METHOD FOR PREPARING SITAGLIPTIN INTERMEDIATE VIA ASYMMETRICAL REDUCTION METHOD

Abstract

Disclosed is a method for synthesizing a sitagliptin intermediate, the method comprising: in the presence of hydrogen and a transition metal catalyst having a chiral phosphine ligand, subjecting a compound of formula II to an asymmetric reductive amination with ammonia or ammonium salt in a proper organic solvent under the condition of adding an acidic additive to produce a compound of formula I, wherein, an R- or S-configuration of a stereocenter is represented by *; the compound of formula I of R configuration can be used to prepare sitagliptin, and a reaction formula is as follows: R.sup.1 and R.sup.2 are each independently selected from hydrogen, C.sub.1-C.sub.12 linear or branched alkyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl and C.sub.7-C.sub.12 arylalkyl. The method has a high yield and a high ee % value, a mild reaction condition and a low production cost, and is simple to operate, convenient to purify, environmental friendly and suitable for industrial production.

##STR00001##

Claims

1. A method for synthesizing sitagliptin intermediate represented by formula I via asymmetric reduction, characterized in that, it comprises the following steps: in the presence of hydrogen and a transition metal catalyst having a chiral phosphine ligand, subjecting a compound of formula II to an asymmetric reductive amination with ammonia or an ammonium salt in a proper organic solvent under the condition of adding an acidic additive to produce sitagliptin intermediate of formula I, with the following reaction formula: ##STR00016## wherein, an R- or S-configuration of a stereocenter is represented by *; and R.sup.1 and R.sup.2 are each independently selected from hydrogen, C.sub.1-C.sub.12 linear or branched alkyl, C.sub.3-C.sub.12 cycloalkyl, C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkynyl and C.sub.7-C.sub.12 arylalkyl.

2. The method according to claim 1, characterized in that, R.sup.1 and R.sup.2 are each independently selected from hydrogen, C.sub.1-C.sub.4 linear or branched alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl and C.sub.7-C.sub.12 arylalkyl.

3. The method according to claim 1, characterized in that, the transition metal catalyst having a chiral phosphine ligand is a transition metal catalyst having a (R)-dm-Segphos ligand.

4. The method according to claim 1, characterized in that, the ammonium salt is selected from an ammonium salt of an inorganic acid or an ammonium salt of an organic acid.

5. The method according to claim 4, characterized in that, the ammonium salt of an inorganic acid is selected from ammonium chloride, ammonium sulfate, or a combination thereof; and the ammonium salt of an organic acid is selected from ammonium acetate, ammonium formate, ammonium salicylate, ammonium benzoate, or a combination thereof.

6. The method according to claim 1, characterized in that, the organic solvent is selected from alcohols, acetonitrile, toluene, N,N-dimethylformamide, 1,2-dichloroethane, or a combination thereof.

7. The method according to claim 1, characterized in that, the organic solvent is selected from alcohols, and the alcohols are selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, benzyl alcohol, or a combination thereof, preferably methanol, ethanol, or a combination thereof.

8. The method according to claim 1, characterized in that, the mole percentage of the catalyst to the compound of formula II is 0.1 to 10.0 mol %.

9. The method according to claim 1, characterized in that, the hydrogen pressure is 2 to 10 MPa in the asymmetric reductive amination.

10. The method according to claim 1, characterized in that, the temperature of the asymmetric reductive amination is 50 to 100° C.

11. The method according to claim 1, characterized in that, the acidic additive is an organic acid.

12. The method according to claim 2, characterized in that, R.sup.1 and R.sup.2 are each independently selected from hydrogen, C.sub.1-C.sub.4 linear or branched alkyl and C.sub.7-C.sub.12 arylalkyl.

13. The method according to claim 2, characterized in that, R.sup.1 and R.sup.2 are each independently selected from hydrogen, methyl, ethyl and benzyl.

14. The method according to claim 3, characterized in that, the transition metal catalyst having a chiral phosphine ligand is a ruthenium catalyst having a (R)-dm-Segphos ligand.

15. The method according to claim 3, characterized in that, the transition metal catalyst having a chiral phosphine ligand is selected from Ru(OAc).sub.2((R)-dm-Segphos) and/or Ru(Cl).sub.2((R)-dm-Segphos).

16. The method according to claim 7, characterized in that, the alcohols are selected from methanol, ethanol, or a combination thereof.

17. The method according to claim 8, characterized in that, the mole percentage of the catalyst to the compound of formula II is 1 to 3 mol %.

18. The method according to claim 11, characterized in that, the acidic additive is selected from salicylic acid, benzoic acid, tartaric acid, p-toluenesulfonic acid, or a combination thereof.

19. A method for synthesizing sitagliptin, comprising the following steps: a) synthesizing sitagliptin intermediate represented by formula I with the method according to claim 1, and b) synthesizing sitagliptin with the sitagliptin intermediate obtained in step a).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0032] To better understand the purposes, technical features and effects of the present invention, the technical solutions of the present invention and the resulting technical effects thereof will be further explained below in combination with the examples.

Example 1: Preparation of Compound C

[0033] ##STR00010##

[0034] Under the protection of nitrogen, compound A (100 g, 0.524 mol), compound B (84 g, 0.583 mol), 4-dimethylaminopyridine (DMAP, 5.2 g, 0.042 mol) and acetonitrile (250 mL) were added sequentially into a 1000 mL three-necked flask, and were cooled to 0˜5° C. While the temperature was kept at 0˜30° C., triethylamine (150 mL, 1.079 mol) was added dropwise into the system. Then the system was cooled to 0˜5° C. While the system was kept not higher than 30° C., pivaloyl chloride (76 mL, 1.17 mol) was added dropwise into the system. After the addition was completed, the system was heated to 40˜45° C. The reaction was completed after 3˜5 hours. Then, the system was cooled to 25˜30° C. and filtrated. The filter cake was washed 2 times with 200 mL of methyl t-butyl ether. The solvent was evaporated (<30° C.) under reduced pressure to one fourth of the volume (in a sticky form), and then 600 mL of dichloromethane was added and stirred for 5 minutes (25˜30° C.). About 300 mL of 1.5 M hydrochloric acid was added dropwise to the system over 15 minutes, adjusting pH=2˜3. Then dichloromethane (DCM) phase was washed with 100 mL of NaCl saturated solution. The organic phase was evaporated (<15° C.) under reduced pressure to one third of the volume, and then 200 mL of n-heptane was added and then evaporated (<15° C.) under reduced pressure to one fourth of the volume. Then the system was supplemented with 50 mL of ethyl acetate and 300 mL of n-heptane and slurried for 2 hours. After suction filtration, the filter cake was washed with 100 mL of solvent (n-heptane:ethyl acetate=10:1) and then dried, obtaining 134.23 g of product, with a yield of 80.7%. ESI: m/z: 317 [M+H].sup.+.

Example 2: Preparation of Compound VI

[0035] ##STR00011##

[0036] Under the protection of nitrogen, acetonitrile (284 mL), compound C (56.7 g, 0.179 mol), and benzyl alcohol (19.4 g, 0.179 mol) were added sequentially into a 250 mL three-necked flask, and then stirred. The system was heated to reflux for about 24 hours (inner temperature of 80˜84° C. is a normal boiling point). The system was then cooled to not higher than 30° C., concentrated, and supplemented with methanol 3 times the volume of the system. The crystallization was conducted at 0˜5° C. for 12 hours, followed by suction filtration, obtaining 47.2 g of product, with a yield of 81.6%. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.37-7.35 (m, 5H), 6.99-6.89 (m, 2H), 5.19 (s, 2H), 3.81 (s, 2H), 3.57 (s, 2H); ESI: m/z: 323 [M+H].sup.+.

Example 3: Preparation of Compound V

[0037] ##STR00012##

[0038] Compound VI (100 g, 0.310 mol), salicylic acid (214 g, 0.898 mol), ammonium acetate (119 g, 1.544 mol), chiral catalyst Ru(OAc).sub.2((R)-dm-Segphos) (2.93 g, 0.003 mol) and methanol (400 mL) were added into a 1000 mL hydrogenation reactor. The system was subjected to nitrogen replacement for 5 times, and to hydrogen replacement for 3 times, and then supplemented with hydrogen to the pressure of 2.5 MPa. The temperature was increased to 40˜50° C., and the pressure was increased to 2.7 MPa. Subsequently, hydrogen was added to the pressure of 3.6 MPa. The temperature was increased to 70˜80° C., and the pressure was 3.6 MPa. The reaction was conducted at a constant temperature. The reaction was monitored with TLC, and completed after about 20 hours. Then the heating was stopped, and the system was cooled to the room temperature. Hydrogen was discharged, and the system was subjected to nitrogen replacement for 3 times, followed by suction filtration of the reaction solution. The resulting filtrate was concentrated, supplemented with 200 mL of sodium carbonate solution, and then extracted with ethyl acetate for 2 times (300 mL×2). The organic phase was concentrated, obtaining 72.96 g of product, with a yield of 95.2% and ee % of 94.2%. .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.26-7.09 (m, 1H), 6.94-6.89 (m, 1H), 3.71 (s, 3H), 3.59-3.49 (m, 1H), 2.84-2.83 (m, 3H), 2.61-2.45 (m, 3H); ESI: m/z: 248 [M+H].sup.+.

Example 4: Preparation of Compound V

[0039] ##STR00013##

[0040] Compound VI (100 g, 0.310 mol), salicylic acid (214 g, 0.898 mol), ammonium acetate (119 g, 1.544 mol), chiral catalyst Ru(OAc).sub.2((R)-dm-Segphos) (2.93 g, 0.003 mol) and methanol (400 mL) were added into a 1000 mL hydrogenation reactor. The system was subjected to nitrogen replacement for 5 times, and to hydrogen replacement for 3 times, and then supplemented with hydrogen to the pressure of 2.0 MPa. The temperature was increased to 90˜100° C. The reaction was conducted at a constant temperature. The reaction was monitored with TLC, and completed after about 20 hours. Then the heating was stopped, and the system was cooled to the room temperature. Hydrogen was discharged, and the system was subjected to nitrogen replacement for 3 times, followed by suction filtration of the reaction solution. The resulting filtrate was concentrated, supplemented with 200 mL of sodium carbonate solution, and then extracted with ethyl acetate for 2 times (300 mL×2). The organic phase was concentrated, obtaining 67.85 g of product, with a yield of 88.5%. ESI: m/z: 248 [M+H].sup.+.

Example 5: Preparation of Compound V

[0041] ##STR00014##

[0042] Compound VI (100 g, 0.310 mol), salicylic acid (214 g, 0.898 mol), ammonium acetate (119 g, 1.544 mol), chiral catalyst Ru(OAc).sub.2((R)-dm-Segphos) (2.93 g, 1 mol %) and methanol (400 mL) were added into a 1000 mL hydrogenation reactor. The system was subjected to nitrogen replacement for 5 times, and to hydrogen replacement for 3 times, and then supplemented with hydrogen to the pressure of 9˜10 MPa. The temperature was increased to 40˜50° C. The reaction was conducted at the constant temperature. The reaction was monitored with TLC, and completed after about 12 hours. Then the heating was stopped, and the system was cooled to the room temperature. Hydrogen was discharged, and the system was subjected to nitrogen replacement for 3 times, followed by suction filtration of the reaction solution. The resulting filtrate was concentrated, supplemented with 200 mL of sodium carbonate solution, and then extracted with ethyl acetate for 2 times (300 mL×2). The organic phase was concentrated, obtaining 73.82 g of product, with a yield of 96.3%. ESI: m/z: 248 [M+H].sup.+.

Example 6: Preparation of Compound IV

[0043] ##STR00015##

[0044] Compound V (32.0 g, 0.129 mol), di-tert-butyl dicarbonate ((Boc).sub.2O 29.5 g, 0.135 mol) and triethylamine (21.2 g, 0.210 mol) were dissolved in ethyl acetate (150 mL). The reaction was conducted at a controlled temperature of 20˜30° C. The reaction was monitored with TLC, and completed after 7 hours. 10 mL of water was added to wash the system, and the organic phase was concentrated to obtain a crude product. The crude product was dissolved in ethanol, and supplemented with 10% sodium hydroxide aqueous solution. The reaction was conducted at a controlled temperature of 20˜30° C. for 2 hours. The reaction was monitored with TLC. After the completion of the reaction, the system was supplemented with 30 mL of water, and the pH was adjusted to 1˜2 with 3M hydrochloric acid. A large amount of solids were precipitated, suction filtrated, and dried, obtaining 36.8 g of product, with a yield of 85.5% and ee % of 99.3%. [a]=+32.3 (c 1.0, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) δ: 7.26-7.03 (m, 1H), 6.94-6.88 (m, 1H), 5.08 (d, J=9.6 Hz, 1H), 4.15 (br, 1H), 2.89 (d, J=7.2 Hz, 1H), 2.63 (d, J=5.2 Hz, 1H), 1.38 (s, 9H); ESI: m/z: 233 [M-Boc].sup.+, 356[M+Na].sup.+.

Examples 7-10

[0045] Compound II was prepared in a similar way with that of Example 2. The results are as shown in Table 1 below.

TABLE-US-00001 TABLE 1 Example No. Reactant 1 Reactant 2 R.sup.1 in compound II Yield 7 Compound C Methanol Methyl 83.1% 8 Compound C Ethanol Ethyl 80.3% 9 Compound C Isopropanol Isopropyl 82.4% 10 Compound C Tert-butanol Tert-butyl 79.7%

Examples 11-18

[0046] Compound I was prepared in a similar way with that of Examples 3-5. The results are as shown in Table 2 below.

TABLE-US-00002 TABLE 2 R.sup.1 in Ratio R.sup.2 in Exam- com- of Hydrogen Reaction com- ple pound Acidic Amination catalyst Pressure temperture pound No. II additive reagent Catalyst (mol %) Sovlent (MPa) (° C.) I ee % Yield 11 Methyl Salicylic Ammonium Ru(OAc).sub.2((R)-dm-Segphos) 0.1 Methanol 2.0 60 Methyl 96.7 95.2% acid acetate 12 Ethyl Salicylic Ammonium Ru(Cl).sub.2((R)-dm-Segphos) 0.5 Methanol 4.0 60 Methyl 95.3 93.5% acid acetate 13 Benzyl Tartaric Ammonium Ru(OAc).sub.2((R)-dm-Segphos) 2 Ethanol 6.0 60 Ethyl 88.6 69.6% acid sulfate 14 Benzyl Benzoic Ammonium Ru(OAc).sub.2((R)-dm-Segphos) 5 Benzyl 6.5 70 Benzyl 89.3 76.2% acid formate alcohol 15 Methyl p-toluene- Ammonium Ru(Cl).sub.2((R)-dm-Segphos) 5 Aceto- 7.1 70 Methyl 93.2 83.5% sulfonic acid salicylate nitrile 16 Methyl Salicylic Ammonium Ru(OAc).sub.2((R)-dm-Segphos) 7 Toluene 8.3 80 Methyl 89.7 70.1% acid benzoate 17 Benzyl Salicylic Ammonium Ru(OAc).sub.2((R)-dm-Segphos) 5 DMF 5.0 90 Benzyl 93.2 67.4% acid acetate 18 Methyl Salicylic Ammonium Ru(Cl).sub.2((R)-dm-Segphos) 8 DCE 10.0 100 Methyl 81.9 62.3% acid formate

Examples 19-21

[0047] In a similar way with that of Example 6, compounds I prepared in Example 11-18 were respectively hydrolysed to obtain compound IV. The results are as shown in Table 3 below.

TABLE-US-00003 TABLE 3 Example No. R.sup.2 in compound I ee % Yield 19 Ethyl 99.2% 82.3% 20 Benzyl 99.6% 84.1% 21 Tert-butyl 99.5% 82.7%

[0048] The description above only provides preferred examples of the present invention, but is not intended to limit the present invention. Any modification, equivalent replacement, and improvement within the spirit and principle of the present invention should be included within the scope of the present invention.