DE1279675B - Process for the production of 19-nor-progesterone - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

German class:

C07c

12 ο -25/05
120-25

Number: 1 279 675

File number: P 12 79 675.7-42 (R 32966)

Filing date: June 20, 1962

Opening day: October 10, 1968

The invention relates to a new process for the production of 19-nor-progesterone, starting from 4,5-seco-3,5,20-trioxo-19-nor-J ⁹ -pregnen.

Several processes are already known for the production of 19-nor-progesterone, namely the 12-stage breakdown of strophanthidine, which gives a yield of 0.07%; Furthermore, a process starting from diosgenin via 3,20-dioxo-5 & -pregnane, which gives a yield of 2% in 14 steps, and two processes starting from diosgenin via 3.17 / S-dihydroxy-17 «- äthinyl-zl ¹ ' ³ ' ^{B (10)} -estratriene, either in 21 steps via 3-methoxy-17 "-acetyl-17/3-acetoxy- ^ i, 3.6 <io) _ _östratr j _{en m} j _te i _ner yield of 0.63% or in 21 steps via S-hydroxy-n-acetyl-J lead ¹ · ³ · ⁸ * ¹⁰⁾ -estratriene with a yield of 0.74% ^for 19-nor-progesterone. All of these processes rely on natural products as starting materials and for this reason and because of the low yields are not technically satisfactory.

The process according to the invention consists in stereoselectively pregnening the 9 (10) double bond of 4,5-seco-3,5,20-trioxo-19-nor- / l ⁸ -pregnen by hydrogenation in the presence of a noble metal catalyst in an alkaline medium reduced to the 9 ", 10 / S compound and the reduced product cyclized in the presence of an acid in a manner known per se.

The process of the invention enables the synthesis of 19-nor-progesterone, starting from 6-methoxytetralone, an easily and cheaply available precursor, which via 5-methoxy-17-hydroxy-Zl ⁶ · ⁷ · ⁹ -des-A-estratriene in the starting compound II used according to the process is converted. 19-nor-progesterone is obtained in a total of 20 steps with a yield of more than 4% (based on 6-methoxytetralone), which in view of the fact that on the basis of various literature references (cf. J. Chem. Soc, 1961, p. 4549, and Bull. Inst. Quim. Univ. Nac. Autonom. Mexico IV [1952], p. 125) an epimerization in the 17-position of the 20-keto compound had to be feared in the last stage of the process according to the invention, represents a surprising result .

In the process according to the invention, the hydrogenation of the starting compound II is carried out in the presence carried out a catalyst, which consists of a noble metal such as palladium or platinum, wherein one works in an alkaline environment.

An acid, for example hydrochloric acid in an acetic acid medium, is used as the cyclizing agent, used.

The starting compound II of the process according to the invention is partly by the process of the process for the preparation of
19-nor-progesterone

Applicant:
Roussel-Uclaf, Paris

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:

Nomime Gerard, Noisy le Sec Seine;
Bucourt Robert, Clichy S / Bois Seine-et-Oise;
Tessier Jean, Paris (France)

Claimed priority:

France of June 28, 1961 (866 332)

French patent 1,370,566. For the production of the described in connection with the example Starting compound II is not sought after in the context of the present invention.

The following example explains the method according to the invention.

example

Production of 19-nor-progesterone
Level A: reduction

31.6 mg of palladium-carbon with 10% palladium hydroxide are added in 25.3 cm of 95% ethanol and 2.5 cm of a 10% ethanolic solution of triethylamine. The catalyst is hydrogenated with hydrogen, then 316 mg of 4,5-seco-3,5,20-trioxo-19-nor-Zl ⁹ -pregnen (II), dissolved in 25.3 ecm of ethanol, are added. It is hydrogenated until the theoretical amount of hydrogen is absorbed, filtered and then evaporated to dryness under vacuum.

The residue consists of 4,5-seco-3,5,20-trioxo-19-nor-pregnane (III) to be used as is for the next stage.

809 620/582

3 4

The compound has not yet been found in the literature. The product appears in the form of white needles,

described. those in alcohol, ether, acetone, benzene and chloroform

Step B: Cyclization h are ^{very soluble in water and Iöslic} ™.

323 mg ^ S-Seco ^^ O-trioxo-W-nor-pre-5 ^An * ^l y ^se : ^C " ^H ™ ° * ~ f ⁶ f ·" ~ " _A9OI

gnan (III) in 6.4 cc of acetic acid added, 0.4 ecm ^be concen-. ^red f ^et · · · £ ^ 9.66%, H 7.86%, O 12.48%;

trated hydrochloric acid and left for one night at room temperature ... C 79.8%, H 7.8%, O 12.4%.

stand temperature. It is then poured into water, neutral. The IR spectrum shows in particular the bands in

sized by adding sodium bicarbonate and an extra 3603 cm " ¹ and 3310 cm" ¹ , then added ether. The extracts are made according to io

Washing with water and drying, filtered and then ^{mute c:} esterification

evaporated to dryness in vacuo. Dissolve 2.08 g of S-methoxy-nß-hydroxy-IVa-ethi-

The residue crystallizes from isopropyl ether. nyl- ^ d ⁵ ' ⁷ ' ⁹ -des-A-estatriene in 20 ecm acetic acid anhy-One receives 166 mg (total yield 58%) 19-nor- dride, add 1 g p-toluenesulfonic acid, stir until progesterone of F. = 144 ° C, [£ x] ² _D ⁰ = + 139 ⁰ (c = 0.5%, 15 dissolution and then left for 24 hours in room chloroform), which is the temperature described in the literature. It is poured into water, stirred benen is identical. ¹ J ₂ hours and extracted with methylene chloride.

The extracts are dried and then taken under

_{TT A} ", _t . , Vacuum evaporated to dryness. The residue

Production of the starting compound _{20 is based on magnesium silicate in} methylene chloride

4,5-seco-3,5,20-tnoxo-19-nor-/ l »-pregnen (II) _{fäfbt Recrystallization in} i _SO p _ropy iäther ER-

Stage A Oxidation holds 5-methoxy-17 (ö-acetoxy-17 * -äthinyl- ^ l ^{517 9} -

des-A-estatria from F. = 93.5 ° C, [<*] f = -54 ^q

3 g of 5-methoxy-17/8-hydroxy-Zl ⁵ ' ⁷ ' ⁹ -des- (c = 1.5%, methanol) are dissolved.

A estatria from F. = 69 ° C, [α] ο ° = + 15 ± 3 ° (c = 1 ° / oj ^a 5 The product results in the form of white kri-methanol), made from 6-methoxytetralone after stallen, which is soluble in alcohol and insoluble in water are L. V e 11 u ζ and co-workers, Comptes rendus de.
l'Academie des Sciences, 250, p. 1084 (1960), in _

400 ecm methylene chloride, adds 100 mg anhydrous Analysis: C ₁₉ H ₂₂ O ₃ - 298.37; Potassium carbonate and 30 g of manganese dioxide are added and the mixture is stirred for 30 calculated ... C 76.48%, H 7.43%; the reaction mixture found 56 hours at room temperature ... C 76.5%, H 7.4%.

rature. It is filtered and the filtrate is evaporated in vacuo

to dryness and the residue crystallizes from stage D: hydration

Ethanol. To yield the 5-methoxy-17-oxo ^ ^{B '7-9} -des- ", _t,

A-estatria from the F. = 89 ° C, [«]? = + 99 ° (e = 1%, 35 ^{a) Manufacture of the} catalyst

Methanol). 200 mg of acidic synthetic resin exchanger are added

The product is obtained in the form of white, star-11 aqueous 1 η-sulfuric acid, stirred for 30 minutes and shaped crystals that are in methyl ethyl ketone and decanted. It is washed with water, then 3 g are added Ethyl acetate very soluble and in the heat in alcohol mereuriacetate and 11 water and stir for 10 minutes, and isopropyl ether are soluble. 40 Decant and wash with water.

Analysis: C ₁₅ H ₁₈ O ₂ = 230.30; b) hydration

calculated ... C 78.23%, H 7.88%; 5 g of 5-methoxy-17/3-acetoxy-17 «-äthinyl-

found ... C 78.2%, H 7.8%. ^ ^{5-7 '9} -des-A-östratrien and 62.5 g of search as described above

45 wrote produced catalyst in 125 ecm of etha-

UV spectrum in ethanol: _{nol and ST are} refluxed _for 7 hours with stirring.

= 279 ΐημ, EKI _n = 91.8; It is filtered, 600 ecm of methylene is added to the filtrate.

= 287.5 πιμ, Εϊ? _η = 79.0. chloride, removes the ethanol by repeating

Washing with distilled water, treated with animal ^

Stage B · Äthynylierune ⁵ ° ^ ° ^ ^e > filtered and then evaporated under vacuum to

Dry. The residue is crystallized from ethanol

They are 30 cc of a 0.99 n-ToluoIlösung of Siert and gives 5-methoxy-17 /? - acetoxy-17-acetyl-sodium tert-amylate in 270 cc of anhydrous benzene, Zi ⁶ - ⁷ - ⁸ -des-A -estratria of the temperature = 130 ° C, [«] !? = + 40 ° brings the mixture in a nitrogen atmosphere to 60 ° C (c = 1%> methanol).

and then bubbled through acetylene for 30 minutes. The product is obtained in the form of white Kribringt to room temperature, adds 40ccm with stirring, which is very soluble in acetone and chloroform, soluble in a benzene solution of 2.173 g in methanol, isopropyl ether and hot alcohol and in dextrorotatory 5-methoxy-17 oxo ^ ^{B '7-9} -of-A-östra- water insoluble, geometries to and leaves the Reaktionsmisehung at room _Λ η οΐ ν _{<: ρ.} ru η - Πή ir · stand temperature for 2 hours. It is then poured into 60 analytical C ₁₉ M ₂₄ U ₄ -JiO ^ water, neutralized by adding acetic acid, calculated ... C7?, L? J ₀ , H 7.65 J ₀ ;

decanted, the aqueous phase extracted with ether, rounded ... C / 2.2 / ₀ , H /, 4 / _Q.

then unites the organic phases, dries and,,.

evaporates to dryness in a vacuum. The residue is ^{btute b:} reduction

recrystallized from cyclohexane and gives the 5-Me- 65 0.786 g of lithium in small thoxy-17 / S-hydroxy-17 "-äthinyl-4 ⁵ ' ⁷ ' ⁹ -des-A-estatriene pieces in 360 ecm of liquid are added with cooling Ammonia, adds 72 ecm of the F. = 98.5 ° C, [a] f = -70.6 ^Q (e = 1%, Me- anhydrous ether and 1.141 g of 5-methoxy-17/9-acetthanol). oxy-17 "-aeetyl-4 ⁶ ' ⁷ⁱ⁹ -des-A-estatriene, dissolved in

150 cc of anhydrous ether to and maintaining the reaction mixture under stirring in nitrogen atmosphere IV ₂ hours at a temperature of -45 ° C. Then slowly add 70 cc of anhydrous methanol and then at -45 ⁰ C over one hour 3.6 g Lithium. The ammonia is evaporated, taken up in a mixture of 300 ecm of water and 200 ecm of ether, washed with water, dried and evaporated to dryness under vacuum. The residue is dissolved in 50 ecm of methanol, 12.5 ecm of hydrochloric acid and 25 ecm of water and refluxed for 1 hour. It is poured into water, extracted with methylene chloride, evaporated to dryness in vacuo and the residue is chromatographed on silica gel. Contains EIuieren with methylene chloride containing 10% acetone, gives amorphous 5-Oxo-20-hydroxy -Δ ^{9-19-nor-pregnene-des-A,} [ «] !? = -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:
λ _ηαχ = 240 ιημ; ICE CREAM. = 557.

Level F: Oxidation

100 mg of 5-oxo-20-hydroxy-Zl ⁹ -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 is 10%, is added 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 sodium bicarbonate and extracted with methylene chloride. After evaporation in vacuo, the extracts give a residue which consists of 5,20-dioxo- Δ ⁹ -19-nor-des-A-pregnen, which is purified by chromatography on silica gel. A white product with a mp = 8O ⁰ C, [oc]% ° = + 53 ° (c = 0.75%) methanol) which is insoluble very soluble in common organic solvents and in water.

Analysis: C ₁₆ H ₂₂ O ₂ = 246.34;
calculated ... C 78.00%, H 9.00%;
found ... C 77.7%, H 8.8%.

UV spectrum in ethanol:
l _max = 239 πιμ; ε = 16200.

Stage G: Formation of the enamine

2 g of 5,20-dioxo-zl 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 the reaction mixture is at a temperature from -5 to -10 ⁰ C stand for 1 hour. The product formed is filtered off with suction, washed with methanol, dried and 5-pyrrolidyl-20-oxo-Zl ⁵ < ¹⁰ i ' ⁹ ( ¹¹ ) -19-nor-des-A-pregnadiene with a ^{temperature of 142 °} C. is obtained, [oc] l ° = + 251 ° (c = 0.5%, pyridine).

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

Analysis: C ₂₀ H ₂₉ ON = 299.44;

calculated ... N4.68%;
found ... N4.7%.

Level H: 3-chloro-4,5-seco-5,20-dioxo-19-nor-
^ J 2, β-pregnadiene

5.16 g of 5-pyrrolidyl-20-oxo-19-nor-, d ^s < ¹⁰ > · ⁹ < ⁿ > -des-A-pregnadiene from F are added. = 142 ° C, [x] f = + 251 ° (c = 0.5%) pyridine), in a nitrogen atmosphere in 40ccm dimethylformamide and then adds 2.88 g of potassium iodide and 3.08 g of 3-dichloro-2-butene to. The reaction mixture is stirred for ₂ hours at 0 ° l ^J / and then allowed to stand overnight at 0 ⁰ C. It is poured into water and extracted with ether. The extracts are washed with a 1% strength aqueous solution of sodium bisulfite and then with water. After drying and filtering, it is evaporated to dryness in vacuo and 5.850 g of product are obtained, which is chromatographed on magnesium silicate. Eluting with methylene chloride gives 5 g of 3-chloro-4,5-seco-5,20-dioxo-19-nor-Zl ² · ⁹ -pregnadiene.
The product is in the form of a pale yellow

Oil that is used as it is.

Level I: 4,5-Seco-3,5,20-trioxo-19-nor-zl ^e -pregnen

Dissolve 5 g of 3-chloro-4,5-seco-5,20-dioxo-19-nor -. /) 2 »" pregnadiene in 5 cc of acetic acid, this solution is added dropwise to 25 cc of sulfuric acid cooled to -15 ⁰ C. , stir at room temperature V for ₂ hours and then pour into water. Sodium bicarbonate is added until it is neutralized, the mixture is extracted with methylene chloride, the extracts are washed with water, dried, filtered and evaporated to dryness in vacuo. The residue is chromatographed on silica gel and eluted with methylene chloride containing 4% acetone. 4.2 g of 4,5-seco-3,5,20-trioxo-19-nor-zl ⁹ -pregnen are obtained.

The product results in the form of an oil of [oc] ² _D ° = + 37 ° (c = 1%, methanol).

35

40

Claims (3)

Patent claims: 1. A process for the preparation of 19-nor-progesterone, characterized in that the 9 (10) double bond of 4,5-seco-3,5,20-trioxo-19-nor-J ⁹ -pregnen by hydrogenation stereoselectively reduced in the presence of a noble metal catalyst in an alkaline medium to the 9 <x, 10 / S compound and the reduced product cyclized in the presence of an acid in a manner known per se. 2. The method according to claim 1, characterized in that one is used as the hydrogenation catalyst Palladium is used and that the alkalinity is effected by the presence of triethylamine. 3. The method according to claim 1, characterized in that the cyclizing agent used is hydrochloric acid used in acetic acid. Considered publications: Comptes rendus, 250: 1084 (1960);
Angewandte Chemie, Vol. 72 (1960), p. 728;
Journ. At the. Chem. Soc, 80, 6118 (1958). 1 sheet of drawings 809 620/582 9.68 © Bundesdruckerei Berlin