[ CAS No. 503614-92-4 ] {[proInfo.proName]}

Name: 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|97%
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Quality Control of [ 503614-92-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 503614-92-4 ]

SDS Specification

Alternatived Products of [ 503614-92-4 ]

Product Details of [ 503614-92-4 ]

CAS No. :	503614-92-4	MDL No. :	MFCD22376657
Formula :	C₂₅H₂₄N₄O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PPUHOTDYJQGTAE-UHFFFAOYSA-N
M.W :	460.48	Pubchem ID :	22240440
Synonyms :

Calculated chemistry of [ 503614-92-4 ]

Physicochemical Properties

Num. heavy atoms :	34
Num. arom. heavy atoms :	17
Fraction Csp3 :	0.28
Num. rotatable bonds :	5
Num. H-bond acceptors :	6.0
Num. H-bond donors :	1.0
Molar Refractivity :	131.57
TPSA :	104.97 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-7.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.03
Log Po/w (XLOGP3) :	2.89
Log Po/w (WLOGP) :	2.54
Log Po/w (MLOGP) :	2.43
Log Po/w (SILICOS-IT) :	2.19
Consensus Log Po/w :	2.62

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-4.56
Solubility :	0.0128 mg/ml ; 0.0000278 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.75
Solubility :	0.0081 mg/ml ; 0.0000176 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.48
Solubility :	0.00153 mg/ml ; 0.00000332 mol/l
Class :	Moderately soluble

Medicinal Chemistry

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

Safety of [ 503614-92-4 ]

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 [ 503614-92-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 503614-92-4 ]

[ 503614-92-4 ] Synthesis Path-Downstream 1~68

1
[ 385425-15-0 ]
[ 148-24-3 ]
[ 503614-56-0 ]
[ 503614-92-4 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; CuI; potassium carbonate; In dimethyl sulfoxide; ethyl acetate;	Example 52 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 (61). A solution of 1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (50, 2.0 g, 6.4 mmol), 1-(4-iodo-phenyl)-piperidin-2-one (60, 2.5 g, 8.3 mmol, 1.3 equiv), and K2CO3 (325 mesh powder, 1.80 g, 12.8 mmol, 2.0 equiv) in DMSO (35 mL) was degassed three times under a steady nitrogen stream before being treated with CuI (244 mg, 1.3 mmol, 20% equiv) and 8-hydroxyquinoline (189 mg, 1.3 mmol, 20% equiv) under N2. The resulting reaction mixture was subsequently degassed three times again before being warmed up to 125 C. for 10 h. When HPLC showed the coupling reaction was complete, the reaction mixture was cooled down to 5-10 C. before being treated with 14% NH4OH aqueous solution (30 mL) and ethyl acetate (30 mL) at 5-10 C. with good stirring. The mixture was stirred for an additional 1 h at 5-10 C. The mixture was filtered through a Celite bed and the Celite bed was washed with water (210 mL). The two layers of the filtrates were separated, and the aqueous layer was acidified by 1 N aqueous HCl solution to pH=4. The mixture was subsequently stirred at 5-10 C. for an additional 1 h. The solids were collected by filtration, washed with water (25 mL), and dried in vacuo at 40-45 C. for 12 h to afford the crude 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 (61, 2.0 g, 2.95 g theoretical, 68%), which was found to be pure enough to do the following reaction without further purification. For 61, CIMS m/z 461 (M++H, C25H24N4O5).

Reference： [1]Patent: US2003/181466,2003,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
[ 675-20-7 ]
[ 473927-64-9 ]
[ 503614-91-3 ]
[ 503614-92-4 ]

Yield	Reaction Conditions	Operation 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%.

Reference： [1]Patent: WO2014/75648,2014,A1 .Location in patent: Page/Page column 13

4
[ 27143-07-3 ]
[ 503614-92-4 ]

Reference： [1]Patent: WO2014/75648,2014,A1
[2]Patent: CN104045637,2016,B
[3]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810
[4]Patent: CN107400131,2017,A

5
[ 473927-69-4 ]
[ 503614-92-4 ]

Reference： [1]Patent: WO2014/75648,2014,A1

6
5-bromo-N-[4-(3,3-dichloro-2-oxopiperidin-1-yl)phenyl]valeroyl amide [ No CAS ]
[ 503614-92-4 ]

Reference： [1]Patent: WO2016/20711,2016,A1
[2]Patent: WO2016/20711,2016,A1

7
3,3-dichloro-1-[4-(2-oxopiperidin-1-yl)phenyl]piperidin-2-one [ No CAS ]
[ 503614-92-4 ]

Reference： [1]Patent: WO2016/20711,2016,A1
[2]Patent: WO2016/20711,2016,A1

8
3-chloro-1-[4-(2-oxopiperidin-1-yl)phenyl]-5,6-dihydropyridin-2(1H)-one [ No CAS ]
[ 503614-92-4 ]

Reference： [1]Patent: WO2016/20711,2016,A1
[2]Patent: WO2016/20711,2016,A1

9
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 ]
[ 503614-92-4 ]

Yield	Reaction Conditions	Operation in experiment
13.6 g	With acetic acid; In water; butan-1-ol;Heating;	21.8 g substance of formula lib obtained in Example 8 is suspended in water, 55 mL of 1 - butanol is added and the mixture is heated. Activated carbon is added to the solution, stirred while hot, then the carbon is filtered off and washed. 2.7 g (45 mmol) of concentrated acetic acid in a solution prepared with 10 mL water is added dropwise to the hot solution under vigorous stirring. The mixture is cooled to room temperature, the precipitated substance is filtered off and washed. After drying 13.6 g (29.5 mmol) of the title substance is obtained. Mp.: 276-278 C. IR (KBr, cm"1): 3407, 2904, 2534, 1710, 1667, 1613, 1516, 1255, 1151. HNMR (DMSO-d6, 400 MHz): 13.19 (bs, 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). CNMR (DMSO-de, 100 MHz): 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.

Reference： [1]Patent: WO2016/20711,2016,A1 .Location in patent: Page/Page column 21-22

10
[ 503614-92-4 ]
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 ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium carbonate; In water; butan-1-ol;Heating;	0.46 g (1 mmol) l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin- l-yl)phenyl]-4, 5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 11c is suspended in aqueous 1-butanol, then 92 mg (1.1 mmol) of sodium bicarbonate is added. The suspension is heated with stirring until dissolution, and then slowly cooled to room temperature. The precipitated substance is filtered, washed and air dried. After drying 0.42 g (0.76 mmol, 76%) of white crystalline substance is obtained. Mp.: 360-364 C IR (KBr, cm"1): 3454, 3260, 2954, 1666, 1646, 1576, 1537, 1512, 1464, 1435, 1383, 1335, 1305, 1285, 1251, 1166, 1145, 1022, 834. HNMR (DMSO-de, 400 MHz): 7.45 (d, J=9.0 Hz, 2H); 7.34 (d, J=8.7 Hz, 2H); 7.26 (d, J=8.7 Hz, 2H); 6.94 (d, J=9.0 Hz, 2H); 4.00 (t, J=6.6Hz, 2H); 3.79 (s, 3H); 3.59 (t, J=5.5 Hz, 2H); 3.18 (t, J=6.6 Hz, 2H); 2.38 (t, J=6.4 Hz, 2H); 1.85 (m, 4H). Elemental analysis: C H N Calculated (%) 54.15 5.63 10.10 Measured (%): 53.93 5.47 10.05
281 mg	With sodium hydrogencarbonate; In N,N-dimethyl acetamide; water; at 100℃;	Heat 54.7 mg sodium hydrogen carbonate and 300 mg l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo- l-piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a mixture of 6.0 mL dimethylacetamide and 1.9 mL demineralized water to 100 C, then cool the solution. Filtrate the solid phase, wash with a small amount of cold dimethylacetamide and dry under an IR lamp. Product: 281 mg white crystal melting point: 345-355 C IR (KBr): 3440, 2936, 1643, 1613, 1514, 1304, 1248, 1164, 1021 cm"1. HNMR (DMSO-de): delta 7.44 (d, 2H, J = 8.7 Hz), 7.34 (d, 2H, J = 8.6 Hz), 7.26 (d, 2H, J = 8.5 Hz), 6.95 (d, 2H, J = 8.7 Hz), 4.00 (t, 2H, J = 6.3 Hz), 3.79 (s, 3H), 3.59 (t, 2H, J = 5.8 Hz), 3.18 (t, 2H, J = 6.4 Hz), 2.38 (t, 2H, J = 5.6 Hz), 1.85 (m, 4H) ppm. ICP-OES: 4.1 m/m% Na (theoretical: 4.8 m/m%) Figure 4 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the sodium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a sodium ion), produced according to the process described above, with characteristic X-ray powder dif- fraction peaks as follows: 2Theta (±0.2 2Theta): 4.15; 6.95; 8; 8.12; 8.72; 9.24; 10.04; 10.72; 12.55; 13.63; 14.37; 14.71; 14.91; 15.86; 16.3; 16.79; 17.26; 17.9; 18.14; 18.54; 18.83; 19.2; 19.44; 20.09; 20.55; 20.7; 21.07; 21.8; 22.34; 22.72; 23.98; 25.11; 25.51; 25.99; 26.5; 27.08; 27.37; 27.91; 28.29; 29.3; 29.53; 29.9; 30.51; 30.96; 31.33; 31.67; 32.27; 32.86; 33.13; 34.34; 34.64; and the most characteristic peaks are as follows: 2Theta (±0.02 2Theta): 4.15; 6.95; 8; 8.12; 10.72; 14.37; 14.71; 14.91; 15.86; 16.3; 16.79; 18.14; 18.54; 18.83; 19.2; 20.09; 20.55; 20.7; 21.07; 21.8; 22.72; 25.11; 25.99; 26.5; 27.08; 27.91; 30.51.

Reference： [1]Patent: WO2016/20711,2016,A1 .Location in patent: Page/Page column 22-23
[2]Patent: WO2016/79549,2016,A1 .Location in patent: Page/Page column 12-13

11
[ 503614-91-3 ]
[ 503614-92-4 ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Patent: US2017/50964,2017,A1 .Location in patent: Paragraph 0886
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810
[3]Patent: CN104045637,2016,B .Location in patent: Paragraph 0072; 0085-0087
[4]Patent: CN110467614,2019,A .Location in patent: Paragraph 0066-0080
[5]Patent: CN107400131,2017,A .Location in patent: Paragraph 0031; 0051-0053
[6]Patent: WO2016/20711,2016,A1 .Location in patent: Page/Page column 21
[7]Patent: WO2016/20711,2016,A1
[8]Patent: WO2016/79549,2016,A1 .Location in patent: Page/Page column 11-12
[9]Patent: CN103896940,2016,B .Location in patent: Paragraph 0044; 0061-0062

12
1-(4-aminophenyl)piperidine-2-one [ No CAS ]
[ 503614-92-4 ]

Reference： [1]Patent: WO2016/20711,2016,A1
[2]Patent: WO2016/20711,2016,A1

13
[ 38560-30-4 ]
[ 503614-92-4 ]

Reference： [1]Patent: WO2016/20711,2016,A1
[2]Patent: WO2016/20711,2016,A1
[3]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810
[4]Patent: CN107400131,2017,A

14
5-bromo-N-[4-(2-oxopiperidin-1-yl)phenyl]valeroyl amide [ No CAS ]
[ 503614-92-4 ]

Reference： [1]Patent: WO2016/20711,2016,A1
[2]Patent: WO2016/20711,2016,A1

15
[ 503614-92-4 ]
[ 743369-26-8 ]
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 ]

Yield	Reaction Conditions	Operation in experiment
261 mg	In N,N-dimethyl acetamide; water; acetonitrile;Heating;	Dissolve 41 mg zinc carbonate and 300 mg l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a warm mixture of 9.0 mL demineralized water, 7.0 mL acetonitrile and 0.5 mL dimethylacetamide, then concentrate the solution to a final volume of 10 mL in vacuum. Cool the solution while stirring, and then continue stirring for 1 hour. Filtrate the resulting solid phase, wash with 1 mL cold acetonitrile and dry under an IR lamp. Product: 261 mg white powder melting point: 291.5-300 C IR (KBr): 3425, 2948, 1672, 1632, 1513, 1300, 1251, 1170, 1147, 1022 cm"1. HNMR (DMSO-de): delta 7.44 (d, 4H, J = 8.9 Hz), 7.34 (d, 4H, J = 8.7 Hz), 7.27 (d, 4H, J = 8.8 Hz), 6.91 (d, 4H, J = 9.0 Hz), 4.03 (t, 4H, J = 6.6 Hz), 3.76 (s, 6H), 3.59 (t, 4H, J = 5.9 Hz), 3.12 (t, 4H, J = 6.6 Hz), 2.38 (t, 4H, J = 6.0 Hz), 1.85 (m, 8H) ppm. ICP-OES: 6.1 m/m% Zn (theoretical: 6.6 m/m%) Figure 7 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the zinc salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a zinc ion), produced according to the process described above, with characteristic X-ray powder diffraction peaks as follows: 2Theta (±0.2 2Theta): 6.86; 7.34; 7.73; 8.03; 8.49; 8.89; 9.42; 9.71; 10.49; 10.95; 11.73; 12.25; 12.7; 14.28; 14.71; 14.94; 15.5; 16.11; 16.44; 16.99; 17.71; 18.09; 18.4; 18.87; 19.14; 19.44; 19.89; 20.24; 20.67; 21.15; 21.53; 21.9; 22.59; 23.1; 23.54; 23.82; 24.34; 24.79; 25.04; 25.5; 25.99; 26.42; 26.81; 27.18; 27.52; 28.2; 28.82; 29.51; 29.94; 30.55; 31.08; 31.66; 32.35; 32.63; 33.2; 33.5; 34.2; and its most characteristic peaks are the following: 2Theta (±0.2 2Theta): 6.86; 7.34; 7.73; 9.71 ; 10.49; 10.95; 11.73; 12.25; 12.7; 14.94; 15.5; 16.11; 16.99; 17.71 ; 18.09; 18.4; 19.89; 20.24; 21.15; 21.53; 21.9; 23.1; 23.54; 23.82; 24.34; 24.79; 25.5; 27.18; 27.52; 28.2.

Reference： [1]Patent: WO2016/79549,2016,A1 .Location in patent: Page/Page column 17

16
[ 503614-92-4 ]
[ 108-91-8 ]
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 ]

Yield	Reaction Conditions	Operation in experiment
329 mg	In ethanol; acetonitrile;Heating;	Warm up 75 cyclohexylamine and 300 mg l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a mixture of 30 mL ethanol and 20 mL acetonitrile. Leave the suspension to cool to room temperature while stirring, and continue stirring for 24 hours. Filtrate the solid substance, wash with 1 mL cold ethanol and dry under an IR lamp. Product: 329 mg white powder melting point: 249.5-259 C IR (KBr): 3441, 2941, 2860, 1674, 1646, 1570, 1540, 1516, 1375, 1298, 1257 cm"1. HNMR (DMSO-de): delta 7.42 (d, 2H, J = 8.6 Hz), 7.34 (d, 2H, J = 8.2 Hz), 7.26 (d, 2H, J = 7.8 Hz), 6.96 (d, 2H, J = 8.1 Hz), 4.00 (t, 2H, J = 6.1 Hz), 3.79 (s, 3H), 3.59 (t, 2H, J = 5.7 Hz), 3.16 (t, 2H, J = 5.9 Hz), 2.88 (m, 1H), 2.38 (t, 2H, J = 5.5 Hz), 1.85 (m, 6H), 1.69 (m, 2H),.1.56 (m, 1H), 1.21 (m, 4H), 1.07 (m, 1H) ppm. Figure 9 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the cyclohexyl ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a cyclohecxyl ammonium ion), produced according to the process described above, with the characteristic X-ray powder diffraction peaks as follows: 2Theta (±0.2 2Theta): 4.15; 5.03; 5.8; 6.85; 7.69; 8.9; 9.22; 10.09; 13.25; 13.74; 14.22; 14.78; 15.51; 16.73; 17.2; 17.82; 18.58; 19.28; 19.6; 20.86; 21.3; 22.39; 23.31; 24.73; 25.53; 26.41; 27.17; 27.81; 29.08; 29.78; 30.24; 31.31; 32.22; 32.81; and the most characteristic peaks are as follows: 2Theta (±0.02 2Theta): 5.03; 6.85; 7.69; 8.9; 15.51; 16.73; 17.2; 17.82; 18.58; 19.28; 19.6; 20.86; 21.3; 23.31

Reference： [1]Patent: WO2016/79549,2016,A1 .Location in patent: Page/Page column 20-21

17
[ 503614-92-4 ]
[ 108-18-9 ]
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 ]

Yield	Reaction Conditions	Operation in experiment
348 mg	In ethanol;Heating;	Dissolve 92 [iL diisopropyl amine and 300 mg l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a warm mixture of 20 mL ethanol and concentrate the solution to half volume in vacuum. Cool the solution to room temperature while stirring, and then continue stirring for 24 hour. Filtrate the solid substance, wash with 1 mL cold ethanol and dry under an IR lamp. Product: 348 mg white powder melting point: 278-281 C IR (KBr): 3463, 2962, 2862, 2763, 1675, 1605, 1511, 1372, 1300, 1249 cm"1. HNMR (DMSO-de): delta 7.43 (d, 2H, J = 8.8 Hz), 7.34 (d, 2H, J = 8.6 Hz), 7.26 (d, 2H, J = 8.5 Hz), 6.97 (d, 2H, J = 8.8 Hz), 4.02 (t, 2H, J = 6.5 Hz), 3.79 (s, 3H), 3.59 (t, 2H, J = 5.8 Hz), 3.27 (m, 2H), 3.19 (t, 2H, J = 6.6 Hz), 2.38 (t, 2H, J = 6.0 Hz), 1.85 (m, 4H), 1.20 (d, 12H, J = 6.4 Hz) ppm. Figure 10 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the diisopropyl ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l- yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a diisopropyl ammonium ion), produced according to the process described above, with characteristic X-ray powder diffraction peaks as follows: 2Theta (±0.2 2Theta): 5.62; 6.78; 7.86; 9.34; 9.9; 10.28; 11.18; 11.56; 12.54; 13.36; 13.85; 14.36; 14.82; 15.6; 16.11; 16.98; 17.5; 18.06; 18.5; 18.76; 19.5; 20.26; 20.65; 20.98; 21.31; 22.43; 23.56; 24.13; 24.76; 25.49; 27.92; 28.74; 29.88; 31.53; 32.87; 33.69; 34.3; 34.72; and the most characteristic peaks are as follows: 2Theta (±0.02 2Theta): 5.62; 6.78; 7.86; 9.34; 9.9; 1 1.18; 1 1.56; 12.54; 13.36; 13.85; 14.82; 16.11; 16.98; 17.5; 18.06; 18.5; 18.76; 19.5; 20.26; 20.65; 20.98; 21.31; 22.43; 23.56; 24.13; 27.92; 29.88.

Reference： [1]Patent: WO2016/79549,2016,A1 .Location in patent: Page/Page column 21-22

18
[ 503614-92-4 ]
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 ]

Yield	Reaction Conditions	Operation in experiment
212 mg	With ammonium carbonate; In ethanol; water;Heating;	Dissolve 31 mg ammonium carbonate and 300 mg l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a warm mixture of 3.0 mL ethanol and 0.6 mL demineralized water, then let the solution cool. After 3 hours of stirring, filtrate the precipitated solid substance, wash with 1 mL cold ethanol and dry under an IR lamp. Product: 212 mg white powder melting point: 280-281.5 C IR (KBr): 3483, 2946, 1661, 1631, 1515, 1303, 1254, 1165, 1141 cm"1. HNMR (DMSO-de): delta 7.44 (d, 2H, J = 8.8 Hz), 7.34 (d, 2H, J = 8.7 Hz), 7.26 (d, 2H, J = 8.7 Hz), 6.96 (d, 2H, J = 8.9 Hz), 4.02 (t, 2H, J = 6.5 Hz), 3.79 (s, 3H), 3.59 (t, 2H, J = 5.8 Hz), 3.17 (t, 2H, J = 6.6 Hz), 2.38 (t, 2H, J = 6.1 Hz), 1.85 (m, 4H) ppm. IC: 3.1 m/m% H4+ (theoretical: 3.8 m/m%) Figure 8 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the ammonium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is an ammonium ion), produced according to the process described above, with the characteristic X-ray powder diffraction peaks also listed in Table 2 as follows: 2Theta (±0.2 2Theta): 7.63; 8.69; 9.1; 9.64; 10.86; 11.48; 12.34; 13.3; 14.11; 14.48; 15.13; 16.35; 16.68; 17.1; 17.41; 18.18; 18.47; 19.24; 19.89; 20.25; 20.53; 21.19; 22.22; 22.86; 23.68; 24.26; 24.75; 25.56; 26.25; 27.5; 28.58; 28.82; 29.52; 29.98; 30.68; 31.73; 33.14; 33.7; and the most characteristic peaks are as follows 2Theta (±0.2 2Theta): 9.64; 13.3; 17.1; 17.41 ; 18.47; 19.89; 22.22; 22.86; 23.68; 24.75; and the most characteristic peaks are as follows 2Theta (±0.2 2Theta): 19.89; 23.68; 24.75.

Reference： [1]Patent: WO2016/79549,2016,A1 .Location in patent: Page/Page column 18-20

19
[ 503614-92-4 ]
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 cesium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
362 mg	With caesium carbonate; In N,N-dimethyl acetamide; water;Heating;	Dissolve 110 mg cesium carbonate and 300 mg l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a warm mixture of 1.6 mL demineralized water and 3.4 mL dimethyla- cetamide, then concentrate the solution to 50-60% volume in vacuum. Cool the solution and stir for 2 hours. Filtrate the precipitated solid substance, wash first with 2x 1 mL cold dimethyla- cetamide and then with 2x 1 mL cold diisopropyl ether, and finally dry it under an IR lamp. Product: 362 mg white powder melting point: 232-234.5 C IR (KBr): 3441, 2934, 1665, 1642, 1603, 1515, 1373, 1297, 1252 cm"1. HNMR (DMSO-de): delta 7.40 (d, 2H, J = 8.8 Hz), 7.34 (d, 2H, J = 8.7 Hz), 7.25 (d, 2H, J = 8.7 Hz), 6.95 (d, 2H, J = 8.9 Hz), 3.98 (t, 2H, J = 6.6 Hz), 3.79 (s, 3H), 3.59 (t, 2H, J = 5.9 Hz), 3.15 (t, 2H, J = 6.5 Hz), 2.38 (t, 2H, J = 6.0 Hz), 1.84 (m, 4H) ppm. IC: 22.8 m/m% Cs (theoretical: 22.4 m/m%) Figure 5 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the cesium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid formula 4b (where M is a cesium ion), produced according to the process described above, with the characteristic X-ray powder diffraction peaks also listed in Table 1 as follows: 2Theta (±0.2 2Theta): 5.88; 6.93; 8.42; 9.53; 11.45; 11.8; 13.94; 14.75; 15.53; 15.95; 16.67; 17.27; 17.62; 18.44; 18.63; 19.16; 19.46; 20.27; 20.63; 20.97; 21.51; 22.26; 22.66; 22.95; 23.16; 23.8; 24.28; 24.67; 25.03; 25.48; 25.98; 26.27; 26.94; 27.29; 27.89; 28.11; 28.54; 28.95; 29.36; 29.81; 30.18; 30.75; 31.48; 32.1; 32.46; 33.22; 33.72; 34.1; 34.61; and the most characteristic peaks are as follows 2Theta (±0.2 2Theta): 5.88; 14.75; 15.53; 16.67; 17.62; 19.16; 20.63; 21.51; 30.75; and the most characteristic peaks are as follows 2Theta (±0.2 2Theta): 5.88; 14.75; 16.67; 19.16.

Reference： [1]Patent: WO2016/79549,2016,A1 .Location in patent: Page/Page column 13-16

20
[ 503614-92-4 ]
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 ]

Yield	Reaction Conditions	Operation in experiment
131 mg	With calcium hydroxide; In water; acetonitrile;Heating;	Dissolve 24 mg calcium hydroxide and 300 mg l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a warm mixture of 3.0 mL demineralized water and 3.0 mL acetonitrile, then evaporate the solution to dryness in vacuum. Dissolve the remaining substance in 3.0 mL acetonitrile and stir for 2 hours at room temperature. Filtrate the resulting solid phase, wash with 1.0 mL cold acetonitrile and dry under an IR lamp. Product: 131 mg white powder melting point: 318-332 C IR (KBr): 3418, 2940, 1664, 1600, 1513, 1385, 1301, 1251, 1167, 1142, 1022 cm"1. HNMR (DMSO-de): delta 7.43 (d, 4H, J = 8.6 Hz), 7.32 (d, 4H, J = 7.5 Hz), 7.25 (d, 4H, J = 8.1 Hz), 6.93 (d, 4H, J = 8.2 Hz), 3.98 (m, 4H), 3.78 (s, 6H), 3.58 (t, 4H, J = 5.6 Hz), 3.17 (m, 4H), 2.39 (t, 4H, J = 5.9 Hz), 1.85 (m, 8H) ppm. ICP-OES: 4.1 m/m% Ca (theoretical: 4.2 m/m%) Figure 6 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the calcium salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a calcium ion), produced according to the process described above, with characteristic X-ray powder dif- fraction peaks as follows: 2Theta (±0.2 2Theta): 4.47; 5.41; 6.26; 6.8; 9.04; 9.55; 11.11; 12.87; 13.97; 14.85; 15.79; 16.57; 18.63; 20.59; 22.2; 23.77; 24.41; 26.35; 27.21; 29.41; and its most characteristic peaks are the following: 2Theta (±0.2 2Theta): 5.41; 14.85; 16.57; 20.59; 22.2; 24.41

Reference： [1]Patent: WO2016/79549,2016,A1 .Location in patent: Page/Page column 16

21
[ 503614-92-4 ]
[ 6674-22-2 ]
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 ]

Yield	Reaction Conditions	Operation in experiment
391 mg	In ethanol;Reflux;	Dissolve 97 [iL l,8-diazabycyclo[5.4.0]undec-7-ene and 300 mg l-(4-methoxyphenyl)-7-oxo-6- [4-(2-oxo-l-piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylic acid of formula 4c as in example 1 in a mixture of 10 mL ethanol on reflux temperature and evaporate the solution to dryness in vacuum. Treat the remaining substance with diisopropyl ether at room temperature and after stirring it overnight, filtrate the solid phase, wash with 2x3 mL diisopropyl ether and dry under an IR lamp. Product: 391 mg off-white powder melting point: 86.5-92 C IR (KBr): 3406, 3239, 3129, 2938, 1665, 1647, 1588, 1541, 1516, 1689, 1457, 1373, 1338, 1324, 1295, 1251, 846 cm-1. HNMR (DMSO-de): delta 11.04 (br s, 1H), 7.40 (d, J = 8.9 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 3.96 (t, Jl = J2 = 6.6 Hz, 2H), 3.79 (s, 3H), 3.59 (t, Jl = J2 = 5.1 Hz, 2H), 3.52 (m, 2H); 3.45 (t, Jl = J2 = 5.8 Hz, 2H), 3.26 (t, Jl = J2 = 5.8 Hz, 2H), 3.16 (t, Jl = J2 = 6.6 Hz, 2H), 2.74 (m, 2H), 2.38 (t, Jl = J2 = 6.2 Hz, 2H), 1.88 (m, 2H), 1.86 (m, 2H), 1.84 (m, 2H), 1.66 (m, 2H), 1.59 (m, 4H) ppm. HNMR (DMSO-d6): delta 168.98, 165.46, 164.78, 158.55, 157.53, 148.36, 141.25, 140.38, 133.57, 131.36, 126.48, 126.37, 126.01, 125.37, 113.33, 55.53, 53.36, 51.34, 50.99, 48.00, 37.80, 32.74, 31.48, 28.46, 26.23, 23.67, 23.15, 22.04, 21.04, 19.18 ppm. COSY: 7.40-6.96, 7.34-7.26, 7.26-7.34, 6.96-7.40, 3.99-3.16, 3.59-1.86, 3.52-1.59, 3.45-1.88, 3.26-1.88, 3.16-3.99, 2.74-1.59, 2.38-1.84, 1.88-3.45,3.26, 1.86-3.59, 1.84-2.38, 1.66-1.59, 1.59- 3.52,2.74,1.66 HSQC: 7.40-126.48, 7.34-126.10, 7.26-126.37, 6.96-1 13.33, 3.99-51.34, 3.79-55.53, 3.59-50.99, 3.52-53.36, 3.45-48.00, 3.26-37.80, 3.16-22.04, 2.74-31.48, 2.38-32.74, 1.88-19.18, 1.86-23.15, 1.84-21.04, 1.66-28.46, 1.59-26.23,23.67 HMBC (7 Hz): 7.40-158.55, 133.57, 7.34-141.25, 7.26-140.38, 6.96-158.55,133.57, 3.99- 157.53,125.37,22.04, 3.79-158.55, 3.52-165.46,48.00,28.46, 3.45-165.46,37.80,19.18, 3.26- 165.46,48.00,19.18, 3.16-148.36, 131.36,125.37,51.34, 2.74-165.46,28.46,23.67, 2.38- 168.98,23.15,21.04, 1.88-48.00,37.80, 1.59-28.46 Selective NOESY: 3.99-7.34,3.16. Selective TOCSY: 2.74-3.52,1.66,1.59, 2.38-3.59, 1.86, 1.84 Figure 11 shows the characteristic X-ray powder diffractogram (measured by CuKa radiation) of the DBU salt of l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-lH-pyrazolo[3,4-c]piridine-3-carboxylic acid of formula 4b (where M is a 1,8- diazabycyclo[5.4.0]undec-7-ene ion), produced according to the process described above, with characteristic X-ray powder diffraction peaks as follows: 2Theta (±0.2 2Theta): 5.44; 6.74; 8; 8.54; 9.18; 10.98; 14.16; 16.35; 16.57; 17.1; 17.92; 18.64; 18.95; 19.45; 20.06; 20.73; 21.7; 22.27; 22.51; 23.33; 24.05; 25.21; 26.11 ; 26.64; 28.05; 30.3; 30.98; 31.58; 33.02; 33.29; and the most characteristic peaks are as follows: 2Theta (±0.02 2Theta): 5.44; 6.74; 9.18; 10.98; 14.16; 16.35; 16.57; 17.1; 17.92; 18.64; 18.95; 19.45; 20.73; 21.7; 22.27; 22.51; 23.33; 25.21; 28.05

Reference： [1]Patent: WO2016/79549,2016,A1 .Location in patent: Page/Page column 22-23

22
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 cesium salt [ No CAS ]
[ 503614-92-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In water;	General procedure: Prepare the 4b carboxylic acid salts listed in the examples below from the "raw" l-(4- methoxyphenyl)-7-oxo-6-[4-(2-oxo-l-piperidinyl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4- c]pyridine-3 -carboxylic acid of formula 4c, prepared in example 1. Dissolve or mix the produced 4b salts in water, and then acidify with 1 M hydrochloric acid solution, that is, release the carboxylic acid. Filtrate the precipitated 4c "purified" carboxylic acid, wash with water and dry in a vacuum drying oven.

Reference： [1]Patent: WO2016/79549,2016,A1 .Location in patent: Page/Page column 12

23
C₂₀H₂₂N₄O₆ [ No CAS ]
[ 503614-92-4 ]

Reference： [1]Patent: CN103896940,2016,B

24
[ 1609409-53-1 ]
[ 503614-92-4 ]

Reference： [1]Patent: CN103896940,2016,B

25
[ 100-01-6 ]
[ 503614-92-4 ]

Reference： [1]Patent: CN103896940,2016,B
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810
[3]Patent: CN107400131,2017,A

26
[ 503614-92-4 ]
[ 541-41-3 ]
C₂₈H₂₈N₄O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 5℃;	The above vacuum-dried compound was added to the reaction flask, and 50 ml of CH2Cl2 was added thereto,1.29 g (10 mm?) Of diisopropylethylamine,The temperature was adjusted to 0 5 C dropping 1. 08g (10mmol) ethyl chloroformate,Maintain 0-5 C reaction 3-5 hours to produce mixed anhydride, TLC follow the reaction until the reaction is complete.

Reference： [1]Patent: CN103896940,2016,B .Location in patent: Paragraph 0044; 0061; 0063

27
[ 454183-28-9 ]
[ 503614-92-4 ]

Reference： [1]Patent: CN103896940,2016,B

28
C₁₃H₁₂N₂O₆ [ No CAS ]
[ 503614-92-4 ]

Reference： [1]Patent: CN103896940,2016,B

29
C₁₀H₁₀N₂O₂ [ No CAS ]
[ 503614-92-4 ]

Reference： [1]Patent: CN103896940,2016,B

30
C₁₅H₁₇ClN₂O₃ [ No CAS ]
[ 503614-92-4 ]

Reference： [1]Patent: CN103896940,2016,B

31
C₁₅H₁₆N₂O₃ [ No CAS ]
[ 503614-92-4 ]

Reference： [1]Patent: CN103896940,2016,B

32
[ 503614-92-4 ]
[ 530-62-1 ]
C₂₈H₂₆N₆O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 20 - 65℃; for 0.5h;	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 ; Mp: 248 to 251 C, yield 88. 2%

Reference： [1]Patent: CN104045637,2016,B .Location in patent: Paragraph 0072; 0088-0090

33
[ 503615-03-0 ]
[ 503614-92-4 ]

Reference： [1]Patent: CN104045637,2016,B
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810
[3]Patent: CN107400131,2017,A

34
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 ]
[ 503614-92-4 ]

Reference： [1]Patent: CN104045637,2016,B
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

35
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 ]
[ 503614-92-4 ]

Reference： [1]Patent: CN104045637,2016,B
[2]Patent: CN107400131,2017,A

36
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 ]
[ 503614-92-4 ]

Reference： [1]Patent: CN104045637,2016,B
[2]Patent: CN107400131,2017,A

37
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 ]
[ 503614-92-4 ]

Reference： [1]Patent: CN104045637,2016,B

38
[ 503614-92-4 ]
[ 503612-88-2 ]

Reference： [1]Patent: US2017/50964,2017,A1

39
[ 503614-92-4 ]
C₂₅H₂₇N₅O₃ [ No CAS ]

Reference： [1]Patent: US2017/50964,2017,A1

40
[ 503614-92-4 ]
3-(hydroxymethyl)-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 ]

Yield	Reaction Conditions	Operation in experiment
75.0%		Triethylamine (2.3 mL, 0.02 mol) was added to a solution of 16(5.0 g, 0.01 mol) in THF (50 mL) at rt. After 30 min, ethyl chloroformate(2 mL, 0.02 mol) was added drop-wise to the solution and stirred for 4 h at 30 C. After being cooled to rt., filtrate was obtained and added drop-wise to a solution of sodium borohydride(0.6 g, 0.02 mol) in H2O (5 mL) at 0 C for 30 min. The solvent was removed in vacuo and the mixture was diluted with CH2Cl2(30 mL) and washed with brine (2 10 mL). The organic phase was dried with Na2SO4 and evaporated in vacuo to yield a light yellow solid (3.6 g, 75.0%). Mp: 115-120 C; MS (ESI) m/z (%): 447.2[M+H]+.
71%		Part C. To a cold (0 C.) solution of the acid (500 mg, 1.09 mmol) from above in THF (10 mL) was added Et3N (0.17 mL, 1.2 mmol) followed by isobutyl chloroformate (0.16 mL, 1.2 mmol). The reaction mixture was stirred for 1 h then NaBH4 (82 mg, 2.2 mmol) was added. After 30 min, a small piece of ice was added and the reaction mixture was stirred for an additional 2 h. The mixture was diluted with EtOAc, washed with 0.1 N HCl and brine, dried (Na2SO4), filtered and concentrated. Purification of the residue on silica gel provided the corresponding alcohol as a white solid (317 mg, 71%): ESI MS m/z 447 (M+H)+.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810
[2]Patent: US2017/50964,2017,A1 .Location in patent: Paragraph 0887

41
[ 503614-92-4 ]
C₂₅H₂₅BrN₄O₃ [ No CAS ]

Reference： [1]Patent: US2017/50964,2017,A1

42
[ 503614-92-4 ]
3-(azidomethyl)-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 ]

Reference： [1]Patent: US2017/50964,2017,A1
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

43
[ 675-20-7 ]
[ 503614-92-4 ]

Reference： [1]Patent: US2017/50964,2017,A1

44
[ 473927-64-9 ]
[ 503614-92-4 ]

Reference： [1]Patent: US2017/50964,2017,A1

45
[ 1575-61-7 ]
[ 503614-92-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810
[2]Patent: CN107400131,2017,A

46
[ 1039914-85-6 ]
[ 503614-92-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

47
[ 881386-01-2 ]
[ 503614-92-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810
[2]Patent: CN107400131,2017,A

48
[ 104-94-9 ]
[ 503614-92-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810
[2]Patent: CN107400131,2017,A

49
C₂₂H₂₂N₄O₆ [ No CAS ]
[ 503614-92-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

50
C₂₂H₂₄N₄O₄ [ No CAS ]
[ 503614-92-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

51
C₂₇H₃₁ClN₄O₅ [ No CAS ]
[ 503614-92-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

52
[ 503614-92-4 ]
1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-3-((3-phenyl-1H-1,2,4-triazol-1-yl)methyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

53
[ 503614-92-4 ]
1-(4-methoxyphenyl)-3-((3-(4-methoxyphenyl)-1H-1,2,4-triazol-1-yl)methyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

54
[ 503614-92-4 ]
3-((3-(4-fluorophenyl)-1H-1,2,4-triazol-1-yl)methyl)-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 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

55
[ 503614-92-4 ]
3-((3-(4-chlorophenyl)-1H-1,2,4-triazol-1-yl)methyl)-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 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

56
[ 503614-92-4 ]
1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-3-((3-(pyridin-4-yl)-1H-1,2,4-triazol-1-yl)methyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

57
[ 503614-92-4 ]
1-(4-methoxyphenyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-3-((3-(pyridin-3-yl)-1H-1,2,4-triazol-1-yl)methyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

58
[ 503614-92-4 ]
1-(4-methoxyphenyl)-3-((5-oxo-3-phenyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

59
[ 503614-92-4 ]
1-(4-methoxyphenyl)-3-((3-(4-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

60
[ 503614-92-4 ]
3-((1H-1,2,3-triazol-1-yl)methyl)-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 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

61
[ 503614-92-4 ]
1-((1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carbonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

62
[ 503614-92-4 ]
1-((1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

63
[ 503614-92-4 ]
3-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-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 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

64
[ 503614-92-4 ]
3-(chloromethyl)-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 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 2800 - 2810

65
[ 545445-44-1 ]
[(4-methoxyphenyl)hydrazino]chloroacetic acid ethyl ester [ No CAS ]
[ 503614-92-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; triethylamine; In water;	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 for ammonia reaction in the preparation of an average of apixaban, the purity of 95.4%.

Reference： [1]Patent: CN106188036,2016,A .Location in patent: Paragraph 0054; 0055

66
[ 67-56-1 ]
[ 503614-92-4 ]
[ 1074365-84-6 ]

Yield	Reaction Conditions	Operation in experiment
89.28%	With sulfuric acid; at 5 - 15℃; for 2h;	To the reaction flask were added 1-p-methoxyphenyl-6- [4- (2-oxopiperidin-1-yl) phenyl] -7-oxo-3a, 4,5,6,7, Hexahydropyrazolo [3,4-c] pyridine-3-carboxylic acid (APIX-Imp05) 20g, methanol 200ml, 5-15 C under stirring, was added dropwise 12ml of concentrated sulfuric acid, 2h,The reaction was concentrated to dryness to give a yellow solid 21.5g, with dichloro 810ml of dissolved solids dissolved in water 810ml washing, liquid separation layer was discarded, the organic layer was dried over anhydrous sodium sulfate 20g, pumpingfilter, Concentrated to dry white white solid impurity Impurity APIX-Imp1518.4g, yield: 89.28%.

Reference： [1]Patent: CN106928220,2017,A .Location in patent: Paragraph 0057-0059; 0065-0067; 0068-0070

67
[ 503614-92-4 ]
N-hydroxy(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 ]

Reference： [1]Patent: CN107400131,2017,A

68
[ 6723-30-4 ]
[ 503614-92-4 ]
N-((tetrahydro-2H-pyran-2-yl)oxy)-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 ]

Yield	Reaction Conditions	Operation in experiment
73.1%		In a 100 mL single-necked flask, Compound IX (0.5 g, 1.1 mmol)Dry methylene chloride 10 mL,One drop of N, N-dimethylformamide,Thionyl chloride (0.3 mL, 4.4 mmol) was added,Heat to reflux for 1 h.Excess thionyl chloride was distilled off under reduced pressure,After drying, the reddish-brown solid residue was dissolved in dry dichloromethane for later use. O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (BXH-2) (0.64 g, 5.5 mmol) was added to a 100 mL three-Dry triethylamine (1.5 mL, 0.011 mol),Dry methylene chloride 10 mL,Ice salt bath, cooled to below -10C ,The above prepared acid chloride was added dropwise, Control temperature does not exceed -10C ,Bi completed,Slowly rise to room temperature for 8h.The reaction solution was added 50mL 10% NaOH aqueous solution washed,Then extracted with dichloromethane 2 × 100mL,100 mL saturated brine, dried over anhydrous sodium sulfate,Dry dichloromethane to give crude,0.96g. The crude product was subjected to column chromatography,Eluent (dichloromethane: methanol = 100: 1),The product 0.45g, yield 73.1%. Yellow solid, m.p. 122-124 C,

Reference： [1]Patent: CN107400131,2017,A .Location in patent: Paragraph 0079-0082

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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

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 503614-92-4 ] {[proInfo.proName]}

Quality Control of [ 503614-92-4 ]

Related Doc. of [ 503614-92-4 ]

Product Details of [ 503614-92-4 ]

Calculated chemistry of [ 503614-92-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 503614-92-4 ]

Application In Synthesis of [ 503614-92-4 ]

[ 503614-92-4 ] Synthesis Path-Downstream 1~68

Pharmaceutical Intermediates of [ 503614-92-4 ]

Apixaban Related Intermediates

Related Functional Groups of [ 503614-92-4 ]

Aryls

Ethers

Amides

Carboxylic Acids

Related Parent Nucleus of [ 503614-92-4 ]

Other Aromatic Heterocycles

Piperidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Pharmaceutical Intermediates of
[ 503614-92-4 ]

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[ 503614-92-4 ]

Related Parent Nucleus of
[ 503614-92-4 ]