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Piperazine or piperidine compound as well as salts, intermediates, preparation method and application thereof

A compound, piperidine technology, applied in the field of medicinal chemical synthesis, can solve the problem of β-cell function damage in patients

Inactive Publication Date: 2013-06-26
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the treatment of type 2 diabetes is mainly based on small molecule oral drugs. Sulfonylureas, glinides, biguanides and thiazolidinediones are commonly used drugs for the treatment of type 2 diabetes, but long-term use of these hypoglycemic drugs can lead to Adverse reactions such as hypoglycemia, weight gain, and β-cell function damage occurred in patients

Method used

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  • Piperazine or piperidine compound as well as salts, intermediates, preparation method and application thereof
  • Piperazine or piperidine compound as well as salts, intermediates, preparation method and application thereof
  • Piperazine or piperidine compound as well as salts, intermediates, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0191] Synthesis of 1-chloroformyl-4-(2,4,5-trifluorophenyl)piperazine(II)

[0192] Dissolve triphosgene (254mg, 0.9mmol) in 10ml of dichloromethane, cool in an ice-salt bath, lower the internal temperature to -5°C to 0°C, slowly add pyridine (219mg, 2.8mmol) and 1-(2, 4,5-Trifluorophenyl)piperazine (500mg, 2.3mmol) in dichloromethane solution, the temperature was controlled below 0°C, the addition was completed in 10 minutes, and the reaction was maintained at 0°C for 1h, the TLC raw material disappeared completely, due to the activity of the acid chloride Higher, difficult to separate II put into the next reaction in the form of crude product.

Embodiment 2

[0194] Synthesis of 1-chloroformyl-4-(2,4,5-trifluorophenyl)piperazine(II)

[0195] Pour excess phosgene into 10ml of dichloromethane, cool in an ice-salt bath, lower the internal temperature to -5°C to 0°C, slowly add triethylamine (282mg, 2.8mmol) and 1-(2,4, 5-Trifluorophenyl)piperazine (500mg, 2.3mmol) in dichloromethane solution, temperature control below 0°C, 10min to complete the addition, maintained at 0°C for 1h, the TLC raw material completely disappeared, due to the high activity of acid chloride , it is not easy to separate II into the next reaction in the form of crude product.

Embodiment 3

[0197] (4-(2,4,5-trifluorophenyl)-1-piperazinyl)(3-trifluoromethyl-5,6-dihydro-[1,2,4]triazol[4,3 Synthesis of -a]-7(8H)-pyrazinyl)methanone (I-1)

[0198] 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine (444mg, 2.3mmol) and Triethylamine (273 mg, 2.7 mmol), the reaction temperature was raised to room temperature, and stirred for 20 h. Add 20ml of saturated sodium bicarbonate solution to terminate the reaction, extract with dichloromethane (20ml×2), combine the organic phases, dry over anhydrous sodium sulfate, filter with suction, concentrate, and perform column chromatography (petroleum ether: ethyl acetate = 1:1) 575 mg of white powdery solid was obtained, and the two-step yield was 57.2%.

[0199] The synthesis method of I-2~I-10 is the same as that of I-1; I-11 is obtained by the condensation reaction between the acylated product and prolinamide, and finally the amide is dehydrated with acetic anhydride; I-6 and I-7 are obtained through condensation...

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Abstract

The invention discloses a piperazine or piperidine compound or salts thereof. The invention also discloses a preparation method of formula I and the preparation method comprises the step of condensing formula II and R7H in a solvent at the temperature of 10-30 DEG C under the action of alkali. The invention also discloses a preparation method of the salts of the formula I, comprising the steps of when formula VII and formula IR3 =H, F or NO2, sequentially carrying out amino protection reaction on the formula II to obtain formula V, carrying out ester hydrolysis on the formula V to obtain formula VI, carrying out condensation reaction on the formula VI and the R7H to obtain formula VII and carrying out deprotection and salification on the formula VII, wherein when formula VIIR3=NO2 and the formula IR3=NH2, the method also comprises the step of nitro reduction after the step of condensation and before the step of deprotection and salification. The invention also discloses a preparation method of intermediates in the formula I compound. The invention also discloses the intermediates in the preparation method of the formula I. The piperazine or piperidine compound or the salts thereof, disclosed by the invention, provides a new direction for the research and the development of DPP-4 (Dipeptidyl Peptidase-4) inhibitors and has important significance on developing the DPP-4 inhibitors.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to piperazine or piperidine compounds with novel structure and potential DPP-4 inhibitory activity, intermediates thereof, pharmaceutically acceptable salts thereof, preparation methods and applications thereof. Background technique [0002] Diabetes is a disease that seriously threatens human health. According to the World Health Organization, there are about 180 million diabetics in the world, 90% of whom are type 2 diabetics, and this number is expected to double by 2030. At present, the treatment of type 2 diabetes is mainly based on small molecule oral drugs. Sulfonylureas, glinides, biguanides and thiazolidinediones are commonly used drugs for the treatment of type 2 diabetes, but long-term use of these hypoglycemic drugs can lead to Adverse reactions such as hypoglycemia, weight gain, and β-cell function damage occurred in patients. The ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D295/205C07D213/75C07D207/09C07D207/16C07D401/12C07D295/185C07D211/78C07D211/62A61P3/10A61P5/50
Inventor 孟祥国蔡正艳周伟澄蒋婧章朱怡君葛渊源严萍萍
Owner SHANGHAI INST OF PHARMA IND CO LTD