* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
(2E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride[ No CAS ]
[ 244768-32-9 ]
[ 500287-72-9 ]
Yield
Reaction Conditions
Operation in experiment
89.6%
b) A mixture of 93.9 g (0. 45 mol) of the hydrochloric acid salt of intermediate [(II),] prepared according to Example A2, and 103.8 g (0.45 mol) of intermediate (III-a) in 0.9 1 of acetonitrile was prepared under nitrogen atmosphere. The mixture was stirred and refluxed for 24 hours, then allowed to cool to 50 C. A solution of K2C03 (124.4 g, 0.9 mol) in H20 (0.45 1) was added over a period of 15-20 minutes at 40-50 C, followed by stirring for 1 hour at 50 C. The precipitate was separated and washed twice with 0.045 1 of acetonitrile, followed by drying at 50C under reduced pressure. 73.3 g of the obtained solid and 400 ml of EtOH were mixed and refluxed for 2 hours, then allowed to cool to room temperature. The precipitate was filtered and the residue was washed with 50 ml of EtOH. The obtained residue was dried overnight at 50C under reduced pressure. Yield: 65.7 g (89. 6 %) of 4-[[4-[[4-(2-cyanoethenyl)-2, 6- dimethylphenyl] amino]-2-pyrimidinyl] amino] benzonitrile (E) (Compound X).
68.6%
A mixture of 93.9 g (0.45 mol) of the hydrochloric acid salt of intermediate (II), prepared according to Example A2, and 109 g (0.4725 mol) of intermediate (III-a) in 1.81 of of acetonitrile was prepared under nitrogen atmosphere. The mixture was stirred and refluxed for 69 hours, then allowed to cool to 55 C. The mixture was filtered and the residue was washed with 200 ml of acetonitrile, followed by drying under reduced pressure at 50C overnight. 144, 6 g (0.3666 mol) of the obtained solid was brought in 1 l of K2CO3 10% aqueous solution. The mixture was stirred at room temperature followed by filtration. The obtained residue was washed twice with water followed by drying at 50C under reduced pressure. The residue was brought in 6.55 1 isopropanol and the mixture was refluxed, then stirred overnight and filtered at room temperature. The residue was dried at 50C under reduced pressure. Yield: 113.2 g [(68.] 6 %) of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino-2-pyrimidinyl]amino]benzonitrile (E) (Compound X).
With toluene-4-sulfonic acid; In 1,4-dioxane; at 100 - 110℃; for 14h;Product distribution / selectivity;
Example 8:Preparation of RilpivirineTo a mixture of 4-(4-chloropyrimidin-2-ylamino)benzonitrile (4.5 gm) as obtained in example 3, (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride (4.07 gm) as obtained in example 7 and p-toluenesulfonic acid monohydrate (4.45 gm) was added 1,4-dioxane (90 ml) under stirring. The mixture was then heated to 100 to 110C and stirred for 14 hours. The solution was then cooled to room temperature and then added saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate and then concentrated to obtain a crude solid.The crude solid obtained above was dissolved in acetone and stirred for 1 hour at room temperature. The separated solid was filtered and then dried to obtain 4 gm of rilpivirine.
135 g
In 1-methyl-pyrrolidin-2-one; at 85 - 95℃; for 16h;
To a mixture of 4-(4-chloropyrimidin-2-ylamino)benzonitrile (85 gm) as obtained in preparative example 1 and (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride (69 gm) as obtained in preparative example 2 was added N- methylpyrrolidone (425 ml) under stirring. The mixture was then heated to 85 to 95C and stirred for 16 hours. The solution was then cooled to room temperature and then added water (1 105 ml). The reaction mass was stirred for 1 hour 30 minutes at room temperature and filtered. The solid obtained was then dried to obtain 135 gm of rilpivirine as a white solid.Chromatographic purity of rilpivirine: 98.6%;Content of Z-isomer: 1.2%.
135 g
In 1-methyl-pyrrolidin-2-one; at 85 - 95℃; for 16h;
Example 1 Preparation of rilpivirine To a mixture of 4-(4-chloropyrimidin-2-ylamino)benzonitrile (85 gm) as obtained in preparative example 1 and (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride (69 gm) as obtained in preparative example 2 was added N-methylpyrrolidone (425 ml) under stirring. The mixture was then heated to 85 to 95 C. and stirred for 16 hours. The solution was then cooled to room temperature and then added water (1105 ml). The reaction mass was stirred for 1 hour 30 minutes at room temperature and filtered. The solid obtained was then dried to obtain 135 gm of rilpivirine as a white solid.
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at -20 - 20℃;Inert atmosphere;
General procedure: A solution of 14a-c (2 mmol), appropriate aryl acetonitrile (3 mmol) and anhydrous DMF (30 mL) was stirred for 0.5 h at -20 C. Then NaH (0.14 g, 3.5 mmol; 60% dispersion in mineral oil) was added portionwise at -20 C under Ar. The mixture was stirred at RT for 48-72 h under Ar, and then stirred under air for another 36-72 h at RT. The resulting mixture was poured into water and extracted with EtOAc. The combined organic layers were dried by Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel; EtOAc/petroleum ether, 1:6 to 1:4) gave 16a-z.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
120K+ Compounds
Competitive Price
1-2 Day Shipping
