- A validated chiral LC method for the enantiomeric separation of repaglinide on immobilized amylose based stationary phase
-
A simple, rapid, isocratic, normal phase chiral HPLC method was developed and validated for the enantiomeric separation of repaglinide, (S)-(+)-2-ethoxy-4-N [1-(2-piperidinophenyl)-3-methyl-1-butyl] aminocarbonylmethyl] benzoic acid, an antidiabetic drug substance. The enantiomers of repaglinide were resolved on a Chiralpak IA (immobilized amylose based stationary phase) column using a mobile phase consisting of n-hexane: ethanol: trifluoroacetic acid (80:20:0.2, v/v/v) at a flow rate of 1.0 mL min-1. The resolution between both enantiomers was greater than 2 in the optimized method. The developed method was extensively validated and proved to be robust, enantioselective, accurate, precise, and suitable for quantitative determination of (R)-enantiomer in bulk drug substance and product.
- Patil, Kiran,Rane, Vipul,Yeole, Ravindra,Shinde, Devanand
-
-
Read Online
- Synthesis process of hypoglycemic drug repaglinide
-
The invention discloses a synthesis process of a hypoglycemic drug repaglinide. The process comprises the following steps: a) by using a compound II (S,S')-3-methyl-1-(2-piperidinophenyl)butylamine asa raw material, dissociating with an alkali, and directly condensing the obtained organic phase containing a compound III repigine with a compound IV 3-ethoxy-4-ethoxycarbonyl phenylacetic acid in the presence of an acylation reagent and an alkali without concentration; b) refining the compound V repaglinide ester crude product obtained after condensation by using an alkane solvent; and c) hydrolyzing in the presence of an alcohol solvent and an inorganic alkali, carrying out acidifying of post-treatment at a proper temperature, and purifying the obtained compound I repaglinide crude productby using an alcohol-water mixed solvent to obtain a repaglinide fine product. The synthesis process provided by the invention simplifies the synthesis steps, has the advantages of environmental protection, simple operation, high yield, low cost and the like, and is a repaglinide synthesis process suitable for industrial large-scale production.
- -
-
-
- Synthesis method of repaglinide
-
The invention discloses a synthesis method of repaglinide, and belongs to the technical field of medicine synthesis. The method comprises the following steps that ortho-halogenated benzaldehyde is taken as a raw material, a 2-piperidine-1-benzaldehyde compound 1 is obtained through piperidine substitution and reacts with (R)-methylpropane-2-sulfinamide to obtain an imine compound 2, then the iminecompound 2 reacts with a 2-methyl-1-propylene Grignard reagent lithium chloride, and through reduction, an S-(+)-1-(2-piperidine phenyl)-3-methyl n-butylamine compound 3 is obtained; then the S-(+)-1-(2-piperidine phenyl)-3-methyl n-butylamine compound 3 and 4-carboxyl methyl-2-ethoxy benzoate are condensed to obtain an S-(+)-2-oxethyl-4-[N-{1-(2-piperidine phenyl)-3-methyl-1-butyl}amine carbonylmethyl]benzoate compound 4; finally, the repaglinide 5 is obtained through hydrolysis. Compared with other technologies, the synthesis method has the advantages that operation is simple, the raw materials are easy to obtain, the yield is high, the cost is low, and the method is environmentally friendly; the product repaglinide has very high optical purity and is suitable for industrial production.
- -
-
-
- Studies on diastereofacial selectivity of a chiral tert-butanesulfinimines for the preparation of (S)-3-Methyl-1-(2-piperidin-1-yl-phenyl)butylamine for the synthesis of repaglinide
-
A new method for the asymmetric synthesis of a series of chiral amines including (S)-3-methyl-1-(2-piperidin-1-yl-phenyl)butylamine (2a) a key intermediate to prepare antidiabetic drug repaglinide by using Ellman's reagent tert-butanesulfinamide. Diastereoselective addition of organometallic reagents to t-butanesulfinimines and followed by acidic and basic treatment. The obtained chiral amines were characterized by NMR, MS and other analytical data.
- Nagarajan, Periyandi,Rajendiran, Chinnapillai,Naidu,Dubey
-
p. 9345 - 9350
(2013/11/19)
-
- Repaglinide Substantially Free of Dimer Impurity
-
The present invention provides highly pure repaglinide substantially free of dimer impurity, and process for the preparation thereof. The present invention also relates to 2-ethoxy-N-[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]-4-[2-[[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzamide, an impurity of repaglinide, and a process for preparing and isolating thereof. The present invention further relates to pharmaceutical compositions comprising solid particles of pure repaglinide substantially free of dimer impurity or pharmaceutically acceptable salts thereof, wherein 90 volume-percent of the particles (D90) have a size of less than about 400 microns. The present invention also provides an optical resolution method of racemic 3-methyl-1-(2-piperidino-phenyl)-1-butylamine and use thereof for the preparation of repaglinide.
- -
-
Page/Page column 13-14
(2010/08/08)
-
- Process for the preparation of substantially optically pure Repaglinide and precursors thereof
-
The invention relates to a process for preparing substantially optically pure Repaglinide and pharmaceutically acceptable salts, solvates and esters thereof, as well as precursors therefore.
- -
-
Page/Page column 15
(2010/05/13)
-
- Pharmaceutically acceprable salts of aporphine compounds of carboxyl group-containing agents and methods for preparing the same
-
The present invention discloses novel pharmaceutically acceptable salts of aporphine compounds and carboxyl-group containing agents. Also, the present invention discloses methods for preparing the pharmaceutically acceptable salts. These pharmaceutically acceptable salts are suitable for use in treating and/or preventing hyperglycemic disease and/or several oxidative stress related diseases.
- -
-
-
- Process for preparing (alphaS)-alpha-(2-methylpropyl)-2-(1-piperidinyl)benzenemethanamine
-
The present invention relates to a process for the preparation of (αS)-α-(2-methylpropyl)-2- (1-piperidinyl)benzenemethanamine of Formula I, which is a key intermediate for the synthesis of Repaglinide.
- -
-
Page/Page column 8
(2009/02/10)
-
- Process for Preparing Ethyl (s)-2-Ethoxy-4-[N-[1-(2-Piperidinophenyl)-3-Methyl-1-Butyl]Aminocarbonyl Methyl]Benzoate and Use Thereof for the Preparation of Repaglinide
-
Described herein is an improved, commercially viable and industrially advantageous process for the preparation of Repaglinide intermediate, ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate. The process provides the Repaglinide intermediate in higher yield and purity compared to the previously disclosed processes, thereby providing for production of Repaglinide and its pharmaceutically acceptable salts in high purity and in high yield.
- -
-
Page/Page column 4
(2008/12/08)
-
- An improved process for repaglinide via an efficient and one pot process of (1S)-3-methyl-1-(2-piperidin-1-ylphenyl)butan-1-amine - A useful intermediate
-
The development of a large-scale synthesis for (1S)-3-methyl-1-(2- piperidin-1-ylphenyl)butan-1-amine (S-(+)-1), a key intermediate of repaglinide (2), is described. The process conditions for S-(+)-1 involving nucleophilic substitution, Grignard reaction, reduction and resolution were optimized and telescoped. The racemization of the undesired enantiomer R-(-)-1 offers a distinctive advantage in terms of cost and overall yield over the existing process. This communication also describes the control of a DCU byproduct obtained during the condensation of S-(+)-1 with phenyl acetic acid derivative 3 in the synthesis of 2. Schweizerische Chemische Gesellschaft.
- Kolla, Naveenkumar,Elati, Chandrashekar R.,Vankawala, Pravinchandra J.,Gangula, Srinivas,Sajja, Eswaraiah,Anjaneyulu, Yerremilli,Bhattacharya, Apurba,Sundaram, Venkataraman,Mathad, Vijayavitthal T.
-
p. 593 - 597
(2007/10/03)
-
- USE OF SUBSTITUTED 2 PHENYLBENZIMIDAZOLES AS MEDICAMENTS
-
The present invention relates to the use of a substituted 2-phenylbenzimidazole of formula I wherein R1, R2, R3, R 4, R5 and m have the meanings given in the claims, for the preparation of a medicament for the treatment or prevention of diseases involving glucagon receptors, as well as new compounds of formula I wherein R1 is a group of formula
- -
-
-
- PROCESS FOR THE PREPARATION OF S(+)-2-ETHOXY-4-[N-{1-(2-PIPERIDINOPHELYL)-3-METHYL-1- BUTYL} AMINOCARBONYLMETHYL]BENZOIC ACID DERIVATIVES
-
The present invention relates to a novel process for the preparation of S(+)-2-ethoxy-4-[N-{1-(2-piperidinophelyl)-3-methyl-1-butyl} aminocarbonylmethyl]-benzoic acid derivatives.
- -
-
-
- METHOD FOR THE PRODUCTION OF PHENYLACETIC ACID DERIVATIVES
-
Disclosed is a method for producing (S) (+) phenylacetic acid derivatives of general formula (I), wherein R1 represents a linear or branched alkyl radical with 1 to 6 carbon atoms or optionally substituted benzyl while R2 represents methyl, ethyl, or propyl. The inventive method is characterized in that a compound of general formula (II), wherein R1 has the meaning indicated above and R3 represents a nucleofuge, or a suitable salt of a compound of general formula (II) is reacted with a compound of general formula (III), wherein R2 has the meaning indicated above and R4 represents hydrogen or a hydrolytically cleavable nucleofuge, whereupon the optionally provided protective group R4 is eliminated.
- -
-
Page/Page column 13-14
(2010/02/09)
-
- Combinations comprising dipeptidylpeptidase-iv inhibitor
-
The invention relates to a combination which comprises a DPP-IV inhibitor and at least one further antidiabetic compound, preferably selected from the group consisting of insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (G6Pase), inhibitors of fructose-1,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, α-glucosidase inhibitors, inhibitors of gastric emptying, insulin, and α2-adrenergic antagonists, for simultaneous, separate or sequential use in the prevention, delay of progression or treatment of conditions mediated by dipeptidylpeptidase-IV (DPP-IV), in particular diabetes, more especially type 2 diabetes mellitus, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis; and the use of such combination for the cosmetic treatment of a mammal in order to effect a cosmetically beneficial loss of body weight.
- -
-
-
- Repaglinide and related hypoglycemic benzoic acid derivatives
-
The structure-activity relationships in two series of hypoglycemic benzoic acid derivatives (5, 6) were investigated. Series 5 resulted from meglitinide (3) when the 2-methoxy was replaced by an alkyleneimino residue. Maximum activity was observed with the cis-3,5-dimethylpiperidino (5h) and the octamethyleneimino (5l) residues. Series 6 resulted from the meglitinide analogon 4 bearing an inversed amido function when the 2-methoxy, the 5- fluoro, and the α-methyl residue were replaced by a 2-piperidino, a 5- hydrogen, and a larger α-alkyl residue, respectively. An alkoxy residue ortho to the carboxy group further increased activity and duration of action in the rat. The most active racemic compound, 6al (R4 = isobutyl; R = ethoxy), turned out to be 12 times more active than the sulfonylurea (SU) glibenclamide (1). Activity was found to reside predominantly in the (S)- enantiomers. Compared with the SUs 1 and 2 (glimepiride), the most active enantiomer, (S)-6al (AG-EE 623 ZW; repaglinide; ED50 = 10 μg/kg po), is 25 and 18 times more active. Repaglinide turned out to be a useful therapeutic for type 2 diabetic patients; approval was granted recently by the FDA and the EMEA. From investigations on the pharmacophoric groups in compounds of type 5 and 6, it was concluded that in addition to the two already known - the acidic group (COOH; S02NH) and the amidic spacer (CONH; NHCO) - the ortho residue R1 (alkyleneimino; alkoxy; oxo) must be regarded as a third one. A general pharmacophore model suitable for hypoglycemic benzoic acid derivatives, SUs, and sulfonamides is proposed (Figure 6). Furthermore, from superpositions of low-energy conformations (LECs) of 1, 2, and (S)-6al, it was concluded that a common binding conformation (LEC II; Figure 10B) may exist and that differences in binding to the SU receptor and in the mechanism of insulin release between repaglinide and the two SUs may be due to specific hydrophobic differences.
- Grell, Wolfgang,Hurnaus, Rudolf
-
p. 5219 - 5246
(2007/10/03)
-
- Phenylacetic acid benzylamides
-
The present application relates to the uses of phenylacetic acid benzylamides and new (S)(+)-2-ethoxy-4-[N-[1-2-piperidino-phenyl)-3-methyl-1-butyl]-aminocarbonylmethyl]benzoic acid and the salts thereof, which have valuable pharmacological properties, namely an effect on the intermediate metabolism, but particularly the effect of lowering blood sugar.
- -
-
-
