173937-91-2

Basic information

• Product Name: atrasentan
• Synonyms: atrasentan;(2R,3R,4S)-4-(1,3-Benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid;(+)-A 127722;A-147627;(2R,3R,4S)-4-(1,3-Benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylic acid;A127722, CID 5310990;Atrasentan (ABT-627)
• CAS NO: 173937-91-2
• Molecular Formula: C₂₉H₃₈N₂O₆
• Molecular Weight: 510.62
• Mol File: 173937-91-2.mol
• Article Data: 8

Chemical Properties

• Melting Point: 122-124°
• Boiling Point: 659.4 °C at 760 mmHg
• Flash Point: 352.6 °C
• Appearance: /
• Density: 1.188 g/cm³
• Vapor Pressure: 2.76E-18mmHg at 25°C
• Storage Temp.: -20°C Freezer, Under inert atmosphere
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 3.49±0.60(Predicted)
• CAS DataBase Reference: atrasentan(CAS DataBase Reference)
• NIST Chemistry Reference: atrasentan(173937-91-2)
• EPA Substance Registry System: atrasentan(173937-91-2)

Safety Data

• Hazardous Substances Data: 173937-91-2(Hazardous Substances Data)

Usage

Uses

Different sources of media describe the Uses of 173937-91-2 differently. You can refer to the following data:
1. Palliative treatment of bone pain due to metastatic prostate cancer and disease progression (endothelin (ETA) receptor antagonist).
2. Atrasentan is a selective antagonist of the endothelin-A (ETA) receptor and binds selectively to the ETA receptor, which may result in inhibition of endothelin-induced angiogenesis and tumor cell proliferation.

InChI:InChI=1/C29H38N2O6.ClH/c1-4-6-14-30(15-7-5-2)26(32)18-31-17-23(21-10-13-24-25(16-21)37-19-36-24)27(29(33)34)28(31)20-8-11-22(35-3)12-9-20;/h8-13,16,23,27-28H,4-7,14-15,17-19H2,1-3H3,(H,33,34);1H/t23-,27-,28+;/m1./s1

Synthetic route

2-[(2R,3R,4S)-4-Benzo[1,3]dioxol-5-yl-3-((S)-4-benzyl-2-oxo-oxazolidine-3-carbonyl)-2-(4-methoxy-phenyl)-pyrrolidin-1-yl]-N,N-dibutyl-acetamide → atrasentan (173937-91-2)

Conditions	Yield
With lithium hydroxide; dihydrogen peroxide In tetrahydrofuran for 0.5h;	78%

5-((E)-2-nitroethenyl)-1,3-benzodioxole (1485-00-3, 22568-48-5) + palladium → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 10 steps 1: 78 percent / DBU / tetrahydrofuran; propan-2-ol / 4 h / Ambient temperature 2: 12.34 g / H2 / Raney nickel / ethanol / 3040 Torr 3: 1.) sodium cyanoborohydride, 2.) bromocresol green, conc. HCl / 1.) THF, EtOH, 2.) THF, EtOH, 20 min 4: 2.775 g / C2H5ONa / ethanol / Heating 5: 91 percent / CH2Cl2 / 1 h / Ambient temperature 6: 95 percent / NaOH 7: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 8: 4 N aq. HCl / dioxane 9: iPr2NEt / acetonitrile 10: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme
Multi-step reaction with 9 steps 1: 78 percent / DBU / tetrahydrofuran; propan-2-ol / 4 h / Ambient temperature 2: 12.34 g / H2 / Raney nickel / ethanol / 3040 Torr 3: 1.) sodium cyanoborohydride, 2.) bromocresol green, conc. HCl / 1.) THF, EtOH, 2.) THF, EtOH, 20 min 4: 91 percent / CH2Cl2 / 1 h / Ambient temperature 5: 95 percent / NaOH 6: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 7: 4 N aq. HCl / dioxane 8: iPr2NEt / acetonitrile 9: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

N,N-dibutylbromoacetamide (40124-27-4) → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: iPr2NEt / acetonitrile 2: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

dibutylamine (111-92-2) + (+-)-2-chloro-1-<6-methoxy-8-nitro-<4>quinolyl>-ethanol → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 95 percent / 1,2-dichloro-ethane / 0.83 h / -20 - 20 °C 2: iPr2NEt / acetonitrile 3: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

Ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4.5-dihydro-3H-pyrrole-3-carboxylate (173864-46-5) → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 8 steps 1: 1.) sodium cyanoborohydride, 2.) bromocresol green, conc. HCl / 1.) THF, EtOH, 2.) THF, EtOH, 20 min 2: 2.775 g / C2H5ONa / ethanol / Heating 3: 91 percent / CH2Cl2 / 1 h / Ambient temperature 4: 95 percent / NaOH 5: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 6: 4 N aq. HCl / dioxane 7: iPr2NEt / acetonitrile 8: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme
Multi-step reaction with 7 steps 1: 1.) sodium cyanoborohydride, 2.) bromocresol green, conc. HCl / 1.) THF, EtOH, 2.) THF, EtOH, 20 min 2: 91 percent / CH2Cl2 / 1 h / Ambient temperature 3: 95 percent / NaOH 4: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 5: 4 N aq. HCl / dioxane 6: iPr2NEt / acetonitrile 7: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

Ethyl 2-(4-methoxybenzoyl)-3-(3,4-methylenedioxy-phenyl)-4-nitro-butanoate (173864-45-4) → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 9 steps 1: 12.34 g / H2 / Raney nickel / ethanol / 3040 Torr 2: 1.) sodium cyanoborohydride, 2.) bromocresol green, conc. HCl / 1.) THF, EtOH, 2.) THF, EtOH, 20 min 3: 2.775 g / C2H5ONa / ethanol / Heating 4: 91 percent / CH2Cl2 / 1 h / Ambient temperature 5: 95 percent / NaOH 6: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 7: 4 N aq. HCl / dioxane 8: iPr2NEt / acetonitrile 9: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme
Multi-step reaction with 8 steps 1: 12.34 g / H2 / Raney nickel / ethanol / 3040 Torr 2: 1.) sodium cyanoborohydride, 2.) bromocresol green, conc. HCl / 1.) THF, EtOH, 2.) THF, EtOH, 20 min 3: 91 percent / CH2Cl2 / 1 h / Ambient temperature 4: 95 percent / NaOH 5: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 6: 4 N aq. HCl / dioxane 7: iPr2NEt / acetonitrile 8: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

ethyl 4-(1,3-benzodioxol-5-yl)-N-tert-butoxycarbonyl-2-(4-methoxyphenyl)pyrrolidine-3-carboxylate → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 95 percent / NaOH 2: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 3: 4 N aq. HCl / dioxane 4: iPr2NEt / acetonitrile 5: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

(2R,3R,4S)-4-Benzo[1,3]dioxol-5-yl-3-((S)-4-benzyl-2-oxo-oxazolidine-3-carbonyl)-2-(4-methoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 4 N aq. HCl / dioxane 2: iPr2NEt / acetonitrile 3: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

(2R,3S,4S)-4-Benzo[1,3]dioxol-5-yl-2-(4-methoxy-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 7 steps 1: 2.775 g / C2H5ONa / ethanol / Heating 2: 91 percent / CH2Cl2 / 1 h / Ambient temperature 3: 95 percent / NaOH 4: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 5: 4 N aq. HCl / dioxane 6: iPr2NEt / acetonitrile 7: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

ethyl c-(1,3-benzodioxol-5-yl)-r-2-(4-methoxyphenyl)pyrrolidine-t-3-carboxylate → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: 91 percent / CH2Cl2 / 1 h / Ambient temperature 2: 95 percent / NaOH 3: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 4: 4 N aq. HCl / dioxane 5: iPr2NEt / acetonitrile 6: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

rac-(2R,3R,4S)-1-(tert-butoxycarbonyl)-4-(benzo[d][1,3]dioxol-6-yl)-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid → atrasentan (173937-91-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) Et3N, t-BuCOCl, 2.) n-BuLi 2: 4 N aq. HCl / dioxane 3: iPr2NEt / acetonitrile 4: 78 percent / aq. LiOH, 30percent aq. H2O2 / tetrahydrofuran / 0.5 h View Scheme

N,N-dibutylbromoacetamide (40124-27-4) + ethyl (2R,3R,4S)-5-(4-methoxyphenyl)-3-(3,4-(methylenedioxy)phenyl)pyrrolidine-3-carboxylate (178739-03-2) → atrasentan (173937-91-2)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile

ethyl (2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate, (S)-(+)-mandelate (195708-14-6) + N,N-dibutylbromoacetamide (40124-27-4) → atrasentan (173937-91-2)

Conditions	Yield
Stage #1: ethyl (2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate, (S)-(+)-mandelate With sodium hydrogencarbonate In water; ethyl acetate at 25℃; Stage #2: N,N-dibutylbromoacetamide With N-ethyl-N,N-diisopropylamine In acetonitrile at 10℃; for 12h; Stage #3: With hydrogenchloride; sodium hydroxide more than 3 stages;

ethyl (2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate, (S)-(+) mandelate (403614-49-3) + N,N-dibutylbromoacetamide (40124-27-4) + N-ethyl-N,N-diisopropylamine (7087-68-5) → atrasentan (173937-91-2)

Conditions	Yield
Stage #1: ethyl (2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate, (S)-(+) mandelate With sodium hydrogencarbonate In water; ethyl acetate at 25℃; Stage #2: N,N-dibutylbromoacetamide; N-ethyl-N,N-diisopropylamine In ethyl acetate; acetonitrile at 110℃; for 16h;

atrasentan (173937-91-2) → Atrasentan hydrochloride

Conditions	Yield
With hydrogenchloride In ethanol; water; ethyl acetate for 0.25h;
With hydrogenchloride In water; ethyl acetate at 0℃; for 2 - 3h; Product distribution / selectivity;
With hydrogenchloride In ethanol; water; ethyl acetate for 0.25h; Product distribution / selectivity;
With hydrogenchloride In ethyl acetate at 0 - 45℃; for 26.5 - 39.5h;

(S)-Mandelic acid (17199-29-0) + atrasentan (173937-91-2) → atrasentan (S)-mandelate salt

Conditions	Yield
In methanol; water at 50℃;

(S)-Mandelic acid (17199-29-0) + atrasentan (173937-91-2) → atrasentan (S)-mandelate salt

Conditions	Yield
In methanol; water at 40℃; Temperature;

(R)-Mandelic Acid (611-71-2) + atrasentan (173937-91-2) → atrasentan R-mandelate salt

Conditions	Yield
In water at 50℃; for 0.25h; Sonication;

Upstream product

• 2881-83-6 ethyl 4-methoxybenzoylacetate 
• 40124-27-4 N,N-dibutylbromoacetamide 
• 178739-03-2 ethyl (2R,3R,4S)-5-(4-methoxyphenyl)-3-(3,4-(methylenedioxy)phenyl)pyrrolidine-3-carboxylate 
• 403614-49-3 ethyl (2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate, (S)-(+) mandelate 
• 7087-68-5 N-ethyl-N,N-diisopropylamine 
• 195708-14-6 ethyl (2R,3R,4S)-(+)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)pyrrolidine-3-carboxylate, (S)-(+)-mandelate 
• 195708-08-8 (2R,3R,4S)-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid ethyl ester 
• 173864-47-6 ethyl c-(1,3-benzodioxol-5-yl)-r-2-(4-methoxyphenyl)pyrrolidine-t-3-carboxylate 
• 173864-47-6 (2R,3S,4S)-4-Benzo[1,3]dioxol-5-yl-2-(4-methoxy-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester 
• 173864-45-4 Ethyl 2-(4-methoxybenzoyl)-3-(3.4-methylenedioxy-phenyl)-4-nitro-butanoate 
• 173864-46-5 ethyl 2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-4,5-dihydro-3H-pyrrole-3-carboxylate 
• 111-92-2 dibutylamine 
• 1485-00-3 5-((E)-2-nitroethenyl)-1,3-benzodioxole 

Downstream Products

• 195733-43-8 Atrasentan hydrochloride 

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