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Process for the preparation of 17α-acetoxy-11β-(4-N,N-dimethyaminonophenyl)- 19-norpregna-4(5),9(10)-diene-3,20-dione

IP.com Disclosure Number: IPCOM000226909D
Publication Date: 2013-Apr-24
Document File: 6 page(s) / 139K

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The IP.com Prior Art Database

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Process for the preparation of 17α-acetoxy-11β-(4-N,N-dimethyaminonophenyl)- 19-norpregna-4(5),9(10)-diene-3,20-dione

     17α-acetoxy-11β-(4-N,N-dimethyaminonophenyl)-19-norpregna- 4(5),9(10)-diene-3,20-dione, referred to as "Compound 1", has the following formula:

Compound 1


Described hereinafter, is a process for the preparation of Compound 1.

The process can be illustrated by the following scheme:

  For the purpose of clarity and as an aid in the understanding of the process, as disclosed herein, the following terms and abbreviations are defined below:

Compound 1a (3,3-ethylenedioxy)-17α-acetoxy-19-norpregna-

               5(10),9(11)-diene-20-one
Compound 1b (3,3-ethylenedioxy)-17α-acetoxy-19-norpregna-5,10- α−epoxy-9(11)-en-20-one
Compound 1c (3,3-ethylenedioxy)-5α-hydroxy-17α-acetoxy-11ß-[4-

(N,N'-dimethylaminophenyl)]-19-norpregna-9(10)-en- 3,20-dione

The process comprises:

1


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  a) oxidising the compound 1a in a suitable solvent, in presence of an hexa-halo- ketone, obtaining the compound of formula compound 1b. Suitable solvents for the oxidation may be a polar aprotic solvents, for example dichloromethane or 3- pentanone. Optionally, compound 1b can be crystallized from a suitable solvent, such as polar aprotic solvents, non polar aprotic solvents or protic solvents. Preferred solvents can be alcohols or ethers. If not isolated, compound 1b can be used directly in the next step to prepare compound 1c, in a one pot manner.

   b) reacting the compound of formula compound 1b and organometallic derivative of N,N-dimethyl-aniline in the presence of a suitable copper catalyst and a suitable solvent, like polar aprotic solvents; and isolating the compound of formula compound 1c by crystallization from a suitable solvent. The reaction can be done at a temperature lower than 20°C.The solvent for the crystallization can be as described above.

  c) treating the compound of formula compound 1c in such a way to obtain deprotectiion and dehydratation, typically by reacting compound 1c with an acid in the presence of a solvent, like polar aprotic solvents, non polar aprotic solvents or protic solvents. Then, compound 1 can be isolated and purified by crystallization from a solvent and anti-solvent system. Suitable solvents are alcohols, ethers or mixtures thereof, like methyl tert-butyl ether (MTBE) isopropanol (IPA). Suitable anti-solvents can be hydrocarbons, like n-heptane, or water.

   The reaction mixture of step a, b and c can be monitor by HPLC, until full conversion.

   Final compound 1can be prepared in a crystalline form, by dissolution of the crude material in hot ethanol, dilution with water and cooling the obtained mixture.

   Another crystalline form of Compound 1 can be prepared by dissolution of the crude material in hot methanol dilution with water and cooling of the obtained mixture.

   The starting compound 1a can be prepared with several processes from different starting materials, for example with the process in the following sche...