DE2234018A1 - TOTAL STEROID SYNTHESIS - Google Patents

Description

Applicant: The Board of Trustees of the Leland Stanford

Junior University, Stanford university, Stanford, California 94305, V. St. A.

Total steroid synthesis

The invention relates to a new total synthesis of steroids and, more particularly, relates to new intermediates and a method for the total syrithesis of dl-progesterone, whose 21- and 17-hydroxy derivatives, dl-androst-4-en-j5,17-dione and the corresponding 19-Nor compounds.

The main stage of the synthesis is the stereoselective condensation of the unsaturated aldehyde ^ (Syntheseplanl) with the phosphorus-containing ylid 9 (synthesis plan II) for formation of diketal dienyn 10, which is shown in synthesis plan III. This also shows the transformation of this dienyns ^ LO through Cycloreactions to an A-Nor steroid 14. The five A »ring can then be opened and closed into a ring of six to the racemic forms of a number of natural steroids as illustrated in Synthesis Plans IV and V. ,

209884/1418

In synthesis plan I, the unsaturated alcohol Ji, (in which R is methyl or tri-lower- ^N alkylsilyl) is obtained by a Grignard reaction between methacrolein and XMgCH ₂ CHpC = CR (where X is chlorine, bromine or iodine) or by a reaction made between CH ₂ = C (CH ₅ ) MgX and R-CaCCH ₂ CH ₂ CHO. The unsaturated alcohol is then converted by the 'orthoacetate-Claisen reaction with a lower alkyl ortho acetate, CH, C (0-lower alkyl), to the enyester ^ ". This ester is subjected to a metal hydride reduction, for example with lithium aluminum hydride, to give the enyne alcohol 3. The alcohol can be oxidized to the corresponding aldehyde with an appropriate oxidizing agent that oxidizes primary alcohols to aldehydes, e.g. with dipyridine-chromium (VI) oxide complex to convert the ester 2 by selective reduction with sodium bis (2-methoxy-ethoxy) aluminum hydride into a mixture that mainly contains the aldehyde 4 with smaller amounts of alcohol 3. ~ *

■ 2 09884 / U18

Synthesis plan I

CH ₅

ι CHO

XMgCH ₂

HI C

fa

CIL «

S -> c

"ι

CH CH,

HO

t HgX

OHC

III

CHo

ι β

HOH ₂ C

CH

CH,

R ι

HI

CH, OH «
, 2

AIkO ₂ C

CH

CH ₂ "

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Synthesis plan II shows the alkylation of 2-methylfuran with 1,4-dibromobutane in the presence of a strong base * eg n-butyllithium with exclusion of water, which leads to 6- (4-butyl bromide) -2-methylfurane Jj ^. This latter compound is then treated with ethylene or propylene glycol in the presence of an acidic catalyst to produce the diketal bromide ^ (n = 2 or j5). The bromide ^, is converted with a source of iodine ions, for example sodium iodide, to the corresponding diketal iodide 7, which in turn is reacted with triphenylphosphine to form the diketalphosphonium iodide 8. By treating this iodide ^ § with phenyllithium in ether, the elements HI were separated and a red solution of the ylide 9 is formed, which is not isolated but is used directly for the condensation with aldehyde 4 .

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(CHg) _n

Synthesis plan II - ^ _

ft _f "5

1— S CHgCHgCHgCH ₂ Br

CH ₂ CH ₃ CH ₂ CH ₂ CH ₃ CH ₂

^N CH ₃ CH ₂ ^ C <CH ₃ CH

9 ·

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According to the synthesis plan III, the unsaturated aldehyde J ^ and the ylide ^ g are condensed in the presence of phenyllithium and the diketaldienyne 10 is obtained, where R '= CH, "or Si (lower alkyl). If the compound 10, in the R ¹ Si (lower alkyl), is treated with silver ions, the tri-lower alkylsilyl group is removed to give compound 10 in which R 'is hydrogen, which, either in the form of a Grignard reagent or alkali metal derivative (R' is MgX, Na, Li etc.), can be condensed with formaldehyde, in which case the compound 10 is obtained, in which R 'is CH ₂ OH.

The diketal compound 10 (R 'is CH or CH ₂ OH) is then subjected to acid hydrolysis, with the formation of the diene-diketone 11 (R "is H or OH). This ketone undergoes aldol condensation under alkaline conditions and gives the cyclopentenone derivative 12 .

If the cyclopentenone 12 is treated with methyl lithium or with methyl magnesium halide and the resulting reaction mixture is hydrolyzed, the cyclopentenol derivative 13 is formed, in which R ^{0 is} CH and R "is H or OH Oxo group, but not the unsaturated bonds reduced, for example sodium borohydride or lithium aluminum hydride, or with an aluminum-low-alkoxy.d (aluminum alcoholates) (Meerwein-Ponndorf-Verley reduction), in which case the secondary alcohol 13 is formed, where R ° H and R "is H or OH.

The cyclization of the cyclopentenone Y £ is carried out by treating at room temperature or below with an acid and a substance HY in which Y is a nucleophilic radical, for example acyloxy. The acidic cyclizing agent can be any protic acid whose dissociation constant is at least about 2 10. This subheading includes formic acid,

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Trifluoroacetic acid, fluorosulfonic acid, trifluoromethanesulfonic acid, picric acid, benzoesulfonic acid and the like; or a Lewis acid such as tin chloride, boron trifluoride, aluminum chloride, zinc chloride and the like. When the acidic cyclizing agent is a protic acid, it can also serve as the substance HY, in which Y is the anion derived from the protic acid. A preferred class of such anions are formyloxy and halogenated lower alkanoyloxy groups with 1 to 4 carbon atoms, with at least one halogen atom in the eC-position, for example chloroacetoxy, dichloroacetoxy, bromoacetoxy, trifluoraeetoxy-jco and ei _t ß -Dibromopropionoxy-, groups. The halogenated lower alkanoyloxy groups can have 1 to 3 halogen atoms, with at least one halogen atom in the oE-position.

The cyclization of the cyclopentenone V £ can also be carried out with a strong acid (trifluoroacetic acid, tin chloride, etc.) and an aprotic nucleophile, e.g. ethylene chloride (Y is .0-CH ₂

I), benzene (Y is CAi _1. ) or sodium iodide (Y is I), V-CH ₂ .

or with water as the nucleophile (Y is OH) will.

If R "in the compound Vp is the hydroxyl group, this can be esterified with a protonic acid during the cycloreactlon in order to introduce the corresponding acyl group»

*. ■ ■

o (-chloropropionoxy-

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- α synthesis pldn III

.CH

+ 9

CH,

ι *
CH,

2'η
^Ν 0

CH,
CH

-CM, '«

K ³ C ι ι

CH

(J

CH,

12th

CH,

CH,

CH

CH ₀ R "

St.

C. t

CHp ι <=

CH ₁

10

CH
ι

CH

CH

Hi

CH,

C-Y

CH,

209884/1418 - 8 -

The product of the cycloreaction is an A-norsterol of the formula lh, in which R ⁰ denotes H or CH, and R ¹ "denotes H or an acyloxy group, preferably a formyloxy group or a halogenated lower alkanoyloxy group with 1 to h carbon atoms, with at least one halogen atom Y is a nucleophilic radical, preferably a formyloxy group or halogenated lower alkanoyloxy group with 1 to h carbon atoms, where at least one halogen atom is in the o ( position.

The synthesis plan IV shows that the enol ester of the formula lh in which R can be hydrolyzed to the 20-oxo-Ä-norpregnen connection 17, ⁰ is H or CH, and R is H or OH ^MW. The connection VJj '. where R "" is the OH group can, if desired, be re-esterified at the 21-position with any desired ester group, preferably a lower alkanoyl of 1 to 6 carbon atoms. The five-membered ring A of compound 17 (in which R ^tt "is H or a lower alkanoyloxy group) is then cleaved by ozonolysis to give the tricyolic triketone 18, (R ⁰ is H or CH ^ JR" ^fi «* H or a lower alkanoyloxy group) to build. The cleavage of the ring A can also be carried out by treatment with ι the compound 1 £ (in which R ⁿ "is H or a lower alkanoyloxy group), with excess osmium tetroxide and subsequent cleavage of the osmate with hydrogen sulfide in order to produce the diol is treated with an excess of blood tetracetate and gives the compound 18 ^ This does not have to be isolated and purified, but can be treated directly with a cyclization catalyst to form d,! - progesterone, its 21-oxy derivatives or the corresponding 19-nor compounds (19; R ⁰ is H or CH,; R ¹ " ¹ is H, OH or a lower alkanoyloxy group)» The cyclization catalyst contains a strong acid (e.g. hydrochloric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, a sulfonic acid resin or the like), a strong base (e.g. sodium hydroxide, potassium hydroxide or the like), an amine (e.g. piperidine, triethylamine or

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or the like) or an amino acid addition salt (for example triethylammonium benzoate, triethylammonium acetate or the like) ,. A 21-acyloxy group (R ¹ '"is a lower alkanoyloxy group), if hydrolyzed during the cycloreaction, can be reintroduced by conventional esterifications.

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Synopsis IV

2234Q18

CH ₂ R '"

C-Y

17th

OC

t ^

16

CH ₀ R ¹ " ¹

18th

19th

20 98 84 / U1 8

Dor way leading to d, l-Androst-4-en ~ j5,17-dione and d, l-l9-nor-Androst-4-en - ^. 17-dione (16 * R "is CH _x or H ), comprises the ozonolysis of the enol ester 14 with subsequent cyclization of the resulting triketone 15

The synthesis plan V shows further conversions of the A-nor-steroid compound Ik in order to obtain useful steroid compounds. The double bond in ring A is protected because the dibromide can be treated with a peracid, such as monoperphthalic acid, and the bromine atoms can then be extracted with zinc to give the 17,20-epoxide 20, (R ⁰ is H or CH ₃ ; R "'is H, OH or OAcyl). By hydrolysis of the latter compound, the epoxide ring is opened to form the 17 c <-hydroxy-A-nor-steroid 21 (R ° is H or CH ₃ ; R""is H or OH). Compound 21, in which R" is "OH, can, if desired, be esterified to form the compounds in which R" is a lower alkanoyloxy group. Compound 21 (R ¹ '"is H or a lower alkanoyloxy group) is then subjected to ozonolysis and the resulting triketone 22 is cyclized to d, l-17 o (-hydroxyprogesterone, its 21-oxy derivatives or the 19-nor analogs, which have the formula 23 (R ° is H or CH,; R "" is H, OH or a lower alkanoyloxy group), thus analogous to the sequence 17>18> ■ 19.

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Synbheaeplan V

CH ₀ R "'

Or-Y

20th

CH ₀ R " ¹¹ * =

raw

hit

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The optically inactive d1 forms of the compounds 16, 19 and 23 can, if desired, be broken down into their optically active Bnantiomers by known processes.

The term "lower Akyl" as used in the description means lower alkyl groups, straight or branched, having 1 to 4 carbon atoms.

The structural formulas of the compounds according to the invention as they are represented by the formulas 1 to 23, by the modes of synthesis, by elemental analysis, by behavior of the compounds in thin layer chromatography (dsc) Vapor phase chromatography analysis (DPC) or by interpretation their infrared spectra (ir), the nuclear magnetic resonance (NMR) and the mass spectra are determined.

The invention is illustrated in more detail by means of the following examples.

example 1

a) 3-Carbethoxy-6-chlorhept-5-en-2-one (cis / trans),

To a solution of 46 g of sodium (2 g atom) in 500 ml of ethanol under reflux, 325 g of ethyl acetoacetate (2.5 mol) were added over a period of time in a 2 liter flask equipped with a mechanical stirrer and a filling funnel added for 30 minutes. The resulting solution of enolate was refluxed for 15 minutes. Then 250 g (2.0 mol) of _{1,3-dichlorobut-2-en (n ß} 1.4675) were added dropwise in such a way that the reflux was maintained, whereby towards the end '. the addition was warmed slightly. After the addition was complete, the mixture was stirred under reflux for a further 4 hours, then the condenser was converted for the distillation and the ethanol was removed as 500 ml of distillate. The remaining product was cooled, water and 1,2η-hydrochloric acid were added and the organic layer was separated. The watery one

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was extracted with ether, the organic layers combined, washed with water and brine, filtered through sodium sulfate. trated and evaporated in vacuo. 485% of a dark yellow oil were obtained (96% based on dichlorobutene). Vapor phase chromatography (DPC) showed 73 % of trans plus ice product together with 20 % ethyl acetoacetate and other volatile substances and 7 % dialkylated products with a long residence time. A small sample was purified by thin layer chromatography over silica gel (1: 3 ethyl acetate: pentane) , R _f 0.27, then distilled at 100 ° C / 0.1 mm. The 3-carbethoxy-6-chlorhept-5-en-2-one was obtained as a colorless oil, η2 ° 1.4640.

b) methyl 4-hexynoate.

242 g of crude 3-carbethoxy-6-chlorohept-5-en-2-one from part a) were added dropwise (at a rate at which reflux was maintained) to 264 g (4 moles) of 85 # potassium hydroxide dissolved in 250 ml of 95 # ethanol were added to a 2 liter three-necked flask which was equipped with a mechanical stirrer, a reflux condenser and a filling funnel. After the addition, the condenser was converted for distillation. I50 ml ethylene glycol and 50 mL of 2-ethoxyethanol (b.p. 133-135 ° C) was added and ethanol / water were distilled off until the pot temperature I30 - I35 had reached ⁰ C. The mixture was then stirred for a further 5 hours at 150-135 ° C. and heated under reflux, the reaction mixture was cooled to about 80 ° C., 1 liter of salt water was added, and the mixture was heated for 2-3 hours at. Stirred at room temperature and then poured into a separatory funnel. ·

After washing with ether (3 x 150 ml) the aqueous solution acidified to pH 6.5 with cold concentrated hydrochloric acid, extracted with chloroform, to pH 1.0 angooüuort and extracted again with chloroform. The extracts which had a pH value of 1.0, were mixed with 200 ml of salt water

209884/1418

wash, filtered through sodium sulfate and evaporated in vacuo. 67.1 g (60 % based on dichlorobutene) of a light brown crystalline pesticide were obtained, namely after removal of the acetic acid by azeotropic distillation with 1,4-dioxane and vacuum drying. A small sample of the acid was purified by crystallization from benzene: pentane and vacuum sublimation, after which 4-hexynonic acid was obtained, which formed colorless needles and had a melting point of 99-100 ° C.

The crude acid was dissolved in 150 ml of dry methylene chloride and 48 g of methanol and heated under reflux for 20 hours with 0.50 g of p-toluenesulfonic acid monohydrate. The reaction mixture was cooled, diluted with saturated sodium bicarbonate solution, separated and the aqueous layer extracted with ether. The pooled organic extracts were washed with saturated sodium bicarbonate solution and the product isolated to give 58 g of an orange oil. After distillation in vacuo through a small Vigreux column were $ 1, Og of methyl 4-hexynoat as a colorless oil whose boiling point at 77 - 78 ° C was mm / 21st

c) 4-hexynal

4-methylhexynoate (25.0 g, 0.20 mol) was dissolved in 100 ml of dry tetrahydrofuran in a 500 ml flask fitted with a mechanical stirrer and a funnel and "dry ice" / acetone cooling. To the stirred solution were added 70 ml of a 5.54 M solution of sodium bis (2-methoxyethoxy) aluminum hydrld in benzene at -70 ° C under dry N _{2 over the course of 1 hour, cooled down to 140 ml (total volume) with dry tetrahydrofuran} Filling funnel added. The product was then stirred for 5 hours at -70 ° C. and then 14.2 ml (11 g, 0.25 mol) of acetaldehyde, boiling point 20-22 ° C., slowly injected. After a residence time of 10 minutes at -70 ° C., the reaction mixture was poured into a mixture of 100 ml of concentrated hydrochloric acid and 500 ml of saturated salt water.

209884 / UIB

The mixture was then extracted with ether and the extracts washed with 50 ml of saturated sodium bicarbonate solution and with 50 ml of salt water, then filtered through Na ^ SC ^ · and evaporated in vacuo at 20 ° C. The crude 4-hexynal was used immediately for the next process step after it had been dried over '^ "molecular sieves in order to remove the ethanol. A purified sample showed the following properties: boiling point 70 ° C./20 ^{mm; n ^ 0 1.4524} ; 2,4-dinitrophenylhydrazone,

Melting point 119.5 - 120 ° C.

d) 2-Methyloct-1-en-6 ~ yn -> - ol (lj R is CiO.

14.4 g (0.6 g atom) of magnesium was dried in a 250 ml flask equipped with a reflux condenser, mechanical stirrer, and a funnel. After the reaction was started under dry N ₂ with about 1 ml of ethylene dibromide in 70 ml of tetrahydrofuran, 36.0 g (0.30 mol) of 2-bromopropylene (n · ^ 1.4425) were added dropwise in such a way that the reflux was maintained without external heating. The Grignard solution was then stirred until it had cooled to room temperature (jK) min. To 1 hour) It was then further cooled in ice-salt to -15 ° C and all of the crude 4-Hexynal from step (c) was added dropwise over 15 minutes. The reaction mixture was stirred for 2 hours at room temperature, saturated ammonium chloride solution was added and the product was extracted with ether. 2J, 50 g of 2-methyloct-l-en-6-yn-3-ol (85 % based on 4-methylhexynoate) were obtained as a pale yellow oil.

Apart from small samples for characterization, the alcohol, which was quite unstable during distillation or chromatography, was used in the raw state in the next process step and the best overall yields were achieved. Thin-layer chromatography (Dsc) on silica gel (1: 2 ethyl acetate: pentane) R _f 0.70 and distillation at 60 ° C./0.05 ram gave a colorless oil.

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2234013

Analysis calculated for C ₉ H ₁ → O: C, 78.21; H, 10.21. found: C, 78.14; H, 10.15.

The nuclear magnetic resonance spectrum (NMR) showed the triplet at 1.76 <? the characteristic of the methylacetylenic radical.

2-Methyloct-l-en-6-yn-3-ol (^, R is CH,) was used as an alternative made from methacrolein and the Grignard reagent from l-bromo-3-pentyn.

If in the above-described preparation of 2-methyloct-ien-6-yn-3-ol (1, R is CH,) the 4-hexynal is replaced by one molar equivalent of 5-trimethylsilyl-4-pentynal [(CH, KSiCsC-CH ₂ CHOj is replaced, 2-methyl-7-trimethylsllylhept-l-en-6-yn-3-ol. Fl, R is Si (CH ^) U «, the intermediate 5-trimethylsilyl-4-pentynal can be obtained by Condensation of 3-dimethoxypropyl chloride [ClCH ₀ CH ₀ CH (OCH,) 2 with lithium acetylide and treatment of the resulting dimethoxypropylacetylene [HC = CCH ₂ CHpCH. (OCH,) ₂ with trimethylsilyl chloride in the presence of butyllithium with subsequent acidic hydrolysis of the acetal (CH ^ ) can be obtained. "p

Example 2

Methyl-trans - ^ - methyldec - ^ - en-S-ynoat (2; R 1st CH ,, Alk is CH,) 11.75 g (85 % pure, 0.0725 mol) 2-Methyloct-l-en- 6-yn-> ol (Example 1) were dissolved in 53 S trimethyl orthoacetate (boiling point 107 108 ° C.) (0.44 mol) (6 equivalents) together with 0.50 g of propionic acid (6.7 ra mol) and the mixture heated for 16 hours in an oil bath at 115 ° C. under Np, with a condenser and a Dean-Stark trap with heating strips. The reaction mixture was cooled, poured into water and extracted with ether. The ethereal extracts were washed 3 times with 1,2η-hydrochloric acid and the product was isolated, 14.24 g of an orange-colored oil being obtained. 28.14 g of the crude ester from two of the reactions described above were distilled in a vacuum through a short Vigreux column in order to obtain 19 »5 S methyl trans- 4-methyldec- ^ -en-8-ynoate as a colorless oil, its Boiling point at

20988A / U18

2234013

'- 19 -

75-77 ° C / O, 1 mm was. (50 % of 4-methylhexynoate) (> 98 % pure by vapor phase chromatography (Dpc) (less than 1 % ice isomer), n ^ ° 1.4694.

Analysis : Calculated for C ₁₂ H ₁ QO ₂ : C, 74.19; H, 9.34 found: C, 73.92; H, 9.26

IR (flow film)) _mQV 3.42; 5.75; 8.64 / rev. The NMR spectrum

* Πι 3.x - / *

showed a singlet at 1.62 <j, characteristic of a methyl group on a trans- trisubstituted olefin bond and a triplet at 1.76 for the methylacetylenic radical.

An analogous procedure can cause 5-trimethylsilyl-4-pentynal to react with trimethyl orthoacetate to give methyl trans- 4-methyl-9-trimethylsilyl non-4-en-8-ynoate 12; R is (CH,), Si, Alk is to give CH 2. ~

Example 3.

trans-4-methyldec-4-en-8-ynal (_4; R is CH,).

4.84 g (25 mmol) of methyl trans- 4-methyldec-4-en-8-ynbate (Example 2) were dissolved in 15 ml of dry tetrahydrofuran in a 250 ml flask equipped with a mechanical stirrer and one with a "dry ice "/ Acetone cooling jacket equipped with a funnel. The solution was cooled to -70 ° C by stirring under dry N _2. From the cooled funnel, 10.5 ml of 3.5 molar sodium bis (2-methoxyethoxy) aluminum hydride diluted in benzene with 11 ml of dry tetrahydrofuran were added over the course of 1 hour. After the addition was complete, the product was stirred for 5 hours and then 3 × 45 ml (2.65 g, 60 mmol) of acetaldehyde were injected dropwise, the mixture was stirred for 10 minutes at -70 ° C. and then in 400 ml of 1.2 η hydrochloric acid poured. After extraction with ether (3 × 75 ml) it was possible to isolate 4.05 g of a colorless oil (98%) , the vapor phase chromatography (DPC) of which showed that it contained 87 % of the desired aldehyde (4) and 13 % of the corresponding alcohol ( 3) included. The alcohol was separated from the aldehyde by activated magnesium silicate chromatography

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(known under the trademark Florisil) and elution of the aldehyde with pentane. A sample of trans -4-methyldec-4-en-8-ynal was obtained in pure form by thin layer chromatography (Dso), silica gel (1: 2 ethyl acetate: pentane) R _f 0.64 and distillation, boiling point: 70 ° C./0.025 mm.

Analysis : Calculated for ^c iiH, g0: C, 80.44; Ή, 9.83 found: C, 80.69; H, 9.75

n ^ ° 1.4824, IR (flux. film) X _max J>Al>',3.69', 5.76, 6.95 / U. The NMR spectrum showed a singlet at 1.57 (f and a triplet at 1.71. There was also a singlet at 9.80 for the aldehyde content.

As an alternative, methyl trans -4-methyldec-4-en-8-ynoate was reduced with lithium aluminum hydride in ether (1 hour at 0 °) to give the trans- 4-methyldec-4-en-8-ynol Vy, R CH,) (boiling point 80 ° C / 0.025 mm). This was oxidized with the dipyridine-chromium oxide complex in methylene dichloride (1.2 hours at 23 ° C.) to give the aldehyde trans- 4-methyldec-4-en-8-ynal (J \ j R is CH-.).

By analogous processes, methyl-trans-4-methyl-9-trimethylsilylnon-4-en-8-ynoate | 2: R is (CH-J, Si, Alk is CHJ to tr_an £ -4-methyl-9-trimethylsilylnon- 4-en-8-ynol 13; R is Si (OHL) -J and / or trans-4-methyl-9-trimethylsilylnon-4-en-8-ynal VQj R is SiCH,). T | be reduced.

Example 4

a) 2-Methyl-5- (4-bromobutyl) furan (5). To an oven-dried 2 liter three-necked flask equipped with a mechanical stirrer and nitrogen inlet were 700 ml of tetrahydrofuran (distilled from lithium aluminum hydride) and 61.5 g (0.75 mol) of 1-methylfuran (distilled from calcium hydride , Boiling point 64 ° C) given, the solution was cooled to -50 ° C and 550 ml of a solution

209884/14 18

223A018

n -Butyllithium in hexane (2.28 M, 0.80 mol) was injected. The temperature was kept between -20 ° C and -30 ° C. The mixture was stirred for 4 hours, the flask was cooled to -60 ° C and 467 g (2.16 mol, 2.9 equiv.) 1,4-dibromobutane ( boiling point of from 82 to 83.5 J ^0, 15 mm, pre-cooled to -25 ° C) were added at once. The clear yellow solution was allowed to stand overnight to slowly warm to room temperature. The reaction mixture was poured into water (250 ml) covered with ether (300 ml) and the organic layer was washed with dilute acid (2 × 50 ml). The aqueous layer was extracted with ether (2 × 100 ml) and the co-poured organic layers were washed with bicarbonate and brine and dried over anhydrous magnesium sulfate. The volatile solvents were removed under reduced pressure and left an orange liquid (about 350 ml) back. The product was distilled through an 8 inch Vigreux column. Hydroquinone (50 mg) was added to prevent free radical reactions. The distillation fractions were identified as follows: Fraction 1, 307 g, boiling point 36 ^° C. / 0.10 mm (dibromobutane); Fraction 2, 30.3 g boiling point 42 ° C / 0.015 mm to 50 ° / 0.15 mm [dibromobutane and 2-methyl-5- (4-bromobutyl) furanj; after redistillation, 22.8 g of 2-methyl-5- (4-bromobutyl) furan, boiling point 50 ° C./0.015 mm, were obtained; Fraction 3, 95.2 g of 2-methyl-5- (4-bromobutyl) furan, boiling point 50 ° C / 0.015 mm, yield} 118 g (72.5 %)

Analysis : Calculated for C ₉ H ₁₅ OBr: C, 49.76; H, 6.04; Br, 36.83 found: C, 49.82; H, 6.10; Br, 36.86

^IR: X III ^m 6.2; 6.4; 9.8; 12.8, u (furan); 8.0; 8.2 (RCH ₀ Br), max / d

nil I.5002. The NMR spectrum showed a singlet at 2.12 δ for the methyl group, a triplet at 3.37 for the protons to the bromine and a singlet at 5.82 for the protons at 03 and C4 on the furan ring.

20988WU18

b) j.-Bromonona-5 , 8-dione-bis (ethylene ketal) (6j η is 2). In a 1 liter three-necked flask fitted with a nitrogen inlet, a mechanical stirrer and a Dean-Stark trap with a condenser, 500 ml of denzene, 180 ml of ethylene glycol (200 g, 3.2 mol), 5.0 g of p-toluenesulfonic acid monohydrate and about 100 mg of hydroquinone are added. The mixture was stirred under reflux for 6 hours to remove the water. Then 111 g (0.51 mol) of 2-methyl-5- (4-bromobutyl) furan (Jj ^ was added, the flask was shielded from light and stirred while continuing to reflux. After hours the mixture was allowed to cool and The brown glycol layer separated off. The benzene layer was washed with saturated bicarbonate (2 × 100 ml) and then with brine (2 × 50 ml), filtered through anhydrous sodium sulfate and the solvent removed under reduced pressure 158 g (165 g theoretical yield) of a light yellow-brown liquid were obtained. The crude product (69 g) was placed in a column of 1 kg 100-200 mesh activated magnesium silicate, known under the trademark Plorisil. Unreacted bromofuran (5) (9.5 g) was eluted with hexane. The desired 1-bromonona-5,8-dione-bis (ethylene ketal) (6) (51 g> 71 % conversion, 88 % yield corrected for the starting material obtained ) was eluted with 15% ether in hexane. Vapor phase chromatography (Dpc) showed> 99 % purity. The analytical sample was prepared by bulb-to-bulb distillation at 140 ° C / 0.05 mm.

Analysis:

for C 1 H 1 O 4 Br: C, 48.28; H, 7.17; Br, 24.74

found: C, 48.39; H, 7.22; Br, 24.84

The NMR spectrum showed a singlet at 1.22 c / "for the methyl group, a singlet at 1.5β for the two methylene groups, between the ketal residues, a triplet at 3.35 and a singlet pair at 3.83 and '3, 85 for the four ketal ethylene groups.

209884 / U18

By replacing the ethylene glycol in the manufacturing process described above by a molar equivalent amount of propylene glycol, 1-bromonona-5,8-dione-bis (propylene ketal) can be obtained (6; nist 5),

Example 3

l -Iodonona-5,8-dione-bis (ethylene ketal) (7; η is 2) A suspension of 59 * 6 g of the above-mentioned l-bromonona-5,8-dione-bis (ethylene ketal) (£ ;, 0.125 mol), 26.4 g of dry sodium iodide (0.176 mol, 1.4 equivalents) and 150 ml of dry 2-butanone were degassed and stirred at 80 ° C. for 40 minutes under nitrogen. The reaction mixture was poured into dilute bicarbonate and the product extracted with ether. The ether layer was washed with a sodium thiosulfate solution, saturated bicarbonate and salt water and then filtered through anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 44.9 g of an almost colorless 1-iodonona-5,8-dione bis (ethylene ketal) (99 % yield) This compound was used immediately in the next step of the process. An analytical sample was prepared by bulb-to-bulb distillation at 145 ° C / 0.05 mm.

Analysis:

Calculated for C ₁₅ H ₂₅ O ^ I: C, 42.18; H, 6.26; I, 54.28.

found . : C, 42.40; H, 6.15; I, 54.54.

The NMR spectrum was similar to that of the corresponding bromine compound and showed a triplet at 5JSOcZ for the protonsc < to iodine.

Using an analogous process, l-Bromonona-5 * 8-dione-bis (propylene ketal) to l-iodonona-5 # 8-dione-bis (propylene ketal) (7; η is 5).

209884/1418

Example 6

Nona-5,8-dione-bis (ethylene ketal) -1-triphenylphosphonium iodide (8; η is 2).

1.13 g (3.1 mmol) of 1-iodonona-5,8-dione-bis (ethylene ketal) (Example 5), 1.14 g of triphenylphosphine (4 , 4 mmol, 1.4 equiv.) And about 5 ml of dry benzene. The solution was degassed and stirred under nitrogen at 80 ° C for hours. The phosphonium salt was precipitated with 20 ml of dry ether. The product floating above was removed and the thick white oil was washed with a further 10 ml of dry ether. This oil was dissolved in 6 ml of dry acetone and from this it began to crystallize. The stirred suspension was cooled to 0 ° C while 30 ml of dry ether was slowly added. After separating the product floating above, the phosphonium salt was washed with 10 ml of dry ether and then dried under reduced pressure. 1.8 l g of nona-5,8-dione-bis (ethylene ketal) -1-triphenylphosphonium iodide (94 % yield) were obtained as a loose, white powder.

Analysis;

for C ₅₁ H ₅₈ O 1 PI: C, 58.86; H, 6.06j P, 4.90; I, 20.06

found: C, 59.00; H, 6.02; P, 4.79; I, 19.52

IR (CHCl ₅ ) X _max 6.33; 6 / 7Si 6.99; 9.02; 14VO7 / U. The NMR

_{5 max} 6.33; 6 / 7Si 6.99; 9.02; The 14VO7 / U spectrum showed similar features to that of the bromide j6 and additionally a multiplet at 3.62 </ "for the CH ₂ -P ⁺ protons and a multiplet at 7.7" - 8.1 for the aromatic protons.

Using a similar process, l-Iodonona-5,8-dione-bis (propylene ketal) to Nona-5,8-dione-bis (propylene ketal) -1-triphenylphosphonium iodide (8; η is 3) can be converted »

2Ü988A / U18

Example 7

7-methylnonadeca-trans, trans-6,10-dien-2-yn-15, il8-dione ~ bis (ethylene ketal) (10; R ¹ is CH ,, - η is 2).

4.45 g (7 mmol) of the phosphonium salt (£ 3; η is 2) (recrystallized from acetone) were _{dispersed in 25 ml of dry tetrahydrofuran under dry N 2} and treated with 7 nil of 1.02 m-phenyllithium in ether. The deep red ylide (9; η is 2) solution obtained was cooled to -70.degree. Then 1.15 g of trans- 4-methyldec-4-en-8-ynal (^), (7 mmol) (> 98 % pure) were added dropwise to 10 ml

injected dry ether. The mixture was stirred for 5 minutes at -70 ° C., warmed to -30 ° C., 8 ml of 1.02 m-phenyllithium were injected into the red ylide solution obtained, which was then stirred for a further 5 minutes. Then 1 ml of methanol was injected dropwise at -30 ° C. * The triphenylphosphine oxide was precipitated immediately. The mixture was stirred at room temperature for a few hours and the product was then poured into water and extracted with ether. After two triturations from the pentane, 2.86 g of the product were isolated as a yellow oil. The triphenylphosphine oxide and volatile impurities were removed by chromatography on activated magnesium silicate (trademark: Plorisil). Eluting with pentane: 10 % ether gave 1.64 g of 7-methylnonadeca- trans , trans- 6,10-dien-2-yn-15,18-dione-bis (ethylene ketal) as a colorless oil. The analytical sample was further purified by thin layer chromatography, silica gel (1: 2 ethyl acetate: pentane), R _f = 0.32, and distillation, boiling point 190 ° C./0.01 mm.

Analysis:

for C ₃₄ H ₅₈ O ^: C, 73.80; H, 9 * 81.

found % C, 74.10; H, 9.70.

IR (flow film) X _max 3.45; 6.90; 7.30; 9.58; 10.30; 10.52 / u. The NMR spectrum showed a singlet at 1.39 for the methyl group at Kotulkohlonntoff, a singlet at 1.63 for a triplet at 1.75, a singlet at 3.94 for four ketalmethylene groups and a multiplet at 5.4 for the viny! hydrogens of the transdiscubstuiorton olefinic bond.

2098 84/1418

By replacing the phosphonium salt (8; η is 2) in the abovementioned compound with the corresponding bis (propylene ketal) (£; η is 2), 7-methylnonadeca- trans , trans- 6, 10-dien-2-yn-15, 18-dione-bis (propylene glycol) (10; R ^r is CH ₃ , η is 3).

By replacing trans- 4-methyidee-4-en-8-ynal in the aforementioned compound with trans- ^l t - methyl-9 ~ trlmethylsilylnon-4-en-8-ynal Q; R is Si (CE ₅ K) can l-trimethylsilyl-6-methyloctadeca- trans, trans- 5,9-dien-1-yn-14, l7-dione-bis (ethylene ketal) £ 10; R ¹ is (CH ^ KSi, η is 2]. This compound can be treated with aqueous alcoholic silver nitrate to replace the trimethylsllyl group with hydrogen to give 6-Me thyloc tadeca-trans_, trans ^ -S * 9-dien-1-yn- 14,17-dione-fais (ethylene ketal) (10; R ¹ is H, η is 2) This latter compound reacts in the presence of a strong base, such as sodium methoxide, with formaldehyde and forms l-hydroxy- 7-methyl-nonadeca- trans , trans- 6,10-dien-2-yn-15 * 18-dione-bis (ethylene ketal) (10; R ¹ is CH ₂ OH, η is 2).

Example 8

7-methylnonadeca-trans, trans-6,10-diene-'2-yn-15, 18-dlon (U ₁ ; R "is H).

2.7'j g of bia-ketal (10; Π ¹ is CII ₅ , η is 2) (Example 7) were dissolved in 100 ml of methanol, _{degassed under N 2} , 30 ml of 0.1 N-hydrochloric acid were added and degassed again under N _2. The reaction mixture was stirred at 40 ° C. _{under N 0 for 6 hours.} Solid sodium bicarbonate was added until the mixture became basic. The solvent was removed in vacuo. Ether and water were then added, and the product was extracted and isolated, 2.25 g of 7-methylnonadeca- trans , trans- 6,10-dlen-2-yn-15> 18-dione being obtained as a pale yellow oil. A sample was purified for analysis by thin layer chromatography, silica gel (1: 2 ethyl acetate: pentane), R _f 0.25, and distilled to give a colorless oil whose boiling point was 190 ° C / 0.01 mm.

209884/1418

Analysis; .

calculated for.G ₂₀ HJ ₀ O ₂ JC, 79 * ^ 2; H, 10.00.

found; v: C, 79 ^ Oj H, 9 * 88 ·

The NMR spectrum showed a singlet at 2.21 (/ "for the methyl ketone group.

By a similar procedure, 1-hydroxy-7-methylnonadeca trans , trans- 6,10-dien-2-yn-15, 18-dione-bis (ethylene ketal) (10; R 'is CHgOH, η is 2) can be hydrolyzed to give l-hydroxy-7-methylnonadeca- trans, trans- 6,10 ~ dien-2-yn-15 » 18-dlon (U; R" is OH) ·

Example <§ -

2- (7-MethyJtrideea-trans, trans-3 , 7-dien-11-ynyl) -3-methylcyclopent-2-enone (12; R "is H).

2.25 g of the crude dione (U; R "is H) (Example 8) were dissolved in 30 ml of methanol and added to 70 ml of a 2 # aqueous sodium hydroxide solution. The resulting solution was degassed under nitrogen and under reflux for 18 hours The methanol was removed in vacuo and the product was diluted with water and extracted with ether. After isolation, 2.20 g of crude cyclopentenone derivative were obtained as a yellow oil. Chromatography on activated magnesium silicate (trademark Florisil) and elution with pentane: ether (9: 1) gave 920 ml of 2- (7 * -methyltrideca- trans , trans- 3,7-dien-11-ynyl) -3-methylcyclopent-2-enone as a colorless oil [46 % based on aldehyde (^ ) J. Vapor phase chromatography showed two peaks, corresponding to 97 % of the trans- disubstituted double bond compound and 3 % of the cis isomer. In a separate experiment, an analytical sample was prepared by purifying by thin layer chromatography on silica gel (1: 4 Ethyl acetate: pentane) R _f Ö, 40, and distillation, boiling point 190 ° C./0.0.5 mm.

Analysis; ...

for C ₂₀ H ₂₈ O: C, 84.45; H, 9.92. found: C, 84.33; H, 9.77.

209804/1418

IR (flow film) i _max 3.43; 5.86; 6.05; 6.94; 7.20; 10.29 Uv (MeOH) X _max 235 nyu (l0.400).

By a similar procedure, 1-hydroxy-7-methylnonadeca trans , trans- 6,10-dien-2-yn-15, 18-dione (U; R "is OH) can be cyclized to give 2- (13-H. ydroxy-7-methyltrideoa- trans , trans- 3,7-dionll-ynyl-3-methylcycylolopent-2-enone (12; R "is OH).

Example 10

cyolopent-2-enol (13; R ⁰ is CH- "R" is H). (0.74 mmol) 210 mg of the cyclopentenone derivative (12; R "is H) (Example 12) were combined in 5 ml of dry ether dissolved with a few crystals of 1,10-phenanthroline. Methyl lithium (2M in ether) was injected dropwise under nitrogen until a permanent yellow-brown color appeared. The mixture was stirred at room temperature for 2 minutes. This mixture was then quenched by adding water dropwise, diluted with additional water, and extracted with ether. 219 mg of a pale yellow oil were isolated which contained 1 ~ (7-methyltrideca- trans , trans- 3,7-dienll-ynyl) -1, 3-dimethylcyclopent-2-enol. Since the alcohol is easily dehydrated and the polyenes obtained polymerize quickly, no analysis was made and the raw material was always used immediately for cyclization in the following reaction.

IR (flux film) 1 ^ _χ 2.70-3.22; 3.38; 6.92; 7.20; 9.20; 10.30 / rev

An analogous process can be used to treat 2- (13-hydroxy-7-methyltrideca trans , trans- 3,7-diene-ll-ynyl) -3-methyloyclopent-2-enone (12; R "is OH) with methyllithium, around 2- (13-hydroxy-7-methyltrideca- trans , trans- 3,7-di-ene-11-ynyl) -1,3-dimethylcyclopent-2-enol (13; R ⁰ is CH 1, R "is OH ) to build.

209884 / U18

Example 11

2- (7-Methyltrideca-trans, trans-3,7-dieή-ll-ynyl ·) -3-fflethyloyclo- 'pent-2-enol (-13; R ° is H, R "is H) can by about Treating 2- (7-methyltridecathahs , trans- 3j7-dien-11-ynyl) -3-methylcyclopent-2-enone (12; R "is H) with sodium borohydride in aqueous ethanol at room temperature for 5 hours.

Similarly, 2- (13-Hydroxy-7 ~ roethyltrideca- trans > trans- 3,7-dienll-ynyl) -3-methylcyclopent-2-enone (12; R "is OH) can be reduced with sodium borohydride to give 2- ( 13-Hydroxy-7-methyltrideca trans , trans- 3,7-diene-11-ynyl) -3-methylcyclopent-2-enol (13; R ⁰ is H, R "is OH). -

Example. 12th

3-Methyl-A-nor-2 ~ prep; nen-20-one (17; R ° is CH ,, R "" is H) 219 mg (0.70 mmol) 2- (7-methyltrideca- trans , trans ~ 3,7-diene-llynyl) -l, 3-dimethylcyclopent-2-enol (Example 10) were in a 10: 1 mixture of dichloroethane (JDest. From Pp ^o c) ^! ~ Ethylene carbonate (24.2 g) dissolved in a 50 ml flask. The mixture was stirred and degassed under Np at 0 ° C. 0.80 ml (1.23 S * 10.8 mmol) of trifluoroacetic acid (boiling point 71-73 ° C.) were added dropwise. The solution got a yellow to possibly deep red color. The reaction mixture was stirred for 11/2 hours at 0 ° C. and a further 0-80 ml of trifluoroacetic acid were added with stirring over a period of 11/2 hours at 0 ° C. To the mixture obtained, 20 ml of a 10 # solution of potassium carbonate in water: methanol (50:50) were added, and the mixture was finally stirred at room temperature for 1 hour. It was then poured into water, extracted with ether and 238 mg of a dark orange oil were isolated therefrom. Vapor phase chromatography showed 70 % 3r-methyl-A-nor-3-pregnen-20-one and 13 % of the corresponding 17 cE isomer together with 6 % unreacted starting material. The crude mixture was immediately ohromatographed on 12 g of activated magnesium silicate (trademark Florisil) using degassed pentane. Pentane

209884/1418

impurities volatile in vapor phase chromatography, followed by 158 mg of the desired product in 10 % ether-pentane. The first fractions were richer in the 17-Qf form. A sample of the product was analyzed mm after distillation at 190 ⁰ C / 0.05. [Single stain on silica gel (1: 2 ethyl acetate ί pentane) R _f 0.69].

Analyoo: bore without for C _o1 H, _o oj C, 83.94; H,

gofundon % C, 83.77; H, 10.62

The rust dor sample was recrystallized from pentane at -20 ° C, 3-methyl-A-nor-3-pregnen-20-one was obtained as colorless flakes, melting point 82-88 ° C, (vapor phase chromatography showed 9.5 # After a further recrystallization, the melting point was 88-89 ° C., IR (CH _x Cl) i _Qv 3.42, 5.86, 6.90, 7.40 / U. The NMR spectrum showed singlets at 0.65 o for the C-19 methyl group, 0.92 for the C-18 methyl group, 1.58 for CH ₅ C = C and 2.13 for the C-21 methyl group.

3-Methyl-A-nor-3 ~ pregnen-20-one was also obtained by treating a methylene dichloride solution of 2- (7-methyltrideca- trans, trans- 3,7-diene-ll-ynyl) -l, 3-dimethylcyclopent- 2-enol made with tin chloride and then with water.

By analogous procedures, 2- (^ -hydroxy ^ -methyltrideca trans , trans_-3,7-diene-11 -ynyl) -1,3-dimethylcyclopent-2-enol (13; R ° is CH- "R" is OH); 2- (7-methyltrideca- trans , trans-3,7-diene-. Ll-ynyl) -3-methylcyclopent-2-enol (15; R is H, R "is H) or 2- ( 13-Hydroxy-7-methyltridecarranS jtrans -3,7-diene-II "ynyl) -3-methylcyclopent-2-enol (13; R ° is H, R" is OH) cyclized with trifluoroacetic acid and hydrolyzed with sodium carbonate to correspondingly the compounds 21-hydroxy-3-methyl-A-nor-> pre "gnen-20-one (17; R ° is CH- *, R""isOH); 3-methyl-A, 19- bisnor-3-pregnen-20-one (17; R ° is H, R "" is H) j or 21-hydroxy-3-methyl-A, 19-bisnor-3-pregnen-20-one (17; R ⁰ is H, R "" is OH)

»• ■ ve

to build.

20988A / U18

21-hydroxy->methyl-A-nor-> pregnen-20-one Qj; R ° is CH ₅ , R ""

is' QH) can be esterified with acetic anhydride, butyrarihydride or caproyl chloride in pyridine and accordingly gives 21-acetoxy -> - methyl-Ä-nor-> pregnen-20-one (JJ; R ⁰ is CH- "R""is OCOCH ₅ ) j 21-butyryloxy-3-methyl-A-nor-3-pregnen-20-one £ 17; R ° is CH "R""is OCO (CH ₂ ) ₂ ChJ or 21-caproyloxy->methyl-A-nor-> pregnen-20-one [l? J R ° is CH" R ""

Example 13 · '■

d,! - Progesterone (lg; R ° is CH ₅ , R ' ^f "is H). A 150 mg sample of 3 ~ methyl-A-nor-3-pregnen-20-one (example la) (about 95 % pure) (0.5 mmol) in 15 ml of methanol and 5 ml of methylene dichloride were placed in the flask "B" of a ruby ozonizer, which contained 14 ml of methylene dichloride saturated with ozone at -70 ° C in the flask "A" (0, 55 mol O ₅ ) .The ozone solution was then slowly forced under pressure into the ketone solution, which was stirred at -70 ° C. After 2 minutes at -70 ° C., the colorless solution was warmed to -15 ° C. and 10 ml Acetic acid, 2 ml of water / water and 1 g of zinc dust were added and the mixture was stirred for 50 minutes at room temperature. The reaction mixture was filtered, diluted with water / water and extracted with ether. The product was isolated and gave 146 mg of triketone (Ig; R ° is CH "R ^u " is H) as a nearly colorless oil (88 %) . Thin layer chromatography showed a major spot at R _f 0.26 on silica (1: 2 ethyl acetate: pentane). IR (flow film) showed X _ma " 3.42 / u, 5.88 (broad). The triketone (18) was not investigated further, but rather subjected to crude aldol condensation.

146 mg of triketone (18) were dissolved in 5 ml of methanol, _{degassed under N 2} and 2 ml of a 5% methanol-potassium hydroxide solution were injected. The reaction mixture was stirred at room temperature for 20 hours, poured into water, extracted with ether and worked up. 126 mg of a pale yellow oil were obtained, which slowly crystallized. The crude product was on a 1000 / U silica gel thin layer chromatography

884/1418

plate (anal. plate R _f = 0.33, 1: 2 ethyl acetate: pentane, identical to d-progesterone ) chromatographed with k: 6 ethyl acetate: pentane (degassed). The main Uv active band yielded 71 mg of crystalline solid. Vapor phase chromatography showed> 95 fo pure, fl> : d progesterone (8.5 ί 1.5). The sample was dissolved in methanol and diluted with ether. After cooling, colorless plates were obtained, the melting point of which was 180-183 ° C. A further recrystallization in methanol gave colorless prisms, melting point 182-185 ° C., corresponded to the mixed melting point with a sample of djl-progesterone, melting point 182-185.5 ° C., horgoatollt according to Johnson et al. Tetrahedron, Suppl. 8, Part II, [Al (1966). According to IR (CH ₂ Cl ₂ ), NRM (CDCl, 60 MHz) and mass spectrum (70 eV), the ^{synthetic sample was identical to natural progesterone, IR (CH} 2 ^C1 2 ^ max ⁵ * ^ ^{0; 5 '88; β} * ⁰⁰ >7> ^li0 '> 10.50; 11.53 / u.

By analogous procedures, 2i ~ acetoxy-3-methyl-A-nor-j5-pregnen-20-one (JJ; R ° is CH ,, R "" is OCOCH-,); 3-methyl-A, 19-bisnor-3-pregnen-20-one (17; R ⁰ is H, R "" is H); or 21-acetoxy-3-methyl-A, 19-bisnor-3-pregnen-20-one (lj; R ⁰ is H, R "" is OCOCH;.) subjected to ozonolysis and aldol cyclization of the intermediate product triketone (l§) and the corresponding compounds are formed, namely d, l-21-hydroxypregn-4f-en-3,20-dione (19; R ° is CH ₃ , R "" is OH); d, l-19-norpregn-4-en-3,20-dione (19; R ° is H, R "" is H); and d, l-21-hydroxy-19-norpregn-4-en-3,20-dione (19; R ° is H, R "" is OH).

Example 14

3-methyl-20-trifluoroacetoxy-A-norpregna-3,17 (20) -diene (l4; R ° is CH ₃ , R " ¹ is H, Y is OCOCP,). ^ *

25 mg of 2- (7-methyltrideca- trans , trans-3,7-dien-11-ynyl) -1,3-dimethylcyclopent-2-enol (Example 10) were in 2 ml of dry olefin-free pentane and 0.20 ml of dry Dissolved dichloroethane. The mixture was cooled to 0 ° C and degassed _{under N 2.} Then 0.12 ml of trifluoroacetic acid was added, one dark

20988A / U18

orange solution resulted. A further addition after 15 minutes of 0.12 ml of the acid did not change the color. The reaction mixture was stirred at 0 ° C. for 1 hour, poured into water, extracted with ether and 30 mg of 3-methyl-20-trifluoroacetoxy-A-norpregna * -3.17 (20) r-diene were thereby obtained as a yellow oil obtain. IR (flow film) 2 _max 3.43; 5.6o (CF ₃ COOR); 5.90 (C = C); 8.20 (CO) showed the expected enol trifluoroacetate structure.

By analogous processes in which instead of trifluoroacetic. acid formic acid (15 minutes in pentane at 23 ° C), or d, ß-dibromopropionic acid is used, corresponding compounds are obtained, namely 3-methyl-20-formyloxy-A-norpregna-3,17 (20) diene (14 ; R ⁰ is CH ₃ , R "'. Is H, Y is OCOH); or« 3-methyl-20- (2,3-dibromopropionoxy) -A-norpregna-3,17 (20) -diene [14; R ⁰ is CH ,, R ^ttl is H, Y is OCOCH (Br) CHoBr].

Similarly, 2- (7-methyltrideca- trans , trans- 3,7-dien-ll-ynyl) -1,3-dimethylcyclopent-2-enol (Example 10) when treated with trifluoroacetic acid and sodium iodide or benzene gives 3-methyl-20-iodo-A-norpregna-3,17 (20) -diene (14; R ° is CH ₃ , R ¹ "is H, Y is I) or 3-methyl-20-phenyl-A -norpregna-3, l7 (20) -diene (l4; R ° is CH ₃ , R '"is H, Y is C ₆ H ₅ ). ~

Similarly, 2- (l3-hydroxy-7-methyltrideca- tran3, trans-3,7 '(llon-n-ynylJ-l ^ -dimothylcyclopont-S-Onol (J ^ R ° lot GII R "lüt OH. ); 2- (7-Mothyltrldü'ca-trans, trans- 3j7-diene-.ll-; methylcyclopent-2-enol (13; R ⁰ is H, R "is H); or 2- (13-hydroxy- 7-methyltrideca- trans , trans- 3,7-dien-11-ynyl) -3-methylcyclopent-2-enol (13; R ⁰ is H, R "is OH) can be cyclized in the presence of trifluoroacetic acid, and accordingly result in 3 -Methyl-20,21-bis- (trifluoroacetoxy) -A-norpregna-3,17 (20) -diene '

I _V ,

R ^w is CH ₃ , R " ^! Is OCOCF ₃ , Y is OCOCF ₃ ); 3-methyl-20-trifluoroacetoxy-A, 19-bisnor-pregna-3, 17 (20) -diene (14; R ⁰ is H. , R " ¹ is H, Y is OCOCF ₃ ); or 3-methyl-20,21-bis (trifluoroacetoxy) -A, 19-bisnorpregna-3,17 (20) -diene (14; R ° is H, R " ¹ is OCOCF ₃ and Y is OCOCF ₃ ) . ~ "

209884/1418

223A018

Example 15

d, l-AndrQst-4-en-3j17-dione (l6; R ° is CH ₃ ) The 3-methyl-20-trifluoroacetoxy-A-norpregna-3,17 (20) -dione according to Example 14 was controlled Subjected to ozonolysis as in Example 13. The triketone obtained (15; R ° is CH-) was subjected to an aldol condensation under which the conditions were the same as in Example 13. The isolated product was a yellow oil (15 mg). Vapor phase chromatography showed a major peak which, when co-injected, was identical to d, l-androst-4-en-3 * 17-dione, which had been prepared by a different method. After partial purification in thin-layer chromatography (silica gel HF ₂ Ch) 90 % pure, the sample showed the same mass spectrum and IR (flow film) / I 3 * 44; 5 * 79; 6.01 and 6.20, such as androst-4-en-3 * 17-dione, which is derived from natural sources.

Similarly, 3-methyl-20-trifluoroacetoxy-A, 19-bisnor-pregna ~ 3.17 (20) -diene (14; R ⁰ is H, R ¹ "is H, Y is OCOCF ₃ ) can be subjected to ozonolysis, to give a triketone (15; R ° is H), which is then cyclized to d, l-19 ~ nor-androst-4-en-3 * 17-dione (16; R ⁰ is H).

Example 16

17 * 20-Epoxy-3-methyl-20-trifluoroacetoxy-A-norpregn-3-en (20; R ⁰ is CH ₃ , R "'is H, Y is OCOCF ₃ ) can be obtained by reacting 3-methyl- 20-trifluoroacetoxy ~ A-norpregna-3,17 (20) -diene (14; R ° is CH ₃ , R " ^! Is H, Y is OCOCF ₃ ) (Example 14) can be prepared with bromine. The 3 * 5-dibromo-3-methyl-20-trifluoroacetoxy-A-norpregn'-17 (20) -ene obtained is treated with monoperphthalic acid in ether solution for 15 hours at room temperature and the dibromo-epoxide is defbrominated with zinc.

Similarly, 3-methyl-20,21-bis (trlfluoroacetoxy) -A ~ norpregna-3,17 (20) -diene (14; R ° is CH ₃ , R " ¹ is OCOCF ₃ , Y is OCOCF ₃ ); 3 -Methyl-20-trifluoroacetoxy-A, 19-blsnorpregna-3 * 17-diene (14;

209804/1418

R is H, R "I is H, Y is OCOCF ₃ ); or 3-Methy1-20,21-bis

(trifluoroacetoxy) -A, 19-bisnorpregna-3,17 (20) -diene (14; R ° is H, R " ^! is OCOCF ,, Y is OCOCF,) to 17; 20-epoxy-3 -methyl-20,21-bis (trifluoraoetoxy) -A-norpregn-3-en (20; R ⁰ is CH ₃ , R " ¹ is OCOCF ₃ , Y is OCOCF ₃ ); 17,20-epoxy-3-methyl-20-trifluoroacetoxy-A, 19-bisnorpregn-3-en (20; R ⁰ is H, R " ¹ is H, Y is OCOCF ₃ ); and 17,20-epoxy, respectively -3-methyl-20,21-bis (trifluoroacetoxy) -A, 19-bisnorpregn-3-en (20; R ° is H, R " ¹ is OCOCF ₃ , Y is OCOCF ₃ ) ..

Example 17

17 (X -hydroxy-3-methyl-A-norpregn-3-en-20-one (21; R ⁰ is CH ,, R "" is H) can be obtained by treating 17 * 2Q-epoxy for about 3 hours 3-methyl-20-trifluoroacetoxy-A-norpregn-3-en (Example 16) can be prepared with sodium methoxide in methanol at room temperature.

Similarly, 17 * 20-epoxy-3-methyl-20,21-bis (trifluoroacetoxy) -A-norpregn-3-en (20; R ° is CH ₃ , R ^MI is OCOCF ₃ , Y is OCOCF ₃ ); 17,20-epoxy-3-methyl-20-trifluoroacetoxy-A, 19-bisnorpregn-3-en (20; R ° is H, R '"is H, Y is OCOCF ₃ ); or 17,20-epoxy 3-methyl-20,21-bis (trifluoroacetoxy) -A, 19-bisnorpregn-3-en (20; R ⁰ is H, R "'is OCOCF ₃ , Y is OCOCF ₃ ) can be subjected to a basic cleavage in accordance with to obtain the following compounds: 17 <X, 21-dihydroxy-3-methyl-A-norpregn-3-en-20-one (21; R ° is CH ₃ , R "" is OH); 17o (-Hydroxy-3-methyl-A, 19-bisnorpregn-3-en-20-one (21; R ° is H, R "" is H); or 17 <X, 21-dihydroxy-3-methyl -A, 19-bisnorpregn-3-en-20-one (21; R ° is H, R "" is OH).

Example l8

d, 1-170 <-Hydroxypregn-4-en-3,20-dlone (23; R ° is CH ,, R "" is H) can be prepared according to the procedure in Example 13, by ozonolysis of 17o ( Hydroxy-3-methyl-A-norpregn-3-en-20-one (Example 17) and acidic aldol condensation of the triketone obtained (22; R ° is CH "R""is H).

20988.A / U18

- J5o -

Similarly, 17o (-Hydroxy-21-acetoxy-5-methyl-A-norpregn-3-en-20-one (21 j R ⁰ is CH ^, R ^{! R} "is OCOCH ^);

17 «-hydroxy-; 3-methyl-A, 19-bisnorpregn -> - en-20-one (21; R ° is H, R""isH); or 170 (-hydroxy-21-acetoxy -> - methyl-A, 19, bisnorpregn-3-en-20-one (21; R ⁰ is H, R "" is OCOCH,) an ozonolysis and aldol condensation of the intermediate products tricyclic ketones (22) to form the corresponding compounds, namely d, l-170 (, 21-dihydroxypregn-4-ene-3,20-dione (23; R ⁰ is CH ₃ , R "" is OH );

d, l-17 (X-Hydroxy-19-norpregn-4-en-3,20-dione (2J; R ° is H, R "" is H); or d, l-170 (, 21-dihydroxy -19-norpregn-4-en-3,20-dione (23; R ⁰ is H, R " ¹ ! Is H).

20988A / U18

In connection with the cyeloreaction according to the synthesis plan III, which leads from cyclopentenol IJ> to the A-nor-steroid 14, it was found that this type of reaction can be carried out with a large number of compounds which have the general formula (where for the sake of simplicity the series formula is used)

The end group B? in this formula 13A - is a lower alkyl group (C ₁ to C ^), a hydroxyl substituted lower alkyl group (e.g. methylol), an acyl substituted lower alkyl group (e.g. acetyl substituted methylol), Trimethylsilyl or any other group compatible with ring closure. R iat hydrogen or the methyl or ethyl group. Z is any of the large number of groups (in the appropriate environment and how they in connection with the synthesis plan III for the reaction 13 under the appropriate conditions - described "14 and in the following examples nlnd) (Uo cycloaddition reaction of Specifically, Z is a group having a carbon atom ( denoted by an asterisk in the following formula 12A ¹ ) which is a carbon atom extending from the point of attachment of Z to the dienyne segment of the molecule is removed

09

2234Q18

Dienyn segment

and under the appropriate conditions becomes cationic and bonds with carbon atom 4 of the dienyne segment comes in.

Examples of such cycling initiators (as they are called shall) and resulting steroids will now be described.

209884 / H18

- 39 Table I.

Cyclizing initiator

Z -

formed steroid .erf. Procedure)

(2a) C. how (2) above ι— ^s \ HS-CH ₂ -CH ₂ -S- | (3) • —β Λ I.

(4) R '

HO-CH2 "CH ₂ -

(5)

if -MBflm 'a · »CH ₃ , b = GH ₃ if - ** ■■ a - H, b - C ₆ H ₅

209H84 / 1418

Table I ("continued)

CH

(7)

R ¹⁰ = H orf.CH ₃ R ¹¹ »H OBt. CH ₃ 209 O8A / H 18

- 4i -

In Table I give the dashed lines in the .Formulas (2). to (8) indicate that the remainder of the molecule is identical to the remainder in formula (I). The molecular parts not shown in the specific examples below below can be found in the literature for the cyclizing effect of Z as follows: Part 2a, see Johnson, Accounts of Chemical Research, January 1968, pages 1-8; also Johnson, J. Am. Chem. Soo ;, 86, 1972 (1964) and Johnson, J. Org. Chem. 22, 478 (1967); Part 4, see Abrams, Bioorganie Chemistry, 1, 242-268 (1971) and Johnson, Accounts of 'Chemical Research, 111 (1968); Parts 6 and 7, see Johnson, J. Am. Chem. Sog. 88, 3859 (1966); Part 8, see Johnson Chemical Communications, oll (1969).

In all examples according to Table I, a steroid (right Column) according to the following general formula:

t
, 6

'■ - Y

6 7 in which Y is a nucleophilic residue, R ^ as stated above, R and R '

Is hydrogen, a methyl or ethyl group and R is a divalent or trivalent group derived from Z (the core carbon atom to which R ^{1 is} bonded is also derived from Z) which forms a 5- or 6-membered ring (the steroid's Α-ring) fused to the adjacent 6-ring (steroid's B-ring). In cases where R is trivalent, one of the bonds (the one shown in the formula below) is a double bond.

A characteristic feature of the cycloreaction of the process according to the invention is to be seen in the fact that when the group Z has an asymmetric center, the substance 13A in: both

20988A / U18

the enantiomeric (.optically active) forms can be obtained, by conventional dissolution methods. The optical one The purity of this cyclization substrate determines the optical quality of the steroid. As an example, let us assume: the group Z from part £ of Table I (R '= CE,) has an asymmetrical one Carbon atom (see asterisk) at the point of attachment to the dienyne moiety. As a result, the cyclization substrate can in both of its dissolved forms are obtained which, after ring closure, the steroid (R '= CH-J in the corresponding dissolved forms give, one of which corresponds to the natural (D) configuration. If the dissolution of the substrate is not carried out racemic cyclization products are formed. In the The following description is - in most cases - the formulas without differentiating the spatial position of R, R, the various hydrogen atoms attached to the steroid rings etc are shown above or below the plane of the rings. It it is assumed that they are arranged as in natural steroids.

The effect of group Z chirality in controlling the optical Activity makes it possible to manufacture steroids that have the D-configuration or the like natural steroids L series (including some new, not yet manufactured) or the racemic (DL) series (including some new, so far not synthesized compounds).

The following examples and synthesis plans serve to illustrate how the selection of the cyclization initiator varies and how the production of steroids can be controlled to known ones To manufacture steroids, new steroids, and those steroids whose structure is ancient except for optical activity.

20 9884 / U18

Synthesis plan Vl

step

Level level,

24,

CH ₂ 25,

CH

27

S level . 6,

, COOCH.

29 ..

ι — i. ■ ΓΤ

step

OH

30th

Ü 9 "8 Ö A / U 1

The compounds shown in Synthesis Plan VI, including those that were not isolated (except for analysis), were identified by elemental analysis, nuclear magnetic resonance spectrum, infrared spectroscopy and - where possible - by the boiling point. The compounds were numbered consecutively, following the compounds in the synthesis plans I to V (starting with 24) and the process steps were marked with (1), (2) etc. In step (1), _24 (a known compound) was reacted at room temperature in a 1: 2 volume ratio of tetrahydrofuran (THF) and 10 % aqueous hydrochloric acid to form compound 25 (boiling point 96-98 ° C / 15mm) , a compound which was converted to dicarboxylate 26 in step (2) by reaction with dimethyl malonate in methyl alcohol with sodium methoxide as the base. In step (j5) the compound 26 was decarboxylated in aqueous hydrochloric acid-acetic acid under reflux for 20 hours and the acid 2 £ obtained was esterified in step (4). When using p-toluenesulfonic acid in a methylene dichloride / methanol solvent, the methyl ester j ^ 8 was obtained. This was reacted with 1,2-ethanedithiol in step (5) to form the thioketal 2Q. At this stage, chloroform was the main solvent with boron trifluoride etherate as the acid catalyst. The reaction was carried out at room temperature for 5 1/2 hours. The boiling point of compound 23 was 173-174 ° C / 0.15 mm. The methyl ester 2 $ was converted to the alcohol ^ O by a standard reduction [kedal, a commercially available form of NaAIn ₂ (OGH ₂ CH ₂ OCH ₃ ) ₂ , in tetrahydrofuran at 0 ° C, 4 hours].

The alcohol was converted to the tosylate ^ O] 51 (tosyl chloride in pyridine at 0 ° C, 2 hours) and the tosylate £ 1 was charged with sodium iodide in acetone at 25 ° C and reacted for a reaction time of 2 hours iodide ^ g. The solvent also contained a small amount of diisopropylethylamine to suppress isomerization of the olefin linkage. In step (9) the iodide was 1.4 equiv. Triphenylphosphine in acetonitrile

209884 / H18

50 ° C converted to phosphonium iodide 33 for 10 hours. Some diisopropylethylamine was also present at this stage, to suppress the isomerization of the olefinic bond. The melting point of the racemic product was 87-91.5 ° C, that of the ^ product at 91-93.5 ° C.

In step (10) the phosphonium iodide with one equiv. Phenyllithium treated in tetrahydrofuran (THF) at room temperature and the ylid ^ 4 formed. This ylid gl · corresponds to the ylid £ of the synthesis plan II. It was not isolated. The reaction mixture from stage (10) was in stage (II) with the aldehyde J ^ implemented to the starting material 35 (a specific example of 13A) for the cycloreaction.

In order for compound 35 to be cyclized, the double bond between carbon atoms 3 and 4 must be a trans group. (Similar to the bond between C ₇ and Cg, which is obtained by the type of synthesisj see above). Usually the cis species dominate. When using the Schlosser modification of the Wittig synthesis | _ygl · Schlosser, Angewandte Chemie, International Edition, 5th, page 126 (1966) J, the trans species are formed in large yield. The way it works is as follows:

The reaction mixture from stage (10), cooled to -78 ° C., is treated with one equivalent of the aldehyde J ^ and the mixture is held for 15 minutes. A slight excess (1.3 equiv.) Of phenyllithium in tetrahydrofuran is then added, the temperature still being maintained at -78 ° C. Then ether is added in order to adjust the solvent ratio (THP / ether) to 1: 1. The temperature was then increased to -30 ° C. and methyl alcohol was added to create the proton which is to replace the proton which had been extracted from an intermediate by phenyllithium. 72 % yield of the desired trans compound 35 was obtained, identified by elemental analysis, nuclear magnetic resonance spectroscopy and infrared spectroscopy.

209884 / U18

The thioketal 35 itself can also be subjected to a cycloreaction to give a previously unknown steroid (Example 19, compound 36) to form, or it can be converted to other compounds which then cyclically form steroids (some of which are new steroids). These steroids (products of the Cycloreaction of 35 or products of the cycloreaction of derivatives of compound 35) can be reacted by processes which are known in steroid chemistry to. modify the structure, e.g. B. keto groups, olefinic groups, hydroxyl groups etc. to introduce. The following examples show this.

As already stated above, the inventive method allow optical selectivity, for. B. the formation of d, l · and d,! Types of steroids. With reference to the ester 29 of synthesis plan VI, the following procedure can be used to represent the optical selectivity.

If the synthesis is carried out as shown in Synthesis Schedule VI, the steroids ultimately produced will be racemic ( d, l ). However, when the ester 29 is hydrolyzed and the corresponding carboxylic acid 29a is formed, it can be broken down into the d and L types by conventional working procedures, which are then converted back to the esters (d ^ 2 ^ and 1-29). Accordingly, when proceeding according to the synthesis plan VI with d ^ 2Q, the ketal 35 and all steroids produced from it are the natural enantiomeric series. Likewise, when 1-2 ^ or dj.1 ^ 29 are used, the ketal "JQ and all steroids made from it are not natural enantiomeric series or the d, l- series.

Similarly, in other approaches to the cyclizer initiator Z an acid can be formed at any corresponding point to split into the d and / or iwrts in the same way will.

The following examples illustrate dl * Am.vinctu.-ig »n Ketal 35 according to the invention.

209884 / H1 8

Example 19

The ketal £ 3 is treated with titanium tetra chloride in 1,2-dichloroethane 10 Treated minutes at -30 ° C and the steroid ^ § and the by-product 37 formed.

CH ₅ -C-Cl

The compounds J5ö and 37 are in a 6: 1 molar ratio (6 by 36, 1 by ^ T) formed. They are inseparable. she were determined by partial decomposition and separation and identification of the products by partial decomposition. The connections 36 and 37 can be treated to cleave the thioketal group and substitute double bonded oxygen:

38 is a mixture of isomers corresponding to 36 and 37.

The thioketal 35 can also be mixed with tin chloride in 1,2 »dichloroethane ο ^^

Treated at -30 C to produce a mixture of 39 ^ nd 40 (6 t 4) to produce:

209884/1418

in which the marcapto group can be split and receive that tene mixture can be oxidized with ozone to the

CH,

= C.

-Group of 39

double-bonded oxygen too

substitute. Example 20

The ketal 35 is treated in a manner similar to that described by Fetizon and Jurion in Chemical Communications, page 382 (1972). It is with 2h equiv. Methyl iodide reacted in a 5: 1 mixture of acetonitrile and water for 20 hours at 50 ° C. in order to substitute the thioketal group with double-bonded oxygen. The ketone 4l is obtained.

209884 / U18

This ketone has been isolated and identified. Its keto group can be reduced to hydroxyl, in which case the hydroxyl compound 42 is formed.

This compound has also been isolated and identified. It was cyclized as follows. The solvent was 1,1-difluoroethane, which contained 8 wt .- ^ trifluoroacetic acid and 12 wt .- ^ ethylene carbonate. The reaction mixture was refluxed at -25 ° C. for 2 hours. Then, 10 $ potassium carbonate was added in 50% aqueous methanol and the mixture heated to 25 ° C and kept as 8 hours. The conversion of the end group CH - * - C am to an end group CEx-CO-

209884/1418

so went on, that a vinyl cation is attached to the acetylenic
Group was formed, from this an enolate derivative and from this an enol, which was finally converted to the ketone. That
Steroid 4; 5, which is shown in its correct spatial structure, can serve as a starting material for other steroids. For example, the following reactions can be carried out by known process steps which lead to progesterone (d-, l · or cLl-, according to a choice made).

C = O

progesterone
46

209884/1418

- 5ΐ · -

The connection 43 can also be in the Pregnan-20-on

being transformed.

Example 23

In the scheme of synthesis plan III, the keto group 12 is converted into a carbinol group by a Grignard reaction, in which R ^{0 is} the methyl group. According to the present example, the keto group is reduced to hydroxyl by lithium aluminum hydride in ether at 23 ° C in the course of one hour. The alcohol 4§ is then formed by adding a 15% aqueous sodium hydroxide solution.

209884/1418

This is by adding 15 * 5 equiv. Trifluoroacetic acid and 32 equiv. Ethylene carbonate is cyclized in 1,2-dichloroethane, the mixture initially being kept at -50.degree. C., then warmed to 0.degree. C. and a further amount (15 * 5 equiv) of trifluoroacetic acid being added and kept at 0.degree. Finally, methanol and aqueous sodium hydroxide are added. Im made a-nor-steroid

CH

the Α-ring can be expanded by conventional process steps or according to the synthesis plan IV or by other appropriate working methods. For example, by ozone in dichloromethane at -78 ° C (5 minutes), then adding zinc and acetic acid at -78 ° C, heated to 23 ° C for 2 hours, the diketone 18 (ρ ^υ = H, R ¹¹¹ = H ) is formed. The ring closure takes place by treatment with an acetic acid-hydrochloric acid solution under reflux [jDaum method, Proc. National Acad. May be. 62 , pp. 325-226 (1969) J, wherein the d, l-19-nor-progesterone 50 is formed;

2098 8 4/1418

The method according to the invention can be further generalized and can be evaluated as follows. The dienyn 13A is cyclized to form a steroid-like product (in some cases along with a nonsteroid by-product as in Example 19, Compounds 36 and 37) · This sfceroid-like product has a 5-ring (the D-ring of the steroid) to which the group

R-Y

is bound.

This group can be converted to a keto group (as in the preparation of compound 43 in Example 20)

_R 6c = O '

which is a progesterone type steroid. As in Example 19, this can be done without isolating the immediate product of the
Cycloreaction II happen. On the other hand, II can be an oxidati-

ven cleavage of the = C

-Group be subjected to im

5-ring to form a keto group:

209884 / U18

This is illustrated in Example 19 by cleavage of the marcapto group from y \ , followed by cleavage of the group

= C - ^ followed by ozone. This route leads to steroids of the ^ Cl

Androstane type.

The steroid-like precursor II or the product in which the

= CL group is replaced by the keto group (as described above ^ * Y

written), can be modified by known methods, to introduce double bonds, hydroxyl groups, keto groups, etc., or to saturate double bonds, etc. Soloho modifications this steroid structure lead to a large number of steroids including known useful steroids such as Progesterone, Pregnan-20-one, 19-nor-Progesterone, Androstane etc.

209884 / -U18

Claims (20)

1. Steroid marked by the " ^Pormel CH _p ^ CH, C HIGH in which R denotes the CH ″ or a Si (lower alkyl) group. 2. Steroid according to claim 1, characterized in that it Is 2-methyloct-1-en-6-yn-3-ol. 3. Process for the preparation of a compound according to claim 1, characterized in that a compound of the formula CHp = C (CH,) - Z is reacted with a compound of the formula .Z ¹ CH ₂ CH ₂ CSC-R, where R is the group CH, or Si (lower alkyl group) ,, one of the groups Z and Z ^{1 is} CHO and the other of these groups is MgX in which X is chlorine, bromine or iodine. 4. Steroid identified by the Pormel CH, C in which R is the CH, groups or a Si (lower alkyl group), and T is a C0 ₂ ~ lower alkyl group, the CHgOH or CHO group. 5. Steroid according to claim 4, characterized in that it is lower alkyl-_trans-4-methyldeo-4-en-8-ynoate. 2098 847 U18 6. Steroid according to claim 4, characterized in that it is trans -4-methyldec-4-en-8-ynol. 7. Steroid according to claim 4, characterized in that it is trans- »4-methyldec-4-en-8-ynal. 8. The method for producing a steroid according to claim 4, in which T is the group CHO, characterized in that a A compound according to claim 1 reacted with a lower-alkyl orthoacetate and the compound obtained according to claim 4, in which T is a COp-lower alkyl group, with sodium bis (2-methoxyethoxy) aluminum hydride is reduced. 9. Process for the preparation of a steroid according to claim 4, in which T is the group CHO, characterized in that a compound according to claim 1 is reacted with a lower-alkyl orthoacetate, the compound obtained according to claim 4, in which T is a COp-low -Alkyl group is reduced with lithium aluminum hydride, the compound obtained according to claim 4, in which T is the group CHpOH, is oxidized with an oxidizing agent which is capable of oxidizing a primary alcohol to aldehyde . 10. Steroid characterized by the formula V, / τ ' --- ^c I CH ₂ CH ₂ + τ- where T ^{1 is} Br, I, or P (C ₆ H ₅ ) y "I" 20988A / U18 11. Steroid according to claim 10, characterized in that it is l-bromonona-5,8-dione-bis (ethylene ketal). 12. Steroid according to claim 10, characterized in that it is l-iodonona-5,8-dione bis (ethylene ketal). 1 ^ · steroid according to claim 10, characterized in that "it Nona-5,8-dione-bis (ethylene ketal) -l-triphenylphosphonium iodide is. 14. A process for the preparation of a steroid according to claim 10, in which T 'P (CgH, -) ^ I "is, characterized in that 2-methylfuran is reacted with 1,4 dibromobutane in the presence of a strong base, the 6- Treated (4-bromobutyl) -2-methylfuran with ethylene or propylene glycol in the presence of an acidic catalyst and a compound is formed according to claim 10, in which T ^{1 is} a Br atom, this compound is treated with a source of iodine ions and a compound according to claim 10 is formed, in which T 'is an iodine atom, and that this compound is reacted with triphenylphosphine and a compound according to claim 10 is formed, is in the ¹ T H ₅₎ ^ ⁺ I ". CH ₂ R " 15. Steroid characterized by the formula Cn-, CHo CC 1 'Jl -C = O HC CH CH ₂ C CH ^ C in which R "is H or OH or a bis-ethylene or bis- propylene glycol ketal . 209884/1418 16. Steroids compound according to claim 15, characterized in that it is 7-Methylnonadeca- trans, t rans- 6,10-dien-2-yn-l5,18-dione bis-äthylenglykolketal is. 17. Steroid according to claim 15, characterized in that it is 7-methylnonadeca- trans , trans- 6,10-dien2-yn-15, 18-dione. 18. Process for the preparation of a ketal compound according to claim 15, in which R "is hydrogen, characterized in that a compound according to claim 10, in which T ^{1 is} P (CgH _c _) -, ⁺ I", is treated with 'phenyllithium , the ylide obtained is reacted with trans -4-methyldec-4-en-8-ynal; or preparation of a compound according to claim 15, in which R "is the OH group, wherein a compound according to claim 10, in which T ^{1 is} P (CgH, -) -, I ~, is treated with phenyllithium, the ylide obtained with a compound according to claim 4, in which T is the CHO group and R is a Si (lower-alkyl group), the resulting diketal des! - (tri-lower-alkylsilylJ-ö-methyloctadeca trans , trans -5.9 -dien-l-yn-l4,177dione treated with silver ions and a diketal of 6-methyloctadeca-trans, trans_-5, 9-dien-l-yn-l4,17-dione is formed, and this compound in the presence of a strong one Base is treated with formaldehyde. 19. Steroid of formula in which T "is the C = 0-0 group or C (R ⁰ ) (OH), where R ^{0 is} H or the CH, group and R ^{11 is} H or OH. 209884 / U18 20. Steroid according to claim 19, characterized in that it is 2- (7-methyltrideca- trans , trans ° 3 _J 7-diene »ll-ynyl) -3-roethyl- ■ cyclopent-2-enone 1st. 21. Otorold according to Annpruoh I9, characterized in that the gg is 2- (7-methyltrldeca- trans _f trans- 3 «7-diene-ll-ynyl) -l _J 3-dimethylcyclopent-2-enol. 22. A method for producing a steroid according to claim I9, in the T "is the CH (OH) group, characterized in that a dioxo compound according to claim 15 under alkaline conditions heated and thereby a cyclization is effected to a compound according to claim 19, in which T "is the C = 0 group is, and that this compound is reacted with a metal hydride. 23. Process for the production of a steroid according to claim 19, in which T "is C (CH 19, in which T "is the C = O group, and that this compound is reacted with methyllithium or methylmagnesium chloride. 24. Steroid characterized by the formula in which R is H or the CH, group and A is selected from the group consisting of 209884 / U'18 -.60 - CH ₂ R "'
CY cu τ> "M
CH ₂ R C = O , C-H, CH ₂ R '"C-" ⁰ and PU P "" CH ₂ R C = O C OH is selected, in which R ¹ "is H, OH or an OAcyl group and Y is an OAcyl or acyl group, which in each case is formyl-
or halogenated lower-alkanoyl-, where at least
is a halogen atom Inet position, and whose R "" is H, OH or a lower alkanoyloxy group. 25. Steroid according to claim 24, characterized in that it is 3-methyl-A-norpregn-3-en-20-one is. 26. A method for producing a steroid according to claim 24, in which A is the group CH ₂ R ¹ " C-Y Il is, characterized in that a compound according to claim 19, in which T "is C (R ⁰ ) (OH), is treated with an acid HY. 27. Steroid characterized by the formula in the R ° H or the CH, group and A ¹ from the compounds of the groups 0
Il
C, CH ₀ R "" I ²
C = O
I.
CH, and C = O C OH 209884 / U18 is selected and R " ^{n is} H, OH or a lower alkanoyloxy group. 28. Steroid according to claim 27, characterized in that R ° the CHU group and A 'the group CH ^ C = O C-H is. 29. Steroid according to claim 27, characterized in that R ^{0 is} the CH-x group and A 'is the C = 0 group. 30. A method for producing a steroid according to claim 27, in to the A 'the group I C ft Il or CH ₂ RC = O C-H is, characterized in that a compound according to claim 24, in the A CY I or /-.TT Tj Il Il CH ₂ R C = O C-H where R "" denotes H or a lower alkanoyloxy group, is ozonated. 31. Process for the preparation of a compound of the formula in the R H or the CH, group and A from the groups CH ₀ R ¹ " ¹ ■ ·" CH ₀ R " ¹¹ 0 I ² M B C = O and C = O C I I C-H C-OH 20 98 84 / U1 is selected where R "" is H or OH or a lower alkanoyl-oxy group is, characterized in that a compound according to claim 27 is treated with a cyclization catalyst, 32. The method according to claim; 51, for the production of d,! - progesterone, characterized in that the compound according to claim 28 is treated with a strong base. Process according to claim 3I for the preparation of d, l-androst-4-en-j5,17-dione, characterized in that the compound according to claim 29 is treated with a strong base. 4. / Process for the production of a steroid, characterized thereby net that first a compound of the formula I. in which R is hydrogen or a lower alkyl groupj R ^ is a lower alkyl group, an OH-substituted lower alkyl group, an acyl-substituted-hydroxyl-lower Mean alkyl group, trimethylsilyl or other group compatible with the cycloreaction; Z is a cyclization initiator having a carbon atom capable of forming a cation and bonding with the carbon 4 of the formula I to form a 5- or 6-membered ring, and that this compound I is subjected to a cyclic reaction is going to make the connection 209884 / U18 II .. ¹ to form in which Y is a group or atom derived from • 7 is a nucleophilic radical in the cyclization stage, R ^{1 is} hydrogen, or a lower alkyl group and is derived from Z. and R is a divalent or trivalent group which is derived from Z, which forms a 5- or 6-ring with the adjacent 6-ring. 35. The method according to claim 3 ^ »characterized in that as Cyclization initiator Z a compound from Table I is used will. 36. The method according to claim ~ $ k or 35 *, characterized in that the cycloreaction is carried out in the presence of a strong acid. 37 · Method according to one of the claims, that the end group up to 36, thereby identified R. C-Y of compound II is converted into a keto group. 38. The method according to claim 37 »characterized in that the end group is converted into the keto group R - ^ - CO-. 20S884 / 1418 39. The method according to claim 37 * characterized in that, the end group is subjected to oxidative cleavage and a keto group is formed as part of the 5-membered ring of the steroid. 40. The method according to claim 38 or 39 *, characterized in that the compound II is modified before the conversion of the end group and the desired steroid is thereby produced as the end product. 41. The method according to claim; 58 or 39 * characterized in that modified the keto group resulting from the conversion of the end group and the desired steroid is formed as the end product. 42. Compounds characterized by the formula in which R, R and Z have the meaning given in claim 34. 43. Compounds according to claim 42, characterized in that Z is selected from the group of compounds given in Table I. 44. Compounds of Formula 209884/1 Al 8 characterized in that R, R, R ', R and Y are those in claim j54 have given meanings. 45. Compounds according to claim 44, characterized in that R is one of the groups given in Table I. 20 9.884 / 1418