HU184729B - Process for the preparation of metal-olefine compounds - Google Patents

Abstract

A process for the preparation of the isomers of a compound of the formula (I> CMR20=CH-X-Z wherein M is lithium, sodium or potassium; R20 is fluorine, chlorine atom or NR alpha R beta in which R alpha and R beta are the same or different and are each C1-3 alkyl; X is oxygen or sulfur; and Z is C1-6 alkyl, phenyl or p-tolyl, in which the ratio of the isomer in which the R20 and XZ groups are trans to that in which they are cis is greater than 70:30, which comprises reacting an ethane derivative of the formula CH2R20-CHQ-X-Z wherein Q is chlorine, bromine, iodine or trimethylamino and R20, X and Z are as defined above, with an organometal compound of the formula RM wherein R is C1-5 alkyl or phenyl and M is as defined above, at from -15 to -120 DEG C. The corresponding isomers of a compound of the formula CHR20=CH-X-Z can be prepared by quenching the reaction product of the ethane derivative and the organometal compound with a proton source such as water. Compounds I (especially the lithium derivative of 1-chloro-2-ethoxy- ethene) are useful for adding a two carbon side chain at the 17-position of a C-3 protected 17-oxo-steroid to produce a 1 6-unsubstituted pregnane which can be converted to 16- substituted corticoids.

Description

The present invention relates to a novel process for the preparation of metal olefin compounds.

Trans-metal olefin compounds of formula IIIB: wherein:

R ₇₀ is chlorine,

X is oxygen

Z is C 1 -C 4 alkyl,

M represents an alkali metal atom - more highly attached to the 17-keto steroid of formula (1) - in the formula

R 4 is hydrogen, fluorine or methyl,

R11 is hydrogen, or an a-ORjj _a or P-ORjj is _a group wherein Rj _a is hydrogen or TMS, provided that when Rj ₍ -OR ₍ j is _a group of _the formula ... .. signifies a single bond in the formula,

Rjg is a hydrogen atom or a methyl group, where the ~ sign indicates that the group may be present in either the α or β configuration;

..... signifies single or double bond - like the corresponding cis isomers. The addition reaction products of the 16-unsubstituted pregnanes (5) of the formula: - wherein R _6, R j and R _if) as defined above,

R 21 is C 1 -C 5 alkyl or phenyl, which can be converted to the corresponding 16-substituted corticoids by useful methods known in the art. The cis-metal-olefin compounds can be summarized by the formula (ΠΙΑ), wherein Rnn, X, Z and M are as previously defined. The metal olefins of the formulas (ΙΤΙΑ) and (IIIB) may be prepared from the corresponding olefins (NA) and (1IB), respectively, wherein R 2 Q, X and Z have the meanings given above. the starting olefins are prepared so that the proportion of trans isomer in the resulting isomeric mixture is as high as possible. On the other hand, the known methods for the preparation of olefins (HA) and (IIB) lead to a very low trans / cis ratio to the final product, that is, to the very opposite result. The process of the present invention provides a mixture of olefins (HA) and (IIB) and through them compounds (IIIA) and (IIIB) with a very high trans / cis ratio greater than 70:30.

Rec. Trav. chim. 77, 753 (1958) discloses a process for converting chloroacetaldehyde diethyl acetal into 1-chloro-2-ethoxyethylene when heated with an acidic catalyst. On page 755, the authors report that the product consisted mainly of the cis isomer. The process of the present invention surprisingly and completely unexpectedly results in a product having a trans / cis ratio greater than 70:30,

Rec. Trac. chim. 74, 271 (1955) relates to the dehydrohalogenation of 1,2-dichloro-2-ethoxyethane, the product of which is 1-chloro-2-ethoxyethylene. The article found on page 274 that the product contained ... about 75% of the cis isomer and 25% of the lower boiling trans isomer.

Chem. Bér. 91, 380 (1958), converted 1,2-dichloro-2-ethoxy-ethane to 1-chloro-2-ethoxyethylene using a tertiary amine and heat. Under the various reaction conditions described, the cis isomer was obtained primarily.

According to German Patent Publication No. 2 210 010, 1,1-dichloro-2-methoxyethane was converted to 1-chloro-2-methoxyethylene by reaction with methoxide. The proportion of cis-isomer (54%) was higher than that of trans-isomer (46%).

Rec. Trav. chim. 70, 289 (1951), dichloroacetaldehyde was reacted with diethyl acetal to form 1-chloro-2-ethoxyethylene using active zinc powder. On page 293, the authors described that the amount of the cis isomer was 4 -5 times greater than the amount of trans isomer.

The order. Ist Lombardo Sci. Pt. Classe Sci. e Nat. 94A, 600 (1960), converted 1,2-dichloro-2-isobutoxyethane to 1-chloro-2-isobutoxyethylene, using tertiary amine and hydrochloric acid, to give a product containing 75-90% of the cis isomer.

All of the above articles agree that the trans isomer is formed in substantially smaller amounts than the cis isomer. However, these are only empirical observations and the possible mechanism is not mentioned in the publications. In 1976, however, E. Taskinen and E. Sainio (Tetrahedron 32, 593 11976 /) reported thermodynamic calculations which showed that the cis isomer was formed predominantly by lower enthalpy.

Thus, one of ordinary skill in the art would, based on both theoretical considerations and previous experimental results, expect that the trans / cis isomer ratio would be substantially less than 50:50. Thus, it is extremely surprising that the process of the present invention provides a mixture of compounds of formula (INA) and (IIIB) and (IIA) and (IIB) in which the ratio of the trans isomer to the cis isomer is higher, than 7030.

The present invention relates to a process for the preparation of metal olefin compounds of the formulas IIIA and IIIB, wherein R 2 Q, X, Z and M are as defined above, by reacting the trans and cis isomer (IIIB) in the product obtained. and (IIIA) greater than 60:30. According to the invention, a compound of the formula I - R2Q, X and Z as defined above, u, is chloro, bromo, iodo or trimethylamino -

At a temperature of -15 to -120 ° C with a compound of the formula R-M, wherein

R is C1-5 alkyl or phenyl, and

M is as previously defined.

The metal olefin compounds of formula IIIA and IIIB can be used to introduce a carbon side chain into the 3-protected 17-keto steroid of formula 2a-e and thus a 16-unsaturated pregnane (/ 5 / formula). This compound is readily converted to 16-substituted useful corticoids. The meaning of the variable substituents in the formulas is detailed below.

The substituted ethane derivatives of formula (I) are either known in the literature or readily prepared by known methods from known compounds. In the substituted ethane derivatives of formula (I), Roq, X, Z and Q are as previously defined. Preferably Z is C 1 or C 2 alkyl.

The compounds of formula R-M are known or can be readily prepared from known compounds by known methods. In the formula R-M, R is preferably a secondary group or a primary C 1-4 alkyl group. The alkali metal designated M may be lithium, sodium or potassium. Preferred is lithium. Preferred examples of compounds of the formula R-M are: η-butyllithium, propyl lithium, sec-butyllithium, n-butyl potassium or isopropyl lithium. Most preferably, n-butyllithium is used.

The substituted ethane derivative (1) and the compound R-M are reacted with one another in anhydrous organic solvent; The organic solvent must be anhydrous because, when water is present, the water reacts with the R-M compound and thus the R-M compound must be taken in excess. Among the organic solvents, ethers such as tetrahydrofuran, dimethoxyethane, diethyl ether, dioxane are preferred. Most preferably, it is a mixture of an ether and a hydrocarbon and / or aromatic solvent, provided that the mixture always contains all ethers. Preferably, the ether should be present in the highest possible concentration. The reaction is preferably carried out in pure tetrahydrofuran. The compound of formula (I) may be added to the compound of formula (R-M), or vice versa.

The reaction is carried out at -15 to -120 ° C, preferably at -30 to 90 ° C, more preferably at -60 to -90 ° C. At higher temperatures, the reaction is faster than at lower temperatures, as will be apparent to those skilled in the art. The reaction is exothermic, so R-M is added very slowly, usually over a period of 15 minutes to 1.5 hours. After the reaction is exothermic, the reaction mixture must be cooled so that the reaction temperature does not exceed -15 ° C. At -90 ° C, the reaction is usually complete in 1 hour, while at -30 ° C it is complete in about 15 minutes. The reaction proceeds at -15 ° C, but the yield is low. However, despite the low yield, the ratio of trans (IIIB) to cis (IIIA) is greater than 70:30.

If, for some reason, a mixture of olefins (IIA) and (IIB) is to be isolated, the substituted ethane (I) is reacted with a reagent (RM), the substituents having the meanings given above, to give a reaction mixture, comprising an olefin of formula IIA and IIB and a metal olefin compound of formula III. In order to maximize the utilization of the starting material of formula I, it is preferable to use at least 1 molar equivalent of R-M, more preferably at least 2 equivalents of R-M. When the reaction is complete (about 1 hour), a proton source is added to the reaction mixture to convert the metal olefin compound (illetve) and (IIIB), respectively, to the olefin compound (IIA) and (IIB). Any weakly acidic compound such as water, alcohol, carboxylic acid, sulfuric acid or ammonium salts should be used as a proton source, but care should be taken not to drop the pH of the mixture below 6. Preferably water, methanol, ethanol, acetic acid or ammonium chloride are used as proton sources. If a pure trans-olefin of formula IIB is desired, it is readily isolated by methods well known in the art, such as fractional distillation. The reaction mixture is then worked up in a manner well known in the art.

In carrying out the process of the invention, it is preferable to use more than 1.5 equivalents of RM reagent per equivalent of substituted ethane of formula (I). More preferably, 1.5-2 equivalents of reagent are used. The reaction is carried out in the same manner and under the same conditions as described above for the preparation of compounds of formulas IIA and IIB, except that 1.5-2 equivalents of RM are preferably used and no proton is used. liabilities. The ratio of trans (IIIB) to cis (IHA) in the reaction mixture is greater than 7030. The trans isomer enriched in the trans isomer (IIIA) and (IIIB) or the pure (IIIB) The trans isomer is then reacted with a protected form of the 17-keto steroid of formula (I) (2a / -2 / 2e) to give a 16-unsaturated pregnane of formula (5) which can be readily converted to a useful 16-substituted krotikoiddá. In the above formulas, R, R, p R ^, _R2 ja as defined above,

R 1 is C 1 -C 5 alkyl, with the proviso that in the case of a ketal, the R 1 groups may be linked together to form an ethylene ketal,

R 1 and R 3 are the same or different and may be C 1-3 alkyl.

The 17-keto compounds of formula (1) -R, R _n and R ga as defined above - are well known, or are readily prepared using well-known methods from known compounds. For example, Δ ^1,4- l7-keto steroid compounds of formula (1) are disclosed in U.S. Patent No. 2,902,559, especially in Example 1. AA ^ UU.j7. keto steroids are also known, for example, from U.S. Pat. No. 2,838,551, particularly Examples 9 and 10. 6-α-methyl-17-keto steroids are known from U.S. Patent No. 3,166,551 (Example 8).

The 16/3-methyl-17-keto steroids of formula (1) are readily prepared from the corresponding 17-keto steroids, e.g., 3,391,169 (Examples 75 and 76), 704,253 (2). and Examples 1-3) and the process described in U.S. Patent 3,275,666.

Scheme B illustrates the utility of the compounds of the invention. The 17-keto steroids of formula (1) must be protected at the 3-carbon before reacting with the mixture of metal olefin compounds of formula (ΙΠΑ) and (IIIB). Androst-4-ene-7,17- dions (Formula (1)), 3-enol ether (Formula (2a)), 3-enamine (Formula (2b)) or ketal (Formula (2c)). The substituents herein have the meanings given above, unless otherwise indicated.

184 725

The enol ethers of formula 2a are prepared by methods well known in the art. See, for example, J. Org. Chem. 26, 3925 (1961). Steroid Reactions, C. Djerassi, Holden-Day, San Francisco, 1963, 42-45 and 3,516,991.

The 3-enaroine derivatives of formula (2b) may also be prepared by methods known in the art, such as, for example, U.S. Patent 3,629,298 and Steroid Reactions 49-53, cited above. page.

Examples of ketals of formula 2c are those described in Steroid Reactions 11-14, supra. of the present invention.

The 3,17-diones of formula (1) may be protected as 3-alkyleneamines of formula (2d) or ketals of formula (2e).

In Scheme B, the compound (2a) may be replaced by the compound (2b) or (2c), since they are all suitable for the corresponding intermediates (3a), (3b) and (3c), (4a). It leads to 21-aldehydes and 16-unsubstituted pregnanes of formula 5a. Similarly, Δ-steroid compounds of formula 2d may be replaced by compounds of formula 2e, which also lead to intermediates of formula 3e, 21-aldehydes of formula 4b, and 16-unsubstituted pregnanes of formula 5b .

If R j | is a hydroxyl group, the α- or β-hydroxyl group must be protected during reaction with the metal olefinic compound. The protecting group (TMS) can then be removed in a manner known in the art.

The protected 17-keto steroid compound (formula (2a), (2b) or (2c)) is reacted with a metal olefin compound corresponding to a mixture of the compounds (IIIA) and (IIIB) or (ΙΠΒ). The metal olefin compounds of the formulas (ΙΠΑ) and (ΠΙΒ) are prepared by the process of the present invention.

The cis-trans mixture (Η1Α) and the HIB or trans (IIIB) metal olefin are quenched in an aprotic solvent such as tetrahydrofuran, pentane, diethyl ether, hexane, toluene. At a temperature of from -60 ° C to -20 ° C, preferably from -60 ° C to -30 ° C, more preferably from -45 ° C, such as a nitrogen atmosphere.

The protected 17-keto steroids of formulas 2a to 2e are suspended in an inert aprotic solvent such as one of the solvents listed above or used in solid form. The use of the same solvent is preferred. The protected 17-keto steroids (2a) to (2e) are cooled to about -60 ° C to -30 ° C, preferably about -45 ° C. The metal olefin compounds of the formulas (ΠΙΑ) and (ΙΠΒ) or (IIIB) and the 17-keto steroid compounds of the formulas (2a) to (2e) are then used at temperatures below -25 ° C, preferably -60 ° C. and at -35 ° C. It is possible to add the metal olefin compound to the protected steroid compound or vice versa. In order to avoid side reactions, it is important to mix the substituted ethane of formula (I) with the metal base before reacting with protected 17-keto steroids.

The olefinic intermediates 3a to 3g may be isolated after about 0.5 to 20 hours. The isolation is preferably carried out after 3 hours, optionally with a suitable precipitant such as water or CON

Rj7 _represents C1-3 alkyl, and Rp is hydrogen, C1-3 alkyl or 2 to 4 carbon atoms,

N is chlorine or bromine,

W represents a bromine atom or an iodine atom.

Preferably, the precipitating agent is methyl iodide, methyl bromide or ethyl iodide, most preferably methyl codide.

In another preferred embodiment, the olefinic intermediates 3a to 3g are not isolated, but are hydrolyzed in an amount of more than 1 equivalent, preferably 6 equivalents, of an acid. The amount of acid is not critical, such as sulfuric acid, phosphoric acid, hydrochloric acid, acetic acid, citric acid. benzoic acid can be used. The reaction mixture is heated to about 25-50 ° C and stirred until the reaction is complete. The progress of the reaction was monitored by TLC. The reaction mixture is worked up and concentrated by conventional means to give the crude 21-aldehyde derivative of general formula (4). Starting from the protected Δ -3-keto steroid compounds 2a-2c, the 21-aldehyde 4 is obviously more closely related to the 21-aldehyde 4a. Similarly, when the process of the present invention is carried out starting from the Δ '-3-keto steroid compounds (Formulas I2d1-I2ej), the aldehyde (4) will more particularly correspond to the formula (4b). In the following, when referring to compounds of formula (4), we mean both compounds of formula (4a) and (4b). The 21-aldehyde (4) is crystallized from solvents such as a mixture of methylene chloride and heptane. When androsst-4,9 (II) -diene-3,17-dione is used as the 17-keto steroid of formula (1) and trans-2-chloro-1-ethoxy-2-lithioethylene is used as the metal olefin compound or the appropriate transcis mixture with a ratio of trans to cis relative to each other greater than 70:30 was used in 4 experiments to give the 21-alehyde 4: 6.6%, 86%, 7%, 84.0% and 83.5% (see Examples 4-7).

The aldehyde of formula 4 is a mixture of two geometric isomers which can be represented by the general formulas 4A and 4B. The two isomers are formed in approximately the same amount. If desired, the 21-aldehydes of Formula 4 can be isolated, but for the purposes of the invention, no isolation is required, or even an unnecessary step, since both 21-aldehyde isomers are converted to the desired 16-unsaturated pregnane of Formula 5. .

Scheme C illustrates a less preferred embodiment of the 21 aldehydes of formula (4) via the separable intermeter (3f) or (3g). Intermediates (3f) and (3g) are prepared by reaction of phosphorus oxychloride (3a) - (3c) and (3d) - (3e) with a base such as pyridine at about -45 ° C. temperature. The corresponding compounds of formula (3f) and (3g) are then reacted with an acid to convert the desired compounds of formula (3a) to (3c) and (3d) and (3e) as previously described. 21-aldehyde.

In the formulas (3a) to (3g), the C2Q double bond is always shown in the trans position. The metal olefin compounds of formula (IIIA) and (IIB) are a cis-trans mixture, and the compounds of general formulas (3a) to (3g) will be a mixture of cis and trans according to the position of the C ₂ Q double bond. If the metal olefin compound (III) used as a starting material is a trans isomer, the double bond at the C 4 position will, of course, also be in the trans position. In the description and in the examples, unless the C20 double bond position is specified, its geometry is the same as that of the metal olefin compound of formula (HI) used as starting material. The fact that the? 20-21 double bond in the compounds of formula (3) is cis-trans or merely trans-geometry is not very significant because, by acid hydrolysis, both isomers are converted to the same 21-aldehyde of formula (4) exists in the form of a geometric isomer. It is noted that Formula 4 illustrates both isomers of 21-aldehyde compounds. Again, it is irrelevant which of the 21-aldehyde isomers is obtained, since both lead to the same 16-unsaturated pregnane compound (formula (5)).

In the acid hydrolysis of compounds 3a to 3d, the 21-aldehydes 4 are deprotected on all compounds, whether protected as ether, enamine or ketal, and the desired general 4 The 21-aldehyde of formula IIa is obtained as a 3-keto compound.

For the compounds of formulas 3b, 3d and 3g, if the reaction medium is slightly acidic, it must be neutralized with a base until the pH is about 3-4, since this pH range has to remove the protecting group.

The 21-aldehydes of formula (4) are converted to the corresponding 6-unsaturated pregnanes of formula (5) by reaction with an alkali metal or alkaline earth metal salt of a carboxylic acid of formula R3COOH in a polar organic solvent. When the 21-aldehyde 4 is saturated at the C position (4a), the resulting 16-unsaturated pregnane 5 is more particularly the corresponding C 6 -unsaturated 16-unsaturated pregnane 5a. pregnane. If the. (4) 21-aldehyde is specifically a Δ ^1, -compound which can be described by the formula (4b), the corresponding (5b) of formula Δ '-16 unsubstituted pregnanes obtained. The 16 unsubstituted pregnanes, i.e. the compounds of formula 5, comprise both of the 16 unsaturated pregnanes of formulas 5a and 5b.

R 6 j is C 1-5 alkyl or phenyl.

Suitable salts of the acids of formula R21COOH include, for example, potassium acetate, sodium acetate, magnesium propionate, calcium butyrate, and sodium benzoate. Examples of organic solvents are dimethylformamide, pyridine, tetrahydrofuran, dimethylacetamide. The preferred solvent is dimethylformamide, while the salt is preferably sodium or potassium acetate. The reaction is carried out at 50-200 ° C, preferably

The reaction is carried out at 100-150 ° C for 4-8 hours, depending on the particular 21-aldehyde (4), salt and solvent. The most conveniently by reacting the crystalline (4) 21-aldehyde is added slowly to dimethylformamide, and ethyl acetate was added, at about 120 ^C under nitrogen. The reaction was monitored by TLC (1: 1 ethyl acetate: hexane). When the reaction is complete, the mixture is cooled and an organic solvent such as toluene is added. The mixture was extracted twice with 5% aqueous sodium chloride solution and washed twice with organic solvent. The organic solutions were combined, dried and concentrated under reduced pressure. 16-unsaturated pregnane (5) is obtained (see Example 8).

The 16-unsaturated pregnanes of formula 5 can be used in the synthesis of several anti-inflammatory steroid compounds. When the substituents R 1 and R 3 are hydrogen and the final product requires substituents other than hydrogen at the sites, this can be accomplished by methods well known to those skilled in the art, without departing from the spirit of the invention. If there is no unsaturation at the C 1 position and an unsaturated compound is required at this position, the compound can be dehydrogenated by known methods. If substitution is required at the Rg or Rg position, unsaturation at the Cj or Cqqj position, the appropriate substituents may be introduced into the 17-keto steroid of formula (1) before starting the synthesis to provide appropriately substituted compounds.

In particular, 21-acetoxy-pregna-4,9 (11), 16-triene-3,20-dione of formula (5) is a useful intermediate in the preparation of commercially valuable steroids. It is well known to those skilled in the art that the 16-unsaturated pregnanes of formula (5) can be converted to 16α-hydroxy, 16α-methyl and 160-methyl steroids.

For example, U.S. Pat. No. 2,864,834 and J. Am. Chem. Soc. 78, 5693 (1956) disclose methods by which 21-acetoxy-pregna-4.9 (II), 16- the triene-3 20-dione can be converted to 9a-fluoro-11 / 3,16a, 17a, 21-tetrahydroxypregna-1,4-diene-3,20-dione (triamcinolone). J. S. Mills et al., J. Am. Chem. Soc., 82, 3399 (1960) describe a method by which 21-acetoxy-pregna-4,9 (II), 16-triene-3,20-dione is readily obtained. convertible to 6a, 9a-difluoro-10,16a, 17a, 21-tetrahydroxypregna-1,4-diene-3,20-dihydro-16,17-acetonide (fluoxinolone acetonide).

U.S. Patent 3,923,985 discloses a method for incorporating a 16a-methyl group into 21-acetoxypregna-1,4,9 (11), 16-tetraene -3,20-dione, and 21-acetoxy-16α-methyl-pregna-1,4,9 (11) -triene-3,20-dione can be prepared. The resulting compound is readily converted to 16a-methyl steroids such as 6a-fluoro-11,177a, 21-trihydroxy-16a-methylpregna-1,4-diene-3,20-dione by methods well known in the art. and 6a, 9a-difluoro-10,17a, 21-trihydroxy-16a-methyl-pregna-1,4-diene-3,20-dione (flumetazone).

As used herein, the term "alkyl groups" is intended to include isomers of alkyl groups, if any.

Example

-Chloro-2-ethoxy-1-lithioethylene - Compound of Formula IIIA and IHB

In a nitrogen atmosphere, 2.4 mmol of 90% 1,2-dichloroethyl ether and 3.6 ml of anhydrous tetrahydrofuran were mixed and the resulting mixture was cooled to below -70 ° C using a dry ice / acetone cooling bath. Thereafter, 3.0 ml of a 1.6 molar solution of n-butyllithium (4-8 mmol) was added dropwise over 11.5 minutes, keeping the temperature below -70 ° C during the addition. After the addition was complete, the temperature of the reaction mixture was allowed to rise to -40 ° C. Almost 20 microliters of benzene are added as an internal standard. Then, low temperature NMR analysis was performed. At -55 ° C, a singlet at a chemical shift of 6.84 delta relative to the external standard tetramethylsilane was observed. This is a singlet corresponding to the vinyl proton of trans-1-chloro-2-ethoxy-1-lithioethylene of formula (ΠΙΒ). If the sample is allowed to warm to 0 ° C, this signal disappears during subsequent NMR analysis, indicating the thermal instability of the compounds.

A sample of the reaction mixture is quenched with water. Subsequent NMR analysis of the resulting organic phase shows that the ratio of trans-1-chloro-2-ethoxyethylene to the cis isomer is greater than 80:20, which in turn indicates that the for the lithio compound prepared in the reaction. The NMR spectrum at -55 ° C in a mixture of tetrahydrofuran and hexane was 6.68 (d, trans isomer, J = 12.0 Hz), 6.39 (d, cis isomer, J = 4, 8 H 2), 5.45 (d, trans isomer, J = 12.0 H 2) and 4.96 (d, cis isomer, J = 4.8 Hz).

PREPARATION

Preparation of 20-Chloro-pregna-4,9 (11), 17 (20) -thyrene-3-one-21-al [4a] 1-chloro-2-ethoxy-1-lithioethylene ( IIIa) and (IIIb). To the reaction mixture prepared in the example is added in one portion 2.16 g of 3-hydroxyandrost-3,5,9 (11) -trien-17-one-3-methyl ether (U.S. Pat. No. 3,516,991). (2a). The mixture was stirred at about -40 ° C for 3.25 hours and then allowed to warm to -10 ° C. 1.8 ml of 6N aqueous hydrochloric acid are added and the organic solvents are removed under reduced pressure. The residue was dissolved in 7.2 ml of methylene chloride and 9 ml of 6N aqueous hydrochloric acid and the mixture was stirred for 18 hours at 20-25 ° C. The reaction mixture was then diluted with methylene chloride (20 mL) and water (60 mL). The organic layer was separated and washed with water (2 x 50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in methylene chloride (3.15 mL) and added dropwise with stirring (26 mL) over 45 minutes. The resulting suspension was stirred at 0-5 ^b C for 30 minutes and filtered. The solid was washed with heptane / methylene chloride (95: 5, 2.25 mL) and pentane (2 x 3 mL) and dried under reduced pressure at about 50 ° C. 20-Chloro-pregna-4,9 (11), 17 (20) -trien-3-one-21-aa-1 is obtained (formula 4a).

Claims (10)

A process for the preparation of compounds of formula (ΠΙΑ) and (IHB) - wherein R20 is chlorine, X is oxygen, Z is C 1 -C 4 alkyl, M is an alkali metal atom in the form of a mixture wherein the ratio of the trans isomer of formula IIIB to the cis isomer of formula (ΠΙΑ) is greater than 70:30, preferably greater than 75:25, characterized in that A compound of formula (I) - O is a chlorine, bromine or iodine atom or a trimethylamino tube powder, Raq, X and Z have the meanings given in the scope, with a compound of formula R-M, M represents an alkali metal atom, preferably a lithium, sodium or potassium atom, R is C 1-5 alkyl or phenyl in the presence of anhydrous organic solvent at a temperature of -15 ° C to -120 ° C. 2. The process of claim 1, wherein the compound of formula R-M, wherein R and M are as defined in claim 1, is used in an amount greater than 1.3 equivalents. 3. The process of claim 1 wherein the compound of formula R-M, wherein R and M are as defined in claim I, is used in an amount of 1.5 to 2 equivalents. 4. A process according to claim 1 wherein R is a reagent of the formula wherein M is a lithium atom, R is as defined in claim 1. 5. A process according to claim 4 wherein n-butyllithium is used as the compound of formula R-M. 6. A process according to claim 1 wherein the starting material is a compound of formula I wherein Z is methyl or ethyl and the other substituents are as defined in claim 1. 7. A process according to claim 6 wherein Z is ethyl and the other substituents are as defined in claim 1. 8. A process according to claim 1 wherein the starting material is a compound of formula I wherein O is chlorine and the other substituents are as defined in claim 1. 9. A process according to claim 1, wherein the reaction is carried out at -30 ° C to -90 ° C. 10. The process of claim 1, wherein Z is an ethyl group of formula (ΠΙΑ) and a compound of formula (ΙΠΒ) wherein the other substituents are as defined in claim 1. 184,729, wherein the ratio of the trans isomer of formula (IIIB) to the cis isomer of formula (HJA) is greater than 70:30, characterized in that 1.5 to 2 equivalents of the compound of formula (IA) Reacts with n-butyllithium · 5 at -45 ° C to -90 ° C 7 drawing