Synthesis technology of 5-aryl-1H-pyrazolopyridine[4,3-d]pyrimidine-7(6H)-ketone

A synthetic process, the technology of pyrazolo, is applied in the field of synthetic process of key pharmaceutical intermediates, which can solve the problems of heavy metal residue hazards, unsuitable for scale-up production, and high price, and achieve shortened reaction time, mild reaction conditions, and improved conversion rate effect

Active Publication Date: 2015-07-29
GUANGZHOU TROJAN PHARMATEC LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] InCl 3 Expensive, high cost, heavy metal residue hazard, not suitable for scale-up production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1，2

[0057]

[0058] 1. Synthesis of imine intermediate (1):

[0059] The reference document European Journal of Medicinal Chemistry, 2014(80), 201-208 reports the synthesis of imine intermediate 1.

[0060] 2, 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2 )Synthesis:

[0061] Add 30g of imine intermediate (1) and 300ml of isopropanol to the four-necked bottle, start stirring, without air or oxygen, and add 15.6g of anhydrous ferric chloride, and keep warm at 55-65°C for reaction . TLC trace. After the reaction was completed, 200ml was distilled off, 450ml of purified water was added, the temperature was cooled to room temperature, suction filtered, and dried to obtain a solid.

[0062] The identification result of product is:

[0063] 1 H NMR (500MHz, d 6 -DMSO): δ11.97(s, 1H), 7.63(d, J=7.5Hz, 1H), 7.48-7.45(m, 1H), 7.13(d, J=7.5Hz, 1H), 7.06-7.03( t,J=7.5Hz,1H), 4.14(s,3H), 4.10(q,2H), 2.76(t,J=7.5Hz,2H), 1.75-1.71(m,2H), 1.32(t...

Embodiment 4

[0068] 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) synthesis:

[0069]

[0070] Add 8.15g of 2-ethoxybenzaldehyde, 9.6g of 1-methyl-3-propyl-4-aminopyrazole-5-carboxamide and 150ml of isopropanol into a 250ml three-necked flask, and stir at room temperature for 3 hours; Oxygen was introduced into the reaction system, 8.56g of anhydrous ferric chloride was added, and the temperature was raised to 60°C for 3 hours; after the reaction was completed, 180ml of purified water was added, cooled to room temperature, suction filtered, and dried to obtain 15.7g of solid. Yield: 91.4%, purity (HPLC) 98.3%.

Embodiment 5

[0072] Synthesis of 5-(4-methylphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (3) :

[0073]

[0074] Add 6.52g of 2-ethoxybenzaldehyde, 9.6g of 1-methyl-3-propyl-4-aminopyrazole-5-carboxamide and 150ml of isopropanol into a 250ml three-necked flask, and stir at room temperature for 3 hours; Oxygen was introduced into the reaction system, 8.56g of anhydrous ferric chloride was added, and the temperature was raised to 60°C for 3 hours to react; about 100ml of isopropanol was evaporated, 180ml of purified water was added, suction filtered, and dried to obtain 14.2g of solid. Yield: 95.50%.

[0075] The identification result of product is:

[0076] 1 H NMR (400MHz, CDCl 3 ): 11.1(br s,1H), 7.5(d,2H,J=11.5Hz), 7.2(d,2H,J=11.34Hz), 7.2(d,2H,J=11.34Hz), 2.7(t, 2H), 2.3(s, 3H), 1.7(m, 2H), 0.98(t, 3H). 13 C NMR (CDCl 3 ,100Hz): 155.1, 148.3, 145.9, 138.7, 129.9, 124.6, 123.3, 113.0, 55.3, 37.8, 27.2, 22.1, 13.8;

[0077] ESI-MS: 282.6[M+H] + .

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Abstract

The invention discloses a synthesis technology of 5-aryl-1H-pyrazolopyridine[4,3-d]pyrimidine-7(6H)-ketone. The synthesis technology comprises the following steps: mixing substituted aryl aldehyde with 1-methyl-3-propyl-4-amino pyrazole-5-formylamine, and contracting the mixture so as to obtain bisiminophosphorane benzyl benzoate; placing the bisiminophosphorane benzyl benzoate in a solvent, and under the common action of a ring forming agent and a pro-oxygenic agent, performing cyclization oxidization so as to obtain the 5-aryl-1H-pyrazolopyridine[4,3-d]pyrimidine-7(6H)-ketone. The synthesis technology disclosed by the invention is mild in reacting conditions, greatly higher in the conversion rate of a cyclization oxidation reaction, short in the reaction time, and less in the side reactions. The reaction can be carried out in different reactors in two steps, and can also be carried out in the same reactor. A stepwise synthesis method is favorable for the quality control of the bisiminophosphorane benzyl benzoate and the purification of products, the adoption of a one-step synthesis method simplifies the synthetizing working procedures and shortens the reaction time, and all the methods can effectively synthetize the 5-aryl-1H-pyrazolopyridine[4,3-d]pyrimidine-7(6H)-ketone. The used reagent is basically non-toxic or low-toxic, and besides, the synthesis technology is low in cost and is low in synthesis cost.

Description

technical field [0001] The invention relates to a synthesis process of a key pharmaceutical intermediate, in particular to a synthesis process of 5-aryl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one. Background technique [0002] Sildenafil (Sildenafil, trade name: Viagra), chemical name 5-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)phenyl]-1-methyl-3 - n-Propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one. Sildenafil citrate is a drug for the treatment of erectile dysfunction and pulmonary hypertension developed and marketed by Pfizer Pharmaceuticals of the United States. Sildenafil is a highly selective phosphodiesterase 5 (PDE5) inhibitor. PDE5 is highly expressed in the corpus cavernosum, while its expression is low in other tissues (including platelets, blood vessels, visceral smooth muscle, and skeletal muscle). Sildenafil selectively inhibits PDE5, enhances the NO-cGMP pathway of nitric oxide, and increases the level of cGMP to cause the relaxation of the smooth muscle of t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 郑庆泉黄世福曹徐涛李永健
Owner GUANGZHOU TROJAN PHARMATEC LTD
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