DE1239306B - Process for the preparation of keto steroids which carry an optionally substituted allyl group in the alpha position to the keto group - Google Patents

Description

TUNDED REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07c

CO 7 J 4 \ fß _{

German class: 12 ο -

Number: 1239

File number: V25919IVb / 12o

Filing date: April 30, 1964

Open date: April 27, 1967

The invention relates to a process for the preparation of keto steroids which are in the α-position to the keto group an optionally substituted AUyl group wear.

The inventive method is characterized in that the mixture is heated, optionally in the AUylgruppe by an alkyl, aralkyl or aryl group substituted Allylenoläther of corresponding keto steroids in a solvent having a boiling point between 100 and 200 ⁰ C, optionally obtained 4-allyl-l ⁵ -3 -ketones isomerized in a manner known per se to the 4-allyl-H-3-ketoncn or the resulting mixture of optionally substituted 16n- and 16 / i-allyl-17-keto steroids in a manner likewise known per se with a strong base, preferably treated with an alkali hydroxide.

The scheme of the rearrangement is given in the following table, in which the conversion of enol ethers of 3-keto, 17-keto and 20-keto steroids into the corresponding, free, α-allyl-substituted Ketones is illustrated.

Process for the preparation of keto steroids, which may be in -position to the keto group carry substituted AUyl group

Applicant:

Francesco Vismara S. p. A., Casatenovo, Como (Italy)

Representative;

Dipl.-Ing. H. Leinweber and Dipl.-Tng. H. Zimmermann, patent attorneys, Munich 2, Rosental 7

Named inventor: Alberto Ercoli, Milan; Dr. Rinaldo Gardi, Carate, Brianza (Italy)

Claimed priority: Italy of May 11, 1963 (34 946), of March 13, 1964 (45 018)

Table I.

a) CH == C - CH - O Ri R ² R3

CH = C - CH

R ⁸

² R ¹

b) CH = C-CH-O R • R ² R <

CH - R ¹ 709 577/376 C - R ² CH
I. - R ^;) 1

continuation

CH - R ¹ C-
H R ⁸ Il
CH - R3

c) CH = C-CH-O
R ¹ R ² R *

0-CH-C = CH

\ R ³ R ²

CH ₃

H ₃ C | l

CH

Ο -CH-C = CH
R ³ R ² Ri

R ² Ri '

CH ₂ - CH - C = CH
CO R ¹ R ² R3

R = H, methyl; Ri, R ² , R ³ = H, alkyl, aralkyl, aryl.

Preferably, the starting oil ethers are in the solvent, ζ. B. toluene, xylene, butyl alcohol, Pyridine, collidine, quinoline, dimethylformamide and the like, boiled under reflux for 4 to 24 hours, and that resulting product is by known methods, for. B. by evaporation and recrystallization or by pouring the reaction mixture into water and removing the precipitate.

The rearrangement is quite general and can occur with any enolizable ketosteroid, such as z. B. a 2-, 3-, 4-, 6-, 11-, 16-, 17- or 20-ketone, can be applied.

Preferred starting materials are the allylenol ethers of 3-keto steroids saturated or J! -unsaturated in ring A, the allylenol ethers of 17-keto steroids and the allylenol ethers of 21-unsubstituted 20-ketosteroids of the pregnane series, as in FIG table above.

The rearrangement can be carried out with allylenol ethers from any 3-ketosteroid of the androstane, 19-Norandrostan-, Pregnan-, 19-Norpregnan-, Cholestan- or 19-Norchoic: .tan series, in particular of optionally I '-unsaturated 3-ketosteroids, the in the 11-position optionally a hydroxy or

5 6

Keto group and in 17-position a ^ -hydroxy or soluble semicarbazone ^ are easily deposited

Acyloxy group and optionally an «-alkyl- can.

or a-alkynyl group or a / I-acetyl group and the allylenol ethers used as starting materials

optionally a «-hydroxy or acyloxy group can be selected from the corresponding lower alkylenol

or the optionally esterified dihydroxyacetone 5 ethers or from enol esters or from lower di-

wear side chain. alkylacetals by exchange reaction with the

If one assumes "Allylenoläthern of 3-keto-chosen allyl alcohol in the presence of a Catalysteroiden the 5a series from [Scheme a) of Table I], sators are prepared. The orbital will Thus, at the end of the reaction, a 2'-allyl is obtained by adding the lower alkylenol-3-keto compound practically the only product. io ether, preferably methyl or ethylenol ether, If, on the other hand, from allylenol ethers of 3-keto or enol esters, preferably enol acetate, or If steroids of the 5 / i series proceeds, the lower dialkyl acetal is obtained, preferably the corresponding one 4a - Allyl - 3 - keto compounds, methyl or diethylacetal, in a suitable one (Scheme b)]. organic solvents), such as benzene, toluene,

If the process according to the invention is applied to 15 hexane, cyclohexane, petroleum ether, tetrahydrofuran, allylenol ether of _1 ⁴ -3-ketosteroids [scheme c) dioxane, methylene chloride or chloroform, and Table I], in particular by using the mixture obtained with the optionally If such enol ethers are heated in neutral solvents, pre-substituted allyl alcohol in the presence of a catalyst, preferably in toluene, then 3 ketones, such as an aromatic sulfonic acid, quenched-4-allyl ^5- steroids are obtained. These can be converted by treating silver oxide or a salt of a weak base with an acid or with a base with migration with strong acids such as pyridine chlorohydrate or the double bond from the 5 (6) to the 4 (5) position. The allylenol ethers obtained in the corresponding 3-keto-4-allyl-I ⁴ -steroids are usually isolated by storing the acidic ones. If the rearrangement of the allylenol catalyst is neutralized, the solvent is evaporated ^{in an ether of the l 4} -3-ketosteroids in a basic 25 and the residue is recrystallized.
Solvent, preferably pyridine, carried out. The allyl ketosteroid obtained according to the invention so no 5-unsaturated derivative is isolated because they serve as intermediates for the production of the basicity of the solvent, the migration of the corresponding alkyl compounds, with which a double bond and the direct formation of the 4-allyl and economical method of manufacture: l'-3-ketosteroids effects. 30 of «-alkyl-substituted cctosteroids now for

For the implementation of the invention is available. This biologically interesting driving can also be done by allylenol ethers of a compound were previously herbeliebigen 17-ketosteroids of androstan- or made by methods, which under drastic conditions, eg. B. 19-norandrostane series [scheme d) of Table I] go out using alkali metals in liquid. The starting steroids can generally run ammonia, with particularly sensitive ones having a 3-digit oxygen function, in particular groups, e.g. B. hydroxy or Dieinen keto oxygen or an a- or / 5-oriented, hydroxyacetonseitenkette, may be disturbed, free, etherified or esterified hydroxyl corresponds other hand can hold the produced according to the invention. Other substituents, such as halogens, keto, or alkylketo compounds by hydrogenation of the allyl hydroxyl or methyl groups, can be converted into the entpentanopolyhydrophenanthrene skeleton with good yields in the cyclo- 40 double bond, for example into 1-, 2-, speaking alkyl compounds. , 6-, 7-, 9-, U- and / or 16-position. without furthermore possibly present in the molecule, the starting 17-allylenol ethers can interfere with the double bonds.
Rings A, B and / or C be saturated or one or The following examples explain the double bonds according to the invention z. B. in 1 (2) -, 4 (5) -, 5 (6) -, 45 according to procedures.
6 (7) - and / or 9 (11) position or an aromatic _D. . ,
RingA included. example 1

If the rearrangement of allylenol ethers is carried out to a mixture of 600 cm ^{3 of} anhydrous 17-ketosteroids, mi-benzene and 6 cm ^{3 of} allyl alcohol are obtained, 150 mg of mixtures of 16 "- and lo / i-AHyl-H-keto compounds are added. 50 p-toluenesulphonic acid is added, then to the gene in which the α-epimer represents 60 to 80%. obtained mixture 3 g of ethylenol ether of the testo, while the / 3-epimer is present in a smaller amount (40 to sterone acetate and removes 20% during the reaction). The two epimers can form ethanol by distillation. Then adds to be separated by fractional crystallization. 0.5 cm ^{3 of} pyridine is added and the mixture is distilled in vacuo. However, the / tf epimer can be obtained quantitatively to dryness. The residue will be taken up with ether by taking the mixture with a strong, and the ether solution is filtered off, base, e.g. B. an alkali hydroxide, treated, dried and evaporated. The residue which has been recrystallized from methanol to convert the ot-epimer into the more stable β-isomer yields the ITp'-acetoxywird. Of course, 3 - allyloxy - J ³ · '- androstadiene (allylenol ether of the esterified hydroxyl groups, if any, are present in the steroid molecule); F. 107 to 109 ^o C; [a] f - -144.5 "rend hydrolyzed by the alkaline treatment. (Dioxane, c ^ 0.5%).

The enol ethers of 21-unsubstituted 20-keto-2 g of the compound thus obtained are in 50 cm ³

Order steroids of the Pregnan range are dissolved from an anhydrous pyridine, and the solution is made

Mixture of ..1 '"(2O) - _and I ²⁰ < ²¹ > -enol ethers. Boiled under reflux for 16 hours. The Claisen rearrangement of such a mixture of allyl reaction mixture in ice containing hydrochloric acid is then

enoläthcrn provides a mixture of 17VAHyI- and water poured. This is how you get a crystalline one

21-Allyl-20-keto compounds, which after known precipitate, which after filtering off, washing with

Methods, e.g. by forming various water and drying 1.9 mg of 4-allyltestosterone acetate

supplies; M.p. 83 to 85 "C; [«]? = + 104 ° (chloroform, c = 0.50 / o).

Example 2

3 g of ethylenol ether of 17a-acetoxyprogesterone in 50 cm ^{3 of} anhydrous tetrahydrofuran are treated with 60 mg of benzenesulfonic acid and 5 cm ^{3 of} allyl alcohol. The mixture is distilled off until the volume has become a quarter, then a few drops of pyridine are added and the solvent is removed in vacuo. The residue taken up in dilute methanol, filtered off and dried gives the S-AHyloxy-Ha-acetoxy ³ - ⁵ -pregnadien-20-one (allylenol ether of 17a-acetoxyprogesterone); F. 108 to UO ⁰ C.

2 g of S-AUyloxy-Hu-acetoxy-I ^3j5 -pregnadien-20-one are dissolved in 50 cm ^{3 of} toluene, and the resulting solution is refluxed for 15 hours. The reaction mixture is then completely evaporated in vacuo. The residue taken up with methanol gives 4-allyl-17o-acetoxy-.l ⁵ -prcgnen-3,20-dione: mp 170 to 172 ⁰ C; [«] !? - + 20 ° (dioxane, c = 0.50 / ₀ ).

The product thus obtained is dissolved in methanol and ^{refluxed with 0.5 cm 3 of} hydrochloric acid. The mixture, which is concentrated in vacuo, gives 4-allyl-17a-acetoxyprogesterone which, after recrystallization, ^{melts at 200 to 201 0} C; [<x] f = + 86 ° (chloroform, c = 0.5%).

3 ° B c i s ρ i e 1 3

3 g of ethylenol ether of androstanolone acetate in 50 cm ^{3 of} anhydrous tetrahydrofuran are treated with 60 mg of p-toluenesulphonic acid and 5 cm ^{3 of} allyl alcohol. The mixture is distilled off for 40 minutes, then treated with 2 drops of pyridine and concentrated in vacuo. The residue taken up with dilute methanol yields 2.5 g of 3-AUyloxy-17 /? - acetoxy-.l ² -5 "-androsten; M.p. 104 to 106 ⁰ C; [a] 'i - + 46 ° (dioxane, c = 0.5%).

2 g of the compound thus obtained are dissolved in 50 cm ^{3 of} toluene and the solution is refluxed for 12 hours. The solvent is evaporated in vacuo, and the residue recrystallized from methanol yields the 2 "-allyl-17 / j-acetoxy-5"-androstan-3-one; F. 128 to 13O ⁰ C; [a]% => + 5 ° (chloroform, c - 0.5%).

Example4

3 g of androsterone acetate-n-diethylacetal in 500 cm ^{3 of} anhydrous isooctane are treated with 30 mg of pyridine tosylate and 10 cm ^{3 of} allyl alcohol. The mixture is distilled off until the volume has become 30 cm ³ , then treated with 2 drops of pyridine and concentrated in vacuo. The residue taken up with methanol gives 2.5 g of 17-AUyloxy-3'-acetoxy-I ¹⁶ -androsten (17-allylenol ether of androsterone acetate); F. 102 to 104X; [a}% ⁵ = - | - 52.5 ° (dioxane, c - 0.5%).

2 g of the H-AHyloxy-Sa-acetoxy-I ¹⁶ -androstene obtained in this way are dissolved in 10 cm ^{3 of} toluene, and the solution is refluxed for 15 hours. The solvent is evaporated in vacuo and the residue yields 1 g of loa-allylandrosterone acetate; M.p. 95 to 96 ⁰ C; [«] ?? '= + 15 ° (dioxane." C = 0.50 / o).

The product thus obtained is dissolved in 100 cm ^{3 of} methanolic sodium hydroxide and the solution is refluxed for about 45 minutes. After evaporation of the solvent, the residue yields 850 mg of 16 />'-allylandrosterone; Mp 179-180 ° C; [a] i ^s - + 98 ° (dioxane, c = 0.5%).

Example 5

2 g of estrone - 3 - cyclopentyl ether - 17 - diethylacetal are dissolved in 300 cm ^{3 of} isooctane and treated with 20 mg of pyridine tosylate and 5 cm ^{3 of} allyl alcohol. The mixture is distilled off for 20 minutes, then treated with 2 drops of pyridine and the solvent is evaporated in vacuo. The residue taken up with dilute methanol gives 1.5 g of 3-cyclopentyloxy-17-allyloxy-1,3,5 (10), 16-oestratetraene (oestrone - 3 - cyclopentyl ether - 17 - allylenol ether); M.p. 63 to 66 ^C C; [α]! ¹ = + 103 ° (dioxane, c - 0.5%).

1 g of the 3-cyclopentyloxy-17-allyloxyl, 3,5 (10), 16-estratetraene obtained in this way is dissolved in 10 cm ^{3 of} toluene, and the solution is refluxed for 20 hours. The solvent is evaporated in vacuo and the residue yields 900 mg of 16-allylestrone-3-cyclopentyl ether. The product thus obtained, which consists of a mixture of the epimeric 16a and 16 /? - allyl compounds, is dissolved in 5% strength methanolic potassium hydroxide, and the mixture is refluxed for 40 minutes. After evaporation of the solvent, the residue diluted with water yields 850 mg of 16/5 allyl · estrone-3-cyclopentyl ether; M.p. 142 to 144 ^° C; \ d \ 'S = + 154 ° (dioxane, c = 0.5%).

Example 6

1 g of 3-cyclopentyloxy-17-allyloxy-1,3,5 (10), 16-oestratetraene is dissolved in 5 cm ^{3 of} pyridine and the mixture is refluxed for 16 hours. After evaporation of the solvent in vacuo, the residue consisting of the mixture of 16% and 16% allylestrone-3-cyclopentyl ether is recrystallized two to three times from methanol-ether mixtures. This gives the loa-AUyl-oestrone-3-cyclopentyl ether; F. 88 to 9O ⁰ C; [a] S ⁵ = H-98.5 ° (dioxane, c = 0.5%). The evaporated in vacuo mother liquor provides the lo / i-Allyl-estrone-S-cyclopentyläther which melts after a further recrystallization at 142-144 ⁰ C. The mixed melting point with the compound obtained in Example 5 remains unchanged.

Example 7

3 g of 20.20 - dimethoxy - 3β - acetoxy - J ⁵ - pregnen in 500 cm ^{3 of} anhydrous dioxane are treated with 30 mg of pyridine tosylate and 10 cm ^{3 of} allyl alcohol. The mixture is distilled off until the volume has become 30 cm ³ , then treated with 2 drops of pyridine and concentrated in vacuo. The residue consisting of a mixture of 20-AHyloxy-3 / i-acetoxy- t ⁵ - ¹⁷ < ^{2 <1} > pregnadiene and 20-allyloxy-3 / I-acetoxy- I ^{5 20} < ²¹ > -pre- <gnadiene becomes dissolved in 50 cm ^{3 of} anhydrous dimethylformamide, and the solution is ^{heated for 15 hours at 115 C} C, then with a 5% methanolic solution of potassium

hydroxyd saponified. The mixture obtained is treated with semicarbazide orhydrate, the 20-semicarbazone of 21-allyl-J ⁵ -pregnen-3 / i-ol-20-one being obtained as a crystalline precipitate. The 17u-allyl- ^{1 5} -pregnen-3 / i-ol-20-one is isolated from the mother liquor; M.p. 193 to 196 ° C; [α]? = -60 ° (dioxane, c - 0.5 ° / q). Hydrolysis of the semicarbazone with sulfuric acid in ethanol gives the 21-allyl-J ⁵ -pregnen-3 /? - ol-20-one; M.p. 105 - -28 ° (dioxane, c - 0.5%).

to 108 ⁰ C; [«] !?

Example 8

Following the procedures described in Examples 1 to 7, the following α-allyl-substituted Make ketosteroids from the starting materials listed in the table below:

Table II

Raw materials end products

3-allyloxy-I ³ S-androstadien-17-one; M.p. 142 to 144 ^° C; [a] _D = -85.5 ° (dioxane)

3-allyloxy-J ^{a 5-} androstadien-17 /? - ol acetate; F. 107 to 109 ⁰ C; [aj _o = -144.5 ° (dioxane)

3 - (/ J-methyl) -allyloxy-J ^{:? 5-} androstadien-17-one; M.p. 160 to 161 ⁰ C; [a] _D = -77 ° (dioxane)

3-cinnamyloxy-. l ³ - ⁵ -androstadien-17-one; M.p. 142 to 143 ^° C; [a] o - -70 "(dioxane)

3-allyloxy-19-nor-J ³ ■ "-androstadien-n / i-ol-acetate; M.p. 110 to HI ⁰ C; [a] _B = -158 ° (dioxane)

3-allyloxy-l ³⁵ -pregnadien-20-one; M.p. 111 to 112 ° C; [α] ο = -56 ° (dioxane)

3 - (/? - methyl) allyloxy-21-acetoxy- l ³⁵ -pregnadien-17a-ol-ll, 20-dione; M.p. 157 to 159 ^° C;
[u] _D = + 20 ° (dioxane)

17-allyloxy-3ii-acetoxy'J ^{5 ((i) 1 (i} -androstadiene;
M.p. 104 to 106 ^c C; [o] _o = -31 = (dioxane)

n-allyloxy-S / i-acetoxy-I ¹⁶ -androsten; M.p. 89 to 92 ⁰ C; [η] ο - -1-37 ° (dioxane)

17-AUyloxy-J ^{4 16} -androstadien-3-one

17-allyloxy l ^l "-5a-androsten-3-one; M.p. 123 to 126 ° C; [a] n - -f 136 ° (dioxane)

¹⁶ -androstadicn

20-Allyloxy-3 /? - acetoxy - .. l ⁵¹⁷ < ² °) -pregnadiene
20-allyloxy- | ii7 <2 ") pregnadien-3-one

20-allyloxy-3 /} - acetoxy-J ⁵ - ^{2 () (21)} -Pregnadien
^ 0-Allyloxy -,. 1 ⁴² »(ai). _pre g _nadien .3. _on 4-allyl- | 5-androstene-3,17-dione; M.p. 135-138 ° C; [ _a ] _D ^ + 111 ° (dioxane)

4-allyl-J ⁴ -androsteno-3,17-dione; M.p. 131 to 133 "C; [ _a ] ₀ ^ + 195 ° (chloroform)

^ Allyl-J ^ androsten-n / i-oW-on-n-acetate; M.p. 111 to 113 ⁰ C; (a] _c = + 23 ° (dioxane)

4- (β-methyl) allyl-J ⁴ -androsteno-3,17-dione; F. III to 113 ⁰ C; [α] ₀ = + 176.5 ° (chloroform)

4- (a-phenyl) -allyl- / l ⁴ -androsteno-3,17-dione; oil; [«]" = Η-180 ° (chloroform)

4-allyl-19-nortestosterone acetate; M.p. 111 to 113 ° C; [ _u ] ₀ = ₊ 46 ^O (chloroform)

4-allyl progesterone; Mp 100-102 ° C; [u] o = + 190 ° (chloroform)

4 - (/} - methyl) allylcortisone acetate; Mp 200-202 ° C; [u] c - + 193.5 ° (chloroform)

lou-allyl-dehydroepiandrosterone acetate; M.p. 132 to 134 ⁰ C; [«], - -58 ° (dioxane)

16 / J-allyl dehydroepiandrosterone acetate; M.p. 145 to 147 ° C; [a] _D = +27.2 ^c: (dioxane)

loess-allyl-dehydroepiandrosterone; Mp 187-189 ° C; [a] o = + 41 ° (dioxane)

16 / i-allyl-epiandrosterone; M.p. 185 to 186 ⁰ C; [ _a ] ₀ = + 100 ° (dioxane)

16a-allyl-J ⁴ -androsteno-3,17-dione; Mp 300-132 ° C; [rt] ₀ ^ = + 91.5 ° (dioxane)

16 | 3-allyl-J ⁴ -androsteno-3,17-dione; M.p. 134 to 136 ⁰ C; [u] o - = + 166 ° (dioxane)

16 /? - allyl-5a-androstane-3,17-dione; M.p. 141 to 142 ° C; [ _a ] ₀ = + 112 ° (dioxane)

16a - (/ J-methyl) allyl dehydroepiandrosterone acetate; Mp 140 to 142 ° C; [a] ₀ = -72 ° (dioxane)

16 / i - () ii-methyl) allyl dehydroepiandrosterone acetate; M.p. 119 to 121 ° C; [a] _D = -22.5 ° (dioxane)

¹ 6 / M / i-methyl) allyl ^: dehydroepiandrosterone; M.p. 161 to 164 ° C; [a] ₀ = + 36.5 ° (dioxane)

17u-allyl-3ß-acetoxy-J ⁵ -pregnen-20-one; Mp 150 to 152 ° C; [a] ₀ = -56 ° (dioxane)

17u-allyl-progesterone; M.p. 154 to 156 ^° C; [a] _D = + 72 ° (dioxane)

21-allyl-3 | Ö-acetoxy-J ⁵ -pregnen-20-one; M.p. 72 to 75 ° C; [α] ρ = -27 ° (dioxane)

21-allyl progesterone; oil; [«]" - + 95 ° (dioxane)

709 577/376

Claims (4)

Patent claims: 1. A process for the preparation of keto steroids which carry an optionally substituted allyl group in the -position to the keto group, characterized in that optionally substituted allylene in the allyl group by an alkyl, aralkyl or aryl group of corresponding keto steroids in a solvent with a boiling point between 100 and 200 ⁰ C is heated, optionally obtained 4-allyl-.J ⁵ -3-ketone in a known manner to the 4-allyl-J ⁴ -3-ketones or isomerized, the resulting mixture of optionally substituted 16 "- and 16 /? - Allyl-17-keto steroids in a manner also known per se with a strong base, preferably with an alkali hydroxide. 2. The method according to claim 1, characterized in that that the reaction in a basic solvent, especially in pyridine, or in a neutral solvent, especially in toluene. 3. The method according to claim 1, characterized in that an optionally substituted allylenol ether of a J ⁴ -3-keto steroid of a saturated in ring A 3-keto steroid of the 5 "series, a 17-Ke.tosteroids or an optionally substituted allylenol ether of a 21 - Unsubstituted 20-keto steroids of the Pregnan range used as starting materials. 4. The method according to claim 1 to 3, characterized in that the obtained 16a and 16 / i epimers by fractional crystallization be separated.