FI65783C - NYTT FOERFARANDE FOER FRAMSTAELLNING AV 6-HALOGEN-11BETA-HYDROXI- 4-PREGNEN-3-ONER - Google Patents

Description

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Patent-od »mtOntywl— '1 AmOkm uthedochutL * i1iU« puMkarad 30-03.8 * 4 (3 ^ (33) (31) PyH «ttrpttociM 18.02.75 USA (US) 5502 * 45 (71) Syntex (USA) Inc. , 3 ** 01 Hillview Avenue, Palo Alto, California 9 * 4301, USA (72) Pasquale G. Gallegra, San Jose, California, USA (7 * 4) Oy Kolster Ab (5 * 4) A new process for the preparation of 6-halogen-11β-hydroxy-11β-pregnene i-3-ones - Nyt förfarande för f ramstSI lning av 6-halogen-11; β-hydrox i -. ^ X- The present invention relates to a new process for the preparation of 6-halo-11/3-hydroxy (625 *) (patent 5 * 4713) -Avdelad frän trap 76027 * 4 (patent 5 ** 713). For the preparation of 4β-pregnen-3-ones of the formula 65783 2 ch2r c = o H0 2

S

*

X

wherein R is H, OH, an alkyl ether or alkyl ester group having 1 to 6 carbon atoms, R is H, OH or a group having 1 to 6 carbon atoms

Λ Λ O

alkyl ester group, R is H, Q-CH 2 or β-CH 2 or R and K together form a group ___ ckC ^ R 5, wherein R 3a R is interdependent

unsubstituted hydrogen atoms or a hydrocarbon group having 1 to 4 carbon atoms, and X is F, Cl or Br, to form a compound of formula II

CH 2 R

c = o HO r2

II

Ϊ

B

An enol ether of the compound of formula 3 65783 1 2, in which R, R and R have the same meaning as above, and by coupling to the enol ether of the formula ch2r c = o H0 \ R1,

^ R ^ UI

k

B

1 2 wherein R, R and R are as defined above, a 6-halogen group, and, if necessary, by hydrolysis of a possible ester protecting group.

The process of the invention is characterized in that the enol ether of formula III is prepared by reacting a compound of formula II with triethyl orthoacetate in the presence of a catalytically effective amount of a strong acid in a solvent mixture containing at least about 40% by weight ethanol and up to about 60% by weight ethanol. a miscible solvent, preferably dimethylated ethylene glycol such as ethylene glycol dimethyl ether, at a temperature of 0 to 100 ° C, preferably 20 to 40 ° C.

When preparing active steroid compounds for use, for example, as anti-inflammatory drugs, it is often necessary to use a readily available compound as the starting material, followed by several steps which may include reacting one portion of the compound to form a protecting group and reacting the other. Thus, when using such a method, it is often necessary to perform extensive series of steps, and there is a certain amount of waste at each step, as a result of which the overall yield of the method may be considerably reduced. Thus, researchers in the field of steroid chemistry are constantly working to develop more efficient reaction methods to improve the overall yield by reducing the number of steps required in the reaction sequence, increasing the yield of each separate step, or using both methods. The overall yield can be improved either by developing a process in which essentially the entire amount of starting material is reacted to form the desired product or to minimize the number of side reactions.

Among the many reaction sequences used to form 6-halo-β- or N'-β-pregnadi or trienes is, as an important step, the conversion of a cortisol-type compound having a 3-oxo-Δ group to an enol ether (i.e., 3- formation of an alkoxy-Δ 'intermediate) by reacting a 3-keto-Δ-steroid with a lower alkyl orthoformate in a suitable solvent such as dioxane in the presence of an acid catalyst such as p-folenesulfonic acid. However, when using a readily available compound such as cortisol (11 / S, 17 Ot, 21-trihydroxy-3,20-dioxypregn-4-ene) having a reactive hydroxy group at positions 21 and 11/3 as a starting material, it has previously been shown to be more preferable. that cortisol (Formula A below) is first reacted with formaldehyde and methylene chloride in hydrochloric acid to form the bis-methylene dioxide (BMD) compound (Formula B below).

CH-OH 0 - I H2 <| 0 - o c = o \ I / CH2 H0 -OH Ho (A) (B) 5,65783 (See, e.g., U.S. Patents 2,888,456 and 2,888,457).

In order to then prevent the formation of the Δ derivative during the subsequent reaction with the lower alkyl orthoformate in the acid due to the dehydration reaction of the 11 / ¾ position OH group and the 9-position H, 11/3-OH is first oxidized, e.g., chromic acid / sulfuric acid -dimethylformamide (DMF),

N2C

xo - o _ ^ yy4> 2

Λ-A. J

o (C)

Compound C is then treated with the lower alkyl orthoformate and acid to give the desired enol ether (D), which can then be further treated as necessary.

v <H

0--0.

/ CH2 ° v / nA '° (C) ->] (D), where R = lower alkyl 6 65783 U.S. Pat. No. 3,082,224 suggests that the dehydration problem can be solved by administering cortisol or cortisol-21-ether. react with a lower alkyl orthoformate in a solvent containing only the corresponding lower molecular weight alcohol and acid catalyst. Using this method, dehydration can be demonstrably reduced to less than 10% and 3-enol ether can be obtained in 65-90% yields.

Similarly, U.S. Patent 3,087,927 discusses the formation of a 3-enol ether intermediate of the type mentioned above.

In that series of reactions, the starting material is, for example, 16-hydroxycortisol or 16-hydroxycortisone. According to the patent, these substances can be reacted in the presence of an inorganic acid with an orthoester of formula 3 4 RC (OR) 3 3 4 wherein R is H or lower alkyl (C 1-3) and R is lower alkyl such as methyl and ethyl , for example, a compound of the formula ch2oh C = 0 is obtained as a reaction product

HO Jr --- Ovr ^ OR4 V

4 RO ^

In particular, the examples show that the reaction is carried out with trimethyl orthoformate in dioxane in the presence of a small amount of methanol and sulfuric acid. U.S. Patent 3,087,927 makes no mention of the dehydration problem addressed in U.S. Patent 3,082,224.

4 7 65783

Previous methods suggest that 11-hydroxy-Δ. -pregnen-3-ones can be reacted to form the corresponding enol ether using: (1) a trialkyl orthoformate and using dioxane as the major solvent and a corresponding lower alkanol (e.g., trimethylformate and methanol or triethyl orthoformate and ethanol) as the minor component, (2) ) triethyl orthoacetate and, for example, dioxane and to a lesser extent ethanol as the main solvent, or (3) triethyl orthoformate with ethanol as the sole solvent.

In order for the reaction to proceed at the desired rate in each of these cases, an acid catalyst is used. It has been found that in the first 9 (11) cases, the main product is the A dehydration product; in the second case, the reagents do not react with each other; and in the third case, dehydration occurs between the 11- and 9-positions and the reaction does not proceed completely. Thus, in each reaction known in the art, the yields of the desired enol ether are low, and when performed in a series of multiple steps, these yields will, of course, reduce the overall yield of the desired final product.

It has now been found that by using the process according to the invention for the formation of 3-enol ether from 3-oxy-A -1Λ / h hydroxy steroid, the following advantages are obtained: 1) dehydration at the 9 (11) position is virtually eliminated; 2) thanks to 1) it is not necessary to first oxidize the 11-hydroxy group to the oxy group for protection purposes, 3) the yield of enol ether increases (due in part to the above-mentioned 1) and 2), and partly also to the completion of the reaction), 4) cheap oxidized hydrocarbon co-solvents such as glyme (ethylene glycol dimethyl ether) can be used with ethanol, 5) for the reaction of steroids with 17 OC, 21-hydroxy groups, these groups do not need to be protected using BMD or other methods, and 6) the above advantages each contribute to the creation of a method which is simpler than the methods previously known in the art.

65783 8 Preparation of 3-enol ether

It is important that triethyl orthoacetate be used as a reagent in the process of the invention. There is a clear difference between triethyl orthoacetate and its analogous triethyl orthoformate. Triethyl orthoacetate has the formula ch3c (och2ch3) whereas triethyl orthoformate has the formula hc (och2ch3)

The chemical side, such as the preparation of aliphatic orthoesters, and general reactions are discussed in "The Chemistry of Aliphatic Orthoesters," American Chemical Society Monograph, HW Post, published by Rienhold, 1943. In general, triethyl orthoacetate can be prepared by several methods, the two most popular being the following equations: (1 ) ch3-oc2h5 + 2c2h5oh —► nh4ci + ch3c (oc2h5) 3 NH-HCl (2) ch2 = c (oc2h5) 2 + c2h5oh -> ch3c (oc2h5) 3 9 05783

Other methods of preparation can be found on page 40 of the above-mentioned publication. Methods of preparation using the reagents of the first equation above are known from P. Sah's article in the Journal of the American Chemical Society, 50, 516 (1928).

Although the theoretical amount of triethyl orthoacetate 4 required to form the 3-enol ether in the reaction with the 3-oxy-Δ steroid is 1 mole of orthoacetate per mole of steroid, due to the special nature of the reaction, triethyl orthoacetate is generally required at least 2 moles per mole of steroid. , and most preferably at least about 3 moles per mole of steroid are used. However, the molar ratio used is not greater than about 5: 1, since a higher ratio has no particular advantage in terms of reaction rate, etc.

In the process of the invention, it is important that the majority of the solvent in the solvent system used is ethanol, i.e. more than about 40% by weight and most preferably about 50% by weight of the solvent mixture is ethanol. Ethanol can be used up to 100%, although it is preferable to use an additional solvent, as mentioned below. The medium must also be substantially dry, i.e. anhydrous. Useful co-solvents are substances which are freely miscible with ethanol in all proportions. Such substances include oxidized hydrocarbons, for example, aliphatic ethers and cyclic ethers such as glycol ethers, dioxane, tetrahydrofuran and tetrahydropyran. Particularly useful in this regard are dimethylated polyethylene glycols of the formula CH_O (CH-CHO) CH_ 3 2 n 3 where n is 1 to 4. These compounds are commonly referred to as "glyme", i.e. glyme (n = 1), diglyme ( n * 2), triglyme (n = 3) and tetraglyme (n = 4). Any of these compounds can be used in the process of this invention alone or in combination as a miscible co-solvent with ethanol. Particularly useful is a mixture of about 50% by weight ethanol and about 50% by weight glyme.

It is further necessary that a catalytic amount of strong organic acid or sulfuric acid be added as a catalyst in the process of this invention. Suitable organic acid catalysts include p-toluenesulfonic acid (PTSA); 2,4-Dinitrobenzenesulfonic acid, trifluoroacetic acid, and other similar acids. P-toluenesulfonic acid or trifluoroacetic acid is mainly used. Catalytic amount of catalyst means the amount required for the reaction to proceed at a reasonable rate. This amount is usually about 0.1 to 20% of the total weight of the steroid and most preferably about 10% by weight.

The reaction conditions under which this reaction can take place are not critical. The temperature can range from 0 to 100 ° C, however, mainly between about 20 and 40 ° C, because at higher temperatures the overall yield decreases due to decomposition reactions.

The pressure may be the same as, or lower or higher than, atmospheric pressure. The reaction time depends on the reaction temperature, and is usually 5 minutes to 3 hours, at 20 to 40 ° C for about 1/2 hour.

The halogenation, which is bromination, or in general chlorination, can be carried out by any 6-position halogenation method known to those skilled in the art. Halogenating agents include N-chlorosuccinimide, N-bromosuccinimide, N, N'-dichlorohydantoin and the like.

In the halogenation step, the 3-enol ether is first isolated from the reagents and solvents of the first step, then the halogenating agent is reacted with the 3-enol ether in a suitable inert solvent under conditions sufficient to cause the formation of the 6-halo-Δ compound. A suitable inert solvent is a solvent that does not react with the 3-enol ether or halogenating agent in a manner that interferes with the reaction. Useful solvents include oxidized hydrocarbons such as tetrahydrofuran, dioxane and diethyl ether, acetone, acetic acid, or mixtures thereof. The reaction is carried out mainly under neutral conditions, i.e. at a pH of about 7 and a temperature between about -5 ° C and about 25 ° C, most preferably about 0 ° C.

More specifically, the halogenation can be performed by reacting the enol ether with dimethyl-N, N'-dichlorohydantoin in a buffered acetone solution at a temperature of about -5 ° C to about 5 ° C for 60 minutes.

The process of this invention relates to the total synthesis of 6-halo-A'-pregnadiene-11 / 3.17 (X, 21-triol-3,20-diones and 6-halo-α'-pregnadiene-11 For the preparation of /3,17Oc.,21-triol-3,20-dithione, especially 6-chloro compounds, described in U.S. Patent 3,232,965 to Ringold et al., With both dienes and trienes. has an anti-inflammatory effect and low salt retention.The method is also useful in the preparation of 16CX, 17CL-acetonide series compounds and other compounds using the above-mentioned compounds as starting materials.

The following examples are presented to illustrate the process of the invention (Examples II, III, V, VI and VII are comparative examples).

Example I

20 g of cortisol-21-acetate was added to a mixture of 100 ml of anhydrous ethanol and 100 ml of ethylene glycol dimethyl ether (glyme). The solution was warmed to 40 ° C and 2 g of p-toluenesulfonic acid (PTSA) was added followed by 24 g of triethyl orthoacetate. The reaction mixture was stirred at 40 ° C until dissolution occurred and then stirred for a further 20 minutes at 40 ° C, cooled to room temperature and 2 ml of pyridine were added. The reaction mixture was slowly poured into a mixture of 520 ml of water and 52 ml of hexane. After 30 minutes at 0-5 ° C, the product was filtered off and washed with water, then 50 ml of hexane and dried in vacuo at 40 ° C. The yield was 90 - almost 100%.

Following the procedure of Example I, but using 2 g of trifluoroacetic acid or 2 g of sulfuric acid instead of PTSA as the acid catalyst, corresponding yields were obtained.

Example II (Comparative Example) The purpose of carrying out this example is to show the differences between the yields and products of the process according to the present invention and the known process currently used for the purpose. In this comparative example, 10 g of cortisol-21-acetate was added to a mixture of 100 ml of anhydrous ethanol, 10 ml of triethyl orthoformate and 0.300 g of 2,4-dinitrobenzenesulfonic acid. The mixture was stirred at room temperature until dissolution occurred. The reaction mixture was stirred for a further 15 minutes and 1 ml of pyridine was added. The solution was concentrated to half its volume and 10 ml of water was added. Concentration was continued until crystallization occurred. About 100 ml of water were added and the product was filtered off, washed well with water and dried to give the corresponding 3-enol ether. In this particular case, some dehydration product appeared, which did not occur at all in Example I, and about 10% of unreacted material remained in this process, as well as a small amount of other undesired products compared to Example I, which left substantially less unreacted material. was determined by plate chromatographic assay (TLC).

Example III (Comparative Example) This example demonstrates that the presence of triethyl orthoacetate is necessary for carrying out the process of the invention. This example otherwise used exactly the technique and amounts of Example I, but the triethyl orthoacetate was replaced with triethyl orthoformate. Analysis of the final products by plate chromatography (TLC) showed that a small amount of starting material remained, but in addition a substantial amount of intermediates and 9 (11i about 10-15% A dehydration product).

Example IV

20 g of cortisol were added to a mixture of 100 ml of anhydrous ethanol and 100 ml of ethylene glycol dimethyl ether, as in Example I. In this example, the procedure of Example I was followed in other respects, but now 0.3 g of 2,4-di-nitrobenzenesulfonic acid and 10 g of triethylorthoacetate were used. The results showed that the reaction was substantially complete, during which about 15% of the 17,21-orthoester of 3-enol ether was formed. The presence of this product has no detrimental effect in the process of the invention, as the product can be allowed to react further and at the end of the reaction sequence the 17,21 orthoester can be easily hydrolyzed to give the desired corresponding 11,6,17 Ot, 21 trihydroxysteroid.

Example V (comparative example)

Otherwise, the same procedure as in Example III was followed, but no ethylene glycol dimethyl ether was used. At the end of the reaction series, a significant amount was still left, i.e. about 10% of the original unreacted starting material. Thus, this also emphasizes the need for the presence of triethyl orthoacetate in order for the reaction to be complete.

65783

Example VI (Comparative Example) This example demonstrates that the process of U.S. Patent 3,087,927 does not yield the desired product.

In order to further demonstrate the importance of the presence of triethyl orthoacetate and also the importance of the fact that the majority of the solvent is ethanol, 30 g of cortisol-21-acetate are suspended in a solution prepared from 300 ml of dioxane, 30.0 ml of trimethyl orthoformate and 1.20 ml anhydrous methanol. To the vigorously stirred suspension is added dropwise 0.60 ml of concentrated sulfuric acid. The suspension thins continuously for the first 5 minutes and complete dissolution has occurred in 6 minutes. 1.80 ml of pyridine are added, after which the faint pink color disappears immediately and the resulting solution is pale yellow in color. Until now, the process is carried out at room temperature. The cooled reaction solution is placed in a separatory funnel, the tip of which is immersed below the surface of a water-ice mixture of 300 ml in a large beaker. The reaction mixture is slowly added over 2-3 hours to a vigorously stirred ice-water mixture. The solid formed is allowed to stand in solution at 5 ° C overnight and then separated by filtration. The product is washed well with water and air dried to give 28.7 g of product. TLC analysis of the product (9) showed that the final product was Δ -21 acetate »

Example VII (Comparative Example) In this example, the same procedure as in Example VI was followed, but anhydrous ethanol was used instead of methanol, and triethylorthoacetate was used instead of trimethyl orthoformate. Following the procedure of Example VI, almost no reaction occurred. This shows how important it is that the majority of the solvent is ethanol and that the process of U.S. Patent 3,086,927 does not give the desired result.

From the above examples and Table I, it can thus be seen that the process of this invention in which a steroid is reacted with triethyl orthoacetate in a solvent consisting predominantly of ethanol and a minor oxidized hydrocarbon solvent such as glyme gives results better than those obtained by known methods. .

14 65783

Table I

**, + ΤΕΌΑ TEöF I Ethanol Glyme H CAT Results I Invention X X X X Reaction complete II Previous method X X X Reaction incomplete III Previous method X X X X Reaction incomplete, A? ^ ^ -dehydration product • ff IV Invention X XXX Reaction complete, trituration of 17,21-orthoesters (not harmful) V Previous Method - XXX Reaction Incomplete VI Previous Method Low Diox- Only Δ '-dehydrate (US 3 087 927) - IMOF methanane X thio product lia VII Previous way Slightly Diox- (US 3,087,927) X mexan X No reaction! nolia * TMOF = triroethyl li-orthoformate; methanol less than 1%; dioxane as the main solvent.

TEOA = triethyl orthoacetate TEOF = triethyl orthoformate H + CAT = acid catalyst - alternatives visible in each example X = substance present = substance not present Cortisol used as starting material is 65783

Example VIII

The following series of reactions correspond to a particularly efficient process for the preparation of 6-chloro-β-pregnene-11β, 17,17,11-triol-3,20-dione from cortisol.

Preparation of cortisol-21-acetate

Reaction: ch2oh CH2OAc C = 0 C = 0

CH CH

HO \ / \ / k - 0 »HO.

φΤ T I chT

Procedural:

Place 400 ml of pyridine in a one-liter flask and add 100 g (0.276 mol) of hydrocortisone (cortisol), which begins to dissolve. Keeping the temperature below 30 ° C over 10 minutes, 163.3 g (1.59 moles) of acetic anhydride are added. The mixture is allowed to stand for one hour at room temperature until the reaction is complete. 300 ml of water are slowly added to the reaction mixture, keeping the temperature below 40 ° C. The reaction mixture is allowed to stand for 20 minutes and then transferred to a 3 liter flask. Within 20 minutes, 1500 ml of saturated aqueous sodium chloride solution are added. The mixture is cooled to 10 ° C, kept for one hour and filtered. The product is washed with water and dried at 50-60 ° C under vacuum. Yield: 110.4 g (110.4% by weight; 99.2% of theory).

65783 BC

Reaction with triethylorthocetate to form 3-enol ether followed by chlorination at the 6-position Reaction: CH 2 OAc. CH2OAc "c = 0 C = 0

HO ^ _ L_ —OH I

HO s / k-- ° H

h + L

CH, OAc c = o

Ha lane ® H0 W ^ LΛτ-0> -> [

Cl

Procedure: Place 550 ml of ethanol, 330 ml of 1,2-dimethoxyethane (glyme) and 110.4 g (0.272 mol) of cortisol-21-acetate in a 2 liter flask. The mixture is heated to 40-42 ° C and a solution of 9 g of p-toluenesulfonic acid in 200 ml of 1,2-dimethoxyethane is added, followed by 116 g of triethylorthoacetate. The temperature is maintained between 38 and 42 ° C.

After 20 minutes, 2.5 g of p-toluenesulfonic acid are added. The mixture is allowed to stand for 30 minutes at 38-42 ° C, then cooled to 8-107 ° C and 12 ml of pyridine are added, followed by a solution of 2.7 g of sodium acetate in 50 ml of water. The pale yellow solution is poured into a mixture of 14 g of sodium acetate, 2.450 ml of water and 288 ml of hexane, then cooled to 10 ° C, kept for 20 minutes, filtered and washed with 800 ml of water containing 1 g of sodium acetate and treated with after 220 ml of hexane.

The wet cake (about 200 g) is placed in a cold mixture (10 ° C) of 13.7 g of sodium acetate in a solution of 184 ml of water and 440 ml of acetone and cooled to 0-5 ° C. While maintaining the temperature below 5 ° C, a solution of 27 g of Halane® (registered trademark; 1,3-dichloro-5,5-dimethylhydratoin) in 120 ml of acetone is added. The mixture is kept at 0-5 ° C for 45 minutes, then a solution of 9.2 g of sodium hydrogen sulphite in 132 ml of water is added and the mixture is slowly drained over 30 minutes into 2200 ml of water and cooled to 0-5 ° C. for one hour, filtered and dried at 45-50 ° C in a vacuum oven. Yield: 107.2 g (97.1% by weight; 89.5% of theory).

Claims (1)

A new process for the preparation of 6-halo-11/5-hydroxy-Δ -pregnen-3-ones of the formula ch2r c = o I 1 H0 -R2 ^ y_r sx where R is H, OH, 1 An alkyl ether or alkyl ester group having 1 to 6 carbon atoms, R 1 is H, OH or an alkyl ester group having 1 to 6 carbon atoms, R 1 is H, O 2 -CH 2, or / --CH-, or R 1 and R 2 Υ * 1- -O r 4 j 4 5 form a group ___ CK ^ R ^ '3 in which R and R independently represent hydrogen atoms or a hydrocarbon group having 1 to 4 carbon atoms, and X is F, Cl or Br, to form a compound of formula II CH 2 R c = o I i HO v / k- - R o \ wv / R ^ II s V. Enol ether of the compound of formula H, wherein R, R and R are as defined above, and coupling to the resulting enol ether of formula 19 6 5 7 8 3 ch2r OO HOv In the case of Jr- -r1 5 R * III CHO ^ <T 2 5 * H 1 2], R, R and R have the same meaning as above, 6-halogen, and, if necessary, by hydrolysis of a possible ester-protecting group, characterized in that the enol ether of formula III is prepared by reacting a compound of formula II with triethyl orthoacetate in the presence of a catalytically effective amount of a strong acid in a solvent mixture containing at least about 40% by weight ethanol and up to about 60% by weight ethanol miscible solvent, preferably dimethylated ethylene glycol, such as ethylene glycol dimethyl ether, at a temperature of 0 to 100 ° C, preferably 20 to 40 ° C. 20 65783 Now obtained for the preparation of 6-halo-11/3-hydroxy-.beta.-pregnen-3-ones with the form In ch2r C = 0 H0 2 X i vilken R betecknar H, OH, en alkylleter- eller alkylestergrupp med 1 - 6 chapters, R is H, OH or an alkyester group with 1 - 2 12 6 cholatom, R is H, Cx-ch, ell / fl-CH_, or R and R ___ q · ^ ^ 4 4 · ^ 5 tillsammans betecknar Gruppen ___ o ^ ^ R ^ 'R oc ^ R is shown in the variation of the vateatomer or in the flask group of 1-4 cholaters, and X is F, Cl or Br, the genome is represented by the enoleter in the form of II ch2r c = o H0 r1 2 ^ ^ ηρ-'νν-Ή xx H