NO750119L - - Google Patents

Description

"Procedure for the manufacture of steroid

[16a, 17-b] 1,4-dioxanes".

The present invention relates to steroid £16a,17-b J , 1,4-dioxane and steroid £16oc,17-bJ 1,4-dioxane with anti-inflammatory action. The steroids according to the present invention comprise 3»20-diketo-pregnenes which contain a 11|3-hydroxy group or an 11-keto group and where in the 16- and 17-positions there is

fused a 1,4-dioxane ring or a 1,4-dioxane ring.

Examples of the steroids mentioned above are steroids having the structural formula

In formula I, and in the description, the substituents have it

meaning given below.

Z represents hydrogen, hydroxyl, acyloxy or halogen;

Y means hydrogen and Y' means hydroxyl or Y and Y'

together means =0;

X means hydrogen or halogen;

P represents hydrogen, methyl or chlorine;

Q represents hydrogen, methyl or fluorine;

R 2 is hydrogen, alkyl or aryl;

Rp means hydrogen, alkyl or arylalkyl;

R^means alkyl, cycloalkyl or aryl and

R^ and R^ may be the same or different and may

be al&yl or aryl.

Steroids of the formula

are useful as intermediates in the preparation of steroid J"16apr7-bJ1,4-dioxanes and steroid [16a,17-bJ1,4-dioxins of formula I. In formula II, and in the description, the substituent means Ap

The substituent Rg used in the description means alkyl or aryl. The symbol R 1 , used in the description, means alkyl or arylalkyl.

Steroids of the formula

are also usable as intermediates in the preparation of the new steroids of formula I. In formula IIa, and in the description, the substituent means or

The dotted line in the 1,2 and 6,7 positions in the steroids according to the invention indicates the presence of any double bonds.

The term "pregnane", as used in the description, denotes pregnanes containing one or more double bonds. Examples of preferred pregnanes are^^-pregnanes,&^<»4->pregnadienes, a '^-pregnadienes and ^'^"'^-pregnatrienes, A^-pregnanes and A "^'4-pregnadienes.

The term "1,4-dioxane ring" used in the description denotes unsubstituted and substituted 1,4-dioxane rings. Examples of substituents are alkyl, arylalkyl, aryl, alkoxy,

aryl alkoxy, alkyl

alkyl

, cycloalkyl, arylalkyl-, aryl

and oxo groups.

The term "1,4-dioxin ring" used in the description denotes unsubstituted and substituted 1,4-dioxin rings. Examples of substituents are alkyl, arylalkyl and aryl groups.

The term "alkyl", as used in the description, includes both straight and branched alkyl groups containing 1 to 8 carbon atoms. Preferred alkyl groups are groups containing 1 to 4 carbon atoms, especially methyl.

The term "cycloalkyl", as used in the specification, denotes cycloalkyl groups containing 3 to 6 carbon atoms.

The term "aryl", as used in the specification, denotes phenyl or phenyl substituted with one or more halogen, alkyl and alkoxy groups. Preferred aryl groups are phenyl and monosubstituted phenyl.

The term "halogen", as used in the description,

denotes fluorine:^chlorine, bromine and iodine.

The term "alkoxy", as used in the description, denotes groups of the structure alkyl-O- where alkyl is as indicated

above. Preferred .Alkoxy groups are groups containing 1 to 4 carbon atoms, especially methoxy"

The term "acyloxy", as used in the description, denotes groups where the acyl moiety is a physiologically acceptable

acid residue derived from an organic or inorganic acid. Examples of monocarboxylic acids are those having the formula R-COOH where R is alkyl, cycloalkyl, arylalkyl or aryl; e.g. acetic acid, propionic acid, valeric acid, cyclohexanecarboxylic acid, phenylacetic acid, benzoic acid and toluylic acids. Examples of polycarboxylic acids are malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid and phthalic acid. Examples of inorganic acids are sulfuric, nitric and phosphoric acids.

Steroids of formula I are physiologically active compounds which have glufcoborticoid and anti-inflammatory action and which can thus be used instead of known glucocorticoids in the treatment of rheumatoid arthritis, and for this purpose they can be administered in the same way as hydrocortisone, the strength can e.g. adjusted according to the relative strength of the particular steroid. In addition, the steroids according to the present invention can be used topically instead of known glucocorticoids in the treatment of skin disorders such as dermatitis, psoriasis, sunburn, neuro-dermatitis, eczema and anogenital pruritus.

When used orally, the compounds according to the present invention can be used in a daily dose range of 0.1 - 200 mg per 70 kg, preferably 0.3 - 100 mg per f0 kg. If they are administered topically, the compounds according to the present invention can be used in the range from 0.01 - 5% by weight, preferably 0.05 - 2.0% by weight in a suitable cream or lotion. The topical method of administration is preferred.

Cycloborate esters of 16α,17-dihydroxysteroids of the formula

is one of the starting materials for the production of steroids with

formula I. Cycloborate esters of formula III are known compounds;

see, for example, U.S. patent 2.83I.OO3. They can be produced by

react the corresponding 16α,17-dihydroxysteroid with boric anhydride in an organic solvent at reflux temperature. Examples of cycloborate esters of formula III which can be used as starting materials are

lip,16a,17,21-tetrahydroxypregn-4-ene-3,20-dione,16,17-cycloborate,

9-fluoro-11p,16a,17,21-tetrahydroxypregn-4-ene-3,20~

dione,16,17-cycloborate,

60c,9-difluoro-llp ,16a,17,21-tetrahydroxypregn-4°ene-3,20-dione, 16,17-cycloborate,

lip,16a,17,21-tetrahydroxy-6a-methylpregn-4-ene-3,20-dione, 16,17-cycloborate,

21-chloro-llp,16a,17-trihydroxypregn-4-ene-3,20-dione,

16„17-cycloborate,

21-chloro-9-fluoro-lip ,16a,17-trih<y>droxy<p>re<g>n^4-ene-3,20-dione, 16,17-cycloborate,

21-chloro-6a,9-difluoro-11p,16a, r^-trihydroxypregn^-ene^^O-dione, 16,17-cycloborate,

21-chloro-6α-fluoro-lip,16α,17-trihydroxypregn-4-ene-3,20-dione, 16,17-cycloborate,

21-chloro-lip,16a,17-trihydroxy-6a-methylpregn-4-ene-3,20-dione, 16,17-cycloborate,

lip,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, lo,17-cycloborate,

9-fluoro-lip,16a,17,21-tetrahydroxypregna-1,4-diene-3920-dione, 16,17-cycloborate,

6a,9-difluoro-llp,16a,17,2l-t etrahydroxypregna=1,4-diene-3920-dione, 16,17-cycloborate,

6a-Fluoro-11p,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate,

lip,16a,17,21-tetrahydroxy-6a-methylpregna-1,4-diene-3,20-dione, 16,17-cycloborate,

21-chloro-lip,16a,17-trihydroxypregna-1,4-diene-3920-dione, 16,17-cycloborate,

21-chloro-9-fluoro-llp,16a,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate,

21-chloro-6a,9-difluoro-11p,16a,17-trihydroxypregna-1,4-diene-3920-dione, 16,17-cycloborate,

21-chloro-6a-fluoro-11p,16a,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate,

21-chloro-llp,16a,17-trihydroxy-6a-methylpregna-1,4-diene-3,20-dione, 16,17-cycloborate,

2-chloro-lip,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate,

2-chloro-9-fluoro-llp,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate,

9-fluoro-llp,16a,17,21-tetrahydroxypregna-1,4,6-triene-3,20-dione, 16,17-cycloborate.

Diazoalkenes of the formula

are also used as starting materials for the preparation of stero-R OH 0 ides of formula I, where-, means ,1 , „ -C=CH- , -CH-CH2- , R^-C-0-CH-CH2-, 0 R1 -C-CH2- or -CH-CHg-, In formula IV they are diazoalkenes where R^ is hydrogen or alkyl known compounds; see for example

Journal of the American Chemical Society 91» 7H (1969)* The preparation of the diazoalkene of formula IV, where R-^ is aryl (eg* 2-phenyl-3-diazo-1-propene) is described in the examples in the specification.

The reaction of a cycloborate ester of formula III with a

the diazoalkene of formula IV gives a steroid of the formula

The reaction can be carried out in an organic solvent, preferably a lower alkanol, such as methanol, at a temperature from approx. -10°C to +40°C within 30 minutes to 4 hours, preferably at 0°C to 20°C within 30 minutes to 1 hour. The steroid and the diazoalkene are converted at least in a ratio of 1:4"

The steroid of formula V can be reacted with m-chloro-perbenzoic acid, and a steroid of the formula is obtained

The reaction can be carried out in an organic solvent, preferably a halogenated hydrocarbon, such as dichloromethane, at a temperature from approx. 0°C to 40°C within 1 hour to 96 hours, preferably at room temperature within 2 hours to 72 hours. The steroid of formula V and m-chloroperbenzoic acid are reacted in a molar ratio of approx. 1:1.

The reaction of a steroid of formula VI, when R^ is alkyl or aryl, with a strong oxidizing agent, such as periodic acid, gives a steroid of the formula

The reaction of a steroid of formula VI, when R^ is hydrogen with a strong oxidizing agent gives a cyclic lactol (formula VIII) which exists in equilibrium with the corresponding aldehyde (formula VIII), i.e.,

These oxidation reactions can be carried out in an organic solvent such as tetrahydrofuran mixed with water at a temperature of approx. 0°C to Q. 0oCs during approx. 1 hour to 8 hours, preferably at room temperature within two hours to 4 hours.

The steroids of formulas VII or VIII can be reacted in a suspension or solution of an organic acid catalyst, such as p-toluenesulfonic acid in an organic solvent such as benzene, and one obtains steroid-2',3',dihydro/I6a,17-b_7l ,4-dioxins of the formula

The reaction can be carried out under reflux conditions in an inert atmosphere during approx. 2 hours to 48 hours, preferably 4 hours to 24 hours.

The reaction of a steroid of formula VIII with an anhydride

of the formula

gives a steroid/~l6a,17-b_/l,4-dioxane of the formula

The reaction can be carried out in an organic solvent, such as pyridine, at a temperature of approx. 0°C to Q.O°C within 30 minutes to 4 hours, preferably at room temperature within 1 hour to 2 hours.

The oxidation.of a steroid of formula VIII with Feti2on's . reagent (Angew. Chem. Internat. Edit., 8, 444 (1969) gives a steroid of the formula

The reaction can be carried out in an organic solvent, such as benzene, toluene etc., at a temperature from approx. 80°C to 110°C during 2 hours to 48 hours, preferably at reflux temperature during 24 hours.

The reaction of a steroid of formulas VII or VIII with sodium borohydride gives a steroid of the formula

The reaction can be carried out in an organic solvent, preferably a lower alkanol, such as methanol, at a temperature from approx. -10°C. to 20°C within 10 to 60 minutes, preferably at approx. 0°C for 10 minutes to 3° minutes.

A 16a-hydroxyethoxy steroid of formula XII can be reacted with a methanesulfonyl halide (methanesulfonyl chloride is preferred), and one obtains a steroid of the formula

The reaction can be carried out in an organic solvent, such as pyridine, in an inert atmosphere, at a temperature from approx. -10°C to 40°C within 30 minutes to 4 hours, preferably at approx. 0°C within 1 hour to 2 hours.

The reaction of a steroid of formula XIII with sodium bicarbonate in a dipolar, aprotic solvent, such as dimethyl sulfoxide, gives a steroid /"16a,17-b/1,4-dioxane of the formula

The reaction can be carried out at a temperature from approx. S0°C to 130°C within 1 hour to 24 hours, preferably at approx. 110°C in. during 2 hours to 4 hours.

Steroid/~l6a,17-b /l,4-dioxanes of formula I, where

<k>1 means RgO-CH-CHg-,

, -CH=CH-, -CH2-CH2- or it^-b-u-i;n-u<n>2-, -un^un-, -uh2-uii2~eixer can be prepared from cycloboratesters of l6a,17-dihyde= roxy- steroids of formula III and diazoethers of formula XV (R7-0)2CHCHN2Diazoethers of formula XV are known compounds; see, for example, Chem. Pray. 100s 1491 (I967)* The reaction of a cycloborate ester of formula III with a diazoether of formula XV gives a steroid of the formula

The reaction can be carried out in an organic solvent, preferably a lower alkanol, such as methanol, at a temperature from approx. -10°C to ^. 0°C until nitrogen evolution ceases. The preferred reaction temperature is from 0°C to 20°C.

The steroid of formula XVI can be reacted with an organic acid, such as p-toluenesulfonic acid, in an organic solvent, such as benzene, and one obtains a steroid/~16a,17-b_7184-dioxane of the formula

The reaction can be carried out at a temperature of approx. 60°C to 140°C during 1 hour to 24 hours, preferably 80°C to 110°C during 2 hours to 4 hours.

The reaction of a steroid of ftormel XVI with a mineral acid, e.g. hydrochloric acid, gives a steroid/~l6oc, 17-b_7l,4-dioxane of formula VIII. The reaction can be carried out in an organic solvent, such as tetrahydrofuran at a temperature from approx. 0°C to 100°C within 1 hour to 24 hours, preferably 40°C to 60°C within 2 hours to 8 hours.

A steroid of formula VIII can be used to prepare a steroid of formula IX (where R^ is hydrogen), a steroid of formula X, a steroid of formula XI and a steroid of formula XIV (where R-^ is hydrogen), by to proceed as indicated above.

Steroid^~16a,17-b_71,4-dioxanes of formula I where A^ means -CHg-CHg- can also be prepared from cycloboratesters of 16a,17-dihydroxy steroids of formula III and 2-(tetrahydropyran-2-yloxy) -1-diazoethane, and the preparation of these appears in the examples below.

The reaction of a cycloborate ester of formula III with 2-(tetrahydropyran-2-yloxy)-1-rdiazoethane gives a steroid of the formula

The reaction can be carried out in an organic solvent, preferably a lower alkanol such as methanol, at a temperature from approx. -10°C to 40°C, preferably 0°C to 20°C. The reaction is continued until nitrogen evolution ceases.

A steroid of formula XVIII can be cleaved with an acid, and a steroid of formula XII is obtained (where R^ is hydrogen).

The cleavage reaction can be carried out in water at a temperature from approx. 0°C to 40°C, preferably at room temperature/ within 1 hour to 24 hours, preferably 2 hours to 8 hours. Both organic and inorganic acids can be used in this reaction. The preparation of a steroid of formula I, where A means -CHg-CHg- from a steroid of formula XII is indicated above.

A steroid of formula I, where ?4 ?5

Ax means -C = C- can be prepared from cycloboratesters of 16α,17-dihydroxysteroids of formula III and diazoethers of formula

The reaction of a cycloborate ester of formula III with a diazoether of formula XIX gives a steroid of the formula ..',

The reaction can be carried out in an organic solvent, preferably a lower alkanol, such as methanol, at a temperature from approx. -10°C to 40°C until nitrogen evolution ceases» The preferred reaction temperature is from 0°C to 20°C.

The reaction of a steroid of formula XX with a mineral acid, e.g. hydrochloric acid, gives a steroid of the formula

The reaction can be carried out in an organic solvent, such as tetrahydrofuran, at a temperature from approx. 0°C to 100°C within 1 hour to 24 hours, preferably 40°C to 60°C within two hours to 8 hours.

A steroid of formula XXI can be reacted with a suspension or solution of an organic acid, such as p-toluenesulfonic acid, in an organic solvent, such as benzene, and one obtains a steroid of the formula

The reaction can be carried out under reflux conditions in an inert atmosphere for 2 hours to 48 hours, preferably 4 hours to 24 hours.

Steroids of formula I containing a double bond in the 6,7-position can be prepared as indicated above by means of a further step where one selectively introduces a carbon-carbon double bond in the 6,7-position either in starting material with formula III or a final product of formulas VIII, IX, X, XI, XIV, XVII or XXII without affecting other functional groups in the steroid. Examples of oxidizing agents that can be used in the synthesis of an acid are 2,3-dichloro-5S6-dicyano-1,4-benzoquinone. One is used approx. 1 mol equivalent of the oxidizing agent per molar equivalent of steroid. The oxidation reaction can be carried out in an organic solvent, such as benzene, toluene, dioxane, etc.; dioxane is preferred. The reaction can be carried out within 1 hour to 96 hours at a temperature from approx. 50°C to 150°C, preferably within 4 to 24 hours at approx. 70°C to 130°C. Alternatively, a borate containing a double bond in the 6,7-position can be prepared from the corresponding, known 6,7-unsaturated 16,17-diols and borane anhydride

Further methods for the preparation of compounds according to the present invention will be known to the person skilled in the art. Steroids according to the present invention which contain a halogen in the 21-position can e.g. produced from it. corresponding 21-hydroxysteroid by reacting the latter compound with an alkyl or arylsulfonyl halide (available methanesulfonyl chloride or p-toluenesulfonyl chloride), in the presence of an organic base, such as pyridine, and one obtains a 21-alkyl-(or aryl-) sulphonyloxy steroid. The 21-alkyl (or aryl) sulfonyloxy steroid can be reacted with an alkali metal halide (e.g. potassium fluoride, lithium chloride, lithium bromide, sodium iodide, etc.), and the corresponding 21-halogen steroid is obtained.

It will be obvious to the person skilled in the art that due to the stability of the dioxane and dioxin ring structures, functional groups represented by the various substituents used in formula I can be added to the steroid nucleus after the addition of the dioxane or dioxin ring.

By using methods known to those skilled in the steroid field, it is also possible to prepare 21-acyloxy steroids according to the present invention from the corresponding 21-hydroxy steroids. Other variations will be obvious to the person skilled in the art.

Preferred compounds are steroids of formula I

where P and Q are hydrogen.

Preferred compounds are steroids of formula I

where X is halogen, especially compounds where X is fluorine.

Preferred compounds are steroids of formula I

where I is hydrogen and Y' is hydroxyl.

Preferred compounds are steroids of formula I,

where A, means -CHp-CH2-,

, RgO—CH—CHg—, or fa» Preferred compounds are steroids of formula I where Z represents hydrogen, hydroxyl, alkyl aryl

or

halogen.

The following examples are given to illustrate the invention.

Example 1

q- fluoro- 5' g . llB. 21- trihydroxypregn- 4.- eno/~ l6a. 17-b_ 7-/"1,4_7dioxane-3,20-dione, 21-acetate

A. l6a- allyl oxv- q- f luor- HB . 17. 21- trihvdroksvpregn- 4°en" °

3. 20- dione

6.6 g of 9-fluoro-11B,16a,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added to a solution of vinyldiazomethane in 1:1 methanol-ether at 0 °C. After stirring for 1 hour, the solvent is evaporated and the residue is dissolved in chloroform and chromatographed on a 150 g silica gel column. Elution with 5% ethyl

acetate in chloroform gives 1.04 g of thin-layer chromatographically pure material. Two recrystallizations from acetone-hexane give 0.5 g of 16oc-allyloxy-9-fluoro-11p, 17,21-trihydroxy-pregn-4-ene-3v20-dione, mp 199-201°C. Analysis. Calcd for C 2 H 2 H 2 FO 2 : C, 66.04; H, 7.62; F, 4.35"

Found: C, 65.82; H, 7.83; F, 4.24.

B. l6a- allvloksv- q- fluorine- HB. 17. 21- trihvdroksvpregn- 4-en- 3,, 20- dione. 21- acetate

A solution of 2.5 g of 16a-allyloxy-9-fluoro-llp,17,21,trihydroxypregn-4-ene-3,20-dione in 25 ml of pyridine is stirred for 2 hours with 2.5 ml of acetic anhydride and the solvent is then removed in vacuum. A solution of the residue in chloroform is washed with 5% hydrochloric acid, water, 10% sodium bicarbonate solution, water and dried. Removal of the solvent in vacuo gives an oil which crystallizes from acetone-hexane, and 2.5 g of 16a-allyloxy=9-fluoro-llp, 17,21-trihydroxypregn-4-3n-3,20-dione, 21- acetate, melting point 189-191°C.

C. ^- fluoro- 116v17121- trihydroxy- 16a-( oxiranyl- methoxy)- pregn- 4- en- 3t20-dione, 21- ac' etate

A solution of 6.44 g of 9-fluoro-16oc-allyloxy-llp,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate in 150 ml of dichloromethane is stirred with 2.88 g of m-chloroperbenzoic acid in 19 hours at room temperature. The resulting solution is washed with a mixture of 10% potassium carbonate solution and 10% sodium sulfite solution, dried, and evaporated in vacuo. The residue is dissolved in dichloromethane and chromatographed on a 125 g silica gel column. Elution with chloroform and a mixture of chloroform-ethyl acetate gives 3.5 g of unreacted starting material in fractions (100 ml) 25-37 and 1.7 g (25.6%) thin-layer chromatography clean product in fractions 49-61•

The product (1.7 g) is recrystallized from acetone-hexane, and 991 mg of e^ material is obtained which has a melting point of 191-192.5°C. A portion of ^ >0Q mg of the material is recrystallized from the same solvent, and 430 mg of 9-fluoro-lip ,17', 2l-trihydroxy-16a-(oxiranyl-methoxy)pregn-4-ene-3,20- dione, 21= acetate, melting point 191-192.5°C.

Analysis. Calculated for CggH^^FOg: C, 63.15; H, 7.13; F, 3.8#*

Found: C, 63.17; H, 6.84; F, 3.64in.

D.. 9-Fluoro-5'| ,lip,21-trihydroxypregn-4-enb/~l6a,17-b_7-/""l,4_7dioxane-3,20-dione, 21-acetate

A solution of 20.1 g of crude 9-fluoro-11p,17,21-trihydroxy-16a-(oxiranyl-methoxy)pregn-4-ene-3,20-dione, 21-acetate in 300 ml of tetrahydrofuran is stirred with a solution of 30 g of periodic acid

in 75 ml of water during 6 3/4 hours. The solution is diluted with water and extracted with chloroform. The chloroform extract is washed with 5% sodium bicarbonate solution, dried and evaporated in vacuo,

and you get 18.2 g of impure product. This material is dissolved in 60 ml of dichloromethane and chromatographed on a 450-g silica gel column. Fractions of 250 ml are collected as the column is eluted with 3 liters of dichloromethane, 3 liters of chloroform and then 3 liters of 19:1 chlorine of o m-et y la c eta*. Fractions 17-21 are beaten

together and evaporated in vacuo, and 4*4g of 9-fluoro-16a-allyloxy-11p,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate is obtained.

Fractions 23-31 are combined and evaporated in vacuo,

and one obtains 8.1 g of slightly contaminated (53»2% based on recovered material) 9-fluoro-5'£,HP ,21-trihydroxypregn-4-eno/~16a,~ 17-b_7/"1,4_7dioxane -3,20-dione, 21-acetate A portion of this material is recrystallized from acetone-hexane and then from acetonitrile, and one obtains the analytical sample, melting point 205-208°C.

Analysis. Calculated for C₂H₂FO₂: C, 62.10; H, 7.50; F, 3.93.

Found: C, 62.22; H, 7.28; F, 3.69.

Example 2

q- fluoro- 2 W - dihydro- llB. 21-dihydroxy-5'-methylpregn-4-eno/~16a,17-b_7/"1,4-7dioxin-3,20-dione, 21-

A acetate 9-fluoro-11p,17,21-trihydroxy-16oc-[2-methyl-2-.propenyl)oxy_7pregn-4-ene-3,20-dione

A solution of 2-methyl-3-diazol-1-propene in 250 ml of ether (prepared from 0.2 mol of N-(2-methyl-2-propenyl)-ethyl carbamate according to JiL; Brewbaker and Hi Hart, J. Anu Chem Soc, 91, 711 (1969)): dilute with 300 ml of methanol and cool to 0°C. A total of 6.5 g of 9-fluoro-llp,16a,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added in portions until the original red color disappears and nitrogen evolution ceases. The solvent is evaporated in vacuo and the residue is dissolved in chloroform and chromatographed on a 100 g silica gel column. Elution with chloroform and chloroform-ethyl acetate gives thin-layer chromatographic homogeneous material which crystallizes from acetone-hexane, and 3.73 g of 9-fluoro-110,17,21-trihydroxy-16a-/T2-methyl-2-propenyl)oxy_7pregn-4 are obtained -ene-3»20-dione, melting point 213-215°C, softens at 198-200°C.

Analysis. Calculated for C₂H₂FO₂: C, 66.64; H, 7.83; F, 4.22.

Found: C, 66.41; H,' 8.03; F, 4.16.

B. 9-Fluoro-11B,17,21-trihydroxy-16a-[(2-methyl-2-propenyl)-oxy_7pregn-4-ene&3»20-dione, 21-acetate

A solution of 3 g of 9-fluoro-11p,17,21-trihydroxy-16>-£(2-methyl-2-propenyl)oxyJ7pregrt-4-ene-3,2t)-dione in 25 ml of pyridine is stirred for 2 hours with 4 ml of acetic anhydride. The solvent is removed in vacuo and the residue is dissolved in chloroform, washed with 5% hydrochloric acid solution, water, 5% sodium bicarbonate solution and dried. Removal of the solvent in vacuo gives a solid which is recrystallized from aceto-hexane, and 2.82 g of the material is obtained which has a melting point of 230-231°C. Recrystallization of 0.6 g of this material from acetone-hexane gives 481 mg of 9-fluoro-11p,17,2l-trihydroxy-16a^"(2-methyl-2-propenyl)oxy_7pregn-4-ene-3,20- dione,, 21-acetate, melting point 230-232°C.

Analysis. Calcd for C 27 H 2 F 0 2 : C, 65.84; H, 7.57" D, 3.86.

Found: C, 65.89; H, 7.56; F, 4.06.

C. 9-fluoro-llp, 17,21-trihydroxy-160c-/" (2-methyl-oxiranyl)-methoxy_7pregn-4-ene-3,20-dione, 21-acetate A suspension of 1.0 g 9 -fluoro-llp,17,2l-trihydroxy-16oc-/" (2-methyl-2-propenyl)oxy_7pregn-4-ene-3,20-dione, 21-acetate in 50 ml of dichloromethane is stirred with 500 mg of m-chloroperbenzoic acid at room temperature for 210 minutes. The resulting solution is washed with a mixture of 10% sodium carbonate solution and 10% sodium sulphite solution, dried and evaporated to give 1.04 g of oil which solidifies. Recrystallization from acetone-hexane gives 793 mg of the material, melting point 221-224°C and 160 mg of the material, melting point 219-224°C. Recrystallization from a mixture of 390 mg of Portion 1 and 160 mg of Portion 2 from acetone-hexane gives 298 mg of 9-fluoro-11p,17,21-trihydroxy-16a- / T (2-methyl-oxiranyl)-methoxy. .7pregn-4-ene-3,20-dione, 21-acetate, melting point 223-227°C. Analysis. Calculated for C^H^FOg: C,. 63.76; H, 7.33; F, 3.74.

Found: C, 63.96; H, 7.10; F, 3.93.

The nuclear magnetic resonance spectrum of this material indicates that it is a mixture of epimers (in a ratio of about 2:1) at the quaternary epoxide carbon atom.

D. q- f luor- HB . 17. 21- trihvdroksv- 16oc-( 2- oxopropoxv)-pregn- 4- en- 3. 20- dione. 21- acetate

A solution of 1.54 g of 9-fluoro-llp,17,21-trihydroxy-16a-/(2-methyl-oxiranyl)methoxy_7pregn-4-ene-3,20-dione, 21-acetate in 50 nil t et raw hy dro fura n is stirred for 270 minutes with a solution of 2.6 g of periodic acid in 20 ml of water. The solution is poured into water and extracted with chloroform. The chloroform solution is washed with 10% sodium bicarbonate solution, dried and evaporated in vacuo, and one obtains an oily residue. This is dissolved in chloroform and chromatographed on a 40 silica gel column. Elution with chloroform gives 4. QO mg of slightly impure product, followed by 990 mg of thin-layer chromatographically homogeneous solid. 99 mg is recrystallized twice from acetone-hexane, and 328 mg of 9-fluoro-11p,17,21-trihydroxy-16a-(2-oxopropoxy)pregn-4-ene-3,20-dione, 21-acetate, melting point 203-208°C are obtained.

Analysis. Calcd for C 2 H 2 H 2 F 2 : C, 63.15; H, 7.13; F, 3.84.

Found: C, 63.01; H, 7.04; F, 4.08.

E« q- f luor- 2'. 3f - dihydro-HB. 21-dihvdroksv-[ 5'- metvl-pregn- 4- eno/- l6a. 17- b._ 7/" l. 4- 7dioxin- 3. 20- dione.

21- acetate

A suspension of 100 mg of p-toluenesulfonic acid in 250 ml of benzene is refluxed with a Dean-Stark trap. The first 50 µl of the azeotropic mixture of benzene-water is discarded and the trap is added to Linde 4A type mole sieves. After refluxing for 30 minutes, the solution is cooled and 1.0 g of 9-fluoro-llp,17,21-trihydroxy-16a-(2-oxopropoxy)pregn-4-ene-3,20-dione, 21-acetate is added. The resulting suspension is refluxed for 5 hours under nitrogen, cooled, diluted with chloroform, washed with 5% sodium bicarbonate solution, water, dried and evaporated. The crude residue is dissolved in a small amount of chloroform and chromatographed on a 20 g silica gel column. Elu-. eration with chloroform gives 805 mg of a material which is recrystallized from acetone-hexane to give $01 mg of 9-fluoro-2',3*7dihydro-11B,21-dihydroxy-5'-methylpregn-4-eno/ "l6a, 17-b_7/" 1,4_7-dioxin-3,20-dione, 21-acetate, mp 233-235°C, cleavage. Analysis. Calculated for C gg H 2 FO--:C, 65.53; H, 6.98.; F, 3.99.

Found: C, 65.78; H, 6.84; F, 4U4»

Example 3

q-fluorine-2'. 3'-dihydro-IIB. 21- dihvdroksv- 5'- metvlpregn-4- eno/" l6a. l7- b 7/" 1. 4 7dicksin- 3. 20- dione

A solution of 886 mg of 9-fluoro-2',3<»>-dihydro-118,21-dihydroxy-5'-methylpr egn-4-enoi/"16a, VJ- hJjT 1,4_7dioxin-3,20-dione . 775 mg of thin-layer chromatographically pure 9-fluoro-2',3<»->dihydro-IIB,21-dihydrobxy-5'-methylpr egn-4-eno/."16a, 17-b_7Z" 1,4-7dioxin- 3,20-dione.

Example 4

9- f luor- 2 *. 31 - diHvdro- llB. 21- dihvdroksv- 5' - f envlpregn-4- eno/" l6a. 17- b_ 7/" 1. 4- 7dioxin- 3. 20- dione. 21- acetate

A. q- fluorine- HB. 17. 21- trihydroxyl6a-/"( 2- phenvl- 2- propenyl) oxy_ 7pregn- 4- ene- 3. 20- dione, 21- acetate a$ N-( 2- phenvl- 2- propenvl) phthalimide

A mixture of 60 g of potassium phthalimide and 66.4 g of α-bromomethylstyrene (prepared according to S. F. Reed, Jr., J. Org. Chem.,

30, 3258 (1965)) in 150 ml of dimethylformamide is refluxed for 2 hours, cooled and diluted with 400 ml of water. The resulting solid is filtered off and dried in vacuo, and 83.4 g of N-(2-phenyl-2-propenyl)phthalimide are obtained. A small sample recrystallized from acetone-hexane has a melting point of 118-121°C.

b) N-(2-phenyl-2-propenyl) ethyl carbamate

A solution of 83 g of N-(2-phenyl-2-propenyl)phthalimide and

30 g of 99$ hydrazine hydrate is refluxed for 270 minutes and cooled. The suspension is treated with 125 ml of concentrated hydrochloric acid and filtered. The solid is washed with four 100 ml portions of water and the filtrate is evaporated in vacuo to a volume of 300 ml. This solution is cooled and mixed with a solution of 60 g of sodium hydroxide in 250 ml of cold water. The resulting solution is extracted four times with 200 ml of ether and the ether solution is dried and evaporated in vacuo, and 30.7 g of oil is obtained. The oil is dissolved in 250 ml of ether, cooled to 0°C and added

33 g of ethyl chloroformate. A solution of 12 g of sodium hydroxide i

30 ml of water is added at the same time as the other half of the methyl chloroformate solution. After 1 hour at 10°C, the ether layer is washed with 5% hydrochloric acid, dried and evaporated in vacuo, and 41.7 g of oil are obtained. Trituration with hexane and filtration gives 33 g of N-(2-phenyl-2-propenyl)ethyl carbamate,'. melting point 41-42.5°c»

c) N-nitroso-N-(2-phenyl-2-propenyl) ethyl carbamate

A solution of 21 ml (29.4 g) of nitrosyl chloride in 60 ml

pyridine (prepared at -25°C) is added over 15 minutes to a solution of 57 g of N-(2-phenyl-2-propenyl)ethylcarbamate in 400 ml of pyridine at -5°C. The solution is stirred for 15 minutes and poured down in. 4 liters of cold water. The oil that separates out is diluted in ether (three portions of 600 ml) and the ether extract is washed successively with 1 liter of 10% hydrochloric acid, water, 1 liter of 5% sodium bicarbonate solution and dried. Removal of the solvent gives 63 g of a red oil showing only minor impurities by thin layer chromatography.

d) 2-phenyl-3-diazol-1-propene

A solution of 63 g of N-nitroso-N-(2-phenyl-2-propenyl)-ethyl carbamate in 300 ml of ether is added to 300 ml of 3M sodium methoxide in methanol at -1 to -2°C over 30 minutes. The solution is stirred for a further 1 hour and then poured into 2 liters of ice water and 100 ml of ether and 100 ml of pentane. The organic layer is separated and kept at 0°C while the aqueous layer is extracted with 300 ml of ether. The combined organic layer is washed with two 1 liter portions of ice water, dried for 10 minutes at 0°C over NaOH tablets and filtered, giving 700 ml of a red

solution.

e') 9- fluoro- llB. 17. 21- trihydroxyl6a- </"( 2- phenyl- 2-propenyl) oxv 7pregn- 4- en- 3. 20- dione

A solution of 2-phenyl-3-diazol-1-propene prepared as indicated above is diluted with 150 ml of cold methanol and stirred well at 0°C and 13 g of 9-fluoro-11B,16a,17,21-tetrahydroxypregn are added in portions -4-ene-3,20-dione, 16,17-cycloborate. The suspension is stirred for 1 hour at 0°C and filtered, and 9.6 g of the final product is obtained. The filtrate is stirred at room temperature for 1 hour with 4 g of cycloborate and the resulting solution is cooled to 0°C and filtered, and 4.2 g of the final product is obtained. The filtrate is evaporated in vacuo and the residue is dissolved in 4.0 ml of 3.1 ether-methanol and cooled to -10°C, and a further 3.0 g of the material is obtained. A small sample recrystallized from acetone-hexane has a melting point of 161-163.5°C.

B. q- fluorine- llB. 17. 21- trihydroxv- l6a-/'"( 2- phenvl- 2-properiyl1) oxv 7pregn- 4- en- 312 0- d ion t 2 l- a c et a t

A solution of 3.0 g of 9-fluoro-118,17,21-trihydroxy-da-/" (2-phenyl-2-propenyl)oxy_7pregn-4-ene-3,20-dione in 3 ml of pyridine gives allowed to stand with 3 ml of acetic anhydride for 2 hours

at room temperature. The solvent is removed in vacuo and the residue is dissolved in chloroform, washed with 5% hydrochloric acid, water, 5% sodium bicarbonate solution and dried. Removal of the solvent gives an oil which crystallizes from acetone-hexane and 2.3 g of the material is obtained. Recrystallization of 600 mg from acetone-hexane gives 510 mg of 9-fluoro-110,17,21-trihydroxy-16a-[(2-phenyl-2-propenyl)oxy_7pregn-4-ene-3,20-dione, 21-acetate , melting point 169-171°C.

Analysis. Calculated for C₂H₂FOy: C, 69.29; H, 7.09; F, 3.42.

Found: C, 69.13; H, 7.11; F, 3.26.

c« 9- f luor- HB. 17. 21- trihvdroksv- l6a-/ T2- f envloxiranvl) -

methoxyri7pregn- 4- en- 3^ 20- dione. 21- acetate

A solution of 555 mg of 9-fluoro-11B,17,21-trihydroxy-16a-/"<*>(2-phenyl-2-propenyl)oxy_7pregn-4-ene-3,20-dione, 21-acetate in 25 ml of dichloromethane is stirred for 330 min with 200 mg of m-chloroperbenzoic acid. The solution is washed with 50 ml of both 5% sodium sulphite solution and 5% potassium carbonate solution. The dichloromethane solution is dried and evaporated, and 5^2 mg of the product is obtained. Recrystallization from acetone hexane gives 360 mg of 9-fluoro-HB, 17,2l-trihydroxy-16a-(2-phenyl-oxiranyl)methoxy-7pregn-4-ene-3,20-dione, 21-acetate.

D« Q- fluoro- HB f17P21- trihydroxv- l6a-( 2- phenvl- 2- oxo-ethoxv) pregn- 4- §n- 3. 20- dione 21- acetate

A solution of 2.4 g of 9-fluoro-11B,17,21-trihydroxy-16a-/~(2-phenyl-oxiranyl)methoxy_7pregn-4-ene-3,20-dione, 21-acetate in 75 nil of tetrahydrofuran is stirred . with a solution of 5 g of periodic acid in 20 ml of water for 270 minutes. The resulting suspension is diluted with 150 ml of water and the solid is filtered and dried in vacuo to give 1.79 g of crude product.

This material is chromatographed on a 40 g silica gel column. Elution with chloroform gives 1.6 g of thin-layer chromatographically pure solid which is recrystallized from acetone hexane, and one obtains 1.42 g of 9-fluoro-116,17,21-trihydroxy-16oc-(2-phenyl-2-oxoethoxy)f?pregn -4-ene-3,20-dione, 21-acetate, melting point 228-230°C. Analysis. Calculated for C^H^F<O>g<:>C, 66.89; H, 6.70; F, 3.41.

Found: C, 67.07; H, 6.69; F, 3.15.

E. 9- fluoro- 2'. V - dihvdro- 113. 21- dihvdfoxv- 5 *- phenylpregn- 4- eno)/"" l6a. 17- b_ 7(/"' l . 4_ 7dioxin- 3. 20- dione.

21- acetate

A suspension of 150 mg of p-toluenesulfonic acid in 300 ml of benzene is refluxed with a Dean-Stark trap. The first 50 ml of the distillate is discarded, molecular sieves of the Linde 4X type are added, and the solution is refluxed for 30 minutes. The solution is cooled, 1.25 g of 9-fluoro-11p,17,21-trihydroxy-16a-(2-phenyl-2-oxoethoxy)pregn-4-ene-3,20-dione, 21-acetate is added, and the solution is run under reflux for 5 hours under nitrogen. The resulting solution is cooled, washed with 5% sodium bicarbonate solution, dried and evaporated in vacuo. The residue is chromatographed on a 20 g silica gel column. Elution with 1:1 hexane-chloroform gives 825 mg of impure product. This material is plate-chromatographed on three 20 x 20 cm-2 mm silica gel plates. After 2 developments with 1:1 chloroform-ethyl acetate, the most important UV-active band is removed and eluted with chloroform, and thin-layer chromatographically pure material is obtained. Recrystallization from benzene gives 380 mg of 9-fluoro-2',3'-dihydro-11B,21-dihydroxy-5*-phenylpregntH-eno-/""l6a, 17-b_7^~1,4_7dioxin-^3^20- dione, 21-acetate, mp 145-147°Ci Analysis. Calcd for C^H^FO^: C, 69.13; H, 6.55; F, 3.53.

Found: C, 68.90; H, 6.73; F, 3.58.

Example 5 Q-fluorine-2'. 3'-dihydro-IIB. 21- dihvdroxypregn- 4- eno-/" 16a. 17- b 7/" l. 4_ 7dioxin- 3. 20- dione. 21- acetate

A suspension of 100 mg of p-toluenesulfonic acid in 250 ml of benzene is distilled to a volume of 200 ml and 1.0 g is added

9-fluoro-5'1,lip,2l-trihydroxypregn-4-eno/~16oc,YJ- hJl"l,4,7-dioxane-3,20-dione, 21-acetate (prepared as indicated in Example 1) . The resulting solution is refluxed with a Dean-Stark trap filled with type 4A molecular sieves for 24 hours under nitrogen. The solution is cooled, diluted with chloroform, washed with 5% sodium bicarbonate solution and dried. After removal of solvent in vacuo, chromatograph the obtained residue on a 20 g silica gel column. Elution with 1:1 dichloromethane-chloroform gives $ 10 mg of pure compound. , Recrystallization from acetone-hexane gives 325 mg of thin-layer chromatographically pure solid in two portions. The mother liquor is purified by preparative thin-layer chromatography on a 20 x 20 cm - 2 mm silica gel plate. After three developments with 9:1 chloroform-ethyl acetate, the most important UV-active band is removed and eluted with chloroform-methanol. After removal of solvent, the residue is crystallized from acetone-hexane, and 96 mg of pure material is obtained te is combined with 325 nig obtained above and recrystallized from acetone-hexane, and 312 mg of 9-fluoro-2' ,3'-dihydro-llp,21-dihydroxypregn-4-eno/~l6oc, r7-b_7 are obtained /~1,4_7dioxin-3,20-dione, 21-acetate, melting point 231-240°C, cleavage. Analysis. Calculated for Cg^H^jFOy*. C, 64.92; H, 6.76; F, 4.11.

Found: C, 64.64; H, 6.54; F, 3.90.

Example 6

9- fluoro- 2'. 3'-dihydro-IIB. 21- dihydroxypregn- 4- eno-. 7" l6a. 17- b_ 7/ l. 4^ 7dioxin- 3. 20- dione

A solution of 700 mg of 9-fluoro-2',3'-dihydro-lip,21-dihydroxypregn-4-eno/"16a,17-b_>7/~1,4_7dioxin-3,20-dione, 21-acetate (prepared as indicated in Example 5) in 75 ml of methanol is cooled to 0° C and 7 ml of 10% potassium carbonate solution is added. After 15 minutes, 20 ml of 20% aqueous acetic acid is added and the resulting solid is filtered and dried in vacuo, and one obtains 31 mg of 9-fluoro-2',3'-dihydro-lip,21-dihydroxypregn-4-eno/~16a,17-b_7/"li4,7dioxin-3,20-dione, melting point 255-258 °C, cleavage.

Example 7 21- chlorine- 9- fluorine- 2«. V - dihvdro- llB- hvdroksv- 5 * - metvlpregna- 1. 4- dieno/" l6a. 17- b_ 7Z" l. 4_. 7dioxin-3.20-dione

A. 21- chlorine- Q- f luor- llB. 16a. 17-trihydroxypregna-l. 4--dien- 3. 20- dion. l6T17- cycloborate

A solution of 15.0 g of 21-chloro-9-fluoro-lip,16a,17-trihydroxypregna-1,4-diene-3,20-dione and 60 g of boron oxide in 750 ml of methanol is refluxed for 1 hour, cooled to 30°C and diluted with 1.5 liters of water. The resulting solid material is filtered and dried in vacuo to give 13.85 g of 21-chloro-9-fluoro-lip,16a,17-trihydroxypregna-1,4-diene-3520-dione,16,17Tcycloborate. ...'

B. 21- chlorine-- 9J- f luor- 110 . 17- dihydroxyl6a-/~ ( 2- methyl- 2-propenyl) oxyT7pregna- l^ 4- diene- 3120-dione

A solution of 2-methyl-3-diazol-1-propene in 150 ml of ether

(prepared from 0.1 mole of N-(2-methyl-2-propenyl)ethyl carbamate after J.L. Brewbaker and H. Hart, J. Am. Chem., Soc, 91, 711 (1969)) is diluted with 50 nil methanol and cooled to 0°C. Total 7 g

21-chloro-9-fluoro-11p,16a,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo and the residue is dissolved in chloroform and chromatographed on an 80 g silica gel column. Elution with chloroform gives thin-layer chromatographically pure material which crystallizes from acetone-hexane, and one obtains 5»4g of 21-chloro-9-fluoro-11p»17-dihydroxy-16a-/~(2-methyl-2-propenyl)oxy_7-pregna -1,4-diene-3,20-dione, melting point 238-240°C. Analysis. Calculated for C 2 H 2 ClFO 2 : C, 64.30; H, 6.91; Cl, 7.59;

F, 4.06.

"Found: c, 64.53; H, 7.04; Cl, 7.74;

F, 4.27.

Ci 21- chlorine- q- f luor- HB. ^- dihydroxy-^ ieoc-/" ( 2- metvl-oxiranyl) methoxy., 7-pregna- l, 4- dieneT3 * 20-dione

A solution of 3.0 g of 21-chloro-9-fluoro-llp,17-dihydroxy-. 16a-/(2-methyl-2-propenyl)oxy_7pregna-1,4-diene-3,20-dione in 100 ml of dichloromethane is stirred with 1.4 g of m-chloroperbenzoic acid for 210 minutes. The solution is washed with a mixture of 10% potassium carbonate solution and 10% sodium sulphite solution, dried and evaporated in vacuo to give an oil which solidifies on standing. Recrystallization from acetone-hexane gives 1.94 g as a first portion and 820 mg as a second portion. Recrystallization of 600 mg of portion 1 from acetone-hexane gives 460 mg of 21-chloro-9-fluoro-llp, ^-dihydroxy-^a-^^-methyloxiranylJmethoxy^-pregna-l^-diene^^O-dione, melting point 193- 236°C.

Analysis. Calcd for C 2 H 2 ClFO 2 : C, 62.16; H, 6.68;

Cl, 7.34; F, 3.93.

Found: C, 62.19; H, 6.67;

Cl, 7.52; F, 4.07.

(The nuclear magnetic resonance spectrum of this material indicates that it contains an approximately 1:1 mixture of epimers at the quaternary oxirane carbon atom.)

D. 21- chlorine- q- f luor- HB. 17-dihydroxyv-l6a-(2-oxo-propoxy)pregna-1.4-diene-3^20-dione

One. solution of 2.16 g of 21-chloro-9-fluoro-llp , 17-dihydroxy-16a-/(2-methyloxiranyl)methoxy_7pregna-1,4-dien-3,20-dione in 50 ral of tetrahydrofuran is stirred with a solution of 5 g of periodic acid in 10 ml of water for 180 minutes. / The solution is diluted with water and extracted with chloroform. The chloroform solution is dried and evaporated in vacuo and the residue is dissolved in chloroform and chromatographed on a 50 g silica gel column. Elution with chloroform and collection of 50 ml fractions , gives 1.8l g of thin-layer chromatographically pure solid material in fractions 9-17» Recrystallization from acetone-hexane gives 1.15 g of the first portion and 0.50 g in portions 2 and 3« Recrystallization from acetone-hexane of 600 mg of the first portion gives 490 mg of 21-chloro-9-fluoro-11p,17-dihydroxy-16a-(2-oxopropoxy)pregna-1,4-diene-3»20-dione, melting point 226-227°C.

Analysis. Calculated for C 2 H 2 ø ClFO 2 : C, 61.51; H, 6.45;

Cl, 7.56; F, 4.05.

Found: C, 61*69; H, £6.35

ci, 7*53; f, 3.94.

E. 21- chlorine- q- fluorine- 2*. 3'- dihvdro- llp- hvdroksv- S'- metvl-pregna-l^-dieno^^a, r7-b_7/~l,4._7dioxin-3,20-dione A suspension of 100 mg of p-toluenesulfonic acid in 250 ml. benzene is run under reflux with a Dean-Stark trap. The first 50 µl of the benzene-water azeotropic mixture are discarded and Linde 4A type mole sieves are added to the trap. After refluxing for 30 minutes, the solution is cooled and 980 mg of 21-chloro-9-fluoro-11p,17-dihydroxy-16a-(2-oxopropoxy)pregna-1,4-diene-3'20-dione are added. The resulting suspension is refluxed for 25 hours under nitrogen, cooled and filtered to give 720 mg of solid. The filtrate is diluted with chloroform, washed with 5% sodium bicarbonate solution, water, dried and evaporated, and 210 mg of material is obtained which, by thin-layer chromatography, is identical to 720 mg of the solid material. These materials are combined, suspended with 50 tol of mineral oil, diluted with chloroform and chromatographed on a 100 g silica gel column. Elution with chloroform gives 850 mg of material which is recrystallized from acetone, and 487 mg of 21-chloro-9-fluoro-2', 3'-dihydro-lip-hydroxy-5'-methylpregna-1,4-dieno^~16oc are obtained , VJ- bJ/^"1,4_/dioxin-3,20-dione, melting point 259-260°C.

Analysis. Calculated for C 2 H 2 H 2 O 2 FCl: C, 63.92; H, 6.26;

Gl, 7.86; F, 4.19.

Found: C, 63.80; H, 6.49; Cl, 8.07; F, 4.13.

Example 8

5f|- ethoxy- 9- fluoro- 116. 21- dihvdroxypregn- 4- eno-A6ct. l7- b_ 7/" 1. 4 7dioxane- 3. 20- dione

A. I6a-( 2. 2- diethoxysvetoxv)- Q- fluoro- 116. 17. 21- trihydroxysvpregn- 4- ene- 3. 20- dione A solution of 2,2-diethoxy-l-diazoethane prepared from 0.0935 mol N-2,2-diethoxyethyl-urea after W. Kirmse and M. Buschhoff, Chem. Pray. 100, I49I (I967)) in 300 ml of 3:2 ether-pentane is diluted with 100 ml of methanol and cooled to 0°C. Total 5.5 g

9-fluoro-llp,lfa,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo and the residue is recrystallized from methanol, and 3.4 g of slightly contaminated material is obtained. This is dissolved in chloroform and chromatographed on an 80 g silica gel column. Elution with chloroform gives 2.95 g of material which is recrystallized from acetone-hexane, and 2.6 g of 16a-(2,2-diethoxyethoxy)-9-fluoro-11p,17,21-trihydroxypregn-4-ene-3 is obtained ,20-dione, melting point 208-210°C.

Analysis. Calcd for CgyH^FOg: C, 63.26; H, 8.07; F»3»71«

Found: C, 63.03; H, 7.86; F, 3.79.

B. 5 ' g- ethoxv- q- f luor- 113. 21- dihydroxyvpregn- 4- eno-r l6ct. 17- b_ 7/ l. 4_ 7dioxane- 3. 20- dione

A suspension of 100 mg of p-toluenesulfonic acid in 250 ml of benzene is refluxed with a Dean-Stark trap. The first 50 ml of the benzene-water azeotropic mixture is discarded and the trap is added to Linde 4A type mole sieves. 17,21-trihydroxypregn-4-ene-3,20-dione. The resulting suspension is refluxed for 2 hours under nitrogen, cooled, diluted with chloroform, washed with 5% sodium bicarbonate solution, water, dried and evaporated. The crude residue (2.25 g) is dissolved in chloroform and chromatographed on a 100 g silica gel column. . Elution with chloroform and 4-1 chloroform-ethyl acetate gives a total of 1.33 g of thin-layer chromatographically pure material. Two recrystallizations from acetone-hexane (the last with charcoal) give 570 rag 5'f-ethoxy-9-fluoro-llp,21-dihydroxypregn-4-eno^~ l6oc, YJ- bJ/ l"! ,4_7dioxane-3, 20-dione, melting point 248-250°C, cleavage.

Analysis. Calculated for C 2 H 2 H 2 F 2 : C, 64.64; H, 7.16; F, 4.10.

Found: C, 64.75; H, 7.02; F, 3.95.

Example 9 ^-methoxy-9-fluoro-113.21-dihydroxypregn-4-eno-r 16a. 17- b It 1. 4_, 7dioxane- 3. 20- dione

A. 16a-(2.2-dimethoxysvetox)-q-fluoro-113.17.21-tri-hydroxypregn-4-ene-3.20-dione A solution of 2,2-dimethoxy-1-diazoethane in 100 ml 6:4 pentane ether (prepared according to W. Kirmse and M. Buschhoff, Chem. Ber., 100, I49I (1967) used for the diethoxy analogue) is diluted with 50 ml of methanol and cooled to 0°C. A total of 2 g of 9-fluoro-118,16a,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added. After nitrogen evolution has ceased, the solvent is removed in vacuo and the residue is dissolved in chloroform and chromatographed on an alumina column (neutral, activity III). Elution with chloroform gives 4$5 mg of slightly contaminated material and then 1.27 g of thin-layer chromatographically pure compound. Recrystallization of 4$5 rag from acetone-hexane yields 175 mg of thin-layer chromatographically homogeneous solid, which is combined with 1.27 g and recrystallized from acetone-hexane, and one obtains 1.09 g of 16a-(2,2-dimethoxyethoxy)-9- fluoro-llp,17,21-trihydroxypregn-4-

en-3,20-dione, melting point 192-194°C.

Analysis. Calculated for C₂H₂FO₂: C, 61.96; H, 7.70; F, 3.94"

Found: C, 62.21; H, 7.79; F, 3.85.

B. 5tg- methoxy- Q- fluoro- 116. 21- dihdroxypregn- 4- eno-[ l6a. 17- b It 1. 4_ 7dioxane- 3. 20- dione

By proceeding as indicated in Example 8B, but substituting 16a-(2,2-dimethoxyethoxy)-9-fluoro-11p,17,21-trihydroxy-cypregn-4-ene-3,20-dione for 2, 2<5-diethoxyethoxy-steroid gives the final product.

Example 10 21-chloro-5>g-ethoxy-9-fluoro-liP-hydroxypregn-4-eno/" 16a, V\- bJ£ 1,4_/dioxane-3,20-dione

A. yl- ethoxv- 9- fluoro- llg. 21-dihydroxypregn- 4- eno-116a,17-b.//- l,4_7dioxane-3,20-dione, 21-mesylate A solution of 950 mg of 5'?-ethoxy-9-fluoro-lip,21-dihydroxypregn -4-eno^*l6a,17-b_7/" 1,4„7dioxane-3,20-dione (prepared as indicated in Example 8) in 10 ml of pyridine is stirred at Q#C with 3 ml of methanesulfonyl chloride for 150 minutes. ice is added and

the mixture is poured onto cold, dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried and evaporated in vacuo, and 1.0 g of impure mesylate is obtained.

B. 21- chloro- 5tE- ethoxy- 9- fluoro- 113- hydroxyprejgn- 4-& no[ l6a,17-b_7Z" l,4_7dioxane-3,20-dione A solution of 1 g of 5<f>g-ethoxy -9-Fluoro-11p,21-dihydroxypregn-4-eno^" 16a,17-b_7/" 1»4_7dioxane-3,20-dione, 21-mesylate in 100 ml of dimethylformamide is refluxed with 4 g of lithium chloride at 3° minutes, cooled and poured onto ice water. The resulting solid was filtered, washed well with water and dried in vacuo to give 7^2 mg of product. This material was dissolved in chloroform and chromatographed on a 20 g silica gel column. Elution with chloroform gives 715 mg thin-layer chromatographically pure solid. Recrystallization from acetone-hexane gives 600 mg of 2i-chloro-5'^-ethoxy-9-fluoro-llp,hydroxypregn-4-eno-£ l6a,17-b_7Z" l,4-7dioxane -3,20-dione, melting point 235-237°C, cleavage.

Analysis. Calculated for C₂H₂ClFO₂: C, 61.91; H, 7.07;

Cl, 7.31 and F, 3.92.

Found: C, 61.75; H, 7.27;

Cl, 7.24; F, 3.85.

Example 11 9-Fluoro-5'^,11p,21-trihydroxypregn-4-eno/"16a,17-b_7-

1,4_7dioxane-3,20-dione

in

A solution of 1.6 g of 16α-(2,2-diethoxyethoxy)-9-fluoro-116,17,21-trihydroxypregn-4-ene-3,20-dione (prepared as indicated in Example 8A) in 200 ml of tetrahydrofuran heated under reflux with 20 ml IN hydrochloric acid for 3 hours. The solution is cooled, evaporated in vacuum to one third of the original volume and diluted with water. The resulting solid is filtered off and dried in vacuo, and 800 mg of product is obtained. Recrystallization from methanol gives 350 mg of 9-fluoro-5'4»liP»21-trihydroxypregn-4-eno-/<*>16a,17-b_7/1,4_7dioxane-3,20-dione, melting point 260-262°C , cleavage.

Analysis. Calculated for C^H^FO^: C, 63.00; H, 7.13; F, 4.33.

Found: C, 62.96; H, 7.07; F, 4.48.

Example 12

9-f luor-5 , 116,21-trihydroxypregn-4-eno/" l6oc, 17-b_7-^"l,4_7dioxane-3,20-dione, 5<f>,21-diacetate To a solution of 1, 3 g of 9-fluoro-5,^,11<p>,21-trihydroxy-pregn-4-eno/"16a,17-b_7/~1,4_7dioxane-3,20-dione (prepared as indicated in Example 11) in 10 ml of pyridine, 5 nil acetic acid is added. The solution is kept at room temperature for 4 hours. The solvent is removed in vacuo and the residue is dissolved in chloroform, washed with dilute hydrochloric acid and dried. The solvent is removed in vacuum and the residue is dissolved in chloroform and chromatographed on a silica gel -column. Elution with chloroform gives 730 mg of impure compound and 506 mg of thin-layer chromatographically pure material. 730 mg of impure material is dissolved in chloroform and plate chromatographed on two 20 x 20 cm - 2 mm silica gel plates. After three developments

with 1:1 chloroform-ethyl acetate, the UV-active band with the lowest R^ is removed in vacuo and the residue is mixed with 506 mg of pure material

and recrystallized from acetone-hexane, and 530 mg of 9-fluoro-5%,lip,21-trihydroxypregn-4-eno/<a>l6a,17-b<_>7Z~l»4-7- are obtained. dioxane-3,20-dione, 5',21-diacetate, melting point 195-197°C. Analysis. Calculated for C 2 H 2 H 2 FO 2 : C, 62.42; H, 6.21; F, 3.66.

Found: C, 62.37; H, 6.44; F, 3»6l.

Example 13 9-Fluoro-5'1,lip,21-trihydroxypregn-4-eno/"16a,17-b_7-/"1,4_7dioxane-3,20-dione, 5f<->valerate, 21-acetate A solution of 9-fluoro-5'1-,lip,21-trihydroxypregn-4-eno/* 16a,17-b_7Zb"1,4_7dioxane-3,20-dione, 21-acetate (prepared as indicated in Example 1) in pyridine is stirred with excess valerian anhydride for 2 hours. The solvent is removed in vacuo and the residue is dissolved in chloroform. The chloroform solution is washed with 5% hydrochloric acid, water, 5% sodium bicarbonate and dried. Removal of

the solvent gives 9-fluoro-5,J| ,lip ,21-trihydroxypregn-4-eno-/""l6a,17-b_7/""1,4_7dioxane-3,20-dione, 5'-valerate, 21-acetate.

Example 14

. 21- chlorine- 9- fluorine- 5.%. 116;rdihYdroxypregna- 1. 4-dieno/" l6a, lf - b _ 7£ 1, 4_ 7dioxane- 3, 20-dione

A. 21- chloro- 16oc-( 2. 2- dietoxvetoxv)- q- fluoro- 116. 17-dihydroxypregna- ln4- diene- 3120-dione

A solution of 2,2-diethoxy-1-diazoethane (prepared from 0.0935 mol of N-2,2-diethoxyethyl urea according to W. Kirmse and M. Buschhoff, Chem. Ber., 100, I49I (1967)) in 300 ml of 3:2 ether-pentane is diluted with 100 ml of methanol and cooled to 0°C. A total of 2.5 g of 21-chloro-9£fluoro-11p,16a,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo and the residue is dissolved in chloroform and chromatographed on an 80 g silica gel column. Elution with chloroform gives 2.16 g of thin-layer chromatographically pure material, which is recrystallized from acetone-hexane, and 1.75 g of 21-chloro-16a-(2,2-diethoxyethoxy)-9-fluoro-11p,17-dihydroxypregna is obtained -1,4-diene-3,20-dione, melting point 200-202°C. Analysis. Calculated for C 2 H 2 gClFO 2 : C, 61.30; H, 7.24;

Cl, 6.70; F, 3.59-Found: C, 61.55; H, 7.24; Cl, 6.68; F, 3.47.

B. 21- chlorine- q- f luor- 5' g, . 118- dihydroxyvpregna- 1. 4-dieno/" 16a, 17- b_ 7Z" 1, 4_ 7dioxane- 3, 20-dione A solution of 1.6 g of 21-chloro-16a-(2,2-diethoxyethoxy)-9 -fluoro-11B,17-dihydroxypregna-1,4-diene-3,20-dione in 200 ml tetrahydrofuran is heated under reflux with 20 ml 1N hydrochloric acid for 5*1/2 hours. The solvent is removed in vacuo and the residue is diluted with water, extracted with chloroform, and the chloroform solution is washed with 5% sodium bicarbonate solution, water, dried and evaporated. The residue is dissolved in chloroform and chromatographed on a 60 g silica gel column. Elution with a mixture of 3:2 chloroform:ethyl acetate gives 1.29 g of pure material which is recrystallized from acetonitrile, and one obtains 940 mg of 21-chloro-9~fluoro-5'%, 118-dihydroxypr egna-1,4- dieno^" 16a, VJ- hJff 1,4_7dioxane-3,20-dione, melting point 242-245°C, cleavage.

Analysis. Calcd for C 2 H 2 H 2 O 2 Cl F: C, 60.72; H, 6.20;

Cl, 7.79; F, 4, i8.

Found: C, 60.52; H, 5.97; Cl, 7.86; F, 4.03.

Example 15

21- chloro- 9- fluoro- 5* g. 118. dihydroxypregna- 1f4- dieno-[ l6pc, ll -\ s j£ 1, 4_ 7dioxane- 3, 20- dione, 5' - acetate

To a solution of 887 mg of 21-chloro-9-fluoro-5'f,116-dihydroxypregna-1,4-dieno/"16a,17-b_7/T 1,4_7dioxane-3,20-dione (prepared as indicated in Example 14) in 5 ml of pyridine, 2 ml of acetic anhydride is added. The solution is kept at ambient temperature for 4 hours. The solvent is removed in vacuo and the residue is dissolved in chloroform, washed with dilute hydrochloric acid and dried. The solvent is removed in vacuum and the residue is dissolved in chloroform and chromatographed on a silica gel column. Elution with chloroform gives 748 mg of material. Recrystallization from acetone-hexane gives 505 mg of slightly contaminated material. Another recrystallization from methanol gives 420 mg of thin-layer chromatographically pure 2l-chloro-9-fluoro-5lip-dihydroxypregna -1,4-dieno/" 16a, 17-b7-/"1,4_7dioxane-3,20-dione, 5'-acetate, mp 242-244°C, cleavage.

Analysis. Calcd for C 2 H 2 O 2 FCI: C, 58.41; H, 6.39;

Cl, 7.50; F, 4.02.

Found: C, 58.23; H, 6.23; Cl, 7.40; F, 4.08.

Example 16

21- chlorine- q- fluorine- 2f. 3'- dihvdro- llB- hydroxypregha-1, 4- dienor16a, VJ - bJf 1, 4_ 7dioxin- 3, 20^ dione A suspension of JOO mg of p-toluenesulfonic acid in 1.1

liter of benzene is heated under reflux with a Dean-Stark trap. The first 100 ml of the distillate is discarded, molecular sieves of the Linde l[k type are added to the trap and the solution is heated under reflux for 30 minutes. The solution is cooled, 2.0 g of 21-chloro-q-fluoro-5'f,11p-dihydroxypregna-1,4-dieno/~16a,17-b_7^" 1,4"7-dioxane-3,20- dione (prepared as indicated in Example 14)" and the resulting suspension is heated under reflux for 36 hours under nitrogen. The suspension is cooled and the benzene is removed in vacuo. The residue is dissolved in chloroform and the chloroform solution is washed with 5% sodium bicarbonate solution, water, dried and evaporated in vacuo The residue is dissolved in chloroform and chromatographed on a 50 g silica gel column. Elution with chloroform gives 985 mg of solid material which is recrystallized from acetone-hexane, and 528 mg of 21-chloro-9-fluoro-2',3'-dihydro-lip is obtained ?hydroxypregna-1,4-dieno/" 16a,17-b_7/~1,4_7dioxin-3,20-dione, melting point 248-250°C, cleavage.

Analysis. Calculated for C 2 <H>ggClFO 2 : C, 63.23; H, 6.00;'

Cl, 8.12; F, 4.35-Found: C, 62.95; H, 5.88; Cl, 8.24; F, 4.22.

Example 17

9- fluoro- llp, 2l- dihydroxypregn- 4- eno/" 16a, r7- b„ 7-^" l>4_ 7- dioxane- 3, 5t, 20- trione, 21- acetate

A solution of 1.2 g of 9-fluoro-5<r>|,lip,21-trihydroxy-pregn-4-eno^16a,17-b_7^"1,4_7dioxane-3,20-dione, 21-acetate ( prepared as indicated in Example 1) in 250 ml of toluene is suspended with 22 g of Feti<:>zon's reagent (V*Balogh, M, Fetizon and M, Golfier, Angéw. Chem. Internat. Edit., 8,. 444 (1969) ) and distilled to a volume of 200 ml. The resulting suspension is heated under reflux under nitrogen for 32 µl/2 hours, cooled, filtered and the resulting solid washed well with chloroform. The filtrate and washings are combined, evaporated in vacuo and the residue chromatographed on a 40 g silica gel column* Elution with chloroform gives 270 mg of an oil which is crystallized from acetone-hexane to give 181 mg of thin-layer chromatographically pure solid.This is combined with 151 mg of identical material, obtained by repeating the reaction in a 1 g order of magnitude, and recrystallizes from acetone-hexane, and one obtains 275 mg of 9-fluoro-llp,21-dihydroxypregn-4-eno/"l6a,17-b_7/~<l>|4_7dioxane-3,5, , 20£fcrion , 21-acet at, melting point 217.5-220°C, cleavage.

Analysis. Calcd for C 2 H 2 H 2 F 2 : C, 62.75; H, 6.53; F, 3"97"

Found: C, 62.6l; H, 6.53; F, 3i73»

Example 18

9- fluoro-llp , 21- dihydroxypregn- 4- eno/'" l6a, 17- b 7-£ 1, 4_ 7dioxane- 3, 20- dione? 2l- acetate

A. 9-fluoro-11p,17,21-t^ihydroxy-16a-/" 2-(tetrahydropyran-2-yloxy)ethoxy 7pregn-4-ene-3,20-dione

a) Tetrahydropyran-2-yloxy-a c etonitri 1

This material is produced according to J. Davoll and D.H.

Laney, J. Chem. Soc. 2129 (I956) and has a boiling point of 78-79°C at 2 mm.

b) 2-(Tetrahydropyran-2-yloxy)ethylamine

A solution of 35 g of tetrahydropyran-2-yloxy-acetonitrile in 100 ml of ether is added dropwise to a suspension of 10 g of lithium aluminum hydride in 100 ml of ether and 100 ml of tetrahydrofuran. The suspension is heated under reflux for 210 minutes, cooled and 25 ml of saturated potassium carbonate solution is added at such a rate as to maintain a suitable reflux. After 90 minutes, the suspension is filtered and the solid is washed with ether. The filtrate is evaporated in vacuo and distilled, and 33.6 g of 2-(tetrahydropyran-2-yloxy)ethylamine is obtained, boiling point 41.5-46°C at 0.5-0.8 mm.

c) N-/~2- ( Tetrahydropyran-2- yloxy) ethyl_ i7urea

A mixture of 33.2 g of 2-(tetrahydropyran-2-yloxy)-ethylamine,. 50 g of ice and a solution of 35 g of potassium isocyanate in 80 ml of water are stirred well while 45>6 ml of 5N hydrochloric acid (cooled to -40°C) is added in one portion. The resulting solution is heated under reflux for 90 minutes, cooled and extracted with four portions of 150 ml each of chloroform. The chloroform extract is dried and evaporated in a vacuum, and 39.6 g of oil is obtained.

d) N-Nitroso-N-^"2-(tetrahydropyran-2-yloxy)" ethyl urea

A solution of 39.6 g of N-/"2-(tetrahydropyran-2-yloxy)-urea in 400 ml of ether and 100 ml of methylene chloride is suspended with 50 g of sodium acetate and cooled to -10°C with mechanical stirring. The

3 g of nitrogen dioxide in 100 ml of ether are added over 3 minutes, the suspension is stirred at -10°C for 20 minutes and then filtered. The filtrate is washed with saturated sodium bicarbonate solution, dried and evaporated, and 41.8 g of a yellow oil are obtained.

e) 2-(Tetrahydropyran-2-yloxy)-1-diazoethane

A solution of 41.8 g of N-nitroso-N-2-(tetrahydropyran-2-yloxy)ethylurea in 200 ml of ether and 100 ml of pentane is added to 450 ml of 1N sodium hydroxide solution at 1°-4°C over 25 minutes. The solution is stirred for a further 30 minutes and the layers are separated. The organic layer is dried over sodium hydroxide tablets at 0°C for 5 minutes and then filtered.

f) 9- Fluoro- llB, 17, 2 l- trihydroxy- l6ct-^ 2- f t etrahydropyran- 2- yloxy) ethoxy_| 7pregn- 4- en- 3»20- dione

A solution of 2-(tetrahydropyran-2-yloxy)-1-diazoethane (prepared from 0.21 mol of the starting material) in 400 ml of 3:1 ether-pentane diluted with 100 ml of cold methanol and stirred well while adding portionwise 5.0 g of 9-fluoro-lip,16a,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate. When nitrogen evolution ceases, the suspension is filtered, and 0.4 g of recovered borate is obtained. The filtrate is evaporated in vacuo, and an oil is obtained which is dissolved in chloroform and chromatographed on a 150 g silica gel column. Elution with 1:1 chloroform-ethyl acetate gives 4.0 g of thin-layer chromatographically pure product. A small sample of similar material is recrystallized from acetone-hexane, and one obtains 9-fluoro-11p,17,21-trihydroxy-16a-/"2-(tetrahydropyran-2-yloxy)ethoxy_7pregn-4-ene-3,20- dione, melting point 196-200°C.

B. 9- Fluoro-llp, 17, 21- trihydroxy- l6g-/ b" 2-( tetrahydropyran-2- yloxy) ethoxy_ 7pregn- 4- en- 3, 20-dione, 21-acetate

A solution of 4.0 g of 9-fluoro-lip,17,21-trihydroxy-16a-^"2-(tetrahydropyran-2-yloxy)ethoxy_7pregn-4-ene-3,20-dione in 50 ml of pyridine is allowed to stand with 5 ml of acetic anhydride for 3 hours. The solvents are removed in vacuo and the residue is dissolved in 1 chloroform and washed with 5% hydrochloric acid, water and 5% sodium bicarbonate solution. Drying and removal of the solvent gives 4.4 g of impure product. Crystallization of a similar sample from acetone-hexane gives 9-fluoro-11p,17,2l-trihydroxy-16a-/~2-(tetrahydropyran-2-yloxy)-ethoxy_7pregn-4-ene-3,20-dione, 21-acetate, m.p. 150- 152°C.

C. q- Fluorine- HB. 17. 21-trihydroxysv-16a-(2-hydroxysvetoxysv)-preffn-4-ene-3, . 20- dione, 21- acetate

Method A

A solution of 4.4 g of 9-fluoro-11p,17,21-trihydroxy-16a-1~ 2-(tetrahydropyran-2-yloxy)ethoxy_7pregn-4-ene-3,20-dione, 21-acetate in 60 ml each of acetic acid and water is stirred for 4 hours and most of the solvent is removed in vacuo. The residue is dissolved in chloroform and washed with 5% sodium bicarbonate solution. Drying and removal of the solvent gives an oil which is crystallized from acetone-hexane, and 2.4 g of 9-fluoro-lip,17,21-trihydroxy-16a-(2-hydroxyethoxy)pregn-4-ene-3 are obtained ,20-dione, 21-acetate,

melting point l62-l65°C. Q

Method B

A solution of 1.98 g of 9-fluoro-5'§,lip,21-trihydroxy-pregn-4-eno-^~l6oc, 17-b_7^"l, 4_7dioxane-3,20-dione, 2l-acetate ( prepared as stated in Example 1) in 100 ml of methanol is cooled to 0° C and 148 mg of sodium borohydride is added. After 9 minutes, the solution is poured into a mixture of ice and 5% hydrochloric acid and extracted with chloroform, and 1.78 g of an oil. This material is chromatographed on a 50 g silica gel column. Elution with 19:1 chloroform-ethyl acetate gives 0.45 g of pure 9-fluoro-llp,17,21-trihydroxy-16ct-(2-hydroxyethoxy)pregn-4-ene -3,20-dione, 21-acetate and a total of 0.35 g impure material.

D. 9- Fluoro- 16a-( 2- mesvoloxethoxy)- 118. 17. 21- trir. hydroxypregn- 4- en- 3. 20-dione. 21-acetate A solution of 0.80 g of 9-fluoro-16oc-(2-hydroxyethoxy)-lip,17,21-trihydroxypregn-4-ene-3,20edione, 21-acetate in 10 ml of pyridine is stirred with 0, 5 ml methanesulfonyl chloride for 90 minutes at 0 C under nitrogen. The solution is poured onto cold 5% hydrochloric acid and extracted with chloroform. The chloroform extract is dried and evaporated, and an oil is obtained which is chromatographed on a 20 g silica gel column. Elution with chloroform gives 521 mg of thin-layer chromatographically pure 9-fluoro-16<x-(2-mesyloxyethoxy)-116, 17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate.

E. 9- Fluoro- llB, 21- dihydroxypregn- 4- eno/" l6a, 17°b- 7-£ ~ 1 , 4^ 7dioxane- 3, 20- dione, 21- acetate

A solution of 521 mg of 9-fluoro-16a-(2-mesyloxyethoxy)-118,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate in 4 ml of dimethylsulfoxide is stirred at 110°C under nitrogen for 2 hours with 600 mg of sodium bicarbonate (dried at 110°C in vacuum). The solution is cooled, poured into 5% hydrochloric acid and extracted with chloroform. The chloroform extract is washed twice with 2% hydrochloric acid, dried and evaporated in vacuo, and 421 mg of an oil are obtained. This material is chromatographed on a 20 g silica gel column. Elution with chloroform gives 331 mg of thin-layer chromatographically pure material which solidifies. Recrystallization from acetone-hexane gives 215 mg of 9-fluoro-118,21-dihydroxypregn-4-eno^" l6a, VJ- bJ//"!,4„7dioxane-3,20-dione, 21-acetate, melting point 275- 280°C, decomposition. Analysis. Calculated for C 2 H 2 H 2 FO 2 : C, 64.64; H, 7.16; F, 4.09.

Found: C, 64.59; H, 7.21; F, 3.98.

Example 19

21- klqr- 9- fluor- 5' £. llB- dihvdroksvpregn- 4- eno-

t l6oc, VJ - bJt 1, 4_ 7dioxane- 3, 20-dione

A. l6a- Allyloxv- q- fluoro- 118. 17. 21- trihvdroxvpregn-4- en- 3. 20- dione. 21-methanesulfonate A solution of 1.0 g of 16a-allyloxy-9-fluoro-118,17,21-trihydroxypregn-4"!-ene-3,20-dione (prepared as indicated in Example IA) in 15 ml of pyridine is stirred at 0°C under nitrogen for 150 minutes with 0.35 ml of methanesulfonyl chloride. The resulting solution is poured onto cooled 5% hydrochloric acid and extracted with chloroform. The chloroform solution is washed with water, dried and evaporated in vacuo to give 1.05 g of residue .

■B. l6a- Allyloxv- 21- chloro- q- fluoro- 118. 17- dihydroxyvpregn- 4- ene- 3, 20- dione

A solution of 1,05 l6a-allyloxy-9-fluoro-118,17,21-trihydroxypregn-4-ene-3,20-dione, 21-methanesulfonate in 65 ml of dimethylformamide is heated under reflux for 1 hour under nitrogen with 1, 05 g of lithium chloride. The solution is cooled, diluted with 400 ml of water and filtered. The solid is dissolved in chloroform, washed with 5% hydrochloric acid, water, dried and evaporated in vacuo, and 800 mg of residue is obtained. This material is dissolved in chloroform and chromatographed on an 18 g silica gel column. Elution with chloroform gives 600 mg of thin-layer chromatographically pure material.

Two recrystallizations from acetone-hexane give 500 mg of 16a-allyl-oxy-21-chloro-9-fluoro-116,17-dihydroxypregn-4-ene-3,20-dione, melting point 224-225°C.

Analysis. Calculated for C 2 H 2 CIFO 2 : C, 63.36; H, 7.09;

01, 7.79; F, 4.18.

Found: c, 63.53; H, 6.97; 01, 7.50; F, 4.14.

C. 21- Chlorine- q- f luor- llB . 17-dihydroxyl6oc-(oxiranyl-methoxy)pregn-4-ene-3.20-dione

By proceeding as indicated in Example 1C, but using 16a-allyloxy-21-chloro-9-fluoro-HB,17-dihydroxypregn-4-ene-3,20-dione instead of 9-fluoro-16a-allyloxy- 116,17,2l-trihydroxy-pregn-4-ene-3,20-dione, 21-acetate gives the final product.

D. 21- Chloro-$- fluoro- 5* g fllB- dihydroxyvpregn- 4- eno-£ 16a, 17- b- 7/" 1, 4- 7dioxane- 3, 20- dione

By proceeding as indicated in Example ID, but using 21-Chloro-9-fluoro-11B,17-dihydroxy-16a-(oxiranylmethoxy)-pregn-4-ene-3,20-dione instead of 9-fluoro- 11B,17,21-trihydroxy-16a-(oxiranyl-methoxy)pregn-4-ene-3,20-dione, 21-acetate, the final product is obtained.

Example 20 21- Chloro- q- fluoro- 2 W - dihydro- llB- hvdroxv- 5'-phenylpregna- 1, 4- dieno/" l6a, VJ - hJ?£ 1, 4. 7dioxin-3. 20-dione A. 21^ Chloro- 9- fluoro- HB, 17- dihydroxy- l6a- r ( 2- phenyl-2- propenyl) oxy„ 7pregna- l14~ di. en- 3r20- dione

A solution of 2-phenyl-3-diazol-1-propene (prepared from 28.5 g of N-(2-phenyl-2-propenyl)ethyl carbamate, prepared as indicated in Example 4) in 700 ml of ether and 50 ml of pentane is diluted with 150 ml of methanol at 0°C and 10 g of 21-chloro-9-fluoro-11B,16a,17-trihydroxypregna-1,4-diene-3,20-dione and 16,17-cycloborate are added in portions. After the nitrogen evolution is ceased, the solvent is removed in vacuo and the residue is recrystallized from methanol, and 6.1 g of 21-chloro-9-fluoro-lip,17-dihydroxy-16o-/" (2-phenyl-2-propenyl)oxyiii are obtained./ -pregna-1,4-diene-3,20-dione, mp 212-214° C. Analysis Calcd for C^qH^CIFO^: C, 68.11;H, 6.48;

Cl, 6.70; F, 3.59-Found: C, 68.37; 6.75; Cl, 6.92; F, 3.49-

B. 21- Chloro- q- fluoro- 116. 17- dihydroxy- 16a-/' ( 2- phenyl1-oxiranyl) methoxy_ 7pregna- lé4- diene- 3, 20-dione A solution of 4.0 g of 21-kior- 9-Fluoro-11p,17-dihydroxy-16a-/"(2-phenyl-2-propenyl)oxy.7pregna-1,4-diene-3,20-dione i

100 ml of dichloromethane is stirred with 1.6 g of m-chloroperbenzoic acid for 1 hour at room temperature. The resulting solution is washed with a mixture of 100 ml each of 5% sodium sulfite solution and 5% sodium bicarbonate solution, dried and evaporated in vacuo to give 4.8 g of impure 21-chloro-9-fluoro-11p,17-dihydroxy-16a -C(2-phenyloxiranyl)methoxy-7-pregna-1,4-diene-3,20-dione.

C 21- Chloro- q- fluoro- 118. 17- dihydroxv- 16a-( 2- oxo- 2-phenylethoxyxv) pregna- 1. 4- diene- 3. 20- dione Single solution of 4.8 g of 21-chloro- 9-Fluoro-11p,17-dihydroxy-16aT/~(2-phenyloxyranyl)methoxy_7pregna-1,4-dien-3,20-dione in 150 ml of tetrahydrofuran is stirred with a solution of 10 g of periodic acid in 40 ml of water for 4 hours . The resulting suspension is diluted with 1 liter of water and filtered. The solid is dried in vacuo and recrystallized from methanol-chloroform, and 2.4 g of 21-chloro-9-fluoro-lip,17-dihydroxy-16a-(2-oxo-2-phenylethoxy)-pregna-1 are obtained, 4=diene-3,20-dione, melting point 266-268°C, cleavage.

Analysis. Calcd for C 2 H 2 ClFO 2 : C, 65.59; H, 6.08; Cl, 6.68;

F, 3.58.

Found: C, 65.28; H, 6.38; Cl, 6.62; F, 3.47.

D. 21- Chlorine- q- fluorine- 2 1 . 3T- dihvdro- 116- hvdroksv- 5'-fehylpregna- 1. 4- dieno^ l6a. l7- b 7 /~ l . to 7- dioxin-3. 20- dione

A suspension of 150 mg of p-toluenesulfonic acid in 750 ml of benzene is heated under reflux with a Dean-Stark trap. The first 150 ml of the azeotrope mixture of benzene-water is discarded and Linde 4A type mole sieves are added to the trap. After refluxing for 30 minutes, the solution is cooled and 1.0 g of 21-chloro-9-fluoro-lip, 17-dihydroxy-16a-(2-oxo-2-phenylethoxy)-

pregna-1,4-diene-3,20-dione. The resulting suspension kept

mes under reflux for .6 hours under nitrogen, cooled, washed with 5% sodium bicarbonate solution, water, dried and evaporated in vacuo, and 955 mg of impure product is obtained. This material is dissolved in chloroform and chromatographed on a 40 g silica gel column. Elution with chloroform gives thin-layer chromatographically pure material which will not crystallize and which is rechromatographed on a 20 g silica gel column. Elution with 3:^ chloroform-hexane gives

525 mg solids. Recrystallization from ethyl acetate-hexane gives 443 mg of 21-chloro-9-fluoro-2'^'-dihydro-11p-hydroxy^-phenylpregna-1^-dieno/* 16a,17-b_7Z"1,4_7dioxin-3,20- dione, melting point 195-197°C.

Analysis. Calculated for C 2 g H 2 O Cl F 0 2 : C, 67.89; H, 5.90; Cl, 6.91;

F, 3.71.

Found: C, 68.02; H, 5.84; Cl, 6.70; F, 3.59.

Example 21 2l-klqr-9-fluoro-118-hydroxypr egna-1,4-di eno-ri6a. l7- b 7ti. Il 7dioxane- 3. 20- dione

A. 21-Chloro-9-fluoro-118,17-dihydroxy-16a-/"2-(tetrahydropyran-2-yloxy)ethoxy_7pregna-1,4-diene-3,20-dione A solution of 2-(tetrahydropyran -2-yloxy)-1-diazo-

ethane (prepared from 0.21 mol of N-[2-(tetrahydropyran-2-yloxy)-ethyl urea as indicated in Example 18) in 400 ml of 3-1 ether-pentane is diluted with 100 ml each of ether and methanol at 0 °C and stirred vigorously while adding 5.0 g of 21-chloro-9-fluoro-116,16a, 17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate. After nitrogen evolution ceases, the solvents are removed in vacuo and the residue is dissolved in chloroform and chromatographed on a 100 g silica gel column. Elution with chloroform gives 3.6 g of solid. Recrystallization from acetone-hexane gives 3.26 g of 21-chloro-9-fluoro-. lip,17-dihydroxy-16a-[2-(tetrahydropyran-2-yloxy)ethoxy_7-pregna-1,4-diene-3,20-dione, melting point 168-170°C.

B. 21- chloro- 9- fluoro- 116. 17- dihydroxy- 16a-( 2- hydroxy-ethoxy) pregna- 1. 4- diene- 3. 20-dione

A solution of 4.2 g of 21-chloro-9-fluoro-11p,17-dihydroxy-16a-^2-tetrahydropyran-2-yloxy)ethoxy_7pregna-1,4-diene-3,20-dione in 150 ml of acetic acid and 75 ml of water is stirred at room temperature for 6 hours; diluted with 1.5 liters of cold water, and the resulting solid is filtered and dried under vacuum to give 2.63 g» Recrystallization from acetone-hexane gives 2.03 g of 2 l-chloro-9-fluoro-118.17 -dihydroxy-16a- (2-hydroxy-ethoxy) per egna-:

1,4-diene-3,20-dione, melting point 226-228°C, cleavage.

Analysis. Calculated for Cg^H^gClFOg:

C, 60.46; H, 6.62; Cl, 7.76; F, 4.16.

Found: C, 60.26; H, 6.49; Cl, 7.88; F, 4.26.

C. 21- chloro- q- fluoro- 118. 17- dihydroxy- 16a-( 2- mescyclox-ethoxy) pregna- 1, 4- diene~ 3. 20-dione

A solution of 1.5 g of 21-chloro-9-fluoro-11p,17-dihydroxy-16a-(2-hydroxyethoxy)pregna-1,4-diene-3,20-dione in 25 ml of pyridine is cooled to 0°C and 0.6 ml of methanesulfonyl chloride is added. After 2 hours, the mixture is poured onto cold dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried and for- . evaporated in vacuo to 2.0 g of impure mesylate.

D. 21- chloro- q- fluoro- 113- hydroxypregna- l. 4- dieno-£ 16a, 17 - bJf 1, 4_/ dioxane- 3, 20- dione

A solution of 2.0 g of 21-chloro-9-fluoro-11p,17-dihydroxy-16a-(2-mesyloxyethoxy)pregna-1,4-diene-3,20-dione in 100 ml of dimethylsulfoxide is stirred at 110°C under nitrogen with 2.0 g of sodium bicarbonate (dried at 110°C in vacuo). After 1 hour, the suspension is cooled, poured into 2 liters of 2.5% hydrochloric acid and extracted with chloroform. The chloroform solution is washed twice with dilute hydrochloric acid, dried and evaporated in vacuo, and 1.4 g of impure product is obtained. This material is dissolved in chloroform and chrome-autographed on a 100 g silica gel column. Elution with chloroform gives 880 mg of material which crystallizes from methanol-chloro-fonti and gives 4^5 mg of 21-chloro-9-fluoro-11p-hydroxypregna-1,4-dieno/"16a,17-b_7/~1"4_7dioxane -3,20-dione, melting point 320-321°C, cleavage.

Analysis. Calculated for<Cg>^HggClFO^:

c, 62.94; H, 6.43; Cl, 8.08; F, 4.33-Found: C, 62.73; H, 6*20; Cl, 8.27; F, 4.27.

Example 22 lip, 21- Dihydroxypregna-l, 4- dieno/" l6oc, 17-b_//"l, 4_ 7-dioxane- 3^ 20- dione. 21- acetate

A. 16ol - £ 2-( Tetrahydropyran-2- yloxy) ethoxy_/- llp , 17, 21-trihydroxypregna- 1. 4~ diene- 3. 20-dione

A solution of 2-(tetrahydropyran-2-yl)oxy-1-diazoethane (prepared from 69.1 g of N-/"~2-tetrahydropyran-2-yl-oxy)ethyl 7-urea according to the procedure indicated in Example 18 ) in 600 ml of 3:1 ether-pentane is stirred with 200 ml of each of ether and methanol at 0° C. 14 g of HP , l6oc, 17,2l-tetrahydroxy-?pregna-l,4-diene are added in portions 3,20-dione, 16,17-cycloborate. After nitrogen evolution has ceased, the solvents are removed in vacuo and the residue is dissolved in chloroform and chromatographed on a 150 g silica gel column. Elution with chloroform and then 1:1 chloroform-ethyl acetate gives 4 .0 g thin-layer chromatographically pure 16a-/"2-(tetrahydropyran-2-yloxy)ethoxy_7-Hp,17,21-trihydroxypregna-1,4-diene-3,20-dione....

B. l6a-/" 2-(Tetrahydropyran-2- yloxy) ethoxy_ 7- lip, 17, 21-trihdroxvpregna- 1. 4- diene- 3. 20g»dione. 21gacetate A solution of 3.75 g l6a-/~ 2-tetrahydropyran-2-yloxy)-ethoxy_7-lip,17,21-trihydroxypregna-1,4-dien-3,20-dione in 15 ml of pyridine and 5 nyl acetic anhydride is kept at room temperature for 4 hours and then the solvents are evaporated in vacuo The residue is dissolved in chloroform and washed with dilute hydrochloric acid, water, dilute sodium bicarbonate solution and dried. Removal of the solvent gives 4.9 g of impure 16a-[2-(tetrahydropyran-2-yloxy)-ethoxy_7-11p,17, 21-Trihydroxypregna-1,4-diene-3,20-dione, 21-acetate.

C. 16a-(2-Hydroxwetoxy)- 118. 17. 21- trihdroxypregna-1. 4- diene- 3. 20- dione. 21- acetate

A solution of 4.9 g of impure 1,16a-[2-(tetrahydropyran-2-yloxy)etoxy-7-11p,17,21-trihydroxypregna-1,4£diene-3,20-dione, 21-acetate in 60 ml each of acetic acid and water is stirred for 6 hours at room temperature. The solvents are removed in

vacuum and the residue is dissolved in chloroform and washed with 5% sodium bicarbonate solution and dried. Removal of the solvent gives

3.9 g of product which is combined with 75 mg of product from another batch and chromatographed on a 90 g silica gel column. Elution with chloroform and then with 1:1 chloroform-ethyl acetate gives 3.7 g of material which crystallizes from acetone-hexane, and one obtains 3.17 g of 16a-(2-hydroxyethoxy)-11|3,17,21-trihydroxypregna-1 ,4-diene-3,20-dione, 21-acetate, melting point 138-140°C.

D." 16a-(2- Mesvloxvetoxv)- 113, 17. 21- trihvdroxvpregna-1. 4- diene- 3. 20- dione. 21- acetate

A solution of 3.0 g of 16ct-(2-hydroxyethoxy)-116,17,21-trihydroxypregna-1,4-diene-3»20-dione, 21-acetate in 15 ml of pyridine is stirred with 0.75 ml of methanesulfonyl chloride at 0°C for 150 minutes. The mixture is poured into 1.5 liters of cold IN hydrochloric acid, stirred briefly and filtered. The resulting solid is dissolved in chloroform, washed with water, dried and evaporated in vacuo to give 4.0 g of impure 16a-(2-mesyloxyethoxy)-116,15,21-trihydroxypregna-1,4-diene-3, 20-dione, 21-acetate.

E. 116, 21- Dihydroxypregna- l, A- dieno/" l6a, 1 * 1 - b J - f 1, 4_ 7-dioxane- 3, 20- dione, 21- acetate

A solution of 4.0 g of crude 16α-(2-mesyloxyethoxy)-113,17,21-trihydroxypregna-1,4-diene-3,20-dione, 21-acetate in 200 ml of dimethylsulfoxide is stirred at 110°C under nitrogen with 4.0 g of sodium bicarbonate for 2 hours. The suspension is cooled, poured into 2 liters of cold 2.5% hydrochloric acid, and extracted with chloroform (three portions of 250 ml). The chloroform solution is washed with two 1 liter portions of 2</>.5% hydrochloric acid, dried and evaporated in vacuo. The residue is dissolved in chloroform and chromatographed on a 66 g silica gel column. Elution with chloroform gives 2.4 g of material which crystallizes from acetone-hexane, and one obtains 1.55 g of 116,21-dihydroxypropegna-1,4-dieno/" 16a, YJ-bJf 1»4_7dioxane-3,20 -dione, 21-acetate, melting point 280-282°Ci

Examples 23-25

By proceeding as indicated in Example 1, but using the steroid indicated in column I instead. 9-fluoro-118,16a,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate gives the steroid indicated in column II.

Examples 26-28

By proceeding as indicated in Example 15, but using the acid anhydride indicated in column I instead of acetic anhydride, one obtains the steroid indicated in column II.

Examples 29-32

By proceeding as indicated in Example 20, but using the steroid indicated in column I in place of 21-chloro-9-fluoro-116,16a,17-trihydroxypregna-1,4-diene-3,20- dione, 16,17-cycloborate gives the steroid listed in column II.

Examples 33-35

By proceeding as indicated in Example 22, but by using the acid anhydride indicated in column I instead of acetic anhydride, the steroid indicated in column II is obtained.

Example 36

21-chloro-5'-(4-chlorophenyl)-q-fluorine-2'. 3'- dihvdro-d ihvdro- liP- hydroxypregna- 1. 4- dieno/" l6aB17- b 7-£ 1, 4„ 7dioxin- 3, 20- dione

By proceeding as indicated in Example 20, but by using 2-(4-iorphenyl)-3-diazo-1-propene instead of 2-phenyl-3-diazo-1-propene, one obtains 21-chloro -5'-(4-chlorophenyl)-9-fluoro-2', 3'-dihydro-118-hydroxypregna-1,4-dieno/* l6a, YJ- bJ£ 1,4_7dioxin-3,20-dione, m.p. 212-214°C, cleavage, softening at 200°C.

Example 37

21- Chloro- 5'-( 1. 1- dimethylethyl)- q- fluoro- 2'. 3'-dihydro-IIB-hydroxypregna-l, 4-dieno/" l6a, 17°bm7° £1,4„7dioxin-3,20-di ion. By proceeding as indicated in Example 7"but by using 2-(1,1-dimethylethyl)-3-diazo-1-propene instead of methyl-3-diazo-1-propene, one obtains 21-chloro-5'-(1,1-dimethylethyl)-9- fluoro-2',3"-dihydro-11p-hydroxypre<g>na-1,4-di eno/"16a,17-b_7-t194„7dioxin-3,20-dione, melting point 240-2j£2°C, cleavage..

Example 38

q- Fluoro- 118. 21- dihvdroxy-' 5t5°metYlpregn- 4- eno-/" 16a, 17- b_ 7^ 1, 4, 7dioxane- 3, 20- dione, 2l- acetate

A. q- Fluorine- llB. 17. 21- trihvdroxv- l6g-( 2£- hydroxyvpro-pbcsy) pregn- 4- en- 3. 20- dione, 2l- acetate A solution of l,o g 9-fluoro-llp,17,2l-trihydroxy-16a -(2-oxopropoxy)pregn-4-ene-3,20-dione, 21-acetate (prepared as indicated in Example 2D) in 80 ml of methanol is cooled to 0°C and 80 mg of sodium borohydride is added. After 10 minutes, pour

the solution into chloroform and extracted with dilute hydrochloric acid. The chloroform solution is dried and evaporated in a vacuum, and impure product is obtained. Chromatography on a 30 g silica gel column, eluting with 9:1 chloroform-ethyl acetate gives 73 mg of the final product.

B. q- Fluorine- HB. 17. 21- trihydroxy- 16a-( 2^- mesvoloxy- propoxy) pregn- 4- ene- 3. 20-dione. 21- acetate

A solution of 700 mg of 9-fluoro-116,17,21-trihydroxy-16a-(2|-hydroxypropoxy)pregn-4-ene-3,20-dione, 21-acetate in 10 ml of pyridine is cooled to 0°C and 0.4 ml of methanesulfonyl chloride is added. After an extra 4 hours, the mixture is stirred, dried and evaporated, and the final product is obtained.

C. 9- Fluorine- ll6. 21- dihydroxyv-' 5tf-- methylpregn- 4- eno-/" l6a, 17 - b _ 7l ~ 1, 4_ 7dioxane- 3, 20- dione, 21- acetate

A solution of 750 mg of 9-fluoro-llp,17,21-trihydroxy-16a-(2|-mesyloxypropoxy)pregn-4-ene-3,20-dione, 21-acetate in 50 ml of dimethylsulfoxide is stirred at 110°C under nitrogen with 1.0 g of sodium bicarbonate. After 2 hours, the reaction mixture is extracted, dried and evaporated, and the final product is obtained.

Example 39

9- Fluorine- llp. 21- dihydroxy- 5,| - phenylpregn- 4- eno-/" 16a, 17- b, 7 [ 1, 4^ 7dioxane- 3, 20- dione, 21- acetate

A. 9- Fluorine- ll6. 17. 21- trihydroxy- 16a-( 2- phenyl- 2-hydroxyethoxy) pregn- 4- ene- 3. 20- dione, 21- acetate A solution of 1.0 g of 9-fluoro-llp,17,21-trihydroxy -16a-(2-phenyl-2-oxoethoxy)pregn-4-ene-3,20'dione, 21-acetate (prepared as indicated in Example 4D) in 80 ml of methanol is cooled to 0°C and 80 mg of sodium borohydride is added. After 10 minutes, the solution is poured into chloroform and extracted with dilute hydrochloric acid. The chloroform solution is dried and evaporated in a vacuum, and the final product is obtained.

B. 9~ Fluoro- 116. 17. 21- trihdroxv- 16a-( 2- mesyloxy- 2-phenylethoxv) pregn- 4- ene- 3. 20- dione. 21- acetate

A solution of 700 mg of 9-fluoro-lip,17,21-trihydroxy-16a-(2-phenyl1^2-hydroxyethoxy)pregn-4-ene-3,20-dione,. 21-acetate in 10 ml of pyridine is cooled to 0°C and 0.4 ml of methanesulfonyl chloride is added. After 4 hours, the mixture is extracted, dried and evaporated, and the final product is obtained.

C. 9- Fluoro- 116. 21- dihydroxyv- 5' g- phenvlpregn- 4- en-/" I6a. l7- b 7/" l. d 7dioxan- 3. 20- dione. 21- acetate

A solution of 750 mg of 9-fluoro-llp,17,21-trihydroxy-16a-(2-mesyloxy-2-phenylethoxy)pregn-4-ene-3,20-dione, 21-acetate in

50 ml of dimethylsulfoxide is stirred at 110°C under nitrogen with

1.0 g sodium bicarbonate. After 2 hours, the reaction mixture is extracted, dried and evaporated, and the final product is obtained.

Example 4- 0

2l- Chlor- Q- f luor- 118- hvdroksv- 5' - met vl- 4' ^ fenvl-pregna- 1, 4- dieno/" 16a, VJ - bJC 1, 4_ 7dioksln- 3, 20- dione

A. 21- Chloro- 9- fluoro- llp, 17- dihydroxy- 16a-/"( 3- oxo- 3- phenylprop- 2- yl) oxy_ 7pregna- l, 4- ?- diene- 3, 20-dione a. N-/' 2-(3-oxo-3-phenylpropyl)_7phthalimide A solution of 58 g of α-bromopropiophenone and 50 g of potassium β-phthalimide in 200 ml of dimethylformamide is heated under reflux for 2 hours under nitrogen, cooled and poured into 500 ml of water.

The resulting mixture is extracted with ether, the ether solution is dried and evaporated in vacuo. A solution of the residue in 200 ml of ether gives the final product as a solid.

b. 2-/"1-(N-phthalimidoethyl)_7-2-phenyldioxolane A solution of 49.9 g of N-/"2-(3-oxo-3-phenylpropyl)"7-phthalimide in 500 ml of toluene is heated under reflux for 13 days with 5 g of p-toluenesulfonic acid and 150 ml of ethylene glycol. The solution is cooled, diluted with chloroform and washed with dilute sodium bicarbonate solution. The chloroform solution is dried and evaporated, and trituration with ether gives 51.5 g of the final product, melting point 127-130°C.

c. 2-(1-Aminoethyl)-2-phenyldioxolane

A solution of 51.5 g of 2-(N-phthalimidoethyl)-7-2-phenyldioxolane in 500 ml of methanol is heated under reflux for 6 hours with 5.7 g of hydrazine. The suspension is cooled, filtered and the solid is washed well with methanol. The filtrate is evaporated in vacuo, and the residue is triturated with dichloromethane and filtered. The filtrate is distilled in vacuo to give 28.25 g of the final product, boiling point 97-100°C at 1.1 mm Hg.

d. 2- Phenyl-2-(1-ethoxycarbonylaminoethyl)dioxolane

A solution of 2-(1-aminoethyl)-2-phenyldioxolane (20 mmol), triethylamine (24 mmol) and ethyl chloroformate (22 mmol) in 100 ml

dichloromethane is dried at 0°C for 2 hours, washed with water, dried and evaporated, and the final product is obtained.

e. 2-Phenyl-2-(2-diazoethyl)dioxolane

By proceeding as in Example 4A (parts c and d); but by using 2-phenyl-2-(1-ethoxycarbonylaminoethyl)dioxolane instead of N-(2-phenyl-2-propenyl)ethylcarbamate you get the final product.....

f. 21- Chloro- q- fluoro- llp, 17- dihydroxy- l6tt-/"( 3-oxo- 3- phenylprop- 2- yl) oxy_ 7pregna- l, 4- diene-3. 20- dione

A solution of 2-phenyl-2-(1-diazoethyl)dioxolane i

312 ether-pentane is diluted with methanol and cooled to 0°C. 21-Chloro-9-fluoro-11p,16a,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo.

The residue is purified and dissolved in tetrahydrofuran. The solution is heated under reflux with hydrochloric acid. The solvent is removed in vacuo and the residue is diluted with water, extracted with chloroform, and the chloroform solution is washed with 5% sodium bicarbonate solution, water, dried and evaporated, and the final product is obtained.

B. 21- Chlor- q^- f luor- llB- hvdroxy- 5' - metvl- 4' - f enylpr egna-l,4-dieno/"l6cc,17-b_7/~l»4 7dioxin-3,20 -dion

A suspension of 150 mg of p-toluenesulfonic acid in 750 ml of benzene is stirred with a Déan-Stark trap. The first 150 ml of the azeotropic mixture benzene-water is discarded and it is added to the trap molsiles of the type Linde 4A« After 30 minutes of reflux, the solution is cooled and 1.0 g of 21-chloro-9-fluoro-llp is added *17 -dihydroxy-16a-/" (3-oxo-3-phenyl-prop-2-yl)oxy_7pregna-1,4-dien-3,20-diOH. The mixture is heated, under reflux for 6 hours under nitrogen, cooled, washed with 5% sodium bicarbonate solution, water, dried and evaporated in vacuum, and the final product is obtained.

Claims (1)

1. Steroid of the general formula and 1,2-dehydro and 6,7-dehydro derivatives thereof, where Z is hydrogen, hydroxyl, acyloxy or halogen; Y means hydrogen and Y <T> means hydroxyl, or T and I' together mean =0; X means hydrogen or halogen; P represents hydrogen, methyl or chlorine; Q means hydrogen, methyl or fluorine; and Ag means <R>1-O=CH2 ; means hydrogen, alkyl or aryl; R 8 means alkyl or aryl Ry means alkyl or arylalkyl. 2. Steroid of the formula and 1,2-dehydro and 6,7-dehydro derivatives thereof, where Z is hydrogen, hydroxyl, acyloxy or halogen; Y means hydrogen and Y <»> means hydroxyl, or Y and Y <1> together mean =0; X means hydrogen or halogen; P represents hydrogen, methyl or chlorine; Q represents hydrogen, methyl or fluorine; means R4 •- ' 0 * ■ -Cfo-alkyl),, or -C-R^; and R 1 and R 2 are the same or different and mean alkyl or aryl. 3. Process for the preparation of the 3" 20 - diketo" pregnene which contains an HB-hydroxy or an 11-keto group and which in the 16- and 17-positions is condensed with a 1,4-dioxane or 1,4 - dioxin ring, characterized by cyclizing the corresponding steroid which contains a hydroxy group in the 17-position and 16-hydroxy group which has an oxo, acetal or methanesulfonyl group on the beta carbon atom. 4. Procedure as stated in claim 3" character sert by that a steroid of the formula and 1,2-dehydro and 6,7-dehydro derivatives thereof, where Z means hydrogen, hydroxyl, acyloxy or halogen; Y means hydrogen and Y' means hydroxyl, or I and Y' together mean =0; X means hydrogen or halogen; P represents hydrogen, methyl or chlorine; Q represents hydrogen, methyl or fluorine; and B-a and ©r are the same or different and represent hydrogen, alkyl or aryl, are treated with an acid catalyst to produce a product of the formula 5. Method as stated in claim 3" characterized in that a steroid of the formula and 1,2-dehydro and 6,7-dehydro derivatives thereof, where Z is hydrogen, hydroxyl, acyloxy or halogen; Y means hydrogen and Y <*> means hydroxyl or Y and Y <*> together means f =0; X means hydrogen or halogen; P represents hydrogen, methyl or chlorine; Z means hydrogen, methyl or fluorine; and fU means alkyl or aralkyl, is treated with an acid to produce a product of the formula wherein R| means hydrogen, alkyl or aralkyl. 6. Method as stated in claim 4" characterized in that the product is dehydrated for production of a product of the formula 7» Method as stated in claim 5 and/or 6, characterized in that R'y is hydrogen. 8. Method as stated in claim 3" characterized in that a steroid of the formula And 1,2-dehydro and 6,7-dehydro derivatives thereof, where Z means hydrogen, hydroxyl, acyloxy or halogen; Y means hydrogen and Y <*> means hydroxyl or Y and Y <»> together means a0; X means hydrogen or halogen; P represents hydrogen, methyl or chlorine; Z represents hydrogen, methyl or fluorine; and R^ and R^ are the same or different and mean alkyl or aryl, is subjected to acid treatment to produce a product with the formula 9" Process as stated in claim 8, characterized in that the starting material is subjected to subsequent treatments with a mineral acid and an organic acid . 10. Method as stated in claim 3 for the production of a steroid of the formula and 1,2-dehydro and 6,7-dehydro derivatives thereof, where Z is hydrogen, hydroxyl, acyloxy or halogen; Y^ is hydrogen and Y <*> is hydroxyl or Y and Y' together mean =0; X is hydrogen or halogen; P is hydrogen, methyl or chlorine; Q is hydrogen, methyl or fluorine; and is hydrogen, alkyl or aryl, characterized by treating a steroid of the formula with sodium bicarbonate in a dipolar aprotic solvent. 11. Process for the preparation of a steroid of the formula and 1,2-dehydro and 6,7-dehydro derivatives thereof, where Z is hydrogen, hydroxyl, acyloxy or halogen; Y is hydrogen and Y<*> is hydroxyl or Y and Yf together mean =0; X is hydrogen or halogen; P is hydrogen, methyl, or chlorine; Q is hydrogen, methyl or fluorine; characterized by oxidizing a steroid of the formula with Feti2 on's reagent. 12. Process for the preparation of a steroid of the formula and 1,2-dehydro and 6,7-dehydro derivatives thereof, where Z is hydrogen, hydroxyl, acyloxy or halogen; Y is hydrogen and Y' is hydroxyl or Y and Y <*> together means =0; X is hydrogen or halogen; P is hydrogen, methyl or chlorine; Q is hydrogen, methyl or fluorine; and is alkyl, cycloalkyl or aryl, characterized by acylating a steroid of the formula with a - acyl group. 13. Method as specified in claims 3 to 12, characterized in that X means fluorine.-14* Method as specified in claims 3 to 12, characterized in that Z means hydroxyl. 15. Process as stated in claims 3 to 12, characterized in that Z is equal to acyloxy. l6* Method as specified in claims 3 to 12, characterized in that Z is halogen. ■ 17. Process as stated in claims 3 to 12, characterized in that Z is chlorine. 18. Process as set forth in claims 3 to 12, characterized in that the product is 9-fluoro-5'i|,116,21-trihydroxypregn-4-eno-/"16a,17-b_7/"1,4.7 dioxane 3,20-dione, 21-acetate. 19. Process as stated in claims 3, "to 12, characterized in that the product is 9-fluoro-2',3'-dihydro-116,2 1-dih <y>d rox <y->5 '-met < y>l - <p> re <g> n-4 -eno/~ <l6> a,1 7- bJ/ <f> 1,4.7-dioxin-3p20-dione, 21-acetate. 20. Process as stated in claims 3 to 12, characterized in that the product is 9-fluoro-2',3'-dihydro-11p,21-dihydroxypregn-4-eno/"16a,17-b_7Z""1,4" 7dioxin- 3,20-dione. 21. Process as stated in claims 3 to 12, characterized in that the product is 21-chloro-9-fluoro-2',3'-dihydro-11B-hydroxy-5'-methylpregna-1,4-dieno/"16a, 17-b„7-C1 * 4-7dioxin-3,20-dione. 22. Method as stated in claims 3 to 12, characterized in that the product is 5'5-ethoxy-9-fluoro-118,21-dihydroxypregn-4-eno-/"16a, IJ-bJf 1,4_7dioxane-3,20 -dion. 23. Method as stated in claims 3 to 12, characterized in that the product is 21-chloro-5, |-one oxy-9-fluoro-116-hydroxypregn-4-eno-/"16a,17-D.7Z" 1 ,4_7dioxane-3,20-dione. 24. Method as stated in claims 3 to 12, characterized in that the product is 9-fluoro-5'|» 116, 21-trihydroxypregn-4-eno-/~16a,17-b»7Z "1,4_7dioxane~3»20-dione. 25. Method as stated in claims 3 to 12, characterized in that the product is 9-fluoro-5 <f> g„116, 21-rtrihydroxypregn-4-eno-/" 16a, Vl-bjf 1,4_7dioxane-3,20 -dione, 5',21-diacetate. 26* Process as set forth in claims 3 to 12, characterized in that the product is 21-chloro-9-fluoro-5'5-dihydroxypregna-1,4-dieno-/"16a,17-b_7/"1» 4„7dioxane-3,20-dione. 27* Process as stated in claims 3 to 12, characterized in that the product is 21-chloro-9-fluoro-5 <*>fi 11B-dihydroxypregna-1,4-dieno-/'"16a,17-b_7/" 1,4-7 dioxane-3,20-dione,5'-acetate. 28. Method as stated in claims 3 to 12, characterized in that the product is 21-chloro-9-fluoro-2*,3*-dihydro-11p-hydroxy-pregna-1,4-disno/ 9 2'^'-dihydro-lie-hydroxy-pregna-1,4-dieno/"1$a,17-b„.7Z"l» 4,»7-dioxin-3,20-dione. 29» Method as specified in claims 3 to 12, characterized in that the product is 9-fluoro-116,21-dihydroxypregn-4-eno/"16a, VJ-bJ <f> fl ,4_7dioxan-3,5'" 20-trione, 21-acetate. 30. Process as stated in claims 3 to 12, characterized in that the product is 21-chloro-9-fluoro-2', 3-dihydro-11B-hydroxy-5'-phenyl-pregna-1,4-dieno/" " 16a, 17-b7* f 1,4_7dioxin-3,20-dione. 31. Method as stated in claims 3 to 12, characterized in that the product is 21-chloro-9~ fluoro-116-hydroxypregna-1,4-dieno-/~16a,17-b_7/"1"4_7dioxane-3, 20-dione. 32. Process as stated in claims 3 to 12, characterized in that the product is 116,21-dihydroxypregna-1,4-dieno/~16a, VJ-bJf 1,4_7dioxane-3,2O-dione, 21-acetate. 33» Method as set forth in claims 3 to 12, characterized in that the product is 21-chloro-5'-(4-chlorophenyl)-9-fluoro-2',3'-dihydro-11B-hydroxypregna-1,4 -dieno-l" l6a, 17-b_7Z"l, 4-7<iioxin-3,20-dione. 34« Process as stated in claims 3 to 12, characterized in that the product is 21-chloro-5'-(1,1-dimethylethyl-9-fluoro-2',3'-dihydro-118-hydroxypregna-1,4 -dieno/~l6ct, If- bjfl, 4_7dioxin-3,20-dione. 35» Method for producing a steroid of the formula and 1,2-dehydro and 6,7-dehydro derivatives thereof, where Z is hydrogen, hydroxyl, acyloxy or halogen; Y is hydrogen and Yf is hydroxyl or Y and Y <»> together means =0; X is hydrogen or halogen; P is hydrogen, methyl or chlorine; Q is hydrogen, methyl 10 or fluorine; and is hydrogen, alkyl or aryl, characterized by converting a steroid of the formula with a diazoalkene of the formula 36. Method as stated in claim 35, characterized in that the product is reacted with sulfuric acid to produce a product of the formula 37° Procedure as stated in requirement J0t ka rakte. -' r i s e r t in that the peracid is m-chloroperbenzoic acid* 38. Process as stated in claims 36 and 37" characterized in that the product is treated with a strong oxidizing agent to produce a product of the formula 39* Method as stated in claim 38, character, e° r i s e r t in that the oxidizing agent is periodic acid. 4-Oi Method for producing a steroid of the formula ^g 1,2-dehydro- and 6,7-dehydro derivatives thereof, where Z is hydrogen, hydroxyl, acyloxy or halogen; Y is hydrogen and Y' is hydroxyl„ or Y and Y <*> together means =0; X is hydrogen or halogen; P is hydrogen, methyl or chlorine; Q is hydrogen, methyl or fluorine; and R]_, is hydrogen, alkyl or aryl, characterized by subjecting a steroid of the formula a borohydride reduction. 41» Method as stated in claim ^(.characterized in that the borohydride is sodium borohydride* 42. Method as stated in claim 40 and 41» k a r a k - in that the product is reacted with a methanesulfonyl halide to produce a product of the formula 43» Process for the preparation of a steroid of the formula and lp2-dehydro and 6,7-dehydro derivatives thereof, where Z is hydrogen, hydroxyl, acyloxy or halogen; Y is hydrogen and Y1 is hydroxyl, or Y and Y" together mean =0; X is hydrogen or halogen; P is hydrogen, methyl or chlorine; 0 is hydrogen, methyl or fluorine; R 1 is hydrogen, alkyl or aryl; and Ry is alkyl”? or aralkyl, characterized by converting a steroid of the formula with a diazoether of the formula 44" Method as stated in claim 43" characterized in that PL is hydrogen. 45" Method as stated in claim 43" characterized in that Ry is alkyl and R^ is alkyl or aryl.