IL27972A - Cyclopentabenzopyrans and naphthopyrans and process for the manufacture thereof - Google Patents

Description

Cyclopentabenzopyrans and naphthopyrans and process for the manufacture thereof The are denoted as As used throughout the specification and appended the term denotes a monovalent substituent consisting solely of carbon and the term with reference to hydrocarbyl denotes groups containing no aromatic but which can be otherwise saturated or an or alkylidene group or an aliphatic group containing olefinic or acetylenic the term denotes a rated hydrocarbyl whether straight or branched the term alkyl denotes an alkyl group having its valence bond from a carbon bonded to at least two the term denotes a group consisting of the residue of a hydrocarbyl monocarboxylic acid formed by removal of the hydroxy1 portion of the carboxyl the term denotes a monovalent saturated cyclic or acyclic group consisting of and oxygen containin only one oxygen in the form of an ether and the terra as applied any of the foregoing denotes a group having a carbon skeleton containing up to and including such as and the Exemplary lower alkylene ties are ethylene and In the formulas presented the various substituents on cyclic compounds are joined the cyclic nucleus by one of a solid line indicating a substituent which is in the above the plane of the a dotted line indicating a substituent which is in the the plane of the or a line indicating a substituent which may be in either the or The of has been arbitrarily cated as the although the products obtained in the examples are all compounds unless otherwise Preferred compounds are those wherein Y is R is especially wherein the dioxy when taken with the of the butyl forms a ring especially especially or is especially when s has a value of the or is transroriented with respect to Subgeneric to the tricyclic compounds of formula I are the 2 alternate nomenclature and the 2 5 alternate nomenclature hereinafte referred to as having the and are 5 9 j nomenclature subst and the alternate nomenclature hereinafter referred to as i represented by the as whierein The and naphthopyrana and ethers thereof the formul wherein T and U are as and is lower or lower oarboxylic The compounds of formula I in which Z is carbonyl can be prepared by reacting a compound of the formula II It will be noted that the monoene and perhydro compounds of this invention can bear a When such a side chain is it is however preferable to perform the reaction sequence with compounds having the oxo moiety of the side chain in proteoted Protection effected by form j monothiaj or analogue or by reduction is preferred reasons more fully explained The second reactant employed in the condensation as generally mentioned above is a dione of the wherein and m are as defined Suitable compounds include and the The conditions for the condensation of ketone with cyclic dione are not narrowly it is particularly when the acyclic ketone is charged as the vinyl a nitrogen or be It is further preferred that an for compounds such as hydro be the reaction ca be conducted in the absence or presence of acid or base promoters Suitable basic promoters include those heretofore known to promote the Michael including inorganic for alkali metal such as sodium hydroxide or potassium and organic including alkali metal for or potassium or and ammonium particularly A preferred class of base promoters are the especially tertiary amines most preferably compounds such as pyridine and the Acid promoters which can be employed include organic carboxylic acids such as acetic acid or benzoic organic sulfonic acids such as and mineral acids such as sulfuric phosphoric hydrochloric the The amount of promoter employed is not narrowly critical end can vary amounts molar amounts The ratio of ketone to is not narrowly although approximately equimolar amounts are Although there is no particular advantage the use of excesses of either the alkanedione can be more readily employed in excess due to its general low solubility in organic cycloalkanedione can be easily recovered from the reaction The reaction temperature is not critical and can vary from j room temperature or below to reflux temperature or The j i condensation is preferably conducted in the presence of an inert solvent to insure a fluid reaction mixture and uniform reactio Primary alcohols are due to their tendency to react with vinyl Suitable solvents include tertiary alcohols such as tert aliphatic and aromatic hydrocarbons such as and the ethers such as diethyl and the chlorinated hydrocarbons such as carbon and the as well as dipolar aprotic solvents such as diraethylsulfoxide the disubstituted amides such as dimethylformamlde or The product of the depending upon the nature of vinyl ketone the reaction promoter can be one or more of the compounds having the When vinyl ketone is a or the product will be a compound of formula when the ketone is a or the reaction conditions are sufficient to convert a if the product will depend upon the When the promoter is an acid or a relatively weak such as or when no promoter is employed at the reaction product obtained from the vinyl ketone is the tricyclic ether When a strong such as sodium or potassium is employed as a a crystalline product having the formula VI is although compounds of formulae IV and V are also present in the reaction the compounds of formulae V and upon treatment with an such as acetic sulfonic or sulfuric readily form the tricyclic enol ether It should also be noted that the conversion of the acyloxy alkoxy groups of compound to a hydroxy group in an aoidic medium accompanied by cyclization to enol ether The condensation of a vinyl ketone of formula II with a cycloalkanedione of formula III is one of the key features of this It is in this condensation that the tical junction of the eventual steroidal product is The condensation of this invention is particularly advantageous in that it involves a unique asymmetric the products of the the dienones of formula have at least two asymmetric centers at positions 5 and permitting theoretically of two or four optical as a result of the condensation of this when using a starting material of ormula II wherein and aro hydrogen only a single racemate of formula results and when using an act v rtin formula whoroin and both hydrogen only a single optical antipode of formula It has further been found that when starting with a compound of formula II with a 7S stereoconfiguration there is obtained the more desirable optical antipode of formula having a to prepare steroidal materials having the more stereoconfiguration by the synthesis of this invention one can either start with the of formula which can be prepared by resolving a racemic of formula or one can resolve at some intermediate stage quent to the condensation with a of formula or one can resolve the steroidal In any the unique asymmetric induction concomitant to the conden of this invention renders the of a single as an more The simultaneous tion of the dienol ether of formula with unique asymmetric j induction is a special advantage of this 1 alkali complex hydrides such as lithium aluminum sodium aluminum and sodium lower alkali complex hydrides such as triraethoxy lithium aluminum hydride and tributoxy lithium and the The alkali complex hydrides are preferred as reducing with the alkaline such as lithium aluminum being cially This reaction is effected in any suitable inert such as and diethyl diisopropyl and Protic such as water or should not be employed when lithium aluminum hydride is the reducing but can be employed with sodium The remaining reaction conditions are not narrowly although it is generally preferred to effect the reduction at reduced about room temperature Temperatures in the range of from about to abou room temperature are normally In the reduction of a dienone of formula to a dienol of formula any keto group in the siae chain symbolized by Y is simultaneously reduced and any acyloxy group is in both cases yielding a corresponding hydroxy Any such chain hydroxy group can be converted to an oxo moiety by treatment by reaction of the ketodiene with a Grignard reagent of the g wherein is as previously defined and X is a halogen having an atomic number of from 17 to chlorine or J This Grignard reaction is conducted in known For the Grignard reagent is prepared by reacting a carbyl halide with magnesium in an ether reaction for ethyl ether or at elevated generally in the range of from about to about The ketodiene then added the Grignard solution at about room although higher or lower temperatures can be The resulting reaction product is hydrolyzed to duce the free which can be as discussed above the alcohols can be prepared by reaction ketodiene with a hydrocarbyl alkali metal compound such as methyl sodium potassium and the If a dienone of formula is to converted to a diene of formula then a starting material of formula wherein the side chain Y includes an oxo group should not be during the course of such conversion any ester moieties present in the side chain will Illustrative examples of the represented by and h 6a 1 3 ethyl cyclopentaCf vinyl 6a y 6 3 6a openta pentyl J and the AS indicated above verted to the of catalytic Suitable catalysts include the noble such as and the as well as Raney other nydrogenation These catalysts can be employed the form of the metal or can be deposited on suitable support such as calcium barium and the Palladium and rhodium are preferred as The nydrogenation is preferably conducted in the presence of inert solvents such as and the The reaction conditions of pressure and temperature are not narrowly and normally a hydrogen pressure of about one atmosphere and a temperature f about room temperature are These ambient conditions are generally preferred to avoid significant nydrogenation of the although more severe for up to about and up to about can be employed if The hydrogenation medium can be or as may be although neutral such as toluene or or basic such as an mixture are preferred for best In hydrogenation of diene of formula leads to the corresponding monoene of formula in the event is an unsaturated the in addition to hydrogenating the ring double also hydrogenates the 7 converting it to an j The compounds of formula prepared by the described hydrogenation contain at least three asymmetric at positions and when is one and at positions and 10a when is With respect to these three centers there i thus eight antipodal configurations By virtue of the unique asymmetric induction of this proceeding from a j racemlc starting material of formula or only four of these antipodes of formula are prepared and proceeding from an J optically active starting material of formula or only I two of these antipodes of formula are by the hydrogenation of this invention and by j appropriate selection of the the dlene of subjected to the hydrogenation there can predominantly be j pared the desired jj the eventual btention of the more desired configuration in the ultimate steroidal products is rendered more facile by the stereoselective reactions provided by this Illustrative examples of the monoenes of formula include j 6a j and the The conversion of monoene of formula to the perhydro compound of formula can be accomplished by reaction of the monoene with a compound having the VIII wherein is as previously That the monoene of formula is reacted with a primary or a carboxylic This reaction is catalyze mineral or organic for hydrochloric phosphoric sulfuric and the Sulfuric acid is the preferred acid arid water the preferred Although not it is desirable to conduct this reaction in the presence an added particularly in the event the compound of formula VIII is In this it is desirable to employ a solvent which is both with water and a solvent for the monoene of formula Solvents of this nature include and the The reaction temperature not and ambient temperature normally higher and lower temperatures could be employed if if converting the compound of formula to a lower ester or a alkyl or where Y is a primary alkyl group of from 1 to 4 carbon atoms reacting compound of the with thionyl chloride in the presence of zinc chloride to form an acid chloride of the formula 0 reacting the acid chloride with a compound of the formula in which is as previously to produce a chloro ketone of the formula reacting the chloro ketone in the form of its for example the ethylenedioxy with reacting the Grignard reagent thus with acrolein to upon a compound of the formula reducing the hydroxy ketone with lithium aluminium hydride to a of the formula and then proceeding as in process The preparation of the starting material of formula II As the tricyclic compounds of this tion are useful as intermediates the preparation of steroid and especially for the synthesis of Z and are as previously In the first step of this reaction the compound of formula I is oxidized to form bicyclic compound by contact with such oxidizing agents as chromic potassium or potassium Jones reagent sulfuric acid and or a chromic acid mixture are ferred as oxidizing The reaction temperature is not narrowly and temperatures in the range of from to about are although ambient temperatures are Bicyclic compound upon treatment with acid or is cyclized to cyclic compound In this it is preferred that the water of reaction be as refluxing during reaction with an azeotroping agent and separating the water from the one may react the compound of Formula X with a dehydrating such as an organic acid anhydride in with an organic acid The cycloolefin is then for example in the presence of a catalyst to form tricyclic compound which is converted to a I steroid by reaction with methyl vinyl ketone to I produce a compound of the series Example 1 A mixture of grams of 7 grams of 0 gram of milliliters of and milliliters of toluene was fluxed under a nitrogen atmosphere for two hours employing a The reaction after was filtered to recover unreacted The filtrate was evaporated to yielding grams of crude A mixture of the crude 1 gram of and 100 milliliters of ether was refluxed for 5 After the resulting solution i was concentrated and 20 milliliters ΐ hexane was added to cause A first crop of 5 obtained which melted at After concentration of the mother liquor and crystallization from a cold a second crop of crystals melting at was Employing similar procedures is prepared by substituting either or for the Example 2 A mixture of grams of grams of 210 milliliters of and 105 milliliters of acetic acid was refluxed for After the crude reaction weighing was extracted with two portions of The remaining which weighed was unreacted The benzene extracts were bined and evaporated to yield 25 grams of crude A solution of this product in hexane was filtered through alumina after evaporation of the hexane and crystallization of the product from a there was obtained grams of melting point 10 Example A mixture of grams of grams of and 50 milliliters of toluene was refluxed for 6 ofthe reaction mixture in the manner described in Example 2 yielded Example 3a A mixture of grams of grams of l6 milliliters of and 80 milligrams of reacted at for 22 Employing the recovery procedures of Example 3 there was obtained Example 4 A mixture of grams of grams of gram of and 16 milliliters of benzene was refluxed for 30 minutes and as described in Example 2 to yield Example A mixture of grams of of 16 milliliters of milliliter of and gram of acid was refluxed for After treatment of the mixture asdescribed in Example there was recovered Example 6 A mixture of grams of grams of 25 milliliters of 5 milliliters of and gram of aluminum propoxide was refluxed under a nitrogen atmosphere for one After as described in Example there was 1 melting point A mixture consisting of grams of grams of and gram of potassium acetate in held at for 20 resulting reaotion mixture was extracted with three 200 milliliter portions of After washing each ether extract with three 100 milliliter portions of the ether extracts were dried over sodium and evaporated to The residue which weighed grams was dissolved in 22 milliliters of and ographed on After elution with hexane and evaporation of the there was recovered the produot melting point The melting point was after sublimation at and Example 8 A mixture of gram of gram of 6 milliliters of and milligrams of sodium hydroxide was 0 compound held at 25 for days to yield the spiro Example 7 The same product was obtained when potassium hydroxide was substituted for sodium Example 9 A mixture of gram of gram of milliliters of and milliliter of a 30 per cent solution of benzyl trimethyl ammonium hydroxide methanol was held at for days and then heated at 50 for 15 hours to produce the spiro product Example 10 A mixture of 100 milligrams of spiro 5 milliliters of and 10 milligrams of acid was held at for 20 After uptake in the manner described in Example and crystallization from there was obtained Example 11 Employing apparatus and procedures similar to those described in Example except that is stituted for there is produced meltin at Example 12 Employing apparatus and procedures similar to those describe Example but substituting there is produced melting at Example 15 Employing apparatus and procedures similar to those described in Example but substituting for there is produced Example 14 Employing apparatus and procedures similar to those described in Example but substituting for there is produced Example 15 Employing apparatus and procedures similar to those described in Example 11 but substituting for there is produced Example 16 Employing apparatus and procedures similar to those described in Example but substituting for there is produced Example 17 A solution of 1 gram of in 20 milliliters of tetrahydrofuran was added over a period to a stirred mixture of 100 milligrams of lithium aluminum hydride in 25 milliliters of tetrahydrofuran maintained at and under a nitrogen After stirring at for an additional a few drops of concentrated sodium hydroxide solution was The resulting solution was filtered and evaporated to give gram of melting at Treatment of milligrams of the product for 20 hours at room temperature with gram of benzoyl chloride in 2 liters of pyridine as a solvent yielded the Treatment of 200 milligrams of the product alcohol for 20 hours at with milliliter of acetic anhydride in 1 liter of pyridine yielded the Example 18 Employing procedures similar to those described in Example 17 i but substituting for the is Example 19 In manner similar to that described in Example 7 is reduced to its corresponding Example Employing procedures similar to those described in Example is reduced to 1 Example 21 Employing procedures similar to those described Example except that is substituted for the Example 22 In a similar to that described in Example is reduced to its corresponding Example A mixture of grams of produced in a manner similar to that described in Example milliliters of milliliters of sodium and gram of 5 per cent was stirred at room ture In a nitrogen The hydrogen uptake stopped after 2 hours at which 520 milliliters had been After addition of milliliter of acetic the catalyst was filtered off and the filtrate evaporated dryness to yield grams of product consisting predominantly of the Example Employing apparatus and procedures similar to those described in Example 23 but substituting the product of Example 18 for that of Example there is produced predominantly Example 25 Employing apparatus and procedures similar to those described in Example 23 but substituting the product of Example 19 for that of Example there is produced antly Example 26 Employing apparatus and procedures similar to those described in Example 23 but the product of Example 18 for that of Example there is produced antl Example 27 Employing apparatus and procedures similar to those described in Example 23 but substituting the product Example 21 for that of Example there is produced antly 6a 6a 7 9 10a Example 28 Employing apparatus and procedures similar to those described in Example 23 but substituting the product of Example 22 for that of Example is produced antly 6a 6a 7 9 2 Example 29 A mixture milligrams as produced in a manner similar to that described in Example 20 milliliters of and 150 milligrams of 5 per cent was hydrogenated under ambient The hydrogen uptake ceased after one after which time 50 milliliters had been After filtering the reaction mixture and evaporation of the there was obtained the product monoenol ether as an oil containing predominantly the Example Employing apparatus and procedures similar to those described in Example 29 but substituting the product Example 11 for that of Example there is produced antly 6a 31 Employing apparatus and procedures similar to those described in Example 29 but substituting the product of Example 14 for that of Example there is produced predominantly 6a Example 32 Employing apparatus and procedures similar those described in Example 29 but substituting product of Example 16 for that of Example there is produced Example 55 Employing apparatus procedures similar to those described in Example 29 substituting the product of Example 12 for that of Example there is produced 6a Example 34 Employing apparatus and similar to those described in Example 29 but substituting the product of Example 13 for that of Example there is produced antly Example A solution of the grams of hydrogenation product obtained in Example 23 in 100 milliliters of acetone and 15 milli ters of IN sulfuric acid was held at 30 After extraction of the reaction mixture with washing with water and sodium bicarbonate drying over sodium filtr tion and there was obtained grams of crude 9a This product on crystallization from an mixture at yielded melting point A second crop weighing melting point was obtained from the mother The melting was increased from after several additional recrystallizations By employing similar procedures but substituting methanol or aoetic acid for the there are obtained the corresponding and Example Employing apparatus and procedures similar to those described in Example 35 but substituting product of Example 24 for that of Sxample there is produced antly Example 37 Employing apparatus and procedures to those described in Example 35 but substituting the product of Example 25 for that of Example there is produced 6 Example 38 Employing apparatus and procedures similar to those described in Example 35 but substituting product of Example 27 for that of Example there is produced antly Example Employing apparatus and procedures similar to those described in Example 35 but substituting the product of Example 26 for that of Example 23 there is produced antly 6 Example 40 Example 28 for that of Example there is produced antly Example 41 Employing apparatus and procedures similar to those described in Example substitutinf the ketone of Example 29 for the diol of Example there is produced Example 42 Employing apparatus and procedures similar to those described in Example 35 substituting the ketone of Example for the diol of Example there is produced antly 6a 4a Example 43 Employing apparatus and procedures similar to those described in Example 35 but substituting the of Example for the diol of Example there is produced antly Example 44 Employing apparatus and procedures similar to those described in Example 35 but substituting the ketone of naphtho Example 45 Employing apparatus and procedures similar to those described in Example 35 substituting the ketone of Example 34 for the diol of Example there is produced antly Example 46 A mixture of 117 milligrams produced in a manner similar to that described in Example 10 milliliters of 5 milliliters of IN sulfuric and 20 milligrams of 5 per cent was hydrogenated at standard temperature and of the reaction product in the manner described in Example followed by crystallization from an gave 6 milligrams of melting By employing similar substituting methanol or acetic acid for the there are obtained the corresponding and A mixture of of g of 50 milliliters of and milliliters of acetic acid was refluxed for hours under l a nitrogen After evaporation under the residue was extracted with cold benzene leaving 400 of unreacted as an Insoluble The benzene solution was then evaporated to yield g active 1 After chromatographing the crude product on followed by crystallization from the product melted at A solution of a portion of the thus obtained enol ether in 25 milliliters of tetrahydrofuran was added over a minute period to a stirred solution of 137 milligrams of lithium aluminum hydride in 30 milliliters of tetrahydrofuran at and under a nitrogen After stirring for an additional 30 minutes at and the addition of to the reaction the mixture was worked up in the manner described in Example to yield grams of optically active 2 5 6ac This product was dissolved in 50 milliliters of toluene and then hydrogenated as described in Example 23 employing 378 Example 49 grams of was dissolved in 500 milliliters of benzene and 20 milliliters of dlethylamlne To this solution there was under vigorous at grams of activated manganese The reaction mixture was then stirred at for 15 hours and then at for 5 The manganese dioxide was then filtered off and the filtrate washed three each with 50 milliliters of j It was then evaporated to dryness at in vacuo yielding a crude product which by thin layer chromatography layer chromatography Silica gel G solvent dlethylamlne 9 detection 50 per cent aqueous acid Visibility of desired product can be improved with I2 was shown to contain mainly plus traces of unreacted starting material This crude product was used without purification or the next grams of milliliters of xylene and milliliters of glacial acetic acid was refluxed for 5 To the resulting solution there was added under refluxing and a nitrogen atmosphere during 15 minutes a solution of grams of the crude product containing dissolved in milliliters of The reaction mixture was then refluxed for 15 minutes The resultant solution was then cooled to with an ice bath and then twice each time with 100 milliliters of then each time with 100 milliliters of saturated solution and then again with 100 milliliters of The aqueous phases were twice each time with 200 milliliters of After evaporation of the combined xylene and benzene solutions at in light brownish crystals were tained which were diluted with 50 milliliters of filtered off after 5 and twice each time with 15 liters of yielding point beige crystals were Further quantities of this product were obtained from the mother liquor by evaporation to dryness and column chromatography using aluminum oxide activity grade and hexane as a Example 50 A solution of grams of chromic acid in liters of sulfuric acid was added a period to a stirred of grams of produced as described Example in 143 milliliters of acetone at After stirring the reaction mixture for an additional hours and there was recovered grams of 7a A solution of this product in 172 milliliters of toluene was with 792 milligrams of acid and refluxed for 3 hours using a water Recovery and purification yielded grams of which on ation from an ether melted Example 51 The product obtained Example 48 was oxidized with a mixture o 2 grams of chromic 5 milliliters of and milliliters of 6N sulfuric acid in the manner described in Example 50 to yield 900 milligrams of This triketone was treated with 205 milligrams of acid in 50 milliliters of toluene described in Example to yield 790 milligrams of After purification by chromatographing silica the product had an optical rotation as mined from a per cent solution in Example 53 Example A mixture of xylene 157 and glacial acetic was refluxed under a nitrogen atmosphere for 2 Then a solution of tetrahydropyranol 25 as prepared in Example xylene was added to the reaction mixture during 15 The mixture was then refluxed for another 15 minutes and then up by extraction with ether 5 washing of the combined extracts with sodium bicarbonate solution and drying over sodium and evaporation of the filtrate at in vacuo to give a crude mixture of 5 6a i and an A mixture of pure acetone and sulfuric acid allowed to stand at room temperature 18 hours The workup by extraction with ether 3 washing of the combined extractor with sodium bicarbonate solution and drying over sodium and evaporation of the filtrate at in vacuo gave a crude mixture of and This mixture was separated by chromatography on gel Elution with ana ether alone afforded pure thin layer one Elution with methanol afforded as an oil layer one A mixture of benzene and aoid 170 was refluxed for 2 The workup by extraction with ether 3 washing of the combined extracts with sodium bicarbonate solution and drying over sodium and evaporation of the filtrate in vacuo gave crude which was graphed on alumina Elution with 1 and afforded pure i layer one Example A solution of in tetrahydrofuran was added at within 15 minutes to a mixture of lithium aluminum hydride 262 in tetrahydrofura with stirring and under a nitrogen The reaction mixture was stirred for an additional JO minutes at and then worked up by careful addition of filtration and evaporation of the filtrate in vacuo at yielding crude layer one was S5 Example A solution of crude obtained by the procedure of Example 65 in pyridine 15 was treated with acetic acid anhydride at room After standing at room temperature for 20 hours the reaction mixture was treated with methanol 23 at After standing 30 minutes it was then extracted with benzene 3 the combined benzene extracts were in saturated NaHC03 solution and again with The benzene extract was then evaporated and the residue purified by graphy on alumina with hexane and afforded pure 7 2 layer Example A mixture of acetone and sulfuric acid was stirred at room temperature for 6 After the workup by extraction with ether washing of the combined extracts with sodium bicarbonate solution and drying over sodium filtra and evaporation of the filtrate at in vacuo crude was This crude product was used for the next A solution of crude in wars treated with vigorous stirring with manganese dioxide at room After stirrin 1 the manganese dioxide was off and washed After evaporation of the combined dichlorethane crude was This crude was used the next A mixture of crude e toluene pyridine and hydroqulnone was with stirring for After extraction with ether washing of the combined extracts with sodium bicarbonate solution and drying over sodium and of filtrate at in vacuo crude was This material was chromatographed on alumina Fractions were taken as and Fractions afforded Example Example A solution of in dimethylformamide 15 is slowly 50 added at to a stirred mixture of chromic acid dlmethyl ormamlde 50 and concentrated sulfuric acid 1 Stirring is continued for another 5 After of the reaction mixture with washing with water and evaporation of the benzene extracts in vacuo at j obtained as an After purification by column 1 ί chromatography on aluminum this ketone is dissolved tetrahydrofuran 25 and added to solution of lithium acetylide from of lithium wire and acetylene in 50 of liquid at with Stirring is then continued hours at the reflux temperature of the reaction After adding dry ammonium chloride 5 and ether 50 to the reaction the ammonia was allowed to After washing the ether phase with water 5 followed by filtration and evaporation in vacuo at tained as an Purification achieved by thick layer tography on silica gel conditions using 5 per cent catalyst i 262 The uptake 88 of hydrogen stopped after 5 The workup by extraction with ether 3 washing of the combined extracts with sodium bicarbonate solution and j over sodium and evaporation of the filtrate at in vacuo gave crude j as an solution of prepared as described in Example 25 of toluene was treated with 50 pyridine and hydroquinone and the resulting mixture refluxed 8 hours using apparatus At the end of the reflux the reaction mixture was the removed by and the filtrate concentrated in vacuo The crude product j hex was chromatographed on 82 of neutral alumina Grade III and the column eluted with The eluted fraotions j contained the desired hich was recrystallized once from i isopropyl giving almost colorless crystals ethyle a sample which upon being recrystall zed from melted at Example To lithium aluminum hydride in tetrahydrofuran at a solution of the pentyl in 75 tetrahydrofuran was added over a period of 15 Upon completion of the addition of pentyl the mixture was stirred at for 1 A small amount of water was then added to the reaction Concentration of the reaction mixture in vacuo gave a yellow liquid which crystallized upon The was collected by A sample of the after recrystalllzatlon four times from dilute methanol and once from melted at Example A solution of i A mixture of crude benzopyran the procedure of Example acetone and sulfuric acid was allowed to stand for 1 hour at room The workup by extraction with ether washing of the combined extracts with i sodium bicarbonate solution and drying over sodium and evaporation of the filtrate at in vacuo afforded crude which was purified i by chromatography on alumina Fractions were taken ether and r Thin layer chromatography analysis1 showed fractions after to be pure 6a 6 obtained and purified as described in Example was dissolved acetone and to this solution of IN was The reaction mixture was allowed to remain at room j ture for hours it was neutralized with sodium bicarbonate diluted with 180 of and extracted three each time with 200 of The extract was washed three times with and the solvent removed to afford a slightly viscous This crude product was on 0 neutral aluminum and the column eluted with and followed by Several of the eluted fractions contained the desired n Gfo Example Crude obtained as described in Example was dissolved in toluene and to solution was added pyridine and 100 The reaction mixture was then refluxed for 8 using a Stark water The workup and chromatography purification was performed as described in Example and afforded e ah d i In order to remove the protective a 1 1 sample of the product obtained above was 5 hours under a nitrogen atmosphere in tetrahydrofuran containing washing of the combined extracts with sodium bicarbonate solution and drying over sodium and evaporation of the filtrate at in vacuo gave crude 87Ο which was purified by chromatography on silica gel 87 Fractions 87 were taken as sodium hydroxide solution was allowed to stand at room temperature for 20 Workup by extraction with ether 3 washing of the combined extracts with sodium bicarbonate solution and drying over sodium and evaporation of the filtrate at in vacuo afforded crude 373 This crude product was used To a solution of crude 373 in acetone a mixture of chromic acid in β sufluric acid was added over a period of minutes with stirring and After this addition the reaction mixture for another hour at room Workup by extraction with ether 3 washing of the combined extracts sodium bicarbonate solution and drying over sodium and evaporation of the filtrate at in vacuo gave crude Thin chromatographic analysis showed two major spots plus three minor The two major spots were separated by chromatography on silica gel 30 Elution with 2 afforded a Elution with 1 afforded the desire product Example Example was dissolved in 0 of A solution of chromium trioxide 1β2 of sulfuric acid was then dissolved into the resultant solution with stirrin at coolin with ice during the course 20 minutes After stirring the reaction mixture for 2 at 100 of water was The reaction mixture was then extracted with 400 benzene and then each time with of The benzene extracts were each time with 200 of water and the combined benzene extracts were then dried over sodium sulfate and evaporated to dryness at in vacuo yielding of as a yellow This was dissolved in 295 of benzene and treated with of sulfonic This mixture was then refluxed for after which it was cooled to washed each time with 100 of each time with 100 of saturated sodium bonate and twice each time with 100 of The aqueous phases were twice each time with 150 of the combined benzene extracts were dried over sodium After evaporation to dryness at crude was obtained as a brown This crude product was then purified by column chromatography with aluminum oxide 265 active Grade The first three fractions were eluted with 4 and contained predominantly fractions were eluted with fractions with These fractions contained purified Fractions were evaporated to dryness at in vacuo and the residue was dissolved in isopropyl ether and diluted with hexane until the solution became After seeding with light beige crystals The crystals were filtered off after a few hours at room ture and washed with an equal amount of ether yielding as yellow crystals melting at Example Employing procedures similar to those described in Example 17 there is produced hexahydrocyclopentaf Example Employing apparatus and procedures similar to those described in Example there are produced and 7 Example Employing apparatus and procedures similar to those described in Example 35 there are produced and perhydrocyclopenta 1 Example Employing apparatus and procedures similar to those described in Example there are prepared which is then converted to dione which is then converted to which is then converted to which is then verted to which is then converted to which is then converted to 13 and which is then converted to 17 Example dissolved in o toluene and hydrogenated in the presence of of palladium During 9 period 850 of is The hydrogenation is at room the end of the reaction period the catalyst is removed by and the solven removed in crude j is chromatographed on 120 neutral alumina Grade j the column eluted with givin a puri j J Example A solution of 5 in tetrahydrofuran is added at within 15 minutes to a mixture of lithium aluminum hydride in tetrahydrofuran with stirring and under a nitrogen The reaction mixture is then stirred for an additiona minutes at and then worked up by careful addition of wate filtration and evaporation of the filtrate in vacuo at yielding crude Example A solution of crude obtained by the procedure of Example in pyridine is treated with acetic acid anhydride at room After standing at temperature for 20 hours the reaction mixture is with methanol at er standing minutes it is then extracted with benzene the combined benzene extracts are washed with HC1 saturated NaHC03 solution and again with The benzene extract is then evaporated and the residue purified by graphy on alumina Elution with hexane and ether lj Jbenzopyran i Identified by thin layer chromatography To a solution of 1 500 in acetone 15 a mixture o 500 in sulfuric acid is added at with stirring during 5 After this the mixture is stirred for another 2 hours at room The workup by extraction with ether washing of the combined extracts with sodium bicarbonate solution and drying over sodium and evaporatio of the filtrate at vacuo affords crude as an acetone and this solution was added within minutes to a solution of chromic acid in dimethylformamlde containing sulfuric The reaction mixture was then stirred hours at room ice and extracted 5 each time with 100 of Afte washing with water and sodium bicarbonate the ether extracts wer dried over sodium filtered and evaporated to in vacuo at yielding crude The crude was cycllzed by it in a solution of methanol containing 5 of sodium The reaction mixture was then stirred for 5 hours at room poured onto and extracted 3 each time with 100 After washing with and sodium bicarbonate the ether extracts were dried over sodium filtered and evaporated to dryness in vacuo at yielding crude butyl This which exhibited a at 248 was chromatography on alumina Grade A solution of optically active in tetrahydrofuran 25 passed through column of was added within 15 minutes to mixture of lithium aluminum hydride in tetrahydrofuran passed through column of with stirring and under a nitrogen The reaction mixture was stirred for an additional minutes at and then worked up careful addition of filtration and evaporation of the filtrate in vacuo at yielding crude optically active ol Thin layer chromatography analysis silica gel plates solvent 1 detection per cent aqueous acid for 15 then iodine at room showed one major spot plus traces of starting The crude was then purified by on alumina 50 Elution with afforded a total of 760 pure optically active j best fraction had rotation of 0 Example A solution of optically active in toluene was hydrogenated under normal conditions using a 5 cent i f 70 The 80 of hydrogen stopped about 10 The catalyst was filtered off and washed with After evaporation crude optically active was Thin layer chromatography analysis showed one major spot plus several mino This crude product was used for the next A mixture of crude optically active prepared as acetone and sulfuric acid 7 was allowed to stand for 1 hour at room Extraction with ether or benzene 3 washing with sodiuraj1 bicarbonate solution and drying over sodium tration and evaporation to dryness at in vacuo afforded crude optically active 672 Thin layer tography analysis gel solvent 1 detection cent aqueous acid for 15 then iodine at room showed major spot plus several minor This crude product was used for the next To a solution of crude optically j 672 prepared as acetone a mixture of chromic acid in 6N sulfuric acid was added at with during 10 this addition was the mixture was stirred for another hours at room ether or benzene 3 washing with sodium bicarbonate solution and drying over sodium filtration and evaporation to dryness at in vacuo afforded crude optically active 525 Thin layer chromatography analysis showed one major spot plus two minor This crude product wa3 used for the next s A mixture optically active oxidation product as toluene 30 and acid 139 was refluxed for 3 Extraction with ether or j benzene 3 with sodium bicarbonate solution drying over sodium filtration and evaporation to dryness at in vacuo gave crude optically active This crude product was purified by chromatography on silica gel Fractions 13 were taken as 1 1 and straight Fractions yielded a total of 320 opticall active Fractions 9 and 10 159 were recrystallized from to give optically active melting at To a stirred solution of optically active 320 in tetrahydrofuran optically active This rial was dissolved in methanol 10 and treated at with 20 per cent aqueous NaOH solution for 15 After extraction with ether or benzene 3 washing with sodiuj bicarbonate solution and drying over sodium j tration and evaporation to dryness at in vacuo crude active was obtained which was again purified by alumina as described Fractions yielded optically active This material was then recrystallized from hexane to give white crystals of optically which was recrystallized from 87 insufficientOCRQuality

Claims (1)

1. CLAIMS 1. Compounds of the general formula: i which is a primary alkyl group of from 1 to 5 carbon atoms; ]¾2 is hydrogen, lower primary alkyl or lower acyl; Y is hydrogen, an alkyl group of from 1 to 6 carbon atoms, a 3-oxobutyl, 3-hydroxybutyl, 3-alkoxybutyl or 3-acyloxybutyl group or a group of the formula* wherein HQ is lower alkylene of from 1 to 5 carbon atoms ; Z \ /0S is carbonyl or a group of the formula ^-C^ wherein Βγ is hydrogen or lower acyl and Kg is hydrogen or lower aliphatic hydrocarbyl; i is 1 or 2; T represents either a single bond; in which case: U represents a single bond; n is 1; r is 1; and Θ is 1; or T represents a double bond; in which case* n is 0; 7. The co methyl, R,j is methyl, and 3 is 2. Θ. The compound according to Claim 4» wherein Y is methyl, R^ is ethyl, and m is 2. 9. A in which , R^, Y and m have the same meaning as in Claim 1. 10, The compound according to Claim 9, wherein Y is methyl, R. is methyl, R7 is hydrogen, and m is 1. 11. A compound of the general formula in which B,^ , ^, RQ, Y and m have the same meaning as in Claim 1. A compound of the general formula 1 - 90 - 27972/2 13. A compound of the general formula In which Ε^, Ϊ and m. have the same meaning as in Claim 1. 14· A compound according to Claim 13, which is the 6 ,9a- rans- or 6a.lOa-trans-isomer. 15. A compound of the general formula ¾ CR7 in which R^, R^, Y and ig have the same meaning as in Claim 1. 16. A compound according to Claim 15 , which is the 6a.9a-trans* or 6a.lOa-trans-isomer. 17. The compound according to Olaim 16, wherein Y is methyl, .^ is methyl, R^ is hydrogen, and m is 1. 18. A compound of the general formula in which R^p. Ry, Rg, Y and si have the same meaning as in Claim 1. - 91 - 27972/2 19. A compound according to Claim 18, which is the 6a.9a- rans- or 6a.lOa-trans-isomer. 20, A compound of the general formula in which R^, R,,, Y, Z and jg have the same meaning as in Claim 1. 21. A compound of the general formula in which IL^, R2» Y and jm have the same meaning as in Claim 1,* 22. A compound according to Claim 21, which is the 6a.9a-trans- or 6a.10-trana-lsome . 23. The compound according to Claim 22, wherein Y is methyl, Rn is methyl, R is hydrogen, and m is 1.· 24 *. A compound of the general formula 92 27972/2 in which R^, R2» R , X and m have the same meaning as in Claim 1. 25. A compound according to Claim 24, which is the 6a.9a-trans- or 6a.l0a-trans-isomer. 26. The compotind according to Claim 25, wherein Y is methyl, R1 is methyl, 2 is hydrogen, ^ is hydrogen, and . m is 1. 27. A compound of the general formula in which ^, 2» ^» RQ» Y and j} have the same meaning as in Claim 1. 28. A compound according to Claim 27, which is the 6a.9a-trans- or 6a.10a-trans-isomer. 29.. A process for the preparation of a compound of the formula I in Claim 1 in which Z is carbonyl, which comprises reacting a compound of the general formula with a compound of the general formula to form a compound of the general formula and, if desired, saturating the 9»9a- or 10,10a-double bond of the compound of formula Ia-1 to form a compound of the general formula and, if desired, introducing a hydroxy, alkoxy or acyloxy group at the a-* position and a hydrogen atom at the 9b- or 10b- position of the compound of formula 3b-l to form a compound of the general formula wherein in the above formulae II, III, (Ia-l), (Ib-1) and (Ic-l) B is hydrogen, lower acyl or lower alkyl, and H^, R2, Y, Z and m have the same meaning as in Claim 1. 30. A process according to Claim 29, wherein a compound of the general formula - 94 - is reacted with a compound of the general formula wherein is an alkyl group of from 1-3 carbon atoms and Y, m and B have the same meaning as in Claims 1 and 29, 31. A process according to Claim 29, wherein the compound of formula II is in the form of one opticall active isomer. 32. A process according to any one of Claims 29 to 31, wherein the reaction of a compound of formula II with a compound of formula III is carried out in the presence of an acid or weak base. 33. A process according to Claim 32, wherein said acid is p-toluene-sulfonic acid or acetic acid* 34. A process according to Claim 32, wherein said weak base is pyridine or aluminium isopropoxide. 35. A process according to Claim 29, wherein in the compound of formula II, B is hydrogen. 36. A process according to Claim 29, which comprises reacting a compound of formula II wherein B is lower acyl or lower alkyl with R compound of formula III and treating the resulting reaction mixture with acid. 37· A process according to Claim 29, which comprises reacting a compound of formula II with a compound of formula III in the presence of a strong base and treating the resulting reaction - 95 - 38. A process according to Claim 37, wherein said strong base is an alkali metal hydroxide. 39. A process according to Claim 29» wherein in a further reaction step a compound of the formula (la-1) in Claim 29 is converted to a compound of the general formula (Ia-2) in Claim 9 by reduction and, if desired, subsequent esterification. 40. A process according to Claim 29, wherein in a further reaction step a compound of the formula (la-1) in Claim 29 is converted to a compound of the general formula (la-3) in Claim 11, by reaction with a lower hydrocarbyl-magnesium bromide (or chloride), hydrolysis and, if desired, subsequent esterification. 41. A process according to Claim 29, wherein in a .further reaction step a compound of the general formula (lb-1) in Claim 29 is converted to a compound of the formula (lb-2) in C aim 15 by reduction and, if desired, subsequent esterification. 42. A process according to Claim 29, wherein in a further reaction step a compound of the general formula (Ib-l) in Claim 29 is converted to a compound of the general formula (lb-3) in Claim 18 by reaction with a lower hydrocarbyl-magnesium bromide (or chloride), hydrolysis and, if desired, subsequent esterifi* cation. 43. A process according to Claim 29, wherein in a further reaction step a compound of the general formula (lc-1) in Claim 29 is converted to a compound of the general formula (lc-2) in Claim 24 by reduction and, if desired, esterification. 44. A process according to Claim 29, wherein in a further reaction step a compound of the general formula (lc-1) in Claim 29 is converted to a compound of the general formula (lc-3) in Claim 27 27972/2 - 96 hydrolysis and, if desired, subsequent esterification. 45. A process according to Claim 29» wherein the compound of formula II is prepared by reacting a compound of the general formula OH with a vinyl magnesium halide to form a compound of the general ormula OH OH YCH2-¾H-CH2-0H2-CH2-CH-GHe0H2 Ila selectively oxidizing the 3-hydroxy group of the compound of formula Ila with manganese dioxide to orm a compound ' of the general formula OH 0 YCH2-CH-CH2-CH2-CH2-C-CH»CH2 lib and, if desired, converting the compound of formula lib to a 7-lower acyl ester or a 7-lower alkyl ether, wherejin formulae IV, Ila and lib Y has the same meaning as in Claim 1. 46. A process according to Claim 29, wherein the compound primary of formula II, in which Y is a alkyl group of from 1 to 4 carbon atoms, is prepared by reaching the compound of the formula with thionyl chloride in the presence of zinc chloride to form an 27972/2 97 0 C1-C-CH2-CH2-CH2C1 reacting the acid chloride with a compound of the formula (¾)2Cd in which has the same meaning as in Claim 1, to produce a chloro ketone of the formula? 0 reacting the chloroketone in the form of its ketal, for example, the ethylenedioxy ketal, with magnesium, reacting the Grignard reagent thus obtained with acrolein to yield, upon hydrolysis, a compound of the formula reducing the form a diol o process of Claim-45. 47. A compound of the formula I in Claim 1, whenever prepared according to the process claimed in any one of Claims 29-46 or by an obvious chemical equivalent thereof. 48. A compound of the formula (ί-1) in Claim 2, whenever prepared according to the process claimed in any one of Claims 29-46 or by an obvious chemical equivalent thereof, 49. A compound of the formula (la) in Claim 3, whenever prepared according to the process claimed in any one of Claims 29-46 or by an obvious chemical equivalent thereof, 27972/2 - 98 - 50. A compound of the formula (Ia-1) in Claim 4» whenever prepared according to the process claimed in any one of Claims 29 - 46 or "by an obvious ohemical equivalent thereof. 51. The compound of the formula (Ia-l) in Claim 4» wherein Y is methyl, TL^ is methyl, and m io 1, whenever prepared according to the process claimed in any one of Claims 29 - 46 or by an obvious chemical equivalent thereof. 52. The compound of the formula (Ia-l) in Claim 4, wherein Y io methyl, is ettyl, and m is 1, whenever prepared according to the process claimed in any one of Claims 29 - 46 or by an obvious chemical equivalent thereof. 53. The compound of the formula (Ia-l) in Claim 4, wherein Y is methyl, is methyl, and m is 2 , whenever prepared according to the process olaimed in any one of Claims 29 - 46 or by an obvious chemical equivalent thereof* 54. The compound of the formula (Ia-l) in Claim 4, wherein Y is methyl, is ethyl, and m is 2 , whenever prepared according to the process claimed in an one of Claims 29 - 46 or by an obvious chemical equivalent thereof. 55. A compound of the formula (Ia-2 ) in Claim 9» whenever prepared according to the process claimed in any one of Claims 29 - 46 or by an obvious chemical equivalent thereof. 56. The compound of the formula (Ia-2 ) in Claim 9» wherein Y is methyl, is methyl, is hydrogen, and m is 1, whenever prepared according to the process claimed in any one of Claims 29 - 46 Or by an obvious chemical equivalent thereof. 27972/2 . - 99 - 57. A compound of the formula (Ia-3) in Claim 11, whenever prepared according to the process claimed in any one of Claims 29 - 46 or by an obvious chemical equivalent thereof. 58. A compound of the formula (lb) in Claim 12, whenever prepared according to the process claimed in any ora of Claims 29 - 46 or by an obvious chemical equivalent thereof. 59.* A compound of the formula (Ib-1) in Claim 13» whenever prepared according to the process claimed in any one of Claima 29 - 46 or by an obvious chemical equivalent thereof. 60. A compound of the formula (Ib-1) in Claim 13, which is the 6a.9a-trans- or 6 .10a-1rans-iaome . whenever prepared Recording to the process claimed in any one of Claims 29 - 46 or by an obvious chemical equivalent thereof. 61. A compound of the formula (Ib-2) in Claim 15» whenever prepared according to the process claimed in any one of Claims 29 - 46 or by an obvious chemical equivalent thereof. 62. A compound of the formula (Ib-2) in Claim 15, which is the 6a.9a-trans- or 6a.lOa-trans-iaomer. whenever prepared according to the process claimed in any one of Claims 29 *· 46 or by an obvious chemical equivalent thereof. 63* 2?he compound according to Claim 62, wherein Y is methyl, is methyl, is hydrogen, an m is 1, whenever prepared according to the process claimed in any one of Claims 29 - 46 or by an obvious chemical equivalent thereof. 64. ; A compound of the formula (Ib-3) in Claim 18, whenever prepared according to the process claimed in any one of Claims 29 - 46 or by an obvious chemical equivalent thereof. 27972/2 1 - 100 - 65. A compound of the formula (Ib-3 ) in Claim 18, which is the 6a.9a-trans- or 6a,10a-trans-i-3omer, whenever prepared according to the process claimed in any one of Claims 29 - 6 or by an obvious chemical equivalent thereof. 66. Λ compound of the formula (Ic) in Claim 20,~ whenever prepared acoording to the process claimed in any on© of Claims 29 - 46 or by an obvious chemical equivalent thereof. 67. A compound of the formula (Ic-1) in Claim 21, whenever prepared according to the process claimed in any one of Claims 29 - 46 or by an obvious chemical equivalent thereof* 68. A compound of the formula (Ic-l) in Claim 21, which is the 6a.9a-trana- or 6a.l0a-tran8-isomer_ whenever prepared according to the process claimed in any one of Claims 29 - 46 or by a obvious ohemlcal equivalen thereof. 69. The compound according to Claim 68, wherein Y is methyl, is methyl, R2 is hydrogen, and m is 1, whenever prepared according to the process claimed in any one of Claims 29 - 46 or by an obvious chemical equivalent thereof. 70. A compound of the formula (Ic-2) in Claim 24, whenever prepared according to the process claimed in any one of Claims 29 - 46 or by an obvious chemical equivalent thereof. 71. A compound of the formula (Ic-2) in Claim 24, which is the 6a.9a-trans- or 6a,lOa-trnna-isomer. whenever prepared according to the process claimed in any one of Claims 29 - 46 or by an obvious chemical equivalent thereof. 72. The compound according to Claim 71, wherein Y is methyl, is me l, R2 is hydrogen, Εγ is hydrogen, and m is 1, 27972/2 - 101 whenever prepared according to the process claimed in any one of Claims 29 * 46 or by an obvious chemical equivalent thereof. 75· A compound of the formulc (Ic-3) in Claim 27» whenever prepared according to the process claimed in any one of, Claims 29 - 46 or by an obvious chemical equivalent thereof. 74· A compound of the formula (lc-3) in Claim 27» which is the 6a,9a-trans- or 6a,10a-trans-i8omer, whenever prepared according to the process claimed in any one of Claims 29 - 46 or by an obvious chemical equivalent thereof. 75. Process for the preparation of compounds of formula I in Claim 1, substantially as hereinbefore d escribed, especially with reference to the foregoing Examples. HD:BH