214398-99-9

Usage

Uses

Used in Pharmaceutical Industry:
(S)-1-(2-Chloroacetyl)pyrrolidine-2-carboxamide is used as a key intermediate in the synthesis of Vildagliptin (V305000), an oral anti-diabetic drug. It plays a crucial role in the development of this medication, which is designed to help manage blood sugar levels in patients with type 2 diabetes by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4).
Additionally, (S)-1-(2-Chloroacetyl)pyrrolidine-2-carboxamide is utilized in the synthesis of impurities related to Vildagliptin, such as Impurity A (H971380). The production and study of these impurities are essential for ensuring the safety, efficacy, and quality control of the final drug product.

Synthetic route

(S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid (23500-10-9) → (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9)

Conditions	Yield
With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate In acetonitrile at 20℃; for 1.5h; Inert atmosphere;	84%
With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate In acetonitrile at 25℃; for 1.5h;	84%
Stage #1: (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 5h; Cooling with ice; Stage #2: With ammonium carbamate In dichloromethane at 20℃; for 6h;	71.2%

chloroacetyl chloride (79-04-9) + L-prolinamide (7531-52-4) → (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9)

Conditions	Yield
With triethylamine In dichloromethane at 5℃; for 2h; Reagent/catalyst; Inert atmosphere;	96%
With triethylamine In dichloromethane at -5 - 0℃; for 0.5h; Inert atmosphere;	96.3%
In tetrahydrofuran at 0℃; Reflux; Large scale;	92%

C7H9Cl2NO2 → (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9)

Conditions	Yield
With ammonia In dichloromethane for 2h;

L-proline (147-85-3) → (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: chloro-trimethyl-silane / acetonitrile / 1 h / 50 °C 1.2: 20 °C 2.1: thionyl chloride / dichloromethane / 1.17 h / 0 - 20 °C 2.2: 2 h View Scheme
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 2.5 h / 65 - 70 °C 2.1: dicyclohexyl-carbodiimide / dichloromethane / 1 h / 0 - 30 °C 2.2: 3 h / 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 3 h / Reflux 2.1: dicyclohexyl-carbodiimide / dichloromethane / 5 h / 20 °C / Cooling with ice 2.2: 6 h / 20 °C View Scheme

methyl (2S)-pyrrolidine carboxylate (2577-48-2) → (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: ammonium hydroxide 2: tetrahydrofuran View Scheme
Multi-step reaction with 2 steps 1: ammonium hydroxide / butan-1-ol / 5 - 30 °C 2: N,N-dimethyl-formamide / -5 - 25 °C / Inert atmosphere View Scheme

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-(2-chloroacetyl)-2-cyanopyrrolidine (565452-98-4)

Conditions	Yield
With 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 0℃; Large scale;	90%

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → 1-glycoloyl-L-proline amide (96166-39-1)

Conditions	Yield
With sodium carbonate In acetone at 50℃; for 5h; Temperature;	93%

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (207557-35-5)

Conditions	Yield
With palladium(II) trifluoroacetate; dichloroacetonitrile; water In acetonitrile at 60℃; for 2h; Catalytic behavior; Temperature; Reagent/catalyst; Solvent; Concentration; Schlenk technique; Inert atmosphere;	95%
With 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 35 - 48℃; for 4h;	90%
With 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 40℃; for 4h;	90%

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-(2-chloroacetyl)pyrrolidin-2-carboxamide hydrochloride (1262802-99-2)

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at 70℃;

8-(5-nitropyridin-2-yl)-8-azabicyclo[3.2.1]oct-3-yl-exo-amine + (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (2S)-1-(2-{[8-(5-nitropyridin-2-yl)-8-azabicyclo[3.2.1]oct-3-yl]exo-amino}acetyl)pyrrolidine-2-carbonitrile

Conditions	Yield
With 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine In acetonitrile	41%

3-hydroxy-1-adamantamine + (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → C17H27N3O3

Conditions	Yield
With potassium carbonate; potassium iodide In tetrahydrofuran at 35℃; for 4h; Temperature; Reflux;

triethylamine (121-44-8) + (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → {2-[(2S)-2-carbamoylpyrrolidin-1-yl]-2-oxoethyl}triethylazanium chloride

Conditions	Yield
In dichloromethane Reflux;	89%

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (2S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile

Conditions	Yield
With trichlorophosphate at -5 - 20℃;

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) + 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile (202460-48-8) → (S)-1-{2-[2-(5-Cyano-pyridin-2-ylamino)-ethylamino]-acetyl}-pyrrolidine-2-carboxylic acid amide

Conditions	Yield
With potassium carbonate In dichloromethane at 0 - 20℃; for 20h;	34%

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine; oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 0.5 h / -78 °C 2: potassium carbonate; potassium iodide / tetrahydrofuran / 5 h / 60 - 65 °C View Scheme
Multi-step reaction with 2 steps 1.1: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 4 h / 35 - 48 °C 2.1: potassium carbonate; potassium iodide / butanone / 40 °C 2.2: 3 h / 38 - 75 °C View Scheme
Multi-step reaction with 2 steps 1.1: trichlorophosphate / -5 - 20 °C 2.1: potassium carbonate; potassium iodide / acetone / 0.25 h / 20 °C 2.2: 40 - 65 °C View Scheme

3-aminoadamantan-1-ol (702-82-9) + (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → vildagliptin (274901-16-5)

Conditions	Yield
Stage #1: (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide With trifluoroacetic anhydride In tetrahydrofuran at 20℃; for 2h; Cooling with ice; Stage #2: 3-aminoadamantan-1-ol With potassium carbonate; potassium iodide In tetrahydrofuran at 40℃; for 8.5h; Time; Reflux;	71%

3-aminoadamantan-1-ol (702-82-9) + (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-[2-(3-hydroxyadamantan-1-ylamino)acetyl]pyrrolidine-2-carboxylic acid amide

Conditions	Yield
With potassium carbonate In dichloromethane at 0 - 20℃; for 20h;

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-{2-[(5-cyanopyridin-2-yl)amino]ethyl-aminoacetyl}-2-cyano-pyrrolidine (247016-69-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / CH2Cl2 / 1 h / 20 °C 2: 34 percent / tetrahydrofuran / 2 h / cooling View Scheme

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile (914070-99-8)

Conditions	Yield
Stage #1: (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide With trifluoroacetic anhydride In tetrahydrofuran at 0 - 20℃; for 6h; Stage #2: With ammonium hydroxide at -20 - 20℃; for 3h;

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → 1-{[(2-phenylethyl)amino]acetyl}-2-pyrrolidinecarbonitrile

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → 1-[2-[(5-nitropyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)pyrrolidine

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-(2-Ethylamino-acetyl)-pyrrolidine-2-carbonitrile

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-(2-Isopropylamino-acetyl)-pyrrolidine-2-carbonitrile

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-(2-tert-Butylamino-acetyl)-pyrrolidine-2-carbonitrile

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-(2-Propylamino-acetyl)-pyrrolidine-2-carbonitrile

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-(2-Cyclopropylamino-acetyl)-pyrrolidine-2-carbonitrile

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-(2-Cyclobutylamino-acetyl)-pyrrolidine-2-carbonitrile

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 2 h / 0 - 20 °C View Scheme

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-[2-(1-Ethyl-propylamino)-acetyl]-pyrrolidine-2-carbonitrile

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-[2-(1,1-Dimethyl-propylamino)-acetyl]-pyrrolidine-2-carbonitrile

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-(2-Butylamino-acetyl)-pyrrolidine-2-carbonitrile

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → (S)-1-[2-(1-Isopropyl-2-methyl-propylamino)-acetyl]-pyrrolidine-2-carbonitrile

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme

Upstream product

• 2577-48-2 methyl (2S)-pyrrolidine carboxylate 
• 23500-10-9 (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid 
• 147-85-3 L-proline 
• 79-04-9 chloroacetyl chloride 
• 7531-52-4 L-prolinamide 

Downstream Products

• 565453-39-6 (S)-1-[2-(3-hydroxyadamantan-1-ylamino)acetyl]pyrrolidine-2-carboxylic acid amide 
• 274901-16-5 vildagliptin 
• 914070-99-8 (S)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile 
• 96166-39-1 1-glycoloyl-L-proline amide 
• 1044676-63-2 vildagliptin 

Relevant academic research and scientific papers

Production method of vildagliptin

and Alkali metal bromides are in vildagliptin or a salt thereof. Use of a crystal form, a deuterated substance, a tritium substitute, and a solvate as a catalyst. The vildagliptin product produced by the method is high in purity and low in impurity content, particularly the product quality control of the vildagliptin bulk drug and/or the pharmaceutical preparation is facilitated. Moreover, the reaction condition is mild, operation and control are convenient, the yield is high, the energy consumption is low, the cost is low, and the method is suitable for industrial production and popularization and application.

Design and synthesis of tetrahydropyridopyrimidine derivatives as dual GPR119 and DPP-4 modulators

Based on the approach of merged pharmacophores of GPR119 agonists and DPP-4 inhibitors, a series of tetrahydropyridopyrimidine compounds were designed as dual GPR119 and DPP-4 modulators with hypoglycemic activity. Seven fragments extracted from DPP-4 inhibitors were hybridized with the scaffold of tetrahydropyridopyrimidine. Among them, compound 51 displayed most potent GPR119 agonistic activity (EC50 = 8.7 nM) and good inhibition rate of 74.5% against DPP-4 at 10 μM. Furthermore, the blood glucose AUC0-2h of 51 was reduced to 19.5% in the oral glucose tolerance test (oGTT) at the dose of 30 mg/kg in C57BL/6N mice, which was more potent than that of vildagliptin (16.4%) at the same dose. The docking study of compound 51 with DPP-4 indicated GPR119 agonists could inhibit DPP-4 to serve as dual GPR119 and DPP-4 modulators.

A new uygur geleg [...] ammonium salt impurity and its preparation method

The invention relates to a new uygur geleg [...] ammonium salt impurity, the glimepiride states uygur [...] ammonium salt the chemical name of the impurity (S)- 2 - (2 - carbamino pyrrolidine - 1 - yl) - N, N, N - triethyl - 2 - oxo ethyl ammonium chloride. The present invention provides a kind of new uygur geleg [...] ammonium salt impurity, the impurity in the existing literature has not been reported in, for vigelegting research further provides reference and conditions; the invention new uygur geleg [...] ammonium salt impurities of the preparation method is convenient, and the resulting high yield and purity, purity can be up to 98.7%, yield can reach 81.6%.

Vildagliptin related substance and preparation method thereof

The invention provides a preparation method of a vildagliptin related substance. The preparation method comprises the following steps: (1) performing hydrolysis reaction on a compound I under a basiccondition to form a compound II; (2) enabling the compound II to react with chloroacetyl chloride to form a compound III as shown in the specification; (3) dehydrating the compound III and trifluoroacetic anhydride (TFAA) to form a compound IV as shown in the specification; (4) enabling the compound IV to react with 3-amino-1-adamantanol to form a compound V as shown in the specification. The synthesis method of the vildagliptin related substance, provided by the invention, is simple in steps, mild in reaction conditions and high in operability, and the related substance meeting the quality requirements can be obtained by simple purification; the preparation method is of great significance for drug development.

Preparation method of vildagliptin intermediate

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.

Acceptor-Controlled Transfer Dehydration of Amides to Nitriles

Palladium-catalyzed dehydration of primary amides to nitriles efficiently proceeds under mild, aqueous conditions via the use of dichloroacetonitrile as a water acceptor. A key to the design of this transfer dehydration catalysis is the identification of an efficient water acceptor, dichloroacetonitrile, that preferentially reacts with amides over other polar functional groups with the aid of the Pd catalyst and makes the desired scheme exergonic, thereby driving the dehydration.

Preparation method of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile

The invention relates to the technical field of medicines, and especially relates to a preparation method of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile. The preparation method least comprises the following steps: L-prolinamide, an acid-binding agent and chloroacetyl chloride are respectively dissolved in a solvent to prepare a material A, a material B and a material C, the material A, the material B and the material C are respectively introduced into a micro-channel reactor and are reacted, a first reaction solution is collected, and undergoes liquid separation, and the obtained upper organic phase is collected; and the upper organic phase and thionyl chloride are respectively introduced into the micro-channel reactor, and are reacted, and a second reaction solution is collected, andis post-treated to obtain the (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile. The micro-channel reactor is used as a reaction container in the invention, so rapid proceeding of the reactions of ispromoted, side reactions are inhibited, the reaction efficiency is improved, and the production cost is greatly reduced.

Preparation method of vildagliptin intermediate

The invention relates to a preparation method of a vildagliptin intermediate. The preparation method comprises the following steps: step 1, dissolving L-prolinamide in a heated organic solvent; step 2, adding chloroacetyl chloride for reaction; and step 3, after the reaction is finished, carrying out filtering, carrying out drip washing on the obtained solid by using the organic solvent in the step 1, and carrying out drying to obtain (S)-1-(2-chloroacetyl)-2-pyrrolidine carboxamide hydrochloride.

Vildagliptin impurity compound and preparation method thereof, detection method and application

The invention relates to a Vildagliptin impurity compound and a preparation method thereof, a detection method and application. The Vildagliptin impurity compound has a structure as shown in the formula (I), wherein R1 is polyhalogenated C1-C4 lower alkyl or CH2R3, and R3 is five-membered/six-membered heterocyclic radical containing an N atom. The heterocyclic radical can be optionally replaced with CN or CONH2. The compound, as a reference substance or standard substance of related substances, can be used in quality control of a Vildagliptin preparation.

Synthesis and evaluation of camphor and cytisine-based cyanopyrrolidines as DPP-IV inhibitors for the treatment of type 2 diabetes mellitus

In this study, bornyl- and cytisine-based cyanopyrrolidines as potent dipeptidyl peptidase-IV (DPP-IV) inhibitors were synthesised. The in vitro inhibiting activities of bornyl- and cytisine derivatives towards DPP-IV were evaluated. Bornyl-based cyanopyrrolidines were shown to have moderate inhibitory activity with regard to DPP-IV (1.27–15.78 μM). A docking study was performed to elucidate the structure-activity relationship of the obtained compounds. The in vivo hypoglycemic activities of the same compounds were evaluated with the oral glucose tolerance test (OGTT) in mice. Bornyl-based cyanopyrrolidines were shown to have good hypoglycemic activity.