214398-99-9

Basic information

• Product Name: (S)-1-(2-Chloroacetyl)pyrrolidine-2-carboxaMide
• Synonyms: (S)-1-(2-Chloroacetyl)pyrrolidine-2-carboxaMide;2-PyrrolidinecarboxaMide,1-(2-chloroacetyl)-, (2S)-;Vildagliptin Impurity 3;vildagliptin Impurity I;-1-(2-Chloroacetyl);(2S)-1-(2-chloroacetyl)pyrrolidine-2-carboxamide
• CAS NO: 214398-99-9
• Molecular Formula: C₇H₁₁ClN₂O₂
• Molecular Weight: 190.62744
• EINECS: 1308068-626-2
• Mol File: 214398-99-9.mol
• Article Data: 39

Chemical Properties

• Melting Point: 133-137℃ (isopropyl ether )
• Boiling Point: 442.5±45.0 °C(Predicted)
• Appearance: /
• Density: 1.353±0.06 g/cm3(Predicted)
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: Chloroform (Slightly, Sonicated), DMSO (Slightly), Methanol (Very Slightly)
• PKA: 15.56±0.20(Predicted)
• CAS DataBase Reference: (S)-1-(2-Chloroacetyl)pyrrolidine-2-carboxaMide(CAS DataBase Reference)
• NIST Chemistry Reference: (S)-1-(2-Chloroacetyl)pyrrolidine-2-carboxaMide(214398-99-9)
• EPA Substance Registry System: (S)-1-(2-Chloroacetyl)pyrrolidine-2-carboxaMide(214398-99-9)

Safety Data

• Hazardous Substances Data: 214398-99-9(Hazardous Substances Data)

Usage

Uses

(S)-1-(2-Chloroacetyl)pyrrolidine-2-carboxamide is used in the synthesis of Vildagliptin (V305000), an oral anti-diabetic drug, and its impurities (H971380) (Impurity A).

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

• 1044676-63-2 vildagliptin 
• 914070-99-8 (S)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile 
• 739366-20-2 (S)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropyl}amide 
• 565452-98-4 1-chloroacetyl-2-cyano-(R)-pyrrolidine 

Relevant articles and documents

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.

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%.

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.