JPS6337797B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing organic compounds. The trans-metallated olefin (B) adds to the 17-ketosteroid (1) better than the corresponding cis isomer (A) to form the 16-unsubstituted pregnane (5), which is the most widely used in the field. It is easily converted into useful 16-substituted corticoids by well-known methods. Metallized olefins (A and B) are prepared from the corresponding olefins (A and B).
It is therefore important to be able to produce olefins () with very high trans to cis ratios.
Known methods of producing olefins () produce mixtures with very low trans to cis ratios,
This is exactly the opposite of what is desired for the synthesis of 16-unsubstituted pregnanes. The present invention solves this problem by producing olefins with a trans to cis ratio greater than 70:30. JFArens et al. Rec.trav.chim.77, 753 (1958)
By heating chloroacetaldehyde diethyl acetal with an acid catalyst in
A method for converting to 2-ethoxyethene is disclosed. On page 755, the authors state that ``the product consisted mostly of the cis isomer.'' The present invention surprisingly and unexpectedly provides a 70:30
resulting in a larger trans-cis ratio. JFArens also Rec.trav.chim.74, 271 (1955)
, 1-chloro-2-ethoxyethane was dehydrohalogenated to produce 1-chloro-2-ethoxyethane.
It was also reported that 2-ethoxyethene was obtained.
On page 274, Arens states that the product is “…approximately 75
% cis isomer and 25% lower boiling trans isomer. S.Hunig and M.Kiessel Chem.Ber.91, 380
(1958) reported the conversion of 1,2-dichloro-2-ethoxyethane to 1-chloro-2-ethoxyethene using a tertiary amine and heat. Under the various reaction conditions reported, the reaction produced was primarily the cis isomer. DE 2210010 reports the reaction of 1,1-dichloro-2-methoxyethane with methoxide to obtain 1-chloro-2-methoxyethene. The cis isomer (54%) is produced more than the trans isomer (46%). DAVanDorp etc. are Rec.trav.chim.70, 289
(1951) reported the conversion of dichloroacetaldehyde diethyl acetal to 1-chloro-2-ethoxyethene by using activated zinc dust. The author (on page 293)
“The yield of the cis isomer is 4% that of the trans isomer.
It was found that the number of cases was ~5 times higher...'' M. Farina et al. Rend.1st Lombardo Sci.
In Pt.1Classe Sci.Mat.e Nat.94A, 600 (1960), 1,2-dichloro-2-i-butoxyethane was treated with tertiary amine and hydrochloric acid.
It was reported that conversion to i-butoxyethene resulted in a product containing 75-90% cis isomer. All of the above literature shows that the trans isomer is formed much less than the cis isomer. These are experimental findings and no possible mechanistic reasons have been reported. However, in 1976
Year E.Taskinen & E.Sainio Tetrahedron32,
593 (1976), based on thermodynamic calculations, reported that it is natural that the cis isomer is predominant because its enthalpy is low. Therefore, based on thermodynamic considerations and previous experiments reported in the chemical literature, one skilled in the art would expect to obtain trans to cis ratios much lower than 50:50. However, the method of the present invention is surprisingly and unexpectedly also capable of isolating 1-chloro-2-alkoxyethenes () with a trans-cis ratio of greater than 70:30 as an intermediate. The only other method known to produce mixtures of 1-chloro-2-alkoxyethene () enriched in trans isomers greater than 70:30 is the opening method, i.e. A trans mixture was prepared and then fractionally distilled. The manufacturing method of the present invention includes the formula

[expression] and

A method for producing a compound represented by the formula, in which the ratio of the trans isomer (B) to the cis isomer (A) is greater than 70:30, the method comprising: A method comprising reacting a compound of the formula R-Metal with a compound of the formula R-Metal at a temperature in the range of -15°C to -120°C. moreover,

[expression] and

A method for producing a compound represented by the formula R-Metal in which the ratio of the trans isomer (B) to the cis isomer (A) is greater than 70:30, the method comprising: The method includes a method of reacting with a compound represented by the formula at a temperature range of -15°C to -120°C, and then terminating the reaction with a proton source. Olefins () are useful as intermediates in the production of metallized olefins (). Metallated olefins () are 16-unsaturated pregnanes (5 ), and it is therefore an object of the present invention to provide an advantageous process for the preparation of this 16-unsaturated pregnane. The present invention will be explained in detail below. The metallated olefin (B) is prepared by reacting substituted ethane () with a compound of the formula R-Metal at a temperature of -15°C to -120°C as shown in Scheme A below. The substituted ethane represented by formula () is known to those skilled in the art or can be easily prepared from known compounds by methods well known in the art. In the case of substituted ethane represented by formula (), R ₂₀ is a chlorine atom. X is an oxygen or sulfur atom, preferably an oxygen atom. Z is alkyl of 1 to 6 carbon atoms, phenyl or p-methylphenyl. Preferably Z is alkyl of 1 to 4 carbon atoms, preferably Z is methyl or ethyl. Q is a good leaving group, ie a chlorine atom. Compounds of the formula R-Metal are known to those skilled in the art or can be readily prepared from known compounds by methods well known in the art. For compounds of formula R-Metal, R is alkyl of 1 to 5 carbon atoms. Preferably R is a secondary or primary alkyl group of 1 to 4 carbon atoms. The metal indicated by Metal is lithium,
It is. It is also preferred that the compound R-Metal is selected from the group consisting of n-butyllithium, propyllithium, s-butyllithium, or i-propyllithium. More preferably, R-Metal is n-butyllithium. Mix substituted ethane () and R-Metal in a dry organic solvent. Organic solvents must be dry. This is because if water is present, it will react with R-Metal and generate excess R-Metal.
This is because it is necessary to use Preferred organic solvents are ethers such as THF, dimethoxyethane, diethyl ether, dioxane and the like.
Most preferably, the organic solvent is THF. The organic solvent may consist of a mixture of ethers and hydrocarbon and/or aromatic solvents, but the mixture must contain at least some ether. Preferably, the ether is present in as high a concentration as possible. The reaction is best carried out in pure THF. Substituted ethane () has the formula R-
It may be added to a Metal compound, or vice versa. The reaction is carried out at -15°C to -120°C, preferably -30°C.
in the temperature range from -90°C, more preferably about -60°C
It is carried out at temperatures between -90°C. At higher temperatures, the reaction proceeds faster than at lower temperatures, as is well known to those skilled in the art. Since the reaction is exothermic, the R-Metal is added very slowly, typically taking 15 minutes to 1.5 hours. Since the reaction is exothermic, the reaction mixture must be cooled so that the reaction temperature does not rise above -15°C. At -90°C, the reaction is usually completed in about 1 hour, while at -30°C, the reaction is completed in about 15 minutes. Although the reaction proceeds at -15°C, the yield is low. In this case, although the yield is low, the ratio of trans isomer (B) to cis isomer (A) is greater than 70:30. If it is desired to isolate the olefin (), the substituted ethane () can be reacted with the R-Metal compound to obtain a mixture of the olefin () and the metallated olefin (). It is preferred to use at least 1 equivalent of R-Metal, and even more preferred to use at least 2 equivalents of R-Metal to ensure maximum utilization of the starting material (). If isolated, once the reaction is complete (approximately 1 hour), the reaction mixture is quenched with a proton source and any metallated olefin ()
are also converted to olefins (A and B). The proton source is any very mild acidic compound, such as water, alcohol (R _a -OH), carboxylic acid (R _b -COOH), sulfuric acid or ammonium salts. Use appropriate amounts, but not so much that the PH of the reaction mixture is less than 6. Preferably, the reaction terminator is selected from the group consisting of water, methanol, ethanol, acetic acid or ammonium chloride. If it is desired to use pure trans-olefin (B), this can be readily obtained by methods well known to those skilled in the art, such as fractional distillation. The reaction mixture can then be worked up by methods well known to those skilled in the art. If the intermediate metallated olefin () is desired, per equivalent of substituted ethane (),
More than 1.5 equivalents of R-Metal are used, more preferably between 1.5 and 2 equivalents. The reaction is 1.5~
The same process is carried out under the same conditions as described above for the preparation of olefin (), except that 2 equivalents of R-Metal are preferred and the reaction is not terminated. The reaction mixture is greater than 70:30 trans isomer (B) enriched metallated olefin mixture (A and B) or pure trans metallated olefin (B) is then combined with the 17-ketosteroid.
By reacting (1) with (2a-2e) in its protected form, 16-unsaturated pregnane (5) is obtained,
It is easily converted to useful 16-substituted corticoids. 17-ketosteroids (1) are well known to those skilled in the art or can be readily prepared from known compounds by methods well known to those skilled in the art. For example, △ ^1.4 −
17-Keto-steroids (1) are known and are described, for example, in US Pat. No. 2,902,410, in particular in Example 1. ^Δ4.9 (11)-17-Keto-steroids (1) are known and described in US Pat. No. 3,441,559, particularly in Example 1. 6〓-fluoro-17-ketosteroid
(1) is publicly known, for example, US Pat. No. 2,838,492,
Specifically described in Examples 9 and 10. 6〓-Methyl-17-ketosteroids (1) are known and are described, for example, in US Pat. No. 3,166,551, in particular in Example 8. 16β-methyl-17-ketosteroid (1) is disclosed in US Pat. No. 3,391,169 (Examples 75 and 76), US Pat. No. 3,704,253
No. (Column 2 and Examples 1 to 3) and No. 3275666
It can be easily produced from the corresponding 17-ketosteroid (1) by the method of No. Scheme B discloses the utility of the present invention. It is represented by formula (1), in which R ₆ is hydrogen or a fluorine atom or a methyl group, R ₁₁ is a hydrogen atom,
α-OR _11a or β-OR _11a (wherein R _11a is a hydrogen atom or TMS), provided that R ₁₁ is −
In the case of OR _11a , 〓 on ring C is a single bond, R ₁₆ is a hydrogen atom or a methyl group, and ~ is
The R ₁₆ group may be in either the α or β configuration,
is a single or double bond.
position must be protected. androst
4-ene-3,17-dione (1) is protected as a 3-enol ester (2a), 3-enamine (2b) or ketal (2c) where R ₃ is alkyl of 1 to 5 carbon atoms, with the proviso that in the case of ketanol, the R ₃ groups can be combined to form an ethylene ketal, R ₃ ' and
R ₃ ″ are the same or different and are alkyl of 1 to 5 carbon atoms. The enol ether (2a) can be prepared by methods well known in the art and described in J.Org.
Chem.26, 3925 (1961), Steroid Reactions,
Edited by Carl Djerassi, Holden Day, San
Francisco1963, P42-45 and US Patent No. 3516991
(Production Example 1). 3-Enamine (2b) can also be produced by methods well known in this field, such as Steroid Reactions P49-53 listed above.
It is described in. Ketal (3c) can also be prepared by well-known methods, for example the Steraid listed above.
Described in Reactions P11-14. Androsta-1,4-diene-3,17-dione (1) is protected as a 3-dialkyleneamine (2d) or a ketal (2e). In scheme B, the compound represented by formula (2a) can be substituted with a compound represented by formula (2b or 2c), and both of these are represented by formula (3a, 3b
or the corresponding intermediate compound represented by 3c),
This produces a 21-aldehyde (4a) and a 16-unsaturated pregnane (5a). Similarly, in the case of Δ′ steroids, the compound of formula (2d) can be replaced by the compound of formula (2e), the latter being replaced by the corresponding intermediate compound of formula (3e), 21−
This produces an aldehyde (4b) and a 16-unsaturated pregnane (5b). When R ₁₁ is hydroxyl, whether α or β, the hydroxyl group must be protected during the metallized olefin (organolithium) reaction. Protecting groups (TMS) can be removed by methods well known to those skilled in the art. The protected 17-ketosteroid (2a, 2b or 2c) is reacted with a metallated olefin (A and B) or (B). Metallized olefin (
A and B) are produced according to the method of the invention. Cis-trans mixtures (A and B) or trans (B) metallated olefins are prepared in an inert non-polar solvent such as THF, pentane, diethyl ether, hexane, toluene from -100°C to -
It is cooled to 20°C, preferably -60°C to -30°C, more preferably -45°C in an inert atmosphere such as nitrogen. The protected 17-ketosteroids (2a-2e) are either suspended in an inert non-polar solvent such as those mentioned above or added as a solid. Preferably, the same solvent is used. The protected 17-ketosteroids (2a-2e) are cooled to about -60°C to -30°C, preferably about -45°C. Metallized olefins (A and B) or (B) and protected
17-ketosteroids (2a-2e) were then heated to −25°C.
Contacting is carried out at a lower temperature, preferably about -60°C to -35°C. Metallized olefins (A and B)
or (B) is a protected steroid (2a~
2e) or the protected steroid can be added to the metallated olefin (). Substitute ethane () to avoid side reactions
, protected 17-ketosteroids (2a-2e)
It is important to mix it with the metal base before contacting it with the metal base. The olefin intermediates (3a-3e) can be isolated after about 0.5 to 20 hours, preferably about 3 hours, if desired with a suitable terminating agent, such as water, _R17a -W,
(R _17a CO) ₂ O or R _17a COM, where R _17a is alkyl of 1 to 3 carbon atoms, thus R ₁₇ is a hydrogen atom, 1 to 3 carbon atoms. This results in an alkyl group of 3 or an acyl group of 2 to 4 carbon atoms. M is a chlorine or bromine atom. W is a bromine or iodine atom. Preferred reaction terminators are methyl iodide, methyl bromide and ethyl iodide. Most preferred is methyl iodide. Alternatively and preferably the olefin intermediates (3a-3e) are hydrolyzed with acid without isolation. More than 1 equivalent of acid is required, preferably about 6 equivalents. The particular acid is not critical; for example, sulfuric acid, phosphoric acid, hydrochloric acid, acetic acid, citric acid, benzoic acid, etc. are all suitable. The reaction mixture is heated to about 25-50°C and stirred until the reaction is complete as analyzed by TLC. The reaction mixture is worked up and concentrated in a conventional manner to obtain the crude 21-aldehyde (4). Protected △ ^4-3 -keto-steroid (2a
Starting from ~2c), the 21-aldehyde (4) formed is clearly the 21-aldehyde (4a).
Similarly, when the process of the present invention is carried out using a protected Δ ^1,4 -3-ketosteroid (2d or 2e) as a starting material, the 21-aldehyde (4) produced becomes the 21-aldehyde (4b). When the term 21-aldehyde (4) is used, it refers to both 21-aldehydes (4a
and 4b) shall apply and include these as appropriate. The 21-aldehyde (4) is crystallized from a solvent such as methylene chloride-heptane. 17-ketosteroid (1) is androst-4.9(11)-diene-
3.17-dione and the 21-aldehyde in 4 experiments when the metallated olefin is trans-2-chloro-1-ethoxy-2-lithioethene or a trans-cis (A and B) mixture in a ratio greater than 70:30. The chemical yield of (4) is 86.6,
They were 86.7, 84.0 and 83.5%. See Examples. 21-Aldehyde (4) is a mixture of the following two geometric isomers produced in approximately equal amounts. Although the isomer 21-aldehyde (4) can be separated if desired, it is not necessary or desirable to do so for the purposes of this invention. Because isomers
This is because any 21-aldehyde (4) is converted to the desired 16-unsaturated pregnane (5). Scheme C shows an alternative, but less preferred, method of preparing 21-aldehyde (4) via an isolable intermediate (3f or 3g). Isolable intermediates (3f and
3g) are obtained from (3a-3c) and (3d and 3e) respectively by reaction with a compound such as phosphorous oxychloride ( _POCl3 ) and a co-reagent base such as pyridine at about -45<0>C. Then each product (3f and 3g)
is converted to the desired 21-aldehyde (4) by reaction with an acid as described above for compounds (3a-3c) and (3d and 3e). The formulas of compounds (3a-3g) all indicate that the _C20 double bond is trans. When the metallated olefin () is a cis-trans mixture, the double bond at _C20 of the compounds (3a to 3g) is a mixture of cis and trans. When the metallated olefin () is the trans isomer, _C20
Of course, the double bond in becomes a transformer. If the cis-trans nature of the _C20 bond is not specifically stated herein, it has the same configuration as the starting metallated olefin compound (), as is well known to those skilled in the art. Whether the C ₂₀ - ₂₁ double bond in the compound of formula (3) is cis-trans or simply trans is that when these are acid-hydrolyzed, the same 21
-Not important as long as both are converted to aldehyde (4). 21-Aldehyde (4) formula is isomer
It is understood that both 21-aldehydes are represented. Again, it is not critical which 21-aldehyde isomer is obtained, as long as both are converted to the same 16-unsaturated pregnane (5). During acid hydrolysis of compounds of formula (3a-3d) to 21-aldehydes (4), the protecting groups are removed from these five compounds, irrespective of whether they were protected as ethers, enamines or ketals; The desired 21-aldehyde (4) is obtained as a 3-keto compound. In the case of enamines (3b, 3d and 3g), if the reaction medium is somewhat too acidic, it must be neutralized with a base to a pH of about 3-4 suitable for removal of the enamine protecting group. 21-Aldehyde (4) is a polar organic solvent with the formula
It is converted to the corresponding 16-unsaturated pregnane (5) by reaction with an alkali metal or alkaline earth metal salt of the carboxylic acid represented by R ₂₁ COOH. When the 21-aldehyde (4) is saturated with C ₁ (4a), the resulting 16-unsaturated pregnane (5) is the corresponding C ₁ unsaturated pregnane (5a). When the 21-aldehyde (4) is the Δ ^1,4 -compound (4b), the corresponding Δ ^1,4 -16-unsaturated pregnane (5b) is obtained. The term 16-unsaturated pregnanes (5) is appropriately applied to and includes both 16-unsaturated pregnanes (5a and 5b). R ₂₁ is 1 carbon atom
~5 alkyl or phenyl. Suitable salts of these acids include potassium acetate, sodium acetate, magnesium propionate, calcium butyrate and sodium benzoate. Suitable organic solvents for the reaction include DMF, pyridine, THF,
Includes DMAC etc. Preferably, the organic solvent is DMF and the salt is sodium or potassium acetate. The reaction temperature varies depending on the specific 21-aldehyde (4), salt and solvent used, and is preferably 50-200°C, preferably 100-200°C.
It is carried out at a temperature of 150°C and is usually completed in 4 to 8 hours. This method uses crystalline 21-aldehyde (4),
This is best done by slow addition to the mixture of DMF and acetate under nitrogen at about 120°C. The reaction was determined by TLC using ethyl acetate-hexane (1:1).
Monitor using. Once 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-extracted twice with an organic solvent. The organic solvents are combined, dried and concentrated under reduced pressure to obtain 16-unsaturated pregnane (5). See Example 8. 16-Unsaturated pregnane (5) is useful in the synthesis of a number of anti-inflammatory corticosteroids. If substituent
If R ₆ and R ₁₆ are hydrogen and it is desired that they are not hydrogen in the final compound, they can be converted into the desired substituents within their definition by methods well known to those skilled in the art. If C-
If no unsaturation is present in 1 and this is desired, the compound can be dehydrogenated by known means. If R ₆ ,
If substitution at R ₁₆ or unsaturation at C-1 or C-9(11) is desired, these substituents are removed prior to synthesis.
17− can be added to ketosteroids (1), thus 16−
When unsaturated pregnanes (5) are obtained, the desired substitutions are obtained in the molecule. In particular, 21-acetoxy pregnar 4,9(11), 16
-triene-3,20-dione (5) is a very useful intermediate in the synthesis of commercially valuable steroids. It is a fact well known to those skilled in the art that 16-unsaturated pregnane (5) can be converted into 16α-hydroxy, 16α-methyl and 16β-methyl steroids. For example, U.S. Pat. No. 2,864,834 and J.Am.
Chem.Soc.78, 5693 (1956) are all 21-acetoxypregner 4,9(11), 16-triene-3,20
-dione (5) to 9α-fluoro-11β, 16α, 17α, 21
-Tetrahydroxypregner 1,4-diene-
A method for converting to 3,20-dione (triamcinolone) is described. J. S. Mills et al. J. Am. Chem.
21-acetoxy pregner 4,9(11), 16-triene-3,20-dione in Soc.82, 3399 (1960)
(5) can be easily converted into 6α,9α-difluoro-11β,16α,
17α,21-tetrahydroxypregner 1,4-
A method for converting diene-3,20-dione to 16,17-acetonide (fluocinolone acetonide) is described. U.S. Patent No. 3,923,985 replaces the 16α-methyl group with the 21-
21 by introducing acetoxy pregner into 1,4,9(11),16-tetraene-3,20-dione(5)
-acetoxy-16α-methyl pregner 1,4,
describes a method for obtaining 9(11)-triene-3,20-dione, which product can be converted into a 16α-methylsteroid, e.g. 6α-
Fluoro-11β, 17α, 21-trihydroxy-16α
- methyl pregner 1,4-diene-3,20-dione (paramethasone) and its 21-acetate,
9α-Fluoro-11β,17α,21-trihydroxy-16α-methyl pregner 1,4-diene-3,
20-dione (dexamethasone) and 6α,9α-difluoro-11β,17α,21-trihydroxy-16α
-Methyl pregner can be converted to 1,4-diene-3,20-dione (flumethasone). The definitions and explanations provided below are for the terms used herein. All temperatures are in degrees Celsius. TLC stands for thin layer chromatography. GC means gas chromatography. THF means tetrahydrofuran. TMS means trimethylsilyl. DMSO means dimethyl sulfoxide. DMF means dimethylformamide. SSB means isomer mixture of hexane. DMAC means dimethylacetamide. PMR stands for Proton Magnetic Resonance Spectroscopy;
Concentration of chemical shaft on the low magnetic field side of TMS (ppm)
It is written in When using solvent pairs, the solvent ratio used is volume/
Volume (v/v). R is alkyl of 1 to 5 carbon atoms or phenyl. R ₃ is alkyl of 1 to 5 carbon atoms, provided that in the case of ketanol the R ₃ groups can be combined to form ethylene ketal. R ₆ is hydrogen or fluorine atom or methyl group. R ₁₁ is a hydrogen atom, α-OR _11a or β-OR _11a , provided that when R ₁₁ is -OR _11a , 〓 in ring C is a single bond. R ₁₆ is a hydrogen atom or a methyl group. R ₁₇ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an acyl group having 2 to 4 carbon atoms. R _17a is alkyl of 1 to 3 carbon atoms. R ₂₀ is a fluorine or chlorine atom or -NR〓R〓. R ₂₁ is alkyl of 1 to 5 carbon atoms or phenyl. R ₃ ′ and R ₃ ″ are the same or different and contain 1 to 1 carbon atom
5 alkyls. R〓 and R〓 are the same or different, and 1 to 1 carbon atom
Three alkyls. R _a is alkyl of 1 to 4 carbon atoms. R _b is alkyl or phenyl of 1 to 6 atoms. M is a chlorine or bromine atom. Q is a chlorine, bromine, iodine atom or trimethylamino group. W is a bromine or iodine atom. X is an oxygen or sulfur atom. Z is alkyl of 1 to 6 carbon atoms, phenyl or p-methylphenyl. Metal is lithium, sodium or potassium. ~ indicates that the R ₁₆ group can have either the α or β configuration. 〓 is a single or double bond. When the expression "alkyl of 0 to 0 carbon atoms" is used, this includes isomers of the alkyl group when present. Without further elaboration, it is believed that one skilled in the art can, using the above description, practice the present invention. Accordingly, the specific preferred embodiments set forth below are merely illustrative and are not intended to limit the invention in any way. Reference example 1 1-chloro-2-ethoxyethene (a and b) 1,2-dichloro-1-ethoxyethane (Ia,
153 mg, purity 90%) and THF (1 ml) in nitrogen.
Cooled to below 40°C. A hexane solution (1.5M, 1.35ml) of n-butyllithium was added dropwise over about 5 minutes. The mixture was stirred for 20 minutes below -40°C. Add water (100μ) and mix the mixture to 20~
The temperature was set to 25℃. When the solution was analyzed by PMR, the ratio of trans:cis 1-chloro-2-ethoxyethene was 78:22. Reference example 2 1-chloro-1-deutero-2-ethoxyethene The method of Reference example 1 was followed, but the reaction was carried out in place of water.
Termination with D ₂ O (100μ) gave the title compound. PMR analysis revealed that trans:
The ratio of cis 1-chloro-1-deutero-2-ethoxyethane was about 80:20. Reference Example 3 20 Chlorpregner 4,9(11),17(20) using 1-chloro-2-ethoxyethene (a and b) as 1-chloro-2-ethoxy-1-lithioethene (a and b) -triene-3-
Preparation of on-21-al (4a) 1,2-dichloro-1-ethoxyethane (Ia,
(1.84g, 90% purity) and dry THF (12ml) were cooled to below -45°C under nitrogen. A hexane solution of n-butyllithium (1.45 M, 15.5 ml) was added dropwise over about 18 minutes. Stir the mixture for an additional 30 minutes,
3-Hydroxyandroster 3,5,9(11)-trien-17-one 3-methyl ether (2a, US Pat. No. 3,516,991, 2.16 g) was added all at once. The mixture was stirred at approximately −40 °C for 3.25 h and −10
The temperature was returned to ℃. Aqueous hydrochloric acid (6N, 1.8ml) was added and the organic solvent was removed under reduced pressure. The residue was dissolved in methylene chloride (7.2 ml) and aqueous hydrochloric acid (6N, 9 ml) and stirred at 20-25°C for 18 hours. The reaction mixture was then diluted with methylene chloride (20ml) and water (60ml). Separate the organic layer, wash with water (2 x 50 ml),
A residue was obtained by drying over sodium sulfate and concentrating under reduced pressure. This material was dissolved in methylene chloride (3.15 ml) with stirring and heptane (26 ml)
ml) was added dropwise over 45 minutes. The resulting slurry was stirred at 0-5°C for 30 minutes and then filtered. The solid was dissolved in heptane-methylene chloride (95:5, 2.25ml).
20-Chlorpregner 4,9(11),17(20)-trien-3-one-
21-R (4a) was obtained. Example 1 21-Hydroxypregner 4,9(11),16-toluene-3,20-dione-21-acetate (5) Anhydrous THF (250 ml) and 1,2-dichloro-1
-Ethoxyethane (I, 22ml, 25.1g) was cooled to -65°C under nitrogen. n-Butyllithium (323 mmole) was added dropwise over 60 minutes while keeping the temperature below -65°C. It was then washed with 10 ml of hexane. The mixture was stirred for approximately 60 minutes. 3-Hydroxyandroster 3,5,9(11)-trien-17-one 3-methyl ether (2a, 33.1 g) was added all at once. The mixture was stirred for 3 hours and then warmed back to -45°C for 1 hour. Cooling was stopped and the mixture was allowed to return to 0°C. Water (14ml) was added followed by hydrochloric acid (6N, 140ml). mix 20
Stir at ~25°C for approximately 12 hours. Methylene chloride (600
ml) and water (600ml) were added. separate the phases,
The aqueous phase was extracted with methylene chloride (2x25ml). The organic layer was dissolved in water (400 ml) and potassium carbonate (10%, 150 ml).
ml). The methylene chloride extracts were combined, dried, and concentrated to obtain crude chloraldehyde (). This solid was dissolved in methylene chloride (56ml) and heptane (45ml) was added. The mixture was dispersed and heptane (350ml) was added dropwise over a period of approximately 2.2 hours. The slurry was stirred for 1 hour at 20-25°C, then 1 hour at 0°C, filtered, and the solid was washed with heptane-methylene chloride (95:5) and hexane (2 x 25ml) and dried to give 20- Chlorpregna-4,9(11),17(20)-trien-3-one-21-
A mixture of isomers of R (4) was obtained. 33.1g (chemical yield 86.6%), PMR ( _CDCl3 ) 1.02, 1.1, 1.37,
5.55, 5.75, 9.7 and 9.9δ. Following this method and making minor changes, it was similarly carried out three times and the following yields (chemical) were obtained:
I got it. Yield (chemical) % 86.7 84.0 83.5 Anhydrous sodium acetate (5.8 g) and DMF were heated and stirred at 120 °C under nitrogen. Crystalline 20-chlorpregner 4,9(11),17(20)-trien-3-one-21
-R (4a, 12 g for the above yield of 86.6%)
Additions were made by adding 2g every 20 minutes.
The mixture was stirred at 120°C for 90 minutes, the reaction was allowed to cool and toluene (100ml) was added. The mixture was extracted with sodium chloride (5%, 2x100ml) and back extracted with toluene (2x20ml). The toluene phase was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound. Melting point 120-124℃,
PMR ( _CDCl3 ) 0.89, 1.35, 2.18, 4.95, 5.55,
5.72 and 6.74δ.

Claims (1)

[Claims] 1 formula [In the formula, R ₂₀ is a chlorine atom, X is an oxygen or sulfur atom, Z is an alkyl having 1 to 6 carbon atoms, phenyl or p-methylphenyl, and Q is a chlorine atom] (alkyl having 1 to 5 carbon atoms) at a temperature range of -15°C to -120°C to form the formulas [Formula] and [Formula] [wherein R ₂₀ , X and Z have the same meanings as above. ] and the ratio of trans isomer (B) to cis isomer (A) is greater than 70:30, or a compound having the formulas [Formula] and [Formula] [wherein R ₂₀ , X and Z has the same meaning as above], and the ratio of trans isomer (B) to cis isomer (A) is greater than 70:30,
In the case of compounds of formulas (A) and (B), the compounds of formulas (A) and (B) are further reacted at a temperature range of -15°C to -120°C, and then the 17-ketosteroid and - The reaction is carried out at a temperature lower than 25°C, and furthermore, the formula R ₂₁ COOH [wherein R ₂₁
means an alkyl or phenyl having 1 to 5 carbon atoms]. [In the formula, R ₆ , R ₁₁ and R ₁₆ are hydrogen atoms, and
R ₂₁ has the same meaning as above.] A method for producing a compound represented by: 2. The method according to claim 1, wherein at least one equivalent of alkyllithium is used in the reaction with the compound of formula 2. 3. The process according to claim 2, wherein at least 2 equivalents of alkyllithium are used in the reaction with the compound of formula 3. 4. The manufacturing method according to claim 1, wherein the alkyllithium is n-butyllithium. 5. The manufacturing method according to claim 1, wherein Z is a methyl group or an ethyl group. 6. The manufacturing method according to claim 1, wherein Z is an ethyl group. 7 The reaction between compound A and alkyl lithium is -30
The manufacturing method according to claim 1, which is carried out at a temperature range of -90°C.