MXPA96004879A - Methods for the synthesis of retinoids 9-cis and its intermediaries novedo - Google Patents

Abstract

Methods are provided for the synthesis of deretinoids, 9-cis, novel intermediates and method for the synthesis of cyclohexadienine nitrites and 9-cis alkyl cisisoid nitriles, as well as 9-cis retinoids made using such methods.

Description

METHODS FOR THE SYNTHESIS OF RETINOIDS 9-CIS AND ITS NEW INTERMEDIARIES FIELD OF THE INVENTION The present invention relates to the synthesis of 9-cis retinoid compounds, and in particular to the synthesis of 9-cis retinoic acid and related compounds, as well as their novel intermediates.

BACKGROUND OF THE INVENTION The role of retinoids such as all-trans retinoic acid, 13-ci s retinoic acid and synthetic analogs of retinoic acid in the mediation of cell growth and differentiation has generated interest in their pharmacological utility to control the treatment of dermatological diseases. , such as psoriasis and acne, as well as oncological applications such as chemotherapy and chemoprevention. Significant advances in elucidating the molecular basis of retinoid action now offer the potential for ref: 23248 to design retinoid compounds with improved therapeutic indices. To date, several retinoic acid receptors have been identified. These receptors are members of a superfamily of intracellular receptors, which function as transcription factors dependent on the ligand. So far, these receptors have been classified into two subfamilies, the retinoic acid receptors (RAR) and retinoid X receptors (RXR). The classification of these subfamilies was based mainly on the differences in the structure of amino acids, sensitivity to different natural and synthetic retinoids, and the ability to modulate the expression of different genes in white. Each subfamily RAR and RXR has three different isomorphs designated RARa, RARß and RAR ?, and RXRa, RXRß and RXR ?. The discovery of multiple retinoid receptors raises questions about the functional properties of the different subfamilies and their isomorphs. Recently, it has been discovered that 9-ci s RA, and other retinoids that have an olefin stereochemistry 9-10 ci s are able to bind to and modulate gene expression via the RARs and RXRs. Heyman et al., Cell, 68: 397 (1992). However, to date, the technique has only provided low cost, non-selective, high-cost methods for producing such compounds. For example, the literature has provided non-selective means for generating 9-10 cis olefinic retinoids, see for example, Robson et al., J. Am. Chem. Soc, 77: 4111 (1955), Marsui et al., J. Viat inol., 4_: 178 (1958), German Patent No. DE1068719, and Aurell et al., Tetrahedron Lett., 31: 5791 (1990), as well as methods for the stereoselective preparation of olefinic union 13-14, see for example, Pattenden et al., J. Chem. Soc. (C), 1984 (1968) and Mayer et al., Experientia, 3_4: 1105 (1978). In addition, Ernst et al., J. Org. Chem., 52: 398 (1987) provides methods for the preparation of alkyl and trimethylsilyl-substituted retinoids via the addition of conjugates of cuprates to acetylenic esters, which use excessive numbers of steps, and importantly the oxidation of an allyl alcohol to an aldehyde, thus destroying the integrity of any 9-10 olefinic union present in the resulting retinoids. Accordingly, it may be desirable to prepare retinoid compounds having olefinic bond 9-10 in the cis configuration in a selective, low cost manner.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides methods for the synthesis of 9-cis retinoids, preferably, 9-cis-retinoic acid in a selective, low cost manner. In particular, the present invention provides a method for producing a 9-ci s retinoid comprising (a) reducing a cyclohexyl ketone in the presence of a base to form a cyclohexadienine, (b) condensing the cyclohexadienine with a source of electrophilic nitrile to form a cyclohexadienine nitrile, (c) adding an alkyl group, in a 1.4 conjugate form, to the cyclohexadienine nitrile to form a cyclohexatriene nitrile, (d) reducing the cyclohexatriene nitrile to the cyclohexatriene aldehyde, and (e) extending the cyclohexatriene aldehyde with an equivalent carbanion, formed by the addition of a base to a phosphonate or phosphine salt to form a reaction product comprising a mixture of retinoid ester stereoisomers, wherein the olefinic bond between the coals 9-10 is in the cis configuration, and the olefinic linkages between the cores 11-12, and 13-14 may be either in the trans configuration or cis Subsequently, the retinoid esters can be hydrolyzed to produce a < • of stereoisomers of retinoic acid, which in turn can be separated to provide the stereoisomers of the individual retinoic acid, preferably 9-cis-retinoic acid. Also provided is a method for producing a 9-ci s retinoid comprising (a) reducing a cyclohexenyl ketone in the presence of a base and a source of electrophilic nitrile to form a cyclohexadienine nitrile, (b) adding an alkyl group, in a 1,4-conjugated form, to the cyclohexadienine nitrile to form a cyclohexatriene nitrile, (c) reducing the cyclohexatriene nitrile to the corresponding cyclohexatriene aldehyde, and (d) extending the cyclohexatriene aldehyde with an equivalent carbanion formed by the addition of a base to a phosphonate or phosphine salt to form a reaction product comprising a mixture of stereoisomers of retinoid ester wherein the olefinic bond between the coals 9-10 is in the ci s configuration, and the olefinic bonds between the coals 11- 12, and 13-14 can be either in the trans or cis configuration. In addition, the present invention provides a method for producing a cyclohexadienine nitrile olefin which comprises reducing a cyclohexenyl ketone in the presence of a base and an electrophilic nitrile source to form a cyclohexadienine nitrile.

In addition, the present invention provides a method for producing a 9-cis alkyliso nitrile comprising (a) condensing a cyclohexadienine with an electrophilic nitrile source to form a cyclohexadienine nitrile, and (b) adding an alkyl group, in a form 1,4-conjugate, to the cyclohexadienine to form a 9-cis-alkyl-cis-nitrile, wherein the olefinic bond 9-10 is in the ci-s configuration. Moreover, the present invention provides a 9-ci s retinoid that according to the method descd above. Preferably such a 9-cis retinoid comprises 9-cis retinoic acid, 9,11-dicy retinoic acid, 9,13 dicyne retinoic acid and 9,11,13 tricis retinoic acid. These and several other advantages characteristic of novelty that characterize the invention will be pointed out with particularity in the appended claims to the present and forming part thereof. However, for a better understanding of the invention, its advantages, and objects obtained through its use, reference has been made to the accompanying drawings and descriptive matter, in which the preferred embodiments of the invention are illustrated and descd.

DETAILED DESCRIPTION OF THE MODALITIES OF THE INVENTION According to a first aspect of the present invention, we have developed a method for synthesizing retinoids. The sequence of steps of this method is shown below.

(A reaction vessel) -78 ° C to 25 »C THF, -78 » 1. KOH EtOH 70ßC In the sequence of the above process, R1 and Rc in each independently represent hydrogen or a straight or branched chain lower alkyl having 1-5 carbon atoms; R3 represents hydrogen or a branched or linear alkyl, alkene or lower alkyne having 1-6 carbon atoms; R4 Rb can each independently represent hydrogen or an alkyl, alkene, aryl or branched or straight chain lower aralkyl having 1-12 carbon atoms; R6 represents an alkyl, alkene or straight or branched chain lower alkyl having 1-5 carbon atoms; R7 represents hydrogen or a pharmaceutically acceptable salt; and the lines drawn between the structures of carbons 11-12, and 13-14, describe olefinic bonds that may be either in the trans or cis configuration. As used in this description, pharmaceutically acceptable salts include, but are not limited to those of pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc, lithium, methylamino, triethylamino, diethylamino, and tris (hydroxymethyl) aminomethane. Additional pharmaceutically acceptable salts are known to those skilled in the art.

The process sequence of the method begins with the reduction of a cyclohexenyl ketone 1, such as ß-ionone (available from Aldrich Chemical, Milwaukee, WI), in the presence of a base, such as lithium diisopropylamide (LDA). , and a chlorodiphosphate, such as diethyl chlorophosphate, to form a cyclohexadienine 2, such as 4- (1 - [2, 6, 6-trimethylcyclohexen-1-yl]) - (but-3-en-1-yl) ). In addition to the LDA as a base, which is preferred, other non-limiting examples of bases useful in this step of the method of the present invention include sodium hydride (NaH), potassium hydride (KH), n-butyl lithium ( n-BuLi), s-butyl lithium (s-BuLi), t-butyl lithium (, t-BuLi), sodium amide (NaNH2), and hexamethyl disilazide of lithium, potassium or sodium. The second step consists of the condensation of cyclohexadienine 2 to a cyclohexadienine 3 nitrile, such as 5- (1- [2,6,6-trimethyl-1-cyclohexen-1-yl]) -pent-2-in. 4-enenitrile, using a source of electrophilic nitrile, such as phenylene cyanate or cyanogen bromide in the presence of a base. The third method of this sequence involves the addition of an alkyl group, in a 1.4 conjugated form, to the cyclohexadienin 3 nitrile to form an essentially pure cyclohexatriene nitrile 4, such as (2Z, 4E) -3-methyl- 5- (1- [2,6,6-Trimethyl-l-cyclohexen-1-yl]) -2,4-pentadienitrile with the double bond 9-10 in the ci s configuration. In this respect the addition of the alkyl group according to this aspect of the method can be carried out using a number of techniques and methods known to those skilled in the art, but preferably the addition reaction is carried out in non-polar solvents, more preferably in hexane or heptane. In the fourth step, the cyclohexatriene nitrile 4 is reduced to the corresponding cyclohexatriene aldehyde ((2Z, 4E) -3-methyl-5- (l- [2,6,6-trimethyl-l-cyclohexen-1-yl]) -2,4-pentadienenal) via a reduction of DIBAL (hydride diisobutyl aluminum) standard in hexane. The fifth step of the sequence involves the extension of the cyclohexatriene aldehyde 5 with an equivalent carbanion formed by the addition of a base (e.g., n-BuLi) to a phosphonate, such as diethyl-3-ethoxycarbonyl-2-phosphonate. metiprop-2-enyl or a phosphine salt (for example triphenyl phosphine) to produce a mixture of stereoisomers of retinoates (retinoid esters) 6, including, mainly, ethyl-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2-trans-4-trans-β-cis-8 -trans-nonatetraenoato. In this respect, the stereoisomers of retinoate 6 present a prevalence of more than 15: 1 of the olefinic bond 13-14 in the trans versus ci s configuration. Non-limiting examples of bases useful in that aspect of the method of the present invention include sodium hydride (NaH), potassium hydride (KH), n-butyl lithium (n-BuLi), s-butyl lithium (s-BuLi) , t-butyl lithium (t-BuLi), sodium amide (NaNHj), in the presence of DMPU. The sixth and final step of the process involves the hydrolysis of retinoates 6 with aqueous methanolic hydroxide (MeOH / KOH) to give the isomers of retinoic acid 7. Examples of retinoid isomers 7 include, without limitation, the major component, acid 3, 7- dime ti 1-9- (2,6,6-trimethyl-l-cyclohexenyl) -2-trans-4-trans-β-cis-8-trans-nona-tetraenoic acid (9,11 cis retinoic acid), and detectable amounts of 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2-trans-4-cis-6-c s-8-trans-nona-tetraenoic acid (acid 9). , 13 dicy retinoic acid), and 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2-trans-4-cis-6-cis-8-trans-nona-tetraenoic acid ( 9,11 dici retinoic acid). After hydrolysis, the isomer of the retinoic acid 7 deviated from the aqueous methanolic hydroxide solution can be selectively crystallized, or alternatively purified by high performance liquid chromatography (CLAP) in semipreparative inverted phase (ODS).

It should be understood by those skilled in the art that certain modifications may be made to the methods described above that remain within the scope of the present invention. For example, steps one and two (i.e. condensation of cyclohexadienine 2) can be combined in a single step, a vessel, by repressing reduced cyclohexenyl ketone 1 with a lithium anion and an electrophilic nitrile source, such as phenyl cyanate in the presence of a base, instead of water in the presence of a base, to directly produce the cyclohexadienin nitrile 3. t Furthermore, it should be understood by those skilled in the art that the synthesis of the present invention can have a wide application beyond the synthesis of the retinoids shown above. For example, the respective condensation and addition of steps two and three can be used to form a variety of alkyl cysoid nitriles and their derivatives (eg, amines, acids, aldehydes, esters) with olefinic bond 9-10 selectively produced in the cis configuration. The synthesis methods described above provide a number of advantages over those currently available, including, importantly, the cost. In this regard, the methods of the present invention use commercially inexpensive and readily available starting materials such as β-ionone versus the more typical starting materials used in existing methodologies, such as β-cyc} C.ocitral, which is at least twenty to forty times more expensive on average than the starting materials used in the methods of the present invention. In addition, the third step in the synthesis method (ie the addition of the alkyl group, in a 1,4-conjugated form, to the cyclohexadienin 3 nitrile to form the cyclohexatriene nitrile 4) allows selective introduction of the double bond 9-10 in the cis configuration, as well, as the ability to place a wide variety of substituents, such as an alkyl, alkene, aryl, aralkyl etc ..., in carbon number 9. In addition, the reagents used through the method are substances Standard organic or inorganic chemistries, readily available and inexpensive with no risk of reported hazard. The invention will be better illustrated by reference to the following non-limiting example.

EXAMPLE 1 The synthesis of the retinoids of the present invention is exemplified by the following synthesis scheme for 9-cis retinoic acid. 4- (1-f2, 6, 6-Trimethylcyclohexan-1-ylp - (but-3-en-l-ino) 2:.

The intermediate 4- (l- [2,6,6-Trimethylcyclohexen-l-yl]) - (but-3-en-l-ino) 2 was prepared from the β-ionone 1 (available from Aldrich Chemicals Inc.) according to the procedures described in E.I. Negishi et al. , J. Org.

Chem., 45: 2526 (1980), the description of which is incorporated herein by reference. - (2, 6, 6-Tri atyl-lc clohex? En-l-il) -pent-2-in-4-enenitrile 3: A 100 mL flask dried to the flame was charged with intermediate 4- ( l- [2,6,6, trimethylcyclohexen-1-yl]) - (but-3-en-l-ino) 2 (1045 g, 6.0 mmol) in tetrahydrofuran (THF) (30 mL) and cooled to - 78 ° C. The solution of n-BuLi in hexane (2.25 M, 2.75 mL, 6.51 mmol) was added slowly and the slightly dark mixture was stirred for 10 min. Phenyl cyanate (prepared from phenyl and cyanogen bromide according to a procedure of R.E.

Murray et al., Synthesi s, 150 (1980), the disclosure of which is incorporated herein by reference) (750 μL, 6.6 mmol) and the mixture was allowed to warm to room temperature (eg, about 20-25 ° C. ). Sodium hydroxide (2 mL of 6 N solution) was added and the mixture was extracted with ethyl acetate (50 mL). The organic layer was further washed with NaOH (2 x 10 mL), water (3 x 10 mL) and brine (2 x 10 mL), dried over MgSO4 and the solvents were evaporated. The residue obtained was virtually pure (by TLC) thin layer chromatography and filtered through a small pad of silica gel using hexane as eluent to remove some basal materials. The solvent was evaporated to give 1.088 g (91% yield) of a slightly yellow oil. Rf 0.75 (hexanes), IR (pure) 2933.2320.2251 (CN), 1590 cpf1; JH NMR (CDC13) d 7.11 (d, J = 16.4 Hz, 1 H), 5.54 (d, J = 16.4 Hz, 1 H), 2.07 (t, J = 4.0 Hz, 2 H), 1.76 (s, 3 H), 1.60 (m, 2 H), 1.46 (5, 6 H). < 2Z, 4E) -3-Methyl-5- (2,6,6-trimethyl-l-cyclohexen-1-yl) -2,4-pentadienitrile, 4: A flame-dried, 50 mL round bottom flask was charged with anhydrous copper iodide (1.09 g, 5.70 mmol) and THF (20 mL) and cooled to 0 ° C. A solution of methyl lithium (4.28 mL of a The solution was 1.4 M in Et20 for a period of 10 minutes until the solution became clear and colorless.The cuprate solution was cooled to -78 ° C using an acetone bath on dry ice, and a solution was added dropwise. from - (2,6,6-Trimethyl-cyclohexen-1-yl) -pent-2-ene-4-enenitrile 3 (544 mg, 2.73 mmol), in THF (10 mL). See for example H. estmijze et al., Tetrahedron letters, 3327 (1979), and Synthesis, 454 (1978), the descriptions of which are incorporated herein by reference. The mixture was stirred at this temperature for 45 minutes, and a solution of saturated ammonium chloride (10 mL) was added. The reaction mixture was then allowed to warm to room temperature.

EtOAc (50 mL) was added and the mixture was washed with 2% fJaOH (2 x 10 mL), followed by washes with saturated NH4C1 (2 x 10 mL), water (2 x 10 mL) and brine (2 x 10). mL). The organic layers were dried over MgSO4 and the solvents were evaporated. The residue obtained was virtually pure (by TLC) and filtered through a small pad of silica gel using hexane: EtOAc (9: 1) as eluent to remove some basal materials. The solvent was evaporated to give 538 mg (92% yield) of a slightly orange yellow oil. Rf 0.75 (hexane: EtOAc (9: 1)), IR (pure) 2933, 2250 (CN), 1590 cm "1,: H NMR (CDC13) 6 6.70 (d, J = 16 Hz, 1 H), 6.59 (d, J = 16.4 Hz, 1 H), 5.09 (s (l H), 2.06 (s 3 H), 2.07 (t, J = 4.0 Hz, 2 H), 1.75 (s, 3 H), 1.62 (m, 2 H), 1.47 (m, 2 H) , 1.04 (s, 6 H). (2Z, 4E) -3-Methyl-5- (2,6,6-trimethyl-l-cyclohexen-1-yl) -2,4-pentadienßnal 5: A flame-dried 25 mL round bottom flask was charged with (2Z, 4E) -2,4-pentadienitril-3-methyl-5- (2,6,6-trimethyl-1-cyclohexen-1-yl) 4 (94.2 mg, 0.438 mmol) and hexane (5.0 mL) and cooled to -78 ° C. Diisobutyl aluminum hydride (480 μL of a 1.0 M solution in hexane, 0.480 mmol) was added dropwise at a rate such that the reaction temperature did not exceed -70 ° C. The mixture was stirred for 5 minutes, and an analysis in thin layer chromatography (TLC) (hexane: EtOAc (9: 1)) indicated that the reaction had been complete (Rf 0.75 for the starting material; Rf 0.7 for the product ). A saturated solution of Rochelle's salt "(1.0 mL) was added and the mixture was warmed to room temperature, EtOAc was added. (10 mL) and the mixture was washed using water (2 x 10 mL) and brine (2 x 10 mL). The organic layers were dried over MgSC and the solvents were evaporated. The residue obtained was virtually pure (by TLC), 90.5 mg, 95% yield; IR (pure) 2958, 2928, 2866, 1668 (C = 0), 1614 (C = C) c "1;? NMR (CDC13; 400 MHz) d (ppm): 10.16 (d, J = 8.0 Hz, CHO ), 7.16 (d, J = 16.0 Hz, vinyl-CH, trans), 6.63 (d, J = 16.0 Hz, vinyl-CH, trans), 5.88 (d, J = 8.0 Hz, ÍH, CH-CHO), 2.69 (s 2 H, ring), 2.14, (s, 3 H, -C- (CH 3) = CH-CHO, cis), 1.80 (s, 3 H, CH 3, ring), 1.11 (s, 6 H, gem-2x CH3).

Ethyl-3,7-dimethyl-9- (2,6,6-trimethyl-l-cyclo-xen-1-yl) -2- trans-4-trans-6-cis-8-trans-nonatetraenoate 6 A solution of diethyl-3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (354 mg, 1.34 mmol) in anhydrous THF (5.0 mL) was cooled to 0 ° C and added with DMPU. (0.5 mL) anhydrous and n-BuLi in hexane (0.56 mL of a 2.35 M solution, 1.33 mmol). The mixture was stirred at this temperature for 20 minutes, then cooled to -78 ° C. A solution of (2Z, 4E) -3-methyl-5- (2,6,6-trimethyl-l-cyclohexen-1-yl) -2,4 pentadienenal 5 (241 mg, 1115 mmol) in THF was slowly added. (3.0 mL). And the reaction mixture was stirred at -78 ° C for an additional 60 minutes. The mixture was allowed to warm to 0 ° C so that the reaction moved to its conclusion, according to that verified by CCF. A saturated solution of ammonium chloride (5 mL) was added and the mixture was extracted using EtOAc (3 x 10 mL). The organic layer was washed with water (2 x 5 mL) and brine (10 mL), dried over MgSO4 and concentrated. The residue was purified on a small chromatography column on silica gel (sgc) to give 296 mg (78% yield) of the desired ester in a ratio of ~15: 1 of the 13-trans: 13-cis isomers. IR (pure) 2928, 1709 cm "1, XH NMR (CDC13; 400 MHz) d (ppm): 70.8 (dd, J = 15, 11.3 Hz, 1 H), 6. 65 (d, J = 16 Hz, 1 H), 6.29 (d, J = 15 Hz, 1 H), 6.23 (d, J = 15 Hz, 1 H), 6.06 (d, J = 11.3 Hz, 1 H), 4.17 (m, J = 7 Hz, 2 H), 2.7 (s, 2 H), 2.33 (s, 3 H), 2.03 (s, 3 H), 1.82 (s, 3 H) 1.29 (t, J = 7, 3 H), 1.1 (s, 6 H). 3,7-Dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2- trans-4-trang-6-cis-8-trang-nonatraeneonic acid 7 A solution of ethyl-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -2-trans-4-trans-6-cis-8-trar.s-nonatetraenoate 6 (275 mg, 8.25 mmol) in ethanol (10 mL) was treated with IN KOH (10 mL) at 70 ° C for 3 hours, cooled to room temperature, acidified with 10% HCl (v: v), and extracted with EtOAC (2 x 20 mL). The organic layer was washed with water (2 x 5 mL) and brine (2 x 5 mL), dried over MgSO4 and the solvent was evaporated. The residue was recrystallized (2 times) by dissolving in a minimum volume of a 9: 1 mixture of ethanol: water (~ 20 ml per gram of material). 9-cis retinoic acid was thus obtained in a highly pure form (by 1 H NMR) as a light yellow solid, yield 85%; pf. 188-190 ° C; IR (KBr, cm "1) 2914, 1670, 1583;: H NMR (CDC13; 400 MHz): d (ppm) 7.20 (d, J = 15.0 Hz, 1 H), 6.65 (d, J = 16.0 Hz, 1 H), 6.28 (d, J = 16.0 Hz, 1 H), 6.25 (d, J = 15.0 Hz, 1 H), 6.06 (d, J = 11.0 Hz, 1 H), 5.80 (s, 1 H) , 2.35 (s, 3 H), 2.05 (t, J = 6.6 Hz, 2 H), 2.01 (s, 3 H), 1.75 (s, 3 H), 1.64 (, 2 H), 1.49 (m, 2 H), 1.04 (s, 6 H).

Although according to the patent statutes, the description and the preferred processing conditions and conditions have been provided, the scope of the invention is not limited thereto or by these. The various modifications and alterations of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. Accordingly, for an understanding of the scope of the present invention, reference is made to the following claims. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, as property contained in the following:

Claims (15)

1. A method for producing a 9-cis retinoid, characterized in that it comprises: (a) reducing a cyclohexenyl ketone in the presence of a base to form a cyclohexadienine of the formula: (b) condensing the cyclohexadienine with a source of electrophilic nitrile to form a cyclohexadienine nitrile; (c) adding an alkyl, alkene, aryl or aralkyl group, in a conjugated form 1, 4, to the cyclohexadienine nitrile to form a cyclohexatriene nitrile of the formula: R1 R2 R4 (d) reducing the cyclohexatriene nitrile to the corresponding cyclohexatriene aldehyde; and (e) extending the aldehyde of the cyclohexatriene with an equivalent carbanion formed by the addition of a base to a phosphonate or phosphine salt to form a reaction product comprising a mixture of stereoisomers of retinoid ester having the general formula: wherein, R1 and R2 each independently represent hydrogen or a straight or branched chain lower alkyl having 1-5 carbon atoms; R3 represents hydrogen or a branched or linear alkyl, alkene or lower alkyne having 1-6 carbon atoms; R4 and R5 each independently represent hydrogen or an alkyl, alkene, aryl or branched or straight chain lower alkyl having 1-12 carbon atoms; R6 represents a straight or branched chain alkyl, alkene or lower alkyne having 1-5 carbon atoms; and the lines drawn in the structures between carbons 11-12, and 13-14, describe olefinic bonds that may be in either trans or cis configuration.

2 . The method according to claim 1, characterized in that it further comprises, after the extension step, hydrolyzing the reaction product with an aqueous methanolic hydroxide to form a mixture of retinoid stereoisomers.

3. The method according to claim 2, characterized in that it further comprises, after the step of hydrolysis, isolating a retinoid stereoisomer having the general formula: wherein R1 to R5 have the meaning specified in claim 1, R7 represents hydrogen or a pharmaceutically acceptable salt and the olefinic bonds 11-12-'and 13-14 are either in trans or cis configuration.

4. The method according to claim 1, characterized in that the electrophilic nitrile source comprises phenyl cyanate or cyanogen bromide.

5. The method according to claim 1, characterized in that the phosphonate or phosphine salt comprises diethyl-3-ethoxycarbonyl-2-methylprop-2-enylphosphonate.

6. The method according to claim 3, characterized in that the 9-cis retinoid is selected from the group consisting of 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2-trans-acid. 4-trans-6-cis-8-trans-nonatetraenoic acid, 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2-cis-4-trans-6-cis-8 -trans-nonatetraenoic, and 3,7-dimethyl-9- (2,6,6-trimethyl-l-cyclohexenyl) -2-trans-4-cis-6-cis-8-trans-nonatetraenoic acid.

7. A method for producing a 9-cis retinoid, characterized in that it comprises: (a) reducing a cyclohexenyl ketone in the presence of a base and a source of electrophilic nitrile to form a cyclohexadienine nitrile of the formula: (b) adding an alkyl, alkene, aryl or aralkyl group, in conjugated form 1, 4, to the cyclohexadienine nitrile to form a cyclohexatriene nitrile; < t (c) reducing the cyclohexatriene nitrile to the corresponding cyclohexatriene aldehyde; and, (d) extending the cyclohexatriene aldehyde with an equivalent carbanion formed by the addition of a base to a phosphonate or phosphine salt to form a reaction product comprising a mixture of stereoisomers of retinoid ester of the general formula: wherein, R1 and R2 can each independently represent hydrogen or a straight or branched chain lower alkyl having 1-5 carbon atoms; R3 represents hydrogen or a branched or linear alkyl, alkene or lower alkyne having 1-6 carbon atoms; R 4 and R 5 can each independently represent hydrogen or an alkyl, alkene, branched or straight chain aralkyl aryl lower having 1-12 carbon atoms; R6 represents a straight or branched chain alkyl, alkene or lower alkyne having 1-5 carbon atoms; and the lines drawn in the structures between carbons 11-12, and 13-14, describe t olefinic bonds that may be in either trans or cis configuration.

8. A method according to claim 7, characterized in that it comprises, after the extension step, hydrolysing the reaction product with aqueous methanolic hydroxide to form a mixture of retinoid stereoisomers.

9. In a method according to claim 8, characterized in that it further comprises, after the step of hydrolysis, isolating a retinoid stereoisomer having the general formula: wherein R1 to R5 have the meaning specified in claim 7, R7 represents hydrogen or a pharmaceutically acceptable salt and the olefinic bonds 11-12 and 13-14 are in either trans or cis configuration. tt

10. The method according to claim 9, characterized in that the 9-cis retinoid is selected from the group consisting of 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2-trans-acid. 4-trans-6-cis-8-trans-nonatetraenoic acid, 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2-cis-4-trans-6-cis-8 -trans-nonatetraenoic, and 3,7-dimethyl-9- (2,6,6-trimethyl-l-cyclohexenyl) -2-trans-4-cis-6-cis-8-trans-n-otheneaenoic acid.

11. A method for producing a cyclohexadienine nitrile olefin, characterized in that it comprises reducing a cyclohexenyl ketone in the presence of a base and a source of electrophilic nitrile to form a cyclohexadienine nitrile of the formula: wherein, R1 and R2 can each independently represent hydrogen or a straight or branched chain alkyl having 1-5 carbon atoms, and R3 represents hydrogen or an alkyl, alkene or lower branched chain or linear alky having 1-6 carbon atoms.

12. A method for producing a 9-cis-alkynyl nitrile, characterized in that it comprises: (a) condensing a cyclohexadienine with an electrophilic nitrile source to form a cyclohexadienine nitrile, and (b) adding an alkyl, alkenyl, aryl or aralkyl group, in a 1,4-conjugated form, to the cyclohexadienine to form a 9-cis alkylsulfide nitrile of the formula: wherein, R1 and R2 can each independently represent hydrogen or a lower straight or branched chain alkyl having 1-5 carbon atoms, R3 represents hydrogen or an alkyl, alkene, or lower straight-chain or branched alkyne having 1-6 carbon atoms; R4 represents hydrogen or a branched or straight chain alkyl, alkene, aryl or aralkyl having 1-6 carbon atoms, and the bond 9-10 is in the cis configuration.

13. A 9-cis retinoid characterized in that it is made according to the method according to claim 1.

14. The 9-cis retinoid according to claim 13, characterized in that it is selected from the group consisting of 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2-trans-4- acid trans-6-cis-8-trans-nonatetraenoic acid, 3,7-dimethyl-9- (2,6,6-trimethyl-l-cyclohexenyl) -2-cis-4-trans-6-cis-8-trans -nonatetraenoic acid, and 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2-trans-4-cis-6-cis-8-trans-n-otheneaenoic acid.

15. 5- (2,6,6-Trimethyl-l-cyclohexen-1-yl) -pent-2-ene-4-enenitrile.