Synthesis method of triazole compound

Abstract

The invention relates to a preparation method of a triazole compound 5. The reaction formula is as follows: # imgabs0 # R1 is selected from # imgabs1 # X1 is selected from O or NH; x2 is selected from hydrogen or fluorine; # imgabs2 # represents a double bond or a single bond; comprising the following steps: (1) carrying out a neat reaction on a compound 1 and diallylamine without a solvent to prepare a compound 2; (2) carrying out Suzuki coupling reaction on the compound 2 and the compound 3 in the presence of a palladium catalyst and alkali to prepare a compound 4; and (3) reacting the compound 4 in the presence of a palladium catalyst and acid to prepare a compound 5. According to the route, a triazole compound 5 is prepared from a brand-new intermediate compound 2 and a brand-new intermediate compound 4; the method has the advantages of simple operation, no exposed amino group, reduction of the risk of impurity generation, no intermolecular impurity, high purity of the final product up to 97.9%, high stability of the whole preparation route, mild and safe reaction conditions, and better conformity to the requirements of industrial production.

Description

Technical Field

[0001] The present invention relates to a method for preparing triazole compounds, belonging to the technical fields of medicine and chemistry. Background Art

[0002] Triazole compounds, as an important class of nitrogen-containing heterocyclic compounds, have extensive application values in the field of medicinal chemistry. The triazole ring in their structure can bind to biological targets through mechanisms such as hydrogen bond interactions and π-π stacking, and has been successfully applied to antibacterial, antifungal, and antitumor drugs. In the antibacterial field, some triazole compounds can interfere with the synthesis of bacterial DNA and RNA, thereby inhibiting bacterial protein synthesis and inducing bacterial apoptosis, effectively combating various antibiotic-resistant bacteria. In the treatment of neuroprotection and neuroinflammatory diseases, triazole compounds can show potential value in treating neurodegenerative diseases and neuroinflammatory diseases by regulating mechanisms such as apoptosis, oxidative stress, and inflammatory responses. In the antitumor field, they are used to inhibit Werner syndrome RecQ DNA helicase (WRN), especially for treating cancers such as high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) cancers, including colorectal cancer, gastric cancer, and endometrial cancer. Therefore, molecular building blocks or intermediates of triazole compounds play a crucial role in drug development.

[0003] 5-(3,6-Dihydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine is a key synthetic intermediate of WRN inhibitor compounds disclosed in international patent WO2024079623A, and its structure is shown as follows:

[0004]

[0005] In the prior art, the synthesis route of 5-(3,6-dihydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine is shown as follows:

[0006]

[0007] There are exposed amino reaction sites in this route, which are prone to generating intermolecular impurities and affecting the final purity of the product. Due to its potential and importance as a molecular building block and intermediate, a simple, safe, and environmentally friendly preparation method needs to be developed. Summary of the Invention

[0008] The present invention provides a method for synthesizing triazole compound 5, and the specific route is shown as follows:

[0009]

[0010] Wherein,

[0011] R1 is selected from X1 is selected from O or NH;

[0012] X2 is selected from hydrogen or fluorine; represents a double bond or a single bond;

[0013] Step (1): Compound 1 and diallylamine are subjected to a neat reaction without solvent to prepare Compound 2;

[0014] Step (2): Compound 2 and Compound 3 are subjected to a Suzuki coupling reaction in the presence of a palladium catalyst and a base to prepare Compound 4;

[0015] Step (3): Compound 4 is reacted in the presence of a palladium catalyst and an acid to prepare Compound 5.

[0016] As a further improvement of the present invention, including but not limited to, the neat reaction system in step (1) reacts in a closed space and is prepared using an autoclave or a sealed tank device;

[0017] As a further improvement of the present invention, including but not limited to, the molar ratio of Compound 1 to diallylamine in step (1) is 1:(1 - 3), preferably 1:(2 - 3);

[0018] As a further improvement of the present invention, including but not limited to, the reaction temperature in step (1) is 80 - 150 °C, preferably 110 - 140 °C;

[0019] As a further improvement of the present invention, including but not limited to, the reaction time in step (1) is 10 - 30 h, preferably 12 - 16 h;

[0020] As a further improvement of the present invention, including but not limited to, after the reaction in step (1) is completed, the system is cooled, water is added, extracted and concentrated, and after the organic phase is dried, Compound 2 is obtained;

[0021] As a further improvement of the present invention, in some embodiments, the above-mentioned Compound 2 can optionally be further purified by column chromatography, and the column chromatography eluent is, for example, petroleum ether.

[0022] As a further improvement of the present invention, the neat reaction without solvent is adopted in step (1) of the present invention, which avoids the use of volatile organic solvents, reduces pollution and waste; omits steps such as solvent evaporation and recovery, reduces energy consumption; is suitable for large-scale production and reduces safety risks.

[0023] As a further improvement of the present invention, including but not limited to, in the step (2), the palladium catalyst is selected from one or more of Pd(dppf)Cl2, Pd(PPh3)4, Pd(OAc)2, Pd(PPh3)2Cl2, Pd2(dba)3, Pd(dba)2 or PdCl2, and preferably Pd(dppf)Cl2;

[0024] As a further improvement of the present invention, including but not limited to, in the step (2), the base is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, potassium acetate, and preferably one or more of sodium carbonate, potassium carbonate, cesium carbonate, and more preferably potassium carbonate;

[0025] As a further improvement of the present invention, including but not limited to, in the step (2), the molar ratio of compound 2, the base and the palladium catalyst is 1:(1 - 10):(0.01 - 0.5), and preferably 1:(1.1 - 3):(0.02 - 0.1);

[0026] As a further improvement of the present invention, including but not limited to, in the step (2), the molar ratio of compound 2 to compound 3 is 1:(1 - 3), and preferably 1:(1.1 - 2);

[0027] As a further improvement of the present invention, including but not limited to, in the step (2), the reaction solvent is selected from one or more of water, tetrahydrofuran, ether, methyl tert-butyl ether, dioxane, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and preferably one or two of water and dioxane;

[0028] As a further improvement of the present invention, including but not limited to, in the step (2), the reaction solvent is a mixed solvent of water and dioxane, and preferably the volume ratio is V 二氧六环 :V 水 =(5 - 12):1, and more preferably the volume ratio is V 二氧六环 :V 水 =(8 - 12):1;

[0029] As a further improvement of the present invention, including but not limited to, in the step (2), the volume dosage mL of the solvent is 6 - 15 times the mass dosage mg of compound 2;

[0030] As a further improvement of the present invention, including but not limited to, in the step (2), the reaction temperature is 50 - 130 °C, and preferably 80 - 110 °C;

[0031] As a further improvement of the present invention, including but not limited to, in the step (2), the reaction time is 1 - 12 h, and preferably 2 - 6 h.

[0032] As a further improvement of the present invention, including but not limited to, after the reaction in step (2) is completed, the system is cooled, filtered, and the filtrate is concentrated and dried to obtain Compound 4.

[0033] As a further improvement of the present invention, in some embodiments, the above-mentioned Compound 4 can optionally be further purified by column chromatography, and the column chromatography eluent is, for example, PE / EA = 3 / 1 to 6 / 1.

[0034] As a further improvement of the present invention, including but not limited to, the palladium catalyst in step (3) is selected from one or more of Pd(PPh3)4, Pd(PCy3)2, Pd(OAc)2, Pd / C, RhCl(PPh3)3, or Pd2(dba)3, and preferably Pd(PPh3)4;

[0035] As a further improvement of the present invention, including but not limited to, the molar ratio of Compound 4 to the palladium catalyst in step (3) is 1:(0.01 - 0.5), and preferably 1:(0.05 - 0.5);

[0036] As a further improvement of the present invention, including but not limited to, the acid in step (3) is selected from one or more of 1,3-dimethylbarbituric acid, barbituric acid, acetic acid, methanesulfonic acid, 5-methylbarbituric acid, or 5,5-diethylbarbituric acid, and preferably 1,3-dimethylbarbituric acid;

[0037] As a further improvement of the present invention, including but not limited to, the molar ratio of Compound 4 to the acid in step (3) is 1:(1 - 10), and preferably 1:(2 - 8);

[0038] As a further improvement of the present invention, including but not limited to, the solvent in step (3) is selected from one or more of methanol, ethanol, tetrahydrofuran, dichloroethane, dichloromethane, or chloroform, and preferably dichloroethane;

[0039] As a further improvement of the present invention, including but not limited to, the reaction temperature in step (3) is 40 - 100 °C, and preferably 60 - 90 °C;

[0040] As a further improvement of the present invention, including but not limited to, the reaction time in step (3) is 8 - 36 hours, and preferably 12 - 20 hours.

[0041] As a further improvement of the present invention, including but not limited to, in step (3), after the reaction is completed, the system is cooled, neutralized, extracted, washed, dried, and then the solvent is removed under reduced pressure to obtain Compound 5.

[0042] As a further improvement of the present invention, in some embodiments, the above-mentioned compound 5 can optionally be further purified by column chromatography, such as reverse-phase column chromatography, and the column chromatography eluent is, for example, acetonitrile.

[0043] The second aspect of the present invention provides a triazole compound, and the structural formula is as follows:

[0044]

[0045] Wherein R is selected from Br or R1, and R1 is as described in the first aspect.

[0046] As a further improvement of the present invention, a preferred structure of a triazole compound is as follows:

[0047]

[0048] The technical effects of the present invention:

[0049] 1. The present invention adopts a brand-new allyl substitution, providing a brand-new preparation route. The route of this substituent has no guiding inspiration in the prior art, has not been applied to the synthesis of similar compounds, and compared with the prior art, it reduces the steps and improves the production efficiency.

[0050] 2. In step (1) of the present invention, an innovative solvent-free (neat) reaction system is adopted, avoiding the use of volatile organic solvents, eliminating solvent pollution and waste liquid generation from the source; simplifying the process flow, eliminating the solvent evaporation and recovery links, and significantly reducing energy consumption; the reaction system is safer and more controllable, realizing green chemical synthesis, and the purity of the prepared compound 2 can reach 100%, which is suitable for industrial scale-up production.

[0051] 3. The reagents used in the route adopted by the present invention are conventional, safe, and have low toxicity, reducing the risks during the operation process.

[0052] 4. The reaction system of the present invention has no exposed amino group, reducing the risk of impurity generation, having no intermolecular impurities, and the purity of the final product is as high as 97.9%. The entire preparation route has high stability.

[0053] 5. The present invention provides a brand-new and feasible route for synthesizing 5-(3,6-dihydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine. This method is synthesized through a new intermediate, with simple operation, fewer steps, safety and stability, and high product purity. Brief Description of the Drawings

[0054] Figure 1 It is the LCMS spectrum of the product obtained in Example 1 of the present invention;

[0055] Figure 2For the product obtained in Example 2 of the present invention 1 H-NMR spectrum;

[0056] Figure 3 For the product obtained in Example 3 of the present invention 1 H-NMR spectrum;

[0057] Figure 4 HPLC spectrum of the product obtained in Example 3 of the present invention. Detailed implementation manners

[0058] The beneficial effects of the present invention will be further described through the following examples. It should be understood that these examples are only for illustrative purposes and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by those of ordinary skill in the art according to the present invention are also included within the scope of the present invention.

[0059] Unless otherwise specified, the raw materials or reagents used in the examples are all commercially available.

[0060] The room temperature mentioned in the examples all refers to 20 - 30 °C. Unless otherwise specified, the reagents are used directly without purification. All solvents are purchased from commercial suppliers, such as Sigma Aldrich, and can be used without treatment.

[0061] Example 1

[0062]

[0063] Compound 1 (102 g, 382.13 mmol) and diallylamine (79.82 g, 820.46 mmol) were mixed and heated to 135 °C in a sealed tank for reaction overnight. After the reaction was completed, the reaction was cooled, water (600 mL) was added, and the mixture was extracted with dichloromethane (3 L). After concentrating the organic phase and drying, it was purified by column chromatography to obtain a pale yellow oily product, Compound 2 (80 g, yield 73%, LCMS purity 100%, retention time RT = 1.646 min). The LCMS spectrum is as Figure 1 shown.

[0064] Example 2

[0065]

[0066] Compound 2 (80 g, 282.51 mmol) was added to dioxane (800 mL) and water (80 mL). Subsequently, 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (89.03 g, 423.77 mmol), Pd(dppf)Cl2 (10.34 g, 14.13 mmol) and K2CO3 (78.09 g, 565.03 mmol) were added successively. After mixing evenly, nitrogen was replaced for protection, and the temperature was raised to 100 °C for reaction for 3 hours. After the reaction was completed, it was cooled to room temperature, filtered, the filtrate was concentrated and dried, and purified by column chromatography with PE / EA = 5 / 1 to obtain the product (50 g, yield 61.8%). 1 The 1H-NMR spectrum is as follows Figure 2 shown.

[0067] Example 3:

[0068]

[0069] Compound 4-1 (50 g, 174.59 mmol) and 1,3-dimethylbarbituric acid (136.31 g, 872.97 mmol) were dissolved in DCE (500 mL). After replacing with argon, Pd(PPh3)4 (20.18 g, 17.46 mmol) was added, and the mixture was stirred at 80 °C for reaction for 16 hours. The reaction solution was cooled to room temperature, saturated NaHCO3 was added, and extraction was carried out with CH2Cl2. The organic layer was washed with saturated brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Purification was carried out through a reverse column (10% acetonitrile) to obtain Compound 5-1 (12.9 g, yield 44%, HPLC purity 97.9%, retention time RT = 3.3246 min). 1 The 1H-NMR spectrum is as follows Figure 3 shown, and the HPLC spectrum is as follows Figure 4 shown.

Claims

1. A method for preparing compound 5, the reaction formula is as follows: Wherein, R1 is selected from X1 is selected from O or NH; X2 is selected from hydrogen or fluorine; represents a double bond or a single bond; It includes the following steps: Step (1): Compound 1 and diallylamine are subjected to a neat reaction without solvent to prepare compound 2; Step (2): Compound 2 and compound 3 are subjected to a Suzuki coupling reaction in the presence of a palladium catalyst and a base to prepare compound 4; Step (3): Compound 4 is reacted in the presence of a palladium catalyst and an acid to prepare compound 5.

2. The preparation method according to claim 1, wherein The neat reaction system in step (1) reacts in a closed space and is prepared using an autoclave or a sealed tank device.

3. The preparation method according to claim 1, wherein The neat reaction in step (1) satisfies one or more of the following conditions: The molar ratio of compound 1 to diallylamine is 1:(1 - 3), preferably 1:(2 - 3); And / or, preferably, the reaction temperature is 80 - 150°C, preferably 110 - 140°C; And / or, preferably, the reaction time is 10 - 30 h, preferably 12 - 16 h.

4. The preparation method according to claim 1, wherein The palladium catalyst in step (2) is selected from one or more of Pd(dppf)Cl2, Pd(PPh3)4, Pd(OAc)2, Pd(PPh3)2Cl2, Pd2(dba)3, Pd(dba)2 or PdCl2, preferably Pd(dppf)Cl2.

5. The preparation method according to any one of claims 1 to 4, characterized in that, The base in step (2) is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, potassium acetate, preferably one or more of sodium carbonate, potassium carbonate, cesium carbonate.

6. The preparation method according to any one of claims 1 to 4, characterized in that, The Suzuki coupling reaction in step (2) satisfies one or more of the following conditions: The reaction solvent is selected from one or more of water, tetrahydrofuran, ether, methyl tert-butyl ether, dioxane, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, preferably one or two of water and dioxane; And / or, preferably, the reaction solvent is selected from a mixed solvent of water and dioxane, preferably with a volume ratio of V 二氧六环 :V 水 =(5 to 12):1, more preferably with a volume ratio of V 二氧六环 :V 水 =(8 to 12):1; And / or, preferably, the reaction temperature is 50 - 130°C; And / or, preferably, the reaction time is 1 - 12 h, preferably 2 - 6 h; And / or, preferably, the molar ratio of compound 2, base and palladium catalyst is 1:(1 - 10):(0.01 - 0.5), preferably 1: (1.1～3)：(0.02～0.1)； And / or, preferably, the molar ratio of compound 2 to compound 3 is 1:(1 - 3), preferably 1:(1.1 - 2).

7. The preparation method according to claim 1, wherein The palladium catalyst in step (3) is selected from one or more of Pd(PPh3)4, Pd(PCy3)2, Pd(OAc)2, Pd / C, RhCl(PPh3)3 or Pd2(dba)3, preferably Pd(PPh3)4.

8. The preparation method according to claim 1, characterized in that, The acid in step (3) is selected from one or more of 1,3-dimethylbarbituric acid, barbituric acid, acetic acid, methanesulfonic acid, 5-methylbarbituric acid or 5,5-diethylbarbituric acid, preferably 1,3-dimethylbarbituric acid.

9. The preparation method according to claim 1, characterized in that, Step (3) satisfies at least one of the following conditions: The molar ratio of compound 4 to acid is 1:(1 - 10), preferably 1:(2 - 8); And / or, preferably, the molar ratio of the compound 4 to the palladium catalyst is 1:(0.01 - 0.5), preferably 1:(0.05 - 0.5); and / or, preferably, the solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, dichloroethane, dichloromethane or chloroform, preferably dichloroethane; And / or, preferably, the reaction temperature is 40 - 100 °C, preferably 60 - 90 °C; And / or, preferably, the reaction time is 8 - 36 hours, preferably 12 - 20 hours.

10. A triazole compound, the structural formula of which is as follows: Wherein R is selected from Br or R1, and R1 is as described in claim 1; For example, it contains the compound 2 or the compound 4-1

Images