GB2046755A - Metalating Olefines - 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

SPECIFICATION Metalating Olefins Trans metalated olefins add to 17-keto steroids better than the corresponding cis isomers to produce 16-unsubstituted pregnanes which can be readily converted by methods well known to those skilled in the art to useful 1 6-substituted corticoids. The metalated olefins are prepared from the corresponding olefin. It therefore is important to be able to prepare the olefin with a very high trans to cis ratio.

J. F. Arens et al. in Rec. trav. chim. 77, 753 (1958) disclose a process to convert chloroacetaldehyde diethylacetal to 1-chloro-2-ethoxyethene by heating with acid catalysts. On page 755 the authors indicate that "The product consisted for the greater part of the cis-isomer." The present invention surprisingly and unexpectedly produces a trans cis ratio of greater than 70:30.

J. F. Arens also reported in Rec. trav. chim. 74,271(1955) dehydrohalogenating 1,2-dichloro-2ethoxyethane to give 1 -chloro-2-ethoxyethene. On page 274 Arens indicates that the product contained " . . . about 75% of the cis isomer and 25% of the lower boiling trans isomer." S. Hunig and M. Kiessel in Chem. Ber. 91,380(1958) reported transforming 1,2-dichloro-2ethoxyethane to 1 -chloro-.2-ethoxyethene by use of a tertiary amine and heat. Under the various reaction conditions reported the reaction produced predominantly the cis isomer.

German Offen. 2,210,010 reports the reaction of 1,1-dichloro-2-methoxyethane with methoxide to give 1 -chloro-2-methoxyethene. The cis isomer was produced (54%) to a greater extent than the trans isomer (46%).

D. A. VanDorp et al. reported in Rec. trav. chim. 70,289 (1951) the conversion of dichloroacetaldehyde diethylacetal to 1 -chloro-2-ethoxyethene by use of activated zinc dust. The authors report (page 293), "The yield of the cisisomer is found to be 4-5 times as great as that of the trans-isomer.

M. Farina et al. reported in Rend. 1 st Lombardo Sci. Pt. 1 Classe Sci. Mat. e Nat. 94A, 600 (1960) that the transformation of 1 ,2-dichloro-2-i-butoxyethane to 1 -chloro-2-i-butoxyethene with a tertiary amine and hydrochloric acid gave a product which contained 7590% of the cis isomer.

All of the above articles indicate that the trans isomer is produced to a much less extent than the cis isomer. These were empirical findings and the possible mechanistic reasons were not reported.

However, in 1976 E. Taskinen and E. Sainio in Tetrahedron 32, 593 (1976) reported that based on thermodynamic calculations the cis isomer should predominate due to its lower enthalpy.

Therefore, based on both theoretical considerations as well as ,previous experiments reported in the chemical literature one skilled in the art would expect to have a trans to cis ratio much less than 50:50. However, the present invention (process) surprisingly and unexpectedly.

The only known method in which a mixture of 1 -chloro-2-alkoxyethenes is produced in which the ratio of the trans to the cis isomer is greater than 70:30 is the indirect method involving production of the cis:trans mixture by conventional processes, followed by fractional distillation.

According to the present invention, the isomers of a compound of the formula CMR20=CH-X-Z Ill or the isomers of a compound of the formula CHR20=CH-X-Z II in which the ratio of the trans isomer to the cis isomer is greater than 70:30, can be produced by a process which comprises reacting an ethane derivative of the formula CH2 R20-CH Q-X-Z with an organometal compound of the formula RM at from -15 to -1200C, the reaction product being quenched with a proton source if the non-metalated product (II) is required.

The olefines of formula 11 are useful as intermediates in the production of the metalated olefines of formula Ill. The metalated olefines are useful for adding a two-carbon side chain to a C-3 protected 17-oxo-steroid to produce a 1 6-unsaturated pregnane which can be readily converted to useful 16substituted corticoids.

In the subsequent description, llA and IIIA refer to the cis isomers of the olefins and lIB and IIIB refer to the trans isomers of the olefins.

The substituted ethanes of formula (I) are either known to those skilled in the art or can readily be prepared from known compounds by methods well known to those skilled in the art. For the substituted ethane of formula (I), R20 is a fluorine or chlorine atom or a NRaRp group where Ra and are the same or different and are alkyl of 1 thru 3 carbon atoms. It is preferred that R20 is a chlorine atom. X is an oxygen or sulfur atom, it is preferred that X is an oxygen atom. Z is alkyl of 1 thru 6 carbon atoms, phenyl or p-methyl-phenyl. It is preferred that Z is an alkyl group of 1 thru 4 carbon atoms, it is more preferred that Z is a methyl or ethyl group. 0 is a good leaving group, a chlorine, bromine or iodine atom or a trimethylamino group. It is preferred that 0 is a chlorine atom.

The compounds of the formula, R-Metal are either known to those skilled in the art or can readily be prepared from known compounds by methods well known to those skilled in the art. For the compound of the formula R-Metal, R is alkyl of 1 thru 5 carbon atoms and phenyl. It is preferred that R is a secondary group or a primary alkyl group of 1 thru 4 carbon atoms. The metal is lithium, sodium, or potassium. It is preferred that the metal is lithium. It is also preferred that the compound R-Metal is selected from the group consisting of n-butyl lithium, propyl lithium, s-butyl lithium, n-butyl potassium or i-propyl lithium. It is more preferred that R-Metal is n-butyl lithium.

The substituted ethane (I) and the R-Metai are mixed in a dry organic solvent. The organic solvent must be dry because if water is present it would react with the R-Metal necessitating the use of extra R-Metal. The preferred organic solvents are ethers such as THF, dimethoxyethane, diethyl ether, dioxane, etc. It is most preferred that the organic solvent is THF. The organic solvent may comprise a mixture of ether and hydrocarbon and/or aromatic solvents provided that the mixture contains at least some ether. It is preferred that the ether be present in as high a concentration as possible. The reaction is best performed in pure THF. The substituted ethane (I) can be added to the compound of the formula R-Metal or the other way around.

The reaction is performed in a temperature range of -1 5" to 1200, preferably -30 to 900, more preferably at about 600 to 900. At higher temperatures the reaction proceeds faster than at the lower temperatures as is well known to those skilled in the art. The reaction is exothermic, therefore, the R-Metal reagent is added very slowly, usually over a period of 1 5 minutes to 1.5 hours.

Because the reaction is exothermic the reaction mixture must be cooled to maintain a reaction temperature not greater than -1 50. At --900 the reaction is usually complete in about 1 hour while at 300 the reaction is complete in about 1 5 minutes. At 150 the reaction proceeds, however, the yield is low. Even though the yield is low, the ratio of trans (1118) to cis (IIIA) isomers is greater than 70:30.

If it is desired to isolate the olefin (II) the substituted ethane (I) is reacted with the R-Metal compound which produces a mixture of the oiefin (II) and the metalated olefin (III). In order to assure that the starting material (I) is maximally utilized it is preferred that at least 1 equivalent of R-Metal be utilized, it is even more preferred that at least 2 equivalents of R-Metal be utilized. When the reaction is complete (about 1 hour) the reaction mixture is quenched with a proton source which converts any metalated olefin (III) to olefin (IIA and lib). The proton source is any very mildly acidic compound such as water, an alcohol (R8-OH), a carboxylic acid (RbCOOH), sulfuric acid or ammonium salts.A sufficient amount is used but not so much that the pH of the reaction mixture becomes less than 6. It is preferred that the quenching agent is selected from the group consisting of water, methanol, ethanol, acetic acid or ammonium chloride. If it is desired to obtain pure trans olefin (lib), it may be readily obtained by methods well known to those skilled in the art such as fractional distillation. The reaction mixture is then worked up as is well known to those skilled in the art.

If the metalated olefin (III) is the desired product of the process of the present invention then preferably greater than 1.5 equivalents of R-Metal/equivalent of substituted ethane (I) are used, more preferably 1.5-2 equivalents. The reaction is performed in the same manner and under the same conditions set forth above for the production of the olefin (II) except that 1.5-2 equivalents of R-Metal are preferred and the reaction is not quenched. The reaction mixture contains a ratio of trans (1118) to cis (IIIA) isomers of greater than 70:30.The metalated olefin mixture (IIIA and I1IB) enriched in the trans isomer (IIIB) or the pure trans metalated olefin (1118) is then reacted with a 1 7-keto steroid (1) in its protected form (2a-2e) to produce a 16-unsaturated pregnane (5) which is readily converted to a useful 16-substituted corticoid.

The 1 7-keto steroids (1) are well known to those skilled in the art or may readily be prepared from known compounds by methods well known to those skilled in the art. For example, the A1,4-1 7- keto steroids (1) are known, see U.S. Patent 2,902,410, in particular Example 1. The A4( 11 )-1 7-keto steroids (1) are known, see U.S. Patent 3,441,559, in particular Example 1. The 6a-fluoro-1 7-keto steroids (1) are known, see U.S. Patent 2,838,492, in particular Examples 9 and 10. The 6a-methyl17-keto steroids (t) are known, see U.S. Patent 3,166,551 in particular Example 8.

The 1 6-methyl-1 7-keto steroids (1) can readily be prepared from the corresponding 17-keto steroid (1) by the processes of U.S. Patents 3,391,169 (Examples 75 and 76), 3,704,253 (Column 2 and Examples 1-3) and 3,275,666.

Chart B discloses the utility of the present invention. The 1 7-keto steroids (1) where R6 is a CHART B

hydrogen or fluorine atom or methyl group; where R1 is a hydrogen atom, a-ORiia or or ss--OR11a; where R1,a is a hydrogen atom orTMS with the proviso that when R" is ORiia, ---in ring C is a single bond; where R,6 is a hydrogen atom or methyl group; where N indicates the R,6 group can be in either the a or p configuration and where - - - is a single or double bond, must be protected at the C-3 position before reaction with the metalated olefin (III). The androst-4-ene-3,1 7-diones (1) are protected as the 3-enol ether (2a), 3-enamine (2b) or ketal (2c).

where R3 is alkyl of 1 thru 5 carbon atoms, with the proviso that with the ketal the R3 groups can be connected to form the ethylene ketal; R3' and R3" are the same or different and are alkyl of 1 thru 5 carbon atoms. The enol ethers (2a) are prepared by methods well known in the art, see J. Org. Chem.

26, 3925 (1961), Steroid Reactions, Edited by Carl Djerassi, Hoyden Day, San Francisco 1963, page 42-45, and U.S. Patent 3,516,991 (Preparation 1). The 3-enamines (2b) are also prepared by methods well known in the art, see U.S. Patent 3,629,298 and Steroid Reactions, supra, page 49-53.

The ketals (3c) are also prepared by well known methods, see Steroid Reactions, supra, page 11-14.

The androsta-1,4-diene-3,1 7-diones (1) are protected as the 3-dialkylenamine (2d) or ketal (2e)

In Chart B, the compound of formula (2a) can be replaced by either the compound of formula (2b or 2c) all of which will produce the corresponding intermediate compound of the formula (3a, 3b or 3c), 21-aldehyde (4a) and 16-unsaturated pregnane (5a). Likewise with the ' steroids the compound of formula (2d) can be replaced by the compound of formula (2e) which will produce the corresponding intermediate compound of the formula (3e), the 21-aldehyde (4b) and the 16-unsaturated pregnane (5b).

When R11 is hydroxyl, either a or k the hydroxyl group must be protected during the metalated olefin (organo lithium) reaction. The protecting group (TMS) can then be removed by means well known to those skilled in the art.

The protected 17-keto steroids (2a, 2b or 2c) are reacted with a metalated olefin (IIIA and 1118) or (IIIB). The metalated olefins (IIIA and IIIB) are prepared according to the process of the present invention.

The cis-trans mixture (IIIA and IIIB) or trans (1118) metalated olefin in an inert aprotic solvent such as THF, pentane, diethyl ether, hexane, toluene is cooled to boo to 2O0, preferably between 600 and 300, more preferably about 450 under an inert atmosphere such as nitrogen.

The protected 1 7-keto steroid (2a-2e) is suspended in an inert aprotic solvent such as those listed above or added as the solid. It is preferable to use the same solvent. The protected 17-keto steroid (2a-2e) is cooled to about 600 to --300, preferably to about -45 . The metalated olefin (IIIA and 1118) or (1118) and the protected 17-keto steroid (2a-2e) are then contacted at a temperature below 250, preferably about --60 to --350. The metalated olefin (IIIA and 1118) or (1118) can be added to the protected steroid (2a-2e) or the protected steroid can be added to the metalated olefin (III).In order to avoid side reactions it is important to premix the substituted ethane (I) with the metal-base prior to the contacting with the protected 1 7-keto steroid (2a-2e).

The olefin intermediate (3a-3e) can be isolated after about 0.5-20 hours, preferably about 3 hours, if it is so desired by quenching the reaction with a suitable quenching agent such as water, R1,aW, (R17aCO)20 or R17aCOM where R17a is alkyl of 1 thru 3 carbon atoms, thereby R1, is a hydrogen atom, alkyl of 1 thru 3 carbon atoms or an acyl group of 2 thru 4 carbon atoms. M is a chlorine or bromine atom. W is a bromine or iodine atom. Preferred quenching agents include methyl iodide, methyl bromide, and ethyl iodide. Most preferred is methyl iodide.

Alternatively and preferably the olefin intermediate (3a-3e) is not isolated but is hydrolyzed by acid, greater than 1 equivalent being required, preferably about 6 equivalents. The particular acid is not critical, acids such as sulfuric, phosphoric, hydrochloric, acetic, citric, benzoic are all suitable. The reaction mixture is warmed to about 2550 and stirred until the reaction is complete as measured by TLC. The reaction mixture is worked up by the usual methods and concentrated to give the crude 21-aldehyde (4). When one starts with the protected A4-3-keto steroid (2a-2c) the 21-aldehyde (4) produced will obviously be the 21 -aldehyde (4a).Likewise when one practices the process of the present invention beginning with the protected A1,4-3-keto steroid (2d or 2e) the 21 -aldehyde (4) produced will be the 21 -aldehyde (4b). The term 21 -aldehyde (4) when used is meant to apply to and include both 21-aldehydes (4a and 4b) when appropriate. The 21-aldehyde (4) is crystallized from solvents such as methylene chloride-heptane. When the 17-keto steroid (1) is androst-4,9(1 1 )-diene- 3,1 7-dione and the metalated olefin is trans-2-chloro-1-ethoxy-2-lithioethene or a trans-cis (IIIA and IIIB) mixture with a ratio of greater than 70:30 the yield of the 21 -aldehyde (4) for 4 experiments was 86.6, 86.7, 84.0 and 83.5% chemical yield, see Examples 4-7.

The 21-aldehyde (4) is a mixture of the 2 geometrical isomers

formed in approximately equal amounts. The isomeric 21 -aldehydes (4) can be separated if desired but for the purposes of the present invention it is not necessary and even undesirable to do so since both isomeric 21 -aldehydes (4) are converted to the desired 16-unsaturated pregnane (5).

Chart C discloses an alternative, but less preferred, process for producing the 21 -aldehyde (4) which is via an isolatable intermediate (3f or 39). The isolatable intermediates (3f and 39) are obtained from (3a-3c) and (3d and 3e) respectively by reaction with a compound such as phosphorous oxychloride (POCI3) with a co-reagent base such as pyridine at about 450 The respective products (3f and 39) are then transformed to the desired 21 -aldehyde (4) by reaction with an acid as described above for the compounds (3a-3c) and (3d and 3e).

CHART C

The formulas for the compounds (3a-3g) all show the double bond at C20 to be trans. When the metalated olefin (III) is a cis-trans mixture then the double bond at C20 of the compounds (3a-3g) would be a mixture of cis and trans isomers. When the metalated olefin (III) is the trans isomer then the double bond at C20 will of course be trans. In the specification and examples when the cis-trans nature of the C20 bond is not specified it will have the geometry as that of the starting metalated olefin compound (III) as is well known to those skilled in the art.Whether the C20~2, double bond is cis-trans or just trans in the compounds of formula (3) is not of great importance inasmuch as upon acid hydrolysis they are both converted to the identical 21-aldehyde (4) which in itself exists in two geometrically isomeric forms. It is understood that the formula for the 21 -aldehyde (4) is meant to and does represent both isomeric 21 -aldehydes. Again, it is not critical as to which 21 -aldehyde isomer is obtained inasmuch as both are converted to the identical 16-unsaturated pregnane (5).

During the acid hydrolysis of the compounds of formula (3a-3d) to the 21-aldehyde (4) the protecting group is removed from these five compounds regardless of whether they were protected as an ether, enamine or ketal and the desired 21-aldehyde (4) is obtained as the 3-keto compound.

In the case of enamines (3b, 3d and 39) if the reaction medium is a little too acidic it should be neutralized with a base to a pH of approximately 3 to 4 which is preferable for removal of the enamine protecting group.

The 21 -aldehydes (4) are converted to the corresponding 16-unsaturated pregnane (5) by reaction with an alkali metal or alkaline earth metal salt of a carboxylic acid of the formula R21COOH in a polar organic solvent. When the 21 -aldehyde (4) is saturated at C, (4a) the 16-unsaturated pregnane (5) obtained is the corresponding C, saturated 16-unsaturated pregnane (5a). When the 21 -aldehyde (4) is the A1,4-compound (4b) the corresponding ' A1,4-1 6-unsaturated pregnane (5b) is obtained. The term 16-unsaturated pregnane (5) is meant to include and apply to both 1 6-unsaturated pregnanes (5a and 5b) when appropriate. R21 is alkyl of 1 thru 5 carbon atoms or phenyl.Suitable salts of these acids include, for example, potassium acetate, sodium acetate, magnesium propionate, calcium butyrate and sodium benzoate. Suitable organic solvents for the reaction include DMF, pyridine, THF, DMAC and the like. It is preferred the organic solvent be DMF and the salt be sodium or potassium acetate. The reaction is conducted in the range of 50200 , preferably 100-1 500 depending on the particular 21-aldehyde (4), the salt and the solvent and is usually complete in 4-8 hours. The process is best performed by using crystalline 21 -aldehyde (4) and adding it slowly to a mixture of DMF and acetate at about 1200 under nitrogen.The reaction is monitored by TLC, ethyl acetate-hexane (1:1). When the reaction is complete it is cooled and an organic solvent such as toluene is added. The mixture is extracted twice with sodium chloride (5%) and back washed twice with an organic solvent. The organic solvents are combined, dried and concentrated under reduced pressure to give the 16-unsaturated pregnanes (5), see Example 8.

The 16-unsaturated pregnanes (5) are useful in the synthesis of a number of anti-inflammatory cortical steroids. If the substituents R6 and R,6 are hydrogen and in the final product it is desired they not be hydrogen they can be transformed to the desired substituent within the scope of their definition by means well known to those skilled in the art. If unsaturation is not present at C-1 and it is desired, the compound may be dehydrogenated by known means. If substitution at R6, R,6 or unsaturation at C-1 or C-9(1 1) is desired these substituents may be added to the 1 7-keto steroid (1) before beginning the synthesis thereby having the desired substitution in the molecule when the 16unsaturated pregnane (5) is obtained.

In particular, 21 -acetoxypregna-4,9( 1 1).1 6-triene-3,20-dione (5) is a very useful intermediate in the synthesis of commercially valuable steroids. It is well known to those skilled in the art that the 16unsaturated pregnanes (5) can be transformed to 1 6a-hydrnxy, 1 6a-methyl and 16,B-methyl steroids.

For example both U.S. Patent 2,864,834 and J. Am. Chem. Soc. 78, 5693 (1956) describe procedures for transforming 21 -acetoxypregna-4,9( 11), 1 6-triene-3,20-dione (5) to 9o'-fluoro- 11ss,16α,17α,21 -tetrahydroxypregna-1 ,4-diene-3,20-dione (triamcinolone). J. S. Mills et al. in J. Am.

Chem. Soc. 82,3399(1960) describe a method by which 21 -acetoxypregna-4,9(11),16-triene-3,20- 21-acetoxypregna-4,9(1 1),16-triene-3,20- dione (5) could readily be transformed to 6α,9α-difluoro-11ss,16α,17α,.21 -tetrahydroxypregna-1 ,4diene-3,20-dione 16,17-acetonide (fluocinolone acetonide).

U.S. Patent 3,923,985 describes a process for the introduction of a 16-methyl group into 21 acetoxypregna-1 ,4,9( 11 ),1 6-tetraene-3,20-dione (5) to give 21 -acetoxy-1 6a-methylpregna- 1,4,9(11 )-triene-3,20-dione which by methods well known to those skilled in the art can be converted to 16cr-methyl steroids such as 6α-fluoro-11ss,17α,21 -trihydroxy-l Ga-methylpregna-l ,4-diene-3,20- dione (paramethasone) and its 21-acetate; 9a-fluoro- 11 , 1 7a,2 1 -trihydroxy- 1 6a-methylpregna-1 ,4- diene-3,20-dione (dexamethasone) and 6a,9a-difluoro-11p,17cr,21 -trihydroxy-1 6-methylpregna- 1 ,4-diene-3,20-dione (flumethasone).

The definitions and explanations below are for the terms as used throughout the entire patent application including both the specification and claims.

All temperatures are in degrees Centigrade.

TLC refers to thin-layer chromatography.

GC refers to gas chromatography.

THF refers to tetrahydrofuran.

TMS refers to trimethylsilyl.

DMSO refers to dimethylsulfoxide.

DMF refers to dimethylformamide.

SSB refers to an isomeric mixture of hexanes.

DMAC refers to dimethylacetamide.

PMR refers to proton magnetic resonance spectroscopy, chemical shifts are reported in ppm (#) downfield from TMS.

When solvent pairs are used, the ratio of solvents used are volume/volume (v/v).

R is alkyl of 1 thru 5 carbon atoms or phenyl.

R3 is alkyl of 1 thru 5 carbon atoms with the proviso that with the ketal the R3 groups can be connected to form the ethylene ketal.

R6 is a hydrogen or fluorine atom or methyl group.

R11 is a hydrogen atom, a-ORiia or P pOR1,a with the proviso that when Rr, is ORiia, - - - in ring C is a single bond.

Riia is a hydrogen atom orTMS.

R.6 is a hydrogen atom or methyl group.

R17 is a hydrogen atom, alkyl of 1 thru 3 carbon atoms or an acyl group of 2 thru 4 carbon atoms.

R17a is alkyl of 1 thru 3 carbon atoms.

R20 is a fluorine or chlorine atom orNRQR .

R2, is alkyl of 1 thru 5 carbon atoms or phenyl.

R3, and R3" are the same or different and are alkyl of 1 thru 5 carbon atoms.

Ra and Rp are the same or different and are alkyl of 1 thru 3 carbon atoms.

Ra is alkyl of 1 thru 4 carbon atoms.

Rb is alkyl of 1 thru 6 carbon atoms or phenyl.

M is a chlorine or bromine atom.

Q is a chlorine, bromine, iodine atom ortrimethylamino group.

W is a bromine or iodine atom.

Xis an oxygen-or sulfur atom.

Z is alkyl-of 1 thru 6 carbon atoms, phenyl or p-methylphenyl.

Metal is lithium, sodium, or potassium.

N indicates the R,6 group can be in either the a or,3 configuration.

- - - is a single or double bond.

When the term "alkyl of thru carbon atoms" is used, it includes isomers of the alkyl group when such exist.

EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limiting of the preceding disclosure in any way whatsoever.

Example 1 1-Chloro-2-ethoxyethene (ila and lib) 1,2-Dichloro-1-ethoxyethane (la, 153 mg., 90% purity) and THF (1 ml.) are cooled to below 400 under nitrogen. n-Butyl lithium in hexane (1.5 M, 1.35 ml.) is added dropwise over about 5 minutes.

The mixture is stirred for 20 minutes at less than 400. Water (100 yI) is added and the mixture brought to 2025 . The solution is analyzed by PMR which indicates a ratio of trans:cis 1 -chloro-2ethoxyethene of 78:22.

Example 2 1 -Chloro-1 -deutero-2-ethoxyethane Following the procedure of Example 1, but quenching the reaction with D2O (100 yl) instead of water, the title compound is obtained. Upon PMR analysis the ratio of trans:cis 1-chloro-1-deutero-2- ethoxyethene is about 80:20.

Example 3 Preparation of 20-chloropregna-4,9(1 I ),I 7(20)-trien-3-on-21 -al (4a) utilizing 1 -chloro-2- ethoxyethene (Ila and lIB) as 1 -chloro-2-ethoxy-I -lithioethane (lIA and Illb) 1 ,2-Dichloro-1 -ethoxyethane (la, 1.84 g., 909/0 purity) and dry THF (12 ml.) are placed under nitrogen and cooled to bellow 450 n-Butyl lithium in hexane (1.45 M, 15.5 ml.) is added dropwise over about 1 8 minutes. The mixture is stirred an additional 30 minutes and 3-hydroxyandrosta 3,5,9(11 )-trien-1 7-one 3-methyl ether (2a, U.S. Patent 3,516,991, 2.16 g.) is added all at once.The mixture is stirred for 3.25 hours at about 400 and then allowed to warm to 100. Aqueous hydrochloric acid (6N, 1.8 ml.) is added and the organic solvents are removed under reduced pressure.

The residue is dissolved in methylene chloride (7.2 ml.) and aqueous hydrochloric acid t6N,9 ml.) and stirred for 18 hours at 2025 . The reaction mixture is then diluted with methylene chloride (20 ml.) and water (60 ml.). The organic layer is separated and washed with water (2x50 ml.), dried over sodium sulfate and concentrated under reduced pressure to a residue. This material is dissolved in methylene chloride (3.15 ml.) with stirring and heptane (26 ml.) is added dropwise over 45 minutes.

The resulting slurry is stirred at 0--50C for 30 minutes and then filtered. The solids are washed with heptane-methylene chloride (95:5, 2.25 ml.) and pentane (2x3 ml.) and then dried at about 500 under reduced pressure to give 20-chloropregna-4,9(1 1 ),1 7(20)-trien-3-on-21-al (4a).

Example 4 20-Chloropregna-4,9( 11 ),1 7(20)-triene-3-on-21 -al (4a) Anhydrous THF (250 ml.) and 1,2-dichloro-1-ethoxy-ethane (I, 22 ml., 25.1 g.) are cooled to 650 under nitrogen. n-Butyl lithium (323 mmole) is added dropwise over 60 minutes keeping the temperature below 650. This is followed by a 10 ml. hexane rinse. The mixture is stirred for about 60 minutes. 3-Hydroxyandrosta-3,5,9(1 1)-triene-17-one 3-methyl ether (2a, 33.1 g.) is added all at once.

The mixture is stirred 3 hours, and then warmed to 450 for 1 hour. The cooling is stopped and the mixture is warmed to 00. Water (14 ml.) is added followed by hydrochloric acid (6N, 140 ml.). The mixture is stirred for about 12 hours at 20-250C. Methylene chloride (600 ml.) and water t600 ml.) are added. The phases are separated and the aqueous phase is extracted with methylene chloride (2x25 ml.). The organic phases are washed with water (400 ml.) and potassium carbonate (10%, 150 ml.). The combined methylene chloride extracts are dried and concentrated to give the crude chloroaldehyde (IV).

The solid is redissolved in methylene chloride {56 ml.) and heptane (45 ml.) is added. The mixture is seeded and heptane (350 ml.) is added dropwise over about 2.2 hours. The slurry is stirred for 1 hour at 2025 ,1 hour at 00, filtered and the solids washed with heptane-methylene chloride (95:5) and hexane (2x25 ml.) and dried to give an isomeric mixture of the title compound, 33.1 g. (86.6% chemical yield). PMR (CDCl3) 1.02, 1.1, 1.37,5.55,5.75,9.7 and 9.9S.

Following the general procedure of Example 4 and making non-critical varations, Examples 5, 6 and 7 give the following yields (chemical) Example Yield (Chemical)% 5 86.7 6 84.0 7 83.5 Example 8 21 -Hydroxypregna-4,9( 11 ),1 6-triene-3,20-dione-21 -acetate (5a) Anhydrous sodium acetate (5.8 g.) and DMF are stirred and heated at 1200 under nitrogen.

Crystalline 20-chloro-pregna-4,9( 11), 1 7(20)-trien-3-one-2 1-al (4a, Example 4, 12 g.) is added by adding 2 gm. every 20 minutes. The mixture is stirred for 90 minutes at 1200, the reaction is cooled and toluene (100 ml.) is added. The mixture is extracted with sodium chloride (5%,2x 100 ml.) and backwashed with toluene (2x20 ml.). The toluene phase is dried over magnesium sulfate and concentrated under reduced pressure to give the title compound, m.p. 120--1240, PMR (CDCl3) 0.89, 1.35, 2.18, 4.95, 5.55, 5.72 and 6.74S.

Claims (21)

Claims

1. A process for the preparation of the isomers of a compound of the formula CM R20=CH-X-Z wherein M is lithium, sodium or potassium; R20 is fluorine, chlorine atom orNR"RA in which R, and are the same or different and are each C13 alkyl; X is oxygen or sulfur; and Z is C16 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 C 1-5 alkyl or phenyi and M is as defined above, at from15 to120 C.

2. A process according to claim 1 where at least 1.5 equivalents of the organometal compound are used with respect to the ethane derivative.

3. A process according to claim 2 wherein up to 2 equivalents of the organometal compound are used with respect to the ethane derivative.

4. A process for the preparation of the isomers of a compound of the formula CHR20=CH-X-Z wherein R20, X and Z are as defined in claim 1, in which the ratio of the trans isomer to the cis isomer is greater than 70:30, which comprises (1) reacting an ethane derivative as defined in claim 1 with an organometal compound as defined in claim 1 at from -15 to -1 200C; and (2) quenching the reaction product with a proton source.

5. A process according to claim 4 wherein at least one equivalent of the organometal compound is used with respect to the ethane derivative.

6. A process according to claim 5 wherein at least 2 equivalents of the organometal compound are used with respect to the ethane derivative.

7. A process according to any of claims 4 to 6 wherein the proton source is water, a C 1-4 alkanol, a C27 alkanoic acid, benzoic acid, an ammonium salt or sulfuric acid.

8. A process according to claim 7 wherein the proton source is water, methanol, ethanol, acetic acid or ammonium chloride.

9. A process according to any preceding claim wherein M is lithium.

10. A process according to claim 9 wherein the organometal compound is n-butyllithium.

11. A process according to any preceding claim wherein the ratio of the trans to the cis isomer is greater than 75:25.

12. A process according to any preceding claim wherein R20 is chlorine.

13. A process according to any preceding claim wherein X is oxygen.

14. A process according to any preceding claim wherein Z is methyl or ethyl.

1 5. A process according to Claim 14 wherein Z is ethyl.

1 6. A process according to any preceding claim wherein Q is chlorine.

1 7. A process according to any preceding claim wherein the reaction is conducted at from -30 to -900C.

1 8. A process for the preparation of the isomers of 1 -chloro-2-ethoxyvinyllithium, in which the ratio of the isomer in which the Cl and OC2H6 groups are trans to that in which they are cis is greater than 70:30, which comprises reacting 1 ,2-dichloro-1 -ethoxyethane with from 1.5 to 2 equivalents of n-butyllithium at from -45 to 900 C.

19. A process for the preparation of the isomers of 1 -chloro-2-ethoxyethane, in which the ratio of the trans isomer to the cis isomer is greater than 70:30, which comprises reacting 1,2-dichloro-l ethoxyethane with more than 2 equivalents of n-butyllithium at from -30 to -900C and quenching the reaction product in water.

20. A process according to claim 1 substantially as described in any of Examples 3 to 7.

21. A process according to claim 4 substantially as described in Example 1 or Example 2.