HU200610B - New process for producing 21-halogen pregnane derivatives - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to a novel process for the preparation of a compound of formula (I) wherein the dotted line between the carbon atoms (2) is further bonded to the preparation of 21-halopromane derivatives which comprises the following: where the dotted lines are as defined above, and R * is C 1-4 alkyl or phenyl, the enolether derivative is reacted with a hypohaloid acid optionally prepared in situ. Scope of the description: 8 pages, Figure 1 -1

Description

The present invention relates to a novel process for the preparation of 21-halo-pregnane derivatives of formula I wherein X is a halogen atom and the dotted line between carbon atoms of 1 (2) may be further substituted.

The 21-halo-pregnane derivatives of formula I are intermediates in the synthesis of corticosteroids (V. Van Reenen, P. P. Shephard, J. Org. Chem. 44, 1582 (1979); P. P. Olivetto, Organic Reactions). in Steroid Chemistry, Vol. H, p. 220, eds. J. Fried, JA Edwards, Van Nostrand Reinhold Company New York, 1972). Corticosteroids have very beneficial therapeutic effects. These compounds are used in medicine primarily as an anti-inflammatory agent, and also for use in the treatment of endocrine disorders, adrenal insufficiency, rheumatic conditions, skin disorders, allergic conditions, eye disorders, respiratory disorders, hematopoietic disorders, and disorders associated with hypertension. One known and highly preferred representative of this type of compound is prednisolone (11β, 17α, 21-trihydroxy-1,4-pregnadiene-3,20-dione). Several methods have been described in the literature for the preparation of 21-halogen pregnane derivatives. One method involves starting with steroids already containing hydroxy groups on carbon 21, preparing their 21-mesyl and 21-thiosyl derivatives and reacting these compounds with an alkali metal halide (lithium chloride, potassium chloride) to form halogen on carbon 21. containing pregnane derivatives. (Such a procedure is described, for example, in European Patent Nos. 4975 and 231958, Japanese Patent No. 79,144,357, and German Patent Nos. 2,655,570 and 2,550,458). Since the compounds of the present invention are intended to be intermediates in the synthesis of 21-hydroxy pregnane derivatives, i.e., 21-halo-pregnanes, it is intended to be used specifically to construct the dihydroxyacetone side chain, so no detailed analysis of these anteriorities is required. J. Elks et al. (J. Chem. Soc. 1958, 4001) by direct halogenation of 3β, 17-dihydroxy-5α-pregn-9 (II) -en-20-one and subsequent hydrolysis of 21-acetoxy-3β, 17-dihydroxy. -5α-pregn-9 (II) -en-20-one was prepared. However, the resulting bromine compound was not isolated and the yield of the final product was not specified.

J. Org. Chem., 44, 1582 (1979), the 17a-hydroxy-21-bromo-4,9 (11) -pregnadiene-3,20-dione of the formula (I) was prepared by -hydroxy-20-methoxy-4,9 (11), 20 (21) -pregnatrien-3-one in dichloromethane, in the presence of pyridine, at 0 ° C was reacted with elemental bromine to give the above product which was they are then hydrolyzed to the corresponding 21-acetoxy derivative. However, neither the recipe nor the 21-bromo derivative obtained as an intermediate is disclosed by the authors. They claimed a yield of 93% of the total reduction series. Hydrogenation with elemental bromine has been attempted in a number of experiments, but with only about 10% lower yields of the final product than the product of the present invention.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a halogenation process which allows the efficient preparation of 21-halo 2 pregnane derivatives which can be used as intermediates to construct the dihydroxyacetone side chain of pharmaceutically valuable corticoid compounds.

In our research, we have surprisingly found that the formula (III) - where the dotted line represents the case of identity (I) Compounds of the formula in the introduction megadotakkal, ^R1 stands for C1-4 alkyl or phenyl group 10 20-enol ethers derivatives can be converted in good yield to 21-halo-20-keto-pregnane derivatives of formula (I) by addition of a hypohaloidal acid to the 20 (21) double bond in the starting compound, optionally prepared in situ.

N-halo-savamidokból.

It has been known in the literature that enol ethers readily react with N-haloacid amides in a buffered medium to form the corresponding α-substituted ketones. (R. Gardi, A. Ercoli, Organic Reactions in Steroid Chemistry, Vol. I, p. 385, ed.

J. Fried, J. A. Edwards Van Nostrand Reinhold Company New York, 1972). This method has not been used in the literature for the preparation of 21-halo-pregnanes. According to the proven mechanism of the double bond binding of hypohaloid acid (DN Kirk, P. P. Hartshom, Steroid Reaction Mechanisms, p. 91, Elsevier Publishing Company, Amsterdam, 1968; GJ Matthews, A. Hossner, Organic Reactions). in Steroid Chemistry, Vol. II, p. 15, edited by J Fried,

JA Edwards, Van Nostrand Reinhold Company, New York, 1972), according to the Markovnikov rule, the bromine cation attacks carbon 21 and the hydroxyl anion moves to carbon 20. Thus, an intermediate of formula (Π) containing an alkyl or phenyl semi-ketal moiety is formed, wherein R ¹ and the dotted lines are as defined above and X is halogen. This intermediate was neither detected nor isolated because the corresponding weak acid medium spontaneously

20-keto derivative.

The process is capable of selectively carrying out the addition of a hypohaloid acid to a 20 (21) double bond in the presence of other double bonds, such as Δ 1,4,9 (11). Our discovery allows us to obtain corticoid synthesis intermediates that contain important structural elements characteristic of corticoids (17a-hydroxy; 4- or 1,4-double bonds; 3,20-diketo function) or additional syntheses (11β50-hydroxy group; 21-hydroxy group). The further conversion of the 21-halo-pregnanes is preferably carried out e.g. the compounds of formula (I) obtained can be converted to the corresponding 2-acetoxy derivatives by boiling with potassium acetate in acetone. Thereafter, derivatives of 9 (11) double bonds are known to yield 11 β-hydroxy-9α-bromo derivatives by hypobromic acid addition, which can be obtained by reductive dehalogenation and subsequent hydrolysis, for example prednisolone [D. H.

R. Barton et al., 1966, J. Am. Chem. Soc. 88, 3016.

Accordingly, the invention provides a process for the preparation of a compound of formula (I) wherein X is a halogen atom and the dotted line (s) between carbon atoms 1 (2) and / or 9 (11) may provide additional valence bond (s).

HU 200610 A

For the preparation of 21-halo-pregnane derivatives, wherein the dotted lines of formula (EB) wherein R ¹ is as defined above and R ¹ is C 1 -C 4 alkyl or phenyl are 20-enol ether derivatives, optionally reacting with a hypohaloidal acid produced in situ.

The starting 20-enol ether derivatives of formula (ΠΙ) may be prepared by methods known in the art (see, for example, Hungarian Patent No. 174,396; U.S. Patent 4,041,055).

The hypohaloidal acids involved in the reaction are preferably prepared in situ from N-haloamides in the presence of water and mineral acids. Among the N-haloamides, for example, N-bromoacetamide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin can be used, typically in an amount of from 1 to 1.5 moles.

The reaction is carried out in a mixture of water and water-miscible solvents. Dioxane, acetone, dimethylformamide may be used as the solvent. As the mineral acid, aqueous perchloric acid is preferred. The reaction may be carried out at temperatures between -20 ° C and 40 ° C. The starting 20-enol ether derivatives are easily converted to 20-keto derivatives by acid. Therefore, it should be ensured that the pH does not fall below 4-5 during the reaction. This is achieved by dropwise addition of an aqueous mineral acid solution to a solution of the 20-enol ether derivative and N-haloic acid amide with stirring.

In a preferred embodiment of the process of the invention, the 20-enol ether derivative of formula (ΙΠ) is dissolved at room temperature in a mixture of water and dioxane, followed by addition of 1.1 moles of N-bromosuccinimide at 0 ° C. 1N aqueous perchloric acid is added dropwise over 1 hour. After completion of the reaction, the reaction mixture was poured into water, the crystals were filtered and dried. The products can be purified by recrystallization or can be used directly in further synthesis steps.

Among the products obtained, 17α-hydroxy-21-bromo-1,4,9 (II) -pregnatriene-3,20-dione is unknown in the literature, 17α-hydroxy-21-bromo-4,9 (II) -pregnadiene. -3,20-dione is mentioned in the literature [J. Org. Chem., 44, 1582 (1979)] but does not disclose its physical constants. The structure of the compounds of the present invention was confirmed by ultraviolet, infrared, 1 ^H- NMR and optical rotation and elemental analysis.

The advantages of the process according to the invention are obvious compared to the processes used to prepare the 21-halo-pregnane derivatives. Addition of a 20 (21) double bond hypohaloid acid

- easy to carry out,

- hand held.

The N-haloacid amides used

- crystalline,

- easy to store,

- measurable.

I would win with the new procedure

- crystalline from water,

- well filterable,

- can be used for further steps without purification.

Any elemental halogen used to date

- Unhealthy,

- polluting the environment, working with them

- difficult,

- dangerous,

the reaction is more difficult to direct towards the desired product.

For example, the use of elemental bromine often results in a side reaction due to the higher reactivity of bromine. The steroid molecule is also in other places

- double bonds,

- it may be brominated in the vicinity of the 3-oxo group, which will lead to a deterioration of the yield.

The same results in the fact that the isolated 21bromine derivative becomes more impure, which is only

- conditionally,

- can be cleaned in a costly way.

The invention is illustrated by the following examples.

Example 1

Preparation of 17α-hydroxy-21-bromo-1,4,9 (II) -pregnatriene-3,20-dione

1.5 g (4.41 mM) of 17α-hydroxy-20-methoxy-1,4,9 (11), 20 (2L) -pregnatetraen-3-one (125%) in 125 ml of dioxane and 25 ml of (0.88 g, 4.88 mM) of N-bromosuccinimide was added with stirring at 0 ° C. To the pale yellow clear solution was added dropwise 8.4 ml of IN perchloric acid solution over 1 hour. After stirring for an additional 30 minutes at 0 ° C, the reaction mixture was poured into 400 ml of ice water. The precipitated crystals were filtered off and dried, yielding 1.7 g of crude 17α-hydroxy-21-bromo-1,4,9 (II) -pregnatriene-3,20-dione. Yield: 95%. Mp .: 200-205 'C. Recrystallized from acetone-petroleum ether (10: 3), mp 208-210 ° C.

Elemental analysis for C 21 H 25 BrO 3 (M 405.33):

Found: C, 62.23%; H, 6.22%; Br, 19.71; Found: C, 62.11; H, 6.13%; Br, 19.25%.

For example, the 17a-hydroxy-21-bromo-1,4,9 (11) -pregnatriene-3,20-dione obtained in the above manner can be converted to the following 17a, 21-dihydroxy-1,4,9 (11) ) -pregnatriene-3,20-dione-21-acetate:

The crude 21-bromo derivative (1.7 g, 4.2 mM) prepared in Example 1 was heated in acetone (40 mL) in the presence of anhydrous potassium acetate (1.7 g, 20.7 mM) for 3 hours. The reaction mixture was then evaporated to dryness. The residue was partitioned between water (20 mL) and dichloromethane (50 mL), and the aqueous phase was re-extracted with dichloromethane (30 mL). The combined organic phases are dried, filtered and evaporated to dryness in vacuo. The dry residue (1.65 g) was recrystallized from 13.2 ml of anhydrous ethanol to give 1.5 g of 17a, 21-dihydroxy-1,4,9 (11) -pregnatriene-3,20-dione-21-acetate. Mp .: 225-227 'C. The physical constants of the product are the same as described in the literature [J. Org. Chem. 29, 1930 (1964)]. Yield: 93%.

Example 2

Preparation of 17α-hydroxy-21-bromo-4,9 (II) -pregnadiene-3 (20-dione)

All of the procedures described in Example 1 were repeated except that 2.4 g (7 mM) of 17α-hydroxy-20-methoxy-4,9 (11), 20 (21) -pregnatrien-3-one (174,396) were obtained. Hungarian Patent Publication No. 4,123,198)

EN 200610 A Transfer. 2.65 g of crude 17α-hydroxy-2L-bromo-4,9 (II) -pregnadiene-3,20-dione are obtained. M.p .: 209-212 ° C. Yield: 93.8%.

This compound was converted to the analog of 17a-hydroxy-21-bromo-1,4,9 (11) -pregnatriene-3,20-dione in 2.1 g of 17a, 21-dihydroxy-4,9 (11) -pregnadiene-3, 20-dione-21-acetate is obtained. The physical constants of the product are the same as described in the literature [J. Chem. Soc. 75, 2273 (1953)]. Yield: 84%.

Claims (3)

PATENT CLAIMS A process for the preparation of a 21-halo-pregnane derivative of the Formula I wherein X is halo and the dotted line between carbon atoms 1 (2) further comprising reacting a compound of Formula (I) wherein dotted lines are as defined above, and R * is a C 1-4 alkyl or phenyl enol ether derivative which is reacted with a hypohaloidal acid, optionally in situ. 2. The process of claim 1 wherein the hypohaloidal acid is hypobromic acid. Process according to claim 1 or 2, characterized in that the hypobromic acid is prepared in situ from N-bromosuccinimide.