Home Cart 0 Sign in  

[ CAS No. 1032900-25-6 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 1032900-25-6
Chemical Structure| 1032900-25-6
Structure of 1032900-25-6 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 1032900-25-6 ]

Related Doc. of [ 1032900-25-6 ]

Alternatived Products of [ 1032900-25-6 ]

Product Details of [ 1032900-25-6 ]

CAS No. :1032900-25-6 MDL No. :
Formula : C28H36ClN5O3S Boiling Point : -
Linear Structure Formula :- InChI Key :VERWOWGGCGHDQE-UHFFFAOYSA-N
M.W : 558.14 Pubchem ID :57379345
Synonyms :
LDK378

Calculated chemistry of [ 1032900-25-6 ]

Physicochemical Properties

Num. heavy atoms : 38
Num. arom. heavy atoms : 18
Fraction Csp3 : 0.43
Num. rotatable bonds : 9
Num. H-bond acceptors : 6.0
Num. H-bond donors : 3.0
Molar Refractivity : 158.71
TPSA : 113.62 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.15 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.96
Log Po/w (XLOGP3) : 6.42
Log Po/w (WLOGP) : 7.06
Log Po/w (MLOGP) : 3.91
Log Po/w (SILICOS-IT) : 4.89
Consensus Log Po/w : 5.45

Druglikeness

Lipinski : 1.0
Ghose : None
Veber : 0.0
Egan : 1.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -7.1
Solubility : 0.0000442 mg/ml ; 0.0000000791 mol/l
Class : Poorly soluble
Log S (Ali) : -8.6
Solubility : 0.0000014 mg/ml ; 0.0000000025 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -10.07
Solubility : 0.0000000479 mg/ml ; 0.0000000001 mol/l
Class : Insoluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 4.25

Safety of [ 1032900-25-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H320-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1032900-25-6 ]

* 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 [ 1032900-25-6 ]

[ 1032900-25-6 ] Synthesis Path-Downstream   1~85

  • 1
  • 5-chloro-N<SUB>2</SUB>-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N<SUB>4</SUB>-(2-(propane-2-sulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride [ No CAS ]
  • [ 1032900-25-6 ]
YieldReaction ConditionsOperation in experiment
96% With sodium hydroxide; In water; at 0 - 5℃;pH 8.0; Zy kadia dihydrochlorate the (37.0g) is added to 200 ml deionized water, to control the temperature to 0-5C, dropwise 2NNaOH aqueous solution, adjusted to pH=8. Adding ethyl acetate to the reaction solution (100 ml) three times of extraction; ethyl ester combined acetic acid, anhydrous sodium sulfate for drying, filtering. The filtrate 15-20 C lower, concentrated under reduced pressure to dry, get 31.5g white solid, yield 96%.
90% With sodium hydroxide; In ethanol; water; at 20 - 50℃; for 2h;Inert atmosphere; To a 500-L enamel reactor was added 16.4 kg of compound 4 obtained in Example 9 and 167.0 kg of purified water, and a roomStir to clear temperature. Then add 196.8kg absolute ethanol. Under nitrogen, the reaction was heated to 50 C. Will be allocated in advanceAn aqueous solution of 2.3 kg of sodium hydroxide and 83.6 kg of purified water was added dropwise to the reaction solution. After the dropwise addition, the reaction solution was slowly cooled to 20 C,Stir for 2 hours. Filtration, with a good mix of 13.0kg of anhydrous ethanol and 18.0kg of purified water mixed solution of wet products. willThe resulting wet product was filtered and dried under vacuum at 50-55 C for 16 hours to give 13.0 kg of ceritinib as a white solid product. Yield90%, purity 99.8%.
87.5% With sodium hydroxide; In water; acetone; at 55℃; Form A of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2- (isopropylsulfonyl)phenyl)-2,4-diamine 7.00 g of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N-(2- (isopropylsulfonyl)phenyl)-2,4-diamine di-hydrochloride and 21.0 g of acetone: water (3:1, v/v) was added to a dry and clean crystallizer at ambient temperature. The mixture was heated to 55 +/- 3 C in about 20 minutes to obtain a clear solution. The hot solution was filtered and 2.6 g of acetone and water was added to the mixture. While heating was maintained, 14.69 g (about 58% by weight) of aqueous NaOH solution was added over a period of about 0.5 hour. The reaction mixture was maintained at 55 + 3 C for an additional 2 hours to yield an off-white slurry. An additional 10.82 g (about 58% by weight) of aqueous NaOH solution was added to the hot solution over a period of 1.5 hours to yield a thick off-white slurry. The slurry was cooled to 20 +/- 3 C over a period of about 45 minutes and 47.0 g of deionized (DI) water was added over about 30 minutes and the off-white slurry was stirred at 20 +/- 3 C for 1 hour. The slurry was filtered and rinsed with 2 x 25.0 g of DI water. The wet cake was dried about 17 hours in a vacuum oven at 50 +/- 3 C and 10 mbar under a N2 purge to yield 6.06 g off-white or tan solid, 5.30 g of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-N-(2- (isopropylsulfonyl)phenyl)-2,4-diamine. Yield: 87.5%. Form A was identified and confirmed by its corresponding XRPD pattern, FT-IR and thermal parameters.
27.2 g With sodium hydroxide; In water; acetone; at 20 - 55℃;pH 12.0; j00114j Ceritinib dihydrochloride salt (34.0 g) was dissolved in acetone (102 mL)and water (34 mL) mixture by stirring at room temperature. The obtained solution was heatedto 50-55C and 10% solution of NaOH was added drop-wise during 20-25 minutes until pH 12.0 value was reached (40 mL of 10% NaOH was added). A suspension was obtained and stirring at 55C was continued for additional 1 hour. Then, 170 mL of water was added dropwise into the suspension while maintaining the temperature at 55 C. The suspension was then cooled to room temperature and was additionally stirred for 1 hour. The solid product was filtered, washed with water (2x124 mL) and vacuum dried at 50-55C for 6 hours. 27.2 g of Ceritinib form A was obtained.
With sodium hydroxide; In water; acetone; at 55℃; 5-Chloro -N- (2- isopropoxy-5-methyl-4- (piperidin-4-yl-phenyl) -N-2- (isopropylsulfonyl) phenyl) -2, 4- diamine dihydrochloride (6.31 g) was added 50mL three-necked flask. 19g of acetone was added an aqueous solution (3: 1, v / v). It was stirred and heated to 55 degrees, about 10g was added dropwise 10% NaOH aq. After completion of the dropwise addition was cooled to room temperature, diluted with 42g of purified water, stirring continued for 1 hour. It was collected by filtration cake. The filter cake was dried in vacuo to give 5-chloro -N- (2- isopropoxy-5-methyl-4- (piperidin-4-yl-phenyl) -N-2- (isopropylsulfonyl) benzene yl) -2,4-diamine. Purity of not less than 99%, no single impurity greater than 0.1%.
With sodium hydroxide; In water; acetone; at 55℃; Example 12 Preparation of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine (LDK-378) 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl) phenyl)-2,4-diamine dihydrochloride (6.31 g) was added to a 50 mL three-necked flask. 19 g of acetone aqueous solution (3: 1, v/v) was added. The mixture was stirred and heated to 55 C., and 10 g of about 10% aqueous NaOH was added dropwise. After the dripping was complete, the mixture was cooled to room temperature, diluted with 42 g of purified water, and continuously stirred for 1 hour. After filtration, the filter cake was collected and dried in vacuum to give 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine. Purity is not less than 99%, and a single impurity is not higher than 0.1%. MS(ESI+):558.1(M+1)+. 1H NMR(DMSO-d6):delta8.44(d, 3.4, 1H), 8.20(s, 1H), 8.02(s, 1H), 7.80-7.82(m, 1H), 7.56-7.60(m, 1H), 7.49(s, 1H), 7.30-7.33(m, 1H), 6.80(s, 1H), 4.49-4.54(m, 1H), 3.42-3.47(m, 1H), 3.02(d, 4.8, 2H), 2.57-2.72(m, 3H), 2.10(m, 3H), 1.47-1.60(m, 4H), 1.21(d, 2.4, 6H), 1.14(d, 2.6, 6H).

  • 4
  • [ 1032900-25-6 ]
  • ((bis(benzyloxy)phosphoryl)oxy)methyl 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate [ No CAS ]
  • 5
  • [ 1032900-25-6 ]
  • (phosphonooxy)methyl 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate [ No CAS ]
  • 6
  • [ 1032900-25-6 ]
  • acetoxymethyl 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate [ No CAS ]
  • 7
  • [ 1032900-25-6 ]
  • [ 814-49-3 ]
  • diethyl (4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)phosphonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With triethylamine; In tetrahydrofuran; at 20℃; for 24h; General procedure: To a mixture of ceritinib (200mg, 0.358mmol) and TEA (51mg, 0.502mmol) in dry THF (10mL), diethyl chlorophosphate or diphenyl chlorophosphate or dibenzyl chlorophosphate (each 0.43mmol) was added by a syringe. The reaction mixture was stirred at room temperature for about 24h until the starting material disappeared by TLC. After the reaction was completed, the reaction mixture was concentrated to afford the crude product, which was purified by silica gel column chromatography to give compound 3a-c respectively.
  • 8
  • [ 1032900-25-6 ]
  • [ 2524-64-3 ]
  • diphenyl (4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)phosphonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With triethylamine; In tetrahydrofuran; at 20℃; for 24h; General procedure: To a mixture of ceritinib (200mg, 0.358mmol) and TEA (51mg, 0.502mmol) in dry THF (10mL), diethyl chlorophosphate or diphenyl chlorophosphate or dibenzyl chlorophosphate (each 0.43mmol) was added by a syringe. The reaction mixture was stirred at room temperature for about 24h until the starting material disappeared by TLC. After the reaction was completed, the reaction mixture was concentrated to afford the crude product, which was purified by silica gel column chromatography to give compound 3a-c respectively.
  • 9
  • [ 1032900-25-6 ]
  • [ 538-37-4 ]
  • dibenzyl (4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)phosphonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With triethylamine; In tetrahydrofuran; at 20℃; for 24h; General procedure: To a mixture of ceritinib (200mg, 0.358mmol) and TEA (51mg, 0.502mmol) in dry THF (10mL), diethyl chlorophosphate or diphenyl chlorophosphate or dibenzyl chlorophosphate (each 0.43mmol) was added by a syringe. The reaction mixture was stirred at room temperature for about 24h until the starting material disappeared by TLC. After the reaction was completed, the reaction mixture was concentrated to afford the crude product, which was purified by silica gel column chromatography to give compound 3a-c respectively.
  • 10
  • [ 1032900-25-6 ]
  • [ 79-22-1 ]
  • methyl 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With dmap; In dichloromethane; at 20℃; General procedure: Chloroformate (0.4mmol) was added to the mixture of ceritinib (150mg, 0.27mmol) and DMAP (99mg, 0.81mmol) in dry dichloromethane (10mL). The reaction mixture was stirred at room temperature for overnight. Dichloromethane was removed under reduced pressure and purified by column chromatography to afford the desired product.
  • 11
  • [ 1032900-25-6 ]
  • [ 541-41-3 ]
  • ethyl 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With dmap; In dichloromethane; at 20℃; General procedure: Chloroformate (0.4mmol) was added to the mixture of ceritinib (150mg, 0.27mmol) and DMAP (99mg, 0.81mmol) in dry dichloromethane (10mL). The reaction mixture was stirred at room temperature for overnight. Dichloromethane was removed under reduced pressure and purified by column chromatography to afford the desired product.
  • 12
  • [ 1032900-25-6 ]
  • [ 17462-58-7 ]
  • sec-butyl 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With dmap; In dichloromethane; at 20℃; General procedure: Chloroformate (0.4mmol) was added to the mixture of ceritinib (150mg, 0.27mmol) and DMAP (99mg, 0.81mmol) in dry dichloromethane (10mL). The reaction mixture was stirred at room temperature for overnight. Dichloromethane was removed under reduced pressure and purified by column chromatography to afford the desired product.
  • 13
  • [ 638-41-5 ]
  • [ 1032900-25-6 ]
  • pentyl 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With dmap; In dichloromethane; at 20℃; General procedure: Chloroformate (0.4mmol) was added to the mixture of ceritinib (150mg, 0.27mmol) and DMAP (99mg, 0.81mmol) in dry dichloromethane (10mL). The reaction mixture was stirred at room temperature for overnight. Dichloromethane was removed under reduced pressure and purified by column chromatography to afford the desired product.
  • 14
  • [ 1032900-25-6 ]
  • [ 22128-62-7 ]
  • C30H37Cl2N5O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% With dmap; In dichloromethane; at 0 - 20℃; Chloromethyl chloroformate (194mg, 2.0mmol) was added to the mixture of ceritinib (558mg, 1.0mmol) and DMAP (305mg, 2.5mmol) in dry dichloromethane (10mL) under 0 C. The reaction mixture was stirred at room temperature for overnight. Dichloromethane was removed under reduced pressure and purified by column chromatography to afford compound 6 in 63% yield. Then compound 6 (200mg, 0.3mmol) and potassium acetate (98mg, 1.0mmol) was added to DMF (10mL). The mixture was reacted at 80 C for 4h. The solvent was removed under reduced pressure and purified by column chromatography to afford compound 7.
  • 15
  • [ 1032903-64-2 ]
  • [ 1032900-25-6 ]
YieldReaction ConditionsOperation in experiment
97% With hydrogenchloride; In ethyl acetate; at 20℃; for 2h; Compound 11 (1.02 g, 1.56 mmol) was dissolved in 15 mL of HCl / EA (4 mol / L) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction solvent was removed by rotary evaporation. The crude product was purified by column chromatography and preparative TLC to give product compound 1 (900 mg, yield 97%).
90.1% With trifluoroacetic acid; In tetrahydrofuran; at 0 - 22℃; for 5h; To a flask were added compound of formula 5a (200 g, 0.305 mol) and THF (1000 mL). The mixture was controlled at 0 C. to 5 C. when TFA (70 g, 0.61 mol) was slowly added. After the TFA dropwise addition, the mixture was kept at 20 C. to 25 C. and stirred for 6 hours. After the reaction, the reaction mixture was concentrated, then was quenched with saturated aqueous sodium bicarbonate (2000 mL) and separated with dichloromethane (CH2Cl2) (500 mL×3). The organic layer was washed with saturated aqueous sodium bicarbonate (1000 mL), and water (500 mL) and saturated aqueous sodium chloride (500 mL), dried over anhydrous sodium sulfate and filtered, and concentrated to obtain the raw product of ceritinib. To the raw product was added i-propanol (IPA) (480 mL). The mixture was heated until dissolved completely, cooled to 30 C., and then kept at 30 C., stirred and crystallized for 3 hours. The resulting mixture was filtered. The filter cake was dried in vacuo at 60 C. for 8 hours to obtain the ceritinib product (compound of formula I) as a white solid (149.9 g, 88.5%), HPLC purity:99.2%.
39% With trifluoroacetic acid; at 20℃; for 1h; 1 (1.7g, 4.88mmol), 2 (1.69g, 4.88mmol), palladium acetate 55 mg, cesium carbonate 4.7g, anhydrous tetrahydrofuran 40 ml, reflux 2h. cooling to room temperature, concentrated to dry. Add 100 ml dioxymethane. Drop 20 ml trifluoroacetic acid. Stirring at room temperature 1h. 20% NaOH to adjust the pH to neutral, water 100 ml, stirring a moment, separating the organic layer, salt is washed with water, concentrated dry crude product ceritinib 2g, acetonitrile and refining pure product ceritinib 1.3g, acetonitrile recrystallization pure product 1.5g. Yield 39%, in order to 1 calculation.
  • 17
  • 2-chloro-4-[2-(propane-2-sulfonyl)phenylamino]-5-nitropyrimidine [ No CAS ]
  • [ 1032900-25-6 ]
  • 18
  • C33H46N6O5S [ No CAS ]
  • [ 1032900-25-6 ]
YieldReaction ConditionsOperation in experiment
A mixture of intermediate 8 (8.0 mmol), a cuprous compound (1.0equiv.) and isobutyl nitrite (1.2 equiv.) in acetone (80 mL) was cooled to 10C. The resulting reaction mixture was stirred for 2 h. The solvent was removed under reduced pressure, 6N HCl aqueous (80mL) was added to the residue and heated to 80C and stirred for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature, neutralised with aqueous NaOH and extracted with EtOAc several times. The combined organic layers were washed with saturated brine, dried over anhydrous Mg2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (DCM-methanol=20:1) to give the corresponding LDK378 as a colourless solid; m.p. 107-109C; MS(m/z) [M + H]+ calcd for C28H37ClN5O3S, 558.2, found 558.1.
  • 19
  • [ 1032900-25-6 ]
  • [ 113426-12-3 ]
  • C30H39Cl(18)FN5O3S [ No CAS ]
  • 20
  • [ 1032900-25-6 ]
  • [ 383-50-6 ]
  • fluoroethyl ceritinib [ No CAS ]
  • 21
  • [ 1032900-25-6 ]
  • C30H39Cl2N5O3S [ No CAS ]
  • 22
  • [ 1032900-25-6 ]
  • C30H39Cl(18)FN5O3S [ No CAS ]
  • 23
  • [ 1032900-25-6 ]
  • fluoroethyl ceritinib [ No CAS ]
  • 24
  • [ 42772-85-0 ]
  • [ 1032900-25-6 ]
  • [ 1032900-27-8 ]
  • 25
  • C36H42ClN5O5S [ No CAS ]
  • [ 1032900-25-6 ]
  • 26
  • [ 761440-16-8 ]
  • [ 1032903-63-1 ]
  • [ 1032900-25-6 ]
  • 27
  • [ 1032900-25-6 ]
  • 5-chloro-N<SUB>2</SUB>-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N<SUB>4</SUB>-(2-(propane-2-sulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.52 g With hydrogenchloride; In isopropyl alcohol; at 65℃; j00133j 0.5 g of Ceritinib base was suspended in 50 mL 2-PrOH at room temperature. While heating, the starting material was dissolved and 2.5 eq of 5-6M HC1 in 2- PrOH (0.448 mL) was added at about 65C. The clear solution was changed from colorless to light yellow and crystallization occurred while cooling the reaction mixture to about 5 5-60C. The obtained suspension was stirred at 55C for additional 1 hour, then cooled to roomtemperature and obtained product was filtered off under reduced pressure. 0.52 g of a light yellow crystalline product was obtained and identified as Form V by XRPD.
  • 28
  • [ 1032900-25-6 ]
  • 5-chloro-N<SUP>2</SUP>-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N<SUP>4</SUP>-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In water; at 20℃;pH 1.0; j00135j 1 g of Ceritinib base (Form Beta) was suspended in 1 mL of deionized H20. The pH of the suspension was adjusted to pH = 1 by addition of 1M HC1 (6 ml). Theobtained suspension was stirred at room temperature overnight and then filtered off. The obtained solid product was found to be Ceritinib hydrochloride Form I.
  • 29
  • 5-chloro-N2-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]pyrimidine-2,4-diamine dihydrochloride [ No CAS ]
  • [ 1032900-25-6 ]
  • 30
  • [ 1032900-25-6 ]
  • [ 148759-55-1 ]
  • N2-(4-(1-(4-azidobutyl)piperidin-4-yl)-2-isopropoxy-5-methylphenyl)-5-chloro-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
66% With potassium carbonate; In N,N-dimethyl-formamide; at 0℃; for 16h; To a white suspension of Certinib (200 mg, 0.305 mmol, 1 eq.) in dry DMF (3 mL) were added, compound 3 (103 mg, 0.457 mmol, 1 .5 eq.) followed by potassium carbonate (126 mg, 0.914 mmol, 3 eq.) at 0C.The reaction mixture was then allowed to stir further for 16 h until completion and monitored by LCMS. After completion of the reaction, the crude mixture was washed with a 1 :1 mixture of EtOAc (50 mL) and water (50 mL). The 2 layers were separated and the organic layers were extracted and subsequently washed with water (1 x 50 mL), saturated NaCI (2x 50 mL), dried over MgS04, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography, poured onto a column of silica (25 g) and eluted with a gradient of heptane/EtOAc. Fractions containing the desired product were combined and concentrated under reduced pressure. Compound 4 was obtained as a white solid (133 mg, 66 %). The analytical data supported the structural assignment expected for compound 4. LCMS for C32H43CIN803S; retention time =1.28 mins, MH+= 655.0. 1 H NMR (400 MHz, DMSO) delta 9.37 (br.s, 1 H), 8.37 (d, J = 1 1 Hz, 1 H), 8.16 (s, 1 H), 7.97 (s, 1 H), 7.74 (d, J = 1 1 Hz, 1 H), 7.53 (m, 1 H), 7.41 (br.s, 1 H), 7.26 (m, 1 H), 6.75 (s, 1 H), 4.48 (p, J = 7.4 Hz, 1 H), 3.98 (dt, J = 12; 4 Hz, 1 H), 3.40 (m, 1 H), 2.91 (br.d, J = 10 Hz, 2H), 2.60 (m, 1 H), 2.25 (m, 2H), 2.04 (s, 3H), 1 .92 (m, 3H), 1 .58 (m, 4H), 1 .49 (m, 4H), 1 .13 (d, J = 6.3 Hz, 6H), 1 .09 (d, J = 6.5Hz, 6H).
  • 31
  • [ 6397-33-7 ]
  • [ 1032900-25-6 ]
  • 32
  • [ 761440-16-8 ]
  • 5-chloro-N2-[2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]pyrimidine-2,4-diamine dihydrochloride [ No CAS ]
  • [ 1032900-25-6 ]
YieldReaction ConditionsOperation in experiment
93% Isopropanol (445 kg)2,5-dichloro-N- (2-(Isopropylsulfonyl) phenyl) pyrimidin-4-amine(70.2 kg, 203 mol,1.15 eq.) And 2-isopropoxy-5-methyl-4- (piperidin-4-yl) aniline dihydrochloride (56.7 kg, 176 mol).The mixture was heated at reflux for about 16 hours.Water (47 kg) was added and the mixture was cooled to 0 C. The solid was filtered and washed with isopropanol / water. To the wet product was added isopropanol (680 kg) and water (55 kg).) Was added and the slurry was heated to reflux.The resulting clear solution was cooled to 0 C.Filtered, vacuum dried,5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2,4-diamine dihydrochloride ( = Ceritinib dihydrochloride;84.5 kg [total amount, containing 10% w / w isopropanol],76.0 kg [100%], yield 68%.Ethanol (155 kg) and water (113 kg)5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2,4-dihydrochloride;45.0 kg [total, containing 10% w / w isopropanol], 40.5 kg [100%], 64.2 mol)The mixture was heated to 55C.Aqueous NaOH (147 L of a 1 M solution, 2.3 eq) was added slowly and then cooled to 20 C.After filtration, the product was recrystallized from ethanol., Vacuum dried,An almost white powder of ceritinib (33.2 kg, 93% yield based on ceritinib dihydrochloride) was obtained.
93% In ethanol; water; isopropyl alcohol; at 55℃; for 16h;Reflux; Large scale; Isopropanol (445 kg) was added to 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (70.2 kg, 203 mol, 1.15 eq.) and 2-Isopropoxy-5-methyl-4-(piperidin-4-yl)aniline dihydrochloride (56.7 kg, 176 mol). The mixture was heated for approx. 16 hours at reflux. Water (47 kg) was added and the mixture cooled to 0 C. The solid was filtered and washed with isopropanol/water. To the wet product, isopropanol (680 kg) and water (55 kg) was added and the slurry heated to reflux. The obtained clear solution was cooled to 0 C., filtered and dried under vacuum to yield 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride (=ceritinib dihydrochloride; 84.5 kg [t.q., contains 10% w/w isopropanol], 76.0 kg [100%], 68% yield). Ethanol (155 kg) and water (113 kg) were added to 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-dihydrochloride; 45.0 kg [t.q., contains 10% w/w isopropanol], 40.5 kg [100%], 64.2 mol) and the mixture heated to 55 C. Aqueous NaOH (147 L of a 1 M solution, 2.3 eq.) was added slowly and then cooled to 20 C. After filtration, the product was recrystallized from ethanol and dried under vacuum to yield ceritinib (33.2 kg, 93% yield based on ceritinib dihydrochloride) as an almost white powder. 1H-NMR (400 MHz, CDCl3): delta=1.33 (d, J=6.8 Hz, 6H), 1.38 (d, J=6.1 Hz, 6H), 1.59-1-78 (m, 5H), 2.18 (s, 3H), 2.75-2.83 (m, 3H), 3.20-3.24 (m, 2H), overlaps 3.28 (sept, J=6.8 Hz, 1H), 4.56 (sept, J=6.1 Hz, 1H), 6.82 (s, 1H), 7.25-7.29 (m, 1H), 7.56 (br. s, 1H), 7.64 (m, 1H), 7.94 (m, 1H), 8.01 (br. s, 1H), 8.16 (br. s, 1H), 8.60 (m, 1H), 9.51 (br. s, 1H) ppm. 13C-NMR (100 MHz, CDCl3): delta=15.4, 18.9, 22.3, 33.9, 38.6, 47.5, 55.4, 71.4, 105.7, 111.0, 120.6, 123.1, 123.7, 124.9, 126.7, 127.3, 131.2, 134.7, 138.3, 138.5, 144.7, 155.3, 155.4, 157.5 ppm, Elemental analysis: calculated (%) for C28H36ClN5O3S: C 60.26, H 6.50, N 12.55, O 8.60 Cl 6.35, S 5.74, found: C 60.15, H 6.45, N 12.72, O 8.58, Cl 6.43, S 5.67.)
74% In 1,2-dimethoxyethane; for 5h;Inert atmosphere; Reflux; Compound 2-c (5.3 g, 16.5 mmol),Compound 1-c (5.7 g, 16.5 mmol) and ethylene glycol diethyl ether (60 ml) were placed in a reaction flask.The reaction was heated to reflux for 5 hours under a nitrogen atmosphere. After the reaction,The reaction solution was cooled to room temperature, and a solid precipitated and was filtered at 60 C.The resulting solid was dissolved in ethanol: water (2:1, v/v, 60 ml).Dissolve and filter hot. The filtrate was cooled to room temperature, and 2N aqueous NaOH solution was added dropwise.The solid was precipitated, filtered, and dried to give Ceritinib (9.2 g, yield 74.0%).
70.0% In 1,2-dimethoxyethane; at 130℃;Inert atmosphere; Compound 9 (3.2g, 10.0mmol), compound 3 (3.46g, 10.0mmol) and 20ml of diethyl ether glycol into the reaction flask, a nitrogen atmosphere, the reaction was heated to reflux at 130 deg C for 4 ~ 6h. After the reaction mixture was stirred at room temperature for a period of time down to, solid separated, was filtered at 60 , and the resulting solid was dissolved in ethanol: water (2: 1, v / v), the clear solution was obtained, hotfilter. Until filtrate is cooled to room temperature, aqueous solution of 2NNaOH, there are plenty of solid precipitation, filtration, drying, namely class white solid color Rui imatinib 3.9g, yield 70.0%.
3.07 kg In isopropyl alcohol; for 24h;Reflux; Large scale; The 2.50kg2,5- dichloro -N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine and 2.50kg2- isopropoxy-5-methyl-4- (piperidin-4 - yl) aniline hydrochloride was added 30kg of isopropanol was heated to reflux for 24 hours, the HPLC monitoring of the reaction end, the raw material to 2,5-dichloro -N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine content of less than 4.0 is determined to complete the reaction.Cooling to 20 ~ 25C for 12 to 14 hours to crystallize with stirring, filtered, washed with isopropyl alcohol three times 1kg.45 dried in vacuo 24 hours to give 5-chloro -N2- (2- isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2- (isopropyl sulfonamide ) phenyl) pyrimidine-2,4-diamine hydrochloride 3.75kg.The 3.75kg5- chloro -N2- (2- isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2,4-diamine hydrochloride was added 40kg of purified water, temperature 10 ~ 15 40% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 6.5 to 7.0, was stirred for 2 hours, filtered, 10kg purified by washing with water 4 times.40 dried for 24 hours in vacuo to give 5-chloro -N2- (2- isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2- (isopropyl sulfonamide ) phenyl) pyrimidine-2,4-diamine as a white powder 3.07kg
5 g With toluene-4-sulfonic acid; In water; isopropyl alcohol; at 140℃; for 24h;Autoclave; To a solution of 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (6.2 g, 0.017 mol) in isopropanol (124 mL), 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline dihydrochloride (5.34 g) and p-toluenesulfonic acid monohydrate (6.83 g) were added. The reaction mass was stirred for 24 hours at 140C in an autoclave. The reaction mass was cooled to 20-25C and the solvent was distilled to provide crude product. The crude product was dissolved in dichloromethane (200 mL) and washed with saturated solution of sodium bicarbonate (2 x 50 mL), followed by brine (2 x 50 mL). The organic layer was dried over sodium sulfate and distilled to afford the crude product. The crude product was purified by silica gel column chromatography using methanol-dichloromethane (Methanol:Dichloromethane 2:98 to 10:90) as eluent to provide the desired compound. Yield: 5.0 g, Purity (by HPLC): 95.8%
To a stirred suspension mass of 17 g (0.052 mole) of 2-isopropoxy-5-methyl-4- (piperdin-4-yl) aniline dihydrochloride [formula-X] in 170 ml of isopropyl alcohol into a flask under nitrogen atmosphere. 18.3 g (0.052 mole) of 2, 5-dichloro-N-(2- (isopropyl sulfonyl) phenyl) pyrimidin-4-amine (formula-XIII) was added. Raised the reaction mass temperature to reflux under nitrogen and maintained for 20 hours. Checked the reaction mass for 2-isopropoxy-5-methyl-4-(piperdin-4-yl) aniline content by TLC. 2-isopropoxy-5-methyl-4-(piperdin-4-yl) aniline was absent. Reaction mas was cooled to 25-30C and stirred the mas for 1 hour. Filtered the solid and washed the solid with 35 ml of isopropyl alcohol. The obtained solid was suspended in 85 ml of isopropyl alcohol. Raised the reaction mass temperature to reflux and maintained for 30 min. Reaction mas was cooled to 25-30C and stirred the mas for 30 min. Filtered the solid and washed the solid with 25 ml of isopropyl alcohol. Dried the compound under vacuum at 55-60C to give 27.0 g of 5-chloro- N2-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N4-[2-(propane-2-sulfonyl) phenyl] pyrimidine -2, 4-diamine di-hydrochloride salt [formula-XIV] with 80.8 % yield by theory. To a stirred solution of 10 g (0.0158 mole) of 5-chloro-N-(2-isopropoxy-5-methyl- (piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl) phenyl)-2,4-diamine di- hydrochloride in 300 ml of purified water and 80 ml of isopropyl alcohol. Filtered the solution for free of foreign particles and washed the flask and funnel with 80 ml of purified and 20 ml of isopropyl alcohol mixed solution. Raised the mass temperature to 55-60C. Adjusted the mass pH to 9.7 with ammonium hydroxide solution while maintaining the mass temperature at 55-60C. Freely movable solid formation was observed. Maintained the mass temperature at 55-60C. Cooled the mass temperature to 25- 30C. Maintained the mass temperature at 25-30C for 2 hours. Filtered the solid and washed the solid with 60 ml of aqueous isopropyl alcohol solution (diluted 50 ml of purified water with 10 ml of isopropyl alcohol). The wet compound was dried under vacuum at 55-60 C for 2 hours to give 8.1 g (91.62% yield) of 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)- N4-[2-(propane-2-sulfonyl) phenyl] pyrimidine -2,4-diamine [Ceritinib crystalline form-A] with 99.8% purity by FIPLC. P-XRD spectra 2Theta values are matched with Ceritinib form-A values.
33.2 kg Synthesis of 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine (ceritinib) Isopropanol (445 kg) was added to 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (70.2 kg, 203 mol, 1.15 eq.) and 2-Isopropoxy-5-methyl-4-(piperidin-4-yl)aniline dihydrochloride (56.7 kg, 176 mol). The mixture was heated for approx. 16 hours at reflux. Water (47 kg) was added and the mixture cooled to 0 C. The solid was filtered and washed with isopropanol/water. To the wet product, isopropanol (680 kg) and water (55 kg) was added and the slurry heated to reflux. The obtained clear solution was cooled to 0 C., filtered and dried under vacuum to yield 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride (=ceritinib dihydrochloride; 84.5 kg [t.q., contains 10% w/w isopropanol], 76.0 kg [100%], 68% yield). Ethanol (155 kg) and water (113 kg) were added to 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-dihydrochloride; 45.0 kg [t.q., contains 10% w/w isopropanol], 40.5 kg [100%], 64.2 mol) and the mixture heated to 55 C. Aqueous NaOH (147 L of a 1 M solution, 2.3 eq.) was added slowly and then cooled to 20 C. After filtration, the product was recrystallized from ethanol and dried under vacuum to yield ceritinib (33.2 kg, 93% yield based on ceritinib dihydrochloride) as an almost white powder. 1H-NMR (400 MHz, CDCl3): delta=1.33 (d, J=6.8 Hz, 6H), 1.38 (d, J=6.1 Hz, 6H), 1.59-1-78 (m, 5H), 2.18 (s, 3H), 2.75-2.83 (m, 3H), 3.20-3.24 (m, 2H), overlaps 3.28 (sept, J=6.8 Hz, 1H), 4.56 (sept, J=6.1 Hz, 1H), 6.82 (s, 1H), 7.25-7.29 (m, 1H), 7.56 (br. s, 1H), 7.64 (m, 1H), 7.94 (m, 1H), 8.01 (br. s, 1H), 8.16 (br. s, 1H), 8.60 (m, 1H), 9.51 (br. s, 1H) ppm. 13C- NMR (100 MHz, CDCl3): delta=15.4, 18.9, 22.3, 33.9, 38.6, 47.5, 55.4, 71.4, 105.7, 111.0, 120.6, 123.1, 123.7, 124.9, 126.7, 127.3, 131.2, 134.7, 138.3, 138.5, 144.7, 155.3, 155.4, 157.5 ppm, Elemental analysis: calculated (%) for C28H36ClN5O3S: C, 60.26, H, 6.50, N, 12.55, O, 8.60 Cl, 6.35, S, 5.74, found: C, 60.15, H, 6.45, N, 12.72, O, 8.58, Cl, 6.43, S, 5.67.)

  • 35
  • 2-isopropoxy-5-methyl-4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-phenylamine [ No CAS ]
  • [ 1032900-25-6 ]
  • 36
  • C35H40ClN5O3S [ No CAS ]
  • [ 1032900-25-6 ]
YieldReaction ConditionsOperation in experiment
97.9% With palladium on activated charcoal; hydrogen; at 35℃; under 7500.75 Torr; Compound 10 (1.0g, 1.5mmol), THF (15ml) and Pd / C (0.1g) put into the hydrogenation reactor, introducing hydrogen to a pressure of 1.0MPa, to maintain about 35 stirring. After completion of the reaction, filtered and evaporated under reduced pressure to give color Rui imatinib, a total of 0.82g yield of 97.9%.
  • 38
  • 4-(5-(propan-2-yloxy)-2-methyl-4-nitro-phenyl)-1-benzyl-pyridinium bromide [ No CAS ]
  • [ 1032900-25-6 ]
  • 39
  • 1-benzyl-4-(5-isopropyloxy-2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine [ No CAS ]
  • [ 1032900-25-6 ]
  • 40
  • C15H20N2O3 [ No CAS ]
  • [ 1032900-25-6 ]
  • 41
  • C15H16N2O3*ClH [ No CAS ]
  • [ 1032900-25-6 ]
  • 42
  • C15H16N2O3*CH4O3S [ No CAS ]
  • [ 1032900-25-6 ]
  • 44
  • [ 375853-82-0 ]
  • [ 1032900-25-6 ]
  • 45
  • [ 1032903-52-8 ]
  • [ 1032900-25-6 ]
  • 46
  • N,N-dibenzyl-4-bromo-2-isopropoxy-5-methylaniline [ No CAS ]
  • [ 1032900-25-6 ]
  • 47
  • N,N-dibenzyl-4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylaniline [ No CAS ]
  • [ 1032900-25-6 ]
  • 49
  • [ 1035230-24-0 ]
  • [ 1032900-25-6 ]
  • 51
  • 1-benzyl-4-(4-(dibenzylamino)-5-isopropoxy-2-methylphenyl)piperidin-4-ol [ No CAS ]
  • [ 1032900-25-6 ]
  • 56
  • [ 1402045-53-7 ]
  • [ 1032900-25-6 ]
  • 57
  • N-(4-bromo-2-isopropoxy-5-methylphenyl)acetamide [ No CAS ]
  • [ 1032900-25-6 ]
  • 58
  • 2-isopropoxy-5-methyl-4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenylamine dihydrochloride salt [ No CAS ]
  • [ 1032900-25-6 ]
  • 59
  • 4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylaniline dioxalate [ No CAS ]
  • [ 1032900-25-6 ]
  • 61
  • N-(4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-methylphenyl)acetamide hydrochloride [ No CAS ]
  • [ 1032900-25-6 ]
  • 62
  • 4-bromo-2-isopropoxy-5-methylaniline [ No CAS ]
  • [ 1032900-25-6 ]
  • 63
  • 2-isopropoxy-5-methyl-4-(pyridin-4-yl)aniline [ No CAS ]
  • [ 1032900-25-6 ]
  • 64
  • C20H26N2O3 [ No CAS ]
  • [ 1032900-25-6 ]
  • 65
  • C29H31N2O(1+)*Br(1-) [ No CAS ]
  • [ 1032900-25-6 ]
  • 66
  • C27H33N2O3(1+)*Br(1-) [ No CAS ]
  • [ 1032900-25-6 ]
  • 67
  • C29H34N2O [ No CAS ]
  • [ 1032900-25-6 ]
  • 68
  • C27H36N2O3 [ No CAS ]
  • [ 1032900-25-6 ]
  • 69
  • [ 761440-16-8 ]
  • [ 1035230-24-0 ]
  • [ 1032900-25-6 ]
YieldReaction ConditionsOperation in experiment
75.4% To a 100 ml three-necked flask equipped with a thermometer was added a compound of formula II (3.8 g, 15.4 mmol, 1.0 equiv) and isopropanol (50 ml), concentrated hydrochloric acid (3.1 g, 30.7 mmol, 2.0 equiv) was added at 30 C below,And the mixture was stirred at room temperature for 1.5 hours.At room temperature, III (5.32 g, 15.4 mmol, 1.0 equiv) was added. The reaction was carried out under reflux for 44 hours. After the reaction,The reaction solution was cooled to room temperature and then stirred at room temperature for 3 hours. There is a lot of solid precipitation.The solid was washed three times with isopropanol to give 6.5 g of a pale yellow solid in a yield of 70.9% and a purity of 85.5%. The above crude product of 6.5 g was recrystallized from acetone: water = 15: 1,To give 4.99 g of a white solid, 75.4% yield, HPLC purity: 99.5%.
2.5 g With N-ethyl-N,N-diisopropylamine; at 80℃;Inert atmosphere; Under the protection of nitrogen, of formula (3) compound (3.5 g, 1 eq), formula (2) compound (2.8 g, 0.8 eq) added to the diisopropyl ethylamine (16.8 g) in, the temperature rose to 80 C reaction, after the reaction is finished, evaporate the organic alkali, adding the ethyl acetate extraction, water washing, adding hydrogen chloride in ethyl acetate solution, stirring 2 hours, filtering to obtain the solid, the solid adjusting pH, filtering, formula (1) compound of the identify switzerland for nepal (2.5 g).
  • 70
  • C20H30N2O3 [ No CAS ]
  • [ 1032900-25-6 ]
  • 71
  • 2,5-dichloro-N-[2-(propan-2-ylsulfanyl)phenyl]pyrimidin-4-amine [ No CAS ]
  • [ 1032900-25-6 ]
  • 72
  • 5-chloro-N<SUP>2</SUP>-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N<SUP>4</SUP>-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine hydrochloride [ No CAS ]
  • [ 1032900-25-6 ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate; In water; ethyl acetate; A saturated aqueous sodium hydrogencarbonate solution (30 ml) was added to the compound of Example 7 and extracted once with ethyl acetate (40 ml).The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The resultant was used without further purification (0.218 g, 84.8%, sticky wax).
  • 73
  • [ 1032900-25-6 ]
  • [ 198211-15-3 ]
  • N<SUP>2</SUP>-(4-((2'S,6'R)-1'-benzyl-2',6'-dimethyl-1,4'-bipiperidin-4-yl)-2-isopropoxy-5-methylphenyl)-5-chloro-N<SUP>4</SUP>-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.151 g 5-Chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2,4-diAmine (0.359 g, 0.643 mmol) and(2S, 6R) -l-benzyl-2,6-dimethylpiperidin-4-one (1.398 g, 6.432 mmol)To a solution of 1,2-chloroethylene (20 mL) at room temperature was addedTo the solution was added NaBH (OAc) 3 (2.045 g, 9.648 mmol)And stirred at the same temperature for 10 minutes.To the reaction mixture was added AcOH (0.074 mL, 1.286 mmol) and further stirred at the same temperature for 72 hours.The reaction mixture was poured into 1N aqueous sodium hydroxide solution and extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and purified by column chromatography (SiO2, 80 g cartridge; methanol / methylene chloride = 5%) and the product was purified by chromatography (SiO2, 12 g cartridge; methanol / methylene chloride = 5% ) And purified and concentrated to give N2- (4 - ((2'S, 4 ', 6'R) -1'-benzyl-2', 6'-dimethyl-1,4'-bipiperidin- -5-chloro-N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2,4-diamine (0.151 g,30.9%) was obtained in the form of a clear hard wax.
  • 74
  • [ 1032900-25-6 ]
  • rac-(2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-one [ No CAS ]
  • N<SUP>2</SUP>-(4-((2'RS,6'RS)-1'-benzyl-2',6'-dimethyl-1,4'-bipiperidin-4-yl)-2-isopropoxy-5-methylphenyl)-5-chloro-N<SUP>4</SUP>-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.107 g 5-Chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4-diamine (0.359 g, 0.643 mmol) and (2S, 6S) -1-benzyl-2,6-dimethylpiperidin-4- NaBH (OAc) 3 (4.090 g, 19.296 mmol) was added to a solution obtained by dissolving 2.796 g (12.864 mmol) of the title compound in 1,2-dichloroethane (20 mL) at room temperature and stirring at the same temperature for 10 minutes. To the reaction mixture was added AcOH (0.074 mL, 1.286 mmol) and further stirred at the same temperature for 72 hours. The reaction mixture was poured into 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and purified by column chromatography (SiO2, 80 g cartridge; methanol / methylene chloride = 5%) and the product was purified by chromatography (SiO2, 12 g cartridge; methanol / methylene chloride = 5% ), And the resultant was purified and concentrated by chromatography (SiO2, 12 g cartridge; chloroform / methanol / aqueous ammonia = 120/10/1) to obtain the desired compound (0.107 g, 21.9%It was obtained in the form of hard wax.
  • 77
  • [ 60710-39-6 ]
  • [ 1032900-25-6 ]
  • 80
  • [ 126781-38-2 ]
  • [ 1032900-25-6 ]
  • 81
  • 4-(1-benzyl-4-piperidyl)-2-isopropoxy-5-methylaniline [ No CAS ]
  • [ 1032900-25-6 ]
  • 82
  • [ 1032903-51-7 ]
  • [ 1032900-25-6 ]
  • 83
  • [ 3612-20-2 ]
  • [ 1032900-25-6 ]
  • 84
  • [ 185-72-8 ]
  • [ 1032900-25-6 ]
  • C34H46ClN5O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In ethanol; at 90℃; The compound 1-1 and the intermediate 3-1 were dissolved in ethanol, DIPEA (3 eq) was added, and the mixture was refluxed at 90 C overnight. After completion of the reaction, the reaction solution was cooled, slowly poured into ice water, extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and mixed with the column. CH2CI2: Mu0Eta (volume ratio) = 30 : 1 to obtain compound S3.
  • 85
  • [ 22633-44-9 ]
  • [ 1032900-25-6 ]
  • C33H44ClN5O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; The compound 1-1 and (3- (bromomethyl) oxetan-3-yl) methanol (2 eq) were dissolved in acetonitrile, (3 eq) diisopropylethylamine (DIPEA) was added, heated to 90 C reflux overnight. After completion of the reaction, the reaction solution was cooled, slowly poured into ice water, extracted three times with ethyl acetate, and the organic phase was washed with saturated brine, dried with anhydrous sodium sulfate and mixed with the column. CH2CI2: Mu0H (volume ratio) = 20 : 1 Compound S1
Same Skeleton Products
Historical Records