NO167983B - 17- (FORMAMIDO-SULPHONYL-METHYL) -STEROIDS AND THEIR PREPARATION. - Google Patents

Description

The present invention relates to 17-(formamido-sulfonyl-methylene)-steroids and a method for their production.

These 17-(formamido-sulfonyl-methylene)-steroids are intermediates in the preparation of 17-(isocyano-sulfonyl-methylene)-steroids.

The present application is divided from Norwegian application 841700 and, as far as prior art and the background of the invention are concerned, reference is made to this.

Steroids are used on a large scale as ingredients for many types of pharmaceutical preparations. Depending on the substituent patterns in the carbon shell, the steroids can be divided into a number of main classes. An important main class of steroids is made up of the corticosteroids. The natural representatives of the corticosteroids are usually produced by the adrenal gland. Corticosteroids are characterized by the presence of a 3-keto group, an A^ bond, an 11-ε-hydroxy group, a 17-α-hydroxy group and a 17-β<->hydroxyacetyl side chain.

For a long time, corticosteroids were made by chemically breaking down bile acids such as cholic acid, desoxycholic acid and glycolic acid. Later, hecogenin, which could be isolated from plants, especially from numerous Agave species, also became an important raw material. Because of the possibility of introducing an 11-hydroxy group by microbiological methods, disgenin, which could be isolated from numerous Discoreacaea species, and stigmasterol, usually isolated from the phytisterol mixture from soy or calabar beans, have become the most important raw material for the production of corticosteroids.

Much attention has been devoted to new, inexpensive raw materials for the synthesis of pharmaceutically active steroids. Therefore, the degradation of the abundantly available soybean-derived sterols sitosterol and capesterol by microbiological methods to 17-oxo-steroids was extensively investigated. As a result, 17-oxo-steroids are readily available at low cost, which makes these compounds, together with the possibility of introducing an 11-hydroxy group by microbiological methods, ideal starting materials for corticosteroid syntheses.

A number of chemical syntheses for the construction of corticosteroid side chains from 17-oxo-steroids are known. For example, in "J.Org.Chem.", 44, 1582 (1979) there is described a method which uses a sulfenate-sulfoxide rearrangement to introduce the 17-(dihydroxyacetone) side chain. Another way is described in "J.C.S.Chem.Comm.", 1981, 775, in which the reaction between 17-oxo-steroids and ethyl isocyanoacetate is described, followed by a number of other reactions, ultimately resulting in the dihydroxyacetone side chain of corticosteroids. Other syntheses of corticosteroid side chains or of compounds that can be used as precursors for these are described in "J.C.S.Chem.Comm.", 1981, 774, "J.C.S.Chem.-Comm.", 1982, 551, "Chem.Ber.", 113 , 1184 (1980) and "J.Org.-Chem.", 1982, 2993.

The present invention relates to the production of intermediate products for the production of 17(isbcyano-sulfonylmethylene)-steroids.

These 17-(formamido-sulfonylmethylene)steroids are characterized by the general formula

there

R 1 means a hydrogen atom or a methyl group, or is absent 1 case a double bond between C^q and Cj_, C5 or Cg,

R2 means a hydrogen atom or a methyl group,

R3 means an alkyl or dialkylamino group or an aryl group, optionally substituted with one or more halogen atoms, alkyl-. alkoxy, nitro or cyano groups and

the rings A, B, C and D optionally contain one or more double bonds, optionally substituted with one or more hydroxy groups, amino groups, oxygen atoms, halogen atoms or alkyl, alkylene, alkoxy or alkoxy-alkoxy groups, and optionally substituted with one or more epoxy, methylene, alkylenedioxy, alkylenedithio or alkyleneoxythio groups.

As mentioned above, the invention relates to a process for the production of the above-mentioned 17-(formamido-sulfonyl-methylene)steroids with formula (II) and this is characterized by reacting a ketone with the general formula

with a sulfonylmethyl isocyanide R3-SO2-CH2-N-C at -20<*> to -80*C.

The reaction is preferably carried out at -30° to -60*C.

Pharmaceutically interesting 21-hydroxy-20-keto-A<16>steroids are prepared by reacting 17-(isocyano-sulfonylmethylene)-steroids with an aldehyde and an alcohol under basic conditions, followed by hydrolysis of the intermediate 17-(2-hydroxy- 3-Oxazolin-4-yl)-[alpha]-steroids. Likewise, interesting 20-keto-A^-steroids are prepared by reacting 17-(isocyano-sulfomethylene)-steroids with an alkylating agent under basic conditions, followed by hydrolysis of the intermediate 20-isocyano-20-sulfonyl-A<16->steroids.

In connection with the background of the present invention, the following has been observed.

EP application no. 7672 contains an example, namely example 60, where a steroid is used for the preparation of a cx-, p-unsaturated sulfonylmethylformamide, and further dehydration of this formamide to the corresponding isocyanide is described, namely example 26. In these examples the starting material was a 3-oxo-steroid.

However, because the 3-oxo group in a steroid is more reactive than the 17-oxo group, mainly due to steric reasons, it is not possible for one skilled in the art to predict that these reactions could also be carried out on the 17-oxo group, especially not because of the known difficulties in reacting p-methylsteric hindered ketones.

In this regard, it should be noted that the reaction of p-methylphenylsulfonylmethylcyanides with 17-oxo-steroids was already known, as appears for example from "Tetrahedron" 31, 2151 and 2157. In these publications, the preparation of 17-a and 17-p cyanosteroids described. As a result of the already mentioned steric hindrance of the 17-oxo group, reaction with p-methylphenylsulfonyl-methylisocyanide to the 17-cyanosteroids can only be carried out using drastic reaction conditions.

It is generally believed that the above-mentioned α-, β-unsaturated formamides, or more precisely their deprotonated anions, are intermediates in the formation of the cyanide compounds.

Using drastic reaction conditions, necessary for the first step of the reaction scheme in light of the steric hindrance of the 17-oxo group, one would expect that the formamides, once formed, would react immediately further to the previously mentioned cyano compounds, and that thus isolation of the α-, β-unsaturated formamides would be impossible.

It was therefore surprising that it was still possible to isolate the desired α-, β-unsaturated formamides instead of the expected cyanides. This could mainly occur by using sufficiently low temperatures, for example temperatures below -20°C, and preferably at -40°C.

As mentioned, the 1-(formamido-sulfonylmethylene)steroids according to the invention are intermediate products in the production of 17-(iso-cyanosulfonylmethylene)steroids and the production of the 17-(formamido-sulfonylmethylene)steroids according to the invention and the subsequent 17-(isocyanosulfonylmethylene)steroids can be carried out in a "one-flask" process.

It is necessary to obtain the desired steroids or to improve the yield, that protective groups can be introduced. The protecting group can be removed after the first or the second reaction step, the former being recommended when the protecting group adversely affects the second reaction step.

Suitable 17-oxo-steroids for the process According to the invention, as mentioned, the 17-oxo-steroids with the general formula:

wherein the steroid is as indicated above. These steroids containing one or more groups that can affect the reaction must be protected in the relevant positions. This can be done by known methods.

For the reaction between 17-oxo-steroids and the sulfonylmethylisocyanides, the general reaction conditions used can be as described by Schollkopf et al. "Angew.Chemie", Int. Ed., 12, 407 (1973 and by Van Leusen et Al, "Reel.Trav.Chim.-Pays Bas" 98, 258 (1982). The temperature during the reaction must be kept below -20° C.

Usually, the reaction is carried out with strong alkaline agents in an organic solvent, preferably in an inert gas atmosphere. Examples of strong alkaline agents are alkali metal alcoholates such as alkali metal t-butylates and alkali metal ethanolates, alkali metal hydrides, alkali metal amines, alkali metal alkyl compounds and alkali metal aryl compounds, where alkali metals are generally lithium, sodium or potassium and amines, preferably alkyl amines. Potassium t-butoxide is preferably used.

The reaction must be carried out at lower temperatures, preferably between -20 and -80°C and preferably between -30 and -60°C, depending on the solvent used.

The reaction is further preferably carried out in a polar organic solvent such as tetrahydrofuran, dimethylformamide, 1,2-dimethoxyethane, hexamethylphosphoric triamide, dioxane, toluene or mixtures thereof. Tetrahydrofuran is preferred. The inert gas atmosphere is preferably formed by nitrogen or argon.

It will be clear that in principle the group R3 in the sulfonyl methyl isocyanides R3-SO2~CH2-N=C to be used can be any group which does not affect the reaction. At the very least, it will be possible to use the classes of sulfonyl isocyanides that have already been used for this type of reaction. Examples of these classes are the compounds where R 3 is aryl, alkyl or dialkylamino, whereby optionally one or more substituents may be present as described above.

Suitable sulfonylmethyl isocyanides are arylsulfonylmethyl isocyanides, where the aryl group is a phenyl or naphthyl group, optionally substituted with one or more halogen atoms, alkyl or alkoxy groups. Preferred arylsulfonylmethyl isocyanides are phenylsulfonylmethyl isocyanides where the phenyl group is optionally substituted with a halogen atom, one or more alkyl groups or an alkoxy group. Particularly preferred are phenylsulfonylmethylisocyanide and p-methylphenylsulfonylmethylisocyanide.

The invention shall be illustrated by the following examples. In these examples, TosMIC means tosylmethylisocyanide (p-methyl-phenylsulfonylmethylisocyanide).

The specific rotation of the compounds was measured using light from the sodium D line.

EXAMPLE 1

Preparation of 3-methoxys-17-(formamido-p-methylphenylsulfonyl-methylenelandrostadlene-3.5-

Potassium t-butoxide (1.26 g) was added to dry tetrahydrofuran (50 ml) after which the suspension was cooled to -50°C. TosMIC (1.17 g) was added to the suspension. After stirring for 1 10 minutes at this temperature 3-Methoxyandrosta-3,5-dien-17-one (1.5 g) was added. The mixture was stirred for 2.5 h at -40/-55°C, followed by the addition of 0.92 g of H 3 PO 3 . -tion sb land I nig was stirred for 20 min and poured into a mixture of 250 ml ice water and 50 ml brine.Extraction with CH 2 Cl 2 , drying over MgSO 4 , evaporation in vacuo and crystallization from hexane/CH 2 Cl 2 gave a-p<->unsaturated formamide ( 1.47 g, 59%).

~ IR (CHCl 3 ) 3396, 3367 (NH), 1699 (C=0), 1654, 1626, 1559

(OC), 1316, 1141, (SO 2 cm-<1. >- NMR (CDCl 3 ) 0.945 (s, 6H), 2.41 (s, 3H), 3.53 (s, 3H), 5.16 ( m, 2H), 7.2-8.2 (m, 6H).

EXAMPLE 2

Preparation of l- a. 2- a-methylene-6-chloro-17-(formamido-p-methylenephenylsulfonylmethylene)androsta- 4.6-dlen-3-one.

Potassium t-butoxide (412 mg, 3.68 mmol) was added to 30 mL of dry THF. The suspension was cooled to -40°C under nitrogen. Then TosMIC (575 mg, 2.94 mmol) was added and after its dissolution the temperature was reduced to -75°C followed by

f

addition of 6-α-chloro-1-α,2-cx-methylene-androsta-4,6-diene-3,17-dione (810 mg, 2.45 mmol). After 5 hours of stirring, TosMIC was no longer present and the formamine mixture was isolated. The resulting material had a melting point of 259-260°C. -<i>H NMR (CDCl 3 ) δ 0.6-0.9 (m, cyclopropyl), 1.002 (s, 3H), 1.204 (s, 3H), 2.46 (s, 3H), 6.3 ( m, 2H), 7.3-8.4 (m, 6H).

EXAMPLE 3

Preparation of 3-methoxy-17-(formamido-t-butylsulfonyl-methylene)androstad-3.5-dlene.

t-Butylsulfonylmethyl isocyanide (4.33 mg, 2.75 mmol) was dissolved in tetrahydrofuran and cooled to -80°C. n-Butyl lithium (1.75 mL, 1.6 N) was added. After 5 min, t-butanol (0.28 mL, 3 mmol) was added followed by 3-methoxyandrosta-3,5-dien-17-one (0.75 g, 2.5 mmol) The temperature was raised to

-40" C and stirred for 1 hour. Potassium t-butoxide (0.5 g) was added and the mixture was stirred for a further period of 1/2 hour. The reaction mixture was poured into ice water containing

20 g per 1 ammonium chloride. Extraction with methylene chloride, evaporation and evaporation in vacuo gave the title compound as a white solid (1.05 g, 91 <g>). - IR (nujol) 3200 (NH), 1700 (C=0), 1655, 1635 (C=C). - <*>H NMR (CDCL3) S 0.8-3.3 (m), 0.99 (s), 1.18 (s), 1.40 (s), 3.57 (s, 2H) , 5.05-5.35 (m, 2H), 7.96, 8.18, 8.66, 8.85 (AB, 2H).

EXAMPLE 4

Preparation of 3-methoxy-17-(formamido-pentamethylphenyl-sulfonylmethylene)androstad-3.5-diene.

The title compound was prepared according to the method described in Example IA. The title compound was obtained in low yield.

EXAMPLE 5

Preparation of 3-methoxy-17-(formamido-p-chlorophenylsulfonyl-methylene)androstad-3.5-dlene.

The title compound was prepared according to the procedure of Example 3A from 3-methoxyandrosta-3,5-diene (1.35 g, 4.5 mmol) and p-chlorophenylsulfonylmethyl isocyanide (1.08 g, 5 mmol).

- Yield: 2.30 g (99 <t>).

- IR (nujol) 1700 (C=0), 1660, 1635, 1590 (OC), 1325, 1150 (so2). - XE nMR (CDC13) S 0.55-2.98 (m), 0.80 (s), 3.21 (s, 3H), 4.50-4.87 (m, 2H), 6.50 -7.50 (m, 6H).

EXAMPLE 6

Preparation of 17-(formamido-p-methylphenylsulfonylmethylene)-androst-4-en-3-one.

Potassium t-butoxide (672 mg, 6 mmol) was added to 40 mL of dry tetrahydrofuran, after which the suspension was cooled to -80°C. TosMIC (936 mg, 3.8 mmol) was added to the suspension at -80°C. After 10 minutes, 3-N-pyrrolidyl)-androsta-3,5-dien-17-one (1.36 g) was added. The mixture was stirred for 5 hours at 40°C and 2.5 hours at -35°C. 0.34 ml of acetic acid was added, followed by 1.2 g of sodium acetate, 1.2 ml of acetic acid and 6 ml of water. After 45 minutes, the reaction mixture was poured into water and extracted with methylene chloride. After drying over MgSC-4, the solvent was evaporated in vacuo. Chromatography over alumina (toluene: acetone 9:2) gave the title compound. - Yield: 0.8 g, melting point 242-245"C (during de-composition). - IR (CHC13) 3395, 3370, (NH), 1700 (C=0); 1663 (C=0), 1320, 1140 (so 2 );- XE NMR (CDCl 3 ) δ 0.93 (s, 3H), 1.15 (s, 3H), 2.43 (s, 3H), 5.75 (s, 1H), 7, 2-8.3 (m).

Claims (3)

1. 17-(formamido-sulfonyl-methylene)-steroids, characterized by the general formula there Ri means a hydrogen atom or a methyl group, or is absent in case of a double bond between Cig and Ci, C5 or Cg, R2 means a hydrogen atom or a methyl group, R3 means an alkyl or dlalkylamino group or a aryl group, optionally substituted with one or more halogen atoms, alkyl-. alkoxy, nitro or cyano groups and the rings A, B, C and D optionally contain one or more double bonds, optionally substituted with one or more hydroxy groups, amino groups, oxygen atoms, halogen atoms or alkyl, alkylene, alkoxy or alkoxy-alkoxy groups, and optionally substituted with one or more epoxy, methylene, alkylenedioxy, alkylenedithio or alkyleneoxythio groups. 2. Process for the production of 17-(formamido-sulfonyl-methylene)-steroids of formula (II) above, kar a k- terized by reacting a ketone with it general formula with a sulfonylmethylisocyanide R3-SO2-CH2-N-C at low temperatures, preferably at -20" to -80°C. 3. Method according to claim 2, characterized in that the reaction takes place at -30° to -60°C.