[ CAS No. 1297538-32-9 ] {[proInfo.proName]}

Name: 1297538-32-9|N-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide|98%
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Quality Control of [ 1297538-32-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1297538-32-9 ]

CAS No. :	1297538-32-9	MDL No. :
Formula :	C₁₉H₁₉ClN₆O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BLIJXOOIHRSQRB-PXYINDEMSA-N
M.W :	398.85	Pubchem ID :	67171867
Synonyms :	ODM-201;BAY-1841788;Nubeqa.	Chemical Name :	N-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide

Calculated chemistry of [ 1297538-32-9 ]

Physicochemical Properties

Num. heavy atoms :	28
Num. arom. heavy atoms :	16
Fraction Csp3 :	0.26
Num. rotatable bonds :	7
Num. H-bond acceptors :	5.0
Num. H-bond donors :	3.0
Molar Refractivity :	103.86
TPSA :	119.62 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-7.48 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.86
Log Po/w (XLOGP3) :	1.76
Log Po/w (WLOGP) :	2.35
Log Po/w (MLOGP) :	0.77
Log Po/w (SILICOS-IT) :	2.83
Consensus Log Po/w :	1.91

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.38
Solubility :	0.165 mg/ml ; 0.000414 mol/l
Class :	Soluble
Log S (Ali) :	-3.89
Solubility :	0.0514 mg/ml ; 0.000129 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.61
Solubility :	0.000981 mg/ml ; 0.00000246 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.86

Safety of [ 1297538-32-9 ]

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

Application In Synthesis of [ 1297538-32-9 ]

* 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.

Upstream synthesis route of [ 1297538-32-9 ]
Downstream synthetic route of [ 1297538-32-9 ]

[ 1297538-32-9 ] Synthesis Path-Upstream 1~5

1
[ 1297537-33-7 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium tetrahydroborate; ethanol In ethanol	100 mg (0.25 mmol) of (S)-5-acetyl-N-( 1 -(3-(3-chloro-4-cyanophenyl)- 1 Hpyrazol- 1 -yl)propan-2-yl)- 1 H-pyrazole-3 -carboxamide (IX) and 5m1 of EtOH were put to reaction flask and 19 mg (0.5 mmol) of sodium borohydride was added slowly as EtOH suspension. The reaction was stirred overnight to completion. 0.5 ml of water and lml of 0.5 M HC1 were added dropwise. The solution was evaporated todryness and 20 nil of DCM was added. The mixture was washed with 10 ml of 1 M NaHCO3 and 10 ml of water followed with drying over Na2SO4. After filtration and evaporation 76 mg of the product was obtained. Yield 76 percent.

Reference： [1] Patent: WO2016/162604, 2016, A1, . Location in patent: Page/Page column 17

2
[ 1297537-33-7 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
214 kg	at 22℃; for 4 h; Large scale	Granular sodium borohydride (15 kg) and EtOH (1370 kg) were placed into the 6.3m3 enamel reaction vessel. The mixture was solubilized by stirring for 30 mm at 22°C. (S)-3 -acetyl-N-( 1 -(3 -(3 -chloro-4-cyano-phenyl)- 1 H-pyrazol- 1 -yl)propan-2-yl)-1H-pyrazole-5-carboxamide (225 kg) was added to the reaction vessel. The mixture was then stirred at 22 °C for 4 hours to complete the reaction. Then pH of the mixture was adjusted to acidic with HC1 in water. Water (800 kg) was then added and the pH of the mixture was set to 7.0 ± 1.0 by addition of NaOH in water. The mixture was warmed to 65 °C and then transferred to 6.3 m3 jacketed steel reaction vessel.The mixture was warmed to 78 °C to dissolve the mixture. The solution was cooled to 64 °C under nitrogen atmosphere. The solution was seeded at 64 °C under mild stirring. The solution was then cooled during 8 h to 30 °C under mild stirring. Thereafter water (2600 kg) was added during 7 - 10 h at 30 °C under mild stirring. The mixture was cooled during 2 h to 20 °C under mild stirring and then stirredfurther for 1 h. The precipitated product was isolated by centrifuge, washed with water and dried under vacuum at 40 - 60 °C to obtain 214 kg of crystalline particles with rounded particle shape.

Reference： [1] Patent: US2014/94474, 2014, A1, . Location in patent: Page/Page column
[2] Patent: WO2018/162793, 2018, A1, . Location in patent: Page/Page column 12

3
[ 154607-01-9 ]
[ 1297538-32-9 ]

Reference： [1] Patent: WO2016/162604, 2016, A1,

4
[ 1297537-35-9 ]
[ 1297538-32-9 ]

Reference： [1] Patent: WO2016/162604, 2016, A1,

5
[ 1297537-37-1 ]
[ 1297538-32-9 ]

Reference： [1] Patent: WO2016/162604, 2016, A1,

[ 1297538-32-9 ] Synthesis Path-Downstream 1~28

1
[ 1297537-33-7 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium borohydrid In ethanol; water	38.f f) f) N-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide Sodium borohydride (0.930 g, 24.57 mmol) and EtOH (105 ml) were placed in to the reaction flask under nitrogen athmosphere. (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (15 g, 37.8 mmol) was added in small portions to keep temperature below 25° C. After 3.5 h sodium borohydride (0.07 g, 1.85 mmol) was added and the mixture was stirred for additional 60 min to complete the reaction. 16 ml of ˜10% HCl in EtOH was added carefully to set pH to 3.5 and the mixture was stirred overnight at RT. Water (30 ml) was added and the stirring was continued for 3 h. The precipitate was filtered, washed with 2*10 ml of cold water:EtOH (1:1) and dried under vacuum to obtain 12.2 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 1.12 (, 3H), 1.39 (d, 3H), 4.24-4.52 (m, 3H), 4.76-4.86 (m, 1H), 5.42 (d, 1H), 6.42 (bs., 1H), 6.94 (d, 1H), 7.82 (d, 1H), 8.00 (bs, 2H), 8.09 (bs, 1H), 8.20 (d, 1H), 13.05 (bs, 1H).
214 kg	With sodium tetrahydroborate; ethanol at 22℃; for 4h; Large scale;	1 Example 1. Preparation of crystalline particles of N-((S)-1-(3-(3-Chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) Granular sodium borohydride (15 kg) and EtOH (1370 kg) were placed into the 6.3m3 enamel reaction vessel. The mixture was solubilized by stirring for 30 mm at 22°C. (S)-3 -acetyl-N-( 1 -(3 -(3 -chloro-4-cyano-phenyl)- 1 H-pyrazol- 1 -yl)propan-2-yl)-1H-pyrazole-5-carboxamide (225 kg) was added to the reaction vessel. The mixture was then stirred at 22 °C for 4 hours to complete the reaction. Then pH of the mixture was adjusted to acidic with HC1 in water. Water (800 kg) was then added and the pH of the mixture was set to 7.0 ± 1.0 by addition of NaOH in water. The mixture was warmed to 65 °C and then transferred to 6.3 m3 jacketed steel reaction vessel.The mixture was warmed to 78 °C to dissolve the mixture. The solution was cooled to 64 °C under nitrogen atmosphere. The solution was seeded at 64 °C under mild stirring. The solution was then cooled during 8 h to 30 °C under mild stirring. Thereafter water (2600 kg) was added during 7 - 10 h at 30 °C under mild stirring. The mixture was cooled during 2 h to 20 °C under mild stirring and then stirredfurther for 1 h. The precipitated product was isolated by centrifuge, washed with water and dried under vacuum at 40 - 60 °C to obtain 214 kg of crystalline particles with rounded particle shape.

Reference： [1]Current Patent Assignee: ORION OYJ - US2014/94474, 2014, A1 Location in patent: Page/Page column
[2]Current Patent Assignee: ORION S R L - WO2018/162793, 2018, A1 Location in patent: Page/Page column 12

2
[ 108-30-5 ]
[ 1297538-32-9 ]
[ 1403334-18-8 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap In tetrahydrofuran; ethyl acetate; N,N-dimethyl-formamide	38.g g) g) 4-(1-(3-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-1H-pyrazol-5-yl)ethoxy)-4-oxobutanoic acid N-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxy-ethyl)-1H-pyrazole-3-carboxamide (1.254 mmol, 0.5 g), dihydrofuran-2,5-dione (1.504 mmol, 0.151 g) and 4-dimethylaminopyridine (0.1254 mmol, 0.015 g) were dissolved in THF (10 ml) and DMF (1 ml). The resulting mixture was stirred at RT for one day after which the temperature was raised to 50° C. for one day. The mixture was stirred at RT over the weekend. During the reaction more dihydrofuran-2,5-dione (50 mg) was added. The solvents were evaporated and the residue was dissolved in EtOAc. The organic phase was washed with 1 M HCl, separated, dried, filtered and evaporated. The crude product was purified by flash chromatography. 352 mg of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.22-1.28 (m, 3H), 1.61-1.69 (m, 3H), 2.54-2.79 (m, 4H), 4.29-4.45 (m, 2H), 4.52-4.64 (m, 1H), 5.97-6.06 (m, 1H), 6.58-6.62 (m, 1H), 6.76-6.80 (m, 1H), 7.50-7.53 (m, 1H), 7.62-7.68 (m, 1H), 7.70-7.77 (m, 1H), 7.90-8.04 (m, 2H).

Reference： [1]Current Patent Assignee: ORION OYJ - US2014/94474, 2014, A1 Location in patent: Page/Page column

3
[ 154607-01-9 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium carbonate / acetonitrile; lithium hydroxide monohydrate / 0.5 h / Inert atmosphere; Reflux 1.2: 2.5 h / 60 - 70 °C / Inert atmosphere 2.1: hydrogenchloride / lithium hydroxide monohydrate / 2 h / 10 °C 2.2: 4 h / 0 - 5 °C 3.1: triphenylphosphine; hydrogenchloride; di-isopropyl azodicarboxylate / ethyl acetate / 10 - 20 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / ethyl acetate / 10 - 20 °C / Inert atmosphere 5.1: sodium tetrahydridoborate; ethanol / ethanol
	Multi-step reaction with 5 steps 1.1: trans-bis(triphenylphosphine)palladium(II) dichloride; anhydrous sodium carbonate / lithium hydroxide monohydrate; tetrahydrofuran / 40 °C 2.1: hydrogenchloride / ethanol / Reflux 3.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 6 h / 0 - 20 °C / Inert atmosphere 3.2: 24 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C / Inert atmosphere 5.1: sodium tetrahydridoborate / tetrahydrofuran; methanol / 20 °C
	Multi-step reaction with 4 steps 1.1: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium carbonate / tetrahydrofuran; lithium hydroxide monohydrate / 3 h / 40 °C / Inert atmosphere 2.1: hydrogenchloride / ethanol / 2 h / 30 °C / Inert atmosphere 3.1: triphenylphosphine / ethyl acetate / 0.5 h / Inert atmosphere 3.2: 3 h / 20 °C / Inert atmosphere 3.3: 1 h / 20 °C / Inert atmosphere 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / -10 °C / Inert atmosphere

	Multi-step reaction with 5 steps 1.1: potassium carbonate; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) / acetonitrile / Inert atmosphere; Reflux 2.1: hydrogenchloride / ethanol / Reflux 3.1: di-isopropyl azodicarboxylate / tetrahydrofuran / 20 °C / Cooling with ice 3.2: Reflux 4.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C 5.1: sodium tetrahydridoborate; ethanol
	Multi-step reaction with 6 steps 1: potassium carbonate; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) / acetonitrile; lithium hydroxide monohydrate / Inert atmosphere; Reflux 2: hydrogenchloride; lithium hydroxide monohydrate; ethanol / Reflux 3: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 4: hydrogenchloride; lithium hydroxide monohydrate / acetonitrile / Reflux 5: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C 6: sodium tetrahydridoborate; ethanol

4
[ 1297537-35-9 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: hydrogenchloride / lithium hydroxide monohydrate / 2 h / 10 °C 1.2: 4 h / 0 - 5 °C 2.1: triphenylphosphine; hydrogenchloride; di-isopropyl azodicarboxylate / ethyl acetate / 10 - 20 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / ethyl acetate / 10 - 20 °C / Inert atmosphere 4.1: sodium tetrahydridoborate; ethanol / ethanol
	Multi-step reaction with 4 steps 1.1: hydrogenchloride / ethanol / Reflux 2.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 6 h / 0 - 20 °C / Inert atmosphere 2.2: 24 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C / Inert atmosphere 4.1: sodium tetrahydridoborate / tetrahydrofuran; methanol / 20 °C
	Multi-step reaction with 4 steps 1.1: hydrogenchloride / lithium hydroxide monohydrate; methanol / 2 h / 10 °C 2.1: triphenylphosphine / ethyl acetate / Inert atmosphere 2.2: 10 - 20 °C / Inert atmosphere 2.3: 30 - 45 °C / Inert atmosphere 3.1: potassium-t-butoxide / toluene / 1 h / 0 °C / Inert atmosphere 3.2: 2 h / 0 - 20 °C / Inert atmosphere 4.1: sodium tetrahydridoborate; ethanol

	Multi-step reaction with 3 steps 1.1: hydrogenchloride / ethanol / 2 h / 30 °C / Inert atmosphere 2.1: triphenylphosphine / ethyl acetate / 0.5 h / Inert atmosphere 2.2: 3 h / 20 °C / Inert atmosphere 2.3: 1 h / 20 °C / Inert atmosphere 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / -10 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: hydrogenchloride / ethanol / Reflux 2.1: di-isopropyl azodicarboxylate / tetrahydrofuran / 20 °C / Cooling with ice 2.2: Reflux 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C 4.1: sodium tetrahydridoborate; ethanol
	Multi-step reaction with 5 steps 1: hydrogenchloride; lithium hydroxide monohydrate; ethanol / Reflux 2: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 3: hydrogenchloride; lithium hydroxide monohydrate / acetonitrile / Reflux 4: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C 5: sodium tetrahydridoborate; ethanol

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/162604, 2016, A1
[2]Yu, Jiang; Zhou, Peiting; Hu, Mingxing; Yang, Liuqing; Yan, Guoyi; Xu, Ruixue; Deng, Yufang; Li, Xinghai; Chen, Yuanwei [European Journal of Medicinal Chemistry, 2019, vol. 182]
[3]Current Patent Assignee: NANJING JUNRUO BIOMEDICAL RES INSTITUTE; JIANGSU JUNRUO PHARMACEUTICAL; HAIMEN BAIKANG PHARMACEUTICAL - CN110590668, 2019, A
[4]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN111116476, 2020, A
[5]Current Patent Assignee: ZHEJIANG NORMAL UNIVERSITY - CN113861115, 2021, A
[6]Xu, Qian; Zhang, Zixiong; Huang, Chenchao; Bao, Qiqi; Zhang, Rongyu; Wu, Meng; Xiao, Xiaohui; Han, Xiaoli; Li, Xiaoyu; Zhou, Jinming [Bioorganic Chemistry, 2022, vol. 124]

5
[ 1297537-37-1 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triphenylphosphine; hydrogenchloride; di-isopropyl azodicarboxylate / ethyl acetate / 10 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 1-propanephosphonic acid cyclic anhydride / ethyl acetate / 10 - 20 °C / Inert atmosphere 3: sodium tetrahydridoborate; ethanol / ethanol
	Multi-step reaction with 3 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 6 h / 0 - 20 °C / Inert atmosphere 1.2: 24 h / 20 °C 2.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C / Inert atmosphere 3.1: sodium tetrahydridoborate / tetrahydrofuran; methanol / 20 °C
	Multi-step reaction with 3 steps 1.1: triphenylphosphine / ethyl acetate / Inert atmosphere 1.2: 10 - 20 °C / Inert atmosphere 1.3: 30 - 45 °C / Inert atmosphere 2.1: potassium-t-butoxide / toluene / 1 h / 0 °C / Inert atmosphere 2.2: 2 h / 0 - 20 °C / Inert atmosphere 3.1: sodium tetrahydridoborate; ethanol

	Multi-step reaction with 3 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl acetamide / 50 - 55 °C 1.2: 1 h / 20 °C 2.1: hydrogenchloride / ethanol / 65 - 70 °C 3.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C
	Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 1.2: 1 h 2.1: hydrogenchloride / ethanol / 65 - 70 °C 3.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C
	Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl acetamide / 50 - 55 °C 1.2: 1 h / 20 °C 2.1: hydrogenchloride / ethanol / 65 - 70 °C 3.1: N-ethyl-N,N-diisopropylamine; 1,1′-carbonyldiimidazole / dichloromethane / 20 °C 4.1: sodium hydroxide / ethanol; lithium hydroxide monohydrate / 20 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 1.2: 1 h 2.1: hydrogenchloride / ethanol / 65 - 70 °C 3.1: N-ethyl-N,N-diisopropylamine; 1,1′-carbonyldiimidazole / dichloromethane / 20 °C 4.1: sodium hydroxide / ethanol; lithium hydroxide monohydrate / 20 °C
	Multi-step reaction with 3 steps 1.1: di-isopropyl azodicarboxylate / tetrahydrofuran / 20 °C / Cooling with ice 1.2: Reflux 2.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C 3.1: sodium tetrahydridoborate; ethanol
	Multi-step reaction with 4 steps 1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: hydrogenchloride; lithium hydroxide monohydrate / acetonitrile / Reflux 3: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C 4: sodium tetrahydridoborate; ethanol

Reference： [1]Current Patent Assignee: ORION OYJ - WO2016/162604, 2016, A1
[2]Yu, Jiang; Zhou, Peiting; Hu, Mingxing; Yang, Liuqing; Yan, Guoyi; Xu, Ruixue; Deng, Yufang; Li, Xinghai; Chen, Yuanwei [European Journal of Medicinal Chemistry, 2019, vol. 182]
[3]Current Patent Assignee: JIANGSU JUNRUO PHARMACEUTICAL; NANJING JUNRUO BIOMEDICAL RES INSTITUTE; HAIMEN BAIKANG PHARMACEUTICAL - CN110590668, 2019, A
[4]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN111087324, 2020, A
[5]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN111087324, 2020, A
[6]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN111087324, 2020, A
[7]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN111087324, 2020, A
[8]Current Patent Assignee: ZHEJIANG NORMAL UNIVERSITY - CN113861115, 2021, A
[9]Bao, Qiqi; Han, Xiaoli; Huang, Chenchao; Li, Xiaoyu; Wu, Meng; Xiao, Xiaohui; Xu, Qian; Zhang, Rongyu; Zhang, Zixiong; Zhou, Jinming [Bioorganic Chemistry, 2022, vol. 124]

6
[ 1297537-33-7 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
85.9%	With sodium tetrahydroborate In tetrahydrofuran; methanol at 20℃;	N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-3/5-(1- hydroxyethyl)-1H-pyrazole-5/3-carboxamide (1a) Compound 1c (656.0 mg, 1.6 mmol), MeOH(8.0 ml) and THF (8.0 ml) were charged to the reaction flask. NaBH4(96.0 mg, 2.4 mmol) was added slowly, which was cooled by icebath. The reaction was stirred for 4 h to completion followed withaddition of water. The mixture was concentrated under vacuum toremove organic solvent and then DCM was added. The resultingmixture was washed with 1M HCl and 1M NaHCO3, respectively.The organic layer was dry over Na2SO4 and evaporated to dryness.After purification on silica using a solvent gradient of 50e90% ethylacetate in hexanes, compound 1a was obtained as a white solid(547.5 mg, yield 85.9%).
80.2%	With sodium tetrahydroborate In ethanol at 0 - 20℃; for 3.5h;	9-13 Example 11 Synthesis of compound represented by formula I At 0°C, compound 6 (39.7 g, 0.1 mmol) was added to EtOH (400 mL), NaBH4(6.8 g, 0.18 mmol)was slowly added, and the reaction was stirred at room temperature for 3.5 h.The reaction solution was cooled to 0°C and slowly added 10% NaHCO3solution (160 mL)dropwise. The mixture was concentrated at room temperature and then added with DCM solution (450 mL) for extraction. The organic layer was separated and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated after the column Chromatography (using a mixed solvent of dichloromethane/methanol with a volume ratio of 30:1) was purified to obtain the compound of formula I, with a yield of 32.1 g, a yield of 80.2%, and an HPLC purity of 99.0%.
76%	With sodium tetrahydroborate; ethanol In ethanol	7 Preparation of N-((S)- 1 -(3 -(3 -chloro-4-cyanophenyl)- 1 H-pyrazol1 -yl)-propan-2-yl)-5 -(1 -hydroxyethyl)- 1 H-pyrazole-3 -carboxamide (IA) 100 mg (0.25 mmol) of (S)-5-acetyl-N-( 1 -(3-(3-chloro-4-cyanophenyl)- 1 Hpyrazol- 1 -yl)propan-2-yl)- 1 H-pyrazole-3 -carboxamide (IX) and 5m1 of EtOH were put to reaction flask and 19 mg (0.5 mmol) of sodium borohydride was added slowly as EtOH suspension. The reaction was stirred overnight to completion. 0.5 ml of water and lml of 0.5 M HC1 were added dropwise. The solution was evaporated todryness and 20 nil of DCM was added. The mixture was washed with 10 ml of 1 M NaHCO3 and 10 ml of water followed with drying over Na2SO4. After filtration and evaporation 76 mg of the product was obtained. Yield 76 %.

76%	With sodium tetrahydroborate; ethanol	9 Example 9: Preparation of N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl) -5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide 100 mg (0.25 mmol) of (S) -5-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl) prop-2-yl)-1H-pyrazole-3-carboxamide (8) and 5mL EtOH were added to the reaction flask, and 19 mg (0.5 mmol) of sodium borohydride was slowly added as an EtOH suspension. The reaction was stirred overnight to completion.0.5 mL of water and 1 mL of 0.5 M HCl were added dropwise.The solution was evaporated to dryness and 20 mL of DCM was added.The mixture was washed with 10 mL of 1M sodium bicarbonate and 10 mL of water, and then dried over anhydrous sodium sulfate.Concentration under reduced pressure gave 76 mg of product. Yield was 76%
	With sodium tetrahydroborate; ethanol	1 4-[1-[(2R)-2-aminopropyl]-1H-pyrazol-3-yl]-2-chloro-benzonitrile 0.16g, 5-acetyl-1H-pyrazole-3-carboxylic acid 0.29 g, 0.2 mL of N,N-diisopropylethylamine, 0.16 g of 1-hydroxy-benzotriazole, and 0.229 g of carbodiimide hydrochloride were mixed, dissolved in a dichloromethane solution, and reacted at room temperature. After the reaction was finished, extraction was carried out through the column to obtain N-((S)-2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-1-methylethyl)-5-acetyl-1H-pyrazole-carboxamide. The above product was dissolved in ethanol solution, reduced with sodium borohydride, extracted and recrystallized to obtain a white powdery solid with a yield of 84%.
	With sodium tetrahydroborate; ethanol	Compound 14a (1.0 eq.), compound 18a (3.0 eq.), DIPEA (2.0 eq.), HOBt (2.0 eq.), and EDCI (2.0 eq.) were dissolved in DCM at r.t. until the reaction was completed. The mixture was extracted with EtOAc and purified to obtain the product ORM-15341. Then, ORM-15341 was dissolved in EtOH and reduced by NaBH4. After completed, the mixture was extracted by EtOAc. The organic phase was concentrated, and the crude product was recrystallized to obtain white solid ODM-201 in 84% yield of two steps. 1H NMR (400 MHz, DMSO-d6, racemate) δ (ppm) 13.06 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.09 (s, 1H), 8.00 (s, 2H), 7.82 (d, J = 2.2 Hz, 1H), 6.95 (d, J = 2.2 Hz, 1H), 6.41 (s, 1H), 5.44 (d, J = 5.0 Hz, 1H), 4.84-4.75 (m, 1H), 4.44 (dd, J = 13.5, 6.3 Hz, 1H), 4.40-4.32 (m, 1H), 4.28 (dd, J = 13.0, 5.1 Hz, 1H), 1.38 (d, J = 6.5 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H)MS-ESI Calcd for C19H20ClN6O2 (M + H)+ 399.1331, found 399.1324.
	With sodium tetrahydroborate; ethanol	Compound 14a (1.0 eq.), compound 18a (3.0 eq.), DIPEA (2.0 eq.), HOBt (2.0 eq.), and EDCI (2.0 eq.) were dissolved in DCM at r.t. until the reaction was completed. The mixture was extracted with EtOAc and purified to obtain the product ORM-15341. Then, ORM-15341 was dissolved in EtOH and reduced by NaBH4. After completed, the mixture was extracted by EtOAc. The organic phase was concentrated, and the crude product was recrystallized to obtain white solid ODM-201 in 84% yield of two steps. 1H NMR (400 MHz, DMSO-d6, racemate) δ (ppm) 13.06 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.09 (s, 1H), 8.00 (s, 2H), 7.82 (d, J = 2.2 Hz, 1H), 6.95 (d, J = 2.2 Hz, 1H), 6.41 (s, 1H), 5.44 (d, J = 5.0 Hz, 1H), 4.84-4.75 (m, 1H), 4.44 (dd, J = 13.5, 6.3 Hz, 1H), 4.40-4.32 (m, 1H), 4.28 (dd, J = 13.0, 5.1 Hz, 1H), 1.38 (d, J = 6.5 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H)MS-ESI Calcd for C19H20ClN6O2 (M + H)+ 399.1331, found 399.1324.
90 g	With methanol; sodium tetrahydroborate at 15 - 30℃; for 2.25h;	1; 4 Example- 1: Preparation of Darolutamide. Methanol (500 ml) was added to (S)-5-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide (100 g) at 25-30°C. Cooled the mixture to 15-20°C. Sodium borohydride (9.51 g) was added to the mixture at 15-20°C and stirred for 45 minutes. Raised the temperature of the mixture to 25-30°C and stirred for 90 minutes. Water (1000 ml) was slowly added to the mixture at 25-30°C and stirred for 6 hours. Filtered the solid, washed with water and dried to get the title compound. Yield: 90.0 g; Purity by HPLC: 98.58% and MR: 178-183°C.
80 %	With sodium tetrahydroborate In ethanol at 20℃;
98.6 %	Stage #1: (S)-5-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide With sodium tetrahydroborate In ethanol at 0 - 20℃; Stage #2: With hydrogenchloride In ethanol	23-27 Example 23 At 0°C, compound VI (39.7 g, 0.1 mol) was added into ethanol (200 mL),Stir and add sodium borohydride (5.7g, 0.15mol) in batches, after the addition is complete,Stir overnight at room temperature. 2.0N HCl (200 mL) was added to the reaction solution,Concentrate to dryness under reduced pressure, add dichloromethane (100mL), wash with 100mL water,Wash with 100mL 2.0N NaHCO3 aqueous solution and 100mL brine,Dry and concentrate under reduced pressure to remove the organic solvent, 100mL ethanol/water (1:1) recrystallization,And vacuum-dried at 50° C. to obtain compound I, namely darolutamide. Yield 98.6%,HPLC purity 99.94%.

Reference： [1]Yu, Jiang; Zhou, Peiting; Hu, Mingxing; Yang, Liuqing; Yan, Guoyi; Xu, Ruixue; Deng, Yufang; Li, Xinghai; Chen, Yuanwei [European Journal of Medicinal Chemistry, 2019, vol. 182]
[2]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN111116477, 2020, A Location in patent: Paragraph 0066-0076
[3]Current Patent Assignee: ORION OYJ - WO2016/162604, 2016, A1 Location in patent: Page/Page column 17
[4]Current Patent Assignee: NANJING JUNRUO BIOMEDICAL RES INSTITUTE; JIANGSU JUNRUO PHARMACEUTICAL; HAIMEN BAIKANG PHARMACEUTICAL - CN110590668, 2019, A Location in patent: Paragraph 0048; 0049
[5]Current Patent Assignee: ZHEJIANG NORMAL UNIVERSITY - CN113861115, 2021, A Location in patent: Paragraph 0048; 0067; 0071-0072
[6]Xu, Qian; Zhang, Zixiong; Huang, Chenchao; Bao, Qiqi; Zhang, Rongyu; Wu, Meng; Xiao, Xiaohui; Han, Xiaoli; Li, Xiaoyu; Zhou, Jinming [Bioorganic Chemistry, 2022, vol. 124]
[7]Xu, Qian; Zhang, Zixiong; Huang, Chenchao; Bao, Qiqi; Zhang, Rongyu; Wu, Meng; Xiao, Xiaohui; Han, Xiaoli; Li, Xiaoyu; Zhou, Jinming [Bioorganic Chemistry, 2022, vol. 124]
[8]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2022/144926, 2022, A1 Location in patent: Page/Page column 8
[9]Szilágyi, Bence; Egyed, Attila; Mándity, István; Nagy, Tamás; Kátai-Fadgyas, Katalin; Volk, Balázs; Keseru, György M. [Synthesis, 2023, vol. 55, # 6, p. 959 - 966] Poszávácz, László; Nagy, Tamás; Kátai-Fadgyas, Katalin; Volk, Balázs [Synthesis, 2023, vol. 55, # 13, p. 2061 - 2069]
[10]Current Patent Assignee: SHANGDONG NEW TIME PHARMACEUTICAL CO LTD - CN115872932, 2023, A Location in patent: Paragraph 0029; 0104-0114

7
[ 2230652-52-3 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: triethylamine; trifluoroacetic anhydride / dichloromethane / 5 h / -10 - 30 °C 2.1: octane / 1 h / Reflux 2.2: 4 h / Reflux 3.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 5 h / 25 - 30 °C 4.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 6 h / 0 °C

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED; CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - WO2018/108130, 2018, A1

8
[ CAS Unavailable ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: octane / 1 h / Reflux 1.2: 4 h / Reflux 2.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 5 h / 25 - 30 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 6 h / 0 °C

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED; CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - WO2018/108130, 2018, A1

9
[ 2230652-54-5 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 5 h / 25 - 30 °C 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 6 h / 0 °C

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED; CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - WO2018/108130, 2018, A1

10
[ 2230652-55-6 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
92.9%	With tetrabutyl ammonium fluoride In tetrahydrofuran at 0℃; for 6h;	21 Example 21: N-((S)-1-(3-(3-chloro-4-cyanophenyl)- 1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)- 1H-pyrazole-3-carboxamide (ODM-201) To a 1 OOmL three-necked flask, 5 -(-1 -(Qert -butyldimet hyl silyl)oxy)ethyl)-N-((S)- 1 -(3- (3 -chloro-4-cyanophenyl)- 1 H-pyrazol- 1 -yl)propan-2-yl)- 1 H-pyrazole-3 -carboxamide (4. Og, 7.79mmol) was added into THF (54mL) at room temperature. Tetrabutylammonium fluoride(15.59mL, 1.Omol/L in THF, 15.59mmol) was added dropwise at 0°C. The reaction solution was stirred for 6h. TLC showed the completion of the reaction. Then the reaction was quenched by water (6OmL) and extracted with ethyl acetate (5OmL). The organic layer was washed with water (3OmLx3)and brine (3OmLx3) and concentrated under reduced pressure to obtain the title compound (ODM-201).Yield 2.88g (92.9%); chemical purity: 99.6%.ESI-MS (m/z): 421[M+Na].‘H-NIVIR (400 MHz, DMSO-d3): =13.03(s, 1H), 8.19(d, J=8.5Hz, 1H), 8.07(s, 1H), 7.97(s, 2H), 7.81(d, J=2.3Hz, 1H), 6.93(s, 1H), 6.40(s, 1H), 5.40(d, J5.OHz, 1H),4.85-4.67(s, 1H), 4.33(m, 3H), 1.38(d, J=6.5Hz, 3H), 1.11(d, J=6.5Hz, 3H).

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED; CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - WO2018/108130, 2018, A1 Location in patent: Page/Page column 30; 31

11
[ 1297537-41-7 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C / Inert atmosphere 2: sodium tetrahydroborate / tetrahydrofuran; methanol / 20 °C
	Multi-step reaction with 2 steps 1.1: potassium <i>tert</i>-butylate / toluene / 1 h / 0 °C / Inert atmosphere 1.2: 2 h / 0 - 20 °C / Inert atmosphere 2.1: sodium tetrahydroborate; ethanol
	Multi-step reaction with 3 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 25 °C / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: copper(l) iodide; potassium <i>tert</i>-butylate / tetrahydrofuran / 1 h / Inert atmosphere 2.2: 12 h / 40 °C / Inert atmosphere 3.1: sodium tetrahydroborate / ethanol / 0 - 20 °C

Reference： [1]Yu, Jiang; Zhou, Peiting; Hu, Mingxing; Yang, Liuqing; Yan, Guoyi; Xu, Ruixue; Deng, Yufang; Li, Xinghai; Chen, Yuanwei [European Journal of Medicinal Chemistry, 2019, vol. 182]
[2]Current Patent Assignee: NANJING JUNRUO BIOMEDICAL RES INSTITUTE; JIANGSU JUNRUO PHARMACEUTICAL; HAIMEN BAIKANG PHARMACEUTICAL - CN110590668, 2019, A
[3]Current Patent Assignee: SHANGDONG NEW TIME PHARMACEUTICAL CO LTD - CN115872932, 2023, A

12
[ 2415967-06-3 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: hydrogenchloride / lithium hydroxide monohydrate; 1,4-dioxane / 3 h / 10 °C 2.1: potassium-t-butoxide / toluene / 1 h / 0 °C / Inert atmosphere 2.2: 2 h / 0 - 20 °C / Inert atmosphere 3.1: sodium tetrahydridoborate; ethanol
	Multi-step reaction with 2 steps 1: hydrogenchloride / ethanol / 65 - 70 °C 2: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C
	Multi-step reaction with 3 steps 1: hydrogenchloride / ethanol / 65 - 70 °C 2: N-ethyl-N,N-diisopropylamine; 1,1′-carbonyldiimidazole / dichloromethane / 20 °C 3: sodium hydroxide / ethanol; lithium hydroxide monohydrate / 20 °C

Multi-step reaction with 3 steps 1: hydrogenchloride; lithium hydroxide monohydrate / acetonitrile / Reflux 2: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C 3: sodium tetrahydridoborate; ethanol

Reference： [1]Current Patent Assignee: NANJING JUNRUO BIOMEDICAL RES INSTITUTE; JIANGSU JUNRUO PHARMACEUTICAL; HAIMEN BAIKANG PHARMACEUTICAL - CN110590668, 2019, A
[2]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN111087324, 2020, A
[3]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN111087324, 2020, A
[4]Xu, Qian; Zhang, Zixiong; Huang, Chenchao; Bao, Qiqi; Zhang, Rongyu; Wu, Meng; Xiao, Xiaohui; Han, Xiaoli; Li, Xiaoyu; Zhou, Jinming [Bioorganic Chemistry, 2022, vol. 124]

13
[ 548797-51-9 ]
[ 1297538-32-9 ]

Reference： [1]Patent: CN110590668,2019,A

14
[ 2451299-27-5 ]
[ CAS Unavailable ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
87.5%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	8 example 8 Add compound 7 (29.72g, 100mmol) and methylene chloride (216mL) to the three-necked flask,Compound 8b (19.59g, 110mmol) was added,Add HBTU (49.30g, 130mmol), stir well and add diisopropylethylamine (25.85g, 200mmol),Reaction at room temperature for 10 to 16 hours. After the reaction was completed, 3% dilute hydrochloric acid solution (216 mL) was slowly added, stirred for 15 minutes, and then separated, and the aqueous phase was extracted once again with 108 mL of dichloromethane.The combined organic phase was washed once with 108 mL of 5% sodium bicarbonate solution, once with 108 mL of saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, added isopropyl alcohol and water to beat,Slowly cool to 0 ~ 5 , filter and dry to obtain compound 10 (34.90g, 87.5%, purity about 99.7%).

Reference： [1]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN111087324, 2020, A Location in patent: Paragraph 0094-0097

15
[ 1297545-68-6 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
93.3%	With sodium hydroxide In ethanol; water at 20℃;	9 Example 9 Add compound 9 (44.09g, 100mmol) and ethanol (220mL) to the three-necked flask, stir evenly, add 5% sodium hydroxide solution (120.0g, 150mmol), react at room temperature for 16 to 24 hours, and concentrate to remove most of the solvent at the end of the reaction , Add dilute hydrochloric acid (3%, 182mL, total 150mmol), heat to 50 55 , slowly cool and beat, filter, and recrystallize the crude product with ethanol and water to recrystallize doramide product 10 (37.21g, 93.3%, purity ≥99.8%).

Reference： [1]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN111087324, 2020, A Location in patent: Paragraph 0098-0101

16
[ 101667-74-7 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 16 h / 100 - 110 °C 2: acetic acid / ethanol / Reflux 3: hydrogenchloride / ethanol / 65 - 70 °C 4: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C
	Multi-step reaction with 5 steps 1.1: 16 h / 100 - 110 °C 2.1: hydrazine hydrate; acetic acid / ethanol / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3.2: 1 h 4.1: hydrogenchloride / ethanol / 65 - 70 °C 5.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C
	Multi-step reaction with 5 steps 1.1: 16 h / 100 - 110 °C 2.1: hydrazine hydrate; acetic acid / ethanol / Reflux 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl acetamide / 50 - 55 °C 3.2: 1 h / 20 °C 4.1: hydrogenchloride / ethanol / 65 - 70 °C 5.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C

	Multi-step reaction with 5 steps 1: 16 h / 100 - 110 °C 2: acetic acid / ethanol / Reflux 3: hydrogenchloride / ethanol / 65 - 70 °C 4: N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole / dichloromethane / 20 °C 5: sodium hydroxide / ethanol; water / 20 °C
	Multi-step reaction with 6 steps 1.1: 16 h / 100 - 110 °C 2.1: hydrazine hydrate; acetic acid / ethanol / Reflux 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl acetamide / 50 - 55 °C 3.2: 1 h / 20 °C 4.1: hydrogenchloride / ethanol / 65 - 70 °C 5.1: N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole / dichloromethane / 20 °C 6.1: sodium hydroxide / ethanol; water / 20 °C
	Multi-step reaction with 6 steps 1.1: 16 h / 100 - 110 °C 2.1: hydrazine hydrate; acetic acid / ethanol / Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3.2: 1 h 4.1: hydrogenchloride / ethanol / 65 - 70 °C 5.1: N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole / dichloromethane / 20 °C 6.1: sodium hydroxide / ethanol; water / 20 °C

Reference： [1]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN111087324, 2020, A
[2]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN111087324, 2020, A
[3]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN111087324, 2020, A
[4]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN111087324, 2020, A
[5]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN111087324, 2020, A
[6]Current Patent Assignee: HANGZHOU CHEMINSPIRE TECH - CN111087324, 2020, A

17
[ CAS Unavailable ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: acetic acid / ethanol / Reflux 2: hydrogenchloride / ethanol / 65 - 70 °C 3: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C
	Multi-step reaction with 4 steps 1.1: hydrazine hydrate; acetic acid / ethanol / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.2: 1 h 3.1: hydrogenchloride / ethanol / 65 - 70 °C 4.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C
	Multi-step reaction with 4 steps 1.1: hydrazine hydrate; acetic acid / ethanol / Reflux 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl acetamide / 50 - 55 °C 2.2: 1 h / 20 °C 3.1: hydrogenchloride / ethanol / 65 - 70 °C 4.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C

	Multi-step reaction with 4 steps 1: acetic acid / ethanol / Reflux 2: hydrogenchloride / ethanol / 65 - 70 °C 3: N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole / dichloromethane / 20 °C 4: sodium hydroxide / ethanol; water / 20 °C
	Multi-step reaction with 5 steps 1.1: hydrazine hydrate; acetic acid / ethanol / Reflux 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl acetamide / 50 - 55 °C 2.2: 1 h / 20 °C 3.1: hydrogenchloride / ethanol / 65 - 70 °C 4.1: N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole / dichloromethane / 20 °C 5.1: sodium hydroxide / ethanol; water / 20 °C
	Multi-step reaction with 5 steps 1.1: hydrazine hydrate; acetic acid / ethanol / Reflux 2.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2.2: 1 h 3.1: hydrogenchloride / ethanol / 65 - 70 °C 4.1: N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole / dichloromethane / 20 °C 5.1: sodium hydroxide / ethanol; water / 20 °C

18
[ 1297537-41-7 ]
[ 1401584-94-8 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
73.2%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran at -10℃; for 2h; Inert atmosphere;	8-10 Example 8 Synthesis of the compound Darolutamide represented by formula I At -10°C, compound 6 (2.61g, 10mmol), compound 7 (1.56g, 10mmol), DIPEA (2.58g, 20mmol) and HATU (3.8g, 10mmol) were added to THF (25mL) and kept at- The reaction was stirred at 10°C for 2h. The reaction solution was quenched by adding saturated NaHCO3 solution (20mL), extracted with EA (25mL), the organic phase was washed with saturated NaHCO3 solution, dried and concentrated, and then column chromatography (column chromatography using dichloromethane and methanol with a volume ratio of 20:1 (Eluted with mixed solvents) to obtain the compound of formula I Darolutamide, the yield is 2.92 g, the yield is 73.2%, and the HPLC purity is 99.3%.

Reference： [1]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN111116476, 2020, A Location in patent: Paragraph 0059-0065

19
[ 2453188-55-9 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 0 °C 3: sodium tetrahydroborate / ethanol / 3.5 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN111116477, 2020, A

20
[ 1297537-45-1 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 3 h / 0 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 0 °C 3: sodium tetrahydroborate / ethanol / 3.5 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: WUHAN JIUZHOU YUMIN PHARMACEUTICAL TECH - CN111116477, 2020, A

21
[ 1297537-41-7 ]
[ 1297537-45-1 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 2: sodium tetrahydroborate; ethanol
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 2: sodium tetrahydroborate; ethanol
	Multi-step reaction with 2 steps 1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 2: sodium tetrahydroborate / ethanol / 24 h / 20 °C

Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 2: sodium tetrahydroborate / ethanol / 24 h / 20 °C

Reference： [1]Current Patent Assignee: ZHEJIANG NORMAL UNIVERSITY - CN113861115, 2021, A
[2]Xu, Qian; Zhang, Zixiong; Huang, Chenchao; Bao, Qiqi; Zhang, Rongyu; Wu, Meng; Xiao, Xiaohui; Han, Xiaoli; Li, Xiaoyu; Zhou, Jinming [Bioorganic Chemistry, 2022, vol. 124]
[3]Szilágyi, Bence; Egyed, Attila; Mándity, István; Nagy, Tamás; Kátai-Fadgyas, Katalin; Volk, Balázs; Keseru, György M. [Synthesis, 2023, vol. 55, # 6, p. 959 - 966]
[4]Poszávácz, László; Nagy, Tamás; Kátai-Fadgyas, Katalin; Volk, Balázs [Synthesis, 2023, vol. 55, # 13, p. 2061 - 2069]

22
[ 37622-89-2 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium hydroxide; methanol; lithium hydroxide monohydrate / 20 °C 2: N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C 3: sodium tetrahydridoborate; ethanol

Reference： [1]Bao, Qiqi; Han, Xiaoli; Huang, Chenchao; Li, Xiaoyu; Wu, Meng; Xiao, Xiaohui; Xu, Qian; Zhang, Rongyu; Zhang, Zixiong; Zhou, Jinming [Bioorganic Chemistry, 2022, vol. 124]

23
[ 2454388-01-1 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: hydrazine hydrochloride / 2 h / 75 °C 2.1: sodium hydroxide / water / 2 h / 90 °C 2.2: 30 min / 5 °C 3.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 4.1: sodium tetrahydroborate / ethanol / 24 h / 20 °C
	Multi-step reaction with 4 steps 1: hydrazine hydrochloride / 2 h / 75 °C 2: sodium hydroxide; water / methanol / 2 h / 20 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 4: sodium tetrahydroborate / ethanol / 24 h / 20 °C

Reference： [1]Szilágyi, Bence; Egyed, Attila; Mándity, István; Nagy, Tamás; Kátai-Fadgyas, Katalin; Volk, Balázs; Keseru, György M. [Synthesis, 2023, vol. 55, # 6, p. 959 - 966]
[2]Poszávácz, László; Nagy, Tamás; Kátai-Fadgyas, Katalin; Volk, Balázs [Synthesis, 2023, vol. 55, # 13, p. 2061 - 2069]

24
[ 2919749-50-9 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: hydrazine hydrochloride / ethanol / 5 h / 70 - 80 °C 2: sodium hydroxide; water / methanol / 2 h / 20 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 4: sodium tetrahydroborate / ethanol / 24 h / 20 °C
	Multi-step reaction with 4 steps 1: hydrazine hydrochloride; hydrogenchloride / ethanol; water / 6 h / 80 °C / pH 2 - 3 2: sodium hydroxide; water / methanol / 2 h / 20 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 4: sodium tetrahydroborate / ethanol / 24 h / 20 °C

25
[ 1401562-12-6 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 4 h / 120 °C / Cooling with ice 2.1: sodium hydride / mineral oil; tetrahydrofuran / 30 min / 5 °C / Inert atmosphere 2.2: 1.5 h / 5 °C / Inert atmosphere 3.1: hydrogenchloride / water / 2 h / 90 °C 4.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 5.1: sodium tetrahydroborate / ethanol / 24 h / 20 °C
	Multi-step reaction with 5 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 4 h / 120 °C / Cooling with ice 2.1: sodium hydride / mineral oil; tetrahydrofuran / 30 min / 5 °C / Inert atmosphere 2.2: 1.5 h / 5 °C / Inert atmosphere 3.1: hydrogenchloride / water / 2 h / Reflux 4.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 5.1: sodium tetrahydroborate / ethanol / 24 h / 20 °C
	Multi-step reaction with 6 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 4 h / 120 °C / Cooling with ice 2.1: sodium hydride / mineral oil; tetrahydrofuran / 30 min / 5 °C / Inert atmosphere 2.2: 1.5 h / 5 °C / Inert atmosphere 3.1: hydrogenchloride / water / 2 h / Reflux 4.1: sodium hydroxide; water / methanol / 2 h / 20 °C 5.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 6.1: sodium tetrahydroborate / ethanol / 24 h / 20 °C

26
[ 37687-24-4 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sodium hydroxide; water / dimethyl sulfoxide / 4 h / 25 °C 2.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 4 h / 120 °C / Cooling with ice 3.1: sodium hydride / mineral oil; tetrahydrofuran / 30 min / 5 °C / Inert atmosphere 3.2: 1.5 h / 5 °C / Inert atmosphere 4.1: hydrogenchloride / water / 2 h / 90 °C 5.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 6.1: sodium tetrahydroborate / ethanol / 24 h / 20 °C
	Multi-step reaction with 6 steps 1.1: sodium hydroxide; water / dimethyl sulfoxide / 4 h / 25 °C 2.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 4 h / 120 °C / Cooling with ice 3.1: sodium hydride / mineral oil; tetrahydrofuran / 30 min / 5 °C / Inert atmosphere 3.2: 1.5 h / 5 °C / Inert atmosphere 4.1: hydrogenchloride / water / 2 h / Reflux 5.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 6.1: sodium tetrahydroborate / ethanol / 24 h / 20 °C
	Multi-step reaction with 6 steps 1.1: water; magnesium hydroxide / ethanol / 14 h / Reflux 2.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 4 h / 120 °C / Cooling with ice 3.1: sodium hydride / mineral oil; tetrahydrofuran / 30 min / 5 °C / Inert atmosphere 3.2: 1.5 h / 5 °C / Inert atmosphere 4.1: hydrogenchloride / water / 2 h / 90 °C 5.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 6.1: sodium tetrahydroborate / ethanol / 24 h / 20 °C

	Multi-step reaction with 6 steps 1.1: water; magnesium hydroxide / ethanol / 14 h / Reflux 2.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 4 h / 120 °C / Cooling with ice 3.1: sodium hydride / mineral oil; tetrahydrofuran / 30 min / 5 °C / Inert atmosphere 3.2: 1.5 h / 5 °C / Inert atmosphere 4.1: hydrogenchloride / water / 2 h / Reflux 5.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 6.1: sodium tetrahydroborate / ethanol / 24 h / 20 °C
	Multi-step reaction with 7 steps 1.1: sodium hydroxide; water / dimethyl sulfoxide / 4 h / 25 °C 2.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 4 h / 120 °C / Cooling with ice 3.1: sodium hydride / mineral oil; tetrahydrofuran / 30 min / 5 °C / Inert atmosphere 3.2: 1.5 h / 5 °C / Inert atmosphere 4.1: hydrogenchloride / water / 2 h / Reflux 5.1: sodium hydroxide; water / methanol / 2 h / 20 °C 6.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 7.1: sodium tetrahydroborate / ethanol / 24 h / 20 °C
	Multi-step reaction with 7 steps 1.1: water; magnesium hydroxide / ethanol / 14 h / Reflux 2.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 4 h / 120 °C / Cooling with ice 3.1: sodium hydride / mineral oil; tetrahydrofuran / 30 min / 5 °C / Inert atmosphere 3.2: 1.5 h / 5 °C / Inert atmosphere 4.1: hydrogenchloride / water / 2 h / Reflux 5.1: sodium hydroxide; water / methanol / 2 h / 20 °C 6.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 7.1: sodium tetrahydroborate / ethanol / 24 h / 20 °C

Reference： [1]Poszávácz, László; Nagy, Tamás; Kátai-Fadgyas, Katalin; Volk, Balázs [Synthesis, 2023, vol. 55, # 13, p. 2061 - 2069]
[2]Poszávácz, László; Nagy, Tamás; Kátai-Fadgyas, Katalin; Volk, Balázs [Synthesis, 2023, vol. 55, # 13, p. 2061 - 2069]
[3]Poszávácz, László; Nagy, Tamás; Kátai-Fadgyas, Katalin; Volk, Balázs [Synthesis, 2023, vol. 55, # 13, p. 2061 - 2069]
[4]Poszávácz, László; Nagy, Tamás; Kátai-Fadgyas, Katalin; Volk, Balázs [Synthesis, 2023, vol. 55, # 13, p. 2061 - 2069]
[5]Poszávácz, László; Nagy, Tamás; Kátai-Fadgyas, Katalin; Volk, Balázs [Synthesis, 2023, vol. 55, # 13, p. 2061 - 2069]
[6]Poszávácz, László; Nagy, Tamás; Kátai-Fadgyas, Katalin; Volk, Balázs [Synthesis, 2023, vol. 55, # 13, p. 2061 - 2069]

27
[ 2919749-47-4 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium hydride / mineral oil; tetrahydrofuran / 30 min / 5 °C / Inert atmosphere 1.2: 1.5 h / 5 °C / Inert atmosphere 2.1: hydrogenchloride / water / 2 h / 90 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 4.1: sodium tetrahydroborate / ethanol / 24 h / 20 °C
	Multi-step reaction with 4 steps 1.1: sodium hydride / mineral oil; tetrahydrofuran / 30 min / 5 °C / Inert atmosphere 1.2: 1.5 h / 5 °C / Inert atmosphere 2.1: hydrogenchloride / water / 2 h / Reflux 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 4.1: sodium tetrahydroborate / ethanol / 24 h / 20 °C
	Multi-step reaction with 5 steps 1.1: sodium hydride / mineral oil; tetrahydrofuran / 30 min / 5 °C / Inert atmosphere 1.2: 1.5 h / 5 °C / Inert atmosphere 2.1: hydrogenchloride / water / 2 h / Reflux 3.1: sodium hydroxide; water / methanol / 2 h / 20 °C 4.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 5.1: sodium tetrahydroborate / ethanol / 24 h / 20 °C

28
[ 2919749-48-5 ]
[ 1297538-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: hydrogenchloride / water / 2 h / 90 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 3: sodium tetrahydroborate / ethanol / 24 h / 20 °C
	Multi-step reaction with 3 steps 1: hydrogenchloride / water / 2 h / Reflux 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 3: sodium tetrahydroborate / ethanol / 24 h / 20 °C
	Multi-step reaction with 4 steps 1: hydrogenchloride / water / 2 h / Reflux 2: sodium hydroxide; water / methanol / 2 h / 20 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 24 h / 20 °C 4: sodium tetrahydroborate / ethanol / 24 h / 20 °C

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
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Prevention
Code	Phrase
P201	Obtain special instructions before use.
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Code	Phrase
P301	IF SWALLOWED:
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P321
P322
P330	Rinse mouth.
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P337	If eye irritation persists:
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P342	If experiencing respiratory symptoms:
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P378
P380	Evacuate area.
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P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
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P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
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Storage
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P401
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Physical hazards
Code	Phrase
H200	Unstable explosive
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H361d	Suspected of damaging the unborn child
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H370	Causes damage to organs
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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. 1297538-32-9 ] {[proInfo.proName]}

Quality Control of [ 1297538-32-9 ]

Related Doc. of [ 1297538-32-9 ]

Product Details of [ 1297538-32-9 ]

Calculated chemistry of [ 1297538-32-9 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1297538-32-9 ]

Application In Synthesis of [ 1297538-32-9 ]

[ 1297538-32-9 ] Synthesis Path-Upstream 1~5

[ 1297538-32-9 ] Synthesis Path-Downstream 1~28

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