DE1243190B - Process for the manufacture of 2-hydroxymethylene steroids - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

did. Ο .:

COTc C 0 7 y

Ί - / 'hi J

German KL: ΙΖο-25 /tagji

Number: 1243 190

File number: Stl64331Vb / 12o

Filing date: March 23, 1959

Open date: June 29, 1967

The present invention relates to a method for Production of 2-hydroxymethylene steroids of the general formula I.

where R is hydrogen or a lower alkyl group, R "is a lower alkyl, alkenyl or alkynyl radical, an optionally ketalized acetyl or oxyacetyl radical or a 1,2-dioxyethyl or 1-oxyethyl radical, X two hydrogen atoms, the grouping

or an oxygen atom, Y and Y 'are hydrogen or each is a methyl group and Z is hydrogen or a Mean hydroxyl group, where Z is limited to the meaning of a hydroxyl group when R ″ a represents lower alkyl, alkenyl or alkynyl radical, and the dashed lines between the carbon atoms 4 and 5 or 6 and 7 mean an optionally present double bond, furthermore about hydroxyl groups present with carboxylic acids having 1 to about 10 carbon atoms and a molecular weight less than about 250 may be esterified and the steroid nucleus optionally substituted can.;

It has now been found that 2-hydroxymethylene steroids the general formula can be prepared by having a corresponding Steroid of the general formula II

II

O--

in which R ", X, Y, Y 'and Z have the above meaning, with a compound of the general formula RCOOR'", in which R is hydrogen or a lower process for the preparation of
2-hydroxymethylene steroids

Applicant:

Sterling Drug Inc., New York, N.Y. (V. St. A.)

Representative:

Dr. F. Zumstein,

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

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

Patent Attorneys, Munich 2, Bräuhausstr. 4th

Named as inventor:

Raymond Otto Clinton,

East Greenbush, N.Y. (V. St. A.)

Claimed priority:

V. St. v. America March 24, 1958 (723148),

dated February 16, 1959

(793 292)

Alkyl radical and R '"is a lower alkyl radical or a lower alkanoyl radical when R is a lower alkyl group is, means in a manner known per se either in the presence of a strong base under anhydrous Conditions or, if in the compound of the general formula RCOOR '"R is a lower alkyl group and R '"denotes a lower alkanoyl group, optionally also in the presence of boron trifluoride, where optionally a 17-oxy group, in particular in the case of 17-oxy-17-alkyl steroids, is protected by esterification if desired, the salt obtained is condensed with an acid into the free oxymethylene compound converts and, if desired, the compound thus obtained with a basic substance to obtain a salt, and that the compound obtained in which R "is a ketalized Means acetyl or ketalized hydroxyacetyl radical, optionally covered in a manner known per se, but steroids of the general formula II, in the Y = Y '= methyl, X = 2 hydrogen atoms, Z = OH and R "- mean methyl or ethyl and the 4 (5) position is unsaturated, and also those in which Y = Y '= methyl, X = 2 hydrogen atoms, Z = OH

so and R "= methyl, in which the 4 (5) -position is saturated, and finally those in which Y = Y '= methyl, X = 2 hydrogen atoms, R "= a ketali-

709 608,464

3 4 **,

Acetyl or hydroxyacetyl group and Z = parenteral administration of ready-to-use hydrogen or OH and the 4 (5) position are brought up. For oral administration is unsaturated, are excluded. they can with carrier substances in tablet form

The nature of the steroid is outside of that to be brought about.

Above definition of the substituents of a 5 The structure of the inventively obtainable Steroids of the general formula I are not critical, it becomes compounds through their synthesis, their ultra can with this restriction any violet and infrared spectrum and through the connection the Östran-, 18-Noröstran-, Androstan-, mood of the analytical values found with Testan, Pregnan or AUopregnan sequence uses the one calculated for the assumed structure will. Proven as substituents for the given io values.

if substituted steroid nucleus, for example hydroxyl, the following examples explain the invention

Acyloxy or oxo groups in 6-, 7-, 11-, 12-, 14- according to methods. For the production of the starting

and / or 16-position, halogen atoms, preferably substances, is within the scope of the present invention

Fluorine or chlorine, for example in 4-, 6-, 7-, 9-, 12- protection not desired, or 21-position, and lower alkyl groups, for example 15

wise in 2-, 4-, 6-, 11- or 16-position, in question. example 1

Carboxylic acids with 1. to about 10 carbon atoms · ....., “,. '

and a molecular weight below about 250, which means .. ··. na.Athynyl ^ -oxymethylene ^ androsten-

in the steroids obtainable according to the invention ge 17 / ϊ-ο1-3-οη

any hydroxyl groups present esterified 20 to a solution ofl ^^ glTa-EthinyM-androsten-

are, for example, formic acid, acetic acid ■ 17/3-ol-3-one in 300 ml of dry pyridine are added

acid, propionic acid, butyric acid, isobutyric acid, Ca- 23 ml of dry ethyl formate and then

Proonic acid, heptanecarboxylic acid, octanecarboxylic acid, a solution of sodium ethylate in ethanol from 2.1 g

Trimethyl acetic acid, carboxyl-substituted lower Al-sodium and 35 ml of absolute ethanol. One lets

carboxylic acids such as succinic acid, cycloalkyl 25 the reaction mixture 42 hours at room temperature

substituted lower alkanecarboxylic acids such as ß-cyclo- rature and then poured onto ice water. By

pentylpropionic acid and /? ~ cyclohexylpropionic acid, adding 218 ml of glacial acetic acid forms a greasy

monocarbocyclic arylcarboxylic acids such as benzoin product that is separated off and dissolved in ether. the

acid, p-toluene carboxylic acid, p-nitrobenzoic acid and ethereal solution is mixed with a solution of 30 g

3,4,5-Trimethoxybenzoic acid, washed by monocarbocyc- 30 Kaliunihydroxyd in 1.51 water, and the

Lische aryl radicals substituted lower alkane or .. aqueous layer is after cooling to 5 ⁰ C with

Alkenecarboxylic acids such as phenylacetic acid, / ί-phenyl- 6N-hydrochloric acid acidified. The unusual product

propionic acid and cinnamic acid and through monocarbo- is filtered off and at 6O ⁰ C in a vacuum

cyclic aryloxy substituted lower alkane phosphorus pentoxide dried. 13.5 g are obtained

carboxylic acids such as p-chlorophenoxyacetic acid. 35 17'-ainyl-2-oxy-methylene-4-androsten-17 / S-ol-3-one.

One way to produce the invention ■. . .

according to available 2-hydroxymethylene steroids of B e 1 s ρ 1 e 1 2

General formula I consists, as stated above, according to the information in Example 1 were

produced in a condensation reaction known per se in: 2-oxymethylene-17Ä-methyl-4,6-androsta-

Presence of a strong base under anhydrous dien-17 /? - ol-3-one; F. = 117 to 123 ⁰ C (uncorrected).

conditions. The strong base used is preferably 2-oxymethylene-17a-niethyl-19-norandrostan-17 / i? -

an alkali metal compound of a lower alcohol, ol-3-one; F. = 206.2 to 210.6 ⁰ C (uncorrected); [x] i ^s =

an alkali amide or hydride is used. +96.1 ± 0.1 ° (1% in chloroform); UV maximum

The oxy group of the one obtainable according to the invention at 283 χαμ (E = 7,800). 2-hydroxymethylene steroids is acidic and forms at 45

the implementation with basic compounds, as in Example 3

for example diethylamine, and especially with strong .... " _o .- _Λ , _η . _Λ . ,, ". .

Bases, such as, for example, with alkyl metal hydroxides, ^a > Allo _P regnan-3 ^ -ol-20-one-20-ath _y lenglyko1ketal

-äthylaten or -hydriden light addition or Al- A mixture of 27.4 g (0.086 MoJ) Allopregnan-

potassium metal salts. 50 3 / J-ol-20-one, 33 ml ethylene glycol, 700 ml benzene and

The new by the inventive method 1 g of p-toluenesulfonic acid is 78 hours with a Compounds that can be produced show endocrinological water separators in the boiling system with re-effectiveness. In particular, they have the hypo-flux heated. After cooling, the reaction will be physically inhibited Properties measured when mixed with 100 ml of 2N sodium hydroxide solution of the endocrine equilibrium, which is shaken and filtered off. 20.5 g of acidification are obtained of the follicle-stimulating hormone and the pregnan-3jS-ol-20-on-20-ethylene glycol ketal from F. = Interstitial Tissue Stimulating Hormone (ICSH) 166 to 169 ° C (uncorrected). After the recrystalline the pituitary secretion is caused, sieren from acetone one obtains the compound in the form whereas they are from estrogenic or androgenic colorless plates with a temperature of 172.5 to 175 ° C (unproperties are practically free. 60 corrected).

These compounds also show anabolic properties,. ..., _ _Λ,. « _Λ _.,,,,". ,

ness and are useful as intermediates for the manufacturing ^b> Allopregnan- ^ O ^ O-dione athylenglykolketal

position of steroid [3,3-c] pyrazoles according to the German one adds 26.5 g of chromium oxide in small amounts

see patent specification 1152101 usable. 425 ml of pyridine from 25 to 30 ° C. This mixture

The compounds 65 obtainable according to the invention are added all at once with a solution of 19.5 g

can by dispersing in an aqueous suspension (0.054 mol) Allopregnan-SjS-ol ^ O-on ^ O-ethylengky-

sion or dissolve in a pharmacologically compatible kolketal in 250 ml of pyridine. The reaction mixture

borrowed oil or an oil-water emulsion in one for is stirred for 18 hours at room temperature, with

11 diluted hot benzene and filtered. The filtered off solid substance is washed with 500 ml of hot benzene, and the combined filtrates are washed four times washed with 500 ml of water each time and once with 200 ml of saturated sodium chloride solution. Then that will organic solvents evaporated in vacuo and the residue triturated with 50 ml of methanol. Filtering the mixture and concentrating the filtrate to a volume of 20 ml gives a small amount of a solid substance. The combined solid substances are made from ethyl acetate recrystallized using activated charcoal and yield 12.6 g of allopregnan-S ^ O-dione ^ O-ethylene glycol ketal in the form of leaflets and plates with a temperature of 190 to 191.5 ° C (uncorrected.)

c) 2-oxymethylene-allopregnane-3,20-dione-20-ethylene glycol ketal

This substance is made from 2.45 g of allopregnan-3,20-dione-20-ethylene glycol ketal, 20 ml of ethyl formate and sodium methylate from 0.33 g of sodium and 15 ml of methanol in 70 ml of pyridine were prepared according to the procedure described in Example 1. You get 2.64 g of the substance that can be used without further purification the next stage is used.

A solution of 2.5 g of 2-oxy-methylene-allopregnan-3,20-dione-20-äthylenglykolketal and 2 ml of 2N hydrochloric acid in 50 ml ethanol is heated for 15 minutes 5O ⁰ C and heated for 2 minutes to boiling. After the solution has been concentrated, the residue is recrystallized from a methylene-ether-pentane mixture (1: 1: 2) and finally from a methylene chloride-pentane device. One obtains 2-oxy-raethylen-allopregnan-3,20-dione, melting point = 198.6 to 203.2 ⁰ C (uncorrected); [(kYo ^s = +111.2 ± 0.1 ° (1% in chloroform).

Analysis of C ₂₂ H ₃₈ O ₃ :

Calculated
found

C 76.70, H 9.36 "/"; C 76.41, H 9.23%.

Example 5

2-Oxymethylenepregnan-3,20-dione was prepared in an analogous manner; F. = 139.8 to 146.0 ⁰ C after recrystallization from methanol; [x]% = + 114.2 + _0.3 ^o (1% in chloroform); also 2-oxymethylene-6 "-methyl-17" -propinyU4-androsten-17 (S-ol-3-one, F. = up to 93 ° C (uncorrected); from 6 * -methyl-17a-propynyl-4- androsten-17 _i ff-ol-3-one ₎ F. = 90 to HO ⁰ C (uncorrected), 2-oxymethylene-4-androsten-ll / ?, 17/9-diol-3-one, F. = 168 up to 190 ° C (uncorrected); UV maximum at 251 and 307 πιμ (E = 11700 or 5200) and 2-oxymethylene-17 ″ -methyl-19-nor-4-androsten-17 / J-ol-3-one, UV maximum at 246 ηιμ (E = 10800).

Claims (1)

Claim: Process for the manufacture of 2-hydroxymethylene steroids the general formula 35 40 Example 4 2-Oxymethylene-4-pregnen-17oc, 21-diol-3, H, 20-trione 2.0 g (0.005MoI) of 4-pregnene47oc, 21-diol-3, ll, 20-trione-21-acetate (Cortisone acetate), 4 ml of ethyl farmide and 1.0 g of sodium hydride are added to 100 ml of pyridine the procedure described in Example 1 brought to implementation, with all measures under Nitrogen. This will be the 21st Acetoxy group saponified, and 1.3 g of 2-oxymethylene-4-pregnen-17λ, 21-diol-3, ll, 20-trione are obtained, UV spectrum maxima at 246 and 293 ηιμ (E = 8000 and 4300, respectively) for the 2-oxymethylene-3-oxo group in addition to a 4-position double bond are characteristic. 55 According to Example 1, 6 ', 17-Λ Dimethylandrostan-17.beta.-ol-3-one, m.p. = 181.6 to 184.6 ⁰ C (uncorrected); [<x]% = +10.3 ± 0.2 ° (1% in chloroform) converted into 2-oxymethylene-6a, 17 (* - diinethylandrostan-17 / J-ol-3-one; F. = 198 to 199.8 ° C (corrected), after recrystallization from acetone; [<x]% = +54.3 + _ 0.1 ° (1% in chloroform); UV maximum at 285 ΐημ (E = 9200). Analysis C ₂₂ H ₃₄ O ₃ : Calculated ... C 76.26, H 9.89 ° / ₀ ; found ... C 75.93, H 9.63%. where R is hydrogen or a lower alkyl group, R "is a lower alkyl, alkenyl or alkynyl group, an optionally coalated acetyl or oxyacetyl radical or a 1,2-dioxyethyl or 1-Oxyäthylrest, X two hydrogen atoms, the grouping ,H or an oxygen atom, Y and Y 'are hydrogen or each is a methyl group and Z is hydrogen or a Denote hydroxyl group, where Z is limited to the meaning of a hydroxyl group when R " represents a lower alkyl, alkenyl or alkynyl radical and the dashed lines between the Carbon atoms 4 and 5 or 6 and 7 denote an optionally present double bond, further comprising any hydroxyl groups present with carboxylic acids having 1 to about 10 carbon atoms and may be esterified to a molecular weight of less than about 250 and the steroid core can optionally be substituted, characterized in that a corresponding Steroid of the general formula II in which R ", X, Y, Y 'and Z have the above meaning with a compound of the general Formula RCOOR '", in which R is hydrogen or a lower alkyl radical and R'" is a lower alkyl radical or a lower alkanoyl rest, when R is a lower alkyl group, means in a manner known per se either in the presence of a strong base under anhydrous conditions or, if in the compound of the general formula RCOOR '"R is a lower alkyl group and R '"denotes a lower alkanoyl group, optionally also in the presence of boron trifluoride, where optionally a 17-oxy group, in particular in the case of 17-oxy-17-alkyl steroids, protected by esterification, condensed, if desired the obtained salt is converted into the free oxymethylene compound with an acid and desired to be obtained the compound thus obtained with a basic substance to obtain a salt converts, and that the compound obtained, in the R ″ a ketalized acetyl or hydroxyacetyl radical means, optionally decetalized in a manner known per se, but with steroids of the general formula II, in which Y = Y '= methyl, X = 2 hydrogen atoms, Z = OH and R " = Methyl or ethyl and the 4 (5) position is unsaturated, also those in which Y = Y ' = Methyl, X = 2 hydrogen atoms, Z = OH and R "= methyl, in which the 4 (5) position is saturated, and finally those in which Y = γ '= methyl, X = 2 hydrogen atoms, R "= a ketalized acetyl or hydroxyacetyl group and Z = hydrogen or OH and the 4 (5) position is unsaturated, except are. 709 608/464 6.67 © Bundesdruckerei Berlin