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Preparation method of sildenafil intermediate

A technology of sildenafil and intermediates, which is applied in the field of preparation of sildenafil intermediate 2-ethoxy-5-benzoic acid, can solve the problems of equipment corrosion, low yield, unfriendly environment and the like, and achieves the Improve production efficiency, reduce production costs, mature and stable processes

Active Publication Date: 2021-12-07
山东安舜制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Other commonly used etherification reagents include diethyl sulfate. Diethyl sulfate is a better etherification agent with high product yield and simple and easy control of etherification process, but dimethyl sulfate belongs to Class 2 carcinogens , skin contact or inhalation are serious hazards, so its procurement is extremely inconvenient. At the same time, the sulfuric acid in the by-products severely corrodes the equipment and is difficult to post-process.
It can be seen that the above two etherification reagents are not only very harmful to the human body, but also not friendly enough to the environment, and the optimal total yield of the reaction in this route is 71%, which is low and difficult to be suitable for industrial production

Method used

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  • Preparation method of sildenafil intermediate
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  • Preparation method of sildenafil intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] 1) Synthesis of 2-N(BOC)-5-sulfonic acid benzoic acid (compound of formula 2)

[0047] Add 50g of 2-amino-5-sulfonic acid benzoic acid into 250ml of dichloromethane, add 55.27g of di-tert-butyl dicarbonate dropwise under temperature control at 20-30°C, then react at 20-30°C for 2 hours, and pass through 250g Wash twice with water to obtain a dichloromethane solution of 2-(N-BOC)-5-sulfobenzoic acid, control the temperature T≤35°C, distill under reduced pressure to dryness, and then add 250ml of dichloromethane, and detect KF≤0.1 %.

[0048] 2) Synthesis of 2-amino-5-(4-methylpiperazin-1-ylsulfonyl)benzoic acid (compound of formula 3)

[0049] (a) Control the temperature at 0-10°C, add 82.2g of thionyl chloride dropwise into the dichloromethane solution of the compound of formula 2, keep the temperature at 0-10°C for 6 hours, and slowly add 500g of water at 0-10°C after the reaction is completed Quenched in a mixed system composed of 50 g of sodium bicarbonate to pH 7-...

Embodiment 2

[0056] 1) Synthesis of 2-N(BOC)-5-sulfonic acid benzoic acid (compound of formula 2)

[0057] Add 50g of 2-amino-5-sulfonic acid benzoic acid into 250ml of dichloromethane, add 55.2g of di-tert-butyl dicarbonate dropwise under temperature control at 20-30°C, then react at 20-30°C for 2 hours, and pass through 250g Wash twice with water to obtain a dichloromethane solution of 2-(N-BOC)-5-sulfobenzoic acid, control the temperature T≤35°C, distill under reduced pressure to dryness, and then add 250ml of dichloromethane, and detect KF≤0.1 %.

[0058] 2) Synthesis of 2-amino-5-(4-methylpiperazin-1-ylsulfonyl)benzoic acid (compound of formula 3)

[0059] (a) Control the temperature at 0-10°C, add 82.1g of thionyl chloride dropwise into the dichloromethane solution of the compound of formula 2, keep the temperature at 0-10°C for 6h, and slowly add 500g of water at 0-10°C after the reaction is completed Quenched in a mixed system composed of 50.1 g of sodium bicarbonate to pH 7-8, a...

Embodiment 3

[0066] 1) Synthesis of 2-N(BOC)-5-sulfonic acid benzoic acid (compound of formula 2)

[0067] Add 50g of 2-amino-5-sulfonic acid benzoic acid into 250ml of dichloromethane, add 55.10g of di-tert-butyl dicarbonate dropwise at a temperature of 20-30°C, and then react at 20-30°C for 2 hours. Wash twice with water to obtain a dichloromethane solution of 2-(N-BOC)-5-sulfobenzoic acid, control the temperature T≤35°C, distill under reduced pressure to dryness, and then add 250ml of dichloromethane, and detect KF≤0.1 %.

[0068] 2) Synthesis of 2-amino-5-(4-methylpiperazin-1-ylsulfonyl)benzoic acid (compound of formula 3)

[0069] (a) Control the temperature at 0-10°C, add 82.3g of thionyl chloride dropwise into the dichloromethane solution of the compound of formula 2, keep the temperature at 0-10°C for 6 hours, and slowly add 500g of water at 0-10°C after the reaction is completed Quenched in a mixed system composed of 50 g of sodium bicarbonate to pH 7-8, and washed with water to...

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Abstract

The invention discloses a preparation method of a sildenafil intermediate. The method comprises the steps of by taking 2-amino-5-sulfonic benzoic acid as an initial raw material, firstly carrying out BOC protection on amino, then chloridizing with thionyl chloride, reacting with N-methyl piperazine, and removing BOC in an acidic environment so as to obtain 2-amino-5-(4-methyl piperazine-1-sulfonyl)-benzoic acid; and then diazotizing and brominating, and etherifying by using ethyl alcohol to obtain a target product. The 2-amino-5-(4-methylpiperazine-1-yl sulfonyl)-benzoic acid is subjected to a diazotization reaction, amino is converted into bromine, then ethyl alcohol is used for etherification, bromoethane and dimethyl sulfate which are high in toxicity are prevented from being used, green and environment-friendly effects are achieved, and large-scale production is facilitated.

Description

technical field [0001] The invention relates to a preparation method of sildenafil intermediate 2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)benzoic acid, belonging to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Sildenafil, chemical name: 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H- Pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine, the molecular formula is C 22 h 30 N 6 o 4 S. Sildenafil is a phosphodiesterase type 5 (PDE5) inhibitor developed by Pfizer Pharmaceuticals of the United States, which can treat male erectile dysfunction and is widely known by its commercial name Viagra (Viagra). [0003] 2-Ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)benzoic acid is an important intermediate for the synthesis of sildenafil, molecular formula: C 14 h 20 N 2 o 5 S, molecular weight: 328.38, structural formula as shown below. [0004] [0005] The synthetic method of 2-ethoxy-5-(4-methylpiperazine-1-sul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/26
CPCC07D295/26
Inventor 王旭瑞许德兵郝红利王红旗张熙琛
Owner 山东安舜制药有限公司
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