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Preparation method of linagliptin and intermediate thereof

A technology for intermediates and compounds, which is applied in the field of preparation of linagliptin and its intermediates, can solve the problems of difficulty in obtaining compound IV, harsh reaction conditions, high market prices and the like, achieves simple and easy operation, reduced reaction steps, cost reduction effect

Active Publication Date: 2016-03-30
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] The method for preparing linagliptin by the above-mentioned rearrangement reaction method has relatively mild reaction conditions, relatively simple operation, and low product impurity content, but the reaction steps are relatively long, the overall yield is low, the cost is high, and the reaction conditions are harsh; and the route uses Compound IV is not easy to obtain, and the market price is expensive
The application of this synthetic method is limited due to the need to use difficult to remove diphenylphosphoryl azide (DPPA) or dangerous azide in the Schmidt and Curtius rearrangement.

Method used

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  • Preparation method of linagliptin and intermediate thereof
  • Preparation method of linagliptin and intermediate thereof
  • Preparation method of linagliptin and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1: the synthesis of compound II

[0048] First, suspend 8-bromo-3,7-dihydro-3-methyl-1H-purine-2,6-dione (24.5g, 100mmol) in 200ml tetrahydrofuran, then add 2-butyne-1- Alcohol (7.71g, 110mmol), triphenylphosphine (31.5g, 120mmol), at room temperature, diethyl azodicarboxylate (DEAD, 20.9g, 120mmol) was added dropwise to the reaction solution, and the TLC monitoring reaction was complete . Wash with saturated brine, dry with anhydrous sulfuric acid, concentrate the organic phase, recrystallize the residue with ethyl acetate, and dry in vacuo to obtain 27.2 g of compound II with a yield of 90.3% and a purity of 99.2% (HPLC method).

Embodiment 2

[0049] Embodiment 2: the synthesis of compound II

[0050] First suspend 8-bromo-3,7-dihydro-3-methyl-1H-purine-2,6-dione (24.5g, 100mmol) in 200ml N,N-dimethylformamide (DMF) , add 2-butyn-1-alcohol (8.41g, 120mmol) and triphenylphosphine (36.7g, 140mmol) successively, at room temperature, add diisopropyl azodicarboxylate (DIAD, 28.3 g, 140mmol), until the TLC monitoring reaction is complete. Purified water was added for crystallization, and the obtained solid was recrystallized with ethyl acetate and dried in vacuo to obtain 28.3 g of compound II with a yield of 94.8% and a purity of 99.5% (HPLC method).

Embodiment 3

[0051] Embodiment 3: the synthesis of compound II

[0052] First, suspend 8-bromo-3,7-dihydro-3-methyl-1H-purine-2,6-dione (24.5g, 100mmol) in 200ml of dichloromethane, then add 2-butyne- 1-alcohol (7.71g, 110mmol), triphenylphosphine (31.5g, 120mmol), and azodicarbonamide (TMAD, 14g, 120mmol) were added dropwise to the reaction solution at room temperature, and the reaction was completed by TLC monitoring. Wash with saturated brine, dry with anhydrous sulfuric acid, concentrate the organic phase, recrystallize the residue with ethyl acetate, and dry in vacuo to obtain 27.7 g of compound II with a yield of 92.8% and a purity of 99.4% (HPLC method).

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Abstract

The invention belongs to the field of pharmaceutical chemicals, and in particular relates to a preparation method of linagliptin and an intermediate thereof. The preparation method comprises the following steps: carrying out Mitsunobu reaction on a compound I and 2-butyne-1-alcohol in an organic solvent in the presence of trialkyl phosphine and an azo-reagent to obtain a linagliptin intermediate compound II; carrying out substitution reaction on the compound II and (R)-3-aminopiperdine by taking isopropanol as a solvent and tri-n-butylamine as an acid-binding agent to obtain a compound III; and carrying out alkylation reaction on the compound III and 4-methyl-2-chloro-methyl-quinazolin to obtain linagliptin. According to the preparation method provided by the invention, the Mitsunobu reaction is innovatively adopted to prepare the compound II, so that the preparation method has the advantages of mild reaction condition, reasonable operation, high selectivity, high product quality and the like. Moreover, by controlling the reaction condition, the compound III and R-3-aminopiperdine or an inorganic acid salt or an organic acid salt thereof are directly subjected to nucleophilic substitution to generate linagliptin, and the method does not have protection and de-protection processes of amino groups, so that the reaction steps are reduced, the reaction process is simpler, the cost is reduced, and the purity of an obtained product is relatively improved.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of linagliptin and an intermediate thereof. Background technique [0002] Linagliptin (linagliptin) is an oral hypoglycemic drug developed by Boehringer Ingelheim Pharmaceutical Company of Germany. It was approved by the US FDA on May 2, 2011, and its trade name is Tradjenta. This product comes as a tablet and is used in combination with diet and exercise to improve blood sugar control in people with type 2 diabetes. [0003] Linagliptin is a purine derivative, its compound structure contains a substituted quinazoline group and a 3-aminopiperidine group, its cultural name: 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; Molecular formula: C 25 h 28 N 8 o 2 ; Molecular weight: 472.54; CAS registration number: 668270-12-0, the structural formula is as fol...

Claims

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Application Information

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IPC IPC(8): C07D473/04
CPCC07D473/04
Inventor 陈雨黄春艳王兆民
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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