Name: 503612-47-3|1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide|98%
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1
[ 503614-91-3 ]
apixaban [ No CAS ]

Yield	Reaction Conditions	Operation 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%.

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[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

2
[ 503614-92-4 ]
apixaban [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%		12.5 g (27.1 mmol) of substance of formula 11c obtained in example 10 is suspended in DMA, then under argon atmosphere 8.0 g (49.3 mmol) of carbonyldiimidazole (CDI) is added, and the mixture is heated to 60 C, and it is maintained at this temperature for 1 hour. Then 18.8 mL (13.7 g, 136 mmol) of triethylamine and 6.25 g (81 mmol) of ammonium acetate are added to the mixture. The stirring is continued for 1 hour. Water is added to the mixture and the suspension is slowly cooled to 20 C. The precipitated substance is filtered off and washed. After drying 11.36 g (24.7 mmol, 91%) of off-white substance is obtained. Mp.: 236-238 C.
90%	With ammonia; In ethylene glycol;Heating; Industrial scale;	General procedure: A solution of 5,6-dihydro-3- (4-morpholinyl) -1- [4- (2-oxo-1-piperidinyl) phenyl]2 (1H) -pyridone and ethyl [(4-methoxyphenyl) hydrazino] chloroacetate,In the triethylamine for the acid binding agent under the conditions of condensation, and then by hydrochloric acid deprotection,The resulting intermediates,In the ethylene glycol under high temperature conditions with ammonia reaction in the preparation of an average of <strong>[503614-92-4]apixaban</strong>, the purity of 95.4%.In the 50L reactor,Add 2 kg of <strong>[503614-92-4]apixaban</strong> crude (purity 95. 4%) and 16L with 10% ammonia in ethylene glycol solution, heated to 90 C dissolved, then add 16L water cooling, stirring at 40 ~ 50 C for 2 hours , Cooling to 0 ~ 10 C. And then filtered to dryness to give 8 kg of a white solid, 90% yield, and an HPLC purity of 99. 97%.
	With triethylamine; In methanol; water; ethyl acetate;	Example 53 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 amide (62). Method A. A suspension of <strong>[503614-92-4]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</strong> (61, 1.5 g, 3.3 mmol) in EtOAc (20 mL) was treated with triethylamine (TEA, 433 mg, 0.60 mL, 4.3 mmol, 1.3 equiv) at room temperature, and the resulting reaction mixture was treated dropwise with iso-butyl chloroformate (587 mg, 0.55 mL, 4.3 mmol, 1.3 equiv) at room temperature. The resulting reaction mixture was subsequently stirred at room temperature for an additional 30 min. When TLC and HPLC showed the mixed anhydride formation reaction was complete, the reaction mixture was poured into a cold (0-5 C.) ammonium hydroxide solution (NH4OH, 28% aqueous solution, 25 mL) with good stirring. The resulting mixture was stirred at room temperature for an additional 4 h. The solids were collected by filtration, washed with a mixture of methanol and water (1:1 v/v, 2*20 mL), and dried in vacuo at 40-45 C. for 12 h to afford the crude desired <strong>[503614-92-4]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</strong> amide (62, 1.06 g, 1.52 g theoretical, 70%) as off-white crystals. For 62, CIMS m/z 460 (M++H, C25H25N5O4).

Reference： [1]Patent: WO2016/20711,2016,A1 .Location in patent: Page/Page column 22
[2]Patent: CN106188036,2016,A .Location in patent: Paragraph 0054; 0055; 0085; 0086
[3]Patent: US2003/181466,2003,A1
[4]Patent: CN103896940,2016,B

3
[ 503612-47-3 ]
[ 503612-76-8 ]

Yield	Reaction Conditions	Operation in experiment
27%	Stage #1: apixaban With boron tribromide In dichloromethane at -20℃; for 3.5h; Stage #2: With water In dichloromethane Cooling with ice;	2.1 EXAMPLE 2; l-(4-3-Methoxyphenyl)-7-oxo-6-(4-(2-oxo-l-piperidinyl) phenyl)-4,5,6,7- tetrahydro-lH-pyrazole-[3, 4-c] pyridine-3-carboxamide; Step 1; l-(4-Hydroxyphenyl)-7-oxo-6-(4-(2-oxo-l-piperidinyl)phenyl)-4.5.6.7- tetrahydro-lH-pyrazole-n^-cipyridine-S-carboxamide:; At about -20 0C, boron tribromide (2.16g, 8.62 mmol) was added dropwise over a period of about 30 minutes to a solution of l-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxo-l- piperidinyl)phenyl)-4,5,6,7-tetrahydro-lH-pyrazole-[3,4-c]pyridine-3-carboxamide (0.50 g, 1.09 mmol) and dry dichloromethane (5OmL). The resulting mixture was stirred at about -20 0C for about 3 hours, and then poured into ice-cold water. Standard extractive work up with dichloromethane provided a crude residue which was purified by silica gel column chromatography (10% methanol in chloroform) to give the title product as an off-white solid (0.130 g, yield = 27%). mp: 160-165 0C; 1H NMR (400 MHz, CDCl3) δ 1.82-1.85 (m, 4H), 2.38 (t, J= 6.2 Hz, 2H), 3.17- 3.20 (m, 2H), 3.57-3.60 (m, 2H), 4.03 (t, J= 6.6 Hz, 2H), 6.79 (d, J= 8.8 Hz, 2H), 7.26-7.36 (m, 5H) 7.42 (br, exchangeable with D2O, IH), 7.7 (br, exchangeable with D2O, IH), 9.78 (br, exchangeable with D2O, IH); IR (KBr) υ 3469, 3162, 2925, 2857, 1673, 1601, 1512, 1296, 837, 754 cm"1; MS 444 (M - 1).

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2010/30983, 2010, A2 Location in patent: Page/Page column 33

4
[ 1074365-84-6 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
81.4%	With sodium methylate; formamide In methanol; N,N-dimethyl acetamide at -5 - 5℃; for 3h;	3; 6; 1 Example 6 At -5 ° C to 5 ° C, 27 g of N,N-dimethylacetamide was added to the reaction flask (100 mL).Compound V (7.0 g, 14.7 mmol),Formamide (6.7 g, 148.8 mmol).Stir and cool down, temperature control -5 ° C ~ 5 ° C,A 30% sodium methoxide methanol solution (3.7 g, 20.6 mmol) was slowly added.Insulation reaction for 1 h,TLC detected no residual of the starting compound V. Continue to incubate for 2 h.Centrifugation. The solid was transferred to a reaction flask (100 mL), and 50 g of ethanol was added for 1 h.Centrifugation. Drying at 50 ° C gave compound I 5.5 g.Yield: 81.4%, HPLC: 99.56%.
	With sodium methylate; formamide In methanol; N,N-dimethyl-formamide at 0℃; Inert atmosphere;
88 %	With sodium methylate In methanol; formamide at 60℃;	4.4 Step 4, Compound D-I is reacted to obtain Apixaban: Dissolve 30 g of compound D-I prepared in Example 3 in 240 ml of methanol, place it in a 500 ml reaction flask, add 6.83 g of sodium methoxide and 50 ml of formamide, stir the reaction, raise the temperature to 60° C., and keep it warm for 4 hours. TLC detects that the raw materials are completely converted. After the reaction, part of the solid was precipitated, and most of the methanol was concentrated under reduced pressure, then 100ml of methanol was added, stirred at room temperature for 30 minutes, and suction filtered. The resulting solid was refined with ethanol to obtain 25.56g of white solid, with a yield of 88% and an HPLC purity of 99.7%.

Reference： [1]Current Patent Assignee: JIANGXI GUOYAO PHARMACEUTICAL - CN110003206, 2019, A Location in patent: Paragraph 0069-0072; 0079-0081; 0082; 0085-0086
[2]Ramirez, Antonio; Mudryk, Boguslaw; Rossano, Lucius; Tummala, Srinivas [Journal of Organic Chemistry, 2012, vol. 77, # 1, p. 775 - 779]
[3]Current Patent Assignee: CHANGZHOU PHARMACEUTICAL FACTORY CO LTD - CN116375703, 2023, A Location in patent: Paragraph 0060-0064

5
[ CAS Unavailable ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium ethoxide In tetrahydrofuran; ethanol for 0.5h;	1b 1 -(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin- 1 -yl)phenyl)-4,5 ,6,7-tetrahydro- 1 H- pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban) Potassium ethoxide solution in Ethanol (24%, 46.9 g, 2.5 eq.) was added dropwise to the suspension of 6-(4-(5-bromopentanamido)phenyl)-l-(4-methoxyphenyl)-7- oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide (28.9 g, 53.48 mmol) in dry Tetrahydrofuran (460 mL). HPLC showed reaction completion after 30 min. Glacial acetic acid (0.9 mL) was added to quench the reaction. Reaction mixture was concentrated in vacuo to give off- white slurry. Water (700 mL) was added and the solid material was filtered off and washed with water (1 L) to afford 20 g of crude product.
1.8 g	With sodium hydride In tetrahydrofuran at 0 - 30℃; for 2h;	10 Preparation of Apixaban (I) In 250 mL 3-neck round bottom flask equipped with mechanical stirrer, thermometer and addition funnel, compound (III) (2.5 gm) and THF (25 mL) were added at 25- 30°C and cooled to 0°C to 5°C. 5-bromovalaroyl chloride (1.85 g) and a solution of triethylamine (1.23 g) in THF (2.5 mL) was added at 0°C to 5°C. The reaction mixture was stirred for 1 hour and 60% sodium hydride (1.58 gm) was added at 0° to 5°C. The reaction mixture was heated to 25°C to 30°C and stirred for 2 hours. Water (50 mL) was added and stirred for 1 hour. The reaction mixture was filtered and washed with water. The wet-cake was dried at 60°C to 65°C_for_8_hours-under- vacuum to obtain 1.8 of apixaban. Example-ll: Preparation of Apixaban (I)
270 mg	With sodium hydroxide at 20 - 50℃; for 8.5h; Cooling with ice;	1 Preparation of Compound Apixaban Compound24(0.3 g) was dissolved in 4.5mL of anhydrous tetrahydrofuran was added a solution of 5-bromo-valeryl chloride (0.30 g) triethylamine (0.16 g of), ice-water cooling.Naturally to room temperature, the reaction mixture was stirred for half an hour, was added sodium hydrogencarbonate (70 mg of) was cooled in an ice-water bath, naturally to room temperature, the reaction mixture was stirred for half an hour, the reaction was heated to 50°C stirred for 8 hours. 5mL was added under ice-water bath the reaction was quenched with water, ethyl acetate (10mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. Crystallization from ethyl acetate with petroleum ether to give 270 mg of white solid, 75% yield.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2013/119328, 2013, A1 Location in patent: Paragraph 0044
[2]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2014/203275, 2014, A2 Location in patent: Page/Page column 39-40
[3]Current Patent Assignee: GANSU HAOTIAN CHEMEXPRESS - CN103342704, 2016, B Location in patent: Paragraph 0027; 0028; 0029; 0037; 0038

6
[ 503612-76-8 ]
[ 77-78-1 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
4.5 g	With potassium carbonate In acetone at 25 - 30℃;	XXVI Preparation of Apixaban In 250 ml four neck equipped round bottomed flask (RBF), acetone (100ml), 1 -(4-hydroxy- 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 amide (10g), potassium carbonate (4.65 g), dimethyl sulphate (DMS) (4.25 g) were charged. Reaction mass was stirred for 3-5 hr at 25-30°C and after completion of reaction, water was added slowly. Reaction mass was stirred 1-2 hrs at 25-30°C. Solid obtained was filtered and washed with water 20 ml. The product was dried at 40-45 °C to obtain 4.5 gm of apixaban. HPLC purity 98.2%.

Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2014/111954, 2014, A1 Location in patent: Paragraph 0161

7
[ 503612-47-3 ]
[ 4637-24-5 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
96.1%	In dichloromethane at 40℃; for 3h;	5.3.2. General procedure for the preparation of intermediates 13a-13f General procedure: DMF-DMA (8.0 mL, 0.06 mol) was added to a solution of 12a-12f (4.59 g, 0.01 mol) in CH2Cl2 (80.0 mL). The reaction was heated to 40 C for 3 h. After cooling to rt, the resultant solid 13a-13f werecollected by concentrating under vacuum. 5.3.2.1. (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(13a). Light yellow solid; Yield: 96.1%; Mp: 178.6-179.9 C;MS (ESI) m/z (%): 515.2 [M+H]+.

Reference： [1]Wang, Yong; Sun, Xiaoqing; Yang, Di; Guo, Zhuang; Fan, Xuxu; Nie, Minhua; Zhang, Feng; Liu, Yue; Li, Yue; Wang, Yulin; Gong, Ping; Liu, Yajing [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5646 - 5661]

8
[ 1421823-20-2 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
87.8%	With sodium methoxide; formamide In methanol; acetonitrile at 5 - 30℃; for 2.5h;	1-4 Example 1: Compound (I) in a mixed solvent of acetonitrile (70 mL) and methanol (10 mL)(10.0 g, 19.1 mmol),Formamide (8.6 g, 190.3 mmol; 10 eq) was added and cooled below 5°C.Thereafter, a 28% sodium methoxide methanol solution (11.0 g, 57.4 mmol; 3 equivalents) was added at the same temperature and stirred for 30 minutes.The mixture was heated to 30° C. and stirred for 2 hours.After confirming the reaction rate by HPLC, the reaction solution was cooled to 5°C and(140 mL) was added and stirred for 1 hour, followed by filtration. Filtrate with water(20 mL) and ethanol (20 mL), and dried under reduced pressure at 40° C. to obtain 7.7 g of apixaban as white crystals.Yield is 87.8%(calculated as apixaban anhydrate).Purity was 99.1%.
	Multi-step reaction with 2 steps 1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 °C 2: sodium methoxide; formamide / N,N-dimethyl-formamide / 5 h / 50 °C
	Multi-step reaction with 4 steps 1: sodium hydroxide; tetrabutylammonium bromide / dichloromethane / 3 h / 20 °C / pH 8 - 9 2: sodium hydroxide / lithium hydroxide monohydrate; tetrahydrofuran / 4 h / 20 °C / pH 12 - 13 3: tetrahydrofuran / 0.5 h / 20 - 65 °C 4: ammonium hydroxide / 1 h / 10 °C

Reference： [1]Current Patent Assignee: DAITO PHARMACEUICAL; DAITO (unclear) - WO2021/261172, 2021, A1 Location in patent: Paragraph 0043-0052
[2]Wang, Yong; Sun, Xiaoqing; Yang, Di; Guo, Zhuang; Fan, Xuxu; Nie, Minhua; Zhang, Feng; Liu, Yue; Li, Yue; Wang, Yulin; Gong, Ping; Liu, Yajing [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5646 - 5661]
[3]Current Patent Assignee: HEBEI UNIVERSITY OF SCIENCES AND TECHNOLOGY - CN104045637, 2016, B

9
[ 503612-47-3 ]
[ 503612-45-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: apixaban With triethylamine In dichloromethane for 0.5h; Stage #2: With trifluoroacetic anhydride In dichloromethane at 30℃;	A (5 g, 0 · olmol) was suspended in 50 ml of dichloromethane and added with ΤAD6.1 ml,After stirring for 30 min,30 degrees slowly under the drop(CF3C0) 20, drop finished, 30 degrees under the reaction 1 ~ 2h.Washed with water to neutral, evaporated to dryness to give a pale yellow solid, ether beaten, and recrystallized from ethyl acetate or methanol to give 3.5 g of a white solid, 79%
72.9%	With triethylamine; trifluoroacetic anhydride In dichloromethane at 30℃; for 3h;	5.3.5. Preparation of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile 17 Triethylamine (0.13 mol, 18.1 mL) was added to a solution of 12a (15.0 g, 33.0 mmol) in DCM (225.0 mL) at 30 °C. After 30 min,trifluoroacetic anhydride (0.13 mol, 18.3 mL) was added dropwiseto the reaction and stirred for 2 h. The organic layer was washed with water and filtered to give a solid. The residue was crystallized with methanol to afford the title compound 17 (10.5 g, 72.9%), Mp:171.3-173.6 C; MS (ESI) m/z (%): 435.3 [M+H]+.
72.9%	Stage #1: apixaban With triethylamine In dichloromethane at 30℃; for 0.5h; Stage #2: With trifluoroacetic anhydride In water for 2h;	5.6.1. Preparation of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile (27) Triethylamine (18 mL, 0.13 mol) was added to a solution of 12(15.0 g, 33.0 mmol) in CH2Cl2 (225 mL) at 30 C. After 30 min, trifluoroacetic anhydride (18 mL, 0.13 mol) was added drop-wise to the solution and stirred for 2 h. The solution was adjusted to pH7 with H2O and the organic phase was evaporated in vacuo. The residue was crystallized with MeOH to afford the title compound 27 as a white solid (10.5 g, 72.9%). Mp: 171.3-173.6 C; MS (ESI)m/z (%): 435.3 [M+H]+.

68.3%

With trichlorophosphate for 1h; Reflux;

1 Synthesis of 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin- 1 -yl) phenyl] -4,5,6,7-Tetrahydro-1H-pyrazolo [3,4-c] pyridine-3-carbonitrile(APX-01) Apixaban (1 g, 2.2 mmol) was added to a 100 mL eggplant-POCl3 (15.3 g, 100 mmol) was added,Then the condenser and drying tube,Warm to reflux for 1 h.The reaction solution was cooled to room temperature,Pour 200mL ice water,Stir until the ice melting, dichloromethane 3 × 100mL extraction,Saturated brine 200mL wash,Drying over anhydrous magnesium sulphate gave a crude product by evaporation of dichloromethane, 0.9 g.The crude product was subjected to column chromatography,Eluent (dichloromethane: methanol = 80: 1),The product 0.67g, yield 68.3%.White solid, m.p. 154-155 ° C.

Reference： [1]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN104513239, 2017, B Location in patent: Paragraph 0206; 0355; 0356
[2]Wang, Yong; Sun, Xiaoqing; Yang, Di; Guo, Zhuang; Fan, Xuxu; Nie, Minhua; Zhang, Feng; Liu, Yue; Li, Yue; Wang, Yulin; Gong, Ping; Liu, Yajing [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5646 - 5661]
[3]Sun, Xiaoqing; Hong, Zexin; Liu, Moyi; Guo, Su; Yang, Di; Wang, Yong; Lan, Tian; Gao, Linyu; Qi, Hongxia; Gong, Ping; Liu, Yajing [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 10, p. 2800 - 2810]
[4]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN107400131, 2017, A Location in patent: Paragraph 0031-0032; 0066-0068

10
[ 503612-47-3 ]
[ 1704504-80-2 ]

Yield	Reaction Conditions	Operation in experiment
62.4%	With methanol; [bis(acetoxy)iodo]benzene; potassium hydroxide at 20℃; for 5h;	5.5.1. Preparation of 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 (24) A mixture of 12a (3.0 g, 6 mmol), Potassium hydroxide (0.9 g,16.0 mmol), iodobenzene diacetate (4.2 g, 15.0 mmol) and methanol(60 mL) was stirred at rt for 5 h. After evaporating in vacuum,the residue was dissolved in a solution of H2O (30.0 mL), dioxane(60.0 mL) and NaOH (0.8 g, 0.02 mol). The mixture was heated to 100 °C for 6 h. The residue was treated with water 10 mL, extractedwith CH2Cl2 (3 10 mL), washed with brine (2 10 mL), dried overanhydrous MgSO4 and concentrated under reduced pressure toafford 24 (2.3 g, 62.4%), Mp: 178.4-179.9 C; MS (ESI) m/z (%):432.3 [M+H]+.
62.4%	Stage #1: apixaban With [bis(acetoxy)iodo]benzene; potassium hydroxide In methanol at 20℃; for 5h; Stage #2: With sodium hydroxide In 1,4-dioxane; water at 100℃; for 6h;	5 5.3.2. Preparation of 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 (13) Iodobenzene diacetate (4.2 g, 15.0 mmol) and KOH (0.9 g,16.0 mmol) were added to a solution of intermediate 12 (3.0 g,6.0 mmol) in MeOH (60 mL). The mixture was stirred at rt. for5 h. After evaporating in vacuo, the residue was dissolved in a solutionof H2O (30 mL), dioxane (60 mL) and NaOH (0.8 g, 0.02 mol).The mixture was heated to 100 C for 6 h. Upon cooling to rt., thereaction mixture was poured into ice-water (20 mL). The aqueouslayer was extracted with CH2Cl2 (3 10 mL). The organic phasewas washed with brine (2 20 mL). Then the organic layer wasdried with Na2SO4, filtered and evaporated in vacuo to afford 13as a brown solid (2.3 g, 62.4%). Mp: 178.4-179.9 C; MS (ESI) m/z(%): 432.3 [M+H]+.

Reference： [1]Wang, Yong; Sun, Xiaoqing; Yang, Di; Guo, Zhuang; Fan, Xuxu; Nie, Minhua; Zhang, Feng; Liu, Yue; Li, Yue; Wang, Yulin; Gong, Ping; Liu, Yajing [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5646 - 5661]
[2]Sun, Xiaoqing; Hong, Zexin; Liu, Moyi; Guo, Su; Yang, Di; Wang, Yong; Lan, Tian; Gao, Linyu; Qi, Hongxia; Gong, Ping; Liu, Yajing [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 10, p. 2800 - 2810]

11
[ 503612-45-1 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
97.5%	With chloro-trimethyl-silane In water at 20℃; for 4h;	5 Example 5: Preparation of 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 100 ml of water was added to the reaction flask, and compound IV (34.88 g, 0.079 mol) was added to the water, the solution was mixed uniformly with stirring, and chlorotrimethylsilane (15.21 g, 0.14 mol) was slowly added dropwise to the reaction solution. ), The temperature was maintained at 20 ° C, and the reaction was stirred for 4 hours to complete the reaction, concentrated under reduced pressure, the obtained solid was washed twice with 100 ml of water, filtered, the obtained solid was recrystallized from ethanol, and 35.36 g of white crystalline compound V was obtained after vacuum drying, Molar yield is 97.5%, purity is 99.94%
94%	With dihydrogen peroxide; sodium hydroxide In ethanol at 0 - 20℃; for 4h;	3 Preparation of apixabine To the reaction flask was added 4.4 g (0.01 mol) of compound 8, 0.44 g (0.01 1 mol) of sodium hydroxide (or other hydroxides as previously described) 30mL ethanol (or other lower alcohols as mentioned above), after the addition of the reaction solution to cool to 0 ~ 5 ° C, slowly dropping 8g 30% hydrogen peroxide, Dripping slowly to room temperature after the incubation reaction 4 hours, liquid phase control to complete reaction, concentrated under reduced pressure, the resulting solid washed with 60mL water 2 times, The obtained solid was recrystallized from ethanol and dried in vacuo to give 4.3 g of white crystals in 94% yield. The molecular structure of the obtained product was characterized by 1H-NMR, 13C-NMR, MS and the spectrum of the product obtained in Example 2.
85%	With water; sodium hydroxide at 10 - 100℃;	7 The preparation step of apixaban Under the normal temperature, the compound of the alkali in the V, the alkali can be sodium hydroxide, lithium hydroxide or potassium hydroxide in the inorganic alkali such as one or several, preferably aqueous sodium hydroxide solution, the temperature is increased to 10 °C -100 °C, stirring reaction 5-60 minutes, preferably 30-40 minutes; after the reaction, to system 20 °C -30 °C, dichloromethane is used for extraction, layered, drying, concentrating under reduced pressure, purification by silica gel column residues, wherein is used for silica gel column purification eluting agent is made up of a methylene chloride and methanol, dichloromethane: methanol volume ratio of 30:1, to obtain white powdery product [...], compound IV with the sodium hydroxide aqueous solution in a molar ratio of 1.0: 1.0-1.0: 20, including the range between any of them of the value range of the promoter, non-limiting examples can be: 1.0 : 4-1.0: 18,1.0: 6-1.0: 16,1.0: 8-1.0: 14,1.0: 10-1.0: 12, preferably in a molar ratio of 1:10, yield: 80-85%.

Reference： [1]Current Patent Assignee: CHANGZHOU HENGBANG MEDICINE - CN110041245, 2019, A Location in patent: Paragraph 0127-0131
[2]Current Patent Assignee: ZHEJIANG TIANYU PHARMACY CO., LTD. - CN104262338, 2016, B Location in patent: Paragraph 0127-0129
[3]Current Patent Assignee: PHARMARESOURCES SHANGHAI CO LTD - CN103923080, 2016, B Location in patent: Paragraph 0065-0069

12
[ CAS Unavailable ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
4.27 g	With ammonia at 0 - 5℃;	1 Compound I Maintain 0-5 ° C, pass ammonia to the reaction flask, TLC follow the reaction until the reaction is complete.The organic layer was washed successively with H20, saturated sodium chloride solution, dried over anhydrous sodium sulfate for 4 h, filtered,The filtrate was concentrated in vacuo to give 4.27 g of a solid compound; the molar yield was 93%, the purity was 99.3%That is, a piperazine class, chemical name:1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo [3,4-c] pyridine-3-carboxamide.

Reference： [1]Current Patent Assignee: CHEMFUTURE PHARMATECH JIANGSU - CN103896940, 2016, B Location in patent: Paragraph 0044; 0061; 0063

13
[ 1904628-10-9 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
3.7 g	With ammonia In propylene glycol at 80 - 85℃; for 6h; Autoclave; Inert atmosphere;	8 EXAMPLE 8 Synthesis of Apixaban Form N-1 from the Compound of Formula (II) in which R is -CH₂CH₂- In an autoclave inerted by nitrogen compound of Example 5 (compound of formula (II) in which R is -CH2CH2-, 8.0g, 1.0eq) and propylene glycol (1,2-propandiol, 80 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, heated to dissolution and diluted with water (16 mL). After stirring at T=95/100° C. for additional 2 h, more water was added (48 mL) and the solution was seeded with Apixaban N-1 form (as prepared in Example 2 or 4). The sus-pension was stirred for 2 h at T=95/100° C., cooled to room temperature and diluted with ethanol (16 mL). After 3 h stirring at T=20/25° C. the slurry was filtered and the wet cake was washed with water (2×8 mL). The solid was dried under vacuum at T=65° C. for 8 h affording Apixaban N-1 form (6.7 g, 0.92 eq). m.p. 237° C. 1H-NMR (400 MHz, DMSO-d6, ppm), δ: 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), δ: 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]Current Patent Assignee: HOLDING F.I.S. S.P.A. - US2016/326171, 2016, A1 Location in patent: Paragraph 0177; 0178

14
[ 1904628-14-3 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
6.5 g	With ammonia In propylene glycol at 80 - 85℃; for 6h; Autoclave; Inert atmosphere;	10 EXAMPLE 10 Synthesis of Apixaban Form N-1 from the Compound of Formula (II) in which R is -CH₂CH₂OCH₂CH₂- In an autoclave inerted by nitrogen compound of Example 7 (compound of formula (II) in which R is -CH2CH2OCH2CH2-, 9.0 g, 1.0 eq) and propylene glycol (1,2-propandiol, 105 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, heated to dissolution and diluted with water (20 mL). After stirring at T=95/100° C. for additional 2 h, more water was added (60 mL) and the solution was seeded with Apixa-ban N-1 form. The suspension was stirred for 2 h at T=95/100° C., cooled to room temperature and diluted with ethanol (20 mL). After 3 h stirring at T=20/25° C. the slurry was filtered and the wet cake was washed with water (2×10 mL). The solid was dried under vacuum at T=65° C. for 8 h affording Apixaban N-1 form (6.5 g, 0.86 eq). mp 237° C. 1H-NMR (400 MHz, DMSO-d6, ppm), δ: 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), δ: 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=0.06%.

Reference： [1]Current Patent Assignee: HOLDING F.I.S. S.P.A. - US2016/326171, 2016, A1 Location in patent: Paragraph 0181; 0182

15
[ 1904628-15-4 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	With ethanol In water at 50℃; for 2.5h;	4 EXAMPLE 4 Preparation of Apixaban Form N-1 from Apixaban 1,2-proprylen glycol hemisolvate on Larger Scale-with Seeding of Form N-1 To a three-necked round-bottomed flask equipped with a thermometer and mechanical stirrer was added Apixaban 1,2-Propylene glycol hemisolvate of formula (V) (85.1 g; 171 mmol), as prepared in Example 1, and a mixture of EtOH/water (2:1) (850 mL, 10 vol.). the resulting suspension was seeded with form N-1 (as prepared in example 2) and it was heated at 50° C. The mixture was maintained at 50° c for 2.5 hours and then it was cooled down to room temperature. The slurry was stirred at room temperature for 2-3 hours. The solid was filtered with a sintered funnel (porosity 2-very good filtration), washed with EtOH: water (2:1) (170 mL, 2 vol.), with water (170 mL, 2 vol.) and dried under vacuum at 50° C. overnight. Apixaban form N-1 was obtained as off-white powder (65.4 g, 83% yield). 1H-NMR analysis shows that the product contains 0.13% of residual Ethanol. K. F. 0.1%. The chemical purity was determinate by HPLC: 99.4%. The starting Apixaban 1,2-Propylene glycol hemisolvate had a purity of 98.3%.

Reference： [1]Current Patent Assignee: HOLDING F.I.S. S.P.A. - US2016/326171, 2016, A1 Location in patent: Paragraph 0149; 0150

16
[ 1629218-34-3 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
1.78 g	With ammonium hydroxide at 10℃; for 1h;	1.6 Synthesis of Compound A 10 mL of tetrahydrofuran was added to the reaction flask, Compound G (2.00 g, 0.8043 mol) was added, N, f-carbonyldiimidazole (CDI) (0.84 g, 0.5252 mol) was added in portions at room temperature with stirring, The reaction was complete after TLC was heated to 65 ° C for 0 · 5 h. Ice water bath to about 10 ° C, add 10mL ammonia (NH3 · H20,0. 0645mol), After the temperature control reaction lh, the reaction was complete and the white solid was precipitated. (2 X 20 mL), then recrystallized from propylene glycol and dried to give 1. 75 g of a white solid compound A - the final product of apaxabine; high performance liquid chromatography (HPLC) as shown in Figure 1 yield 88.2%

Reference： [1]Current Patent Assignee: HEBEI UNIVERSITY OF SCIENCES AND TECHNOLOGY - CN104045637, 2016, B Location in patent: Paragraph 0072; 0088-0090

17
[ 1449510-64-8 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
270 mg	With sodium hydroxide In tetrahydrofuran; ethanol for 12h; Reflux;	2 Preparation of Compound Apixaban Compound24(0.3 g) was dissolved in 4.5mL of anhydrous tetrahydrofuran was added a solution of 5-chloro-valeryl chloride (0.20 g) triethylamine (0.16 g of), ice-water cooling.Naturally to room temperature, the reaction was stirred for a half hour, the reaction was quenched with 5mL of water, ethyl acetate (10mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was dissolved in a mixed solvent of 2mL of ethanol and 2mL of tetrahydrofuran was added sodium hydroxide (0.15 g of), the reaction was heated at reflux for 12 hours, concentrated under reduced pressure, to the residue water was added 5mL dichloromethane (10mL × 2) and extracted The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under pressure to recover the solvent crude, petroleum ether crystallized from ethyl acetate to give an off-white solid 270mg, 75% yield.
	With sodium hydride In N,N-dimethyl acetamide; mineral oil at 0 - 5℃; for 2h;	9 Example-9 Preparation of Apixaban (I) In 250 mE 3-neck round bottom flask equipped with mechanical stirrer, thermometer and addition flannel, compound (hA) (1 g, 2.01 mmol) in dimethylacetamide (5 mE) and 60% NaR (145 mg, 6.02 mmol) were stirred at 0-5° C. for 2 hours. The progress of the reaction was monitored by HPEC. Methanol (3 mE), methylene dichloride (12 mE) and water (5 mE) were added. The reaction mixture was heated to 30-40° C. and the separated aqueous layer was extracted with methylene dichioride (3 mE). The combined organic layer was washed with water (5 mE). The organic layer was separated and distilled under vacuum at 45-50° C. The residue was stirred at reflux for 1 hour with methanol (5 mE), filtered and washed with methanol. The product was dried at 60° C. under vacuum till constant weight.

Reference： [1]Current Patent Assignee: GANSU HAOTIAN CHEMEXPRESS - CN103342704, 2016, B Location in patent: Paragraph 0039; 0040; 0041; 0050; 0052
[2]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US9603846, 2017, B2 Location in patent: Page/Page column 25

18
[ CAS Unavailable ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
270 mg	With potassium <i>tert</i>-butylate In tetrahydrofuran; ethanol for 12h; Reflux;	3 Preparation of Compound Apixaban Compound24(0.3 g) was dissolved in 4.5mL of anhydrous tetrahydrofuran was added a solution of 5-iodo-pentyl chloride (0.44 g of) triethylamine (0.16 g of), ice-water cooling.Naturally to room temperature, the reaction was stirred for a half hour, the reaction was quenched with 5mL of water, ethyl acetate (10mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude was dissolved in a mixed solvent of 2mL of ethanol and 2mL of tetrahydrofuran was added potassium t-butoxide (0.47 g of), the reaction was heated at reflux for 12 hours, concentrated under reduced pressure, to the residue water was added 5mL dichloromethane (10mL × 2) and the combined organic phase was dried over anhydrous sodium sulfate, and concentrated under pressure to recover the solvent crude, petroleum ether crystallized from ethyl acetate to give an off-white solid 270mg, 75% yield.

Reference： [1]Current Patent Assignee: GANSU HAOTIAN CHEMEXPRESS - CN103342704, 2016, B Location in patent: Paragraph 0053; 0054; 0063; 0064; 0065

19
[ 503612-47-3 ]
[ CAS Unavailable ]
[ 534-07-6 ]
[ 503612-79-1 ]

Yield	Reaction Conditions	Operation in experiment
1.2%	Stage #1: apixaban; 1,3-Dichloroacetone at 130℃; for 24h; Stage #2: dimethyl amine In water for 48h;	96 Example 96 3-{4-[(dimethylamino)methyl]-1,3-oxazol-2-yl}-1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one Example 96 3-{4-[(dimethylamino)methyl]-1,3-oxazol-2-yl}-1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one To 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (0.142 g, 0.31 mmol) was added excess 1,3-dichloroacetone (0.2 g). The reaction was heated to 130° C. for 24 h. The reaction was cooled and excess 40% NMe2 in water was added and the resulting mixture stirred for 48 h. Repeated purification by HPLC and freeze-drying afforded 2 mg (1.2%) of a white solid; High Resolution Mass Spec (M+H)+ for C30H33N6O4 541.2582.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2017/50964, 2017, A1 Location in patent: Paragraph 0869

20
[ 503612-47-3 ]
[ 534-07-6 ]
[ 503614-89-9 ]

Yield	Reaction Conditions	Operation in experiment
42%	at 130℃; for 24h;	99.A Part A. Part A. To 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (1 g, 2 mmol) was added excess 1,3-dichloroacetone (2 g). The reaction was heated to 130° C. for 24 h. The reaction was cooled and purification by chromatography using 0-3% MeOH in CH2Cl2 afforded 0.53 g (42%) white solid; 1H NMR (CDCl3) δ 7.75 (s, 1H), 7.53 (d,j=8.8 Hz, 2H), 7.37 (d,j=8.8 Hz, 2H), 7.27 (d,j=8.8 Hz, 2H), 6.93 (d,j=9.1 Hz, 2H), 4.60 (s, 2H), 4.19 (t,j=6.6 Hz, 2H), 3.81 (3H, s), 3.60 (m, 2H), 3.42 (t,j=6.6 Hz, 2H), 2.57 (m, 2H), 1.95 (m, 4H) ppm

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2017/50964, 2017, A1 Location in patent: Paragraph 0873

21
[ 67-56-1 ]
[ 503612-47-3 ]
[ 1704504-79-9 ]

Yield	Reaction Conditions	Operation in experiment
5 g	Stage #1: methanol With potassium hydroxide at 20℃; for 0.166667h; Stage #2: apixaban With [bis(acetoxy)iodo]benzene at 20℃; for 2h;	K0H (1.55 g, 0.08 mol) was added to 150 ml of methanol, stirred at 20 ° C for 10 min,After dissolving, add (5g, 0.01 lmo 1) A and 3.5g iodobenzoacetate. After stirring at 20 ° C for 2 h, the reaction solution changed from turbidity to pale red transparent liquid.The solvent was evaporated to give 5 g of a red solid,The resulting solid is taken directly.

Reference： [1]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN104513239, 2017, B Location in patent: Paragraph 0209; 0238; 0405; 0406

22
[ CAS Unavailable ]
[ 503612-47-3 ]
[ 50-00-0 ]
[ 1704503-41-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	at 20℃; for 1h; Reflux;	3.8 g, 8.3 mmol) of apaxabine, (0.82 g, 9 mmol) of piperidine was added to a 250 ml syringe,(0.73 g, 9 mmol) of 37% formaldehyde solution at room temperature for 0.5 h, then heated to reflux for 0.5 h, cooled to precipitate a solid and filtered to obtain 3.7 g of product yield 80%.

Reference： [1]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN104513239, 2017, B Location in patent: Paragraph 0227; 0235; 0462; 0463

23
[ 623-12-1 ]
[ 2222840-76-6 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
25.82 g	With copper(l) iodide; sodium hydroxide In N,N-dimethyl-formamide at 70℃; for 9h; Inert atmosphere;	2.6 7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazole [3,4-c Pyridine-3-carboxamide 9 (16.88 g, 2.0 mol) was mixed with 4-methoxychlorobenzene 10 (15 g, 2.4 mol), 50% sodium hydroxide solution (120 ml), organic solvent N, N- Dimethylformamide (60ml) with catalyst copper iodide in nitrogen Under the protection of gas, the mixture was thoroughly stirred and reacted at 70 ° C for 9 hours to form an alkylation reaction to form 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxoperpipe). Pyridin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazole[3,4-c]pyridine-3-carboxamide 11 (25.82 g, 3.67 mol).

Reference： [1]Current Patent Assignee: Dong Dandan - CN108178757, 2018, A Location in patent: Paragraph 0017

24
[ 2231798-69-7 ]
[ 438056-68-9 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
45%	Stage #1: 3-carbamoyl-4-(2-hydroxyethyl)-1-(4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid With thionyl chloride at 20 - 75℃; for 3h; Stage #2: 1-(4-aminophenyl)piperidine-2-one With potassium <i>tert</i>-butylate In toluene at 20 - 25℃; for 15h;	10 Example 10: Preparation of 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. To a stirred solution of compound X (0.05g, 0. l637mmoles) thionyl chloride (0.25mL, 5V) was added at 20°C to 30°C. The reaction mixture was heated at 75°C for 3h, solvent was evaporated under reduced pressure, toluene (1 .OmL), potassium t-butoxide (0.1 lg,0.49 13 mmoles) and compound VII (0.031g, 0.1637 mmoles) was added at 20°C to 30°C, stirred for 15h at 25°C. The reaction mixture was quenched using water (5mL), extracted with ethyl acetate (lOmL), dried over an hydrous sodium sulphate and organic layer evaporated under reduced pressure to yield crude compound. The crude compound was purified using column chromatography to yield off white to white solid compound of formula (I)(0.033g, 45% yield)with HPLC purity 99.87%, LCMS: 477[M+H2Oj, ‘H-NMR (DMSO, 400 MHz): 1.841-1.851 (4H, m), 2.383 (2H, m), 3.20 (2H, m), 3.59 (2H, m), 3.80 (3H, s), 4.05 (2H, m),7.00 (2H, m), 7.26 (2H, m), 7.35 (2H, m), 7.44 (1H, d), 7.51 (2H, m), 7.72 (1H, s).

Reference： [1]Current Patent Assignee: THE KALYANI GROUP - WO2018/127936, 2018, A1 Location in patent: Page/Page column 23; 24

25
[ 2231798-68-6 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium <i>tert</i>-butylate In toluene at 20 - 25℃;	11 Example 11: Preparation of 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. To a stirred solution of compound IX (2.9g, 0.0052 moles) in toluene (290mL), potassium tbutoxide (3.5g, 0.0313 moles) was added lot wise for 1.5h at 20°C to 25°C. The reaction mixture was stirred at 20°C to 25°C for 6 to 8h, quenched using water (200mL), stirred for additional lh and filtered, washed with water (5OmL), dried under reduced pressure to yield crude compound. The crude compound was purified by recrystallization using in acetone:water (8:2, 25V) to yield off white to white solid of compound (I) (2.Og, 83% yield), with HPLC purity 99.93%,LCMS: 477 [M+H2Oj, ‘H-NMR (DMSO, 400 MHz): 1.841-1.851 (4H, m), 2.383 (2H, m), 3.20 (2H, m), 3.59 (2H, m), 3.80 (3H, s), 4.05 (2H, m), 7.00 (2H, m), 7.26 (2H, m), 7.35 (2H, m), 7.44 (1H, d), 7.51 (2H, m), 7.72 (1H, s).

Reference： [1]Current Patent Assignee: THE KALYANI GROUP - WO2018/127936, 2018, A1 Location in patent: Page/Page column 24; 25

26
[ 2231798-71-1 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium hydroxide In methanol; water at 25 - 35℃;	12.2 Example 12.2 To a stirred solution of aq. NaOH (llSg, 2.87 moles) in 1.78L water and 1.78L methanol was added compound XIII (178g, 0.3591 moles) at 25°C to 30 °C. The resultant mixture was heated to 30°C to 35 °C for 4 to 6h. Water (1.78L, 1OV) was then added at 20°C to 25 °C, stirred for additional 10 mm, filtered the reaction mixture and washed with water twice (3.56L, by), dried under reduced pressure to yield crude compound I. The crude compound was purified by recrystallisation in mixture of toluene: methanol (2:1, 15V) to yield off white to white solid of compound (I) (11 8g, 72% yield) with HPLC purity 99.88%.

Reference： [1]Current Patent Assignee: THE KALYANI GROUP - WO2018/127936, 2018, A1 Location in patent: Page/Page column 25; 26

27
[ 503612-47-3 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
70%	With hydrogenchloride In water at 40 - 45℃; for 3.16667h;	2 In a 500 mL flask,Add 9.2 g (0.02 mol) of apixaban,Add 60g of 1mol/L hydrochloric acid,After stirring for 10 minutes,Warm up to 40 ~ 50 ° C,Reaction for 3 h. The mixture was cooled, and the solvent was evaporated to dryness. The residue was purified by column chromatography (mobile phase methanol / methylene chloride), and the main product was evaporated to dryness to yield 6.7 g of a yellow solid. HPLC purity: 98%, yield 70%

Reference： [1]Current Patent Assignee: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD. - CN108912119, 2018, A Location in patent: Paragraph 0021-0035

28
[ 6026-86-4 ]
[ 1423803-24-0 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
89.2%	With sodium tetrahydroborate In methanol; toluene at 50 - 100℃; for 11h;	9; 2 Example 9: Preparation of apixaban (I) To a 500 ml four-necked flask equipped with a stirring, thermometer, reflux condenser and dropping funnel, 30 g of methanol and 30 g of toluene were added.3.8 g (0.01 mol) of 1-(4-methoxyphenyl)-7-oxo-6-(4-aminophenyl)-4,5,6,7-tetrahydro-1H prepared in Example 7. -pyrazolo[3,4-c]pyridine-3-carboxamide (VI),1.2 g of sodium borohydride, 1.8 g (0.014 mol) of methyl 5-oxo-n-pentanoate,The reaction was stirred at 50 to 55 ° C for 6 hours, and then the reaction was stirred at 95 to 100 ° C for 5 hours while recovering methanol by distillation.Cool to 20 to 25 ° C, acidify the system with a 20 wt% aqueous solution of ammonium chloride pH 4.0-4.5,Filtration, the filter cake was washed twice with water, 20 g each time, and 20 g of methanol was washed once.Drying gave 4.1 g of apixaban in a yield of 89.2% and a liquid phase purity of 99.7%.

Reference： [1]Current Patent Assignee: XINFA PHARMACEUTICAL CO LTD - CN110204541, 2019, A Location in patent: Paragraph 0088-0091; 0097; 0098

29
[ 22668-36-6 ]
[ 1423803-24-0 ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
87.1%	With sodium tris(acetoxy)borohydride In ethanol; toluene at 50 - 100℃; for 11h;	10 Example 10: Preparation of apixaban (I) To a 500 ml four-necked flask equipped with a stirring, thermometer, reflux condenser and dropping funnel, 30 g of ethanol and 30 g of toluene were added.3.8 g (0.01 mol) of 1-(4-methoxyphenyl)-7-oxo-6-(4-aminophenyl)-4,5,6,7-tetrahydro-1H prepared in Example 8. -pyrazolo[3,4-c]pyridine-3-carboxamide (VI),3.5 g of sodium triacetoxyborohydride, 2.2 g (0.015 mol) of ethyl 5-oxo-n-pentanoate,The reaction was stirred at 50 to 55 ° C for 6 hours, and then the reaction was stirred at 95 to 100 ° C for 5 hours while recovering ethanol by distillation.Cool to 20 to 25 ° C, acidify the system with a 20 wt% aqueous solution of ammonium chloride pH 4.0-4.5, filter, filter cake washed twice with water,Each time 20 g, 20 g of methanol was washed once and dried to obtain 4.0 g of apixaban, the yield was 87.1%, and the liquid phase purity was 99.8%.

Reference： [1]Current Patent Assignee: XINFA PHARMACEUTICAL CO LTD - CN110204541, 2019, A Location in patent: Paragraph 0092; 0093

30
[ 59-67-6 ]
[ 503612-47-3 ]
[ 2387907-19-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	In 2,2,2-trifluoroethanol; acetone at 40℃; for 24h;	1-71 Add 0.182g of nicotinic acid and 0.68g of apixaban to 4ml of 0.5% trifluoroethanol, stir at 40C for 24h, add 6ml of acetone, and stir at the same temperature for 2 hours. Filter to obtain white crystals. Dry in a drying cabinet at 40 C under vacuum for 4 h to obtain 0.79 g of white crystals. The molar yield is 89%.

Reference： [1]Current Patent Assignee: GUANGZHOU BAIYUNSHAN PHARMACEUTICAL HOLDINGS CO., LTD. - CN110452240, 2019, A Location in patent: Paragraph 0039-0042; 0054-0103

31
[ 503614-91-3 ]
[ CAS Unavailable ]
[ 503612-47-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 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 With trifluoroacetic acid; trimethyl orthoformate In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: formamide With sodium methylate In N,N-dimethyl-formamide at 40℃;	1.4 Step 4 Dissolve Intermediate 3 (35g, 71.6mmol) in anhydrous N, N-dimethylformamide (180mL), and add trimethyl orthoformate (1.5g according to the water content of DMF) to this solution ), Trifluoroacetic acid (1.5g), stirred for 30min, at 0 , add formamide (32g, 716mmol), slowly add sodium methoxide (5.8g, 107.4mmol), warm to 40 reaction 4-5h, TLC shows After the reaction was completed, the reaction solution was cooled to room temperature, and ice water (350 mL) was slowly added to the reaction solution, which was sufficiently stirred until a precipitate precipitated, filtered off with suction, and dried by air blowing at 50 ° C. to obtain crude A47-3 (28.5 g).

Reference： [1]Current Patent Assignee: JIANGSU KANION PHARMACEUTICAL CO., LTD. - CN110862389, 2020, A Location in patent: Paragraph 0058-0059; 0063

32
[ 503612-47-3 ]
[ 110-16-7 ]
[ 2434624-53-8 ]

Yield	Reaction Conditions	Operation in experiment
45.3 g	In methanol; 2,2,2-trifluoroethanol at 30 - 35℃; for 19h;	3 Example 3: Preparation of apixaban / maleic acid eutectic form III At room temperature, 11.3 g of maleic acid, 60 g of apixaban, 350 ml of trifluoroethanol, and 170 mL of methanol were added to the reaction bottle, and stirred for 1 hour to dissolve.Keep the resulting solution at 30-35 ° C, continue stirring for 18 hours, and then control the cooling rate at 10-15 ° C / hour, cool the crystallization solution to 0-5 ° C for crystallization, and crystallization for 5 hours.A large amount of crystals precipitated, and the resulting crystals were filtered and washed with a small amount of methanol, and then vacuum-dried at 55 ° C for 24 hours to obtain 45.3 g of apixaban / maleic acid co-crystal.After testing, the obtained co-crystal is apixaban / maleic acid co-crystal form III.The X-ray powder diffraction data of the sample are shown in Figure 7 and Table 3;The TGA pattern is shown in Figure 8; the DSC pattern is shown in Figure 9.

Reference： [1]Current Patent Assignee: ZHEJIANG TIANYU PHARMACEUTICAL - CN110922403, 2020, A Location in patent: Paragraph 0100-0103

33
[ 503612-47-3 ]
[ 147-85-3 ]
[ 2434624-56-1 ]

Yield	Reaction Conditions	Operation in experiment
54.3 g	In methanol; 2,2,2-trifluoroethanol at 30 - 35℃; for 19h;	4 Example 4: Preparation of apixaban / L-proline eutectic form IV At room temperature, 11.3 g of L-proline, 60 g of apixaban, 350 ml of trifluoroethanol, and 170 mL of methanol were added to the reaction bottle. After stirring for 1 hour to dissolve, the resulting solution was kept at 30 to 35 ° C. and stirring was continued for 18 hours. ,Then control the cooling rate of 10-15 / hour, the crystallization solution is cooled to 0 ~ 5 crystallization,After 6 hours of crystallization, a large number of crystals precipitated,The resulting crystals were filtered and washed with a small amount of methanol, and then vacuum dried at 55 ° C for 24 hours54.3 g of apixaban / L-proline co-crystal was obtained.After testing, the resulting eutectic is Apixaban / L-proline eutectic Form IV.The X-ray powder diffraction data of the samples are shown in Figure 10 and Table 4;The TGA pattern is shown in Figure 11; the DSC pattern is shown in Figure 12.

Reference： [1]Current Patent Assignee: ZHEJIANG TIANYU PHARMACEUTICAL - CN110922403, 2020, A Location in patent: Paragraph 0104-0107

34
[ 503612-47-3 ]
[ 87-69-4 ]
[ 2434624-59-4 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; 2,2,2-trifluoroethanol at 30 - 35℃; for 19h;	5 Example 5: Preparation of apixaban / L-tartaric acid eutectic form V At room temperature, 19.6 g of L-tartaric acid, 60 g of apixaban, 350 ml of trifluoroethanol, and 170 mL of methanol were added to the reaction bottle. After stirring for 1 hour to dissolve, the resulting solution was kept at 30 to 35 ° C. and stirring continued for 18 hours.Then control the cooling rate of 10-15 / hour, the crystallization solution is cooled to 0 ~ 5 crystallization,After 6 hours of crystallization, a large number of crystals were precipitated.The crystals were filtered and washed with a small amount of methanol,It was then vacuum dried at 55 ° C for 24 hours to obtain apixaban / L-tartaric acid co-crystal.After testing, the resulting eutectic is Apixaban / L-tartaric acid eutectic Form V.The X-ray powder diffraction data of the samples are shown in Figure 13 and Table 5;The TGA pattern is shown in Figure 14; the DSC pattern is shown in Figure 15.

Reference： [1]Current Patent Assignee: ZHEJIANG TIANYU PHARMACEUTICAL - CN110922403, 2020, A Location in patent: Paragraph 0108-0111

35
[ 503612-47-3 ]
[ 141-82-2 ]
[ 2756586-22-6 ]

Yield	Reaction Conditions	Operation in experiment
53.5 g	In methanol; 2,2,2-trifluoroethanol at 30 - 35℃; for 19h;	1 Example 1: Preparation of crystalline form I of apixaban / malonic acid eutectic At room temperature, add 10.2 g of malonic acid, 60 g of apixaban, 350 ml of trifluoroethanol, and 170 mL of methanol to the reaction flask, stir for 1 hour to dissolve, and then keep the resulting solution at 30 to 35 ° C., and continue stirring for 18 hours.Then control the cooling rate of 10-15 / hour, the crystallization solution is cooled to 0 ~ 5 crystallization, crystallization 5 hours, a large number of crystals are precipitated, the resulting crystals are filtered and washed with a small amount of methanol, and then vacuum dried at 55 for 24 hours53.5 g of apixaban / malonic acid co-crystal was obtained.After testing, the resulting eutectic is crystalline form I of apixaban / malonic acid eutectic.The X-ray powder diffraction data of the samples are shown in Figure 1 and Table 1; the TGA pattern is shown in Figure 2; the DSC pattern is shown in Figure 3.

Reference： [1]Current Patent Assignee: ZHEJIANG TIANYU PHARMACEUTICAL - CN110922403, 2020, A Location in patent: Paragraph 0092-0095

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	503612-47-3	MDL No. :	MFCD11977295
Formula :	C₂₅H₂₅N₅O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QNZCBYKSOIHPEH-UHFFFAOYSA-N
M.W :	459.50	Pubchem ID :	10182969
Synonyms :	BMS-562247-01

Num. heavy atoms :	34
Num. arom. heavy atoms :	17
Fraction Csp3 :	0.28
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	132.7
TPSA :	110.76 Å²

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) :	-7.51 cm/s

Log Po/w (iLOGP) :	3.6
Log Po/w (XLOGP3) :	2.24
Log Po/w (WLOGP) :	1.94
Log Po/w (MLOGP) :	2.03
Log Po/w (SILICOS-IT) :	1.95
Consensus Log Po/w :	2.35

[ CAS No. 503612-47-3 ] {[proInfo.proName]}

Quality Control of [ 503612-47-3 ]

Related Doc. of [ 503612-47-3 ]

Product Details of [ 503612-47-3 ]

Calculated chemistry of [ 503612-47-3 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 503612-47-3 ]

Application In Synthesis of [ 503612-47-3 ]

[ 503612-47-3 ] Synthesis Path-Downstream 1~35

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

Log S (ESOL) :	-4.14
Solubility :	0.0333 mg/ml ; 0.0000724 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.2
Solubility :	0.0289 mg/ml ; 0.0000629 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.7
Solubility :	0.000925 mg/ml ; 0.00000201 mol/l
Class :	Moderately soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.48

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling