4-Amino-3,5-dichloroacetophenone: Intermediate for Clenbuterol & Organic Synthesis

4-Amino-3,5-dichloroacetophenone is an important aromatic organic synthesis intermediate. Its molecule contains an amino group, chlorine atoms and an acetyl group; it is highly reactive and can participate in reduction, substitution and coupling reactions. Industrially, it is typically prepared from p-aminophenylacetone via low-temperature chlorination and recrystallisation. Its primary use is in the synthesis of cough and asthma medications such as clenbuterol hydrochloride (Clenbuterol), and 4-Amino-3,5-dichloroacetophenone is also employed in the preparation of chlorinated aromatic alcohols and heterocyclic compounds, finding widespread application in the pharmaceutical, pesticide and fine chemicals sectors.

4-Amino-3,5-dichloroacetophenone in chemical synthesis

Synthesis of 4-Amino-3,5-dichloroacetophenone: Weigh 7.9 g (59.2 mmol) of NCS in a 250 ml three-necked flask, add 60 ml of MeCN, stir to dissolve, and slowly add 4-aminoacetophenone (4 g, 29.6 mmol) dissolved in 50 ml of acetonitrile into the reaction using a constant pressure dropping funnel. The device was added dropwise in half an hour and stirred at room temperature for 3 hours. Most of the solvent was distilled off, and the mixture was stirred and dissolved, and then washed three times with 50 ml of purified water, and the organic phase was collected and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to give the titled acetophenone intermediate 4-amino-3,5-dichloroacetophenone 4.8 g (yield: 80%), and the product 4-amino-3-chloroacetophenone 0.9 was obtained. g, a yield of 18%, can be used in Example 5 as a starting material for the preparation of bromoclobuterol.[1]

Synthesis of 4-amino-3,5-dichlorobromoacetophenone from 4-amino-3,5-dichloroacetophenone: 4.8 g (23.7 mmol) of 4-amino-3,5-dichloroacetophenone was weighed into a 250 ml round bottom flask, and 60 ml of EA (ethyl acetate), 60 ml of CHCl3 and 20 ml of CH3CH2OH solvent were added thereto, and the mixture was stirred and dissolved at reflux temperature. 7.8 g (35 mmol) of copper bromide was weighed and added to the reaction apparatus for a total reaction time of 2 hours. The filter cake was washed with hot water, and the filter cake was washed three times with 20 ml of CH 2 Cl 2 , and the filtrate was transferred to a separating funnel. The filtrate was washed three times with 50 ml of pure water, and the organic phase was collected and dried over anhydrous sodium sulfate. After filtration, the solvent was dried and recrystallized from 5.0 g of 75% by weight of ethanol to give 4-amino-3,5-dichlorobromoacetophenone.

Clenbuterol and Impurity Analysis Related to 4-Amino-3,5-dichloroacetophenone

Clenbuterol is a β2 agonist with some structural and pharmacological similarities to epinephrine and salbutamol, but its effects are more potent and longer-lasting as a stimulant and thermogenic drug. It causes an increase in aerobic capacity, central nervous system stimulation, blood pressure, and oxygen transportation. It increases the rate at which body fat is metabolized while increasing the body’s basal metabolic rate (BMR). It is commonly used for smooth muscle-relaxant properties as a bronchodilator and tocolytic. By bromination of 4-amino-3,5-dichloroacetophenone with Br2 in CHCl3 to give 4-amino-3,5-dichloro-alpha-bromoacetophenone, m.p. 140-5 C, which is condensed with tert-butylamine in CHCl3 to 4-amino-3,5-dichloro-alpha-tertbutylaminoacetophenone hydrochloride, m.p. 252-7 C; this product is finally reduced with NaBH4 in methanol. In the synthesis of clenbuterol hydrochloride, first step was a double chlorination of 4-aminoacetophenone through an electrophillic aromatic substitution reaction to yield 4-Amino-3,5-dichloroacetophenone. Due to the ortho/para directing, amino group and the meta directing, electron withdrawing, acetyl group, chlorination of 4-aminoacetophenone occurs primarily at the 3 and 5 positions over the 2 and 6 positions. Therefore, under chlorination would produce only the mono chlorinated impurity, 4-amino-3- chloroacetophenone. Under these conditions, over chlorination does not result in the addition of chlorine to the 2 and 6 positions because the amino and acetyl groups do not direct that addition. Even though chlorides are ortho/para directing and direct to the 2 and 6 position, chlorides are also deactivating. After close observation on this chlorination reaction, it was noted that the formed mono chlorinated impurity (4-amino-3-chloro acetophenone) caused the formation of process related impurity (bromoclenbuterol) in clenbuerol synthesis. [2]

References

[1]CN109912434A

[2]Kannasani RK, Battula SR, Sannithi SB, Mula S, Babu VVV (2016) Synthesis and Characterization of Bromoclenbuterol. Med Chem (Los Angeles) 6:546-549. doi:10.4172/2161-0444.1000397

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