875573-69-6

Basic information

• Product Name: Estra-1,3,5(10)-triene-3,17-diol,7-[9-[(4,4,5,5,5-pentafluoropentyl)thio]nonyl]-,17-acetate,(7a,17b)-
• Synonyms: (7a,17b)-7-[9-[(4,4,5,5,5-Pentafluoropentyl)thio]nonyl]-estra-1,3,5(10)-triene-3,17-diol 17-acetate;(7R,8R,9S,13S,14S,17S)-3-hydroxy-13-Methyl-7-(4-(4,4,5,5,5-pentafluoropentylthio)butyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl acetate;(7alpha,17beta)-7-[9-(4,4,5,5,5-pentafluoropentyl)thio]nonyl]estra-1,3,5(10)- triene-3-diol-17oxyethyl;(7α,17β)-7-[9-(4,4,5,5,5-pentafluoropen tyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3-diol-17oxyethyl;Fulvestrant Intermediates-6(N-2);(7α,17β)-7-[9-(4,4,5,5,5-pentafluoropentyl)thio]nonyl]estra- 1,3,5(10)- triene-3-diol -17oxyethyl;(7a,17b);-7-(9-((4,4,5,5,5-Pentafluoropentyl)
• CAS NO: 875573-69-6
• Molecular Formula: C₃₄H₄₉F₅O₃S
• Molecular Weight: 632.81
• EINECS: 1592732-453-0
• Product Categories: API
• Mol File: 875573-69-6.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 631.4±55.0 °C(Predicted)
• Appearance: /
• Density: 1.19
• Storage Temp.: Sealed in dry,Room Temperature
• PKA: 10.26±0.70(Predicted)
• CAS DataBase Reference: Estra-1,3,5(10)-triene-3,17-diol,7-[9-[(4,4,5,5,5-pentafluoropentyl)thio]nonyl]-,17-acetate,(7a,17b)-(CAS DataBase Reference)
• NIST Chemistry Reference: Estra-1,3,5(10)-triene-3,17-diol,7-[9-[(4,4,5,5,5-pentafluoropentyl)thio]nonyl]-,17-acetate,(7a,17b)-(875573-69-6)
• EPA Substance Registry System: Estra-1,3,5(10)-triene-3,17-diol,7-[9-[(4,4,5,5,5-pentafluoropentyl)thio]nonyl]-,17-acetate,(7a,17b)-(875573-69-6)

Safety Data

• Hazardous Substances Data: 875573-69-6(Hazardous Substances Data)

Usage

Uses

7-[9-[(4,4,5,5,5-Pentafluoropentyl)thio]nonyl]-,17-acetate,(7α,17β)-estra-1,3,5(10)-triene-3,17-diol is an impurity of Fulvestrant (F862500), a novel steroidal estrogen antagonist reported to lack any partial agonist activity. Antineoplastic (hormonal).

Synthetic route

(+)-(7α)-[9-bromononyl]estra-1,3,5(10)-triene-3-ol-17β-yl acetate (875573-66-3) + C6H9F5N2S*ClH → 17-O-acetyl-S-deoxo-fulvestrant (875573-69-6)

Conditions	Yield
Stage #1: (+)-(7α)-[9-bromononyl]estra-1,3,5(10)-triene-3-ol-17β-yl acetate; C6H9F5N2S*ClH With potassium hydroxide In N,N-dimethyl-formamide at 0 - 10℃; for 1.5h; Stage #2: With acetic acid In ethyl acetate; N,N-dimethyl-formamide for 0.166667h;	85%

1-methanesulfonyloxy-4,4,5,5,5-pentafluoropentane (252947-01-6) + C29H44O3S → 17-O-acetyl-S-deoxo-fulvestrant (875573-69-6)

Conditions	Yield
With potassium carbonate In acetonitrile for 48h; Inert atmosphere; Reflux;	80%

(+)-(7α)-[9-bromononyl]estra-1,3,5(10)-triene-3-ol-17β-yl acetate (875573-66-3) + 4,4,5,5,5-pentafluoro-1-pentanethiol (148757-88-4) → 17-O-acetyl-S-deoxo-fulvestrant (875573-69-6)

Conditions	Yield
With sodium hydroxide In N,N-dimethyl acetamide; water at 20℃; for 0.6h; Product distribution / selectivity;

1-methanesulfonyloxy-4,4,5,5,5-pentafluoropentane (252947-01-6) + BrH*C29H46N2O3S → 17-O-acetyl-S-deoxo-fulvestrant (875573-69-6)

Conditions	Yield
With sodium hydroxide In N,N-dimethyl acetamide; water at 20℃; for 1h; Product distribution / selectivity;

C29H44O3 → 17-O-acetyl-S-deoxo-fulvestrant (875573-69-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: copper(I) bromide; lithium bromide / acetonitrile / 24 h / 20 °C 2: 2,2'-azobis(isobutyronitrile) / toluene / 1.5 h / Reflux 3: hydrazine hydrate / tetrahydrofuran / 4 h / 20 °C 4: potassium carbonate / acetonitrile / 48 h / Inert atmosphere; Reflux View Scheme

C31H44O4 → 17-O-acetyl-S-deoxo-fulvestrant (875573-69-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 2,2'-azobis(isobutyronitrile) / toluene / 1.5 h / Reflux 2: hydrazine hydrate / tetrahydrofuran / 4 h / 20 °C 3: potassium carbonate / acetonitrile / 48 h / Inert atmosphere; Reflux View Scheme

C33H48O5S → 17-O-acetyl-S-deoxo-fulvestrant (875573-69-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrazine hydrate / tetrahydrofuran / 4 h / 20 °C 2: potassium carbonate / acetonitrile / 48 h / Inert atmosphere; Reflux View Scheme

19-nortestosterone (434-22-0) → 17-O-acetyl-S-deoxo-fulvestrant (875573-69-6)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: toluene-4-sulfonic acid / 1 h / Reflux 2.1: N-Bromosuccinimide / N,N-dimethyl-formamide; water / 1.25 h / 0 - 7 °C / Inert atmosphere 2.2: 2 h / 0 °C / Reflux; Inert atmosphere 3.1: copper(I) bromide / tetrahydrofuran / 0.75 h / -20 °C / Inert atmosphere 3.2: 0.5 h / -20 - 20 °C 4.1: copper(I) bromide; lithium bromide / acetonitrile / 24 h / 20 °C 5.1: 2,2'-azobis(isobutyronitrile) / toluene / 1.5 h / Reflux 6.1: hydrazine hydrate / tetrahydrofuran / 4 h / 20 °C 7.1: potassium carbonate / acetonitrile / 48 h / Inert atmosphere; Reflux View Scheme

4,4,5,5,5-pentafluorpentan-1-ol (148043-73-6) → 17-O-acetyl-S-deoxo-fulvestrant (875573-69-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / acetonitrile / 4 h / 20 °C / Inert atmosphere 2: potassium carbonate / acetonitrile / 48 h / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 2 h / 20 °C / Cooling with ice 2: ethanol / Reflux 3: sodium hydroxide / water; methanol / 24 h / Inert atmosphere; Reflux View Scheme
Multi-step reaction with 3 steps 1.1: thionyl chloride; triethylamine / dichloromethane / 2 h / 0 - 20 °C 2.1: isopropyl alcohol / 80 - 85 °C 3.1: potassium hydroxide / N,N-dimethyl-formamide / 1.5 h / 0 - 10 °C 3.2: 0.17 h View Scheme

3,17β-diacetoxy-estra-3,5-diene (4999-76-2) → 17-O-acetyl-S-deoxo-fulvestrant (875573-69-6)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide / N,N-dimethyl-formamide; water / 1.25 h / 0 - 7 °C / Inert atmosphere 1.2: 2 h / 0 °C / Reflux; Inert atmosphere 2.1: copper(I) bromide / tetrahydrofuran / 0.75 h / -20 °C / Inert atmosphere 2.2: 0.5 h / -20 - 20 °C 3.1: copper(I) bromide; lithium bromide / acetonitrile / 24 h / 20 °C 4.1: 2,2'-azobis(isobutyronitrile) / toluene / 1.5 h / Reflux 5.1: hydrazine hydrate / tetrahydrofuran / 4 h / 20 °C 6.1: potassium carbonate / acetonitrile / 48 h / Inert atmosphere; Reflux View Scheme

6-dehydro-19-nortestosterone acetate (2590-41-2) → 17-O-acetyl-S-deoxo-fulvestrant (875573-69-6)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: copper(I) bromide / tetrahydrofuran / 0.75 h / -20 °C / Inert atmosphere 1.2: 0.5 h / -20 - 20 °C 2.1: copper(I) bromide; lithium bromide / acetonitrile / 24 h / 20 °C 3.1: 2,2'-azobis(isobutyronitrile) / toluene / 1.5 h / Reflux 4.1: hydrazine hydrate / tetrahydrofuran / 4 h / 20 °C 5.1: potassium carbonate / acetonitrile / 48 h / Inert atmosphere; Reflux View Scheme

(7α,17β)-7-[9-(methanesulfonyloxy)nonyl]estra-1,3,5(10)-triene-3,17-diol-17-acetate + S-(4,4,5,5,5-pentafluoropentyl)isothiourea methanesulfonate → 17-O-acetyl-S-deoxo-fulvestrant (875573-69-6)

Conditions	Yield
With sodium hydroxide In methanol; water for 24h; Inert atmosphere; Reflux;

1-methanesulfonyloxy-4,4,5,5,5-pentafluoropentane (252947-01-6) → 17-O-acetyl-S-deoxo-fulvestrant (875573-69-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol / Reflux 2: sodium hydroxide / water; methanol / 24 h / Inert atmosphere; Reflux View Scheme

1,1,1,2,2-pentafluoro-5-chloro-n-pentane → 17-O-acetyl-S-deoxo-fulvestrant (875573-69-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: isopropyl alcohol / 80 - 85 °C 2.1: potassium hydroxide / N,N-dimethyl-formamide / 1.5 h / 0 - 10 °C 2.2: 0.17 h View Scheme

17-O-acetyl-S-deoxo-fulvestrant (875573-69-6) → (+)-(7α)-[9-(4,4,5,5,5-pentafluoropentylsulfanyl)nonyl]estra-1,3,5(10)-triene-3,17β-diol (153004-31-0)

Conditions	Yield
Stage #1: 17-O-acetyl-S-deoxo-fulvestrant With potassium hydroxide In methanol at 40℃; for 2h; Stage #2: With acetic acid In methanol; ethyl acetate for 0.166667h;	78.2%
With methanol; potassium hydroxide at 20℃; for 1 - 4h; Product distribution / selectivity;

17-O-acetyl-S-deoxo-fulvestrant (875573-69-6) → ICI 182,780-17β-acetate (261506-24-5)

Conditions	Yield
With sodium periodate In tetrahydrofuran; methanol; water at 5 - 20℃;

17-O-acetyl-S-deoxo-fulvestrant (875573-69-6) → (7R,8R,9S,13S,14S,17S)-13-methyl-7-(9 - ( (4 , 4 , 5, 5 , 5-pentafluoropentyl)thio)nonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta-[a]phenanthren-17-yl acetate

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine / dichloromethane / -10 °C 2: potassium acetate; tricyclohexylphosphine; palladium diacetate / acetonitrile / 80 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: pyridine / dichloromethane-d2 / -10 °C 2: palladium diacetate; tricyclohexylphosphine / acetonitrile / 80 °C View Scheme
Multi-step reaction with 2 steps 1: pyridine / dichloromethane 2: palladium diacetate; tricyclohexylphosphine / acetonitrile / 80 °C View Scheme

17-O-acetyl-S-deoxo-fulvestrant (875573-69-6) → (7R,8R,9S,13S,14S,17S)-13-methyl-7-(9 - ( (4 , 4 , 5, 5 , 5-pentafluoropentyl)thio)nonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta-[a]phenanthren-17-ol

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine / dichloromethane / -10 °C 2: potassium acetate; tricyclohexylphosphine; palladium diacetate / acetonitrile / 80 °C / Inert atmosphere 3: potassium hydroxide / methanol; tetrahydrofuran / 4 h / 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1: pyridine / dichloromethane-d2 / -10 °C 2: palladium diacetate; tricyclohexylphosphine / acetonitrile / 80 °C 3: potassium hydroxide; methanol / tetrahydrofuran / 4 h / 0 - 20 °C View Scheme

17-O-acetyl-S-deoxo-fulvestrant (875573-69-6) → C38H58BF5O4S

Conditions	Yield
Multi-step reaction with 4 steps 1: pyridine / dichloromethane / -10 °C 2: potassium acetate; tricyclohexylphosphine; palladium diacetate / acetonitrile / 80 °C / Inert atmosphere 3: potassium hydroxide / methanol; tetrahydrofuran / 4 h / 0 - 20 °C 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 0 °C View Scheme

17-O-acetyl-S-deoxo-fulvestrant (875573-69-6) + trifluoromethylsulfonic anhydride (358-23-6) → (7R,8R,9S,13S,14S,17S)-13-methyl-7-(9 - ( (4 , 4 , 5, 5 , 5-pentafluoropentyl)thio)nonyl)-3-(((trifluoromethyl)sulfonyl)oxy)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]-phenanthren-17-yl acetate

Conditions	Yield
With pyridine In dichloromethane at -10℃;	0.7 g
With pyridine In dichloromethane-d2 at -10℃;
With pyridine In dichloromethane

17-O-acetyl-S-deoxo-fulvestrant (875573-69-6) → ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)boronic acid

Conditions	Yield
Multi-step reaction with 4 steps 1: pyridine / dichloromethane-d2 / -10 °C 2: palladium diacetate; tricyclohexylphosphine / acetonitrile / 80 °C 3: potassium hydroxide; methanol / tetrahydrofuran / 4 h / 0 - 20 °C 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 0 °C View Scheme
Multi-step reaction with 4 steps 1: pyridine / dichloromethane 2: palladium diacetate; tricyclohexylphosphine / acetonitrile / 80 °C 3: methanol; potassium hydroxide / tetrahydrofuran 4: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 0 °C View Scheme

17-O-acetyl-S-deoxo-fulvestrant (875573-69-6) → ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)thio)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)boronic acid

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine / dichloromethane 2: palladium diacetate; tricyclohexylphosphine / acetonitrile / 80 °C 3: methanol; potassium hydroxide / tetrahydrofuran View Scheme

17-O-acetyl-S-deoxo-fulvestrant (875573-69-6) → fulvestrant (129453-61-8)

Conditions	Yield
With sodium periodate In methanol; water at 20℃; for 24h; Cooling with ice;

Upstream product

• 875573-66-3 (+)-(7α)-[9-bromononyl]estra-1,3,5(10)-triene-3-ol-17β-yl acetate 
• 252947-01-6 1-methanesulfonyloxy-4,4,5,5,5-pentafluoropentane 
• 2590-41-2 6-dehydro-19-nortestosterone acetate 
• 4999-76-2 3,17β-diacetoxyoestra-3,5-diene 
• 148043-73-6 4,4,5,5,5-pentafluorpentan-1-ol 
• 434-22-0 19-nortestosterone 
• 148757-88-4 4,4,5,5,5-pentafluoropentane-1-thiol 

Downstream Products

• 129453-61-8 fulvestrant 
• 1853279-29-4 ((7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)boronic acid 
• 261506-24-5 fulvestrant 17β-acetate 
• 153004-31-0 (+)-(7α)-[9-(4,4,5,5,5-pentafluoropentylsulfanyl)nonyl]estra-1,3,5(10)-triene-3,17β-diol 

Relevant articles and documents

Fulvestrant preparation method

The invention provides a new fulvestrant synthesis method, which has characteristics of mild reaction condition, simple route and high yield and high purity of each reaction intermediate, can obtain high-purity fulvestrant through re-crystallization without column chromatography, and is suitable for industrial production. The specific technical scheme of the present invention comprises that a compound represented by a formula I and a reagent are subjected to a halogenation reaction in a solvent to generate a compound represented by a formula II; the compound represented by the formula II and thiourea are subjected to a reflux reaction in a solvent to generate a compound represented by a formula III; the compound represented by the formula III and a compound represented by a formula IV aresubjected to a nucleophilic substitution reaction and a hydrolysis reaction in an alkali solution and an organic solvent to generate a compound represented by a formula V; and the compound representedby the formula V is oxidized with an acetic acid hydrogen peroxide oxidation system in a solvent to obtain fulvestrant.

PROCESS AND INTERMEDIADES FOR THE PREPARATION OF 7-ALKYLATED STEROIDS

A process for preparing compounds of formula (I), or a salt, solvate or stereoisomer thereof, including Fulvestrant, which process comprises free radical to a compound of formula (III), or a salt, solvate or stereoisomer thereof. The invention also refers to intermediates of said process.