DE1272290B - Process for the bromination of the 21-position of 16-methylene-17alpha-hydroxy-20-keto steroids of the 5alpha-pregnane series which are optionally unsaturated in the 9 (11) position - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. α .:

C07c

German KL: 12 ο-25/05

Number: 1272 290

File number: P 12 72 290.6-42 (G 35812)

Filing date: August 29, 1962

Opening day: July 11, 1968

The invention relates to a process for bromination the 21-position of 16-methylene-17a-hydroxy-20-keto steroids the 5 "pregnan series, which may have a double bond in the 9 (11) position.

For bromination of steroid ketones in position to the keto group with bromine in the presence of a strong one Acid, various solvents have heretofore been used, e.g. B. halogenated hydrocarbons, such as chloroform, or cyclic ethers such as dioxane or tetrahydrofuran. The use of such However, solvent can cause relatively low yields and bromination can run unselective, d. that is, steroids that have other positions that can be attacked by bromine, in particular isolated double bonds, e.g. B. in the 9 (11) position, can also be brominated in other ways can.

It has now been found that the 21-position of 16-methylene-17'-hydroxy-20-keto steroids 5 "-Pregnan series, which may have a double bond in the 9 (11) position, with bromine can brominate in the presence of a strong acid by acting on the appropriate steroid of bromine in a lower primary alkanol containing at least 2 carbon atoms, optionally with the addition of a further inert organic solvent, or in a corresponding C 1 -C alkoxyalkanol subject.

The 16-methylene-17'-hydroxy-20-ketosteroid used according to the invention the 5 "-pregnan series, which may have a double bond in the 9 (11) position has, may contain one or more other substituents, such as a 3-hydroxy, 3-acyloxy, 11-hydroxy or 11-acyloxy group. The inventive Process gives the desired 21-bromo derivatives in good yield, regardless of whether the steroid used of the type described above also contains other positions that are bromination are accessible.

The process according to the invention was found to be advantageous for the bromination of 17α-hydroxy-16-methylen-5 "-pregn-9-en-20-ones as well as 3,17 "-dihydroxy-16-methylen-5" -pregnan-20-ones bearing a lower acyloxy group in the II /? position, for example of 11/3 acetoxy-3,17a-dihydroxy-16-methylen-5 "-pregnan-20-one; this results in particularly good yields of the desired 21-bromosteroids achieved.

In the process according to the invention, primary alkanols containing 2 to 4 carbon atoms are preferred contain, or mixtures that essentially

Process for the bromination of the 21-position of
optionally unsaturated in the 9 (11) position
16-methylene-17a-hydroxy-20-keto steroids
5a-pregnan series

Applicant:

Glaxo Laboratories Limited,

Greenford, Middlesex (Great Britain)

Representative:

Dr. F. Zumstein,

Dipl.-Chem. Dr. rer. nat. E. Assmann

and Dipl.-Chem. Dr. R. Koenigsberger,

Patent Attorneys, 8000 Munich 2, Bräuhausstr. 4th

Named as inventor:
Gordon Hanley Phillipps,
Frances Ann Nice, née Clark,
Greenf ord, Middlesex (Great Britain)

Claimed priority:

Great Britain 28 August 1961
(31 061, 31 060),
dated August 17, 1962
(31 061, 31 060)

consist of such alkanols, e.g. B. absolute ethanol, industrial spirit or propanol is used. In addition, the relevant Al-

koxyalkanols, e.g. B. Ethoxyethanol, can be used. It can be beneficial to add a small amount to the alkanol add another inert organic solvent to facilitate dissolution of the steroid. Among the appropriate solvents that are used

include cyclic ethers, such as tetrahydrofuran or dioxane. The steroid ketone must but do not completely dissolve in the alkanol or alkoxyalkanol during the bromination, some of it can also be in suspension.

The strong acid is preferably used in an amount such that it is suitable for the brominated Steroid is at least equivalent, with suitable proportions between 1 and 10 or even 12 equivalents Acid lying. The acid used should preferably be anhydrous as far as the reactants allow. A suitable acid is Hydrogen chloride.

809 569/565

3 4

The strong acid is the reaction mixture ^ «- dihydroxy-lö-methylen-Sa-pregn ^ -en ^ O-one, favorable as a solution in the lower alkanol or F. = 193 to 195 °, and a second yield of Alkoxyalkanol added. 1.34 g; (11.5%), F. = 175 °, then 193 to 195 °, with

The bromination is favorable at temperatures similar to the infrared spectrum,
carried out between 0 and 35 ⁰ C, preferably at ⁵ CHO-

Room temperature. A favorable embodiment ^ ₁ ^M J ' ₊ r ^ m / zoi u ο co /
of the inventive method is Βψ * & net ... C L I., _6/0, Ά 8.5 / ";

Bromine, e.g. B. dissolved in the alkanol or alkoxy found ... C 71.3 / ₀ , H 8.6 / ₀ .

alkanol, slow, e.g. B. within 60 to 100 minutes Example 2

th, to a solution or suspension of the steroid in ίο _. «"., "^.,,

the alkanol or alkoxyalkanol, which causes the strong bromination of 3 ^ 17 «-dihydroxy-

Contains acid, add. The bromine can be added to the solution 16-methylen-5 "-pregn-9-en-20-one

or suspension of the steroid also as pure liquid a) In n-butanol 1.0 g steroid, suspended in 20 ml

Bromine was added, the solution, or sus- n-butanol, was stirred and a 7.7 normal pension was stirred very vigorously. Another inexpensive solution of hydrogen chloride in 2.64 ml of n-butanol procedure for introducing the bromine into the was added. Then a solution of solution or suspension of the steroid consists of 0.83 g of bromine in 17.9 ml of n-butanol, which in the cold bromine vapors emitted by a gas stream, e.g. B. Stick- was made and then on room temperature material to be carried along to initiate. Under the door warmed up, the alkanol reacted with 20 drops within 90 minutes. After a further 10 minutes the yellow bromine became slow, and it is therefore necessary to dilute the solution with about 11% of water and use that from an excess of bromine. The product found (1.15 g) was filtered off, washed with water that about 1.1 moles of bromine per mole of steroid and dried,
are suitable if the bromine is undiluted as a liquid qu g _r Q.
speed or steam is added while considerably 35 ² ^ ^{31 3} "
more, ie about 1.6 moles of bromine per mole of steroid. Calculated ... Br 18.9 I ₀ ;

must be turned when the bromine is dissolved in the getunden ... Br 16.3 / ₀ .

Alkanol or alkoxyalkanol is added. The 1.13 g of the crude bromine compound were with

under all special conditions optimal bromine- 3.0 g potassium acetate in 25 ml acetone for 4 hours The amount can be quickly refluxed with stirring by means of a simple experiment. By concentrating determine. the reaction mixture and adding water

The following examples illustrate that 1.04 g of crude product were obtained according to the invention, corresponding to the tetrazolium Procedure. The temperatures are given in Celsius test, which indicates the presence of about 78% degrees indicated. To the favorable effect of the 21-acetoxy-3 / ?, 17 "-dihydroxy-16-methylene-5" -pregner according to the invention Procedure to prove 35 9-en-20-on indicated.

the 21-bromine obtained according to the process was b) In ethylene glycol monomethyl ether. 1.0 g steroid

binding in each case in the corresponding 21-Acetoxyver- in 20 ml of ethylene glycol monomethyl ether were with

bond transferred, for which in the context of the present 4.0 normal hydrogen chloride in 5.1 ml ethylene glycol

no protection is sought for the invention. treated colmonomethyl ether, then with 0.595 g

Example 1 ⁴ ° bromine ^m 10.7 ml of the same solvent reacted,

". ? ".," - ^., As described in a). The crude bromine compound

Bromination of 3 ^, 17 "dihydroxy ₍₁ ^^ _{m} in a) iso] ated (Br found of} 1 to _5, 25%).

16-methylen-5 "-pregn-9-en-20-one ^ g _{g of this} compound were treated with potassium acetate,

10.0 g of finely divided 20-ketone in 200 ml of absolute as described in a), treated and yielded 1.044 g

Ethanol were during the addition of a 8.9 nor- 45 crude product, which gave the tetrazolium test and which

paint solution of hydrogen chloride in 23 ml (7 mol) presence of about 64% 21-acetoxy-20-ketone

Ethanol stirred vigorously and one indicated 2 minutes later.

Solution of 7.45 g (1.6 mol) of bromine in 155 ml of ethanol Example 3

(produced in the cold and then at room temperature

temperature allowed to come) within 95 minutes _to-5 o ^ "" Tf T ^

dripped. After a further 5 minutes, the solution became 16-methylene-5'-prepregn-9-en-20-one

gradually diluted with water to about 41; the 5.3 g of bromine (1.1 mol) were in vapor form with

precipitated product (12.23 g, 99%) was filtered off a stream of nitrogen into a suspension of trated, washed with water and 3 / ?, 17 <x-dihydroxy-16-methylen-5a-pregn-9-en-20-one at 60 ° in vacuo dried. 55 (10.335 g) in 150 ml of absolute ethanol and 10.5 ml

CHO Br ^- lOnormal alcoholic hydrogen chloride inside

⁸ D ³¹ u r> 10 no / h ^a lb 65 minutes initiated. This mixture was

Calculated ... Br 18.9 J ₀ ; Stirred for 5 minutes and mixed with 750ml ice water

gelunden ... Br 18, / / ₀ . _{The 2} L bromide was filtered off, with cold

For 21-acetoxylation, which is not claimed here, washed 60 water and dried in vacuo at 50 °, 12.2 g of the product obtained and 36 g of yield: 12.48 g (98.3%), mp = 185 ° (decomposition) , dry potassium acetate for 4 hours with stirring in [«] z> = -32.4 ° (c = 1.0, CHCl ₃ ).
280 ml of acetone heated under reflux. The insulation q w O Br *
of the product by concentration and dilution ^z * ^{31 3} .

with water gave the 21-acetate as buff 65 Calculated ... Br 18, y J ₀ ;
solid (11.54 g, 99%) (Br found 0.9%). The found ... Br I8, y / ₀ .

Recrystallization of 11.44 g from acetone gave 12.3 g of the crude product for 21-acetoxylation first yield 8.67 g (75.8%) of 21-acetoxy-3/3, 21-bromide with 36.9 g of potassium acetate in 310 ml of acetone

20th

Stirred at reflux for 3.75 hours. The mixture was filtered while hot and the residue was washed with hot acetone. The filtrate was diluted with 50 ml of water, evaporated to a slurry and rediluted with 400 ml of water. The crude 21-acetate was filtered off, washed with water and dried at 50 ° in vacuo. Yield: 11.98 g, m.p. 183 °, l »] _D => -19.1 ° (c = 1.0, CHCl ₃ ).

11.90 g of the crude acetate were crystallized from acetone ίο and gave 9.32 g (78.9% in total)> F. = 194 to 195 °, [x] _D = -20.9 ° (c = 1.0 , CHCl ₃ ), side chain analysis 97%

The mother liquors were concentrated and cooled to yield a second portion, 0.57 g, [<x] d = -29 °, which was recrystallized from acetone and 0.23 g (2.0%), mp = 193-194 °, [<x] _D = -21.3 °.

Example 4

Bromination and acetoxylation of
3 / 3,17ix-dihydroxy-16-methylene-5 "-pregn-9-en-20-one

11.6 g of bromine (1.25 mol) were added under nitrogen to a suspension of 3 ^, 17 "-dihydroxy-16-methylene-5" -pregn-9-en-20-one (20 g) in 300 ml of industrial Methyl spirit and 20 ml of 10normal alcoholic hydrogen chloride were added dropwise over the course of 90 minutes. The mixture was stirred for 5 minutes and poured into 1.5 liters of ice water. The 21-bromide was filtered off, washed with water and dried. The crude 21-bromide was treated with potassium acetate in acetone as described in Example 3 and the product was crystallized from acetone. Yield of 21-acetoxy-3 / 9.17 <% -dihydroxy-16-methylene-5 "-pregn-9-en-20-one 17.75 g (76.2%), [«] _D = -19 , 3 ° (c = 1.0, CHCl ₃ ), m.p. = 193 °.

Example 5

Bromination and acetoxylation of
3 / ?, 17 "-dihydroxy-16-methylene-5" -pregn-9-en-20-one

2.56 g of bromine (1.6 mol) were vaporized with a stream of nitrogen in a suspension of 3.445 g of 3 / S, 17iX-dihydroxy-16-methylen-5 "-pregn-9-en-20-one in 50 ml of dry initiated n-propanol and 3.5 ml of 10normal alcoholic hydrogen chloride within one hour. The mixture was stirred for 5 minutes and poured into 250 ml of ice water. The crude 21-bromide was isolated, treated with potassium acetate in acetone as described in Example 3 and the product was crystallized from acetone. Yield: 2.80 g of 21-acetoxy-3je, 17 "-dihydroxy-16-methylene-5" -pregn-9-en-20-one (69.6%), [<x] _D = -20.6 ° (c = 1.0, CHCl ₃ ), m.p. = 192 to 194 °.

Example 6

Bromination of ll _j S-acetoxy-3 e _j, 17 '-dihydroxy-16-methylene-5 "pregnan-20-one in absolute ethanol

A solution of 100 g of H ^ -acetoxy-3j5,17 «-dihydroxy-16-methylene-5« -pregnan-20-one in 2.0 _# l of absolute ethanol was treated with 230 ml of absolute ethanol, which in terms of dry hydrogen chloride gas 8 , 9 were normal. The mixture was stirred for 5 minutes; then a solution of

55 60 g (1.52 mol) of bromine in 1.521 absolute ethanol, which had been prepared at about -30 ° and slowly warmed to 20 °, were added over the course of 100 minutes, the temperature of the reaction mixture being from 20 to 21 °. After the addition of the bromine solution was complete, the reaction solution was stirred for 5 minutes until the light yellow color had disappeared, and then slowly poured into 40 liters of water with stirring. The mixture was stirred for 1 hour, the reaction product was collected, washed neutral with water and dried at 60 ° in vacuo for 16 hours. 118.3 g (99%) of the 21-bromide were obtained, mp = 177 °, [<x] _D = + 23.4 ° (c = 1.0 dioxane).

For acetoxylation were 116.4 g of the obtained 21-bromide in 2,761 acetone, the 307 g of anhydrous potassium acetate contained, heated under stirring for 2 ¹ I reflux for ₂ hours. The mixture was filtered while hot, the filter cake was washed with hot acetone and the filtrate and the washing liquids were concentrated to a small amount, whereupon water was added dropwise until crystallization began. The mixture was distilled under reduced pressure to remove residual acetone, then diluted with an additional 5 liters of water. After stirring for 30 minutes, the 21-acetate was filtered off, washed neutral with water and dried at 60 ° for 16 hours. Yield: 111.5 g (100% of the 21-bromide), m.p. = 216 to 218 °, [oi] _D = + 37.1 ° (c = 1.0 dioxane).

106.5 g of the product were dissolved in 1.251 methylene chloride, 25 g of activated charcoal were added and the mixture was stirred at 20 ° for 30 minutes and then filtered through kieselguhr. The filtrate was washed with water and distilled until 500 ml of distillate had passed over. Isopropyl ether was then added and the solution concentrated at atmospheric pressure until all of the methylene chloride was removed. Crystallization was completed by aging the mixture at 20 °. The crystals were collected, washed with isopropyl ether and dried at 60 ° in vacuo. 93.3 g (86.7% of theory, based on the 21-deoxy compound) 11 ^, 21-diacetoxy-3 | S, 17 "-dihydroxy-16-methylen-5" -pregnan-20-one were obtained, F. = 223 to 226 °, [x] d = + 37.3 ° (c = 1.0 dioxane).

Claims (1)

Claim: Process for the bromination of the 21-position of 16 - methylene -17 «- hydroxy - 20 - ketosteroids der 5fX pregnancies, which may have a double bond in the 9 (11) position, with bromine in the presence of a strong acid, thereby characterized in that one has a corresponding steroid under the action of bromine in a lower primary alkanol containing at least 2 carbon atoms, optionally with the addition of a further inert organic solvent, or in a corresponding one C-alkoxyalkanol subjects. Legacy Patents Considered:
German patents No. 1169 928, 1179 548. 809 569/565 7.68 © Bundesdruckerei Berlin