HU222729B1 - Intermediates using for the production of 19-nor-steroids and process for producing them - Google Patents

Abstract

Field of the Invention The present invention relates to compounds of formula (XI): (XI) wherein RA R20 is hydrogen, - (CH2) n-SO2-NR'A wherein RA and R'A, which may be the same or different, are hydrogen, or, optionally, halogen-substituted C 1 -C 6 alkyl, n is an integer from 1 to 8, R 21 is oxo or R 10 is a general group wherein R p is a hydroxyl protecting group, and a dashed line indicates that there is a single or double bond in the site. The invention also relates to processes for the preparation of compounds. ŕ

Description

The present invention relates to novel intermediates for the preparation of phenoxyalkylsulfonamide or 19-norsteroids containing a phenoxyalkylsulfonylurea chain at the Ιΐβ-position and a process for their preparation.

The intermediates of the invention are represented by the general formula (XI).

In the formula z ^A

R ²⁰ is hydrogen, - (CH ₂ ) _n -SO ₂ -N

A group of formula R'a in which

R _a and R ' _a , which may be the same or different, are hydrogen or (C 1 -C 6) alkyl optionally substituted with halogen, n is an integer from 1 to 8,

R ²¹ is an oxo group or a group of the formula R _p O, in which R _p is a hydroxyl protecting group, and the dashed line means that a single or double bond is present at the site.

More particularly, the present invention relates to compounds of formula (IV) which form a more narrow group of compounds of formula (XI):

which are compounds of formula XI wherein R ²⁰ is

Ra

Z

- (CH ₂ ) _n -SO ₂ -N wherein

Ra

R a and R ' _a are as defined above, and at least one of R _A and R' _A is other than hydrogen, R ²¹ is oxo, and the position of the double bonds is within the formula and a smaller group of compounds of formula XI Compounds of formula (V),

which are compounds of formula (XI) wherein R ²⁰ is hydrogen and R ²¹ is RpO, Rp is as defined above, the position of the double bonds in the formula, and a smaller group of compounds of formula (XI) Compounds of formula VI,

SO ₂ NH ₂ (CH 2) _n

which are compounds of formula XI wherein R 20 is

Ra

Z

- (CH ₂ ) _n -SO ₂ -N,

R'a wherein R _A and R ' _A are hydrogen, R ²¹ is RpO, wherein Rp is as defined above, and the position of the double bonds is as defined.

The novel intermediates are useful in the preparation of compounds of formula (I) which possess significant pharmacological properties. In the general formula (I)

R ¹⁷ and R ¹⁷ 'are as defined

- R ¹⁷ and R ¹⁷ 'together form a ketone, or

- R ¹⁷ is hydroxy or acyloxy having up to C atoms and R ¹⁷ 'is hydrogen, alkyl, alkenyl or alkynyl having up to 8 carbon atoms, which are optionally substituted,

- R ³ is hydrogen, straight or branched or up to 8 carbon atoms

EN 222 729 B1 is a linear alkyl group or an acyl group containing up to 12 carbon atoms,

R ¹ and R ² may be the same or different and are hydrogen, C 1 -C 8 straight or branched chain or cyclic alkyl, which may be optionally substituted, up to C 12 acyl, aryl or aralkyl, which may be optionally substituted and wherein the alkyl group contains up to 6 carbon atoms and the aryl group is mono- or polycyclic and may contain one or more heteroatoms selected from oxygen, nitrogen and sulfur; or

R ¹ is a monosubstituted carbamoyl group, where the substituent is a straight or branched chain alkyl or cyclic alkyl group, or an aryl or aralkyl group containing up to 8 carbon atoms, which may also be optionally substituted, and wherein the alkyl group is up to 6 carbon atoms is a mono- or polycyclic group which may also contain one or more heteroatoms selected from oxygen, nitrogen and sulfur; and

R ² is hydrogen, or

- R ¹ and R ² together with the nitrogen atom to which they are attached form a 6-membered heterocyclic nitrogen containing optionally a second heteroatom selected from nitrogen, oxygen and sulfur and optionally substituted with C 1 -C 4 alkyl or oxo, or

- R ¹ and R ² together form a dialkyl methylene-amino group, wherein 1-4 carbon atoms in the alkyl groups and n is an integer of <18th

The present invention also relates to salts of compounds of formula XI, for example, when compounds of formula XI contain an amino group, they are mentioned with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, propionic acid, benzoic acid, maleic acid, with succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid or alkanesulfonic acid such as methane or ethanesulfonic acid or arylsulfonic acid such as benzenesulfonic acid or paratoluenesulfonic acid, and arylcarboxylic acids.

Preferred compounds of formula XI are those wherein n is 5 or 6 and the other substituents are as defined above.

The present invention also relates to a process for the preparation of compounds of formula XI. According to the invention, the process is carried out by treating a compound of formula II,

wherein the phenol group is optionally protected,

A) reacting with a halogen derivative of formula III,

X- (CH ₂ ) _n -SO ₂ -NR _A R ' _A (III) wherein X is halogen, n, R _A and R' _A are as defined above and then the compound of formula IV is obtained,

wherein n, R _A and R _A are as defined above; obsession

B) reacting the ring A with an aromatizing agent and protecting the hydroxy group at position 3, then removing the protecting group from the phenol group at position 11 by a selective reaction and then obtaining the compound of formula V,

wherein Rp is a hydroxyl protecting group, is opened or reacted with a compound of formula IIP,

X- (CH ₂ ) _n -SO ₂ -N = CH-N (Alk ₁ ) (Alk ₂ ) (III ') wherein X is halogen, (AUq) and (Alk ₂ ) are C 1 -C 4 alkyl, and n is an integer <8, then the resulting imine is hydrolyzed and the resulting compound of formula VI is obtained,

wherein n and Rp are as defined above, and

optionally forming a salt with an acid or a base.

The reaction of the compound of formula (II) with the compound of formula (III) is preferably carried out in the presence of a strong base such as sodium hydride in a dipolar aprotic solvent such as dimethylformamide, for example at room temperature.

In the preparation of compounds of formula VI, the compound of formula II in which the phenol group 11 is optionally protected is preferably first

The reaction is carried out with a flavoring agent such as palladium hydroxide on magnesium oxide in methanol and the hydroxy group 3 is protected, for example benzyl chloride, in the presence of potassium carbonate in acetone and finally refluxed for 7 hours. the phenol moiety is selectively deprotected, for example by saponification, e.g. in the presence of potassium hydroxide in methanol, or in the presence of sodium hydroxide in methanol, and the resulting intermediate of formula V is reacted with a compound of formula III ' in the presence of sodium hydride in a dipolar aprotic solvent such as dimethylformamide and the resulting imine is subjected to acid hydrolysis, e.g. with hydrochloric acid in ethanol / tetrahydrofuran.

Protecting groups useful for protecting reactive groups, such as hydroxyl protecting groups, are selected from those commonly used in organic chemistry, especially peptide chemistry. FR 2,499,995 discloses a non-exhaustive list of these groups, as well as appropriate removal procedures. Suitable protecting groups are also found in Protective group in organic synthesis (Greene and Wuts (1991), Wiley Publisher).

Examples of protecting the phenol group at the 11-position of the compound of formula II include acetyl, benzoyl or tert-butyldimethylsilyl.

Examples of protecting the hydroxyl group at the 3-position of the compounds of formula (V) and (VI) include acetyl, benzoyl or benzyl.

For example, the reaction of the hydroxyl group 3 compound with the benzyl group may be carried out with benzyl chloride in the presence of a strong base such as sodium hydride, in an aprotic dipolar solvent such as dimethylformamide at room temperature or in the presence of a less strong base such as potassium carbonate in acetone with boiling. This protecting group is resistant to hydrolysis or saponification.

When the intermediates contain protected reactive groups, the corresponding unsubstituted compound is prepared with standard reagents. A list of such protecting groups, as well as appropriate (non-exhaustive) removal procedures, is found in FR-2,499,995 and in Protective group in organic synthesis (Greene and Wuts (1991), Wiley Publisher).

By way of example, when the phenol is protected with an acetyl group, the deprotection can be effected with a saponifying agent such as potassium hydroxide in an alcoholic medium, when the phenol is protected with a tertiary where the hydroxy group at position 3 is protected with a benzyl group, the removal of this protecting group is preferably accomplished by hydrogenolysis, for example in the presence of a palladium catalyst on hydrogen in carbon in an ethyl acetate / ethanol solvent mixture.

According to the invention, it is preferred that:

- the use of compounds of the formula III in which X is preferably iodine,

- Compounds of formula IIP wherein X is preferably iodine.

The starting compounds are known, for example, from European Patent Application No. 0,384,482, or may be prepared by the methods described in the present invention.

Among the novel intermediates of the present invention, the preparation of which is described in the experimental section:

N-butyl-5- [4- (3,17-dioxo-estra-4,9-diene-11β-yl) -phenoxy] -N-methyl-pentanesulfonamide,

5- [4- (3,17-dioxo-4,9-dien-l ^ yl) phenoxy] -N- (2,2,3,3,4,4,4-heptafluoro-butyl) - N-methylpentanesulfonamide, β- (4-hydroxyphenyl) -3 - [(phenylmethyl) oxy] oestral, 3,5 (10) -trien-17-one,

5- [4- [17-Oxo-3 - [(phenylmethyl) oxy] - [estra-1,3,5 (10) triene-11β-yl] phenoxy] pentanesulfonamide.

The compound of formula (II) used in the process of the invention is known from the European patent application EP 0,384,842 (preparation of Example 43).

The experimental part describes the preparation of compounds of formulas III and IIP. These compounds are generally known and may be prepared by methods analogous to those described in the experimental section.

The invention is illustrated by the following examples, but is not intended to be limited thereto.

Preparation 1

N - [(dimethylamino) methylene] -5-iodo-pentyl-sulfonamide

Step A: 5-Chloro-pentanesulfonamide

2.5 g of 5-chloropentylsulfonyl chloride [see Bull. Soc. Chim. Belg. (1965), 74 21] 2.5 ml of 28% aqueous ammonium hydroxide solution are added dropwise to a solution of 30 ml of tetrahydrofuran in an inert gas atmosphere at 0-5 ° C. The temperature was allowed to rise from 3 ° C to 16 ° C and the mixture was stirred at room temperature for 2 hours. The tetrahydrofuran is then distilled off in vacuo, the residue is taken up in water, extracted with methylene chloride, washed with water and then with anhydrous sodium chloride solution, dried and concentrated in vacuo. 2.05 g of the expected compound are obtained. Mp 62 ° C.

IR spectrum: in trichloromethane (CHCl ₃ ):

-NH ₂ 3448 cm ^-1

3352 cm

-SO ₂ 1344 cm1150 αη ^_1

-NH ₂ 1545 cm ^-1

Step B: 5-Chloro-N - [(dimethylamino) methylene] pentylsulfonamide

To a solution of 1.5 g of the compound obtained in the preceding step in 8 ml of dimethylformamide is added dropwise at room temperature 1.29 ml of

HU 222 729 Bl

Ν, Ν-dimethylformamide dimethyl acetal. After stirring at room temperature for 3 hours, the solution was poured into 1% sodium hydrogen sulfate solution, extracted with ethyl acetate, washed with water followed by saturated aqueous sodium chloride solution, dried and evaporated to dryness in vacuo. 1.809 g of the expected compound are obtained.

IR (CHC1 _3):

-N = CH-N <1629 cm- *

-SO ₂ 1349 cm- *

1119 cm- *

Step C: N - [(Dimethylamino) methylene] -5-iodo-pentanesulfonamide

To a solution of 2.09 g of the compound prepared in the preceding step in 31.5 ml of methyl ethyl ketone (E. E.C.) is added 2.98 g of sodium iodide and the mixture is refluxed for 4 hours. After cooling, water was added, the mixture was extracted with ethyl acetate, washed with water and brine, dried and evaporated to dryness in vacuo. 2.69 g of the expected compound are obtained.

IR (CHC1 _3):

-N = CH-N <1629 cm- *.

Preparation 2

N-butyl-5-iodo-N-methyl-pentane-sulfonamide

Step A: N-Butyl-5-chloro-N-methylpentylsulfonamide

To a solution of 510-chloropentylsulfonyl chloride (410 mg) in methylene chloride (10 mL) was added N-butylmethylamine (0.47 mL) under an inert gas. The temperature rises from 13 ° C to 26 ° C, after which the mixture is cooled to 0-5 ° C, 0.55 ml of triethylamine is added and stirred at room temperature for 2 hours. The reaction mixture was poured into aqueous 1M hydrochloric acid, extracted with methylene chloride, washed with water, brine, dried and evaporated to dryness in vacuo. 486 mg of the desired compound are obtained.

IR (CHC1 _3):

-SO ₂ N <1334 cm- *, 1142 cm- *.

Step B: N-Butyl-5-iodo-N-methylpentylsulfonamide

To a solution of the compound prepared in the previous step (449 mg) in methyl ethyl ketone (4.5 ml) was added sodium iodide (526 mg) and the mixture was stirred at reflux for 4 hours. After cooling and evaporation of the methyl ethyl ketone in vacuo, water was added to the residue, the mixture was extracted with ethyl acetate, washed with water, brine, dried and evaporated to dryness in vacuo. 572 mg of the desired compound are obtained.

IR (CHC1 _3):

-SO ₂ N <1334 cm * cm * 1141.

Preparation 3

N- (2,2,3,3,4,4,4-heptafluoro-butyl) -5-iodo-N-methyl-pentane-sulfonamide

Step A: 5-Chloro-N- (2,2,3,3,4,4,4-heptafluorobutyl) -N-methylpentylsulfonamide

To a solution of 5-chloro-pentanesulfonyl chloride (200 mg) in methylene chloride (5 ml) was added 500 mg of N- (2,2,3,3,4,4,4-heptafluorobutyl) -N-methylamine hydrochloride. Prepared according to Example 75 of EP 384842, 0.55 ml of triethylamine is added at 0-5 ° C and stirred for 2 hours at room temperature. Water is added, the mixture is extracted with methylene chloride, extracted with water and then with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness in vacuo. 378 mg of the desired compound are obtained.

IR (CHC1 _3):

-SO ₂ N <1354 cm * 1341 cm *

1148 cm-1, impurity C = O 1730 cm-1.

Step B: N- (2,2,3,3,4,4,4-Heptafluorobutyl) -5-iodo-N-methylpentanesulfonamide

Sodium iodide (300 mg) was added to a solution of the compound prepared in the preceding step (355 mg) in methyl ethyl ketone (3 ml) and the mixture was refluxed for 4 hours. The solvent was evaporated in vacuo, the residue was taken up in water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate solution, then brine, dried and evaporated to dryness in vacuo. 425 mg of the desired compound are obtained in the form of a colorless oil which slowly crystallizes.

IR (CHC1 _3):

N-SO ₂ - 1354 cm *, 1341 cm *,

1148 cm -1.

Preparation of Example 1 $ 1- (4-Hydroxyphenyl) -3 - [(phenylmethyl) oxy] estra-1,3,5 (10) -trien-17-one

Step A: 11β- [4- (Benzoyloxy) phenyl] estra-4,9-diene-3,17-dione

To a solution of 8.758 g of lipo- (4-hydroxyphenyl) -estra-4,9-diene-3,17-dione (prepared according to Example 43 of EP 384842) in 92 ml of acetone and 27 ml of 1 m aqueous sodium hydroxide. 3 ml of benzoyl chloride are added dropwise at 0-5 ° C under an inert gas atmosphere. At the end of the benzoyl chloride addition, the precipitation of the benzoate was observed, the suspension was stirred for 10 minutes in an ice bath, and then poured into 0.1M aqueous hydrochloric acid for 30 minutes, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution. and evaporate to dryness in vacuo. 12.98 g of crude product are obtained, which is crystallized from methylene chloride / isopropyl ether. 9.93 g of the expected compound are obtained. Melting point: 196 ° C.

IR (CHC1 _3):

> Position 17

C = O Ar-O-CO-Ph-ketone: 1736 cm-* (F) conjugated ketone: 1659 cm-1,

1602 cm- *, aromatic C = C: 1505 cm- *,

1490 cm -1.

Step B: 11β- [4- (Benzoyloxy) phenyl] -3-hydroxy-estra-1,3,5 (10) -trien-17-one

To a solution of 10.07 g of the compound obtained in the preceding step in 104 ml of methanol are added 10.1 g of 20%

EN 222 729 pall 1 palladium hydroxide on magnesium oxide. After refluxing for 1.5 hours, the reaction mixture was cooled, the slurry filtered, the insoluble catalyst washed with methylene chloride / methanol (50:50) and the filtrate evaporated to dryness in vacuo. The residue, purified by chromatography on silica gel (10.72 g), was eluted with ethyl acetate / cyclohexane (40:60, v / v). 7.72 g of the expected compound are obtained. Melting point: 265 ° C.

IR (CHC1 _3):

-OH: 3599 cm- ¹ > C = O: 1733 cm- ¹ (F)

1611 cm- ¹ 1602 cm- ¹ aromatic C = C: 1585 cm- ¹

1508 cm ^-1

Step C: 11β - [4- (Benzoyloxy) phenyl] -3 - [(phenylmethyl) oxy] estra-1,3,5 (10) -trien-17-one

To a solution of 6.462 g of the compound obtained in the preceding step in 110 ml of acetone are added 3.82 g of potassium carbonate and 4.9 ml of benzyl bromide (Fluka A007832). The mixture was refluxed for 7 hours, cooled and evaporated to dryness in vacuo. The residue was taken up in ethyl acetate and the mixture was poured into 0.5 M hydrochloric acid. It was then re-extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried and evaporated to dryness in vacuo. 12.2 g of a residue are obtained, which is purified by chromatography on silica gel. The eluent was ethyl acetate / cyclohexane (25:75, v / v). 6.68 g of the expected compound are obtained.

IR (CHC1 _3):

> C = O: 1734 cm ^-1 complex

1604-1608 cm ¹ ,

1586 cm ^-1 , aromatic C = C: 1576 cm ^-1 ,

1508 cm ^-1 ,

1501 cm- ·.

Step D: 11β- (4-Hydroxyphenyl) -3 - [(phenylmethyl) oxy] estra-1,3,5 (10) -trien-17-one

To a solution of 6.64 g of the compound obtained in the preceding step in 87.5 ml of methanol and 87.5 ml of tetrahydrofuran are added 12 ml of a 2M aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 1 hour and then poured into 0.5M aqueous hydrochloric acid. The resulting solution was extracted with ethyl acetate, and the organic layer was washed with water, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, dried and evaporated to dryness in vacuo. 6.52 g of crude product are obtained, which is crystallized from methylene chloride. 4.62 g of the expected compound are obtained. Melting point: 240 ° C.

IR (CHC1 _3): OH: 3600 cm ^-1 > C = O: 1733 cm ^-1 1613 cm ^-1 1594 cm ^-1 aromatic C = C: 1574 cm ^-1 1513 cm ^-1 1500 cm ¹

Example 1

5- [4- [17-Oxo-3 - [(phenylmethyl) oxy] estra-1,3,5 (10) trien-11-yl] phenoxy] pentylsulfonamide

Step A: N - [(Dimethylamino) methylene] -5- [4- [17-oxo3 - [(phenylmethyl) oxy] estra-1,3,5 (10) -triene-11] β-yl] phenoxy-pentyl-sulfonamide

2.92 g of the compound prepared according to Step D of the preparation of Example 1 are suspended in 69 ml of dimethylformamide and 403 mg of 50% oil in sodium hydride and stirred for 25 minutes under an inert gas. 67 g of Preparation 1

A solution of the compound prepared in Step C) in dimethylformamide (25 mL). The suspension was heated to 50 ° C to give a solution over 10 minutes, which was stirred at this temperature for another hour and 15 minutes. The reaction mixture was cooled to room temperature and poured into a 1% aqueous solution of sodium hydrogen sulfate, then extracted with ethyl acetate, washed with water, saturated aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried and evaporated to dryness in vacuo. 6.75 g of a residue are obtained, which is purified by chromatography on silica gel. Elution was carried out with ethyl acetate. 3.82 g of the expected compound are obtained.

IR (CHC1 _3):

At position 17> C = O: 1733 cm ^-1

-N = CH-: 1629 cm- ¹

1611 cm ^-1 (shrug) 1575 cm ^-1 aromatic C = C: 1512 cm -1, 1500 cm ^-1

-SO ₂ -: 1349 cmB) step 5- [4- [17-Oxo-3 - [(phenylmethyl) oxy] estra-1,3,5 (10) -trien-11 H -yl] - phenoxy] pentylsulfonamide To a suspension of 3.818 g of the compound obtained in the preceding step in 59 ml of methanol and 28 ml of tetrahydrofuran is added 17.7 ml of pure concentrated hydrochloric acid (22 ° C, 1.18 g / cm ³ ) under an inert gas atmosphere. The mixture was heated at 80 ° C for 1.5 hours and then cooled, poured into saturated aqueous sodium bicarbonate solution, extracted, washed with saturated aqueous sodium chloride solution, dried and evaporated to dryness in vacuo. 4.15 g of a residue are obtained, which is purified by chromatography on silica gel. The eluent was ethyl acetate / cyclohexane 60:40 (v / v). 2.89 g of the expected compound are obtained.

IR (CHC1 _3):

-NH ₂ : 3444 cm ^-1 ,

3350 cm ^-1 ,

At position 17> C = O: 1733 cm ^-1 ,

1616 cm ^-1 , aromatic C = C: 1580 cm ^-1 ,

-NH ₂ : 1545 cm ^-1 .

Example 2

Step A: N-Butyl-N-methyl- [5- [4- (3,17-dioxo-estra-4,9-diene-11'-yl) -phenoxy] -pentylsulfonamide mg 50% in sodium oily 362.5 mg of lip- (4-hydroxyphenyl) -estra-4,9-diene-3,17-dione (preparation of Example 43 of EP 384842) was added to a suspension of hydride hydride in 6 ml of dimethylformamide under an inert gas atmosphere. )

After stirring for 30 minutes at room temperature, a solution of 417 mg of Preparation 2, Step B, in 1.5 ml of dimethylformamide was added. During the addition, the temperature was allowed to rise from 23 ° C to 27 ° C and the mixture was stirred for 45 minutes. The reaction mixture was poured into 1M aqueous hydrochloric acid, extracted with ethyl acetate, washed with water, saturated aqueous sodium thiosulphate solution and finally with saturated aqueous sodium chloride solution, dried and evaporated to dryness in vacuo. 883 mg of a residue is obtained, which is purified by chromatography on silica gel. The eluent was ethyl acetate / cyclohexane 60:40 (v / v). 433 mg of the desired compound are obtained.

IR (CHC1 _3):

17 position> C = O: 1735 cm ^-1 diene: 1658 cm ^-1

1609 cm ^-1

C.dbd.C + 1600 ^cm-1 (sh), aromatic C = C 1580 ^cm-1

1509 cm ^-1 (strong)

1333 cm ^-1

-SO ₂ N <: 1140 cm ^-1

Step B: N-Butyl-N-Methyl- [5- [4- (3-acetoxy-17? -Oxoestra-1,3,5 (10) trien-11-yl) -phenoxypentyl] sulfonamide

1. Aromatization

To a solution of the compound prepared in the previous step (404.5 mg) in methylene chloride (4 ml) was added acetic anhydride (0.32 ml) and acetyl bromide (0.16 ml) under an inert gas at 0-5 ° C. The mixture was stirred at this temperature for 15 minutes and then at room temperature for 1 hour and 15 minutes.

Example 3

Step A: (2,2,3,3,4,4,4-Heptafluorobutyl) -N-methyl- [5- [4- (3,17-dioxo-estra-4,9-diene-11 ') yl) phenoxy] -Npentil sulfonamide

To a solution of 255 mg of Ip- (4-hydroxyphenyl) -estra-4,9-diene-3,17dione (preparation of Example 43 of EP 384842) in 4.5 ml of dimethylformamide was added 40 ml of % sodium hydride in oil. The mixture was stirred for 30 minutes at room temperature and then 400 mg of Preparation 3 was added

The compound prepared according to Step B) was stirred at room temperature for 45 minutes. The reaction mixture was poured into 1M aqueous hydrochloric acid, extracted with ethyl acetate, washed with a saturated aqueous sodium thiosulfate solution and then with a saturated aqueous sodium chloride solution, dried and evaporated to dryness in vacuo. 600 mg of a residue are obtained, which is purified by chromatography on silica gel. The mixture was eluted with ethyl acetate / G-benzyl 55:45 (v / v). 335 mg of the desired compound are obtained.

IR (CHC1 _3):

At position 17> C = O: 1735 cm- ¹ : 1658 cm- ¹

1609 cm-C = C + 1580 cm- ¹ aromatic C = C: 1509 cm- ¹

1342 cm ^-1

Step B: 5- [4- (3,17-Dihydroxy-estra-1,3,5 (10) -trien-11-yl) -phenoxy] -pentyl] -N- (2,2,3) , 3,4,4,4-heptafluoro-butyl) -N-methyl-sulfonamide

1. Aromatization

430 mg of the compound prepared in the preceding step

To a solution of 3.5 ml of methylene chloride is added 0.35 ml of acetic anhydride and 0.20 ml of acetyl bromide at 0-5 ° C, and the mixture is stirred for 40 minutes at room temperature.

Claims (5)

PATENT CLAIMS Where / ^RA R ²⁰ is hydrogen, ~ (CH ₂ ) _n -SO ₂ -N A group of formula R'a in which Ra and R ' _a , which may be the same or different, are hydrogen or (C 1 -C 6) -alkyl optionally substituted with halogen, n is an integer from 1 to 8, R ²¹ is oxo or RpO, wherein Rp is a hydroxyl protecting group, and the dashed line means that a single or double bond is present at the site. Compounds of general formula (IV) which form a narrower group of compounds of formula (XI) wherein R _a and R ' _A are as defined in claim 1 and at least one of the substituents is other than hydrogen and the position of the double bonds in the formula by. 3. Compounds of formula (V) forming a narrower group of compounds of formula (XI) Wherein Rp is as defined in claim 1. 4. Compounds of formula (XI) are compounds of formula (VI), which is a narrower stone layer, wherein (n) and Rp are as defined in claim 1. 5. A process for the preparation of the compounds of the general formula (XI) according to claim 1 and their salts, characterized in that a compound of the formula (II) in which the phenol group is optionally protected, A) The compound of formula (IV) is reacted with a halogen derivative of formula (III), X- (CH ₂ ) _n -SO ₂ -NR _A R ' _A (III) wherein X is halogen, n, R _A and R' _A are as defined above, and then the compound of formula IV is obtained wherein n, R _A and R ' _A are as defined above; obsession B) To prepare compounds of formula V, ring A is reacted with an aromatiser and the hydroxy group at position 3 is protected, then the phenol group at position 11 is deprotected by selective reaction and the resulting compound of formula V wherein R _p is a hydroxyl protecting group, or is reacted or optionally reacted with a compound of formula (III '), X- (CH ₂ ) _n -SO ₂ -N = CH-N (Alk ₁ ) (Alk ₂ ) ( _II P) wherein X is halogen, (Alk ₁ ) and (Alk ₂ ) are C 1 -C 4 alkyl, and n is an integer of 1 to 8, and the resulting imine is hydrolyzed and the resulting compound of formula (VI) wherein n and Rp are as defined above is recovered and, if desired, converted to its salt.