A kind of preparation method of linagliptin and its intermediate
What is Al technical title?
Al technical title is built by PatSnap Al team. It summarizes the technical point description of the patent document.
The technology of a compound and methyl group is applied in the field of preparation of linagliptin and its intermediates, and can solve the problems such as difficulty in obtaining compound IV, harsh reaction conditions, long reaction steps, etc., and achieves simple and easy operation, reduced reaction steps, The effect of mild reaction conditions
Active Publication Date: 2017-08-15
SHANDONG LUOXIN PHARMA GRP CO LTD
View PDF6 Cites 2 Cited by
Summary
Abstract
Description
Claims
Application Information
AI Technical Summary
This helps you quickly interpret patents by identifying the three key elements:
Problems solved by technology
Method used
Benefits of technology
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
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more
Image
Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
Click on the blue label to locate the original text in one second.
Reading with bidirectional positioning of images and text.
Smart Image
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).
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more
PUM
Login to view more
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
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more
Application Information
Patent Timeline
Application Date:The date an application was filed.
Publication Date:The date a patent or application was officially published.
First Publication Date:The earliest publication date of a patent with the same application number.
Issue Date:Publication date of the patent grant document.
PCT Entry Date:The Entry date of PCT National Phase.
Estimated Expiry Date:The statutory expiry date of a patent right according to the Patent Law, and it is the longest term of protection that the patent right can achieve without the termination of the patent right due to other reasons(Term extension factor has been taken into account ).
Invalid Date:Actual expiry date is based on effective date or publication date of legal transaction data of invalid patent.
Login to view more 
Login to view more