HU197025B - Process for producing 21-benzoyloxy-pregnene derivatives - Google Patents

Abstract

Novel prepn. of known corticoid and corticoid intermediate pregnene derivs. (I). R1 in formula (1) represents 1-4C atom alkyl gps., R2 a hydrogen atom, 2-4C atom, alkanoyl gp. or benzoyl gp. R3 a hydrogen atom, hydroxyl gp. or 2-4C atom alkanoyloxy or 1-3C atom alkoxy gp. Ring 'A' is of general formula (1) or (2) where R4 is a hydrogen atom or a methyl gp., R5 is a hydroxyl gp., 2-4C atom alkanoyloxy gp. or 1-3C atom alkoxy gp. R6 is a hydroxyl gp., 2-4C atoms contg. alkoxy gp., oxo gp. or 2-3C atoms alkylene-di:thio-gp. - Dotted lines in the formulae represent single or multiple available valencies with the proviso that R3 is restricted to be no other than a hydrogen atom if the dotted line between C atoms no.9 and 10 only represent a single available valency.

Description

The present invention relates to a novel process for the preparation of pregnene derivatives of formula I wherein R 'is benzoyl, ring A may be of formula (1) or (2) wherein

R ² is C 1 -C 3 alkoxy, R ³ is hydroxy, C 2 -C 4 alkanoyloxy, or ethylenediothio, and the dotted lines represent one or more additional valence bonds in the particular chain.

The novel process of the present invention provides the known 21-hydroxy pregnene derivatives of pharmaceutical importance. For example, compounds of formula (I) wherein R * is hydrogen or acetyl, A is (2) wherein R ³ is oxo, and

There are double bonds between carbon atoms 4 and 5, valuable natural mineralocorticoids (deoxy-corticosterone and acetate). Further, the industrial importance of the compounds of formula I is that they can be used as starting materials for the synthesis of corticosteroids with valuable biological activity which contain a dihydroxyacetone side chain on carbon 17.

The 21 - hydroxypregnene derivatives are e.g. D.

H. R. Barton et al., J. Chem. Soc. Chem. Commun. 551 (1982), have been prepared starting from 17 (nitromethylene) steroids. The carbon atom 21 is formed by saturation of the 17 (20) - double bond and the formaldehyde reaction. The resulting 21 - hydroxy - 20 - nitro steroid yields to the 20 - oxo - 21 - hydroxy steroids in a further 3 steps (21 - acylation, reduction with a chromium (II) --carbyl moiety to 20 - oxime and hydrolysis of the oxime). The disadvantage of this process compared to the claimed process is that it involves much more reaction steps.

L. Nedelec et al. (J. Chem. Soc. Chem. Commun. 775 (1981)) hydrolyze 20-formylamino-21-hydroxypregn-17-ene to 20-oxo-21-hydroxypregnane. As an intermediate, a 21 - formyloxy derivative is mentioned here, so hydrolysis is a 2 step process. These reactions are described for other types of compounds than those described herein.

The process of the present invention is based on novel pregnene derivatives. It has now been found that boiling 20-acylamino-pregnene derivatives of formula II with acetic acid provides 21-benzoyloxy intermediates. Hydrolysis of these under mild alkaline conditions gives the 21 - hydroxy derivatives.

The present invention therefore relates to a novel process for the preparation of pregnene derivatives of formula (I) wherein R ¹ and the ring A, including R ² and R ³ and the dotted lines have the meanings given in the introduction, which comprises: a novel pregnene derivative of the formula wherein Ring A, including R ² and R ³ , and dotted lines are as defined above, R ⁴ is phenyl, and wavy lines indicate that the corresponding substituents may be linked in two different positions to carbon atom - boil with aqueous acetic acid.

The compounds of formula (1) thus formed, wherein ring A, including R ² and R ³ , and the dotted lines are as defined above, and R ¹ is benzoyl, are hydrolyzed in a manner known per se to the known 21-OH compounds which a C2-C4 alkane arm can be acylated in a manner known per se. In a compound of formula (I), wherein R ¹ and the dotted lines are as defined above, wherein ring A is a moiety of formula (2) wherein R ³ is ethylenediothio, the ethylenedithio is known per se, by hydrolysis or by oxidative or alkylation hydrolysis to the oxo group.

In a preferred embodiment of the process of the invention, the pregnene derivatives of formula (I) are prepared by boiling the compounds of formula (II) in aqueous, preferably 90% acetic acid, until the reaction is complete. The reaction was monitored by thin layer chromatography. The reaction usually takes 1-3 hours. The reaction mixture was poured into ice-water, and the product was isolated by filtration or extraction and purified by chromatography or crystallization.

The 21-acyl group of the compounds of formula (I) according to the invention can be hydrolyzed in a known manner, for example in an alkanol with an aqueous alkali metal hydrogencarbonate, the 21-hydroxyl group can be acylated in a manner known per se, and Converted into an oxo group (see, e.g., Β., T. Gröbel, D. Seebach, Synthesis, 1977, 357; French Patent No. 2202116). These known modifications are not part of the process of the invention.

The pregnene derivatives of formula (11) used in the process of the present invention are novel compounds which may be prepared, for example, by using a known 17-oxo steroid derivative of formula (III) wherein R ² and R ^{3 are} within ring A and cze; dotted lines are as defined above, with an azlactone derivative of formula IV wherein R ⁴ is phenyl, in the presence of titanium tetrachloride, and then treated with an organic base to give a derivative of formula V, aot R ⁴ , ring A and R ² and R ³ , as well as dotted lines and wavy lines, are as defined above, reacted with a C 1-3 alkali metal alcoholate and the resulting needle compound of formula VI, wherein R ⁴ , Ring A and R ² and R ³ and the dotted and wavy lines are as defined above and R ⁵ is C 1-3 alkyl is reduced with a complex aluminum hydride.

An advantage of the process of the invention over the known processes is that the valuable 21-hydroxypregnene derivatives can be obtained in a simple manner by a two-step hydrolysis.

The following examples illustrate the process of the invention. In the examples, TLC _Rf: values refer to 0.2 mm thick layer of silica gel 60 (Merck) layer. Development: Sulfuric acid injection and heating at 110'C

-2197,025

Example 1

- pregnene - 3β, 21 - diol - 20 - on - 21 - benzoate

8.75 g (20 mM) of 20-benzoylamino-5,17-pregnadiene-30,21-diol are suspended in 175 ml of 90% acetic acid and refluxed for 2 hours while the reaction mixture is clear. The solution was cooled and poured into 2 L of 10% ice-cold saline with stirring. The precipitate was filtered off and washed with water until neutral. After drying, 9.11 g of product is obtained which is a mixture of the title compound and 5-pregnene-3β, 21-diol-20-one-3-acetate 21-benzoate.

The crude product was chromatographed on a silica gel column with benzene: ethyl acetate: acetone (8: 1: 1).

Fractions R ₍ = 0.9) contain 5 pregnene-3β, 21-diol-20-one-3-acetate-21 benzoate, which was evaporated to give 3.08 g (34%) of crystalline product.

Mp: 161-162 ° C.

The _Rf value evaporation taking about 0.5 fractions 5.34 g (58%) of crystalline title compound, which melted at 180-181'C. [α] _D = +55.9 ′ (c = 0.5, in chloroform)

For example, the 20-benzoylamino-5,17-pregnadiene-30,21-diol starting material of this example can be prepared as follows:

the step

- (2 '- phenyl - 5' - oxo - 2 '- oxazolin - 4' - ylidene) - 5 - androstene - 30 - ol - acetate.

ml of dry tetrahydrofuran with stirring at 0 to +5 ° C for half an hour

A solution of titanium tetrachloride (6.6 ml, 60 mM) in carbon tetrachloride (13 ml) is added dropwise. A solution of 6.6 g (20 mM) of dehydroepiandrosterone acetate and 3.54 g (22 mM) of 2-phenyl-2-oxazolin-5 in 40 ml of tetrahydrofuran is then added over a period of about 20 minutes, followed by stirring for another 20 minutes. After 10 hours, 10 ml of pyridine was added dropwise over 1.5-2 hours. The reaction mixture was allowed to warm to room temperature and after 2 hours was quenched with 100 ml of ice-cold 10% brine. The product was extracted with dichloromethane (3 x 60 mL), the dichloromethane solution was washed neutral with water, then dried and evaporated. The crystalline residue (9.9 g) was washed with isopropyl ether to give 7.80 g of the title product, a mixture of Z / E isomers and mp 182-185 ° C.

Yield: 82%.

Step b)

3β - Hydroxy - 20 - benzoylamino - 5,17 - pregnadiene - 21 - acid - methyl ester

Dissolve 1.2 g of metal sodium in 160 ml of methanol and stir with 12.44 g (26.3 mM) of

17 - (2 '- Phenyl - 5' - oxo - 2 '- oxazoline - 4' - ifidene) - 5 - androstene - 3β - olacetate prepared in step a) is added to the solution. The temporary suspension dissolves after a few minutes.

After stirring at room temperature for 40 minutes, the reaction mixture was poured into 400 ml of ice-cold water, filtered and washed with water until neutral. After drying, 12.0 g of the title compound is obtained, m.p. 138-140 ° C and a mixture of Z / E isomers. Yield: 98%. After chromatography on a silica gel column with chloroform - ethyl acetate (3: 1), the isomers can be separated. The E isomer (R _F = 0.49) melts at 140-141 ° C, the Z isomer (R _F = 4), 35) is 246-247 ° C.

step c)

Benzoylamino-5,17-pregnadiene-30,21 diol

To a solution of 5.97 g (12.8 mM) of 30-hydroxy-20-benzoylamino-5,17-pregnadiene-21-acid methyl ester prepared in step b) in 100 ml of dry tetrahydrofuran under nitrogen, stirring At -10 DEG C., dropwise a solution of 33.5 g (116 mM) sodium bis (methoxyethoxy) aluminum hydride in 70% toluene, which was previously diluted with 75 ml of toluene. The precipitation at the beginning of the reaction dissolves later. The reaction mixture was further stirred at -5 'C, and after 1 hour, the excess reagent was quenched by the dropwise addition of ethanol (24 mL). The mixture is concentrated to one third of its volume and taken up in 300 ml of a 20% aqueous solution of potassium sodium tartrate. The product was extracted with ethyl acetate (4 x 100 mL), and the organic layer was washed neutral with 10% aqueous saline, then dried and evaporated. The crystalline residue was washed on the filter with 5 mL of isopropyl ether to give 5.0 g of the title product, a mixture of Z / E isomers and mp 183-185 ° C.

Yield: 89%.

Example 2

- pregnene - 3β, 21 - diol - 20 - on - 3 - acetate 21 - benzoate

The 5-pregnene 30.21-diol -20-011-21-benzoate prepared in Example 1 was dissolved in 2 g (4.5 mM) of a mixture of 15 ml of anhydrous benzene, 1.2 ml of pyridine and 0.94 ml of acetic anhydride. and the solution is refluxed for 4 hours. The reaction mixture was cooled, diluted with 30 mL of benzene, washed with brine, 5% aqueous hydrochloric acid, and again with brine, dried and evaporated to dryness. This gave 1.7 g (82%) of the title compound, m.p. 161-162 ° C.

[α] D = + 43.6 ° (c = 0.5, in chloroform)

The product is identical to the product isolated in Example 1 at a Rf = 0.9.

Example 3

- pregnene - 30,21 - diol - 20 - on - 3 - acetate 21 - benzoate

The crude product prepared according to Example 1 which is 5-pregnene-3β, 21-diol-20-on-21 3

A mixture of 197 025 benzoate and 5-pregnene-3β, 2ΐ-diol-20-one 21-benzoate was acylated as in Example 2.

Yield: 3.97 g; mp 159-160 'C.

The product is the same as that obtained in Example 2.

Example 4 (Subsequent Step Following the Process of the Invention)

- pregnene - 3β, 21 - diol - 20 - on

5 g of the crude product prepared according to Example 1, which is a mixture of 5-pregnene-3β, 21-diol-20-one-21 benzoate and 5-pregnene-3β, 21-diol-20-one 21-benzoate, 200 ml. slurry in methanol and add 15 g of potassium bicarbonate in 28 ml of water. The reaction mixture was refluxed for 3 hours, then the solvent was evaporated and the residue was taken up in 300 ml of water. The product was extracted with dichloromethane (3 x 150 mL). The organic layer was washed with brine (2 x 100 mL) and evaporated to dryness to give a foamy residue (3.07 g), which was chromatographed on a silica gel column using benzene: ethyl acetate: acetone (8: 1: 1). 2.24 g of crystalline product are obtained, m.p. 174-176 ° C.

^[?] D ⁼ + 9 ° (c = l, chloroform)

Example 5

- pregnene - 3β, 21 - dipl - 20 - on - 3,21 - diacelate

1 g (3 mM) of 5-pregnene-3β, 21-diol-20-one prepared in Example 4 is dissolved in a mixture of 10 ml of acetic acid and 2 ml of acetic anhydride, 0.1 g of p-toluenesulfonic acid is added and 5 g at room temperature are added. stir for 1 hour. The reaction mixture was poured into 100 ml of ice water, the precipitate was filtered off and washed with water until neutral. After drying, 1.24 g of product are obtained, m.p. 167-168 ° C, which is recrystallized from methanol.

Yield: 99%.

] a = + 24.1 ° (c = 0.5, in chloroform)

Example 6

benzoyloxy - 4 - pregnene - 3,20 - dione - 3 ethylenediothioacetal

Starting from 9.6 g (18.8 mM) of 20-benzoylamino-21-hydroxy-4,17-pregnadiene-3-one-3-ethylenedithioacetal, the procedure of Example 1 was repeated except that the crude product was not chromatographed. . 6.96 g (72%) of the title compound are obtained, m.p. 179-181 ° C.

[[alpha]] _D = + 192.8 '(c = 1.5, in chloroform)

The starting material of this example is 20-benzoylamino-21-hydroxy-4,17-pregnadiene-3-one.

For example, 3-ethylenediformite may be prepared as follows:

the step

- (2 '- Fe yl - 5' - oxo - 2 '- oxazoline - 4 - ifidene) - 4 - andrstene - 3 - one - ethylenediothioacetal to tetrahydrofuran at 0 to +5 ° C over 30 minutes 13.6 ml ( A solution of titanium tetrachloride (123 mM) in carbon tetrachloride (25 ml) was added dropwise. Then at constant temperature

7.47 g (20.6 mM) of 4-androstene-3,17-dione-3-ethylenediothioacetal (JR Williams, GM Sarkisian: Synthesis, 32, 1974), and 3.7 g (23 mM) of 2-phenyl- A solution of 2-oxazoline-5-one in 40 ml of tetrahydrofuran was added dropwise to 2 ml of pyridine after 2 hours, allowed to warm to room temperature, and after 2 hours was quenched with 200 ml of ice-cold brine. After extraction with dichloromethane, the organic phase is washed neutral with brine, dried and evaporated to give an oily product which is chromatographed on a column of silica gel (600 g, 96: 4 benzene / acetone). g, m.p. 266-267 ° C. This represents the greater part of the apolar geometric isomer in the given system.

The isomer mixture was separated from the column as a single fraction. Concentration gave 4.87 g of product: mp 217-219 ° C.

Total yield: 68%.

Step b)

- Benzoylamino - 4,17 - pregnadiene - 3 - onethylenedithioacetal - 21 - acid - methyl ester

To a solution of sodium methylate in 0.39 g of sodium metal and 50 ml of methanol at room temperature with stirring, 17 - (2 '- phenyl - 5' - oxo - 2 '- oxazoline - 4' - ifidene) prepared in the previous step a - 4 - androstene -3-one - ethylene dithioacetal

7.10 g (14 mM) was added. To the resulting suspension was added 40 mL of tetrahydrofuran. During the reaction, the substance dissolves. After 1.5 hours, the reaction mixture was poured into 1800 mL of water and the precipitated crystalline material was collected. The still wet product was dissolved in ethyl acetate, washed neutral with water, dried over magnesium sulfate and evaporated. 7.56 g of a foamy residue are obtained, which is recrystallized from isopropyl ether.

Yield: 7.00 g (93%) m.p. 144-146 ° C (a mixture of Z / E isomers).

step c)

- benzoylamino - 21 - hydroxy - 4,17 - pregnadiene - 3 - one - ethylenedithioacetal

2.66 g (4.9 mM) of the 20-benzoylamino-4,17-pregnadiene-3-one ethylene-dithioace-4197 026 dish-21-acid methyl ester prepared according to the previous step b.

Example 1 is reduced according to step c). The reaction mixture is processed in the same way and treated

2.52 g (100%) of the title compound are obtained as an oil.

The isomers were separated on a silica gel column using chloroform-ethyl acetate (3: 1) as eluent. R _f = recrystallized from occurring around 0,6 isomer (0.87 g) from ethyl acetate melts at 220-222 ° C.

Example 7

dithioacetal of pregnene - 3,20 - dione - 21 - ol - 3 - ethylene

1 g (1.95 mM) of 21-benzoyloxy-4-pregnene-3,20-dione-3-ethylenedio-dithioacetal prepared in Example 6 is suspended in 40 ml of methanol and 2 g of potassium bicarbonate are added to 5.7 ml. water. The suspension is refluxed for two hours. A solution is formed temporarily and then a precipitate is formed again. The methanol was evaporated and the residue was triturated with 50 ml of water. The precipitate was filtered off and washed with water until neutral. After drying, 0.77 g (97%) of product is obtained, m.p. 202-204 ° C, which is recrystallized from ethyl alcohol.

[ _α ] D = + 189 ° (c = 1, in chloroform)

Example 8

- Pregnene - 3,20 - Dion - 21 - Ol - Benzoate (Deoxygen - Corticosterone - Benzoate)

To a suspension of 1.4 g of red mercury oxide, 0.82 ml of boron trifluoride diethyl etherate and 7.7 ml of 85% water in tetrahydrofuran was stirred at room temperature, 1.65 g (3.23 mM) of the product prepared according to Example 6. A suspension of benzoyloxy 4-pregnene-3,20-dione-3-ethylenedithioacetal in 10 ml of tetrahydrofuran was added. After stirring for 20 minutes, the reaction mixture was stirred with 100 mL of dichloromethane and filtered clean with Hyflo Super Targ (Fluka) filtration aid. The filtrate was washed with 10% aqueous potassium carbonate solution, then brine, dried and evaporated. 1.19 g of a crystalline residue are obtained, which is chromatographed on a silica gel column with benzene: ethyl acetate: acetone (8: 1: 1). Yield: 1.06 g (76%) of the title compound, m.p. 205-207 ° C.

[a] "= +198" (c = 1, in chloroform)

Example 9

- Pregnene - 3,20 - Dion - 21 - Ol - Benzoate (Deoxygen - Corticosterone - Benzoate)

1.27 g (2.7 mM) of 21-benzoyloxy-4-pregnene-3,20-dione-3-ethylenedithioacetate prepared in Example 6 are dissolved in 25 ml of acetone and 2 ml of methyl iodide and three drops of water are added. . The reaction mixture was refluxed for 30 hours. The solvent was evaporated and the residue was dissolved in 100 ml of chloroform to give 100 g of Brockmann II. pass through a column of aluminum oxide. The purified solution was evaporated and the resulting crude product was crystallized from ethyl acetate.

Yield: 0.68 g (58%); mp 203-207 'C.

The product was the same as that of Example 8.

Example 10

- pregnene - 3.20 - nut - 21 - ol (deoxy - corticosterone)

2.5 g (5.7 mM) of 4 pregnene-3,20-dione-21-ol-benzoate from Example 9 were hydrolyzed according to Example 4, except that the crude product was extracted with ethyl acetate. the ethyl acetate layer was washed with water and evaporated to dryness. The residue was recrystallized from ethyl acetate / diisopropyl ether. Yield:

1.89 g (99%) of the title product; 132-135 ° C.

Y] = + 175 ° (c = 0.5, in ethyl alcohol)

Example 11

- Pregnen - 3,20 - Dion - 21 - Ol - Acetate (Deoxy - Corticosterone - Acetate)

1.16 g (3.5 mM) of 4-pregnene-3,20-di-21-ol prepared in Example 10 were acetylated as in Example 2.

Yield: 1.16 g (89%) m.p. 156-158 ° C.

[α] _D = + 174 ° (c = 1, in dioxane)

Example 12

- benzoyloxy - 4.9 (11) - pregnadiene - 3.20 dione - 3 - ethylenedithioacetal

Starting from 3.64 g (7.2 mM) of 20-benzoylamino-21-hydroxy-4,9 (11), 17-pregnatriene-3-one-3-ethylenedithioacetal, all proceed as in Example 1, except the crude product was chromatographed on a silica gel column using chloroform: ethyl acetate (3: 1). This gave 2.08 g (57%) of the title compound, m.p. 201-203C, which was recrystallized from ethyl acetate.

[α] _D = + 194.5 ° (c = 0.5, in chloroform)

The starting material of this example, 20-benzoylamino-21-hydroxy-4,9 (11), 17-pregnatrien-3-one-3-ethylenedithioacetal, may be prepared, for example, as follows:

the step

4,9-Androstadiene-3,17-dione-3-ethylenediothiectal

13.8 g of 4,9-androstadiene-3,17-dione (Hungarian Patent Application No. 3725/83) are dissolved in 550 ml of methanol and 12.4 ml of 1,2-ethanedithiol, and the solution is cooled to 25 ° C and with stirring 12 ml of boron trifluoride - ethyl

197,025 liters of ether are added. Meanwhile, the temperature of the reaction mixture is maintained at 25 with gentle cooling. After a few minutes, crystalline material begins to precipitate. Stirring is continued for 15 minutes at room temperature. The suspension was cooled in an ice-water bath, and after 1 hour the precipitated product was filtered off and washed with a little methanol. 13.25 g of product are obtained which is crystallized from ethanol. Yield: 11.5 g, m.p. 179-180 ° C [α] _D = + 233.6 ° (c = 1, in chloroform)

4.97 g (9.7 mM) of Example 12 21-benzoyloxy-4,9 (11) -pregnadiene-3,2 '' -dione-3-ethylenediedithalcelyl in Serbia were prepared in Example 8. Example 2 except that the crude product is not chromatographed but is recrystallized from ethyl acetate with warm charcoal clarification.

1.8 g (42%) of the title compound are obtained, m.p. 176-177 ° C.

[α] _D = +175.1 '(c ==1, in chloroform)

Step b)

-, (2 '- Phenyl - 5' - oxo - 2 '- oxazolin - 4' - ylidene) - 4,9 - androstadiene - 3 - one - Ethylenedithioacetal

Starting from 3.27 g (9 mM) of 4,9-androstadiene-3,17-dione-3-ethylenedio-dithioacetal prepared in the previous step a) was carried out as in Example 6 a). The crude product was chromatographed on a silica gel column with benzene-acetone (96: 4). The title product is isolated as a mixture of two isomers (Rf = 0.8-0.9). Yield:

3.58 g (78%), m.p. 178-179 ° C.

c) tearing

- Benzoylamino - 4,9,17 - Pregnatriene - 3 - one - Ethylenedithioacetal - 21 - Acid - Methyl Ester

Starting from 4.54 g (9 mM) of 17 - (2'-phenyl-5'-oxo-2'-oxazolin-4'-ylidene) -4.9 androstadiene-3-one ethylene dithioacetal prepared according to the previous step b). as in Example 6, step b). Yield: 4.38 g (91%) of the title compound which is a mixture of two isomers.

The two isomers are separated by silica gel column chromatography with a 9: 1 mixture of benzene and acetone. The isomer occurring at R f = 0.75 at 127 'C, the corresponding isomer at R f 50 being 170' Con. Recrystallization from the crude product with ethyl acetate affords the more polar isomer pure.

Step d)

- Benzoylamino - 21 - Hydroxy - 4,9,17 - Pregnatriene - 3 - one - Ethylenedithioacetal

The 20-benzoylamino-4,9,17-pregnatrien-3-one-ethylenedithioacetal-21-acid methyl ester (R _r = 0.50, more polar isomer) obtained in step c) is 1.0 g. was reduced according to Example 1, step c).

Yield: 0.88 g (93%) of the title compound, m.p. 212-213 ° C, recrystallized from methanol, and consisting of a single stereoisomer.

Example 13

Benzoate of 4,9 (11) -pregnadiene-3,20-di-21-ol

Example 14

4.9 (11) -pregnadiene-3.20-dione 21-ol-3 ethylenedio-dithioacetal g (3.9 mM) of the benzoyloxy-4.9 (11) -pregnadiene-1.20-dione 21 prepared in Example 12. 3-ethylenedithioacetal was hydrolyzed by the method of Example 4. The crude product was recrystallized from ethyl alcohol to give 0.93 g (58%) of the title product, m.p. 180-184 ° C.

[α] D = + 110 ° (c = 1, in chloroform)

Example 15

4.9 (11) -pregnadiene-3.20-dion-21-ol [9 (11) -hydro-corticoslcron] g (2.2 mM) of the 4.9 (11) -pregnadiene prepared in Example 13. The 21-ol-benzoate was hydrolyzed according to Example 4, except that the crude product was chromatographed on a silica gel column using chloroform: ethyl acetate (3: 1). 0.65 g (89%) of the title compound is obtained, m.p. 147-150 ° C.

[α] _D = + 70.2 '(c = 0.5, in chloroform) / Example 6

- methoxy - 21 - benzoyloxy - 19 - nor 1,3,5 (10) - pregnatriene - 20 - on

Starting from 6.45 g (15 mM) of 3-methoxy-20-benzoylamino-19-nor-pregna-1,3,5 (10), 17-tetraene-21, all proceed as in Example 1, except to give crude product by ner chromatography but by recrystallization from alcohol. Yield: 6.13 g (94%) of the title compound, mp 151-152'C.

[a] "= +129.5" (c = 1, in chloroform)

EXAMPLE 3 3-methyl-20-benzoylamino-19-nor-pregna 1,3,5 (10), 17-tetraen-21-ol -1 for use as starting material for the starting compound may be prepared as follows:

the step

- Hydroxy - 17 - (2 '- phenyl - 5' - oxo - 2 '- oxazolin - 4' - ylidene) - estra - 1,3,5 (10) - triene - methyl ether

-6197 A mixture of titanium tetrachloride (6.6 ml, 60 mM) and carbon tetrachloride (13 ml) was added dropwise to 025 ml of dry tetrahydrofuran at 0 to +5 ° C. A solution of 5.68 g (20 mM) of estrone methyl ether and 4.0 g of 5 (25 mM) 2 - phenyl - 2 - oxazolin - 5 in 110 ml of tetrahydrofuran is then added at constant temperature. Thereafter, pyridine (10 ml) was added dropwise to the reaction mixture at constant temperature for 1.5 hours, stirred at room temperature for 3 hours, and the reaction mixture was quenched with ice-cold 10% aqueous saline (200 ml). The product was extracted with dichloromethane and the solution was washed with water to neutral, dried and evaporated. An oily residue is obtained which crystallizes on treatment with diisopropyl ether. The crude product (7.0 g) was recrystallized from ethyl acetate followed by acetone. 1.76 g of the expected product are obtained, m.p. 193-194 ° C. The mother liquors were evaporated to dryness and the residue purified by silica column chromatography in 96: 4 mixture of benzene and acetone - chromatography eluting with an additional 3.55 g of product is available in 20 cfm R _F value of about 0.7 to 0.8, a melting point of 162 ° C (the the ratio of isomers here differs from the previous fraction).

Yield: 62% (1st + 2nd generation)

Step b)

- methoxy - 20 - benzoylamino - 19 - nor - pregna - 1,3,5 (10), 17 - tetraene - 21 - acid - methyl ester

3-Hydroxy-17- (2'-phenyl-5'-oxo-2'-oxazolin-4'-yl-13'-diene) -estra-1,3,5 (10) -tronone prepared in the previous step a) methyl ether

Starting at 4.28 g, proceed as in Example 1 (b). Yield: 4.38 g (95%) of product. 184-194 'C (mixture of isomers).

step c)

- methoxy - 20 - benzoylamino - 19 - nor - pregna - 1,3,5 (10), 17 - tetraene - 21 - ol

3-Methoxy 20-benzoylamino-19-nor-pregna 1,3,5 (10), 17-tetraene-21-acid-inethyl ester prepared according to the preceding step b).

3.20 g (6.9 mM) was reduced according to Example 1, step c). The oily title compound obtained as a crude product is recrystallized from methanol.

Yield: 2.85 g (95%), m.p. 164-166 ° C

Claims (1)

Claims A novel process is the pregnene derivatives of formula (I) wherein R ¹ is benzoyl, ring A may be of formula (1) or (2) wherein R ² represents a 1-3 alkenoyl alkoxy group, 1+ represents a hydroxy group, a C 2 -C 4 alkanoyloxy group, or an ethylenedio thio group, and the dotted lines represent one or more further valence bonds which may be present, characterized in that a new pregnene derivative of the formula - where ring A, including R ^? , R ³ , and dotted lines are as defined above, R ⁴ is phenyl, and wavy lines indicate that the substituents may be attached to the carbon atom in two positions - boiling with aqueous acetic acid.