Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
  • C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
  • C07C403/14—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by doubly-bound oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
  • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
  • C07C45/60—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in six-membered rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/09—Geometrical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

• the present invention relates to the stereospecific synthesis of polyene compounds, such as eicosanoids and retinoids.
• polyene compounds such as eicosanoids and retinoids.
• a cis olefin is generated via a lactol ring opening with complete retention of double bond configuration.
• an extended conjugated olefinic chain is present and important for biological effects.
• Many of the compounds within the arachidonic acid cascade are important modulators of inflammation.
• leukotriene 34 has been detected in fluid from involved tissue in rheumatoid arthritis, gout, psoriasis and ulcerative colitis. (Bhattacherjee et al . , Ann . N. Y. Acad. Sci . , 524:307 (1984)).
• the absolute stereochemistry of the olefinic series is often an important feature of these compounds.
• retinoid members of the steroid/thyroid superfamily of receptors are responsive to compounds referred to as retinoids, which include retinoic acid, retinol (vitamin A) , and a series of natural and synthetic derivatives which have been found to exert profound effects on development and differentiation in a wide variety of systems.
• retinoids include retinoic acid, retinol (vitamin A)
• vitamin A vitamin A
• Novel members of the steroid/thyroid superfamily of receptors have been identified which are not responsive to retinoic acid, • called retinoid X receptors.
• 9-o ' s-retinoic acid has been demonstrated to have affinity for retinoid X receptors (Heyman et al., Cell, 68:397 (1992)), and other retinoids having 9-10 cis olefin geometry have been found to selectively activate retinoid X receptors.
• R 1 represents a lower or branched alkyl having 1-12 carbons, or phenyl, and can be methyl only if R 2 is hydrogen or a lower alkyl having 1- 8 carbons;
• R 2 represents hydrogen, a lower alkyl having 1-8 carbons, or halogen, or R 1 and R 2 taken together form a phenyl, cyclohexyl, or cyclopentyl ring;
• R 4 represents hydrogen, a lower alkyl having 1-8 carbons, or a halogen
• R 5 represents hydrogen, a lower alkyl having 1-8 carbons, or halogen.
• R 1 represents a lower or branched alkyl having 1-12 carbons, or phenyl, and can be methyl only if R 2 is hydrogen or a lower alkyl having 1- 8 carbons;
• R 2 represents hydrogen, a lower alkyl having 1-8 carbons, or halogen, or R 1 and R 2 taken together form a phenyl, cyclohexyl, or cyclopentyl ring or one of the following:
• R 4 represents hydrogen, a lower alkyl having 1-8 carbons, or a halogen
• Z, Z', Z", and Z' each independently, represent C, S, 0, N, or a pharmaceutically acceptable salt, but not 0 or S if attached by a double bond to another such Z or if attached to another such Z which is 0 or S, and not N if attached by a single bond to another such Z which is N; and the dashed lines in the structures depict optional double bonds.
• pharmaceutically acceptable salts include but are not limited to: hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulfuric, citric, maleic, acetic, lactic, nicotinic, succinic, oxalic, phosphoric, malonic, salicylic, phenylacetic, stearic, pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic, methylamino, methanesulfonic, picric, tartaric, tri- ethylamino, dimethylamino, and tris (hydroxymethyl)amino- methane. Additional pharmaceutically acceptable salts are known to those of skill in the art.
• the preferred process sequence begins with the use of a commercially available aldehyde ⁇ -cyclocitral I and the well established Reformatsky reaction. (Dugger eta/., ]. Org. Chem., 45:1181 (1980) ; Gedye et al., Can. ). Chem., 53:1943 (1975) ; Cainelli eta/., J.C.S. Perkin I 1597 (1979)). This step constructs the 9-10 olefin bond in the desired cis-orientation, as shown (II) .
• the second step consists of reduction of the lactone to a protected aldehyde (lactol) which is necessary for chain length extension.
• lactol protected aldehyde
• the reduction is achieved with 1 equivalent of diisobutylaluminum hydride and is sensitive toward work-up.
• Other reducing agents such as lithium aluminum hydride and sodium bis(2-methoxyethoxy)aluminum hydride can give the same product III but in diminished yield.
• the third step of this sequence involves a unique and novel lactol ring opening under the presence of acid to afford the aldehyde IV. This step constitutes a major advantage over existing syntheses of the aldehyde IV previously reported in the literature.
• the ring opening is very sensitive to the pKa of the acid, the concentration of the acid, the concentration of the reactant in the solvent, and the temperature of the reaction.
• the reaction can be run in chlorinated solvents (CHCL 3 , CH 2 CL 2 , C1CH 2 CH 2 C1) , apolar solvents (benzene, toluene) , or coordinating solvents (diethylether, tetrahydrofuran) .
• the choice of acids includes: para- toluene sulfonic acid, pyridinium hydrochloride, trichloro- or trifluoro-acetic acid, acetic acid, sulfuric acid, nitric acid, tartaric acid, oxalyic acid, and in particular hydrochloric acid.
• This third step can also be used to achieve the desired stereochemical orientation of olefin bonds for other polyene natural products, such as leukotriene B 4 , dehydroneral, etc., and synthetic analogs. Illustrative examples of such compounds are shown below:
• the fourth step of this sequence includes the selective formation of the C-ll and C-13 olefin bonds simultaneously.
• This reaction has been reported in the literature (Kryshtal et al., Izvestiya Akad. Nauk USSR, Seriya Khim., 11:2544 (1990)), but never with better than 5:1 ratio of 13-trans to 13-cis olefin formation.
• a lithium coupled base in tetrahydrofuran in the presence of a coordinating solvent, such as dimethyl piperidine urea allows the formation of the 11,13-trans- olefin bonds in a greater than 15:1 ratio.
• solvents including diethyl ether, 1,4-dioxane, t-butyl- methyl ether, dimethyl formamide, dimethyl sulfoxide, methanol, ethanol, benzene, toluene, dichloromethane, chloroform, pyridine, and acetonitrile are less effective for overall yield of the desired 11,13-ditrans olefin product.
• Other bases e.g., sodium hydride, sodium methoxide, sodium amide, potassium t-butoxide, potassium hydride, potassium di-isopropylamide, lithium diisopropylamide, lithium b/s-trimethylsilylamide
• bases are less effective than n-butyl lithium.
• the reaction can be completed at -78°C or up to room temperature.
• the hydrolysis of the ester V to the acid VI is a standard saponification reaction. We have found that the reaction proceeds better in ethanol than ethanol due to the better solubility in the former solvent.
• One example of a VI compound is 9-c/s-retinoic acid. 11 - cis and 13 - cis retinoids and other related compounds, as illustrated below, can also be prepared using this process scheme.
• the oil was slurred up in hexane (500 ml) and cooled to -20°C in the refrigerator.
• the first crop of solid material was 77 g.
• the filter cake was rinsed again with THF (2 x 500 ml) and concentrated to an oil with solid. Addition of hexane (300 ml) gave another 54 g of product for a total of 131 g (79%) .
• reaction solution was cooled and allowed to stir at -78°C for 0.25 hour before the aldehyde (75.4 g, 345 mmol) was added in 50 ml of tetrahydrofuran.
• the reaction was stirred at -78°C for another 0.5 hours, then quenched by the addition of 200 ml of saturated ammonium chloride solution.
• the aqueous solution was extracted with diethylether (3 x 500 ml) , and the combined organic extracts washed with brine and dried over magnesium sulfate.
• the crude reaction products (primarily 9 -cis-13 -trans retinoate and 9, 13-di-c/s-retinoate) were collected by concentration in vacuo to give a red-orange oil.
• the crude ester was taken up in 100 ml of 20% Et 2 0/Hexane and filtered through 500 g of silica gel (230-400 mesh) which was rinsed with another 700 ml of eluent .
• the ester was concentrated to an orange oil (100.4 g, 93%) which looked very clean by NMR.
• the 13 E/Z ratio was > 15:1.

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• 1994
  • 1994-04-21 CA CA002160240A patent/CA2160240A1/en not_active Abandoned
  • 1994-04-21 AU AU67721/94A patent/AU671752B2/en not_active Ceased
  • 1994-04-21 WO PCT/US1994/004440 patent/WO1994024082A1/en not_active Application Discontinuation
  • 1994-04-21 EP EP94915855A patent/EP0695285A4/de not_active Ceased
  • 1994-04-21 EP EP97122793A patent/EP0839788A1/de not_active Withdrawn
  • 1994-04-21 JP JP6523586A patent/JPH08509229A/ja active Pending

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