Home Cart 0 Sign in  

[ CAS No. 500287-72-9 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 500287-72-9
Chemical Structure| 500287-72-9
Structure of 500287-72-9 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 500287-72-9 ]

Related Doc. of [ 500287-72-9 ]

Alternatived Products of [ 500287-72-9 ]

Product Details of [ 500287-72-9 ]

CAS No. :500287-72-9 MDL No. :MFCD11046372
Formula : C22H18N6 Boiling Point : -
Linear Structure Formula :- InChI Key :YIBOMRUWOWDFLG-ONEGZZNKSA-N
M.W : 366.42 Pubchem ID :6451164
Synonyms :
R278474;TMC278;DB08864

Calculated chemistry of [ 500287-72-9 ]

Physicochemical Properties

Num. heavy atoms : 28
Num. arom. heavy atoms : 18
Fraction Csp3 : 0.09
Num. rotatable bonds : 5
Num. H-bond acceptors : 4.0
Num. H-bond donors : 2.0
Molar Refractivity : 110.41
TPSA : 97.42 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.3 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.23
Log Po/w (XLOGP3) : 4.55
Log Po/w (WLOGP) : 4.88
Log Po/w (MLOGP) : 2.37
Log Po/w (SILICOS-IT) : 4.04
Consensus Log Po/w : 3.82

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -5.12
Solubility : 0.00275 mg/ml ; 0.00000752 mol/l
Class : Moderately soluble
Log S (Ali) : -6.32
Solubility : 0.000176 mg/ml ; 0.00000048 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -7.78
Solubility : 0.00000614 mg/ml ; 0.0000000167 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 3.29

Safety of [ 500287-72-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 500287-72-9 ]

* 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.

  • Downstream synthetic route of [ 500287-72-9 ]

[ 500287-72-9 ] Synthesis Path-Downstream   1~64

  • 1
  • [ 4336-70-3 ]
  • [ 500293-29-8 ]
  • 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile [ No CAS ]
  • [ 500287-72-9 ]
YieldReaction ConditionsOperation in experiment
5%; 7% A mixture of (cyanomethyl)triphenylphosphonium chloride (0.0022 mol) and potassium tert.-butoxide (0.0022 mol) in THF (7 ml) was stirred at 5 C. for 30 minutes under N2 flow, then stirred at 5 C. for 30 minutes. A mixture of intermediate 13 (0.0015 mol) in THF (7 ml) was added. The mixture was stirred for 8 hours in darkness, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (1.4 g) was purified by column chromatography over silica gel (eluent: toluene/iPrOH/NH4OH 96/4/0.1; 15-40 mum). Two fractions (F1, F2) were collected and the solvent was evaporated. Yield: 0.165 g of F1 (E/Z=32/68) (30%) and 0.225 g of F2 (E/Z=0/10) (41%). F2 was crystallized from CH3CN/diethyl ether. Yield: 0.036 g of compound 1 (7%). F1 was purified by column chromatography over kromasyl (eluent: toluene/iPrOH 98/2; 5 mum). The pure fractions were collected and the solvent was evaporated. Yield: 0.029 g of compound 10 (5%).
  • 2
  • [ 107-13-1 ]
  • [ 374067-85-3 ]
  • 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile [ No CAS ]
  • [ 500287-72-9 ]
YieldReaction ConditionsOperation in experiment
55% With triethylamine; tris-(o-tolyl)phosphine;palladium diacetate; In acetonitrile; at 150℃; A mixture of intermediate (IV-a) (0.00021 mol), prepared according to Example A4, acrylonitrile (CH2=CH-CN) (0.00213 mol), Pd (OAc) 2 (0.000043 mol), N,N-diethylethanamine (0.000043 mol) and tris (2-methylphenyl) phosphine (0.00021 mol) in CH3CN (7 ml) was stirred in a sealed vessel at 150C overnight. H20 was added. The mixture was extracted with CH2C12. The organic layer was separated, dried (MgS04), filtered and the solvent was evaporated. The residue (0.15 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/ethyl acetate 80/20; 15-40 mum). Fraction 1 was collected and the solvent was evaporated, yielding 0.045g of 4-[[4-[[4- [(2-cyanoethenyl)-2,6-dimethylphenyl] amino]-2-pyrimidinyl]amino] benzonitrile (E/Z=80/20). The solid was crystallized from diethylether. Yield: 0.035g of 4-[[4-[[4- (2-cyanoethenyl)-2, 6-dimethylphenyl] amino]-2-pyrimidinyl] amino] benzonitrile (E) (Compound X) [(55%).]
With palladium diacetate; triethylamine; tris-(o-tolyl)phosphine; In acetonitrile; at 150℃;Sealed tube; A mixture of intermediate 58 (0.00021 mol), prepared according to Example A11, acrylonitrile (CH2?CH-CN) (0.00213 mol), Pd(OAc)2 (0.000043 mol), N,N-diethylethanamine (0.000043 mol) and tris(2-methylphenyl)phosphine (0.00021 mol) in CH3CN (7 ml) was stirred in a sealed vessel at 150 C. overnight H2O was added. The mixture was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (0.15 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/ethyl acetate 80/20; 15-40 mum). Fraction 1 was collected and the solvent was evaporated, yielding 0.045 g of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (E/Z=80/20). The solid was crystallized from diethylether. Yield: 0.035 g of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (E) (compound 1) (55%).
  • 4
  • [ 3095-47-4 ]
  • [ 500287-72-9 ]
  • 6
  • [ 823786-21-6 ]
  • [ 500287-72-9 ]
  • 7
  • [ 708254-90-4 ]
  • [ 500287-72-9 ]
  • 9
  • C19H16IN5 [ No CAS ]
  • [ 107-13-1 ]
  • 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile [ No CAS ]
  • [ 500287-72-9 ]
YieldReaction ConditionsOperation in experiment
With sodium acetate;palladium 10% on activated carbon; In N,N-dimethyl acetamide; at 140℃; 4, 41g (10 mmol) of intermediate (IV-b) and 15 ml of N,N-dimethylacetamide were brought in a 100 ml flask under nitrogen. To this mixture were added 0,98g of sodium acetate (12 mmol), 107 mg (0,1 mmol Pd) of Pd/C] 10% (wet) and [1] mi (15 mmol) of acrylonitrile. The mixture was heated at 140C and the evolution of the reaction was followed by liquid chromatography. The reaction yielded 4-[[4-[[4-(2-cyanoethenyl)-] 2,6-dimethylphenyl] amino]-2-pyrimidinyl] amino] benzonitrile (E/Z=80/20) which can be worked up to yield 4-[[4-[[4-(2-cyanoethenyl)-2, 6-dimethylphenyl] amino]-2- pyrimidinyl] amino] benzonitrile (E) as described above in Example B2.
With palladium 10% on activated carbon; sodium acetate; In N,N-dimethyl acetamide; at 140℃;Inert atmosphere; 4.41 g (10 mmol) of intermediate 59 and 15 ml of N,N-dimethylacetamide were brought in a 100 ml flask under nitrogen. To this mixture were added 0.98 g of sodium acetate (12 mmol), 107 mg (0.1 mmol Pd) of Pd/C 10% (wet) and 1 ml (15 mmol) of acrylonitrile. The mixture was heated at 140 C. and the evolution of the reaction was followed by liquid chromatography. The reaction yielded 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (E/Z=80/20) which can be converted to 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (E) as described above in Example B1Ba).
  • 10
  • (2E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride [ No CAS ]
  • [ 244768-32-9 ]
  • [ 500287-72-9 ]
YieldReaction ConditionsOperation 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.

  • 11
  • [ 500287-72-9 ]
  • [ 882054-49-1 ]
YieldReaction ConditionsOperation in experiment
86% With N-Bromosuccinimide; In acetonitrile; at 20℃; for 4h; N-bromosuccinimide (0.0393 mol) was added portion wise at room temperature to Intermediate I (0.0327 mol), the preparation of which has been described in WO-03/016306, in CH3CN (100 ml). The mixture was stirred at room temperature for 4 hours. The precipitate was filtered off, washed with CH3CN and dried yielding 10.08 g of the desired end product. The filtrate was evaporated and purified by column chromatography (eluent: CH2CI2 100; 35-70 mum). The pure fractions were collected, the solvent was evaporated and the residue was crystallized from CH3CN. Yielding : 2.4 g of Intermediate 2. The two fractions were collected. Total yield: 12.48 g of Intermediate 2 (86 %, melting point: > 250C).
86% With N-Bromosuccinimide; In acetonitrile; at 20℃; for 4h; N-bromosuccinimide (0.0393 mol) was added portion wise at room temperature to Intermediate I (0.0327 mol), the preparation of which is described in WO-03/016306, Ui CH3CN (IOO mI). The mixture was stirred at room temperature for 4 hours. The EPO <DP n="30"/>precipitate was filtered off, washed with CH3CN and dried yielding 10.08 g of the desired end product. The filtrate was evaporated and purified by column chromato¬ graphy (eluent: CH2CI2 100; 35-70 mum). The pure fractions were collected, the solvent was evaporated and the residue was crystallized from CH3CN. Yield : 2.4 g of Compound L The two fractions were collected. Yield: 12.48 g of Compound I (86 %, melting point: > 250C).
86% With N-Bromosuccinimide; In CH3CN; at 20℃; for 4h; Example Al: Preparation of intermediate 2 Intermediate 1 Intermediate 2N-bromosuccinimide (0.0393 mol) was added portion wise at room temperature to Intermediate L, the preparation of which has been described in WO-03/016306 (0.0327 mol) in CH3CN (100 ml). The mixture was stirred at room temperature for 4 hours. The precipitate was filtered off, washed with CH3CN and dried yielding 10.08 g of the desired end product. The filtrate was evaporated and purified by column chromatography (eluent: CH2Cl2 100; 35-70 mum). The pure fractions were collected, the solvent was evaporated and the residue was crystallized from CH3CN. Yielding : 2.4 g of Intermediate 2. The two fractions were collected. Yielding: 12.48 g of Intermediate 2 (86 %, melting point: > 250C).
86% With N-Bromosuccinimide; In acetonitrile; at 20℃; for 4h; Example 1 : Preparation of intermediate 2Intermediate 1 Intermediate 2N-bromosuccinimide (0.0393 mol) was added portion wise at room temperature to Intermediate 1 (0.0327 mol), the preparation of which is described in WO-03/016306, in CH3CN (100 ml). The mixture was stirred at room temperature for 4 hours. The precipitate was filtered off, washed with CH3CN and dried yielding 10.08 g of the <n="31"/>desired end product. The filtrate was evaporated and purified by column chromatography (eluent: CH2Cl2 100; 35-70 mum). The pure fractions were collected, the solvent was evaporated and the residue was crystallized from CH3CN. Yield : 2.4 g of Intermediate 2. The two fractions were collected. Total yield: 12.48 g of intermediate 2 (86 %, melting point: > 2500C).

  • 12
  • [ 500287-72-9 ]
  • C22H17ClN6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
59% With N-chloro-succinimide; In acetonitrile; at 20℃; for 4h; N-chlorosuccinimide (0.000327 mol) was added portion wise at room temperature to Intermediate I (0.000273 mol) in CH3CN (5 ml). The mixture was stirred at room temperature for 4 hours. The precipitate was filtered, washed with CH3CN and dried. Yield: 0.065 g of intermediate 3 (59 %, melting point: > 250C).
59% With N-chloro-succinimide; In CH3CN; at 20℃; for 4h; Example A2: Preparation of intermediate 3 Intermediate 3 EPO <DP n="51"/>N-chlorosuccinimide (0.000327 mol) was added portion wise at room temperature to Intermediate 1 (0.000273 mol) in CH3CN (5 ml). The mixture was stirred at room temperature for 4 hours. The precipitate was filtered, washed with CH3CN and dried. Yielding: 0.065 g (59 %, melting point: > 2500C).
  • 13
  • [ 500287-72-9 ]
  • C22H17IN6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With Iodine monochloride; calcium carbonate; In ethanol; dichloromethane; water; at 20℃; for 24h; A suspension Of CaCO3 (1.64g) in water (30ml) was added to a suspension of intermediate I (0.0273 mol) in EtOH (180ml). Iodine chloride (ICl) in CH2Cl2 (IN) (22.5ml) was added dropwise. The mixture was stirred at room temperature for 24 hours, then cooled to 0C and filtered. The filtrate was dried under vacuo, then taken up in EtOH (180ml), filtered, washed with EtOH and CH3CN and dried. Yield: 8.5g . Part of the filtrate was evaporated. The residue was crystallized from hot CH3CN. The precipitate was filtered off and dried. Yielding: 1.54g of intermediate 5 (total yield 78%).
78% With Iodine monochloride; calcium carbonate; In ethanol; dichloromethane; water; at 20℃; for 24h; A suspension Of CaCO3 (1.64g) in water (30ml) was added to a suspension of intermediate 1 (0.0273 mol) in EtOH (180ml). Iodine chloride (ICl) in CH2Cl2 (IN) (22.5ml) was added dropwise. The mixture was stirred at room temperature for 24 hours, then cooled to 0C and filtered. The filtrate was dried under vacuo, then taken up in EtOH (180ml), filtered, washed with EtOH and CH3CN and dried. Yield: 8.5g. Part of the filtrate was evaporated. The residue was crystallized from hot CH3CN. The precipitate was filtered off and dried. Yield: 1.54g (total yield 78%).
  • 14
  • [ 104-15-4 ]
  • [ 500287-72-9 ]
  • (E)-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]pyrimidinyl]amino]benzonitrile tosylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 45℃; <strong>[500287-72-9]Rilpivirine</strong> base form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45C. p-Toluenesulfonic acid monohydrate (171 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and the resulting solution was then added portion- wise to the solution containing <strong>[500287-72-9]Rilpivirine</strong> base at 45C with stirring. Precipitation was observed upon mixing. The reaction mixture was removed from the heat source and stirring was continued at room temperature for about 17 h. The precipitate was isolated by filtration to give <strong>[500287-72-9]Rilpivirine</strong> p-toluenesulfonate Form 1, as indicated by XRD.
1 g In acetone; at 20℃; for 1h; Example 11 Preparation of Tosylate Salt of <strong>[500287-72-9]Rilpivirine</strong> [0092] <strong>[500287-72-9]Rilpivirine</strong> (1 gm) was dissolved in acetone (50 ml) and then added a solution of p-toluene sulfonic acid (0.4 gm) in acetone (20 ml). The reaction mass was stirred for 1 hour at room temperature and filtered. The solid obtained was dried to give 1 gm of to sylate salt of <strong>[500287-72-9]rilpivirine</strong>.
  • 15
  • [ 97-67-6 ]
  • [ 500287-72-9 ]
  • rilpivirine L-malate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 45℃; <strong>[500287-72-9]Rilpivirine</strong> base Form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45C. L-Malic acid (121 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and the resulting solution was then added portion- wise to the solution containing <strong>[500287-72-9]Rilpivirine</strong> base at 45C with stirring. The reaction mixture was removed from the heat source and stirring was continued at room temperature for about 17 h. A precipitate formed and was isolated by filtration to give <strong>[500287-72-9]Rilpivirine</strong> L-malate Form 1. Drying of this material in a vacuum oven at 50C for 18 h afforded the same polymorphic form as was identified prior to drying.
  • 16
  • [ 87-69-4 ]
  • [ 500287-72-9 ]
  • rilpivirine L-tartrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 45℃; <strong>[500287-72-9]Rilpivirine</strong> base form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45C. L-tartaric acid (135 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at roomtemperature and the resulting solution was then added portion- wise to the solution containing <strong>[500287-72-9]Rilpivirine</strong> base at 45C with stirring. The reaction mixture was removed from the heat source and stirring was continued at room temperature for about 17 h. The mixture was then cooled to -18C and maintained at this temperature overnight, and then returned to ambient temperature. To the mixture was then added diethyl ether (6 mL), leading to the formation of a precipitate. The precipitate was isolated by vacuum filtration and the filter cake was washed with diethyl ether to give amorphous <strong>[500287-72-9]Rilpivirine</strong> L-tartrate as a white solid, both before and after drying in a vacuum oven at 60C overnight. The samples were found to be amorphous.
  • 17
  • [ 110-16-7 ]
  • [ 500287-72-9 ]
  • rilpivirine maleate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 45℃;Product distribution / selectivity; <strong>[500287-72-9]Rilpivirine</strong> base Form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45C. Maleic acid (105 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and the resulting solution was then added portion- wise to the solution containing <strong>[500287-72-9]Rilpivirine</strong> base at 45C with stirring. The reaction mixture was removed from the heat source and precipitation was observed after stirring for about 20 min. The stirring was continued at room temperature for about 17 h. The precipitate was isolated by filtration to give <strong>[500287-72-9]Rilpivirine</strong> maleate form 1. Drying of this material in a vacuum oven at 50C for 17 h afforded the same polymorphic form as was identified prior to drying, as confirmed by XRD analysis.
  • 18
  • [ 141-82-2 ]
  • [ 500287-72-9 ]
  • rilpivirine malonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 45℃; <strong>[500287-72-9]Rilpivirine</strong> base form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45C. Malonic acid (94 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and the resulting solution was then added portion-wise to the solution containing <strong>[500287-72-9]Rilpivirine</strong> base at 45C with stirring. The reaction mixture was removed from the heat source and stirring was continued at room temperature for about 17 h. The mixture was then cooled to - 18C and maintained at that temperature over a period of 10 days. A precipitate formed and was isolated by vacuum filtration at -15C to room temperature to give <strong>[500287-72-9]Rilpivirine</strong> malonate Form 1 as a pale yellow solid. Drying of this material in a vacuum oven at 50C for 17 h afforded <strong>[500287-72-9]Rilpivirine</strong> malonate Form 1.
  • 19
  • [ 75-75-2 ]
  • [ 500287-72-9 ]
  • 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile methanesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 45℃; <strong>[500287-72-9]Rilpivirine</strong> base Form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45C. Methanesulfonic acid (87 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and the resulting solution was then added portion- wise to the solution containing <strong>[500287-72-9]Rilpivirine</strong> base at 45C with stirring. The reaction mixture was removed from the heat source and stirring was continued at room temperature for about 17 h. A precipitate formed and was isolated by filtration to give <strong>[500287-72-9]Rilpivirine</strong> mesylate Form 1 as indicated by XRD.
  • 20
  • [ 110-15-6 ]
  • [ 500287-72-9 ]
  • rilpivirine succinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 45℃;Product distribution / selectivity; <strong>[500287-72-9]Rilpivirine</strong> base Form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45C. Succinic acid (106 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and the resulting solution was then added portion- wise to the solution containing <strong>[500287-72-9]Rilpivirine</strong> base at 45C with stirring. The reaction mixture was removed from the heat source and stirred at room temperature for about 17 h. leading to precipitation. The precipitate was isolated by filtration to give <strong>[500287-72-9]Rilpivirine</strong> succinate Form 1. Drying of this material in a vacuum oven at 50C for 18 h afforded the same polymorphic form as was identified prior to drying.
  • 21
  • (E)-3-(4-amino-3,5-dimethylphenyl)-2-acrylonitrile hydrochloride [ No CAS ]
  • [ 244768-32-9 ]
  • [ 500287-72-9 ]
YieldReaction ConditionsOperation in experiment
58% (E)-3-(4-Amino-3,5-dimethylphenyl)acrylonitrile hydrochloride (48 g, 0.23 mol) and 4-(4-chloropyrimidin-2-ylamino)benzonitrile (55.7 g, 0.24 mol, 1.05 eq) were mixed with acetonitrile (480 mL, 10V) at 25C affording a yellow suspension. The suspension was stirred and heated to reflux (82C). Stirring was continued at the same temperature for 48 h, and the suspension was then cooled to 50C over a period of 0.5 h. A solution of potassium carbonate (63.5 g, 0.46 mol, 2 eq) in water (240 mL) was added dropwise over 15 min at 50C, and stirring was continued for another 1 h. The resulting solid was isolated by vacuum filtration, washed with acetonitrile/water (40+30 ml) and air-dried on the filter. The air-dried filter cake (74.2 g) was mixed with EtOH (abs) (410 mL, 5.5V vs. crude Rilpivirine), and the resulting slurry was heated to reflux (78C) with stirring. The hot suspension was stirred for 2 h at 78C, and then cooled to 25C over a period 0.5 h. The resulting solid was isolated by vacuum filtration; the filter cake was washed with EtOH (abs) (75 ml) and dried in a vacuum oven (10 mbar) at 50C for 16 h to afford Rilpivirine base form II (48.9 g, 58.1% yield, 98.4% purity) as a yellow solid.
4 g With toluene-4-sulfonic acid; In 1,4-dioxane; water; at 100 - 110℃; for 14h; Example 8 Preparation of Rilpivirine [0088] To 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 110 C. 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. [0089] 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.
  • 22
  • [ 77-92-9 ]
  • [ 500287-72-9 ]
  • 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile citrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 45℃; <strong>[500287-72-9]Rilpivirine</strong> base form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45C. Citric acid (173 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and the resulting solution was then added portion-wise to the solution containing <strong>[500287-72-9]Rilpivirine</strong> base at 45C with stirring. The reaction mixture was removed from the heat source and stirring was continued at room temperature for about 17 h. The mixture was then cooled to - 18C for 2 h and then returned to ambient temperature. About 15 V of the mixture were removed by distillation with a rotary evaporator and then diethyl ether (6 mL) was added leading to the formation of a precipitate. The precipitate was isolated by vacuum filtration and the filter cake was washed with diethyl ether (1 mL) to give amorphous <strong>[500287-72-9]Rilpivirine</strong> citrate as a white solid, both before and after drying in a vacuum oven at 60C over night. The samples were found to be amorphous.
3.4 g With acetic acid; at 90 - 95℃; for 0.166667h;Inert atmosphere; EXAMPLE 7Preparation of <strong>[500287-72-9]Rilpivirine</strong> citrate salt.A 1 L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was purged with N2. The flask was charged <strong>[500287-72-9]rilpivirine</strong> free base, obtained from Example 4 (6 gms) and acetic acid (33 ml). The reaction temperature was raised to 90C to 95C and citric acid (4.2 gms) was added at same temperature. The reaction mixture was stirred for 10 minutes and water (33 ml) was added at temperature 65C to 70C.The reaction mixture was allowed to cool to 25C to 35C and stirred for 1 hour. Precipitated solid was filtered and washed with water (8 ml). The wet product was dried at about 60C to about 65C under reduced pressure to provide the <strong>[500287-72-9]rilpivirine</strong> citrate salt (Yield: 6.6 gms). The dry compound was taken in a 1 L round bottom flask and was charged acetic acid (24 ml). Heated to about 85C and stirred for 30 minutes. Thereaction mixture was allowed to cool to 25C to 35C and stirred for 1 hour. Precipitatedsolid was filtered and washed with water (90 ml). The wet product was dried at about60C to about 65C under reduced pressure to provide the title compound.Yield: 3.4 gmsHPLC Purity: 99.64%Z-isomer: 0.09%, Formula II: Not detected, Formula III: Not detected, Formula IV: Not detectedThe XRPD is set forth in Fig. 01
  • 23
  • [ 594-45-6 ]
  • [ 500287-72-9 ]
  • rilpivirine ethanesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 45℃; Ethanesulfonic acid 95% (104 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and was then added dropwise to a stirred solution of <strong>[500287-72-9]Rilpivirine</strong> base form II (0.30 g, 0.82 mmol) in THF (6 mL, 20V) at 45C. Precipitation was observed. The reaction mixture was cooled to room temperature for 30 min and stirring was continued at the same temperature for 17 h. The reaction mixture was then filtered to give the title compound. The filter cake was dried in a vacuum oven at 50C for 17 h. A white solid was obtained. XRD analysis of the solid indicated the same polymorphic form as was identified in the wet material.
  • 24
  • [ 64-19-7 ]
  • [ 500287-72-9 ]
  • rilpivirine acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 50℃;Product distribution / selectivity; <strong>[500287-72-9]Rilpivirine</strong> base form II (0.30 g, 0.82 mmol) was mixed with acetic acid (1.5 mL, 5V) and heated to 50C with stirring to form a solution. Stirring was continued for about 10 min and then water (1.5 mL, 5 V) was added to the yellow solution. The resulting off- white suspension was stirred at 50C for 1 h, and was then cooled to room temperature. Stirring was continued at ambient temperature for 22 h and the reaction mixture was filtered to isolate a solid, which was identified as form IV by XRD. Drying of this material in a vacuum oven at 50C for 24 h afforded the same polymorphic form (IV) as was identified prior to drying.
  • 25
  • [ 500287-72-9 ]
  • rilpivirine phosphate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With phosphoric acid; In tetrahydrofuran; at 45℃; for 1h;Product distribution / selectivity; A mixture of phosphoric acid 85% (104 mg, 0.90 mmol, 1.1 eq) in THF (3 mL, 10V) was added to <strong>[500287-72-9]Rilpivirine</strong> base Form II (300 mg, 0.82 mmol). The resulting slurry was stirred with heating (45C) for 1 h, after which time the reaction mixture was cooled to room temperature. Stirring of the reaction mixture was continued at room temperature overnight, during which time a solid precipitate formed. The solid was isolated by filtration; the filter cake was washed with cold THF (1 mL) and dried in a vacuum oven at 50C overnight to give <strong>[500287-72-9]Rilpivirine</strong> phosphate Form 3 as a white solid. An XRD analysis is provided in Figure 5.
  • 26
  • [ 500287-72-9 ]
  • rilpivirine hydrobromide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogen bromide; In tetrahydrofuran; at 45℃;Product distribution / selectivity; <strong>[500287-72-9]Rilpivirine</strong> base Form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45C. HBr 48% (152 mg, 0.90 mmol, 1.1 eq) was mixed with THF (3 mL) at roomtemperature and the resulting solution was then added portion- wise to the solution containing <strong>[500287-72-9]Rilpivirine</strong> base at 45C with stirring. Precipitation was observed upon mixing. The reaction mixture was removed from the heat source and stirring was continued at room temperature for about 17 h. The precipitate was isolated by filtration to give <strong>[500287-72-9]Rilpivirine</strong> HBr form 1.Drying of the aforementioned material in a vacuum oven at 50C for 17 h afforded the same polymorphic form as was identified prior to drying, as confirmed by XRD analysis.
  • 27
  • [ 500287-72-9 ]
  • 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
<strong>[500287-72-9]Rilpivirine</strong> base form II (15.3 g, 41.8 mmol) was mixed with acetic acid (80 mL, 5.2V) at 25C affording a yellow suspension. The suspension was stirred and heated to 90C to obtain a brownish solution, whilst stirring for 15 min. The solution was then heated to 95C, filtered and the filter washed with acetic acid (4.6 mL, 0.3V). The resulting filtrate was cooled to 80C and HC1 32% (4.14 ml, 41.8 mmol, 1 eq) was added in one portion, to afford an off-white suspension. The suspension was heated to 85C and stirred at the same temperature for 10 min. Water (84 mL, 5.5V) was added dropwise over a period of 10 min, and stirring was continued for 0.5 h. The mixture was then cooled to 25C over 1 h. A solid precipitated and was isolated by vacuum filtration, washed with water (2x7.65mL, 0.5V) and the filter cake was dried in a vacuum oven (10 mbar) at 50C for 15 h to afford <strong>[500287-72-9]Rilpivirine</strong> HC1 Form A.
With hydrogenchloride; In methanol; dichloromethane; at 0℃; for 1h; Example 10:Preparation of <strong>[500287-72-9]rilpivirine</strong> hydrochloride <strong>[500287-72-9]Rilpivirine</strong> (1.3 gm) as obtained in example 8 was dissolved in a mixture of methanol and methylene chloride (1:2; 72 ml). To the solution was passed dry hydrochloride gas until the precipitation obtained. The reaction mixture was stirred for 1 hour at 0C and filtered. The solid obtained was dried to give 0.8 gm of <strong>[500287-72-9]rilpivirine</strong> hydrochloride.
15.0 g With hydrogenchloride; acetic acid; In water; at 65℃;Inert atmosphere; EXAMPLE 6Preparation of <strong>[500287-72-9]Rilpivirine</strong> hydrochloride.A 1 L round bottom flask fitted with a mechanical stirrer, thermometer socket, additionfunnel was purged with N2. The flask was charged pure <strong>[500287-72-9]rilpivirine</strong> base, obtained fromExample 5 (15.0 gms) in acetone (450 ml). The reaction mass was raised at a temperature of about 55C to get a clear solution and filtered to obtain reaction mass. The resulting reaction mass was charged acetic acid (120 ml) and distilled out acetone under vaccum till -7V acetic acid remains in the flask. The reaction mass was Heated to about 65C. Aqueous hydrochloric acid (4.05 ml) was added at 65C and then water (120 ml) was added. The reaction mixture was allowed to cool to 25C to 35C andstirred for 1 hour. Precipitated solid was filtered and washed with water (30 ml). The wetproduct was dried at about 50C under vaccume to provide the title compound.Yield: 15.0 gmsHPLC Purity: 99.95%Z-isomer: 0.02%, Formula II: Not detected, Formula III: Not detected, Formula IV: Notdetected
0.8 g With hydrogenchloride; In methanol; dichloromethane; at 0℃; for 1h; Example 10 Preparation of <strong>[500287-72-9]Rilpivirine</strong> Hydrochloride [0091] <strong>[500287-72-9]Rilpivirine</strong> (1.3 gm) as obtained in example 8 was dissolved in a mixture of methanol and methylene chloride (1:2; 72 ml). To the solution was passed dry hydrochloride gas until the precipitation obtained. The reaction mixture was stirred for 1 hour at 0 C. and filtered. The solid obtained was dried to give 0.8 gm of <strong>[500287-72-9]rilpivirine</strong> hydrochloride.
86 g With hydrogenchloride; In methanol; isopropyl alcohol; at 25℃; for 2h;Reflux; Example 2 Preparation of <strong>[500287-72-9]rilpivirine</strong> hydrochloride <strong>[500287-72-9]Rilpivirine</strong> (135 gm) as obtained in example 1 was suspended in methanol (1350 ml) and then heated to reflux for 20 minutes. To the reaction mixture was added a solution of hydrochloric acid in isopropanol (6N, 675 ml) at reflux and maintained for 1 hour. The reaction mass was then cooled to room temperature and stirred for 1 hour at room temperature. The solid obtained was collected by filtration and then dried to obtain 86 gm of <strong>[500287-72-9]rilpivirine</strong> hydrochloride.
Concentrated hydrochloric acid (7.5 ml; excess) and subsequently water (100 ml) isadded to a suspension of <strong>[500287-72-9]rilpivirine</strong> (10.42 g) in IPA (100 ml) and the mixture isheated up to moderate reflux while an lPNwater mixture (1:1) (140 ml) is gradually added in several parts. After I h of heating to boiling, Norit - activated carbon (1.1 g) is carefully added to the obtained solution, the solution is further heated up to boiling for I h and filtered through a kieselguhr layer on pre-heated frit. The obtained solutionis left to cool down to it under stirring and after 2 more hours at rt it is cooled down to10C for I h. The crystals are aspirated, washed with 30 ml of a 1:1 mixture of IPA/water and dried in vacuo at 50C. 8.55 g (58.3%) of <strong>[500287-72-9]rilpivirine</strong> hydrochloride is obtained, UPLC 91.2%, 7-isomer 0.2%, hydroxy derivative 8.0%.

  • 28
  • [ 500287-72-9 ]
  • rilpivirine sulfate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sulfuric acid; In tetrahydrofuran; at 45℃; for 1h;Product distribution / selectivity; A mixture of sulfuric acid 98% (90 mg, 0.90 mmol, 1.1 eq) in THF (3 mL, 10V) was added to <strong>[500287-72-9]Rilpivirine</strong> base Form II (300 mg, 0.82 mmol). The resulting slurry was stirred with heating (45C) for 1 h, after which time the reaction mixture was cooled to room temperature. Stirring of the reaction mixture was continued at room temperature overnight, during which time a solid precipitate formed. The solid was isolated by filtration. The filter cake was washed with cold THF (1 mL) and dried in a vacuum oven at 50C overnight to give <strong>[500287-72-9]Rilpivirine</strong> sulfate Form 1 as a white solid.
  • 29
  • [ 98-11-3 ]
  • [ 500287-72-9 ]
  • rilpivirine benzenesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 45℃; Benzenesulfonic acid 90% (160 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and was then added dropwise to a stirred solution of <strong>[500287-72-9]Rilpivirine</strong> base form II (300 mg, 0.82 mmol) in THF (6 mL, 20V) at 45C. Precipitation was observed. The reaction mixture was cooled to room temperature for 30 min and stirring was continued at the same temperature for 17 h. The reaction mixture was then filtered to give <strong>[500287-72-9]Rilpivirine</strong> benzenesulfonate Form 1. The filter cake was dried in a vacuum oven at 50C for 17 h. A white solid was obtained. XRD analysis of the solid indicated the same polymorphic form as was identified in the wet material.
  • 30
  • [ 87-62-7 ]
  • [ 500287-72-9 ]
  • 31
  • [ 500287-72-9 ]
  • [ 1399384-91-8 ]
YieldReaction ConditionsOperation in experiment
With toluene-4-sulfonic acid; In acetone; at 20℃; for 1h; Example 11 :Preparation of tosylate salt of <strong>[500287-72-9]rilpivirine</strong><strong>[500287-72-9]Rilpivirine</strong> (1 gm) was dissolved in acetone (50 ml) and then added a solution of p-toluene sulfonic acid (0.4 gm) in acetone (20 ml). The reaction mass was stirred for 1 hour at room temperature and filtered. The solid obtained was dried to give 1 gm of tosylate salt of <strong>[500287-72-9]rilpivirine</strong>.
  • 35
  • [ 500287-72-9 ]
  • [ 700361-47-3 ]
YieldReaction ConditionsOperation in experiment
86 g With hydrogenchloride; In methanol; water; isopropyl alcohol; for 1h;Reflux; <strong>[500287-72-9]Rilpivirine</strong> (135 gm) as obtained in example 1 was suspended in methanol (1350 ml) and then heated to reflux for 20 minutes. To the reaction mixture was added a solution of hydrochloric acid in isopropanol (6N, 675 ml) at reflux and maintained for 1 hour. The reaction mass was then cooled to room temperature and stirred for 1 hour at room temperature. The solid obtained was collected by filtration and then dried to obtain 86 gm of <strong>[500287-72-9]rilpivirine</strong> hydrochloride.Chromatographic purity of <strong>[500287-72-9]rilpivirine</strong> hydrochloride: 99.9%;Content of Z-isomer: 0.08%.
87.5 g With hydrogenchloride; In methanol; acetone; at 0 - 20℃; for 1h; <strong>[500287-72-9]Rilpivirine</strong> (100 gm) was suspended in a mixture of methanol (1500 ml) and acetone (2200 ml). The contents were heated to reflux and maintained for 30 minutes at reflux to obtain a clear solution. The solution was treated with carbon and stirred for 10 minutes. The reaction mass was filtered through celite bed and then concentrated to obtain a residual solid. The residual solid was stirred for 30 minutes, filtered and then dried. To the solid thus obtained was added methanol and then the reaction mass was passed dry hydrochloride gas until the precipitation obtained at 0C. The temperature of the reaction mass was raised to room temperature and stirred for 1 hour at room temperature. The separated solid was filtered and then dried to obtain 87.5 gm of <strong>[500287-72-9]rilpivirine</strong> hydrochloride crystalline monohydrate as an off white solid.Chromatographic purity of <strong>[500287-72-9]rilpivirine</strong> hydrochloride monohydrate: 99.93%;Content of Z-isomer: 0.05%.
  • 36
  • 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile citrate [ No CAS ]
  • [ 500287-72-9 ]
YieldReaction ConditionsOperation in experiment
2 g With potassium carbonate; In water; at 20℃; for 3h;Inert atmosphere; EXAMPLE 8Preparation of Rilpivirine hydrochloride.A 1 L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was purged with N2. The flask was charged rilpivirine citrate salt, obtained from Example 7 (3 gms), 30 ml of 10% aqueous potassium carbonate solution (2.73 gms ofpotassium carbonate was dissolved in 27.3 ml of water). The reaction mixture was stirred for 3 hours at room temperature and filtered and washed with water (6 ml). The wet product was dried at about 50C to about 55C under reduced pressure to provide rilpivirine base (Yield: 2 gm). The dry compound was taken in a round bottom flask and was charged acetic acid (10 ml). Heated to about 85C and stirred for 20 minutes.Aqueous hydrochloric acid (0.6 ml) was added at 85C and then water (12 ml) was added. The reaction mixture was allowed to cool to 25C to 35C and stirred for 1 hour. Precipitated solid was filtered and washed with water (2 ml). The wet product was dried at about 60C to about 65C under reduced pressure to provide the title compound.Yield: 2.1 gmsHPLC Purity: 99.93%Z-isomer: 0.06%, Formula II: Not detected, Formula III: Not detected, Formula IV: Not detected
  • 37
  • [ 144-62-7 ]
  • [ 500287-72-9 ]
  • 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile oxalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
3.3 g With acetic acid; at 90 - 95℃; for 0.166667h;Inert atmosphere; EXAMPLE 9Preparation of <strong>[500287-72-9]Rilpivirine</strong> oxalate salt.A 1 L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was purged with N2. The flask was charged <strong>[500287-72-9]rilpivirine</strong> free base, obtained from Example 4 (3 gms) and acetic acid (16.5 ml). The reaction temperature was raised to90C to 95C and oxalic acid (0.87 gms) was added at same temperature. The reaction mixture was stirred for 10 minutes and water (16.5 ml) was added at temperature 65C to 70C. The reaction mixture was allowed to cool to 25C to 35C and stirred for 1 hour. Precipitated solid was filtered and washed with ?vater (4 ml). The wet product was dried at about 60C to about 65C under reduced pressure to provide the title compound.Yield: 3.3 gms. -HPLC Purity: 98.89% VZ-isomer: 0.63% VThe XRPD is set forth in Fig. 02
  • 38
  • [ 1135-24-6 ]
  • [ 500287-72-9 ]
  • 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile ferulate [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.3 g With acetic acid; at 90 - 95℃; for 0.166667h;Inert atmosphere; EXAMPLE 10Preparation of <strong>[500287-72-9]Rilpivirine</strong> ferulate salt.A round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was purged with N2. The flask was charged <strong>[500287-72-9]rilpivirine</strong> free base, obtained fromExample 4 (1 gin) and acetic acid (5.5 ml). The reaction temperature was raised to 90C to 95C and ferulic acid (0.61 gms) was added at same temperature. The reaction mixture was stirred for 10 minutes and water (5.5 ml) was added at temperature 65C to 70C. The reaction mixture was allowed to cool to 25C to 35C and stirred for 1 hour. Precipitated solid was filtered and washed with water (2 ml). The wet product was driedat about 60C to about 65C under reduced pressure to provide the title compound. Yield: 1.3 gms.HPLC Purity: 98.95%Z-isomer: 0.54%
  • 39
  • 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile hydrochloride [ No CAS ]
  • [ 500287-72-9 ]
YieldReaction ConditionsOperation in experiment
18.6 g With potassium carbonate; In water; at 20℃; for 3h;Inert atmosphere; EXAMPLE 4Preparation of Rilpivirine free baseA 1 L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was purged with N2. The flask was charged rilpivirine hydrochloride crude, obtained from Example 1 (23 gms), 10% aqueous potassium carbonate solution (21.09 gms of potassium carbonate was dissolved in 208.90 ml of water). The reaction mixturewas stirred for 3 hours at room temperature and filtered and washed with water (50 ml).The wet product was dried at about 50C to about 55C under reduced pressure toprovide the title compound.Yield: 18.6 gmsHPLC Purity: 95.77% Z-isomer: 2.82%, Formula II: 0.03%, Formula III: 0.04%, Formula IV: 0.08%
1.359 g With potassium carbonate; In water; for 1.5h; The aniline derivative I (hydrochloride 940 mg, 4.5 mmol) and chloropyrimidine 2(1092 mg, 4.76 mmol, 1.05 equiv.) is dosed into a flask (50 ml), acetonitrile (18 ml) isadded and the thick suspension is heated up in an inert atmosphere at the bath temperature of 84C for 69 hours. After cooling, the crystals are aspirated, washed with acetonitrile (3+1 ml) and dried in a vacuum drier at 50C overnight. Off-white crystals are obtained (1.467 g, 81%). This rilpivirine hydrochloride (1.423 g) is stirred with a 10% aqueous solution of K2C03 (11 ml) for 1.5 h. The yellow crystals are aspirated, washed with water (2x5 ml) and dried in a vacuum drier at 50C overnight. Yellow crystals are obtained (1.359 g). These crystals (1.310 g) are stIrred up in IPA(2-propanol) (60 ml), the mixture is refluxed for 2 hours and then stirred at it overnight. The crystals are aspirated, washed with 1PA (2x5 ml) and dried in a vacuum drier at 50C overnight. Light yellow crystals of the base are obtained (1.359 g). Total yield 77.82%, HPLC 95.19%, Z-isomer 0.43%.
  • 40
  • [ 1538550-43-4 ]
  • [ 873-74-5 ]
  • [ 500287-72-9 ]
YieldReaction ConditionsOperation in experiment
40 g With toluene-4-sulfonic acid; In isopropyl alcohol; at 20 - 85℃; for 4h; Example 5:Preparation of rilpivirineTo a mixture of (E)-3-( 4-(2-chloropyrimidin-4-ylamino )-3,5-dimethylphenyl)acrylonitrile ( 40 gm), 4-aminobenzonitrile (17 gm), isopropanol ( 400 ml)5 and p-toluenesulfonic acid (20 ml) were added at room temperature. The reaction mixturewas then heated to 80 to 85C and stirred for 4 hours. The reaction mass was then cooledto 0C and pH was adjusted to 10 to 11 with aqueous ammonia solution. The separatedsolid was filtered and then dried to provide 40 gm of rilpivirine.Chromatographic purity: 96.0%;10 Content of Z-isomer: 3.5%.
  • 41
  • [ 500292-90-0 ]
  • [ 244768-32-9 ]
  • [ 500287-72-9 ]
YieldReaction ConditionsOperation in experiment
68.6% In acetonitrile; for 69h;Inert atmosphere; Reflux; Compound 1 was also prepared as follows: (0510) A mixture of 93.9 g (0.45 mol) of the hydrochloric acid salt of intermediate 3, prepared according to Example A1c), and 109 g (0.4725 mol) of intermediate 5 in 1.81 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 50 C. overnight. 144.6 g (0.3666 mol) of the obtained solid was brought in 11 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 50 C. under reduced pressure. The residue was brought in 6.551 isopropanol and the mixture was refluxed, then stirred overnight and filtered at room temperature. The residue was was dried at 50 C. 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 1).
  • 42
  • [ 114886-15-6 ]
  • [ 500287-72-9 ]
  • 43
  • C12H16N2O [ No CAS ]
  • [ 500287-72-9 ]
  • 44
  • C14H17N3 [ No CAS ]
  • [ 500287-72-9 ]
  • 45
  • 3-(4-amino-3,5-dimethylphenyl)acrylonitrile [ No CAS ]
  • [ 500287-72-9 ]
  • 46
  • [ 500292-92-2 ]
  • [ 500287-72-9 ]
  • 47
  • [ 500292-94-4 ]
  • [ 244768-32-9 ]
  • [ 500287-72-9 ]
YieldReaction ConditionsOperation in experiment
20% at 150℃; for 1h; A mixture of intermediate 3 (0.034 mol) and intermediate 5 (0.0174 mol) was stirred at 150 C. for 1 hour and taken up in K2CO3 10%/CH2Cl2/CH3OH. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (10 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/ethyl acetate 80/20; 15-40 mum). Fraction 1 was crystallized from iPrOH. The precipitate was filtered off and dried. Yield: 1.3 g of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (E) (compound 1) (20%).
  • 48
  • 4-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile [ No CAS ]
  • [ 500287-72-9 ]
  • 49
  • 4-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile [ No CAS ]
  • 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile [ No CAS ]
  • [ 500287-72-9 ]
  • 50
  • [ 244768-32-9 ]
  • 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile [ No CAS ]
  • [ 500287-72-9 ]
  • 51
  • [ 823786-21-6 ]
  • 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile [ No CAS ]
  • [ 500287-72-9 ]
  • 52
  • [ 500287-72-9 ]
  • 4-{4-[4-(2-cyano-ethyl)-2,6-dimethyl-phenylamino]-pyrimidin-2-ylamino}-benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
27% With palladium on activated charcoal; hydrogen; In methanol; at 20℃; under 2250.23 Torr; for 5h; A mixture of compound 1 (0.0004 mol) and Pd/C (0.07 g) in CH3OH (10 ml) was hydrogenated at room temperature for 5 hours under a 3 bar pressure of H2, then filtered over celite, washed with CH2Cl2 and the solvent was evaporated till dryness. The residue was crystallized from DIPE. The precipitate was filtered off and dried. The residue (0.7 g) was purified by column chromatography over kromasyl (eluent: CH2Cl2/CH3OH 100/0 to 99/1; 5 mum). The pure fractions were collected and the solvent was evaporated. The residue (0.06 g) was crystallized from DIPE. The precipitate was filtered off and dried. Yield: 0.04 g of compound 24 (27%).
  • 53
  • C11H12N2*(x)ClH [ No CAS ]
  • [ 244768-32-9 ]
  • [ 500287-72-9 ]
  • 54
  • C11H12N2*(x)ClH [ No CAS ]
  • [ 244768-32-9 ]
  • 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile [ No CAS ]
  • [ 500287-72-9 ]
YieldReaction ConditionsOperation in experiment
8.7% In 1-methyl-pyrrolidin-2-one; at 95℃; for 17h;Molecular sieve; NMP (80 ml; 0.09% of water, dried 4A MS - molecular sieves) is added to a mixture of 8.35 g (40 mmol) of 1.HCI and 10.84 g (47 mmol) of 2 and the mixture is heated upto 95C NMP (80 ml; 0.09 % of water, dried 4A MS - molecular sieves) is added for17 h. A solution of sodium carbonate (50 g of Na2CO3, topped up with water to 500ml) is gradually added to the mixture cooled down to 30C until pH 7.5-8 is obtained(58 ml in total). Then, water (200 ml) is gradually added and the suspension is stirredat the room temperature (it) for 3 h. The solid substance is aspirated on glass frit,washed with aqueous DMF (1:2 vol./vol.; 30 ml) and dried. 15.13 g (103.2%) of thecrude product is obtained; UPLC 72.5%, Z-isomer 8.7%, hydroxy derivative 13.3%.
  • 55
  • 3-(4-amino-3,5-dimethylphenyl)acrylonitrile [ No CAS ]
  • [ 244768-32-9 ]
  • [ 500287-72-9 ]
  • 56
  • 3-(4-amino-3,5-dimethylphenyl)acrylonitrile [ No CAS ]
  • [ 244768-32-9 ]
  • 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile [ No CAS ]
  • [ 500287-72-9 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; at 160 - 165℃; for 1h; The aniline derivative I (hydrochloride 710 mg, 3.38 mmol) is dosed into a flask (50ml), DCM (dichloromethane) (10 ml) and a 10% aqueous solution of potassiumcarbonate (5 ml) are added. The suspension slowly passes into a solution while being stirred at it. The organic phase is separated, dried and evaporated until dry at a reduced pressure. The base of the aniline derivative 1 (582 mg, 99.32%) is obtained. Chloropyrimidine 2 (401 mg, 1.7 mmol) is added to it and the mixture is melted in abath at a temperature of 160-165C for 1 hour. After cooling, a 10% aqueous solution of K2C03 (5 ml), as well as a solvent mixture of DCM and methanol (2:1, 10 ml) are added to the mixture. The organic layer is separated, evaporated and the obtained evaporation product (0.9 g) is purified by column chromatography, eluent DCM/ethylacetate 80:20. The product is obtained in the 51.8% yield (330 mg), HPLC 84.18%, Z25 isomer 14.8%.
  • 57
  • 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile [ No CAS ]
  • [ 500287-72-9 ]
YieldReaction ConditionsOperation in experiment
97.8% With succinic acid; In acetonitrile; at 60℃;Large scale; Industrial scale; 3.66 kg of Lipivirin and 1.18 kg of succinic acid were added to 36 L of acetonitrile,Heated to 60 C,The mixture is stirred at the same temperature for 1 to 2 hours,Cooled to room temperature,Filtration gave a white solid,A mixed solvent of 24.2 L of N, N-dimethylformamide and water (45% of N, N-dimethylformamide and 55% of water) was added,Heated to reflux, so that all the dissolved,Adding activated carbon decolorization,Filtered, cooled to 0 to 10 C,Crystallization at this temperature for 5 ~ 8h,Filtration gave a white solid,This solid was added to 30 L of purified water,Add triethylamine and,Filtered, dried at 55 C,A white solid 3.15kg, yield: 97.8%
  • 58
  • [ 500287-72-9 ]
  • [ 882054-59-3 ]
  • 59
  • [ 500287-72-9 ]
  • [ 882187-59-9 ]
  • 60
  • [ 500287-72-9 ]
  • C27H25N7O2 [ No CAS ]
  • 61
  • [ 500287-72-9 ]
  • C30H25N7O2 [ No CAS ]
  • 62
  • [ 500287-72-9 ]
  • [ 951792-38-4 ]
  • 63
  • [ 199671-26-6 ]
  • [ 500287-72-9 ]
  • C30H32N6O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
General procedure: RPV (1 mol) was dried by azeotroping from anhydrous pyridine and then suspended in anhydrous THF and cooled to -80C under argon. Sodium bis(trimethylsilyl) amide (NaHMDS) (2 mol, 1.0 M solution in THF) was added to the mixture and stirring was continued for 10 minutes. Iodomethyl esters (1.2 mol, solution in THF) was added drop-wise to the deprotonated parent compound and the mixture was stirred for 48 hours at room temperature. The reaction mixture was then cooled to 0C and quenched with aqueous saturated ammonium chloride solution. The solvent was removed under vacuum, and the desired prodrugs were isolated on a silica column chromatography. The purified MRPV prodrugs were characterized using mass spectrometry, high performance liquid chromatography (HPLC), Fourier- transform infrared spectroscopy (FTIR), and nuclear magnetic resonance (NMR) spectroscopy.
  • 64
  • [ 500288-66-4 ]
  • [ 500287-72-9 ]
YieldReaction ConditionsOperation in experiment
93.9% With trichlorophosphate at 20℃; Reflux; 3 Synthesis of compound V: Add compound VI (10.00g, 26.0mmoL) and 80ml phosphorous oxychloride as solvent in a 500mL three-necked flask. Stir for 2-3h at 20-30, then heat to reflux for 3h. TLC tracked until the compound VI remained unchanged, the temperature was lowered to 5-10°C, the stirring was continued for 1 h, and then suction filtered and dried to obtain 9.05 g of a light yellow solid, which was the crude compound V, with a yield of 95.0%. Add all the above-mentioned light yellow solids into a 500ml three-necked flask containing 300ml of acetone, heat it to clear, and then add 0.8g of activated carbon. Incubate and stir for 1 hour. After filtering while hot, the filtrate is spin-dried to obtain 8.50 g of a white solid, which is a pure product of compound V, with a purity of 99.74% and a yield of 93.9%.
Same Skeleton Products
Historical Records

Similar Product of
[ 500287-72-9 ]

Chemical Structure| 700361-47-3

A1354920[ 700361-47-3 ]

(E)-4-((4-((4-(2-Cyanovinyl)-2,6-dimethylphenyl)amino)pyrimidin-2-yl)amino)benzonitrile hydrochloride

Reason: Free-salt