AU2012202868A1 - Process for the production of 3-oxo-pregn-4-ene-21,17-carbolactones by the metal-free oxidation of 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes - Google Patents

Abstract

Abstract This invention relates to processes for the production of 3-oxo-pregnane-21,17 carbolactones of formula (11) as well as 3-oxo-pregn-4-ene-21,17-carbolactones of formula (Ill) by the metal-free oxidation of 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes of formula (1). In addition, the invention relates to the dichloromethane hemisolvate of 613, 713, 15B,166-dimethylene-3-oxo-17a-pregnan-5B-ol-21,17-carbolactone (IV) as such as well as to a process for the production of drospirenone. Documn~r4 - 15/5/12

Description

Australian Patents Act 1990 - Regulation 3.2 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Process for the production of 3-oxo-pregn-4-ene-21,17-carbolactones by the metal-free oxidation of 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes The following statement is a full description of this invention, including the best method of performing it known to me: P/00/0l 1 5951 WO 2007/009821 PCT/EP2006/007287 Process for the Production of 3-Oxo-pregn4-ene-21,17-carbolactones by the Metal-Free Oxidation of 17-(3-Hydroxypropyl)-3,17-dihydroxyandrostanes This invention relates to processes for the production of 3-oxo-pregnane-21,17-carbo 5 lactones as well as 3-oxo-pregn-4-ene-21,17-carbolactones, in particular processes for the production of 3-oxo-17a-pregnane-21,17-carbolactones as well as 3-oxo-17a pregn-4-ene-21,17-carbolactones. In addition, the invention relates to the dichloro methane hemisolvate of 6p,7p;15p,16p-dimethylene-3-oxo-17a-pregnan-5p1-o-21,17 carbolactone. 10 Examples of pharmacologically active steroid-21,17-carbolactones are eplerenone (9a,1 1 a-epoxy-7a-methoxycarbonyl-3-oxo-1 7a-pregn-4-ene-21,17-carbolactone), dro spirenone (6p,7p;15p,16p-dimethylene-3-oxo-17a-pregn-4-ene-21,17-carbolactone), spironolactone (7a-acylthio-3-oxo-17a-pregn-4-ene-21,17-carbolactone), canrenone (3 15 oxo-17a-pregna-4,6-diene-21,17-carbolactone), and prorenone (6p,7p-methylene-3 oxo-1 7a-pregna-4,6-diene-21,17-carbolactone). The build-up of the steroid-21,17-spirolactone can be carried out by oxidation of the corresponding 17-hydroxy-17-(3-hydroxypropyl) steroid 0 OH OH Oxidation 20 with suitable oxidizing agents such as chromic acid (Sam et al. J. Med. Chem. 1995, 38, 4518-4528), pyridinium chlorochromate (EP 075189), pyridinium dichromate (Bittler et al; Angew. Chem. [Applied Chem.] 1982, 94, 718-719; Nickisch et al. Liebigs Ann. Chem. 1988, 579-584), or potassium bromate in the presence of a ruthenium catalyst 25 (EP 918791). The clearly pronounced formation of by-products by a number of secon dary reactions is disadvantageous in the oxidation process of the prior art with chro mium(VI) derivatives, by which the isolation of the pure product is hampered and the yield is reduced. The by-product profile is improved namely by the ruthenium-catalyzed oxidation (EP 918791), and thus also the yield increases. The use of transition metals in 30 the production of pharmaceutical active ingredients, however, is generally associated with the drawback that the removal of heavy metal traces is already connected with an elevated expense. Moreover, large amounts of heavy metal-containing wastes accumu- WO 2007/009821 PCT/IEP2006/007287 2 late in the production, and said wastes can be removed only in an intensive and costly way. The object of this invention therefore consists in making available an alternate process 5 for the production of 3-oxo-pregnane-21,17-carbolactones as well as 3-oxo-pregn-4 ene-21,17-carbolactones from the corresponding 17-(3-hydroxypropyl)-3,17-dihydroxy androstanes that makes it possible to produce the target compounds with a higher yield and purity. This object was achieved according to the invention in that the 17-(3-hydroxypropyl) 10 3,17-dihydroxyandrostanes of general formula I in which RR OH sRo h R HO gR R R R Rs" in which R5 is hydrogen, hydroxy; Rea is hydrogen, together with R' a double bond, or together with R' a 15 -CH2 group; R 6b is hydrogen, together with R'b a -CH2 group or a double bond; R 7a is hydrogen, C1-C4-alkyl, C1-C4-alkoxycarbonyl, C1-C4-thioacyl or together with Rea a -CH2 group;

R

1 7 is hydrogen, or together with R a -CH2 group; 20 R9 is hydrogen, together with R" a double bond, or together with R" an epoxy group -0-;

R

1 0 is hydrogen, methyl, or ethyl; R" is hydrogen, together with R9 a double bond or together with R9 an epoxy group -0-; 25 R"1 is hydrogen, methyl or ethyl; R's is hydrogen, C 1

-C

4 -alkyl, together with R 1 6 a -CH 2 group or a double bond,

R

1 6 is hydrogen, together with R' 5 a -CH 2 group or a double bond, WO 2007/009821 PCT/IEP2006/007287 3 are reacted with an organic or inorganic hypochlorite as an oxidizing agent in the pres ence of catalytic amounts of a 2,2,6,6-tetramethylpiperidine-N-oxide derivative to form the 3-oxo-pregnane-21,17-carbolactones of Formula II 0 1 R1

R

R e,R R Rb R7

~R

7 O , . ra 5 R If R 5 is a hydroxy group, the compounds of formula |1 can be converted in the presence of an acid at pH < 5 with water being eliminated into compounds of formula III 0

R

0 *R1R RR Rh R 15 7a R I R 10 Metal-free oxidations of alcohols to the corresponding aldehydes, ketones, carboxylic acids, lactols, and lactones are collectively referred to in the survey article of W. Adam et al., Chem. Rev. 2001, 101, 3499-3548. Metal-free oxidations in the presence of 2,2,6,6-tetramehylpiperidine-N-oxide (TEMPO) are described by van Bekkum et al. in Synthesis 1996, 1153-1174. 15 Primary alcohols can be oxidized to aldehydes with sodium bromite (NaBrO 2 ) or cal cium hypochlorite [Ca(OC 2 )] in the presence of TEMPO derivatives [S. Torii et al. J. Org. Chem. 1990, 55, 462-466]. Sodium hypochlorite (NaOCI) can also be used as an oxidizing agent (Org. Synth. 69, 212). 20 The oxidation of secondary alcohols to ketones and in particular the oxidation of primary alcohols to carboxylic acids (or with suitable diols to lactones) requires a co-catalyst (P. L. Anelli et al., J. Org. Chem. 1987, 52, 2559-2562). As a co-catalyst, a bromide (gen erally KBr or NaBr) is used. The addition of bromide ions can be useful even in the oxi- WO 2007/009821 PCTiEP2006/007287 4 dation of primary alcohols to aldehydes (P. L. Anelli et al., J. Org. Chem. 1987, 52, 2559-2562). The danger of the formation of bromine-containing by-products under oxidative condi tions is disadvantageous in the use of bromides as co-catalysts. This oxidation method 5 is especially suitable for the oxidation of primary alcohols to the corresponding alde hydes. Without the addition of bromide, the TEMPO-catalyzed oxidation of secondary alcohols to the corresponding ketones requires higher excesses of hypochlorite [3-4 molar equivalents of Ca(OCl) 2 , thus 6-8 molar equivalents of OCr; (S. Tori et al. J. Org. 10 Chem. 1990, 55, 462-466)]. The oxidative lactonization of 1,4-diols proceeds in many stages via the aldehyde, which first forms lactol in an intermediate stage; the quasi-secondary hydroxy group of said lactol must then be further oxidized. The oxidative lactonization of 1,4-diols there fore requires still harder conditions (at least equimolar amounts of the TEMPO deriva 15 tive (J. M. Bobbitt et al., J. Org. Chem. 1991, 56, 6110-6114) or other oxidizing agents in connection with increased amounts of the TEMPO catalyst (J. Einhorn, J. Org. Chem. 1996, 61, 7452-7454; in the presence of a bromide addition: S. D. Rychnovsky, J. Org. Chem. 1999, 64, 310-312; in the presence of bromide ions produced in situ from the oxidizing agent sodium bromite: S. Torii, J. Org. Chem. 1990, 55, 462-466). In view of 20 the prior art, it was therefore surprising that oxidative lactonization on the D-ring and the oxidation of the secondary 3-hydroxy group of the 17-(3-hydroxypropyl)-3,17 dihydroxyandrostanes of general formula I (altogether three oxidation stages) can be performed successfully at the same time under mild conditions in the presence of cata lytic amounts of TEMPO derivatives. In addition, it was surprising that the process ac 25 cording to the invention can be performed with only 1.0 to 2.0 equivalents of hypochlo rite per oxidation stage, thus altogether 3.0 to 6.0 molar equivalents of hypochlorite quite without the co-catalytic bromide additions. The process according to the invention is performed with a total of at least 3 molar 30 equivalents of alkali hypochlorite, organic hypochlorite or at least 1.5 molar equivalents of alkaline-earth hypochlorite as oxidizing agent; preferably with 3-6 molar equivalents of alkali hypochlorite, or 1.5-3 molar equivalents of alkaline-earth hypochlorite, espe cially preferably 3-4 molar equivalents of alkali hypochlorite or 1.5-2 molar equivalents of alkaline-earth hypochlorite.

WO 2007/009821 PCT/EP2006/007287 5 The concentration of the aqueous hypochlorite solution during the oxidation is prefera bly adjusted such that it is 0.8 to 1.1 mol of hypochlorite/kg. Sodium hypochlorite, potassium hypochlorite, calcium hypochlorite or tert-butyl hy 5 pochlorite are preferably used as oxidizing agents. The 2,2,6,6-tetramethylpiperdine-N-oxide derivatives (TEMPO derivatives) are used in catalytic amounts, whereby the amount is preferably 1-5 mol%, especially preferably 1 1.5 mol%. Suitable TEMPO derivatives are, i.a., the 2,2,6,6-tetramethylpiperidine-N-oxide 10 (TEMPO), the 4-methoxy-2,2,6,6-tetramethylpiperidine-N-oxide (4-MeO-TEMPO) as well as the 4-benzyloxy-2,2,6,6-tetramethylpiperidine-N-oxide (4-BnO-TEMPO). TEMPO is preferably used according to this invention, especially preferably in an amount of 1-5 mol%, quite especially preferably 1-1.5 mol%. The oxidation is carried out in an organic solvent or in a two-phase solvent-water mix 15 ture, whereby the solvent is selected such that both the TEMPO derivative and the compounds of formula I can be well dissolved therein. The reaction is preferably performed in a two-phase system. The process according to the invention is quite preferably performed in a dichloromethane-water mixture. 20 The oxidation is performed according to the invention at a temperature of 0 to 20 0 C, preferably at 10-20*C. During the oxidation, the pH of the reaction solution is to be at least 8.0; preferably 8.5 to 10.0; especially preferably 9.0 to 9.5. The pH can suitably be adjusted with a suitable Br6nsted acid, such as organic acids 25 (e.g., acetic acid) or inorganic acids (HCI, H 2

SO

4 , H 3

PO

4 ) or acid salts of multivalent acids (bicarbonates, hydrogen sulfates, hydrogen phosphates, etc.). Alkali bicarbon ates, especially preferably potassium bicarbonate, are preferably used. The oxidation reaction is brought to a halt by adding a reducing agent to quench excess hypochlorite reagent. For this purpose, any reducing agent with corresponding redox 30 potential that is known to one skilled in the art is suitable. An aqueous alkali hydrogen sulfite solution is preferably used according to this invention. Sodium or potassium hy drogen sulfite (NaHSO or KHSO 3 ), the aqueous solution of sodium or potassium disul fite (Na 2

SO

2 0 or K 2

S

2 0 5 ) is especially preferably used.

WO 2007/009821 PCT/EP2006/007287 6 If, in the reaction mixture, the excess hypochlorite reagent at pH < 5 is quenched thus without the addition of a base or a basic buffer, or in the presence of a further acid addi tion, the 3-oxo-pregnane-21,17-carbolactones of formula II (if R = OH) thus eliminate 5 water, and equally the 3-oxo-pregn-4-ene-21,17-carbolactones of formula Ill are formed in the reaction mixture. The completion of the oxidation reaction at a pH of less than 5 makes possible the production of compounds of formula Ill in a one-pot process. If, in the reaction mixture, the excess hypochorite reagent is quenched with the addition of a base or a basic buffer at pH > 5, the 3-oxo-pregnane-21,17-carbolactones of for 10 mula il can be isolated. The completion of the oxidation reaction at a pH of more than 5 makes possible the specific production of compounds of formula 11. Since in the case R 5 = OH the solubility of the compounds of formula il in comparison to the compounds of formula Ill in organic solvents is lower, the specific isolation of the compounds of formula || as an intermediate on the path to compounds of formula IlIl 15 offers the special advantage of the possibility of a more effective purification (e.g., by crystallization). The purified intermediates can be reacted according to the methods that are known in the literature with a suitable acid (such as, e.g., sulfuric acid, hydrochloric acid, para-toluenesulfonic acid, etc.) to form compounds of formula Ill (EP 0918791). 20 To adjust the pH, any suitable inorganic or organic base or any suitable buffer or any suitable buffer system can be used. The base or buffer is preferably added mixed or in parallel to the reaction mixture with the reducing agent. According to this invention, sodium phosphate (Na 3

PO

4 ) is preferably used as a basic buffer. 25 17-(3-Hydroxypropyl)-3,17-dihydroxyandrostanes of general formula I can be obtained, e.g., starting from the correspondingly substituted 3-hydroxy-17-ketoandrostanes by the addition of propargyl alcohol at C-1 7 and subsequent hydrogenation of the triple bond (EP 918791, EP 51143, DE 3026783) or as described by N. W. Atwater in J. Org. Chem. 1961, 26, 3077 and in US 4,069,219 or in the documents cited therein. 30 The corresponding 3-hydroxy-1 7-ketoandrostanes can be produced in turn from the correspondingly substituted 3-hydroxyandrost-5-en-17-one (EP 51143, DE 3026783).

WO 2007/00982 1 PCTIEP2006/007287 7 R O R Ri R .6b

R

1 0 R 7 a R1 R.6 work-up at pH < 5wrk-up at pH > 5 R5= OH W 0 0 RR R 10Ris189l Rs 0 RR R 5 OH R 1 .. %R R Rh 1' 5 Acid R7bR 1 laR 0 - R 07a ~~?

R

WO 2007/009821 PCT/EP2006/007287 8 The process according to the invention is suitable especially for the production of 3-oxo 17a-pregnane-21,17-carbolactones of formula Ila 0 R, Rb Rs OH:eaR b 5 R as well as 3-oxo-17ct-pregn-4-ene-21,17-carbolactones of formula lila, O R, R ,,R9 RI OA . RA Ilila R in which the substituents R have the following meaning: 10 Rea is hydrogen or together with R 7 a a -CH 2 group; R'6 is hydrogen, together with R 7 b a -CH 2 group, or a double bond;

R

7 a is hydrogen, C-C 4 -alkoxycarbonyl, or C 1

-C

4 -thioacyl; R 7 is hydrogen, or together with Reb a -CH 2 group, R9 is hydrogen, together with R 1 1 a double bond or together with R 1 15 an epoxy group -O-;

R'

0 is hydrogen, or methyl; R" is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group -0-;

R

1 5 is hydrogen, together with R 1 6 a -CH 2 group or a double bond; 20 R" is hydrogen, together with R 1 5 a -CH 2 group or a double bond; WO 2007/009821 PCT/EP2006/007287 9 whereby as starting materials, the 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes of general formula la OH RR RR 7b. HO OH R R la 5 are used. The process according to the invention for the production of compounds of formulas Ila and Illa, 10 in which Rea, R 7 a, R 9 , R" are hydrogen; Rob and R 7 b together are a -CH 2 group; R10 is methyl;

R'

5 and R' 6 together are a -CH 2 group; 15 thus compounds lIb as well as Ilib, whereby the compound of formula lb is used as a starting material is quite especially suitable.

WO 2007/009821 PCT/EP2006/007287 10 OH HO OH lb oxidation 0 O OH ||lb work-up at pH < 5 work-up at pH > 5 R= OH dichloromethane O O acid :1/2 CH 2 Cl 2 OH Ollb IV Another aspect of this invention is the poorly soluble dichloromethane-hemisolvate IV 5 that is formed, surprisingly enough, from compound lib when the process according to the invention is performed in dichloromethane and is worked up, basic, at pH > 5. Dur ing the oxidation, this poorly soluble product precipitates, and thus the influence of the oxidizing agent and thus possible further reactions, which can result in the formation of by-products, are evaded.

WO 2007/009821 PCT/EP2006/007287 11 The dichloromethane-hemisolvate IV is distinguished by a strict and constant melting point, which is 121 *C, while compound I1b melts at 188*C. DSC (Differential Scanning Calorimetry) measurements have shown that compound IV is stable up to the melting 5 point. After the reaction is completed, the precipitation of compound IV from the reaction solu tion by adding a non-polar solvent, preferably an ether, especially preferably diisopropyl ether, is completed. The non-polar oxidation and elimination products that are produced with the oxidation remain largely dissolved in the ether-dichloromethane mixture, which 10 makes possible an extremely slight isolation of the compound IV at a high purity. In this way, compound IV with a yield of 82% is obtained. The thus obtained product contains no more than 6% steroidal contaminants and can easily be reacted without further purification according to known methods with a suitable acid to form dro spirenone Illb (EP 918791). The synthesis variant that runs through the isolated com 15 pound IV offers the additional advantage of a considerably higher total yield at Illb by a simpler and more effective purification in the final stage. The total yield at Illb is 77%, around 7% higher than according to the Ru-catalyzed oxidation process and subse quent water elimination and even around 21% higher than according to the one-pot process according to EP 075189 (Tab. 1). 20 As an alternative, lb can be oxidized to lIb and converted directly to Illb in the same pot by the reaction mixture being worked up under acidic conditions at pH < 5. Tab. 1: Comparison of the Yields of the Process According to the Invention Compared to the Process of the Prior Art Process Yield (% of Theory) lb -+ lb lib -+ Ilb Total (la-lllb) Process According 82 94 77 to the Invention (in the form of IV) Ru-Catalyzed Oxi- 75 94 70 dation According to EP 918791 Cr0 3 Oxidation Ac- not isolated not isolated 56 cording to EP 075189* 25 *See Table on page 7 EP 918791 WO 2007/009821 PCT/EP2006/007287 12 This invention is explained in more detail based on the examples below, without being limited thereto. 5 Production Process General Operating Procedure I (GOP1): Synthesis of Compounds of Formula il 76.9 mmol of a compound of formula I is dissolved or suspended in 135 ml of dichloro 10 methane. First, 0.15 g (1 mmol) of TEMPO is added to the mixture at 15*C. The addi tion of a solution that consists of 134 g of a 15.25% aqueous sodium hypochlorite solu tion (230.7 mmol) and 8.20 g (82 mmol) of potassium bicarbonate in 114 ml of water is carried out, whereby a pH-value of 9.1 is set. After the reaction is completed, the ex cess oxidizing agent is quenched at 15 0 C by adding an aqueous solution that consists 15 of 12.5 g (76.5 mmol) of sodium phosphate and 10.6 g (55.8 mmol) of sodium disulfite (Na 2

S

2 0 5 ) and 121 ml of water. The product of formula il is isolated from the organic phase by being precipitated from the reaction solution by adding 240 ml of diisopropyl ether, continuing to be stirred for 3 hours at 25 0 C, being filtered off and dried. As an alternative, the product that is al 20 ready partially precipitated during the reaction depending on solubility in dichloro methane can be dissolved again by adding dichloromethane, and the organic phase is separated and redistilled in diisopropyl ether. The product that is precipitated in this case is filtered off with 300 ml of water, washed and dried. 25 General Operating Procedure 2 (GOP2): Synthesis of Compounds of Formula IlIl in a One-pot Process 76.9 mmol of a compound of formula I is dissolved or suspended in 135 ml of dichloro methane. First, 0.15 g (1 mmol) of TEMPO is added at 15*C to the mixture. The addi tion of a solution that consists of 134 g of a 15.25% aqueous sodium hypochlorite solu 30 tion (230.7 mmol) and 8.20 g (82 mmol) of potassium bicarbonate in 114 ml of water is carried out, whereby a pH-value of 9.1 is set. After the reaction is completed, the ex cess oxidizing agent is quenched at 15 0 C by adding an aqueous solution of 10.6 g (55.8 mmol) of sodium disulfite (Na 2 S20 5 ) in 121 ml of water. The pH of the reaction solution is set at pH < 5 by adding dilute, aqueous sulfuric acid, 35 and stirring is continued at room temperature until the reaction is complete.

WO 2007/009821 PCT/EP2006/007287 13 The isolation of the product of formula IlIl is carried out analogously to the isolation of the compounds of formula 11 according to GOP1, whereby the neutral washed organic phase is redistilled on diisopropyl ether. The product that is precipitated in this case is 5 filtered off, washed with 300 ml of water and dried. General Operating Procedure 3 (GOP3): Synthesis of Compounds of Formula IlIl Starting from Compounds of Formula 11, in which R' = OH: 0.1 mol of a compound of formula 11, in which R 5 = OH, obtained according to GOP1, is 10 suspended in 65 ml of tetrahydrofuran or dioxane and acidified to a pH of 1 by adding 5 ml of 20% sulfuric acid. At room temperature, stirring of the reaction mixture is contin ued until dehydration is completed. The isolation of the product of formula Ill is carried out by precipitation by means of the addition of 90 ml of water. The precipitated product is filtered off with water, washed 15 neutral and dried. Example 1 6P,7p; 15 p, 1 6p-Dimethylene-3-oxo-1 7a-pregnan-5p3-ol-21,17 carbolactone-dichloromethane hemisolvate (IV): 20 According to GOPI, 30 g (0.0769 mol) of 17a-(3-hydroxypropy)-6p,7p;15 p,16p3 dimethylene-androstane-33,5 p,1 7p-triol is reacted. During the reaction, the product 6 1,71;15p,16p-dimethylene-3-oxo-17a-pregnan-5p-ol 21,17-carbolactone accumulates in the form of its dichloromethane hemisolvate. After excess oxidizing agent is destroyed and after working-up according to GOP1, 27 g of 25 60,7p; 15p,16-dimethylene-3-oxo-17a-pregnan-513-ol-21,17-carbolactone dichloromethane hemisolvate (0.0630 mol) = 82% of theory is isolated. [a]o20 = -61* (c = 1.0; CHCl 3 ); melting point = 121'C; 1 H-NMR (400 MHz, CDCl 3 ): 6 = 0.52 (q J = 5.5 Hz, IH, 21 a-H [of the 15,16-methylene bridge]), 0.68-0.78 (m, 2H, 20-H [of the 6,7-methylene bridge]), 0.89-0.97 (m, 1H, 6-H), 30 0.93 (s, 3H, 19-H), 0.99 (s, 3H, 18-H), 1.19-1.52 (m, 7H), 1.54-1.85 (m, 6H), 1.92 (dd J = 3.8 and 11.8 Hz, 1H, 14-H), 2.06-2.16 (m, 1H, 22-H), 2.17-2.27 (m, 1H, 2a-H), 2.32 2.69 (m, 5H), 2.96 (d J = 15.6 Hz, 1H, 4ct-H), 5.30 (s, 1H, CH 2

C

2

).

WO 2007/009821 PCT/EP2006/007287 14 "C-NMR (400 MHz, CDC1 3 ): 6 = 9.97 (CH 2 , C-21), 11.63 (CH 2 , C-20), 16.74 (CH, C 15), 16.79 (CH, C-7), 17.29 (CH 3 , C-19), 19.83 (CH 3 , C-18), 21.75 (CH 2 , C-11), 24.31 (CH, C-16), 24.76 (CH, C-6), 29.35 (CH 2 , C-23), 30.70 (CH 2 , C-22), 33.96 (CH, C-8), 5 34.47 (CH 2 , C-1), 36.26 (CH 2 , C-2), 37.31 (CH 2 , C-12), 40.25 (C, C-10), 41.81 (C, C 13), 47.59 (CH, C-9), 52.18 (CH, C-14), 53.44 (CH 2 Cl 2 ), 53.48 (CH 2 , C-4), 75.57 (C, C 5), 96.24 (C, C-17), 176.63 (C, C-24), 210.56 (C, C-3). MS (El, 70eV) /e = 384 (M*); /e = 366 (M*-H 2 O); n/e = 314 (M*-C 4 HSO); mle = 111 (C7C11O); m/e = 91 (C 6

H

1 10*); m/e = 55 (C 3

H

3 0); n/e = 43 (C 2

H

3 O*). 10 IR: 8 = 3483 cm-' (OH); & = 1757 cm-' (C=0, lactone); 3 = 1708 cm-' (C=0); 8 = 1200 cm' (0-C=0); 4 = 1011 cm 1 (C-0) Example 2 60,70; 15p,16f-Dimethylene-3-oxo-1 7ca-preg-4-ene-21,17-carbolactone (lib): 15 According to GOP2, 30 g (0.0769 mol) of 17a-(3-hydroxypropyl)-6p,7p;15p,16p dimethylene-androstane-3p,5p,17-triol is reacted. After excess oxidizing agent is de stroyed according to GOP2, the reaction mixture is acidified with 10% sulfuric acid solu tion to a pH of 1 and stirred for 30 minutes at 25*C. After working-up according to GOP2, 21.5 g of 6 p,7p;150,160-dimethylene-3-oxo-17a-preg-4-ene-21,17-carbolactone 20 (0.059 mol) = 76.7% of theory is isolated. [ID22 = -182* (c = 0.5 CHC 3 ); melting point = 201.30C; UV (MeOH): E265 = 19,000; most important 'H-NMR data (CDC13): 6 = 0.40-0.67 (m, 1H, cyclopropyl H), 1.01 (s, 3H, 18 H), 1.11 (s, 3H, 19-H), 6.04 (s, 1H, 4-H) (D. Bittler, H. Hofmeister, H. Laurent, K. Nick 25 isch, R. Nickolson, K. Petzoldt, R. Wiechert; Angew. Chem. Int. Ed. Engl. 1982, 21, 696-697]; MS (El, 70eV) /e = 366 (M'); m/e = 338 (M*-CO); m/e = 351 (M*-CH 3 ); significant fragments: n/e = 111; n/e = 136; m/e = 199, m/e = 217; n/e = 242; m/e = 255; n/e = 268; n/e = 293 [interpretation: See W. Krause, G. Kuehne; Steroids 1982, 40, 81-90].

WO 2007/009821 PCT/EP2006/007287 15 Example 3 6p,7p:1 5p, 1 6-dimethylene-3-oxo-1 7a-preg-4-ene-21,17-carbolactone (Illb): 5 According to GOP3, 30 g (70,25 mmol) of 6p,7p:15p,16f-dimethylene-3-oxo-17a pregnane-5p-ol-21,17-carbolactone dichlormethane hemisolvat (from Example 1) is reacted to yield 24.30 g of drospirenone (yield: 94.5%).

Claims (5)

1. Process for the production of 3-oxo-pregnane-21,17-carbolactones of for mula 11 0 11R R m R 10 ,,,R' R 1 Fb RN R'I O . IR' 5 R in which R 5 is hydrogen, hydroxy; R6" is hydrogen, together with R 5 a double bond, or together with R 78 a -CH 2 group; 10 R6b is hydrogen, together with R7b a -CH 2 group or a double bond; R 7 " is hydrogen, C-C 4 -alkyl, C-C 4 -alkoxycarbonyl, C-C 4 -thioacyl or together with R8" a -CH 2 group, R'b is hydrogen, or together with Reb a -CH 2 group; R9 is hydrogen, together with R" a double bond, or together with R 1 an 15 epoxy group -0-; R 10 is hydrogen, methyl, or ethyl; R" is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group -0-; R 13 is hydrogen, methyl or ethyl; 20 R' 5 is hydrogen, C-C 4 -alkyl, together with R 1 6 a -CH 2 group or a double bond; R' is hydrogen, together with R 15 a -CH 2 group or a double bond; WO 2007/009821 PCT/EP2006/007287 17 comprising the reaction of compounds of formula I RR OH RR R R I 5 with at least 3 molar equivalents of an organic or inorganic hypochlorite as oxidizing agent in the presence of catalytic amounts of a 2,2,6,6-tetramethylpiperdine-N-oxide derivative at a pH of at least 8.0. 10 2. Process according to claim 1 for the production of 3-oxo-1 7a-pregnane-21,17 carbolactones of formula Ila 0 R R 0 ,,, R 1 R" OHje R 6 R in which R63 is hydrogen or together with R 7 a a -CH 2 group; 15 R6b is hydrogen, together with R'h a -CH 2 group, or a double bond; R 7 a is hydrogen, C 1 -C 4 -alkoxycarbonyl, or C 1 -C 4 -thioacyl; R 7 b is hydrogen, or together with R 6 b a -CH 2 group, R 9 is hydrogen, together with R" a double bond or together with R" an epoxy group -0-; 20 R'" is hydrogen, or methyl; R" is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group -0-; R's is hydrogen, together with R 16 a -CH 2 group or a double bond; R 16 is hydrogen, together with R 15 a -CH 2 group or a double bond; WO 2007/009821 PCT/EP2006/007287 18 wherein compounds of formula la OH R R ,..% .' OH R'R HO OH R R" la 5 are reacted.

3. Process according to claim 1 or 2 for the production of the compound of for mula lib, 10 10 O OH ||Ib whereby the compound of formula lb OH OH HO OH lb 15 is used as a starting material. WO 2007/009821 PCT/EP2006/007287 19

4. Process for the production of 3-oxo-pregn-4-ene-21,17-carbolactones of for mula Ill 0 R R m R 1 0 R R 1 I 7b R R 6b R *ll eaR R 5 in which R" is hydrogen, together with R 5 a double bond, or together with R 7 " a -CH 2 group; Reb is hydrogen, together with R'b a -CH 2 group or a double bond; R 7 a is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -thioacyl or 10 together with R" a -CH 2 group, R 7 b is hydrogen, or together with R6b a -CH 2 group; R9 is hydrogen, together with R" a double bond, or together with R" an epoxy group -0-; R 10 is hydrogen, methyl, or ethyl; 15 R" is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group -0-; R 13 is hydrogen, methyl or ethyl; R's is hydrogen, C 1 -C 4 -alkyl, together with R 1 6 a -CH 2 group or a double bond, 20 R'6 is hydrogen, together with R's a -CH 2 group or a double bond; WO 2007/009821 PCT/EP2006/007287 20 comprising the following steps: a) the reaction of compounds of general formula I R~w. OH 5 R in which R 5 is hydroxy; Rea, R6b, R 7 a, R7b, R 10 , R", R 13 , R 15 , R'e have the same meaning as in formula IlIl, 10 with at least 3 molar equivalents of an organic or inorganic hypochlorite as an oxidizing agent in the presence of 1-5mol% of a 2,2,6,6-tetramethyl-piperidine-N-oxide derivative at a pH of at least 8.0 and at a temperature of 0--15 0 C, in dichloromethane or in a two phase dichloromethane-water mixture, 15 to form the compounds of formula 11 0 11 R' R R 10 RR 1 6 R 7 b R 0 R R 6,Rb b) subsequent elimination of water at pH < 5, optionally in the presence of an acid. WO 2007/009821 PCT/IEP2006/007287 21

5. Process for the production of 3-oxo-pregn-4-ene-21,17-carbolactones of for mula IlIl 0 R~r, R R10 9 18i R R R R R' 6bR I eR 5 in which Re 61 is hydrogen, together with R 5 a double bond, or together with R 7 a -CH 2 group; R6b is hydrogen, together with Rib a -CH 2 group or a double bond; R 7 " is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -thioacyl or 10 together with Rsa a -CH 2 group, Rib is hydrogen, or together with R8b a -CH 2 group; R 9 is hydrogen, together with R" a double bond, or together with R" an epoxy group -0-; R 1 0 is hydrogen, methyl, or ethyl; 15 R" is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group -0-; R1 3 is hydrogen, methyl or ethyl; R 1 5 is hydrogen, C 1 -C 4 -alkyl, together with R's a -CH 2 group or a double bond, 20 R'6 is hydrogen, together with R' 5 a -CH 2 group or a double bond; WO 2007/009821 PCT/EP2006/007287 22 comprising the following steps: a) the reaction of compounds of general formula I A R1OH -.. OH R RI HO R 7a R 5 in which Rs is hydroxy; Rea, Rsb, R 7 ", R b, R 10 , R", R 3 , R4s, R's have the same meaning as in formula IlIl, 10 with at least 3 molar equivalents of an organic or inorganic hypochlorite as an oxidizing agent in the presence of catalytic amounts of a 2,2,6,6-tetramethyl-piperidine-N-oxide derivative at a pH of at least 8.0, in dichloromethane or in a two-phase dichloro methane-water mixture; 15 to form the compounds of formula II 0 RR ... ) R

130. R 1 0 ,,R R 1 6 R 7 bR' R RIs O~ s 7a R ,R b) the isolation of compounds of formula 11 20 c) subsequent elimination of water at pH < 5, optionally in the presence of an acid. WO 2007/009821 PCT/IEP2006/007287 23 6. Process according to claim 4 or 5 for the production of 3-oxo-1 7a-pregn-4-ene 21,17-carbolactones of formula Illa 0 R ,,R9 RU R R OA . R * Ilila eR 5 in which Rea is hydrogen or together with R7, a -CH 2 group; Reb is hydrogen, together with R7b a -CH 2 group, or a double bond; R 7 a is hydrogen, C-C 4 -alkoxycarbonyl, or C-C 4 -thioacyl; R7b is hydrogen, or together with R6b a -CH 2 group, 10 R 9 is hydrogen, together with R" a double bond or together with R" an epoxy group -0-; R 1 0 is hydrogen, or methyl; R" is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group -0-; 15 R' 5 is hydrogen, together with Re a -CH 2 group or a double bond; R16 is hydrogen, together with R" 5 a -CH 2 group or a double bond, wherein the compounds of formula la H R 10 , R 16 6a R 20 are reacted. WO 2007/009821 PCT/EP2006/007287 24 7. Process according to any one of claims 4, 5 or 6 for the production of a com pound of formula Ilib 0 O Illb 5 whereby the compound of formula lb OH OH HO OH lb is used as a starting material. 10 8. Process for the production of dichloromethane hemisolvate IV: 0 :1/2 CH 2 Cl 2 OH IV comprising the following steps: WO 2007/009821 PCT/EP2006/007287 25 a) the reaction of compounds of general formula lb OH OH HO OH lb 5 with at least 3 molar equivalents of an organic or inorganic hypochlorite as an oxidizing agent in the presence of catalytic amounts of a 2,2,6,6-tetramethyl-piperidine-N-oxide derivative at a pH of at least 8.0, in dichloromethane or in a two-phase dichloro 10 methane-water mixture; b) the isolation of compounds of formula il 9. Process according to any one of the claims 5 through 8, wherein 1-5 mol% of 15 the 2,2,6,6-tetramethylpiperidine-N-oxide derivative is used. 10. Process according to any one of the claims 5 through 10, wherein 1-1.5 mol% of 2,2,6,6-tetramethylpiperidine-N-oxide is used. 20 11. Process according to one of the preceding claims, wherein 3-6 molar equiva lents of alkali hypochlorite are used. 12. Process according to one of the preceding claims, wherein 3-4 molar equiva lents of sodium hypochlorite are used. 25 13. Process according to one of the preceding claims, wherein the pH of the reac tion solution is between 8.5 and 10.0. 14. Process according to one of the preceding claims, wherein the pH of the reac 30 tion solution is set with potassium bicarbonate. WO 2007/009821 PCT/EP2006/007287 26 15. Process according to one of the preceding claims, wherein the reaction tem perature is 0 to 15 0 C. 5 16. Process according to one of the preceding claims, wherein after the oxidation reaction is completed, a reducing agent for quenching excess hypochlorite reagent is added to the reaction mixture. 17. Process according to claim 16, wherein the reducing agent is added with the 10 addition of a base or a basic buffer at a pH of more than 5. 18. Process according to any one of claims 16 or 17, wherein an aqueous alkali hydrogen sulfite solution is used as a reducing agent. 15 19. Process according to one of claims 16 through 18, wherein as a reducing agent, sodium hydrogen sulfite or potassium hydrogen sulfite is used in the form of the aqueous solution of sodium disulfite or potassium disulfite. 20. Process according to one of claims 17 to 19, wherein sodium phosphate 20 (Na 3 PO 4 ) is used as a base or a basic buffer. 21. 60,70; 1 5p, 1 6p-dimethylene-3-oxo-1 7a-pregnan-5p3-ol-21,17-carbolactone dichloromethane hemisolvate. 25 22. Process for the production of drospirenone comprising reacting 6p,7p; 1 5p, 1 6p dimethylene-3-oxo-1 7a-pregnan-5p-ol-21,17-carbolactone-dichloromethane hemisol vate with an acid. 23. Process according to claim 22, wherein the acid is sulfuric acid, hydrochloric 30 acid or para-toluenesulfonic acid.