DE1593356A1 - New Pregnan Series Halogen Compounds and Processes for Making Same - Google Patents

Description

File number: P 15 93 356.9
Applicant: Spofa. *.
Hein sign: 1041

New halogen compounds of the Pregnan range and Terfahren to manufacture the same

The invention relates to novel halogen compounds of the pregnane series of the general formula I.

CH ₁

wherein X is a halogen atom such as fluorine, chlorine or bromine and R is an alkyl radical with 1-5 carbon atoms,

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¹ '*>. ■ A '-.- v 9. v 4. 9. 1

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with a further double bond in the 1,2-position can be, as well as a process for the production of the same

It is known that the therapeutic effectiveness of steroid compounds of the 3-X "to-A *" -pregnadiene or 3-keto- Δ '"* ♦ pregnatriene series is increased considerably by introducing a halogen atom into the 6-position (J. Am.Chem.Soc. 81, 54-85 »1959) ·

Compounds with a 3-keto-6-halogen- Δ ** -diene grouping or analogous derivatives with a further double bond in the 1,2-Sü.lung can be prepared by known processes, either by direct dehydrogenation of the 3-keto - -6-halogen- Δ -pregnane grouping (J.Am.Chem.Soc.81, 3485t 1959) or by epoxidation of the 6,7 double bond in a 3-keto- Δ * ^f -pregnadiene derivative and by dehydrating cleavage of the 6,7-epoxy derivatives formed with a hydrogen halide (J.Am.Chem.Soc.82, 1230, 1960), optionally by cis addition of chlorine to the 6,7 double bond of a 3-keto- Δ ** --pregnadlen derivative and by subsequent dehydrochlorination. Apart from the relatively low yields, none of the processes mentioned could be used for the 16-kethylene or 17-x-acyloxy-16-methylene derivatives.

It has been found that new halogen compounds of the pregnane series of the general formula I are reliable and in satisfactory. Yields by a process

00983 1/1802 ^Q AD OR * g / nAl

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which forms the subject of the present invention can produce. The essence of this process lies in that you have a 6-halogen derivative of 16-methylene-17 c * -acyloxyprogesterons of the general IOrmel II

wherein X and E are the same as in formula I, where the configuration of the 6-substituent can be XK or i , to the corresponding J-Hkoxy-o-halogen-Λ "-diene of the general partial formula III

wherein R * is an alkyl radical having 1-6 carbon atoms and X is the same as in formula I, enoletherifissiert and this is dehydrated in the 6,7-position, wherein

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-A-

one optionally on the same side in the 1,2-pitch introduces another double bond.

For enol etherification of the 6-halogen derivatives of the general formula II can be used with Torteil elder of the organic ortho acids, such as orthoformic or carbonic acid, with alkanols with 1-6 carbon atoms and you work in the presence of acidic catalysts, such as conc. Sulfuric acid, p-toluenesulfonic acid, sulfosalicylic acid or camphor sulfonic acid, in anhydrous organic solvents such as dioxane, tetrahydrofuran or alkanols with 1-6 carbon atoms, which are identical to the alcohol residue in the ortho acid ester used. The temperature does not play a decisive role in this reaction, according to the The chosen modification of the GrunA process can be carried out at a temperature from ^{0 0} to the boiling point of the reaction mixture, but usually not above 10 ^{0 0. The} reaction time corresponds to the selected temperature and the other conditions; -24- hours off. At most, the absence of water, even in the atmospheric humidity, is of fundamental importance for the favorable course of the river, since otherwise the course of the bio-etherification deteriorates considerably.

They dehydrate the obtained 3-alkoxy derivatives of the general formula III can be obtained by the action of unsubstituted or substituted ohinones, for example p-benzoquinone, o-benzoquinone, p-Toluchiaoa,

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1,4-Haphthoquinone, 2,3, 5-trichlorobenzoquinone-i, 4, Ohloranil or 2,3-DiChIOr-S, 6-dikyanbenzoquinone, dehydrate. Organic solvents, for example aromatic hydrocarbons, such as benzene and its homologues, alkanols with 1-6 carbon atoms, esters of these alkanols with aliphatic acids with 1-4 carbon atoms, ketones, such as acetone, or cyclic ethers, such as tetrahydrofuran or diolene, are used for the reaction medium. optionally in the presence of an acidic catalyst, for example p-nitrophenol. The reaction in this stage can be carried out at temperatures from ⁰ ° C. to the boiling point of the reaction mixture. The reaction time can vary within wide limits, depending on the experimental conditions chosen.

If you want to introduce another double bond in the 1,2-position into the end product, you can do this Operation by the action of dehydrating agents such as 2,3-Diohlor-5 »6-dikyanbenzoohinon or selenium dioxide, carry out. Such a process is particularly advantageous in which the introduction of the double bond in the 1,2-position is carried out simultaneously in one step with the dehydration in the 6,7-position carried out by the action of agents serving for this purpose, i.e. Ohloranil or 2,3-dichloro-5,6-dikyanbenzoquinone, which are used in molar excess, however, more vigorous reaction conditions are necessary, for example longer boiling of the reaction mixture, with the addition of an acidic catalyst, such as anhydrous hydrogen chloride in a suitable organic solvent already mentioned "

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The compounds of general formula I prepared according to the invention are distinguished by excellent gestagenic properties after parenteral and especially after oral administration, which far outperform analogous unsubstituted compounds. d -acetoxypregna- -4f6-diene-3,20-dione in the Clauberg test on infantile female rabbits after oral administration a more than 130 greater progestative activity than progesterone after parenteral administration and than a number of other known perorally active gestagens «. (Steroids 4,4-15,1964).

You can find compounds of general formula I in Administer all indications of the gestagenic substances in common drug fora, e.g. as tablets, injection suspensions, suppositories, etc.

The following examples are intended to illustrate the invention in greater detail explain without restricting them in any way

Example

1. To a solution of 3 g of 6 ß-chloro-i6-methylene-17 <X - -ac et oxy progesterone in 45 ml abs. 1 ml of a 3% methanolic HgSO1 solution is added to methanol and 3 ml of ethyl formic acid ester, and the reaction mixture is refluxed for 4 hours. Then it is mixed with 0.5 ml of pyridine, it is cooled and left to crystallize

- 7 009831/1802 ^bath

eggs. The precipitated crystalline 3-methoxy-6-

iToC -acetoxypregna- Δ ^ ^t?

-20-on "eyes off" and dries. Ϊ. 168 - 172 ⁰ C,

| ° - -245 ⁰ C, λ J ^ ^H - 251 ψ (log £ »4.37)? Infrared spectrum (cm " ¹ ): 1735, 1261, 1240 (AcO) j 1711 (C-20 ketone)} 1644, 1620, 845 (Δ ^{3> 5} ) ϊ 895 (16-methylene). This compound has been found in the literature not yet described.

2. In a manner analogous to Example 1, using Clay methyl orthocarbonate and under catalytic The same product is obtained with the effect of 0.4 g of p-toluenesulfoic acid.

3 · A solution of 3 g of 6 ß-chloro-i6-ethylene-17c <--acetoxyprogeeteron in 35 ml of dioxane is mixed with 6.0 g of ethyl orthoformate and 150 mg of p-toluenesulphonic acid and left to stand at room temperature. 0.3 ml of pyridine is then added, the precipitate which has separated out is filtered off, and 50 ml of water is added slowly while cooling and stirring. The precipitated precipitate is sucked off, washed with water and dried. Pure 3-ethoxy-6-chloro: r-i6-methylene-17o <--acetoxypregna ^ tS-dien ^ O-one, Ϊ is obtained by recrystallization from a methanol-benzene mixture. 176 to 177 ⁰ C, ^H

-238 ⁰ G, λ ^ 2 ^H * 251 mn (log t * 4.36), infrared spectrum (om " ¹ )! 1735, 1261, 1240 (JLcO)? 1711 (0-20-ketone); 1644, 1620, 845 (A ³ » ⁵ ), 895 (16-lfethylene). This compound has not yet been described in the literature.

0 09831/1802 'bad ORiGJNAL

Aue 6 ß-Ohlor-16-methylen -17 ck -kaproyloxyprogesteron dae 3-A.ethoxy ~ 6-ehlor-16- -methylene-17 <λ -kaproyloxy-pregna- ^ jS-diene- ^ is obtained in an analogous manner O-on, ζ £ * - 251 ψ (log £ * 4.36).

4. A solution of 3.0 g of SoL -chloro-16-methylene-17 cK -acetoxy-progesterone in 35 ml of tetrahydrofuran and 6.0 g of ethyl orthoformate is mixed with 0.150 g of sulfoialicylic acid and left to stand at room temperature over a fold. Working up as in Example 3 wins to 3-lethoxy-6-C hlor-i6-methylene-17 o (-aeetoxypregna-3,5-dien-20-one, 1 175 - 177 ⁰ O that "with the compound prepared according to Example 3 is identical.

In an analogous manner, one obtains from 6 S -Bromo-16-methylene -17 oC -acetoxyprogesterone the corresponding 3-ethoxyö-bromo-ie-methylen-n-c * -acetoiypregna-3,5-dien-20-one and from 6 ß-fluoro-16-methylene-17c <-acetoxyprogesterone the corresponding 3-ethoxy-6-fluoro-16-methylene-17 <A-acetoxypregna-3,5-dien-2O-one.

5 · To a solution τοη 500 mg 3-ethoxy-6-chloro-16-methylene-17 ° < -acetozyprogesteron in 10 ml Dioiane one adds a solution τοη 270 mg 2,3-2> chloro-5,6 -dikyanbenxoquinone in 5 ml Ibian and 0.05 ml water. After standing for 24 hours at room temperature, the reaction mixture is evaporated to dryness in vacuo, the residue is dissolved in benzene and the solution is chromatographed on a (activity II according to Brockmann) under the same

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early control with thin layer chromatography. After separating off a small amount of a less polar impurity in the first eluates (42 ag), it is isolated by evaporating the main fractions in a yield of τοη 251 ng dae 6-0hlor-i6-aetnylen-17 <* -acetoxypr * gna-4,6- diene-3,20-dione, which "constant after Umkrietallisieren from methanol at 199 - 200 ⁰ C melts. OJ J ⁰ * -137 ° (OHCl ₅ , c «1.0), ^x _max -285 ψ (log £ = 4.32), infrared spectrum (cm ~ ¹ ) i 1735, 1260, 1242 (aetoxyl bathochromic shift of the Μητίτητιτη «around 7 compared to the 16-unsubstituted analogue), 1660, 16Ο5, 1590, 882 (6-chloro-3-keto-4,6-dienj identical to the chromophore of the 16-unsubstituted analogue), 1711 (C-20 Ketone), 895 (16-methylene). Analysis - _{Calculated for C 24} H ₂₉ O ₄ Cl (416.95): 69.13 * C, 7.01 * H, 8.50 * Cl; found s 69.00 * C, 6.83 * H, 8.50 * Cl *

This compound has not yet been described in the literature.

In an analogous manner, 3-ethoxy'-6-bromo-16- methylene-17 oL -aeetoxypregna ^ iS-dien- ^ O-one is converted into the corresponding 6-bromo-16-methylene-17 ° i -acetoxypregna-4 , 6- -dien-3,20-dione and 3-ethoxy-6-fluoro-16- * ethylβn-17o <--acetoxypregna-3,5-dien-20-one into the corresponding 6- riuor-16- methylene-17 oi -acetoiypregna-4,6-diene-3,20- -dione.

6. A mixture of 2 g of 3-Methoiy-6-chloro-16-methylene-17 o ( -acetoxypregna ^ iS-dien ^ O-one and 2 g of chloranil in 35 ml of tert-butanol is boiled under for two hours

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. - -, - 10 BAD ORIGINAL

Reflux. After cooling, the reaction mixture is filtered, the piltrate is evaporated to dryness and extracted the Bücketand with benzene. They are similar to Chromatography of the "benzene extracts" carried out in Example 5 gives all the main product the 6-chloro-16-methylene-17 -o ^ -acetoxypregna- ^ e-diene-J ^ O-dione, which is identical to the product in Example 5.

By implementing the 3-ethoxyderiyate under otherwise The same product is obtained under the same conditions.

7 · In a manner analogous to Example 6, but in Ae thy I-acetate, toluene or dioxane, the end product is obtained in practically the same yields

8. In an analogous manner to Example 6, but using clay 0.5 g of p-nitrophenol as a catalyst » the reaction time is about a half shorter, the yields being retained.

9 · In a manner analogous to Examples 6-8, however when replacing the chloranil with p-senzoquinone, o-benzoquinone, 1,4-baphtoquinone, p-toluohinone or 2,3,5-trichloro-p-quinone, the same 6-chloro- 16-me ^ jthylen-i 7 oC -acetoxypregna-4,6- -diene-3,20-dione.

10. A genius eh ron 1 g of 3-ethoxy-6-chloro-16-methylene

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-17 ek -kaproyloxypregna ^ S-dien ^ O-one, 1 g of ghloranil and ^υ , 5 g of p-nitrophtnol in ethyl acetate boils under reflux for every hour. After working up the reaction mixture similarly to that in Example 6, it was then processed

-kaproyloxypregna-4,6-diea- ° C [> j | ° «128 °

-3,20-dione,?. 110 - 114 ° C [> j | ° «128 ° (CHCl ₃ , c - 1.1), * ²⁸⁵ Ψ ~ ( ^1ο β ^έ " 4f30) in infrared spectra (approx " ¹ ) t

17351 1261, 1242 (caproyloxy group) i 1711 (C-20 ketone)} 1660, 1605, 1590, 882 (6-chloro-3-keto-4,6-diene) f 895 (16-methylene). The Analyaen-Firgebnieee ativaen with the calculated values. This bond has not yet been described in the literature

11. A solution of 500 bg 6-chloro-16-methylene-17 o <--acetoxy-pregna-4,6-diβn-3 _t 20-dione and 400 ag 2,3-dichloro-5,6-dikyanben " Ocliinon in 20 ml of dioxane is boiled for 30 hours under the flow of water. The reaction agent is diluted with old water, the precipitate that has separated out is filtered off, extracted with old benzene, and the benzene solution is washed with old water, an I-LAOH solution, with old water and dried. Lach filter this solution over 3 g of Al ₂ O _3, distilled from the Lo sungsalttel la Takuua and the residue recrystallized from methanol, whereby the 6-chloro-16-ethylene-i? ^ -acetoxy-pregna-1,4, 6-triβn-3,20-dione pure. P. 227 - 229 ° 0, f ° <-j | ⁰ "-217 ° (CHCl ₃ , c - 1.0) |

* aax * ²²⁹ * ²⁵⁸ » ²⁹⁷ Ψ ( ^l0 « £ "*» ⁰¹ i * »° J *» ° 5) | Infrared spectra (approx ~ ¹ ) j 1735, 1259, 1240 (acetoxy group)? 1711 (0-20-ketone) i 1659, 1623, 1603 (3-keto-1,4,6, -triene); 880-900 (16-methylene). The analysis results stiaaan alt the calculated values via a. This binding has not yet been described in the literature.

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12. A solution of 500 mg of S-ethoxy-ö-chloro-ie-methylen-17 <* -acetoxypregna ^ S-dien ^ O-one in 15 ml tert. Butanol is refluxed for 60 hours with 650 mg of 2,3-dichloro-5,6-dikyanobenzoquinone. Thereafter the solvent is distilled off and the residue is dissolved in a benzene-ethyl acetate mixture. This solution is shaken with a 2 N NaOH solution, then with water, dry them with anhydrous magnesium sulfate and evaporate them to dryness. Obtained after recrystallization of the residue from methanol the same product as in Example 11.

13 "A solution of 500 mg of 3-Thylen-17 d ^ i -acetoxypregna 5-dien-2O-one, 1.0 g of chloranil and 500 mg of p-nitrophenol in 15 ml of isoamyl alcohol is boiled for 60 hours while the reaction mixture and works RückfluB similar to example 12. Hs main product one have the corresponding 6-chloro-1 _P 4,6-trien »which is identical to the compound from Examples 11 and 12. FIG.

14. To a solution of 1.0 g of 3-1 -methylene-17 << -acetoxypregna ^ tS-dien ^ O-one in 10 ml of benzene is added a solution of 520 mg of 2,3-Diohlor- -5,6 -dikyanbenzoquinone in 8 ml of benzene too. A rich, black precipitate forms within a few minutes. Hydrogen chloride gas is passed into the reaction mixture while cooling to room temperature until the original color reappears. The excess hydrogen chloride is removed

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by. Bubbling through the reaction mixture with nitrogen and filter the solution through an ALGCL lens, The same is obtained by evaporating the solvent and crystallizing the residue from methanol Product as in Examples 11 to 13.

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Claims (1)

Patent claims before: 1. Heue halogen compounds of the Pregnan series of general formula 1 .--- OCOR wherein Z is a halogen atom, such as fluorine, chlorine or bromine and R is an alkyl radical having 1-5 carbon atoms means, it being possible for there to be a further double bond in the 1,2-position. 2. ö-chloro-ie-methylene-i? <X -acetoxypregna- ^ ö-dien- -3,20-dione. 6-bromo-1 _w 6-methylene-17c <-acetoxypregna-4,6-diene--3,20-dione. 4 6-fluoro-16-methylene-17 <X -acetoxypregna-4,6-diene- -3,20-dione. 6-chloro-16-methylene-17 σ (. -Kaproyloxypregna-4 »6-diene- -3 »20-dione. - 15 - Documents (/ -, ι. - _a ι - ■. _ _Λ Äi.Jerungsgea. V. 4. 009831/1802 ORfGiNAL 6. 6-chloro-16-methylene-170 < -acetoiypregna-1, 4,6- -triene-3,20-dione. 7. 3-lfethoxy-6-chloro-i6-ethylene i7 o <-acetoxypregna- - Λ ^5t5 -diene-2O-one. 8. 3-ethoxy-6-chloro-16-ethylene-17fX -acetoxypregna- -3 _t 5-dien-2O-one. 9. 3-ethoxy-6-chloro-16-methylene-T7 o (-kaproyloxypregna-3 _f 5-dien-20-one. 10. 3-Ethoxy-6-fluoro-16-ethylene-170 < -acetoxypregna- -3,5-diene-2O-one. 3-i.ethoxy-6-broa-i6-aethylene-i7 <X -acetoxypregna- -3,5-diene-20-one. .Verfahren but production τοη new halogen compounds of the general formula I ---- OCOR - 16 - BAD OBiGiNAL 00983 1/1802 wherein X is a halogen atom such as fluorine, chlorine or bromine and R denotes an alkyl radical having 1-5 carbon atoms, with another in the 1,2-position Can be bobble weave, marked daduroh, that a halogen derivative of 16-Methyleitf 7 <X -acyloxyprogesterons of the general formula II wherein X and R are the same as in formula I, where the configuration of the 6-substituent Z <X or can be β, to the corresponding 3-II] coxy- * 6-halogen ~ Δ - '♦ ^ - serve the general partial formula III wherein R * is an alkyl radical with 1-6 carbon atoms - 17 - 00983 1/1802 ^BATH and X is the same as in formula I, enoletherified and dehydrated this in the 6.7 division, where appropriate, at the same time, a further double bond is introduced into the 1,2-position. 13 method according to claim 12,
characterized, that the enol etherification of the 6-halogen derivatives of the general formula II by the action of organic orthoic acid esters, advantageously ortho-ameic acid or orthocarbonic acid esters, with alkanols having 1-6 carbon atoms, advantageously methyl or Ethyl esters, in the presence of acidic catalysts, such as conc. Sulfuric acid or organic sulfonic acids, e.g. p-toluenesulphonic acid, sulfa salicylic acid or Camphor sulfoic acid, in anhydrous organic solvents, e.g.! Tetrahydrofuran, dioxane or alkanols with 1-6 carbon atoms 14. The method according to claim 12,
characterized, that the dehydration is in the 6.7 division at the 3-alkoxy derivatives of the general partial formula III by the action of unsubstituted or substituted ohinones, for example p-benzoquinone, o-benzoohinone, p-ioluchinone, 1,4-naphthoquinone, 2,3i5-iErichlorbenzoquinone-1,4, Ohloranil or 2,3-dichloro-5,6-dikyanbenzoquinone, in organic solvents, for example aromatic hydrocarbons, such as benzene and its homologues, alkali - 18 - BATH ORIGINAL 0 0 9831/1802 nolen having 1-6 carbon atoms, esters of said alkanols with aliphatic acids having 1-4 carbon atoms, ketones, such as acetone or cykuschen ethers such as tetrahydrofuran or dioxane, optionally in the presence of an acid catalyst such as p-2iitrophenol, at temperatures of from ⁰ ° C carried out up to the boiling point of the reaction mixture 15 · Method according to claims 12 and 14 » characterized, that the dehydrogenation in the 6,7-position in the alkoxy derivatives of the general formula III is carried out simultaneously with the introduction of the 1,2-double bond by the action of dehydrating agents, advantageously by the action of a substituted ghinone, in particular chloranil or 2,3-dichloro 5 _f 6-dikyanbenzoquinone, which is used in excess of at least 1 mol, in organic solvents, for example aromatic hydrocarbons such as benzene and its homologues, alkenols with 1-5 carbon atoms, advantageously tert. Sutanol or isoamyl alcohol, or cyclic ethers, such as tetrahydrofuran or dioxane, at the boiling point of the reaction mixture for at least 30 hours, optionally in the presence of an acidic catalyst, advantageously anhydrous hydrogen chloride, d «. 00983 1/1802