19457-55-7

Usage

Uses

1,2-Dihydro Exemestane is a related compound of Exemestane (E957000).

InChI:InChI=1/C20H26O2/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/h11,14-16H,1,4-10H2,2-3H3/t14-,15-,16-,19+,20-/m0/s1

Upstream product

• 50-00-0 formaldehyd 
• 63-05-8 Androstenedione 
• 905-30-6 3-(1'-pyrrolidinyl)-androsta-3,5-dien-17-one 
• 57144-06-6 3-methoxyandrosta-3,5-dien-17-one 
• 53-43-0 dehydroepiandrosterone 
• 109-87-5 Dimethoxymethane 
• 94962-42-2 3-Methoxy-6-formyl-androstadien-(3,5)-on-⁽¹⁷⁾ 
• 104352-15-0 3-Methoxy-6-hydroxymethyl-17-oxo-androstadien-(3,5) 
• 462-95-3 formaldehyde diethyl acetal 
• 972-46-3 3-Aethoxy-androstadien-(3,5)-on-⁽¹⁷⁾ 
• 897-06-3 Androsta-1,4-diene-3,17-dione 

Downstream Products

• 107868-30-4 exemestane 
• 2241-94-3 6α-methylandrost-4-ene-3,17-dione 
• 5696-36-6 6β-methylandrost-4-ene-3,17-dione 

Relevant academic research and scientific papers

C-6α- vs C-7α-Substituted Steroidal Aromatase Inhibitors: Which Is Better? Synthesis, Biochemical Evaluation, Docking Studies, and Structure-Activity Relationships

C-6α and C-7α androstanes were studied to disclose which position among them is more convenient to functionalize to reach superior aromatase inhibition. In the first series, the study of C-6 versus C-7 methyl derivatives led to the very active compound 9 with IC50 of 0.06 μM and Ki = 0.025 μM (competitive inhibition). In the second series, the study of C-6 versus C-7 allyl derivatives led to the best aromatase inhibitor 13 of this work with IC50 of 0.055 μM and Ki = 0.0225 μM (irreversible inhibition). Beyond these findings, it was concluded that position C-6α is better to functionalize than C-7α, except when there is a C-4 substituent simultaneously. In addition, the methyl group was the best substituent, followed by the allyl group and next by the hydroxyl group. To rationalize the structure-activity relationship of the best inhibitor 13, molecular modeling studies were carried out.

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.

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.

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.

Synthesis and aromatase inhibition by potential metabolites of exemestane (6-methylenandrosta-1,4-diene-3,17-dione)

Exemestane (6-methylenandrosta-1,4-diene-3,17-dione; FCE 24304) is an orally active irreversible aromatase inhibitor which is in phase II clinical evaluation for the potential therapy of postmenopausal breast cancer. A series of exemestane analogs, with modifications at the 6-methylene group and with additional reduction at the 17-keto group, were synthesized as potential metabolites and tested in vitro for their effect on human placental aromatase. All these new analogs were found to be less potent in inhibiting aromatase than exemestane. The most effective compound was the 17β-hydroxy- derivative (compound 2), which is 2.6-fold less potent than exemestane [50% inhibitory concentration (IC50) 69 and 27 nM, respectively]. The various C- 6 modified derivatives of the 17-oxo series were found to inhibit the aromatase enzyme in the following descending order: 6-methylene (exemestane) > 6-spirooxirane (6) > 6β-hydroxymethyl (11) > 6-hydroxymethyl (7) > 6β- carboxy (13), showing IC50 values of 27, 206, 295, 2,300, and 7,200 nM, respectively. The 17β-hydroxy analogs of some of the above mentioned compounds were also synthesized (3, 4, 12) and found to be 3-8-fold less potent than the corresponding 17-keto analogs.

4-substituted 6-alkylidenandrosteine-3,17-dione derivatives and process for their preparation

The invention relates to 4-substituted 6-alkylidenandrostene-3,17-dione derivatives of the following formula STR1 wherein each of R1, R2 and R3 is, independently, hydrogen or C1 -C6 alkyl; R4 is hydrogen of fluorine; (x) represents a single or double bond; and R is, especially, a hydroxy or mercapto or amino group or a functional derivative thereof. The compounds of the invention show aromatase inhibitory activity and may be useful, for instance, in the treatment of hormone-dependent tumors and of prostatic hyperplasia.