DE1122951B - Process for the preparation of 21-í¸-cis-tetrahydrophthalic acid half-esters of 3,20-dioxo-21-hydroxy-pregnane compounds unsaturated in ring A. - Google Patents

Description

The present invention relates to a process for the preparation of the 21-half esters of therapeutically active 3,20-dioxo-21-hydroxy-pregnane compounds with / l ⁴ -cis-tetrahydrophthalic acid which are unsaturated in the A ring.

The 21-hemitetrahydrophthalates are of particular importance of deoxycorticosterone, cortisone, hydrocortisone, 9-fluorocortisone, 9-fluoro-hydrocortisone, Aldosterone, 1-dehydro-cortisone, 1-dehydrohydrocortisone, l-dehydro-9 \ -fluoro-hydrocortisone and -cortisone, 1-dehydro-9 \ -fluoro-16 \ -hydroxy-hydrocortisone and -cortisone, 1-dehydro-6 "-methyl-hydrocortisone and -cortisone, 1-dehydro-6" -chlor- and -o-v-fluoro-hydrocortisone and -cortisone, 1-dehydro-9 \ -fluoro-16 \ -methyl- and -16 / 3-methyl-hydrocortisone and cortisone and 1-dehydro-aldosterone too. These new esters have a high level of adrenal hormone activity and are useful in the treatment of numerous pathological conditions, including those that require anti-inflammatory therapy or even life-sustaining treatment in the event of failure symptoms require. A particular advantage of the process products is that they with organic or inorganic bases reacting neutrally, relatively stable aqueous solutions of the corresponding salts and can therefore be applied in aqueous solution.

The esters of the invention are obtained when 1 ⁴ -cis-tetrahydrophthalic acid of the formula

COOH

COOH

or their functional derivatives, such as halides, esters, anhydrides or salts, which are known per se Way with in ring A unsaturated 3,20-dioxo-21-hydroxy-pregnane compounds or their reactive functional 21 derivatives, in particular Halides, in the presence or absence of diluents and / or condensation agents and the obtained 21-hemitetrahydrophthalates optionally converted into their salts in a likewise known manner.

To obtain the salts, the 21-half esters are used in a manner known per se, e.g. B. with alkali metal hydroxides, carbonates, bicarbonates, in particular with sodium bicarbonate, and also with organic Bases such as ethanolamine, diethanolamine, triethanolamine, Dibenzylethylenediamine, ephedrine, or l-phenyl-2-methyl-aminopropane implemented.

Method of manufacture

of 2 lJ ^4- cis-tetrahydrophthalic acid half-ester of 3,20-dioxo unsaturated in ring A

21-hydroxy pregnane compounds

Applicant:
CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36, Neuer Wall 10

Claimed priority:

Switzerland of March 28th (No. 57 620)

and July 11, 1958 (No. 61 635)

Dr. Albert Wettstein and Dr. Ludwig Ehmann,

Basel, Switzerland),
have been named as inventors

The 3,20-dioxo-21-hydroxy-pregnane compounds used as starting materials and unsaturated in ring A are known or are prepared by methods known per se. 16 «-Alkyl-20-oxopregnane compounds can be obtained by treating / l ^le -20-oxo-pregnenverbindungen with alkylmagnesium halides in the presence of copper (I) halides, advantageously in the presence of tetrahydrofuran and in the absence of alkyl halide, and decomposition of the 20- Metal enolates can be obtained. If one also wishes to introduce a 17'-hydroxyl group, it is expedient to treat the 20-metal enolates obtained in the above-mentioned alkylation with an acylating agent, such as an acid anhydride or halide, and the products thus obtained are oxidized with an organic peracid; the na-hydroxy-loa-methyl-pregnan-20-ketones are formed by hydrolysis. In these compounds, double bonds z. B. introduced in 4 (5) - and / or 1 (2) -position, a double bond in 9 (11) -position from compounds substituted by a hydroxyl group in lla-position according to known methods and finally in 3-position a Zl ⁴ -3-keto group and, if it

209 507/343

wishes a halohydrin group in 9λ, 1 1 / S position to be introduced. According to these methods you can, for. B. the highly effective 16 "-Methyl-9" -fluoro-prednisolone produce.

Compounds with a halogen substituent in the 6-position, such as the 6 *, 9 <% - difluoro-16ix-methylprednisolone, can e.g. B. can be obtained by using compounds of the formula

CH ₂ - Ri

OH

in which R _{1 denotes} a free or esterified hydroxyl group, X denotes hydrogen or 1 chlorine or fluorine atom, Y 2 denotes hydrogen atoms, an oxo group or hydrogen and a free or esterified hydroxyl group, R ₂ denotes hydrogen, a free or esterified hydroxyl group or an alkyl group, and the have a free or ketalized oxo group in the 3- and / or 20-position, treated with hydrochloric or hydrofluoric acid or an agent releasing them, converted ketalized oxo groups in the 3- or 3.20-position into free oxo groups, resulting 5 <x -Hydroxy-6 /? - chlorine and 5 "-Hydroxy-6 /? - fiuor compounds dehydrated, zl ⁴ -3-oxo-6ß-chloro- and / J ⁴ -3-oxo-6i3-fiuorpregnene in 6- Position isomerized by treatment with mineral acid, the compounds obtained are optionally dehydrated in the 1 (2) position and esterified hydroxy groups are hydrolysed or free hydroxy groups are esterified and / or 11-hydroxy compounds are dehydrogenated to 11-oxo compounds. The 5,6-epoxides to be used can be prepared from js.e. compounds by treatment with an organic peracid.

The process according to the invention is described in more detail in the following examples. The temperatures are given in degrees Celsius.

example 1

7.2 g of 1-dehydrocortisone and 6.0 g of tetrahydrophthalic anhydride are dissolved in 50 cm ^{3 of} pyridine and left to stand under nitrogen at room temperature. After 70 to 80 hours, free ketol can no longer be detected with blue tetrazole and sodium hydroxide solution in the cold. The reaction solution is then ^{poured onto 1000 cm 3 of an} ice-water mixture (1: 1). It is acidified with dilute hydrochloric acid, whereupon the reaction product precipitates. The precipitate is extracted with a chloroform-tetrahydrofuran mixture (3: 2) and the extract is first washed several times with dilute hydrochloric acid and finally with water. The acidic reaction products are now exhausted exhaustively with cold, dilute sodium bicarbonate solution, which contains a little saturated soda solution, and separated from existing components. The sodium bicarbonate extracts, filtered blank, are acidified with dilute hydrochloric acid. The precipitated reaction product is filtered off with suction, washed thoroughly with water and dried. 8.3 g of 1-dehydrocortisone-21-hemitetrahydrophthalate are obtained: mp 189 ° to 191 °; Md + 146.3 ° (c = 1 ° / o..in dioxane); k _max (fine spirit) 240 πιμ, ε = 15 350; Equivalent weight (titration): 513. With blue tetrazole and sodium hydroxide solution, the product does not immediately turn blue in the cold. For the preparation of the water-soluble sodium salt of 1-dehydro-cortisone-21 -hemitetrahydrophthalates

ίο 2.05 g of l-dehydrocortisone-21-hemitetrahydrophthalate are dissolved in 20 cm ^{3 of} fine spirits; ^{40 cm 3 of} 0.1 N sodium hydroxide solution are then added while cooling with ice. The solution is filtered blank and lyophilized. 2.16 g of the sodium salt of 1-dehydrocortisone-21-hemitetrahydrophthalate are obtained. The pH of the 2.5% aqueous solution is 6.3, measured with Lyphan paper No. 670. The sodium salt of 1-dehydrocortisone-21-hemitetrahydrophthalates gives with methanolic blue tetrazole and double normal sodium

Ao lye does not immediately turn blue in the cold.

In an analogous manner, 1-dehydro-

cortisone 21 hemitetrahydrophthalate and triethanolamine the water-soluble triethanolamine salt of l-dehydro-cortisone-21-hemitetrahydrophthalates.

Example 2

7.2 g of 1-dehydro-hydrocortisone and 6.0 g of tetrahydrophthalic anhydride are dissolved in 50 cm ^{3 of} pyridine and heated on the boiling water bath under nitrogen for 30 minutes. The cooled reaction solution, which with blue tetrazole and sodium hydroxide solution no longer turns blue in the cold, is then introduced into 1000 cm ^{3 of} an ice-water mixture (1: 1) and acidified to Congo with dilute hydrochloric acid. The reaction product which precipitates out is extracted with ethyl acetate and the ethyl acetate extract is washed first with dilute hydrochloric acid and then with water. The acidic reaction products are exhaustively extracted with ice-cold dilute sodium bicarbonate solution, which contains a little soda solution, and separated from the neutral components. The sodium bicarbonate extracts are acidified with dilute hydrochloric acid and the precipitated product is taken up in ethyl acetate. The ethyl acetate solution is washed free of hydrochloric acid, dried, filtered and concentrated, 1-dehydro-hydrocortisone-21-hemitetrahydrophthalate crystallizing out: Yield = 7.55 g, melting point 233 ° to 234 °; [x] T + 84 ± 3 ° (c = 1 ° / ₀ in dioxane); X _m ax (fine spirit) 244 πιμ,

ε = 15200; Equivalent weight (titration): 503. The product is in with blue tetrazole and sodium hydroxide solution the cold no immediately appearing blue discoloration.

To produce the water-soluble sodium salt of 1-dehydro-hydrocortisone-21-hemitetrahydrophthalate, 2.05 g of 1-dehydro-hydrocortisone hemitetrahydrophthalate, dissolved in 20 cm ^{3 of} fine spirits, are admixed with 40 cm ^{3 of} 0.1 ln sodium hydroxide solution while cooling with ice. The clear filtered solution is lyophilized.

2.16 g of the sodium salt of 1-dehydro-hydrocortisone-21-hemitetrahydrophthalate are obtained. The pn of 2.5% strength aqueous solution of ^e n is 6.9, as measured by Lyphan-paper no. 670. The sodium salt of l-dehydro-hydrocortisone 21 are -hemitetrahydrophthalates with methanolic Blautetrazol and 2N sodium hydroxide solution is no immediate blue colouration .

In an analogous manner, 1-dehydro-hydrocortisone-21-hemitetrahydrophthalate is obtained and diethano-

5 6

amine the diethanolamine salt of the 1-dehydro-hydro product gives with blue tetrazole and sodium hydroxide solution in

cortisone-21-tetrahydrophthalates. the cold does not immediately turn blue.

Example 3 Example 5

100.0 g of 1-dehydro-hydrocortisone and 83.5 g of tetra-5 7.9 g of l-dehydro-fluorohydrocortisone and 6.0 g

hydrophthalic anhydride are dissolved in 695 cm ^{3 of} pyridine tetrahydrophthalic anhydride in 70 cm ³

dissolved and lutidine in a nitrogen atmosphere at 20 to 25 °, 85 hours under nitrogen at 20

left to stand for 72 hours, after which it is allowed to stand at up to 25 °, after which no free ketol means

Blue tetrazole and caustic soda in the cold no more free blue tetrazole and caustic soda in the cold

Ketol can be detected more. The reaction solution io can be detected. The work-up takes place

is stirred in 12 l of an ice-water mixture according to Example 4 and gives 8.3 g of l-dehydro-9 «-fluor-

(approx. 1: 1) entered and with 835 cm ^{3 of} concen-hydrocortisone-21-hemitetrahydrophthalate: mp. 195 bis

trated hydrochloric acid, dissolved in 21% water, Congo acidic 203 °; X _max (fine spirit) 243 ηιμ, ε = 15,300; Equi-

posed. The precipitated reaction weight (titration): 515 is extracted. The product is added

products with a total of 8 liters of a chloroform-tetra- * 5 blue tetrazole and sodium hydroxide solution in the cold, none

hydrofuran mixture (3: 2) and washes the extracts instant blue color,

first with dilute hydrochloric acid and then with. .

Water. The acidic reaction products are now an example

using dilute, ice-cold sodium bicarbonate solution, 3.94 g of 1-dehydro ^ ic-fluoro-10-hydroxide, which contains a little soda solution, are dissolved, separated from the 2 ° hydrocortisone and 3.0 g of tetrahydrophthalic acid neutrals. The sodium bicarbonate extracts, filtered with a little anhydride in 50 cm ^{3 of} pyridine and left blank for 65 hours on filter asbestos, stand at 20 to 21 ° under nitrogen; then you can acidify with stirring. The precipitated react blue tetrazole and sodium hydroxide solution in the cold no free ion product is sucked off, with water thoroughly ketol can be detected. The reaction Washed and dried in vacuo at 40 to 50 ° overall ² 5 ³ solution of ice-water is poured into 500 cm, with desiccated. The yield is 133.1 g of 1-dehydrated hydrochloric acid acidified to Congo blue and extracted with hydrocortisone-21 -hemitetrahydrophthalate, the amor-chloroform-tetrahydrofuran mixture (3: 2) exhausted product compared to the crystallized fend. After the chloroform tetra-ester (cf. Example 1) has a much lower melting point: hydrofuran extract with dilute hydrochloric acid pyridine melting point. 145 to 150 °; [x] l ° ^o -j-86.9 ± 3 ° ( _c = 0.5 ° / ₀ in 30 has washed free, the acidic reaction is dioxane); Ej ^% 244 ηιμ (fine spirit) = 294; Equi-products with dilute sodium bicarbonate solution, valent weight (titration): 512. The product, with the slightly dilute soda solution added, does not extract blue tetrazole and sodium hydroxide solution in the cold. The alkaline extracts turn blue immediately after they appear. evaporate the solvent residues in a vacuum

For the preparation of the water-soluble sodium salt 35 room temperature with the help of something

des 1 - dehydro - hydrocortisone - 21 - hemitetrahydro - decolorizing carbon and filter asbestos filtered blank. Man

phthalates dissolve 2.05 g of 1-dehydro-hydrocortisone acidified with dilute hydrochloric acid, suck out the

21-hemitetrahydrophthalate in 30 cm ^{3 of} fine spirits and precipitated reaction product, wash it off with plenty

^{gives 40 cm 3 of} 0.1 N sodium bicarbonate water while cooling with ice and dries it in a vacuum

solution added. The clear, filtered solution becomes lyophilic 40 40 to 50 °. 4.5 g of l-dehydro-9 «-fluor-

sated. 2.1 g of the sodium salt of 1-dehydro-16 "-hydroxy-hydrocortisone-21-hemitetrahydrophtha-

hydrocortisone-21-hemitetrahydrophthalates. The profile. F. 145 to 150 °; K _max (fine spirit) 299 ηιμ,

The product is easily soluble in water. ε = 15,000; Equivalent weight (titration): 541.

_. . . ,. .. Example 7

Example 4 ⁴ S ^F

3.7 g of l-dehydro-6x-methyl-hydrocortisone and 3.0 g

A solution of 7.9 g of l-dehydro-9x-fluorocortisone tetrahydrophthalic anhydride in 50 cm ³ and 6.0 g of tetrahydrophthalic anhydride in 50 cm ^{3 of} pyridine are left to stand at room temperature for 65 hours at 20 ° to 25 ° under nitrogen . The reaction is then poured for 72 hours, after which with blue tetrazole and 50 solution on 600 cm ^{3 of an} ice-water mixture (1: 1), sodium hydroxide solution is not acidified in the cold with dilute hydrochloric acid and extracted with a blue coloration is to be observed. To the chloroform-tetrahydrofuran mixture (3: 2). The Ex work-up is the reaction solution to 1000 cm ³ tract is first discharged with dilute hydrochloric acid pyridine-ice-water mixture (1: 1), washed with free and then made Congo acidic with dilute sodium hydrochloric acid and with chlorobicarbonate solution, which Contains some soda, exhaustively extracted form-tetrahydrofuran mixture (3: 2). The undressed. The alkaline extracts are degassed, the extract is first washed with dilute saline, filtered and acidified with dilute hydrochloric acid and water; then one pulls the acidic reactivates. The precipitated reaction product is suctioned off with dilute sodium bicarbonate, washed thoroughly with water and the solution, which is mixed with some soda solution, is dried from 60 ° in a vacuum at 40 to 50 °. The yield reaches and separates it from any neutral components present. 4.2 g of l-dehydro-OÄ-methyl-hydrocortisone ^ l-hemi-The plain filtered sodium bicarbonate extracts tetrahydrophthalate. 180 to 185 °; X _max (fine spirits) are acidified with dilute hydrochloric acid, the aus- 244 ηιμ, ε = 15,620; Equivalent weight (titration): precipitated reaction product filtered off with suction, with water 513.

thoroughly washed and dried. 65 Example 8 are obtained
8.2 g l-dehydro ^ x-fluorocortisone ^ l-hemitetrahydro-

phthalate: mp 195-200 °; X _max (fine spirit) 243 ηιμ, 7.9 g of l-dehydro-oa-chlorohydrocortisone and 6.1 g

ε = 15200; Equivalent weight (titration): 521. The tetrahydrophthalic anhydride are in 75cm ³

Dissolved pyridine and left to stand for 70 hours at 20 to 25 ° under nitrogen, after which the reaction to free ketol with blue tetrazole and sodium hydroxide solution is negative in the cold. The reaction solution is poured into 1500 cm ^{3 of an} ice-water mixture (1: 1) and made Congo acidic with dilute hydrochloric acid. The precipitated reaction product is taken up in ethyl acetate. The ethyl acetate extract is first washed free of pyridine with dilute hydrochloric acid and water, then the acidic reaction products are shaken out with dilute, cold sodium bicarbonate solution which contains a little soda. The alkaline extracts are degassed in the cold, then filtered blank with the aid of filter asbestos and acidified with dilute acetic acid. The precipitated reaction product is filtered off with suction, washed with plenty of water and dried in vacuo at 50 to 60 °. 9.3 g of 1-dehydro-oa-chlorohydrocortisone ^ l -hemitetrahydrophthalate are obtained. M.p. 215 to 225 °; X _max (fine spirit) 244ΐημ, ε = 14900; Equivalent weight (titration): 530.

In an analogous manner, l-dehydro-6a-fluorohydrocortisone becomes by reaction with tetrahydrophthalic anhydride with 82% yield 1-dehydro-6 c \ -fluoro-hydrocortisone-21 -hemitetrahydrophthalate obtained.

To prepare the water-soluble sodium salt of l-dehydro-oa-chlorohydrocortisone ^ l-hernitetrahydrophthalates, 2.17 g of l-dehydro-6 "-chlorohydrocortisone-21-hemitetrahydrophthalate are dissolved in 30 cm ^{3 of} fine spirits and with ice cooling with 40 cm ³ 0 , 1 η-sodium hydroxide solution added. The clear, filtered solution is lyophilized using a known technique. 2.2 g of the sodium salt of 1-dehydro-6'-chlorohydrocortisone-21-hemitetrahydrophthalate are obtained.

35 Example 9.

A solution of 13.2 g of deoxycorticosterone and 12 g of tetrahydrophthalic anhydride in 100 cm ^{3 of} pyridine is allowed to stand under nitrogen at 20 to 25 ° for 80 hours, after which the reaction to free ketol with blue tetrazole and sodium hydroxide solution is negative in the cold. For work-up, the reaction solution is poured into 2000 cm ^{3 of an} ice-water mixture (1: 1), acidified with phosphoric acid and extracted with a chloroform-tetrahydrofuran mixture (3: 2). The extract is washed free of pyridine with dilute phosphoric acid and water. The acidic reaction products are then shaken out with dilute, cold sodium bicarbonate solution containing a little soda. The alkaline extracts are degassed in the cold, filtered clear and acidified with dilute phosphoric acid. The precipitated reaction product is filtered off with suction, washed out with plenty of water and dried. 18.5 g of deoxycorticosterone-21-hemitetrahydrophthalate are obtained. 163 to 164 °; /.max (fine spirit) 241 ΐημ, ε = 16700; Equivalent weight (titration): 475. With blue tetrazole and sodium hydroxide solution, the product does not immediately turn blue in the cold.

To prepare the water-soluble sodium salt of deoxy-corticosteron-21-hemitetrahydrophthalate, 4.82 g of deoxy-corticosterone-21-hemitetrahydrophthalate are dissolved in 50 cm ^{3 of} methanol and 100 cm ^{3 of} Ο, ΐη sodium bicarbonate solution are added while cooling with ice. The solution is filtered blank and lyophilized using a known technique. 5.2 g of the sodium salt of deoxy-corticosterone-21-hemitetrahydrophthalate are obtained.

Example 10

7.2 g of hydrocortisone and 6.0 g of tetrahydrophthalic anhydride are kept in 50 cm ^{3 of} pyridine for 60 hours at 20 to 25 ° C. under nitrogen. The reaction solution, which with blue tetrazole and sodium hydroxide solution no longer turns blue in the cold, is poured into 1000 cm ^{3 of an} ice-water mixture (1: 1) and acidified with dilute hydrochloric acid. The precipitated reaction product is taken up in ethyl acetate. The ethyl acetate solution is washed with dilute hydrochloric acid. The acidic reaction products are then extracted with dilute sodium bicarbonate solution containing some soda. The alkaline extracts, filtered blank, are acidified with dilute hydrochloric acid. The precipitated reaction product is filtered off with suction, washed with water and dried in vacuo at 50 to 60 °. The yield is 9.1 g of hydrocortisone-21-hemitetrahydrophthalate. M.p. 148 to 150 °; X _max (fine spirit) 242πψ, ε = 16000; Equivalent weight (titration): 507. With blue tetrazole and sodium hydroxide solution, the product does not immediately turn blue in the cold.

Cortisone is obtained in an analogous manner by reaction with tetrahydrophthalic anhydride cortisone-21 -hemitetrahydrophthalate.

Example 11

7.56 g of 9% fluorohydrocortisone and 6.0 g of tetrahydrophthalic anhydride are left to ^{stand in 100 cm 3 of} collidine for 60 hours under nitrogen at room temperature, after which free ketol can no longer be detected with blue tetrazole and sodium hydroxide solution in the cold. The following work-up is carried out according to Example 4 and gives 7.9 g of 9'-fluoro-hydrocortisone-21-hemitetrahydrophthalate; Xmax (fine spirit) 241 m μ, ε = 15100.

In an analogous manner, from 9 «-Fluorcortison and tetrahydrophthalic anhydride with 87 ° / ₀ yield 9a-fluoro-21-cortisone -hemitetrahydrophthalat; Xmax (fine spirit) 239 m μ, ε = 15200.

Example 12

0.36 g of aldosterone and 0.18 g of tetrahydrophthalic anhydride are left ^{to stand in 5 cm 3 of} pyridine under nitrogen at room temperature until free aldosterone can no longer be detected. It is poured onto ice water and acidified with dilute phosphoric acid. The precipitated reaction product is taken up in a chloroform-tetrahydrofuran mixture (3: 2) and the extract is washed out with dilute ice-cold phosphoric acid. The acidic reaction products are then extracted with ice-cold dilute sodium bicarbonate solution. The sodium bicarbonate extracts are immediately acidified again with ice-cold dilute phosphoric acid and the acidic reaction products which have precipitated are taken up in a chloroform-tetrahydrofuran mixture (3: 2). After evaporation, the washed and dried extract yields 0.42 g of aldosterone-21-hemitetrahydrophthalate; Xmax (fine spirit) 241 m μ, ε = 15 500. If the above ester is _{mixed with CrO 3} glacial acetic acid according to the information from Reichstein et al., Hch. Chim. Acta, 38 (1955), pp. 1423 to 1437, the 21-tetrahydrophthalic acid ester of corticosterone-18-acid (18 - »- II) lactone is obtained, which has a band at 5.64 μ in the IR .

In an analogous manner, 1-dehydro-aldosterone is obtained by reaction with tetrahydrophthalic acid

9 10

anhydride ° / ₀ yield amorphous sodium hydroxide solution in the cold, no on-1 -dehydro-aldosterone 21 -hemitetrahydrophthalat directly in pyridine with 75 miles. indicates emerging blue color; X _max (fine spirit) 244 ηιμ,

ε = 15100.

^eis P ^ie For the production of the water-soluble sodium salt

7.8 g of l-dehydro-9a-fluoro-16a-methyl-hydrocortisone 5 des l-dehydro-oa-chloro-loa-methyl-hydrocortisone and 6.0 g of tetrahydrophthalic anhydride are converted into 21-hemitetrahydrophthalates, 1.40 g of 1 -Dehydro-50cm ³ pyridine dissolved and heated under nitrogen for 6a-chloro-16a-methyl-hydrocortisone-21 -hemitetra-30 minutes on the boiling water bath. hydrophthalate dissolved in 15 cm ^{3 of} fine spirits, under ice-die cooled reaction ^{solution, which with blue cooling mixed with 25 cm 3} Ο, ΐη-sodium hydroxide solution and tetrazole and sodium hydroxide solution in the cold no blue io lyophilized. 1.4 g of the sodium salt of the dye are obtained, and ^{1-dehydro-6a-chloro-16 α-methyl-hydrocortisone is then added to 1000 cm 3 of} an ice-water mixture (1: 1) and 21-hemitetrahydrophthalate is added as white , amorphous made Congo acidic with dilute hydrochloric acid. The powder, which is very easily soluble in water and the reaction product precipitated in blue, is extracted with tetrazole and dilute sodium hydroxide solution in the cold with ethyl acetate, and the ethyl acetate extract is washed with no immediate blue coloration, next with dilute hydrochloric acid and then with water. In an analogous manner, 1-dehydro-

The acidic reaction products are diluted with ice-cold 6a-fluoro-16a-methyl-hydrocortisone and tetrahydro-diluent Sodium bicarbonate solution, some soda phthalic anhydride in pyridine that in aqueous solution contains added, exhausted exhaustively and alkalis easily soluble l-dehydro-oa-fluoro-loa-mevon the neutral parts separately. The ethyl hydrocortisone-21-hemitetrahydrophthalate is acidified. Sodium bicarbonate extracts with dilute hydrochloric acid. The same procedure is used to win through

and takes up the precipitated product in ethyl acetate reaction of tetrahydrophthalic anhydride. The ethyl acetate solution is washed free of hydrochloric acid, 1-dehydro-6α-fluoro-16/3-methyl-hydrocortisone is dried, filtered and concentrated, 1-dehydro-1-dehydro-6λ-fluoro-16/3 -methyl-hydrocortisone 9a -fluoro-16a-methyl-hydrocortisone-21 -hemitetra- 25 21-hemitetrahydrophthalate and from it the hydrophthalate crystallizes out in water. Yield = 7.2g. The easily soluble sodium salt of the l-dehydro-6 a-fluorine product does not give an immediate blue coloration when exposed to blue tetrazole and sodium hydroxide solution in 16 β -methyl-hydrocortisone -21-hemitetrahydrophthat the cold; lates and with l-dehydro-6α-chloro-16/3-methyl-hydro-Fp. 206 to 236 ° (polymorphism!). The amorphous, auscortisone l-dehydro-6 α-chloro-16 / J-methyl-hydroprecipitated product melts indistinctly at 155 to 227 °; 30 cortisone-21-hemitetrahydrophthalate and from it the λ-max (fine spirit) 240 ιτιμ, ε = 16000. [λ] " ⁰ = + 63 ° in water easily soluble sodium salt of 1-dehydro- (c = 0.5 ° / o ^m dioxane). 6a-chloro-16/3-methyl-hydrocortisone-21-hemitetra-

For the preparation of the water-soluble sodium salt hydrophthalates, which is diluted with blue tetrazole and of 1-dehydro-9 "-fluoro-16a-methyl-hydrocortisone-sodium hydroxide solution in the cold no immediate blue-21-hemitetrahydrophthalates 1.9 g of 1-dehydro- 35 will show color. 9a-fluoro-16a-methyl-hydrocortisone-hemitetrahydro- Example 15

phthalate, dissolved in 20 cm ^{3 of} fine spirit, with ice cooling

40 cm ^{3 of} 0.1 η sodium hydroxide solution were added. The blank 3.90 g of 1-dehydro-9a-fluoro-16a-methyl-cortisone

The filtered solution is lyophilized, and hydrocortisone-21-hemitetrahydrophthalate is obtained with 3.0 g of tetrahydrophthalic anhydride in the sodium salt of 1-dehydro-9 «-fluoro-16α-methyl-40 30 cm ^{3 of} pyridine under nitrogen for 30 minutes. The pH is heated to a boiling water bath, after which one of the 2.5% aqueous solution is 6.9, measured sample with blue tetrazole and dilute sodium hydroxide solution with Lyphan paper No. 670 -Dehydro-9λ-fluoro-16 "-methyl-hydrocortisone- shows more. The cooled reaction solution is added to 21-hemitetrahydrophthalates with methanolic ice water, acidified with dilute acetic acid blue tetrazole and double normal sodium hydroxide solution and no blue coloration after standing overnight. sucked, washed out with water and dried.

In an analogous manner from 1-dehydro one receives 5.2 g of l-dehydro ^ a-fluoro-loa-methyl-9 "-fluoro-16" -methyl-hydrocortisone-21-hemitetracortisone-21-hemitetrahydrophthalate, which with blue hydrophthalate and diethanolamine, diethanoi- 5 ° tetrazole and dilute sodium hydroxide solution in the cold amine salt of 1-dehydro-9 "-fluoro-16" -methyl-hydro- does not give an immediately occurring blue coloration; cortisone-21-tetrahydrophthalates. A _max (fine spirit) 241 ηιμ, ε = 14600.

. The water-soluble sodium salt of 1-dehydro-

Example 14 9a-fluoro-16 α-methyl-cortisone-21 - hemitetrahydro-

4.09 g of 1-dehydro-6a-chloro-16a-methyl-hydro- 55 phthalates is obtained by adding 2.7 g of 1-decortisone and 3.00 g of tetrahydrophthalic anhydride hydro ^ a-fluoro-loa-methyl-cortisone ^ l -hemitetrawerden dissolved in 30 cm ^{3 of} pyridine. The hydrophthalate is heated and dissolved in 50 cm ^{3 of} fine spirits and, after dissolving under nitrogen, it is lyophilized for 30 minutes on the addition of 50 cm ^{3 of} Ο, ΐη sodium hydroxide solution. boiling water bath, after which a sample with blue is obtained 2.7 g of the sodium salt of l-dehydro-9a-fluorotetrazole and dilute sodium hydroxide solution in the cold ⁶ ° loa-methyl-cortisone ^ l-hemitetrahydrophthalates, which no longer gives an immediate blue coloration. with blue tetrazole and dilute sodium hydroxide solution in the The cooled reaction solution is in ice water cold no immediately appearing blue color is entered. It is acidified with glacial acetic acid. After standing- In an analogous manner, 1-dehydro-

leave overnight, the precipitated reaction 9a-fluoro-16 ^ -methyl-cortisone and tetrahydrophthalic product is suction filtered, washed out with water and the 1-dehydro-9 α-fluorine dried ^{6 5 acid anhydride in pyridine.} The yield is 4.7 g of 1-dehydro-16 /? -Methyl-cortisone-21 -hemitetrahydrophthalate and 6a-chloro-16a-methyl-hydrocortisone-21-hemitetra- obtained therefrom by reacting with the equivalent amount of hydrophthalate, which with blue tetrazole and dilute caustic soda in fine liquor, followed by a lyophili-

11 12

The easily water-soluble sodium salt of the same procedure is obtained by conversion

l-Dehydro-9 (X-fluoro-16/3-methyl-cortisone-21-hemi- setting of tetrahydrophthalic anhydride with 1-detetrahydrophthalates. hydro-oa ^ a-difluor-loa-methyl-cortisone the 1-De-

·, _1Λ hydro-6 ", 9ix-difluor-16" -methyl-cortisone-21-hemi-

Example 16 ₅ tetrahydrophthalate and from it that easily in water

3.92 g of 1-dehydro-9 "-fluoro-16/3-methyl-hydro-soluble sodium salt of 1-dehydro-6a, 9 <x -fluorocortisone and 3 g of tetrahydrophthalic anhydride are 16" -methyl-cortisone-21- hemitetrahydrophthalates and dissolved in 50 cm ^{3 of} pyridine and heated under nitrogen with l-dehydro-6 ", 9" -difluoro-16 /? - methyl-cortisone for 30 minutes to 90 to 95 °. For 1-dehydro-6 ", 9" -difluoro-16/3 -methyl-cortisone work-up, the cooled reaction mixture is poured from 21-hemitetrahydrophthalate and from it in water onto ice and, after acidification, with the readily soluble sodium salt of the oil. Dehydro-6 ", 9 <x -di-dilute acetic acid left to stand overnight. On the next day fluor-lo / I-methyl-cortisone ^ l-hemitetrahydrophthan, suck off, wash with water lates, which are then dried with blue tetrazole and dilute sodium bicarbonate. The yield is 4.9 g caustic in the cold no immediate blue coloration 1 - Dehydro - 9 <x - fluorine -16 /? - methyl - hydrocortisone - 15 give.

21-hemitetrahydrophthalate, which is obtained with blue tetrazole and analogously to the above information, is also obtained

In the cold, dilute sodium hydroxide solution does not show any direct from tetrahydrophthalic anhydride and 6%, 9% dibare blue coloration; X _max (fine spirits) 239 to fluoro-16 λ-methyl-, 6 ", 9" - dichloro -16 "-methyl-, 240πιμ, ε = 15200. oa ^ -Difluor-loß-methyl-, 6", 9 " -Dichlor-16/3-me-

To produce the water-soluble sodium salt of thylcortisone and hydrocortisone, the half-esters of l-dehydro-9 * -fluoro-16 /? -Methyl-hydrocortisone tetrahydrophthalic acid and the corresponding 21-hemitetrahydrophthalates are used to produce 2.7 g of 1-dehydro - the water-soluble monosodium salts of 21-hemi-9 "-fluoro-16/3-methyl-hydrocortisone-21 -hemitetra- tetrahydrophthalate des 6", 9 "-difluoro-16" -methylhydrophthalate dissolved in 50 cm ^{3 of} fine spirits and after cortisone, des 6sc, 9 * -dichlor-16 * -methyl-cortisone, addition of 50 cm ³ Ο, ΐη-sodium hydroxide solution lyophilized according to the known 25 desoa ^ -Difluor-lö / S-methyl-cortisone ^ esoa ^ Ä-Di-technique. 2.8 g of the sodium salt chloro-16/5-methyl-cortisone, des 6 ", 9 * -difluoro-16" -medes l-dehydro ^ a-fluoro-loß-methyl-hydrocortisone-thyl-hydrocortisone, des 6 ", 9" -Dichlor-16 "-methyl-21-hemitetrahydrophthalates, which with blue tetrazole hydrocortisone, des 65c, 9" -difluoro-16/3-methyl-hydro- and dilute sodium hydroxide solution in the cold no cortisone and the oa ^ ic -Dichlor-lo / J-methyl-hydro immediate blue coloration. 30 cortisone, which with blue tetrazole and dilute sodium hydroxide solution in the cold show no immediate blue coloration Example 17.

4.10 g of l-dehydro-6a, 9 * -difluoro-16 «-methyl-hydro-

cortisone and 3.0 g of tetrahydrophthalic anhydride, 4.27 g of 1-dehydro-9 "-fluoro-6" -chlor-16 "-methyl are dissolved in 40 cm ^{3 of} pyridine and hydrocortisone and 3.0 g of tetrahydrophthalic acid to 90 to 95 for 30 minutes under nitrogen ° heated. The anhydride is ^{cooled in 50 cm 3 of} pyridine under nitrogen, the reaction solution is applied to ice and water for 30 minutes on the boiling water bath, acidified with acetic acid, and then heated. The cooled reaction mixture is left to stand for hours, expediently overnight, poured into ice water and the whole is acidified with suction, washed out with water and dried. dilute acetic acid. After leaving to stand for 5.1 g of 1-dehydro-6 ″, 9 ″ -difluoro-16 ″ -me-night, the reaction product is filtered off with suction, with ethyl hydrocortisone-21-hemitetrahydrophthalate, which is washed out with water and dried. The yield of blue tetrazole and dilute sodium hydroxide solution in the cold is 5.2 g of 1-dehydro-9 "-fluoro-6" -chloro-16% - methyl shows no immediate blue coloration; X _max (fine 45 hydrocortisone-21-hemitetrahydrophthalate, which with fuel) 244 ηιμ, ε = 15 200. Blue tetrazole and dilute sodium hydroxide solution in the cold

There is no immediate blue coloration for the production of the water-soluble sodium salt; X _m ax (enemy 1-dehydro-6 ", 9" difluoro-16 "-methyl-hydro- sprit) 243 ΐημ to 244, ε = 14900th
Cortisone-21-hemitetrahydrophthalates is the 1-De- For the production of the water-soluble sodium salt hydro - 6 ", 9" - difluor - 16 "- methyl-hydrocortisone-50 des l-dehydro-9" -fluoro-6 "-chlor-16 <x-methyl-hydro-21-hemitetrahydrophthalate dissolved in fine spirits and cortisone-21-hemitetrahydrophthalates, 2.8 g, after adding 1 equivalent of sodium hydroxide solution, are lyophilized 1-dehydro-9'-fluoro-6'-chloro-16'-methyl -hydrosized. The sodium salt of 1-dehydrocortisone-21-hemitetrahydrophthalate obtained was dissolved in 50 cm ^{3 of} fine 6 ″, 9 λ-difluoro-16 λ-methyl-hydrocortisone-21 hemisphere and, after addition of 50 cm ^3, 0.1 n-sodium tetrahydrophthalates is lyophilized with blue tetrazole and lye according to known technology. 2.8 g of sodium salt of 1-dehydro-9'-fluorine blue coloration are obtained with dilute sodium hydroxide solution in the cold; Yield 95% 6 "- chlorine -16" - methyl - hydrocortisone - 21 - hemitetra-

In an analogous manner, 1-dehydrohydrophthalates is obtained, which is diluted with blue tetrazole and

6 <x, 9 «-difluoro-16/3-methyl-hydrocortisone and tetra-sodium hydroxide solution in the cold no immediate blue

hydrophthalic anhydride gives the l-dehydro-6 ", 9" -di- 60 color.

fluoro-16/3-methyl-hydrocortisone-21 -hemitetrahydro- is obtained in an analogous manner from 1-dehydrophthalate and from it after reaction with 1 equivalent of 9 "-fluoro-6" -chloro-16/3-methyl-hydrocortisone and tetra-sodium hydroxide solution and lyophilizing the l-dehydro-9 «-fluorine-soluble which is slightly hydrophthalic anhydride in water Sodium salt of 1-dehydro-6 ", 9" -difluoro-OÄ-chloro-loess-methyl-hydrocortisone ^ 1-hemitetrahydro-16/3-methyl-hydrocortisone-21 -hemitetrahydrophtha- 65 phthalate and from it by reacting with 1 equivalent Lates that with blue tetrazole and dilute sodium hydroxide solution and lyophilizes that in water easily lye in the cold there is no immediate blue coloration. loß-methyl-hydrocortisone ^ l-hemitetrahydrophthala-

tes, which with blue tetrazole and dilute sodium hydroxide solution does not immediately turn blue in the cold.

According to the above information, the 21-hemitetrahydrophthalate and the water-soluble sodium salts of the 21- Hemitetrahydrophthalate des 6 * -Cbior-9a-rluor-16λ: -methyl-cortisone, X _max (fine spirit) 240 ηιμ, _ε = 15 100, des o ^ -Chlor ^ -fluor-loac-methyl-cortisone, ίο / l _mO j; (fine spirit) 239bis240m _i ix, s = 15500, OeSOa-CIuOr-9Ä-fluoro-16 \ -methyl-hydrocortisone, X _max (fine spirit) 242 ηιμ, ε = 15310, and des 6 * -Chlor-9 * - fluorine-16/5-methyl-hydrocortisone, x _ma x (rectified spirit) ηιμ 242, ε = 15300; the products obtained do not give an immediate blue coloration when exposed to blue tetrazole and dilute sodium hydroxide solution in the cold.

Example 19

4.08 g of 6x-chloro-16x-methyl-cortisone and 3.00 g of tetrahydrophthalic anhydride are dissolved in 35 cm ^{3 of} pyridine and heated under nitrogen for 30 minutes on the boiling water bath, after which a sample of the reaction solution with blue tetrazole and dilute sodium hydroxide solution in the In contrast to the non-esterified steroid, cold no longer shows an immediate blue coloration. The cooled reaction solution is poured into ice water. It is acidified with glacial acetic acid and, after standing overnight, the precipitated reaction product is filtered off with suction, washed with water and dried. The yield is 4.5 g of ox-chloro-losc-methyl-cortisone-21-hemitetrahydrophthalate which, when exposed to blue tetrazole and dilute sodium hydroxide solution, no longer shows an immediate blue coloration in the cold.

To prepare the water-soluble sodium salt of 6 "-chloro-16 * -methyl-cortisone-21-hemitetrahydrophthalate, 1.40 g of 6 * -chloro-16" -methyl-cortisone-21-hemitetrahydrophthalate are dissolved in 20 cm ^{3 of} fine spirits, with cooling mixed with 25 cm ³ O, ln sodium hydroxide solution and lyophilized. 1.4 g of the sodium salt of OÄ-chloro-lox-methyl-cortisone-21-hemitetrahydrophthalate are obtained, which is readily soluble in water and does not immediately turn blue when exposed to blue tetrazole and dilute sodium hydroxide solution.

By reacting tetrahydrophthalic anhydride with 6'-fluoro-16a-methyl-cortisone, one obtains in the same way the 6 »-fluoro-16 (X-methyl-cortisone-21-hemitetrahydrophthalate and from it the sodium salt of ΟΛ-Fluorloa-methyl-cortisone ^ l-hemitetrahydrophthalates, which is easily soluble in water, with OÄ-chloro-loß-methyl-cortisone the 6 "-chloro-16 /? - methyl-cortisone-21-hemitetrahydrophthalate and from it the sodium salt of 6 chloro-16/3-methyl-cortisone-21-hemitetrahydrophthalates, which is easily soluble in water, with ocx-fluoro-lo / S-methyl-cortisone the 6 "-fluoro-16/3-methyl-cortisone-21-hemitetrahydrophthalate and from it the sodium salt of 6'-fluoro-16 /? -methyl-cortisone-21, which is easily soluble in water -hemitetrahydrophthalates, with OÄ-chloro-lo ^ -methyl-hydrocortisone the ΟΛ-chloro-16 (X-methyl-hydrocortisone-21-hemitetrahydrophthalate and from it the water-soluble diethanolamine salt of 6 "-chloro-16" -methyl-hydrocortisone-21 -hemitetrahydrophthalates, with 6 * -fluoro-16 «> methyl-hydrocortisondas o ^ -Fluoro-lOÄ-methyl-hydrocortisone- ^ l-hemitetrahydrophthalate and from it the water-soluble sodium salt of 6 * -fluoro-16 * -methyl-hydrocortisone-21-hemitetrahydrophthalates, with 6r «-Chlor-16ß-methyl-hydrocortisone the 6 "-chloro-16/5-methyl-hydrocortisone-21-hemitetrahydrophthalate and from it the water-soluble triethanolamine salt of 6 "-Chlorlöjff-methyl-hydrocortisone ^ l-hemitetrahydrophthalates and with 6 ”-fluoro-16 /? -methyl-hydrocortisone the 6-fluoro-16 / S-methylhydrocortisone -21 -hemitetrahydrophthalate and from it the water-soluble sodium salt des oa-fluoro-lojö-methyl-hydrocortisone ^ l-hemitetrahydrophthalates; the resulting half-esters of tetrahydrophthalic acid and the corresponding water-soluble ones With blue tetrazole and dilute sodium hydroxide solution, salts do not immediately turn blue in the cold.

Example 20

2.0 g of potassium bicarbonate are added with stirring to 1.70 g of cis-zl ^{4 -tetrahydrophthalic acid in 45 ml of acetone.} The reaction mixture foams up; after the evolution of carbonic acid has subsided, the mixture is heated within 30 minutes to the boiling point of the acetone and maintained at this temperature for 15 hours. A solution of 4.70 gI ¹ ' ⁴ -11 / 3,17a-dihydroxy-3,20-diketo-21-iodo-pregnadiene in 50 ml of acetone is then allowed to flow in over the course of 30 minutes. It is rinsed with 10 ml of acetone and the reaction mixture is kept boiling for 5 hours. The course of the reaction is followed by thin-layer chromatography according to E. Stahl on silica gel [system dioxane-water (9: 1) and benzene-ethyl acetate (3: 7), indicator sulfuric acid 50%]; after 4 hours no more starting material can be detected in the reaction mixture. The reaction mixture is cooled and poured onto ice water. It is acidified with dilute ice-cold hydrochloric acid and extracted with a chloroform-tetrahydrofuran mixture (3: 2). The extract is first washed twice with ice water and extracted six times with 20 ml of 0.5N sodium bicarbonate solution, which contains 2 ml of 2N sodium carbonate solution added. The alkaline-aqueous extracts are then degassed in vacuo at room temperature to remove any residual solvent present. Then 0.1 g of filter asbestos is added, stirred for 3 hours and filtered off with suction. The clear, colorless filtrate is acidified with dilute hydrochloric acid while stirring. The precipitated product is filtered off with suction, washed with water and dried in vacuo at 40 to 50 °. The yield is 2.7 g of prednisolone-21 hemitetrahydrophthalate.

Claims (2)

PATENT CLAIMS: 1. Process for the preparation of 21-Zl ⁴ -cis-tetrahydrophthalic acid half-esters of 3,20-dioxo-21-hydroxy-pregnane compounds unsaturated in ring A, characterized in that the corresponding 21-alcohols or their functional 21- Derivatives in a manner known per se with tetrahydrophthalic acid of the formula ^ \ ^ COOH ^^ COOH or their reactive functional derivatives and the 21-hemitetrahydrophthalates obtained optionally converted into their salts in a likewise known manner. 15 16 2. The method according to claim 1, characterized in that the documents considered: draws the resulting 21-Hemitetra U.S. Patent No. 2,656,366; hydrophthalate with sodium hydroxide or sodium Izvest. Akad. Nank S. S. S. K., Otdel. Khim. Nank, bicarbonate or di- or triethanolamine or vol. 1954, pp. 329 to 337 (reported in Chem. Abstr., Dibenzylethylenediamine converts. 5 Vol. 49 [1955], p. 5329). ® 209 507/343 1.62