107868-30-4

Usage

InChI:InChI=1/C20H24O2/c1-12-10-14-15-4-5-18(22)20(15,3)9-7-16(14)19(2)8-6-13(21)11-17(12)19/h6,8,11,14-16H,1,4-5,7,9-10H2,2-3H3/t14?,15?,16?,19-,20+/m1/s1

Synthetic route

17β-hydroxy-6-methylen- androsta-1,4-dien-3-one (122370-91-6) → exemestane (107868-30-4)

Conditions	Yield
With Jones reagent In acetone at -20℃; Jones oxidation; Inert atmosphere;	100%
With jones reagent In acetone at -20℃; for 0.25h;	85%
With Jones reagent In acetone at 0℃; Product distribution / selectivity;

6α-hydroxymethylandrosta-1,4-diene-3,17-dione (933455-74-4) → exemestane (107868-30-4)

Conditions	Yield
Stage #1: 6α-hydroxymethylandrosta-1,4-diene-3,17-dione With methanesulfonyl chloride; triethylamine In dichloromethane at 0 - 30℃; Stage #2: With methanol; potassium hydroxide at 40 - 50℃;	90%

17-hydroxyimino-6-methylenandrosta-1,4-diene-3-one → exemestane (107868-30-4)

Conditions	Yield
With toluene-4-sulfonic acid In water; acetone at 25 - 30℃; for 10h; Solvent; Reagent/catalyst; Temperature; Jones Oxidation; Inert atmosphere;	88.2%

6-methylene-androst-4-ene 3,17-dione (19457-55-7) → exemestane (107868-30-4)

Conditions	Yield
With N,O-Bis(trimethylsilyl)trifluoroacetamide; chloranil; trifluorormethanesulfonic acid In toluene at 108 - 110℃; for 0.75h; Product distribution / selectivity; Heating / reflux;	81.8%
With trifluorormethanesulfonic acid; N,O-Bis(trimethylsilyl)trifluoroacetamide; chloranil In toluene Inert atmosphere; Reflux;	81%
With tert-butyldimethylsilyl chloride; 2,3-dicyano-5,6-dichloro-p-benzoquinone In 1,4-dioxane at 0 - 20℃;	30.2%

methanol (67-56-1) + 6β-hydroxymethylandrosta-1,4-diene-3,17-dione (121021-51-0) → (6S,8R,9S,10R,13S,14S)-6-(methoxymethyl)-10,13-dimethyl-7,8,9,10,11,12,13,14,15,16-decahydro-3H-cyclopenta[a]phenanthrene-3,17(6H)-dione + exemestane (107868-30-4)

Conditions	Yield
With hydrogenchloride at 20℃; for 24h;	A 8% B 60%

6-Methylen-4-androsten-3,17-dion (19457-55-7, 51154-17-7) → exemestane (107868-30-4)

Conditions	Yield
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In dimethyl sulfoxide; toluene at 85℃; for 48h; Inert atmosphere; Large scale;	56.7%

Androsta-1,4-diene-3,17-dione (897-06-3) → exemestane (107868-30-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 20 h / Heating 2: 1.10 g / benzene; ethanol; H2O / 5 h / 20 °C 3: 60 percent / conc. HCl / 24 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: hydroxylamine hydrochloride; sodium acetate / water; ethanol / 6 h / Inert atmosphere; Reflux 2.1: N,N-dimethylammonium chloride / i-Amyl alcohol / 2 h / Inert atmosphere; Reflux 2.2: 15 h / 140 °C 3.1: toluene-4-sulfonic acid / water; acetone / 10 h / 25 - 30 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: orthoformic acid triethyl ester; toluene-4-sulfonic acid / tetrahydrofuran / 12 h / 40 - 45 °C / Large scale 2: tetrahydrofuran; ethanol / 10 h / 40 - 45 °C / Large scale 3: hydrogenchloride / tetrahydrofuran; ethanol / 1 h / Large scale 4: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / dimethyl sulfoxide; toluene / 48 h / 85 °C / Inert atmosphere; Large scale View Scheme

1α,3-dipyrrolidinylandrosta-3,5-dien-17-one (67737-88-6) → exemestane (107868-30-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.10 g / benzene; ethanol; H2O / 5 h / 20 °C 2: 60 percent / conc. HCl / 24 h / 20 °C View Scheme

1-dehydrotestosterone (846-48-0) → exemestane (107868-30-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) Me2NH*HCl / 1.) isoamyl alcohol, reflux, 2 h, 2.) isoamyl alcohol, reflux, 15 h 2: 85 percent / Jones reagent / acetone / 0.25 h / -20 °C View Scheme

C21H28O5S (861395-77-9) → exemestane (107868-30-4)

Conditions	Yield
With potassium hydroxide In methanol; dichloromethane; water at 25℃; Heating / reflux;

pyrographite (7440-44-0) + 6-methylene-androst-4-ene 3,17-dione (19457-55-7) + tert-butyl alcohol (75-65-0) → exemestane (107868-30-4)

Conditions	Yield
With selenium(IV) oxide In ethyl acetate

6-hydroxymethyl-androsta-1,4-diene-3,17-dione → exemestane (107868-30-4)

Conditions	Yield
With toluene-4-sulfonic acid In toluene at 80 - 90℃; under 315 Torr; for 4h; Purification / work up;
With toluene-4-sulfonic acid In toluene at 90℃; for 3h; Purification / work up;
With camphor-10-sulfonic acid In toluene at 90℃; for 7h; Purification / work up;
With (1S)-10-camphorsulfonic acid In ethyl acetate at 70 - 80℃; for 32h; Purification / work up;
Stage #1: 6-hydroxymethyl-androsta-1,4-diene-3,17-dione With pyridine; p-toluenesulfonyl chloride at 0℃; for 48h; Stage #2: With potassium hydroxide In methanol; water at 65℃; for 2h; Purification / work up;

dehydroepiandrosterone (53-43-0) → exemestane (107868-30-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: toluene / 1 h / 120 °C / Inert atmosphere 1.2: 0.33 h / 20 °C / Inert atmosphere 1.3: 3 h / 20 °C / Inert atmosphere 2.1: orthoformic acid triethyl ester; toluene-4-sulfonic acid / ethanol; tetrahydrofuran / 3 h / 40 °C 2.2: 4 h / 40 °C 3.1: Arthrobacter simplex ATCC6946 culture / aq. buffer / 33 °C / Microbiological reaction View Scheme

3-Aethoxy-androstadien-(3,5)-on-(17) (972-46-3) → exemestane (107868-30-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrahydrofuran; ethanol / 10 h / 40 - 45 °C / Large scale 2: hydrogenchloride / tetrahydrofuran; ethanol / 1 h / Large scale 3: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / dimethyl sulfoxide; toluene / 48 h / 85 °C / Inert atmosphere; Large scale View Scheme

6-methyleneandrostenediol ketal → exemestane (107868-30-4)

Conditions	Yield
With toluene-4-sulfonic acid In tetrahydrofuran; water at 20 - 25℃; for 10h; Inert atmosphere;

exemestane (107868-30-4) → FCE27353 (184972-12-1)

Conditions	Yield
With 3-chloro-benzenecarboperoxoic acid In dichloromethane for 48h; Ambient temperature;	80%

exemestane (107868-30-4) → C20H24N6O2

Conditions	Yield
With copper(l) iodide; tert-Butyl peroxybenzoate; trimethylsilylazide In acetonitrile at 50℃; for 6h; Reagent/catalyst; Solvent; Schlenk technique; Inert atmosphere; Green chemistry;	75%

exemestane (107868-30-4) → 6α-methylandrost-4-ene-3,17-dione (2241-94-3) + C20H30O2 + 6β-methylandrost-4-ene-3,17-dione (5696-36-6)

Conditions	Yield
With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; 5%-palladium/activated carbon In ethanol for 18h; Reflux; stereoselective reaction;	A n/a B 62% C n/a

formaldehyd (50-00-0) + exemestane (107868-30-4) → C21H24O2

Conditions	Yield
With N,N-dimethylammonium chloride In ethanol at 78℃; for 3h; Temperature; Mannich Aminomethylation;	54.1%

4-Fluorobenzenesulfonyl chloride (349-88-2) + exemestane (107868-30-4) → (6S,8R,9S,10R,13S,14S)-6-(((4-fluorophenyl)sulfonyl)methyl)-10,13-dimethyl-7,8,9,10,11,12,13,14,15,16-decahydro-3H-cyclopenta[a]phenanthrene-3,17(6H)-dione

Conditions	Yield
With fac-tris(2-phenylpyridinato-N,C2')iridium(III); tris-(trimethylsilyl)silane In acetonitrile at 20℃; for 16h; Irradiation; diastereoselective reaction;	50%

exemestane (107868-30-4) → 6-methylandrosta-1,4,6-trien-17β-ol + 17β-hydroxy-6-methylen- androsta-1,4-dien-3-one (122370-91-6)

Conditions	Yield
With sodium tetrahydroborate; acetic acid; trifluoroacetic acid In dichloromethane; acetonitrile at 20℃; for 11h; Inert atmosphere;	A 11.3 mg B 39%

Bromotrifluoromethane (75-63-8) + exemestane (107868-30-4) → C21H25F3O3 + C21H25F3O3

Conditions	Yield
With cobalt(II) tetrafluoroborate hexahydrate; N-isopropyl-N,2-dimethylpropan-2-amine In water; N,N-dimethyl-formamide; acetonitrile at 65℃; for 24h; Sealed tube;	A 30% B 33%

Bromotrifluoromethane (75-63-8) + exemestane (107868-30-4) → C21H25F3O3 + C21H25F3O3

Conditions	Yield
With cobalt(II) tetrafluoroborate hexahydrate; N-isopropyl-N,2-dimethylpropan-2-amine In N,N-dimethyl-formamide; acetonitrile at 65℃; for 24h;	A 30% B 33%

nitromethane (75-52-5) + exemestane (107868-30-4) → 6α-(2-Nitroethyl)androsta-1,4-dien-3,17-dion (911856-13-8)

Conditions	Yield
With sodium ethanolate In ethanol for 22h; Michael addition; Heating;	32%

exemestane (107868-30-4) → 6α-spirooxiranandrosta-1,4-diene-3,17-dione + 6α-spirooxiranandrosta-1,4-diene-3,17-dione

Conditions	Yield
With formic acid; dihydrogen peroxide In dichloromethane at 20℃; for 96h;	A 21% B 76.1 mg

L-Cysteine (52-90-4) + exemestane (107868-30-4) → 6-methylcysteinylandrosta-1,4-diene-3,17-dione

Conditions	Yield
With potassium hydroxide In methanol at 20℃; for 24h; Inert atmosphere;	13%

exemestane (107868-30-4) → 1α,2α-epoxy-6-methylenandrost-4-ene-3,17-dione

Conditions	Yield
With dihydrogen peroxide; sodium hydroxide In methanol; water at 0 - 20℃; for 24.5h;	11%

exemestane (107868-30-4) + diethyl malonate (105-53-3) → Diethyl-2-(3,17-dioxoandrosta-1,4-dien-6β-ylmethyl)-malonat

Conditions	Yield
With sodium In ethanol for 7h; Michael addition; Heating;	6%

exemestane (107868-30-4) → 6α-(2-Oxoethyl)androsta-1,4-dien-3,17-dion (911856-14-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 32 percent / NaOEt / ethanol / 22 h / Heating 2.1: KOH / methanol / 3 h / 20 °C 2.2: 31 percent / aq. H2SO4 / methanol / 4 h / cooling View Scheme

exemestane (107868-30-4) → Dimethyl-4-[(3,17-dioxoandrosta-1,4-dien-6α-yl)methyl]-2,6-dimethyl-3,5-pyridindicarboxylat

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 32 percent / NaOEt / ethanol / 22 h / Heating 2.1: KOH / methanol / 3 h / 20 °C 2.2: 31 percent / aq. H2SO4 / methanol / 4 h / cooling 3.1: 58 percent / acetic acid / 22 h / 20 - 60 °C 4.1: 87 percent / CAN / acetone; H2O / 0.5 h View Scheme

exemestane (107868-30-4) → Dimethyl-4-[(3,17-dioxoandrosta-1,4-dien-6α-yl)methyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridindicarboxylat (911856-15-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 32 percent / NaOEt / ethanol / 22 h / Heating 2.1: KOH / methanol / 3 h / 20 °C 2.2: 31 percent / aq. H2SO4 / methanol / 4 h / cooling 3.1: 58 percent / acetic acid / 22 h / 20 - 60 °C View Scheme

exemestane (107868-30-4) → 6-Hydroxymethylexemestane

Conditions	Yield
Multi-step reaction with 2 steps 1: 80 percent / 50percent m-chloroperbenzoic acid / CH2Cl2 / 48 h / Ambient temperature 2: 38 percent / 20percent aq. HClO4 / tetrahydrofuran / 3 h / Ambient temperature View Scheme

exemestane (107868-30-4) → 6α/β-hydroxy-6α/β-hydroxymethylandrosta-1,4-diene-3,17-dione

Conditions	Yield
Multi-step reaction with 2 steps 1: 80 percent / 50percent m-chloroperbenzoic acid / CH2Cl2 / 48 h / Ambient temperature 2: 42 percent / 20percent aq. HClO4 / tetrahydrofuran / 3 h / Ambient temperature View Scheme

Upstream product

• 67737-88-6 1α,3-dipyrrolidinylandrosta-3,5-dien-17-one 
• 861395-77-9 C₂₁H₂₈O₅S 
• 7440-44-0 pyrographite 
• 19457-55-7 6-methyleneandrosta-4-ene-3,17-dione 
• 75-65-0 tert-butyl alcohol 
• 19457-55-7 6-Methylen-4-androsten-3,17-dion 
• 972-46-3 3-Aethoxy-androstadien-(3,5)-on-⁽¹⁷⁾ 
• 53-43-0 dehydroepiandrosterone 
• 933455-74-4 6α-hydroxymethylandrosta-1,4-diene-3,17-dione 
• 846-48-0 1-dehydrotestosterone 
• 897-06-3 Androsta-1,4-diene-3,17-dione 
• 67-56-1 methanol 
• 121021-51-0 6β-hydroxymethylandrosta-1,4-diene-3,17-dione 
• 122370-91-6 17β-hydroxy-6-methylen- androsta-1,4-dien-3-one 

Downstream Products

• 122370-91-6 17β-hydroxy-6-methylen- androsta-1,4-dien-3-one 
• 159354-61-7 1α,2α-epoxy-6-methylenandrost-4-ene-3,17-dione 
• 152764-31-3 6β-spirooxiranandrosta-1,4-diene-3,17-dione 
• 152764-31-3 6α-spirooxiranandrosta-1,4-diene-3,17-dione 
• 2241-94-3 6α-methylandrost-4-ene-3,17-dione 
• 5696-36-6 6β-methylandrost-4-ene-3,17-dione 
• 184972-11-0 6α/β-hydroxy-6α/β-hydroxymethylandrosta-1,4-diene-3,17-dione 
• 152764-26-6 6-hydroxymethylandrosta-1,4,6-triene-3,17-dione 
• 184972-12-1 FCE₂₇₃₅₃ 

Relevant academic research and scientific papers

Increased yield of biotransformation of exemestane with β-cyclodextrin complexation technique

In this study, 6-methylenandrosta-4-ene-3,17-dione and Hydroxypropyl- β-cyclodextrin (HP-β-CD) were used to form a complex, which could be then biotransformed by Arthrobacter simplex ATCC6946 to obtain the antitumor drug exemestane. The complex was analyzed by UV, DSC and TG techniques, while the products were analyzed by HPLC, NMR and MS. These results confirmed that the β-cyclodextrin not only improved the water-solubility of 6-methylenandrosta-4-ene-3,17-dione, but also greatly enhanced the biocompatibility during the biotransformation process. This result may be applied to other precursors which have poor aqueous solubility in the biotransformation processes.

A practical Δ1-dehydrogenation of Δ4-3-keto-steroids with DDQ in the presence of TBDMSCl at room temperature

A mild and efficient Δ1-dehydrogenation of Δ4-3-keto-steroids with DDQ in the presence of tertbutyldimethylchlorosilane at room temperature was developed.

1,2-Dehydrogenation of steroidal 6-methylen derivatives. Synthesis of exemestane

The development of an efficient dehydration method of steroidal 4-en-3-ones by using chloranil and BSTFA in the presence of triflic acid in refluxing toluene allowed us, starting from testosterone, to set a large-scale procedure for the synthesis of the anti-cancer drug exemestane in 70% overall yield.

Preparation method of exemestane

The invention discloses a preparation method of exemestane, relates to the field of an anti-cancer drug, and particularly relates to exemestane. The preparation method of the exemestane includes stepsof preparing 6-methylene androstenone glycol acetone; under the nitrogen protection, orderly adding paraformaldehyde, dimethylamine hydrochloride and isoamyl alcohol in a four-opening reaction bottle; heating and backflowing water for 2 hours; adding androstenone glycol acetone, preserving temperature and stirring at 140 DEG C; performing high performance liquid chromatography tracking detectionreaction; finishing reaction for 15 hours, and cooling to room temperature; adding distilled water to wash; after layering, drying it by anhydrous magnesium sulfate, depressurizing and recycling solvent; performing column chromatography on silica gel to obtain white solid; secondly, preparing exemestane; orderly adding 6-methylene androstenone glycol acetone, p-toluenesulfonic acid and tetrahydrofuran in a four-opening bottle under the nitrogen protection. The preparation method is simple in technical route, easy to obtain raw materials, low in cost, high in yield, and overcomes the defects existed in the prior art; therefore, the preparation method is applicable to industrial production.

Industrial production method of exemestane

An industrial production method of exemestane comprises the following steps: adding androsta-1,4-diene-3,17-dione, anhydrous ethanol, triethyl orthoformate and p-toluenesulfonic acid into a reactor, stirring above added materials, carrying out rotary drying, and crystallizing the obtained dried mixture to obtain an intermediate YXMT01; sequentially adding the intermediate YXMT01, anhydrous ethanol, tetrahydrofuran, 37% formaldehyde, N-toluidine and p-toluenesulfonic acid into the reactor, and carrying out rotary drying to obtain an intermediate YXMT02; sequentially adding the intermediate YXMT02, ethyl acetate and hydrochloric acid into the reactor, precipitating, carrying out suction filtration to obtain white solid, and re-crystallizing the white solid with toluene to obtain an intermediate YXMT03; and sequentially adding the intermediate YXMT03, toluene and IBX into the reactor, stirring the added substances, cooling the obtained substance, concentrating the obtained filtrate, and re-crystallizing the obtained concentrate to obtain white solid YXMT. The method has the advantages of avoiding of uncontrollability of a one-kettle method in industrial production, cheap sources of raw materials, easiness in control of the process operation, high yield, stable quality, and suitableness for industrial production.

Exemestane synthesis technology

The invention discloses an exemestane synthesis technology. The technology comprises the steps of 6-methylene-androst-4-en-3,17-dione synthesis, crude exemestane synthesis and purification. The technology has the advantages of simple route, easily available raw materials, high yield, and suitableness for domestic industrial production.

Exemestane intermediate oxime compound, and preparation method and application thereof

The invention discloses an exemestane intermediate 17-oximino-6-methyleneandrost-1,4-diene-3-one, and a preparation method and an application thereof. Most of existing methods have the defect of low total yield, and are not suitable for industrial production. The invention discloses the exemestane intermediate 17-oximino-6-methyleneandrost-1,4-diene-3-one with a novel structural formula. The preparation method comprises the following steps: dimethylamine hydrochloride and paraformaldehyde are refluxed with water in isoamyl alcohol; 17-oximino-androstadienone is added for carrying out a Mannich reaction, such that 17-oximino-6-methyleneandrost-1,4-diene-3-one is obtained; and exemestane can be prepared through the hydrolysis of 17-oximino-6-methyleneandrost-1,4-diene-3-one. The method is simple, and has high industrialization value.

PROCESS FOR THE PREPARATION OF EXEMESTANE

The present invention relates to an efficient and cost-effective process for the preparation of 6- methylenandrost-1,4-diene-3,17-dione (exemestane) by dehydrogenation of 6-methylenandrost-4- ene-3,17-dione using an dehydrogenating agent in the presence of an acid catalyst and at least one co-oxidant in an organic solvent.

Crystalline polymorph of exemestane

New crystalline polymorph of exemestane characterized by a powder X-ray diffraction pattern having peaks at 10.7±0.1, 15.9±0.1, and 18.1±0.1 2-theta degree.

Process for obtaining 6-Alkylidenandrost-1,4-diene-3one

6-alkylidenandrost-1,4-dien-3-ones of general formula (I), wherein R is H o alkyl; R1 y R2, independently of one another, represent H, OR3, OC(=O) R4 or O-(GPH), wherein R3 is H; C1-C6 alkyl or aryl; R4 is H or C1-C6 alkyl,; and GPH is a hydroxyl protecting group; or R1 and R2, together with the carbon atom to which they are bonded, form a carbonyl group or equivalent or a cyclic ketal; can be obtained by a process comprising subjecting the corresponding 6-alkyliden-4-androsten-3-one to a dehydrogenation reaction in the 1,2 position in the presence of a quinine, a silylating agent and a strong acid.