875573-69-6

Usage

Uses

Used in Pharmaceutical Industry:
Estra-1,3,5(10)-triene-3,17-diol,7-[9-[(4,4,5,5,5-pentafluoropentyl)thio]nonyl]-,17-acetate,(7a,17b)is used as an impurity in Fulvestrant, a novel steroidal estrogen antagonist. It is important to monitor and control the presence of this impurity in pharmaceutical formulations to ensure the safety, efficacy, and quality of the drug.
Used in Antineoplastic (Hormonal) Applications:
As an impurity of Fulvestrant, Estra-1,3,5(10)-triene-3,17-diol,7-[9-[(4,4,5,5,5-pentafluoropentyl)thio]nonyl]-,17-acetate,(7a,17b)may have potential applications in antineoplastic (hormonal) therapy. Fulvestrant is known for its use in treating hormone receptor-positive metastatic breast cancer, and the presence of this impurity could potentially impact the overall effectiveness and safety of the treatment.

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 academic research and scientific papers

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.

A new compound and its preparation method and elimination method (by machine translation)

The invention relates to medical and chemical field, provides a new compound, the compounds have the formula I structure, is preparing novel anti-breast cancer drug of fulvestrant in the process more difficult to avoid one of the impurity. The present invention provides a compound of formula I of the synthetic route, and to reduce or avoid the preparation of fluorine Uygursi Qun produced in the process of method, and in its generated after the method of removing it, not only reduces the growing into this impurity the waste of raw materials, also there to have ruled out the impurities to the rear edge of fulvestrant to purification of the product and the impact of the yield. (by machine translation)

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.

Process for the preparation of 7alpha-alkylated 19-norsteroids

Processes useful in the preparation of pharmaceutical compounds such as fulvestrant and processes for the preparation of fulvestrant.