- 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.
- Li, Guang,Li, Fushuang,Deng, Le,Fang, Xiaolan,Zou, Hui,Xu, Kangpin,Li, Tian,Tan, Guishan
-
-
Read Online
- 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.
- Chen, Kaixiong,Liu, Chang,Deng, Le,Xu, Guangyu
-
-
Read Online
- 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.
- Marcos-Escribano, Andrés,Bermejo, Francisco A.,Bonde-Larsen, Antonio Lorente,Retuerto, Jesús Iglesias,Sierra, Ignacio Herráiz
-
-
Read Online
- 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.
- -
-
Paragraph 0010; 0011; 0013
(2018/07/30)
-
- 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 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.
- -
-
Paragraph 0041; 0042; 0043; 0044; 0045
(2016/11/14)
-
- 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.
- -
-
Paragraph 0010
(2016/11/28)
-
- 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.
- -
-
Page/Page column 13-14
(2010/08/04)
-
- 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.
- -
-
Page/Page column 1
(2009/01/24)
-
- 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.
- -
-
Page/Page column 9
(2009/07/10)
-
- PROCESS FOR PREPARING AROMATASE INHIBITOR EXEMESTANE
-
The present invention discloses modified process for preparing aromatase inhibitor Exemestane involving suitable oxidizing agents in suitable solvents.
- -
-
Page/Page column 5-6
(2009/09/05)
-
- Process for preparing aromatase inhibitors
-
A process of making an aromatase inhibitor of formula (I) wherein each of R1, R2, R3, and R4, independently, is hydrogen, halogen, or C1-C6 alkyl, comprising reacting a compound of formula (II) with an acid in the presence of a suitable solvent. A new crystalline form of exemestane and is also disclosed.
- -
-
Page/Page column 3-4
(2008/12/08)
-
- (S)-6-methyloxaalkyl exemestane compounds and related methods of use
-
6-Methyloxaalkyl exemestane compounds and related compositions, as can be used, chemotherapeutically, to inhibit growth and proliferation of cancer cells.
- -
-
Page/Page column 3
(2008/06/13)
-
- PHARMACEUTICAL COMPOSITIONS AND METHODS COMPRISING A COMBINATION OF A SELECTIVE ESTROGEN RECEPTOR MODULATOR AND AN AROMATASE INHIBITOR
-
The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a 2-(-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1 -yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol or a pharmaceutically acceptable salt or prodrug thereof and an aromatase inhibitor. Particularly, the present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylj-5,6,7,8- tetrahydronaphthalene-2-ol or a pharmaceutically acceptable salt or prodrug and an aromatase inhibitor selected from aminoglutethimide; formestane; atamestane; anastrazole; fadrozole; finrozole; letrozole; vorozole; 4-[N-(4-bromobenzyl)-N-(4-cyanophenyl)amino]-4H-1 ,2,4-triazole or exemestane, or a pharmaceutically acceptable salt thereof.
- -
-
Page/Page column 12
(2008/06/13)
-
- Derivatives of exemestane - Synthesis and evaluation of aromatase inhibition
-
The irreversible aromatase inhibitor exemestane (6) reacts with nitromethane and sodium ethanolate to yield the Michael adduct 9. The aldehyde 10 is obtained by Nef reaction of the nitro compound 9 and affords the 1,4-dihydropyridine (DHP) 11 by Hantzsch reaction using methyl β-aminocrotonate in acetic acid. The new compounds showed a reduced inhibitory potency towards aromatase (IC50 values: 9, 0.91 μM; 10, 2.5 μM; 11, 10 μM) compared to 6 (IC50 = 0.23 μM). The 1,4-DHP 11 was dehydrogenated with CAN or electrochemically (E1/2 = 1.18 V) to yield the corresponding pyridine 12.
- Goelitzer,Bonnekessel,Jones,Palusczak,Hartmann
-
p. 575 - 581
(2007/10/03)
-
- EXEMESTANE AND ITS INTERMEDIATES AND METHODS OF MAKING THE SAME
-
A method is provided for preparing an aromatase inhibitor of formula (I) wherein each of R1, R2, R3, R4, independently, is hydrogen, halogen or Cl-C6 alkyl. In one form, the aromatase inhibitor is exemestane wherein each of R1, R2, R3, R4 is hydrogen. In the method, a compound of formula (II) wherein R1, R2, R3, R4 are as defined above and R is alkylene, is reacted with a deprotonating agent and a compound of the formula R5SO2X wherein R5 is C1-C5 alkyl and X is halogen so as to obtain a compound of formula (III) wherein R1, R2, R3, R4, R5 are as defined above. The compound of Formula (III) is then reacted with a base to form an aromatase inhibitor of formula (I).
- -
-
Page/Page column 18-24
(2008/06/13)
-
- 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.
- Buzzetti,Di Salle,Longo,Briatico
-
p. 527 - 532
(2007/10/02)
-
- Improvement in the synthesis of 6-methylene derivatives of androsta-1,4-diene-3,17-dione
-
The invention relates to a new process for the preparation of known aromatase inhibitors of the following formula (I) wherein, each of R1 and R3, independently, is hydrogen or C1-C6 alkyl;, R2 is hydrogen, halogen or C1-C6 alkyl; and, R4 is hydrogen or fluorine;, the process comprising submitting to Mannich reaction a com-pound of formula (II) wherein, R1, R2, R3 and R4 are as defined above and R is a lower alkyl group, and then dehydrogenating the respective 6-methylene-3-oxo-Δ4-steroid derivative thus obtained.
- -
-
-
- 6-substituted androsta-1,4-diene-3,17-diones
-
The invention relates to 6-alkylidenandrosta-1,4-diene-3,17-dione derivatives, having the following general formula STR1 wherein each of R and R2, independently, is hydrogen or C1 -C6 alkyl and R1 is hydrogen, halogen or C1 -C6 alkyl, which are useful in therapy, in particular in the treatment of hormone-dependent cancers.
- -
-
-