Method for preparing sitagliptin phosphate

Abstract

The invention discloses a synthesis process of sitagliptin phosphate, which comprises the following steps: fully mixing (R)-3-(benzyloxy amino)-1-(3-(trifluorophenyl)-5, 6-dihydro-[1, 2, 4] triazolo [4, 3-a] pyrazine-7 (8H)-yl)-4-(2, 4, 5-trifluorophenyl) butane-1-one, trifluorophosphoric acid, a catalyst Cu (OAc) 2. H2O and a mixed solvent, reacting for 1-2 hours at the temperature of 5-10 DEG C, and after the reaction is finished, separating and purifying to obtain the sitagliptin phosphate. Sitagliptin phosphate is obtained through solvent evaporation and recrystallization. The synthesis process provided by the invention depends on green chemistry principles, such as ultraviolet light catalysis, microwave heating, an optimized solvent system and mild reaction conditions. The methods not only are beneficial to improving the reaction efficiency, but also can reduce the use of harmful solvents and reduce the risk of environmental pollution, and conform to the current trend of green chemistry and sustainable development.

Description

Technical Field

[0001] The present disclosure relates to a method for preparing sitagliptin phosphate. Background Art

[0002] As an important anti - diabetic drug, Phosphate Sigliptin has good clinical efficacy and is widely used in the treatment of type 2 diabetes. Sitagliptin is a selective DPP - 4 inhibitor, which can effectively inhibit the activity of dipeptidyl peptidase - 4 (DPP - 4), thereby prolonging the half - life of incretins such as GLP - 1, promoting insulin secretion, and reducing blood glucose levels. Its phosphate - form drug has higher stability and better solubility, can release the drug more efficiently in the body, and further enhance its efficacy.

[0003] The synthetic method of sitagliptin initially passed through traditional organic synthesis routes, such as olefin addition reactions, reduction reactions, etc. Early synthetic methods mostly relied on relatively complex chemical reaction steps and harsh reaction conditions. Therefore, the demand for catalysts was high, and the yield and selectivity in the synthesis process were often not ideal. Summary of the Invention

[0004] To solve the above problems, the present disclosure provides a method for preparing sitagliptin phosphate, and the method includes the following steps:

[0005] Step 1: Synthesize the chiral alcohol ester (S) - methyl 4 - (2,4,5 - trifluorophenyl) - 3 - hydroxybutyrate

[0006] Add methyl 4 - (2,4,5 - trifluorophenyl) - 3 - oxobutyrate and lithium aluminum hydride into a reaction flask, dissolve them in methanol, add Ru(bpy) 3 Cl 2 as a photocatalyst, place the reaction system under an ultraviolet light irradiation device, react at 40 - 60 °C for 1 - 3 hours to generate the chiral alcohol ester (S) - methyl 4 - (2,4,5 - trifluorophenyl) - 3 - hydroxybutyrate. After the reaction is completed, separate and purify by silica gel column chromatography, and use a dichloromethane / methanol mixed solvent as the elution solvent; after purification, obtain the target product (S) - methyl 4 - (2,4,5 - trifluorophenyl) - 3 - hydroxybutyrate;

[0007] Step 2: Synthesize the chiral lactam four - membered ring (R) - N - benzyloxy - 4 - [1 - methyl - (2,4,5 - trifluorophenyl)] - 2 - azetidinone

[0008] Dissolve (S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutyric acid methyl ester, O-benzyloxyhydroxylamine hydrochloride and lithium hydroxide in tetrahydrofuran, place the reaction system in a microwave heating device, control the reaction temperature at 30-40° C., and use microwave heating for 0.5-1 hour. After the reaction is completed, cool and perform liquid-liquid extraction with ethyl acetate and water, and remove the organic solvent by solvent evaporation to finally obtain the target product (R)-N-benzyloxy-4-[1-methyl-(2,4,5-trifluorophenyl)]-2-azetidinone;

[0009] Step 3: Synthesis of (R)-3-(benzyloxyamino)-1-(3-(trifluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one

[0010] (R)-N-benzyloxy-4-[1-methyl-(2,4,5-trifluorophenyl)]-2-azetidinone, 3-trifluoromethyl-1,2,4-triazolo[4,3-a]piperazine hydrochloride and NiCl 2 Add to acetonitrile; control the reaction temperature at 20-30° C., use microwave heating for 0.5-1 hour, after the reaction is completed, perform liquid-liquid extraction, extract with ethyl acetate and water mixture, and obtain (R)-3-(benzyloxyamino)-1-(3-(trifluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1-one by solvent evaporation and recrystallization;

[0011] Step 4: Synthesis of Sitagliptin Phosphate

[0012] (R)-3-(benzyloxyamino)-1-(3-(trifluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one, trifluorophosphoric acid, and catalyst Cu(OAc) 2 ·H 2 O. The mixed solvent is fully mixed and reacted at 5-10° C. for 1-2 hours. After the reaction is completed, sitagliptin phosphate is obtained by solvent evaporation and recrystallization.

[0013] The wavelength of the ultraviolet light is 320-290nm.

[0014] The mass ratio of methanol to dichloromethane in the dichloromethane / methanol mixed solvent is 1:5-10.

[0015] In step 3, the mass ratio of ethyl acetate to water in the ethyl acetate water mixture is 1:0.5-2.

[0016] The microwave power is 150 - 350 W.

[0017] The mixed solvent in the mixture is a mixed solvent of methanol, acetonitrile, and ethyl acetate.

[0018] The mass ratio of the methanol, acetonitrile, and ethyl acetate is 2 - 3:0.8 - 1.2:1.

[0019] Advantages of the present invention:

[0020] By using ultraviolet photocatalysis and microwave heating technologies, the reaction rate and efficiency are improved.

[0021] The innovative catalytic method improves the reaction selectivity and yield.

[0022] The green catalytic and low-temperature reaction conditions reduce the dependence on harmful chemicals and conform to the principles of green chemistry.

[0023] Using a relatively economical catalyst reduces the reaction cost.

[0024] The above and other features, aspects, and advantages of the present application are more easily understood with reference to the following detailed description. Description of the Drawings

[0025] Figure 1 It is the infrared spectrum of the sample obtained in Example 1.

[0026] Figure 2 It is the 1 1H-NMR spectrum of the sample obtained in Example 1.

[0027] Figure 3 It is the 13 13C-NMR spectrum of the sample obtained in Example 1.

[0028] Figure 4 It is the 31 31P-NMR spectrum of the sample obtained in Example 1.

[0029] Figure 5 It is the COSY spectrum of the sample obtained in Example 1.

[0030] Figure 6 It is the DMSO-d6 spectrum of the sample obtained in Example 1. Specific Embodiments

[0031] Example 1

[0032] Step 1: Synthesize methyl (S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutyrate

[0033] Add 0.61 mol of methyl 4-(2,4,5-trifluorophenyl)-3-oxobutyrate and 1.16 mol of lithium aluminum hydride to a reaction flask, dissolve them in 750 g of methanol, and add 0.5 mol% of Ru(bpy) 3 Cl 2 as a photocatalyst. Place the reaction system under an ultraviolet light (365 nm) irradiation device and react at 50 °C for 2 hours to produce chiral alcohol ester (S)-methyl 4-(2,4,5-trifluorophenyl)-3-hydroxybutyrate. After the reaction is completed, separate and purify by silica gel column chromatography, and use a dichloromethane / methanol mixed solvent (8:1) as the elution solvent; after purification, the target product (S)-methyl 4-(2,4,5-trifluorophenyl)-3-hydroxybutyrate is obtained; its yield is 92.1%, the ee value is 99.45%, and the purity is 98.21%.

[0034] Step 2: Synthesize chiral lactam four-membered ring (R)-N-benzyloxy-4-[1-methyl-(2,4,5-trifluorophenyl)]-2-azetidinone

[0035] Dissolve 0.56 mol of (S)-methyl 4-(2,4,5-trifluorophenyl)-3-hydroxybutyrate, 0.61 mol of O-benzyloxyhydroxylamine hydrochloride and 0.55 mol of lithium hydroxide in 260 g of tetrahydrofuran. Place the reaction system in a microwave heating device, control the reaction temperature at 35 °C, and heat with microwave for 1 hour. After the reaction is completed, cool and perform liquid-liquid extraction with 500 g of ethyl acetate and 500 g of water, and remove the organic solvent by solvent evaporation method. Finally, the target product (R)-N-benzyloxy-4-[1-methyl-(2,4,5-trifluorophenyl)]-2-azetidinone is obtained; its yield is 82.3% and the purity is 98.32%.

[0036] Step 3: Synthesize (R)-3-(benzyloxyamino)-1-(3-(trifluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one

[0037] Add 0.4 mol of (R)-N-benzyloxy-4-[1-methyl-(2,4,5-trifluorophenyl)]-2-azetidinone, 0.5 mol of 3-trifluoromethyl-1,2,4-triazolo[4,3-a]piperazine hydrochloride and 5 g of NiCl 2It was added to 300 g of acetonitrile; the reaction temperature was controlled at 30 °C, and it was heated by microwave for 1 hour. After the reaction was completed, liquid-liquid extraction was carried out, and it was extracted with an ethyl acetate-water mixed solution. (R)-3-(Benzyloxyamino)-1-(3-(trifluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one was obtained by solvent evaporation and recrystallization; its yield was 81.0%, and its purity was 98.11%.

[0038] Step 4: Synthesis of Sitagliptin Phosphate

[0039] 0.3 mol of (R)-3-(Benzyloxyamino)-1-(3-(trifluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one, 0.4 mol of trifluorophosphoric acid, and 2 mol% of the catalyst Cu(OAc) 2 ·H 2 O, 600 g of a mixed solvent (methanol, acetonitrile, ethyl acetate 2:1:1) were fully mixed and reacted at 8 °C for 1 hour. After the reaction was completed, sitagliptin phosphate was obtained by solvent evaporation and recrystallization. Its yield was 92.1%, the ee value was 99.76%, the purity was 99.87%, and the relevant spectra are shown in Figures 1-6 。

[0040] Example 2

[0041] Step 1: Synthesis of chiral alcohol ester (S)-Methyl 4-(2,4,5-trifluorophenyl)-3-hydroxybutyrate

[0042] 0.6 mol of methyl 4-(2,4,5-trifluorophenyl)-3-oxobutyrate and 1.1 mol of lithium aluminum hydride were added to a reaction flask, dissolved in 800 g of methanol, and 0.6 mol% of Ru(bpy) 3 Cl 2 was used as a photocatalyst. The reaction system was placed under an ultraviolet light (365 nm) irradiation device and reacted at 55 °C for 1.7 hours to generate chiral alcohol ester (S)-Methyl 4-(2,4,5-trifluorophenyl)-3-hydroxybutyrate. After the reaction was completed, it was separated and purified by silica gel column chromatography, and the elution solvent used was a dichloromethane / methanol mixed solvent (9:1); the target product (S)-Methyl 4-(2,4,5-trifluorophenyl)-3-hydroxybutyrate was obtained after purification; its yield was 92.3%, the ee value was 99.46%, and the purity was 98.10%.

[0043] Step 2: Synthesis of chiral lactam four-membered ring (R)-N-Benzyloxy-4-[1-methyl-(2,4,5-trifluorophenyl)]-2-azetidinone

[0044] 0.52 mol of (S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutyric acid methyl ester, 0.61 mol of O-benzyloxyhydroxylamine hydrochloride and 0.6 mol of lithium hydroxide were dissolved in 300 g of tetrahydrofuran, and the reaction system was placed in a microwave heating device. The reaction temperature was controlled at 36° C. and microwave heating was performed for 1 hour. After the reaction was completed, the mixture was cooled and liquid-liquid extraction was performed with 600 g of ethyl acetate and 400 g of water. The organic solvent was removed by solvent evaporation to finally obtain the target product (R)-N-benzyloxy-4-[1-methyl-(2,4,5-trifluorophenyl)]-2-azetidinone; the yield was 82.5% and the purity was 98.29%.

[0045] Step 3: Synthesis of (R)-3-(benzyloxyamino)-1-(3-(trifluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one

[0046] 0.41 mol (R)-N-benzyloxy-4-[1-methyl-(2,4,5-trifluorophenyl)]-2-azetidinone, 0.51 mol 3-trifluoromethyl-1,2,4-triazolo[4,3-a]piperazine hydrochloride and 6 g NiCl 2 310 g of acetonitrile was added; the reaction temperature was controlled at 28° C. and microwave heating was used for 0.9 hour. After the reaction was completed, liquid-liquid extraction was performed and extracted with a mixture of ethyl acetate and water. (R)-3-(benzyloxyamino)-1-(3-(trifluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1-one was obtained by solvent evaporation and recrystallization; the yield was 81.3% and the purity was 98.31%.

[0047] Step 4: Synthesis of Sitagliptin Phosphate

[0048] 0.32 mol (R)-3-(benzyloxyamino)-1-(3-(trifluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one, 0.43 mol trifluorophosphoric acid, 3 mol% catalyst Cu(OAc) 2 ·H 2 O, 500g of mixed solvent (methanol, acetonitrile, ethyl acetate 1.8:1.2:1) were fully mixed, and the reaction was carried out at 8°C for 0.9 hour. After the reaction, sitagliptin phosphate was obtained by solvent evaporation and recrystallization, with a yield of 94.9%, an ee value of 99.72%, and a purity of 99.89%.

[0049] Comparative Example 1

[0050] Same as Step 1 of Example 1, but in Step 1, the photocatalyst used is Ir(dF(CF 3 )ppy) 2 Cl, and the ultraviolet light wavelength is 385 nm, replacing Ru(bpy) 3 Cl 2 . The yield of the target product obtained is 88.5%, the ee value is 98.20%, and the purity is 98.12%.

[0051] Comparative Example 2

[0052] Same as Step 1 of Example 1, but in Step 1, the photocatalyst used is calcium titanate, and the ultraviolet light wavelength is 390 nm, replacing Ru(bpy) 3 Cl 2 . The yield of the target product obtained is 89.2%, the ee value is 97.75%, and the purity is 98.22%.

[0053] Comparative Example 3

[0054] Same as Step 1 of Example 1, but in Step 1, aluminum fluoride trihydrate is used to replace lithium aluminum hydride, and the photocatalyst used is Ir(dF(CF 3 )ppy) 2 Cl, and the ultraviolet light wavelength is 385 nm, replacing Ru(bpy) 3 Cl 2 . The yield of the target product obtained is 87.3%, the ee value is 95.38%, and the purity is 98.19%.

[0055] Comparative Example 4

[0056] Same as Steps 2 and 3 of Example 1, but in Steps 2 and 3, microwave heating is not used, and instead, a conventional heating pad is used for heating. The yield of Step 2 is 72.2%, the purity is 98.24%, the yield of Step 3 is 71.8%, and the purity is 98.26%.

[0057] Comparative Example 5

[0058] Same as Step 4 of Example 1, but a phosphoric acid solution with the same phosphorus element content is used to replace trifluorophosphoric acid. The yield is 85.8%, the ee value is 99.56%, and the purity is 99.86%.

[0059] Comparative Example 6

[0060] Same as Step 4 of Example 1, but an N-heterocyclic carbene palladium catalyst is used to replace the addition of Cu(OAc) 2 ·H 2 O. The yield is 87.6%, the ee value is 99.64%, and the purity is 99.83%.

[0061] It can be seen that Ru(bpy) 3 Cl 2 is used as a photocatalyst, and combined with ultraviolet light irradiation, the ultraviolet photocatalysis makes the reaction more selective, enhances the precision of chiral control, and ensures the high yield and high purity of the target product (S)-methyl 4-(2,4,5-trifluorophenyl)-3-hydroxybutyrate.

[0062] It can be seen that NiCl 2 is used as a catalyst to help promote the synthesis reaction. This choice of substituting the copper catalyst helps to reduce the reaction cost, and the nickel catalyst is usually more stable and has stronger catalytic activity in the reaction.

[0063] It can be seen that microwave heating technology is adopted. This method can significantly increase the reaction rate and improve the selectivity of the product. Microwave heating can provide a uniform heating environment, avoid side reactions caused by uneven heating in traditional heating methods, and shorten the reaction time, thereby improving the overall reaction efficiency.

[0064] It can be seen that Cu(OAc) 2 ·H 2 O and trifluorophosphoric acid are used, which can effectively improve the selectivity of the reaction, thereby increasing the yield and purity of sitagliptin phosphate.

[0065] As mentioned above, the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A method for preparing sitagliptin phosphate, characterized in that: The method comprises the following steps: Step 1: Synthesis of chiral alcohol ester (S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutyric acid methyl ester Add 4-(2,4,5-trifluorophenyl)-3-oxobutyric acid methyl ester and lithium aluminum hydride into a reaction bottle, dissolve them in methanol, add Ru(bpy)3Cl2 as a photocatalyst, place the reaction system under an ultraviolet light irradiation device, react at 40-60 degrees Celsius for 1-3 hours to generate chiral alcohol ester (S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutyric acid methyl ester, and after the reaction, separate and purify by silica gel column chromatography, using a dichloromethane / methanol mixed solvent as the elution solvent; after purification, obtain the target product (S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutyric acid methyl ester; Step 2: Synthesis of chiral lactam four-membered ring (R)-N-benzyloxy-4-[1-methyl-(2,4,5-trifluorophenyl)]-2-azetidinone Dissolve (S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutyric acid methyl ester, O-benzyloxyhydroxylamine hydrochloride and lithium hydroxide in tetrahydrofuran, place the reaction system in a microwave heating device, control the reaction temperature at 30-40° C., and use microwave heating for 0.5-1 hour. After the reaction is completed, cool and perform liquid-liquid extraction with ethyl acetate and water, and remove the organic solvent by solvent evaporation to finally obtain the target product (R)-N-benzyloxy-4-[1-methyl-(2,4,5-trifluorophenyl)]-2-azetidinone; Step 3: Synthesis of (R)-3-(benzyloxyamino)-1-(3-(trifluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one (R)-N-benzyloxy-4-[1-methyl-(2,4,5-trifluorophenyl)]-2-azetidinone, 3-trifluoromethyl-1,2,4-triazolo[4,3-a]piperazine hydrochloride and NiCl2 are added to acetonitrile; the reaction temperature is controlled at 20-30°C, and microwave heating is used for 0.5-1 hour. After the reaction is completed, liquid-liquid extraction is performed, and extraction is performed with a mixed solution of ethyl acetate and water. (R)-3-(benzyloxyamino)-1-(3-(trifluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1-one is obtained by solvent evaporation and recrystallization; Step 4: Synthesis of Sitagliptin Phosphate (R)-3-(benzyloxyamino)-1-(3-(trifluorophenyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1-one, trifluorophosphoric acid, a catalyst Cu(OAc)2·H2O, and a mixed solvent are fully mixed, and reacted at 5-10° C. for 1-2 hours. After the reaction is completed, sitagliptin phosphate is obtained by solvent evaporation and recrystallization.

2. A method for preparing sitagliptin phosphate according to claim 1, characterized in that, The wavelength of the ultraviolet light is 320-290nm.

3. A method for preparing sitagliptin phosphate according to claim 1, characterized in that, The mass ratio of methanol to dichloromethane in the dichloromethane / methanol mixed solvent is 1:5-10.

4. A method for preparing sitagliptin phosphate according to claim 1, characterized in that, In the step 3, the mass ratio of ethyl acetate to water in the ethyl acetate water mixture is 1:0.5-2.

5. A method for preparing sitagliptin phosphate according to claim 1, characterized in that, The microwave power is 150-350W.

6. A method for preparing sitagliptin phosphate according to claim 1, characterized in that: The mixed solvent is a mixed solvent of methanol, acetonitrile and ethyl acetate.

7. A method for preparing sitagliptin phosphate according to claim 1, characterized in that: The mass ratio of the methanol, acetonitrile and ethyl acetate is 2-3:0.8-1.2:1.

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