Ethynylation of 17-keto steroids to produce commercially important 17α-ethynyl-17β-hydroxy steroids is well known to those skilled in the art. See, for example, U.S. Pat. Nos. 2,272,131, 2,843,609, 2,723,280, 3,275,666, 3,275,666, 2,877,240, 3,470,217, 4,041,055, 3,927,046, Steroids by Fieser and Fieser, Reinhold Publishing Co, New York, 1959, 557-591 and J. Am. Chem. Soc. 1956, 78, 2477.
A general method for this reaction consists in reacting the 17-keto steroid with dipotassium acetylide, which can be used with Δ4-3-keto steroids without having to protect the carbonyl group at position 3. However, this process is not suitable for 16-methylene-17-keto steroids due to the steric hindrance of these systems, which reduces the reactivity and induces the formation of different impurities.
Ethynylation of 16-methylene-17-keto steroids is commercially important because the resulting 16-methylene-17-α-ethynyl-17-β-hydroxy products are intermediates in the preparation of therapeutically valuable compounds, such as e.g. Nestorone® or melengestrol acetate.
Other metallo-acetylides, such as mono- and di-magnesium acetylides, have been used in the ethynylation of 16-methyl-17-keto steroids (U.S. Pat. No. 3,704,253), though low yields have been obtained (lower than 50%) due to the need of chromatographic purification and the formation of dimers as the main impurity. Example II in U.S. Pat. No. 3,704,253 discloses lower than 30% yield in the magnesium-acetylide addition to a 16-methylene-17-keto steroid.
Better results have been achieved using monolithium acetylide, which can be obtained by reacting acetylene with n-butyllithium at low temperature, preferably below −70° C. in dilute solution as reported by Midland in J. Org. Chem. 1975, 40, 2250. The use of monolithium acetylide in the preparation of ethynyl-carbinols is disclosed e.g. in Fieser & Fieser, reagents for Organic Chemistry Vol. 1, Wiley, New York, 1967, p 573.
However, monolithium acetylide easily decomposes to the corresponding dilithium acetylide (which is insoluble and precipitates) just by increasing the temperature or concentrating the solution. This is an important drawback in relation with its reactivity and availability in the reaction medium. Consequently, its use is limited to very low temperatures in order to keep the monolithium acetylide system (see U.S. Pat. Nos. 4,055,562, 4,567,001). This prevents its efficient application in more hindered systems such as 16-methylene derivatives.
To prevent formation of dilithium acetylide, complexing agents (e.g. ethylendiamine) able to stabilize monolithium acetylide are used. Monolithium acetylide-ethylenediamine complex is sold commercially. Nevertheless, complex formation highly reduces its reactivity. As a consequence, though ethynylation of reactive ketones can be achieved (U.S. Pat. No. 4,320,236), low yields are obtained in more sterically hindered systems such as 16-methyl-17-keto steroids (U.S. Pat. No. 3,704,253; Example 4).
This problem is partially solved by the use of more hindered amines (see U.S. Pat. No. 4,614,621), e.g. diisopropylamine (Example 1) or triethylamine (Example 13), allowing to perform the reaction at a temperature between −20 and −40° C. without decomposition of the monolithium acetylide. However, if reaction conditions are prolonged, dilithium acetylide is formed at a constant rate. No yields or purity data are mentioned in this document. This US patent, discloses the use of monolithium acetylide complexed with hindered amines in the synthesis of e.g. melengestrol acetate through the following sequence:

WO 97/23498 describes a similar synthetic process as above but on a compound having an ethyl group at position 18 and lacking the methyl radical at position 19 (Examples 4 and 5):

In this case, ethynylation is achieved by using a high excess of monolithium acetylide, generated in situ from nBuLi (7 mol) and gaseous acetylide at −70° C. The reaction is carried out at −40° C. for 2.5 h, giving rise to the ethynylated product with moderate yield (67%).
Use of lithium (trimethylsilyl)acetylide in the ethynylation of 17-keto steroids was disclosed in Tetrahedron 2010, 66, 4068-4072. Lithium (trimethylsilyl)acetylide was generated by reacting trimethylsilylacetylene with nBuLi at −40° C. and the ethynylated product was further desilylated by treatment with catalytic TBAF, giving rise to mestranol and levonorgestrel in 90%. However, these esteroids are not substituted at position 16 and are therefore more reactive and less prone to produce undesired side products than the corresponding 16-methylene substituted steroids.

In general, reaction conditions disclosed in the prior art for the ehtynylation of 16-methyl- or 16-methylene-17-keto steroids refer to the use of magnesium acetylides (U.S. Pat. No. 3,275,666) that afford very poor yields, or the use of unstable lithium acetylide, which has to be generated in situ by reacting flammable acetylene gas with bases difficult to handle as BuLi at very low temperature (from −70 to −40° C.). Yields reported in the prior art for this type of 16-substituted systems are low or moderate (WO 97/23498, Examples 4 and 5) with the need in some cases of high excess of lithium acetylide.
As a consequence, it is still necessary to develop a process for the ethynylation of hindered steroids, such as 16-methylene-17-keto derivatives, that overcomes all or part of the problems associated with the known processes belonging to the state of the art. Specially, more efficient, easier and/or industrially applicable processes would be desirable.
Document WO 93/15103 refers to the synthesis of steroid intermediates through a process comprising ethynylation of 16-methyl-17-keto stereroids having a hydroxy or carbonate group at position 9. Use of lithium trimethylsilylacetylide as an alternative to lithium acetylide in this process is disclosed. No advantages of the use of the silyl-substituted compound are mentioned.
However, use of lithium trisubstitutedsilylacetylides in the ethynylation of 16-methylene-17-keto stereroids has not been reported in the prior art. Inventors have observed that lithium trisubstitutedsilylacetylides can be efficiently used in the preparation of 16-methylene-17-α-ethynyl-17-β-hydroxy compounds. In addition, inventors have surprisingly observed that the use of this alkynylating agent provides an improved process for obtaining 16-methylene-17-α-ethynyl-17-β-hydroxy compounds compared to the use of lithium acetylide or other ethynylating agents used in the prior art for preparing this type of compounds.