- Novel preparation process of linagliptin
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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.
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- Novel preparation process of linagliptin
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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.
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- Method for preparing high-purity linagliptin
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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.
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Paragraph 0015-0016
(2021/03/31)
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- Preparation method of linagliptin
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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.
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Paragraph 0009; 0032; 0034-0036; 0038
(2021/06/21)
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- Preparation method of linagliptin for treating type II diabetes mellitus
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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.
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Paragraph 0085-0094
(2021/03/30)
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- Industrial preparation method of linagliptin
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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.
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- Linagliptin intermediate compound V
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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.
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- Linagliptin intermediate compound IV
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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.
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- Route for synthesizing diabetes medicine linagliptin
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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.
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- Preparation method for linagliptin and intermediate thereof
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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.
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Paragraph 0033; 0041-0043; 0044-0065
(2020/04/17)
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- METHOD FOR PRODUCING LINAGLIPTIN
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PROBLEM TO BE SOLVED: To provide a novel method for producing linagliptin suitable for large-scale industrial production by solving the problem of a conventional method for producing linagliptin, in which: an impurity less likely to remove is generated in a removing step of a t-butyloxy carbonyl group which is a protective group; and a compound which is not suitable for industrial production must be used in the reaction of the removing step. SOLUTION: A method for synthesizing linagliptin (Compound 1) from compound 4 comprises following steps A and B: (step A) a step of dissolving compound 4 in a hydrophilic organic solvent and then incubating it under acidic conditions; and (step B) after completion of step A, a step of collecting the aqueous layer part to incubate it under basic conditions of pH 11 or higher. In the formula, Boc represents a t-butyloxy carbonyl group. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPO&INPIT
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Paragraph 0061-0067
(2020/07/03)
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- CRYSTALLINE LINAGLIPTIN INTERMEDIATE AND PROCESS FOR PREPARATION OF LINAGLIPTIN
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The present invention provides novel crystalline forms B1 and B2 of linagliptin intermediate of structural formula V and methods for production of novel crystalline form of linagliptin intermediate represented by the following structural formula V.
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- Preparation method of linagliptin for treating diabetes
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The invention provides a preparation method of linagliptin. The preparation method comprises the following steps: in the presence of cuprous chloride catalyst, cyclizing 2-aminoacetophenone and a corresponding amide, which are taken as starting materials, to obtain a quinazoline compound; and in addition, sulfonyl is easier to remove compared with halogen, and is introduced into reaction raw materials, sulfonyl is easier to be replaced in subsequent substitution reaction, and a high-yield coupling product is obtained. The method has the advantages of short reaction route, high yield and few byproducts, lowers the production cost, and is beneficial to industrial production.
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- INTERMEDIATES AND PROCESSES FOR THE PREPARATION OF LINAGLIPTIN AND ITS SALTS
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The present invention relates to new intermediates for the synthesis of Linagliptin and of its salts and a process for its preparation involving said intermediates.
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Page/Page column 12; 13; 14
(2019/12/04)
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- PREPARATION METHODE OF 5-PHENYL PENTYL HEXAHYDRO CYCLOPENTAFURAN COMPOUNDS AND CYCLOHEPTANOATE COMPOUNDS
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The present invention relates to a novel linagliptin salt compound, a method for manufacturing the same, and linagliptin prepared from the novel linagliptin salt compound. The method according to the present invention can provide the method for manufacturing the novel linagliptin salt compound by using picolinic acid which is not harmful to the human body. In addition, it is possible to manufacture a novel linagliptin picolinate having properties similar to or better than linagliptin. Furthermore, it is possible to manufacture high purity linagliptin from the novel linagliptin salt compound.COPYRIGHT KIPO 2020
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Paragraph 0048-0051
(2020/02/20)
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- Improved method for preparation process of linagliptin
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The invention relates to an improved method for preparation process of linagliptin, which mainly comprises the step of performing hydrolysis to remove Boc protection to prepare linagliptin under the action of Lewis acid. According to the method, the defects of more byproducts and lower purity in the linagliptin preparation process by Boc removal protection in the conventional method are avoided, the adopted route is mild in process condition and simple to operate, the generation of byproducts during Boc removal can be effectively controlled, the product purity is high, and the method is suitable for industrial production.
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Paragraph 0004; 0008; 0009
(2020/01/08)
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- Preparation method of linagliptin
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The invention provides a preparation method of linagliptin for treating type II diabetes mellitus. The preparation method comprises the following steps: in the presence of alkali, taking 8-bromo-3,7-dihydro-3-methyl-7-(2-butynyl)-1H-purine-2,6-dione and (R)-3-aminopiperidine dihydrochloride to react in ethanol; after reaction is finished, filtering and concentrating; adding water and regulating the pH (Potential of Hydrogen) value to be acidic; extracting through an organic solvent; removing byproducts, residual raw materials and other impurities; regulating the pH value to be alkaline; extracting a water layer through the organic solvent again and concentrating; recrystallizing through the ethanol to obtain a compound 8-[(R)-3-amino-piperidine-1-yl]-3,7-dihydro-3-methyl-7-(2-butynyl)-1H-purine-2,6-dione; taking the compound 8-[(R)-3-amino-piperidine-1-yl]-3,7-dihydro-3-methyl-7-(2-butynyl)-1H-purine-2,6-dione, 4-methyl-2-chloro-methylquinazoline and potassium carbonate to react in theorganic solvent, so as to prepare the linagliptin. According to the preparation method, intermediates and the product are obtained by relatively high yield and purity; the reaction period is shortened and the production cost is reduced; guarantees are provided for finally obtaining the high-purity linagliptin.
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Paragraph 0025-0028
(2019/06/07)
-
- A preparation method of advantage geleg sandbank (by machine translation)
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The invention relates to a preparation method of Linagliptin. According to the preparation method, potassium carbonate or sodium carbonate is taken as an alkali; an iodine-containing inorganic salt is taken as a catalyst; N-methyl-2-pyrrolidone (NMP) or N,N-Dimethylformamide (DMF) is taken as a solvent; 8-bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1H-purine-2,6-dione is reacted with a (R)-3-aminopiperidine compound firstly at 40 to 50 DEG C; after reaction, 2-(chloromethyl)-4-methylquinazoline is directly added for reaction so as obtain a compound D; and the compound D is subjected to step 1-2 to prepare Linagliptin. The preparation method is capable of shortening reaction time, and increasing yield.
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Paragraph 0050; 0051
(2018/08/03)
-
- Chiral 8 - (3 - amino-piperidin - 1 - yl) - xanthine preparation method
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The invention relates to a preparation method of chiral 8-(3-aminopiperidine-1-yl)-xanthine. The preparation method comprises following steps: protecting the amino group of 3-aminopiperidine, and then subjecting 3-aminopiperidine to carry out reactions with 1-[3-nitrile-piridine-2-yl]-3-methyl-7-(2-butyne-1-yl)-8-bromine xanthine. The preparation method has a high reaction yield, guarantees the purity of 8-(3-aminopiperidine-1-yl)-xanthine, and is suitable for industrial production.
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Paragraph 0070; 0076; 0078
(2017/08/25)
-
- A preparation method of advantage geleg sandbank
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The invention discloses a preparation method for Trajenta. The Trajenta is a high-purity Trajenta which is prepared by taking a raw material 8-bromo-7-(2-butynyl)-3-methylxanthine, namely a compound a as basic material, selecting appreciate reaction material ratio, reaction time and reaction conditions in substitution, deprotection and other reaction steps. The preparation method has the beneficial effects that a novel method for preparing the Trajenta is provided, and dimer impurities generated in the reaction process are effectively avoided, so that the high-purity Trajenta is obtained, the raw material of the reaction are easily available, the production cost is low, and industrial production requirement of the Trajenta can be met to the greatest extent.
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- Compound I and (R)- 3 - amino piperidine hydrochloride II, its preparation method and its application in the synthesis of advantage geleg sandbank
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The invention discloses a preparation method of 3-aminopiperidine and its derivative with optical activity and an application of the compound and its derivative in synthesis of a dipeptidyl peptidase-IV inhibitor Linagliptin. According to the preparation
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Paragraph 0281-0282; 0283; 0286-0291; 0294-0295
(2017/10/22)
-
- Intermediates of linagliptin or analogues thereof and preparing method of the linagliptin or analogues thereof
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The invention provides intermediates which are inorganic acid salts or organic acid salts of compounds shown as a formula II and a preparing method thereof and also discloses a method of preparing linagliptin or analogues thereof by utilizing the intermediates which are the inorganic acid salts or organic acid salts of the compounds shown as the formula II. The method includes steps of 1) adding a solvent into the inorganic acid salts or organic acid salts of the compounds shown as the formula II, adding an acid into the mixture and reacting, 2) adjusting the pH value to 7-13, performing concentration, and then performing extraction, washing, drying and filtration to obtain a crude product of the linagliptin or analogues thereof, and 3) recrystallizing the crude product prepared in the step 2) to obtain the linagliptin or analogues thereof. The intermediates are particularly suitable for industrial production of the linagliptin or analogues thereof, a production process is simple, the yield is high, the cost is low and the purity of the prepared linagliptin or analogues thereof is high.
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Paragraph 0134-0137
(2017/05/18)
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- Process for preparing linagliptin
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The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a process for preparing linagliptin, and the process for preparing the linagliptin comprises the following steps: t-butoxycarbonyl protection removal of an intermediate II in C1-C6 saturated fatty acid as a solvent under the effect of trifluoroacetic acid to obtain the linagliptin, wherein a reaction formula is as shown in the specification. The process has the positive progress effect that through technical improvement of the reaction system, content of trifluoroacetylation impurities in a final product of the linagliptin is controlled to be 0.05% or below 0.05%, and the yield loss due to impurity control can be reduced, so that the synthetic cost of the final qualified product is reduced, and the process is more suitable for industrialization production.
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Paragraph 0022-0027
(2017/08/26)
-
- A advantage Ralli sandbank intermediate and its preparation method and application
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The present invention relates to a linagliptin intermediate, a preparation method and applications thereof, wherein the linagliptin intermediate has the structure represented by general formulas (II) and (IV), and X is halogen. According to the present invention, the compound of the present invention is the solid and has characteristics of low production cost, easy purification and easy storage, linagliptin can be efficiently prepared, and the method is suitable for industrial scale production.
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- PROCESS FOR THE PREPARATION OF A XANTHINE-BASED COMPOUND
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This invention relates to a method for preparation of a xanthine-based compound, as well as to intermediates useful in such preparation.
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- A method for preparing advantage Geleg sandbank (by machine translation)
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The invention discloses a method for preparing advantage Geleg sandbank, comprising the following steps: the tert-butoxy-carbonyl-Leigh geleg sandbank (g) is added to the methanol aqueous solution, the stirring is then started, in an inert atmosphere and heating to reflux of the reaction is carried out under the state, get advantage Geleg sandbank, wherein the reaction temperature is 25-50°C, the reaction time is 3-12h, tert-butoxy-carbonyl-Leigh geleg sandbank (g) with the weight proportion of the methanol water solution 100 : (400-550). Method for preparing advantage Geleg sandbank of this invention, is under the protection of inert gas and methanol aqueous solution Boc protecting group on the method, no longer need expensive trifluoro acetate-DCM Boc protecting group on the reaction, only use the cheap methanol-water systems can be, and after treatment is simple, and three suitable the reaction of acid-DCM system, generating a plurality of impurities, the after-treatment and purification process is extremely tedious. Furthermore, it is also possible to avoid the use of the strong acid intermediate (g) and row Gurley sandbank impurity such as in the breaking of amide linkage. (by machine translation)
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- Simple preparation method of high-purity linagliptin
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The invention relates to a simple preparation method of high-purity linagliptin. The method includes the steps of making 8-bromine-3-methyl xanthine and 1-bromo-2-butyne react, directly adding 2-chloromethyl-4-methylquinazoline without processing after reaction is completed, preparing a key intermediate 8-bromine-7-(2-butyne-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-diketone of linagliptin through a one-pot method, making the intermediate react with (R)-3-piperidinamine dihydrochloride after being filtered and separated to obtain a linagliptin solution, and obtaining a linagliptin pure product after processing the linagliptin solution. The key intermediate is prepared through the one-pot method, operation is convenient, and yield is increased; the key intermediate reacts with (R)-3-piperidinamine dihydrochloride after being separated, and therefore high-purity linagliptin is obtained, and the requirements for production and declaration of pharmaceutical enterprises are met to the maximum extent.
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- A method for synthesizing advantage Geleg sandbank (by machine translation)
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The invention discloses a method for synthesizing advantage Geleg sandbank, comprising the following steps : (1) the 8- [...] the 3 [...] methyl xanthine (a) and the 1 [...] -2 the butyne [...] (b) reaction, from the 3 [...] methyl -7 the [...] (2 the [...] butyne-l-yl) - 8 the [...] bromo-xanthine (c) ; (2) the 3 [...] methyl -7 the [...] (2 the [...] butyne-l-yl) - 8 the [...] bromo-xanthine (c) and 2 the [...] methyl -4 the methyl [...] quinazoline (d) reaction, to obtain the 1 [...] [(4 the [...] methyl quinazoline -2 the [...] ) methyl] - 3 the [...] methyl -7 the [...] (2 the [...] butyne -1 the [...] yl) - 8 the xanthine [...] (e) ; (3) to the 1 [...] [(4 the [...] methyl quinazoline -2 the [...] ) methyl] - 3 the [...] methyl -7 the [...] (2 the [...] butyne -1 the [...] yl) - 8 the xanthine [...] (e), (R) - 3 the ??Boc-amino piperidine (f), the potassium carbonate and acetonitrile added into the reactor, and they are uniformly mixed, under the state of the heating under reflux for reaction, the tert-butoxy-carbonyl-Leigh geleg sandbank (g) ; (4) the tert-butoxy-carbonyl-Leigh geleg sandbank (g) removing the protecting group Boc in aqueous solution of methanol, to obtain advantage Geleg sandbank. The synthetic method of this invention has no environmental pollution, high yield, no impurities. (by machine translation)
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- Industrial production method of linagliptin
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The invention provides an industrial production method of linagliptin. The method includes: adding In accordance with the molar ratio of 8-bromo-7-(2-butyne)-3-methylxanthine and 2-chloromethyl-4-methyl quinazoline into a dipolar aprotic organic solvent according to a mole ratio, then adding alkali and potassium iodide, performing crystallization, and conducting filtering and drying to obtain an intermediate I; adding the intermediate I and in accordance with the molar ratio (R)-3-t-butyloxycarborylamino piperidine into the dipolar aprotic organic solvent according to a mole ratio, then adding alkali, performing crystallization, and conducting filtration washing to remove inorganic salt, reducing pressure and removing the solvent to obtain a crude product, and then carrying out crystallization by methanol and isopropanol to obtain an intermediate II; and adding the intermediate II and a deprotection reagent into a reaction solvent according to a volume ratio, performing crystallization to obtain a crude product, then conducting recrystallization with ethanol, and carrying out filtering and drying to obtain a linagliptin final product. The method provided by the invention can greatly shorten the production cycle, save the production cost, obtain intermediates with higher purity, and achieve better impurity removal effect. The method is safe and reliable, is simple and easy to operate, and has good repeatability.
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- Preparation method for linagliptin
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The invention belongs to the technical field of bulk drug preparation and particularly relates to an improvement in a preparation method for linagliptin. According to the preparation method for linagliptin, the particle diameter of an acid-binding agent anhydrous sodium carbonate used in a linagliptin two-step condensation reaction is controlled on a micron order, an iodide catalyst is not needed during the reaction, similarly, the reaction temperature is decreased, reaction time is shortened, the two-step reaction is changed into a one-pot reaction, and a key intermediate E compound with high purity and yield is prepared. The preparation method is suitable for industrial mass production of linagliptin, and finally linagliptin with high purity and yield is obtained.
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Paragraph 0051
(2016/10/10)
-
- New Trajenta crystal form and preparation method thereof
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The invention belongs to the technical field of pharmaceutical chemistry and particularly relates to a new Trajenta crystal form and a preparation method thereof. The crystal form has good chemical stability and crystal form purity and is easy to prepare on a large scale, operation is easy, and the crystal form can be better suitable for preparation of pharmaceutical preparations and large-scale production, and has a broad application prospect.
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Paragraph 0044-0045
(2016/10/08)
-
- Synthesis and characterization of process-related impurities of antidiabetic drug linagliptin
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Linagliptin, a xanthine derivative, is a highly potent, selective, long-acting and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. During the process development of linagliptin, five new process-related impurities were detected by high performance liquid chromatography (HPLC). All these impurities were identified, synthesized, and subsequently characterized by their respective spectral data (MS, HRMS, 1H-NMR, 13C-NMR and IR) as described in this article. The identification of these impurities should be useful for quality control and the validation of the analytical method in the manufacture of linagliptin.
- Huang, Yiwen,He, Xiaoqing,Wu, Taizhi,Zhang, Fuli
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- LINAGLIPTIN SOLID DISPERSION
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The present invention provides a novel amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
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- AN IMPROVED PROCESS FOR PREPARING LINAGLIPTIN AND ITS KEY INTERMEDIATES
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The present invention relates to a process for the preparation of Linagliptin or a pharmaceutically acceptable slat thereof. Further aspects of the present invention relates to process for the preparation of Linagliptin key intermediate, having purity more than 98.0 %.
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- PROCESS AND INTERMEDIATES FOR THE PREPARATION OF LINAGLIPTIN
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The present invention relates to a process for the synthesis of Linagliptin and intermediates useful for its preparation.
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- METHOD FOR PREPARING AN IMPORTANT INTERMEDIATE OF LINAGLIPTIN
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The present invention discloses an improved process for preparing an important intermediate of linagliptin. In particular, disclosed are a process for preparing a compound V which is an important intermediate of linagliptin and has the structure V, and an industrial process of preparing linagliptin having excellent chemical and optical purities, which is an inhibitor of dipeptidyl peptidase-4 (DPP-IV), from the compound V. The process employs a phase-transfer catalyst, is high in yield, easy and simple to handle, environmentally friendly, suitable for industrial mass production, and can be implemented by a “one-pot process”.
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- A PROCESS FOR PREPARATION OF 1H-PURINE-2,6-DIONE, 8-[(3R)-3-AMINO-1-PIPERIDINYL]-7 (2-BUTYN-1-YL)-3,7-DIHYDRO-3-METHYL-1-[(4-METHYL-2QUINAZOLINYL) METHYL] AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
-
The present invention discloses the process for preparation of 1H-Purine-2,6-dione, 8- [(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl- 2quinazolinyl) methyl].
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Page/Page column 6; 7
(2015/08/03)
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- PROCESS FOR THE PREPARATION OF LINAGLIPTIN AND AN INTERMEDIATE THEREOF
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The present invention provides an improved process for the preparation of linagliptin and an intermediate thereof.
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Page/Page column 13
(2015/02/19)
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- AMORPHOUS FORM OF LINAGLIPTIN AND PROCESS FOR PREPARATION THEREOF
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The present invention relates to an amorphous form of linagliptin and processes for the preparation thereof. The invention also relates to a pharmaceutical composition comprising therapeutically effective amount of an amorphous form of linagliptin and use of said composition for treatment of diabetes especially type-I or type-II, prediabetes or reduction of glucose tolerance.
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Paragraph 0141
(2015/02/25)
-
- PROCESS FOR THE PREPARATION OF DIPEPTIDYLPEPTIDASE INHIBITORS
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Provided is a process for the preparation of linagliptin of Formula I, comprising deprotecting a compound of Formula II wherein R1 and R2 together with the nitrogen to which they are attached form a phthalimido group, wherein the aromatic ring of the phthalimido group is substituted with one or more R3 substituents selected from the group consisting of halogen, alkyi, nitro and amino; or R1 is H and R2 is selected from the group consisting of trialkylsilyl, 2-trialkylsilylethoxycarbamates, acetyl, trihaloacetyl, 9-fluorenylmethoxycarbonyl, trityl, alkylsulfonyl, arylsulfonyl, diphenylphosphine and sulfonylethoxycarbonyl.
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Paragraph 0161
(2015/09/23)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF LINAGLIPTIN
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The present invention relates to a process for preparing Linagliptin by purifying the intermediate compounds converting the purified intermediates into Linagliptin. The present invention also relates to the preparation of an amorphous Linagliptin.
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- STABLE AMORPHOUS FORM OF LINAGLIPTIN
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The present invention relates to a stable amorphous form of linagliptin, a process for its preparation, a pharmaceutical composition comprising it, and its use for the treatment of type 2 diabetes mellitus.
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Page/Page column 7
(2014/06/23)
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- Discovery of highly potent DPP-4 inhibitors by hybrid compound design based on linagliptin and alogliptin
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Highly potent DPP-4 inhibitors have been identified by hybrid compound design based on linagliptin and alogliptin. The most promising compound 2h (IC50 = 0.31 nM) exhibited 8.5-fold and 2.5-fold more potent activity than that of alogliptin (IC50 = 2.63 nM) and linagliptin (IC 50 = 0.77 nM), respectively. Compound 2h had a good inhibition selectivity for DPP-4 over DPP-8/9 and thus was selected for further biological evaluation, including oral glucose tolerance, plasma DPP-4 inhibitory activity, pharmacokinetic profile, acute toxicity and hERG inhibition. The assay results showed that 2h displayed significant in vivo glucose-lowering effect and low risk of toxicity. Further studies are expected to confirm 2h as a potential drug candidate for the treatment of type 2 diabetes.
- Lai, Zeng-Wei,Li, Chunhong,Liu, Jun,Kong, Lingyi,Wen, Xiaoan,Sun, Hongbin
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p. 547 - 560
(2014/07/21)
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- LINAGLIPTIN SOLID DISPERSION
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The present invention provides a novel amorphous solid dispersion of linagliptin in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
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Page/Page column 5
(2014/02/15)
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- SOLID STATE FORMS OF LINAGLIPTIN
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The present invention provides solid state forms of Linagliptin, processes for preparing the solid state forms, and pharmaceutical compositions thereof.
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- IMPROVED PROCESS FOR PREPARATION OF PURE LINAGLIPTIN
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The present application provides a process for preparation of Linagliptin reacting (R)-piperidine-3-amine of Formula II or an acid addition salt thereof with 1-[(4-methyl- quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine of Formula III in the presence of a suitable base in an inert organic solvent.
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Page/Page column 14
(2013/07/19)
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- AMORPHOUS FORM OF LINAGLIPTIN AND PROCESS FOR PREPARATION THEREOF
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The present invention relates to an amorphous form of linagliptin and processes for the preparation thereof. The invention also relates to a pharmaceutical composition comprising therapeutically effective amount of an amorphous form of linagliptin and use of said composition for treatment of diabetes especially type-I or type-II, prediabetes or reduction of glucose tolerance.
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Page/Page column 17
(2013/12/03)
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- Process for the preparation of Linagliptin
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The present invention relates to processes for the preparation of 8-(3R)-3-aminopiperidinyl)-7-butyn-2-yl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione and novel intermediates useful in its synthesis.
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- PROCESS FOR THE PREPARATION OF LINAGLIPTIN
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The present invention relates to processes for the preparation of 8-(3R)-3-aminopiperidinyl)-7-butyn-2-yl-3 -methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione and novel intermediates useful in its synthesis.
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- 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin- 2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes
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A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.
- Eckhardt, Matthias,Langkopf, Elke,Mark, Michael,Tadayyon, Moh,Thomas, Leo,Nar, Herbert,Pfrengle, Waldemar,Guth, Brian,Lotz, Ralf,Sieger, Peter,Fuchs, Holger,Himmelsbach, Frank
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p. 6450 - 6453
(2008/04/12)
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