1297537-33-7

Basic information

• Product Name: 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide
• Synonyms: 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide
• CAS NO: 1297537-33-7
• Molecular Weight: 396.836
• Mol File: 1297537-33-7.mol
• Article Data: 9

Chemical Properties

• Melting Point: 210 - 212?C
• Boiling Point: 714.7±60.0 °C(Predicted)
• Density: 1.41±0.1 g/cm3(Predicted)
• CAS DataBase Reference: 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide(CAS DataBase Reference)
• NIST Chemistry Reference: 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide(1297537-33-7)
• EPA Substance Registry System: 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide(1297537-33-7)

Safety Data

• Hazardous Substances Data: 1297537-33-7(Hazardous Substances Data)

Usage

Uses

ORM-15341 is a metabolite of Darolutamide. Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models.

Synthetic route

3-acetyl-1H-pyrazole-5-carboxylic acid + (S)-4-(1-(2-aminopropyl) 1H-pyrazol-3-yl)-2-chlorobenzonitrile (1297537-41-7) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate at 10 - 20℃; Inert atmosphere;	87.5%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere;	79.5%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere;

(S)-4-(1-(2-aminopropyl) 1H-pyrazol-3-yl)-2-chlorobenzonitrile (1297537-41-7) + C6H5ClN2O2 → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 3h;	87.1%

2-chloro-4- (1H-pyrazol-3-yl)benzonitrile (1297537-37-1) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triphenylphosphine / ethyl acetate / 0.25 h / Inert atmosphere 1.2: 20 °C 2.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dichloromethane / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride; diisopropyl (E)-azodicarboxylate; triphenylphosphine / n-heptane; dichloromethane; water; ethyl acetate 2: water View Scheme
Multi-step reaction with 2 steps 1: triphenylphosphine; hydrogenchloride; di-isopropyl azodicarboxylate / ethyl acetate / 10 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 10 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 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; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C / Inert atmosphere View Scheme

3-acetyl-1H-pyrazole-5-carboxylic acid + (S)-4-(1-(2-aminopropyl) 1H-pyrazol-3-yl)-2-chlorobenzonitrile (1297537-41-7) + 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran (96042-30-7) + isopropyl alcohol (67-63-0) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
In water

2-Chloro-4-(1H-pyrazol-5-yl)benzonitrile hydrochloride (1297537-39-3) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: methanol; water 2: hydrogenchloride; diisopropyl (E)-azodicarboxylate; triphenylphosphine / n-heptane; dichloromethane; water; ethyl acetate 3: water View Scheme

4-bromo-2-chlorobenzonitrile (154607-01-9) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile; water / 0.5 h / Inert atmosphere; Reflux 1.2: 2.5 h / 60 - 70 °C / Inert atmosphere 2.1: hydrogenchloride / water / 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; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 10 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: trans-bis(triphenylphosphine)palladium dichloride; sodium carbonate / water; 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; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C / Inert atmosphere View Scheme

2-Chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (1297537-35-9) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride / water / 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; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 10 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 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; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: hydrogenchloride / water; 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 tert-butylate / toluene / 1 h / 0 °C / Inert atmosphere 3.2: 2 h / 0 - 20 °C / Inert atmosphere View Scheme

(S)-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl-2-yl)amino tert-butyl ester → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride / water; 1,4-dioxane / 3 h / 10 °C 2.1: potassium tert-butylate / toluene / 1 h / 0 °C / Inert atmosphere 2.2: 2 h / 0 - 20 °C / Inert atmosphere View Scheme

5-acetyl-1H-pyrazole-3-carboxylic acid ethyl ester (37622-89-2) + (S)-4-(1-(2-aminopropyl) 1H-pyrazol-3-yl)-2-chlorobenzonitrile (1297537-41-7) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
Stage #1: (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile With potassium tert-butylate In toluene at 0℃; for 1h; Inert atmosphere; Stage #2: 5-acetyl-1H-pyrazole-3-carboxylic acid ethyl ester In toluene at 0 - 20℃; for 2h; Inert atmosphere;	15.4 g

2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (548797-51-9) → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile; water / 0.5 h / Inert atmosphere; Reflux 1.2: palladium catalyst / 2 h / 60 - 70 °C / Inert atmosphere 2.1: hydrogenchloride / water; methanol / 2 h / 10 °C 3.1: triphenylphosphine / ethyl acetate / Inert atmosphere 3.2: 10 - 20 °C / Inert atmosphere 3.3: 30 - 45 °C / Inert atmosphere 4.1: potassium tert-butylate / toluene / 1 h / 0 °C / Inert atmosphere 4.2: 2 h / 0 - 20 °C / Inert atmosphere View Scheme

C23H29ClN4O4 → 5-acetyl-N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1H-pyrazole-3-carboxamide (1297537-33-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 0 °C View Scheme

Upstream product

• 1297537-41-7 (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile 
• 1297537-37-1 2-chloro-4-(1H-pyrazol-5-yl)benzonitrile 
• 1297537-39-3 2-Chloro-4-(1H-pyrazol-5-yl)benzonitrile hydrochloride 
• 1297537-35-9 2-Chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile 
• 154607-01-9 4-bromo-2-chlorobenzonitrile 
• 37622-89-2 5-acetyl-1H-pyrazole-3-carboxylic acid ethyl ester 
• 949034-45-1 5-acetyl-1H-pyrazole-3-carboxylic acid 
• 548797-51-9 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 
• 96042-30-7 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran 
• 67-63-0 isopropyl alcohol 
• 1297537-37-1 2-chloro-4- (1H-pyrazol-3-yl)benzonitrile 

Downstream Products

• 1297540-28-3 (S)-3-acetyl-N-(1-(3-(4-cyano-3-(methylthio)phenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide 
• 1297538-32-9 N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide 
• 1297540-05-6 1-(5-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-1H-pyrazol-3-yl)ethyl 2-(dimethylamino)acetate 
• 1297538-32-9 N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-5-[(1RS)-1-hydroxyethyl]-1H-pyrazole-3-carboxamide 
• 1403334-18-8 4-(1-(3-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)-1H-pyrazol-5-yl)ethoxy)-4-oxobutanoic acid 

Relevant articles and documents

SUBSTITUTED PYRAZOLE COMPOUNDS, COMPOSITIONS CONTAINING SAME, AND USE THEREOF

The present invention provides substituted pyrazole compounds, compositions containing same, and use thereof. The substituted pyrazole compounds comprise a compound represented by formula (I) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof. The compound represented by formula (I) can serve as a tissue selective androgen receptor modulator (SARM), particularly serving as a drug for treating prostate cancer and other AR-dependent conditions and diseases in which AR antagonism is desired.

Synthesis process of darolutamide

The invention relates to a synthesis process of darolutamide. Compared with an existing synthetic process route in which the reaction steps are 10 steps or more, the process of the invention has the advantages of less reaction steps in the route, high reaction yield of each step, simplicity and convenience in operation, and effective improvement of the total yield and industrial operability of thereaction.

Discovery and biological evaluation of darolutamide derivatives as inhibitors and down-regulators of wild-type AR and the mutants

Androgen receptor (AR) has been a target of prostate cancer (PC) for nearly six decades. Recently, downregulating or degrading AR and the mutants especially the splice variant 7 (AR-V7) lacking ligand binding domain (LBD) emerged as an advantageous therapeutic approach to overcome drug resistance. Here, the structural modification of darolutamide resulted in the discovery of dual-action AR inhibitors and down-regulators. Unlike other traditional AR antagonists targeting the AR-LBD, compounds 4k and 4b not only inhibit the activities of wt-AR and AR-F876L mutant but also downregulate the protein expression of full-length (AR-full) and AR variant 7 (AR-V7) at mRNA level. In cell proliferation assays, compounds 4k and 4b exhibited better antiproliferative activities than darolutamide and enzalutamide against AR-V7-positive 22Rv1 cells and VCaP cells. In addition, 4k demonstrated better antitumor activity than clinically used enzalutamide in castration-resistant VCaP xenograft model. Collectively, combining the activities of AR inhibition and downregulation, compound 4k is proposed as an advantageous lead compound to disrupt AR signaling and overcome resistance.