Process for synthesizing A-nor and A-nor-18-homo-steroids

The present invention is directed to a process for synthesizing A-nor and A-nor-18-homo-steroids. The invention is concerned with providing a total synthesis for the compounds called Dinordin and 18-homo-Dinordin. The preparation of other compounds will also be evident.

The present invention is related to a process for synthesizing A-nor and 
A-nor-18-homo-steroids. The invention is particularly concerned with 
providing a total synthesis for the compounds called Dinordrin and 
18-homo-Dinordrin although the preparation of other related compounds will 
also be evident. 
Dinordrin (1a) and 18-homo-Dinordrin (1b) in the form of their propionate 
esters, may be structurally illustrated as follows: 
##STR1## 
These compounds have been reported to have unusual fertility inhibitor 
properties. For example, Dinordrin appears to be about ten times more 
potent than Anordrin (the dipropionate of 2.alpha., 
17.alpha.-diethynyl-A-nor-5.alpha.-androstane-2.beta., 17.beta.-diol). See 
P. Crabbe, H. Fillion, Y. Letourneux, E. Diczfalusy, A. R. Aedo, J. W. 
Goldzieher, A. A. Shaikh, and V. D. Castracane, Steroids, 1979, 33, 85; P. 
Crabbe, D. Andre and H. Fillion, Tetrahedron Letters, 1979, 893. 
Prior procedures for preparing 1a and 1b and generally similar products, 
including Anordrin, are inconveniently lengthy and low yielding and there 
is a real need for a versatile, short, total synthetic scheme for 
preparing these products. The principle object of the present invention is 
to provide such a process. A more specific object is to provide a 
relatively short synthetic route which affords the desired products in a 
convenient manner and in good yield. Other objects will also be 
hereinafter evident. 
Broadly speaking, the products which may be prepared according to the 
present process include those of the Formula I: 
##STR2## 
wherein n=1 or 0, R is methyl or ethyl; R.sub.1 is hydrogen or 
##STR3## 
wherein A is preferably lower alkyl, cycloalkyl or aryl; and R.sub.2 is 
hydrogen or methyl. It will be appreciated that Dinordrin is represented 
by Formula I when n=1, R is methyl, R.sub.1 is a propionate and R.sub.2 is 
hydrogen while, in 18-homo-Dinordrin, R is ethyl, R.sub.1 is a propionate 
and R.sub.2 is hydrogen. 
Anordrin is represented by Formula I when n=1, R and R.sub.2 are both 
methyl and R.sub.1 is 
##STR4## 
It will be appreciated that the products are normally prepared as mixtures 
of the 2.alpha., 17.alpha.-ethynyl and 2.beta., 17.alpha.-ethynyl isomers. 
The 2.alpha., 17.alpha. isomer is preferred for biological use. 
The reaction scheme involved in the present process is represented below: 
##STR5## 
The process of the invention involves the use of an approach described by 
Schering A. G. (see (a) G. Sauer, U. Eder, G. Haffer, G. Neef, and R. 
Wiechert, Angew. Chem. Int. Ed. Engl., 14, 417 (1975); (b) R. Wiechert, 
Angew. Chem. Int. Ed. Engl., 16, 506 (1977) and references therein). There 
is, however, no indication in the Schering disclosures of the possibility 
of preparing A-nor steroids using this approach. 
The starting material for the synthesis of Dinordrin is the known optically 
active trans-fused bicyclic diketo-sulfone (1) described in the 
above-mentioned Schering A. G. publications. The crystalline dione (1) is 
reacted in a non-polar solvent with the anion prepared from 
6-(1,3-dioxolan-2-yl)-3-oxoheptanoic acid methyl ester (2), in the 
presence of sodium or potassium hydride. A triketo-derivative (3) is 
obtained and this is immediately hydrolized, cyclized and decarboxylated 
with base, to afford the enone (4) in high yield. 
Catalytic hydrogenation of the conjugated ketone (4) gives the dione (5). 
Acid hydrolysis liberates the cycloethylene ketal, thus providing the 
crystalline trione (6). 
Cyclization of the tricyclic intermediate (6) in methanol solution in the 
presence of a base gives a mixture of isomeric enones (7) and (8). This 
mixture can either be separated or immediately submitted to a Birch 
reduction, followed by oxidation with pyridinium chlorochromate, thus 
providing the corresponding saturated 2,17-dione (9). This material is 
shown to be identical by usual criteria (m.p., I.R., N.M.R., etc.) with an 
authentic sample of the dinor-dione (9), see: P. Crabbe, H. Fillion, Y. 
Letourneux, E. Diczfalusy, A. R. Aedo, J. W. Goldzieher, A. A. Saikh, and 
V. D. Castracane, Steroids, 33, 85 (1979). This confirms the correct 
configuration at all asymmetric centres, in particular the A:B trans 
stereochemistry, i.e. the cyclization process and the Birch reduction of 
both isomers (7) and (8) are completely stereoselective. 
Treatment of the diketo-steroid (9) with an excess of lithium 
acetylide-ethylenediamine complex under known conditions, furnishes a 
mixture of 2.alpha.- and 2.beta.-isomers, of which the desired 
2.alpha.-ethynyl steroid (10) may be separated by chromatography. Further 
esterification of the diol may be performed under known conditions. 
The same reaction sequence may be applied to the known optically active 
7.alpha.-.beta.-ethyl-6H-7,7.alpha.-dihydroindane-1,5-dione to give the 
corresponding 18-homo dinor-steroid. 
In addition the same synthetic route may also be applied to the synthesis 
of A-dinor-steroids (i.e. n in Formula I is 0 so that ring A is a 
four-member ring) using 5-(1,3-dioxolan-2-yl)-3-oxohexanoic acid methyl 
ester.

The invention is illustrated by the following example: 
EXAMPLE 
(a) 5-(1,3-Dioxolan-2-yl)-2-hexanone 
##STR6## 
22.8 g (0.2 Mol) Hexanedione-2,5, 12.4 g (0.2 Mol) ethylene glycol, and 0.5 
g p-toluenesulphonic acid were refluxed for 18 hours in toluene on a 
Dean-Stark apparatus. Then the solution was washed twice with NaHCO.sub.3 
-solution, dried over K.sub.2 CO.sub.3 and concentrated in vacuo. The 
remaining oil was distilled over a 20 cm-Vigreux column. The middle 
fractions were redistilled to give the monoketal as a colourless liquid, 
b.p. 100.degree.-103.degree./15 mm. 
Alternatively the monoketal may also be prepared as follows: 
A solution of 2,5-hexadione (23.4 ml, 0.2 mole) and ethyleneglycol (45 ml, 
0.8 mol) in toulene (125 ml) was stirred in an ice bath for 15 min. After 
this time concentrated sulfuric acid (5 ml, 0.09 mole) was added and 
stirring was continued for 30 min. The lower layer containing mainly 
ethyleneglycol was separated and extracted with toluene twice. The 
combined organic layers were washed with a sodium bicarbonate solution 
(water and NaCl saturated solution). Toluene was evaporated and the 
remaining viscous liquid containing the starting material contained the 
mono and di-ketals. These were separated by vacuum distillation, affording 
the expected monoketal. 
NMR (CDCl.sub.3): 1.30 (s, 3H); 2.10 (s, 3H); 1.65-2.65 (m, 4H); 3.85 
p.p.m. (s, 4H). 
IR: 1718 cm.sup.-1. 
(b) 6-(1,3-Dioxolan-2-yl)-3-oxoheptanoic Acid Methyl Ester 
##STR7## 
4.32 g Sodium hydride (50% in oil) were washed with pentane, dried and 
suspended in 30 ml of dry ether. At reflux temperature were added 5.40 g 
dimethyl carbonate (60 mMol) and then a solution of 4.74 g monoketal (30 
mMol) in 20 ml of dry ether. After 4 hours the gas evolution was finished. 
The mixture was hydrolysed with 5 ml of ethanol, poured on a solution of 7 
ml of acetic acid in 100 ml of water, neutralized with NaHCO.sub.3 and 
extracted with ether. The aqueous layer was extracted two more times with 
ether. The extracts were dried over K.sub.2 CO.sub.3 and evaporated. The 
residue was distilled in vacuo, to give the ester as an oil. 
NMR (CDCl.sub.3): 1.30 (s, 3H); 1.60-2.70 (m, 4H); 3.40 (s, 2H); 3.62 (s, 
3H); 3.85 p.p.m. (s, 4H). 
IR: 1750, 1718 cm.sup.-1. 
(c) 
##STR8## 
240 mg Sodium hydride (50% in oil, 5 mMol) were suspended in 20 ml of dry 
toluene. With stirring a solution of 640 mg (2 mMol) of crystalline 
sulfone (1) (m.p. 92.degree.-94.degree.; [.alpha.].sub.D +179.degree.) and 
550 mg (2.5 mMol) ketal ester (2) in 20 ml of toluene was added over a 
period of 15 min. After 2 hours the solvent was removed in vacuo. The 
alkylation product was not isolated, but hydrolysed, cyclized and 
decarboxylated to give the unsaturated ketone (4). 
##STR9## 
The residue was dissolved in 20 ml of methanol and a solution of 0.5 g NaOH 
in 5 ml of water was added. After 10 hours, methanol was evaporated in 
vacuo and the aqueous solution was extracted with ether to remove 
paraffine (from NaH). The aqueous layer was acidified with acetic acid and 
extracted 3 times with methylene chloride. The extracts were dried over Mg 
SO.sub.4 and evaporated in vacuo. The residue was refluxed in 30 ml of 
toluene for 30 min. Then the solvent was removed and the residue purified 
by chromatography (20 g SiO.sub.2, toluene/ethyl-acetate 4:1), affording 
the enone (4) as a colourless oil. 
(d) 
##STR10## 
506 mg (1.6 mMol) of Enone (4) were dissolved in 50 ml of ethanol and 0.5 
ml of triethylamine. 50 mg of Pd on charcoal (5%) were added and the 
mixture was stirred at room temperature for 5 hours. The catalyst was 
filtered off, the solvent evaporated and the residue dissolved in 30 ml of 
acetone and 2 ml of 1n HCl. After 30 min. the mixture was neutralized with 
NaHCO.sub.3, acetone was removed in vacuo; the aqueous solution was 
extracted 4 times with CH.sub.2 Cl.sub.2, the extracts dried over 
MgSO.sub.4 and evaporated. The residue was recrystallized from 
hexane/ether, providing the triketone (6), m.p. 133.degree.-134.degree., 
[.alpha.].sub.D +129.degree.; 
NMR (CDCl.sub.3): 0.94 (s, 3H); 1.00-3.20, m; 2.20 p.p.m. (s). 
IR (Nujol): 1742, 1705 cm.sup.-1. 
MS (70 eV): 274 (M-2), 258, 233, 220, 219 (100%), 177, 163. 
(e) 
##STR11## 
276 mg (1 mMol) Trione (6) were refluxed for 10 hours in a solution of 1.7 
g KOH in 30 ml of methanol. After evaporation of the solvent, water was 
added, acidified with acetic acid, neutralized with NaHCO.sub.3 and 
extracted three times with CH.sub.2 Cl.sub.2. The extracts were dried over 
K.sub.2 CO.sub.3 and the solvent removed in vacuo. The residue 
crystallized from ether/hexane, to give a crystalline material, m.p. 
135.degree.-138.degree., mixture (1:1) of (7) and (8). 
The pure .DELTA..sup.1,10 -isomer (8) was obtained by recrystallization 
from hexane: m.p 182.degree.-184.degree.; [.alpha.].sub.D +51.degree.; 
U.V..sub.max 229 nm (.gamma.13,000). 
NMR (CDCl.sub.3): 0.88 (s, 3H); 0.92 (s, 3H); 0.65-3.00 (m, 18H); 5.67 
p.p.m. (s, 1H). 
IR (Nujol): 1740, 1702 cm.sup.-1. 
MS (70 eV): 259 (M+1); 258 (M.sup.+, 100%); 240, 214, 202, 187, 174, 173, 
160, 159, 149, 146, 145, 134, 132, 131, 119, 117, 108, 107, 106, 105, 97, 
96, 95, 94, 93, 91, 81, 79, 77, 67, 66, 65, 55, 53, 51. 
(f) 
##STR12## 
50 mg (0.19 mMol) of the enone isomer mixture in 2 ml of dry ether were 
added to a solution of 100 mg of lithium in 20 ml of liquid ammonia. After 
30 min, 1 g of ammonium chloride was added and the ammonia was allowed to 
evaporate. The residue was dissolved in water and extracted four times 
with methylene chloride. The extracts were dried over MgSO.sub.4 and 
stirred overnight with 0.5 g of Pyridinium chlorochromate. It was 
hydrolyzed with potassium carbonate solution, separated, washed with 1 n 
HCl, dried over MgSO.sub.4 and evaporated. The resulting oil was purified 
by chromatography on 2 g of silica gel (Toluene/ethyl acetate 9:1), to 
furnish a colourless oil, which crystallized on standing. M.p. (from 
hexane) 148.degree.-115.degree.. Recrystallization gave the pure sample of 
(9): m.p. 158.degree.-160.degree.; [.alpha.].sub.D +262.degree.. 
IR (Nujol): 1738 cm.sup.-1 (identical with the spectrum of an authentic 
sample). 
(g) 
A current of dry acetylene was passed for 30 minutes through a solution 
maintained at 0.degree. to 5.degree. C., of 250 mg of the dione 9 of step 
(f) dissolved in 5 ml anhydrous dimethylsulfoxide (DMSO) to which 272 mg 
of lithium acetylide-ethylene diamine complex had been added. The reaction 
mixture was allowed to stand overnight at room temperature after which it 
was mixed with water. The reaction product comprising about a 3:2 mixture 
of isomeric 2-ethynyl derivatives was recovered and, after chromatography, 
the desired 2.alpha., 17.alpha.-diethynyl-2.beta., 
17.beta.-dihydroxy-A-nor-5.alpha.-estrane (10) was obtained, separated 
from the 2.beta.-isomer (11). The separation was accomplished by thin 
layer chromatography using a 7 to 3 cyclohexane-ethyl acetate mixture as a 
solvent system. 
The corresponding diesters, e.g. diacetates, dipropionates, divalerates, 
dibutyrates, dibenzoates, dienanthates, diundecanoates and the like may be 
prepared from the diol (10) by conventional esterification techniques. For 
example, the diol (about 700 mg.) may be dissolved in about 3-5 ml of 
anhydrous pyridine with the addition of acid anhydride. The reaction 
mixture is then heated on an oil bath (110.degree.-115.degree. C.) 
overnight after which methanol is added to remove excess anhydride. The 
reaction mixture is cooled and the diester extracted, washed and fried, 
solvent being removed by vacumm. The pure diester isomers may be obtained 
by chromatography or the diester may be prepared by esterification of the 
separated hydroxy isomer. For example, esterification with propionic 
anhydride of the 2.beta.-hydroxyl isomer (m.p. 145.degree.; 
[.alpha.].sub.D -6.degree.) gives Dinordrin in the optically active form. 
The diesters may also be prepared by reacting the diols with the 
appropriate acid chloride in inert solvent under mild reaction conditions. 
Diethers may also be prepared by, for example, reacting the diol with 
dihydropyran in the presence of an acid such as p-toluene sulfonic acid. 
Monoethers may also be prepared in conventional fashion. 
It is to be noted that, while the foregoing example is concerned with the 
preparation of 2.alpha., 17.alpha.-diethynyl-2.beta., 
17.beta.-dihydroxy-A-nor- 5.alpha.-estrane (Dinordrin), the corresponding 
18-homo product may be prepared in similar fashion using the known 
methylene sulfone 7.alpha.-.beta.-ethyl-6H-7,7a -dihydroindane-1,5dione as 
starting material. 
The sulfone starting material used in the example was prepared by treatment 
of optically active (+) 7.alpha.-.beta.-methyl-6H-7, 7a 
-dihydroindane-1,5-dione with paraformaldehyde and benzenesulfinic acid in 
triethanolamine, and acetic acid, followed by catalytic hydrogenation in 
the presence of palladium on charcoal. (See again G. Sauer, U. Eder, G. 
Haffer, G. Neef, and R. Wiechert, Angew Chem. Intern. Ed., 1975, 14, 417). 
The sulfone was obtained in crystalline form (m.p. 92.degree.-94.degree.; 
[.alpha.].sub.D +179.degree.). The corresponding ethyl starting material 
may be obtained in the same way. 
It will be recognized that the procedure described above is short, 
flexible, and easy to perform, thus constituting a useful synthetic 
approach to the indicated class of biologically important A-nor steroids. 
It is noteworthy that the cyclization reaction of the intermediates (3), 
followed by catalytic reduction of the enones (4), condensation and Birch 
reduction of the cyclopentenones (7) and (8) afforded the dione (9) with 
the correct stereochemistry at all asymmetric centers, thus showing the 
total synthetic scheme to be extendible to A-nor-steroids with the 
A:B-trans configuration. 
The scope of the invention is defined in the following: