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[ CAS No. 1022150-12-4 ] {[proInfo.proName]}

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Chemical Structure| 1022150-12-4
Chemical Structure| 1022150-12-4
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Product Details of [ 1022150-12-4 ]

CAS No. :1022150-12-4 MDL No. :MFCD20482137
Formula : C22H22N6O Boiling Point : -
Linear Structure Formula :- InChI Key :GPSQYTDPBDNDGI-MRXNPFEDSA-N
M.W : 386.45 Pubchem ID :58223272
Synonyms :

Calculated chemistry of [ 1022150-12-4 ]

Physicochemical Properties

Num. heavy atoms : 29
Num. arom. heavy atoms : 21
Fraction Csp3 : 0.23
Num. rotatable bonds : 4
Num. H-bond acceptors : 5.0
Num. H-bond donors : 2.0
Molar Refractivity : 116.77
TPSA : 90.88 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.48 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.47
Log Po/w (XLOGP3) : 3.06
Log Po/w (WLOGP) : 3.42
Log Po/w (MLOGP) : 2.73
Log Po/w (SILICOS-IT) : 2.35
Consensus Log Po/w : 3.0

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.44
Solubility : 0.0142 mg/ml ; 0.0000367 mol/l
Class : Moderately soluble
Log S (Ali) : -4.64
Solubility : 0.00895 mg/ml ; 0.0000232 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -6.9
Solubility : 0.0000488 mg/ml ; 0.000000126 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.71

Safety of [ 1022150-12-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338-P310 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1022150-12-4 ]

* 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 [ 1022150-12-4 ]

[ 1022150-12-4 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 1022150-11-3 ]
  • [ 1022150-12-4 ]
YieldReaction ConditionsOperation in experiment
98% With hydrogenchloride; In methanol; water; at 50℃; Compound (IV) (Pgi = Pg2 = Boc) (2.93 g, 5 mmol) was dissolved in MeOH (15 ml), then 33% HC1 (3 ml) was added, and the reaction mass was heated at 50C for 4 st with intensive stirring (note: a foam is forming during the reaction due to isolation of gaseous by-products). After completion of the reaction the resulting solution was cooled to room temperature and evaporated to dryness (note: the vapor contains HC1). Saturated Na2CO3 solution (5 ml) was added to the dry residue and the mixture was extracted with EtOAc (3 x 10 ml). The extract was dried over Na2SO4 and evaporated in vacuum. Yield 1.89 g (98%), white amorphous mass.
92% With hydrogenchloride; In methanol; at 20℃; for 2h; Compound 2.5g (5.1mmol) of formula 10 was added to the methanol solution in 25ml of hydrochloric acid, stirred at room temperature 2hour. Concentrated under reduced pressure, the residue was added 30ml of water, extracted with ethyl acetate, the organic phase was washed with 5% aqueousSodium hydroxide solution was washed until neutral. The organic phase was concentrated under reduced pressure to give a pale yellow oil 1.82g, yield 92%
91% With hydrogenchloride; In ethyl acetate; for 0.5h; Tert-butyl-( 1R)-3-4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine- 1- carboxylate (3 g) was dissolved in 3 M HC1-EtOAc (15 mL). After 30 mm the solution was treated with saturated sodium bicarbonate solution. The organic layer was separated and the water layer extracted with DCM (3x10 mL). The organic layers were combined and dried over Na2504. Evaporation of the solvent gives 2.1 g (91%) 3-(4- phenoxyphenyl)- 1 -[(3R)-3 -piperidyl]pyrazolo[3 ,4-d]pyrimidin-4-ammne.
88% With trifluoroacetic acid; at 20℃; for 12h; Intermediate (9) (48.6 g, 0.1 mol) was added to trifluoroacetic acid (200 mL) and reacted at room temperature for 12 h (TLC confirmed the completion of the reaction).Then, it was neutralized with Na2CO3 solution and extracted with CH2Cl2. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give Intermediate (10) (3.40 g, yield 88%).
85% With trifluoroacetic acid; In dichloromethane; at 20℃; In the reaction flask,(R) -1-Boc-3- (4-amino-3- (4-phenoxyphenyl)Pyrazolo [3,4-D] pyrimidin-1-yl) piperidine (8 g, 16.4 mmol) was added to a solution of trifluoroacetic acid (40 ml)And methylene chloride (40 ml)Room temperature reaction overnight.Point plate (TLC) After confirming that the reaction is complete,After neutralization with saturated Na2CO3 solution to pH 7-8,Extracted with dichloromethane (DCM), the organic phases were combined, dried over anhydrous sodium sulfate,The product was purified by column chromatography (5.4 g, yield 85%).
83% With hydrogenchloride; In 1,4-dioxane; water; at 20℃; for 16h; The (R) - tert-butyl-3- (4-amino-3- (4-phenoxyphenyl) lH-pyrazolo [3,4-d]pyrimidin-1-yl) -1-piperidine - carboxylate (1.28g, 2.63mmol) was dissolved in1,4-dioxane (6mL), and then the reaction mixture was added to hydrochloric acid (6mL,4mol / L) was stirred for 16h at room temperature, the reaction after the addition ofdilute sodium hydroxide aqueous solution was adjusted to PH = 9, extracted withdichloromethane (150mL × 3), brine (60mL), dried over anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure, the crude product was purified bysilica gel column chromatography ( dichloromethane / methanol (V / V) = 12 / 1-6 / 1),to give the product (840mg, 83%).
81.1% With hydrogenchloride; In water; at 20℃; In room temperature,To the above reaction solution was added concentrated hydrochloric acid (2.3 vol)The compound (7) is converted into the compound (8).Raw material conversion is complete,Rotate most of the solvent.To the crude was added DCM (6 vol) and water (6 vol)Dispensing.The organic phase was extracted once with water (6 vol).Consolidate the aqueous phase,Wash with DCM (6Vol) three times.Water phase adjusted to pH 9-10,Precipitation of a large number of solid compounds 8,Yield 81.1%
80% To a solution of Intermediate 3 (4.4 g, 9.0 mmol) in CH2Cl2 (20 ml) was added TFA (2.8 ml, 36.2 mmol). After stirring 2 hrs at room temperature, the solvent was removed and the residue was partitioned between ethyl acetate (250 ml) and dilute aq. K2CO3. The organic layer was dried (MgSO4), filtered and concentrated to 70 ml. The resulting solution was stirred and 4.0M HCl in dioxane (4 ml) was added to provide a thick light orange precipitate. The precipitate was collected by filtration and washed with ethyl acetate (50 ml). The material was then partitioned between ethyl acetate (300 ml) and dilute aq. K2CO3. The organic layer was dried (MgSO4), filtered and concentrated to provide 2.78 g (80%) of Intermediate 4 as a light yellow foam.
64% With trifluoroacetic acid; In dichloromethane; at 20℃; for 12h; Step 5A mixture of (R)-tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidm-l-yl]piperidine~l~carboxylate (700 mg, 1.44 mmol, 1.00 equiv) indichioromethane ( 100 mL) and irifluoroacetic acid (20 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum to yield 580 mg of crude (R)- 3-(4-phenoxyphenyl)-l -(piperidin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-4-aniine as a yellow
With trifluoroacetic acid; In dichloromethane; at 20℃; for 12h; A mixture of (R)-tertbutyl 3[4-amino-3-(4-phenoxyphenyl) 1H-pyrazolo[3,4 d]pyrimidin.yl]piperidinet-carboxylate (700 mg, I A4 mmol, 1,00 equiv) in dichloromethane (100 mL) and trifluoroacetic acid (20 mL) was stirred at room temperature for 12 Ii. The reaction mixture was concentrated under vacuum to yield 580 mg of crude (R) 3-(4-phenoxyphenyl)-1-piperidin-3-yi)-1R-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow oil.
With trifluoroacetic acid; In dichloromethane; at 20℃; for 12h; Step 5. A mixture of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (700 mg, 1.44 mmol, 1.00 equiv) in dichloromethane (100 mL) and trifluoroacetic acid (20 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum to yield 580 mg of crude 3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow oil.
With trifluoroacetic acid; In dichloromethane; at 20℃; for 12h; Step 5 A mixture of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (700 mg, 1.44 mmol, 1.00 equiv) in dichloromethane (100 mL) and trifluoroacetic acid (20 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum to yield 580 mg of crude 3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow oil.
0.2 g With trifluoroacetic acid; In dichloromethane; Diisopropyl diazodicarboxylate (DAID, 1.2 ml) was added to a solution of 1-tert-butyloxycarbonyl-3-(S)-hydroxypiperidine ( 1.0 g,) and triphenylphosphine (2.59g) in tetrahydrofuran (50.0ml). To the resulting yellow solution, 3-(p-phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine (1.0g). was added and warmed till dissolution, and stirred overnight at room temperature. The reaction mixture was filtered and the solvent was distilled under vacuum to get an oily residue, which was further purified by flash chromatography (30-50 % ethyl acetate/ hexane) on silicagel to give 0.3 g (0.3 w/w) of tert-butyloxycarbonyl-(1S)-1-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine as a light brown solid. The resulting solid was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (0.6 ml) was added to it. After completion of reaction, water was added to reaction mass, followed by addition of methyl tert-butyl ether (20.0 ml). The layers were separated and the aqueous layer was basified with potassium carbonate and extracted with dichloromethane (15.0 ml x 2). The organic layer dried over sodium sulfate, filtered and evaporated to yield 0.2 g (0.6 w/w) of title compound as light yellow oil.
22.4 g 1L three bottles to join4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine 20 g (66 mmol)S-1-tert-butoxycarbonyl-3-hydroxypiperidine (26.6 g, 132 mmol); triphenylphosphine (51.9 g, 198 mmol) was added to dry tetrahydrofuran (400 mL) and cooled to 5-10 C.Under nitrogen, 40 g (198 mmol) of diisopropyl azodicarboxylate was slowly added dropwise to the flask and the reaction was carried out at 30 C for 12 hours. The reaction solution was cooled to 0 to 10 C, and 20 g of 36% hydrochloric acid was added dropwise(198 mmol), and the temperature was raised to 40 C for 1 hour.Water was added, stirred, extracted three times with dichloromethane, and the aqueous phase was collected and washed with hydrogenSodium hydroxide solution to adjust the water phase into alkaline (pH> 10), precipitate solid, filter, collect solid, blast 50 baking 12 hours(4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo (3,4-d) pyrimidin-4-amine (V) 22.4 g, molar yield 87.9%. (HPLC purity 99.6%; optical purity ?99.8%).

  • 2
  • [ 1022150-13-5 ]
  • [ 1022150-12-4 ]
  • C37H47N9O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% With HATU; In N,N-dimethyl-formamide; at 20℃; for 0.5h; To a solution of Intermediate 4 (0.1 g, 0.26 mmoles) and Intermediate 5 in DMF (2 mL) was added HATU (98 mg, 0.26 mmoles). The reaction solution was stirred 30 min at room temperature then diluted with EtOAc (50 mL) and washed with dilute aq. NaHCO3 (2×50 mL). The organic layer was dried (MgSO4), filtered and then concentrated. The resulting residue was purified by flash chromatography (10% MeOH/CH2Cl2) to provide 0.12 g (68%) of Intermediate 6.
  • 11
  • [ 1022150-12-4 ]
  • [ 372-09-8 ]
  • [ 1412418-10-0 ]
YieldReaction ConditionsOperation in experiment
56% With 1,1'-carbonyldiimidazole; In dichloromethane; at 20℃; for 24h; Step 6. A mixture of 3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (580 mg, 1.50 mmol, 1.00 equiv), carbonyldiimidazole (365 mg, 2.25 mmol, 1.50 equiv) and 2-cyanoacetic acid (190 mg, 2.24 mmol, 1.49 equiv) in dichloromethane (100 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with 100 mL of dichloromethane and washed with 3x100 mL of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/l) to give 380 mg (56%) of 3-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a white solid.
380 mg With 1,1'-carbonyldiimidazole; In dichloromethane; at 20℃; for 24h; A mixture of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4 d]pyrimidin-4-amine (580 mg, 1.50 mmol, 1.00 equiv), carbonyldiimidazole (365 mg, 2.25 mmol, 1.50 equiv) and 2cyanoacetic acid (190 rug, 2.24 mniol, 1.49 equiv) in dichloromethane (100 mE) was stirred at room temperature for 24 h. The reaction mixture was diluted with 100 mE of dichloromethane and washed with 3x 100 mE of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/ methanol (100 /1) to give 380 mg (56%) of (R)-3-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-4-oxopropanenitrile as a white solid.
380 mg With 1,1'-carbonyldiimidazole; In dichloromethane; at 20℃; for 24h; Step 6 A mixture of 3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (580 mg, 1.50 mmol, 1.00 equiv), carbonyldiimidazole (365 mg, 2.25 mmol, 1.50 equiv) and 2-cyanoacetic acid (190 mg, 2.24 mmol, 1.49 equiv) in dichloromethane (100 mL) was stirred at room temperature for 24 h. The reaction mixture was diluted with 100 mL of dichloromethane and washed with 3*100 mL of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with dichloromethane/methanol (100/1) to give 380 mg (56%) of 3-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a white solid.
  • 12
  • C29H27N5O3 [ No CAS ]
  • [ 1022150-12-4 ]
  • 13
  • C30H28N6O3 [ No CAS ]
  • [ 1022150-12-4 ]
YieldReaction ConditionsOperation in experiment
With 10 wt% Pd(OH)2 on carbon; hydrogen; In methanol; at 55 - 60℃; under 2250.23 Torr; Switch the solvent to 10V MeOH. Add Pd(OH2)/C(0.3eq) and stir the mixture at 55-60 C under 3Bar H2. Filter the reaction mixture and wash the cake with MeOH. Combine the MeOH solution of crude I and concentrate to 2-3VAdd dropwise H20 (5-6V) into the MeOH solution (a lot of off-white solid separated out). Filter the mixture and wash the cake with MeOH/H20 (IV/ IV). The solid was dried under vacuum at 40-45 C to obtain I in 80% yield (over 3 steps) in 92.5% purity.
  • 14
  • C28H27N5O [ No CAS ]
  • [ 1022150-12-4 ]
  • 15
  • (R)-1-(1-benzylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]
  • [ 1022150-12-4 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; 10 wt% Pd(OH)2 on carbon; In methanol; at 40 - 50℃; Charge 0.1 eq Pd(OH)2/C and 2eq HC1(4M MeOH solution). Heat to 45-50C Stir the mixture in R2 at 40-50C. The desired product was obtained from this procedure. (ESI):m/z =387.0 (M+l)
With palladium 10% on activated carbon; hydrogen; In methanol; In a lOOmL RBF charge Methanol (lOv) 50mLand (R)-l-(l-benzylpiperidin-3-yl)-3-(4- phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine 5.0g, purge the reaction mass with Nitrogen gas. Charge 10% Palladium on carbon) 50% wet) l .Og and purge the reaction mass with Nitrogen gas. Maintain the reaction mass under stirring with Hydrogen pressure for about 10-12hrs. Concentrate reaction mass, obtained residue was used for further process without purification. (0086) Yield: 4.0gm
  • 17
  • C13H19N3O2*2ClH [ No CAS ]
  • [ 1022150-12-4 ]
  • 18
  • [ 1612774-50-1 ]
  • [ 1022150-12-4 ]
  • 19
  • C12H19N3*2ClH [ No CAS ]
  • [ 1022150-12-4 ]
  • 20
  • [ 330786-24-8 ]
  • [ 143900-44-1 ]
  • [ 1022150-12-4 ]
YieldReaction ConditionsOperation in experiment
85% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 25℃;Inert atmosphere; Large scale; To 200L reaction kettle adding 124.60 kg tetrahydrofuran, are added under stirring 3 - (4 -)-1H-[34-D]-4-(SM1)(4.00kg1eq)(S)-1-Oxycarbonyl -3 - hydroxy piperidine (SM2) (7.96 kg, 3eq), triphenylphosphine (10.40 kg, 3eq). 25[...] (will be 8.00 kg, 3eq azo-phthalic acid diisopropyl ester soluble in 8.00 kg of in tetrahydrofuran),325(TLCMonitoring: ethyl acetate: methanol=10:1). Stirring under reduced pressure distillation. Temperature control 15 C, dropwise 24.00kg325The reaction is complete (TLC monitoring: dichloromethane: ethyl acetate=5:3). Dichloromethane is used for extraction of the aqueous phase(60.00kg)45.00kgStirring 30 minutes later, the static layering, the minute eliminates upper organic phase. The remaining aqueous phase is added to the 200L anti-1535.00kg 20(9.60Kg sodium hydroxide into 38.40 kg of pure water), the use of pH test paper monitoring reaction solution, pH=5 - 6(2)100LAdding 19.20v ethanol, 0.10 kg of activated carbon, heated to 75 C reflux stirring 2 hours. 1.60kg100LStop heating, water bath cooling, stirring crystallization, when the temperature is reduced to 25 C, thermal crystallization 2 hours. 5.60kg6012Powder 3.75 kg, yield: 85%.
80.45% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 30℃; for 25h; Intermediate 4 A mixture of about 60.67 g (0.2 mol) of (S) -2- (hydroxymethyl) piperidine-1-carboxylic acid tert-(0.3 mol) was dissolved in 360 mL of THF while 78.698 (0.3 1 01) triphenylphosphine was added. (0.3mol) of diisopropyl azodicarboxylate and 300mL of tetrahydrofuran solution, lh drop complete system slowly warming up to 30 C insulation reaction 24h, the system temperature to 0-5 (: After the reaction was complete, the solvent was evaporated, and 450 mL of methylene chloride (DCM) was added. The mixture was stirred at room temperature for 10 min, filtered, and the filtrate was bubbled with hydrogen chloride gas. The mixture was stirred for 4 h. After the reaction was complete, The organic layer was washed with 5% sodium hydrogencarbonate solution to neutral and then saturated brine, and the organic layer was dried and filtered to dryness to obtain about 62.18 g of intermediate 5 in a yield of 80.45%.
69% 6) Add IM6 (4.5 g, 0.015 mol) in sequence to a 250 mL three-necked flask. N-Boc Hydroxylpiperazine (3.6 g, 0.018 mol), Triphenylphosphine (7.9 g, 0.03 mol) and tetrahydrofuran (45 mL) were cooled in an ice bath. DIAD (6.1 g, 0.03 mol) was added dropwise with stirring. The temperature was controlled to not exceed 20 degrees Celsius. After the addition was complete, the mixture was stirred at room temperature for about 5 hours. Add 45 mL concentrated hydrochloric acid to the reaction flask and stir at room temperature for about 5 h. The tetrahydrofuran was concentrated and removed, poured into 150 mL of water and washed with dichloromethane. The aqueous layer was adjusted to neutral pH with potassium carbonate and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give IM7 (4.0 g , 69%).
52% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 24h; A solution of 3 -(4-phenoxyphenyl)- 1H-pyrazolo [3 ,4-d]pyrimidin-4-amine (1.00 g, 3.29mmol) in 60 mL of THF was treated with triphenylphosphine (2.59 g, 9.89 mmol), (S)-3-hydroxy-N-Boc-piperidine (1.99 g, 9.89 mmol), and diisopropylazodicarboxylate (1.95 mL, 9.89 mmol) and stirred for 24 h at room temperature. The reaction was concentrated and partially purified by chromatography over silica gel (25-70% EtOAc:Hexane, then 5% MeOH:CHC13 eluent). The resulting semi-crude product (contaminated with triphenylphosphonium oxide) wasdirectly treated with 4M HC1 in dioxane and stirred for 4h at room temperature. The mixture was concentrated and the crude material washed repeatedly with Et20 to afford (R)-3-(4- phenoxyphenyl)- 1 -(piperidin-3 -yl)- 1H-pyrazolo [3 ,4-d]pyrimidin-4-amine as a white solid. (0.67 g, 52%); ?H NMR (400 MHz, DMSO-d6) oe 9.38 (m, 1H), 9.25 (m, 1H), 8.47 (s, 1H), 7.66 (m, 2H), 7.45 (m, 2H), 7.24- 7.09 (m, 5H), 5.16 (m, 1H), 3.58 - 3.37 (m, 2H), 3.31 (d, J= 12.4 Hz,1H), 3.01 (m, 1H), 2.14 (m, 2H), 1.94 (m, 2H). ?H NMR (400 MHz, DMSO-d6) oe 9.46- 9.29 (m,1H), 9.25 (s, 1H), 8.47 (s, 1H), 7.73 - 7.60 (m, 2H), 7.49 - 7.41 (m, 2H), 7.24 - 7.09 (m, 5H),5.23 - 5.08 (m, 1H), 3.58 - 3.37 (m, 3H), 3.31 (d, J 12.4 Hz, 1H), 3.09-2.93 (m, 1H), 2.23 -2.06 (m, 2H), 2.05 - 1.84 (m, 2H); HRMS (ESI-TOF) (m/z) [M+H] calcd for C22H23N60387.19279, found 387.19248.
45% To a 500 mL reaction flask was added 155 mL of tetrahydrofuran, and the mixture was added successively with stirring3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-D] pyrimidin-4-amine (SM1) (5 g, 1 eq)(S) -1-tert-butoxycarbonyl-3-hydroxypiperidine (SM2) (4.97 g, 1.5 eq), triphenylphosphine (13 g, 3.0 eq). A solution of diisopropyl azodicarboxylate in tetrahydrofuran was added dropwise over 30 minutes under a controlled temperature of 25 C (10 g of 3.0 eq diisopropyl azodicarboxylate was dissolved in 10 mL of tetrahydrofuran). After completion of the dropwise addition, the temperature was maintained at 25 C and the reaction was continued for 5 hours (TLC monitoring: ethyl acetate: methanol = 10: 1). Distillation under reduced pressure. The temperature was maintained at 15 C, 30 mL of concentrated hydrochloric acid was added dropwise to the residue, and the reaction was carried out for 30 minutes. After completion of the dropwise addition, the temperature was maintained at 25 C and the reaction was continued for 2 hours. The aqueous phase was extracted three times with dichloromethane (75 mL each) to leave the aqueous phase. Extracted once with 50 mL of ethyl acetate. The remaining water was thoroughly stirred and the temperature was controlled to 15 C. About 45 g of a 20% aqueous solution of sodium hydroxide was added dropwise. The reaction solution was monitored using a pH test paper at a pH of 5 to 6 (about 30 minutes) to give a pale yellow solid. The solid was recrystallized twice from ethanol to give 2.87 g of an off-white powder in a yield of 45%.

  • 21
  • [ 1022150-12-4 ]
  • [ 814-68-6 ]
  • ibrutinib [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With sodium hydrogencarbonate; In 2-methyltetrahydrofuran; at -5 - 0℃; for 1h;Inert atmosphere; Under nitrogen protection,The compound of formula 6 (10 g, 0.026 mol) was dissolved in 2-methyltetrahydrofuran (100 mL)A solution of 7% sodium bicarbonate (4.37 g, 0.052 mol) (62 mL)Down to -5 C,Acryloyl chloride (2.34 g, 0.026 mol)And 2-methyltetrahydrofuran (10 mL)Dripping completed keeping stirring below 0 reaction 1h. The reaction solution is stratified,The aqueous phase was extracted with 2-methyltetrahydrofuran (100 mL)The combined organic phase,Followed by adding 7% sodium bicarbonate solution was washed (100mL)And water (100 mL)Dried over anhydrous sodium sulfate,Concentrate in vacuo to a dry white foamy solid 10.5 g,Yield 92.1%,Recrystallization from ethyl acetate and n-heptane gave 10.0 g of white crystals,Yield 95.0%, chemical purity of 99.6%, optical purity of 99.5%.
95% With sodium hydrogencarbonate; In 2-methyltetrahydrofuran; water; at -5 - 0℃; for 1h;Inert atmosphere; The compound of Formula 8 (10 g, 0.026 mol) was dissolved in 2-methyltetrahydrofuran (100 mE), and a 7% aqueous solution (62 mE) of sodium bicarbonate (4.37 g, 0.052 mol) was added under the protection of nitrogen atmosphere. The reaction temperature was then reduced to-5 C., and a solution of acryloyl chloride (2.34 g, 0.026 mol) in 2-methyltetrahydrofuran (10 mE) was slowly added dropwise. Afier completing the addition, the reaction temperature was kept below 0 C., and meanwhile the reaction solution was stirred for 1 h, and then layered. After the aqueous phase was extracted with 2-methyltetrahydrofuran (100 mE), the organic phases were combined, washed sequentially with a 7% aqueous solution (50 mE) of sodium bicarbonate and water (50 mE), dried over anhydrous sodium sulfate, and then concentrated in vacuo to dryness to afford 10.5 g of a white foamy solid in 92.1% yield. The solid was recrystallized from ethyl acetate and n-heptane to afford 10.0 g of a white crystal in 95.0% yield, 99.6% chemical purity and 99.5% optical purity.
93.9% With potassium carbonate; In dichloromethane; at 0℃;Inert atmosphere; Under the protection of nitrogen, intermediate (IV) (3.87 g, 10 mmol), potassium carbonate (2.78 g, 20 mmol) and dichloromethane (20 mL) were added to the reaction flask.The system was cooled to 0 C, 10 mL of a solution of acryloyl chloride (0.93 g, 10 mmol) in dichloromethane was added dropwise, and the mixture was stirred at room temperature until the intermediate (IV) disappeared.The reaction was stopped, washed with water (30 mL × 3), dried over anhydrous sodium sulfate, and filtered, and evaporated to dryness to afford i 1 (I) (4.14 g, yield: 93.9%).
91% With 2,6-di-tert-butyl-4-methyl-phenol; potassium carbonate; In dichloromethane; water; at 20 - 30℃; for 1h; H2O (28 mL, S vol), compound 8 (5.58 g, 14.45 mmol, 1.0 equiv), K2CO3 (2.20 g, 15.9 mmol, 1.1 equiv), and DCM (75 mL, 15 vol) were added to a reactor equipped with a thermocouple and an overhead stirrer at 20-30C. Butylated hydroxytoluene (BHT) (32 mg, 0.14 mmol, 0.01 equiv) was added to the reaction mixture at 20-30C. A solution containing distilled acryloyl chloride (1.17 mL, 14.45 mmol, 1.0 equiv) in DCM (11.16 mL, 2 vol) was slowly added over a 0.5 hr period to the reaction mixture while maintaining the temperature at 30C. The solution was stirred for 0.5 hr at 20-30C. When the reaction was complete as determined by HPLC analysis, the phases were allowed to separate and the aqueous layer was removed. The organic layer was concentrated under reduced pressure at 45C. The residue was chromatographed on a column of silica gel with MeOH/DCM (3:97) to provide ibrutinib (7.29 g, 91%). H1 NMR (400 Hz, MHz, MeOH) delta 8.24 (s, 1H), 8.27 (s, 1H), 7.68 (d, J=8.4 Hz, 4H), 7.42 (m, 4H), 7.19 (m, 2H), 7.15 (d, J=8.4 Hz, 4H), 7.10 (m, 2H), 6.67 (dd, J=16.6, 10.6 Hz, 1H) , 6.83 (dd, J=16.6, 10.6 Hz, 1H), 6.22 (d, J=16.8 Hz, 1H), 6.15 (d, J=16.8 Hz, 1H), 5.78 (d, J=10.4 Hz, 1H), 5.64 (d, J=10.4 Hz, 1H), 4.86 (m, 2H), 4.65 (d, J=12.4 Hz, 1H), 4.22 (m, 1H), 3.88 (dd, J=13.0, 9.4 Hz, 1H), 3.51 (m, 1H), 4.28 (m, 1H), 4.12 (m, 1H), 3.33 (m, 1H), 3.22 (t, J=10.4 Hz, 1H), 2.23 (m, 2H), 2.38 (m, 2H), 2.08 (m, 2H), 1.72 (m, 2H).
90% With potassium carbonate; In dichloromethane; at -2 - 10℃; The compound (8) was added to the reaction flask,(1eq),DCM (27 vol) and potassium carbonate (1.5 eq).The system down to -2 ~ 10 ,dropPlus acryloyl chloride(0.95 eq)Of DCM (13 vol) solution.The reaction is completed,Add water (10Vol) to separate the solution.The aqueous phase was extracted twice with DCM (10 vol).Combine organic phase,Washed three times with 1 N HCl (10 Vol)Saturated sodium bicarbonate (10Vol) once,Saturated salt water (10Vol) once.Dried over anhydrous sodium sulfate,Filtration to dry the crude productThe The crude product was purified to give compound 9,Yield 90%.
90.2% With N-ethyl-N,N-diisopropylamine; sodium hydroxide; In dichloromethane; at -5 - 20℃; for 3h; Compound II (115.8 g, 0.3 mol), diisopropylethylamine (42.6 g, 0.33 mol), sodium hydroxide (1.2 g, 0.03 mol) and dichloromethane (1.5 L) were added to the reaction flask. At -5 C, acryloyl chloride (30.0 g, 0.33 mol) was added dropwise, and the mixture was reacted at room temperature for 3 h. After completion of the reaction, a 5 % aqueous solution of citric acid (1.5 L) was added to the system, and the organic layer was separated. The methylene chloride was removed under reduced pressure to give an oily mixture, which was then taken to a mixture of 60% aqueous methanol (2L), and the mixture was warmed to the system and then stirred at 5 to 10 deg. Filter out the solids,After drying, 119.1 g of pale solid (I) was obtained, the yield was 90.2%
85% 10.8 g (30 mmol) under nitrogen protection(R)-5-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carbonitrileCompound VI was added to 30 mL of formamide and placed in a microwave synthesizer at 100 C for 30 min.TLC detection reaction is complete, plus 200mL saturated NaCl solution diluted, and then added ethyl acetate extraction, washing, standing, stratification, pour the lower aqueous layer,The organic phase was washed twice with saturated NaCl solution, and the organic layer was concentrated and purified by a column chromatography to obtain 10 g (24 mmol) of a white solid. The white solid and 50 mL of sodium hydroxide solution (2.5 mol/L) were added to 50 mL of methanol. Reflow reaction 7h,After the end of the reaction was detected by TLC, the solvent was derotated and 100 mL of ethyl acetate was added to dissolve the solvent. Then 100 mL of saturated NaCl solution was added and washed.Let stand, stratify, pour the lower water layer, wash the organic phase twice with saturated NaCl solution, concentrate the organic phase, the crude product is not separatedUsed directly in the next step, and the obtained crude product and 2.4 g (26 mmol) of acryloyl chloride were added to 200 mL of dry dichloromethane.Add 4.8g (48mmol) of triethylamine, stir the reaction for 2h at room temperature, and spin down the solvent under reduced pressure after the end of the TLC test.Add 200mL ethyl acetate to dissolve, add 100mL saturated NaCl solution, wash, stand, layer, pour the lower aqueous layer, organic phaseThen wash twice with saturated NaCl solution and concentrate the organic phase.The crude product was recrystallized from anhydrous ethanol to obtain 11.2 g of the ibrutinib compound I as a white solid with an ee value of 99.3% and a reaction yield of 85%.
62% With triethylamine; In dichloromethane; at 0℃; for 4h; The above amine (106 mg, 275 jimol) in 2 mL of DCM at 0C was treated with triethylamine (0.15 mL, 1.10 mmol) and acryloyl chloride (29 jiL, 360 jimol). The reaction was stirred for 4 h and washed with 5% aq. citric acid and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. Purification by column chromatography over silica gel (2- 10% MeOH/CHC13 eluent) afforded ibrutinib as a white solid (76 mg, 62%). ?H NMR (400MHz, DMSO-d6) oe 8.25 (s, 1H), 7.66 (m, 2H), 7.44 (m, 2H), 7.15 (m, 5H), 6.87 (dd,J= 16.5,10.5 Hz, 0.5H), 6.72 (dd, J 16.5, 10.5 Hz, 0.5H), 6.10 (dd, J 28.3, 17.3 Hz, 1H), 5.71 (d, J12.2 Hz, 0.5H), 5.59 (d, J= 10.1 Hz, 0.5H), 4.70 (m, 1H), 4.55 (d, J= 12.5 Hz, 1H), 4.21 (m,1H), 4.06 (m, 0.5H), 3.70 (m, 0.5H), 3.20 (m, 1H), 3.00 (m, 0.5H), 2.27 (m, 1H), 2.11 (m, 1H), 1.92 (m, 1H), 1.58 (m, 1H); HRMS (ESI-TOF) (m/z) [M+H] calcd for C25H25N602 441.20335, found 441.20321.
1.6 g With triethylamine; In dichloromethane; for 3h;Cooling with ice; 1.82g of the above oil was dissolved in 20ml of dichloromethane was added 1.4g of triethylamine and 0.46g acryloylChlorine, under the ice bath for 3 hours. The reaction mixture was added water 20ml, separate the organic phase. The organic phase was washed with dilute hydrochloric acidWashed until neutral, dried, and concentrated to dryness under reduced pressure to white solid 1.8g, 86% yield. 2g of the crude product with 15ml of ethyl acetate and n-heptane mixed solvent (1: 1 volume ratio) to give 1.6g of white solid was recrystallized, HPLC purity 99.6% detection.
With triethylamine; In dichloromethane; 3-(4-Phenoxyphenyl)-l -[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g) was dissolved in DCM (25 niL) and NEt3 (0.47 niL) was added, following dropwise addition of acryloyl chloride (0.104 niL) dissolved in DCM (5 niL). The reaction mixture was washed with IN citric acid solution and then with brine. The organic layer was dried with Na2S04. A solvent exchange was performed with benzonitrile. After filtration of the solution (0.2 muiotaeta pore size) and evaporation of the solvent at 50C 1 - [(3R)-3- [4-amino-3 -(4-phenoxyphenyl)pyrazolo[3 ,4-d]pyrimidin- 1 -yl] - 1 - piperidyl]prop-2-en-l-one was obtained.
With triethylamine; In tetrahydrofuran; at 25 - 30℃; for 18h; To a solution of acryloyl chloride (0.06g) in tetrahydrofuran (15.0 ml), a mixture of triethylamine (0.1 g) and (1S)-1-[(3R)-3-piperidyl]-3-(p-phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine (0.2g) in tetrahydrofuran (7.8 ml) was added. The reaction mixture was stirred at 25-30 C for 18 hous and filtered. The solvent was removed under vacuum to obtain crude ibrutinib, which was further purified by column chromatography on silica gel to obtain pure ibrutinib as crystalline solid.
2.15 g With triethylamine; In dichloromethane; for 2h; Prepared in the same manner as in Example 1b of CN101610676A:Into a 200 mL three-necked flask were placed 3.86 g of Intermediate (R) -3- (4-phenoxyphenyl) -1- (nyidin-3-yl) -1H-pyrazolo [3,4- d] Pyrimidin-4-amine and 35 ml of dichloromethane, stirring was started. Add 4.2mL triethylamine, slowly dropping lmL of acryloyl chloride, add the reaction continued to complete 2 hours. After the reaction was completed, the organic layers were washed with 5% citric acid and brine, respectively, for delamination. The organic layer was dried over MgSO4 and spun dry. The residue was purified by column chromatography (methylene chloride / methanol = 25/1) to give 2.15 g of ibrutinib powder.

  • 22
  • [ 1022150-12-4 ]
  • (2E)‐4‐[4‐(2‐[(tert‐butoxy)carbonyl]amino}ethyl)piperazin‐1‐yl]but‐2‐enoic acid [ No CAS ]
  • tert-butyl (R,E)-(2-(4-(4-(3-(4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)carbamate [ No CAS ]
  • 24
  • [ 1022150-12-4 ]
  • (R,E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidin-1-yl)-4-(4-(2-aminoethyl)piperazin-1-yl)but-2-en-1-one [ No CAS ]
  • 25
  • [ 1022150-12-4 ]
  • (R,E)-N-(2-(4-(4-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo-[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)-3-(5,5-difluoro-1,3,7,9-tetramethyl-5H-dipyrrolo-[1,2-c:2′,1′-f][1,3,2]diazaborinin-2-yl)propanamide [ No CAS ]
  • 26
  • [ 1022150-12-4 ]
  • C53H58BF2N11O4 [ No CAS ]
  • 27
  • [ 1022150-12-4 ]
  • C39H47N9O3 [ No CAS ]
  • 28
  • [ 1022150-12-4 ]
  • C36H44N12O3 [ No CAS ]
  • 29
  • [ 1022150-12-4 ]
  • C47H57N13O4 [ No CAS ]
  • 30
  • [ 1022150-12-4 ]
  • (R)-3-amino-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo-[3,4-d]pyrimidin-1-yl)piperidin-1-yl)propan-1-one hydrochloride [ No CAS ]
  • 31
  • [ 1022150-12-4 ]
  • (R)-2-amino-1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)propan-1-one hydrochloride [ No CAS ]
  • 32
  • [ 1022150-12-4 ]
  • (R)-2-amino-1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-hydroxypropan-1-one hydrochloride [ No CAS ]
  • 33
  • [ 1022150-12-4 ]
  • (R)-2-amino-1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride [ No CAS ]
  • 34
  • [ 1022150-12-4 ]
  • (2R)-2-amino-1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-hydroxybutan-1-one hydrochloride [ No CAS ]
  • 35
  • [ 1022150-12-4 ]
  • (2R,3R)-2-amino-1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-methylpentan-1-one hydrochloride [ No CAS ]
  • 36
  • [ 1022150-12-4 ]
  • [ 79-03-8 ]
  • (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one [ No CAS ]
  • 37
  • [ 1022150-12-4 ]
  • [ 75-36-5 ]
  • (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidin-1-yl)ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
1 g With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -45 - -40℃; for 0.333333h; A mixture of (R)-(3-(4-phenoxyphenyl)-1 -Qiperidin-3-yl)-1 H-pyrazolo[3,4-d] pyrimidin-4-amine (1 gm) and dichloromethane (30 ml) was cooled to -40 to -45C.Diisopropylethylamine (0.66 gms) followed by a solution of acetyl chloride (0.2 gms) in dichioromethane (15 ml) was added to the reaction mixture at -40 to -45C and stirred for 20 mins. Ethanol and water were added to the reaction mixture at -40 to -45C. 1% aqueous sodium hydroxide solution was added to the reaction mixture at -40 to -45C and raised the temperature of the reaction mixture to 0-5C. Both the organic and aqueous layers wereseparated. The organic layer was washed with iN hydrochloric acid solution followed by 5%aqueous sodium carbonate solution and 5% aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 1 gm.
  • 38
  • [ 1022150-12-4 ]
  • [ 141-75-3 ]
  • (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)butan-1-one [ No CAS ]
  • 39
  • [ 1022150-12-4 ]
  • [ 3282-30-2 ]
  • (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidin-1-yl)-2,2-dimethylpropan-1-one [ No CAS ]
  • 40
  • [ 5856-77-9 ]
  • [ 1022150-12-4 ]
  • (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2,2-dimethylbutan-1-one [ No CAS ]
  • 41
  • [ 7065-46-5 ]
  • [ 1022150-12-4 ]
  • (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3,3-dimethylbutan-1-one [ No CAS ]
  • 42
  • [ 1022150-12-4 ]
  • [ 4023-34-1 ]
  • (R)-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)(cyclopropyl)methanone [ No CAS ]
  • 43
  • [ 1022150-12-4 ]
  • [ 5239-82-7 ]
  • (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-cyclopropylethanone [ No CAS ]
  • 44
  • [ 68947-43-3 ]
  • [ 1022150-12-4 ]
  • (R)-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)(1-methyl-piperidin-4-yl)methanone [ No CAS ]
  • 45
  • [ 1022150-12-4 ]
  • [ 54699-92-2 ]
  • (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(4-methyl-piperazin-1-yl)ethanone [ No CAS ]
  • 46
  • [ 1022150-12-4 ]
  • [ 124-63-0 ]
  • (R)-1-(1-(methylsulfonyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]
  • 47
  • [ 1022150-12-4 ]
  • [ 594-44-5 ]
  • (R)-1-(1-(ethylsulfonyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]
  • 48
  • [ 10147-36-1 ]
  • [ 1022150-12-4 ]
  • (R)-3-(4-phenoxyphenyl)-1-(1-(propylsulfonyl)piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]
  • 49
  • [ 4530-20-5 ]
  • [ 1022150-12-4 ]
  • (R)-(2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-oxoethyl)carbamate tert-butyl ester [ No CAS ]
  • 50
  • [ 1022150-12-4 ]
  • [ 3303-84-2 ]
  • C30H35N7O4 [ No CAS ]
  • 51
  • [ 1118-68-9 ]
  • [ 1022150-12-4 ]
  • (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-(dimethylamino)ethanone [ No CAS ]
  • 52
  • [ 1022150-12-4 ]
  • [ 3744-87-4 ]
  • C30H35N7O4 [ No CAS ]
  • 53
  • [ 3262-72-4 ]
  • [ 1022150-12-4 ]
  • C30H35N7O5 [ No CAS ]
  • 54
  • [ 1022150-12-4 ]
  • [ 22838-58-0 ]
  • C32H39N7O4 [ No CAS ]
  • 55
  • [ 1022150-12-4 ]
  • [ 2592-18-9 ]
  • C31H37N7O5 [ No CAS ]
  • 56
  • [ 1022150-12-4 ]
  • [ 55721-65-8 ]
  • C33H41N7O4 [ No CAS ]
  • 57
  • [ 1022150-12-4 ]
  • [ 16937-99-8 ]
  • C33H41N7O4 [ No CAS ]
  • 58
  • [ 506-68-3 ]
  • [ 1022150-12-4 ]
  • (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonitrile hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
47 mg With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 0.833333h; R)-3-(4-phenoxyphenyl)- 1 -(piperidin-3-yl)- 1JJ-pyrazolo[3,4-d]pyrimidin-4-amine (51 mg, 0.13 mmol) was dissolved in 3 mL DMF. To the stirred solution were added diisopropylethylamine (DIEA, 96 aL, 0.55 mmol) and then cyanogen bromide (Aldrich, 5.OM in acetonitrile, 66 aL, 0.33 mmol). The mixture was stirred at Pt for 50 m, diluted with water and acetic acid, subjected to reverse phase preparative HPLC to isolate the title compound (1) as JJC1 salt (47 mg). MS found as (M+Hfb 412.0, (M-H)- 410.2. UV: X259 nm.
  • 59
  • [ 5305-40-8 ]
  • [ 1022150-12-4 ]
  • 61
  • (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanol [ No CAS ]
  • [ 1022150-12-4 ]
  • 62
  • (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanone [ No CAS ]
  • [ 1022150-12-4 ]
  • 63
  • (4-amino-6-chloropyrimidin-5-yl)(4-phenoxyphenyl)methanone [ No CAS ]
  • [ 1022150-12-4 ]
  • 64
  • [ 1022150-12-4 ]
  • [ 79-10-7 ]
  • ibrutinib [ No CAS ]
YieldReaction ConditionsOperation in experiment
89.2% 2L into the reaction bottle 450mLDMF, 14 . 4g (0.2mol) Propenecarboxylic acid, 114.07g (0.3mol) HATU, 38.775g (0.3mol) DIPEA, stirring the mixture at room temperature for 1h to system adding dropwisely 77.29g intermediate 5 and 350mLDMF configuration solution, 40-60min the drop finishes. TLC central control, after the reaction is complete by adding 450 ml water, 10g sodium chloride, at the same time by adding 500 ml ethyl acetate stirring layered, for water 300mLX3 ethyl acetate extraction, combined with the organic layer, organic layer using 600 ml saturated salt water washing, the organic phase drying, get crude according to Lu Tini after concentrating, the crude product of ethyl acetate and normal heptane refined and get HPLC? 99% pure product of 75.59g yield: 89.2%.
86.1% Methanesulfonyl chloride (3.2 g, 28 mmol), Li2CO3 (2.21 g, 30 mmol) was added to acetonitrile (100 mL)Mixing, acrylic acid (2.02 g, 28 mmol)Added to the reaction mixture, stirred for 10h.The intermediate (10) (5 g, 13 mmol) was added to the prepared mixed solution of the mixed anhydride, and the mixture was stirred at 50 C for 30 minutes and then detected by TLC. The reaction of the starting material was completed.Add water and stir, the aqueous phase is extracted twice more with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give ibrutinib (white solid, 4.9 g, yield: 86.1%).
45% With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h; (7) IM7 (1.5 g, 0.004 mol), acrylic acid (0.3 g, 0.004 mol), HBTU (1.8 g, 0.005 mol), DIPEA (1.0 g, 0.008 mol) and dichloromethane were sequentially added to a 100 mL three-neck flask. (45 mL), stirred for about 4 h at room temperature, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, which was recrystallized from isopropanol to give ibrutinib (0.8 g, 45%).
2 g With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 10 - 30℃; In a 100m I, RBF charge DCM (20v) 80mL, (R)-3-(4-phenoxyphenyl)-l-(piperidin-3-yl)-lH- py ra/.o 1 o f 3.4-d ] p yri m i d i n-4-am ine (l.OEq) 4.0g, 1 -Ethyl -3 -(3- dimethylaminopropyl)carbodimide (EDCI.HC1) (2.0Eq) 4.0g, Acrylic acid (2.5Eq)1.86gand Triethyl amine (8.0Eq) 8.37gatlO-30C. Maintain the reaction for about 3-5hrs and then charge water and work up with DCM, acidic and basic wash the organic layer. Concentrate and purify by column chromatography using DCM: Methanol solvent system. (0090) Yield: 2.0 gm

  • 65
  • [ 25268-16-0 ]
  • [ 1022150-12-4 ]
  • 66
  • [ 1022150-12-4 ]
  • [ 625-36-5 ]
  • (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidin-1-yl)-3-chloropropyl-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% With sodium hydrogencarbonate; In tetrahydrofuran; at -20℃; for 3h;Inert atmosphere; The reaction flask was charged with 250 ml of THF, 20 g of compound A, 10 g of sodium bicarbonate (2.3 eq), and the nitrogen protection was lowered to -20C. A mixture of 7.2 g of 3-chloropropionyl chloride (1.05 eq) and 50 ml of THF was added dropwise, and the reaction was complete after 3 hours of incubation. Return to room temperature 15 ~ 25 C, filtration, 200ml EA shower cake, the mother liquor was combined and washed with 150ml of 1% aqueous hydrochloric acid, and then washed with three 150ml saturated sodium chloride, saturated sodium bicarbonate, saturated sodium chloride three times, The upper light yellow organic phase. The temperature was controlled at T?40C. The organic phase was concentrated under reduced pressure and dried to give 23.5 g of compound B as an off white solid. The yield was 99%.
94.9% With sodium acetate; In water; at 5 - 15℃; for 1h;Inert atmosphere; A compound (1.0 g) and anisole (19.9 ml) as shown in Formula 1 were added to a 100 ml jacketed bottle.Nitrogen protection, adding 1.41 g of sodium acetate and water (1 g),Adjust the temperature to an internal temperature of 5 to 15 C.3-Chloropropionyl chloride (0.975 g) was slowly added dropwise, and stirring was continued for 1 hour.Let stand layering,The organic phase was washed with 7% aqueous sodium hydrogencarbonate (8.0 g).The organic phase is concentrated to 4 to 5 ml under reduced pressure at 20 to 25 C.Add ethyl acetate (5g),Concentrate to 4 to 5 ml under reduced pressure.The operation of adding additional ethyl acetate and concentrating was repeated twice.Add ethyl acetate (7g),An ethyl acetate solution (12.5 g) containing 1.2 g of Compound 3 was obtained, and refrigerated at a low temperature (0 to 5 C).The yield of the compound 3 was 94.9%.The purity was 98.5%.Contains no related substance (R)-N-(1-(1-acryloylpiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole [3.4-d]pyrimidine-4 -based) acrylamide.
87.9% Compound XVII-A (80g, 0.207mol), 0.16g of BHT (=butylated hydroxy toluene) and Me-THF (656.0g) were added into a 2L jacket reactor equipped with over-head stirring. After stirring for 20min at 10C, 7% aq. NaHCO3 (752g, 0.627mol) was added and then 3- chloropropionyl chloride (25.2g, 0.198mol) was slowly added via a dropping funnel over 1h under nitrogen atmosphere/protection at 10C. After stirring the reaction mixture at 10C for 1h, the other part of 3-chloropropionyl chloride (2.61g, 20.5mmol) was diluted with Me-THF (32g, 0.4X) and then slowly added into the reactor over 30min at 10C. After stirring for 30min at 10C, the aqueous phase was separated out and the Me-THF solution containing Compound XVII-1 was washed with 7% NaHCO3 (200g, 0.167mol). Finally, 676.7g 2-Me-THF solution of Compound XVII-1 (this is referred to below as Solution A) was obtained with a purity of 97.68 %. [00188] There were two methods to isolate Compound XVII-1 as a solid: crystallization from Me-THF/n-heptane and crystallization from EtOAc/n-heptane. The detailed descriptions of crystallization of Compound XVII-1 from Me-THF/n-heptane and EtOAc/n-heptane are summarized below. [00189] Crystallization from Me-THF/n-heptane: The Me-THF solution of Compound XVII-1 (obtained from 20g of Compound XVII-A, HPLC purity: 97.68%; i.e. one quarter of Solution A referred to above) was added into a 500mL jacket flask with mechanical stirring for azeotropic distillation. First, the Me-THF solution was concentrated to 4-5V under vacuum (jacket temperature: 28C) and then fresh and dried Me-THF (200mL) was added. This distillation cycle was repeated two times and then distillation endpoint was 4-5V. The anti- solvent n-heptane (80ml) was then slowly added into reactor over 2h at 15C. After being stirred for another 1-2h at 15C, the mixture was filtered and the cake was washed with 1V Me-THF/n- heptane (20mL, v/v=1/1). After drying the wet cake at 35C for 16hrs under vacuum, 23.25g Compound XVII-1 was isolated as white solid with the HPLC purity of 98.36% in isolated yield of 88.7%. [00190] Crystallization from EtOAc/n-heptane: The Me-THF solution of Compound XVII-1 (obtained from 20g Compound XVII-A, HPLC purity: 97.68%; i.e. one quarter of Solution A referred to above) was added into a 500mL jacket flask with mechanical stirring, and then it was concentrated to 4-5V under vacuum (jacket temperature: 28C). EtOAc (200mL) was added into the residue and then the mixture was concentrated to 4-5V again. This distillation cycle was repeated three times and then a lot of white solid precipitated out. The anti-solvent n- heptane (80ml) was then slowly added into reactor over 2h at 15C. After being stirred for another 1-2h at 15C, the mixture was filtered and the cake was washed with EA/n-heptane (20mL, v/v=4/4). After drying the wet cake at 35C for 16hrs under vacuum, 21.7g Compound XVII-1 was isolated as white solid with the HPLC purity of 98.57% in isolated yield of 87.9%. [00191] Characterizing Data for Compound XVII-1 [00192] Data may be obtained to characterize Compound XVII-1, for example mass spectrometry data, melting point and/or NMR (nuclear magnetic resonance) data (e.g. proton and/or carbon). In this case, case was obtained to characterize Compound XVII-1 by, amongst other things, NMR, which characterizing data is referred to in the Figures as follows: [00193] Figure 1- 1H NMR of Compound XVII-1 [00194] Figure 2- 13C NMR of Compound XVII-1 [00195] Figures 3, 4 and 5- NMR NOE (Nuclear Overhauser Effect) of Compound XVII-1 [00196] Figures 6, 7, 8 and 9- NMR HMBC (Heteronuclear Multiple-bond Correlation Spectroscopy) of Compound XVII-1 [00197] Where a NOE NMR is referred to, this is a spectroscopic method known to those skilled in the art. It is a two-dimensional NMR spectroscopy method. The NOE occurs through space (hence those atoms in close proximity will display a NOE) rather than the usual spin-spin coupling effects seen by proton and carbon NMR. Where a HMBC NMR is referred to, this is a specific spectroscopic method also known by those skilled in the art. It is also a two- dimensional NMR spectroscopy method. It is used to detect heteronuclear correlations over longer ranges of about 2-4 bonds. [00199] A screening exercise was done testing a variety of bases in this process reaction, and where the end-products as a result of the reaction were measured i.e. percentage of remaining starting material (Compound XVII-A), desired product (Compound XVII-1) and Compound I (i.e. ibrutinib) as a by-product. [00200] Use of organic bases (3-CPC refers to 3-chloropropionyl chloride): Use of inorganic bases: Schotten-Baumann conditions
830 mg With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -20 - -10℃;Inert atmosphere; Under a nitrogen atmosphere, 50 mL of dichloromethane was added to a 100 mL three-necked flask, followed by the addition of intermediate-1:(R) -3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine(YLTN-1)(1.00 g, 1 eq), N, N-diisopropylethylamine (0.40 g, 1.2 eq), cooled to -20 to -10 C, and 3-chloropropionyl chloride (1.46 g, 1 eq)After the completion of the dropwise addition, the solution was clarified by turbidity and the stirring was continued for 20 to 30 minutes. The LC-MS was detected, the raw material disappeared, distilled under reduced pressure, and the dichloromethane was distilled off to the distillate to obtain crude product by column chromatography,The elution ratio was methanol: ethyl acetate = 1:10, 400 mL of the eluent was collected, distilled under reduced pressure, and the solvent was distilled off to distill off the distillate. A white powder of 830 mg was obtained(R) -1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) -3-chloropropan-1 -one.

  • 67
  • [ 1022150-12-4 ]
  • (E)-4-(4-(14-(((3S,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)amino)-14-oxo-3,6,9,12-tetraoxatetradecyl)piperazin-1-yl)but-2-enoicacid [ No CAS ]
  • tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-(14-(4-((E)-4-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)-3,6,9,12-tetraoxatetradecanamido)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h; To a stirred solution of (E)-4-(4-(14-(((3S,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino) propanamido)-2-cyclohexylacetyl)-5-(((R)-1,2,3,4- tetra hyd ronaphtha len-1-yl)ca rba moyl)pyrrolidi n-3-yl)a mino)-14-oxo-3,6,9,12- tetraoxatetradecyl)piperazin-1-yl)but-2-enoic acid (148 mg, 0.153 mmol), (R)-3-(4- phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (64.8 mg, 0.168mmcl, prepared as described in Org. Biomol. Chem., 2015, 13, 5147-5157) and DIPEA (0.133 mL, 0.763 mmcl) in DMF (1 mL) was added HATU (69.6 mg, 0.183 mmcl) and the mixture stirred at rt for 1 h. The reaction mixture was directly loaded onto a reverse phase (C18) cartridge (30g) and eluted with a 45-95% acetonitrile-water (ammonium carbonate modifier) gradient, however the product failed to elute. The column was flushed with MeOHand the eluent evaporated in vacuo, then the residue partitioned between DCM (20 mL) and water (20 mL) and the phases separated using a hydrophobic frit. The organic layer was concentrated under a stream of nitrogen to give the title compound (130 mg) in 80% purity (by LCMS) as an orange solid. LCMS: RT = 1.39 mins, [(M-i-2H)/2] = 670.4 (80% pure).
  • 68
  • [ 2051-76-5 ]
  • [ 1022150-12-4 ]
  • ibrutinib [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -10℃;Inert atmosphere; Large scale; Under the protection of nitrogen, for 50L in the reactor are sequentially added 13.30 kg methylene chloride, in the middle of the-1(1k g1eq)(0.40kg1.2eq)NN--10Next, the start of the dropping of the dichloromethane solution acrylic anhydride (will be 0.39 kg, 1 . 2eq acrylic anhydride dissolved in0.40kg)90Thermal insulation -10 C, fully stirring until the raw material the reaction is complete (TLC detection, methanol: ethyl acetate: three150.05)40kg 520Minutes, standing liquid, removing the aqueous phase, concentrated evaporate dichloromethane to the condenser in the liquid-dropped. 5.13kg620.005kgActive carbon, thermal insulation 60 C, stirring 20 minutes, is still hot filtration. The filtrate under stirring the temperature to 35 C,9.75kg60304 hours, filtering, cake 1.5 kg ethanol and pure water (1: 1.5) system leaching a, the resulting40120.68kg80
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -10℃; for 0.5h;Inert atmosphere; Under nitrogen, 50 mL of dichloromethane, intermediate-1 (5 g, 1 eq), N, N-diisopropylethylamine (2 g, 1.2 eq) was added sequentially to a 100 mL three-necked flask. -10 temperature conditions, dropwise addition of acrylic anhydride (1.96g, 1.2eq) in dichloromethane was added dropwise for 30 minutes, after the addition was complete, the turbid solution became clear, -10 insulation, sufficiently stirred The reaction was complete (TLC detection, methanol: ethyl acetate: triethylamine = 1: 5: 0.05). The reaction solution was washed with 200 mL of 5% aqueous citric acid solution, the aqueous phase was removed, and the dichloromethane was concentrated and distilled off. Ibrutinib crude: 3.63g.
  • 69
  • [ 940890-90-4 ]
  • [ 1022150-12-4 ]
  • 70
  • [ 1022150-12-4 ]
  • (E)-1-(R)-3-(4-amino-3-(4-phenoxy-phenyl)-1H-pyrazole[3,4-d]pyrimidine-1-yl)piperidine-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrole-6 (3H)-yl)-2-but-en-1-one [ No CAS ]
  • 71
  • [ 1022150-12-4 ]
  • (S,E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1Η-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-(2-oxa-6-aza-spiro[3.3]hept-6-yl)butan-2-en-1-one [ No CAS ]
  • 72
  • [ 1022150-12-4 ]
  • (E)-1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-yl)-4-((1R,4R)-2-thia-5-azabicyclo[2.2.1]hept-5-yl)butan-2-en-1-one [ No CAS ]
  • 73
  • [ 1022150-12-4 ]
  • (R,E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-yl)-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)but-2-en-1-one [ No CAS ]
  • 74
  • [ 99083-25-7 ]
  • [ 1022150-12-4 ]
  • (R,Ε)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1Η-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidine-yl)-4-bromobut-2-en-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% In dichloromethane; for 0.166667h;Cooling with ice; (R) -3-(4-Phenoxyphenyl)-1-(piperidine-3-yl)-1H-Pyrazolo[3, 4-d] pyrimidine-4-amine (1.58g, 4.09mmol) dissolved into the dichloromethane (20mL). (E)-4-bromide-2-enoyl chloride (0.90g, 5mmol) slowly add in ice-water bath, reaction under the ice-water bath till 10 min added the water (30mL), extraction with dichloromethane (100 mLX3), washed with saturatedbrine (30 mL), dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The crude product was purified by silicagel column chromatography (Dichloromethane/methanol (V/V) =30/1), then we get product (1.48g, 68%).
  • 75
  • [ 1022150-12-4 ]
  • (E)-6-(morpholin-4-yl)hex-2-enoic acid [ No CAS ]
  • (R,E)-1-(3-(4-amino-3-(4-phenoxyphenyl)1H-pyrazolo [3,4-d]pyrimidin-1-yl)piperazinepiperidin-1-yl)-6-morpholino-2-en-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
21% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 4h; (E) -6- morpholino-hex-2-enoic acid (141mg, 0.71mmol) was dissolved in DMF(15mL), and were added HOBt (112mg, 0.83 mmol), EDCI (239mg, 1.25mmol), 3-(4-phenoxyphenyl) -1 - ((3R) -3- piperidinyl) pyrazolo [3,4-d] pyrimidin-4-amine (161mg,0.42mmol), stirred at room temperature 4h, two chloride extraction (50mL × 3), washedwith brine (20 mL), dried over anhydrous sodium sulfate, the solvent was distilled offunder reduced pressure, the crude product was purified by chromatography (methylenechloride / methanol (V / V) = 12/1 -8/1) to give the product (50mg, 21%).
  • 76
  • [ 101-55-3 ]
  • tert-butyl-(R)-3-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylate [ No CAS ]
  • [ 1022150-12-4 ]
  • 77
  • (3R)-3-[4-(benzyloxycarbonylamino)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylic acid benzyl ester [ No CAS ]
  • [ 1022150-12-4 ]
YieldReaction ConditionsOperation in experiment
99% With palladium on activated charcoal; From N4,N?-(Cbz)2-protected compound (IV) (Pgi = Pg2 = Cbz) using standard hydrogenation conditions in the presence of Pd/C catalyst, compound (II) was obtained in 99% yield. The analytical data of this product correspond to that of the above mentioned product (II) obtained from N4,N1-(Boc)2-protected compound (IV) (Pgi = Pg2 = Boc).
  • 80
  • C16H10N2O2 [ No CAS ]
  • [ 1022150-12-4 ]
  • 81
  • C18H14N2O2 [ No CAS ]
  • [ 1022150-12-4 ]
  • 83
  • [ 330786-24-8 ]
  • [ 1126736-20-6 ]
  • [ 1022150-12-4 ]
YieldReaction ConditionsOperation in experiment
84.8% Compound 11 (39.08 g, 198.2 mmol), compound 9 (20.0 g, 65.95 mmol), triphenylphosphine (51.81 g, 198.2 mmol), and THF (500 mL) were added into a four-necked round bottom flask equipped with a mechanical stirrer and a thermometer under nitrogen at 30C. A solution containing diisopropyl azodicarboxylate (40 mL, 198.2 mmol) in THF (40 mL) was slowly added over 1.5 hr period of whilst maintaining the reaction mixture temperature at 30C. The solution was stirred for 3 hr at 20-30C. When the reaction was complete as determined by HPLC analysis, the solution was concentrated under reduced pressure (40-50 ton) at 45C to about 120 mL. MeOH (240 mL) was added to the reaction mixture at 30C. To the crude compound 12 and 12a/MeOH solution, an aqueous solution of 25% NaOH (32 g, 198.2 mmol) was added at 30C. The solution was stirred for 2 hr at 20-30C. When the reaction was complete as determined by HPLC analysis, SM HCl (aq) (66.95 mL) was slowly added while maintaining the temperature at 55C. The mixture was stirred at 45-55C for 3 hr. When the reaction was complete as determined by HPLC analysis, the reaction mixture was concentrated under reduced pressure (10-50 ton) at 45C to about 140 mL. Water (280 mL) was added to the reaction mixture and the solution was concentrated under reduced pressure (10-50 ton) at 55C to about 140 mL. Water (240 mL) and EtOAc (400 mL) was added to the reaction mixture at 30C. The mixture was stirred at 20-30C for 10-20 min and then the phases were allowed to separate and the aqueous layer was saved. 1M HCl (200 mL) was added to the organic layer and stirred at 20-30C for 10-20 min. The phases were allowed to separate and the organic layer was removed. The aqueous layers were combined and EtOAc (200 mL, 10 vol) was added to the combined aqueous layers at 30C. The mixtures were stirred at 20-30C for 10-20 min. The phases were allowed to separate and the organic layer was removed. 25% NaOH was added to the remaining aqueous layer to adjust the pH of the aqueous layer to 8-11 while maintaining the temperature at 20-30C. After the reaction mixtures stirred for 3 hr at 20-30C, the solid was filtered and the wet cake was washed with water (23 mL). The wet cake was dried below 50C under vacuum and nitrogen to afford compound 8 (21.6 g, 84.8%). H1 NMR (400Hz, MHz, DMSO) delta 8.24 (s, 1H), 7.68-7.64(m, 2H), 7.47-7.41 (m, 2H), 7.21-7.11 (m, SH), 4.71-4.65(m, 1H), 3.09-3.06 (m, 1H), 2.97-2.90 (m, 1H), 2.50-2.45(m, 1H), 2.16-2.01 (m, 2H), 1.77-1.74 (m, 1H), 1.61-1.52(m, 1H).
  • 84
  • [ 557-24-4 ]
  • [ 1022150-12-4 ]
  • (R,Z)-4-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-4-oxobut-2-enenitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 8.0h; (R) -3- (4-phenoxyphenyl) -1- (piperidin-3-yl)Pyrazolo [3,4-D] pyrimidine-4-amine (193 mg, 0.5 mmol)Maleic acid (67 mg, 0.58 mmol),1-hydroxybenzotriazole (HOBT) (95 mg, 0.7 mmol)And 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (134 mg, 0.7 mmol)Was dissolved in anhydrous DCM (10 ml)Diisopropylethylamine (DIEA) (271 mg, 2.1 mmol) was added,Stir at room temperature for 8 h.Add ethyl acetate diluted after washing,The aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate,The residue was purified by column chromatography to give compound 6 (140 mg, yield 60%).
  • 85
  • [ 10443-65-9 ]
  • [ 1022150-12-4 ]
  • (R)-1-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-2-bromoprop-2-en-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 8h; (R) -3- (4-phenoxyphenyl)(Piperidin-3-yl) -1H-pyrazolo [3,4-D] pyrimidine-4-amine (193 mg, 0.5 mmol)2-bromoacrylic acid (88 mg, 0.58 mmol),1-hydroxybenzotriazole (HOBT) (95 mg, 0.7 mmol)And 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (134 mg, 0.7 mmol)Was dissolved in anhydrous DCM (10 ml)Diisopropylethylamine (DIEA) (271 mg, 2.1 mmol) was added,Stir at room temperature for 8 h.Add ethyl acetate diluted after washing,The aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate,Purification column chromatography gave Compound 1 (195 mg, yield 75%).
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