US 3819636 A
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.flhis. invention at Page 3,819,636 4a,10-(ME'I'HANIMINOMETHANO) PHENANTHRENE DERIVATIVES Karel Wiesner, Fredericton, New Brunswick, Canada, assignor to American Home Products Corporation, NewYork,N.Y.w p No Drawing. Application Sept. 15, 1970, Ser. No. 7 2, 508, now Patent N 3,7 3 437,. d eaMar-zt 1 which is a continuation-impartofabandoned application'Ser. No. 846,962, Aug. 1, 1969. Divided and this application Oct. 30, 1972, Ser. No. 302,376
Int. Cl. C07d 39/00 US. Cl. 260-285 7 Claims ABSTRACT OF THE DISCLOSURE This is a division.of application Ser. No. 72,508, filed Sept 15, 1970, now U.S.'Pa t 3,723,437, Mar. 27, 1973.
,which' is a continuation-impart ofmy earlier-filed US.
Patent Application Ser. No. 846,962, filed Aug. 1, 1969,
This invention relates to a novel series of methaniminomethanophenanthrenes, the processes for their preparation and to intermediates used for their preparation.
More specifically, this invention relates to substituted 2H 4a,l0 (methaniminomethano)phenanthrene derivatives which may be represented by formula I,
in which R represents a hydrogen or lower alkyl and ring C of the methaniminomethanophenanthrene nucleus represents a substituted Ecyclohexane ring with optional substitution selected from the group,
on 0 on 3 no R a, l v 9.1.1
des ignated a, b, c, and respectively andiR of .cyclohexane ring-d represents a lower-:alkyl, benzyl or phenethyl. v I t includes thet non-toxic, pharmaceutically acceptable acidradditionnsalts Qf thecmethaniminometh 3,819,636 Patented June 25, 1974 anophenanthrenes of this-' invention. Such salts are prepared from suitable-acids, such as inorganic acids for instance, hydrochloric, hydrobromic, sulfuric, phosphoric,
.or sulfamic acid; or organicacids, for instance, ,ac,etic,
,preferably, with an excess in an organic solvent such as ether or an ethanol-ether mixture. Alternatively, an acid salt of the base, say the hydrochloride, can be reacted with a salt such as the ammonium salt of an organic acid in an aqueous mixture to form an insoluble salt by double decomposition.
The novel methaniminomethanophenanthrenes of this invention have been found to possess interesting pharmacological properties which render them useful as synthetic medicinals. More particularly these compounds in standard pharmacological tests, for example, in procedures similar to those described by Ralph Banziger in Pharmacologic Techniques in Drug Evaluation, Year Book Medical Publishers, page 392, for the testing of analgesic agents, have exhibited utility as analgesic agents, as do the analgesics, morphine and phenazocine. However, unlike morphine and phenazocine, the methanobenzazocines of this invention are substantially free of deleterious pharmacodynamic eifects. An example of suuh a deleterious effect is the excitatory effect of morphine on the central nervous system observed in both mice, see D. L. J. Bilbey et al., Brit. J. PharmacoL, 15, 540 (1960), and man, see L. A. Woods in Pharmacology in Medicine, V. A. Drill, Ed., 2nd ed., McGraw-Hill Book Company, pages 218- 221. The lack of excitation properties for the methanobenzazocines is demonstrable in pharmacological procedures, such as, for example, the procedure used by Bilbey, see reference cited above.
The compounds of this invention exhibit other desirable pharmacological properties. They possess, for example, antimicrobial properties against a number of gram-negative microorganisms such as, for example, Pseudomonas aeruginosa, Escherichia coli, Aerobacter aerogenes, Salmonella pullorum, Proteus mirabilz's and Proteus vulgaris, and against a number of fungi such as, for example, Candida abicans, Microsporum gypseum and Trichophyton granulosum. These antimicrobial properties may be demonstrated by standard tests such as those described in Antiseptics, Disinfectants, Fungicides and Sterilization, G. F. Reddish, Ed., 2nd. ed., Lea and Febriger, Philadelphia, 1957.
When the methaniminomethanophenanthrene derivatives of this invention are employed as analgesic agents in warm-blooded animals, e.g. rats, either alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice. For example, they may be administered orally in solidform containing such excipients as starch, milk sugar, and so forth.
They may also be administered orally in the form of solution or they maybe injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.
The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it Will vary with the particular host under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage 0 is increased by small increments until the optimum efi'ect under the circumstances is reached. In general, the compounds of this invention are most desirably administered 3 1 at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects and preferably at a level that is in a range of from about 1.0 mg. to about 200 mg. per kilo although as aforementioned variations will occur. However, a dosage level that is in the range of from about mg. to about 75 mg. per kilo is most satisfactory. Such doses may be administered once or twice a day, as required.
In preparing the compounds of this'invention we prefer to use the following procedure.
An important aspect of this invention is the innovation of a facile synthesis of the novel ketolactams of II t in which R is as defined above, said ketolactams being the key intermediates for the preparation of the compounds of this invention.
The preparation of the ketolactams of formula II may formula II In practising the preparation of the ketolactams of formula II, the starting material of formula III, 7- methoxy-2-tetralone, described by G. B. Diamond and M. D. Soffer, J. Am. Chem. Soc., 74, 4126 (1952), is converted to the ketoester IV by alkylation with ethylbromoacetate. A convenient method for accomplishing this alkylation is the method described by G. Stork et aL, .I. Am. Chem. Soc., 85, 207 (1963) via an enamine derivative, for example, the corresponding pyrrolidine intermediate. The ketoester IV is then transformed to the ketoester V (R =CH COOC H by treating the corresponding alkali metal enolate of the former, for example the sodium enolate, with 2-methyl-1,3-dioxolane-2-propanol p-toluenesulfonate. (For the preparation of the latter compound, see Example 2, below.)
After hydrolysis of the ketoester V to its corresponding free acid V (R =CH COOH) preferably by treatment with a base such as sodium hydroxide, the free acid is converted to the azide V (R =CH CON by treatment with lower alkyl chloroformate, for example, ethyl chloroformate, in the presence of a base, for example, triethylamine, followed by sodium azide treatment. The resulting azide V (R =CH CON rearranges on the warming in an inert solvent, for example, toluene, to yield the isocyanate V (R =CH N=C=O).
The above isocyanate on treatment with sodium hydride in an inert solvent, for example, toluene, readily furnishes the ketolactam VI (R =H).
At this particular point of the process, it has been found to be exceedingly convenient to introduce the lower alkyl group, which is eventually the group represented by R in the compounds of this invention of formulaI. Said introduction is accomplished by allowing the formation of ketolactam VI (R =H), described above, to go to completion, in the reaction mixture. The reaction mixture, which now contains the said lactam in the form of its corresponding sodium salt, is then treated with an excess of a suitable lower alkyl halide, for example, methyl iodide or ethyl chloride, to furnish the corresponding N-lower alkyl ketolactam, for example, the N-methyl ketolactam VI (R =CH or the N-ethyl ketolactam VI (R =C H respectively.
The ketolactams of formula VI when treated with acetone and p-toluenesulfonic acid, are converted to the corresponding diketolactams of formula VII. .The latter compounds are then transformed to their corresponding novel lactams of formula II by treatment with p-toluenesulfonic acid in an inert solvent such as toluene. These latter compounds are the preferred key intermediates for the preparation of the compounds of this invention.
The compounds of this invention of formula I in which R is as defined above and ring C is represented by cyclohexane ring a, may be obtained by treating the corresponding key intermediates of formula II, described above, with lithium aluminum hydride.
The compounds of this invention of formula I in which R is as defined above and ring C is represented by cyclohexane ring b, may be prepared in two reaction steps, whereby the key intermediates of formula II are first reduced to the ketolactams of formula VIII,
in which R is as defined above, which in turn are reduced to the desired compound of formula I in which R is as defined above and ring C is represented by cyclohexane ring b.
In practice, the act of reducing the key intermediates of formula II to the ketolactams of formula VIII has been found to yield one isomer of the ketolactam VIII when the reduction is performed with a catalyst, for example 10% palladium on charcoal, in the presence of hydrogen; whereas, another isomer of the ketolactam VIII is obtained when the reduction is performed by means of lithium in ammonia. For conveneince these two isomers are designated isomers A and B, respectively. These two isomers are a result of the newly introduced asymmetric center at carbon atom 10a of the methaniminomethanophenanthrene nucleus.
Subsequent reduction with lithium aluminum hydride of the A and B isomers of the ketolactams of formula VIII furnishes the corresponding A and B isomers of the methaniminomethanophenanthrenes of formula I in which R is as defined above and ring C is represented by cyclohexane ring 12., as defined above. I
The compounds of this invention of formula I'in which R is as defined above and ring C is the cyclohexane ring c. are prepared from the key intermediate II by a process which may be illustrated as follows:
cu o CH} O 6 I KI,
(ring 0 eyein- N-H hexane ring 3.)
in which R is as defined above.
In practicing this latter process a key intermediate of formula II is reduced with sodium borohydride to yield to allylic alcohol IXa. The latter compound is converted to its corresponding mesylate, IXb, which is transformed to the diene X by warming in an organic base such as, for example collidine.
Alternatively, the diene X may be prepared by converting the allylic alcohol IXa to its corresponding benzoate and then subliming the benzoate under reduced pressure.
Irradiation by an ultraviolet wave source, for example, a mercury lamp, of a solution of the diene in an inert solvent, for example, ethanol, in the presence of oxygen and a catalyst, for example, eosin, followed by chromatography of the crude product on silica gel affords the -hydroxy-i ,fi-unsat11rated keto-lactam is then reduced with hydrogen in the presence of a catalyst, such as, for example, 10% palladium on charcoal, to yield the -hydroxy ketolactam XIII.
Alternatively, the 'y-hydroxy ketolactam XIII may be prepared by irradiating with an ultraviolet wave source, for example, sunshine, a solution of the diene X in an inert solvent, for example, ethanol, in the presence of oxygen and a catalyst, for example, eosin, followed by hydrogenation of the total reaction mixture in the presence of a catalyst, for example, platinum oxide, to afford a mixture of the diol XVI, with lesser quantities of the desired -hydroxyketolactam XIII and the diepoxide XVII.
Subsequent treatment of this product mixture with an oxidizing agent, for example, sodium dichrornate, converts the diol XVI to the desired 'y-hydroxy ketolactam XIII.
The 'yhydroxy ketolactam XIII, prepared as described above, is then dehydrated, preferably by treatment with thionyl chloride in pyridine to furnish the figy-unsaturated ketolactam XIV. Treatment of the latter compound with an acid, for example, hydrochloric acid, yields the o e-unsaturated ketolactam XV as a mixture of two isomers, which are readily separated by chromatography. Again,
for convenience these isomers are designated A and B and result from the newly introduced asymmetric center at carbon atom 10a of the methanimiomethanophenanthrene nucleus.
Subsequent reduction with lithium aluminum hydride of the A and B isomers of the cap-unsaturated ketolactam of formula XV yields the corresponding A and B isomers of the methaniminomethanophenanthrenes of formula I in which R is as defined above and ring C is represented by cyclohexane ring 0, as defined above.
The compounds of this invention of formula I in which R is as defined above and ring C is represented by cyclohexane ring d, as defined above, are prepared from the liq-unsaturated ketolactam of formula XIV in which R is as defined above by a process which may be illustrated as follows:
In practicing this latter process, the iv-unsaturated ketolactam XIV, described above, is converted to the corresponding ketal of formula XVIII by treatment with a meth'anolic solution of methyl or the formate in the presence of an acid catalyst, preferably p-toluenesulfonic acid. Subsequent pyrolysis of this ketal readily affords the methoxydiene of formula XIX. This pyrolysis reaction may be conveniently performed by heating the ketal of formula XVIII in a boiling solution of an inert solvent which has a boiling point between to 200 C. for example, xylene. Treatment of the methoxydiene of formula XIX with a suitable reducing agent, preferably lithium aluminum hydride, in an inert solvent, for example, tetrahydrofuran furnishes the methoxydiene amine of formula XX. The latter compound is now subjected to a Diels-Alder reaction, see L. F Fieser and M. Fieser, Advanced Organic Chemistry, Reinhold Publishing Corporation, New York, N.Y., 1961, pp. 206-211, with methyl vinyl ketone to give the methyl ketone of formula XXI. This reaction is accomplished readily by boiling a solution of the methoxydiene amine XX in methyl vinyl ketone. The methylketone XXI thus obtained may now be treated with an appropriate lower alkyl, benzyl, or phenethyl Grignard reagent, for example, methyl magnesium, bromide, ethyl magnesium chloride, propyl magnesium iodide, benzyl magnesium iodide or phenethyl magnesium bromide, in an inert solvent, for example, ether, to give the methaniminomethanophenanthrenes of formula I in which R is as defined above, and ring C is represented by cyclohexane ring at in which R is a lower alkyl group, a benzyl or a phenethyl.
The following Examples will illustrate further this invention.
1'. (ring C cyclohexane ring ,1.)
7 EXAMPLE 1 1,2,3,4-Tetrahydro-7-methoxy-2-oxo-l-naphthaleneacetic acid ethyl ester (IV) 7-Methoxy-2-tetralone (III, 500 g.), in benzene (1300 ml.) under dry nitrogen, is treated with pyrollidine (300 ml.) and boiled for 5 hours. Water formed during the reaction is collected in a Dean-Stark water trap. The solution of tetralone enamine 3%? 1600, 1575 cm.- is cooled in ice, treated cautiously with ethyl bromoacetate (780 ml.), and then heated to reflux. After 24 hours, water (1700 ml.) is added and heating is continued for another 5 hours. The reaction mixture is then cooled and the organic phase is separated. The organic phase is rinsed with water (1000 ml.), dried and distilled. The fraction boiling from 160-170 C. at 90 micron is identified as the title compound by infrared (IR) and nuclear magnetic resonance (NMR) spectra:
1720 cm.- (unresolved doublet) and TCDC13 7.0 (d.), 5.85 (q.), 8.75 (t.) (CH CO C H EXAMPLE 2 2-Methyl-1,3-dioxolane-2-propanol p-toluenesulfonate Ethyl acetoacetate (2,000 g.) in benzene (3,300 ml.) containing ethylene glycol (1,065 g.) and toluene-p-sulphonic acid (2 g.) is boiled for 30 hours. Water formed during the reaction is collected in a Dean-Stark water trap. The reaction mixture is distilled. The fraction boiling from 110-120 C. at 18 mm. is cautiously added to lithium aluminum hydride (200 g.) in ether (3000 ml.). After 1 hour saturated aqueous sodium potassium tartrate (2000 ml.) is added and the resulting supernatant ether phase decanted, dried, and distilled. The fraction boiling at 90 C. at 18 mm. is dissolved in dry pyridine (850 ml.) at C. and treated with p-toluenesulfonyl chloride (1130 g.). After 3 hours the mixture is diluted with ether (1000 ml.), exhaustively extracted with water (8X1 1.), dried and evaporated. The resulting oil, the title compound, is sufiiciently pure for immediate use.
EXAMPLE 3 1,2,3,4 Tetrahydro 7 methoxy 1 [2 (2 methyl- 1,3 dioxolan 2 yl)ethyl] 2 oxo-l-naphthaleneacetic acid ethyl ester (V, R :CH COOC H 1,2,3,4 Tetrahydro 7 methoxy-Z-oxo-l-naphthaleneacetic acid ethyl ester (IV, 200 g.), prepared as described in Example 1, in dry benzene (1500 ml.) under nitrogen is treated with sodium hydride (38.5 g. of 55% dispersion in oil) and boiled for one hour. After being cooled, the mixture is treated with a dry solution of 2-methyl-1,3- dioxolane-2-propanol p-toluenesulfonate (250 g.), prepared as described in Example 2, in dry benzene (500 ml.) and then boiled for 16 hours. The mixture is cooled, rinsed with ice water (2X3 1.), dried and evaporated to yield the title compound;
1723 (unresolved), 945 cm. and 1CDCl 6.21 (s., unresolved), 9.2 (s.).
EXAMPLE 4 1,2,3,4 Tetrahydro 7 methoxy 1 [2 (2 methyl- 1,3 dioxolan 2 yl)ethyl] 2 oxo-l-naphthaleneacetic acid (V, R =CH C0OH) The corresponding ethyl ester of the title compound (313 g.), prepared as described in Example 3, is heated at an oil bath temperature of 90 C., with aqueous sodium hydroxide (5,000 ml. of 5% w./-v.) for 90 minutes.
'After being cooled, the aqueous phase is decanted, ex-
tracted with dichloromethane (2X 200 ml.) and then the CHOla max.
1770, 1708, 945 CHIS EXAMPLE 5 1,2,5,6 Tetrahydro 9 methoxy 3 methyl 1 [2-(2- methyl 1,3 dioxolan 2 yl)ethyl]-1,5-methano-3- benzaZocine-4,11(3H)-dione (V1; R =CH The title compound of Example 4 g.), prepared as described in Example 4, in dry tetrahydrofuran (800 ml.) magnetically stirred at 5 C., is treated successively with triethylamine (31.9 ml.), ethyl chloroformate (21 ml.), and, after 2 hours, sodium azide (36 g.) in distilled water ml.). After a further 1 hour, all the while maintaining the temperature below 0 C., the reaction'mixture is decanted, evaporated to reduced bulk and partitioned between dichloromethane (350 ml.) and aqeuous sodium bicarbonate (100 ml. of 10% w./v.). The organic phase is further rinsed with distilled water (2 100 ml.), dried and evaporated to yield the corresponding azide (V, R =CH CON 19153 2145, 1708, 945 cm.- This, in dry toluene (1000 ml.), is heated at an oil bath temperature of C. for 50 minutes. The resulting solution of the corresponding isocyanate (V, R =CH N=C=O),
2255, 1708, 945 cm.- is cooled, and treated with sodium hydride (17.5 g. of 55% dispersion in oil), and then heated to boiling. During the first hour a vigorous evolution of hydrogen occurred concurrently with the formation of a gelatinous precipitate. This, the sodium salt of the secondary lactam (VI, R=H), is treated in situ with methyl iodide g.) and reflux is maintained for an additional 1% hour. The reaction mixture is then cooled, rinsed with distilled water (7000 ml.) and is dried and evaporated to yield the title compound, the N-methyl ketolactam VI (R =OH CHC a max.
1735, 1650, 945 cm.- and 'rCDCl 6.08 (s.), 6.20 (s.), 7.20 (s.), 8.65 (s.).
In the same manner, but using an equivalent amount of ethyl chloride instead of methyl iodide, 1,2,5,6-tetrahydro 9 methoxy 3 ethyl-1-[2-(2-methyl-l,3-dioxolan 2 yl)ethyl] 1,5 methano 3 benzazocine- 4,11(3H)-dione, the N-ethyl ketolactam '(VI, R =C H is obtained.
In the same manner, but eliminating the treatment with methyl iodide and subsequent reflux, 1,2,5,6-tetrahydro-9- methoxy 1 [2 (2 methyl 1,3 dioxolan 2 yl) ethyl] 1,5 methano 3 benzazocine-4,l1(3H)-dione, the secondary lactam (VI, R =H),
3400, 1740, 1675, 945 cm. and 1CDC1 6.05 (s.), 6.20 (s.), 8.65 (s.), is obtained.
EXAMPLE 6 1,2,5,6 Tetrahydro 9 methoxy 3 methyl-1-(3-oxobutyl) 1,5 methano 3 benzazocine 4,11(3H) dione (VH, R =CH The title compound of Example 5 (80.3 g.), prepared as described in Example 5, in distilled acetone (600 ml.) containing p-toluenesulfonic acid (3 g.) is boiled for 1.5 hours. The bulk of the solvent is distilled under reduced ml.). The extract dried and then evaporated to yield the title compound;
1660, 1720, 1740 cm." "and TCDCI 6.26 (s.), 7.21 (s.), 7.94 (s.).
In theisame manner, but using'an equivalent amount of the N-ethyl ketolactarn VI, R =C H or the secondarylac'tarrr (VI, R -=-H), both prepared as described in Example 5, instead of the title compound of Example 5, 3-ethyl- 1,2,5,6 tetrahydro 9 methoxy-1-(3-oxobutyl)- 1,5 methano 3-benzazocine-4,1'1(3H)-dione, the diketolactam (VII, R =C H and 1,2,5,6-tetrahydro-9-methoxy-l-(B-oxobutyl) 1,5 methano 3 benzazocine- 4,1'1(3H);dione, the diketolactam (VII, R -=H), are obtained,respectively.
7 EXAMPLE 7 3,4,9',10 Tetrahydro 6' methoxy 12 methyl 421,10- (methaniminomethano)phenanthrene 2,11(2H) dione R1=C3) i V The title compound of Example 6 (35 g.), prepared as described in Example 6, in dry toluene (2000 ml.)
containing p-toluenesulfonic acid (11 g.), is boiled for 3 hours. Water formed during the reaction is collected in a Dean-Stark water trap. The cooled mixture is rinsed with aqueous .sodium bicarbonate (300 ml. of
w./v.) and distilled Water (2X 500 m1.), dried and evaporated to, drynessrThe crude residue is purified by chromatography on silica gel (2100 g.) with chloroformmethanol (98:2 v./v,) being used to elute the pure title compound; mp. 160-162" C.,
1650, 1680 cm.- and EtOH maz- ,230 12,100 and 280 2200 m;:..
EXAMPLE 8 3,4,9,10 Tetrahydro 6 methoxy 12 methyl-(2H)- 4a,10 (methaniminomethano)phenanthren 2 01 (I, R =CH iand ring C is cyclohexane ring a) The title compound of Example 7 (7.25 g.) prepared .as described in Example 7, in dry tetrahydrofuran (90 ml.) containing lithium aluminum-hydride (1.9 g.), is heated under reflux for 15 hours. The tetrahydrofuran is then distilled under reduced pressure and the excess of lithium aluminum hydride is decomposed using saturated aqueous sodium potassium tartrate. The mixture is then extracted with chloroform (3X 40 ml.) which is then rinsed with diluted aqueous hydrochloric acid. The acidic aqueous phase is rendered basic. with potassium hydroxide and extracted with chloroform (2X 50 ml.). The chloroform extract is dried with magneisum sulfate, filtered and evaporated to dryness to yield the title compound; mass spectrum: calculated 285; found, 285.
The title compound is further characterized as its hydrochloride salt, m.p. 190 C.
In the same manner, but using an equivalent amount of the ketolactam (H, R =C H or the ketolactam (II, R =H), both prepared as described in Example 7, instead of the title compound of Example 7, 12-ethyl-3,4,9,10- tetrahydro 6 methoxy 2(H) 4a,10 (methanirninomethano)phenanthren-2-ol (I, R =C H and ring C is cyclohexane ring a) and 3,4,9,10-tetrahydro-6-methoxy- 2(H) 4a,10 (methaniminomethano)phenanthren-Z-ol (I, R =H and ring C is cyclohexane ring a), are obtained, respectively.
EXAMPLE 9 Isomers A and B of 3,4,10,10 a-Tetrahydro-6-methoxy-12- methyl-(9H) 4a,10 (methaniminomethano)phenanthren-3-ol (I, R =CH and ring C is cyclohexane ring The title compound of Example 7 (88 mg.), prepared as described in Example 7, in methanol (20 ml.) containing water (100 mg.) and sodium borohydride (90 mg.) is stirred at room temperature for two hours. The solvent is evaporated and the residue partitioned between chloroform (50 ml.) and aqueous hydrochloric acid (20 ml. of 1 N). The aqueous phase is rinsed with additional chloroform (2x 50 ml.) and the total chloroform phase rinsed with water (30 ml.) dried, and evaporated to yield allylic alcohol IXa, 3,4,9,10-tetrahydro-Z-hydroxy-6-methoxy-12- methyl-4a,10 (methaniminomethano)phenanthren 11- one (IXa, R =CH 35803300, 1630 cm." and 1' CDCI 4.38 (d.), 6.25 (s.), 7.30 (s.). The allylic alcohol IXa (24 mg.) is treated in dry tetrahydrofuran at 0 C., containing dry pyridine (0.15 ml.) with methane sulfonyl chloride (0.1 ml.). After 2 hours, the mixture is diluted with Water (30 ml.) and extracted with chloroform (3 X 30 ml.) which is then rinsed with water (20 ml.). The total chloroform phase is dried and evaporated to yield the corresponding mesylate of the allylic alcohol, IXb;
CH 013 max.
1650, 1350, 1175 CHI-1. The mesylate (28 mg.) in collidine (5 ml.) is heated at an oil bath'temperature of 175 C. for 17 hours. The reaction mixture is then diluted with water (50 ml.) and extracted with chloroform (3x 30 ml.) which is dried and evaporated to dryness to yield an oil. Purification of the oil by chromatography on silica gel yields the diene X, 9,10-dihydro-6-methoxy-1Z-methyl- 4a,10-(methaniminomethyano)phenanthren-l 1 (4H) one 3);
279 mu (5,500). The latter compound (46 mg.) in dry ethanol (20 ml.) containing eosin (1 mg.) as catalyst, is irradiated at 20 C. using a watt mercury lamp while oxygen is bubbled through the solution. After 15 hours, the mixture is evaporated and the crude product is purified by chromatography on silica gel to give the pure -hydroxy-a,/3-unsaturated keto lactam 3,4,10,10atetrahydro-10a-hydroxy-6-methoxy-12 methyl 4a,'10- (methani-minomethano)phenanthrene 3,11(9H) dione (XII, R =CH 1675, 1640 cm. and
EtOH IDBI- 224 (9100) 278 (2300) mm. This 'y-hydroxy-a,fl-unsaturated ketolactam (30 mg.) in 50 ml. of dry ethanol is hydr'ogenated at room temperature and normal pressure in the presence of 10% palladium on charcoal (10 mg). After 2 hours, the mixture is filtered and evaporated to yield the 'y-hydroxy ketolactam, 1,2,3,4,10,10a-hexahydro- 10a-hydroxy-6-methoxy-l2-methyl-4a,10 (methaniminomethano)phenanthrene-3,1 1(9H)-dione (XIII,
01101 max. 3
3600-3300, 1710, 1140 cm.- and AEtOH 1720, 1640 cm? and 220 (3000), 280 (720) mg. The latter compound (10 mg.) in ethanol (10 ml.) containing aqueous hydrochloric acid (100 mg. of 5 N is boiled for one hour. The solvent is evaporated and water m1.) is added to the residue. The mixture is extracted with chloroform (3X 10 ml.). The extract is dried and then evaporated to yield a mixture of the A and B isomers of the 01,,8-11115311113tfid ketolactam, 3,4,10,l0a-tetrahydro-6-methoxy-12-methyl-4a,10-
(methaniminomethano)phenanthrene 3,1l(9H) dione (XV, R =CH These isomers are separated by chromatography on silica gel: Isomer A 7011018 1675, 1640 cm. and
223 (10000), 281 (2500) mg; Isomer B 703013 1675, 1640 cmr and AEtOH max.
3560 cmr and m.p. 208-210 C.,
C H 013 max.
3450 cm.- respectively.
Alternatively, the diene X of this example in which R =CH may be prepared in the following manner: a solution of the allylic alcohol IXa (R =CH 70.0 g.) prepared as described in this Example, in dry tetrahydrofuran (500 ml.) and dry pyridine (27 ml.), is treated dropwise with benzoyl chloride (36 ml.) while being stirred and cooled in an ice bath. Stirring is then continued at room temperature for 20 hours. The reaction mixture is filtered, the white solid rinsed with dichloromethane (20 ml.) and the solvent evaporated under reduced pressure to about 200 ml. The residual solution is partitioned between water (500 ml.) and chloroform (3 100 ml.). The chloroform layer is separated and rinsed with saturated aqueous sodium bicarbonate, dried (MgSO and evaporated to yield the crude oily N-methyl 12 lactam IXc (R =CH This crude N-methyl lactam is pyrolyzed under reduced pressure (0.5 mm.) in a tube which is heated to 200 C. at one end by a small furnace. The sublimate, which is a mixture of the desired diene X and benzoic acid collects on the unheated end of the tube. The subimate is dissolved in chloroform. The chloroform solution is rinsed with saturated sodium bicarbonate and water, dried and evaporated to give the desired diene X (R =CH mp. 142-145 C. (dec.), identical to the diene X (R =CH prepared by the other procedure of this example.
Again alternatively, the 'y-hydroxy ketolactam XIH (R =CH of this Example may be prepared in the following manner: A solution of the diene X (R =CH 11.7 g.) prepared as described in this Example, in ethanol (675 ml. of containing eosin (30 mg.) is exposed to sunlight while oxygen is bubbled through the solution for seven hours. Platinum oxide (2 g.) is then added and the mixture agitated under hydrogen for 20 hours at room temperature and pressure. The reaction mixture is then filtered and evaporated ,under reduced pressure to a mixture containing the diepoxide (XVII (R =CH [1,10a: 2,3 diepoxy 1,3,4,9,10,10a-hexahydro-6-methoxy-12-methyl-2H 4a,10 (methanoiminomethano) phenanthren-l l-one], the diol XVI (R =CH [1,3,4, 9,10,10a hexahydro 3,10a dihydroxy-6-methoxy-12- methyl (2H) 4a,10-(methanoiminomethano)phenanthren-ll-one, mp. 286-288 C. (after recrystallization from methanol)] and the desired 'y-hydroxyketolactam XIII (R=CH This mixture in glacial acetic acid ml.) containing sodium dichromate dihydrate (7.0 g.) is stirred for 2 hours at room temperature. The solvent is then evaporated under reduced pressure and the residue is partitioned between aqueous sodium bicarbonate (500 ml. of 5% w./v.) and chloroform (3X 200 ml.). The chloroform layer is separated and rinsed with water (200 ml.), dried (MgSO and evaporated. The residue is crystallized from ethanol to afford the 'yhydroxy ketolactam XHI (R =CH m.p. 274276 C. (dec.), identical to the ketolactam, 1,2,3,4,l0,10a hexahydro-10ahydroxy 6 methoxy-12-methyl-4a,10 (methaniminomethano)phenanthrene 3,ll(9H)-dione, prepared by the other procedure of this example.
In the same manner, but using an equivalent amount of the ketolactam (II, R =C H or the ketolactam (II, R =H), both prepared as described in Example 7, instead of the title compound of Example 7, the A and B isomers of 12 methyl 3,4,l0,10a-tetrahydro-6-methoxy- (9H) 4a,10 (methaniminomethano)phenanthren-3-0l (I, R =C H and ring C is cyclohexane ring C) and 3,4,10,10a-tetrahydro 6 methoxy-(9H)-4a,10-(methaniminomethano)phenanthren-3-ol (I, R =H and ring C is cyclohexane ring C), are obtained, respectively, via the respective intermediate, the 3,7 unsaturated ketolactams of formula XIV, 3,4,9,l0 tetrahydro-6-methoxy-4a,10- (methaniminomethano)phenanthrene 3,11(2H) dione (XIV, R =H) and l2-ethyl-3,4,9,l0 tetrahydro-6-methoxy-4a,10 (methaniminomethano)phenanthrene-3,11- (2H)-dione (XIV, R =C H EXAMPLE 10 1,2,3,4,9,l0-Hexahydro 3,6 dimethoxy-a,N-dimethyl-aphenethyl 3,10a etheno-4a,IO-(methaniminomethano)phenanthrene-2-methanol (I, R =CH and ring C is cyclohexane ring d in which R is phenethyl).
A mixture of 3,4,9,l0-tetrahydro-6-methoxy-l2-methylr 4a,10 (methanirninomethano)phenanthrene 3,l1(2H)- dione (298 mg; XIV, R =CH prepared as described in Example 9, in absoluted methanol (9 ml.) containing ptoluenesulfonic acid (60 mg.), and methyl orthoformate is stirred and boiled for 45 minutes. The mixture is then partitioned between dilute aqueous sodium bicarbonate (50 ml.). The chloroform layer is separated and rinsed with brine (15 ml.), dried (MgSO and evaporated to 13 yield the ketal XVIII -(R- '=CH 3,4,9,10-tetrahydro- 2900 and 1630 antp This latter compound (400 mg.) is stirred and boiled in dry'fxylene (20 nj'l'l.) for one hour. The solvent is evaporated under reduced pressure and the residue is purified by a 2909 and 1630 emf.
'IZhis methoxydiene (956 mg.) in dry tetrahydrofuran (17= ml.) is stirred and boiled with lithium aluminum hydride (310 mg.) ,for 1.5 hours. Excess of lithium aluminum hydride is decomposed with saturated aqueous sodium'potassium tartrate and the mixture extracted with chloroform (3 X 30 ml.). The chloroform extract is dried (Mg'SO and evaporated to give the methoxydiene amine XX (-R =CH 9,;-dihydro 3,6 dimethoxy-lZ-methyl lH la,10 (methaniminometliano)phenanthrene, as an oil, I I I 3OOO -and 1665 e'm. i I
This iiietlio'xydiene amine (916- mg.) in methyl vinyl keton e(6 "ml:) is boiled and:"stirred for 20 hours. The
lvent-i evaporated uiidr reducedipressure and the resi- -dtieisfl.;dlssolve d in' d-ichloromethane ml.) which is then extractedfayith dilute 'sulfrie acid ('30 ml. of 3%). The aqueous *phasesi's furtherextracted with chloroform (2X ml) 'amd -then rendered alkaline with ammonium hyoxide. The" aqueous phase is then extracted with chlorofor'in 3' 2'5' mll); dried (MgSO and evaporated to yield *the methyl-keton of formula XI- (R =CH 1,2,3,4,9,10-
h'exahydro -3,6"- dimethoxy N-methyl-3,10a-etheno-4a, F 10- (methaniminomethano)phenanthren-2-yl methyl keto 'nea as anoil,
corresponding hydrochloric acid I I I 5, 232-234 C. after recrystallization "fro'rn kEhloroform-ether and then ethanol-ether The methyl ketone of forrii'ulaXI (R =CH 950 mg), j "-is treated with the solution of the entfphehethyl magnesium bromide, prethe reaction mixture is treated with mif iohii im' cliloride 100 ml.), the parated"and"the water layer is re-extrac't e'd with enter "(2X ml.) ."The organic phase is dried (MgSO and evaporated. The resulting oily residue is purified by chromatography on alumina (act. III-IV), elution with petroleum ether and benzene) to afford the title compound, 1 I
v drochlofic acid addition salt of The title compound is characterized further by its picric acid addition salt, m.p. 222 C. after recrystallization from ethanol.
In the same manner as described in this Example, but using an equivalent amount of methyl magnesium brovmide, ethyl magnesium chloride, propyl magnesium iodide,
or benzyl magnesium iodide instead of phenethyl magnesium bromide,
1,2,3 ,4,9,10-hexahydro-3,6-dimethoxy-a,a,N-trimethyl- 3 ,10a-etheno-4a, 3 0- (methaniminomethano )phenanthrene- Z-methanol,
a-ethyl-1,2,3,4,9,10-hexahydro-3,6-dimethoxy-a-N-dimethyl-3,10a-etheno-4a, IO-(methaniminomethano phenanthrene-Z-methanol,
1,2,3,4,9, l 0-hexahydro-3 ,6-dimethoxy-u,N -dimethy1-aproy1-3 l0a-etheno-4a, 1 0- methaniminomethano )phenanthrene-2-methanol, and
a-benzyl-1,2,3,4,9,10-hexahydro-3,6-dimethoxy-u,N-dimethyl-3,10a-etheno-4a,10-(meth'animinomethano) phenanthrene-Z-methanol may be obtained, respectively.
In the same manner as described in this Example, but using an equivalent amount of the iq-unsaturated ketolactams of formula XIV (R =H) and formula XIV (R -C H described in Example 10, instead of 3,4,9,10- tetrahydro 6 methoxy-12-methyl-4a,IO-(methaniminomethano)phenanthrene-3,l1(2H)-dione together with the appropriate Grignard reagent, such as, methyl magnesium bromide, ethyl magnesium chloride, propyl magnesium iodide, benzyl magnesium iodide, or phenethyl magnesium bromide,
and their corresponding N-ethyl derivatives may be obtained, respectively.
1. A compound of the formula wherein R is hydrogen or lower alkyl, R is lower alkyl, benzyl or phenethyl; or acid addition salts thereof with pharmaceutically acceptable acids.
2. 1,2,3,4,9,10 Hexahydro-3,6-dimethoxy-a,N-dimethyl-a-phenethyl 3,10a etheno-4a,10-(methaniminomethano)phenanthrene-Z-methanol, as claimed in claim 1.
3. The hydrochloric acid addition salt of 1,2,3,4,9,10- hexahydro 3,6 dimethoxy-a,N-dirnethyl a phenethyl- 3,1'0a etheno-4a,10-(methaniminomethano)phenanthrene- Z-methanol, as claimed in claim 1.
4. l,2,3,4,9,10 Hexahydro 3,6 dimethoxy-c ,a,N-trimethyl 3,10a-etheno-4a,1@(methaniminomethano)phenanthrene-Z-methanol, as claimed in claim 1.
5. a-Ethyl 1,2,3,4,9,10-hexahydro-3,6-dimethoxy-u,N- dimethyl 3,10a etheno 4a,IO-(methaniminomethano) phenanthrene-Z-methanol, as claimed in claim 1. V
6. 1,2,3,4,9,10 Hexahydro-3,6-dimethoxy-a,N-dimethyl o: propyl-3,10a-etheno-4a,IO-(methaniminomethano) phenanthrene-Z-methanol, as claimed in claim 1.
7. a Benzyl-1,2,3,4,9,10-hexahydro 3,6 dimethoxya,N dimethyl 3,108. etheno-4a,IO-(methaniminomethano)phenanthrene-Z-methanol, as claimed in claim 1.
References Cited UNITED STATES PATENTS 10/1950 Schnider 260-285 4/ 1964 Cafon 260285 5/1969 Bentley 260 285 9/ 1969 Bartels 260-285 10/1969 Bentley 260285 Bentley 260,- 285 10 DONALD G. DAUS, Primary Examinei"