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Preparation method of flupirtine derivative and preparation of inorganic acid salts of flupirtine derivative

A technology of inorganic acid salts and derivatives, applied in the field of preparation of flupirtine derivatives and inorganic acid salts thereof, can solve the problems of reduced activity, influence on drug stability, low drug content and the like

Pending Publication Date: 2019-10-11
西安都创医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The impurities contained in the drug are the main factors affecting the purity of the drug. If the drug contains impurities exceeding the limit, it may change the physical and chemical constants, the appearance and properties of the drug, and affect the stability of the drug; the increase of impurities will inevitably increase the content of the drug. Low or reduced activity, significantly increased toxic and side effects

Method used

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  • Preparation method of flupirtine derivative and preparation of inorganic acid salts of flupirtine derivative
  • Preparation method of flupirtine derivative and preparation of inorganic acid salts of flupirtine derivative
  • Preparation method of flupirtine derivative and preparation of inorganic acid salts of flupirtine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] (a) Substituting compound 1 with p-fluorobenzylamine to prepare compound 2:

[0056] 2-Amino-3-nitro-6-chloropyridine (compound 1) (50.0 g, 288 mmol, 1.00 eq) was dissolved in isopropanol (500 mL), p-fluorobenzylamine (39.7 g, 317 mmol, 1.10 eq ) and TEA (32.0g, 317mmol, 1.10eq), heated to reflux for 10h. Thereafter, the reaction solution was poured into water (1.5 L), slowly cooled to 5° C. and stirred for 30 minutes. Filter and wash the filter cake with water (500 mL). The filter cake was collected and dried to obtain 60 g of a yellow solid (Compound 2), with a yield of 79.4%.

[0057] (b) Compound 2 is subjected to a reduction reaction to prepare compound 3:

[0058] Compound 2 (60 g, 229 mmol, 1.00 eq) was dissolved in methanol (600 mL), and Pd / C (6.0 g) was added under nitrogen protection. The reactor was replaced with hydrogen for 3 times, and then the reaction was stirred at room temperature under hydrogen (30 psi) for 5 h. Afterwards, the reaction solut...

Embodiment 2

[0066] (a) Substituting compound 1 with p-fluorobenzylamine to prepare compound 2:

[0067] 2-Amino-3-nitro-6-chloropyridine (compound 1) (50.0g, 288mmol, 1.00eq) was dissolved in N,N-dimethylformamide (500mL), and p-fluorobenzylamine (39.7 g, 317mmol, 1.10eq) and K 2 CO 3 (43.8g, 317mmol, 1.10eq), heated at 100°C for 6h. Thereafter, the reaction solution was poured into water (1.5 L), slowly cooled to 5° C. and stirred for 30 minutes. Filter and wash the filter cake with water (500 mL). The filter cake was collected and dried to obtain 55.2 g of a yellow solid (Compound 2), with a yield of 73.1%.

[0068] (b) Compound 2 is subjected to a reduction reaction to prepare compound 3:

[0069] Compound 2 (55.2g, 210mmol, 1.00eq) was dissolved in methanol (552mL), and Pd(OH) was added under nitrogen protection 2 / C (2.76g). The reactor was replaced with hydrogen for 3 times, and then the reaction was stirred at room temperature under hydrogen (30 psi) for 8 h. Afterwards...

Embodiment 3

[0077] (a) Substituting compound 1 with p-fluorobenzylamine to prepare compound 2:

[0078] 2-Amino-3-nitro-6-chloropyridine (compound 1) (50.0g, 288mmol, 1.00eq) was dissolved in methanol (500mL), p-fluorobenzylamine (39.7g, 317mmol, 1.10eq) was added and Pyridine (25.1g, 317mmol, 1.10eq), heated to reflux for 12h. Thereafter, the reaction solution was poured into water (1.5 L), slowly cooled to 5° C. and stirred for 30 minutes. Filter and wash the filter cake with water (500 mL). The filter cake was collected and dried to obtain 37.9 g of a yellow solid (Compound 2), with a yield of 50.1%.

[0079] (b) Compound 2 is subjected to a reduction reaction to prepare compound 3:

[0080] Compound 2 (37.9 g, 145 mmol, 1.00 eq) was dissolved in ethanol (380 mL), and Pd / C (6.0 g) was added under nitrogen protection. The reactor was replaced with hydrogen for 3 times, and then the reaction was stirred at room temperature under hydrogen (30 psi) for 8 h. Afterwards, the reactio...

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PUM

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Abstract

The invention relates to a preparation method of a flupirtine derivative and a preparation of inorganic acid salts of the flupirtine derivative. The flupirtine derivative is shown in a chemical formula 1, wherein the flupirtine derivative is an important impurity produced in a flupirtine maleate synthesizing and / or storage process. By adopting the preparation methods, the flupirtine derivative andthe inorganic acid salts thereof can be prepared with high yields, and the reaction yield of each step can reach 55% or above.

Description

technical field [0001] The invention relates to the field of medicine synthesis and analysis, in particular to a preparation method of flupirtine derivatives and inorganic acid salts thereof. Background technique [0002] Flupirtine Maleate, scientific name: ethyl 2-amino-6-[(4-fluorobenzyl)amino]pyridine-3-carbamate maleate, CAS number: 75507-68-5 , formula C 19 h 21 FN 4 o 6 , with a molecular weight of 420.39, is a non-opioid analgesic that acts on the central nervous system. Its mechanism of action is a selective neuronal potassium channel opener, which has triple effects of pain relief, muscle relaxation and neuroprotection. As a moderate-strength non-opioid central analgesic, flupirtine maleate is not addictive to opioid analgesics, and has no inhibitory effect on the respiratory and cardiovascular systems; it also has good tolerance and low neurotoxicity. Toxicity, protection of nerves and lymphocytes and other properties, so it can be used for the treatment of v...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 单玉庆帅宝奎
Owner 西安都创医药科技有限公司
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