(12) United States Patent (10) Patent No.: US 8,524,693 B2 Iglesias Retuerto Et Al

USOO8524693B2

(12) United States Patent (10) Patent No.: US 8,524,693 B2 Iglesias Retuerto et al. (45) Date of Patent: Sep. 3, 2013

(54) PROCESS FOR OBTAINING USPC ...... 552/513; 514/173, 178, 182, 175; 17-SPIROLACTONES IN STEROIDS 1 file f 1 hh 540/41 See application file for complete search history. (75) Inventors: Jesus Miguel Iglesias Retuerto, Boecillo-Valladolid (ES); Luis Gerardo (56) References Cited Gutiérrez Fuentes, Boecillo-Valladolid (ES); Antonio Lorente Bonde-Larsen, us. PATENT DOCUMENTS Boecillo-Valladolid (ES) 3.32. A E typical or 544.94 4,345,984 A * 8/1982 Mihelich. 204,157.69 (73) Assignee: Crystal Pharma, S.A., 4.416,985. A 1 1/1983 Petzoldt et al. Boecillo-Valladolid (ES) 6,121465. A 9, 2000 Mohr et al. 7,144,551 B2 * 12/2006 Helton et al...... 422/37 - r 7,585,971 B2 9, 2009 Costantino et al. ( c ) Notice: Subject tO any disclaimer, the term of this 2010/0261896 A1 ck 10, 2010 Nickisch et al...... 540, 15 patent is extended or adjusted under 35 U.S.C. 154(b) by 352 days. FOREIGN PATENT DOCUMENTS EP 1571153 A2 2, 2005 (21) Appl. No.: 12/816,406 EP 1746101 A1 T 2005 WO 2006061309 A1 6, 2006 (22) Filed: Jun. 16, 2010 OTHER PUBLICATIONS (65) Prior Publication Data Bandini, Marco, et al., “A Nonclassical Stereoselective Semi-Syn thesis of Drospirenone via Cross-Metathesis Reaction.” Synthesis, US 2011/O144363 A1 Jun. 16, 2011 2008, pp. 3801-3804, No. 23. Bittler, Dieter, et al., “Synthesis of spirorenone, a novel highly active (30) Foreign Application Priority Data aldosterone antagonist.” Angewandte Chemie, 1982, pp. 718-719. vol. 94, No. 9. Jun. 16, 2009 (EP) ...... O9382096 * cited by examiner (51) Int. Cl. A6 IK3I/58 (2006.01) Primary Examiner — Barbara P Badio A6 IK3I/585 2006.O1 (74) Attorney, Agent, or Firm — Tristan A. Fuierer; Moore & (2006.01) Van Allen, PLLC A6 IK3I/56 (2006.01) C07, 2L/00 (2006.01) (57) ABSTRACT CO7I 53/00 (2006.01) (52) U.S. Cl. The invention relates to processes for obtaining steroids with USPC ...... s14/173.514.17s. 514,178, s14/182, allya Spirolactone obtaining group, 6.f3,7f8: position"particularly153,16,8-dimethylene-3-oxo-17C.- industri 540/41:552/513 pregn-4-ene-21, 17-carbolactone, commonly known as Dro (58) Field of Classification Search spirenone, as well as to intermediates useful in said process. CPC ...... C07J 21/00; C07J 53/00; A61 K31/56; A61K31/58: A61K31/585 14 Claims, No Drawings US 8,524,693 B2 1. PROCESS FOR OBTAINING 17-SPIROLACTONES IN STEROIDS

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. S 119(a) HO of European Patent Application No. EP09382096.7 for 3 steps “Process for Obtaining 17-Spirolactones in Steroids' 10 filed on Jun. 16, 2009 in the name of Jesus Miguel IGLESIAS RETUERTO et al., which is incorporated herein in its entirety.

FIELD OF THE INVENTION

The invention relates to processes for obtaining steroids with a spirolactone group in position 17, particularly to 3 steps industrially obtaining 6.3.7B:15 B.16.f3-dimethylene-3-oxo 17C-pregn-4-ene-21, 17-carbolactone, commonly known as Drospirenone, as well as to intermediates useful in said pro 25 CCSS,

30 BACKGROUND OF THE INVENTION

The compounds referred to in the invention can be, for

example, Drospirenone, Spirorenone or Prorerone, with par ticular interest in Drospirenone of formula (I): 35

(I) 40

This process has the following main drawbacks: the non diastereoselective introduction of cyclopropyl in position 6.7, 50 which forces performing purifications by means of non-in dustrial techniques such as column chromatography, and the instability of the lactone group in position 17, which can be isomerized, particularly in acid medium, as has been described in Steroids, 71,745-50, 2006 and in EP 91.8791 B1, 55 giving rise to the isolactone, which is one of the main impu Drospirenone particularly has a progestogenic, antiminer rities associated to the end product. alocorticoid and antiandrogenic activity; it is therefore being In particular, to prevent the isomerization of the lactone used in pharmaceutical compositions for its use as a contra and the appearance of the isolactone as an associated impurity ceptive. which is very difficult to purify, it is desirable to use a syn Many chemical processes for obtaining it have been 60 thesis route in which the introduction of the lactone group as described, in which the main synthetic difficulties are: the a final step of the synthesis is achieved and in which further arrangement of the cyclopropyl groups in the Beta configu more the reaction conditions when it is formed are controlled. ration and the introduction of the lactone group. U.S. Pat. No. 4,416,985 describes a process in which the DE 2 652 761, in which this compound was first described, 65 diastereoselective introduction of cyclopropyl in position 6,7 describes a synthetic route for obtaining it in which the lac is resolved and the lactone is obtained in the last synthesis tone group is introduced in early steps of the synthesis: steps: US 8,524,693 B2

HO HO OH OH

wherein the lactone is introduced simultaneously by means of adding a propargyl alcohol which is Subjected to a hydroge nation and subsequent oxidation of the tetraol formed to yield the desired product. However, the oxidation conditions of the final step, in the 30 presence of a toxic oxidant such as CrO, give rise to a product which is purified by a chromatographic column and in which the partial isomerization of the lactone formed occurs both due to the acid medium used and due to the presence of chromium salts aiding in the isomerization. 35 EP 91.8791 B1 shows the drawbacks set forth above and proposes as a solution mitigating the final oxidation condi tions of the tetraol intermediate by means of using catalytic Various oxidation conditions are described, such as for amounts of ruthenium trichloride in the presence of sodium 40 example the use of MnO, Oppenauer oxidation conditions, bromate. Under these conditions, the 5-3-hydroxy derivative: NaClO in the presence of TEMPO etc. In this case, the Dro spirenone obtained is also purified by column chromatogra phy. Other patents or patent applications following the same 45 strategy of partial or complete oxidation of the tetraol inter mediate under oxidizing conditions are, for example: EP 1828222 B1 and EP 1746101 B1. As it can be seen, the strategy of all the synthetic proposals for introducing the lactone group as a final step of the Syn 50 thesis is a complete or partial oxidation reaction of the tetraol intermediate, followed by elimination in acid medium to yield Drospirenone. In all the cases, the final conditions of the last step involve oxidation reagents which complicate the purification of the end product and elimination conditions in 55 acid medium which enable the appearance of impurities is isolated as an intermediate, which gives rise to the final derived from the degradation of the lactone, such as for Drospirenone by means of eliminating the hydroxyl group in example the isolactone. acid medium under controlled conditions, thus preventing the It is therefore necessary to develop an alternative process appearance of the isolactone. for obtaining steroid derivatives with a spirolactone function 60 Under these conditions, the isolation of Drospirenone with which overcomes all or part of the problems associated with a chromatographic purity of only 93% and the need to use the known processes belonging to the state of the art. chromatographic techniques if a product with a higher purity SUMMARY OF THE INVENTION is to be obtained are described. US 2005/1924.50 also uses the tetraol intermediate to, by 65 The invention faces the problem of providing a process for means of its oxidation, directly obtain final Drospirenone or preparing steroids, and particularly Drospirenone, which by previously isolating the lactol derivative: allows introducing the lactone group in position 17, prefer US 8,524,693 B2 5 ably as a last synthesis step, and which prevents using oxi

dizing reagents complicating the final purification or acid (I) conditions favoring the degradation of the end product, with the appearance, for example, of the isolactone. The solution provided by the invention is based on the fact that the inventors have surprisingly observed that it is possible to introduce, in a non-oxidative manner, a lactone group, by means of introducing an alkynyl ester, particularly a propar gyl ester, in position 17 of a derivative of 6?.7f8:15 B.16.f3 dimethylene-17-carbonyl steroid of formula (IV) defined 10 below, to give rise to a derivative of 6?.7f8:15 B, 16.f3-dimeth ylene-17-beta-hydroxy-17-O-carboxyalkyl-ethynyl steroid of formula (III) defined below. A process Such as the one provided by the present invention 15 has a number of advantages since the side chain with the carboxyl group in the form of ester, necessary for Subse quently creating the Spirolactone, is introduced in a single which comprises providing a compound of formula (III) synthesis step. and Subjecting said compound to: The present invention therefore provides an efficient pro 1) optionally, deprotection of the hydroxyl in position 3 cess for obtaining derivatives of 6?.7 B.15 B, 16.f3-dimethyl when R' is a hydroxyl-protecting group, ene-17-hydroxy-17-carboxy-alkylethynyl steroids of for 2) oxidation of the hydroxyl group in position 3 to yield mula (III), or solvates thereof, which constitute synthetic a compound of formula (II) intermediates useful in the synthesis of steroids, particularly, Drospirenone. 25 Thus, in an aspect, the invention relates to a compound of (II) formula (III) COR

(III) 30

wherein R is that previously defined in connection with the 40 compound of formula (III), and wherein Subjecting said compound of formula (II) to a sequence of R is C-C alkyl, C-C cycloalkyl, aryl or benzyl; and reactions selected from sequences A, B and C wherein R" is hydrogen or a hydroxyl-protecting group; Sequence A comprises: or a solvate thereof. a1) subjecting a compound of formula (II) to an elimi In another aspect, the invention relates to a process for 45 nation or an elimination/saponification reaction to obtaining a compound of formula (III), which comprises yield the intermediate of formula (IIa): reacting a compound of formula (IV) (IIa) (IV) 50

with a propargyl ester of formula (V): 60 H=COR (V) wherein R is H. C-Cs alkyl, C-Cs cycloalkyl, aryl wherein RandR' are defined as above, in the presence of or benzyl: a base. 65 a2) Subjecting said compound of formula (IIa) to a In another aspect, the invention relates to a process for hydrogenation reaction in the presence of a Pt or Pd obtaining Drospirenone (I) catalyst to yield the intermediate of formula (Ic): US 8,524,693 B2 8 -continued (IIc) (IId) COR O

i. w ?.

15 wherein R is that previously defined, and a3) Subjecting said compound of formula (IIc) to treat wherein R is that previously defined, and ment in acid conditions to render Drospirenone (I), c2) Subjecting a compound of formulae (IId) and/or (IIe) wherein steps a2) and a3), alternatively, take place in to treatment in acid conditions to render Drospirenone one-pot form; (I), Sequence B comprises: wherein steps c1) and c2) alternatively take place in b1) Subjecting a compound of formula (II) to a hydro one-pot form. genation reaction in the presence of a Pd catalyst to 25 In another aspect, the invention is aimed at a process for yield the intermediate of formula (IIb) obtaining Drospirenone (I):

(IIb) (I) 30

comprising providing a compound of formula (III) as defined above, followed by and 45 d1) Subjecting said compound of formula (III) to a b2) Subjecting said compound of formula (IIb) to a hydrogenation reaction in the presence of a metal hydrogenation reaction in the presence of a Pt catalyst catalyst to yield the intermediate of formula (VI) to render Drospirenone (I); wherein steps b1) and b2) alternatively take place in one-pot form; and 50 (VI) Sequence C comprises: c1) Subjecting a compound of formula (II) to a hydroge nation reaction in the presence of a Pt catalyst to yield the intermediates of formulae (IId) and/or (IIe) 55

(IIe) OH/ COR RO 60 OH

wherein R is that previously defined, d2) deprotecting the hydroxyl group in position 3 of said 65 compound of formula (VI) when R' is a protecting group, followed by a transesterification reaction to render the compound of formula (VII) US 8,524,693 B2 10 -continued

(VII)

d3) oxidizing the compound of formula (VII) to render the compound of formula (IId)

(IId)

or a solvate thereof, wherein R, R' and R are as they have 35 been defined above.

DETAILED DESCRIPTION OF THE INVENTION

and In the context of the present invention, the following terms d4) Subjecting the compound of formula (IId) to an 40 have the meaning detailed below: The term "C-C alkyl refers to a radical derived from a elimination reaction to render Drospirenone (I). linear or branched alkane, containing from 1 to 8, preferably In another aspect, the invention relates to a compound from 1 to 6 carbon atoms ("C-C alkyl”), and which is selected from the following list: attached to the rest of the molecule by a single bond. 45 Examples of alkyl groups include methyl, ethyl, propyl. butyl, penty1 and hexyl. As used herein, the term "C-C cycloalkyl refers to a radical derived from a cycloalkane, containing from 3 to 8, preferably from 3 to 6 ("C-C cycloalkyl) carbon atoms. 50 Examples of cycloalkyl groups include cyclopropyl and cyclobutyl. As defined herein, the term “aryl” refers to a radical derived from an aromatic hydrocarbon containing from 6 to 14, pref 55 erably from 6 to 10 carbonatoms, for example, phenyl, tolyl, OH Xylyl, naphthyl, etc. COR As used herein, the term "hydroxyl-protecting group'

includes any group capable of protecting a hydroxyl group. Illustrative examples of said hydroxyl-protecting groups have 60 been described by Green T. W. et al. in “Protective Groups in Organic Synthesis', 3rd Edition (1999), Ed. John Wiley & Sons. Examples of hydroxyl-protecting groups include silyl ethers, ethers, esters, Sulfonates, Sulfenates, Sulfinates, car bonates and carbamates. The hydroxyl-protecting group is 65 preferably a silyl radical of formula Si(R)(R)(R), wherein R. R. R. represent, independently from one another, C-C, alkyl or C-C cycloalkyl. US 8,524,693 B2 11 12 Likewise, the compounds described in the present inven -continued tion can be in crystalline form, either as free compounds or as OH solvates (for example, hydrates) and it is understood that both COEt, forms are within the scope of the present invention. Solvation methods are generally known in the art. Suitable solvates are pharmaceutically acceptable Solvates. Compound of Formula (III) In an aspect, the invention relates to a compound of for mula (III) 10 or a solvate thereof.

(III) Process for Obtaining a Compound of Formula (III) In another aspect, the invention relates to a process, here COR 15 inafter referred to as the “process of the invention', for obtaining a compound of formula (III)

(III)

COR

25 wherein R is C-C alkyl, C-C cycloalkyl, aryl or benzyl; and R" is hydrogen or a hydroxyl-protecting group; 30 wherein or a solvate thereof. R is C-C alkyl, C-C cycloalkyl, aryl or benzyl; and In a particular embodiment, R is C-C alkyl, preferably R" is hydrogen or a hydroxyl-protecting group; C-C alkyl, more preferably ethyl. or a solvate thereof, In another particular embodiment, R' is selected from which comprises reacting a compound of formula (IV) hydrogen and a silylated hydroxyl-protecting group. Prefer 35 ably, R' is selected from hydrogen, trimethylsilyl and tert butyldimethylsilyl. (IV) In another particular embodiment, R is linear or branched C-C alkyl and R' is selected from hydrogen and a silylated 40 hydroxyl-protecting group. In another more particular embodiment, R is ethyl and R' is preferably selected from hydrogen, trimethylsilyl and tert-butyldimethylsilyl.

According to a particular embodiment, the compound of 45 RO formula (III) is selected from: OH

wherein R' is that previously defined, COEt, 50 with a propargyl ester of formula (V) ROC=H (V) wherein R is that previously defined, in the presence of a base. 55 The process of the invention comprises reacting the com pound of formula (IV) with an anion of the propargyl ester

which is generated by means of the reaction of a base with a propargyl ester (V). CO2Et and 60 To put the process of the invention into practice, various propargyl esters can be used, particularly of the group con sisting of ethyl propiolate, methyl propiolate, tert-butyl pro piolate, isobutyl propiolate, and mixtures thereof. In a par ticular and preferred embodiment, the propargyl ester is ethyl 65 propiolate. The base used in the process of the invention can be any organic or inorganic base capable of abstracting the proton of US 8,524,693 B2 13 14 a propargyl ester. Illustrative non-limiting examples of According to another particular embodiment, when using organic or inorganic bases which can be used include amides tetrahydrofuran/dimethylformamide (THF/DMF) mixtures Such as lithium diethylamide, lithium diisopropylamide as the solvent and Sodium amide as the base, the typical (LDA), lithium hexamethyldisilazide (HMDSLi), lithium reaction temperature is between 0° C. and 5° C. and the amide, Sodium amide, etc., lithium alkylides such as butyl reaction time is approximately 3-4 hours. lithium, hexyllithium, etc.; sodium hydride, lithium hydride, According to another particular embodiment, when using or any other similar inorganic base which is considered toluene as the solvent and lithium amide as the base, the capable of abstracting the proton of propargyl esters. One or reaction temperature is about 25°C. and the reaction time is more organic and/or inorganic bases can be used. In a par 10 approximately 2-4 hours. ticular embodiment of the invention, the organic base is According to another particular embodiment, when using selected from lithium diethylamide, HMDSLi (lithium hex toluene as the solvent and lithium amide as the base, the reaction temperature is about 40° C. and the reaction time is amethyldisilazide). LDA (lithium diisopropylamide) and approximately 1-3 hours. mixtures thereof, and the inorganic base is selected from 15 lithium amide, sodium amide and mixtures thereof. More According to another particular embodiment, when using toluene as the solvent and HMDSLi as the base, the reaction preferably the base is lithium amide. temperature is about 0°C. and the reaction time is approxi In a particular embodiment, the reaction of the compound mately 0.5-3 hours. of formula (IV) with the propargyl ester (V) is carried out in a suitable organic solvent, such as an ether, for example, an In any of these cases, a significant increase in the reaction acyclic ether (e.g. diisopropylether, etc.) or a cyclic ether temperature can involve an increase of impurities, mainly (e.g., tetrahydrofuran (THF), a dioxane, etc.), a halogenated derived from the polymerization of the propargyl ester and Solvent Such as, for example, dichloromethane, etc., or in an also a reduction in the final yield. aromatic solvent such as, for example, toluene, etc. The process of the invention allows obtaining compounds The addition reaction of the process of the invention is 25 of formula (III) with a high degree of purity and with high preferably carried out in the presence of an excess of base. For yields, typically of approximately 80%, or higher. example, when lithium amide in toluene is used, the use of The compounds of formula (III) obtained can be used between 2 and 20 equivalents of base against 1 equivalent of directly or can be purified by means of conventional and industrially acceptable processes Such as, for example, by the steroid of formula (IV), preferably between 4 and 14 30 equivalents of base, is required. means of a crystallization process. Illustrative non-limiting The amount of propargyl ester (V) can also vary within a examples of suitable solvents for said crystallization include broad range, typically between 1 and 6 equivalents, prefer ethyl acetate, toluene, heptane, methyl tert-butyl ether, dichloromethane (DCM), etc., and mixtures thereof. In a ably between 1.2 and 2 equivalents, with respect to the steroid preferred embodiment, said solvent is selected from ethyl of formula (IV). 35 acetate, toluene, dichloromethane, heptane and mixtures Although the background documents found indicate, for thereof. example, that the lithium anions obtained from propargyl esters readily decompose at temperatures greater than -78° In a particular embodiment, when, in the compound of C., (see for example: J. Org. Chem., 45, 28, 1980, J. Am. formula (III), R is ethyl and R' is a tert-butyldimethylsilyl 40 (TBDMS) group, the product can be purified in toluene or Chem. Soc., 122, 10033, 2000, Fieser and Fieser's Reagents toluene? heptane to yield the corresponding toluene hemisol for Organic Synthesis, Vol 8, p. 259, Wiley Interscience and Vate. Synthesis, 679, 1977), the inventors have surprisingly found According to another particular embodiment, when, in the that both the formation of the anion of the propargylester with compound of formula (III), R is ethyland R' is hydrogen, the a base and its Subsequent addition to the steroid can be per 45 product can be purified in DCM or DCM/heptane. formed at higher temperatures without this involving the According to a particular embodiment, the formation reac decomposition of any particular compound. Therefore, in a tion of a compound of formula (III) is performed by means of particular embodiment, the temperature at which the process the reaction of a compound of formula (IV) wherein R' is a of the invention is performed ranges between -10°C. and 60° TBDMS group and a compound of formula (V) wherein R is C., not being necessary to perform the reaction in the drastic 50 an ethyl group, using 8 equivalents of lithium amide in tolu cooling conditions described in the prior art of typically -76° ene, giving rise to the corresponding compound of formula C. The process of the invention Surprisingly overcomes the (III) which is isolated in the form of toluene hemisolvate with drawbacks set forth in the prior art (see J. Am. Chem. Soc., 83, a yield greater than 80%. 2944, 1961), which describes the formation of trimers and 55 According to another particular embodiment, the forma other derivatives of propargyl esters upon reacting with cata tion reaction of a compound of formula (III) is performed by lysts at room temperature or above. means of the reaction of a compound of formula (IV) wherein The reaction rate depends on both the temperature and the R" is a TBDMS group and a compound of formula (V) solvent used, where at a temperature comprised between -10° wherein R is an ethyl group, using 2 equivalents of HMDSLi C. and 60° C. the reaction takes place in a time period of 60 in toluene, giving rise to the corresponding compound of between 15 minutes and 12 hours, typically comprised formula (III) which is isolated in a yield of about 77%. between 30 minutes and 6 hours. The starting products of formula (IV), wherein R is H. can In a particular embodiment, when the reaction is carried be obtained by methods known in the state of the art as out using tetrahydrofuran as a solvent and lithium amide as a mentioned, for example, in U.S. Pat. No. 4,416,985, U.S. Pat. base, the typical reaction temperature is comprised between 65 No. 4,435,327 or in EP 1828222, which describe obtaining 0° C. and 5° C. and the reaction time is approximately 2-3 keto derivatives in position 17 according to the following hours. synthetic scheme: US 8,524,693 B2 16

The compounds of formula (IV) wherein R' is a hydroxyl which comprises protecting group can in turn be obtained from the compound 25 providing a compound of formula (III) of formula (IV) wherein R' is H. by means of protecting the hydroxyl group by methods known in the state of the art for the protection of hydroxyl groups, such as, for example, by (III) means of those described by Green T. W. et al. in “Protective COR Groups in Organic Synthesis”, 3' Edition (1999), Ed. John 30 Wiley & Sons (ISBN 0-471-16019-9). In a particular embodiment, the compounds of formula (IV) wherein R is a TBDMS group or a TMS (trimethylsilyl) group are obtained by means of the reaction of the compound 35 (IV) wherein R' is H with tert-butyldimethylsilyl chloride or with trimethylsilyl chloride, respectively, in DMF and in the wherein presence of a base such as, for example, triethylamine. These R is selected from C-Cs alkyl, C-Cs cycloalkyl, aryl compounds can be crystallized in DMF/water. 40 and benzyl, and R" is selected from hydrogen and a hydroxyl-protect In another aspect, the invention relates to the use of said ing group: steroids of formula (III) or solvates thereof, as intermediates or a solvate thereof, and useful in the synthesis of steroids with a spirolactone group in Subjecting said compound of formula (III) to: 1) optionally, deprotection of the hydroxyl group in position 17, preferably in the synthesis of Drospirenone (I). 45 position 3 when R' is a protecting group, and Process for Obtaining Drospirenone (I) 2) oxidation of the hydroxyl group in position3 to render Another aspect of the present invention relates to a process a compound of formula (II) for obtaining Drospirenone (I) 50

(II)

COR

(I) 55

60 wherein R is that previously defined, and Subjecting said compound of formula (II) to a sequence of reactions selected from sequences A, B and C (below). In a particular embodiment, R is linear or branched C-Cs 65 alkyl, preferably C-C alkyl, more preferably ethyl. In another particular embodiment, R' is hydrogen or a silylated hydroxyl-protecting group, preferably, in a more US 8,524,693 B2 17 18 particular embodiment, R' is hydrogen, trimethyl-silyl or tert-butyldimethylsilyl. COR In another particular embodiment, R is linear or branched HO C-C alkyl and R' is hydrogen or a silylated hydroxyl-pro tecting group. Preferably, in a more particular embodiment, R is ethyl and R' is hydrogen, trimethylsilyl or tert-butyldim ethylsilyl. Particular embodiments of the invention include the use of HO 10 compounds of formula (III) in which: OH R is ethyl and R' is hydrogen; (III) R is ethyl and R' is tert-butyldimethylsilyl; or R is ethyl and R' is trimethylsilyl. If necessary, the hydroxyl group deprotection reaction 1) 15 COR can be carried out by conventional methods, for example, HO according to any of the methods described by Green TWetal. in “Protective Groups in Organic Synthesis”, 3" Edition (1999), Ed. John Wiley & Sons (ISBN 0-471-16019-9). It will depend, among other things, on the nature of the hydroxyl protecting group.

When the protecting group R' in the compound of formula OH (III) is a silyl group, it can be readily eliminated using for (II) example fluoride salts, inorganic acids such as hydrochloric 25 acid in ethanol, organic acids such as formic acid in tetrahy drofuran or para-toluenesulfonic acid and in some occasions, oxidative media such as 2.3-dichloro-5,6-dicyanobenzo quinone (DDQ). 30 wherein R is that previously defined. Particularly, when said protecting group R' is trimethylsi This step can be carried out by means of any oxidation lyl (TMS) or tert-butyldimethylsilyl (TBDMS), fluoride salts reaction which allows transforming a hydroxyl group into a Such as pyridinium fluoride, potassium fluoride or ammo carbonyl group, following for example the processes nium fluoride can be used for its elimination. Tetrabutylam described in U.S. Pat. No. 4,416,985, U.S. Pat. No. 6,121,465, monium fluoride in a solvent Such as tetrahydrofuran and at 35 EP 1571153 or EP 1828222, by means of using reagents such room temperature is more preferably used, the yields as 2.2.6,6-tetramethylpiperidine-1-oxide (TEMPO), calcium obtained being quantitative or almost quantitative. hypochlorite, trichloroisocyanuric acid or mixtures thereof. The compounds of formula (III) obtained after step 1) can be used directly or can be purified by means of conventional In a particular embodiment, the transformation of a com 40 pound of formula (III) wherein R is ethyl into the correspond and industrially acceptable processes such as, for example, by ing ketone of formula (II) is performed through the use of means of a crystallization process. Illustrative non-limiting trichloroisocyanuric acid in the presence of TEMPO in a examples of suitable solvents for said crystallization include two-phase system formed by a dichloromethane/tetrahydro dichloromethane, heptane, toluene, methyl tert-butyl ether furan and water/sodium or potassium bicarbonate mixture at and mixtures thereof. In a preferred embodiment, said solvent 45 room temperature. is selected from dichloromethane and dichloromethane/hep The compounds of formula (II) so obtained can be used tane. In a particular embodiment, when R is an ethyl group, directly or can be purified by means of conventional and the compound of formula (III) can be crystallized in dichlo industrially acceptable processes Such as, for example, by romethane and dichloromethane/heptane. 50 means of a crystallization process. Illustrative non-limiting Alternatively, when the protecting group R' in the com examples of suitable solvents for said crystallization include pound of formula (III) is an ether derivative such as, for dichloromethane, heptane, toluene, methyl tert-butyl ether example, methoxymethyl ether, tetrahydropyranyl ether, or and mixtures thereof. In a preferred embodiment, said solvent 2-methoxy-ethoxymethyl ether, they can be eliminated by is selected from dichloromethane, toluene and mixtures 55 thereof with heptane. According to a particular embodiment, using acid media. when R is an ethyl group, the compound of formula (II) can be When the protecting group R' in the compound of formula purified by means of crystallization in dichloromethane (III) is an ester derivative such as, for example, a phenyl ester, (DCM), toluene, DCM/heptane or toluene/heptane. it can be eliminated by using fluoride salts such as tetrabuty The compound of formula (II) obtained can subsequently lammonium fluoride or methanolic sodium hydroxide. 60 be transformed into Drospirenone (I) by means of a sequence When the protecting group R' in the compound of formula of reactions selected from sequences A, B and C which are (III) is a trihaloacetate, particularly trifluoroacetate, it can be detailed below. eliminated in mild basic conditions. Sequence A comprises: The compound of formula (III) wherein R' is H can be 65 al) Subjecting a compound of formula (II) to an elimina converted into the intermediate of formula (II) by means of an tion or an elimination/saponification reaction to yield oxidation reaction (step 2): the intermediate of formula (IIa): US 8,524,693 B2 19 20

2 (IIa) COR

(II) wherein R is H. C-C alkyl, C-C cycloalkyl, aryl or benzyl: 15 a2) Subjecting said compound of formula (IIa) to a hydro genation reaction in the presence of a Pt or Pd catalyst to yield the intermediate of formula (IIc):

(IIc)

(IIa)

wherein R is that previously defined, and 35 a3) Subjecting said compound of formula (IIc) to treatment in acid conditions to render Drospirenone (I), (III) wherein steps a2) and a3), alternatively, take place in one pot form. 40 In a particular embodiment, when R is an ethyl group, the elimination reactional) is carried out: According to the invention, the first elimination reaction in tetrahydrofuran using potassium bisulfate or para-tolu Stepal) can take place in: enesulfonic acid at room temperature, to render the ester a) an acid medium, comprising organic or inorganic acids, (IIa), or Such as, for example, p-toluenesulfonic acid or potas 45 in water using lithium hydroxide at room temperature, to render the acid (III), or sium bisulfate in catalytic or equimolecular amounts and in methanol using sodium carbonate at 0°C., to render the in a solvent, such as, for example, THF, ethyl acetate, ester (IIa). ethanol or dichloromethane; under these conditions, the If desired, the intermediate of formula (IIa), obtained in reaction preferably takes places at room temperature Stepal), can be used directly in the hydrogenation step a2) or, (about 18°C.-25° C.), or in 50 alternatively, it can be isolated and purified by recrystalliza b) a basic medium, comprising, for example, Sodium car tion or precipitation, using solvents such as toluene, ethyl acetate and mixtures thereof with heptane. bonate, Sodium hydroxide, lithium hydroxide, etc., in The hydrogenation reaction step a2) is performed by amounts from 1 to 3 equivalents, in a solvent Such as using Pt or Pd as a catalyst at atmospheric pressure and in the THF, methyl-THF, acetonitrile, methanol, isopropanol, 55 presence of solvents such as ethanol or ethyl acetate, and toluene or water, under these conditions the reaction can preferably at room temperature, to render the compound of take place at a temperature from 0°C. to room tempera formula (IIc). ture. In the hydrogenation reaction, it is possible to directly At the first stage of step a1), elimination of the hydroxylat obtain Drospirenone (I) or also a mixture of Drospirenone (I) 60 with the non-lactonized intermediate (Ic), wherein the latter, C5 position occurs to afford the intermediate of formula (IIa), either spontaneously or with Subsequent treatment in acid which may be an acid (R—H) or an ester (R—C-Cs alkyl, medium according to step a3, can be transformed into Dro C-Cs cycloalkyl, aryl or benzyl). spirenone (I). The acid conditions in step a3) can be estab Saponification of the ester (IIa), as a second stage, to render lished by using both organic and inorganic acids such as, for the acid intermediate of formula (IIi) takes place when the 65 example, para-toluenesulfonic acid or potassium bisulfate, reaction is performed with a basic medium and be kept under typically in catalytic amounts; the reaction can take place at stirring, wherein R is hydrogen, as shown below: room temperature. US 8,524,693 B2 21 22 Steps a2) and a3) can alternatively take place in one-pot Under these conditions, both oxidative and acid conditions form by means of an acid treatment comprising the addition to are avoided while obtaining Drospirenone (I). the compound of formula (IIa) of an organic or inorganic acid, Sequence C comprises: preferably in a catalytic manner, in a solvent such as, for c1) Subjecting a compound of formula (II) to a hydrogena example, tetrahydrofuran, ethyl acetate or ethanol, followed tion reaction in the presence of a Pt catalyst to yield the by the addition of a catalyst such as Pt/C or Pd/C under intermediates of formulae (IId) and/or (IIe) hydrogenation conditions at atmospheric pressure. Sequence B comprises:

b1) Subjecting a compound of formula (II) to a hydrogena (IIe) tion reaction in the presence of a Pd catalyst to yield the 10 intermediate of formula (IIb)

(IIb) 15

(IId)

and b2) subjecting said compound of formula (IIb) to a hydro genation reaction in the presence of a Pt catalyst to 30 render Drospirenone (I); wherein steps b1) and b2) alternatively take place in one wherein R is that previously defined, and pot form. c2) Subjecting a compound of formulae (IId) and/or (IIe) to According to sequence B, the compounds of formula (II) treatment in acid conditions to render Drospirenone (I); can directly give rise to Drospirenone (I) by means of a 35 wherein steps c1) and c2) alternatively take place in one catalytic hydrogenation process depending on the type of pot form. catalyst chosen. In a particular embodiment, these two steps c1) and c2) Thus, when a compound of formula (II) is first subjected to can be performed in a one-pot process, without eliminating hydrogenation conditions in the presence of a Pd catalyst, the catalyst. preferably Pd/C, followed by a second step in which a Pt 40 Alternatively, sequence C can be performed in two steps, catalyst, preferably Pt/C, is added, both performed at atmo wherein once the hydrogenation has taken place, the reaction spheric pressure, Drospirenone (I) is directly obtained. mixture is subjected to filtration to recover the catalyst, fol In a particular embodiment, this process can be performed lowed by an acid treatment to give rise to Drospirenone (I). in the form of a one-pot process, in which first a Pd catalyst The hydrogenation reaction step c1) is preferably carried and then a Pt catalyst are added. 45 out using Pt/C as a catalyst at atmospheric pressure and using Alternatively, the intermediate (IIb) obtained as an inter Solvents such as ethanol or ethyl acetate. This step c1 is mediate during the hydrogenation with Pd can be initially preferably performed at room temperature. isolated, for example by means of filtration, and it can Sub During the hydrogenation reaction step c1), the reduction sequently be transformed into Drospirenone (I) in the pres 50 of the propargyl ester to yield the intermediate of formula ence of a Pt catalyst, the same solvent or another different one (IIe) and the partial transesterification of the latter to obtain being able to be used in both steps. the lactone of formula (IId) are observed. Both intermediates The intermediate (IIb) can optionally be isolated and puri are present at the end of the hydrogenation process in a fied, if necessary, using for example DMF/water, and can variable ratio. Subsequently be subjected to catalytic hydrogenation in the 55 The mixture of both intermediates is subjected to treatment presence of Pt/C to give rise to Drospirenone (I). under acid conditions step c2) for their transformation into In a particular embodiment, when the hydrogenation reac Drospirenone (I) by means of the elimination of the hydroxyl tion of the compound of formula (II) is performed with Pd/C group in the case of the intermediate of formula (IId) and by at atmospheric pressure in a solvent Such as ethyl acetate or means of the elimination of the hydroxyl group and intramo ethanol, there is an elimination of the hydroxyl group in 60 lecular transesterification to yield the lactone in the case of the position 5 and a partial reduction of the alkyne to yield the intermediate of formula (IIe). corresponding alkene derivative which, by means of an To establish the acid conditions, both organic and inorganic intramolecular transesterification process, gives rise to the acids, such as for example para-toluenesulfonic acid or potas unsaturated lactone (IIb). Under these reaction conditions, sium bisulfate, in catalytic or equimolecular amounts, can be the subsequent addition of a Pt catalyst is required to be able 65 used; solvents such as tetrahydrofuran, ethyl acetate, ethanol to reduce the unsaturated lactone (IIb) to the saturated lactone or dichloromethane can be used; and the reaction preferably (I) or Drospirenone. takes place at room temperature. US 8,524,693 B2 23 24 In a preferred embodiment, the invention provides a pro cess for obtaining Drospirenone (I) which comprises a) protecting a compound of formula (IVa) (IIf) COEt (IVa) O

HO OH e) Subjecting the compound of formula (IIf) to an elimina 15 tion reaction to yield the intermediate of formula (IIg) to render a compound of formula (IVb)

(Ig) (IVb) O 2O COEt

TBDMSO OH f) Subjecting the compound of formula (IIg) to a hydroge wherein TBDMS is tert-butyldimethylsilyl: 30 nation reaction in the presence of a Pt catalyst to yield b) reacting said compound of formula (IVb) with a com the intermediate of formula (IIh) pound of formula (Va) H=CO-Et (Va) to render a compound of formula (IIIb) 35 (IIh)

(IIIb)

COEt 40

45 and g) Subjecting the compound of formula (IIh) to treatment in the presence of an acid to render Drospirenone (I). wherein TBDMS is tert-butyldimethylsilyl: According to the invention, in a particular embodiment, the c) deprotecting the protected hydroxyl group in position 3 50 protection reaction of step a) is carried out using a TBDMS of said compound of formula (IIIb) to render a com triflate or halide in the presence of a base and an organic pound of formula (IIIc) Solvent. In a preferred embodiment, the base is an organic base, preferably an amine, and the Solvent is a Suitable organic solvent Such as an ether, a halogenated Solvent or

(IIIc) 55 DMF. In a more particular embodiment, the reaction takes place in the presence of TBDMS chloride using triethylamine COEt as the base and DMF as the solvent. The reaction conditions for step b) are the same as those mentioned above in relation to the process of the invention 60 i.e., the process for obtaining a compound of formula (III) by reacting a compound of formula (IV) with a propargylester of formula (V). In a particular embodiment, the reaction is carried out in the presence of lithium amide or HMDSLi as a d) oxidizing the hydroxyl group in position 3 of said com- 65 base and an aromatic solvent, preferably toluene. pound of formula (IIIc) in the presence of an oxidizing Step c can be carried out using fluoride salts such as pyri species to yield a compound of formula (IIf) dinium fluoride, potassium fluoride, ammonium fluoride or US 8,524,693 B2 25 26 tetrabutylammonium fluoride. In a particular embodiment, to render a compound of formula (IIIb) the reaction is carried out using tetrabutylammonium fluoride (IIIb) in a solvent, e.g., an ether, preferably tetrahydrofuran. COEt The oxidation of the hydroxyl group step d) is preferably carried out in the presence of an oxidizing reagent such as TEMPO, calcium hypochlorite, trichloroisocyanuric acid or mixtures thereof. In a particular embodiment, the reaction is carried out using trichloroisocyanuric acid in the presence of TEMPO and a two-phase system formed by a mixture of dichloromethane/tetrahydrofuran and water/sodium bicar 10 bonate. TBDMSO The dehydration step step e) preferably takes place in HO acid medium Such as, for example, para-toluenesulfonic acid or potassium bisulfite in the presence of an organic solvent wherein TBDMS is tert-butyldimethylsilyl: Such as, for example, tetrahydrofuran, ethyl acetate, ethanol 15 c) deprotecting the protected hydroxyl group in position 3 or dichloromethane. In a particular embodiment, the reaction of said compound of formula (IIIb) to render a com is carried out using para-toluenesulfonic acid in a medium pound of formula (IIIc) comprising tetrahydrofuran. In a particular embodiment, the hydrogenation reaction step f) is performed using Pt/C as a catalyst in a hydrogen atmosphere, preferably at an overpressure, e.g., an overpres sure of 0.1 bar (10 Pa), and in the presence of ethyl acetate. Finally, treatment of the compound of formula (IIh) to render Drospirenone (I) step g) can be performed, in a 25 particular embodiment, with para-toluenesulfonic acid or potassium bisulfite in the presence of an organic solvent Such as, for example, tetrahydrofuran, ethyl acetate, ethanol or dichloromethane. In a more particular embodiment, the reac tion is carried out using para-toluenesulfonic acid in a 30 medium comprising ethyl acetate. In another preferred embodiment, the invention provides a d) oxidizing the hydroxyl group in position 3 of said com process for obtaining Drospirenone (I) which comprises: pound of formula (IIIc) in the presence of an oxidizing a) protecting a compound of formula (IVa) 35 species to yield a compound of formula (IIf):

(IVa) (IIf)

40 COEt

HO 45 OH e) Subjecting the compound of formula (IIf) to an elimina to render a compound of formula (IVb) tion and Saponification reaction to yield the intermediate 50 of formula (IIi) (IVb) (III)

TBDMSO OH 60

wherein TBDMS is tert-butyldimethylsilyl: b) reacting a compound of formula (IVb) with a compound of formula (Va) 65 f) Subjecting the compound of formula (IIi) to a hydroge nation reaction in the presence of a Pt or Pd catalyst to H=CO-Et (Va) yield the intermediate of formula (II) US 8,524,693 B2 27 28 Finally, treatment of the compound of formula (II) to (II) render Drospirenone (I) step g) can be performed, in a particular embodiment, with para-toluenesulfonic acid or potassium bisulfite in the presence of an organic solvent Such s as, for example, tetrahydrofuran, ethyl acetate, ethanol or dichloromethane. In a more particular embodiment, the reac tion is carried out using para-toluenesulfonic acid in a medium comprising ethyl acetate. In another aspect, the invention relates to a process for 10 obtaining Drospirenone (I) which comprises providing a compound of formula (III) as defined above followed by d1) Subjecting said compound of formula (III) to a hydro and genation reaction in the presence of a metal catalyst to g) Subjecting the compound of formula (II) to treatment in 15 yield the intermediate of formula (VI) the presence of an acid to render Drospirenone (I). (VI) According to this preferred embodiment of the invention, the protection reaction of the compound of formula (IVa) to yield the compound of formula (IVb) step a), in a particular embodiment, is carried out using a TBDMS triflate or halide in the presence of a base and an organic Solvent. In a preferred embodiment, the base is an organic base, preferably an amine, and the solvent is a Suitable organic solvent such as an ether, a halogenated solvent or DMF. In a particular embodiment, the reaction takes place in the presence of TBDMS chloride 25 using triethylamine as the base and DMF as the solvent. In step b), the reaction conditions of the compound of wherein R is that previously defined, formula (IVb) with the compound of formula (Va) to yield a d2) deprotecting the hydroxyl group in position 3 of said compound of formula (IIIb) are the same as those mentioned 30 compound of formula (VI) when R is a protecting above in relation to the process of the invention for obtaining group, followed by a transesterification reaction to ren the compounds of formula (III) i.e., the process for obtaining der the compound of formula (VII) a compound of formula (III) by reacting a compound of formula (IV) with a propargyl ester of formula (V). In a particular embodiment, the reaction is carried out in the pres 35 (VII) ence of HMDSLi and an aromatic solvent, preferably toluene. The deprotection of the hydroxyl in position 3 of a com pound of formula (IIIb) to yield a compound of formula (IIIc) step c) can be carried out using fluoride salts such as pyri dinium fluoride, potassium fluoride, ammonium fluoride or 40 tetrabutylammonium fluoride. In a particular embodiment, the reaction is carried out using tetrabutylammonium fluoride in an ether solvent, preferably tetrahydrofuran. The oxidation of the hydroxyl group in position 3 of the compound of formula (IIIc) to yield a compound of formula 45 (IIf) step d) is preferably carried out in the presence of an oxidizing reagent such as, for example, TEMPO, calcium hypochlorite, trichloroisocyanuric acid or mixtures thereof. d3) oxidizing the compound of formula (VII) to render the In a particular embodiment, the reaction is carried out using compound of formula (IId) trichloroisocyanuric acid in the presence of TEMPO and a 50 two phase system formed by a mixture of DCM/THF and water/sodium bicarbonate. (IId) The dehydration step step e) of a compound of formula

(IIf) to yield the intermediate of formula (III) takes place in a basic medium such as, for example, Sodium carbonate, 55 Sodium hydroxide, lithium hydroxide (e.g., lithium hydrox ide monohydrate), etc. in the presence of a solvent such as, for example, tetrahydrofuran, methyl-tetrahydrofuran, acetoni trile, methanol, isopropanol, toluene or water. In a particular embodiment, the reaction is carried out using lithium hydrox 60 ide monohydrate in a medium comprising water. The hydrogenation reaction of the compound of formula (III) to render the intermediate of formula (II) step f), in a particular embodiment, is performed using a Pd/C or Pt/C, preferably Pt/C, as the catalyst in a hydrogen atmosphere, 65 and preferably at an overpressure, e.g., an overpressure of 0.1 bar d4) Subjecting the compound of formula (IId) to an elimi (10 Pa), in the presence of ethyl acetate. nation reaction to render Drospirenone (I). US 8,524,693 B2 29 30 In a particular embodiment, in the compound of formula Such as pyridinium fluoride, potassium fluoride, ammonium (III), R is C-C alkyl. In another particular embodiment, Ris fluoride, etc., can be used for its elimination. linear or branched C-C alkyl, preferably C-C alkyl, more The oxidation reaction d3) providing the compound of preferably ethyl. formula (IId) can in turn be carried out by means of any In another particular embodiment, in the compound of 5 oxidation reaction which allows transforming a hydroxyl formula (III), R' is hydrogen. In another particular embodi group into a carbonyl group, following for example the pro ment, in the compound of formula (III), R' represents a hydroxyl-protecting group Such as, for example, a silyl group, cesses described in U.S. Pat. No. 4,416,985, U.S. Pat. No. particularly a tert-butyldimethylsilyl group or a trimethylsilyl 6,121.465, EP 1571153 and EP 1828222, by means of using 10 reagents such as TEMPO, calcium hypochlorite or trichlor group; an ether or an ester. In a particular embodiment, in the oisocyanuric acid. compound of formula (III), R is selected from hydrogen and a silylated hydroxyl-protecting group, preferably hydrogen, In a particular embodiment, the transformation of the com trimethylsilyl or tert-butyldimethylsilyl. pound of formula (VII) into the corresponding ketone of In another particular embodiment, R is linear or branched formula (IId) is performed through the use of trichloro-iso C-Cs alkyl and R' is selected from hydrogen and a silylated 15 cyanuric acid in the presence of 2.2.6,6-tetramethyl-piperi hydroxyl-protecting group. Preferably, R is C-C alkyl and dine-1-oxide (TEMPO) in a two-phase system formed by a R" is selected from hydrogen, trimethylsilyl and tert-bu dichloromethane/tetrahydrofuranand water/sodium or potas tyldimethylsilyl. sium bicarbonate mixture at room temperature. Particular embodiments of the invention include the use of The compounds of formula (IId) obtained can be used compounds of formula (III) in which: directly or can be purified by means of conventional and R is ethyl and R' is hydrogen; or industrially acceptable processes such as for example by R is ethyl and R' is tert-butyldimethylsilyl; or means of a crystallization process. Illustrative non-limiting R is ethyl and R' is trimethylsilyl. examples of suitable solvents for said crystallization include In a particular embodiment, the hydrogenation reaction d1) 25 dichloromethane, heptane, toluene, methyl tert-butyl ether or is carried out in the presence of a Pd or Pt catalyst, a Pd/C or mixtures thereof. In a preferred embodiment, said solvent is Pt/C catalyst is preferably used. selected from dichloromethane, toluene and mixtures thereof In a preferred embodiment, the hydrogenation step d1) is with heptane. In a particular embodiment, the compound of performed using Pd/C as a catalyst at atmospheric pressure, formula (IId) can be crystallized in DCM or DCM/heptane. using solvents such as ethanol or ethyl acetate, and preferably 30 Step d4) for transforming the compound of formula (IId) at room temperature. into Drospirenone can be performed by using the conditions The compounds of formula (VI) obtained can be used described in U.S. Pat. No. 6,933,395 and EP 1746101. directly in the following step or alternatively they can be Another aspect of the invention relates to the following isolated or purified by feasible methods from the industrial 35 intermediate compounds in the synthesis of Drospirenone (I): point of view Such as, for example, by means of crystalliza tion or precipitation techniques, using solvents such as ethyl acetate, toluene or mixtures thereof with heptane. According to a particular embodiment, the intermediate of formula (VI) wherein R is an ethyl group and R' is a TBDMS group is 40 purified by means of crystallization in ethyl acetate?heptane. The compounds of formula (VI) wherein R' is hydrogen can be directly transformed into the compound of formula (VII) by treatment in acid medium, in which there is an intramolecular transesterification reaction to yield the corre 45 O sponding lactone. OH To establish the acid conditions, both organic and inorganic COR acids, such as for example para-toluenesulfonic acid or potas HO / sium bisulfate, in catalytic or equimolecular amounts, can be s used, using solvents such as tetrahydrofuran, ethyl acetate, 50 ethanol or dichloromethane, in which the reaction preferably takes place at room temperature. The compound of formula (VII) obtained in d2) can be isolated or purified by means of crystallization or precipita tion techniques, using for example a DMF/water mixture. 55 RO In the event that R' is a protecting group, such as a silyl OH derivative, its prior elimination in step d2) by means of using COR acid media or by means of fluoride salts additionally causes HO /1 the simultaneous formation of the lactone to give rise to w compound of formula (VII). 60 In a particular embodiment, when R' is a silyl protecting group the deprotection step d2) is carried out using fluoride salts, inorganic acids such as hydrochloric acid in ethanol, organic acids such as formic acid in tetrahydrofuran or para toluenesulfonic acid. 65 O Particularly, when the protecting group R is trimethylsilyl OH (TMS) or tert-butyldimethylsilyl (TBDMS), fluoride salts US 8,524,693 B2 31 32

-continued -continued O

or a solvate thereof.

COR The following examples illustrate the invention and should e1 15 not be considered as limitative of the invention.

EXAMPLES Example 1 Synthesis of 6?.7 B.15 B, 16.f3-dimethylene-3B-tert or a solvate thereof, wherein R, R' and Rare those previously 25 butyldimethylsilyloxy-5(3-hydroxy-androstan-17-one defined. (IVb) In a particular embodiment, the intermediate compounds are selected from: 30

COEt,

HO OH (IVa) 40

COEt,

TBDMSO OH

(IVb) 50

67.5 ml (0.48 moles) of triethylamine and 68.5 g (0.45 mol) 55 of tert-butyldimethylsilyl chloride were added to a mixture under stirring, formed by 100 g (0.30 mol) of 6?.7f8:15B, 16.f3 dimethylene-3?.5 B-dihydroxy-androstan-17-one (IVa) and 500 ml of dimethylformamide at room temperature, the resulting mixture was maintained under stirring for 45 min 60 utes. Then, 2000 ml of water were added to the reaction mixture and maintained under stirring for half an hour, the obtained suspension was filtered and washed with another 1000 ml of water. The filtered solid was dried, obtaining 132.9 65 g of 6?.7f8:15 B.16.3-dimethylene-3?-tert-butyldimethylsily loxy-5 B-hydroxy-androstan-17-one (IVb) (yield 98.8%). The product had the following spectroscopic characteristics: US 8,524,693 B2 33 34 'H-NMR (400 MHz, 75° C., DMSO-de 8): 0.05 (3H, s, Example 3 CH. Si), 0.07 (3H, s, CH, Si), 0.40-1.70 (18H, m), 0.79 (3H, s), 0.84 (3H, s), 0.90 (9H, s, CH, C Si), 2.00-2.20 (2H, Addition of ethyl propiolate. Synthesis of 6?.7 B.15B, m), 3.75 (1H, broads), 4.05 (1H, broads). 163-dimethylene-3?-tert-butyldimethylsilyloxy-5B, 'C-NMR (100 MHz, 40° C., DMSO-de 8): -5.2 (CH, 5 17 B-dihydroxy-17C.-(2-ethoxycarbonyl)-ethynyl Si), -5.0 (CH, Si), 10.2, 13.1, 17.1, 17.6, 18.6, 19.8, 21.3, androstane (IIIb) 22.1, 25.3, 25.6 (3xCH C Si), 25.8, 28.1, 33.1, 34.9, 42.2, 44.1, 51.6, 68.5, 72.2, 214.0 (C=O). 10 O

Example 2 Her 15

Synthesis of 6?.7 B.15 B, 16.f3-dimethylene-3B-trim TBDMSO ethylsilyloxy-5B-hydroxy-androstan-17-one (IVc) OH (IVb) 2O COEt HO O e1

He 25

TBDMSO HO OH OH (IIIb) (IVa) 30 O a) By Direct Addition: 37.4 g (1.63 mol) of lithium amide were added to a stirred Solution at room temperature and in an inert atmosphere, 35 formed by 50 g (0.11 mol) of 6?.7f8:15 B, 16 B-dimethylene 3f-tert-butyldimethylsilyloxy-5'-hydroxy-androstan-17 one (IVb) and 1000 ml of toluene, and after another 15 min TMSO utes, 13.7 ml (0.13 mol) of ethyl propiolate were added, the OH reaction mixture was maintained under stirring for another 4 (IVc) 40 hours. Then, 30 ml of water were added and the solvent was distilled under reduced pressure until reaching a final Volume of 250 mL. Then 750ml of ethylacetate and 1000 ml of water were added and the obtained mixture was maintained under stirring for half an hour. The two phases obtained were sepa 6.8 ml (0.048 mol) of triethylamine and 5.7 g (0.045 mol) 45 rated and the aqueous phase was extracted again with 250 ml of trimethylchlorosilane were added to a mixture under stir of ethyl acetate. The organic phases obtained were pooled and washed successively with 1000 and 500 ml of water. Part of ring formed by 10 g (0.03 mol) of 6?.7 B.15 B, 16.f3-dimethyl the solvent was removed under reduced pressure until reach ene-3?.5 B-dihydroxy-androstan-17-one (IVa) and 50 ml of ing a final volume of 150 mL, 500 ml of heptane were added dimethylformamide at room temperature, the resulting mix 50 and part of the solvent was again removed under reduced ture was maintained under stirring for 45 minutes. Then, 200 pressure until a final volume of 150 ml. The obtained suspen ml of water were added to the reaction mixture and main sion was cooled at 5°C., filtered and washed with cold hep tained under stirring for half an hour, the obtained Suspension tane. The obtained solid was dried and 51.7 g of 6?.7f8:15 B. was filtered and washed with another 100 ml of water. The 163-dimethylene-3?-tert-butyldimethylsilyloxy-5 B.17 B 55 dihydroxy-17 B-(2-ethoxycarbonyl)-ethynyl-androstane filtered solid was dried, obtaining 12.0 g of 6?.7f8:15 B, 16.f3 (IIIb) were obtained in the form of toluene hemisolvate (yield dimethylene-3?-trimethylsilyloxy-5B-hydroxy-androstan 78.1%). 17-one (IVc) (yield 98.5%). The product had the following It was possible to obtain the desolvated product by dissolv spectroscopic characteristics: ing the previously obtained hemisolvate in ethyl acetate and 60 evaporating the solvent to dryness. The solid thus obtained 'H-NMR (400MHz, DMSO-d 8): 0.10 (9H, s, CH, Si), was dried in an oven to provide the solvent-free form. The 0.40-1.00 (3H, m), 0.78 (3H, S (CH), 0.82 (3H, S (CH), obtained product had the following spectroscopic properties: 1.00-1.80 (15H, m), 1.90-2.20 (3H, m), 3.85 (1H, broads), Toluenehemisolvate: 'H-NMR (400MHz, 40°C., DMSO 3.97 (1H, broads). de 8): 0.02 (3H, s, CH, Si), 0.04 (3H, s, CH, Si), 0.20 'C-NMR (100 MHz, DMSO-d, 8): 0.1 (3xCH, Si), 65 0.30 (1H, m), 0.35-0.45 (1H, m), 0.50-0.80 (3H, m), 0.74 (6H, 13.3, 17.1, 18.3, 19.7, 21.5, 22.2, 25.3, 33.2, 35.0, 42.1, 44.9, s, CH, 18+CH19), 0.84 (9H, s, 3xCH C Si), 0.95-1.15 51.8, 68.2, 71.9, 215.0 (C=O). (6H, m), 1.20 (3H, t, J=8.0 HZ, CH Et), 1.25-1.70 (8H, m), US 8,524,693 B2 35 36 1.75-1.85 (1H, m), 2.00-2.10 (1H, m), 3.87 (1H, s, OH), 4.01 ethyl acetate were added. The two phases obtained were (1H, m, H3), 4.15 (2H, q, J=8.0 HZ, CH, Et), 5.95 (1H, s, OH). separated. The solvent was removed under reduced pressure. Desolvated product: 'H-NMR (400 MHz, 40°C., DMSO The residue was purified by column chromatography to yield de 8): 0.02 (3H, s, CH, Si), 0.04 (3H, s, CH, Si), 0.20 0.77 g of 6?.7 B.15B, 16? 3-dimethylene-3?-tert-butyldimeth 0.30 (1H, m), 0.35-0.45 (1H, m), 0.50-0.80 (3H, m), 0.74 (6H, ylsilyloxy-5?,17f8-dihydroxy-17? 3-(2-ethoxy-carbonyl)- s, CH3 18+CH3 19), 0.84 (9H, s, 3xCH3-C Si), 0.95-1.15 ethynyl-androstane (IIIb) were obtained (yield 76.9%). (6H, m), 1.20 (3H, t, J=8.0 Hz, CH3 Et), 1.25-1.70 (8H, m), 1.75-1.85 (1H, m), 2.00-2.10 (1H, m), 3.87 (1H, s, OH), 4.01 (1H, m, H3), 4.15 (2H, q, J=8.0 HZ, CH2 Et), 5.95 (1H, s, OH). 10 'C-NMR (100 MHz, 40° C., DMSO-de 8): -5.2 (CH Example 4 Si), -4.9 (CH, Si), 8.8, 10.8, 11.2, 13.9, 14.2, 16.6, 17.6, 18.7, 19.7, 22.1, 22.6, 25.6 (3xCH C Si), 26.4, 28.2, Synthesis of 6 B,7B:15 B, 16B-dimethylene-3,3,5 B 17 B 29.0, 33.6, 34.1, 38.5, 42.5, 44.3, 53.3, 61.8, 68.6, 72.1, 76.8, trihydroxy-17C.-(2-ethoxycarbonyl)-ethynyl-andros 78.3 (C=), 91.4 (C=), 153.1 (C=O). 15 tane (IIIc) b) By Reverse Addition: 0.5 g (0.001 mol) of 6 B,7B:15 B, 16 B-dimethylene-3 B-tert butyldimethylsilyloxy-5(3-hydroxy-androstan-17-one (IVb) were added to a stirred solution at room temperature and in an inert atmosphere, formed by 0.37 g (0.016 mol) of lithium amide and 0.14 ml (0.0013 mol) of ethyl propiolate in 10 ml of toluene, and was maintained under stirring at the same temperature for 4 hours. The processing of the reaction was performed according to what is described in the previous example in which direct addition is used, to give rise to 0.5g 25 of 6?.7f8:15 B.16.3-dimethylene-3?-tert-butyldimethylsily HO loxy-5 B.17 B-dihydroxy-17? 3-(2-ethoxycarbonyl)-ethynyl OH (IVa) androstane (IIIb) in the form of toluene hemisolvate. Example 3a 30 Synthesis of 6.B.7B:15 B, 16 B-dimethylene-3,3-tert butyldimethylsilyloxy-5(3,17f8-dihydroxy-17C-(2- ethoxycarbonyl)-ethynyl-androstane (IIIb) 35

(IIIc) 40

0.1 g (0.006 mol) of lithium amide were added to a stirred TBDMSO 45 OH Solution at room temperature and in an inert atmosphere, formed by 0.1 g (0.003 mol) of 6 B,7B:15 B,16,8-dimethylene (IVb) 3f3,53-dihydroxy-androstan-17-one (IVa) and 2 ml of tolu ene. After 15 minutes, 0.06 ml (0.0013 mol) of ethyl propi olate were added and the reaction mixture was maintained 50 under stirring for 4 hours. Once the reaction had ended, 0.1 ml of water were added and the solvent was distilled under reduced pressure. The residue was purified by column chro matography to yield 0.05 g of 6?.7f8:15 B, 16.f3-dimethylene TBDMSO 55 3f3,5B,17f8-trihydroxy-17C.-(2-ethoxy-carbonyl)-ethynyl-an HO drostane (IIIc) (45% molar yield). The product had the (IIIb) following spectroscopic properties: 'H-NMR (400 MHz, DMSO-de 8): 0.20-0.30 (1H, m), A solution was formed by 1.0 g (22 mmol) of 6?.7 B.15B, 60 0.35-0.45 (1H, m), 0.74 (6H, s, CH, 18+CH19), 1.21 (3H, t, 16.f3-dimethylene-3?, tertbutyldimethylsilyloxy-5'-hy J=8.0 Hz, CH3 Et), 0.55-1.75 (17H, m), 1.75-1.85 (1H, m), droxy-androstan-17-one (IVb) in 10 ml oftoluene is cooled at 2.00-2.10 (1H, m), 3.81 (1H, broads, H3), 4.16 (2H, q, J-8.0 a temperature between 0 and 5° C. and 0.46 ml of ethyl HZ, CH, Et), 4.30 (1H, broads, OH), 4.78 (1H, broads, OH), propiolate were added, the reaction mixture was maintained 5.93 (1H, broads, OH). under stirring. Then, 4.5 ml (44 mmol) of HMDSLi 1M in 65 'C-NMR (100 MHz, DMSO-de 8): 8.8, 10.9, 13.9, 14.3, THF were added to the stirred solution. Once the reaction had 16.6, 18.1, 18.8, 22.0, 26.4, 28.0, 34.1, 38.5, 42.5, 43.8, 53.0, ended (approximately 30 minutes), 5 ml of water and 20 ml of 61.9, 66.0, 72.5, 76.8, 78.3 (C=), 91.4 (C=), 153.1 (C=O). US 8,524,693 B2 37 38 Example 5 Example 6

Synthesis of 6 B.7B:15 B,16B-dimethylene-3,3,5 B 17 B Synthesis of 6 B,7B:15 B, 16B-dimethylene-3,3,5 B 17 B trihydroxy-17C.-(2-ethoxycarbonyl)-ethynyl-andros trihydroxy-17C.-(2-ethoxycarbonyl)-ethynyl-andros tane (IIIc) tane (IIIc) by the deprotection of (IIIb)

O 10

He 15

TMSO OH (IVc) COEt HO e21 (IIIb)

Hip 25

TMSO OH (III) 30 COEt HO e21 (IIIc) 35

HO OH 40 70 ml of a 1 M solution in THF (0.07 mol) of tetrabuty (IIIc) lammonium fluoride were added to a solution formed by 37.5 g (0.064 mol) of 6?.7f8:153,16 B-dimethylene-3?-tert-bu tyldimethylsilyloxy-5 B.173-dihydroxy-17C.-(2-ethoxycar bonyl)-ethynyl-androstane (IIIb) in the form of toluene hemi 45 solvate and 375 ml of THF. The reaction mixture was 0.75 g (0.03 moles) of lithium amide were added to a stirred maintained under stirring at room temperature for one hour Solution at room temperature and in an inert atmosphere, and 375 ml of water were subsequently added, the organic formed by 1 g (0.002 moles) of 6?.7f8:15 B, 16 B-dimethylene solvent was removed by distillation under reduced pressure, 3f6-trimethylsilyloxy-5 B-hydroxy-androstan-17-one (IVc) 50 375 ml of methylene chloride were added and the two phases and 20 ml of toluene and after another 15 minutes, 0.27 ml obtained were separated. The organic phase was washed with (0.003 moles) of ethyl propiolate were added, the reaction 375 ml of water and distilled exchanging the solvent by mixture was maintained under stirring for another 4 hours. addition of heptane. The obtained Suspension was maintained Once the reaction had ended, 0.1 ml of water were added and 55 under stirring at room temperature and the solid was finally the solvent was distilled under reduced pressure. The residue isolated by filtration and washing with more heptane. The was redissolved in tetrahydrofuran (10 ml) and 2 ml of a 1 M product was dried in an oven to obtain 27.14 g of 6?.7f8:15 B. solution in THF (0.002 moles) of tetrabutylammonium fluo 163-dimethylene-3?.5 B, 17 B-trihydroxy-17C.-(2-ethoxy-car ride were added. The reaction mixture was maintained under bonyl)-ethynyl-androstane (IIIc) (yield 99.4%). The product stirring at room temperature for one hour and 10 ml of water 60 had the following spectroscopic properties: were Subsequently added, the organic solvent was removed 'H-NMR (400 MHz, DMSO-d 8): 0.20-0.30 (1H, m), by distillation under reduced pressure and the resulting prod 0.35-0.45 (1H, m), 0.74 (6H, s, CH, 18+CH19), 1.21 (3H, t, uct was purified by silica gel column chromatography to J=8.0 Hz, CH3 Et), 0.55-1.75 (17H, m), 1.75-1.85 (1H, m), provide 0.74 g of 6?.7f8:153,16 B-dimethylene-3?.53.17 B-tri 65 2.00-2.10 (1H, m), 3.81 (1H, broads, H3), 4.16 (2H, q, J-8.0 hydroxy-17C.-(2-ethoxycarbonyl)-ethynyl-androstane (IIIc) HZ, CH2 Et), 4.30 (1H, broads, OH), 4.78 (1H, broads, OH), (70% molar yield). 5.93 (1H, broads, OH). US 8,524,693 B2 39 40 Example 7 Example 8

Synthesis of 6 B.7B:15|B,16 B-dimethylene-5(B 17 B Synthesis of 6?.7 B:15 B.16.3-dimethylene-17f8-dihy dihydroxy-17C-(2-ethoxycarbonyl)-ethynyl-an droxy-17C.-(2-ethoxycarbonyl)-ethynyl-androst-4- drostan-3-one (IIf) en-3-one (IIg)

HO OH OH (IIIc) (IIIc)

30 (IIf) (Ig) A solution formed by 37.5g of sodium bicarbonate in 375 ml of water was added to a solution at room temperature and 3.9 g (0.02 mol) of p-toluenesulfonic acid were added to a under stirring formed by 25 g (0.058 mol) of 6?.7 B.15B, 16? 35 solution at room temperature formed by 17.5 g (0.041 mol) of dimethylene-3?.5.3.17 B-trihydroxy-17C.-(2-ethoxycarbo 6.f3,7B...15?.16? 3-dimethylene-5(3,17f8-dihydroxy-17C.-(2- nyl)-ethynyl-androstane (IIIc), 425 ml of methylene chloride ethoxy-carbonyl)-ethynyl-androstan-3-one (IIf) in 175 ml of and 100 ml of THF. Then, 0.55 g (0.0035 mol) of 2.2.6,6- tetrahydrofuran. The obtained mixture was maintained under tetramethyl-piperidine-N-oxide (TEMPO) and 17.4 g (0.075 stirring for 2 hours and was then neutralized with 2.8 ml (0.02 mol) of trichloroisocyanuric acid (TCCA) were added in 40 mol) of triethylamine. The solvent was removed by distilla portions to the two-phase mixture. The reaction mixture was tion under reduced pressure and 175 ml of toluene and 175 ml maintained under stirring for 1 hour and the phases were of water were added to the residue formed. The two phases separated, the aqueous phase was extracted once more with obtained were separated and the organic phase was distilled 50 ml of methylene chloride and the pooled organic phases until reaching a final volume of 105 ml, 175 ml of heptane were washed with an aqueous solution of 375 ml of sodium 45 metabisulfite at 7% and with 375 ml of water. The solvent was were then added. The solvent was distilled until a final vol removed by distillation under reduced pressure until reaching ume of 105 ml and the product was precipitated by adding a final volume of 75 ml, 125 ml of heptane were added and the heptane. It was maintained under stirring at room temperature mixture of solvents was distilled again until a final volume of for one hour, filtered and washed with heptane. The product 75 ml. The obtained suspension was filtered and washed with 50 was dried in an oven and 18.2 g of 6?.7 B.15B, 16.f3-dimethyl heptane. 21.8g of 6f,7B...15?.16(3-dimethylene-5(3,17f8-dihy ene-17f8-dihydroxy-17C.-(2-ethoxy-carbonyl)-ethynyl-an droxy-17C.-(2-ethoxycarbonyl)-ethynyl-androstan-3-one drost-4-en-3-one (IIg) were obtained in the form of toluene (IIf) were obtained (yield 86.6%). The obtained product was solvate (yield 75.4%). The isolated product has the following also recrystallized using toluene. The product had the follow spectroscopic properties: ing spectroscopic properties: 55 Toluene solvate: 'H-NMR (400 MHz, DMSO-de 8): 0.30 'H-NMR (400 MHz, DMSO-de 8): 0.25-0.35 (1H, m), 0.40 (1H, m), 0.81 (3H, s, CH, 18), 0.75-0.85 (2H, m), 0.90 0.40-0.55 (1H, m), 0.60-0.85 (3H, m), 0.77 (3H, s, CH,). 0.78 1.05 (2H, m), 1.00 (3H, s, CH 19), 1.05-1.15 (3H, m), 1.20 (3H, s, CH), 0.95-1.20 (3H, m), 1.21 (3H, t, J=8.0 HZ, CH (3H, t, J=8.0 Hz, CH, Et), 1.40-1.70 (7H, m), 1.70-1.80 (1H, Et), 1.30-1.70 (8H, m), 1.90-2.05 (2H, m), 2.10-2.25 (2H, m), m), 1.90-1.95 (1H, m), 2.10-2.25 (1H, m), 2.27 (3H, s, CH 3.01 (1H, d. J=8.0 Hz, H.), 4.15 (2H, q, J=8.0 HZ, CH, Et), 60 4.52 (1H, broads, OH), 5.96 (1H, broads, OH). Tol), 2.40-2.55 (1H, m), 4.15 (2H, q, J–8.0 HZ, CH, Et), 5.87 'C-NMR (100 MHz, DMSO-de 8): 8.8 (CH), 12.0 (1H, s, H4), 6.00 (1H, broads, OH), 7.10-7.25 (5H, HAr, Tol). (CH), 13.8 (CH), 15.6 (CH), 16.5 (CH), 17.5 (CH), 18.0 'C-NMR (75 MHz, DMSO-d 8): 9.5 (CH), 14.5 (CH), (CH), 21.6 (CH), 24.1 (CH), 26.4 (CH), 33.9 (CH), 34.0 16.2 (CH), 16.9 (CH), 17.8 (CH), 18.6 (CH), 19.1 (CH), (CH), 36.1 (CH), 38.2 (CH), 39.6 (CH), 42.6 (C), 45.4 65 20.1 (CH), 21.4 (CH), 21.7 (CH), 27.0 (CH), 34.3 (CH), (CH), 52.5 (C), 53.8 (CH), 61.8 (CH), 75.0 (C), 76.8 (C), 34.7 (CH), 37.1 (CH), 37.6 (CH), 38.7 (C), 43.0 (C), 52.0 78.3 (=C), 91.4 (=C), 153.1 (COO), 210.2 (C=O, C3) (CH), 53.0 (CH), 62.5 (CH), 77.5 (=C), 78.9 (=C), 91.7 (C US 8,524,693 B2 41 42 17), 125.6 (C4), 125.9 (CH Ar, Tol), 128.8 (2xCH Ar, Tol), Example 8b 128.5 (2xCH Ar, Tol), 138.0 (C Ar, Tol), 153.7 (C5), 171.9 (COO), 1970 (C3). Synthesis of 6?.7 B:15 B.16.3-dimethylene-17f8-dihy The product can be obtained in desolvated form. To that 5 droxy-17C-(2-carbonyl)-ethynyl-androst-4-en-3-one end, the solvate was stirred in ethyl acetate for 1 hour, filtered (IIi) and washed with ethyl acetate.

10 Example 8a

Synthesis of 6?.7 B.15B, 16.f3-dimethylene-17f8-dihy droxy-17C.-(2-ethoxycarbonyl)-ethynyl-androst-4- 15 en-3-one (IIg)

(IIf)

30 (IIf) (III)

35 A suspension was formed by 10.0 g (0.024 mol) of 63.7 B; 15B, 16.f3-dimethylene-5B, 17(3-dihydroxy-17C.-(2-ethoxy carbonyl)-ethynyl-androstan-3-one (IIf) in 60 ml of water at 40 room temperature. 2.0 g (0.048 mol) of lithium hydroxide (Ig) monohydrate was added to the Suspension under stirring. The obtained mixture was maintained under stirring for 15 hours and was then adjusted to pH1 with a solution of hydro 45 chloric acid 1M, 60 ml of ethyl acetate was added. The two phases obtained were separated. The organic phases were A solution was formed by 10.0 g (0.024 mol) of 6?.7 B.15B, distilled and 60 ml of toluene were added. The toluene phase 16.f3-dimethylene-5B.173-dihydroxy-17O-(2-ethoxy-carbo was distilled up to 30 ml. The suspension was cooled to 0°C., nyl)-ethynyl-androstan-3-one (IIf) in 60 ml of methanol at maintained under stirring, filtered and washed with toluene. room temperature. The solution was cooled to 0/5° C. and 4.5 50 The product (III) was obtained in the form of toluene g (0.043 mol) of sodium carbonate was added to the solution solvate (yield 96%). under stirring. H-NMR (400 MHz), 8: 0.32 (1H, q, J=8.0 Hz), 0.80 (3H, The obtained mixture was maintained under stirring for 2 s, H18), 0.75-0.85 (2H, m), 1.00 (3H, s, H19). 0.90-1.05 (2H, hours and was then adjusted to pH 7 with a solution of hydro 55 m), 1.05-1.25 (2H, m), 1.40-1.70 (1H, m), 1.70-1.80 (1H, m), chloric acid 1M. The solvent was removed by distillation 1.94 (1H, dd, J-2.0, 8.0 Hz), 2.15 (1H, d, J=16.0 Hz, H2), under reduced pressure and 50 ml of dichloromethane was 2.40-2.60 (1H, m, H2), 5.87 (1H, s, H4), 5.92 (1H, broads, added. OH), 13.5 (1H, broads, COOH). Toluene peaks: 2.26 (3H, m, The two phases obtained were separated and the aqueous 3H), 7.05-7.25 (5H, m, H–Ar). phase was then adjusted to pH3 with a solution of hydrochlo 60 'C-NMR (100 MHz), 8:8.9 (CH), 16.2 (CH), 17.1 (CH3 ric acid 1M and was extracted twice with dichloromethane. C18), 18.0 (CH3 C19), 18.5 (CH2), 18.6 (CH), 19.6 (CH2), The organic phases were distilled and 50 ml of toluene 20.7 (CH), 26.4(CH), 33.7 (CH2), 34.1 (CH), 36.5 (C, C18), were added. The suspension was cooled to 0°C., maintained 37.0 (CH2), 38.0 (CH2, C2), 42.3 (C, C19), 51.3 (CH), 52.2 under stirring, filtered and washed with toluene. 65 (CH), 78.0 (=C), 78.1 (=C), 89.8 (C, C17), 124.9 (CH, C4), The product (IIg) was obtained in the form of toluene 154.4 (C, C5), 171.3 (C, COOH), 196.4 (C, C3). solvate (yield 54%). MS (m/z): 381 (M+1, 100%). US 8,524,693 B2 43 44 Example 9 Example 9a Synthesis of 6?.7 B:15 B.16.3-dimethylene-3-oxo 17C.-pregn-4-ene-21, 17-carbolactone (Drospirenone Synthesis of 6?.7 B:15 B, 16.f3-dimethylene-3-oxo (I)) 17C-pregn-4-ene-21, 17-carbolactone (Drospirenone (I))

OH OH (Ig) (III)

(IIh) 30 (II)

(I) (I) 0.45g of 5% Pt/C (50% moisture) were added to a solution 45 formed by 9 g (0.018 mol) of 6?.7f8:15 B, 16 B-dimethylene 17 B-dihydroxy-17C.-(2-ethoxycarbonyl)-ethynyl-androst-4- 0.5g of 5% Pt/C (50% moisture) were added to a solution en-3-one (IIg) and 180 ml of ethyl acetate. The system was formed by 5 g (0.01 mol) of 6?.7f8:153,16 B-dimethylene first purged with nitrogen and then with hydrogen and stirred 17 B-dihydroxy-17C.-(2-carbonyl)-ethynyl-androst-4-en-3- under a hydrogen atmosphere at an overpressure of 0.1 bar for 50 one (III) and 100 ml of ethyl acetate. The system was first 75 minutes. The catalyst was eliminated by filtration and purged 10 minutes with nitrogen and then with hydrogen and washed with 180 ml of ethyl acetate. 0.9 g (0.0036 mol) of stirred under a hydrogen atmosphere at an overpressure of p-toluenesulfonic acid were added to the filtered solution of 0.15 bar for 4 hours. The catalyst was eliminated by filtration 6.f3,7B...15?.16? 3-dimethylene-17f8-dihydroxy-17C.-(2- and washed with 100 ml of ethyl acetate. 0.05 g (0.0002 mol) ethoxycarbonyl)-ethyl-androst-4-en-3-one (IIh) and main 55 tained under stirring at room temperature for 1 hour. It was of p-toluenesulfonic acid were added to the filtered solution neutralized by adding 0.63 ml (0.0036 mol) of triethylamine of 6?.7 B:15 B, 16.f3-dimethylene-17f8-dihydroxy-17C.-(2-car and 30 ml of water were then added, two phases were bonyl)-ethyl-androst-4-en-3-one (II) and maintained under obtained which were then decanted. The solvent was elimi stirring at room temperature for 1 hour. It was neutralized by nated under reduced pressure and was changed for isopropyl 60 adding 0.05 ml (0.0003 mol) of triethylamine and 15 ml of acetate until a final volume of 45 ml. It was cooled to 0/5°C., water were then added; two phases were obtained which were filtered and washed with isopropyl acetate. 4.5 g of 6?.7f8: then decanted. The solvent was eliminated under reduced 15 B, 16.f3-dimethylene-3-oxo-17f8-pregn-4-ene-21, 17-carbo pressure and was changed for isopropyl alcohol. It was cooled lactone (drospirenone) (I) were obtained. The product thus to a temperature between 0°C. and 5°C., filtered and washed obtained had a purity greater than 99%. It was possible to 65 with isopropyl alcohol. 3.0 g of 6?.7f8:15 B, 16.f3-dimethylene increase the purity of the obtained product by recrystalliza 3-oxo-17C.-pregn-4-ene-21, 17-carbo-lactone (Drospirenone tions in isopropyl acetate. (I)) were obtained. US 8,524,693 B2 45 Example 10

Synthesis of 6?.7 B:15 B.16.3-dimethylene-3-oxo 17o-pregn-4,20-diene-21, 17-carbolactone (20A drospirenone (IIb)) a) Starting from 6 B.7 B:15 B.16.f3-dimethylene-5B.17 B-di hydroxy-17C.-(2-ethoxycarbonyl)-ethynyl-androstan-3-one (IIf).

(Ig)

(IIf)

(IIb)

0.1 g of 5% Pd/C (50% moisture) were added to a solution formed by 1 g of 6?.7 B:15 B.16.3-dimethylene-17? 3-hydroxy 17C.-(2-ethoxycarbonyl)-ethynyl-androst-4-en-3-one (IIg) in the form of toluene solvate and 20 ml of ethyl acetate. The system was first purged with nitrogen and then with hydrogen (IIb) and stirred under a hydrogen atmosphere at an overpressure of 0.1 bar for 1 hour. The catalyst was filtered and washed with ethyl acetate. The solvent was evaporated to dryness to 0.1 g of 5% Pd/C (50% moisture) were added to a solution 40 formed by 1 g of 6?.73:15 B, 16.f3-dimethylene-5(3,17(3-dihy provide 0.65 g of 6?.7f8:153,16,8-dimethylene-3-oxo-17C.- droxy-17C.-(2-ethoxycarbonyl)-ethynyl-androstan-3-one pregn-4.20-diene-21, 17-carbolactone (20A-drospirenone (IIf) and 20 ml of ethyl acetate. The system was first purged (IIb)) (Yield: 89%). with nitrogen and then with hydrogen and was maintained under stirring under a hydrogen atmosphere at an overpres 45 Example 11 sure of 0.1 bar for 1 hour. The catalyst was filtered and washed with ethyl acetate. The solvent was evaporated to dryness and the resulting residue was redissolved in 3 ml of dimethylfor Synthesis of drospirenone (I) from 20A-drospirenone mamide, the product was then precipitated by adding 10 ml of (IIb) water. The obtained suspension was filtered and washed with 50 water to obtain 0.6 g of 6?.7f8:15?,1613-dimethylene-3-oxo 17C.-pregn-4,20-diene-21, 17-carbolactone (20B-dro spirenone) (IIb) (yield: 70%). The isolated product had the following spectroscopic properties: 'H-NMR (400 MHz, DMSO-de 8): 0.45-0.60 (1H, m), 0.70-1.00 (3H, m), 0.91 (3H, s, CH), 1.01 (3H, s, CH), 1.00-1.30 (6H, m), 1.30-1.80 (5H, m), 2.10-2.20 (1H, m), 2.30-2.35 (1H, m), 5.90 (1H, s, H4), 6.12 (1H, d, J=8.0 Hz), 7.93 (1H, d, J=8.0 Hz). 'C-NMR (100 MHz, DMSO-de 8): 9.0, 16.4, 17.0, 18.4, 18.5, 19.3, 20.1, 20.6, 20.8, 33.6, 36.6, 36.9, 41.1, 51.2, 98.1, 118.2, 125.0, 159.8, 171.1, 1722, 1964. b) Starting from 6,3,7B...15 B.16.f3-dimethylene-17? 3-hy 65 droxy-17C.-(2-ethoxycarbonyl)-ethynyl-androst-4-en-3-one (IIb) (Ig). US 8,524,693 B2 47 48 -continued butyldimethylsilyloxy-5(3,17f8-dihydroxy-17C-(2-ethoxy carbonyl)-ethyl-androstane (VIb) were thus obtained (yield 90%). The isolated product had the following spectroscopic properties: 'H-NMR (400MHz, DMSO-d 8): 0.02(3H, s, CH, Si), 0.04 (3H, s, CH, Si), 0.35-0.45 (1H, m), 0.55-0.65 (1H, m), 0.74 (6H, s, 2xCH), 0.87 (9H, s, CH, C Si), 0.70-0.90 (4H, m), 1.16 (3H, t, J=8.0 Hz, CH, Et), 1.00-1.80 (18H, m), 2.05-2.15 (1H, m), 3.84 (1H, broads, OH), 4.02 (2H, q, J-8.0 10 HZ, CH, Et), 4.28 (1H, broads, OH). 'C-NMR (100 MHz, DMSO-d 8):-5.3 (CH, Si), -5.0 (CH, Si), 7.9, 14.1, 14.3, 15.8, 17.6, 18.7, 19.3, 22.0, 25.6, (I) 27.9, 29.1, 32.2, 34.1, 36.4, 42.2, 44.0, 52.6, 59.6, 68.6, 72.3, 15 80.2, 173.8. 0.1 g of 5% Pt/C (50% moisture) were added to a solution Example 13 formed by 1 g (0.003 mol) of 20A-drospirenone (IIb) in 20 ml of ethyl acetate. The system was first purged with nitrogen Synthesis of 6?.7 B.15 B, 16.f3-dimethylene-3B5B and then with hydrogen and stirred under a hydrogen atmo dihydroxy-17C.-pregnano-21, 17-carbolactone (VII) sphere at an overpressure of 0.1 bar for 1 hour. The catalyst was filtered and washed with ethyl acetate. The solvent was evaporated to dryness to provide 0.9 g of Drospirenone (I) (yield 90%). COEt 25 HO ? Example 12 Synthesis of 6?.7 B:15 B, 16.f3-dimethylene-3B-tert butyldimethylsilyloxy-5(3,17f8-dihydroxy-17C-(2- ethoxycarbonyl)-ethyl-androstane (VIb) 30 TBDMSO OH

(VIb)

TBDMSO OH

(IIIb) COEt 45 HO ? (VII)

22 ml (0.022 mol) of a 1 M solution of tetrabutylammo 50 nium fluoride in THF were added to a solution at room tem perature formed by 11 g (0.02 mol) of 6?.7 B:15 B.16.f3-dim TBDMSO ethylene-3?-tert-butyldimethylsilyloxy-5?,17f8-dihydroxy OH 17O-(2-ethoxycarbonyl)-ethyl-androstane (VIb) and 220 ml 55 of THF, the reaction mixture was maintained under stirring (VIb) for at least 1 hour. Once the reaction had ended, 220 ml of water were added and the organic solvent was removed by 1.5g of 5% Pd/C (50% moisture) were added to a solution distillation under reduced pressure, 220 ml of methylene formed by 15 g (0.026 mol) of 6?.7f8:15 B, 16 B-dimethylene chloride were then added and the two phases formed were 3f-tert-butyldimethylsilyloxy-5?,17(3-dihydroxy-17? 3-(2- 60 separated by decantation. The organic phase was distilled to a ethoxycarbonyl)-ethynyl-androstane (IIIb) in the form of residue giving rise to 7.6 g of 6?.7f8:15 B, 16.f3-dimethylene toluene hemisolvate and 150 ml of ethyl acetate. The system 3f3,53-dihydroxy-17C.-pregnano-21, 17-carbolactone (VII) was first purged with nitrogen and then with hydrogen and (yield 87.5%). The isolated product had the following spec stirred under a hydrogen atmosphere at an overpressure of 0.1 troscopic properties: bar for 1 hour. The catalyst was filtered, the solid was washed 65 'H-NMR (400 MHz, DMSO-de 8): 0.25-0.50 (2H, m), with ethyl acetate and the solvent was evaporated until reach 0.55-0.70 (2H, m), 0.75 (3H, s, CH,). 0.77 (3H, s, CH), ing a residue. 12.4 g of 6?.7f8:15 B, 16 B-dimethylene-3?-tert 0.80-1.50 (10H, m), 1.50-1.75 (4H, m), 1.75-1.80 (1H, m), US 8,524,693 B2 49 50 1.95-2.05 (2H, m), 2.25-2.60 (4H, m), 3.81 (1H, broads), Example 15 4.33 (1H, broads), 4.80 (1H, broads). 'C-NMR (100 MHz, DMSO-de 8): 9.9, 10.9, 14.1, 16.5, 18.7, 19.6, 21.7, 23.7, 27.8, 28.9, 30.0, 33.6, 36.6, 39.8, 41.2, Synthesis of drospirenone (I) from 6,3,7f8:15B,16? 44.0, 45.1, 51.4, 65.9, 72.6, 95.8, 176.4. 5 dimethylene-3-oxo-5B-hydroxy-17C-pregnano-21, 17-carbolactone (IId) Example 14 Synthesis of 6?.7 B:15 B.16.3-dimethylene-3-oxo-5B hydroxy-17C.-pregnano-21, 17-carbolactone (IId) 10 O

O O

15 -- O

-e- O 2O OH (IId) HO O OH

(VII) 25 O O

O 30

35 (I) O OH

(IId) 40 Drospirenone (I) was obtained by eliminating the hydroxyl A solution of 10g of sodium bicarbonate in 100 ml of water group in position 5 using the conditions already described for was added to a solution formed by 7 g (0.016 mol) of 6B,7B; SEASE example in U.S. Pat. No. 6,933,395 column 6. 17-carbolactone (VII), 120 ml of methylene chloride and 28 ml of tetrahydrofuran, and was maintained under stirring enough so that the two phases were mixed at room tempera 45 ture while 0.15 g (0.00096 mol) of 2.2.6,6-tetramethyl-pip eridine-N-oxide (TEMPO) and 4.84 g (0.021 mol) of trichlor- Example 16 oisocyanuric acid (TCCA) were added in portions. The reaction mixture was maintained under stirring for at least another hour, the phases were decanted and the organic phase 50 Synthesis of drospirenone (I) from 6B,7B...15B.16B was washed successively with a 7% aqueous solution of 100 dimethylene-5(3,17 B-dihydroxy-17C.-(2-ethoxycarbo ml of sodium metabisulfite and 100 ml of water. The obtained nyl)-ethynyl-androstan-3-one (IIf) organic phase was distilled under reduced pressure until a final volume of 20 ml, 70 ml of heptane were then added, where a suspension was formed which was filtered, the obtained solid was washed with heptane and dried to obtain 5.6 g of 6?.7 B.15B, 16.f3-dimethylene-3-oxo-5B-hydroxy 17C.-pregnano-21, 17-carbolactone (IId) (yield, 80%). The isolated product had the following spectroscopic properties: 'H-NMR (400 MHz, DMSO-de 8): 0.35-0.45 (1H, m), 0.45-0.60(1H, m), 0.60-0.75 (2H, m), 0.78 (3H, s, CH,). 0.81 (3H, s, CH), 1.00-1.20(3H, m), 1.25-1.75 (8H, m), 1.90-2.10 (3H, m), 2.10-2.20 (2H, m), 2.30-2.50 (3H, m), 2.50-2.60 (1H, m), 2.97 (1H, d, J=8.0 Hz H), 4.50 (1H, broads, OH). 'C-NMR (100 MHz, DMSO-de, 8): 10.2, 12.7, 15.8, 17.0, 18.1, 20.3, 22.0, 24.4, 24.9, 29.5, 30.7, 34.2, 34.4, 36.8, 37.1, (IIf) 41.9, 45.8, 51.6, 54.4, 75.8, 96.4, 177.0, 210.7. US 8,524,693 B2 51 52 -continued wherein COEt R is C-C alkyl, C-C cycloalkyl, aryl or benzyl; and HO ? R" is hydrogen or a hydroxyl-protecting group; 5 or a solvate thereof. 2. The compound according to claim 1, selected from: a compound of formula (III) wherein R is hydrogen or a silylated hydroxyl-protecting group selected from tri - 10 ethylsilyl and tert-butyldimethylsilyl, a compound of formula (III) wherein R is linear O

(IIe) branched C-C alkyl, and a compound of formula (III) wherein R is linear O branched C-C alkyl and R' is hydrogen or a silylated 15 hydroxyl-protecting group selected from the group con sisting of trimethyl-silyl and tert-butyldimethylsilyl. 3. The compound according to claim 1, selected from:

COEt,

(IId) 25

CO2Et, and

(I) COEt, 0.2 g of 5% Pt/C (50% moisture) were added to a solution 40 formed by 1 g of 6?.73:15 B, 16.f3-dimethylene-5(3,17(3-dihy droxy-17C.-(2-ethoxycarbonyl)-ethynyl-androstan-3-one (IIf) and 20 ml of ethyl acetate. The system was first purged with nitrogen and then with hydrogen and was maintained under stirring under a hydrogen atmosphere at an overpres 45 sure of 0.1 bar for 1 hour. The catalyst was filtered and washed with ethyl acetate. 0.1 g of p-toluenesulfonic acid was added or a solvate thereof. to the resulting solution of a mixture formed by (IIe) and (IId) in approximately 50% each and stirred for at least 30 minutes. 4. A process for obtaining a compound of formula (III) 0.1 ml of triethylamine were added and the solvent was 50 evaporated to dryness to obtain 0.74 g of drospirenone (I). Yield: 86%. (III) COR The invention claimed is: 55 1. A compound of formula (III): (III)

COR 60

wherein R is C-C alkyl, C-C cycloalkyl, aryl or benzyl; and 65 R" is hydrogen or a hydroxyl-protecting group; or a solvate thereof, US 8,524,693 B2 53 54 which comprises reacting a compound of formula (IV) Subjecting said compound of formula (III) to: 1) optionally, deprotection of the hydroxyl group in position3 when R' is a protecting group, and (IV) 2) oxidation of the hydroxyl group in position3 to render a compound of formula (II)

(II)

OH wherein R' is that previously defined, with a propargyl ester of formula (V) 15 OH H=COR (V) wherein R is that previously defined, in the presence of a base. wherein R is that previously defined, and 5. The process according to claim 4, wherein the base is Subjecting said compound of formula (II) to a sequence of selected from the group consisting of lithium diethylamide, reactions selected from sequences A, B and C, wherein lithium diisopropylamide, lithium hexamethyldisilazide, Sequence A comprises: lithium amide, Sodium amide, lithium hydride, sodium a1) subjecting a compound of formula (II) to an elimi nation or an elimination/saponification reaction to hydride and mixtures thereof. 25 6. The process according to claim 4, wherein the reaction of yield the intermediate of formula (IIa): the compound of formula (IV) and the compound of formula (V) is carried out in the presence of an organic solvent selected from the group consisting of diethyl ether, diisopro (IIa) pyl ether, tetrahydrofuran, dioxane, dichloromethane and 30 toluene. 7. A process for obtaining Drospirenone (I)

(I) 35

Vitt 40 wherein R is H, C, -Cs alkyl, C-C cycloalkyl, aryl or benzyl: a2) Subjecting said compound of formula (IIa) to a hydrogenation reaction in the presence of a Pt or Pd catalyst to yield the intermediate of formula (Ic): 45 which comprises (IIc) COR providing a compound of formula (III) HO ? 50

(III)

COR 55

wherein R is that previously defined, and 60 a3) Subjecting said compound of formula (IIc) to treat ment in acid conditions to render Drospirenone (I), wherein wherein steps a2) and a3), alternatively, take place in R is selected from the group consisting of C-C alkyl, one-pot form; C-Cs cycloalkyl, aryland benzyl; and Sequence B comprises: R" is selected from the group consisting of hydrogen 65 b1) Subjecting a compound of formula (II) to a hydro and a hydroxyl-protecting group; genation reaction in the presence of a Pd catalyst to or a solvate thereof, and yield the intermediate of formula (IIb) US 8,524,693 B2 55 56 to render a compound of formula (IVb) (IIb) (IVb) O

TBDMSO 10 OH

wherein TBDMS is tert-butyldimethylsilyl: b) reacting said compound of formula (IVb) with a com and 15 pound of formula (Va) b2) Subjecting said compound of formula (IIb) to a H=CO-Et (Va) hydrogenation reaction in the presence of a Pt catalyst to render Drospirenone (I); to render a compound of formula (IIIb) wherein steps b1) and b2) alternatively take place in one-pot form; and (IIIb)

Sequence C comprises: c1) Subjecting a compound of formula (II) to a hydroge nation reaction in the presence of a Pt catalyst to yield COEt the intermediates of formulae (IId) and/or (IIe) 25 (IIe) p:/-co I I III

30 wherein TBDMS is tert-butyldimethylsilyl: c) deprotecting the protected hydroxyl group in position 3 of said compound of formula (IIIb) to render a

(IId) 35 compound of formula (IIIc)

(IIIc)

40 COEt

45 OH

wherein R is that previously defined, and d) oxidizing the hydroxyl group in position 3 of said c2) Subjecting a compound of formulae (IId) and/or (IIe) compound of formula (IIIc) in the presence of an to treatment in acid conditions to render Drospirenone 50 oxidizing reagent to yield a compound of formula (I), (IIf) wherein steps c1) and c2) alternatively take place in one-pot form;

(IIf) or alternatively, 55 a) protecting a compound of formula (IVa) COEt (IVa) O

HO OH 65 e) Subjecting the compound of formula (IIf) to an elimi nation reaction to yield the intermediate of formula (Ig) US 8,524,693 B2 57 58 to render a compound of formula (IIIb) (Ig) (IIIb)

COEt

10 TBDMSO HO f) Subjecting the compound of formula (IIg) to a hydro genation reaction in the presence of a Pt catalyst to wherein TBDMS is tert-butyldimethylsilyl: yield the intermediate of formula (IIh) 15 c) deprotecting the protected hydroxyl group in position 3 of said compound of formula (IIIb) to render a compound of formula (IIIc)

(IIh)

HO and HO 30 g) Subjecting the compound of formula (IIh) to treatment in the presence of an acid to render Drospirenone (I); d") oxidizing the hydroxyl group in position 3 of said compound of formula (IIIc) in the presence of an or alternatively, oxidizing reagent to yield a compound of formula a') protecting a compound of formula (IVa) 35 (IIf)

(IVa) (IIf)

40 COEt

HO 45 OH

to render a compound of formula (IVb) e') subjecting the compound of formula (IIf) to an elimi nation and Saponification reaction to yield the inter 50 mediate of formula (IIi) (IVb) (III) COOH 55

TBDMSO OH 60

wherein TBDMS is tert-butyldimethylsilyl: b') reacting a compound of formula (IVb) with a com pound of formula (Va) 65 f) subjecting the compound of formula (IIi) to a hydro genation reaction in the presence of a Pt or Pd catalyst H=CO-Et (Va) to yield the intermediate of formula (II) US 8,524,693 B2 59 60

(II) (VII) HO -oil . 5

O 10

15 and d3) oxidizing the compound of formula (VII) to render g) Subjecting the compound of formula (II) to treatment the compound of formula (IId) in the presence of an acid to render Drospirenone (I); or alternatively 2O (IId) providing a compound of formula (III)

(III) 25 COR

and 35 d4) Subjecting the compound of formula (IId) to an elimination reaction to render Drospirenone (I). wherein 8. The process according to claim 7, wherein the hydroxyl R is C-C alkyl, C-C cycloalkyl, aryl or benzyl; and group deprotection step is carried out in the presence of a R" is hydrogen or a hydroxyl-protecting group; 40 fluoride salt. or a solvate thereof, 9. The process according to claim 7, wherein the oxidation followed by step is carried out in the presence of an oxidizing reagent. d1) Subjecting said compound of formula (III) to a 10. The process according to claim 7, wherein the elimi hydrogenation reaction in the presence of a metal nation reaction is carried out in the presence of para-toluene catalyst to yield the intermediate of formula (VI) 45 Sulfonic acid or potassium bisulfate or Sodium carbonate, wherein the elimination and saponification reaction is carried out in the presence of lithium hydroxide. (VI) COR 11. The process according to claim 7, wherein the treat ment step under acid conditions is carried out using para "k ... i? 50 toluenesulfonic acid or potassium bisulfate. 12. The process according to claim 7, wherein the Pd catalyst is Pd/C and the Pt catalyst is Pt/C.

55 13. A compound selected from the group consisting of: RO OH

wherein R is that previously defined, d2) deprotecting the hydroxyl group in position 3 of said compound of formula (VI) when R' is a protecting 65 group, followed by a transesterification reaction to OH render the compound of formula (VII) US 8,524,693 B2 61 62 -continued wherein R is C-C alkyl, C-C cycloalkyl, aryl or benzyl; and O R is C-Cs alkyl, Cs-Cs cycloalkyl, aryl or benzyl; or a solvate thereof. 5 14. The compound according to claim 13, selected from the group consisting of:

COEt,

CO2Et, and

COR

35 or a solvate thereof.