Preparation method of vildagliptin intermediate

Abstract

Belonging to the technical field of heterocyclic compounds, the invention provides a preparation method of a vildagliptin intermediate. The preparation method includes: adding prolinamide into a solvent, performing stirring and heating to dissolve prolinamide; performing cooling, adding propylene oxide as an acid-binding agent, and adding chloroacetyl chloride dropwise under stirring; carrying outcondensation reaction at the end of adding; lowering the temperature and performing heat preservation; conducting filtering, washing the filter residue, and performing drying to obtain (S)-1-(2-chloracetyl)pyrrolidine-2-amide. The method has the advantages of simple process, mild reaction conditions, high product purity and the like.

Description

technical field

[0001] The application relates to a preparation method of vildagliptin intermediate (S)-1-(2-chloroacetyl)pyrrolidine-2-amide, which belongs to the technical field of heterocyclic compounds. Background technique

[0002] Diabetes mellitus (DM) is one of the most important non-communicable diseases currently threatening human health. In 2015, the number of patients worldwide reached 415 million. As a big country with diabetes, the prevalence of diabetes in my country continues to rise and has reached 11.6% of the total population, of which more than 90% are type 2 diabetes mellitus (T2DM). Diabetes and its complications seriously affect the quality of life of patients, and bring a heavy burden to patients, the national economy, and medical insurance. Current interventions for T2DM mainly include diet control and the use of oral and / or injectable hypoglycemic agents on the basis of exercise therapy. Dipeptidyl peptidase-4 (dipeptidyl peptidase-4, DPP-4) inhib...

Examples

Embodiment 1

[0026] Weigh 20.0g of L-prolineamide in a 250mL four-neck flask, add 200mLTHF, heat up to 40°C under stirring to dissolve L-prolineamide, cool down to 0°C after dissolving, add 20.2g of propylene oxide (2.00eq ), dropwise added 35.4g of chloroacetyl chloride (1.79eq), and gradually produced a white suspension. After 3 hours of dropwise addition, the heat preservation reaction was carried out for 2 hours, and suction filtration gave a white solid, washed with a small amount of THF, and dried in vacuo at 40°C to obtain 24.8 grams of the product. The yield was 74.4%, and the content detected by HPLC was 99.52%.

Embodiment 2

[0028] Weigh 20.0g of L-prolineamide into a 250mL four-neck flask, add 150mL of dichloromethane, heat up to 40°C under stirring to dissolve L-prolineamide, cool down to 0°C after dissolving, add 20.2g of propylene oxide (2.00eq), 35.4g chloroacetyl chloride (1.79eq) was added dropwise, and the solid produced during the dropwise addition formed a spherical shape. After the dropwise addition was completed, the heat preservation reaction was carried out for 2 hours, and the viscous solid was filtered by HPLC detection and contained a large amount of unreacted prophylamine Aminoamide, experiment failed.

Embodiment 3

[0030] Weigh 20.0g of L-prolinamide in a 250mL four-neck flask, add 150mL of acetonitrile, heat up to 40°C under stirring to dissolve L-prolineamide, cool down to 0°C after dissolving, add 20.2g of propylene oxide (2.00 eq), 35.4g chloroacetyl chloride (1.79eq) was added dropwise, and the solid produced during the dropwise addition formed a spherical shape. After the dropwise addition, the insulation reaction was carried out for 2h, and the viscous solid HPLC detected by filtration contained a large amount of unreacted prolineamide , the experiment failed.

technical field

[0001] The application relates to a preparation method of vildagliptin intermediate (S)-1-(2-chloroacetyl)pyrrolidine-2-amide, which belongs to the technical field of heterocyclic compounds. Background technique

[0002] Diabetes mellitus (DM) is one of the most important non-communicable diseases currently threatening human health. In 2015, the number of patients worldwide reached 415 million. As a big country with diabetes, the prevalence of diabetes in my country continues to rise and has reached 11.6% of the total population, of which more than 90% are type 2 diabetes mellitus (T2DM). Diabetes and its complications seriously affect the quality of life of patients, and bring a heavy burden to patients, the national economy, and medical insurance. Current interventions for T2DM mainly include diet control and the use of oral and / or injectable hypoglycemic agents on the basis of exercise therapy. Dipeptidyl peptidase-4 (dipeptidyl peptidase-4, DPP-4) inhib...

Examples

Embodiment 1

[0026] Weigh 20.0g of L-prolineamide in a 250mL four-neck flask, add 200mLTHF, heat up to 40°C under stirring to dissolve L-prolineamide, cool down to 0°C after dissolving, add 20.2g of propylene oxide (2.00eq ), dropwise added 35.4g of chloroacetyl chloride (1.79eq), and gradually produced a white suspension. After 3 hours of dropwise addition, the heat preservation reaction was carried out for 2 hours, and suction filtration gave a white solid, washed with a small amount of THF, and dried in vacuo at 40°C to obtain 24.8 grams of the product. The yield was 74.4%, and the content detected by HPLC was 99.52%.

Embodiment 2

[0028] Weigh 20.0g of L-prolineamide into a 250mL four-neck flask, add 150mL of dichloromethane, heat up to 40°C under stirring to dissolve L-prolineamide, cool down to 0°C after dissolving, add 20.2g of propylene oxide (2.00eq), 35.4g chloroacetyl chloride (1.79eq) was added dropwise, and the solid produced during the dropwise addition formed a spherical shape. After the dropwise addition was completed, the heat preservation reaction was carried out for 2 hours, and the viscous solid was filtered by HPLC detection and contained a large amount of unreacted prophylamine Aminoamide, experiment failed.

Embodiment 3

[0030] Weigh 20.0g of L-prolinamide in a 250mL four-neck flask, add 150mL of acetonitrile, heat up to 40°C under stirring to dissolve L-prolineamide, cool down to 0°C after dissolving, add 20.2g of propylene oxide (2.00 eq), 35.4g chloroacetyl chloride (1.79eq) was added dropwise, and the solid produced during the dropwise addition formed a spherical shape. After the dropwise addition, the insulation reaction was carried out for 2h, and the viscous solid HPLC detected by filtration contained a large amount of unreacted prolineamide , the experiment failed.

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