DE1290935B - Process for the preparation of 3, 20-dioxo-19-nor-delta 4, 9-pregnadiene - Google Patents

Description

American authors recently reported that the method from Tetrahedron Letters, 1961 (3), p. 128, position of 19-nor- <d ^{4> 9} -3-keto-steroids, corresponds to a new known method. -The temperature class of biologically active steroid compounds, the conditions of this process are not described on (see MeI Per elm a η and coworkers, 4,5-Seco-3,5,20-trioxo-19-nor-Zl ⁰ - Pregnen applicable, J. Am. Chem. Soc, 82 [1960], 2402/2403). 5 because in the required alkaline environment the

Among the connection configuration at carbon atom 17 listed by the authors is the 3,20-dioxo-19-nor-Zl ⁴ⁱ⁹ -preg-time enolization of the 20-keto group, but this connection could not do what is not problematic in the gonan series. can be isolated in their pure state. However, if the reaction according to the invention at a

The present invention relates to a new encryption io temperature at ⁰ ° C is carried out, ⁹ -Pregnadien is selectively drive for the preparation of 3,20-dioxo-19-nor-3,20-dioxo-19-nor-zl ⁴ 'obtained that from-

J ⁴ ' ⁸ -pregnadien. Which is free from 17a-ismers in the case of the solute according to the invention.

drive interconnections occurring are new The following example whose last three stages are on

Substances. the reaction scheme illustrates that

The method of the invention allows the methods of the invention to be produced. Position of pure 3,20-dioxo-19-nor-ZI ^4> "-pregnadiene

by total synthesis, so that one is no longer on expensive example

Relies on natural products as raw materials. Production of 3,20-Dioxo-19-nor-zl * · »-pregnadiene (I)

The process according to the invention consists in stage A ^- oxidation

that one has 5-methoxy-17 /? - hydroxy-, d ^s ' ⁷ ' ⁹ -des-A-oestra- ao

trien with an alkaline oxidizing agent in one dissolve 3 g of 5-methoxy-17 | S-hydroxy-Zl ⁵ ' ⁷ ' ⁹ -des-

is oxidized in a known manner, the 5-Me-A-estatriene obtained from F. = ^O C, [a] ² ₀ ^{0 D} = +15 ± 3 (c == l _^0/0, thoxy-17-oxo ^ ^{5 '7' 9} -des-A-östratrien in alkaline methanol) 69, according to the method of Milieu in a manner known per se in 17a-position L. Veil uz and coworkers, Comptes rendus de äthinyliert, the resulting 5-methoxy-17 / S-hydroxy-25 l'Acadomie des Sciences, 250, p. 1084 (1960), in 400 ecm 17a-äthinyl-Zl ⁵ ''' ⁹ -des-A-oestratien with a funk- methylene chloride, adds 100 mg of anhydrous potassium tional derivative of a carboxylic acid in itself carbonate and 30 g of manganese dioxide and stirs esterified in the known manner in 170 degrees, the resulting reaction mixture for 56 hours at room temperature. Ethynyl derivative in the presence of a queeksilver salt. It is filtered, the filtrate is evaporated in vacuo to a known manner, the dryness formed is evaporated and the residue is crystallized from 5-methoxy-17i3-acetoxy-17o-acetyl-zl ^s : ⁷ ' ⁹ - des-A-estra-ethanol. To yield the 5-methoxy-17-oxo- _<d ^{5 '7-9} -des- -triene. in a manner known per se, a reduction according to - A-estatrien of F. = 89 ⁰ C, [a] i ° - = H-99 ° (c = 1% »Birch and subsequent hydrolysis with hydrochloric acid methanol).

subjects, the obtained 5-oxo-20-hydroxy-zl ⁹ -l9-nör- The product results in the form of white, star-

des-A-pregnen with the help of an acidic oxidizing agent 35-shaped crystals which are oxidized in methyl ethyl ketone and in a manner known per se in the 20-position, ethyl acetate is very soluble and in hot alcohol and the 5,20-dioxo-Zl ⁱ⁾ -19 obtained -nor-des-A-pregnen are soluble with hot isopropyl ether, a small excess of a secondary amine - - ·

at a temperature of -5 to -10 ° C. Absence analysis: C ₁₅ H ₁₈ O ₂ = 230.30. an acidic catalyst selectively in the 5-position 4 ° Calculated .. · C 78.23%, H 7.88%; reacted, the enamine obtained was found with 1,3-dichloro- ... C78.2%, H7.8%.

2-butene condensed in a manner known per se, the "

Condensation product in a manner known per se, UV spectrum in ethanol: acid hydrolyzed and the 4,5-seco-3,5,20- λτηαχ = 279πιμ,} * _m = 81.8; trioxo-19-nor- / d ⁹ -pregnen with the help of an alkaline 45 ληαχ = 287.5 ηιμ., l? _ra = 79.0. In addition, at a temperature around O ⁰ _{C selectively:}

desired 3,20-Dioxo-19-nor-Zl ⁴ ' ⁹ -pregnadien eye- The compound has not yet been found in the literature

lized. described.

A preferred Ausfünrungsform of the invention stage B ■ ethynylation

according to the method is characterized by the following features

drawn: 30 ecm of a 0.99 n-toluene solution are added

Sodium tert-amylate in 270 ecm anhydrous benzene,

a) For the formation of 5-monoenamine. is pyrrolidine brings the mixture under nitrogen to -6O ⁰ C and

in a slight excess, of less than 10% of the i _e j _{tet 30} minutes acetylene. One brings to theoretical amount is applied; ₅₅ room temperature, add 40 ecm one with stirring

b) the condensation of the enamine II with 1,3-di- benzene solution of 2.173 gin methanol dextrorotatory chloro-2-butene in the presence of potassium 5-methoxy-17-oxo-Zl ^{5 '7-9} -des-A estatria closed and iodide made; the reaction mixture at room temperature for 2 hours

_N y. TT j ι j T ^ - j - j. J 1 χ TTT stand. It is then poured into water, neutralized through

c) the acid _{hydrolysis of the condensation product III 6o z be VOQ Essi ä} decanted, which is extracted with the help of a mixture of sulfuric acid _wä | _{ri phase} J * j ^ _{then combine the}

and acetic acid carried out; ^^ _{phases) dries} ^ _{evaporates in vacu} ^ _m

d) as an alkaline cyclizing agent, sodium becomes dry. The residue is made from cyclohexane tert-amylate, dissolved in toluene, is used. recrystallizes and gives 5-methoxy-17/3-hydroxy-

65 17oc-äthinyl-Zl ^s ' ⁷ ' ^I) -des-A-estatrien from F. = 98.5 ⁰ C,

In the German Auslegeschrift 1201 345 [oi] i ° = -70.6 ° (c = 1%, methanol), already a process for the cyclization of a 4,5-sexo The product results in the form of white

3,5-dioxo-gonens suggested at room temperature, needles that are in alcohol, ether, acetone, and benzene

■ Chloroform very soluble and insoluble in water are.

Analysis: C ₁₇ H ₂₀ O ₂ = 256.33.
Calculated ... C 78.66%, H 7.86%, O 12.48%;
found ... C 79.8%, H 7.8%, O 12.4%.

The IR spectrum shows in particular the bands at 3603 and 3310 cm " ¹ .

The compound has not yet been described in the literature.

Stage C: esterification

Level E: reduction

0.786 g of lithium are added in small pieces to 369 ecm of liquid ammonia with cooling, 72 ecm of anhydrous ether and 1.141 g of 5-methoxy-17/3-acetoxy-17 «-acetyl-I ⁵ ' ^{7 are added} ; ⁹ -des-A-östratrien dissolved in 150 cc of anhydrous ether to and maintaining the reaction mixture under stirring in nitrogen atmosphere IVa hours at -45 ⁰ C. is then added slowly ίο 70 cc of anhydrous methanol and then at -45 ° C in 3.6 g lithium over one hour. The ammonia is evaporated, taken up in a mixture of 300 ecm water and 200 ecm ether, washed with water, dried and evaporated to dryness in a vacuum.

2.08 g of 5-methoxy-17 ^ -hydroxy-17'-ethinyl-zl ⁵ⁱ⁷ ' ⁹ -des-A-estatriene are dissolved in 20 ecm of acetic anhydride, 1 g of p-toluenesulphonic acid is added, and the mixture is stirred until the residue becomes in 50 ecm methanol, 12.5 ecm dissolution and then allowed to dissolve in room hydrochloric acid and 25 ecm water for 24 hours and stand at temperature for 1 hour. It is poured into water, stirred and refluxed. It is poured into water for an extra V for ₂ hours and extracted with methylene chloride. The hiert with methylene chloride, evaporated in vacuo to the extracts are dried and then dry in vacuo and chromatographed the residue evaporated to dryness. The residue is dissolved in silica gel. Elute with methylene chloride, which decolorizes 10% methylene chloride over magnesium silicate. Contains acetone, gives amorphous 5-oxo-20-hydroxy-

/ l ⁹ -19-nor-des-A-pregnen, [κ] 1 ° = -23.3 ° (c = 1.3%, methanol).

The product is very soluble in acetone, benzene and chloroform and not very soluble in ether.

UV spectrum in ethanol:

= 240 πιμ,} *, = 557.

Recrystallization from isopropyl ether gives 5-methoxy-17/3-acetoxy-17 "-äthinyl-Zl ⁵ " - ° -des-A-estatriene with a temperature of 93.5 ° C, [«] ?? = -54 ° (c = 1.5%, methanol).

The product emerges in the form of white crystals that are soluble in alcohol and insoluble in water are.

Analysis: C ₁₉ H ₂₂ O ₃ = 298.37.
Calculated ... C 76.48%, H 7.43%;
found ... C76.5%, H7.4 ° / ₀ .

The compound has not yet been described in the literature.

Level D: water retention
a) Preparation of the catalyst

The compound has not yet been described in the literature.

Level F: Oxidation

100 mg of 5-oxo-20-hydroxy-Zl ⁰ -19-nor-des-A-pregnen are dissolved in 10 ecm of acetic acid, 0.25 ecm of a solution of 600 mg of chromium trioxide in 5 ecm of acetic acid, which contains 10% Contains water, the reaction mixture is stirred at room temperature for 1 hour, then 0.5 ecm of methanol is added and the mixture is left to stand for 45 minutes. It is poured into water, neutralized by adding

200 g of acidic synthetic resin exchanger are added
11 Normal aqueous sulfuric acid, stir 30 minutes 40 sodium bicarbonate and extract with methylene and decanted. Wash with water, then add chloride. The extracts are obtained by evaporation

a residue of 5,20-dioxo- Δ ⁹ -19-nor-des-A-pregnen under vacuum, which is purified by chromatography on silica gel. A white product with a mp = 8O ⁰ C, [oc] l ° = + 53 ° (c = 0.75%, methanol), which is very soluble in the usual organic

3 g of mercury acetate and 11 water are added and the mixture is stirred 10 mins. It is decanted and washed with water.

b) hydration

Add 5 g of S-Methoxy-U / J-acetoxy ^ a-ethynyl-Zl ^{5-7 '9} -des-A-östratrien and 62.5 g of the catalyst obtained as described above in 125 cc of ethanol and heated with stirring 7 hours to reflux. It is filtered, 600 ecm of methylene chloride is added to the filtrate, the alcohol is removed by washing several times with distilled water, treated with animal charcoal, filtered and then evaporated to dryness under vacuum. The residue is recrystallized from ethanol to yield 5-methoxy-17 / S-acetoxy-17a-acetykd ^{s '7' 9} -des-A-östratrien mp = 13O ⁰ C, [*] "== + 40 ° ( c = 1%, methanol).

The product results in the form of white crystals that exist in acetone, benzene and chloroform are very soluble, soluble in isopropyl ether and hot alcohol, and insoluble in water.

Solvents and is insoluble in water.

Analysis: C ₁₆ H ₂₂ O ₂ = 246.34.
Calculated ... C78.00%, H9.00%;
found ... C77.7%, H8.8%.

UV spectrum in ethanol:

= 239 πιμ, ε = 16,200.

60

Analysis: C ₁₉ H ₂₄ O ₄ = 316.38.
Calculated ... C 72.12%, H 7.65%;
found ... C72.2%, H7.4%.

The compound has not yet been described in the literature.

The compound has not yet been described in the literature.

Stage G: Formation of the enamine II

2 g of 5,20-dioxo-d ⁹ -19-nor-des-A-pregnen are added to 0.74 ecm of pyrrolidine. The dissolution is effected by gentle heating. The mixture is cooled and added 5 cc of anhydrous methanol and then leaving the reaction mixture at -5 to -10 ⁰ C for 1 hour filters. The product formed is filtered off with suction, washed with methanol, dried, and 5-pyrrolidyl-20-oxo-Zl ^B ( ¹⁰ > ⁹ < ¹¹ >> -19-nor-des-A-pregnadiene (II) of F. = 142) is obtained ⁰ C, [»yg = + 251 ° (c == 0.5%, pyridine).

The product is in the form of yellow needles, which are soluble in benzene and sparingly soluble in alcohol.

Analysis; C ₂ OH ₂₁₉ ON = 299.44.

λ Calculated 7 .. N 4.68%;
. found ... N 4.7%.

The compound has not yet been described in the literature.

Level H: ^^
. . 19-nor'J ² ' ⁹ -pregnadien (IlI)

10

- ■ is brought 5.16 g of 5-pyrrolidyl-20-oxo-19-nor-I ^ "io), i) (ii), des.A-pregnadiene (n), mp = 142 ° C, [ «] *> == + 251 ° (c = 0.5%, pyridine) under nitrogen in 40 ecm of dimethylformamide and then add 2.88 g of potassium iodide and 3.08 g of 3-dichloro-2-butene. The reaction mixture is-with geöriihrt 0 ⁰ C I ¹ I ₂ hours and then allowed to stand at east ° C overnight. It is poured into water and extracted with ether. The • extracts are washed with an aqueous 1% sodium • bisulfite solution and then with water. After drying and filtering, the mixture is evaporated to dryness in vacuo and 5.850 g of product are obtained, which is chromatographed on calcium silicate. Eluting with methylene chloride gives 5 g of SrChlor ^^ - seco-S ^ O-dioxo-19-nor-Zl ² ' ⁹ -pregnadiene (III),

The product is in the form of a pale yellow oil which is used as it is for the following process stage. . '". ..".,' .--

The connection has not yet been made in the literature described. ,. ■ · .. ..- ·

4,5-SecQ-3,5,20-trioxo-19-nor- ^ ⁹ -pregnen (IV)

'- ■ One solves "5 g

^ a. ^ pregnadiene (III) in 5 ecm: acetic acid, bring this solution drop by drop. in sulfuric acid cooled to -15 ° C. in 25 ecm, stirred at room temperature for about an hour and then poured into water. Sodium bicarbonate is added until neutralization, extracted with methylene chloride, the extracts washed with water, dried, filtered and evaporated in vacuo .to dryness .. The residue is chromatographed on silica gel and eluted with methylene chloride, which contains 4% acetone. 4.2 g of 45-seco-3,5,20-trioxo-19rnor-Zl ⁹ -pregnen (IV) are obtained. __. That. The product is in the form of an oil, [«]» = + 37 ° (C = 1%, methanol).

The compound has not yet been described in the literature.

Level K: 3,20-Dioxo-19-nor-zl ⁴ ' ⁹ -pregnadiene (I)

1.67 g of 4,5-seco-3,5,20-trioxo-19-nor- <d ⁹ -pregnen (IV) are dissolved in 70 ecm of anhydrous toluene, cooled, to 0 ° C. amd.f then 4.2 ecm of a 1.28 η-toluene-S5 solution of sodium tert-amylate.

The reaction mixture is stirred at 0 ° C. under nitrogen for 2 hours and 20 minutes. Then added to 0.4 cc of acetic acid, washed with ^, _ .'Wasser, dried and "evaporated in vacuo to M 'dryness. The residue crystallizes easily, after washing with ether and left to stand in an ice bath. .MAN purified by chromatography on Magnesium silicate, eluting with methylene chloride and subsequent recrystallization from methanol with 50% water.

Yield: 1 g (about 60% der.Theorie) of 3,20-diketo-19-nor-J ^{4 '9} -Pregnadien (I), mp = 104 ⁰ C, [φ ⁰ = -209 ° (c = 0.5%, methanol).

The product arises in the form of white Crystals that are found in common organic solvents, such as alcohol, ether, acetone, and benzene Chloroform, very soluble, sparingly soluble in cyclohexane and isopropyl ether and insoluble in water.

Analysis: C ₂₀ H ₂₈ O ₂ = 298.4.

Calculated ... C 80.49%, H 8.78%; found ... C 80.4%, H 8.8%.

UV spectrum:

λτηίΐεχίοη 236 ΐημ, \ f _n - 163;

Hwn 303 ηιμ, \ f _m = 70O ₅ ε = 20,900.

Claims (5)

Patent claims: 1. A process for the preparation of 3,20-dioxo-19-nor-Zl * ' ⁹ -pregnadiene, characterized in that 5-methoxy-17 | 8-hydroxy-2J ^B - ⁷ ' ⁸ -des-A-estratriene oxidized with an alkaline oxidizing agent in a manner known per se, the 5-methoxy-17-oxo-Zl ^s - ⁷ > ⁹ -des-A-estatriene obtained is ethinylated in an alkaline medium in a manner known per se in the 17 "position, the obtained 5-Methoxy-17 _/ e-.hydroxy-17a-äthinyl- ^ l ⁵ ' ⁷ ' ⁹ -des-A-oestratriene esterified with a functional derivative of a carboxylic acid in a known manner in 17ß control, the ethynyl derivative obtained in the presence of a mercury salt hydrated in a manner known per se, the 5-methoxy-17 _i 8-acetoxy-17 "-acetyl-4 ^B ' ⁷ ' ⁹ -des-A-estatriene formed in a manner known per se, a reduction according to Birch and subsequent hydrolysis Subjected with hydrochloric acid, the resulting 5-oxo-20-hydroxy-4 ⁹ -19-nor-des-A-pregnen with the help of an acidic oxidizing agent in a known manner in the 20-position oxydi ert, the obtained 5; 20-dioxo-Zl ⁹ -19-nor-des-A-pregnen with a slight excess of a secondary amine at a temperature of -5 to -10 ° C in the absence of an acidic catalyst selectively in the 5-position reacts, the enamine obtained is condensed with 1,3-dichloro-2-butene in a manner known per se, the condensation product is acid hydrolyzed in a manner known per se and the 4,5 - seco - 3,5,20 - trioxo -19 - obtained nor - Δ ⁹ - pregnen with the help of an alkaline agent at a temperature around ^{0 0} C selectively cyclized to the desired 3,20-dioxo-19-nor-4 ⁴ ' ⁹ -pregnadiene. 2. The method according to claim 1, characterized in that that pyrrolidine is used as the secondary amine to form the 5-monoenamine. 3. The method according to claim 1, characterized in that the condensation of the obtained Enamins with 1,3-dichloro-2-butene in the presence of potassium iodide. 4. The method according to claim 1, characterized in that that the acid hydrolysis of the condensation product with the aid of a mixture of Sulfuric acid uride acetic acid performs. 5. The method according to claim 1, characterized in that .man as an alkaline cyclizing agent Sodium tertiary amylate, dissolved in toluene, is used. ■ * 5 ° - 1 sheet of drawings