Claims
- 1. A compound of the formula: ##STR56## wherein R.sub.3 is --CH.sub.2 R.sub.4, lower alkyl, or hydrogen; R.sub.4 is hydroxy, or hydroxy protected with a hydrolyzable ether or ester group or OR.sub.8 '; R.sub.6 is hydroxy or hydroxy protected with a hydrolyzable ether or ester group; R.sub.8 ' is lower alkyl; R.sub.9 is lower alkyl or fluoro; and R.sub.9 ' is hydrogen or lower alkyl; with the proviso that when R.sub.9 is lower alkyl, R.sub.9 ' is lower alkyl;
- or enantiomers or racemates thereof.
- 2. The compound of claim 1 wherein said compound is 3,3abeta,4,5,6,6abeta-hexahydro-4 beta[4-fluoro-3 alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-methyl-2-oxo-2H-cyclopenta[b]furan.
- 3. A compound of the formula: ##STR57## wherein R.sub.4 is hydrogen, lower alkyl or; R.sub.19 is fluoro or lower alkyl; R.sub.19 ' is hydrogen or lower alkyl; with the proviso that when R.sub.19 is lower alkyl, R.sub.19 ' is lower alkyl; or enantiomers or racemates thereof.
- 4. The compound of claim 3 wherein said compound is 3,3abeta,4,5,6,6abeta-hexahydro-4beta(4,4-dimethyl-3-oxo-1-trans-octenyl)-5-alphamethyl-2-oxo-2H-cyclopenta[b]furan.
- 5. The compound of claim 3 wherein said compound is 3,3abeta,4,5,6,6abeta-hexahydro-4beta(4-fluoro-3-oxo-1-trans-octenyl)-5-alpha-methyl-2-oxo-2H-cyclopenta [b]furan.
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a divisional application of Ser. No. 780,878-Holland et. al., filed Mar. 24, 1977, now abandoned, which in turn is a divisional application of Ser. No. 614,044, Holland et al., filed Sept. 17, 1975, now U.S. Pat. No. 4,036,871, which in turn is a divisional application of Ser. No. 480,458, Holland et al. filed July 18, 1974, now U.S. Pat. No. 4,052,446, which in turn is a continuation-in-part of U.S. application Ser. No. 386,117, filed Aug. 6, 1973, now abandoned. Also related to this application is U.S. patent application Ser. No. 300,633, Rosen and Kienzle filed Oct. 25, 1972, U.S. patent application Ser. No. 381,322, Rosen and Kienzle filed July 20, 1973 and U.S. patent application Ser. No. 317,589, filed Dec. 22, 1972, Jernow and Rosen.
In accordance with this invention, a process has been discovered for preparing prostaglandin active compounds of the formula: ##STR1## wherein R is hydrogen or lower alkyl; R.sub.2 is hydroxy; R.sub.3 is hydrogen or taken together with R.sub.2 to form oxo; R.sub.1 is hydrogen, lower alkyl, carboxy, lower alkoxy carbonyl, --CH.sub.2 OR.sub.8 and ##STR2## R.sub.8 is hydrogen or lower alkyl; R.sub.9 ' is hydrogen; lower alkyl or fluoro; and R.sub.9 is hydrogen or lower alkyl; and the dotted bond can be optionally hydrogenated; from a compound of the formula: ##STR3## wherein R.sub.4 is lower alkyl, hydrogen or --COOR'.sub.1 ; R.sub.1 ' is hydrogen or lower alkyl; R.sub.6 is hydroxy protected with a hydrolyzable ether or ester group; and R.sub.9 and R.sub.9 ' are as above.
In accordance with this invention, new and novel prostaglandin compounds of the formula: ##STR4## wherein R, R.sub.2 and R.sub.3 are as above; R.sub.1 " is lower alkyl, hydrogen, carboxy, lower alkoxy carbonyl, --CH.sub.2 OR.sub.8 or ##STR5## and R.sub.8, R.sub.9, and R.sub.9 ' are as above; with the proviso that when R.sub.9 and R.sub.9 ' are all hydrogen, R.sub.1 " is lower alkoxycarbonyl, --CH.sub.2 OR.sub.8 or ##STR6## and the dotted bond can be optionally hydrogenated have been prepared which have cardiovascular activity, induce labor in pregnant females; are useful for terminating pregnancies and for combatting gastro-hyperacidity. The compounds of formula I-A are also useful as bronchodilators.
As used throughout this application, the term "lower alkyl" includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms, such as methyl, ethyl and propyl, preferably methyl. As used herein, the term "lower alkoxy" comprehends groups having from 1 to 7 carbon atoms such as methoxy and ethoxy. As also used herein, the term "lower alkanoic acids" comprehends an alkanoic acid of 1 to 7 carbon atoms such as formic acid and acetic acid. As further used herein, the term "halogen" or "halo", unless otherwise stated, comprehends fluorine, chlorine, bromine and iodine.
In the process of this invention, all compounds having one or more asymmetric carbon atoms can be produced as racemic mixtures. These racemic mixtures which are obtained can be resolved at the appropriate steps in the process of this invention by methods well known in the art discussed more fully below, whereupon subsequent products may be obtained as the corresponding optically pure enantiomers.
In the pictorial representation of the compounds given throughout this application, a thickened tapered line ( ) indicates a substituent which is in the beta-orientation (above the plane of the molecule), a dotted line ( ) indicates a substituent which is in the alpha-orientation (below the plane of the molecule) and a wavy line ( ) indicates a substituent which is in either the alpha- or beta-orientation or mixtures of these isomers. It is to be understood that the pictorial representations of the compounds given throughout the specification are set forth for convenience and are to be construed as inclusive of other forms including enantiomers and racemates and are not to be construed as limited to the particular form shown.
As also used herein, the term "aryl" signifies mononuclear aromatic hydrocarbon groups such as phenyl, tolyl, etc. which can be unsubstituted or substituted in one or more positions with a lower alkylenedioxy, a halogen, a nitro, a lower alkyl or a lower alkoxy substituent, and polynuclear aryl groups such as naphthyl, anthryl, phenanthryl, azulyl, etc., which can be substituted with one or more of the aforementioned groups. The preferred aryl groups are the substituted and unsubstituted mononuclear aryl groups, particularly phenyl. The term "aryl lower alkyl" comprehends groups wherein aryl and lower alkyl are as defined above, particularly benzyl. The term "aryl lower alkanoic acid" comprehends acids wherein "aryl" and "lower alkanoic acid" are as defined above, particularly benzoic acid.
As still further used herein, the term "carboxy protected with a group convertible thereto by hydrolysis" comprehends any conventional organic acid protecting group which can be removed by hydrolysis. The preferred organic acid protecting groups are the esters. Any conventional ester that can be hydrolyzed to yield the acid can be utilized as the protecting group. Exemplary esters useful for this purpose are the lower alkyl esters, particularly methyl and ethyl ester, the aryl esters, particularly phenyl ester and the aryl lower alkyl esters, particularly benzyl ester.
As used herein, the term "hydrolyzable ester or ether group" designates any ester or ether which can be hydrolyzed to yield the hydroxy group. Exemplary ester groups useful for this purpose are those in which the acyl moiety is derived from a lower alkanoic, an aryl lower alkanoic, phosphoric, carbonic or a lower alkane dicarboxylic acid. Among the acids which can be utilized to form such ester groups are the acid anhydrides and the acid halides, preferably chlorides or bromides, with the lower alkanoic acid anhydrides, e.g., acetic anhydride and caproic anhydride, the aryl lower alkanoic acid anhydrides, e.g., benzoic acid anhydrides, lower alkane dicarboxylic acid anhydrides, e.g, succinic anhydride, and chloroformates, e.g., trichloroethylchloroformate, being preferred. A suitable ether protecting group is, for example, the tetrahydropyranyl ether or 4-methoxy-5,6-dihydro-2H-pyranyl ether. Others are arylmethyl ethers such as benzyl, benzyhydryl, or trityl ethers or alpha-lower alkoxy lower alkyl ether, for example, methoxymethyl or allylic ethers, or trialkyl silyl ethers such as trimethyl silyl ether or dimethyl-tert-butyl silyl ethers.
Where R.sub.1 " in the compound of formula I-A is --CH.sub.2 OR.sub.8, the preferred compounds are those where at least one of R.sub.9 or R.sub.9 ' is other than hydrogen. Where R".sub.1 in the compound of formula I-A is lower alkoxycarbonyl, the preferred compounds are those where at least one of R.sub.9 or R.sub.9 ' is other than hydrogen.
The compounds of formula I wherein R.sub.2 and R.sub.3 form an oxo group, i.e., the compounds of the formula: ##STR7## wherein R, R.sub.1, R.sub.9 and R.sub.9 ' are as above; and the dotted bond can be optionally hydrogenated; are useful in the same manner as prostaglandin E.sub.2. The compounds of formula I-B are especially valuable for preventing hyperacidity in the stomach and for broncho-dilation. On the other hand, the compounds of formula I-A where R.sub.2 is hydroxy and R.sub.3 is hydrogen, i.e., the compounds of the formula: ##STR8## wherein R, R.sub.1, R.sub.9 and R.sub.9 ' are as above and the dotted bond can be optionally hydrogenated; are useful in the same manner as prostaglandin F.sub.2 .alpha..
The prostaglandins E.sub.1, E.sub.2 and F.sub.2.alpha. have the ability to modify the activity of the alimentary and reproductive smooth muscles to block mucous and enzyme secretions by the stomach, to stimulate the synthesis of adrenal corticoids, to modify blood pressure and lipolysis. Since the compounds of formulae I-B and I-C have prostaglandin E.sub.1, E.sub.2 and F.sub.2.alpha. activity, the compounds of formulae I-B and I-C also possess these valuable properties. Furthermore, the compounds of formula I-B and I-C are active in the same manner as these prostaglandins in inducing labor and pregnancy in females and for therapeutically terminating pregnancy. The compounds of formula I-B are useful in the same manner as the prostaglandin E.sub.2 in that they lower blood pressure and inhibit blood platelet aggregation. On the other hand, the compounds of formula I-C are blood pressure raising agents in the same manner as prostaglandin F.sub.2.alpha..
That the compounds of formula I-B are effective anti-ulcerogenic compounds can be seen by the fact that the ED.sub.50 of a compound such as 7-[3 alpha methyl-5-oxo-2 beta-(3 alpha-hydroxy-4-fluoro-1-trans-octenyl)-1-alpha-cyclopentyl]-cis-5-heptenoic acid is 0.47 i.p. and 0.001 p.o. when administered to rats by the following test:
Rats were fasted 16 hours prior to the subcutaneous administration of Indomethacin at 100 mg/kg. Simultaneously with the Indomethacin dose, the test compounds were administered intraperitoneally at three dose levels and dosed orally at six dose levels. These doses of the test compounds were repeated every thirty minutes for six hours (12 doses). After six hours, the animals were killed and the stomachs were examined for ulceration or hemorrhage. Protection from incidence of ulceration was used to determine activity. Five mice were used per dose level and ED.sub.50 values were calculated.
The compounds of formula I can be used by the pharmaceutical and veterinary arts in a variety of pharmaceutical or veterinary preparations. In these preparations, the new compounds are administerable in the form of tablets, pills, powders, capsules, injectables, solutions, suppositories, emulsions, dispersions, feed pre-mixes and in other suitable forms. The pharmaceutical or veterinary preparations which contain the compound of formula I are conveniently admixed with a non-toxic pharmaceutical organic carrier or a non-toxic pharmaceutical inorganic carrier. Typical of pharmaceutically acceptable carriers are, for example, water, gelatin lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly and other conventionally employed pharmaceutically acceptable carriers. The pharmaceutical preparations may also contain nontoxic auxiliary substances such as emulsifying, preserving and wetting agents and the like, as for example, sorbitan monolaurate, triethanol amine oleate, polyoxyethylene sorbitan, dioctyl sodium sulfosuccinate and the like.
The daily dose administered for the compounds will of course vary with the particular novel compounds employed because of the very potency of the compounds, the chosen route of administration and the size of the recipient. The dosage administered is not subject to definite bounds but it will usually be in effective amounts of the pharmacologically function of the prostaglandin. Representative of a typical method for administering the prostaglandin compounds of formula I is by the injectable type administration route. By this route, a sterile solution containing the prostaglandin of formula I can be administered intraveneously at the rate of 0.01 microgram to 0.15 microgram per minute per kilogram of body weight. The compound to be administered by the injectable route is in a form suitable for injection such as mixed with a sterile aqueous solution having incorporated therein an agent that delays adsorption such as aluminum monostereate and the like.
For administering the compounds of formula I to domestic animals or laboratory animals, the compounds are prepared in the form of a food pre-mix such as mixing with dried fish meal, oatmeal and the like, and the prepared pre-mix is added to a regular feed thereby administering the compound to the domestic or laboratory animal in the form of a feed.
The compound of formula I-C wherein R.sub.1 is --CH.sub.2 OR.sub.8 and R is hydrogen, i.e., a compound of the formula: ##STR9## wherein R.sub.8, R.sub.9 and R.sub.9 ' are as above; can be prepared from a compound of the formula: ##STR10## wherein R.sub.6, R.sub.9 and R.sub.9 ' are as above; via the following intermediates: ##STR11## wherein R.sub.6, R.sub.9 and R.sub.9 ' are as above; ##STR12## wherein R.sub.6, R.sub.9 and R.sub.9 ' are as above; and R.sub.6 ' is hydroxy protected by a hydrolyzable ether or ester group; or --OR.sub.8 ' and R.sub.8 ' is lower alkyl. ##STR13## wherein R.sub.6, R.sub.6 ', R.sub.9 ' are as above; ##STR14## wherein R.sub.6 ' and R.sub.6 are as above.
The starting material of formula II-A when R.sub.9 and R.sub.9 ' are hydrogen and its method of preparation is disclosed in U.S. patent application Ser. No. 300,633, filed Oct. 25, 1972, Kienzle et al. (please note formula XXI-C and Example 20 in Ser. No 300,633). The compound of formula II-A is converted to the compound of formula III by treating the compound of formula II-A with borane. In carrying out this reaction, temperature and pressure are not critical and the reaction can be carried out at room temperature and atmospheric pressure. On the other hand, elevated or lower temperatures can be utilized. Generally, it is preferred to carry out this reaction at a temperature of from -20.degree. C. to +50.degree. C. This reaction is generally carried out in the presence of an inert organic solvent. In carrying out this reaction, any conventional inert organic solvent can be utilized. Among the preferred solvents are the ether solvents such as diethyl ether, tetrahydrofruan, dioxane, etc.
The compound of formula III is converted to the compound of formula IV by either esterifying or etherifying the free hydroxy group. Any conventional method of etherifying or esterifying the hydroxy group to form a conventional hydrolyzable ether or ester group can be utilized in carrying out this reaction. The preferred protecting group formed by R.sub.6 ' is tetrahydropyranyloxy. On the other hand, where R.sub.6 ' is --OR.sub.8 ' this compound is formed by etherification with a lower alkyl halide. Any of the conditions conventional in forming a lower alkyl ether can be utilized in this conversion.
The compound of formula IV is converted to the compound of formula V by treating the compound of formula IV with a reducing agent. In carrying out this reaction, any conventional reducing agent which will selectively reduce a keto-group to a hydroxy-group can be utilized. Preferred reducing agents are the hydrides, particularly the aluminum hydrides such as alkali metal aluminum hydride, and the borohydrides such as alkali metal borohydrides, with diisobutyl aluminum hydride being particularly preferred. Also, this reaction can be carried out utilizing di-(branched chain lower alkyl)boranes such as bis(3-methyl-2-butyl)borane. In carrying out this reaction, temperature and pressure are not critical and the reaction can be carried out at room temperature and atmospheric pressure or at elevated or reduced temperatures and pressures. Generally, it is preferred to carry out this reaction at a temperature of from -10.degree. C. to the reflux temperature of the reaction mixture. This reduction reaction can be carried out in the presence of an inert organic solvent. Any conventional inert organic solvents can be utilized in carrying out this reaction. Among the preferred solvents are dimethoxy ethylene glycol, and the ethers such as tetrahydrofuran, diethyl ether and dioxane.
The compound of formula VI is obtained from the compound of formula V by reacting the compound of formula V with phosphonium salts of the formula: ##STR15## wherein R.sub.10, R.sub.10 ', R.sub.10 ' is aryl or di(lower alkyl)-amino; and Y is halogen.
In accordance with this invention, it is found that the compound of formula V will react with the compound of formula X to produce a compound of the formula VI with a predominately cis double bond at the 5 position of the acid chain in a solvent medium containing hexamethylphosphoramide utilizing sodium bis-trimethylsilylamide as a base. If solvents other than hexamethylphosphoramide or bases other than sodium bis-trimethylsilylamide are utilized, the compound of formula VI will form, if at all, in poor yields. However, conventional inert organic solvents may be mixed with the hexamethylphosphoramide to form the solvent medium in accordance with this invention. If other solvents are utilized, these solvents can be conventional inert organic solvents. On the other hand, the solvent system can contain only the hexamethylphosphoramide. Therefore, this reaction is carried out utilizing hexamethylphosphoramide as the solvent and sodium bistrimethylsilyl-amide as the base. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and pressure. However, if desired, higher or lower temperatures can be utilized. Generally, it is preferred to carry out this reaction at a temperature of from 0.degree. to 50.degree. C.
The process whereby a cis double bond is formed at the 5-position of the heptenoic acid chain can be applied to a process for preparing natural prostaglandins. In this process, a compound of the formula: ##STR16## wherein R.sub.6 is as above; reacted with a compound of formula X to form a compound of the formula: ##STR17## wherein R.sub.6 is as above; and where the double bond at the 5-position of the heptenoic acid moiety has a predominately cis configuration. This reaction is carried out in the solvent medium containing hexamethylphosphoramide and in the precense of sodium bis-trimethylsilylamide as the base. The reaction is carried out utilizing the same conditions described in connection with the reaction of a compound of formula V with a compound of formula X to form a compound of formula VI.
The compound of formula VI is converted to the compound of formula I-D by aqueous hydrolysis where the hydroxy group is protected via an ether linkage. Any conventional method of ether hydrolysis can be utilized. Among the preferred methods of ether hydrolysis is by treating the compound of formula VI with an aqueous acid. On the other hand, where R.sub.6 ' forms --CH.sub.2 OR.sub.8 ', this ether linkage is not a conventional hydrolyzable ether group and conventional ether hydrolysis will not remove the lower alkyl group. On the other hand, where R.sub.6 forms an ester linkage, the hydroxy group can be regenerated by treatment with a base in an aqueous medium. Any conventional method of ester hydrolysis can be utilized in this conversion.
On the other hand, the compound of formula VI above can be converted to a compound of the formula: ##STR18## wherein R.sub.8, R.sub.9 and R.sub.9 ' are as above; via an intermediate of the formula: ##STR19## wherein R.sub.6, R.sub.6 ', R.sub.9 and R.sub.9 ' are as above.
The compound of formula VI is converted to a compound of formula VIII by treating the compound of formula VI with an oxidizing agent. Any conventional oxidizing agent which will convert a hydroxy group to an oxo group can be utilized in carrying out this reaction. Among the preferred oxidizing agents are chromate oxidizing agents such as chromium trioxide. Any of the conditions conventional in utilizing these oxidizing agents can be utilized to carry out this reaction. The compound of formula VIII is converted to the compound of formula VII by hydrolysis in the same manner as described in connection with the hydrolysis of a compound of formula VI.
Where R.sub.1 in the compound of formula I-C is hydrogen or lower alkyl and R is hydrogen and the double bond is unhydrogenated, this compound has the following formula: ##STR20## wherein R.sub.4 ' is lower alkyl or hydrogen, and R.sub.9 and R.sub.9 ' are as above.
This compound can be prepared from a compound of formula II where R.sub.4 is hydrogen or lower alkyl via the following intermediates: ##STR21## wherein R.sub.4 ', R.sub.6, R.sub.9 and R.sub.9 ' are as above; ##STR22## The compound of formula II where R.sub.4 is hydrogen or lower alkyl is converted to the compound of formula V-A in the same manner as described in hereinbefore for the conversion of a compound of formula IV to a compound of formula V. The compound of formula V-A is converted to the compound of formula VI-A by reaction with the compound of formula X in the manner described hereinbefore with regard to the conversion of a compound of formula V to a compound of formula VI. The compound of formula VI-A can be converted to a compound of the formula I-E by hydrolysis of the protecting group R.sub.6 in the manner described in connection with the conversion of a compound of the formula VI to a compound of the formula I-D.
On the other hand, the compound of formula VI-A can be oxidized to a compound of the formula: ##STR23## wherein R.sub.4 ', R.sub.6, R.sub.9 and R.sub.9 ' are as above in the same manner as described in connection with the oxidation of a compound of formula VI to a compound of formula VIII. The compound of formula VIII-A can be converted to the compound of the formula: ##STR24## wherein R.sub.4 ', R.sub.9 and R.sub.9 ' are as above; by hydrolysis in the manner described in connection with the conversion of the compound of formula VI to a compound of the formula I-D.
The compounds of formula VI, VI-A, VIII and VIII-A can be converted to a compound of the formula: ##STR25## wherein R.sub.2, R.sub.3, R.sub.9 and R.sub.9 ' are as above; and R.sub.7 is --CH.sub.2 OR.sub.8 or lower alkyl or hydrogen, by hydrogenation. Any conventional method of hydrogenation such as catalytic hydrogenation can be utilized to carry out this conversion. Among the preferred methods of hydrogenation is by reacting the compounds of formula VI, VI-A, VIII and VIII-A with hydrogen in the presence of a noble metal catalyst such as platinum or palladium under conditions conventional for such hydrogenation. After hydrogenation, the protecting group can be removed by hydrolysis.
The compounds of formulae I-D, I-E, VII, VII-A and IX can be converted to a compound of the formula: ##STR26## wherein R.sub.2, R.sub.3, R.sub.7, R.sub.9 and R.sub.9 ' are as above; R' is lower alkyl; and the dotted bond can be optionally hydrogenated; by esterification with diazomethane or a reactive derivative of a lower alkanol such as a lower alkyl halide. Any conventional conditions utilizing in this esterifiying method can be utilized in forming the compound of formula XI from the compounds of formulae I-D, I-E, VII, VII-A or IX. On the other hand, the compound of formula XI can be formed form the compounds of the formulae VI, VI-A, VIII or VIII-A where R.sub.6 and R.sub.6 ' are hydroxy protected with hydrolozable ether group by esterification as described above to form a compound of the formula: ##STR27## wherein R', R.sub.2, R.sub.3, R.sub.9 and R.sub.9 ' are as above; R.sub.4 " is hydrogen, lower alkyl, or --CH.sub.2 R.sub.6 "; and R.sub.6 " is hydroxy protected with a hydrolozable ether group and the dotted bond can be optimally hydrogenated.
The compound of formula II wherein R.sub.1 ' is lower alkyl, can be converted to the compound of formula I wherein R.sub.1 is: ##STR28## via the following intermediates: ##STR29## wherein R.sub.1 ', R.sub.6, R.sub.9 and R.sub.9 ' are as above; ##STR30## wherein R.sub.6, R.sub.9 and R.sub.9 ' are as above.
The compound of formula II wherein R.sub.4 is --COOR.sub.1 ', R.sub.1 ' is lower alkyl, R.sub.9 and R.sub.9 ' are hydrogen and their methods of preparation are disclosed in Ser. No. 300,633, filed Oct. 25, 1972, Rosen et al. (note compound XXI-C and Example 20 in Ser. No. 300,633, filed Oct. 25, 1972). The compound of formula II where R.sub.4 is --COOR.sub.1 and R.sub.1 ' is lower alkyl is converted to the compound of formula XII in the same manner as described above in connection with the conversion of a compound of formula IV to formula V.
The compound of formula XII is converted to the compound of formula XIII by reacting the compound of formula XII with the compound of formula X in the presence of dimetylsulfoxide and an alkali metal hydride base. The dimethylsulfoxide can be utilized as a solvent as well as a reactant in this reaction. On the other hand, any conventional inert organic solvent can be utilized in admixture with dimethylsulfoxide as the organic solvent medium. In carrying out this reaction, alkali methal hydride is utilized as the base. On the other hand, the alkali metal hydride can be combined with dimethylsulfoxide in the form of an alkali metal methyl sulfinylmethylide in this reaction. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. On the other hand, higher or lower temperatures can be utilized. Generally, it is preferred to carry out this reaction at a temperature of from -10.degree. C. to +50.degree. C.
The compound of formula XIII is converted to a compound of the formula: ##STR31## wherein R.sub.9 and R.sub.9 ' are as above;
by hydrolysis in the same manner as described in connection with the hydrolysis of a compound of the formula VI.
The compound of formula XIII can be converted to a compound of the formula: ##STR32## wherein R.sub.9 and R.sub.9 ' are as above; by hydrogenation in the same manner as described in the conversion of compounds of the formulae VI or VIII to a compound of the formula IX above.
The compound of formulae XIV and XV can be converted by esterification with a lower alkanol in the manner described in connection with the esterification of a compound of formulae I-D, VII and IX to form a compound of the formula: ##STR33## wherein R.sub.1 ', R.sub.9 and R.sub.9 ' are as above; and the dotted bond can be optionally hydrogenated.
The compound of formula XIII can be converted to a compound of the formula: ##STR34## wherein R.sub.6, R.sub.9 and R.sub.9 ' are as above; by oxidation in the manner described in connection with the oxidation of a compound of the formula VI to a compound of the formula VII. The compound of formula XV can be hydrolyzed in the manner of the compound of formula VIII and, if desired, hydrogenated, and/or esterified in the manner described above to produce a compound of the formula: ##STR35## wherein R.sub.9, R.sub.9 ' and R are as above; and the dotted line can be hyrogenated.
Where R.sub.1 in the compound of formula I is carboxy or lower alkoxycarbonyl, this compound can be prepared from a compound of formula XII via the following intermediate: ##STR36## wherein R.sub.5 is alkoxycarbonyl or carboxy; and R.sub.9, R.sub.9 ' and R.sub.6 are as above. The compound of formula XVII is prepared from the compound of formula XII by reacting the compound of formula XII with a compound of formula X in the same manner as described in connection with the reaction of a compound of the formula V with a compound of formula X.
Where R.sub.6 is an esterified hydroxy group in the compound of formula XVII, basic hydrolysis will produce a compound of the formula: ##STR37## wherein R.sub.9 and R.sub.9 ' are as above. Any conventional means of basic hydrolysis to cleave an ester group can be utilized in carrying out this conversion. On the other hand, R.sub.6 in the compound of formula XVII is an etherified hydroxy group, this compound is converted to the compound of the formula: ##STR38## wherein R.sub.9, R.sub.9 ' and R.sub.5 are as above; by acid hydrolysis. Any conventional method of acid hydrolysis generally used in hydrolyzing ether groups can be utilized in this conversion. The compound of formula XX can, if desired, be converted to a compound of formula XIX by basic hydrolysis in the manner described above.
If desired, the compound of formula XX can be esterified with a lower alkanol or a lower alkyl halide by conventional esterification techniques in the manner described above to produce a compound of the formula: ##STR39## wherein R.sub.9, R.sub.9 ', R.sub.5 and R' are as above.
The compound of formula XIX, XX and XXI can be converted to a compound of the formula: ##STR40## wherein R.sub.5, R.sub.9, R.sub.9 ' and R are as above; by hydrogenation in the manner described above in connection with the conversion of a compound of formulae VI and VIII to a compound of the formula IX.
The compound of formula XVII can be oxidized in the manner described in connection with the oxidation of a compound of formula VI to form a compound of the formula: ##STR41## wherein R.sub.5, R.sub.9, R.sub.9 ' and R.sub.6 are as above.
The compound of formula XXIV can be hydrolyzed in the manner of the compound of formula XVII and, if desired, esterified and/or hydrogenated in the manner described hereinbefore to form a compound of the formula: ##STR42## wherein R.sub.5, R.sub.9, R.sub.9 ' are as above; and the dotted bond can be optionally hydrogenated.
Where R.sub.6 is an ether group, the preferred ether groups are 2-tetrahydropyranyloxy and dimethyl-tert-butylsilyloxy. These ether starting materials of formula II are prepared from compounds of the formula: ##STR43## wherein R.sub.9 and R.sub.9 ' are as above. The compounds of formula II-B where R.sub.9 and R.sub.9 ' are hydrogen and their method of preparation are disclosed in U.S. patent application Ser. No. 300,633, filed Oct. 25, 1972, Rosen et al. (Please note compound XXI-C and Example 14 of U.S. patent application Ser. No. 300,633). The compounds of formula II-B are etherified in the conventional manner by reacting with an alcohol or a reactive derivative thereof under conditions conventional in the art.
The compound of formula II can be obtained by first reacting a compound of the formula: ##STR44## wherein R.sub.4 is as above; with either a phosphorane of the formula: ##STR45## wherein R.sub.10, R.sub.10 ', R.sub.10 ", R.sub.9, R.sub.9 ' and Y are as above; or a phosphonate of the formula: ##STR46## wherein R.sub.9 and R.sub.9 ' are as above; and R.sub.15 and R.sub.15 ' are aryl, aryloxy or lower alkoxy; to form a compound of the formula: ##STR47## wherein R.sub.4, R.sub.9 and R.sub.9 ' are as above; followed by reducing the compound of formula XXXV to form a compound of the formula: ##STR48## wherein R.sub.4, R.sub.9 and R.sub.9 ' are as above; and finally etherifying or esterifying the free hydroxy group.
The reaction of the compound of formula XXVIII with the phosphonium salt of formula XXIX to produce a compound of formula XXXV is carried out via a Wittig reaction. Any of the conditions conventional in Wittig reactions can be utilized in carrying out this reaction.
The reaction of the compound of formula XXVIII with the phosphonate of formula XXX to produce a compound of formula XXXVI is carried out via a Horner reaction. Any of the conditions conventional in Horner type reactions can be utilized in carrying out this reaction.
The compound of formula XXVIII where R.sub.4 is --COOR.sub.1 ' and its method of preparation is disclosed in U.S. Patent Application Ser. No. 300,633, filed Oct. 25, 1972, Rosen et al. (Please note the compound of formula III and Example 12 of Ser. No. 300,633). The compound fo formula XXVIII where R.sub.4 is lower alkyl or hydrogen and its method of preparation is disclosed in U.S. Patent Application Ser. No. 381,322, filed July 20, 1973. (Please note, the compound of formula XVI and Examples 43 and 44 of Ser. No. 381,322). The disclosure of both U.S. Patent Application Ser. No. 300,633 and Ser. No. 381,322 are incorporated by reference.
The compound of formula XXX, where R.sub.9 is fluoro, and R.sub.9 ' is hydrogen or lower alkyl, is prepared by reacting a lithium salt of the formula: ##STR49## wherein R.sub.15 is as above; with a compound of the formula: ##STR50## wherein R.sub.25 is lower alkyl, and R.sub.9 ' is as above. Any of the conditions conventional for reacting a lithium salt with an ester to form an addition product can be used in this reaction.
The compound of formula XXX where R.sub.9 is alkyl and R.sub.9 ' is hydrogen or alkyl can be prepared by reacting the compound of formula XXXI with a compound of the formula: ##STR51## wherein R.sub.25 is as above and X is a halogen. Any of the conditions conventional in forming addition products by reacting a lithium salt with an acid chloride can be used in carrying out this reaction.
The compound of formula XXIX where R.sub.9 and R.sub.9 ' are not both hydrogen are prepared by reacting a compound of the formula: ##STR52## wherein R.sub.19 is hydrogen, lower alkyl or fluoro; and R.sub.19 ' is lower alkyl or hydrogen with the proviso that at least one of R.sub.19 and R.sub.19 ' is other than hydrogen; and X is as above; with a compound of the formula: ##STR53## wherein R.sub.10, R.sub.10 ' and R.sub.10 " are as above utilizing conventional Wittig conditions.
The compound of formula XXXVI can be obtained by treating the compound of formula XXXV with a reducing agent. In carrying out this reaction, any conventional reducing agent which will selectively reduce a keto-group to a hydroxy group can be utilized. Preferred reducing agents are the hydrides, particularly the aluminum hydrides, such as the alkali metal aluminum hydrides, and the borohydrides, such as the alkali metal borohydrides, with zinc borohydride being quite particularly preferred. In carrying out this reaction, temperature and pressure are not critical, and the reaction can be carried out at room temperature and atmospheric pressure or at elevated or reduced temperatures and pressures. Generally, it is preferred to carry out this reaction at a temperature of from -10.degree. C. to the reflux temperature of the reaction mixture. This reduction reaction can be carried out in the presence of an inert organic solvent. Any conventional inert organic solvent or water can be utilized in carrying out this reaction, such as the conventional, inert organic solvents hereinbefore mentioned. Among the preferred solvents are dimethoxy ethylene glycol and the ethers, such as tetrahydrofuran, diethyl ether and dioxane.
The compound of formula XXXVI may be separated into its two isomers by conventional means to produce one isomer of the formula: ##STR54## and the other isomer of the formula: ##STR55## wherein R.sub.4 is as above. Any conventional means of separation such as column chromatography, vapor phase chromatography, etc., can be utilized to carry out this separation. Either of these isomers can be utilized in accordance with this reaction to produce the compound of formula I. The configuration of the hydroxy group on the octenyl side chain will be carried through the process of this invention so that the hydroxy group on the octenyl side chain in the compound of formula I will have the same configuration as it has in the starting material of formula XXXVI-A or XXXVI-B.
The compound of formulae XXXVI, XXXVI-A and XXXVI-B can be converted to a compound of the formula II by esterifying or etherifying the free hydroxy group with a hydrolyzable ether or ester protecting group. This esterification or etherification can be carried out by conventional esterification or etherification procedures. Among the preferred hydrolyzable ester groups are lower alkanoyloxy with acetoxy being especially preferred. Among the preferred hydrolyzable ether groups are included tetrahydropyranyl.
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
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4001281 |
Kienzle et al. |
Jan 1977 |
|
Divisions (3)
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Number |
Date |
Country |
| Parent |
780878 |
Mar 1977 |
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| Parent |
614044 |
Sep 1975 |
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| Parent |
480458 |
Jul 1974 |
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Continuation in Parts (1)
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Number |
Date |
Country |
| Parent |
386117 |
Aug 1973 |
|
Patent Grant
4246402
