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[ CAS No. 503614-91-3 ] {[proInfo.proName]}

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Chemical Structure| 503614-91-3
Chemical Structure| 503614-91-3
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Product Details of [ 503614-91-3 ]

CAS No. :503614-91-3 MDL No. :MFCD18072444
Formula : C27H28N4O5 Boiling Point : -
Linear Structure Formula :- InChI Key :PULNLYVCJSOXKS-UHFFFAOYSA-N
M.W : 488.54 Pubchem ID :22240488
Synonyms :

Calculated chemistry of [ 503614-91-3 ]

Physicochemical Properties

Num. heavy atoms : 36
Num. arom. heavy atoms : 17
Fraction Csp3 : 0.33
Num. rotatable bonds : 7
Num. H-bond acceptors : 6.0
Num. H-bond donors : 0.0
Molar Refractivity : 140.69
TPSA : 93.97 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.74 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.45
Log Po/w (XLOGP3) : 3.58
Log Po/w (WLOGP) : 3.02
Log Po/w (MLOGP) : 2.84
Log Po/w (SILICOS-IT) : 3.13
Consensus Log Po/w : 3.4

Druglikeness

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

Water Solubility

Log S (ESOL) : -5.01
Solubility : 0.00475 mg/ml ; 0.00000973 mol/l
Class : Moderately soluble
Log S (Ali) : -5.24
Solubility : 0.00281 mg/ml ; 0.00000576 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -6.56
Solubility : 0.000136 mg/ml ; 0.000000278 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 3.81

Safety of [ 503614-91-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 503614-91-3 ]

* 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 [ 503614-91-3 ]

[ 503614-91-3 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 675-20-7 ]
  • [ 473927-64-9 ]
  • [ 503614-91-3 ]
YieldReaction ConditionsOperation in experiment
67% With potassium phosphate; N,N`-dimethylethylenediamine;copper(l) iodide; In toluene; for 48h;Inert atmosphere; Reflux; Example 5. Synthesis of a compound of formula (II): l-(4- methoxyphenyl)-6-[4-(2-oxo-piperidinyl)phenyl]-7-oxo-4,5,6,7-tetrahydro- l//-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl esterII IICompound II, prepared as in Example 4 (35.90 g, 69.40 mmol) is suspended in 250 ml of toluene in a 1L 4-necked flask equipped with coolant, thermometer and magnetic stirrer, in nitrogen atmosphere, delta-valerolactam (13.74 g, 138.60 mmol), K3PO4 (30.25 g, 142.50 mmol) and Cul (2.54 g, 13.34 mmol) are then added in sequence. The suspension obtained is degassed 3 times at room temperature; N,N'-dimethylethylenediamine (1.65 ml, 26.78 mmol) is then added and the mixture is heated to reflux temperature. After 48 h the end-of-reaction mixture is filtered through a Buchner funnel, and the filter is washed with 200 ml of toluene. The toluene phase is washed with a solution of Na2S2O3 (50 g in 160 ml of H2O, 2x80 ml), 15% NH3 (2x80 ml) and a saturated solution of NaCl (1x80 ml). The organic phase is anhydrified on (Na2SO4), filtered and evaporated under low pressure. A solid product is obtained (37 g), which is crystallised by AcOEt. After crystallisation the product is obtained as a pure white solid (22.7 g, yield 67%).1H NMR (300 MHz, DMSO-dtf): 67.47 (2H, dd, J0=8.7 Hz, Ar-H), 7.32 (2H, dd, Jo=9.0 Hz, Ar-H), 7.28 (2H, dd, J0=8.7 Hz, Ar-H), 6.90 (2H, dd, Jo=9.0 Hz, Ar-H), 4.32 (2H, q, J=6.9 Hz, COOCEbCH^, 4.06 (2H, t, J=6.6 Hz, CH2CH2N), 3.79 (3H, s, Ar-OCH3), 3.57 (2H, m, N(¾CH2CH2CH2CO) 3.19 (2H, t, J=6.6 Hz, ¾CH2N), 2.36 (2H, m, NCH2CH2CH2CH2CO), 1.83 (4H, m, NCH2CH2CH2CH2CO), 1.31 (3H, t, J=6.9 Hz, COOCH2CH3).
29% With potassium carbonate;copper(l) iodide; 1,10-Phenanthroline; In dimethyl sulfoxide; at 130℃; for 24h;Inert atmosphere; Step 6; Ethyl l-(4-methoxyphenyl)-7-oxo-6-r4-(2-oxo-l-piperidin-l-yl)phenyl)- 4.5.6.7-tetrahydro-lH-pyrazole-|"3.4-clpyridine-3-carboxylate:; A mixture of ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4, 5, 6, 7-tetrahydro-lH-pyrazolo [3,4c] pyridine-3-carboxylate (8.0 g, 15.47 mmol), delta-valerolactam (2.14 g, 21.61 mmol), potassium carbonate (2.52 g, 18.23 mmol) and dimethylsulfoxide (80 mL) was degassed with nitrogen for about 30 minutes. Cuprous iodide (0.530 g, 2.78 mmol) and 1,10-phenanthroline (0.150 g, catalytic) were then added to the mixture. The mixture was heated at about 130 0C for about 24 hours, cooled to ambient temperature, and water (150 mL) was added. Standard extractive work up with ethyl acetate provided a crude residue which was purified by silica gel column chromatography (4% methanol in chloroform) to give the title compound as an off- white solid (2.2 g, yield = 29%). mp: 150-153 0C; 1H NMR (400 MHz, CDCl3) delta 1.43 (t, J= 7.2 Hz, 3H), 1.92-1.94 (m, 4H), 2.50-2.60 (m, 2H), 3.31 (t, J= 6.4 Hz, 2H), 3.58-3.59 (m, 2H), 3.8 (s, 3H), 4.12 (t, J= 6.8 Hz, 2H), 4.46 (q, J= 6.6 Hz, 2H), 6.90 (d, J= 9.2 Hz, 2H), 7.25 (d, J= 9.6 Hz, 2H) 7.34 (d, J= 8.8 Hz, 2H), 7.47 (d, J= 8.8 Hz, 2H); IR (KBr) upsilon 3454, 2982, 2934, 2876, 1711, 1676, 1645, 1513, 1254, 1146, 1024, 838 cm"1; MS: 487 (M - 1).
28% With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 140℃; for 24h; Part A. A mixture of 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (5 g, 9.7 mmol), K2CO3 (1.5 g, 110 mmol), piperidine-2-one (1.2 g, 11.6 mmol), CuI (228 mg, 1.2 mmol), and DMSO (10 mL) was heated at 140 C. for 24 h. The solution was cooled to rt, diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and evaporated. Purification of the residue by column chromatography provided the corresponding aryl lactam (1.3 g, 28%): ESI MS m/z 489 (M+H)+.
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; at 110℃; for 6h;Inert atmosphere; Sealed tube; The preparation was carried out in an inert atmosphere (argon). Ethyl 6-(4-iodophenyl)-l-(4- methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (536 mg; 1.04 mmol) was dissolved in 5 ml of cyclopentyl methyl ether in a 10 ml sealable pressure container. Piperidin-2-one (128 mg; 1.30 mmol), Cul (10 mg; 0.052 mmol), K3PO4 (440 mg; 2,1 mmol) and N,N'-dimethylethylenediamine (37 mg; 0.42 mmol) were added. A stirrer was inserted in the container and it was closed under an inert atmosphere. Being stirred by a magnetic stirrer the mixture was heated up in an oil bath to 110 C for 6 h. After cooling the reaction mixture was diluted with a solvent, the solid salts were isolated by filtration and thoroughly washed on the filter. The filtrate was concentrated and the crude product was obtained in the yield of 84%.
40 g Example 7Preparation of ethyl 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1 -piperidinyl)phenyl]4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c]pyridine-3-carboxylatePiperidin-2-one (95.5 g) was added to toluene (2000 ml) and the mixture was heated to reflux while removing the collected water through Dean-Stark apparatus under nitrogen atmosphere. The reaction mass was cooled to room temperature and then stirred for 15 minutes under nitrogen atmosphere at the same temperature, followed by the addition of ethyl 6-(4-iodophenyl)- 1 -(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro- 1 F1-pyrazolo[3 ,4-cjpyridine-3-carboxylate (100 g). The resulting mixture was stirred for 15 minutes under nitrogen atmosphere, followed by the addition of potassium carbonate (28.5 g) and then stirring for 15 minutes under nitrogen atmosphere. Cuprous iodide (14.6 g) and 8- hydroxyquinoline (11.2 g) were added to the reaction mass and then heated to reflux under nitrogen atmosphere, followed by portion-wise addition of potassium carbonate (28.5 g x 3) for every 5 hours. After reaction completion, the reaction mass was filtered and thenwashed with toluene (200 ml x 2). The resulting filtrate was washed with 30% aqueous hypo solution (2 x 100 ml). Aqueous ammonia (100 ml) was added to the resulting toluene layer and then stirred for 3 hours at room temperature. The separated solid was filtered, washed with toluene (100 ml) and then dried the material at 70C for 5 hours to produce 40 g of ethyl 1 -(4-methoxyphenyl)-7-oxo-6- [4-(2-oxo- 1 -piperidinyl)phenyl]-4,5 ,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (Purity by HPLC: 99%; Melting range: 148.8C - 150C).

  • 2
  • [ 503614-91-3 ]
  • apixaban [ No CAS ]
YieldReaction ConditionsOperation in experiment
97.8% 4.88 g of Intermediate 1, 4.5 g of formamide, 0.14 g of tetrabutylammonium chloride, and 50 ml of dichloromethane were added to a 250 mL three-necked flask at room temperature, and stirred.The ice bath was cooled to 0 to 5 C, and 5.4 g of sodium methoxide was slowly added at this temperature range.After the completion of the dropwise addition, the temperature was maintained at 0 to 5 C for 30 minutes, and then the ice bath was naturally raised to 20 to 25 C for 4 hours, and the TLC monitoring intermediate 1 disappeared.100 ml of water was added to the synthesis solution, and the mixture was stirred for half an hour, and the reaction solution was allowed to stand for stratification.After separating the dichloromethane layer and concentrating the dichloromethane to dryness,The residue was dried in vacuo to give a pale yellow solid, 4.50 g.Yield: 97.8%, purity: 98.35%.
95.9% Under nitrogen protection,The compounds shown in room temperature I are shown below48.8 g (100 mmol)And aminoborane1.5 g (50 mmol)Add to the flaskDMFIn the premix15 min; then the phase transfer catalyst (mass ratio of 5: 1 composition of tetrabutylammonium iodide and polyethylene glycol)7.3g,Nano zinc oxide2.4g(Average particle diameter 50 nm)And ammonium sulfate19.8 g (150 mmol)Was added to the above-obtained mixture95 CStirring reaction3 hours.Cooled to room temperature, into the ice water,Dichloromethane, combined with methylene chloride and concentrated, washed three times, then ethanol recrystallization, drying apaxabine 44.1g, the yield was 95.9%, purity 99.73%.
95.1% With ammonia; In acetonitrile; at 120℃; under 2250.23 Torr; for 9h; Compound (2) (4.9 g) and 170 Ml of acetonitrile were successively added to a stainless steel autoclave, sealed, and ammonia was introduced.Gas, heated to 120 C, maintaining the pressure at 0.3MPa, reaction for 9 hours, the reaction was stopped. After the reactor is cooled to room temperature, it is turned on.After filtration, the filter cake was washed with ethanol and dried to give 4.37 g of a white solid mp 236-239 C., yield 95.10%, HPLC purity.97.85%
91.7% With ammonia; In ethanol; at 60℃; under 2250.23 Torr; for 8h;Autoclave; A solution of 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl 3) phenyl] -4,5,6,7-tetrahydro -1H-pyrazole [3,4-c] pyridine-3-carboxylate, 150 ml of ethanol was added successively to a stainless steel autoclave,Ammonia, heated to 60 C, keep the pressure at 0.3Mpa, react for 8 hours, stop the reaction, cool to room temperature, open the reactor, tooThe filter cake was washed with ethanol and dried to give 4.2 mg of apixabine in a yield of 91.7% and a purity of 98.41% (HPLC).
91.48% With ammonia; In methanol; at 65 - 70℃; for 24h;Autoclave; The Mixture of product of example-VIII (25 g, 0.051 mol) and Methanolic solution of ammonia (200 ml, 15-18%, w/w) were heated at 65-70 C. in a Autoclave for 24 hrs. The solvent was evaporated under low pressure and solid residue obtained was suspended in 175 ml water and left under stirring for 2 hr. solid filtered through Buchner funnel and washed with water (50 ml*2), dried in vacuum at 60 C. to afford the desired product. Yield: 21.5 g, 91.48%
91.3% Add DMF (25 mL) and formamide (5.80 g, 128 mmol) to start stirring.Add intermediate 1 (3.12g,6.4 mmol) The feed port was closed and the temperature was controlled at 50 C for 30 minutes.Trimethyl orthoformate (0.34 g, 3.2 mmol) and trifluoroacetic acid (0.15 g, 1.3 mmol) were added and stirred at 50 C for 1 hour.Add sodium methoxide-methanol solution (30 wt%, 2.10 g),The reaction was stirred at a temperature of 50 C for 3 hours.Purified water (5 mL) was added, and the dropping time was controlled for 15 minutes, and the temperature was controlled at 50 C for 1 hour.Purified water (25 mL) was added dropwise.The dropping time is controlled at 40 minutes.Cool down to 25 C, stir and crystallize for 9 hours, filter,The crude apixaban was dried to 2.54 g, and the molar yield was 86.4%.Example 3 Preparation of ApixabanAdd 20 mL of DMF to the reaction flask and start stirring.Add crude apixaban (2.54g, 5.5mmol) and the temperature rises toStir at 75 C for 30 minutes. The temperature was lowered to 25 C, stirred for 9 hours, filtered, and 25 mL of isopropanol was added to heat to 80 C.Stir for 7 hours. After the end of the stirring, the temperature was lowered to 25 C, stirred and decanted for 12 hours, filtered and dried to obtain apixaban.2.32 g, molar yield 91.3%.
90% With ammonia; In ethylene glycol; at 120℃; for 1h;Sealed tube; Ethyl 1-(4-memoxyphenyl)-7-oxo-6-[4-(2-oxol-piperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H- pyrazol-[3,4-c]pyridine-3-carboxylate (4.5 g; 9.2 mmol) was sealed in an ampoule with 40 ml of ethylene glycol containing 15% by weight of ammonia. The ampoule was placed in an oil bath and heated up to 120C for 1 h. After cooling the reaction mixture was poured to 50 ml of ethanol. The crystalline product was separated in the yield of 90%.
90% With sodium methylate; formamide; In N,N-dimethyl-formamide; at 40℃; for 6h; 5.0 g (10 mmol) of the compound of structure (VI) was dissolved in 100 mL of anhydrous DMF at 0 C, To this solution was added 4.0mL (100 mmol) of formamide, 0. 83 g (13 mmol) of sodium methoxide was added and the temperature was raised to 40 C for 6 h. The reaction was cooled to room temperature, poured into 100mL of water, precipitation of light brown solid, stirring 1h, filtration, drying,A piperazine classes were 4.1g crude, yield was 87%.The crude product of apixaban was added to 80 mL of ethanol-water (10: 1, v / v) mixed solvent at room temperature,After heating to reflux, the solid was completely dissolved, cooled to 0 C, standing 2h, suction filtration, drying, the white crystalline apixaban 3. 6g, 90% yield, purity 99. 8%
89.1% With ammonia; In methanol; at 80℃; for 5h; The 5 L reaction flask was charged with 242.3 g of 0.5 g (0.57 mol) of compound IX and 20% methanol in ammonia, The solution was heated to 80 C for 5 h, the reaction was complete by HPLC, the reaction was stopped, the system was cooled to room temperature and stirred for 2 h. The mixture was filtered and washed with a small amount of methanol and dried to obtain 234.4 g of albofaban (yield 89.1 %),
88.43% With ammonia; In methanol; chloroform; at 95 - 105℃; under 11251.1 - 15001.5 Torr; for 24h;Autoclave; 48. 8 g (0.1 mol) of compound 6 was added to 500 mL with magnetic stirring. In the high-pressure reaction tank,0 C _5 C73. 2 g of chloroform and 146. 4 g of a methanolic solution of ammonia (40% w / w)Close the reaction tank, heating to 95 C _105 C, pressure 1.5mPa-2. OmPa,The reaction was carried out for 24 hours,After cooling to 0-5 C,Atmospheric pressure, open cans,The reaction was terminated by TLC. TooFilter cake to 40mL methanol washing, drying,To 40. 59 g(88.43% yield) White crystals.
85% With sodium methylate; formamide; In N,N-dimethyl-formamide; at 0 - 30℃; Example-8 Preparation of Apixaban (0069) To a solution of 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-Pyrzolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (100 g) in N,N-dimethyl formamide (500 ml) was added formamide (92 g) under stirring at ambient temperature. The reaction mixture was cooled to 0-5 C., followed by addition of sodium methoxide solution (100 ml) at below 5 C. The reaction mass was stirred for 30 min at 0-5 C. and the temperature was raised to 25-30 C. and maintained for 3-4 hrs. After completion, the reaction mass was quenched with water (1000 ml) and stirred for 30 min. The resultant solid was filtered, washed with water (200 ml)/methyl tertiary butyl ether (200 ml) and dried at 40-50 C. for 10-12 hrs to obtain 75 g of the title compound (85%).
85% With sodium methylate; formamide; In N,N-dimethyl-formamide; at 0 - 30℃; To a solution of l-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-l-yl)-phenyl]-4, 5,6,7- tetrahydro-lH-Pyrzolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (100 g) in N,N-dimethyl formamide (500 ml) was added formamide (92 g) under stirring at ambient temperature. The reaction mixture was cooled to 0-5 C, followed by addition of sodium methoxide solution (100 ml) at below 5 C. The reaction mass was stirred for 30 min at 0-5 C and the temperature was raised to 25-30 C and maintained for 3-4 hrs. After completion, the reaction mass was quenched with water (1000 ml) and stirred for 30 min. The resultant solid was filtered, washed with water (200 ml) / methyl tertiary butyl ether (200 ml) and dried at 40-50 C for 10-12 hrs to obtain 75 g of the title compound (85%).
76% With ammonia; In methanol; at 45℃;Inert atmosphere; Example 6. Synthesis of compound of formula (I): l-(4- Methoxyphenyl)-6-[4-(2-oxo-piperidinyl)phenyl]-7-oxo-4,5,6,7-tetrahydro- l//-pyrazolo[3,4-c]pyridine-3-carboxyamide: Apixaban (I)The compound of formula II, prepared as in Example 5 (17.50 g, 35.82 mmol), is suspended in 100 ml of 33% NH3 and 200 ml of MeOH in a 1L 4-necked flask equipped with coolant, thermometer and magnetic stirrer, in nitrogen atmosphere, and heated to 45. MeOH (250 ml) is added until completely dissolved, and the solution is left under stirring for 2h. Another addition of 33% NH3 (50 ml) is performed, and the progress of the reaction is monitored by TLC (AcOEt/MeOH 9: 1) and HPLC. After 18h the solvent is evaporated under low pressure, and the solid residue obtained is suspended in 200 ml of H2O and left under stirring for 2h. The white solid is filtered through a Buchner funnel, and washed with H2O (50 ml). The product of formula (I) is stove-dried at 50C to a constant weight (12.60 g, yield 76%). The HPLC purity of the product exceeds 99%.1H NMR (300 MHz, CDC13): 67.47 (2H, dd, J0=8.7 Hz, Ar-H), 7.31(2H, dd, J0=8.7 Hz, Ar-H), 7.23 (2H, dd, J0=8.7 Hz, Ar-H), 6.93 (2H, dd, J0=8.7 Hz, Ar-H), 6.83 (1H, s, N-H), 5.53 (1H, s, N-H), 4.1 1 (2H, t, J=6.6 Hz, CH2CH2N), 3.81 (3H, s, Ar-OCH3), 3.59 (2H, m, NCH2CH2CH2CH2CO) 3.37 (2H, t, J=6.6 Hz, CH2CH2N), 2.55 (2H, m, NCH2CH2CH2CH2CO), 1.93 (4H, m, NCH2CH^CH2CH2CO).
76.2% With sodium methylate; formamide; In N,N-dimethyl-formamide; at 50℃; for 5h; General procedure: A mixture of CH3ONa (4.10 g, 0.075 mol), methanamide (15.8 g,0.35 mol), intermediates 11a-11f (0.05 mol) and DMF (100 mL) was stirred at 50 C for 4 h. After being cooled to rt, the reaction mixture was poured into ice-water. The precipitate was filtered and dried to afford products 12a-12f. 5.3.1.1. 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide(12a). White solid; Yield: 76.2%; Mp: 177.4-178.3 C; MS (ESI) m/z (%): 482.2 [M+Na]+.
76.2% With sodium methylate; formamide; In N,N-dimethyl-formamide; at 50℃; for 4h; A mixture of CH3ONa (4.1 g, 0.08 mol), formamide (15.8 g,0.35 mol) and intermediate 11 (24.4 g, 0.05 mol) in DMF(100 mL) was stirred at 50 C for 4 h. Upon cooling to room temperature(rt.), the reaction mixture was poured into ice-water(50 mL). The resulting precipitate was filtered, washed with H2O(20 mL) and dried under reduced pressure to afford product 12as a white solid (17.5 g, 76.2%). Mp: 177.4-178.3 C; MS (ESI) m/z(%): 482.2 [M+Na]+.
75% With ammonia; In ethylene glycol; at 115 - 120℃; for 1.5h;Autoclave; Example 3 Preparation of l-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7-tetrahydro- lH-pyrazolo [3,4-c] pyridine-3-carboxamide. Ethyl l-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7tetrahydro-lH- pyrazolo[3,4-c]pyridine-3-carboxylate (100 gm) is heated with Ethylene glycol-NH3 (5-6 % w/w) (1000 ml) in pressure reactor at 115-120C for 1.5 hrs. After the completion of reaction it is cooled to 35-40Cand the product is precipitated by addition of water (600 ml). The solid is filtered and dried. Yield 75%.
70.6% With ammonia; In methanol; for 4h;Sealed tube; Reflux; Compound VIII (1 g, 2 mmol) was added to the reaction vessel,40mL 10% NH3.MeOH solution was added,Sealed reactor,Warmed to reflux for 4h.The reaction solution was cooled to room temperature,The reaction solvent was evaporated under reduced pressure,An off-white solid 0.9g,36mL (methanol: water = 4: 1) mixed solution was recrystallized,Placed in the refrigerator freezer,Filtered by suction to give a white solid 0.65g, m.p 169-171 C, yield 70.6%.
70.3% With sodium methylate; formamide; In methanol; N,N-dimethyl-formamide; at 0 - 20℃; for 5h;Green chemistry; 9.52 g of apixaban intermediate V was dissolved in 95 mL of N,N-dimethylformamide,Add 9.5 mL of formamide and add the mass percentage at 0 C to 5 C.A 20% solution of 30% sodium methoxide in methanol (the mass percentage refers to the percentage of the mass of sodium methoxide to the total mass of the methanol solution of sodium methoxide) is stirred at 15 C. to 20 C. for 4 hours.190 mL of water was added, and the mixture was stirred at 15 C. to 20 C. for 1 hour, filtered and washed with methyl tert-butyl ether.After drying, 24 mL of N,N-dimethylformamide was added, and the mixture was heated to 75 C. After dissolution, 96 mL of methyl tert-butyl ether was slowly added, and the temperature was lowered to 5 C. to 10 C. and stirred for 1 hour.The mixture was filtered, washed with methyl tert-butyl ether, dried and dried under vacuum at -0.01 MPa to -0.1 MPa and 45C to 55C for 8 to 12 hours to obtain 6.29 g of apixaban III in a yield of 70.3%. The HPLC purity was 99.91% and the maximum single impurity was 0.056%.
68% With ammonia; In ethylene glycol; at 120℃; for 4h;Sealed tube; Part F. To ester from Part E (4.8 g, 0.009 mol) was added 5% NH3 in ethylene glycol (40 mL) and the mixture was heated to 120 C. for 4 h in sealed vessel. Water was added and the resulting solid was collected. Purification by silica gel chromatography using 0-10% MeOH/CH2Cl2 as eluent afforded 3.5 g of a white solid. A portion of the solid was recrystallized from CH2Cl2/EtOAc to afford 2.5 g of the title compound. The remaining solid and filtrate material was recrystallized from isopropyl alcohol to afford an additional 0.57 g for a total of 3.07 g (68%): 1H NMR (CDCl3) delta 7.49 (d,j=8.8 Hz, 2H), 7.37 (d,j=9.1 Hz, 2H), 7.26 (d,j=8.8 Hz, 2H), 6.98 (s, 1H) 6.95 (d,j=9.2 Hz, 2H), 6.28 (s, 1H), 4.14 (t,j=6.6 Hz, 2H), 3.81 (s, 3H), 3.61 (m, 2H), 3.39 (t,j=6.6 Hz, 2H), 2.63 (t,j=6.2 Hz, 2H), 1.96 (m, 4H) ppm.
61% With ammonium hydroxide; In methanol; at 80 - 90℃; for 10h;Autoclave; Intermediate-E (35g, 0.0716 moles) is suspended in 30 % aq. ammonia solution. Mixture was heated to 80-90C in an autoclave. Aqueous ammonia develops in- build pressure ofl-2 kg. Progress of the reaction is monitored on TLC/HPLC. When reaction was completed in -l0 hrs, reaction mass is cooled to RT and diluted with water. Product is filter and washed with water, dried at 60-65 c to obtain crude apixaban 23-25 gm with HPLC purity 98.5%. This crude product contains acid impurity approx-1.0-l.5%. Crude apixaban is further dissolved in MDC and washed with 2.0-5.0% bicarbonate solution. MDC layer is then concentrated under reduced pressure and crystallize using mixture of solvents methanol water to obtain pure apixaban with l-IPLC purity >99% (yield 6 1%).
27.65% With ammonia; In ethylene glycol; at 120℃; for 7h;sealed tube; l-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxo-l-piperidinyl)phenyl)-4.5.6.7- tetrahydro-lH-pyrazole-r3,4-clpyridine-3-carboxamide:; In a sealed tube, a mixture of ethyl l-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxo-l-piperidin-l-yl) phenyl)-4,5,6,7- tetrahydro-lH-pyrazole-[3,4-c]pyridine-3-carboxylate (0.50 g, 1.024 mmol), 5% ammonia in ethylene glycol (2 mL) was heated at about 120 0C for about 7 hours. The mixture was cooled and diluted with water (50 mL). The resulting precipitant was collected by filtration and dried in vacuo. The resulting residue was purified by preparative EtaPLC on a KROMASIL 100 C-18 (30x250mm) column (0.01M ammonium acetate/ methanol (1: 1); flow rate 20 mL / min; T / %B: 0 / 30, 10 / 80, 20 / 80, 20.1 / 30; UV: 210 nm). The title compound was purified as an off-white solid (0.130 g, yield = 27.65%). mp: 145-149 0C; 1H NMR (400 MHz, CDCl3) delta 1.92-1.94 (m, 4H), 2.55-2.56 (m, 2H), 3.37 (t, J=I. Q, 2H), 3.58-3.59 (m, 2H), 3.82 (s, 3H), 4.12 (t, J= 6.6 Hz, 2H), 5.47 (br s, IH), 6.84 ( br s, IH), 6.93 (d, J= 8.8 Hz, 2H), 7.25 (d, J= 8.0 Hz, 2H) , 7.34 (d, J= 8.4, 2H), 7.47 (d, J= 8.8 Hz, 2H); IR (KBr) upsilon 3453, 3305, 3251, 3178, 3052, 2947, 2859, 1673, 1609, 1512, 1459, 1400, 1330, 1297, 1250, 1151, 1107, 1022, 986 cm"1; MS 460 (M + 1).
With ammonia; In propylene glycol; at 100℃;Sealed tube; Ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl-4, 5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate (1 g) and a solution of 5% NH3 in propylene glycol (8 mL, 11 equiv.) were added to a 25 mL head space vial equipped with a magnetic stirrer. The vial was sealed, heated to 100C and stirred overnight. A white slurry was obtained and the reaction mixture subsequently became clear. The reaction mixture was then cooled to room temperature. A solid precipitated and was separated by filtration, washed with ethanol (10 vol.) and dried overnight in a vacuum oven at 40C. The resulting product was analyzed by XRPD to give a pattern of Apixaban crystalline Form I.
28 mg With sodium methylate; formamide; In dimethyl sulfoxide; at 0 - 30℃; for 2.5h; A solution of 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7- tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (35 gm,0.072 mmol) in dimethyl sulphoxide (175ml) and formamide (32.26 gm,0.72 mmol) was cooled to 0-5C and sodium methoxide solution (31 gm) was added drop wise at 0-5C and stirred for 30 min . The temperature of the reaction mass was raised to 25-30C and stirred for 2hrs. After completion of reaction, water was added to the reaction mass and stirred for 1 hr. The precipitated solid was filtered and washed with water and methyl tert-butyl ether. The wet cake was dissolved in a mixture of methylene di chloride and methanol (7:3) (900ml) and washed with 5% aq. NaOH solution. The organic layer was washed with water and concentrated under vacuum. The obtained solid was taken in acetone and stirred for 1 hr. The solids were filtered and washed with acetone. The solid material was dried under vacuum at about 45-50C for 12hrs to afford 28gm of apixaban (HPLC purity>99%)
With ammonia; In methanol; at 45℃; under 6000.6 Torr;Autoclave; Ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4, 5,6,7- tetrahydro-1H- pyrazolo[3,4-c]pyridine-3-carboxylate and methanol (1500 ml) were added to a autoclave vessel, and the vessel was flushed with nitrogen. After feeding anhydrous ammonia gas (8.0 kg/cm 99.99%), the reaction mass temperature was raised to 45 C and stirred. After completion of the reaction, the ammonia was vented to a scrubber. Thereafter, the reaction mass was cooled to 35 C and concentrated under reduced pressure to dryness. Methylene dichloride (2000 ml) and ethyl acetate (2000 ml) were added to the concentrated mas and the contents were heated to 50 C. The resulting mixture was cooled to 25-35 C and filtered to afford 1-(4-methoxy-phenyl)-7-oxo-6-(4-(2-oxopiperidin-1- yl)phenyl)- 4,5,6,7-tetrahydro-1H-pyrazolo-[3,4-c]pyridine-3-carboxamide. (0113) The obtained solid was recrystallized in a mixture of methanol (800 ml) and water (2400 ml) to produce apixaban.
65 g With ammonia; In ethylene glycol; at 120℃; for 2h;Autoclave; Example 8Preparation of Apixaban Ethyl 1 -(4-methoxyphenyl)-7-oxo-6- [4-(2-oxo- 1 -piperidinyl)phenyl] -4,5 ,6,7-tetrahydro-1H-pyrazolo[3,4-c)pyridine-3-carboxylate (100 g) and 5% ammonia solution in ethylene glycol (1000 ml) were taken into an autoclave at room temperature and the mixture was heated to 120C, followed by stirring for 2 hours. After reaction completion, the reaction mass was cooled to room temperature, followed by the addition of water (3000 ml) andthen stirring for 1 hour. The separated solid was filtered, washed with water (200 ml) and then dried the material at 60C for 4 hours to produce 65 g of Apixaban.
With sodium methylate; formamide; In isopropyl alcohol; at 65 - 70℃; for 2h; Example-11 Preparation of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo piperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Formula-1) A mixture of ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate compound of formula-11 (50 g), formamide (150 ml), sodium methoxide (30 ml) and isopropanol (300 ml) was heated to 65-70 C. and stirred for 2 hours at 65-70 C. Cooled the reaction mixture to 0-5 C. and stirred for 30 minutes at 0-5 C. Filtered the precipitated solid and washed with isopropanol. Methanol (150 ml) was added to the obtained solid, the reaction mixture was heated to 65-70 C. and stirred for 15 minutes at 65-70 C. Cooled the reaction mixture to 0-5 C. and stirred for 30 minutes at 0-5 C. Filtered the precipitated solid, washed with methanol and then dried to get title compound. Yield: 35 g. MR: 230-235 C.; HPLC purity: 98%. The PXRD of the crystalline solid obtained from the above example is matches with the PXRD of crystalline form-M of the present invention.
Methanol (12.75 dm3) and 255 g 2 (0.522 mol) were charged into a 20 dm3 four-necked round-bottomed flask,equipped with a KOH guard tube, a mechanical stirrer, anda gas inlet tube. The reaction mass was stirred at RT for 10 min, diluted with 2.55 dm3 dichloromethane, and then stirred again for 10 min at RT. There after, ammonia gaswas bubbled for 5 h into the resulting mixture which was maintained at 0-5 C during this period. The reaction wasthen allowed to stir at RT for 72 h and concentrated underreduced pressure at <45 C upon completion. The crudematerial obtained was stirred with 1.275 dm3 methanol for15 min at 65 C; the mixture was then cooled to RT andstirred for 30 min. The separated product was filtered,washed with 510 cm3 methanol, and finally dried at 60 Cfor 8 h to obtain 1 (190 g, 79%, 99.5% purity by HPLCanalysis) as an off-white solid. 1H NMR spectral data of 1(see Supplementary Material for details) were found to beconsistent with the values reported in Ref. [8].
56 g In propylene glycol; at 80 - 85℃; under 3000.3 Torr; for 6h; In an autoclave inerted by nitrogen Apixaban ethyl ester (65 g, 1.0eq) and propylene glycol (1,2-propan diol, 455 mL) were charged and the vessel was pressurized with ammonia at p=4bar and T=80/85 C. for 6 h. The mixture was then transferred in a round bottom flask washing the autoclave with propylene glycol (65 mL), heated to dissolution and diluted with water (130 mL). After stirring at T=95/100 C. for additional 2 h, more water was added (390 mL) and the solution was seeded with Apixaban N-1 form. The suspension was stirred for 2 h at T=95/100 C., cooled to room temperature and diluted with ethanol (130 mL). After 3 h stirring at T=20/25 C. the slurry was filtered and the wet cake was washed with water (2×130 mL). The solid was dried under vacuum at T=65 C. for 8 h affording Apixaban N-1 form (56.0 g, 0.917eq). m.p. 237 C. 1H-NMR (400 MHz, DMSO-d6, ppm), delta: 7.74 (s, 1H), 7.53 (d, J=12Hz, 2H), 7.47 (s, 1H), 7.37 (d, J=8Hz, 2H), 7.30 (d, J=12Hz, 2H), 7.02 (d, J=8Hz, 2H), 4.07 (t, J=8Hz, 2H), 3.82 (s, 3H), 3.61 (t, J=4Hz, 2H), 3.23 (t, J=8Hz, 2H), 2.41 (t, J=4Hz, 2H), 1.87 (m, 4H). 13C-NMR and DEPT 135 NMR (100 MHz, DMSO-d6, ppm), delta: 169.3 (C), 163.7 (C), 159.6 (C), 157.1 (C), 142.0 (C), 141.9 (C), 140.3 (C), 133.5 (C), 133.1 (C), 127.3 (C), 126.8 (CH), 126.5 (CH), 125.7 (CH), 113.9 (CH), 56.0 (CH3), 51.3 (CH2), 33.1 (CH2), 23.5 (CH2), 21.5 (CH2), 21.4 (CH2). ESI-MS m/z=460 ([M+H]+). KF=0.08%.

Reference: [1]Patent: CN107936015,2018,A .Location in patent: Paragraph 0007; 0011; 0039-0040; 0046-0047; 0053-0054; 0060
[2]Patent: CN106117201,2016,A .Location in patent: Paragraph 00312; 0032; 0033; 0034; 0035; 0036; 0037-0060
[3]Patent: CN104628724,2017,B .Location in patent: Paragraph 0029; 0030; 0033; 0034; 0037; 0038; 0041; 0042
[4]Synthetic Communications,2013,vol. 43,p. 72 - 79
[5]Patent: CN106117200,2016,A .Location in patent: Paragraph 0028; 0046; 0047; 0048
[6]Patent: US2017/15663,2017,A1 .Location in patent: Paragraph 0149
[7]Patent: CN109627242,2019,A .Location in patent: Paragraph 0035-0038; 0041-0044
[8]Patent: WO2014/75648,2014,A1 .Location in patent: Page/Page column 15
[9]Patent: CN105254630,2016,A .Location in patent: Paragraph 0061; 0062; 0063
[10]Patent: CN104892601,2017,B .Location in patent: Paragraph 0020; 0050-0051
[11]Patent: CN103694237,2016,B .Location in patent: Paragraph 0120-0122
[12]Patent: US2017/313695,2017,A1 .Location in patent: Paragraph 0069
[13]Patent: WO2017/187245,2017,A1 .Location in patent: Page/Page column 14
[14]Journal of Medicinal Chemistry,2007,vol. 50,p. 5339 - 5356
[15]Patent: WO2012/168364,2012,A1 .Location in patent: Page/Page column 19-20
[16]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5646 - 5661
[17]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810
[18]Patent: WO2014/72884,2014,A1 .Location in patent: Page/Page column 11
[19]Patent: CN107400131,2017,A .Location in patent: Paragraph 0031; 0057-0059
[20]Patent: CN107955002,2018,A .Location in patent: Paragraph 0114; 0117
[21]Patent: US2017/50964,2017,A1 .Location in patent: Paragraph 0751
[22]Patent: WO2015/111073,2015,A3 .Location in patent: Page/Page column 13
[23]Patent: WO2010/30983,2010,A2 .Location in patent: Page/Page column 32
[24]Patent: WO2013/119328,2013,A1 .Location in patent: Paragraph 0050
[25]Patent: WO2014/111954,2014,A1 .Location in patent: Paragraph 0135
[26]Patent: WO2015/162551,2015,A1 .Location in patent: Page/Page column 16-17
[27]Patent: WO2015/177801,2015,A1 .Location in patent: Page/Page column 27
[28]Patent: WO2016/20711,2016,A1
[29]Patent: WO2016/20711,2016,A1
[30]Patent: US2015/353541,2015,A1 .Location in patent: Paragraph 0135
[31]Patent: CN103896940,2016,B
[32]Patent: WO2017/13079,2017,A1 .Location in patent: Paragraph 00188
[33]Patent: CN104045637,2016,B
[34]Monatshefte fur Chemie,2017,vol. 148,p. 1477 - 1482
[35]Patent: US2016/326171,2016,A1 .Location in patent: Paragraph 0183; 0184
[36]Patent: US2016/326171,2016,A1
[37]Patent: US2016/326171,2016,A1
[38]Patent: US2016/326171,2016,A1
  • 3
  • [ 503614-91-3 ]
  • [ 75-24-1 ]
  • [ 109-81-9 ]
  • [ 503612-86-0 ]
YieldReaction ConditionsOperation in experiment
120 mg (11%) In n-heptane; ethyl acetate; toluene; Example 103 1-(4-Methoxy-phenyl)-3-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one To N-methylethylene diamine (0.47 mL, 5 mmol) in toluene (25 mL) at 0 C. was added 2M trimethylaluminum in heptane (2.7 mL, 5 mmol) and, after stirring for 20 min, <strong>[503614-91-3]1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester</strong> (0.88 g,1.8 mmol) was added and the reaction was heated to 100 C. for 24 h. The reaction was quenched with water and MeOH, dried (Na2SO4), filtered, and concentrated. The residue was suspended in EtOAc and filtered. Purification by HPLC and freeze-drying afforded 120 mg (11%) of a white solid; Mass Spec (M+H)+499.3.
  • 4
  • chloro((4-methoxyphenyl)hydrazono]acetic acid ethyl ester [ No CAS ]
  • [ 545445-44-1 ]
  • [ 503614-91-3 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; triethylamine; In ethyl acetate; Example 55 1-(4-Methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (65). A solution of chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (34, 470 mg, 1.3 mmol) in EtOAc (4 mL) was treated with 3-morpholin-4-yl-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-5,6-dihydro-1H-pyridin-2-one (63, 334 mg, 1.3 mmol, 1.0 equiv) at 0-5 C. under N2, and the resulting reaction mixture was treated with triethylamine (TEA, 263 mg, 0.33 mL, 2.6 mmol, 2.0 equiv) at 0-5 C. under N2. The reaction mixture was then warmed up to room temperature for 30 min before being warmed up to reflux for an additional 6 h. When HPLC and TLC showed that the reaction was complete, the reaction mixture was cooled down to 5-10 C. before being treated dropwise with a 4.0 N aqueous HCl solution (1.7 mL, 6.5 mmol, 5.0 equiv) at 0-5 C. The resulting mixture was stirred at 5-20 C. for 4 h. The resulting slurry was then treated with water (10 mL) and EtOAc (10 mL) before the two layers were separated. The aqueous layer was extracted with EtOAc (2*10 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was directly purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (65, 423 mg, 635 mg theoretical, 67% for two steps) as pale-yellow solids, which solidified upon standing in vacuo at room temperature. For 65, CIMS m/z 489 (M++H, C27H28N4O5).
  • 5
  • [ 503614-91-3 ]
  • [ 503612-88-2 ]
YieldReaction ConditionsOperation in experiment
30 mg (58%) With lithium borohydride; phosphorus tribromide; In tetrahydrofuran; dichloromethane; acetic acid; Example 105 1-(4-Methoxy-phenyl)-3-methyl-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one To <strong>[503614-91-3]1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester</strong> (0.59 g,1.2 mmol) in THF (25 mL) was added 2M LiBH4 in THF(0.96 mL,1.9 mmol) and the reaction was heated to reflux for 2.5 h. To the crude alcohol were added CH2Cl2 (25 mL) and PBr3 (0.14 mL) and the reaction was stirred 24 h. Extraction with CHCl3, washing with water, and drying (Na2SO4) afforded a crude bromo-compound. The bromo-compound was heated in AcOH (15 mL) and activated Zn (0.39 g, 6 mmol) at 120 C. for 24 h. Purification by HPLC and freeze-drying afforded 30 mg (58%) of a white solid; High Resolution Mass Spec (M+H)+for C25H27N4O3 431.2092.
  • 6
  • [ 503614-91-3 ]
  • [ 503612-90-6 ]
YieldReaction ConditionsOperation in experiment
47 mg (48%) With MeMgBr; In tetrahydrofuran; Example 107 3-(1-Hydroxy-1-methyl-ethyl)-1-(4-methoxy-phenyl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-one To <strong>[503614-91-3]1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester</strong> (0.1, 0.2 mmol) in THF (15 mL) at 0 C. was added MeMgBr (0.21 mL,0.6 mmol) and the reaction was stirred at rt for 24 h. The reaction was quenched with water and purified by HPLC to afford 47 mg (48%) of a white solid; Mass Spec (M+H)+475.
  • 7
  • [ 503614-91-3 ]
  • [ 124-41-4 ]
  • [ 1074365-84-6 ]
  • 9
  • 5-chloropentanoic acid [4-(5-morpholin-4-yl-6-oxo-3,6-dihydro-2H-pyridin-1-yl)phenyl]amide [ No CAS ]
  • [ 503614-91-3 ]
  • 10
  • [ 545445-44-1 ]
  • [ 473927-63-8 ]
  • [ 503614-91-3 ]
YieldReaction ConditionsOperation in experiment
85% With triethylamine; potassium iodide; In dichloromethane; at 42 - 45℃; Product of example-VA (14.2 g, 0.04 mol), TEA (17 mL, 0.12 mol), and KI (0.64 g, 0.004 mol) were added to a solution of the product of example-VI (11.3 g, 0.044 mol) in MDC (80 mL) at room temperature. The mixture was stirred at 42-45 C. for 12-15 hrs and then cooled to 0 C. To the resulting mixture was added 4.0N hydrochloric acid (50 mL, 0.02 mol) drop wise and stirred at room temperature for 2-4 hrs. Thereafter water (100 mL) was added to the mixture to separate the organic layer. The aqueous layer was extracted with MDC, 50 mL and then the combined organic extracts were washed with brine (2*100 mL), and concentrated to dryness. Recrystallization of the residue from EtOAc and drying in vacuum afforded product as cream colored solid. Yield: 16.58 g, 85%. Purity: 99.5+%
35 g Example-10 Preparation of ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (Formula-11) A mixture of 3-morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one compound of formula-8 (30 g), sodium carbonate (26.83 g) and acetone (150 ml) was heated to 45-50 C. (Z)-ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate compound of formula-9 (32.5 g) was added to the reaction mixture at 45-50 C. and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 25-30 C. and aqueous hydrochloric acid (50 ml) in 50 ml of water was added to it at 25-30 C. Stirred the reaction mixture for 2 hours at 25-30 C. Water was slowly added to the reaction mixture and stirred for 45 minutes at 25-30 C. Filtered the obtained solid and washed with water. The obtained solid was recrystallized from toluene (150 ml) to get the title compound. Yield: 35 gm; MR: 155-160 C.; HPLC purity: 97%.
  • 16
  • C11H11ClN2O3 [ No CAS ]
  • [ 503614-91-3 ]
  • 19
  • [ 1415831-80-9 ]
  • [ 503614-91-3 ]
  • 20
  • [ 1415831-82-1 ]
  • [ 503614-91-3 ]
  • 21
  • [ 881386-12-5 ]
  • [ 503614-91-3 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; ethanol;Inert atmosphere; Alkaline conditions; Dry tetrahydrofuran (THF) (5 L) was loaded to the reactor followed by Ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(5-bromovaleroylamino)phenyl]-4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridine-3-carboxylate. The wall of the vessel was washed with additional THF (1 L). The reactor was purged with nitrogen. Ethoxide solution in ethanol was slowly added using cannula during 30 min. Reaction temperature did not exceed 25 C. Reaction was monitored with HPLC. Additional amount of reagent was added if needed. Reaction was quenched with glacial acetic acid (12 mL), water (24 L) was added Off-white solid separated, mixture was agitated for additional 12 hrs. Solids were filtered off using nutsche filter, washed with water (5 L) and pre-dried using infra red - drier. Crude product was dissolved in refluxing 2-butanone (8.7 mL per gram of the starting compound), resulting solution was cooled to 55 C, methyl tert-butyl ether (MTBE) (4.35 mL per gram of the starting compound was added and resulting mixture was cooled to room temperature. Separated solids were filtered off, washed with MTBE and dried in vacuo to give 550 g (64 %) off-white solid. Second crop was obtained by processing of the mother liquor
  • 22
  • [ 1609409-54-2 ]
  • [ 503614-91-3 ]
  • 23
  • 4-methoxyphenylhydrazine hydrochloric acid salt [ No CAS ]
  • [ 1609409-53-1 ]
  • [ 503614-91-3 ]
YieldReaction ConditionsOperation in experiment
90% In water; isopropyl alcohol; at 50 - 55℃; Example 2 Preparation of Ethyl l-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-l-yl)phenyl)-4,5,6,7- tetrahydro-lH-pyrazolo [3,4-c] pyridine-3-carboxylate. Ethyl {5 -hydroxy-6-oxo- 1 - [4-(2-oxopiperidin- 1 -yl)phenyl] - 1 ,2,3 ,6-tetrahydropyridin-4- yl}(oxo)acetate (100 gm) is stirred with 4-Methoxy phenyl hydrazine hydrochloride (49.72 gm) in aqueous Isopropyl alcohol (2000ml) at 50-55C for 1 hr. After the reaction completion Isopropyl alcohol is distilled completely and the product is crystallized from mixture of Ethyl acetate and ethanol (1300 ml). The solid is filtered and dried. Yield 90%
  • 25
  • [ 675-20-7 ]
  • [ 473927-64-9 ]
  • [ 503614-91-3 ]
  • [ 503614-92-4 ]
YieldReaction ConditionsOperation in experiment
36%; 30.3% With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In N,N-dimethyl-formamide; at 90℃; for 20h;Inert atmosphere; Sealed tube; The preparation was carried out in an inert atmosphere (argon). Ethyl 6-(4-iodophenyl)-1-(4- methoxyphenyl)-7-oxo-4,5,6,7-tetrahycho-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (0.538 g; 1.04 mmol) was dissolved in 1 ml of DMF in a sealable pressure container fitted with a magnetic stirrer; piperidin-2-one (0.15 g; 1.5 mmol), Cul (18.4 mg; 0.096 mmol), K3PO4 (0.457 g; 2.15 mmol) and N,N'-dimemylethylenediamine (15 mu; 0.136 mmol) were added. Being intensively stirred, the mixture was heated in an oil bath to 90C for 20 hours. The conversion was monitored with HPLC. After the above mentioned period the reaction mixture contained 36% of the product 30.3% of the acid V and 2.5% of the starting compound. After cooling the reaction mixture was diluted with water and the product was extracted with ethyl acetate. After concentration the product was obtained in the yield of 0.237 g, i.e. 48.6%, with the HPLC content of the desired substance of 68%.
  • 27
  • [ 545445-44-1 ]
  • [ 27143-07-3 ]
  • [ 503614-91-3 ]
YieldReaction ConditionsOperation in experiment
89.9% With triethylamine; potassium iodide; In ethyl acetate; for 24h;Reflux; (14 mmol) of the compound of the formula (IV) and 4. 0 g (16 mmol)The compound of structure (V) was added to 150 mL of ethyl acetate,0.35 g (2 mmol) of KI, 6.8 ml (49 mmol) of triethylamine was added and refluxed for 24 h, Cooled to 0C degrees, dropping 4M dilute hydrochloric acid 20mL, stirring at room temperature 2h, filtration, a small amount of cold ethyl acetate washing, water hit the public, about 50 C blast drying,To obtain crude product 6. 5g, yield 94. 6%, and then recrystallized from ethyl acetate, To obtain 5.8 g of a solid, powdery product,The yield was 89% and the purity was 99.8%.
76% With triethylamine; In ethyl acetate; toluene; at 85℃; for 7h; Toluene (25 mL) was added to the reaction flask.Triethylamine (2.60 g, 25.7 mmol) and ethyl acetate (25 mL),Starting material A (2.80 g, 10.9 mmol) and starting material B (3.00 g, 8.4 mmol),The temperature was raised to 85 ° C by heating and stirred for 7 hours.The reaction solution was cooled to 25 °C. Adding a hydrochloric acid solution to the reaction solution,The dropping time is controlled at 25 minutes and the temperature is controlled at 30 °C.After the dropwise addition was completed, the reaction was stirred at 30 ° C for 1 hour.15 mL of purified water was added and stirred for 30 minutes. Filter the filter cake,Add 20 mL of isopropanol for washing.Drying apixaban intermediate 1 13.12g,The molar yield was 76.0percent.
54 mg With triethylamine; potassium iodide; In ethyl acetate; at 25 - 80℃; for 24h; In 3 lit four neck equipped round bottomed flask (RBF) equipped, ethyl acetate (2.5L), 3- morpholino-l-[4-(2-oxopiperidin-l-yl)phenyl]-5,6-dihydropyridin-2(1H)-one (50gm,), acetic acid 2-chloro-2-[-(4-methoxyphenyl)hydrazinylidene]ethyl ester (36.1 gm) , ethyl amine (57 gm) and potassium iodide (2.4 gm) were added sequentially at about 25-30C . The reaction mass was heated to about 75-80C for about 24 hrs. After completion, the reaction mass was cooled to about 0 - 5C and dilute hydrochloric acid was added slowly to the reaction mass at about 0- 5C. The temperature of the reaction mass was raised to about 25-30C and stirred for 2 hrs. Water was added to the reaction mass and stirred for 15 min. The layers were separated and the organic layer was washed with aq. sodium carbonate solution followed by water. The organic layer was partially concentrated under vacuum and cooled to about 25-30C. Isopropyl ether was added to the reaction mass and stirred for 1 hr. The precipitated solid was filtered and washed with isopropyl ether. The solid was dried under vacuum at 45-50C for 12hrs to afford 54 gm of 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H- pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (HPLC purity>99%)
The compound of formula (VIII) was prepared according to the method disclosed in the Journal Synthetic Communication, 2013, vol. 43, pag. 72-79, in particular, the paragraph entitled "Ethyl 1 -(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (2)" at pag.78, starting from the compound of formula (IX) prepared according to the example 2.

  • 28
  • 1-(4-aminophenyl)-5,6-dihydro-3-(4-methylpiperazine-1-yl)pyridin-2(1H)-one [ No CAS ]
  • [ 503614-91-3 ]
  • 29
  • 5,6-dihydro-3-(4-methylpiperazin-1-yl)-1-(4-(2-oxopiperidin-1-yl)phenyl)pyridine-2(1H)-one [ No CAS ]
  • [ 503614-91-3 ]
  • 31
  • C32H40N6O5 [ No CAS ]
  • [ 503614-91-3 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; at 25 - 35℃; 5,6-dihydro-3-(4-methylpiperazin-1-yl)-1-(4-(2-oxopiperidin-1-yl)phenyl)pyridin- 2(1H)-one (100 g, 0.27 moles), triethylamine (82.4 g, 0.81 moles), and potassium iodide (4.4 g, 0.026 moles) were added sequentially to a solution of (Z)-ethyl 2-chloro-2-(2-(4- methoxyphenyl)hydrazono acetate (83.6 g, 0.33 moles) in ethyl acetate (2000 ml) at 25-35 C. The reaction mass temperature was raised to reflux. After completion of the reaction, mass was cooled to 0-5 C and 6.0 N hydrochloric acid (180 ml) was added slowly. Stirring of reaction mass was continued at 25-35 C. After completion of the reaction, the organic phase was separated and the aqueous phase was extracted with ethyl acetate (300 ml). The combined organic phase were washed with water (500 ml) followed by a saturated sodium chloride solution (500 ml). The organic layer was concentrated under vacuum and crystalized with ethanol to afford ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)- 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-carboxylate.
  • 33
  • 5,6-dihydro-3-(4-methylpiperazine-1-yl)-1-(4-nitrophenyl)pyridin-2(1H)-one [ No CAS ]
  • [ 503614-91-3 ]
  • 35
  • 3-chloro-5,6-dihydro-1-(4-iodophenyl)-piperidin-2-one [ No CAS ]
  • [ 503614-91-3 ]
  • 40
  • 5-bromo-N-[4-(3,3-dichloro-2-oxopiperidin-1-yl)phenyl]valeroyl amide [ No CAS ]
  • [ 503614-91-3 ]
  • 41
  • 3,3-dichloro-1-[4-(2-oxopiperidin-1-yl)phenyl]piperidin-2-one [ No CAS ]
  • [ 503614-91-3 ]
  • 42
  • chloro((4-methoxyphenyl)hydrazono]acetic acid ethyl ester [ No CAS ]
  • 3-chloro-1-[4-(2-oxopiperidin-1-yl)phenyl]-5,6-dihydropyridin-2(1H)-one [ No CAS ]
  • [ 503614-91-3 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In butan-1-ol; at 70℃;Inert atmosphere; 14.56 g (47.8 mmol) of the substance of formula 12 obtained in the example 7 is suspended in 1- butanol under argon atmosphere, then 17.10 g (66.6 mmol) of ethyl-(2£')-chloro[(4- methoxyphenyl)hydrazono] acetate of formula obtained of formula 3a is added. The mixture is heated above 70 C internal temperature with continuous stirring, then 37.0 mL (27.0 g, 267 mmol) triethylamine mixed in with 1-butanol is added. To the obtained solution 8.3 g (208 mmol) of sodium hydroxide in aqueous solution is added dropwise. The solution is filtered and then stirred at a temperature above 50 C for two hours. The suspension is cooled, filtered, washed on the filter and dried. 22.6 g of material containing a small amount of sodium chloride is obtained.
  • 43
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid sodium salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
22.6 g With sodium hydroxide; In water; butan-1-ol; at 50℃; for 2h; 14.56 g (47.8 mmol) of the substance of formula 12 obtained in the example 7 is suspended in 1- butanol under argon atmosphere, then 17.10 g (66.6 mmol) of ethyl-(2£')-chloro[(4- methoxyphenyl)hydrazono] acetate of formula obtained of formula 3a is added. The mixture is heated above 70 C internal temperature with continuous stirring, then 37.0 mL (27.0 g, 267 mmol) triethylamine mixed in with 1-butanol is added. To the obtained solution 8.3 g (208 mmol) of sodium hydroxide in aqueous solution is added dropwise. The solution is filtered and then stirred at a temperature above 50 C for two hours. The suspension is cooled, filtered, washed on the filter and dried. 22.6 g of material containing a small amount of sodium chloride is obtained.
  • 44
  • [ 503614-91-3 ]
  • [ 503614-92-4 ]
YieldReaction ConditionsOperation in experiment
99% With water; lithium hydroxide; In tetrahydrofuran; methanol; at 20℃; for 1h; Part B. To a solution of the ester from above (500 mg, 1.02 mmol) in THF (5 mL), MeOH (3 mL), and H2O (2 mL) was added LiOH (52 mg, 1.2 mmol) at rt. The reaction mixture was stirred for 1 h, acidified with Dowex-50W-hydrogen ion-exchange resin, filtered, and evaporated to provide the corresponding acid as a white solid (471 mg, 99%) which was used without further purification: ESI MS m/z 461 (M+H)+.
90.0% With sodium hydroxide; In methanol; water; at 60℃; for 1h; Intermediate 11 (30.0 g, 0.06 mol) and NaOH (9.4 g, 0.18 mol) were added to a solution of MeOH and H2O (300 mL, MeOH:H2O = 5:1). The mixture was stirred at 60 C for 1 h. Upon cooling to rt., the solvent was removed under vacuum, and then H2O(100 mL) was added to the mixture. The solution was adjusted to pH 2-3 with 3 N HCl, and then the resulting precipitate was filtered and dried under reduced pressure to afford a white solid(25.4 g, 90.0%). Mp: 129-132 C; MS (ESI) m/z (%): 459.1 [M-H]-.
89.9% With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 4h;pH 12 - 13; 20 mL of tetrahydrofuran, 20 mL of water was added to the reaction flask, Sodium hydroxide (0.73 g, 0183 mol) was added, And Compound F (3.00 g, 0. 0061 mol), System pH is about 12 ~ 13, room temperature stirring reaction 4h after TLC to determine the reaction is complete. Stop the reaction, Dropping dilute hydrochloric acid to pH 2 ~ 3, precipitation of white solid, filter, filter cake washed with water (3 X20 mL) and dried to give 2.53 g of a white solid compound G
85.4% With water; lithium hydroxide; In dichloromethane; for 1h;Reflux; At 20 C to 25 C, compound III (R = Et, 20g, 41.0mmol) and dichloromethane (200mL) were added to a three-necked flask (500mL).The solution was stirred and heated to dissolve. After the dissolution was clear, a 10% lithium hydroxide aqueous solution (18 g, 75.0 mol) was added dropwise.After completion of the dropwise addition, the reaction was refluxed for 1 h, and no raw material compound III was detected by TLC.Water (100 mL) was added, stirred, allowed to stand, and separated. The aqueous phase was added dropwise with 5 mol / L hydrochloric acid (15 mL) at 20 C to 25 C, and the mixture was kept under stirring for 2 hours.filter.The solid was transferred to a three-necked flask (250 mL), ethanol (150 mL) was added, and the solution was clarified by increasing the temperature and reflux. Then, activated carbon (0.2 g) was added, and the mixture was decolorized by stirring for 30 min.Drying at 50 C gave 16.1 g of compound II.
43.4% With hydrogenchloride; In water;pH 3; Compound VII (20 g, 0.049 mol) was added to a 250 mL three-necked flask,Dry tetrahydrofuran (200 mL),Triethylamine (10.2 mL, 0.073 mol),Cooling to 0 C, 5-chlorovaleryl chloride (9.4 mL, 0.073 mol) was added in portions,After adding 60 reaction 2h.Then cooled to -10 C, sodium tert-butoxide (12.1 g, 0.16 mol) was added in portions,Join the process of controlling the temperature below 0 ,After the addition was warmed to 50 reaction 4h.The tetrahydrofuran was distilled off under reduced pressure,To the residue was added saturated sodium carbonate aqueous 200mL slurry,A solid precipitation,Filter products,Yellow solid,9.45 g, m.p. 151-154 C,Yield 39.4%.To the remaining aqueous phase was added dropwise 10% aqueous hydrochloric acid,Adjust pH to 3, a large number of solid precipitation,Filtered to give a pale yellow solid,The structure was confirmed to be 1- (4-methoxyphenyl)-7-oxo-6- [4- (2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (IX), 10.4 g, m.p. 196-198 C, yield 43.4%.
0.68 g With water; sodium hydroxide; In butan-1-ol; at 50 - 60℃; for 2h; 0,73 g (2.4 mmol) of the substance of formula 12 obtained in the example 7 is suspended in 1- butanol under argon atmosphere, then 0.83 (3.2 mmol) of ethyl-(2£)-chloro[(4- methoxyphenyl)hydrazono] acetate of formula 3a is added. The mixture is heated above 70 C internal temperature, then 1.8 mL (1.31 g, 13.0 mmol) triethylamine mixed with 1-butanol is added. To the obtained solution is slightly cooled back and 0.40 g (10.0 mmol) of sodium hydroxide in aqueous solution is added dropwise. The solution is stirred at a temperature between 50-60 C for two hours. An aqueous solution of 1.4 g concentrated acetic acid is added and then it is acidified with 1 : 1 hydrochloric acid. The solid substance is filtered and washed. After drying 0.68 g (1.5 mmol, 62%) of the title substance is obtained. Mp.: 274-276 C.
26.30 g With lithium hydroxide monohydrate; water; In N,N-dimethyl acetamide; Add 2.705 g lithium hydroxide monohydrate dissolved in 191 mL demineralized water dropwise under 5 minutes to 29.0 g ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidinyl)phenyl]- 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxilate of formula 4a, produced according to figure 3 and dissolved in dimethylacetamide (238 mL DMA). Stir the mixture overnight and then pour it slowly onto 1790 g 5% solution of NaCl, then extract with isopropyl acetate. Sepa- rate the aqueous phase and acidify it with 1 M aqueous hydrochloric acid solution, that is, release the carboxylic acid under 10-15 C temperature. Filtrate the precipitated white substance and wash with distillated water, then dry it. Product: 26.30 g beige colored solid substance melting point: 270.5-274 C IR (KBr): 3407, 2904, 2534, 1710, 1667, 1613, 1516, 1255, 1151 cm"1. HNMR (DMSO-de): delta 13.19 (br s, 1H), 7.44 (d, 2H, J = 8.9 Hz), 7.35 (d, 2H, J = 8.7 Hz), 7.28 (d, 2H, J = 8.7 Hz), 7.00 (d, 2H, J = 9.0 Hz), 4.06 (t, 2H, J = 6.5 Hz), 3.80 (s, 3H), 3.59 (t, 2H, J = 5.9 Hz), 3.19 (t, 2H, J = 6.5 Hz), 2.38 (t, 2H, J = 6.2 Hz), 1.85 (m, 2H), 1.84 (m, 2H) ppm. CNMR (DMSO-d6): delta 169.02, 163.06, 159.39, 156.66, 141.58, 139.91, 139.48, 133.06, 132.71, 126.98, 126.86, 126.50, 126.17, 113.61, 55.64, 50.99, 50.93, 32.77, 23.17, 21.39, 21.07 ppm.
With potassium hydroxide; In tetrahydrofuran; at 50℃; To the reaction flask was added 4.88 g (10 mmol) of Compound II, 50 ml of THF, 0. 56 g (10 mmol) of KOH,After the addition, the temperature was raised to 50 C and the reaction was allowed to proceed for 3-5 hours. LCMS followed the reaction until compound II reacted completely.Ice water bath to 0-5 C, slowly adding lmol / L HC1 to the reaction solution to adjust pH to about 6,Fully agitated to precipitate (ie, the corresponding carboxylic acid product) precipitated, filtered and vacuum dried at 50 C.

  • 45
  • 1-(4-aminophenyl)piperidine-2-one [ No CAS ]
  • [ 503614-91-3 ]
  • 46
  • 5-bromo-N-[4-(2-oxopiperidin-1-yl)phenyl]valeroyl amide [ No CAS ]
  • [ 503614-91-3 ]
  • 47
  • [ 2067-33-6 ]
  • [ 503614-91-3 ]
  • 48
  • 3-chloro-1-(4-iodophenyl)-5,6-dihydropyridin-2(1H)-one [ No CAS ]
  • [ 503614-91-3 ]
  • 49
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid zinc salt [ No CAS ]
  • 50
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ammonium salt [ No CAS ]
  • 51
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid cyclohexylammonium salt [ No CAS ]
  • 52
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid diisopropylammonium salt [ No CAS ]
  • 53
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid 1,8-diazabycyclo[5.4.0]undec-7-ene salt [ No CAS ]
  • 54
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid calcium salt [ No CAS ]
  • 55
  • ethyl 1-(4-methoxyphenyl)-7a-morpholino-6-(4-nitrophenyl)-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate [ No CAS ]
  • [ 503614-91-3 ]
  • 56
  • 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo- 1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester [ No CAS ]
  • [ 503614-91-3 ]
  • 57
  • 1-(4-methoxyphenyl)-6-(4-aminophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester [ No CAS ]
  • [ 503614-91-3 ]
  • 58
  • ethyl 6-(4-(5-chloropentanamido)phenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate [ No CAS ]
  • [ 503614-91-3 ]
YieldReaction ConditionsOperation in experiment
88.3% With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; at 20℃; for 3h;pH 8 - 9; 20 mL of dichloromethane was added to the reaction flask, Sodium hydroxide (0. 61 g, 0.0152 mol) was added successively, Tetrabutylammonium bromide ( · 48g, 000015mol) And compound Epsilon (4.00g, 0.0076mol), the system pH was 8 ~ 9, room temperature stirring reaction 3h TLC determines the reaction is complete. The reaction was stopped and the mixture was stirred with 30 mL of water. The organic layer was separated and washed with water (3X 30 mL) The organic layer was dried over anhydrous sodium sulfate. The filtrate was evaporated under reduced pressure and evaporated to remove the solvent to give a white solid which was recrystallized from ethyl acetate and dried to give 3.28 g of white solid compound F;
80.3% With sodium hydride; In N,N-dimethyl-formamide; at 0℃; for 1h; General procedure: Compounds 10a-10f (0.05 mol) and NaH (3.6 g, 0.15 mol) were added in DMF (270 mL) at 0 C, and then stirred for 1 h. The reaction mixture was poured into ice-water (200 mL).The aqueous layer was extracted with CH2Cl2 (3 100 mL). The organic phase was washed with water (3 100 mL), brine (200 mL) and dried with Na2SO4, filtered and evaporated in vacuo. The residue was triturated with methanol to give the title compounds 11a-11f as white solid.
  • 59
  • [ 503614-91-3 ]
  • (E)-N-((dimethylamino)methylene)-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide [ No CAS ]
  • 60
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-3-(1H-1,2,4-triazol-3-yl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 61
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-5-(4-(2-oxopiperidin-1-yl)phenyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one [ No CAS ]
  • 1-(4-methoxyphenyl)-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-(4-(2-oxopiperidin-1-yl)phenyl)-1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one [ No CAS ]
  • 63
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-3-(5-methyl-1H-1,2,4-triazol-3-yl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 64
  • [ 503614-91-3 ]
  • 3-(5-(methoxymethyl)-1H-1,2,4-triazol-3-yl)-1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 65
  • [ 503614-91-3 ]
  • 3-(5-(tert-butyl)-1H-1,2,4-triazol-3-yl)-1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 66
  • [ 503614-91-3 ]
  • 3-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)-1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 67
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-3-(5-(tetrahydrofuran-2-yl)-1H-1,2,4-triazol-3-yl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 68
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid hydrazide [ No CAS ]
YieldReaction ConditionsOperation in experiment
80.3% With hydrazine hydrate; at 80℃; for 3.5h;Reflux; A solution of 11a (10.0 g, 20.0 mmol) in hydrazine hydrate(60.0 mL) was stirred at 80 C for 3.5 h. The hydrazine hydrate was distilled. Solid was filtered and washed with water to afford 19(7.8 g, 80.3%), Mp: 168.3-170.6 C; MS (ESI)m/z (%): 497.2 [M+Na]+.
  • 69
  • [ 503614-91-3 ]
  • (Z)-N'-(1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl)-N,N-dimethylformohydrazonamide [ No CAS ]
  • 70
  • [ 503614-91-3 ]
  • 3-(4-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)-1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 71
  • [ 503614-91-3 ]
  • 3-(4-(3-(dimethylamino)propyl)-4H-1,2,4-triazol-3-yl)-1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 72
  • [ 503614-91-3 ]
  • 3-(4-(3-(diethylamino)propyl)-4H-1,2,4-triazol-3-yl)-1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 73
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-6-[4-(2-oxopiperidin-1-yl)phenyl]-3-[4-(3-(morpholin-4-yl)-propyl)-4H-1,2,4-triazol-3-yl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 74
  • [ 503614-91-3 ]
  • 2-(1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl)-N-phenylhydrazine-1-carboxamide [ No CAS ]
  • 75
  • [ 503614-91-3 ]
  • N-(4-methoxyphenyl)-2-(1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl)hydrazine-1-carboxamide [ No CAS ]
  • 76
  • [ 503614-91-3 ]
  • 2-(1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl)-N-(2-(trifluoromethyl)phenyl)hydrazine-1-carboxamide [ No CAS ]
  • 77
  • [ 503614-91-3 ]
  • 1-(4-methoxy-phenyl)-3-(5-oxo-4-phenyl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 78
  • [ 503614-91-3 ]
  • 1-(4-methoxy-phenyl)-3-[4-(4-methoxy-phenyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 79
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-3-[5-oxo-4-(2-trifluoromethyl-phenyl)-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 80
  • [ 503614-91-3 ]
  • 3-amino-1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 81
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-3-(1H-pyrrol-1-yl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 82
  • [ 503614-91-3 ]
  • 3-(2-((dimethylamino)methyl)-1H-pyrrol-1-yl)-1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 83
  • [ 503614-91-3 ]
  • 3-(2-((diethylamino)methyl)-1H-pyrrol-1-yl)-1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 84
  • [ 503614-91-3 ]
  • 1-(4-methoxyphenyl)-3-(2-(morpholinomethyl)-1H-pyrrol-1-yl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]
  • 85
  • C20H22N4O6 [ No CAS ]
  • [ 503614-91-3 ]
Same Skeleton Products
Historical Records

Pharmaceutical Intermediates of
[ 503614-91-3 ]

Apixaban Related Intermediates

Chemical Structure| 385425-15-0

[ 385425-15-0 ]

1-(4-Iodophenyl)piperidin-2-one

Chemical Structure| 536759-91-8

[ 536759-91-8 ]

Ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Chemical Structure| 503615-07-4

[ 503615-07-4 ]

Ethyl 6-(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Chemical Structure| 473927-64-9

[ 473927-64-9 ]

Ethyl 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

Chemical Structure| 27143-07-3

[ 27143-07-3 ]

Ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate

Related Functional Groups of
[ 503614-91-3 ]

Aryls

Chemical Structure| 503615-07-4

[ 503615-07-4 ]

Ethyl 6-(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Chemical Structure| 503614-92-4

[ 503614-92-4 ]

1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid

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Chemical Structure| 503614-56-0

[ 503614-56-0 ]

Ethyl 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Chemical Structure| 473927-64-9

[ 473927-64-9 ]

Ethyl 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Chemical Structure| 536759-91-8

[ 536759-91-8 ]

Ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Ethers

Chemical Structure| 503615-07-4

[ 503615-07-4 ]

Ethyl 6-(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Chemical Structure| 503614-92-4

[ 503614-92-4 ]

1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid

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Chemical Structure| 503614-56-0

[ 503614-56-0 ]

Ethyl 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Chemical Structure| 473927-64-9

[ 473927-64-9 ]

Ethyl 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Chemical Structure| 536759-91-8

[ 536759-91-8 ]

Ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Amides

Chemical Structure| 503615-07-4

[ 503615-07-4 ]

Ethyl 6-(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Chemical Structure| 503614-92-4

[ 503614-92-4 ]

1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid

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Chemical Structure| 503614-56-0

[ 503614-56-0 ]

Ethyl 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Chemical Structure| 473927-64-9

[ 473927-64-9 ]

Ethyl 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Chemical Structure| 536759-91-8

[ 536759-91-8 ]

Ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Esters

Chemical Structure| 503615-07-4

[ 503615-07-4 ]

Ethyl 6-(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Chemical Structure| 503614-56-0

[ 503614-56-0 ]

Ethyl 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Chemical Structure| 473927-64-9

[ 473927-64-9 ]

Ethyl 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Chemical Structure| 536759-91-8

[ 536759-91-8 ]

Ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Chemical Structure| 951626-95-2

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Ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate

Similarity: 0.75

Related Parent Nucleus of
[ 503614-91-3 ]

Other Aromatic Heterocycles

Chemical Structure| 503615-07-4

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Ethyl 6-(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Chemical Structure| 503614-92-4

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1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid

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Ethyl 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Ethyl 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

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Piperidines

Chemical Structure| 503614-92-4

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1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid

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Chemical Structure| 147770-06-7

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(S)-Ethyl 2-ethoxy-4-(2-((3-methyl-1-(2-(piperidin-1-yl)phenyl)butyl)amino)-2-oxoethyl)benzoate

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tert-Butyl 2'-(tert-butyl)-7'-oxo-6',7'-dihydro-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazole]-1-carboxylate

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Chemical Structure| 889945-69-1

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tert-Butyl 4-(1H-indazol-3-yl)piperidine-1-carboxylate

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(Z)-N-(1-Chloro-1-(4-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide

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