Industrialization-suitable preparation method of high-purity trelagliptin succinate

A technology of troxagliptin succinate and succinic acid, which is applied in the field of preparation of troxagliptin succinate, can solve the problems of difficult to obtain high-purity products and easy to produce more impurities, and achieve easy operation and low impurity Less, the effect of mild reaction conditions

Active Publication Date: 2016-02-10
REGENEX PHARMA LTD
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  • Abstract
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  • Application Information

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Problems solved by technology

[0008] 2) 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2 H -pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile reacts with (R)-3-amino-pyrimidine dihydrochloride, due to the presence of two amino attack sites, more impurities are likely to be produced, and post-processing is difficult Get a product with higher purity

Method used

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  • Industrialization-suitable preparation method of high-purity trelagliptin succinate
  • Industrialization-suitable preparation method of high-purity trelagliptin succinate
  • Industrialization-suitable preparation method of high-purity trelagliptin succinate

Examples

Experimental program
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Effect test

Embodiment 1

[0041] Synthesis of 2-bromomethyl-4-fluorobenzonitrile:

[0042] A mixture of 4-fluoro-2-methylbenzonitrile (2g, 14.8mmol), N-bromosuccinimide (NBS) (2.64g, 15mmol) and AIBN (0.10g) in dichloromethane was refluxed for 1h. The reaction was cooled to room temperature. Wash with sodium bisulfite solution, sodium carbonate solution, and saturated sodium chloride solution. The organic solvent was concentrated to obtain 2.5 g of oily 2-bromomethyl-4-fluorobenzonitrile (yield 87%).

[0043] Amino-1-piperidine)-3-methyl-2,4 ( 1H, 3H )-Synthesis of dihydropyrimidinedione:

[0044] Combine 3-methyl-6-chlorouracil (0.6g, 3.8mmol), (R)-3-(trifluoroacetyl-)amino-piperidine (0.8g, 4.0mmol) and DIPEA (1.4ml, 8mmol) ) The mixture in absolute ethanol (10ml) is stirred at 80°C until the reaction is complete. Add water, the solid will separate out and filter. 1.11 g of 6-[3-(trifluoroacetyl-)amino-1-piperidine]-3-methyl-2,4( 1H, 3H )-Dihydropyrimidinedione (92.4% yield).

[0045] (R)-2-[(6-(3-A...

Embodiment 2

[0050] Synthesis of 2-bromomethyl-4-fluorobenzonitrile:

[0051] A mixture of 4-fluoro-2-methylbenzonitrile (2g, 14.8mmol), bromine (2.64g, 15mmol) and benzoyl peroxide (BPO) (0.10g) in chloroform was refluxed for 6h. The reaction was cooled to room temperature. Wash with sodium bisulfite solution, sodium carbonate solution, and saturated sodium chloride solution. The organic solvent was concentrated to obtain 2.5 g of oily 2-bromomethyl-4-fluorobenzonitrile (yield 86.3%).

[0052] Amino-1-piperidine)-3-methyl-2,4 ( 1H, 3H )-Synthesis of dihydropyrimidinedione:

[0053] Combine 3-methyl-6-chlorouracil (0.6g, 3.8mmol), (R)-3-(phthaloyl-)amino-piperidine (0.8g, 4.0mmol) and triethylamine (1.4 ml, 8mmol) in absolute ethanol (10ml) was stirred at 60°C until the reaction was complete. Add water, the solid will separate out and filter. 1.11 g of 6-[3-(phthaloyl-)amino-1-piperidine]-3-methyl-2,4( 1H, 3H )-Dihydropyrimidinedione (92.1% yield).

[0054] (R)-2-[(6-(3-Amino-piperidin-1-...

Embodiment 3

[0059] Synthesis of 2-bromomethyl-4-fluorobenzonitrile:

[0060] A mixture of 4-fluoro-2-methylbenzonitrile (2g, 14.8mmol), N-bromosuccinimide (NBS) (2.64g, 15mmol) and AIBN (0.10g) in chloroform was refluxed for 2h. The reaction was cooled to room temperature. Wash with sodium bisulfite solution, sodium carbonate solution, and saturated sodium chloride solution. The organic solvent was concentrated to obtain 2.88 g of oily 2-bromomethyl-4-fluorobenzonitrile (yield 91%).

[0061] Amino-1-piperidine)-3-methyl-2,4 ( 1H, 3H )-Synthesis of dihydropyrimidinedione:

[0062] Combine 3-methyl-6-chlorouracil (0.6g, 3.8mmol), (R)-3-(tert-butoxycarbonyl-)amino-piperidine (0.8g, 4.0mmol) and DIPEA (1.4ml, 8mmol) ) The mixture in absolute ethanol (10ml) is stirred at 70°C until the reaction is complete. Add water, the solid will separate out and filter. 1.15 g of 6-[3-(tert-butoxycarbonyl-)amino-1-piperidine]-3-methyl-2,4( 1H, 3H )-Dihydropyrimidinedione (93.5% yield).

[0063] (R)-2-[(6-...

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Abstract

The invention relates to a novel industrialization-suitable preparation method of high-purity trelagliptin succinate and aims to solve the problem of generation of much intermediate impurity, complex after treatment and high cost in the prior art. The invention discloses the preparation method of the trelagliptin succinate, which is different from the reported preparation methods. The preparation method of the trelagliptin succinate is mild in conditions, is environment-friendly, is high in conversion rate and is high in finish product quality.

Description

technical field [0001] The invention relates to a preparation method of trexagliptin succinate. Background technique [0002] Trelagliptin succinate (Trelagliptinsuccinate) is a long-acting selective dipeptidyl peptidase-4 (DPP-4) inhibitor developed by Takeda Pharmaceutical, Japan. DPP-4 inhibitors can prolong the activity of glucagon-like in vivo The half-life of polypeptide-1 (GLP-1) exerts an effective glucose-dependent insulinotropic effect, thereby increasing plasma insulin levels and reducing blood sugar levels. Trexagliptin succinate, once a week, controls blood sugar levels through selective and sustained inhibition of DPP-4. Its efficacy has been confirmed in all trials, and it has good safety and tolerability. At present, the drug is in the registration stage in Japan, and is in the phase II clinical stage in Europe and the United States. [0003] The chemical formula of Trexagliptin was first disclosed in the patent CN1926128A applied by Japan Takeda Pharmaceut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07C51/41C07C55/10
CPCY02P20/55
Inventor 陈与华卢平平陈伟强何清袁永玲汤丹左联卢智俊
Owner REGENEX PHARMA LTD
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