Synthesis method of sitagliptin intermediate

Abstract

The invention provides a synthesis method of a sitagliptin intermediate, and belongs to the technical field of synthesis of organic drug intermediates. The synthesis method of the sitagliptin intermediate comprises the following steps: under the conditions of visible light irradiation, a photocatalyst and an oxidant, reacting 1, 1-dimethyl ethyl 5, 6-dihydro-1, 2, 4-triazolo [4, 3-a] pyrazine-7 (8H)-carboxylic acid tert-butyl ester with trifluoromethyl sulfinate in a solvent, removing Boc protection and salifying to generate 3-(trifluoromethyl)-5, 6, 7, 8-tetrahydro-[1, 2, 4] triazolo [4, 2, 4] triazolo [4, 3-a] pyrazine-7 (8H)-carboxylic acid tert-butyl ester. The invention relates to a [1, 2, 3-a] pyrazine hydrochloride compound (namely a sitagliptin intermediate). The synthesis method of the sitagliptin intermediate has the characteristics of mild conditions, simplicity and convenience in operation, environment friendliness, easiness in obtaining raw materials, excellent compatibility of substrate functional groups and high reaction yield.

Description

Technical Field

[0001] The invention belongs to the technical field of organic drug intermediate synthesis, and particularly relates to a method for synthesizing a sitagliptin intermediate. Background Art

[0002] Sitagliptin is a dipeptidyl peptidase 4 (DPP-4) inhibitor that can improve blood sugar control in patients with type II diabetes by increasing the level of active incretin hormones. It has the advantages of rapid oral absorption, no effect on food intake, fewer doses, good compliance, fewer adverse reactions, high safety, and can be used in combination with other drugs.

[0003] Figure 2 Schematic diagrams of two synthetic routes of sitagliptin under the prior art.

[0004] like Figure 2 As shown in the figure, there are two classical synthetic routes for sitagliptin: the first is a three-step method, which is based on As the starting material, it is generated by two steps of reaction Sitagliptin is obtained through enzyme-catalyzed reaction. The second route is a four-step method, which also uses As the starting material, it is synthesized by two steps Sitagliptin is obtained by enamination and catalytic hydrogenation. It can be seen that no matter which route is used, it must go through This intermediate, The synthesis requires the use of

[0005] visible, It is an unavoidable key intermediate in the synthesis route of sitagliptin.

[0006] Figure 3 The present invention is a schematic diagram of two synthetic routes of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride under the prior art.

[0007] like Figure 3 As shown, There are two classic synthetic routes: the first synthetic route requires a low temperature (below -20 ° C) environment, and has more by-products, which has more limitations; the second route has a relatively simple functional group conversion and has certain route advantages. Prepared ) Reference patent WO2004058266 can quantitatively obtain the reaction product, but the first step reaction ( Prepared ) is more difficult.

[0008] Above In the second step of the second synthetic route, it is reported [1] Trimethyl (trifluoromethyl) silane was used as the trifluoromethyl source, but the reaction yield was low, only 10%. [2] The use of trifluoromethyl copper phosphorus complex [Ph4P] is described + [Cu(CF3)2] - The reaction requires a high temperature of more than 100°C and a yield of only 52%.

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

[0010] [2]Organic Chemistry Frontiers(2019),6(14),2324-2328 Summary of the invention

[0011] The present invention is conducted to solve the above-mentioned problems, and its purpose is to provide a method for synthesizing a sitagliptin intermediate.

[0012] The present invention provides a method for synthesizing a sitagliptin intermediate, which has the following characteristics: S10, After the trifluoromethanesulfinate, the photocatalyst and the oxidant are mixed in a solvent and reacted for a certain period of time under the conditions of room temperature and visible light irradiation, a S20, removed under acidic conditions The tert-butyloxycarbonyl in the tert-butyloxycarbonyl group is salified to obtain a sitagliptin intermediate, which is 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, and its structural formula is

[0013] The method for synthesizing the sitagliptin intermediate provided by the present invention may also have the following characteristics: wherein, in step S10, The molar ratio of trifluoromethanesulfinate, photocatalyst and oxidant is 1:(1-3):(0.05-0.22):(1.5-3).

[0014] The synthetic method of the sitagliptin intermediate provided by the present invention may also have the following characteristics: wherein, The molar ratio of trifluoromethanesulfinate, photocatalyst and oxidant is 1:(1.8-3.0):(0.10-0.13):(1.8-2.1).

[0015] In the synthesis method of the sitagliptin intermediate provided by the present invention, it can also have the following characteristics: wherein, in step S10, the trifluoromethylsulfinate includes any one or more of sodium trifluoromethylsulfinate, potassium trifluoromethylsulfinate, ammonium trifluoromethylsulfinate or lithium trifluoromethylsulfinate, 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 dichloroethane.

[0016] The synthetic method of the sitagliptin intermediate provided by the present invention may also have the following characteristics: wherein the trifluoromethylsulfinate is sodium trifluoromethylsulfinate, the photocatalyst is riboflavin, the oxidant is ammonium persulfate, and the solvent is DMSO.

[0017] The method for synthesizing the sitagliptin intermediate provided by the present invention may also have the following characteristics: wherein, in step S10, the room temperature is 10° C. to 30° C., and the reaction time is 15 h to 18 h.

[0018] The method for synthesizing the sitagliptin intermediate provided by the present invention may also have the following characteristics: wherein, in step S10, the visible light is provided by an LED light source with a wavelength of 380 nm to 460 nm, and the power of the LED light source is 5 W to 30 W.

[0019] The method for synthesizing the sitagliptin intermediate provided by the present invention may also have the following characteristics: wherein the wavelength is 420nm to 440nm, and the power is 10W to 15W.

[0020] In the synthesis method of the sitagliptin intermediate provided by the present invention, the following features may also be present: wherein step S20 comprises the following sub-steps: S21, After mixing with ethyl acetate solution of HCl, heating and stirring are performed to obtain a reaction solution; S22, evaporating the reaction solution to dryness to obtain a sitagliptin intermediate.

[0021] The method for synthesizing the sitagliptin intermediate provided by the present invention may also have the following characteristics: wherein, in step S21, the concentration of HCl in the ethyl acetate solution is 2 mol / L, the heating temperature is 35° C. to 45° C., and the stirring time is 2 h.

[0022] Functions and Effects of the Invention

[0023] According to the synthesis method of the sitagliptin intermediate involved in the present invention, under the conditions of visible light irradiation, photocatalyst and oxidant, 1,1-dimethylethyl 5,6-dihydro-1,2,4-triazolo[4,3-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester reacts with trifluoromethylsulfinate in a solvent, and then undergoes Boc deprotection and salt formation to generate a 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride compound.

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

[0025] Figure 1 Schematic diagram of the reaction mechanism for preparing tert-butyl 5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine-7(8H)-carboxylate in step S10 of an embodiment of the present invention;

[0026] Figure 2 Schematic diagrams of two synthetic routes of sitagliptin under the prior art;

[0027] Figure 3 The present invention is a schematic diagram of two synthetic 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, objectives and effects of the present invention easy to understand, the following examples are combined with the accompanying drawings to specifically illustrate the synthesis method of a sitagliptin intermediate of the present invention.

[0029] <Example>

[0030] This embodiment provides a method for synthesizing 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 synthetic method of the sitagliptin intermediate in this embodiment comprises the following steps:

[0032] S10, in a 10 mL quartz reaction tube, Sodium trifluoromethanesulfinate, a photocatalyst and an oxidant are mixed and dissolved in a solvent according to a molar feed ratio of 1:(1-3):(0.05-0.22):(1.5-3), and then reacted for 15h-18h at 10°C-30°C and 380nm-460nm wavelength visible light irradiation, during which the reaction progress is tracked by a thin layer chromatography plate.

[0033] After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The extract was 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 Schematic diagram of the reaction mechanism for preparing tert-butyl 5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine-7(8H)-carboxylate in step S10 of an embodiment of the present invention.

[0036] like Figure 1 As shown, the reaction mechanism of the photocatalytic reaction in step S10 is as follows: the photocatalyst is excited and converted into a highly active excited state compound [PC*] under visible light irradiation, and electron transfer and H transfer occur with the substrate to generate substrate free radicals. The trifluoromethyl source sodium trifluoromethanesulfinate simultaneously undergoes electron transfer under the action of the oxidant in the reaction system to generate trifluoromethyl free radicals, which then add to the substrate free radicals to generate products.

[0037] S20, removing the Boc group and salifying to obtain a sitagliptin intermediate, comprising the following sub-steps:

[0038] S21, will After mixing with 2 mol / L HCl in ethyl acetate, the mixture was heated and stirred at 35°C to 45°C for 2 h to obtain a reaction solution;

[0039] S22, evaporating the reaction solution to dryness to obtain a sitagliptin intermediate.

[0040] In this example, three samples were prepared according to the above-mentioned synthesis method of sitagliptin intermediate, which were respectively recorded as sample 1, sample 2 and sample 3.

[0041] The specific parameters and final yields of samples 1 to 3 during the preparation process are shown in Table 1. Note as compound 1)

[0042] Table 1 (Specific parameters and final yields of samples 1 to 3 during 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 = 5.8Hz, 2H), 3.64 (t, J = 5.8Hz, 2H)

[0045] Therefore, this example successfully prepared 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, which has the structural formula Sitagliptin intermediates.

[0046] <Comparative Example>

[0047] In this comparative example, the specific parameters in the preparation process were adjusted according to the synthesis method of the sitagliptin intermediate provided in the embodiment to examine the effects of different reaction conditions on the reaction.

[0048] Among them, a total of 13 groups of experiments were carried out, and the specific parameters in the 13 groups of experiments and the yields of the final products are shown in Table 2.

[0049] Table 2 (Specific parameters in 13 groups of experiments and yields of final products)

[0050]

[0051] In addition, the reaction temperature of experimental groups 1 to 12 was controlled at 10°C to 30°C, and the reaction temperature of experimental group 13 was controlled at 45°C to 55°C.

[0052] As shown in Table 2 above, experimental groups 1 to 7 investigated the influence of the catalyst. The experiments showed that the synthesis method of the sitagliptin intermediate of this embodiment has a strong selectivity for the catalyst, and basically does not react in sodium fluorescein and cerium trichloride. The yield in eosin Y is also very low. Riboflavin has the highest yield. Other catalysts such as 4CzIPN and rhodamine also have good catalytic effects, but not as good as riboflavin.

[0053] Experimental groups 8 and 9 mainly investigated the effect of solvent on the reaction. It can be seen that DMSO is the optimal solvent for the reaction, and the yields of other solvents are reduced.

[0054] Experimental group 13 shows that increasing temperature is not beneficial to the reaction.

[0055] Experimental groups 2, 9 and 12 show that increasing the oxidant equivalent does not improve the reaction.

[0056] Functions and Effects of the Embodiments

[0057] The present embodiment provides a method for directly introducing a trifluoromethyl functional group into a substrate 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester under visible light irradiation at room temperature in the presence of an inexpensive catalyst, and then removing the Boc protection to synthesize 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride with high selectivity. The reaction conditions are mild, the environment is friendly, and it is conducive to industrial production and application.

[0058] This embodiment uses a 10W-15W LED visible light source, which is safe, energy-saving, cheap and readily available.

[0059] The sodium trifluoromethanesulfinate used in this embodiment is cheap, easily available, and has a wide range of applications.

[0060] The catalyst riboflavin used in this embodiment is cheap and readily available, and has high product conversion efficiency.

[0061] The byproduct of the experiment in this embodiment is sodium sulfate, which is safe, non-toxic and environmentally friendly.

[0062] Those skilled in the art should understand that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for synthesizing a sitagliptin intermediate, characterized in that: The following steps are involved: S10, After the trifluoromethanesulfinate, the photocatalyst and the oxidant are mixed in a solvent and reacted for a certain period of time under the conditions of room temperature and visible light irradiation, a S20, removed under acidic conditions The tert-butyloxycarbonyl in the mixture is salified to obtain the 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 2. The method for synthesizing a sitagliptin intermediate according to claim 1, wherein: in, In step S10, The molar ratio of trifluoromethanesulfinate, photocatalyst and oxidant is 1:(1-3):(0.05-0.22):(1.5-3).

3. The method for synthesizing a sitagliptin intermediate according to claim 2, wherein: in, The molar ratio of trifluoromethanesulfinate, photocatalyst and oxidant is 1:(1.8-3.0):(0.10-0.13):(1.8-2.1).

4. The method for synthesizing a sitagliptin intermediate according to claim 1, wherein: in, In step S10, the trifluoromethanesulfinate salt includes any one or more of sodium trifluoromethanesulfinate, potassium trifluoromethanesulfinate, ammonium trifluoromethanesulfinate or lithium trifluoromethanesulfinate. 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. The solvent includes any one or more of DMSO, acetonitrile or dichloroethane.

5. The method for synthesizing a sitagliptin intermediate according to claim 4, wherein: in, The trifluoromethanesulfinate is sodium trifluoromethanesulfinate, the photocatalyst is riboflavin, the oxidant is ammonium persulfate, and the solvent is DMSO.

6. The method for synthesizing a sitagliptin intermediate according to claim 1, wherein: in, In step S10, the normal temperature is 10°C to 30°C. Reaction time: 15h~18h.

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

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

9. The method for synthesizing a sitagliptin intermediate according to claim 1, wherein: in, Step S20 includes the following sub-steps: S21, will Mixing with ethyl acetate solution of HCl and heating with stirring to obtain a reaction solution; S22, evaporating the reaction solution to dryness to obtain the sitagliptin intermediate.

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

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