KR20160146124A

KR20160146124A - Improved method of sitagliptin

Info

Publication number: KR20160146124A
Application number: KR1020150082814A
Authority: KR
Inventors: 정헌석; 송태흥; 장도연; 이유진
Original assignee: 동방에프티엘(주)
Priority date: 2015-06-11
Filing date: 2015-06-11
Publication date: 2016-12-21
Also published as: KR101772898B1

Abstract

The present invention relates to an improved process for the preparation of citagliptin, comprising the steps of preparing and deprotecting N- Boc protected sytagliptin using a diphenyl phosphite suitable for mass production processes as a reaction reagent .

Description

Improved method of sitagliptin < RTI ID = 0.0 >

The present invention relates to an improved process for the preparation of citagliptin.

Sitagliptin is the first DPP-IV inhibitor for the treatment of type 2 diabetes. The chemical structure of sitagliptin is represented by the following chemical formula 1, and the compound name is (R) -3-amino-1- (3- (trifluoromethyl) -5,6- ] triazolo [4,3- a] pyrazin -7 (8 H) - yl) -4- (2,4,5-trifluorophenyl a) butane-1-one.

[Chemical Formula 1]

Currently, a single formulation of citriptyl phosphate monohydrate is marketed under the trade name Januvia (TM).

Citagliptin was first disclosed in International Patent Publication No. WO2003-004498 (Patent Document 1). In the above Patent Document 1, as shown in the following Reaction Scheme 1, a step (i) of coupling an N- Boc-protected compound represented by the following formula (2) with a triazolepiperazine hydrochloride represented by the following formula Boc protected < RTI ID = 0.0 > cyproglitin < / RTI > And (ii) deprotecting the N- Boc-protected sytagliptin represented by the following general formula (4) to produce sitagliptin represented by the following general formula (1); To prepare cytarglytine. &Lt; Desc / Clms Page number 2 >

[Reaction Scheme 1]

(In the above Reaction Scheme 1, Boc represents tert -butoxycarbonyl group)

In the above Patent Document 1, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) was used as a carboxyl activating agent in the coupling reaction (i step) 1-hydroxybenzotriazole (HOBT) is used. Although the EDC reagent is frequently used in the field of organic synthesis, it is disadvantageous in that it is inexpensive and less reactive because it is a very expensive reagent which is unsuitable for mass production. The HOBT anhydrides that are used together are explosive and therefore present a very large hazard in handling. As a result, according to Patent Document 1, the coupling reaction time is long for about 14 hours, and the yield of the obtained product is very low, which is less than 40%, which is not suitable for commercial mass production.

International Patent Publication No. WO2009-064476 (Patent Document 2) discloses a process for the coupling reaction (step (i)) of the N- Boc-protected compound represented by Chemical Formula 2 and the triazolepiperazine hydrochloride represented by Chemical Formula 3 Discloses a method using N, N' -dicyclohexylcarbodiimide (DCC), dimethylaminopyridine (DMAP) and triethylamine (TEA). In Patent Document 2, it is meaningful to propose a coupling reaction condition that excludes the use of expensive EDC and the use of HOBT having explosive property, but the DCC which is used alternately is a substance which is allergen to the human body and is very harmful to workers. Then, the by-product that would be produced by using the reagent DCC N, N'- dicyclohexyl urea by its solubility in the actual synthesis is very similar to the N- Boc-protected sitagliptin represented by Formula 4 N, N'- Since it is difficult to remove dicyclohexylurea by-products, there is a fatal disadvantage that the final product purity is lowered. The coupling reaction time using the DCC reagent takes about 12 hours or more.

International Patent Publication No. WO2012-099381 (Patent Document 3) discloses a process for the coupling reaction (step (i)) of the N- Boc-protected acid compound represented by Formula 2 and the triazolepiperazine hydrochloride represented by Formula 3 Discloses a method using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N -methylmorpholine. Patent Document 3 is a very effective method because the reaction time is as short as about 1 hour, but CDMT has a limitation in commercial use as an expensive reagent.

Also, in International Patent Publication No. WO2014-023930 (Patent Document 4), a coupling reaction (Step (i)) of the N- Boc-protected acid compound represented by Formula 2 and the triazolepiperazine hydrochloride represented by Formula 3 is carried out As a condition, a method of using a phenylboronic acid derivative is disclosed. According to Patent Document 4, there is a disadvantage that the reflux reaction must be performed in a high-boiling solvent for a long time due to the low reactivity of the phenylboronic acid derivative.

The coupling reaction conditions shown in the above Patent Documents 1 to 4 are briefly summarized in Table 1 below.

division Reaction reagent Reaction temperature /
Reaction time Remarks Patent Document 1 EDC,
HOBT At room temperature /
14 hours Use expensive or explosive hazard reagents Patent Document 2 DCC At room temperature /
15 hours Use of harmful reagents
Byproducts are difficult to separate Patent Document 3 CDMT At room temperature /
More than 1 hour Use expensive reagent Patent Document 4 2-chlorophenylboronic acid Reflux temperature /
48 hours The reaction temperature is high and the reaction time is too long.

As shown in Table 1, there are disadvantages that the reagent used in the coupling condition (step i) of the above reaction scheme 1 is expensive, there is a danger of explosion, or the reactivity is low and the reaction temperature is high and the reaction time is long have.

As another manufacturing method, International Patent Publication No. WO2004-087650 (Patent Document 5) discloses a process for producing an N- OBn protected compound represented by the following formula (2a) and a triazolopiperazine or its hydrochloride to the coupling reaction condition as for preparing N- OBn protected sitagliptin, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC-HCl) and N- methyl morpholine (NMM) is used.

[Reaction Scheme 2]

(In the above Reaction Scheme 2, OBn represents a benzyloxy group)

However, the method of Patent Document 5 also uses an expensive EDC reagent. Further, in order to remove the benzyloxy group (BnO) used as the amine protecting group, expensive Pd / C catalyst and high pressure , The production cost is increased and the price competitiveness is deteriorated.

International Patent Publication No. WO2003-004498 International Patent Publication No. WO2009-064476 International Patent Publication No. WO2012-099381 International Patent Publication No. WO2014-023930 International Patent Publication No. WO2004-087650

The present invention relates to a process for the preparation of sitagliptin comprising the steps of preparing and deprotecting N- Boc-protected sitagliptin, wherein a reaction reagent suitable for on-site production is selectively used to maximize reactivity under mild reaction conditions It is a primary object to provide a method for producing improved citagliptin.

In detail, the present invention relates to a process for preparing N- Boc-protected cyproglitine, which comprises the steps of: (1) reacting diphenyl phosphite suitable for mass- Lt; RTI ID = 0.0 > of Lipine. &Lt; / RTI >

In order to solve the above-mentioned problems, the present invention is characterized by a process for producing cigulgiptin comprising the following steps:

(I) at least one amine base selected from the group consisting of tri (C ₁ -C ₆ alkyl) amine, N- (C ₁ -C ₆ alkyl) morpholine, pyridine, and quinoline and diphenylphosphite (DPP) under the presence, to the N- Boc-protected Acid N- Boc-protected sitagliptin represented by the compound and to, the following formulas 4 to the triazolo piperazine hydrochloride coupling reaction represented by the formula (3) represented by the formula (2) Producing; And

(In the above, Boc represents tert -butoxycarbonyl group)

(Ii) deprotecting the N- Boc-protected cyproglitine represented by the following formula (4) with hydrochloric acid to prepare cytarglyptin represented by the following formula (1).

(In the above, Boc represents tert -butoxycarbonyl group)

Further, the present invention relates to a method for preparing cyproglitine, which further comprises crystallizing N- Boc-protected cyproglitine of formula (4) as described above to purify by isopropyl alcohol (step (i-1) .

The present invention also relates to a process for preparing cytarglyphine phosphate monohydrate by reacting cytargyline represented by the above formula (1) in an aqueous solution of isopropyl alcohol and phosphoric acid at a temperature of 40 ° C to 90 ° C (step iii); Which is obtained in the form of a phosphate by further performing the method of the present invention.

The present invention relates to a coupling reaction for the preparation of N- Boc-protected cyproglitine represented by Chemical Formula 4, which is a key intermediate of citagliptin, which is harmless to the human body, easy to handle, it is possible to select the diphenyl phosphite and optimize the reaction conditions to complete the coupling reaction at a high yield in a short reaction time even under mild conditions.

Therefore, the production method of the present invention is useful for mass production of citagliptin.

Hereinafter, the method for preparing Citagliptin according to the present invention will be described in more detail.

(Step i) coupling an N- Boc protected acid compound represented by the following formula 2 with a triazolepiperazine hydrochloride represented by the following formula 3 to obtain an N- Boc protected sytagliptin represented by the following formula 4 .

(In the above, Boc represents tert -butoxycarbonyl group)

In the coupling reaction, EDC, DCC, CDMT, phenylboronic acid derivatives and the like have been used as a carboxyl activator in the conventional method, but most of the reagents are expensive or have low reactivity and should be reacted at a high temperature and for a long time And the like. In order to overcome such disadvantages, the present invention is characterized in that the coupling reaction is carried out in the presence of diphenyl phosphite (DPP) represented by the following general formula (5) and an amine base.

[Chemical Formula 5]

The amount of diphenyl phosphite represented by the formula 5, based on the N- Boc-protected Acid compound of formula (2) is from 1: 1 to 2 mole ratio, preferably 1: 1 to 1.5 molar ratio, to more preferably Can be used in a molar ratio of 1: 1 to 1.2.

In the coupling reaction, an amine base is used for the purpose of further improving the reactivity. The amine base may include at least one member selected from tri (C ₁ -C ₆ alkyl) amine, N- (C ₁ -C ₆ alkyl) morpholine, pyridine, quinoline and the like. Specific examples of the amine base include trialkylamines such as trimethylamine, triethylamine and triisopropylamine; Morpholines such as N -methylmorpholine and N- propylmorpholine; And aromatic amines such as pyridine, quinoline, and the like. The amount of the amine base used may be in the range of 1: 6 to 9 molar ratio based on the N- Boc protected acid compound represented by the formula (2).

Also, the N- Boc protected compound represented by the above formula (2) and the triazolepiperazine hydrochloride represented by the above formula (3), which are used as a starting material in the coupling reaction, are known compounds. The stoichiometric reaction molar ratio between the starting materials is 1: 1, and in view of the efficiency of the reaction, it is preferable to use the triazolepiperazine hydrochloride represented by the formula 3 in an amount of 1.1-1.5 molar ratio in an excess amount.

In addition, the coupling reaction proceeds smoothly in the range of -10 ° C to 35 ° C. However, considering the commercial mass production, it is preferable to conduct the reaction at a temperature around room temperature (approximately 10 ° C to 30 ° C).

When the coupling reaction is carried out under the above reaction conditions, the reaction can be completed within 1 hour.

(Step i-1) The N- Boc-protected sytagliptin of Formula 4 prepared by the coupling reaction is purified by recrystallization.

The solvent used for recrystallization may be selected from alcohols such as methanol, ethanol and isopropyl alcohol, halogenated hydrocarbons such as dichloromethane, aliphatic hydrocarbons such as hexane, nitriles such as acetonitrile, ethers such as tetrahydrofuran and the like At least one selected from the group consisting of Preferably, the recrystallization solvent is an alcohol solvent, particularly preferably isopropyl alcohol. In addition, the crystallization method can be carried out by a method commonly used by a person skilled in the art.

In the present invention, by further performing the purifying step by recrystallization, it is possible to obtain an effect of further improving the yield and purity of the target in the subsequent deprotection reaction or phosphorylation reaction.

(Ii) deprotecting the N- Boc-protected cyproglitine represented by the following formula (4) to prepare cyproglitine represented by the following formula (1).

(In the above, Boc represents tert -butoxycarbonyl group)

In the present invention, hydrochloric acid (HCl), trifluoroacetate (CF ₃ COOH), hydrofluoric acid the tert introduced simply as an amine protecting group using an acid (acid) selected from the group consisting of (HF), etc.-butoxy carbonyl group (Boc) Can be removed. The specific deprotection method can be carried out by a method commonly used by those skilled in the art.

(Step iii) is a step for preparing the phosphate monohydrate of cyglaginin represented by the above formula (1). Specifically, Citagliptin represented by Formula 1 is placed in a mixed solution of isopropyl alcohol and an aqueous solution of phosphoric acid and reacted at 40 ° C to 90 ° C to prepare citagliptine phosphate monohydrate. In the present invention, it is possible to obtain cytarglyptin or cytarglyphine phosphate monohydrate as a high-yield and high-purity substance through the intermediate synthesis process of the above-described formula (4) using diphenyl phosphite.

The present invention as described above will be described in more detail based on the following examples. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.

[Example]

Example 1. Preparation of N- Boc protected cytarglyptin

A flask (R) -3- - a (tert-butoxycarbonylamino) -4- (2,4,5-trifluorophenyl) butanoic noik Acid (3.0 g, 9.00 mmol), pyridine (6.0 mL, 8.3 mmol After dropwise addition of diphenylphosphite (DPP; 1.90 mL, 9.90 mmol) to the mixture over 10 min and stirring at room temperature for 30 min, 3- (trifluoromethyl) -5,6,7,8- Tetrahydro [l, 2,4] triazolo [4,3- a ] pyrazine hydrochloride (2.26 g, 9.90 mmol) was added and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed by TLC, dichloromethane (6 mL) and purified water (6 mL) were added. After stirring at room temperature for 30 minutes, the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate (0.1 g), concentrated under reduced pressure, and then crystallized with isopropyl alcohol (9 mL) to give the title compound (3.81 g, 83.37%).

Example 2. Preparation of sitagliptin

To the methanol (11 mL) was added N- Boc protected sitagliptin (3.81 g, 7.51 mmol) and c-HCl (1.6 mL, 52.56 mmol) was added dropwise at 15 ° C or lower for 10 minutes, And the mixture was stirred for 3 hours. After completion of the reaction was confirmed by TLC, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was fractionated using ethyl acetate (8 mL), purified water (2 mL) and 1 N aqueous sodium hydroxide solution (11 mL). The aqueous layer was extracted with ethyl acetate (4 mL X 2 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (2.93 g, 95.81%).

Example 3. Preparation of Citergliptine Phosphate Monohydrate

Citraglitine (2.93 g, 7.19 mmol) was added to isopropanol (20 mL) and an aqueous 85% (w / w) phosphoric acid solution (0.85 g, 8.63 mmol) was added dropwise. The temperature of the reaction product was raised to 75 캜, stirred for 3 hours, cooled to room temperature, stirred for 16 hours, and filtered under reduced pressure. Isopropanol (5.9 mL) and purified water (5.9 mL) were added to the obtained wet cake, and the temperature was raised to 45 ° C to dissolve all of the solid. The reaction solution was stirred at 45 캜 for 30 minutes, then cooled to room temperature, stirred for 1 hour, cooled to 0 to 3 캜 and stirred for further 2 hours and then filtered under reduced pressure to obtain the title compound (3.13 g, 83.21% &Lt; / RTI >

Comparative Example 1. Preparation of N- Boc protected cytarglyptin (see International Patent Publication No. WO2003-004498)

(50.1 mg, 0.15 mmol) and 3- (4-chloro-phenyl) -thiazole were added to a solution of (3R) -3 - [(1,1- dimethylethoxy- (trifluoromethyl) -5,6,7,8-tetrahydro-1,2,4-triazolo [4,3- a] was added to dichloromethane (5 mL) to pyrazine (39.2 mg, 0.20 mmol) Was added 1-hydroxybenzotriazole (HOBT; 54.5 mg, 0.42 mmol) at 0 ° C. The reaction was stirred at 0 < 0 > C for 10 min, then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC; 96.6 mg, 0.50 mmol) was added. The ice bath was removed and the reaction was stirred at ambient temperature for 14 hours. The mixture was concentrated and the product was purified by flash chromatography (silica gel, 100% ethyl acetate) to give the title compound as a solid (29 mg, 38.02%).

Comparative Example 2. Preparation of N- Boc protected cytarglyptin (see International Patent Publication No. WO2009-064476)

(40 g, 0.12 mol) was added to a solution of (3R) -3 - [(1,1-dimethylethoxy-carbonyl) -amino] -4- (2,4,5-trifluorophenyl) Was dissolved in dimethylformamide (240 mL), and the mixture was stirred in a cold water bath for 30 minutes. In another flask, N, N' -dicyclohexylcarbodiimide (DCC; 32.21 g, 0.16 mol) was dissolved in dimethylformamide to prepare 200 mL of DCC solution. DCC solution (70 mL) was slowly added to a solution of (3R) -3 - [(1,1-dimethylethoxy-carbonyl) -amino] -4- (2,4,5-trifluorophenyl) And added dropwise to a solution of 3- (trifluoromethyl) -5,6,7,8-tetrahydro-1,2,4-triazolo [4,3- a ] pyrazine hydrochloride (32.94 g, 0.14 mol) and triethylamine g, 0.24 mol) was added and stirred for 10 minutes. 4-Dimethylaminopyridine (8.8 g, 0.07 mol) was added to the reaction solution, 65 mL of DCC solution was slowly added dropwise, and the reaction solution was stirred overnight at room temperature. The mixture was filtered under reduced pressure and washed with dimethylformamide (50 mL x 2), then the solvent was concentrated and extracted with ethyl acetate (1400 mL). The organic layer was washed sequentially with 5% citric acid (90 mL), 10% citric acid (60 mL), saturated sodium bicarbonate (100 mL) and dried over anhydrous sodium sulfate. The mixture was concentrated to give a beige solid. To the solid was added isopropanol (300 mL) and refluxed to completely dissolve to obtain a yellow solution. The solution was cooled to room temperature and stirred overnight. Upon completion of the reaction, the reaction mixture was filtered under reduced pressure, and the filtrate was washed with isopropanol and dried at 40 DEG C overnight to obtain the title compound (52 g, 85%).

Comparative Example 3. Preparation of N- Boc protected cytarglyptin (see International Patent Publication No. WO 2014-023930)

3- tert -Butoxycarbonylamino-4- (2,4,5-trifluorophenyl) butanoic acid (5 g) was dissolved in xylene (500 mL), Hunig's base (5 mL) A dean stark trap was installed. To the reaction solution was added 3- (trifluoromethyl) -5,6,7,8-tetrahydro-1,2,4-triazolo [4,3- a ] pyrazine hydrochloride (5 g) and stirred at room temperature for 5 minutes 3-chlorophenylboronic acid (2.34 g) was added, and the mixture was refluxed for 48 hours. When the reaction was completed, the reaction solution was cooled to room temperature, purified water (50 mL) was added, and the organic layer was separated. The separated organic layer was washed twice with 1N HCl (25 mL) and once with 6% NaHCO ₃ (25 mL) and purified water (25 mL). The organic layer was dried over anhydrous sodium sulfate, charcoal filtered and the solvent was concentrated. Diisopropyl ether (25 mL) was added to the concentrate, stirred for 2 hours, filtered, and then dried at 50 DEG C for 12 to 15 hours to obtain the title compound (6.0 g, 78.84%).

The yields of N- Boc-protected cyproglitine prepared through the coupling reaction of Example 1 and Comparative Examples 1 to 3 are summarized in Table 2 below.

division Reaction conditions yield(%) reagent Temperature time Example 1 DPP Room temperature One 83.37 Comparative Example 1 EDC,
HOBT Room temperature 14 38.02 Comparative Example 2 DCC Room temperature 15 85 ^* Comparative Example 3 2-chlorophenylboronic acid Reflux temperature 48 78.84 * HPLC analysis confirmed that dicyclohexylurea contained 11.676% impurities.

Claims

A process for the preparation of sitagliptin comprising the steps of:
(I) at least one amine base selected from the group consisting of tri (C ₁ -C ₆ alkyl) amine, N- (C ₁ -C ₆ alkyl) morpholine, pyridine, and quinoline and diphenylphosphite (DPP) under the presence, to the N- Boc-protected Acid N- Boc-protected sitagliptin represented by the compound and to, the following formulas 4 to the triazolo piperazine hydrochloride coupling reaction represented by the formula (3) represented by the formula (2) Producing; And

(In the above, Boc represents tert -butoxycarbonyl group)
(Ii) deprotecting the N- Boc-protected cyproglitine represented by the following formula (4) with hydrochloric acid to prepare cytarglyptin represented by the following formula (1).

(In the above, Boc represents tert -butoxycarbonyl group)

The method according to claim 1,
(I-1) crystallizing N- Boc-protected sytagliptin represented by Formula 4 with isopropyl alcohol and purifying; &Lt; / RTI > further comprising the steps of:

3. The method according to claim 1 or 2,
(Iii) introducing sitagliptin represented by Formula 1 into a mixed solution of isopropyl alcohol and phosphoric acid aqueous solution and reacting at 40 ° C to 90 ° C to prepare citagliptin phosphate monohydrate; &Lt; / RTI > further comprising the steps of:

The method according to claim 1,
Wherein the amine base is at least one selected from the group consisting of trimethylamine, triethylamine, triisopropylamine, N -methylmorpholine, pyridine and quinoline.

3. The method of claim 2,
Wherein said amine base is pyridine. &Lt; RTI ID = 0.0 > 11. < / RTI >

The method according to claim 1,
Wherein the reaction molar ratio of the compound represented by Formula 2 to the compound represented by Formula 3 is 1: 1.

The method according to claim 1,
Wherein the amount of the diphenyl phosphite compound used is 1: 1 to 1.5 molar ratio with respect to the compound represented by the formula (2).

The method according to claim 1,
Wherein the amine base is used in an amount of 1: 6 to 9 molar relative to the compound represented by the general formula (2).

The method according to claim 1,
Wherein the reaction is carried out at a temperature of from < RTI ID = 0.0 > 10 C < / RTI > to < RTI ID = 0.0 > 30 C. < / RTI >