207557-35-5

Usage

Uses

Used in Pharmaceutical Industry:
(2S)-1-(Chloroacetyl)-2-pyrrolidinecarbonitrile is used as a key intermediate for the synthesis of dipeptidyl peptidase IV (DPP-IV) inhibitors, specifically for the production of Vildagliptin (V305000). This application is significant because DPP-IV inhibitors play a vital role in managing type 2 diabetes by reducing blood glucose levels and improving insulin sensitivity.
As a result, (2S)-1-(Chloroacetyl)-2-pyrrolidinecarbonitrile is essential in the development of medications that help control and manage diabetes, offering a promising avenue for the treatment of this prevalent metabolic disorder.

InChI:InChI=1/C7H9ClN2O/c8-4-7(11)10-3-1-2-6(10)5-9/h6H,1-4H2/t6-/m0/s1

Upstream product

• 214398-99-9 (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide 
• 147-85-3 L-proline 
• 147-85-3 L-proline 
• 56-86-0 L-glutamic acid 
• 1119-33-1 (S)-2-Amino-pentanedioic acid 5-ethyl ester 
• 7531-52-4 L-prolinamide 
• 96166-39-1 1-glycoloyl-L-proline amide 
• 79-04-9 chloroacetyl chloride 
• 228244-04-0 tert-butyl (2S)-2-cyanopyrrolidine-1-carboxylate 
• 204387-53-1 (2S)-pyrrolidine-2-carbonitrile 
• 79-11-8 chloroacetic acid 
• 204387-54-2 (2S)-pyrrolidine-2-carbonitrile 4-methylbenzene-1-sulfonic acid 
• 42429-27-6 L-prolinamide hydrochloride 
• 15761-39-4 1-(tert-butoxycarbonyl)-L-proline 

Downstream Products

• 247016-69-9 (S)-1-{2-[(5-cyanopyridin-2-yl)amino]ethyl-aminoacetyl}-2-cyano-pyrrolidine 
• 274901-16-5 vildagliptin 
• 739365-95-8 tert-butyl N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]carbamate 

Relevant academic research and scientific papers

Synthesis of main impurity of vildagliptin

A four-step synthesis of the main impurity of vildagliptin has been easily accomplished with high-yielding starting from L-proline. This compound can be used as a reference marker in an analytical method to determine the chemical purity of the vildagliptin.

Design, synthesis, biological screening, and molecular docking studies of piperazine-derived constrained inhibitors of DPP-IV for the treatment of type 2 diabetes

Novel piperazine-derived conformationally constrained compounds were designed, synthesized, and evaluated for in vitro Dipeptidyl peptidase-IV (DPP-IV) inhibitory activities. From a library of compounds synthesized, 1-(2-(4-(7-Chloro-4-quinolyl)piperazin-1-yl)acetyl)pyrrolidine (2g) was identified as a potential DPP-IV inhibitor exhibiting better inhibitory activity than P32/98, reference inhibitor. The in vivo studies carried out in STZ and db/db mice models indicated that the compound 2g showed moderate antihyperglycemic activity as compared to the marketed drug Sitagliptin. A two-week repeated dose study in db/db mice revealed that compound 2g significantly declined blood glucose levels with no evidence of hypoglycemia risk. Furthermore, it showed improvement in insulin resistance reversal and antidyslipidemic properties. Molecular docking studies established good binding affinity of compound 2g at the DPP-IV active site and are in favor of the observed biological data. These data collectively suggest that compound 2g is a good lead molecule for further optimization studies.

Bis-morpholinophosphorylchloride, a novel reagent for the conversion of primary amides into nitriles

Bis-morpholinophosphorylchloride (Bmpc), in the presence of a base, is an efficient dehydrating agent for both aromatic and aliphatic primary amides, and gives corresponding nitriles under mild conditions in god yields and purity. During the reaction the enantiomeric integrity remains intact.

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.

PROCESS FOR THE PREPARATION OF VILDAGLIPTIN

The present invention relates to process for the preparation of Vildagliptin. The present invention involves an ecologically friendly process by avoiding the dehydrating agent and use of reagents that are less expensive, easier to handle and its cost effective industrial applicable process.

A facile method to synthesize vildagliptin

An efficient and high-yielding synthetic method for the preparation of vildagliptin via four steps is reported. The process starts from L-proline and involves a successful reaction with chloroacetyl chloride in tetrahydrofuran to afford (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid, followed by a reaction with acetonitrile in the presence of sulfuric acid to give (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile. This is then reacted with 3-aminoadamantanol to give vildagliptin. 3-Aminoadamantanol is prepared from 1-aminoadamantane hydrochloride via oxidation with sulfuric acid/nitric acid and boric acid as the catalyst followed by ethanol extraction. The overall yield is 95%.

Preparation method of high chiral purity (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile

The invention discloses a preparation method of high chiral purity (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile, the preparation method comprises: S1, in the presence of a solvent and an acid-binding agent, carrying out a coupling reaction on L-proline and chloracetyl chloride to obtain an intermediate I; s2, in the presence of a solvent and sodium iodide, carrying out cyclization reaction on the intermediate I in an alkaline environment to obtain an intermediate II; s3, in the presence of a solvent and an ammonolysis agent, carrying out ammonolysis ring-opening reaction on the intermediate II to obtain an intermediate III; and S4, in the presence of a solvent and phosphorus oxychloride, carrying out chlorination and dehydration reaction on the intermediate III to obtain (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile. The method has the advantages of high chiral purity, simple steps, easily available and cheap raw materials, convenient post-treatment and high yield, and is suitable for industrial production.

PYRROLIDINE AND PIPERIDINE COMPOUNDS

The present technology provides pyrrolidine and piperidine compounds or pharmaceutically acceptable salts thereof, preparation processes thereof, pharmaceutical compositions comprising the same, and uses thereof. In particular, said compounds may be usefully applied in the treatment and prevention of FAP-mediated diseases.

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.

Synthesis method of vildagliptin

The invention discloses a synthesis method of vildagliptin. The method comprises the following steps: performing esterification reaction on L-glutamic acid and ethanol to obtain L-glutamic acid-gamma-ethyl ester; reducing the L-glutamic acid-gamma-ethyl ester under the action of potassium borohydride to obtain L-proline; mixing L-proline with ethyl chloroformate for reaction to obtain acid anhydride; further reacting the acid anhydride with amine to obtain amide; dehydrating the amide under the action of phosphorus pentoxide to obtain an intermediate 1; performing substitution reaction on theintermediate 1 and chloroacetyl chloride to obtain an intermediate 2; and further reacting the intermediate 2 with 3-amino-1-adamantanol to obtain vildagliptin. The method has the advantages that fewimpurities are generated in the vildagliptin preparation process, the yield of the prepared vildagliptin is high, and compared with the prior art, the process is simpler, and the vildagliptin preparation cost is greatly reduced.