CN102838603B - Preparation method of intermediate compound of sitagliptin - Google Patents

Abstract

The invention discloses a preparation method of sitagliptin intermediate compound I as shown in formula I, which comprises the following steps: in an organic solvent, in an unsubstituted C ₁ to C ₆ saturated fatty acid or a halogen-substituted C ₁ -C ₆ saturated fatty acid, and under the action of borohydride, the compound II can be subjected to the reduction reaction of the carbon-carbon double bond as shown below; wherein, R is a methyl group or a carbamoyl group. The preparation method of the present invention avoids the use of precious metals as catalysts, and has low cost, simple post-treatment, high product yield, high chemical purity and optical purity, de% greater than 99.5%, and can be successfully used for sitagliptin The synthesis is suitable for industrial production.

Description

A kind of preparation method of intermediate compound of sitagliptin

technical field

The present invention specifically relates to a preparation method of an intermediate compound of sitagliptin.

Background technique

Sitagliptin (English name: Sitagliptin), chemical name: 7-[1-oxo-3R-3-amino-4-(2,4,5-trifluorophenyl)butyl]-3-tri Fluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine, as shown in Structural Formula 1: it is a kind of bismuth developed by Merck & Co. Peptidyl peptidase-Ⅳ (DPP-Ⅳ) inhibitors are clinically used to treat type Ⅱ diabetes.

During the preparation of sitagliptin, the construction of chiral amino group is the main point of the synthetic route. At present, in the preparation method of sitagliptin, the main method for constructing a chiral amino group is as follows:

Route 1: (Reference: WO2004/085378)

In this route, the chiral amino group of sitagliptin is constructed through a hydrogenation reduction reaction involving rhodium metal and chiral ferrocenyl diphosphine. The main disadvantage of this method is that two very expensive reagents, metal rhodium and chiral ferrocene ligand, are used, which greatly increases the cost and is difficult to be suitable for large-scale industrial production.

Route 2: (Reference: WO2004/085661)

In this route, by introducing S-phenylglycylamide as a chiral auxiliary agent, platinum oxide catalytic hydrogenation induces the required chiral amino group, and then debenzylation to obtain sitagliptin. The disadvantage of this method is also that the platinum oxidation catalyst is a precious metal, which increases the cost of the route and is difficult to be suitable for large-scale industrial production.

Route 3: (Reference: WO2009/085990)

This route uses the chiral auxiliary agent R-α-methylbenzylamine instead of S-phenylglycineamide, but also uses expensive platinum oxide as a catalyst to induce chiral amino groups.

Although the prior art has reported several methods for the preparation of sitagliptin, they have one or more disadvantages, such as the use of expensive reagents (platinum oxide, rhodium catalyst, etc.), increased protection and deprotection steps, and the like. Therefore, it is necessary to develop a simple, economical and industrialized synthetic route.

Contents of the invention

The technical problem to be solved by the present invention is to overcome defects such as the need to use expensive reagents in the existing method for preparing a key intermediate of sitagliptin, which is very costly and unsuitable for industrialization, and provides a The preparation method of the key intermediate I of sitagliptin completely different from the prior art. The preparation method of the present invention avoids the use of precious metals as catalysts, and has low cost, simple post-treatment, high product yield, high chemical purity and optical purity, de% greater than 99.5%, and can be successfully used for sitagliptin The synthesis is suitable for industrial production.

Therefore, the present invention relates to the preparation method of the intermediate compound I of sitagliptin as shown in formula I, which comprises the following steps: in an organic solvent, in an unsubstituted C ₁ ~C ₆ saturated fatty acid or halogen (such as F) Under the action of substituted C ₁ -C ₆ (such as C ₁ -C ₃ ) saturated fatty acids and borohydride, compound II can be subjected to the reduction reaction of the carbon-carbon double bond as shown below;

Wherein, R is methyl or carbamoyl.

Wherein, the organic solvent can be a common solvent for this type of reduction reaction in the art, and the present invention is particularly preferably one or more of tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether and acetonitrile, more preferably of tetrahydrofuran. The amount of the organic solvent can be used in conventional chemical reactions, which is preferably 5-10 ml/g compared with the volume and mass of compound II.

In the present invention, the borohydride is a borohydride reagent commonly used in reduction reactions in the art, and sodium borohydride or potassium borohydride is particularly preferred in the present invention. The amount of said borohydride can be the conventional amount in this type of reduction reaction in the art, and the present invention particularly prefers the following amount range: the molar ratio of said borohydride to compound II is preferably 1: 1 to 2 : 1.

In the present invention, the unsubstituted C ₁ -C ₆ saturated fatty acid is preferably formic acid, acetic acid, propionic acid, butyric acid or trimethylacetic acid, preferably formic acid. The halogen (such as F) substituted C ₁ -C ₆ saturated fatty acid is preferably trifluoroacetic acid.

The amount of the unsubstituted C ₁ -C ₆ saturated fatty acid or halogen (such as F) substituted C ₁ -C ₆ (such as C ₁ -C ₃ ) saturated fatty acid can be the conventional amount used in this type of reduction reaction in the art , the present invention particularly preferably uses the following amount: the unsubstituted C ₁ to C ₆ saturated fatty acid or halogen (such as F) substituted C ₁ to C ₆ (such as C ₁ to C ₃ ) saturated fatty acid and borohydride The molar ratio is preferably 3:1-6:1.

In the present invention, the temperature of the reduction reaction can be a temperature commonly used in this type of reduction reaction in the art, and the present invention is particularly preferably from 0°C to -40°C, and most preferably from -25 to -35°C (such as -30°C ).

In the present invention, the time of the reduction reaction can be detected by conventional detection means until the completion of the reaction, generally 1-20 hours.

In the present invention, the various conditions of the reduction reaction described above can be carried out according to the conditions in this type of reduction reaction in the art, except for the above-mentioned special description.

After the above reduction reaction is completed, pure compound I can be obtained through simple post-treatments, such as extraction, extraction, washing, drying, concentration, and recrystallization.

The intermediate compound I of the present invention can be prepared by a conventional method for debenzylating sitagliptin, for example, can refer to the method for preparing sitagliptin in the literature related to route 2 or 3 in the background technology of this application, Or document WO2004/085378 to prepare sitagliptin.

In the present invention, the compound II can be prepared by referring to the methods of the prior art. For example, when R in compound II is carbamoyl, it can be prepared by referring to document WO2004/085378; when R in compound II is methyl, it can be prepared by referring to document WO2009/085990.

In the present invention, de% refers to diastereomer excess, that is, the absolute value of the amount of one diastereomer minus the amount of the other diastereomer, and then divided by the sum of the two. Its general definition is as follows: de % = (amount of diastereomer a - amount of diastereomer b) / (amount of diastereomer a + amount of diastereomer b ).

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

Unless otherwise specified, the reagents and raw materials used in the present invention are all commercially available.

The positive progress effect of the present invention is: the preparation method of the present invention avoids the use of precious metals as catalysts, the cost is low, and the post-treatment is simple, the product yield is high, the chemical purity and optical purity are high, and the de% value is greater than 99.5%. , can be successfully used in the synthesis of sitagliptin, and is suitable for industrial production.

Detailed ways

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

Example 1: 7-[1-oxo-3R-3-(1R-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)butyl]-3-trifluoro Preparation of methyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (R in general formula I is methyl)

Add sodium borohydride (0.448g, 11.8mmol) into tetrahydrofuran (21mL), cool down to 0-5°C, keep below 5°C and add formic acid (3.253g, 70.8mmol) dropwise, stir at 10°C for 1h, then cool down to -30°C ℃, kept at -30 ℃ and added dropwise 7-[1-oxo-3-(1R-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)butan-2- Alkenyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (R is methyl in the general formula II) ( 3.000 g, 5.9 mmol) in tetrahydrofuran (9 mL), react at -25 to -30 ° C for 18 hours, add saturated sodium carbonate solution (40 mL) to terminate the reaction, extract 3 times with 50 mL of ethyl acetate, combine the organic phases, wash with saturated brine for 3 Minor to neutral, dried over anhydrous sodium sulfate, concentrated, recrystallized from isopropanol (15 mL) and petroleum ether (15 mL) to obtain 1.955 g of solid, yield 65.0%, purity>99.5%, de%>99.5%. Melting point: 132-134°C. MS (ES+): m/z 512 (M+H). ¹ H-NMR (CD ₃ CN): δ1.13(m, 3H); 2.45(m, 1H); 2.61(m, 3H); 2.95(m, 1H); 3.78(m, 2H); , 2H,); 4.08 (s, 1H); 4.85 (m, 2H); 7.00 (m, 4H); 7.14 (m, 3H).

Example 2: 7-[1-oxo-3R-3-(1R-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)butyl]-3-trifluoro Preparation of methyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (R in general formula I is methyl)

Add sodium borohydride (0.448g, 11.8mmol) into ethylene glycol dimethyl ether (30mL), cool down to 0-5°C, keep below 5°C, add trifluoroacetic acid (4.036g, 35.4mmol) dropwise, and stir at 10°C After 1h, the temperature was lowered to -40°C, and 7-[1-oxo-3-(1R-1-phenylethylamino)-4-(2,4,5-trifluoro Phenyl)but-2-enyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (general formula II where R is methyl) (3.000g, 5.9mmol) in ethylene glycol dimethyl ether (9mL), react at -40°C for 1 hour, add saturated sodium carbonate solution (20mL) to terminate the reaction, and extract 3 times with 50mL of ethyl acetate , combined the organic phases, washed 3 times with saturated brine until neutral, dried over anhydrous sodium sulfate, concentrated, recrystallized with isopropanol (15 mL) and petroleum ether (15 mL) to obtain 1.890 g of solids, yield 62.8%, purity > 99.5 %, de%>99.5%. Melting point: 132-134°C. MS (ES+): m/z 512 (M+H). ¹ H-NMR (CD ₃ CN): δ1.13(m, 3H); 2.45(m, 1H); 2.61(m, 3H); 2.95(m, 1H); 3.78(m, 2H); , 2H,); 4.08 (s, 1H); 4.85 (m, 2H); 7.00 (m, 4H); 7.14 (m, 3H).

Example 3: 7-[1-oxo-3R-3-(1R-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)butyl]-3-trifluoro Preparation of methyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (R in general formula I is methyl)

Add potassium borohydride (0.319g, 5.9mmol) into acetonitrile (21mL), cool down to 0-5°C, keep below 5°C, add trimethylacetic acid (3.611g, 35.4mmol) dropwise, stir at 10°C for 1h, then cool down To -30°C, keep dropping 7-[1-oxo-3-(1R-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)butane at -30°C -2-enyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (R in general formula II is methyl base) (3.000g, 5.9mmol) in acetonitrile (9mL), react at -30°C for 20 hours, add saturated sodium carbonate solution (20mL) to terminate the reaction, extract 3 times with 50mL of ethyl acetate, combine the organic phases, wash with saturated brine for 3 Sub-to-neutral, dried over anhydrous sodium sulfate, concentrated, recrystallized from isopropanol (15 mL) and petroleum ether (15 mL) to obtain 1.850 g of solid, yield 61.5%, purity>99.5%, de%>99.5%. Melting point: 132-134°C. MS (ES+): m/z 512 (M+H). ¹ H-NMR (CD ₃ CN): δ1.13(m, 3H); 2.45(m, 1H); 2.61(m, 3H); 2.95(m, 1H); 3.78(m, 2H); , 2H,); 4.08 (s, 1H); 4.85 (m, 2H); 7.00 (m, 4H); 7.14 (m, 3H).

Example 4: 7-[1-oxo-3R-3-(1R-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)butyl]-3-trifluoro Preparation of methyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (R in general formula I is methyl)

Add potassium borohydride (0.637g, 11.8mmol) into tetrahydrofuran (21mL), cool down to 0-5°C, keep below 5°C and add acetic acid (4.248g, 70.8mmol) dropwise, stir at 10°C for 1h, then cool down to 0°C , keep dropping 7-[1-oxo-3-(1R-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)but-2-ene at -30°C Base]-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (R in general formula II is methyl) (3.000 g, 5.9 mmol) in tetrahydrofuran (9 mL), reacted at 0°C for 16 hours, added saturated sodium carbonate solution (40 mL) to terminate the reaction, extracted 3 times with 50 mL of ethyl acetate, combined the organic phases, washed 3 times with saturated brine until neutral, It was dried over anhydrous sodium sulfate, concentrated, and recrystallized from isopropanol (15 mL) and petroleum ether (15 mL) to obtain 1.920 g of solid, yield 63.8%, purity>99.5%, de%>99.5%. Melting point: 132-134°C. MS (ES+): m/z 512 (M+H). ¹ H-NMR (CD ₃ CN): δ1.13(m, 3H); 2.45(m, 1H); 2.61(m, 3H); 2.95(m, 1H); 3.78(m, 2H); , 2H,); 4.08 (s, 1H); 4.85 (m, 2H); 7.00 (m, 4H); 7.14 (m, 3H).

Example 5: 7-[1-oxo-3R-3-(1S-1-phenyl-1-carbamoylmethylamino)-4-(2,4,5-trifluorophenyl)butyl Preparation of ]-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (R in general formula I is carbamoyl)

Add sodium borohydride (0.562g, 14.8mmol) into tetrahydrofuran (28mL), cool down to 0-5°C, keep below 5°C, add formic acid (4.085g, 88.8mmol) dropwise, stir at 10°C for 1h, then cool down to -30°C ℃, kept at -30 ℃ and added dropwise 7-[1-oxo-3-(1S-1-phenyl-1-carbamoylmethylamino)-4-(2,4,5-trifluorobenzene Base) but-2-enyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (in general formula II R is carbamoyl) (4.000g, 7.4mmol) in tetrahydrofuran (12mL) solution, react at -30°C for 16 hours, add saturated sodium carbonate solution (40mL) to terminate the reaction, extract 3 times with 50mL of ethyl acetate, combine the organic phases, Wash with saturated brine 3 times until neutral, dry over anhydrous sodium sulfate, concentrate, recrystallize with isopropanol (20mL) and petroleum ether (20mL) to obtain 2.610g of solid, yield 65.1%, purity>99.5%, de%> 99.5%. Melting point: 206-208°C. MS (ES+): m/z 541 (M+H). ¹ H-NMR (CD ₃ CN): δ2.54(m, 2H); 2.75(m, 2H); 3.15(m, 1H); 3.92(m, 2H); 4.06(m, 2H,); d, 1H); 4.87 (m, 2H); 7.10 (m, 4H); 7.21 (m, 3H).

Example 6: 7-[1-oxo-3R-3-(1S-1-phenyl-1-carbamoylmethylamino)-4-(2,4,5-trifluorophenyl)butyl Preparation of ]-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (R in general formula I is carbamoyl)

Add potassium borohydride (0.799g, 14.8mmol) into methyl tert-butyl ether (28mL), cool down to 0-5°C, keep below 5°C, add trifluoroacetic acid (5.061g, 44.4mmol) dropwise, and stir at 10°C After 1h, the temperature was lowered to -30°C, and 7-[1-oxo-3-(1S-1-phenyl-1-carbamoylmethylamino)-4-(2, 4,5-Trifluorophenyl)but-2-enyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a] Pyrazine (R in general formula II is carbamoyl) (4.000g, 7.4mmol) in methyl tert-butyl ether 12mL) solution, react at -30°C for 1 hour, add saturated sodium carbonate solution (30mL) to terminate the reaction, acetic acid Ethyl 50mL was extracted 3 times, the organic phases were combined, washed 3 times with saturated brine until neutral, dried over anhydrous sodium sulfate, concentrated, recrystallized with isopropanol (20mL) and petroleum ether (20mL) to obtain 2.640g of solid, the yield 65.8%, purity>99.5%, de%>99.5%. Melting point: 206-208°C. MS (ES+): m/z 541 (M+H). ¹ H-NMR (CD ₃ CN): δ2.54(m, 2H); 2.75(m, 2H); 3.15(m, 1H); 3.92(m, 2H); 4.06(m, 2H,); d, 1H); 4.87 (m, 2H); 7.10 (m, 4H); 7.21 (m, 3H).

Example 7: 7-[1-oxo-3R-3-(1S-1-phenyl-1-carbamoylmethylamino)-4-(2,4,5-trifluorophenyl)butyl Preparation of ]-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (R in general formula I is carbamoyl)

Add sodium borohydride (0.562g, 14.8mmol) into acetonitrile (28mL), cool down to 0-5°C, keep below 5°C and add propionic acid (3.286g, 44.4mmol) dropwise, stir at 10°C for 1h, then cool down to - 30°C, keep dropping 7-[1-oxo-3-(1S-1-phenyl-1-carbamoylmethylamino)-4-(2,4,5-trifluoro Phenyl)but-2-enyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (general formula II where R is carbamoyl) (4.000g, 7.4mmol) in acetonitrile (12mL) solution, react at -30°C for 20 hours, add saturated sodium carbonate solution (40mL) to terminate the reaction, extract 3 times with 50mL ethyl acetate, and combine the organic phases , washed with saturated brine 3 times until neutral, dried over anhydrous sodium sulfate, concentrated, recrystallized with isopropanol (20mL) and petroleum ether (20mL) to obtain 2.580g of solid, yield 64.3%, purity>99.5%, de% >99.5%. Melting point: 206-208°C. MS (ES+): m/z 541 (M+H). ¹ H-NMR (CD ₃ CN): δ2.54(m, 2H); 2.75(m, 2H); 3.15(m, 1H); 3.92(m, 2H); 4.06(m, 2H,); d, 1H); 4.87 (m, 2H); 7.10 (m, 4H); 7.21 (m, 3H).

Example 8: 7-[1-oxo-3R-3-(1S-1-phenyl-1-carbamoylmethylamino)-4-(2,4,5-trifluorophenyl)butyl Preparation of ]-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (R in general formula I is carbamoyl)

Add sodium borohydride (0.562g, 14.8mmol) into acetonitrile (28mL), cool down to 0-5°C, keep below 5°C and add butyric acid (3.907g, 44.4mmol) dropwise, stir at 10°C for 1h, then cool down to - 10°C, kept at -10°C and added dropwise 7-[1-oxo-3-(1S-1-phenyl-1-carbamoylmethylamino)-4-(2,4,5-trifluoro Phenyl)but-2-enyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (general formula II R is carbamoyl) (4.000g, 7.4mmol) in acetonitrile (12mL) solution, reacted at -10°C for 10 hours, added saturated sodium carbonate solution (40mL) to terminate the reaction, extracted 3 times with 50mL ethyl acetate, combined the organic phase , washed with saturated brine 3 times until neutral, dried over anhydrous sodium sulfate, concentrated, recrystallized with isopropanol (20mL) and petroleum ether (20mL) to obtain 2.340g of solid, yield 58.3%, purity > 99.5%, de% >99.5%. Melting point: 206-208°C. MS (ES+): m/z 541 (M+H). ¹ H-NMR (CD ₃ CN): δ2.54(m, 2H); 2.75(m, 2H); 3.15(m, 1H); 3.92(m, 2H); 4.06(m, 2H,); d, 1H); 4.87 (m, 2H); 7.10 (m, 4H); 7.21 (m, 3H).

Example 9: 7-[1-oxo-3R-3-amino-4-(2,4,5-trifluorophenyl)butyl]-3-trifluoromethyl-5,6,7,8 - Preparation of tetrahydro-1,2,4-triazol[4,3-a]pyrazine (sitagliptin)

7-[1-oxo-3R-3-(1R-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)butyl]-3-trifluoromethyl- 5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine (R in general formula I is methyl) (3.000g, 5.87mmol) was dissolved in methanol 30mL and In 3 mL of water, add acetic acid (0.88 g, 14.68 mmol) and 20% palladium hydroxide on carbon (0.9 g, 30% wt), add hydrogen to a pressure of 1.0 MPa, react at 50 ° C for 14 hours, remove the catalyst by suction filtration, and concentrate to obtain Solid 1.94g, yield 81.2%, purity>99.5%, ee%>99.5%. Melting point: 118-120°C. MS (ES+): m/z 408 (M+H). ¹ H-NMR (CDCl ₃ ): δ2.48(m, 2H); 2.73(m, 2H); 3.56(m, 1H); 4.08(m, 4H); 4.94(m, 2H); 1H); 7.07 (m, 1H).

Claims (5)

1. a preparation method of intermediate compound I of sitagliptin as shown in formula I, it is characterized in that comprising the following steps: in organic solvent, under the effect of formic acid or trifluoroacetic acid, and borohydride, will Compound II carries out the reduction reaction of the carbon-carbon double bond as shown below; Wherein, R is a methyl group or a carbamoyl group, and the temperature of the reduction reaction is -25 to -35°C. 2. The preparation method according to claim 1, characterized in that: the organic solvent is one or more of tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether and acetonitrile. 3. the preparation method as claimed in claim 1 is characterized in that: described borohydride is sodium borohydride or potassium borohydride. 4. The preparation method according to claim 1, characterized in that: the molar ratio of borohydride to compound II is 1:1-2:1. 5. The preparation method according to claim 1, characterized in that: the molar ratio of formic acid or trifluoroacetic acid to borohydride is 3:1-6:1.