KR20110095672A - Preparation method of sitagliptin and amine salt intermediate used therein - Google Patents

Abstract

PURPOSE: A method for preparing sitagliptin using an intermediate is provided to prepare sitagliptin of high yield and high purity. CONSTITUTION: A method for preparing sitagliptin comprises: a step of reacting a compound of chemical formula 4 with amine of NR^1R^2R^3 and crystallizing to prepare amine salt of chemical formula 5; and a step of reacting the amine salt with trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine(TFT) to reduce a azido group. In chemical formula R^1, R^2, and R^3 are indenpendently H, C1-5 alkyl, benzyl, 1-phenyl ethyl, or 2,2-diphenyl ethyl.

Description

Method for preparing cytagliptin and amine salt intermediate used in the same {PREPARATION METHOD OF SITAGLIPTIN AND AMINE SALT INTERMEDIATE USED THEREIN}

The present invention relates to a method for preparing cytagliptin that can be used as a dietary supplement and exercise therapy adjuvant for patients with type 2 protein, and an amine salt intermediate used therein.

Cytagliptin of Formula 1 is a drug that selectively inhibits the second generation of dipeptidyl peptidase IV to maintain incretin concentration, and was in the form of cytagliptin phosphate monohydrate in October 2006. first it has been approved by the FDA as a dietary and exercise supplements the two proteins patients, is being sold as the current janyu a single agent in South Korea or the United States via (Januvia ^TM) or oral complexes Jane janu meth (Janumet ^TM) for with metformin .

[Formula 1]

Until now, various methods for preparing cytagliptin have been reported. As an example, International Patent Publication WO 2005/097733 discloses a rhodium catalyst ([Rh (cod) Cl] ₂ ) and chiral diphosphine, as shown in Scheme 1 below. Disclosed is a method for preparing cytagliptin through a process of stereoselectively reducing enamine using a ligand. However, this method requires an additional purification process of cytagliptin in order to control stereoselectivity and increase isomer purity at the end of the reaction, and the purification yield is only 72%.

Scheme 1

Accordingly, the present inventors have continued research on the economic and easy method for preparing citagliptin and its intermediates. As a result, the present inventors have found that citagliptin is efficiently purified by increasing the purity and isomer purity of the intermediate through the purification of the intermediate through amine salts. It was found that the present invention can be produced, and the present invention was completed.

International Patent Publication WO 2005 / 097733A1 (MERCK & CO., INC.) 2005.10.20.

It is therefore an object of the present invention to provide an efficient method for preparing cytagliptin and intermediates used therein.

According to the above object, the present invention comprises the steps of a) reacting a compound of formula (4) with an amine of formula NR ¹ R ² R ³ and then crystallizing to obtain an amine salt of formula (5); And b) reacting an amine salt of formula 5 with 3-trifluoromethyl-5,6,7,8-tetrahydro- [1,2,4] triazolo [4,3-a] pyrazine (TFT) It provides a method for preparing cytagliptin, and the amine salt intermediate of the general formula (5) used therein, comprising the steps of reducing the azido group after the reduction:

[Formula 4]

[Chemical Formula 5]

Wherein R ¹ , R ² and R ³ are each independently H, C _1-5 alkyl, benzyl, 1-phenylethyl or 2,2-diphenylethyl; Or N, R ¹ , R ² and R ³ are linked together in a ring to form a pyridine, piperidine, morpholine, pyrrolidine or piperazine ring.

According to the method for preparing cytagliptin according to the present invention, the purity of the intermediate and the purification process by the amine salt intermediate of (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid and By increasing the isomer purity, the cytagliptin as the target compound can be easily produced in high yield and high purity.

Hereinafter, a preferred method for preparing cytagliptin according to the present invention will be described in detail through Reaction Scheme 2 below.

Scheme 2

Wherein X is halogen; L is mesyl, tosyl, benzenesulfonyl or trifluoromethanesulfonyl; R is linear or branched C _1-5 alkyl; R ¹ to R ³ are as defined in formula (5).

Step 1

Step 1 arylated the (S) -epichlorohydrin through the Grignard reaction, and then epoxidation and vinylation reaction to sequentially (2R) -1- (2,4) , 5-trifluorophenyl) -4-penten-2-ol.

Step 1a)

First, 2,4,5-trifluorobenzene halide is organometalized for the Grignard reaction, and then a catalytic amount of copper halide (CuX) is added dropwise, and (S) -epichlorohydrin is slowly added at low temperature. By dropwise addition and arylation reaction, (2S) -3- (2,4,5-trifluorophenyl) -1-chloro-2-propanol can be produced.

The organometallization process for the Grignard reaction may be performed by reacting 2,4,5-trifluorobenzene halide with an organic halogenated alkyl such as magnesium (Mg) and 1,2-dibromoethane, or magnesium and iodine Or with isopropylmagnesium chloride ( i- PrMgCl). In this case, as the 2,4,5-trifluorobenzene halide, 2,4,5-trifluorobenzene bromide, 2,4,5-trifluorobenzene chloride, or the like may be used, and one of them alone may be used. Or two or more types can be mixed and used.

As the copper halide, CuI, CuBr, CuBrS (CH ₃ ) ₂ , or the like may be used. One of these may be used alone or in combination of two or more thereof.

In addition, the oxysilanes such as (S) -epichlorohydrin may use the (S) or (R) isomers, each of these isomers are readily available commercially.

Step 1b)

Subsequently, the prepared (2S) -3- (2,4,5-trifluorophenyl) -1-chloro-2-propanol was dissolved in an organic solvent, followed by the addition of a strong base to epoxidation reaction (2S) -2. -(2,4,5-trifluorobenzyl) -oxysilane can be prepared.

Tetrahydrofuran, diethyl ether and the like can be used as the organic solvent. In addition, as the strong base, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide and lithium hydroxide may be used, and one of these may be used alone or in combination of two or more thereof. More preferably, sodium hydroxide can be used.

Step 1c)

Subsequently, (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane prepared above is subjected to vinylation with vinylmagnesium halide in the presence of a catalytic amount of copper halide to selectively introduce a vinyl group into a terminal group. 2 (2R) -1- (2,4,5-trifluorophenyl) -4-penten-2-ol can be prepared.

As the copper halide, CuI, CuBr, CuBrS (CH ₃ ) ₂ , or the like may be used. One of these may be used alone or in combination of two or more thereof. The vinyl magnesium halide may be used vinyl magnesium bromide or vinyl magnesium chloride, one of these may be used alone or in combination of two or more. In addition, the reaction may be carried out in a solvent such as tetrahydrofuran, diethyl ether.

In this step, the reaction of step 1c may be carried out after the reaction of step 1b with or without removing the organic solvent, preferably, the reaction of step 1c is continuously performed without removing the organic solvent. The reason for this is that (2S) -2- (2,4,5-trifluorobenzyl) -oxysilane is highly volatile and evaporates with the solvent in the solvent removal process. This is because (2R) -1- (2,4,5-trifluorophenyl) -4-penten-2-ol is difficult to obtain reproducibly when the epoxidation reaction and the vinylation reaction proceed.

Step 2

Step 2 is a hydroxy group by reacting (2R) -1- (2,4,5-trifluorophenyl) -4-penten-2-ol prepared in Step 1 with an activator having a methanesulfonyl group or a tosyl group (2S) -1- (2-azido-4-pentenyl) -2,4,5-trifluorobenzene of Formula 3 by introducing azido groups by activating azido reaction Step.

The activator may be a compound having a methanesulfonyl group or a tosyl group, such as mesyl chloride, p -tosyl chloride, benzenesulfonyl chloride, trifluoromethanesulfonyl chloride, and the like. Can be mixed and used.

It is preferable to perform the said azido reaction using the compound which has azido groups, such as sodium azide.

Step 3

Step 3 is to oxidize the alkenyl group in (2S) -1- (2-azido-4-pentenyl) -2,4,5-trifluorobenzene prepared in Step 2 by using an oxidizing agent By introducing to (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid of formula (4).

As the oxidizing agent, NaIO ₄ , NaMnO ₄ , KMnO ₄ , H ₂ CrO ₄ , OsO ₄ , NaOCl, or the like may be used. One of these may be used alone or in combination of two or more thereof. At this time, the oxidizing agent is preferably used in an amount of 1 to 5 molar equivalents to 1 molar equivalent of (2S) -1- (2-azido-4-pentenyl) -2,4,5-trifluorobenzene. .

The reaction in the step 3 is preferably carried out in the presence of a catalyst, the catalyst may be used, such as RuCl ₃ , RuO ₄ , OsO ₄ , KMnO ₄ , one of these alone or mixed two or more Can be used. The catalyst is preferably used in an amount of 0.0001 to 0.1 molar equivalents relative to 1 molar equivalent of (2S) -1- (2-azido-4-pentenyl) -2,4,5-trifluorobenzene.

Step 4

Step 4 is a chemical formula (5) by reacting (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid prepared in Step 3 with various amines in an organic solvent to crystallize it. (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid amine salt is prepared.

As the amines, primary, secondary and tertiary amines may be used, and benzylamine, (R) or (S) -methylbenzylamine, 2,2-diphenylethylamine, dibenzylamine, dicyclohexylamine, 0.8 to 10 equivalents of diisopropylamine, diisopropylethylamine, diphenylamine, triethylamine, pyridine, morpholine and the like can be used.

The crystallization may be carried out in a solvent such as toluene, ethyl acetate, n-hexane, methyl butyl ether, heptane, etc., and may be used alone or in combination of two or more thereof.

Step 5

Step 5 was prepared by (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid amine salt of formula 5 prepared in step 4 3-trifluoromethyl-5,6 Reaction with (7,8-tetrahydro- [1,2,4] triazolo [4,3-a] pyrazine (TFT) to give (3R) -3-azido-1- (3-trifluoro) Rommethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -4- (2,4,5-trifluorophenyl)- Step of preparing butan-1-one.

In this step, before the condensation reaction with TFT, the compound of formula 5 is removed with amine salt under inorganic or organic acid conditions and (3R) -3-azido-4- (2,4,5-trifluoro) by carboxyl activator. The step of activating the carboxyl group in rophenyl) -butyric acid is preferred.

At this time, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and the like can be used as the inorganic acid, and formic acid, acetic acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid and the like can be used as the organic acid. The carboxyl group activator may be thionyl chloride, oxalyl chloride, phosphoryloxychloride, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide (EDC), N, N'-dicyclohexylcar Bodyimide (DCC), 1,1'-carbonyldiimidazole (CDI), DCC and 1-hydroxybenzotriazole (HOBt), DCC and 1-hydroxysuccinimide, and the like, may be used. It can be used individually by 1 type or in mixture of 2 or more types.

Step 6

Step 6 comprises (3R) -3-azido-1- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3 prepared in step 5 above. -a] pyrazin-7-yl) -4- (2,4,5-trifluorophenyl) -butan-1-one reduces the azido group to produce cytagliptin.

In this case, as a reducing agent for reducing azido groups, PPh ₃ / H ₂ O, PPh ₃ / HCl, PPh ₃ / NH ₄ OH, PPh ₃ / H ₂ S, etc. may be used, and Raney Ni, Pd, Pt, Pd / In the presence of metal catalysts such as C, Pd / Al ₂ O ₃ , Pd (OH) ₂ / C, hydrogen, HCOOH, (NH ₄ ) O ₂ H, NH ₂ NH ₂ , BH ₃ , NaBH ₄ , Zn and HCl, etc. May be used as the reducing agent.

The cytagliptin thus prepared may be further reacted with phosphoric acid or the like to prepare a phosphate salt.

In the conventional cytagliptin synthesis method, an additional purification process is required to increase the purity and isomer purity of the cytagliptin, and thus the yield is greatly reduced. However, when the purification process through (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid amine salt is introduced as in the present invention, the purity of the intermediate and the isomer purity are 98%. In addition, it can be increased to 99.8% ee, which is advantageous in that cytagliptin can be synthesized in high yield without further purification to increase isomer purity.

Accordingly, the present invention provides purity of the intermediate through the purification process by the amine salt of (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid, which can be made at low cost. And by increasing the isomer purity, the cytagliptin as the target compound can be easily produced in high yield and high purity.

In addition, the (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid amine salt of Formula 5 used as an intermediate in the method for preparing cytagliptin according to the present invention itself It is a novel compound. Accordingly, the present invention also provides these compounds.

Preferred amine salt intermediates include (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid (R) -methylbenzylamine salt of formula 5a, or 3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid (S) -methylbenzylamine salt

[Formula 5a]

[Formula 5b]

Example

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1: Preparation of 1-chloro-3- (2,4,5-trifluorophenyl)-(2S) -propanol

25 g of 2,4,5-trifluorobenzene bromide was added dropwise to 75 mL of tetrahydrofuran (THF) under nitrogen atmosphere. After cooling to −20 ° C. 60.4 mL of 2M i-PrMgCl (in THF) was added for 10 minutes. At this time, the temperature was maintained at 0 to 3 ° C. After cooling to −10 ° C. for 1 hour, 1.81 g of Cu (I) I was added. After further stirring at the same temperature for 30 minutes, 13.9 mL of (S) -epichlorohydrin diluted in 13.9 mL of THF was added dropwise for 30 minutes. Stirred at −10 ° C. for 1.5 hours, heated to 0 ° C. and further stirred for 1 hour. 250 mL of 2N HCl was added, followed by stirring at room temperature for 30 minutes. 125 mL of dichloromethane (MC) was added thereto, the organic layer was separated, and washed twice with 250 mL of water. The organic layer was dried over anhydrous MgSO ₄ , filtered, and the organic solvent was removed under reduced pressure to obtain 26.6 g of the target compound (yield: 100%).

¹ H-NMR (300 MHz, CDCl ₃ ): δ 7.17-7.08 (1H, m), 6.96-6.88 (1H, m), 4.11-4.01 (1H, m), 3.66 (1H, dd, J = 7.6, 11.3 ), 3.49 (1H, dd, J = 7.6, 11.3), 2.93-2.78 (2H, m), 2.39 (1H, d, J = 5.3)

Example 2: Preparation of (2R) -1- (2,4,5-trifluorophenyl) -4-penten-2-ol

Step 1) 26.6 g of 1-chloro-3- (2,4,5-trifluorophenyl)- ( 2S ) -propanol prepared in Example 1 and 53.2 mL of methanol were added to the reactor, followed by stirring. 35.6 mL of 5N NaOH was slowly added for 20 minutes and then stirred for 15 minutes. After confirming that the TLC phase reaction was completed, 266 mL of H ₂ O and 79.8 mL of n-hexane were added. The water layer was extracted once more with 53.2 mL of n-hexane, and the organic layers were collected and washed three times with 106 mL of water. The organic layer was dried over anhydrous MgSO ₄ and filtered, and then 133 mL of n-hexane was further used.

Step 2) 66.5 mL of THF was added to the filtered solution and then cooled to −20 ° C. under a nitrogen atmosphere. After addition of 1.13 g of Cu (I) I, 1.6M vinylmagnesium bromide (in THF) was slowly added dropwise for 1 hour. After further stirring for 30 minutes, after confirming that the TLC phase reaction was completed, the temperature was raised to 0 ° C. 266 mL 2N HCl was added and stirred at room temperature for 30 minutes. The organic layer was separated and washed three times with 266 mL of water. The organic layer was dried over anhydrous MgSO ₄ , filtered, and the organic solvent was removed under reduced pressure to obtain 23.8 g of the target compound (yield: 93%, purity: 95%, isomer purity: 99.2% ee).

¹ H-NMR (300MHz, CDCl ₃ ): δ 7.15 ~ 7.06 (1H, m), 6.94 ~ 6.86 (1H, m), 5.85 ~ 5.79 (1H, m), 5.20 ~ 5.14 (2H, m), 3.90 ~ 3.85 (1H, m), 3.82 (1H, dd, J = 4.6, 18.5), 2.69 (1H, dd, J = 7.9, 14.0), 2.37-2.32 (1H, m), 2.24-2.17 (1H, m) , 1.86 (1H, Br)

Example 3: Preparation of (2S) -1- (2-azido-4-pentenyl) -2,4,5-trifluorobenzene

Step 1) 23.98 g of (2R) -1- (2,4,5-trifluorophenyl) -4-penten-2-ol prepared in Example 2 and 150 ml of ethyl acetate were added to a reactor under a nitrogen atmosphere. Then cooled to 0 ° C. 16.59 mL of triethylamine and 1.39 g of 4-dimethylaminopyridine (DMAP) were added sequentially, followed by dropwise addition of 9.21 mL of methanesulfonic acid for 15 minutes. After confirming that the TLC phase reaction was completed, 240 mL of water was added and the organic layer was separated. Wipe with 24 mL of 1N HCl and 120 mL of water, and washed twice with 240 mL of brine. The organic layer was dried over anhydrous MgSO ₄ , filtered and the organic solvent was removed under reduced pressure.

Step 2) The obtained residue was dissolved in 120 mL of DMF, and then mixed with 9.58 g of NaN ₃ dissolved in 36 mL of water. After warming to 75 ° C., the mixture was stirred for 2 hours and cooled to room temperature after confirming that the TLC phase reaction was completed. 240 mL of water and 120 mL of n-hexane were added to separate an organic layer, and the mixture was washed twice with 240 mL of water. After drying over anhydrous MgSO ₄ and filtering, the organic solvent was removed under reduced pressure to give the target compound 25.3g (yield: 94%).

¹ H-NMR (300MHz, CDCl ₃ ): δ 7.11 ~ 7.02 (1H, m), 7.97 ~ 6.87 (1H, m), 5.89 ~ 5.80 (1H, m), 5.23 ~ 5.17 (1H, m), 3.63 ~ 3.59 (1H, m), 2.87 (1H, dd, J = 4.7, 18.7), 2.68 (1H, dd, J = 7.9, 13.7), 2.38-2.17 (2H, m)

Example 4: Preparation of (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid

At room temperature, 65.26 g of potassium permanganate and 149 mL of water were dissolved in a reactor, and then 149 mL of acetone was added and stirred for 30 minutes. 24.9 g of (2S) -1- (2-azido-4-pentenyl) -2,4,5-trifluorobenzene prepared in Example 3 after cooling to -20 ° C. and dissolved in 74.5 mL of acetone. Was added slowly for 1 hour. At this time, the reaction temperature did not exceed -10 ° C. After 2 hours of stirring at -20 ° C, 500 mL of 6N HCl and 250 mL of ethyl acetate (EA) were added thereto, followed by stirring for 1.5 hours. The organic layer was separated, extracted with excess 100 mL of EA, and the organic solvent of the organic layer was removed under reduced pressure. The obtained residue was dissolved in 250 mL of EA and washed three times with 250 mL of water. The organic layer was dried over anhydrous MgSO ₄ , filtered and the organic solvent was removed under reduced pressure to give 26.2 g of the target compound (yield: 98%, purity: 82%, isomer purity: 96.6% ee).

¹ H-NMR (300MHz, CDCl ₃ : δ 10.5 (1H, br), 7.17 ~ 7.05 (1H, m), 7.02 ~ 6.87 (1H, m), 4.14 ~ 4.03 (1H, m), 2.94 ~ 2.78 (2H , m), 2.65-2.51 (2H, m)

Example 5: Preparation of (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid (R) -methylbenzylamine salt

20 g of (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid prepared in Example 4 was added dropwise to 66.9 mL of EA. 13.2 mL (R) -methylbenzylamine (MBA) was added slowly over 15 minutes. After stirring for 10 minutes, 214 mL of n-hexane was added slowly to give a solid, which was filtered after 1 hour. The resultant was dried for 12 hours in an oven at 40 ° C. to obtain 22.0 g of the target compound (yield: 75%, purity: 98%, isomer purity: 99.8% ee).

¹ H-NMR (300 MHz, CDCl ₃ : δ 7.61 (COOH, br), 7.39-7.28 (5H, m), 7.01-6.90 (2H, m), 4.25-4.18 (1H, m), 3.81-3.72 (1H , m), 2.69 (1H, dd, J = 14.0, 4.8), 2.48 (1H, dd, J = 14.0, 5.6), 2.08 (2H, d, J = 6.7), 1.52 (3H, d, J = 6.8 )

Example 6: Preparation of (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid 2,2-diphenylethylamine salt

EA 21 mL of 3.0 g of (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid (purity: 82%, isomer purity: 96.6% ee) prepared in Example 4 Was added drop wise. 2.28 g of 2,2-diphenylethylamine was added and stirred for 1 hour, and then the resulting solid was filtered. The resultant was dried for 12 hours in an oven at 40 ° C. to obtain 4.17 g of the target compound (yield: 60%, purity: 98.8%, isomer purity: 99.7% ee).

¹ H-NMR (300MHz, CDCl ₃ : δ 7.34 ~ 7.03 (10H, m), 7.17 ~ 7.01 (1H, m), 6.94 ~ 6.88 (1H, m), 4.18 (1H, t), 3.95 (1H, m ), 3.38 (2H, d, J = 8.0), 2.83 (1H, dd, J = 14.2, 5.1), 2.71 (1H, dd, J = 14.2, 8.3), 2.33 (2H, m)

Example 7: Preparation of (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid dibenzylamine salt

3.0 g of (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid (purity: 82%, isomer purity: 96.6% ee) prepared in Example 4 was prepared in EA 7.5. was added dropwise to mL. 2.24 mL of dibenzylamine was added slowly over 15 minutes. After stirring for 10 minutes, 22.5 mL of n-hexane was added slowly to give a solid, which was filtered after 1 hour. The resultant was dried for about 12 hours in an oven at 40 ° C. to obtain 4.1 g of the target compound (yield: 78%, purity: 98.5%, isomer purity: 98.0% ee).

¹ H-NMR (300MHz, CDCl ₃ : δ 7.38 ~ 7.26 (10H, m), 7.17 ~ 7.01 (1H, m), 6.94 ~ 6.88 (1H, m), 4.00 (1H, m), 3.87 (4H, S ), 2.85 (1H, dd, J = 14.2, 5.2), 2.72 (1H, dd, J = 14.2, 8.3), 2.42 (2H, d, J = 7.1)

Example 8: (3R) -3-azido-1- (3-trifluoromethyl-5,6-dihydro-8 H Preparation of [[1,2,4] triazolo [4,3-a] pyrazin-7-yl) -4- (2,4,5-trifluorophenyl) -butan-1-one

Step 1) 31.2 g of (3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid (R) -methylbenzylamine salt prepared in Example 5 was added to 218 mL of dichloromethane. After melting, 156mL of 2N HCl was added thereto and stirred. The organic layer was separated, washed three times with 312 mL of water, dried over anhydrous MgSO ₄ , and filtered.

Step 2) 12.0 mL of thionyl chloride and 0.64 mL of DMF were added to the solution, followed by refluxing for 3 hours. After confirming that the NMR phase reaction was completed, the remaining thionyl chloride and solvent were removed under reduced pressure.

Step 3) 100 mL of MC was added to dissolve the residue. This solution was saturated bicarbonate in which 11.4 g of 3-trifluoromethyl-5,6,7,8-tetrahydro- [1,2,4] triazolo [4,3-a] pyrazine hydrochloride was dissolved at 10 캜 or lower. It was slowly added dropwise to 100 ml of sodium solution. After stirring for 1 hour at room temperature, the water layer was removed. The organic layer was dried over anhydrous MgSO ₄ , filtered, and the organic solvent was removed under reduced pressure to obtain 33.8 g of the target product (yield: 95%).

¹ H-NMR (300MHz, CDCl ₃ : δ 7.20 ~ 7.11 (1H, m), 6.99 ~ 6.90 (1H, m), 5.20 ~ 4.96 (2H, m), 4.28 ~ 4.05 (5H, m), 2.98 ~ 2.67 (4H, m)

Example 9: Preparation of Cytagliptin

Methyl in the Example 8 the (3R) -3- azido-1- (3-trifluoromethyl prepared from 5,6-dihydro -8 H - [1,2,4] triazolo [4,3- a] To 33.6 g of pyrazin-7-yl) -4- (2,4,5-trifluorophenyl) -butan-1-one, 22.4 g of triphenylphosphine and 336 mL of THF were added, and the temperature was increased to 50 ° C. . After stirring for 2 hours, 101 mL of ammonia water was added and stirred for 10 hours. After THF was removed under reduced pressure, 168 mL of 2N HCl and 336 mL of EA / n-hexane (5: 3) mixed solvent were added and stirred. After separating the layers, the water layer was washed three times with 336 mL of an EA / n-hexane (5: 3) mixed solvent. After neutralization by adding 16.8 mL of ammonia water to the water layer, the mixture was extracted three times with EA 168 mL. The organic layer was dried over anhydrous MgSO ₄ , filtered, and the organic solvent was removed under reduced pressure to obtain 37.3 g of the target compound (yield: 90%, purity: 99.7%, optical purity: 99.8% ee).

¹ H-NMR (300 MHz, CDCl ₃ : δ 7.14-7.06 (1H, m), 7.00-6.88 (1H, m), 5.13-4.88 (2H, m), 4.24-3.80 (4H, m), 3.58 (1H , m), 2.85-2.66 (2H, m), 2.61-2.46 (2H, m), 2.11 (3H, br)

Example 10 Preparation of Cytagliptin Phosphate Salts

17.5 g of cytagliptin prepared in Example 9 was dissolved in 220 mL of IPA and 18 mL of H ₂ O. After adding 5.6 mL of phosphoric acid slowly, the temperature was raised to 70 ° C. and stirred for 3 hours. After cooling to room temperature and stirring for about 10 hours, the resulting solid was filtered. The resultant was air-dried for about 12 hours at 40 ℃ drying oven to obtain 20.3 g of the target compound (yield: 95%).

¹ H-NMR (300MHz, D ₂ O: δ 7.23 ~ 7.10 (1H, m), 7.08 ~ 7.00 (1H, m), 4.88 ~ 4.78 (2H, m), 4.25 ~ 4.17 (2H, m), 3.97 ~ 3.89 (3H, m), 3.02-2.77 (4H, m)

Claims (13)

a) reacting a compound of Formula 4 with an amine of Formula NR ¹ R ² R ³ and then crystallizing to obtain an amine salt of Formula 5; And
b) reacting an amine salt of formula 5 with 3-trifluoromethyl-5,6,7,8-tetrahydro- [1,2,4] triazolo [4,3-a] pyrazine (TFT) A method for preparing cytagliptin, comprising the step of reducing the following azido groups:
[Chemical Formula 4]

[Chemical Formula 5]

Wherein R ¹ , R ² and R ³ are each independently H, C _1-5 alkyl, benzyl, 1-phenylethyl or 2,2-diphenylethyl; Or N, R ¹ , R ² and R ³ are linked together in a ring to form a pyridine, piperidine, morpholine, pyrrolidine or piperazine ring.
The method of claim 1,
In step a), the amine of the formula NR ¹ R ² R ³ may be selected from benzylamine, (R) -methylbenzylamine, (S) -methylbenzylamine, 2,2-diphenylethylamine, dibenzylamine, dicyclo Hexylamine, diisopropylamine, diisopropylethylamine, diphenylamine, triethylamine, pyridine or morpholine, The process for producing citagliptin.
The method of claim 1,
The amine of the formula NR ¹ R ² R ³ in step a) is used in the amount of 0.8 to 10 molar equivalents to 1 molar equivalent of the compound of Formula 4, the method for producing citagliptin.
The method of claim 1,
The crystallization of step a) is carried out in at least one organic solvent selected from the group consisting of toluene, ethyl acetate, n-hexane, methyl butyl ether and heptane, the method for producing citagliptin.
The method of claim 1,
Reduction in the step b), characterized in that carried out using a reducing agent selected from the group consisting of PPh ₃ / H ₂ O, PPh ₃ / HCl, PPh ₃ / NH ₄ OH, and PPh ₃ / H ₂ S Method for producing cytagliptin.
The method of claim 1,
The compound of Formula 4 is prepared by activating the hydroxyl group of the compound of the formula (2), and then prepared by oxidizing azido, characterized in that the preparation method for cytagliptin:
(2)

The method of claim 6,
The hydroxyl group activation of the compound of Formula 2 is carried out using an activator selected from the group consisting of mesyl chloride, p -tosyl chloride, benzenesulfonyl chloride, trifluoromethanesulfonyl chloride and mixtures thereof. Method for producing cytagliptin.
The method of claim 6,
The oxidation reaction is carried out using an oxidizing agent selected from the group consisting of NaIO ₄ , NaMnO ₄ , KMnO ₄ , H ₂ CrO ₄ , OsO ₄ , NaOCl, and mixtures thereof, a method for producing cytagliptin .
The method of claim 6,
Compound of Formula 2,
i) organometallizing the 2,4,5-trifluorobenzene halide and subsequently reacting with copper halide and (S) -epichlorohydrin;
ii) epoxidation of the product of step i) using a strong base in an organic solvent; And
iii) a method of producing citagliptin, characterized in that it comprises the step of reacting the product of step ii) with vinylmagnesium halide in the presence of copper halide.
10. The method of claim 9,
Step iii) is carried out without removing the organic solvent after the reaction of step ii), a method for producing cytagliptin.
10. The method of claim 9,
The strong base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and mixtures thereof; The copper halide is selected from the group consisting of CuI, CuBr, CuBrS (CH ₃ ) ₂ and mixtures thereof; The vinyl magnesium halide is selected from the group consisting of vinyl magnesium chloride, vinyl magnesium bromide and mixtures thereof, a method for producing citagliptin.
(3R) -3-azido-4- (2,4,5-trifluorophenyl) -butyric acid amine salt of formula (5):
[Chemical Formula 5]

Wherein R ¹ , R ² and R ³ are each independently H, C _1-5 alkyl, benzyl, 1-phenylethyl or 2,2-diphenylethyl; Or N, R ¹ , R ² and R ³ are linked together in a ring to form a pyridine, piperidine, morpholine, pyrrolidine or piperazine ring.
The method of claim 12,
(3R) -3-azido-4- (2,4,5-trifluorophenyl), characterized in that the amine salt is (R) -methylbenzylamine salt or (S) -methylbenzylamine salt. Butyric acid amine salt.