Synthetic method of trelagliptin, trelagliptin synthesized through method and trelagliptin synthesis intermediate

A synthetic method and intermediate technology, applied in the synthesis of trexagliptin, the field of synthetic intermediates of trexagliptin, can solve unfavorable safety production and environmental protection, unstable cost of benzyl bromide intermediates, and strong irritation of intermediates and other problems, to achieve the effect of reducing synthesis cost, low price and easy synthesis

Active Publication Date: 2016-05-04
HEBEI GUOLONG PHARMA CO LTD
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Problems solved by technology

[0020] This existing method can synthesize Trexagliptin (2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4 -dioxo-1(2H)-pyrimidinyl]methyl]-4-fluorobenzonitrile), however, the existing synthesis method using 5-fluoro-2-bromotoluene as raw material, in cyanide The steps all use highly tox

Method used

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  • Synthetic method of trelagliptin, trelagliptin synthesized through method and trelagliptin synthesis intermediate
  • Synthetic method of trelagliptin, trelagliptin synthesized through method and trelagliptin synthesis intermediate
  • Synthetic method of trelagliptin, trelagliptin synthesized through method and trelagliptin synthesis intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] The synthetic method of Trexagliptin is as follows:

[0048] Step 1: Synthesis of Intermediate-1 (2-chloromethyl-4-fluorobenzonitrile)

[0049] Mix 21.2 g (0.14 mol) of 2-hydroxymethyl-4-fluorobenzonitrile and 80 g of thionyl chloride under stirring at room temperature, gradually raise the temperature to 70° C., stir and reflux for 2 hours, and TLC detects that the reaction is complete. Recover excess thionyl chloride, concentrate until there is no liquid drop to obtain intermediate 1 (2-chloromethyl-4-fluorobenzonitrile), add 2 times the mass volume of toluene, and set aside.

[0050] Step 2: Intermediate-2(2-[(6-Chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl)methyl]-4- Synthesis of fluorobenzonitrile).

[0051] Add 22.5g (0.14mol) of 6-chloro-3-methyluracil and 29mL of N,N-diisopropylethylamine (DIPEA) into 70mL of N-methylpyrrolidone, and stir at room temperature for 30min. Slowly add 23.8 g (0.14 mol) of toluene solution of Intermediate-1 (intermediate 1...

Embodiment 2

[0055] The synthetic method of Trexagliptin is as follows:

[0056] Step 1: Synthesis of Intermediate-1 (2-chloromethyl-4-fluorobenzonitrile)

[0057] At room temperature, 21.2 g (0.14 mol) of 2-hydroxymethyl-4-fluorobenzonitrile and 74.2 g of thionyl chloride were mixed under stirring, and the temperature was gradually raised to 75° C., stirred and refluxed for 5 hours, and the reaction was complete by TLC. Recover excess thionyl chloride, concentrate until there is no liquid drop to obtain intermediate 1 (2-chloromethyl-4-fluorobenzonitrile), add 2 times the mass volume of toluene, and set aside.

[0058] Step 2: Intermediate 2 (2-[(6-Chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl)methyl]-4-fluoro Synthesis of benzonitrile).

[0059] Add 22.5g (0.14mol) of 6-chloro-3-methyluracil and 29mL of N,N-diisopropylethylamine (DIPEA) into 70mL of N-methylpyrrolidone, and stir at room temperature for 30min. Slowly add 23.8 g (0.14 mol) of toluene solution of Intermediate 1...

Embodiment 3

[0063] The synthetic method of Trexagliptin is as follows:

[0064] Step 1: Synthesis of intermediate 1 (2-chloromethyl-4-fluorobenzonitrile)

[0065] Mix 21.2 g (0.14 mol) of 2-hydroxymethyl-4-fluorobenzonitrile and 126 g of thionyl chloride under stirring at room temperature, gradually raise the temperature to 70° C., stir and reflux for 2 hours, and TLC detects that the reaction is complete. Recover excess thionyl chloride, concentrate until there is no liquid drop to obtain intermediate 1 (2-chloromethyl-4-fluorobenzonitrile), add 2 times the mass volume of toluene, and set aside.

[0066] Step 2: Intermediate 2 (2-[(6-Chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl)methyl]-4-fluoro Synthesis of benzonitrile).

[0067] Add 22.5g (0.14mol) of 6-chloro-3-methyluracil and 29mL of N,N-diisopropylethylamine (DIPEA) into 70mL of N-methylpyrrolidone, and stir at room temperature for 30min. Slowly add 38.02 g (0.224 mol) of toluene solution of Intermediate 1 (Intermedia...

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Abstract

The invention discloses a synthetic method of trelagliptin, trelagliptin synthesized through the method and a trelagliptin synthesis intermediate. The synthetic method of trelagliptin comprises the following steps: 1, taking 2-hydroxymethyl-4-fluorobenzonitrile as a starting raw material, and conducting a chlorination reaction, so that 2-chloromethyl-4-fluorobenzonitrile is obtained; 2, taking the 2-chloromethyl-4-fluorobenzonitrile as an intermediate, and conducting a condensation reaction, so that 2-[(6-chlorine-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-4-fluorobenzonitrile is obtained; 3, taking the 2-[(6-chlorine-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-4-fluorobenzonitrile as an intermediate, and conducting an ammonolysis reaction, so that trelagliptin alkali is obtained. By means of the method, use of high-toxicity copper cyanide is avoided, safety of the synthesis process is improved, environment friendliness is achieved, the formed chloro intermediate is more stable, and no irritation is caused.

Description

technical field [0001] The present invention relates to a synthetic method of trexagliptin, in particular to a synthetic method of trexagliptin, trexagliptin synthesized by the method and a synthetic intermediate of trexagliptin. Background technique [0002] Trexagliptin is a once-weekly dipeptidyl peptidase IV (DPP-4) inhibitor that controls blood glucose levels through selective and sustained inhibition of DPP-4. DPP-4 is an enzyme that triggers the inactivation of incretins (glucagon-like peptide-1 (GLP-1) and diabetes-dependent insulinotropic polypeptide (GIP), two incretins in blood glucose It plays an important role in regulation.Inhibition of DPP-4 can increase blood glucose level-dependent insulin secretion, thereby controlling blood glucose levels. [0003] Trexagliptin, a DPP-4 inhibitor, was submitted based on efficacy and safety data from several phase III clinical trials in Japanese patients with type 2 ROMAN type 2 diabetes. The curative effect of troglifloz...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07C253/30C07C255/50
CPCC07C253/30C07C255/50C07D401/04
Inventor 殷殿书杜玉民张恺王亚博魏赛丽尚伟定赵毅莎闫永娜张清江王春发
Owner HEBEI GUOLONG PHARMA CO LTD
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