668270-12-0

Basic information

• Product Name: Linagliptin
• Synonyms: linagliptin;8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione;(R)-8-(3-Amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione;1H-Purine-2,6-dione, 8-((3R)-3-amino-1-piperidinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-((4-methyl-2-quinazolinyl)methyl)-;Bi 1356;Ondero;8-[(3R)-3-aMinopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-Methyl-1-[(4-Methylquinazolin-2-yl)Methyl]-2,3,6,7-tetrahydro-1H-purine-2,6-dione;8-[(3R)-3-AMino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-Methyl-1-[(4-Methyl-2-quinazolinyl)Methyl]-1H-purine-2,6-dione
• CAS NO: 668270-12-0
• Molecular Formula: C25H28N8O2
• Molecular Weight: 472.54
• EINECS: 1308068-626-2
• Product Categories: Amines;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;API;Pharmaceutical raw material;Inhibitor;Linagliptin;TRADJENTA
• Mol File: 668270-12-0.mol

Chemical Properties

• Melting Point: 202 ºC
• Boiling Point: 661.189 °C at 760 mmHg
• Flash Point: 353.675 °C
• Appearance: /
• Density: 1.39
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.717
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Sparingly), DMSO (Slightly), Methanol (Slightly)
• PKA: 10.01±0.20(Predicted)
• CAS DataBase Reference: Linagliptin(CAS DataBase Reference)
• NIST Chemistry Reference: Linagliptin(668270-12-0)
• EPA Substance Registry System: Linagliptin(668270-12-0)

Safety Data

• Hazardous Substances Data: 668270-12-0(Hazardous Substances Data)

Usage

Uses

Different sources of media describe the Uses of 668270-12-0 differently. You can refer to the following data:
1. Linagliptin (TrajentaR, TradjentaTM, TrazentaTM, TrayentaTM) is an oral, highly selective inhibitor of dipeptidyl peptidase-4 and is the first agent of its class to be eliminated predominantly via a nonrenal route. Linagliptin is indicated for once daily use for the treatment of adults with type 2 diabetes mellitus.
2. A novel potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor with potential use in the treatment of type 2 diabetes.
3. dipeptidypeptidase inhibitor, antidiabetic
4. highly potent CD26 inhibitor
5. Labeled Linagliptin, intended for use as an internal standard for the quantification of Linagliptin by GC- or LC-mass spectrometry.

Treatment of Type 2 diabetes

Linagliptin acts to lower blood glucose levels by inhibiting the enzyme DPP-4, thereby preventing the degradation of the incretin hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide) and attenuating postprandial glucose excursions. By selectively targeting DPP-4, linagliptin potentially causes a more physiologically based control of glucose-dependent postprandial glucose excursions and of fasting blood glucose, both of which are mediated by effects of glucose on insulin and glucagon secretion. An advantage of linagliptin is that since incretin-stimulated release of insulin is glucose dependent, linagliptin is associated with a low incidence of hypoglycaemia. Moreover, DPP-4 inhibitors have a low potential for drug-drug interactions (with the exception of saxagliptin, which is metabolized by cytochrome P450 [CYP] 3A4/5), are generally well tolerated and have minimal or neutral effects on bodyweight.

Pharmacokinetics

Linagliptin shows modest oral bioavailability, and it is rapidly absorbed. The maximum plasma concentration at steady state is reached on average 1.5 hours after administration of linagliptin 5 mg, once daily . Linagliptin half-life is 131 hours. No relevant food effects were observed on the absorption profile of linagliptin. Unlike other DPP-4 inhibitors, linagliptin excretion is not performed by the kidneys, but rather through the enterohepatic system.

Originator

Boehringer Ingelheim (United States)

Definition

ChEBI: A xanthine that is 7H-xanthine bearing (4-methylquinazolin-2-yl)methyl, methyl, but-2-yn-1-yl and 3-aminopiperidin-1-yl substituents at positions 1, 3, 7 and 8 respectively (the R-enantiomer). Used for treatment of type I diabetes.

Brand name

Tradjenta

Clinical Use

Type 2 diabetes mellitus

Synthesis

The synthesis of linagliptin began from commercially available 8-bromo-3-methylxanthine (171). Sequential alkylations of guanine derivative 171 at N-7 with butyn-2-yl bromide in the presence of N,N-diisopropylethylamine and N-1 with 2- (chloromethyl)-4-methylquinazoline (173) in the presence of potassium carbonate, yielded N1,N7-dialkylated xanthine 174 in 85% yield. This material was further condensed with (R)-3-Bocaminopiperidine (175) in the presence of potassium carbonate to give aminopurine dione 176 in 88% yield. Finally, the primary amine of 176 was liberated with trifluoroacetic acid in methylene chloride to produce linagliptin (XV) in 91% yield.

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: effects possibly reduced by rifampicin.

Metabolism

Minimal metabolism to inactive metabolites. Approximately 80% is eliminated in the faeces and 5% in the urine.

InChI:InChI=1/C25H28N8O2/c1-4-5-13-32-21-22(29-24(32)31-12-8-9-17(26)14-31)30(3)25(35)33(23(21)34)15-20-27-16(2)18-10-6-7-11-19(18)28-20/h6-7,10-11,17H,8-9,12-15,26H2,1-3H3/t17-/m1/s1

Upstream product

• 334618-23-4 3-(R)-aminopiperidine dihydrochloride 
• 853029-57-9 2-bromo-1-(but-2-ynyl)-4-methyl-6-((4-methylquinazolin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-5,7-(4H,6H)-dione 
• 1352756-66-1 (R)-piperidine-3-amine dibenzoyl-D-tartrate 
• 666816-98-4 8-bromo-7-(but2-yn-1-yl)-3-methyl-3,7-dihydro-1H-purine-2,6–dione 
• 127294-73-9 (R)-piperidin-3-ylamine 
• 93703-24-3 3-methyl-8-bromoxanthine 
• 1233245-24-3 linagliptin phosphate 
• 1076-22-8 3-methylxanthine 
• 109113-72-6 2-chloromethyl-4-methylquinazoline 
• 1186123-48-7 (R)-isopropyl piperidin-3-ylcarbamate 
• 666816-91-7 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)piperidin-1-yl]xanthine 
• 886588-63-2 (R)-7-(but-2-yn-1-yl)-8-(3-(1,3-dioxoisoindolin-2-yl)piperidin-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine2,6-dione 
• 141-43-5 ethanolamine 
• 454709-06-9 7-but-2-ynyl-8-chloro-3-methyl-3,7-dihydro-purine-2,6-dione 

Relevant articles and documents

Novel preparation process of linagliptin

The invention discloses a novel preparation process of linagliptin. 8-bromo-3-methyl xanthine (SM1) is used as an initial raw material, DMF is used as a solvent and reacts with 1-bromo-2-butyne (SM2)under the alkaline condition to obtain an intermediate I, then the intermediate I reacts with 2-chloromethyl-4-methyl quinazol (SM3) under the solvent system to obtain an intermediate II, the intermediate II and (R) 3-aminopiperidine dihydrochloride (SM4) are subjected to a substitution reaction, and finally anti-type 2 diabetes drug linagliptin (I) is prepared. By adopting a one-pot method, the method has the advantages that the raw material cost is low, the yield is high, the post-treatment operation of each step of chemical reaction in multi-step reaction is reduced, the production period is greatly shortened, few impurities are generated in the reaction, the product quality is high, the use amount of chemical reagents is relatively reduced, and the method is relatively green and environment-friendly, and is beneficial to industrial production.

Novel preparation process of linagliptin

The invention discloses a novel preparation process of linagliptin. 8-bromine-3-methyl xanthine (SM1) is used as an initial raw material, DMF is used as a solvent to react with 1-bromine-2-butyne (SM2) under an alkaline condition to obtain an intermediate I, then the intermediate I reacts with 2-chloromethyl-4-methyl quinazol (SM3) under the solvent system to obtain an intermediate II, and the solvent system reacts with (R)-3-Boc-aminopiperidine (SM4) under the alkaline condition to obtain an intermediate III; and the protecting group is dissociated by using acid to obtain the linagliptin (I) for resisting type 2 diabetes mellitus. By adopting a one-pot method, the method has the advantages that the raw material cost is low, the yield is high, the post-treatment operation of each step of chemical reaction in multi-step reaction is reduced, the production period is greatly shortened, few impurities are generated in the reaction, the product quality is high, the use amount of chemical reagents is relatively reduced, and the method is relatively green and environment-friendly, and is beneficial to industrial production.

Preparation method of linagliptin for treating type II diabetes mellitus

The invention provides a preparation method of linagliptin for treating type II diabetes mellitus, which comprises the following steps: by using methylurea and ethyl cyanoacetate as raw materials, carrying out cyclization reaction to form a compound II, carrying out bromination reaction on the compound II to generate a compound III, carrying out condensation reaction on the compound III and 1-amino-2-butyne to generate a compound IV, making the compound IV, formic acid and an iodine source react in an organic solution to generate a compound V, reacting the compound V and a compound VI under the conditions of DMF and anhydrous potassium carbonate, reacting with (R)-3-Boc-aminopiperidine (VIII), and recrystallizing to obtain a pure target compound I, namely linagliptin. The invention provides a novel preparation method of linagliptin, which has the advantages of simple method, high reaction yield, avoidance of side reaction, cheap raw materials, reduction of the reaction cost, increase of the yield of the target compound, and suitableness for industrial large-scale production.

Method for preparing high-purity linagliptin

The invention discloses a method for preparing high-purity linagliptin, which takes a linagliptin crude product (purity of 98.76%) as an initial raw material; since the purity cannot reach the qualitystandard of a raw material medicine, the high-purity linagliptin is obtained by the following process scheme: adding an organic solvent into the linagliptin crude product for dissolving, dropwise adding an acid solution for extraction, and separating liquid; then adding an organic solvent into the water phase, dropwise adding an alkaline solution for extraction, separating liquid, and evaporatingthe organic phase to dryness under reduced pressure; dissolving the decompressed and evaporated solid in an organic solvent, and performing cooling crystallization to obtain a high-purity target product linagliptin solid. According to the method for preparing the high-purity linagliptin, the purity can reach 99.99% at most; compared with the prior art, solvents such as methyl acetate and acetonitrile are used, toxicity is low, a mother liquor solvent can be recycled, and environmental pollution is reduced. The method is simple and easy to operate and convenient for industrial large-scale production.

Preparation method of linagliptin

The invention relates to a preparation method of linagliptin. The method comprises the following steps: taking a raw material I, namely 2-chloromethyl-4-methylquinazoline, and a raw material II, namely 8-bromo-7-(2-butynyl)-3-methyl-1H-purine-2, 6 (3H, 7H)-diketone as raw materials, performing reaction to obtain an intermediate III, namely 8-bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methylquinazoline-2-yl)-methyl]-1H-purine-2, 6-diketone, and performing reaction with a raw material IV: (R)-3-aminopiperidine hydrochloride to prepare a target product. In the reaction process, a protecting group does not need to be added, the step of removing the protecting group after the reaction is completed is omitted, and the generation of reaction byproducts in the process of removing the protecting group is reduced. The solvents used in the method are beneficial to recycling, low in price, environment-friendly, green and environmentally friendly, and the obtained product is high in yield, high in purity and suitable for large-scale production.

Route for synthesizing diabetes medicine linagliptin

The invention relates to synthesis of a diabetes medicine linagliptin and particularly relates to a new preparation method for 1-[(4-methylquinazoline-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-bromo-xanthine.

Linagliptin intermediate compound V

The invention belongs to the field of pharmaceutical chemicals, and provides a linagliptin intermediate compound V and an important intermediate for synthesizing linagliptin by using the intermediateV. The method solves the problems of self-coupling of linagliptin intermediates and generation of large impurities in the prior art, and the synthesized novel intermediate compound V has the advantages of high yield, simple operation, significantly reduced production cost, and suitableness for industrial production.

Linagliptin intermediate compound IV

The invention belongs to the field of pharmaceutical chemicals, and discloses a linagliptin intermediate IV and a novel route for synthesizing an important linagliptin intermediate from the linagliptin intermediate IV. The linagliptin intermediate IV synthesized in the invention has the advantages of high yield, simple operation, substantial reduction of production cost, suitableness for industrial production; and the synthesis route solves the problems of self-coupling of linagliptin intermediates and generation of large impurities in the prior art.

Industrial preparation method of linagliptin

The invention belongs to the technical field of medicines, and particularly relates to an industrial preparation method of linagliptin. The preparation method comprises the following steps: adding N,N-dimethylacetamide into a reaction kettle, sequentially adding 8-bromo-7-(2-butyne)-3-methylxanthine, 2-chloromethyl-4-methylquinazoline, anhydrous sodium carbonate, anhydrous potassium carbonate andmethyl tert-butyl ether, and sequentially heating, cooling, stirring, filtering, carrying out HPLC monitoring and the like to obtain intermediates I and II, thereby finally obtaining linagliptin. Theindustrial preparation method of linagliptin provided by the invention is simple, high in intermediate purity, low in environmental pollution and low in cost, and meets the requirements of industrialmedicinal products.

Preparation method for linagliptin and intermediate thereof

The invention discloses a preparation method for linagliptin and an intermediate thereof. In the process of preparation of a linagliptin intermediate D from a compound 8-bromine-7-(2-butynyl)-3, 7-dihydro-3-methyl-1-[(4-methyl-2-quinazoline)methyl]-1H-purine-2, 6-dione, on one hand, a mixed solvent of acetonitrile and an aprotic polar solvent is adopted, so that the reaction time is shortened, andon the other hand, by increasing the water adding amount in the post-treatment process, crystals are separated out through heat preservation at 56-74 DEG C and then cooled, the content of impuritiescontained in the crystals is reduced, and the purity of a product is improved; in the step of removing tert-butyloxycarboryl protection, reaction liquid is directly added into alkali liquor in a reverse dripping mode in post-treatment, impurities generated due to improper post-treatment are reduced, and the reaction yield is increased. According to the preparation method, linagliptin with high purity and high yield can be obtained, and the preparation method is suitable for industrial production.