US3231566A

US3231566A - Hydrocyanation process

Info

Publication number: US3231566A
Application number: US261215A
Authority: US
Inventors: Nagata Wataru
Original assignee: Shionogi and Co Ltd
Current assignee: Shionogi and Co Ltd
Priority date: 1962-03-02
Filing date: 1963-02-26
Publication date: 1966-01-25
Anticipated expiration: 1983-01-25
Also published as: DE1468624C3; GB998980A; CH456587A; DE1468624B2; DE1468624A1

Description

United States Patent 3,231,566 HYDROCYANATION PROCESS Wataru Nagata, Hyogo Prefecture, Japan, assignor to Shionogi & Co. Ltd, Osaka, Japan No Drawing. Filed Feb. 26, 1963, Ser. No. 261,215 Claims priority, application Japan, Mar. 2, 1962, 3 8,428 14 Claims. (Cl. 260239.55)

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. However, 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.

While the addition of hydrocyanic acid to O B-unsaturated ketones has been accomplished by various methods, there has been heretofore made no attempt for the direct introduction of a cyano group into the angular position of any polycyclic compound except only two methods, the one relating to the introduction of a cyano group into the 5-position of steroids having a A -3-ketone structure by the treatment of the said starting steroids with alkali metal cyanide or alkaline earth metal cyanide in the presence of a hydroxylated organic solvent [Bowers et al.: US. 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. BulL, vol. 9, p. 79 (1961)]. However, it has been found that these known methods must be executed under carefully regulated reaction conditions for obtaining the objective angular nitrile in a higher yield, because the once produced angular nitrile is readily hydrolyzed according to the basicity of the employed cyanating agent. Even if careful control is made, it is difiicult to inhibit completely the by-production of the hydrolysate of the angular nitrile. The inevitable hydrolysis unfavorably results in the decreased yield of the objective angular nitrile and the contamination of the same with the hydrolysate. It has been also found that the scope for which the said known methods can be applied is limited to a certain extent. For instance, the introduction of a cyano group into the 8-position of steroids or D-homosteroids is unsuccessfully accomplished by them. It has been also found that, according to the said known methods, there has been generally obtained an isomeric mixture of the objective nitrile, in most cases, contaminated with an isomeric mixture of the by-produced hydrolysate. As each of them is usually produced at a considerable amount, the isolation of each compound may be rather troublesome, and it may be impossible to produce only a certain compound of them in a predominant yield. These and other disadvantages of the known methods are now overcome by the process of the present invention.

According to the present invention, 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. It may be also noted that the angular cyanation which has never been accomplished by any known methods can be realized by the process of this invention. For instance, the introduction of a cyano group into the 8-position of steroids or D-homosteroids can be successfully carried out. Thus, the process of the present invention has a broader application scope than the known methods have. It may be further noted that the process of the present invention can be executed under a relatively mild reaction condition comparing with the known methods and is applicable to instable compounds. These and other advantages of this invention will be apparent to those conversant with the art to which this invention pertains from the subsequent description.

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:

[AlRRRCN] (A) wherein 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.

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:

AlRR'H (D) wherein R and R each has the same significance as designated above with hydrocyanic acid in a substantially anhydrous medium [Equation III]. Therefore, 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. As the aluminum compound (B),

there may be exemplified 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. Examples of 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. Although 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. Particularly, 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. Otherwise stated, the use of a combination of hydrocyanic acid or a di(lower) alkyl aluminum cyanide of Formula C wherein R and R each represents a lower alkyl group such as dimethyl aluminum cyanide, diethyl aluminum cyanide, dipropyl aluminum cyanide and dibutyl aluminum cyanide with a tri- (lower) alkyl aluminum of Formula B wherein R and R each represents a lower alkyl group such as trirnethyl aluminum, triethyl aluminum, tripropyl aluminum and tributyl aluminum is practically preferred.

As the reaction medium, there may be employed an inert non-polar solvent such as benzene, ether, tetrahydrofuran and dioxane. The presence of water causes unfavorable loss of the said cyanating agent. Therefore, it is preferable that the solvent be dried prior to use.

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. However, strict control of reaction temperature and reaction time is not necessary.

As the cyanating agent, i.e., the aluminum compound (B), the aluminum cyanide compound (C) and the aluminum hydride compound (D), is generally combustible in atmosphere, the previous replacement of the air in a reaction vessel with an inert gas such as nitrogen is preferred. However, such replacement is not needed, when 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. However, 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 typical example of the practical procedures for carrying out the process of the present invention is as follows:

An 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.

The conversion in the process of the present invention is generally representable by the following partial formulae:

Although the present hydrocyanation process possesses a number of advantageous characteristics as previously stated, it is especially notable that there is produced in general a 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] predominantly in a good yield, when the process is adopted for the angular cyanation of a polycyclic compound. For comparison, the results obtained by the application of a known hydrocyanation process using potassium cyanide and ammonium chloride in dimethylformamide [Nagata et al.: J. Org. Chem., vol. 26, p. 2413 (1961)] and the present hydrocyanation process using hydrocyanic acid and triethyl aluminum in tetrahydrofuran to various polyisocyclic compounds are shown in the following the solution in the said insert solvent. table:

TABLE Known Hydrocyanation Present Hydrocyanation Process- Process-- Starting Material Product Yield Total Yield Total Ratio of Yield Ratio 01' Yield ClszTrans (percent) OiszTrans (percent) d1-2,3,4,5,6,7,8,8b-Octahydronaphthalen-Z- dl-2-Oxo-cis and transdecahydronaphtha- 1:2 67 1:24

one. lene-8arcarbonitrile. dl-7a-Acetyloxy-2,3,4,5,6,7,8,9,10,12,13,14 (II-Ya-AOGtYIOXY-Z-OXOlIGtIQdGCahYdIOPhGD- 3:4 75 1:9 72

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. 5oz,l3a-al1dlOSt8J1e-18-I1itl'i1e. 4,9 (11)-Androstadiene-3,17-dione 3,17-]t))i0X 2-ix and 55-9 (11) -andr0stene-5- 1:3. 5 69 1:9

car onr r1 e. (ll-3a-Acetyloxy-D-homo-18-n0r-5fl-0(11),- dl-3a-Aeetyloxy-l7-oxo-D-h0m0-5B-9(11)- 55 13(17a)-androstadien-17-one. androstene-lS-nitrile. dl-3-Methoxy-18,l9-bisnor-l,3,5(10),13(l7)- dl-3-Methoxy-20-ox0-19-nor-l,3,5(10)-pregna- 1 2. 5:1 78 1:10 1 8t) pregnatetraen-ZO-one. triene-ls-nitrile and its epimer. I 7-Oxocholesterol acetate 3fi-Atcefyloxy-7-oxo-5a-cholestane-5-carbo- 43 m n e. 3,3-Ethylenedioxy-lh-hydroxy-D-homo-18- 3, 3-Ethylenedioxy-l7a-hydroxy-l1-0xo-D- 90 73 nor-5, 12-androstadien-l1-one. homo-5-androstene-18-nitrile. 3fl-Acetyloxy-8, 22-ergostadien-11-one lid-fleetyloxy-ll-oxo-5a-22-ergostene-S-carbo- 0 70 n r e. 5

NOTE: 1 The 1,3,6 (lOpregnatriene-l8-nitrile. 3 Trans product alone.

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. Especially, it should be noted that 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. In the field of steroid chemistry, for instance, it has been well known that the existence of 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.

The following examples set forth illustratively presently-preferred embodiments of the present invention. In these examples, ml.=millilitre(s), g.=gram(s), mg.=milligram(s), and C. =degrees centigrade. Other abbreviations each have conventional significances.

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 eluate with petroleum ether-benzene (9:l-4:1) is evaporated to give crude d1- 2 oxo cis decahydronaphthalene S a-carbonitrile (125 mg.) as an oil. The subsequent eluates with petroleum 6 ether-benzene (4:1)-benzene are evaporated and crystallized from a mixture of ether and pentane to give dl-2- oxo-trans decahydronaphthalene 8a carbonitrile (389 mg.). The mother liquor and the above obtained oily d1- 2-oxo-cis-decahydronaphthalene-8a carbonitrile are combined together and subjected to semicarbazone formation according to a per se conventional procedure whereby dl- 2-oxo-cis-decahydronaphthalene-8a carbonitrile semicarbazone (147 mg.) is obtained as crystals melting at 204 to 207 C. (crystallized from a mixture of chloroform 13,14 dodecahydrophenanthren 2 one (12fi,13a,14,8) (1.03 g.) in anhydrous tetrahydrofuran (15 ml.), there are added a solution of hydrocyanic acid (165 mg.) in anhydrous tetra-hydrofuran (1.45 ml.) and a solution of triethyl aluminum (1.36 g.) in anhydrous tetrahydrofuran (10 ml.) while cooling with ice, and the resultant mixture is allowed to stand for 1.5 hours at room temperature (15 to 30 C.) in nitrogen atmosphere. 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 residue (968 mg.) is combined with ethyleneglycol (25 ml.) and p-toluenesulfonic acid (30 mg), heated for 10 minutes in an oil bath (bath temperature, C.) and then condensed under reduced pressure. The condensate is shaken with chloroform. The chloroform extract is washed with dilute aqueous sodium hydroxide, dilute hydrochloric acid and water in order and the solvent removed to give an oily substance (965 mg.). 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. When each of the above obtained loetals is hydrolyzed by heating with 70% acetic acid on a steam bath for 20 minutes, there is obtained the corresponding free oxo compound, i.e., dl-7a-acetyloxyl-2-oxotetradecahydrophenanthrene-lla-carbonitrile as crystals melting at to 152 C. and dl-7a-acetyloxy-Z-oxotetradecahydrophenanthrenellfi-carbonitrile as crystals melting at to 196 C.

The starting material of this example, dl-7a-acetyloxy- 2,3,4,5,6,7,8,9,10,12,13,14 dodecahydrophenanthren 2 one (125,801,148), is prepared from 6-methoxy-2-tetra- 7 lone [Nagata et al.: Tetrahydron Letters, N0. 17,- p. 27 (1960)] according to the following scheme:

Condensation with vinyl methyl ketone in the presence of sodium methoxide in methanol.

Reduction with lithium in liquid ammonia.

OHaO

Treatment with a mineral acid.

CHQO Acetylatlon with acetic anhydride in pyridine.

-OCOCH:

Example 3 OCHa OCH;

To a solution of diethyl aluminum chloride (4.20 g.) in anhydrous tetrahydrofuran (1-6 ml.), there is added a solution of hydrocyanic acid (675 mg.) in anhydrous tetrahydrofuran (6 ml.) while cooling with ice in nitrogen atmosphere. The resultant mixture is added to a solution of dl-l-oxo 7 methoxy 1,2,3,4,'9,10 hexahydrop henanthrene ['Stork et al.: I. Am. Chem. Soc., vol 69, p. 29 36 (1947) (1.14 g.) in anhydrous tetrahydrofuran (5 ml.) and allowed to stand for 47 hours at room temperature to C.). 2 N sodium hydroxide ml.) is dropwise added to the reaction mixture while cooling with ice and shaken with ether. The ether extract is washed with Water and evaporated to give the residue (1.30 g.), which is crystallized from a mixture of acetone and ether to give d1 1 oxo 7 methoxy 1,2,3,4,9,10 hexahydrop'henanthrene 4aa-carbonitrile (188 mg.) as crystals melting at 150 to 152 C. The mother liquor is evaporated. 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. 25 66 8)] (3.458 g.) in tetrahydrofuran (35 ml.) while cooling with ice, and the resulting mixture is allowed tostand at room temperature (15 to 30 C.) for 18 hours. The reaction mixture is portionwise added to a mixture of 4 N sodium hydroxide (40 ml.) and ice and then shaken with chloroform. The chloroform layer is washed with 2 N sodium hydroxide cooled with ice and water in order, dried over anhydrous sodium sulfate and the. solvent removed under reduced pressure. The residue is crystallized from methanol to give 1,'1,4a/3 trimethyl-tetradecahydrophenanthren-7-one- 8afl-carbonitrile (2.2187 g.) as crystals melting at 144 to RI: .359 2245, 1723 cmr Analysis.--Calcd. for C H ON: C, 79.07; H, 9.95; N. 5.12. Found: C,78.*66; H, 9.85; N, 5.23.

Example 5 C Ha CH J=O a CElaCOO To a solution of 3,8-acetyloxy-5,16-pregnadien-20-one [Gould: US. Patent 2,752,370] (372 mg.) in tetrahydrofuran (4 ml.) there are added a solution of triethyl alumi- '9 num (343 mg.) in tetrahydrofuran (2 m1.) and a solution of hydrocyanic acid (54.1 mg.) in chloroform (0.5 ml.), and the resultant mixture is allowed to stand at room temperature (15 to 30 C.) for 2.5 hours. The reaction mixture is added to a mixture of 2 N sodium hydroxide and ice and then shaken with ether. 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.

To a solution of 4-cholesten-3-one [Butenandt et al.: Chem. Ber., vol. 69, p. 882 (1936)] g.) in anhydrous tetrahydrofuran (50 ml.), there are added a solution of hydrocyanic acid (1.05 g.) in anhydrous tetrahydrofuran (20 ml.) and a solution of triethyl aluminum (8.9 g.) in anhydrous tetrahydrofuran (125 ml.) while -cooling with ice, and the resultant mixture is allowed to stand at room temperature to 30 C.) for 3 hours in nitrogen atmosphere. The 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 Example 7 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

10 chromatographed on alumina 15 g.). The eluates with petroleum ether-benzene (4: 1-2:1)-benzene are crystallized from ethanol to give 3-oxo-5 3-cholestane-5-ca-rbonitrile (262 mg.) as crystals melting at 117 to 121 C. and 3-oxo-5a-cholestane-5 carbonitrile (197 mg.) as crystals melting at to C.

Example 8 OCOGH:

To a solution of '19-nortestosterone acetate (17B-acety1oxy-4-estren-3-0ne.) '[Birchz Chem. Soc., p. 367 (1950)] (20.60 g.) in anhydrous tetrahydrofuran (30 ml.),there is added a solution of triethyl'aluminum (18.6

g.) and hydrocyanic acid (2.65 .g.) in anhydrous tetrahydrofuran 120 m1.) while cooling with ice, and the resultant mixture is allowed to stand at room temperature (15 to 30 C.) for 1 hour in a vessel provided with a tube of calcium chloride. The reaction mixture is dropwise added to 2N sodium hydroxide (500 ml.) cooled with ice and then shaken with a mixture of chloroform and ether (4:1). The extract .is washed with dilute aqueous sodium hydroxide and water in order, dried over anhydrous sodium sulfate and .the solvent removed under reduced pressure. The residue is crystallized from acetone to give 17fi-acetyloxy 3-oxo-Sa-estrane-S-carbonitrile (14.5 g.) as crystals melting at 209 to 211 C. The mother liquor is chromatographed to give a small amount of 17,8-acetyloxy-3-oxo-5fl-estrane-5-carbonitrile melting at 213 to 214 C.

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 condensate is added to a mixture of 2 N sodium carbonate and ice and shaken with chloroform. The chloroform extract is washed with water, dried and evaporated to give an oily residue (161 mg.), which is chromatographed on neutral alumina (8 the eluates From the eluate with petroleum ether-benzene with petroleum ether-benzene (3:7-2:8)-benzene, the eluate with benzene-chloroform (7:3) and the eluate with benzene-chloroform (5:5), there are obtained dl 3/3 acetyloxy 17-oX0-D- homo-5ot-androstane-l8-nitrile ethyleneketal (19 mg.)

as crystals melting at 235 to 237 C. dl-3fi-acetyloxy-l7- oxo-D-homo-5a,13m-androstane 18 nitrile ethyleneketal (24 mg.) as crystals melting at 22 1 to 226 C., dl-3fi-hydroXy-17-oxo-D-homo-5a,l3a-androstane-18 nitrile ethyleneketal (18 mg.) as crystals melting at 222 to 223 C. and d1 3,8 hydroxy 17-oxo-D-homo-5u-androstane-18- nitrile ethyleneketal (16 mg.) as crystals melting at 209 to 212 C., respectively.

The starting material of this example, dl-Bfi-acetyloxy- D-homo-l8-nor-5 a-13-( l7a)-androsten-17 one,

pre-

pared from 6-methoxy-2-tetralone according to the following scheme:

O CH;

Condensation with B-diethylaminoethyl ketone in the presence of methoxide.

sodium OOH;

Condensation with fl-diethylaminoethyl methyl ketone in the presence of sodium methoxide.

(1) Reduction with lithium liquid ammonia and ethanol.

(2) Reflex with hydrochloric acid in methanol.

Acetylation with acetic anhydride and pyridine.

CHaOOO I The product of this example, dl-3fl-acetyloxy-17-oxo-D- homo-Sa-androstane-l8-nitrile, can be converted into 3,8- -75 hydroxy-20-oxo-5a-l6-pregnene-ene B-acetate according to the following scheme, the latter being well-known as an intermediate in the synthesis of cortical hormones [e.g., Wall: U.S. Patent 2,666,770; Buck et al.: US, Patent CHsOOO CHaCOO CHaCQO- CHaCOO- O HO 0 3g] 0 (1) Decomposition with Ketalation ethylcue-glycol and ptoluenesulionic Reduction with lithium aluminum hydride, followed by hydrolysis.

Acetylation with acetic anhydride and pyridine.

Hydrazone-iormation with hydrazine and triethylene glycol.

potassium hydroxide (2) Acetylation with acetic anhydride and pyridine.

Deketalation with acetic acid.

(i) Grignard reaction with methylmagnesium iodide, followed by treatment with Water.

' 2 Acetylation with acetic anhydride and pyridine.

Dehydration with phosphorus oxychloride in pyridine.

1(1) Oxidation with osmium tetroxide.

(2) Reduction with hydrogen sulfide.

(3) Oxydatiou with periodic acid.

treating with triethylamine acetate.

crnooo CHzC Example 10 To a solution of triethyl aluminum (1.93 ml.) in anhydrous tetrahydrofuran (20 ml.), there are added a solution of hydrocyanic acid (270 mg.) an anhydrous tetrahydrofuran (2.37 ml.) and a solution of 4,9(11)- androstadiene-3,17-dione [Heyl et al.: J. Am. Chem. Soc., vol. 77, p. 488 (1955)] (1 g.) in anhydrous tetrahydrofuran (20 ml), and the resultant mixture is allowed to stand for 4 hours at room temperature (15 to 30 C.). 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

crystals melting at 236 to 238 C.

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.). After addition of a small amount of methanol to the reaction mixture for decomposing excess of the reagent, 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. Both crystals are combined together and recrystallized from a mixture of acetone and ether to give (ll-3ozacetyloxy l7 0x0 D homo-5fi-9(11)-androstene-18- nitrile as crystals melting at 249 to 251 C.

Analysis.Calcd. for C H O N: C, 74.33; H, 8.22; N, 3.94. Found: C, 74.31; H, 8.26; N, 3.92.

The starting material of this example, dl-3a-acetyloxy- D-homo-18-nor-5fi-9( l 1),13( 17a) androstadien-17-one, is prepared from dl-17-methoxy-D-homo-18-nor-4,8,13, 1'5,17-androstapentaen-3-one [cf. Example 9 of the present specification] according to'the followingscheme:

OCH3

Hydrogenation using palladium carbon.

OCHz

(1) Reduction with lithium in O ;(1) Reduction with liquid ammonia l lithium aluminum and ethanol. hydrlde. (2) Hydrolysis with (2) Reflux with sodium hydroxide. HO- hydrochloric acid in CHaCOQ" V H methanol. i 1 CH0 =0 (I) Hydrazone formation Enoiesterification O with hydrazine and with isopropenyl triethyleneglycol; acetate and 1 ,followed by decomp-toluenesulfonic acid. 5 v DOSition with H0 potassium hydroxide. V P 3 I v CHaCOO" (2) Acetylation with l H acetic anhydrideand H pyridine. V 1) Treatment with 2 o C 00 in acetic a x (2) Treatment with O lithium bromide and lithium carbonate in dimethylformamide Deketalatiou with C HaC OO-- (3) Acetylation with acetic anhydride 0 H3O i H and pyridine.

Enoletherification Wlth ethyl Ortho' (i) Grlanard reaction formetem the with methyhnagnesium presence of pyridine iodide, followed by in ethanoltreatment with water.

0133600" 0 18000 (2) Acetylation with acetic H a H anhydride and pyridine.

phosphorus oxychloride in pyridine.

Hydrolysis with acetic acid.

1 8 0 5 emcee-- (1) Oxydation with 1 I osmiumtetroxide.

I CHaCOO" (2) Reduction with v ",1 hydrogen sulfide.

f on! I WOHu OE- 1 v Oxidation with The product of this example, dI-Sa-acetyloxy-l'I-oxo- D-homo-5,8-9(11)-androstene-18-nitrile, can be converted into dl-3a-acetyloxy-5p-9(11),16-pregnadien-20- one according to the following scheme, the latter being readily converted into cortisone in a per se conventional periodic acid. manner [Callow et al.: J. Chem. Soc., p. 4739 (1956); Kritchcvsky etaL: I. Am. Chem. Soc., vol. 74, p. 483 0113600" UN 7 CH: 0

o A 011: I

(31 10 Cyclizatioh hy Ketalatlon with V treatin with ethylene glycol and .triethylamine p-toluenesulionic acid. acetate.

0113000" QHaCOO CH: o Ff] CHaCOO-- y Example 12 CHZCOO" H\/ -a CHaCOO- A solution of dl-3 a-acetyloXy-D-homo-1 8-nor-5 13-9 1 1 13(17a)-androstadien-17-one (2.80 g.) in anhydrous tetrahydrofuran (30 ml.) is dropwise added to a solution of triethyl aluminum (3.62 g.) and hydrocyanic acid (1.08 g.) in anhydrous tetrahydrofuran (50 ml.) While cooling with ice, and the resultant mixture is allowed to stand at room temperature (15 to 30 C.) overnight. After addition of ethanol (6 ml.) while cooling with ice and then ice-water, the reaction mixture is shaken with ether. The ether layer is washed with water, dried over anhydrous sodium sulfate and the solvent removed to give an oily substance (2.97 g.). The oily substance is crystallized from ether to give dl-3a-acetyloxy-17-oxo-D-homo-5B- 9(11)-androstene-18-nitrile (1.094 g.) as crystals melting at 244 to 246 C. The mother liquor is chromatographed on alumina whereby additional crystals (437 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.

dl-3-methoxy 20 oxo-19-nor-1,3,5(10)-pregnatriene- 18-nit1 ile.

IR: pggf 2246, 1714, 1611, 1579, 1500 cm? hfifiif m (log e): 279 (2.203), 286 (2.070)

Analysis.Calcd. for C H O N: C, 77.98; H, 7.79; N, 4.33. Found: C, 77.98; H, 7.79; N, 4.32.

dl-S-methoxy 20 oxo-19-nor-13,17-1,3,5(10)-pregnatriene-18nitrile.

IR: VCHOII 2252, 1712, 1610, 1577, 1500 cm.

Condensation with 1- bromo-4,4-ethylenedioxypentane in the presence of sodium hydride in toluene.

CHsO

Reduction with metallic lithium in liquid ammonia.

CHsO

Oxidation with chromic acid in pyridine.

CHaO

Deketalation with hydrochloric acid.

Oyclization by refluxing with the sodium methoxide in methanol.

CHQO

The product of this example, dl-3-methoxy-20-oxo-19- nor 1,3,5 ()-pregnatriene-18-nitrile, can be converted into dl-estrone 3-m'ethyl ether according to the. following scheme, the latter being a known physiologically active (2) Hydrolysis with sodium Hydroxide.

CHO

GHa O l (1) Hydrazone formation with hydrazine CHaO (2) Decomposition with potassium hydroxide.

I CH3 0 j l/ O p 0 Deketalation with acetic acid.

CHaO

/ Enolesterification with acetic anhydride and p-toluene-sul fonic acid. GHBO r (fi-OCOCH:

' Ozonolysis.

. -P- CHzO- CHaO Example 14 CH:COO

CHaCOO- :0

To a solution of aluminum triisopropoxide (1.15 g.)

in anhydrous benzene (20 m1.), there are added hydrocyanic acid (1.6 ml.) and 7aoxocholestenol acetate [Windaus et a1.: 'Ann., vol. 520, p. 98 (1955)] (500mg), and the resultant mixture is allowed to stand for 3 days at room temperature (15 to 30 C.). The reaction mixture is poured into 2 N sodium hydroxide and the henz'ene layer is separated. The water layer is shaken with ether and the ether layer is combined with the above separated benzene layer, washed with water, dried and evaporated to give the residue (487 mg.), which is chromatographed on alumina (15 g.). 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. The subsequent eluates with benzenechloroform (2:1)-chloroform are-crystallized from a mixture of methanol and ether to give 3/8-hydroxy-7-oxo-5a-cholestane-S-carbonitride (41 mg.) as crystals melting atv 162 to 166C. 7

3,5-cholestadien-7-one. Y

335 acetyloxy 7 oxo Sm-cholestane-S-carbonitrile.

' Analysis.-Calcd. for C H O N: C, 76.45; H,

10.06; N, 3.46. Found: C, 76.71; H,'10.09; N, 2.98.

21 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:

NOH

[Eda

[ZQQ

The product of this example, 3,3-ethylenedioxy-17uhydroxy-11-oxo-D-homo-5-androstene 18-nitrile, can be converted into 3,20-dioxo-115,21-dihydroxy-4-pregnen- 18-oic acid (11-18) lactone ZI-acetate according to the following scheme, the latter being a known compound and useful as an inter-mediate in the synthesis of mineral corticoids -[Von Euw et al.: Helv. Chim. Acta, vol. 38, p. 1423 (1955)]:

Beckmann rearrangement with p-acetamidohenzene sultonyl chloride in pyridine.

Ketalation with ethylene ycol and p-toluenesulionic acid.

(1) Hydrolysis with 1 sodium hydroxide in butanol.

-- (2) Esterification with diazomethaue.

Cyelization by refluxing with potassium tbutoxide in benzene.

Reduction with sodium borohydride.

Sulionylation with methanesulionyl chloride and pyridine.

Hydrolysis and deacidation with potassium carbonate.

Oxidation with osmium tetroxide.

(2) Decomposition with hydrogen sulfide pyridine.

Won,

NW 011 Oxidation with periodic acid.

Cyclization by heating with trimethylamine acetate.

Reduction using palladiumcarbon catalyst.

Deketalation with acetic acid.

Oxidation with sodium bichromate.

(1) Acid chloride formation with oxalyl chloride (2) Diazotizatlon wlth diazomethane.

Treatment with acetic acid.

'- I t miococn' Example 17 CH: C 00 I To a solution of 11-oxo-8,9-dehydrotigogenin acetate [Djerassi et al.: J. Am. Chem. Soc., vol. 75, p. 3496 (1953)] (200 mg.) in anhydrous tetrahydrofuran (6 ml.), there are added a solution of hydrocyanic acid (81 mg.) in anhydrous tetrahydrofuran (0.72 ml.) and a solution of triethyl aluminum (490 mg.) in anhydrous tetrahydrofuran (3.4 ml.), and the resultant solution is allowed to stand at room temperature (15 to 30 C.) overnight in a vessel with stopper. The reaction mixture is poured onto ice-water containing a small amount of sodium hydroxide and shaken with chloroform. The chloroform extract is washed with water, dried and the solvent evaporated in 'vacuo. 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.

To a solution of 3B-acetyloxy-5a-8-pregnen-11,20-dione [Barton et al.: J. Chem. Soc., p. 747 (1954)] (100 mg.) in anhydrous tetrahydrofuran (3 ml.), there are added a solution of triethyl aluminum (250.3 mg.) in anhydrous tetrahydrofuran (1.75 ml.) and a solution of hydrocyanic acid (42.2 mg.) in anhydrous tetrahydrofuran (0.37 ml.) while cooling with ice, and the resultant mixture is allowed to stand at room temperature to 30 C.) overnight. The reaction mixture is combined with a mixture of 2 N sodium hydroxide and ice and shaken with chloroform. The chloroform extract is washed with water, dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The crystalline residue (120 mg.) is crystallized from methanol to give BB-acetyloxy- 8-cyano-5a-pregnane-11,20-dione (35 mg.) as crystals melting at 232 to 233 C. The mother liquor is chromatographed on alumina (4 g.), elutedwith benzene-chloroform (9:1) and crystallized from methanol whereby additional crystals (31.5 mg.) of the same substance are recovered. [M +97.9:2 (CHCl Analysis.Calcd. for C24H3304N: C, H, N, 3.51. Found: C, 72.07; H, 8.29; N, 3.58.

To a solution of 3,8-acetyloxy-8,22-ergostadien-1l-one [Schoenewaldt et al.: J. Am. Chem. Soc., vol. 74, p. 2696 (1952)] (300 mg.) in anhydrous tetrahydrofuran (4 ml.), there are added a solution of triethyl aluminum (753 mg.) in tetrahydrofu-ran (5.3 ml.) and a solution of hydrocyanic acid (125 mg.) in tetrahydrofuran (0.96 ml.) while cooling with ice, and the resultant mixture is allowed to stand at room temperature (15 to 30 C.) for 18 hours. 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.

[a] +38.9i2 (CHCl IR: yfiti? 2230, 1737, 1720, 1220, 1261, 1239 cm. Analysis.Calcd. for C31H4703NI C, 77.29; H, 9.84;

N, 2.91. Found: C, 77.19; H, 9.87; N, 2.81.

Example 20 I CN CS/a H H a To a solution of 3,3:17,17-bisethylenedioxy-5,S-androstadien-11-one (500 mg.) in anhydrous tetrahydrofuran (8 ml.), there are added a solution of triethyl aluminum (1.014 g.) in tetrahydrofuran (8 ml.) and 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 chloroform extract is washed with 2 N sodium hydroxide and water in order, dried over anhydrous sodium sulfate and evaporated under reduced presure. The thus-obtained crude product (566 mg.) is crystallized from a mixture of acetone and ether (1:1) to give 3,3:17,17-bisethylenedioxy- S-cyano-S-androsten-ll-one (323 mg.) as white needles melting at 199.5 to 200.5 C. [a] +61.3i2

(CHCl 2 5)2 F IR: 131392234, 1712, 1663, 1103, 1092 MIL Analysis.Calcd. for C H O N: C, 69.71; H, 7.56; N, 3.39. Found: C, 69.89; H, 7.60; N, 3.24.

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:

To a solution of 17,20:20,21-bismethylenedioxy-3,3- ethylenedioxy-S,8-pregnadien-1l-one (640 mg.) in anhydrous tetrahydrofuran 13 ml.), there are added a solution of triet-hyl aluminum (1.15 g.) in tetrahydrofuran (1.38 ml.) and a solution of hydrocyanic acid (195 mg.) in tetrahydrofuran (1.7 ml.) while cooling with ice, and the resultant mixture is allowed to stand for 14 hours at room temperature (15 to 30 C.). 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 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

(CHCL3(C2H5)2O' (99: 1)

IR: 732 2230, 1716, 1070, 1100, 1080 cmr AnalysisCalcd. for C26H33O7N: C, 66.22; H, 7.05;

' N, 2.97. Found: c, 66.40; H, 7.19; N, 2.85.

Treatment with formaldehyde and hydrochloric acid.

0 Ketalation with ethylene glycol and p-toluenesullonic acid.

? [SQ/J Example 22 Y 011350 N 011330 If To a solution of l-methyl-1,2,3,4,4b,5,6,7,9,10-decahydro 1,4a(10aH) methanoiminomethanophenanthren- 7-one N-methanesulfonate (3.78 g.) in anhydrous tetrahydrofuran ml.), there are added a solution of hydrocyanic acid (119 mg.) in anhydrous tetrahydrofuran (7.5 ml.) and a solution of diethyl aluminum chloride (4.85 g.) in tetrahydrofuran (30 ml.) while cooling with ice, and the resultant mixture is allowed to stand at room temperature (15 to 30 C.) for 48 hours in a vessel with stopper. The 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.

1-methyl SaB-cyano-1,2,3,4,4b,5,6,7,8,8a,9,IO-dodeoahydro 1,4a(IOaH)-methanoimino-methanophenanthren- 7-one N-methanesulfonate.

11 L172??? 2240, 1720, 1335,1150 cm.-

Analysis.Ca1cd. for C H O N S: C, 62.62; H, 7.74; N, 7.69. Found: C, 62.64; H, 7.92; N, 7.37.

1 methyl-Saa-cyano-1,2,3,4,4b,5,6,7,8,8a,9,10-dodecahydro 1,4a(10aH)-methanoiminomethanophenanthren- 7-one N-methanesulfonate.

IR: 1122i? 2238, 1718, 1340, 1150 cm.-

Analysis.Calcd. for C H O N S: C, 62.62; H, 7.74; N, 7.69. Found: C, 62.77; H, 7.80; N, 7.56.

p The starting material of this example, 1-methyl-l,2,3, 4,4b,5,6,7,9,IO-decahydro 1,4a(10aH) methanoiminomethanophenanthren-fione N-methanesulfonate, is prephenanthrene [Stork et al.: J. Am. Chem. Soc.,.vo1. 69, p. 2936 (1947)] according to the. following scheme:

Hydrocyanation with hydrocyanic acid and diethyl aluminum chloride.

Condensation with triphenylmethoxymethyl phosphonium chloride in the presence of butyl lithium.

OCH:

(1) Treatment with an acid. (2) Methylation with methyl iodide and potassium butoxide in butanol.

Cyclization with sodium hydroxide and ethanol.

OCH:

Reduction with lithium alumi- -num hydride.

Reduction with lithium in liquid ammonia.

Esterification with methanasulionyl chloride and sodium hydroxide.

' I CHsSO N OCHz Treatment with hydrochloric acid .in methanol.

The product of this example, 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.

What is claimed is:

1. A process which comprises reacting a polyhydropolycyclic a ti-unsaturated ketone with a complex anion of the formula:

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 in a substantially anhydrous medium to introduce a cyano group into the position corresponding to the [at-position to the carbonyl group.

2. A process according to claim 1, wherein the reaction is carried out at a temperature from room temperature to reflux temperature.

3. A process according to claim 1, at leastone of R, R and R" being lower alkyl.

I 4. A process which comprises reacting polyhydropolycyclic a,B-unsaturated ketone of which the B-position corresponds to an angular position with complex anion of the formula:

wherein 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.

5. A process which comprises reacting D-homo-steroid having a, 8-unsaturated ketone structure of which the 5- position corresponds to an angular position with complex anion of the formula:

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 in a substantially anhydrous medium at a temperature from room temperature to reflux temperature to introduce a cyano group into the said angular position.

6. A process which comprises reacting 2,3,4,5,6,7,

31 8,8b-octahydronaphthalen-Z-one with complex anion of the formula:

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 in a substantially anhydrous mediumat a temperature from room temperature to reflux temperature to introduce a cyano group into the Sa-position.

7. A process which comprises reacting polyhydrotriisocyclic il-unsaturated ketone of which the B-position corresponds to an angular position with a complex anion of the formula:

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 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.

8. A process which comprises reacting polyhydrotetraisocyclic cap-unsaturated ketone of which the fl-position corresponds to an angular position with a complex anion of the formula: V

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 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-l8,19-bisnor-1,3,5(l0),l3(1f7)pregnatetraen-ZO-one, 7-oxocholesterol acetate, 3,3-e'thylenedioxy-lh-hydroxy. D V homo-18-nor-5, IZ-androstadienll-one, 11 oxo-8,9 dehydrotigogenin acetate, 3j3-acetyloxy-fia-pregnen 11,20 dione, 3a-acetyloxy-8',22- ergostadien-l l-one, 3,3: 17,17 bis ethylenedioxy-iS-androstadien-l l-one and 17,20:20,21 bismethylenedioxy- 3 ,3-ethylenedioxy-5,8-pregnadien-1l-one.

9. 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:

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 in a substantially anhydrous medium at a temperature from room temperature to reflux temperature to introduce a cyano group into the 8a-position.

v 10. 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:

AlRR'CN wherein 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 the fl-position to the carbonyl group.

1 1. 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:

wherein 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.

12. The process according to claim 10, which is followed by treatment of the resulting product with a member selected from the group consisting of aqueous acidic solution and aqueous alkaline solution.

13. 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:

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:

wherein 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.

14. A process according to claim 13, wherein the 0:,13- unsaturated ketone is a A -11-keto compound and the cyano group is introduced into the 8-position.

formula:

References Cited by the Examiner Nagata et al., J. Org. Chem. (1961), vol. 26, pages 2413-2420.

LEWIS GOTTS, Primary Examiner,

Claims

1. A PROCESS WHICH COMPRISES REACTING A POLYHYDROPOLYCYCLIC A,B-UNSATURATED KETONE WITH A COMPLEX ANION OF THE FORMULA: