Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
  • C07J53/002—Carbocyclic rings fused
  • C07J53/004—3 membered carbocyclic rings
  • C07J53/008—3 membered carbocyclic rings in position 15/16

Definitions

• This invention relates to processes for the production of 3-oxo-pregnane-21,17-carbo-lactones as well as 3-oxo-pregn4-ene-21,17-carbolactones, in particular processes for the production of 3-oxo-17 ⁇ -pregnane-21,17-carbolactones as well as 3-oxo-17 ⁇ -pregn4-ene-21,17-carbolactones.
• the invention relates to the dichloro-methane hemisolvate of 6 ⁇ ,7 ⁇ ;15 ⁇ ,16 ⁇ -dimethylene-3-oxo-17 ⁇ -pregnan-5 ⁇ -ol-21,17 carbolactone.
• Examples of pharmacologically active steroid-21,17-carbolactones are eplerenone (9 ⁇ ,11 ⁇ -epoxy-7 ⁇ -methoxycarbonyl-3-oxo-17 ⁇ -pregn-4-ene-21,17-carbolactone), drospirenone (6 ⁇ ,7 ⁇ ;15 ⁇ ,16 ⁇ -dimethylene-3-oxo-17 ⁇ -pregn-4-ene-21,17-carbolactone), spironolactone (7 ⁇ -acylthio-3-oxo-17 ⁇ -pregn-4-ene-21,17-carbolactone), canrenone (3-oxo-17 ⁇ -pregna-4,6-diene-21,17-carbolactone), and prorenone (6 ⁇ ,7 ⁇ -methylene-3-oxo-17 ⁇ -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 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 (EP 918791).
• 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
• the object of this invention therefore consists in making available an alternate process 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.
• R 5 is hydrogen, hydroxy
• R 6a is hydrogen, together with R 5 a double bond, or together with R 7a a —CH 2 group;
• R 6b is hydrogen, together with R 7b a —CH 2 group or a double bond;
• R 7a is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -thioacyl or together with R 6a a —CH 2 group;
• R 7b is hydrogen, or together with R 6b a —CH 2 group
• R 9 is hydrogen, together with R 11 a double bond, or together with R 11 an epoxy group -O-;
• R 10 is hydrogen, methyl, or ethyl
• R 11 is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group -O-;
• R 13 is hydrogen, methyl or ethyl
• R 15 is hydrogen, C 1 -C 4 -alkyl, 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, are reacted with an organic or inorganic hypochlorite as an oxidizing agent in the presence 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
• R 5 is a hydroxy group
• the compounds of formula II can be converted in the presence of an acid at pH ⁇ 5 with water being eliminated into compounds of formula III
• Primary alcohols can be oxidized to aldehydes with sodium bromite (NaBrO 2 ) or calcium hypochlorite [Ca(OCl 2 )] in the presence of TEMPO derivatives [S. Torii et al. J. Org. Chem. 1990, 55, 462-466].
• Sodium hypochlorite (NaOCl) can also be used as an oxidizing agent (Org. Synth. 69, 212).
• 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 therefore requires still harder conditions (at least equimolar amounts of the TEMPO derivative (J. M. Bobbilt 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.
• the process according to the invention is performed with a total of at least 3 molar 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, especially preferably 3-4 molar equivalents of alkali hypochlorite or 1.5-2 molar equivalents of alkaline-earth hypochlorite, most preferably 3.0-3.5 molar equivalents of alkali hypochlorite on 1.5-1.75 molar equivalents of alkaline-earth hypochlorite.
• the concentration of the aqueous hypochlorite solution during the oxidation is preferably adjusted such that it is 0.8 to 1.1 mol of hypochlorite/kg.
• Sodium hypochlorite, potassium hypochlorite, calcium hypochlorite or tert-butyl hypochlorite are preferably used as oxidizing agents.
• TEMPO derivatives 2,2,6,6-tetramethylpiperidine-N-oxide derivatives
• 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 (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 mixture, 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.
• the oxidation is performed according to the invention at a temperature of 0 to 20° C., e.g., 0 to 15° C., preferably at 10-20° C.
• 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 Brönsted acid, such as organic acids (e.g., acetic acid) or inorganic acids (HCl, H 2 SO 4 , H 3 PO 4 ) or acid salts of multivalent acids (bicarbonates, hydrogen sulfates, hydrogen phosphates, etc.).
• a suitable Brönsted acid such as organic acids (e.g., acetic acid) or inorganic acids (HCl, H 2 SO 4 , H 3 PO 4 ) or acid salts of multivalent acids (bicarbonates, hydrogen sulfates, hydrogen phosphates, etc.).
• Alkali bicarbonates especially preferably potassium bicarbonate
• the oxidation reaction is brought to a halt by adding a reducing agent to quench excess hypochlorite reagent.
• any reducing agent with corresponding redox potential that is known to one skilled in the art is suitable.
• An aqueous alkali hydrogen sulfite solution is preferably used according to
• the 3-oxo-pregnane-21,17-carbolactones of formula II (if R 5 ⁇ OH) thus eliminate water, and equally the 3-oxo-pregn-4-ene-21,17-carbolactones of formula III 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 III in a one-pot process.
• 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 formula II 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 II.
• 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.
• sodium phosphate (Na 3 PO 4 ) is preferably used as a basic buffer.
• 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-17 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 U.S. Pat. No. 4,069,219 or in the documents cited therein.
• the corresponding 3-hydroxy-17-ketoandrostanes can be produced in turn from the correspondingly substituted 3-hydroxyandrost-5-en-17-one (EP 51143, DE 3026783).
• the process according to the invention is suitable especially for the production of 3-oxo-17 ⁇ -pregnane-21,17-carbolactones of formula IIa as well as 3-oxo-17 ⁇ -pregn-4-ene-21,17-carbolactones of formula IIIa, in which the substituents R have the following meaning:
• R 6a is hydrogen or together with R 7a a —CH 2 group
• R 6b is hydrogen, together with R 7b a —CH 2 group, or a double bond;
• R 7a is hydrogen, C 1 -C 4 -alkoxycarbonyl, or C 1 -C 4 -thioacyl
• R 7b is hydrogen, or together with R 6b a —CH 2 group
• R 9 is hydrogen, together with R 11 a double bond or together with R 11 an epoxy group -O-;
• R 10 is hydrogen, or methyl
• R 11 is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group —O—;
• R 15 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; whereby as starting materials, the 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes of general formula Ia are used.
• R 6a , R7a, R 9 , R 11 are hydrogen
• R 6b and R 7b together are a —CH 2 group
• R 10 is methyl
• R 15 and R 16 together are a —CH 2 group; thus compounds IIb as well as IIIb, whereby the compound of formula Ib is used as a starting material is quite especially suitable.
• Another aspect of this invention is the poorly soluble dichloromethane-hemisolvate IV that is formed, surprisingly enough, from compound IIb when the process according to the invention is performed in dichloromethane and is worked up, basic, at pH>5. During 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, thereby providing the hemisolvate IV in good purity.
• the dichloromethane-hemisolvate IV is distinguished by a strict and constant melting point, which is 121° C., while compound IIb melts at 188° C. DSC (Differential Scanning Calorimetry) measurements have shown that compound IV is stable up to the melting point.
• isolation or “isolated” and the like as used herein mean separation of the subject compound (e.g., that of the Formula II) at a pH>5 (preferably in the presence of methylene chloride) from the reaction solution in which it is prepared; or separation of the subject compound by crystallization and/or precipitation; or separation (e.g., substantially) from the non-polar oxidation or elimination products in the reaction solution in which the compound of Formula II is prepared; or separation from the reaction solution in a form whereby no more than 6% of steroidal contaminants are present in the resultant product (based on total weight therof).
• a pH>5 preferably in the presence of methylene chloride
• Ib can be oxidized to IIb and converted directly to IIIb in the same pot by the reaction mixture being worked up under acidic conditions at pH ⁇ 5.
• TABLE 1 Comparison of the Yields of the Process According to the Invention Compared to the Process of the Prior Art Yield (% of Theory) Process Ib ⁇ IIb IIb ⁇ IIIb Total (Ia ⁇ IIIb) Process According to 82 94 77 the Invention (in the form of IV) Ru-Catalyzed Oxidation 75 94 70 According to EP 918791 CrO 3 Oxidation not isolated not isolated 56 According to EP 075189* *See Table on page 7 EP 918791
• a compound of formula I 76.9 mmol of a compound of formula I is dissolved or suspended in 135 ml of dichloromethane.
• 0.15 g (1 mmol) of TEMPO is added to the mixture at 15®C.
• the addition of a solution that consists of 134 g of a 15.25% aqueous sodium hypochlorite solution (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.
• the excess oxidizing agent is quenched at 15° C.
• aqueous solution that consists of 12.5 g (76.5 mmol) of sodium phosphate and 10.6 g (55.8 mmol) of sodium disulfite (Na 2 S 2 O 5 ) and 121 ml of water.
• the product of formula II 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° C., being filtered off and dried.
• the product that is already partially precipitated during the reaction depending on solubility in dichloromethane 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.
• a compound of formula I 76.9 mmol of a compound of formula I is dissolved or suspended in 135 ml of dichloromethane.
• 0.15 g (1 mmol) of TEMPO is added at 15° C. to the mixture.
• the addition of a solution that consists of 134 g of a 15.25% aqueous sodium hypochlorite solution (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.
• the excess oxidizing agent is quenched at 15° C. by adding an aqueous solution of 10.6 g (55.8 mmol) of sodium disulfite (Na 2 S 2 O 5 ) in 121 ml of water.
• the pH of the reaction solution is set at pH ⁇ 5 by adding dilute, aqueous sulfuric acid, and stirring is continued at room temperature until the reaction is complete.
• the isolation of the product of formula III is carried out analogously to the isolation of the compounds of formula II according to GOP1, whereby the neutral washed organic phase is redistilled on diisopropyl ether.
• the product that is precipitated in this case is filtered off, washed with 300 ml of water and dried.
• the isolation of the product of formula III is carried out by precipitation by means of the addition of 90 ml of water.
• the precipitated product is filtered off with water, washed neutral and dried.

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