in detail below with reference to specific examples, and it should be understood that the following specific embodiments are only illustrative of the present invention and are not intended to limit the scope of the present invention.
Example 1
Synthesis of Compound I:
6-bromo-7-azaindole (V, 10.00 g, 0.051 mol, 1.0 equiv.) was dispersed in 100mL of N, N-dimethylacetamide, and potassium ferrocyanide (9.35 g, 0.025 mol, 0.5 equiv.), palladium acetate (0.57 g, 2.54mmol, 5 mol%), triethylenediamine (DABCO, 0.85 g, 7.62 mmol, 15 mol%) were added. After the addition, the temperature is raised to 120 ℃ for reaction for 16 hours, and the reaction is finished by TLC detection. The reaction was cooled to room temperature, poured into 400mL of ice water, filtered, extracted 2 times with ethyl acetate (100 mL x 2), and the organic phases were combined. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a yellow solid 5.92 g, yield: 81.6 percent.
1H NMR（400M Hz，CDCl3）(ppm) 12.27 (s, 1H), 8.19 (d, J = 7.96 Hz, 1H), 7.85 (dd, J = 3.40, 2.36 Hz, 1H), 7.63 (d, J = 8.04 Hz, 1H), 6.65 (dd, J = 3.44,1.44 Hz, 1H) purity: 97 percent.
LC-MS(ESI+): m/z 143.80 (M+H)。
Example 2
Synthesis of Compound I:
6-bromo-7-azaindole (V, 10.00 g, 0.051 mol, 1.0 equiv.) was dispersed in 100mL of N, N-dimethylformamide, and potassium ferrocyanide trihydrate (6.46 g, 0.015 mol, 0.3 equiv.), palladium acetate (0.23 g,1.02 mmol, 2 mol%), triethylenediamine (DABCO, 0.46 g, 4.08 mmol, 8 mol%) were added. After the addition, the temperature is raised to 100 ℃ for reaction for 24 hours. TLC reaction was complete, cooled to room temperature, the reaction was poured into 400mL of ice water, filtered, extracted 2 times with ethyl acetate (100 mL x 2), and the organic phases were combined. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a pale yellow solid 4.98 g, yield: 68.2 percent.
1H NMR（400M Hz，CDCl3）（ppm）: 12.27（s，1 H），8.19（d，J = 7.96 Hz, 1 H），7.85（dd，J = 3.40, 2.36 Hz, 1 H），7.63（d，J = 8.04 Hz, 1 H），6.65（dd，J = 3.44,1.44 Hz, 1 H）。
Example 3
Synthesis of Compound II:
1-benzoyl-6-bromo-7-azaindole (VII, 14.20 g, 0.047 mol, 1.0 equiv.) was dispersed in 100 mLN, N-dimethylacetamide, and potassium ferrocyanide (8.68 g, 0.024 mol, 0.5 equiv.), palladium acetate (0.53 g, 2.35 mmol, 5 mol%), triethylenediamine (DABCO, 0.79 g, 7.05 mmol, 15 mol%) were added. After the addition, the temperature is raised to 100 ℃ for reaction for 24 hours, and the TLC detection shows that the reaction is finished. The reaction was cooled to room temperature, poured into 400mL of ice water, filtered, extracted 2 times with ethyl acetate (100 mL x 2), and the organic phases were combined. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 10.32 g of a yellow solid, yield: 88.4 percent.
1H NMR（400M Hz，CDCl3）：（ppm）8.04-8.02（m，2 H），7.80-7.78（m，2H），7.70-7.66（m，1H），7.60-7.51（m，3H），6.77（d，J = 3.96 Hz, 1H）。
LC-MS(ESI+): m/z 248.28 (M+H)
Example 4
Synthesis of Compound II:
1-benzoyl-6-bromo-7-azaindole (VII, 5.00 g, 0.017 mol, 1.0 equiv.) was dispersed in 50 mLN, N-dimethylacetamide, and potassium ferrocyanide trihydrate (4.21 g, 0.010 mol, 0.6 equiv.), palladium acetate (0.37 g, 1.66 mmol, 10 mol%), triethylenediamine (DABCO, 0.37 g, 3.32 mmol, 20 mol%) were added. The temperature is increased to 80 ℃ for reaction for 36 hours, and the TLC detection reaction is finished. The reaction mixture was cooled to room temperature, poured into 300 mL of ice-water, filtered, extracted 2 times with ethyl acetate (100 mL x 2), and the organic phases were combined. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a yellow solid 3.28 g, yield: 79.9 percent.
The technical means disclosed in the invention scheme are not limited to the technical means disclosed in the above embodiments, but also include the technical scheme formed by any combination of the above technical features. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and such improvements and modifications are also considered to be within the scope of the present invention.
Claims (10)
1. The preparation method of the 6-cyano-7-azaindole and the derivatives thereof is characterized in that the synthetic process route is as follows:
wherein, in formula (1), R is a hydrogen atom or a benzoyl group;
in formula (2), R is a hydrogen atom or a benzoyl group.
2. The preparation method of 6-cyano-7-azaindole and derivatives thereof according to claim 1, characterized by the following steps: dissolving the compound shown in the formula (1) in a solvent, and reacting with an organic base and a cyaniding reagent under the action of a catalyst to obtain a final product shown in the formula (2).
3. The process for preparing 6-cyano-7-azaindole and its derivatives according to claim 2, characterized in that: the molar ratio of the compound represented by the formula (1) to the catalyst is 1: 0.001-1.
4. The process for preparing 6-cyano-7-azaindole and its derivatives according to claim 2, characterized in that: the catalyst is palladium acetate.
5. The process for preparing 6-cyano-7-azaindole and its derivatives according to claim 2, characterized in that: the molar ratio of the catalyst to the organic base is 1: 0.1-10.
6. The process for preparing 6-cyano-7-azaindole and its derivatives according to claim 2, characterized in that: the organic base is triethylene diamine.
7. The process for preparing 6-cyano-7-azaindole and its derivatives according to claim 2, characterized in that: the molar ratio of the compound shown in the formula (1) to the cyaniding reagent is 1: 0.01-10.
8. The process for preparing 6-cyano-7-azaindole and its derivatives according to claim 2, characterized in that: the cyaniding reagent is potassium ferrocyanide or potassium ferrocyanide trihydrate.
9. The process for preparing 6-cyano-7-azaindole and its derivatives according to claim 2, characterized in that: the solvent is any one or more of N, N-dimethylformamide and N, N-dimethylacetamide.
10. The process for preparing 6-cyano-7-azaindole and its derivatives according to claim 2, characterized in that: the reaction temperature is 78-180 ℃.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101671300A (en) * | 2009-09-28 | 2010-03-17 | 南京第一农药集团有限公司 | Method for preparing 2-cyano-3, 6-dichloropyridine |
| WO2012095463A1 (en) * | 2011-01-12 | 2012-07-19 | Novartis Ag | Oxazine derivatives and their use in the treatment of neurological disorders |
| CN110036004A (en) * | 2016-07-13 | 2019-07-19 | 希洛斯医药品股份有限公司 | The inhibitor of cell cycle protein dependent kinase 7 (CDK7) |
| WO2019143719A1 (en) * | 2018-01-16 | 2019-07-25 | Syros Pharmaceuticals, Inc. | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
| CN110229100A (en) * | 2019-06-05 | 2019-09-13 | 南京焕然生物科技有限公司 | A kind of preparation method of different sulphur cyanato -3- (trifluoromethyl) pyridine -2- cyano of 5- |
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- 2020-06-10 CN CN202010521180.3A patent/CN111675708A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101671300A (en) * | 2009-09-28 | 2010-03-17 | 南京第一农药集团有限公司 | Method for preparing 2-cyano-3, 6-dichloropyridine |
| WO2012095463A1 (en) * | 2011-01-12 | 2012-07-19 | Novartis Ag | Oxazine derivatives and their use in the treatment of neurological disorders |
| CN110036004A (en) * | 2016-07-13 | 2019-07-19 | 希洛斯医药品股份有限公司 | The inhibitor of cell cycle protein dependent kinase 7 (CDK7) |
| WO2019143719A1 (en) * | 2018-01-16 | 2019-07-25 | Syros Pharmaceuticals, Inc. | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
| CN110229100A (en) * | 2019-06-05 | 2019-09-13 | 南京焕然生物科技有限公司 | A kind of preparation method of different sulphur cyanato -3- (trifluoromethyl) pyridine -2- cyano of 5- |
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