Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/22—Bridged ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
  • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J75/00—Processes for the preparation of steroids in general
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
  • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

Definitions

• the present invention relates to a hydrocyanation process generally applicable in the field of organic chemistry, and particularly to a process for introducing a cyano group into the B-position of an c p-unsaturated ketone. More particularly, it relates to a process which is suitable for the introduction of a cyano group into the angular position of polycyclic compound having an a,,8-unsaturated ketone structure of which the ,8-position corresponds to the said angular position.
• the process of the present invention is generally applicable to an organic compound having an c p-unsaturated ketone structure.
• the advantages of the process can be well exhibited in the cyanation, especially the angular cyanation, of polycyclic compound having an a ti-unsaturated ketone structure.
• Patent 3,050,518 and the other relating to the introduction of a cyano group into the angular position of steroids or D-homosteroids lacking a substituent of the said angular position and possessing an 0:,B-l1IlSfltlll'3'ttid ketone structure of which the B-position corresponds to the said angular position by treating the said starting steroids or D-homosteroids with alkali metal cyanide in the presence of ammonium halide in an inert solvent medium [Nagata et al.: Tetrahedron Letters, No. 17, p. 27 (1960); J. Org. Chem., vol. 26, p. 2413 (1961); Chem. Pharm.
• the hydrolysis of the once-produced angular nitrile seen in the known ICC methods can be completely inhibited. Therefore, the yield of the objective nitrile is necessarily increased. Adding to this advantage, it may be especially noted that the yield ratio of each isomer, i.e., cis-isomer and transisomer, according to the process of the present invention is remarkably one-sided, comparing with that obtained in the known methods. Thus, the process of the present invention may be advantageously adopted, when the production of the trans-form angular nitrile [the angular nitrile wherein the rings on both sides of the cyano group are condensed with each other by a trans juncture] is intended.
• the process of the present invention comprises reacting an organic compound, especially a polycyclic compound, having an afi-LIIISEitUIated ketone structure substantially with a complex anion represented by the formula:
• R represents a lower alkyl group (e.g., methyl, ethyl, propyl, butyl) or a lower alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy) and R and R" each represents a lower alkyl group (e.g., methyl, ethyl, propyl, butyl), a lower alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy), a halogen atom (e.g., chlorine, bromine) or a cyano group in a substantially anhydrous medium to introduce a cyano group into the position corresponding to the B-position of the cud-unsaturated ketone structure in the said starting compound.
• R represents a lower alkyl group (e.g., methyl, ethyl, propyl, butyl) or a lower alkoxy group (e.g., methoxy, ethoxy, prop
• the complex anion (A) can be produced, for instance by treating an aluminum compound represented by the formula:
• AlRR'R (B) wherein R, R and R each has the same significance as designated above with hydrocyanic acid in a substantially anhydrous medium [Equation 1] or treating the aluminum compound (B) with an aluminum cyanide compound represented by the formula:
• AlRRCN (C) wherein R and R each has the same significance as designated above in a substantially anhydrous medium [Equation 11], the aluminum cyanide compound (C) being prepared by treating an aluminum hydride compound represented by the formula:
• the process of the present invention may be actually performed by treating an organic compound, especially a polycyclic compound, having an afiunsaturated ketone structure With a combination of hydrocyanic acid or the aluminum cyanide compound (C) with the aluminum compound (B) in a substantially anhydrous medium.
• an organic compound especially a polycyclic compound, having an afiunsaturated ketone structure
• hydrocyanic acid or the aluminum cyanide compound (C) with the aluminum compound (B) in a substantially anhydrous medium.
• tri(lower)alkyl aluminum di- (lower) alkyl alumnium lower alkoxide, lower alkyl aluminum di(lower)alkoxide, aluminum tri(lower)alkoxide, di(lower) alkyl aluminum halide, lower alkyl aluminum dihalide, di(lower)alkyl aluminuim cyanide, lower alkyl aluminum halide cyanide and the like.
• the aluminum cyanide compound (C) may be di- (lower)alkyl aluminum cyanide, lower alkyl aluminum dicyanide, di(lower)alkoxy aluminum cyanide, lower alkoxy aluminum dicyanide, lower alkyl lower alkoxy aluminum cyanide, etc.
• the aluminum hydride compound (D) may include, for instance, di(lower) alkyl aluminum hydride, lower alkyl lower alkoxy aluminum hydride, di- (lower) alkoxy aluminum hydride, lower alkyl aluminum hydride cyanide and the like.
• any complex anion represented by Formula A is effective in the process of the present invention, an alkyl alumium complex anion of Formula A wherein at least one of R, R and R is a lower alkyl group possesses a relatively high activity.
• a tri(lower)alkyl aluminum cyanide complex anion of Formula A wherein R, R and R" each reppresents a lower alkyl group is very active, and can be the most broadly employed.
• reaction medium there may be employed an inert non-polar solvent such as benzene, ether, tetrahydrofuran and dioxane.
• an inert non-polar solvent such as benzene, ether, tetrahydrofuran and dioxane.
• the reaction may be carried out at a temperature from room temperature to 30 C.) to reflux temperature, preferably around room temperature, for about 0.5 hour to about 100 hours.
• reflux temperature preferably around room temperature
• strict control of reaction temperature and reaction time is not necessary.
• the cyanating agent i.e., the aluminum compound (B), the aluminum cyanide compound (C) and the aluminum hydride compound (D)
• the previous replacement of the air in a reaction vessel with an inert gas such as nitrogen is preferred.
• an inert gas such as nitrogen
• the cyanating agent is employed in the form of By the execution of the said cyanation reaction, there may be produced the addition product of the fragments the complex anion (A) to the starting eve-unsaturated ketone or the hydrocyanic acid adduct of the objective nitrile.
• the former addition product is readily hydrolyzed in the presence or absence of an acid or an alkali, usually in the course of the recovery operation, to give the objective nitrile or the hydrocyanic acid adduct thereof.
• the latter adduct is also readily hydrolyzed with an aqueous alkaline solution such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate to the objective nitrile.
• a ti-unsaturated ketone is combined with a mixture of hydrocyanic acid and tri(lower)alkyl aluminum in a substantially anhydrous inert organic solvent medium, and the resultant mixture is allowed to stand at room temperature (15 to 30 C.). After several hours, the reaction mixture is treated with an aqueous alkaline solution while cooling with ice and shake with a waterim-miscible organic solvent. The organic solvent phase is washed with water, dried and the solvent removed whereby the corresponding saturated ketone possessing a cyano group at the ii-position to the carbonyl group is obtained.
• dodeeahydrophenanthren-Z-one dodeeahydrophenanthren-Z-one. anthrene-lia and llfi-carbonitrile. 4-Cholesten-3-one 3-0X0-5a and 5/3-cholestane-B-carbonitrile- 1:1 82 1:2 85 17fl-Aeetyloxy-4estren-3-one 17fl-Acetyloxy-3-ox0-5a and 5/3-estrane-5 1;10 78 carbonitrile. dl-Bfi-Acetyl0xy-D-homo-18-nor-501-13(17a)- dl-3fl-Acetyloxy17oxo-D-homo-5a and 3:5 66 1:18 80 androsten-17-one.
• yield ratio represents that of an epimer of dl-B-methoxy-20-oxo-19-nor-1,3,5(10)-preg1iatriene-l8-nitrile:dl-3-meth0xy-ZQ-QxQ-l9-nor-
• the process of the present invention is valuable as a hydrocyanation process generally applicable to 11,3- unsaturated ketones.
• the economical process for introducing a cyano group directly to an angular position of polycyclic calf-unsaturated ketones of which the ⁇ 3-position corresponds to the said angular position is provided by the present invention for the first time.
• the thus introduced angular cyano group can be converted into a variety of carbon-containing functional groups such as iminomethyl, aminomethyl, hydroxymethyl, formyl, carboxyl, acetyl and methyl. Accordingly, the present invention makes it possible to produce economically a number of known or unknown polycyclic compounds possessing a substituent at the angular position.
• a methyl group or a formyl group at the Eli-position in the steroid nucleus is indispensable for display of effective physiological activities.
• the cyano group at the angular position of polycyclic compounds can be converted into a formyl group or a methyl group by reducing the angular nitrile with lithium aluminum hydride followed by hydrolysis to the angular aldehyde, which is subjected to hydrazone-for-mation followed by decomposition with potassium hydroxide to give the angular methyl compound. Therefore, the present hydrocyanation process can be adopted in the synthesis of physiologically active steroids from compounds lacking an angular methyl or formyl group at the position corresponding to the 13fl-position of the former. Furthermore, it has been recently disclosed that S-cyano steroids possess anti-pituitary activity and are useful as antiestrogenic agents [Bowers et al.: US. Patent 3,050,518]. Accordingly, the present hydrocyanation process is also of value in the production of these and other physiologically active steroidal angular nitriles.
• Example 1 To a solution of triethyl aluminum (6.85 g.) in anhydrous tetrahydrofuran (40 ml.) there is added a solution of hydrocyanic acid (1.08 g.) in anhydrous tetrahydrofuran ml.) while cooling with ice in nitrogen atmosphere. The resulting mixture is added to a solution of dl-2,3,4,5,6,7,8,8b octahydronaphthalen 2 one [Bergmann et al.: Bull. Soc. Chem. France, p. 290 (1957)] (3.0 g.) in anhydrous tetrahydrofuran (40 ml.) and allowed to stand for 1 hour at room temperature to 30 C.).
• the reaction mixture is gradually added to 2 N sodium hydroxide (100 ml.) cooled with ice and shaken with chloroform.
• the chloroform layer is washed with water, dried and the solvent removed to give the residue (3.46 g.), which is crystallized from a mixture of ether and pentane to obtain dl 2 oxo-trans decahydronaphthalene-8a-carbo-nitrile (2.137 g.) as crystals melting at 56 to 58 C.
• the mother liquor is evaporated and the resultant amorphous substance (1.24 g.) chromatographed on alumina (30 g.).
• the reaction mixture is added to 2 N sodium hydroxide (20 ml.) cooled with ice and shaken with ether and chloroform in order.
• the ether extract and the chloroform extract are combined together, washed with 2 N hydrochloric acid and water in order, dried over anhydrous sodium sulfate and the solvent removed to give the crystalline residue (1.074 g.).
• the residue is crystallized from acetone to give (ll-70cacetyloxy 2 oxotetradecahydrophenanthrene-1lot-carbonitrile (76 mg.) as crystals melting at 149 to 151 C.
• the mother liquor is evaporated.
• the oily substance is combined with pyridine (3 ml.) and acetic anhydride (1 ml.), allowed to stand at room temperature (15 to 30 C.) overnight and treated according to an ordinary separation procedure to give the crystalline substance (1.074 g.), which is crystallized from a mixture of methanol and chloroform (4:1) to obtain dl 7a acetyloxy-Z-oxotetradecahydrophenanthrene-lla-carbonitrile ethyleneketal (322 mg.) as crystals melting at 167 to 168 C.
• the mother liquor is chromatographed on alumina whereby dl-7a-acetyloxy-2- oxotetradecahydrophenanthrene 11a carbonitrile ethyleneketal (314 mg), dl 7a acetyloxy 2 oxotetradecahydrophenanthrene 11/3 carbonitrile ethyleneketal (78 mg.) as crystals melting at 195 to 202 C. and a mixture thereof (147 mg.) are obtained.
• the amorphous residue (1.20 g.) is dissolved in ethanol (16 ml.), combined with a solution of semicarbazide hydrochloride (640 mg.) and anhydrous sodium acetate (710 mg.) in water (4.5 ml.) and refluxed for 2 hours.
• the precipitates are collected by filtration to give a semicarbazone (677 mg.) as crystals melting at 223 to 228 C.
• the mother liquor is evaporated, and the amorphous substance (746 mg.) is chromatographed on alumina (22 g.) and eluted with chloroform-methanol (99:1) to give a semicarbazone mg.) as crystals melting at 222 to 230 C.
• the semicarbazone is combined with the previously obtained semicarbazone and refluxed with a mixture of 2 N hydrochloric acid (60 ml.) and benzene (40 ml.) for 2 hours.
• the reaction mixture is shaken with ether.
• the ether extract is washed with 2 N sodium carbonate, ice-water and saturated aqueous sodium chloride in order and evaporated to give the residue (623 mg), which is crystallized fractionally from a mixture of acetone and ether to obtain dl-l-oxo-7-methoxy-1,2,3,4,-9,- 1O heXahydrOphen-anthrene-4aa-carbonitrile (2.21 mg.) as crystals melting at to 152 C. and dl-l-oxo-7-methoxy- 1,2,3,4,9,10-hexahydrophenanthrene-4afi-carbonitrile (31 mg.) as crystals melting at 128 to 130 C.
• Example 4 A H A H To a solution of triethyl aluminum (9.6 1 g.) in tetrahydrofuran (65 ml.), there is added dropwise a solution of hydrocyanic acid (1.52 g.) in tetrahydrofuran (10 ml.) while cooling with ice. To the resultant mixture, there is added a solution of 1,1,4af3-trimethyl-1,2,3,4,10,4ba,5,6,- 7,9,4a 810au-dodecahydrophenanthren-7-one [Barltrop et al.: J. Chem. Soc., p.
• the ether layer is Washed with 2 N hydrochloric acid and water, dried over anhydrous sodium sulfate and the solvent removed to give the residue which is crystallized from a mixture of acetone and ether to obtain '3fi-acetyloxy-ZO-oxo-5-pregnene-16a-carbonitrile (262 mg.) as crystals melting at 190 to 1940 C.
• reaction mixture is gradually added to 2 N sodium hydroxide (100 ml.) and shaken with ether.
• the ether extract is washed with 2 N hydrochloric acid and Water in order, dried over anhydrous sodium sulfate and the solvent removed.
• the residue (11.2 g.) is crystallized from ethanol to give 3-oxo-5a-cholestane-5-carbonitrile (3.67 g.) as crystals melting at 170 to 180 C.
• the mother liquor is chromatographed on alumina to give the additional crystals (4.835 g.) of 3-OXO-5oc-Ch0l68- tane S-carbonitrile, 3-oxo SB-cholestane-5-carbonitrile (2.346 g.) as crystals melting at 112 to 122 C., the hydrolysate of 3-oxo-5/3-cholestane-5-carbonitrile (596 mg.) as crystals melting at 196 to 198 C. and (the mixture with the hydrolysate of 3-oxo-a-cholestane-S-carbonitrile (956 mg).
• Example 6 To a solution of triethyl aluminum (400 mg.) in anhydrous benzene ml.), there are added'hydrocyanic acid (0.15 ml.) and 4-cholesten-3-one (500 mg.) while cooling with ice, and the resultant mixture is allowed to stand at room temperature (15 to C.) overnight. A small amount of methanol is added to the reaction mixture for decomposition of excess of triethyl aluminum. After addition of 2 N sodium hydroxide (20 ml.) while cooling with ice, the benzene layer .is separated. The water layer is shaken with ether and the ether layer combined with the above separated benzene layer. The combined organic solvent layer is washed with water, dilute hydrochloric acid and water in order, dried and evaporated under reduced pressure. The residue (577 mg.) is
• Example 9 CHaCOO OHaCOO To a solution of dl-3fl-acetyloxy-D-homo-18-nor-5u- 13'(17a)4androstene17-one (480 mg.) in anhydrous tetrahydrofuran (6 ml.), there are added 17.2% triethyl aluminum solution in tetrahydrofuran (3.4 ml.) and 15.3% hydrocyanic acid solution in tetrahydrofuran (0.6 ml.) while cooling with ice, and the resultant mixture is allowed to stand for 2.5 hours at room temperature (15 to 30 C. The reaction mixture is added to ice water alkalized with 2 N sodium hydroxide and shaken with a mixture of ether and chloroform (3:1).
• the extract is washed with 2 N sodium hydroxide and aqueous sodium chloride in order, dried over anhydrous sodium sulfate and the solvent removed.
• the crystalline reisdue is crystallized from a mixture of chloroform and acetone (1:2) to give dl-3 ,B-acetyloxy-17-oxo-D-homo-5aandrostane-18 nitrile (302 mg.) as crystals melting at 223 to 225 C.
• the mother liquor is chromatographed on neutral alumina (4 g). From the eluate with petroleum ether-benzene (:5), there is obtained dl-3B-acetyloxy-17-oxo-D-homopressure to a volume.
• the reaction-mixture is added to a mixture of 2 N sodium hydroxide and ice and shaken with a mixture of ether and chloroform (2.5: 1').
• the extract is washed with 2 N sodium hydroxide and aqueous sodium chloride in order while cooling at 0 C., dried over anhydrous sodium sulfate and evaporated under reduced pressure.
• the residue (1.12 g.) is crystallized from methanol to give 3,17-dioxo-a9(11)-androstene-5-carbonitrile (830 mg.) as crystals melting at 249 to 255 C.
• the mother liquor is evaporated to dryness to give an amorphous substance (263 mg).
• the amorphous .substance is combined with p-toluenesulfonic acid hydrate (13 mg.) and ethyleneglycol ml.) and heated for 1.5 hours at 80 C.
• the resulting mixture is neutralized with ethanolic potassium hydroxide, poured onto ice-water and shaken with chloroform.
• the chloroform extract is treated according to a conventional recovery procedure to give the residue, which is chromatographed on neutral alumina.
• From the eluate with petroleum ether-benzene there is obtained 3,3:17,17-bisethylenedioxy-5fl-9(11)- androstene-S-carbonitrile (118 mg.) as crystals melting at 191 to 192.5 C.
• From the subsequent eluate with benzene-chloroform there is obtained 3,3:17,1'7-'bisethylenedioxy-5a-9(11)-androstene-5-carbonitrile (7 mg.) as
• Example 11 To a solution of dl-.3a-acetyloxy-D-homo-l8-nor-5B- 9(11) ,13(17a)-androstadien-1'7-one (240 mg.) in anhydrous tetrahydrofuran (3 ml.), there is dropwise added a solution of triethyl aluminum (0.45 ml.) and hydrocyanic acid (0.52 ml.) in anhydrous tetrahydrofuran (7 ml.) while cooling with ice, and the resultant solution is allowed to stand for 2 hours at room temperature (15 to 30 C.).
• the resultant mixture is poured into cold 2 N hydrochloric acid and shaken with a mixture of ether and chloroform (3:1).
• the extract is washed with 2 N sodium hydroxide and water in order, dried over anhydrous sodium sulfate and evaporated under reduced pressure.
• the thus-obtained residue is crystallized from a mixture of acetone, ether and pentane to give the crystals (111 mg.) melting at 240 to 251 C.
• the mother liquor is chromatographed on neutral alumina whereby .the additional crystals 10 mg.) are obtained.
• a solution of triethyl aluminum (0.43 ml.) and hydrocyanic acid (0.17 ml.) in tetrahydrofuran ml.) is combined with a solution of dl-3-methoxy-18,19-bisn0r-1,3, 5(10),13(17)-pregnatetraen-20-one (188 mg.) in tetrahydrofuran (5 ml.) and allowed to stand overnight in a flask with stopper.
• the reaction mixture is combined with 2 N hydrochloric acid (50 ml.) at C. and shaken with chloroform.
• the chloroform extract is washed with water, dried over anhydrous sodium sulfate and the solvent removed to give the residue (201 mg), which is crystallized from a mixture of acetone and ether to o tain dl-3-methoxy-20-oxo-19-nor-1,3,5(10) pregnatriene- 18-nitrile (37 mg.) as crystals melting at 196 to 199 C.
• the mother liquor is chromatographed on alumina to give the additional crystals (I l mg.) of the same compound and dl-3-meth0xy-20-oXo-19-nor-13E,17-1,3,5(10)-preg- 18 natriene-lS-nitrile (15 mg.) as crystals melting at to 164 C.
• the elua-te with petro- 1eum ether-benzene (4:1) is crystallized from a mixture of ether and methanol to give 3,5-chlolestadien-7-one (1.7 mg.) as pillars melting at 112.5 to 113 C.
• the subsequent eluates with petroleum ether-benzene (1:'1)-benzene-chloroform (4:1) are crystallized from methanol to give 3B-acetyloxy-7-oxo-5u-ehloestane-5- carb'onitrile (274 mg.) as needles melting at 202 to 204 C.
• Example 15 OHaOOO To a solution of triethyl aluminum (421 mg.) in ether (1.50 g.), there are added a solution of hydrocyanic acid (217 mg.) in ether (1.00 g.) while cooling with ice and then a solution of 7-oxocholesterol acetate (500 mg.) in ether ml.). The resultant mixture is allowed to stand at room temperature (15 to 30 C.) for 48 hours. After addition of a small amount of methanol to the reaction mixture for decomposing excess of the reagent, the resulting mixture is poured onto ice-water and shaken with ether.
• the ether extract is Washed with 2 N sodium hydroxide, water, 2 N hydrochloric acid and water in order, dried over anhydrous sodium sulfate and evaporated to give the residue (537 mg), which is crystallized from a mixture of methanol and ether to obtain 3,8-acetyloxy-7-oxo-5acholestane-S-carbonitrile (306 mg.) as plates melting at 197 to 200 C.
• the mother liquor is chromatographed whereby the additional crystals (166 mg.) of the same compound are obtained.
• Example 16 iz d [305 To a solution of 3,3-ethylenedioxy-17a-hydroxy-D- homo-18-nor-5,12-androstadien-1l-one (286 mg.) in tetrahydrofuran ml.), there is added a solution of triethyl aluminum (2.34 ml.) and hydrocyanic acid (1.02 ml.) in tetrahydrofuran (5 ml.), and the resultant mixture is allowed to stand at room temperature (15 to C.) for 25 hours. After addition of ice for decomposing the reagent, the reaction mixture is poured onto 2 N sodium hydroxide while cooling with ice and shaken with chloroform.
• the chloroform extract is washed with 2 N sodium hydroxide and water in order while cooling with ice, dried over anhydrous sodium sulfate and evaporated under reduced pressure.
• the thus-obtained crystalline residue (314 mg.) is crystallized from a mixture of dichloromethane and methanol to give 3,3-ethyleneidioxy 17a hydroxy 11 oxo D homov 5 andro- 22 17-trione 17-oxime [Nagata et al.: US. Patent 3,055,917] according to the following scheme:
• Oxidation with osmium tetroxide Oxidation with osmium tetroxide.
• the crystalline residue (225 mg.) is crystallized from a mixture of chloroform and methanol to give 8- cyano-ll-oxotigogenin acetate (114 mg.) as crystals meltving at 300 to 302 C.
• the mother liquor is chromatographed on alumina and eluted with benzen'e' benzenechloroform (9:1) whereby a small amount of the additional crystals of the same substance is obtained.
• 12.8:2 (CHCl IR: 1123;? 2240, 1725 (BBL-1 Analysis.Calcd. for C H O N: C, 72.40; H, 8.71; N, 2.81. Found: C, 72.39; H, 8.80; N, 3.00.
• the reaction mixture is added to ice-water and shaken with chloroform.
• the chloroform extract is washed with 2 N sodium hydroxide and water in order, dried over anhydrous sodium sulfate and evaporated under reduced pressure.
• the thus-obtained crude crystals (354 mg.) are recrystallized from a mixture of chloroform and methanol to give 3,8-acetyloxy-11-oxo- 5a-22-erogstene-8-carbonitrile (181 mg.) as white scales melting at 218 to 220 C.
• the mother liquor is chromatographed on alumina and eluted with petroleum etherbenzene (8:2 1:1) whereby additional crystals (38 mg.) of the same compound are obtained.
• Example 20 I CN CS/a H H a
• a solution of 3,3:17,17-bisethylenedioxy-5,S-androstadien-11-one 500 mg.
• anhydrous tetrahydrofuran 8 ml.
• a solution of triethyl aluminum 1.014 g.
• a solution of hydrocyanic acid mg. in tetrahydrofuran (1.8 ml.) while cooling with ice.
• the resultant mixture is allowed to stand at room temperature (15 to 30 C.) for 15 hours.
• the reaction mixture is added to ice-water and shaken with chloroform.
• the starting material of this example 3,3:17,17-bisethylenedioxy-S,S-androstadien-1l-one, is prepared from 9a-bromo-1 1 fi-hydroxy-4-androstene-3 ,17-dione [Lenhard et al.: J. Am. Chem. Soc. vol. 77, p. 6665 (1955)] according to the following scheme:
• the chloroform extract is washed with 2 N sodium hydroxide and water in order, dried over anhydrous sodium sulfate and evaporated under reduced pressure.
• the thusobtained crude product (770 mg.) is chormatographed on alumina, eluted with benzene and crystallized from a mixture of dichloromethane and methanol (1:1) to give 17,20:20,21 l bismethylenedioxy 3,3 ethylenedioxy 8 cyano-S-pregnen-ll-one (407 mg.) as white needles melting at 220 to 223 C. '13.9:2
• reaction mixture is poured onto a mixture of sodium hydroxide (5 g.) in ice-Water (20 ml.) and shaken with chloroform.
• the chloroform layer is washed with water, dried over anhydrous sodium sulfate and the solvent removed.
• the residue (3.08 g.) is crystallized from a mixture of acetone and ether to give 1-methyl-8a/8-cyano-L2, 3,4,4b,5,6,7,8,8a,9,10 dodecahydro-1,4a(10aH)-methanoiminomethanophenanthren-7-one N-methanesulfonate (1.54 g.) as crystals melting at 223 to 225 C.
• the mother liquor is chromatographed on alumina whereby the additional crystals (390 mg.) of the said compound and l-methyl 8a cyano-1,2,3,4,4b,5,6,7,8,8a,9,10-dodecahydro-1,4a(10aH) methanoiminomethanophenanthren- 7-one N-methanesulfon-ate (355 mg.) as crystals melting at 209 to 211 C. are recovered.
• vl-methyl-iiafi-cyano-1,2,3, 4,4b,5,6,7,8,8a,9,l0 dodecahydro-1,4a(l0aH)-methanoiminomethanophenanthren-7-one N-methanesulfonate is useful as an intermediate in the synthesis of a naturally existing alkaloid, atisine.
• a process which comprises reacting a polyhydropolycyclic a ti-unsaturated ketone with a complex anion of the formula:
• R is a member selected from the group consisting of lower alkyl and lower alkoxy and R and R each is a member selected from the group consisting of lower alkyl, lower alkoxy, halogen and cyano in a substantially anhydrous medium to introduce a cyano group into the position corresponding to the [at-position to the carbonyl group.
• R is a member selected from the gfiomp consisting of lower alkyl and lower alkoxy and R and R" each is a member selected from the group consisting of lower alkyl, lower alkoxy, halogen and cyano in a substantially anhydrous medium to introduce a cyano group into the said angular position.
• R is a member selected from :the group consisting of lower alkyl and lower alkoxy and R and R" each is a member selected from the group consisting of lower alkyl, lower alkoxy, halogen and cyano in a substantially anhydrous medium at a temperature from room temperature to reflux temperature to introduce a cyano group into the said angular position.
• R is a member selected from the group consisting of lower alkyl and lower alkoxy and R and R" each is a member selected from the group consisting of lower alkyl, lower alkoxy, halogen and cyano in a substantially anhydrous mediumat a temperature from room temperature to reflux temperature to introduce a cyano group into the Sa-position.
• R is a member selected from the group consisting of lower alkyl and lower alkoxy and R and R each is a member selected from the group consisting of lower alkyl, lower alkoxy, halogen and cyano in a substantially anhydrous medium at a temperature from room temperature to reflux temperature to introduce a cyano group into the said angular position
• the polyhydrotriisocyclic cap-unsaturated ketone being a member selected from the group consisting of 7aaacetyloxy-2,3,4,5,6,7,8,9,l0,12,13, 14-dodecahydrophenanthrene-Z-one, l oxo-7-methoxy- 1,2,3,4,9,1 hexahydrophenanthrene and 1,1,4aB-trimethyl 1,2,3,4,4a[',4ba, 5,6,7,9,l0,10aa-dodecahydrophenanthren-7-one.
• R is a member selected from the; group consisting of lower alkyl and lower alkoxy and R and R" each is a member selected from the group consisting of lower alkyl, lower alkoxy, halogen and cyano in a substantially anhydrous medium at a temperature from room temperature to reflux temperature to introduce a cyano group into the said angular position, the polyhydrotetraisocyclic a,fi-unsaturated ketone being a member selected from the group consisting of 4-cholesten-3-one, 19-nortestosterone acetate, 30: acetyloxy-D- homo-18-nor-5ow13(17a-2undrosten- 1 7-one, 4,9 1 1 )-androstadiene-3, 17 -dione, 3 oc-EICC- tyloxy-D-ho'mo l 8 nor-5a-9(11) l 3 17a) -androstadien- 17 -one, 3-melthoxy-
• a process which comprises reacting 1-methyl-1,2,3, 4,4-b,5,6,7,9,19-decahydro 1,4a(aH) methanoiminomethanophenanthren 7 one N-methanesulfonate with complex anion of the formula:
• R is a member selected from the group consisting of lower-alkyl and lower alkoxy and R and R" each is a member selected from the group consisting of lower alkyl, lower alkoxy, halogen and cyano in a substantially anhydrous medium at a temperature from room temperature to reflux temperature to introduce a cyano group into the 8a-position.
• a process which comprises intermixing polyhydropolycyclic c e-unsaturated ketone in a substantially anhydrous medium with 'an aluminum compound of the wherein R is a member selected from the group consisting of lower alkyl and lower alkoxy and R and R" each is a member selected from the group consisting of lower alkyl, lower alkoxy, halogen and cyano and with a member selected from the group consisting of hydrocyanic acid and an aluminum cyanide compound of the formula:
• a process which comprises inter-mixing polyhydropolycyclic a,/8-unsaturated ketone of which the fi-position corresponds to an angular posit-ion in a substantially anhydrous medium with an aluminum compound of the formula AlRR'R" wherein R is a member selected from the group consisting of lower alkyl and lower alkoxy and R and R" each is a member selected from the group consisting of lower alkyl, lower alkoxy, halogen and cyano and with a member selected from the group consisting of hydrocyanic acid and an aluminum cyanide compound of the formula:
• R, R' and R" each has the same significance as designated above, whereby in ensuing reaction a cyano group is introduced into said ketone in said angular position, hydrolysis of the resultant angular nitrile being inhibited.
• a process which comprises intermixing a member selected from the group consisting of cyclopentanopolyhydrophenanthrenes and cyclohexanopolyhydrophenanthrenes having an 0a, ⁇ 3-1111S21tl11'3t6d ketone structure of which the fl-position corresponds to an angular position and an aluminum compound of the formula:
• R is a member selected from the group consisting of lower alkyl and lower alkoxy and R and R each is a member selected from the group consisting of lower alkyl, lower alkoxy, halogen and cyano and with a member selected from the group consisting of hydrocyanic acid and an aluminum cyanide compound of the formula:
• R, R and R" each has the same significance as designated above, whereby in ensuing reaction a cyano group is introduced into said polyhydrophcnanthrene in said angular position.

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Cited By (3)

• 1963
  • 1963-02-26 US US261215A patent/US3231566A/en not_active Expired - Lifetime
  • 1963-02-28 CH CH255963A patent/CH456587A/de unknown
  • 1963-03-01 DE DE19631468624 patent/DE1468624B2/de active Granted
  • 1963-03-01 GB GB8396/63A patent/GB998980A/en not_active Expired

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