A method for synthesizing a sitagliptin intermediate

Abstract

The application provides a synthesis method of a sitagliptin intermediate, and belongs to the technical field of organic drug intermediate synthesis. The synthesis method of the sitagliptin intermediate in the application is characterized in that under the conditions of visible light irradiation, a photocatalyst and an oxidant, 1,1-dimethylethyl 5,6-dihydro-1,2,4-triazolo[4,3-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester and trifluoromethyl sulfinic acid salt are reacted in a solvent, then Boc protection is removed and salt formation is performed, and finally, 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride compound (i.e. the sitagliptin intermediate) is generated. The synthesis method of the sitagliptin intermediate in the application has the characteristics of mild conditions, simple operation, green environmental protection, easy-to-obtain raw materials, excellent substrate functional group compatibility and high reaction yield.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic pharmaceutical intermediate synthesis, and particularly relates to a synthesis method of a sitagliptin intermediate. BACKGROUND

[0002] Sitagliptin belongs to dipeptidyl peptidase 4 (DPP-4) inhibitors, and can improve blood glucose control by increasing the level of active intestinal incretin in type II diabetes patients. Sitagliptin has the advantages of rapid oral absorption, no influence on eating, less taking frequency, good compliance, less adverse reactions, high safety, and combination with other drugs.

[0003] Figure 2 are two synthesis route diagrams of sitagliptin in the prior art.

[0004] As shown in Figure 2 , there are two classical synthesis routes of sitagliptin: the first route is a three-step method, which takes as a starting material, generates through two-step reactions, and then obtains sitagliptin through enzyme catalysis reaction; the second route is a four-step method, which also takes as a starting material, synthesizes through two-step reactions, and then obtains sitagliptin through enamine and catalytic hydrogenation reactions. It can be seen that, no matter which route, the intermediate has to be experienced, and the synthesis of needs to use

[0005] It can be seen that is a key intermediate that cannot be avoided in the synthesis route of sitagliptin.

[0006] Figure 3 are two synthesis route diagrams of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride in the prior art.

[0007] As shown in Figure 3 , there are two classical synthesis routes of : the first synthesis route needs to use a low-temperature (-20℃ or below) environment, and has more by-products, which has more limitations; the second route has a single functional group conversion, and has certain route advantages, and the second step reaction preparing can quantitatively obtain a reaction product, but the first step reaction preparing is difficult.

[0008] The above-mentioned In the second step of the second synthetic route, it is reported that [1] trimethyl(trifluoromethyl)silane is used as a source of trifluoromethyl group, but the reaction yield is low, only 10%; there is also a literature [2] recorded that phosphonium [Ph4P] + [Cu(CF3)2] - participate in the reaction, the reaction condition requires high temperature above 100℃, and the yield is only 52%.

[0009] [1] J. Am. Chem. Soc. 2020, 142, 46, 19480-19486

[0010] [2] Organic Chemistry Frontiers (2019), 6(14), 2324-2328 SUMMARY

[0011] The present application is to solve the above problems, and aims to provide a synthesis method of a sitagliptin intermediate.

[0012] The present application provides a synthesis method of a sitagliptin intermediate, which has the following characteristics: comprising the following steps: S10, mixing trifluoromethyl sulfinate, a photocatalyst and an oxidant in a solvent, and then reacting under the conditions of room temperature and visible light irradiation for a certain time to obtain S20, removing the tert-butyloxycarbonyl group in under acidic conditions and salifying to obtain a sitagliptin intermediate, the sitagliptin intermediate being 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, and the structural formula thereof being

[0013] In the synthesis method of the sitagliptin intermediate provided by the present application, the following characteristics can also be possessed: in step S10, the molar ratio of trifluoromethyl sulfinate, photocatalyst and oxidant is 1:(1-3):(0.05-0.22):(1.5-3).

[0014] In the synthesis method of the sitagliptin intermediate provided by the present application, the following characteristics can also be possessed: in step S10, the molar ratio of trifluoromethyl sulfinate, photocatalyst and oxidant is 1:(1-3):(0.05-0.22):(1.5-3).

[0015] ​In the synthesis method of the sitagliptin intermediate provided by the application, the method can further have the following features: in step S10, the trifluoromethyl sulfinate salt comprises any one or more of sodium trifluoromethyl sulfinate, potassium trifluoromethyl sulfinate, amine trifluoromethyl sulfinate or lithium trifluoromethyl sulfinate, the photo-catalyst comprises any one or more of eosin Y, riboflavin or rhodamine B, the oxidant comprises any one or more of ammonium persulfate, potassium persulfate, sodium persulfate or oxygen, and the solvent comprises any one or more of DMSO, acetonitrile or dichloroethane.

[0016] In the synthesis method of the sitagliptin intermediate provided by the application, the method can further have the following features: in step S10, the trifluoromethyl sulfinate salt is sodium trifluoromethyl sulfinate, the photo-catalyst is riboflavin, the oxidant is ammonium persulfate, and the solvent is DMSO.

[0017] In the synthesis method of the sitagliptin intermediate provided by the application, the method can further have the following features: in step S10, the normal temperature is 10-30℃, and the reaction time is 15-18h.

[0018] In the synthesis method of the sitagliptin intermediate provided by the application, the method can further have the following features: in step S10, the visible light is provided by an LED light source, the wavelength is 380-460nm, and the power of the LED light source is 5-30W.

[0019] In the synthesis method of the sitagliptin intermediate provided by the application, the method can further have the following features: the wavelength is 420-440nm, and the power is 10-15W.

[0020] In the synthesis method of the sitagliptin intermediate provided by the application, the method can further have the following features: step S20 comprises the following sub-steps: S21, mixing the sitagliptin intermediate obtained in step S10 with an ethyl acetate solution of HCl to obtain a reaction liquid; and S22, evaporating the reaction liquid to obtain the sitagliptin intermediate. In the synthesis method of the sitagliptin intermediate provided by the application, the method can further have the following features: step S21, after mixing with the ethyl acetate solution of HCl, the reaction liquid is heated and stirred to obtain a reaction liquid; and S22, the reaction liquid is evaporated to obtain the sitagliptin intermediate.

[0021] In the synthesis method of the sitagliptin intermediate provided by the application, the method can further have the following features: in step S21, the concentration of HCl in the ethyl acetate solution is 2mol / L, the heating temperature is 35-45℃, and the stirring time is 2h.

[0022] Effects of the application

[0023] The synthesis method of the sitagliptin intermediate according to the present application is characterized in that under the conditions of visible light irradiation, a photocatalyst and an oxidant, 1,1-dimethylethyl 5,6-dihydro-1,2,4-triazolo[4,3-a]pyrazine-7(8H)-carboxylate and trifluoromethylsulfinate are reacted in a solvent, and then Boc protection is removed and salification to generate 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride.

[0024] Therefore, the synthesis method of the sitagliptin intermediate according to the present application has the characteristics of mild conditions, simple operation, green environmental protection, easy-to-obtain raw materials, excellent substrate functional group compatibility and high reaction yield. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 is a reaction mechanism schematic diagram of preparing 5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester in step S10 of the embodiment of the present application;

[0026] Figure 2 is a schematic diagram of two synthesis routes of sitagliptin under the prior art;

[0027] Figure 3 is a schematic diagram of two synthesis routes of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride under the prior art. DETAILED DESCRIPTION

[0028] In order to make the technical means, creative features, purposes and effects realized by the present application easy to understand, the following embodiments will make a specific description of the synthesis method of a sitagliptin intermediate of the present application in combination with the drawings.

[0029] <EMBODIMENT>

[0030] The present embodiment provides a synthesis method of a sitagliptin intermediate. The sitagliptin intermediate is 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, and its structural formula is

[0031] The synthesis method of the sitagliptin intermediate in the present embodiment includes the following steps:

[0032] S10, in a 10 mL quartz reaction tube, The sodium trifluoromethylsulfinic acid, the photocatalyst and the oxidant are mixed in the solvent according to the molar ratio of 1: (1-3): (0.05-0.22): (1.5-3), and then the mixture is irradiated by visible light with the wavelength of 380-460 nm at 10-30 ℃ for 15-18 h, during which the reaction process is tracked by using a thin layer chromatography plate.

[0033] After the reaction is completed, water is added, and the reaction mixture is extracted with ethyl acetate, and then the extracted solution is concentrated and purified by silica gel column chromatography to obtain

[0034] In this step, the photocatalyst includes any one or more of eosin Y, riboflavin or rhodamine B; the oxidant includes any one or more of ammonium persulfate, potassium persulfate, sodium persulfate or oxygen; and the solvent includes any one or more of DMSO, acetonitrile or 1,2-dichloroethane.

[0035] Figure 1 is a schematic diagram of the reaction mechanism for preparing 5,6-dihydro-3- (trifluoromethyl) -1,2,4-triazolo [4, 3-a] pyrazine-7 (8H) -carboxylic acid tert-butyl ester in step S10 of the embodiment of the present application.

[0036] As shown in Figure 1 , the reaction mechanism of the photocatalytic reaction in step S10 is as follows: the photocatalyst is excited to form a high-activity excited state compound [PC*] under visible light irradiation, and then the electron transfer and H transfer occur between the compound [PC*] and the substrate to generate a substrate radical; the sodium trifluoromethylsulfinic acid is oxidized by the oxidant in the reaction system to generate a trifluoromethyl radical, and then the trifluoromethyl radical is added to the substrate radical to generate the product.

[0037] S20, the Boc group is removed and salted to obtain a sitagliptin intermediate, including the following sub-steps:

[0038] S21, the is mixed with a 2 mol / L HCl ethyl acetate solution, and then heated and stirred at 35-45 ℃ for 2 h to obtain a reaction solution;

[0039] S22, the reaction solution is evaporated to obtain the sitagliptin intermediate.

[0040] Three samples are prepared according to the above-mentioned synthesis method of the sitagliptin intermediate, and are denoted as sample 1, sample 2 and sample 3.

[0041] Specific parameters and final yields of the sample 1-3 in the preparation process are shown in Table 1. denoted as compound 1)

[0042] Table 1 (specific parameters and final yields of the sample 1-3 in the preparation process)

[0043]

[0044] As shown in Table 1 above, sample 1: 1 H-NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 4.61 (s, 2H), 4.44 (t, J = 5.8 Hz, 2H), 3.64 (t, J = 5.8 Hz, 2H); sample 2: 1 H-NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 4.61 (s, 2H), 4.44 (t, J = 5.8 Hz, 2H), 3.64 (t, J = 5.8 Hz, 2H); sample 3: 1 H-NMR (400 MHz, DMSO-d 6 ): δ (ppm) = 4.61 (s, 2H), 4.44 (t, J = 5.8 Hz, 2H), 3.64 (t, J = 5.8 Hz, 2H)

[0045] Therefore, the 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, i.e., the sitagliptin intermediate with the structural formula of , is successfully prepared in this example.

[0046] <Comparative Example>

[0047] In this comparative example, the specific parameters in the preparation process are adjusted according to the synthesis method of the sitagliptin intermediate provided in the example, so as to investigate the influence of different reaction conditions on the reaction.

[0048] Among them, 13 groups of experiments are conducted, and the specific parameters in the 13 groups of experiments and the yield of the final product are shown in Table 2.

[0049] Table 2 (specific parameters in 13 groups of experiments and yield of final product)

[0050]

[0051] Note: the reaction temperature of experimental groups 1-12 is controlled at 10-30°C, and the reaction temperature of experimental group 13 is controlled at 45-55°C.

[0052] As shown in Table 2 above, experimental groups 1-7 investigate the influence of the catalyst, and experiments show that the synthesis method of the sitagliptin intermediate in this example is relatively strong in catalyst selection, and basically does not react in sodium fluorescein and cerium trichloride, and the yield in eosin Y is also very low. Riboflavin has the highest yield, and other catalysts such as 4CzIPN and rhodamine also have good catalytic effect, but not as good as riboflavin.

[0053] The experiment groups 8 and 9 mainly investigate the influence of solvents on the reaction, and it can be seen that the solvent DMSO is the optimal solvent for the reaction, and the yield corresponding to other solvents is reduced.

[0054] The experiment group 13 shows that the increase of temperature does not benefit the reaction.

[0055] The experiment groups 2, 9 and 12 show that the increase of the equivalent of the oxidant does not improve the reaction.

[0056] Effects of the embodiment

[0057] The embodiment provides a method for directly introducing a trifluoromethyl functional group under visible light irradiation by selecting a substrate 5, 6-dihydro-[1, 2, 4] triazol [4, 3-a] pyrazine-7 (8H) -carboxylic acid tert-butyl ester under the action of a cheap catalyst under room temperature by taking trifluoromethyl sulfinate as a trifluoromethyl source, and then performing Boc protection, and high-selectivity synthesis of 3-(trifluoromethyl)-5, 6, 7, 8-tetrahydro-[1, 2, 4] triazol [4, 3-a] pyrazine hydrochloride, the reaction condition is mild, the environment is friendly, and the industrial production application is facilitated.

[0058] The embodiment uses a power 10W-15W LED visible light source, is safe and energy-saving, and is cheap and easy to obtain.

[0059] The sodium trifluoromethyl sulfinate used in the embodiment is cheap and easy to obtain, and is widely applicable.

[0060] The catalyst riboflavin used in the embodiment is cheap and easy to obtain, and the product conversion efficiency is high.

[0061] The by-product of the experiment in the embodiment is sodium sulfate, which is safe, non-toxic and environment-friendly.

[0062] Those skilled in the art should understand that the present application is not limited to the above-mentioned embodiments, and the above-mentioned embodiments and descriptions in the specification are only to illustrate the principles of the present application, and various changes and improvements can be made without departing from the spirit and scope of the present application, and these changes and improvements all fall within the scope of the present application. The scope of protection of the present application is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing a sitagliptin intermediate, characterized in that, Includes the following steps: S10, will Trifluoromethyl sulfinate, a photocatalyst, and an oxidant are mixed in a solvent and reacted for a certain period of time under room temperature and visible light irradiation to obtain... S20 is removed under acidic conditions. The sitagliptin intermediate is obtained by salt formation from the tert-butyloxycarbonyl group in the sitagliptin. The sitagliptin intermediate is 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, with the following structural formula: The photocatalyst includes any one or more of 4CzIPN, riboflavin, or rhodamine B. The oxidant includes any one or more of ammonium persulfate, potassium persulfate, sodium persulfate, or oxygen.

2. The method for synthesizing the sitagliptin intermediate according to claim 1, characterized in that: in, In step S10, The molar ratio of trifluoromethyl sulfinate, photocatalyst and oxidant is 1:(1~3):(0.05~0.22):(1.5~3).

3. The method for synthesizing the sitagliptin intermediate according to claim 2, characterized in that: in, The molar ratio of trifluoromethyl sulfinate, photocatalyst and oxidant is 1:(1.8~3.0):(0.10~0.13):(1.8~2.1).

4. The method for synthesizing the sitagliptin intermediate according to claim 1, characterized in that: in, In step S10, the trifluoromethyl sulfinate includes any one or more of sodium trifluoromethyl sulfinate, potassium trifluoromethyl sulfinate, amine trifluoromethyl sulfinate, or lithium trifluoromethyl sulfinate. The solvent includes any one or more of DMSO, acetonitrile, or dichloroethane.

5. The method for synthesizing the sitagliptin intermediate according to claim 4, characterized in that: in, The trifluoromethyl sulfinate is sodium trifluoromethyl sulfinate, the photocatalyst is riboflavin, the oxidant is ammonium persulfate, and the solvent is DMSO.

6. The method for synthesizing the sitagliptin intermediate according to claim 1, characterized in that: in, In step S10, the ambient temperature is 10℃~30℃. The reaction time is 15 to 18 hours.

7. The method for synthesizing the sitagliptin intermediate according to claim 1, characterized in that: in, In step S10, the visible light is provided by an LED light source with a wavelength of 380nm to 460nm and a power of 5W to 30W.

8. The method for synthesizing the sitagliptin intermediate according to claim 7, characterized in that: in, The wavelength is 420nm to 440nm, and the power is 10W to 15W.

9. The method for synthesizing the sitagliptin intermediate according to claim 1, Its features are: Step S20 includes the following sub-steps: S21, will The reaction solution was obtained by mixing the ethyl acetate solution of HCl with the solution and then heating and stirring. S22, the reaction solution is evaporated to dryness to obtain the sitagliptin intermediate.

10. The method for synthesizing the sitagliptin intermediate according to claim 9, characterized in that: in, In step S21, the HCl concentration in the ethyl acetate solution is 2 mol / L, the heating temperature is 35℃~45℃, and the stirring time is 2h.

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