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Preparation method of avanafil

A technology of avanafil and intermediates, applied in the field of medicine, can solve the problems of difficult industrialization, high industrialization cost, and low yield, and achieve the effects of easy industrialized production, low industrialized cost, and simple process operation

Active Publication Date: 2015-04-22
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In the chlorination / addition reaction process from compound C to compound E in the above-mentioned route two, adopt expensive catalyst (as palladium chloride, nickel acetate etc.) and cocatalyst (as triphenylphosphine, tri-n-butylphosphine etc. ), and the yield is not high, it is difficult to industrialized production, and the microwave condition is used in the chlorination addition step, and the industrialization is difficult; and the condensation step adopts more expensive condensing agents such as TBTU, HATU, HBTU, BOP and bases such as DBU Accelerator, and the yield is not high, resulting in higher cost of industrialization

Method used

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  • Preparation method of avanafil
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  • Preparation method of avanafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: Preparation of 2-hydroxypyrimidine-4-carbamate isopropyl ester (intermediate I)

[0040] Dissolve 60g (0.540mol, M=111.1) cytosine in 600ml of dichloromethane, add 186.6g of potassium carbonate (1.35mol, M=138.21), then add di-tert-butyl dicarbonate (0.702 mol, M=218.25) in dichloromethane solution (dissolve 153.0g di-tert-butyl dicarbonate in 60ml dichloromethane), after the dropwise addition, keep warm for 1-2 hours, filter, and distill under reduced pressure to obtain an oily solid , intermediate I was prepared.

Embodiment 2

[0041] Embodiment 2: Preparation of ethyl 6-amino-2-hydroxypyrimidine-5-carboxylate (intermediate II)

[0042]Dissolve the intermediate I prepared in Example 1 in 450ml of hexamethyldisilazane, heat to 80-100°C for 1-3 hours, evaporate hexamethyldisilazane under reduced pressure; then add 360ml of di Chloromethane, after stirring evenly, add 62.4g of ethyl chloroformate (0.594mol, M=108.52) to cool down to 0-10°C, add 180.0g of aluminum trichloride (1.35mol, M=133.34) in batches, heat preservation reaction 1 -2 hours, then heat up to 20-30°C and keep it warm for 2-3 hours, add the feed solution dropwise to 600ml ice water containing 2% hydrochloric acid, stir for 0.5 hours, filter, and the filtrate is statically separated, and the water phase is 300ml×2 Extract with dichloromethane, combine the organic phases, wash twice with 300ml×2 5% sodium bicarbonate solution, dry over anhydrous sodium sulfate, filter, distill under reduced pressure, and dry to obtain 82.0g light yellow s...

Embodiment 3

[0043] Example 3: Preparation of ethyl 6-(3-chloro-4-methoxy-benzylamino)-2-hydroxypyrimidine-5-carboxylate (intermediate III)

[0044] The obtained 60g intermediate II (0.327mol) was dissolved in 300ml of dichloromethane, 90.5g of potassium carbonate (0.655mol, M=138.21) and 0.6g of potassium iodide (1%, M=138.21) were added, and then 81.8 g compound 2 (3.47mol, M=235.5), keep the temperature at 25-30°C for 3-4 hours, after the reaction is complete under TLC control, filter, the filtrate is distilled under reduced pressure, add 200ml of methanol and stir at 25-30°C for 0.5-1 hours, filtered, washed with 50ml of methanol, and dried to obtain 106.8g of intermediate III, with a yield of 96.5%; ESI (m / z): 338.

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Abstract

The invention discloses a preparation method of avanafil. The method comprises the steps: carrying out amino protective reaction for cytosine (compound 1) which is used as a starting raw material and di-tert-butyl dicarbonate ester to obtain an intermediate I; enabling the intermediate I to firstly react with hexamethyl-disilazane and then to have friedel-crafts reaction with ethyl chloroformate in the existence of aluminum trichloride to obtain an intermediate II; preparing an intermediate III by virtue of substitution reaction between the intermediate II and 4-bromomethyl-2-chlorine-1-metoxybenzene; facilitating the reaction between the intermediate III and sulfonyl chloride to generate activated ester, and then enabling the activated ester to have condensation reaction with L-prolinol to obtain an intermediate IV, and carrying out the hydrolysis reaction for the intermediate IV to obtain an intermediate V; enabling the intermediate V to firstly react with CDI and then to have acylation reaction with 2-pyrimidinemethanamine oxalate to obtain avanafil. According to the method, raw materials for the reaction in each step are simple and easy to obtain, the operation is simple, the yield is high, the cost is low, and the industrialized production is easy to realize.

Description

technical field [0001] The invention relates to a preparation method of avanafil, which belongs to the technical field of medicine. Background technique [0002] Avanafil, chemical name: 4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2 -pyrimidinylmethyl)-5-pyrimidinemethanesulfonamide; Molecular formula: C 23 h 26 ClN 7 o 3 ; Molecular weight: 483.95; Structural formula is: [0003] [0004] Avanafil is a drug developed by Vivus, an American company authorized by Mitsubishi Tanabe Pharmaceutical Co., Ltd. of Japan, for the treatment of male erectile dysfunction. It was approved by the FDA on April 27, 2012 and marketed in the United States under the trade name Stendra. [0005] There are two main synthetic routes of avanafil reported in the literature at present, wherein the patent WO0119802 discloses a method based on 4-chloro-2-methylthiopyrimidine-5-carboxyethyl ester and 3-chloro-4 methoxybenzyl Amines are used as starting materials...

Claims

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Application Information

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IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 杨庆坤张雷雷周先国李保勇吴柯张兆珍董廷华周学文李亚鹏
Owner 山东安信制药有限公司
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