sitagliptin phosphate 7- [ (3R) -3-amino-1-oxo-4- (2, 4, 5-trifluorophenyl) butyl]-5,6,7,8-tetrahydro-3-trifluoromethyl-1, 2,4-triazolo [4,3-a]The pyrazine phosphate synthesis method has a plurality of methods, wherein the reaction conditions required by the (S) -biphenyl diphenylphosphine-ruthenium chloride synthesis method are mild, the operation of each step of reaction is simple, the feasibility is relatively high, the used reagent is relatively cheap and easy to obtain, but the used asymmetric hydrogenation catalyst (S) -biphenyl diphenylphosphine-ruthenium chloride- [ (S) -Binap-RuCl)₂ ]Is expensive and is not suitable for mass production.

Disclosure of Invention

The invention aims to overcome the defects of the prior art, and provides the preparation method of sitagliptin phosphate, the catalyst and the hydrogen source are cheap and easy to obtain, the catalyst can be recycled and reused in the production process, the obtained product has high purity, and the batch production of the sitagliptin phosphate serving as a hypoglycemic medicament is facilitated.

The purpose of the invention is realized as follows: a preparation method of sitagliptin phosphate, which takes 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoic acid methyl ester I as a raw material, comprises the following steps:

step one, carrying out asymmetric reduction on a raw material I by using an N-heterocyclic carbene-palladium catalyst to obtain a compound chiral alcohol ester s-4- (2, 4, 5-trifluorophenyl) -3-hydroxy methyl butyrate II;

step two, performing intramolecular condensation cyclization on the compound II to obtain a compound chiral lactam four-membered ring (R) -N-benzyloxy-4- [ 1-methyl- (2, 4, 5-trifluorophenyl) ] -2-azetidinone III;

step three, the compound III is opened in a ring under an alkaline condition to obtain a compound (R) -3- (benzyloxyamino) -4- (2, 4, 5-trifluorophenyl) butyric acid IV;

step four, the compound IV is condensed to form amide to obtain a compound (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-ketone V;

step five, catalytically reducing the nitrogen heterocyclic carbene palladium catalyst recovered in the step one by the compound V to remove benzyloxy and form phosphate to obtain sitagliptin phosphate VI;

the reaction formula of the preparation method is as follows:

the N-heterocyclic carbene palladium catalyst is one of Pd (IPr-NHC) (acac) Cl, pd (IPr-NHC) (acac) OAc, pd (IPr-NHC) (dba) Cl and Pd (IPr-NHC) (dba) OAc; the hydrogen source is one of ammonium formate, hydrazine hydrate, formic acid, methanol, ethanol, formaldehyde and citric acid.

Preferably, in the first step, the dosage of the N-heterocyclic carbene-palladium catalyst is 0.2-1%, the dosage of the hydrogen source is 1-3 times of equivalent, the ee value of the enantioselectivity is more than or equal to 99.0%, and the yield is more than 90%.

Preferably, in the fifth step, the dosage of the N-heterocyclic carbene-palladium catalyst is 0.5-1%, the dosage of the hydrogen source is 1-3 times of equivalent, the ee value of the enantioselectivity is more than or equal to 99.0%, and the yield is more than 90%.

And (3) passing the reaction liquid after the reaction in the step one through silica gel and leaching the reaction liquid with methanol, fully soaking the leached silica gel with methanol and chloroform, and evaporating the methanol and the chloroform to obtain the recycled N-heterocyclic carbene-palladium catalyst which can be used in the step five.

Due to the adoption of the technical scheme, the invention has the beneficial effects that: the invention adopts cheap and easily-obtained N-heterocyclic carbene-palladium catalyst to replace the original expensive asymmetric hydrogenation catalyst (S) -biphenyl diphenyl phosphine-ruthenium chloride- [ (S) -Binap-RuCl)₂ ]The production cost is reduced, the enantioselectivity and the yield of key production steps are improved, the purity of the obtained final product is high, and meanwhile, the hydrogen source adopted in a matching way is low in price and easy to obtain, so that the batch production of the drug sitagliptin phosphate for reducing the blood sugar is facilitated; the N-heterocyclic carbene-palladium catalyst adopted by the invention can be recycled and reused in the subsequent production steps, thereby further reducing the production cost and being beneficial to the batch production of the hypoglycemic drug sitagliptin phosphate.

Detailed Description

The technical scheme of the invention is further specifically described by the following embodiments.

Example one

Step one, dissolving 120g (0.49 mol) of compound 4- (2, 4, 5-trifluorophenyl) -3-oxobutyric acid methyl ester (I), 0.6g (0.2 mol) of catalyst Pd (IPr-NHC) (acac) Cl and 45g (0.98 mol) of formic acid in 600g of methanol, stirring for reaction for 2 hours at 65 ℃ under the protection of nitrogen, and after the reaction is finished, passing the reaction solution through silica gel and washing with methanol. The washed silica gel was thoroughly soaked in methanol and chloroform to distill off methanol and chloroform, and 0.4g of the recovered catalyst was obtained. Adding 21g (0.53 mol) of sodium hydroxide aqueous solution 600g into the reaction solution, carrying out reflux reaction for 1 hour, reducing pressure after the reaction is finished, evaporating methanol, adding 110g (1.1 mol) of concentrated hydrochloric acid and 320g of toluene, layering, cooling the toluene layer to 0 ℃, crystallizing for 4 hours, filtering, and drying to obtain 104.8g of off-white solid compound (II), wherein the yield is 91.1%, the melting point is 82-84 ℃, the ee value is 99.0%, and the purity is 98%.

Step two, 100g (0.43 mol) of off-white solid compound (II), 75g (0.47 mol) of O-benzyloxyhydroxylamine hydrochloride, 18g (0.43 mol) of lithium hydroxide monohydrate were added to 200g of tetrahydrofuran and 750g of water. 107g (0.56 mol) of N-ethyl-N' -dimethylaminopropylamine carbodiimide hydrochloride was added thereto at 25 ℃ to react for 2 hours. After the reaction, 650g of ethyl acetate was added for extraction, and the organic phase was distilled under reduced pressure and 300g of tetrahydrofuran was added to obtain tetrahydrofuran slurry. 100g (1.28 mol) of diisopropyl azodicarboxylate was slowly added dropwise to a solution of 168g (1.28 mol) of triphenylphosphine in 200g of tetrahydrofuran at 0 ℃ and then added dropwise to the tetrahydrofuran slurry while controlling the temperature to 10 ℃ or lower. After the dripping is finished, the temperature is raised to 25 ℃ and the reaction lasts for 12 hours. After completion of the reaction, 1.25g of acetic acid was added, and tetrahydrofuran was distilled off under reduced pressure. Then adding 600g of methanol and 60g of water, heating to 35 ℃, stirring for dissolving, cooling to-5 ℃, crystallizing for 2 hours, filtering, and drying to obtain 101.5g of a gray solid compound (III), wherein the yield is 73.9%, and the purity is 98%.

Step three and step four, 100g (0.29 mol) of the gray solid compound (III) and 18g (0.43 mol) of lithium hydroxide monohydrate were dissolved in 250g of tetrahydrofuran and 300g of water and reacted at 20 ℃ for 2 hours. The temperature was reduced to 10 ℃ and 35g (0.43 mol) of methanesulfonic acid was slowly added. Adding ethyl acetate 500g for extraction, and evaporating the solvent to obtain the compound (IV). 800g of acetonitrile was added, 82g (0.36 mol) of 3-trifluoromethyl-1, 2, 4-triazolo [4,3-a ] piperazine hydrochloride was added, the temperature was decreased to 0 ℃ and 29g (0.29 mol) of N-methylmorpholine and 82.8g (0.43 mol) of N-ethyl-N' -dimethylaminopropylamine carbodiimide hydrochloride were added to the mixture to react for 1 hour. 400g of water and 700g of ethyl acetate are added, the layers are separated and the organic phase is washed with 430g of a 10% aqueous potassium bicarbonate solution and 430g of a 20% sodium chloride solution. The solvent was distilled off under reduced pressure to obtain 123.1g of a brown solid compound (V), yield 73.7%, purity 98%.

Step five, dissolving 100g (0.19 mol) of brown solid compound (V), 0.4g (0.2 mol) of recycled catalyst Pd (IPr-NHC) (acac) Cl, 41g (0.64 mol) of ammonium formate in 500g of methanol, vacuum degassing, protecting with nitrogen, stirring and reacting for 2 hours at 65 ℃, passing the reaction solution through silica gel and leaching with methanol after the reaction is finished, concentrating under reduced pressure, adding 100g of water, heating to 50 ℃, adding 20g (0.25 mol) of phosphoric acid aqueous solution with the mass fraction of 85%, heating to 65-70 ℃, keeping the temperature and reacting for 30 minutes, cooling to 50 ℃, keeping the temperature for 1 hour to obtain slurry, slowly adding 1000g of methanol, keeping the temperature at 50 ℃ for 1 hour, cooling to room temperature, stirring and crystallizing for 18 hours to obtain crystals, leaching with 100g of 2 methanol, and drying at 50 ℃ to obtain 136.9g of white solid powder sitagliptin phosphate, wherein the yield is 89%, the melting point is 215 ℃, the e value is 99.5%, and the purity is 99.8%.

Example two

Step one, 100g (0.41 mol) of compound 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoic acid methyl ester (I), 0.5g (0.2 mol) of catalyst Pd (IPr-NHC) (acac) OAc, 38g (0.6 mol) of ammonium formate are dissolved in 500g of methanol, the reaction is carried out for 2.5 hours under the protection of nitrogen and stirring at 60 ℃, and after the reaction is finished, reaction liquid passes through silica gel and is rinsed by methanol. The silica gel after the washing was sufficiently soaked with methanol and chloroform to distill off methanol and chloroform, and 0.3g of the recovered catalyst was obtained. Adding 500g of aqueous solution of 18g (0.45 mol) of sodium hydroxide into the reaction solution, carrying out reflux reaction for 1 hour, reducing pressure after the reaction is finished, evaporating methanol, adding 92g (0.9 mol) of concentrated hydrochloric acid and 267g of toluene, layering, cooling the toluene layer to 0 ℃, crystallizing for 4 hours, filtering, and drying to obtain 87.2g of an off-white solid compound (II), wherein the yield is 91.0%, the melting point is 82-84 ℃, the ee value is 99.0%, and the purity is 98%.

In the second step, 80g (0.34 mol) of the off-white solid compound (II), 60g (0.38 mol) of O-benzyloxyhydroxylamine hydrochloride and 14g (0.33 mol) of lithium hydroxide monohydrate were added to 160g of tetrahydrofuran and 600g of water. 86g (0.45 mol) of N-ethyl-N' -dimethylaminopropylamine carbodiimide hydrochloride was added thereto at 20 ℃ and reacted for 2.5 hours. After the reaction, 520g of ethyl acetate was added for extraction, and the organic phase was distilled under reduced pressure and 240g of tetrahydrofuran was added to obtain tetrahydrofuran syrup. 80g (1.02 mol) of diisopropyl azodicarboxylate was slowly added dropwise to a solution of 134g (1.02 mol) of triphenylphosphine in 160g of tetrahydrofuran at 0 ℃ and the temperature was controlled to 10 ℃ or lower, and then the tetrahydrofuran slurry was added dropwise. After dropping, the temperature is raised to 20 ℃ for reaction for 15 hours. After the reaction, 1.0g of acetic acid was added, and tetrahydrofuran was distilled off under reduced pressure. Then adding 180g of methanol and 48g of water, heating to 30 ℃, stirring for dissolving, cooling to-5 ℃, crystallizing for 2 hours, filtering and drying to obtain 81.1g of gray solid compound (III), wherein the yield is 73.8 percent and the purity is 98 percent.

In the third and fourth steps, 80g (0.23 mol) of the gray solid compound (III) and 14g (0.33 mol) of lithium hydroxide monohydrate were dissolved in 200g of tetrahydrofuran and 240g of water and reacted at 20 ℃ for 2 hours. The temperature was reduced to 10 ℃ and 28g (0.34 mol) of methanesulfonic acid was slowly added. Adding 400g of ethyl acetate for extraction, and evaporating the solvent to obtain the compound (IV). 640g of acetonitrile was added, 66g (0.29 mol) of 3-trifluoromethyl-1, 2, 4-triazolo [4,3-a ] piperazine hydrochloride was added, the temperature was lowered to 0 ℃ and 23g (0.23 mol) of N-methylmorpholine and 66.2g (0.34 mol) of N-ethyl-N' -dimethylaminopropylamine carbodiimide hydrochloride were added to react for 1 hour. 320g of water and 560g of ethyl acetate are added, the layers are separated and the organic phase is washed with 344g of 10% aqueous potassium bicarbonate solution and 344g of 20% sodium chloride solution. The solvent was distilled off under reduced pressure to obtain 98.3g of a brown solid compound (V) in 73.6% yield and 98% purity.

Step five, dissolving 80g (0.15 mol) of brown solid compound (V), 0.3g (0.2 mol) of recycled catalyst Pd (IPr-NHC) (acac) Cl and 33g (0.52 mol) of ammonium formate in 400g of methanol, vacuum degassing, protecting with nitrogen, stirring and reacting for 2 hours at 65 ℃, passing the reaction solution through silica gel and leaching with methanol after the reaction is finished, concentrating under reduced pressure, adding 80g of water, heating to 50 ℃, adding 16g (0.2 mol) of phosphoric acid aqueous solution with the mass fraction of 85%, heating to 65-70 ℃, keeping the temperature and reacting for 30 minutes, cooling to 50 ℃, keeping the temperature for 1 hour to obtain slurry, slowly adding 800g of methanol, keeping the temperature at 50 ℃ for 1 hour, cooling to room temperature, stirring and crystallizing for 18 hours to obtain crystals, filtering to obtain crystals, leaching with 80g of 2 methanol, drying at 50 ℃ to obtain 109.5g of white solid powder sitagliptin phosphate, wherein the yield is 88.9%, the melting point is 215 ℃, and the e value is 99.4% and the purity is 99.6%.

EXAMPLE III

Step one, dissolving 150g (0.61 mol) of compound 4- (2, 4, 5-trifluorophenyl) -3-oxobutyric acid methyl ester (I), 0.75g (0.2 mol) of catalyst Pd (IPr-NHC) (dba) Cl, 58g (1.16 mol) of hydrazine hydrate in 750g of methanol, stirring for reaction for 1.5 hours at 70 ℃ under the protection of nitrogen, and leaching the reaction solution through silica gel and methanol after the reaction is finished. The washed silica gel was thoroughly soaked in methanol and chloroform to distill off methanol and chloroform, and 0.5g of the recovered catalyst was obtained. Adding 750g of aqueous solution of 26g (0.65 mol) of sodium hydroxide into the reaction solution, carrying out reflux reaction for 1 hour, reducing pressure after the reaction is finished, evaporating methanol, adding 138g (1.4 mol) of concentrated hydrochloric acid and 400g of toluene, layering, cooling the toluene layer to 0 ℃, crystallizing for 4 hours, filtering, and drying to obtain 130.7g of off-white solid compound (II), wherein the yield is 91.0%, the melting point is 82-84 ℃, the ee value is 99.0%, and the purity is 98%.

In the second step, 130g (0.56 mol) of the off-white solid compound (II), 98g (0.61 mol) of O-benzyloxyhydroxylamine hydrochloride and 23g (0.55 mol) of lithium hydroxide monohydrate were added to 260g of tetrahydrofuran and 975g of water. 139g (0.73 mol) of N-ethyl-N' -dimethylaminopropylamine carbodiimide hydrochloride was added thereto at 30 ℃ and reacted for 1.5 hours. After the reaction, 845g of ethyl acetate was added for extraction, and the organic phase was distilled under reduced pressure and 390g of tetrahydrofuran was added to obtain tetrahydrofuran syrup. 130g (1.66 mol) of diisopropyl azodicarboxylate was slowly added dropwise to a solution of 218g (1.66 mol) of triphenylphosphine in 260g of tetrahydrofuran at 0 ℃ and the tetrahydrofuran slurry was added dropwise thereto while controlling the temperature at 10 ℃ or lower. After dropping, the temperature is raised to 30 ℃ for reaction for 10 hours. After completion of the reaction, 1.63g of acetic acid was added, and tetrahydrofuran was distilled off under reduced pressure. Then adding 780g of methanol and 78g of water, heating to 35 ℃, stirring for dissolving, cooling to-5 ℃, crystallizing for 2 hours, filtering, and drying to obtain 131.8g of a gray solid compound (III), wherein the yield is 73.8%, and the purity is 98%.

In the third and fourth steps, 130g (0.38 mol) of the gray solid compound (III) and 23g (0.55 mol) of lithium hydroxide monohydrate were dissolved in 350g of tetrahydrofuran and 390g of water and reacted at 20 ℃ for 2 hours. The temperature was reduced to 10 ℃ and 46g (0.56 mol) of methanesulfonic acid was slowly added. Adding 650g of ethyl acetate for extraction, and evaporating the solvent to obtain a compound (IV). 1040g of acetonitrile was added, 107.g (0.47 mol) of 3-trifluoromethyl-1, 2, 4-triazolo [4,3-a ] piperazine hydrochloride was added, the temperature was decreased to 0 ℃ and 38g (0.38 mol) of N-methylmorpholine and 107.6g (0.56 mol) of N-ethyl-N' -dimethylaminopropylamine carbodiimide hydrochloride were added to the mixture to react for 1 hour. 520g of water and 910g of ethyl acetate were added, the layers were separated and the organic layer was washed with 559g of a 10% aqueous solution of potassium hydrogencarbonate and 559g of a 20% solution of sodium chloride. The solvent was distilled off under reduced pressure to obtain 159.9g of a brown solid compound (V) in 73.6% yield and 98% purity.

Step five, dissolving 140g (0.27 mol) of brown solid compound (V), 0.6g (0.2 mol) of recycled catalyst Pd (IPr-NHC) (acac) Cl and 57g (0.89 mol) of ammonium formate in 700g of methanol, vacuum degassing, protecting with nitrogen, stirring and reacting for 2 hours at 65 ℃, passing through silica gel and leaching with methanol after the reaction is finished, concentrating under reduced pressure, adding 140g of water, heating to 50 ℃, adding 28g (0.35 mol) of phosphoric acid aqueous solution with the mass fraction of 85%, heating to 65-70 ℃, keeping the temperature and reacting for 30 minutes, cooling to 50 ℃, keeping the temperature for 1 hour to obtain slurry, slowly adding 1400g of methanol, keeping the temperature at 50 ℃ for 1 hour, cooling to room temperature, stirring and crystallizing for 18 hours, filtering to obtain crystals, leaching with 140g of 2 methanol, and drying at 50 ℃ to obtain 191.5g of white solid powder sitagliptin phosphate, wherein the yield is 88.9%, the melting point is 215 ℃, and the e value is 99.53% and the purity is 99.7%.

According to the preparation method disclosed by the embodiment, the N-heterocyclic carbene-palladium catalyst in the step one can be recycled and reused in the step five, after the cheap and easily available N-heterocyclic carbene-palladium catalyst and a hydrogen source are adopted, the ee values of the enantioselectivities in the step one and the step five are more than or equal to 99.0%, the yield is more than 90%, the yield of the prepared powdery sitagliptin phosphate is more than 88%, the purity is more than 99.5%, and the preparation method meets the requirement of batch production.

Finally, it should be noted that the above-mentioned embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the same, and although the present invention is described in detail with reference to the above-mentioned embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the specific embodiments of the present invention without departing from the spirit and scope of the present invention, and all the modifications or equivalent substitutions should be covered in the claims of the present invention.

Claims

1. The preparation method of sitagliptin phosphate is characterized in that 4- (2, 4, 5-trifluorophenyl) -3-oxobutyric acid methyl ester I is used as a raw material, and comprises the following steps:

firstly, carrying out an asymmetric reduction reaction on a raw material I and a hydrogen source through a nitrogen heterocyclic carbene palladium catalyst to obtain a compound chiral alcohol ester s-4- (2, 4, 5-trifluorophenyl) -3-hydroxy methyl butyrate II;

step four, the compound IV is condensed to form amide to obtain a compound (R) -3- (benzyloxy amino) -1- (3- (trifluorophenyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) -4- (2, 4, 5-trifluorophenyl) butane-1-ketone V;

the reaction formula of the preparation method is as follows:

2. The method for preparing sitagliptin phosphate according to claim 1, characterized in that: in the first step, the dosage of the N-heterocyclic carbene-palladium catalyst is 0.2-1%, the dosage of the hydrogen source is 1-3 times of equivalent, the ee value of the enantioselectivity is more than or equal to 99.0%, and the yield is more than 90%.

3. The method for preparing sitagliptin phosphate according to claim 1, characterized in that: in the fifth step, the dosage of the N-heterocyclic carbene-palladium catalyst is 0.5-1%, the dosage of the hydrogen source is 1-3 times of equivalent, the ee value of the enantioselectivity is more than or equal to 99.0%, and the yield is more than 90%.

4. The method for preparing sitagliptin phosphate according to claim 1, characterized in that: and (4) passing the reaction liquid after the reaction in the step one through silica gel, leaching the reaction liquid with methanol, fully soaking the leached silica gel with methanol and chloroform, and evaporating the methanol and the chloroform to obtain the recycled N-heterocyclic carbene-palladium catalyst which can be used in the step five.