DE1593307C - Process for the preparation of gonatriene derivatives - Google Patents

Description

The present invention relates to a process for the preparation of gonatriene derivatives of the general Formally:

OH

• M.

in which R here and below is a methyl or ethyl radical, R 'is an alkyl radical with 1 or 2 carbon atoms, an alkenyl radical with 2, 3 or 4 carbon atoms or an alkynyl radical with 2, 3 or 4 carbon atoms which may be substituted by one or more halogen atoms.

It is particularly advantageous as the alkynyl radical dan ethynyl radical, -Cs CH, the chloroethinyl radical, -C s CCl, the propynyl radical, -C = C-CH ₃ , the 3,3,3-trifluoropropynyl radical, —Cs C-CF ₃ , and the butadiynyl radical, - Cs C - Cs CH, to choose.

Gonatrienes of the general formula I are already known. These compounds, which have valuable endocrine properties, are described in German Offenlegungsschrift 1,291,337. According to the patent mentioned, the compounds of general formula I are obtained by the following process: ₊

An S-oxo-IT / S-hydroxy-Bβ-alkyl-gena-4,9,11-triene is used with hydroxylamine or a lower alkyl derivative of hydroxylamine, converted the obtained 3 - oximido -17/3 - hydroxy -13/9 - alkyl - gona-4,9,11-triene by oxidation according to the Oppenauer method into 3-oximido-17-oxo-13 ^ -alkyl-gona-4,9,11-triene, subjects this to the action of an organometallic derivative with the formation of the corresponding one S-Oximido-rZ / J-hydroxy-na-organo-lS / J-alkylgona-4,9, ll-triens, whose 3-oximido group is then cleaved by acid hydrolysis, with a gonatrium of the general formula I is obtained.

Schematically, the known method consists in the keto group in the 3-position of the used To block 3-oxo-17-hydroxysteroids, to convert the alcohol group in the 17-position into a keto group, to introduce a hydrocarbon radical in the 17 "position and finally the 3-keto group again to release.

So far it has been assumed that because of the reactivity of the double bond systems 4-5, 9-10 and 11-12 the usual methods of blocking the keto function in steroid chemistry, such as the methods of Formation of cyclic acetates, enol ethers or enamines, are not feasible, and that the The best way to accomplish the intended blocking is to form a 3-oximido group.

It has now been found, and here lies the completely surprising feature of the method according to the invention, that the protection of the keto group in the 3-position of the steroid used is very satisfactory Way can be effected by ketalization. It was also found that the ketalization of the 3-keto function of a 3,17-dioxosteroid, i.e. the starting compound of the new synthesis of gonatrienes of the general formula I, which is the object of the present invention, can be effected selectively, so that the 17-keto function is left intact.

It was also found that the release of the Keto group in the 3-position can be carried out very easily in the final stage of the new synthesis.

The new process for the preparation of gonatrienes of the general formula I according to the present Invention, the reaction scheme of which is attached, consists in the fact that a 3,17-Dioxo-13 / J-R-gona-4,9,11-triene, II, with an alkylene glycol of the formula

HO - (CH ₂ ), * - OH
10

where η is the number 2, 3 or 4, the 3-alkylene dioxy-17-oxo-13/3-R-gona-4,9, ll-triene obtained is ketalized with an organometallic derivative in an anhydrous medium and in the presence of an acidic catalyst , the organic radical of which is represented by R ', where R' has the meaning given above, to a 3-alkylenedioxy-17/3-hydroxy-Γ7λ-R'-13 /? - R-gona-4,9, ll -triene, IV, reacted, subjecting it to acid hydrolysis and the desired 3 - oxo -17 /? - hydroxy-17Ä-R'-13/9-R-gona-4,9, ll-triene, I, isolated.

According to a preferred embodiment, the above method can also be characterized by the following features can be characterized:

a) as alkylene glycol, the action of which is subjected to the 3,17-dioxo-13/3-R-gona-4,9, ll-triene, one uses ethylene glycol, and one works in the presence of oxalic acid in an organic one Solvents such as dichloroethane or chloroform;

b) as an organometallic derivative, the action of which is 3-alkylenedioxy-17-oxo-13/3-R-gona-4,9, ll-triene one uses an alkyl magnesium halide such as the iodide or bromide of Methyl or ethyl magnesium, an alkyl lithium, such as methyl lithium, an alkenyl magnesium halide such as vinyl magnesium bromide or Allyl magnesium bromide, an alkynyl magnesium halide, such as ethynyl magnesium chloride or bromide, propynyl magnesium chloride or bromide, an alkali metal acetylide such as lithium acetylide, a haloalkynyl alkali, such as chloroethinyl lithium, and a butadiynyl alkali metal, such as butadininyl-lithium;

c) the acid hydrolysis of 3-alkylenedioxy-17 / S-hydroxy-17a-R'-13/5-R-gona-4,9, ll-triene is made with the aid of an aqueous mineral acid or organic acid, such as aqueous hydrochloric acid or aqueous Acetic acid.

Example I.

Manufacture of 3-Oxo-13 / S-ethyI-17oc-ethinyl-17jS-hydroxy-gona-4,9, ll-triene

Level a

Production of 3-ethylenedioxy-17-oxo-

13 / S-ethyI-gona-4,9, ll-trien, III

(with R = - CH ₂ - CH ₃ and

R = - CH2 - CH ₂ -)

1745 mg of 3,17-dioxo-13/3-ethyl-gona-4,9,11-triene and 262 mg of anhydrous oxalic acid are added to 8.7 cm ^{3 of} glycol and 87 cm ^{3 of} anhydrous 1,2-dichloroethane, and the mixture is heated 6 Hours under reflux. The condensed dichloroethane is dried on silica gel before it is recycled.

3 4

It is then cooled, then poured into water, which is washed with water, over sodium sulfate saturated with sodium bicarbonate, and extracted with dried and evaporated to dryness; you get Methylene chloride. 1.296 g of crude product, which is chromatographed on silica gel

The extracts are washed with water, dried, graphed and eluted with methylene chloride, which evaporates 2% acetone to dryness and a residue containing 5 is obtained; After evaporation of the eluate, it is taken up on 70 g of aluminum oxide, eluting with residue, in methylene chloride, adsorbed on a mixture of benzene-cyclohexane (1: 1) chromium-magnesium silicate and matographed with methylene chloride. The eluate obtained is eluted to dryness containing 1% acetone; 782 mg are obtained evaporated, and the residue of the product, made into a paste with ether, which is obtained by recrystallization from 1051 mg (corresponding to 52% yield) of 3-ethyl acetate and then from a mixture of lendioxy-17-oxo-13/5 -ethyl-gona-4,9, ll-triene. F. = 150 benzene-cyclohexane (1: 1) purifies; you get up to 151 ⁰ C. in this way the 3-oxo-13/9-ethyl-17a-ethinyl-17 ^ hy-

The product is obtained in the form of colorless droxy-gona-4,9, ll-triene in the form of a solid, the needles, which are sparingly soluble in alcohol and ether, melts at 154 ° C, [k] _d = +84.6 ° (c = 0.41%, and soluble in benzene and chloroform. 15 ethanol).

I. R. spectrum (chloroform) shows the presence of _

be of conjugated double bonds by analyzing: C ₂₁ H ^ U ₂ - JUS, 4.
Band at 6.18 µ. Calculated ... C 81.78%, H 7.84%:

found ... C 81.8%, H 7.8%.
UV spectrum (ethanol): ₂₀

l _max 302 ma Ε} * = 930 ε = 30300 UV spectrum in ethanol:

λ ,,, αχ at 239 to 240 ma ε = 5,920

As far as is known, in the literature this connection is inflexion at 272 ma = 3450

not yet described. ) _ _max at 344 ma ε = 29 850

The starting compound 3.17-dioxo-13 / I-ethyl-25

gona-4,9, ll-trien was named after the patent application. As far as is known, this compound is in the literature

The method described in R 42 353 IVb / 12o has not yet been described,
placed.

Level B example IL

Production of 3-ethylenedioxy-13 /? - äthyl- _r ° production of 3-oxo-17jÖ-hydroxy-

17Ä-ethinyl-17/5-hydroxy-gona-4,9, ll-triene, IV 13/5-ethyl-17: \ - methyl-gona-4,9, ll-triene, I.

(with R = CH., - CH ₃ , R "= - CH, -CH, -, (with R = - CH, -CH ₃ and R '= -CH ₃ )

R '= - C ξ CH) c. ρ λ

Level a

150 cm ^{3 of} tetrahydro-35 , ., ■ · ,,,.

furan and 50 cm ^{3 of} an essential solution of the production of 3-Athyendioxy-

1.95n-methylmagnesium bromide, warmed to 40 to 17-oxo-13E-ethyl-gona-4,9, ll-tnen III

45 ° C, passes 3 ¹ / hours a stream of acetylene, a, L ^ ^1, ^ ~ u "TMS ³ χ

adds 1.235 g of 3-ethylenedioxy-17-oxo-13 / S-äthyI- ^R CH ₂ -CH ₂ -)

gona-4,9, ll-triene, dissolved in 25 cm ^{3 of} tetrahydrofuran, 40 1745 mg of 3,17-dioxo-13/5-ethyl-gona are added and the reaction mixture is stirred for 10 minutes at 4,9,11-triene and 262 mg anhydrous oxalic acid at 45 ° C; cooled to room temperature, and can be 8.7 cm ³ glycol and 87 cm ³ of anhydrous 1,2-dichloro-48 hours at about +10 ⁰ C are, then poured ethane and heated for 6 hours under reflux. The con mixture in an ice-cold, saturated solution of condensed dichloroalhanum is dried over silica gel, ammonium chloride and extracted with methylene 45 before it is recycled.

chloride; the combined organic phases are then cooled and then poured into

washed with water, dried over sodium sulfate, water saturated with sodium bicarbonate and extra- and steamed to dryness; 150 g of 3 ethylene are obtained with methylene chloride.

dioxy -13 /? - ethyl - 17ä - äthinyl -17 /? - hydroxy - gona- The extracts are washed with water, dried,

4,9,11-triene, which is evaporated to dryness as it is for the next 50, and a residue is obtained, the Process stage used. one on 70 g of aluminum oxide, eluting with a

As far as is known, this compound is in the literature a mixture of benzene and cyclohexane (1: 1) chromatonoch not described. graphed. This eluate is evaporated to dryness,

and the residue made into a paste with ether gives stage C 55 1051 mg (corresponding to a yield of 52%)

tr .π ο / ^ -, -, n-,, ■, *, -, ι S-Äthylen-dioxy-n-oxo-Dß-äthyl-gona ^^ ll-trien,

Production of 3-Oxo-13 / S-ethyl-17a-athmyl- _F _ ^ _{50 to 15} j ° c

17 / S-hydroxy-gona-4,9, ll-triene, I.
(with R = -CH ₂ -CH ₃ and

R '= - C = CH) _6o ^{Mule B}

1.50 g of the 3-ethylenic _Λ obtained in stage B are dissolved, " ^he f ^eIlun S _o ^Von 3-Äthylendioxy-

dioxy - 13 / J - ethyl - 17 "- äthinyl -17/3 - hydroxy - gona- 17 ^ hydroxy-13 ^ -ethyl-17" -methyl-gona-

4,9,11-triene in 150 cm ^{3 of} methanol, mixed with 15 cm ³ . 4 ou _D ,

Acetic acid and 7.5 cm ^{3 of} water and leave for 1 hour at << ^{with R} 7 ~ ^ "^ V ₁ ^3> ^ u ~ T ³

Stand at room temperature; pour the reac- 65 ^{and R CH} 2 CH, -)

tion mixture in 1500 cm ^{3 of} water, add sodium- Man dissolves 897.5 mg of 3-ethylenedioxy-17-oxo-

bicarbonate to neutrality and extracted with 13 /? - ethyl-gona-4,9, ll-triene in 27.5 cm ^{3 of} anhydrous

Methylene chloride; the combined organic phases are tetrahydrofuran, the solution cools to a temperature

temperature of 5 ° C and adds 11 cm ^{3 of} an ethereal solution of l, 95n-methylmagnesium bromide to within 5 minutes with stirring. The stirring is continued for 1 hour and then left to ^{stand at 0 °} C. for 24 hours. It is poured into a saturated, ice-cold solution of ammonium chloride and stirred.

It is extracted with methylene chloride, the extracts are washed with water, dried and evaporated to dryness and receives 951mg S-ethylenedioxy-n / I-hydroxylS ^ -äthyl-na-methyl-gona- ^ ll-triene, which is used without further purification for the following synthesis stage

As far as is known, this compound has not yet been described in the literature.

15 level C

Production of 3-oxo-17 /? - hydroxy-13 /? - ethyl-17a-methyl-gona-4,9, ll-triene, I.

(with R = - CH ₂ - CH ₃ , R '= - CH ₃ ) · \ ₀

951 mg of the 3 - ethylenedioxy - Ylβ - hydroxy -13 /? - Ethyl-17 "-methyl-gona-4,9, ll-triene in 95 cm ^{3 of} methanol, add 9.5 cm ^{3 of} acetic acid and 5 cm ^{3 of} water and the mixture is allowed to stand at room temperature for 1 hour.

It is poured into water, neutralized by adding sodium bicarbonate, extracted with methylene chloride, washes the extracts with water, dries and evaporates to dryness under vacuum.

The residue obtained is chromatographed on magnesium silicate, eluting with methylene chloride, which contains 6% acetone.

The eluate is evaporated to dryness and the residue, after successive recrystallization from a mixture of benzene and cyclohexane (1: 1) and then from ethyl acetate, gives 3-oxo -Ylβ- hydroxy -13 / S-ethyl-17α-methyl-gona- 4,9,11-triene, m.p. = 154 ° C, [«] § · = -41.9 ° (c = 0.7%, ethanol).

The product is sparingly soluble in ether and soluble in alcohol, acetone, benzene and chloroform.

UV spectrum (ethanol):
Imax 343 ΐημ E \ f _o = 1030 ε = 30730

Analysis: C ₂₀ H ₂₀ O ₂ = 298.41.

Calculated ... C 80.49%, H 8.78%;
found ... C80.6%, H8.7%.

B e i s ρ i e 1 III

Manufacture of 3-oxo-17/5-hydroxy

17 "-äthinyl-oestr-4,9, ll-trien, I.
(with R = - CH ₃ and R '= - C s CH)

Level a

Production of 3-ethylenedioxy

17-oxo-estra-4,9, ll-triene, III
(with R = CH ₃ and R "= -CH ₂ -CH ₂ -)

The following reaction mixture is heated for 21 hours with recycling to reflux:

3,17-dioxo-estra-4,9, ll-triene 2 g

Chloroform 100 cm ³

Ethylene glycol 10 cm ³

anhydrous oxalic acid 0.285 g

Before recycling, the chloroform is dried over calcium sulfate.

It is then cooled to room temperature, 0.9 cm ^{3 of} triethylamine are added, the whole is poured into water which is saturated with sodium bicarbonate, decanted, the aqueous phase is extracted in several portions with methylene chloride, the combined extracts are washed with water, dried and evaporated under vacuum to dryness. The crude product is taken up in 6 cm ^{3 of} methanol containing 1% pyridine, cooled on ice, filtered off with suction, the residue is washed with ice-cold methanol, dried in vacuo and 327g3-ethylenedioxy-17-oxo-oestra-4 is obtained , 9, ll-trien, m.p. = 156 ° C, [«]? = + 40.7 ° (c = 0.9%, chloroform).

The compound is soluble in alcohols when heated; it is soluble in ether, acetone, and benzene Chloroform and insoluble in water.

As far as is known, this product has not yet been described in the literature.

The starting compound is according to that described in patent application R 40 726 IVb / 12o Method made.

Level B.

Production of 3-Ethylenedioxy-17 "-äthinyl-17/3-hydroxy-estra-4,9, ll-triene, IV
(with R = CH ₃ , R '= - C = CH,
R "= -CH ₂ -CH ₂ -)

Mixing with stirring 150 cm ³ of tetrahydrofuran and 50 cm ³ of an ethereal solution of methyl magnesium bromide 1.95 n-heated to about 40 to 45 ⁰ C, passes a 3 hours, an acetylene, a solution of 1.177 g of 3-ethylenedioxy-17 -oxo-estra-4,9,11-triene ³ of tetrahydrofuran at 25 cm, the reaction mixture is stirred for 10 minutes at 45 ° C, cooled to room temperature and is allowed for 48 hours at about + 10 ⁰ C are then poured in the whole a saturated, ice-cold solution of ammonium chloride, extracted in several portions with methylene chloride, washed the combined extracts with water, dried over sodium sulfate and evaporated to dryness. 1.43 g of 3-ethylenedioxy-17a-äthinyl-17/3-hydroxy-estra-4,9, ll-triene are obtained, which is used as it is for the next stage of synthesis.

As far as is known, this compound has not yet been described in the literature.

Level C

Production of 3-Oxo-17 «-äthinyl-

17 _i 5-hydroxy-estra-4,9, ll-triene, I.
(with R = CH ₃ and R '= - C s CH)

1.43 g of the 3-ethylenedioxy-17 «-ethinyl- Ylβ -hydroxy-estra-4,9,1-triene obtained in stage B are dissolved in 150 cm ^{3 of} methanol, 15 cm ^{3 of} acetic acid and 7.5 cm ^{3 are added} Water, the reaction mixture is allowed to stand at room temperature for 1 hour, then poured into water, mixed with sodium bicarbonate until neutral, extracted in several portions with methylene chloride, the combined extracts washed with water, dried over sodium sulfate and evaporated to dryness. 1.234 g of crude product are obtained, which is chromatographed on silica gel and eluted with methylene chloride containing 2% acetone; the eluate is evaporated, the residue is taken up in methylene chloride and chromatographed on magnesium silicate

45

and eluted with methylene chloride containing 1% acetone.

745 g of the product are obtained, which is purified by recrystallization from isopropyl ether. The 3-oxo-17a-äthinyl-17) S-hydroxy-estra-4,9,11-triene is insoluble in water; it is soluble in alcohols, ethers, acetone, benzene, and chloroform; M.p. = 169 ° C, [ctyg = + 63 ° (c = 0.5%, ethanol).

UV spectrum

at 342 πιμ
at 238 ΐημ

IO

ε = 29100
ε = 5920

Analysis: C ₂₀ H ₂₂ O ₂ = 294.38.

Calculated ... C 81.59%, H 7.53%;
found ... C81.6%, H7.6%.

Example IV

Production of 3-oxo-17a-butadiynyl-17 /? - hydroxy-estra-4,9, ll-triene, I.

(with R = - CH ₃ and
R '= -Cs CC = CH)

Level a

Production of 3-ethylenedioxy

17-oxo-estra-4,9, ll-triene, III

(with R = - CH ₃ and R "= -CH ₂ -CH ₂ -)

The following reaction mixture is refluxed for 21 hours with recycling:

3,17-dioxo-estra-4,9, ll-triene 2 g

Chloroform 100 cm ³

Ethylene glycol 10 cm ³

anhydrous oxalic acid 0.285 g

40

The chloroform is dried over calcium sulfate before being recycled.

It is then cooled to room temperature, 0.9 cm ^{3 of} triethylamine is added, the whole is poured into water which is saturated with sodium bicarbonate, decanted, the aqueous phase is extracted several times with methylene chloride, the combined extracts are washed with water, dried and evaporated under vacuum to dryness. The crude product is taken up in 6 cm ^{3 of} methanol containing 1% pyridine, cooled on ice, filtered off with suction, the residue is washed with ice-cold methanol, dried under vacuum and 1.327 g of 3-ethylenedioxy-17-oxo-oestra is obtained 4,9,11 - triene, m.p. = 156 ° C [* YS = + 40.7 ° (c = 0.9%, chloroform).

55 Level B

Production of 3-ethylenedioxy-17oi-butadiynyl-17 / S-hydroxy-estra-4,9, ll-triene, IV
(with R = -CH ₃ , R '= - C = C-Cs CH and R "= -CH ₂ -CH ₂ -)

^{1 cm 3 of} freshly prepared butadiyne is dissolved in 10 cm ^{3 of} tetrahydrofuran under a nitrogen atmosphere, the temperature of the product being kept in the region of 0 ^° C. Then, while stirring, 5 cm ^{3 of} an in-solution of butyllithium in petroleum ether are added. Vigorous external cooling is maintained.

A solution of 0.490 g of S-ethylenedioxy-n-oxo-oestra-4,9,11-triene in 5 cm ^{3 of} tetrahydrofuran is added to the solution thus prepared. Maintaining the reaction mixture under stirring, 2 ¹ J ₂ hours on an ice water bath. It is then poured into 200 cm ^{3 of} water, the precipitate is exhaustively extracted in four portions with methylene chloride, the methylene chloride phases are combined, dried over sodium sulfate, filtered and evaporated to dryness; In this way, 3-ethylenedioxy-17a-butadiynyl-17jS-hydroxy-estra-4,9,1-triene is obtained, which is used as it is for the following synthesis step.

As far as is known, this compound has not yet been described in the literature.

Level C

Production of 3-oxo-17 "-butadiinyl-17ß-hydroxy-estra-4,9, ll-triene, I.

(with R = - CH ₃ and
R '= -C = CC = CH)

The entire product obtained in stage B is dissolved in 50 cm ^{3 of} methanol; 5 cm ^{3 of} acetic acid and 2.5 cm ^{3 of} water are added. After standing for 1 hour at room temperature, it is neutralized with a saturated solution of sodium bicarbonate and the aqueous phase is extracted exhaustively with methylene chloride, the organic phase is dried and evaporated to dryness.

In this way, 0.591 g of 3-oxo-17a-butadiynyl-17 / J-hydroxy-estra-4,9, ll-triene is obtained in the form of an amorphous yellow compound. The crude product is purified by chromatography on silica gel eluting with methylene chloride containing increasing amounts of acetone. From the fractions containing 2% acetone, 0.383 g of crude product can be isolated, which is found to be homogeneous on thin-layer chromatography.
IR spectrum

Presence of hydroxyl groups,
Presence of a - C ξ C group.
Presence of a 4,9,11-triene structure,
Absence of a carbonyl function in the 17-position,

The spectrum differs from that of the 17-ethinyl compound.

UV spectrum (ethanol)
l _max 238 πιμ
341 Γημ

The product comes in the form of a microcrystalline powder that is slightly yellow in color and soluble is in alcohol, ether, acetone, benzene and chloroform and insoluble in water.

As far as is known, this compound has not yet been described in the literature.

In the reaction scheme: R denotes an alkyl group with 1 to 2 carbon atoms, R 'denotes an alkyl group with 1 or 2 carbon atoms, an alkenyl group with 2, 3 or 4 carbon atoms or an alkynyl group with 2, 3 or 4 carbon atoms and R "denotes an alkylene group, - (CH ₂ ) «-, where η is the number 2, 3 or 4.

109538/359

Claims (3)

Patent claims: 1. Process for the preparation of gonatriene derivatives of the general formula in which here and below R is a methyl or ethyl radical and R 'is an alkyl radical with 1 or 2 carbon atoms, an alkenyl radical with 2, 3 or 4 carbon atoms or an alkynyl radical with 2, 3 or 4 carbon atoms, which is represented by one or « several halogen atoms can be substituted, mean, characterized in that that one is a 3,17-dioxo-13/3-R-gona-4,9, ll-triene of the general formula R O O' with an alkylene glycol of the formula HO- (CHa) _n -OH, where η is the number 2, 3 or 4, catalyzed in an anhydrous medium and in the presence of an acidic catalyst, the 3-alkylene- dioxy-17-oxo-13 /? - R-gona-4,9, ll-trien of the general " a formula R O in the R "here and in the following -
represents, with an organometallic derivative, with an organic radical R ', where R' has the meaning given above, reacts, and the resulting 3 - alkylenedioxy -17 «- R '- Π β - hydroxy-13/3-R-gona- 4,9, ll-triene of the general formula R ' OH R ' .0 subjected to acid hydrolysis and so the 3-oxo-17 «-R'-17/3-hydroxy-13j8-R-gona-4,9 ₅ ll-triene is obtained. 2. The method according to claim 1, characterized in that there is ethylene glycol as the alkylene glycol used and in the presence of oxalic acid in dichloroethane or chloroform as organic Solvent works. 3. The method according to claim 1, characterized in that the acid hydrolysis of 3-alkylenedioxy - Πβ - hydroxy - 17oc - R '- 13jß - R - gona-4,9,11-triene is carried out with aqueous hydrochloric acid or aqueous acetic acid. 1 sheet of drawings