JPH10501232A - Method for synthesizing 9-cis retinoid and novel intermediate thereof - Google Patents

Abstract

  (57) [Summary] Methods of synthesizing 9-cis retinoids, novel intermediates and methods of synthesizing cyclohexadienine nitrile and 9-cis alkyl cisoid nitriles and 9-cis retinoids prepared using such methods are provided.

Description

DETAILED DESCRIPTION OF THE INVENTION            Method for synthesizing 9-cis retinoid and novel intermediate thereof                              TECHNICAL FIELD OF THE INVENTION   The present invention relates to the synthesis of 9-cis retinoid compounds and in particular to 9-cis retinoids. The present invention relates to the synthesis of acid and its related compounds and novel intermediates thereof.                                Background of the Invention   All-trans retinoic acid, 13-cysteine, in mediating cell growth and differentiation The role of retinoids, such as retinoic acid and synthetic retinoic acid analogs, Pharmacological benefits for controlling the treatment of diseases such as psoriasis and acne, as well as Raises interest in oncological applications such as chemotherapy and chemoprevention ing. Significant advances in elucidating the molecular basis of retinoid activity are now being revised. It offers the possibility of designing retinoid compounds with improved therapeutic indices.   To date, several receptors for retinoic acid have been identified. These receptors , As a ligand-dependent transcription factor It is a member of the superfamily of functioning intracellular receptors. Currently these receptors Has two subfamilies, retinoic acid receptors (RARs) and retinoid X Receptors (RXRs) have been classified. The classification of these subfamilies is primarily Differences in amino acid structure, various naturally occurring and synthetic retinoids And the ability to regulate the expression of different target genes. Each RA The R and RXR subfamilies consist of three distinct isoforms (RARa, RARbeta and And RARγ, and RXRα, RXRβ and RXRγ). Multiple Discovery of a retinoid receptor in a different subfamily and its isoforms Raise the issue of various characteristics.   Recently, other reticles with 9-cis RA and 9-10 cis olefin stereochemistry have been developed. Noids bind to RARs and RXRs and regulate gene expression through these (Heyman et al.,Cell,68: 39 7 (1992)). However, to date, the art has found such compounds Provided only a low yield, nonselective and expensive production process. For example, the literature is 9- Non-selective methods for producing 10 cis olefin retinoids (eg, Robson et al. (Robson) et al.J. Am. Chem. Soc.,77: 4111 (1955), Matsui (Mat sui) et al.J. Viatminol.,4178 (1958), German Patent DE 1068 No. 719 and Aurel et al.Tetrahedron Lett.,31: 5791 ( 1990)), and stereoselective methods for preparing 13-14 olefinic bonds (For example, Pattenden et al.,J. Chem. Soc. (C), 1984 (19) 68) and Mayer et al.Experientia,341105 (1978) See).   Furthermore, through the conjugate addition of cuprate to acetylene ester For preparing alkyl-substituted retinoids and trimethylsilyl-substituted retinoids However, the method uses an excessive number of steps, and importantly allyl. Using the oxidation of alcohols to aldehydes, whereby the resulting retinoids Destroys the integrity of the 9-10 cis-olefin bond present in Ernst (Erns t) et al.J. Org. Chem.,52: 398 (1987)).   Therefore, a retinoid compound having a 9-10 olefin bond in a cis configuration is selected. It is desirable to prepare it in a targeted and low cost manner.                                Summary of the Invention   The present invention relates to the selective production of 9-cis retinoids, preferably 9-cis retinoic acid. And provide a low-cost synthesis method. In particular, the present invention produces 9-cis retinoids in order to, (A) reduction of cyclohexenyl ketone in the presence of a base to give cyclohexadienine Produces (B) condensing the cyclohexadienin with an electrophilic nitrile source to form cyclohexadiene; Produces eninenitrile, (C) adding an alkyl group to the cyclohexadienine nitrile in a 1,4-conjugated manner To produce cyclohexatriene nitrile, (D) converting the cyclohexatriene nitrile to a corresponding cyclohexatrienaldehyde And then (E) carbohydrate formed by addition of a base to a phosphonate or phosphine salt Extending the cyclohexatriene aldehyde with an anion equivalent to form a retinoid A mixture of stele stereoisomers (where the olefinic bond between carbons 9-10 is in cis configuration And the olefinic bond between carbons 11-12 and 13-14 is in the trans configuration. Or cis configuration). Provide a method of signing. Thereafter, the retinoid ester is hydrolyzed to form retino A mixture of the formic acid stereoisomers may be formed, and the mixture is then separated and separated into individual resins. Can provide a tynoic acid stereoisomer, preferably 9-cis retinoic acid You.   Further, for producing 9-cis retinoid, (A) Reduction of cyclohexenyl ketone in the presence of a base and an electrophilic nitrile source To produce cyclohexadienine nitrile, (B) adding an alkyl group to the cyclohexadienine nitrile in a 1,4-conjugated manner To produce cyclohexatriene nitrile, (C) reducing the cyclohexatriene nitrile to form a corresponding cyclohexatriene Make it rudehid and then (D) formed by adding a base to a phosphonate or phosphine salt Extending the cyclohexatrienaldehyde with a carbanion equivalent to form retino A mixture of stereoisomers of amides (where the olefinic bond between carbons 9-10 is Olefinic bond between carbons 11-12 and 13-14 Configuration or cis configuration). And a method characterized by the following.   The present invention further relates to cyclohexenyl in the presence of a base and an electrophilic nitrile source. A method for reducing cycloketone to form cyclohexadieninenitrile A method for producing clohexadienin nitrile is also provided.   Further, the present invention provides (A) condensing cyclohexadienin with an electrophilic nitrile source to form cyclohexadien Produces garlic nitrile, then (B) adding an alkyl group to the cyclohexadienin in a 1,4-conjugated mode, 9-cis alkyl cisoid nitriles with 10 olefin bonds in cis configuration Generate files A method for producing 9-cis alkyl cyanoid nitrile is provided.   Furthermore, the present invention provides a 9-cis retinoid produced according to the above method. I do. Such 9-cis retinoids are 9-cis retinoic acid, 9,11-di- Cis retinoic acid, 9,13-dicis retinoic acid and 9,11,13-tricy It is preferred to include retinoic acid. These and the various features that characterize the invention Other advantages and novel features are set forth in the claims appended hereto and forming a part hereof. In particular point out. However, the accompanying preferred embodiments of the invention are illustrated and described. BRIEF DESCRIPTION OF THE DRAWINGS The drawings and written description have been obtained in accordance with the invention, its advantages and its use. Good to refer to for a better understanding of                          DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION   According to a first aspect of the present invention, the inventors have developed a method for synthesizing retinoids. The sequence of steps in this method is described below.   In a series of the above processes, R¹And R^TwoIs each independently hydrogen or 1-5 May represent a lower linear or branched alkyl having carbon atoms of;   R^ThreeIs hydrogen or lower branched or straight chain alkyl having 1 to 6 carbon atoms, May indicate an alkene or alkyne;   R^FourAnd R^FiveIs independently hydrogen or a lower branched chain having 1 to 12 carbon atoms Or may represent a straight chain alkyl, alkene, aryl or aralkyl;   R⁶Is a lower linear or branched alkyl having 1 to 5 carbon atoms, alkene or Or alkyne;   R⁷Represents hydrogen or a pharmaceutically acceptable salt;   The dashed line between carbons 11-12 and 13-14 in the structural formula Olefinic bond which may be in any of the following configurations.   Pharmaceutically acceptable salts for use herein include pyridine, ammonium, Piperazine, diethylamine, nicotinamide, formic acid, urea, sodium, potassium , Calcium, magnesium, zinc, lithium, methylamino, triethyl Contains amino, dimethylamino and tris (hydroxymethyl) aminomethane But not limited to these. Still other pharmaceutically acceptable salts are It is well known to those skilled in the art.   A series of processes of the method involves the use of lithium diisopropylamide (LDA) or the like. In the presence of a base and chlorodiphosphate such as diethyl chlorophosphate , Β-ionone (Aldrich Chemical 1), Milwaukee Cyclohexenyl ketones (available from Milwaukee, Wisconsin) Starting from the reduction of (1), 4- (1- [2,6,6-trimethylcyclohexene- 1-yl])-(but-3-en-1-yne) and the like. ). In addition to LDA as a base, at this stage of the method of the invention Other non-limiting examples of preferred useful bases include sodium hydride (NaH), potassium hydride (KH), n-butyllithium (n-BuLi) , S-butyllithium (s-BuLi), t-butyllithium (t-BuLi) , Sodium amide (NaNH_Two) And lithium, potassium or sodium F Xamethyldisyl azide.   The second step involves the electrophilic nitrile source (phenyl cyanate or odor) in the presence of a base. 5- (1- [2,6,6-trimethyl-1-cyclohexyl) using cyanide Xen-1-yl])-pent-2-yn-4-ennitrile It consists of the condensation of the cyclohexadienine (2) to sadieninnitrile (3).   The third step in this reaction sequence involves the conversion of the alkyl group to cyclohexadi Addition to eninenitrile (3), having a 9-10 double bond in cis configuration (2Z, 4E) -3-Methyl-5- (1- [2,6,6-trimethyl-1-cyclohexene -1-yl])-2,4-pentadienitrile For producing triennitrile (4). In this regard, the method The addition of an alkyl group according to the embodiment of the invention can be accomplished by a number of techniques and methods familiar to those skilled in the art. Preferably, the addition reaction is a non-polar solvent, most preferably Or with hexane or heptane.   In the fourth step, the cyclohexatrienenitrile (4) is converted to a standard in hexane. The quasi DIBAL (aluminum diisobutyl hydride) reduction gives the corresponding cyclo Hexatrienaldehyde (5) ((2Z, 4E) -3-methyl-5- (1- [2 , 6,6-Trimethyl-1-cyclohexen-1-yl])-2,4-pentadie. Nnar).   The fifth step of this reaction sequence is mainly ethyl-3,7-dimethyl-9- (2,6,6 -Trimethyl-1-cyclohexen-1-yl) -2-trans-4-trans Retinoic acid esters containing -6-cis-8-trans-nonatetraenoate (Retinoid ester) To form a mixture of stereoisomers of (6), -3-ethoxycarbonyl-2-methylprop-2-enyl phosphonate and the like A phosphonate or phosphine salt (eg, triphenylphosphine) is added to a base ( Carbanion equivalents formed by addition of e.g. n-BuLi) And elongation of cyclohexatrienaldehyde (5). In this regard, The retinoic acid ester stereoisomer (6) has a 13-trans configuration versus a cis configuration. It shows more than 15: 1 prevalence of 14 olefinic bonds. The method of the present invention Mushroom Examples of bases useful in embodiments of the invention include, but are not limited to, DM In the presence of PU, sodium hydride (NaH), potassium hydride (KH), n- Butyl lithium (n-BuLi), s-butyl lithium (s-BuLi), t- Butyllithium (t-BuLi) and sodium amide (NaNH)_Two)including .   The sixth and final stage of the process involves the conversion of retinoic acid ester (6) to methanol. Hydrolysis with an aqueous solution of a neutral hydroxide (MeOH / KOH) yields retinoic acid isomers Related to obtaining (7). Examples of the retinoid isomer (7) include, but are not limited to, The main component, 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexe Nyl) -2-trans-4-trans-6-cis-8-trans-nona-tetra Enoic acid (9-cis retinoic acid) and detectable amounts of 3,7-dimethyl-9- ( 2,6,6-trimethyl-1-cyclohexenyl) -2-cis-4-trans-6 -Cis-8-trans-nona-tetraenoic acid (9,13 dicis retinoic acid) and And 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2-trans-4-cis-6-cis-8-trans-nona-tetraenoic acid (9 , 11 dicis retinoic acid). After hydrolysis, the desired retinoic acid The compound (7) is selectively crystallized from an aqueous methanolic hydroxide solution, or As a method, semi-preparative reversed-phase (ODS) high-performance liquid chromatography (HPLC) ).   It will be appreciated by those skilled in the art that certain modifications to the above methods may be made within the scope of the present invention. Will be understood. For example, the first and second stages (ie, cyclohexane Condensation of xadienin (2) is carried out in the presence of a base instead of water in the presence of a base. With lithium anions and electrophilic nitrile sources such as phenyl cyanide One step by quenching the original cyclohexenyl ketone (1) Cyclohexadieninenitrile (3) is directly combined with a one-pot reaction on the floor Can be generated.   Furthermore, the synthesis of the present invention has a broader application than the retinoid synthesis described above. Those skilled in the art will understand what can be done. For example, each of stages 2 and 3 The condensation and addition involve the formation of 9-10 olefinic bonds selectively produced in the cis configuration. Having various alkyl cyanidonitriles and derivatives thereof (eg, amines, acids Aldehydes, esters).   The above synthesis methods are more costly than currently available, importantly including cost. Provide many advantages. In this regard, β-cyclocitral (the substance On average at least 20 to 40 times more expensive than the starting material used in the The present invention relates to more typical starting materials utilized in existing processes such as The method uses commercially available, inexpensive and readily available starting materials such as β-ionone. To use. In addition, the third step in the synthesis method (ie, in a 1,4-conjugated manner) The addition of an alkyl group to cyclohexadieninenitrile (3) To form an ennitrile (4)) with a selective 9-9 double bond in the cis configuration. Introduction and a wide variety of substitutions such as alkyl, alkene, aryl, aralkyl It is possible to introduce a substituent at carbon number 9. Further use through the method Reagents are standard, readily available, and have been reported to be hazardous. No organic or inorganic chemicals that are not expensive.                                 Example 1   The retinoid of the present invention was synthesized according to the following 9-cis retinoic acid synthesis scheme. Is exemplified.              4- (1- [2,6,6-trimethylcyclohexene            -1-yl])-(but-3-en-1-yne) (2):   The intermediate 4- (1- [2,6,6-trimethylcyclohexen-1-yl])-( But-3-en-1-yne) (2) was converted to β-ionone (1) (Aldrich Chemi). (Available from Cals) according to the previously described method (Negishi (EI Negishi) et al.J. Org. Chem.,45: 2526 (1980) The indications are incorporated herein by reference)).             5- (2,6,6-trimethyl-1-cyclohexene-           1-yl) -pent-2-yn-4-ennitrile (3):   Add 100 mL of a flame-dried flask to tetrahydrofuran (THF) (3 0-mL) of the intermediate 4- (1- [2,6,6-trimethylcyclohexene-1-i). ])-(But-3-en-1-yne) (2) (1.045 g, 6.0 mmol) And cooled to -78 ° C. Solution of n-BuLi in hexane (2.25M; 2 .75 mL, 6.15 mmol) was added slowly and the slightly dark mixture was added to 10 Stirred for minutes. Phenyl cyanide (Murray (RE. Murray et al., Synthesis, 150 (1980) (the disclosure of which is incorporated herein by reference). (750 μL, 6.6 mmol) prepared according to the method of The mixture was warmed to room temperature (e.g., about 20-25C). Sodium hydroxide( (2 mL of a 6N 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. Wash with water (2 × 100 L), MgSO_FourAnd the solvent was evaporated. Profit The residue obtained is substantially pure (by TLC) and has several baselines Through a short pad of silica gel using hexane as eluent to remove And filtered. The solvent was evaporated and 1.088 g (91%) of a slightly yellow oil was obtained. % Yield). Rf 0.75 (hexane), IR (freshness) 2933, 2320 , 2251 (CN), 1590 cm^-1;¹HNMR (CDC1_Three) Δ 7.11 (d , J = 16.4 Hz, 1H), 5.54 (d, J = 16.4 Hz, 1H), 2.07 (T, J = 4.0 Hz, 2H), 1.76 (s, 3H), 1.60 (m, 2H), 1.46 (m, 2H), 1.04 (s, 6H).        (2Z, 4E) -3-methyl-5- (2,6,6-trimethyl-     1-cyclohexen-1-yl) -2,4-pentadienitrile (4):   Anhydrous copper iodide (1.09 g, 5.7 g) was placed in a 50 mL flame dried round bottom flask. 0 mmol) and THF (20 mL) and cooled to 0 ° C. Methyllithium (Et_Two4.28 mL of a 1.4 M solution in O) was added until the solution was clear and colorless. Add slowly over 10 minutes. Dry the cuprate solution in a dry ice-acetone bath Cool to −78 ° C. using 5- (2,6,6-trimer) in THF (10 mL). Tyl-1-cyclohexen-1-yl) -pent-2-yn-4-ennitrile A solution of 3 (544 mg, 2.73 mmol) was added dropwise. West Mige mijze) et al., Tetrahedron letters, 3327 (1979) and Synthesis, 454 (1978), the disclosure of which is incorporated herein by reference. See). The mixture is stirred at this temperature for 45 minutes and saturated ammonium chloride A solution (10 mL) was added. The mixture was then warmed to room temperature. EtOAc ( 50 mL), wash with 2% NaOH (2 × 10 mL), then add saturated N H_FourCl (2 × 10 mL), water (2 × 10 mL) and saline (2 × 10 mL) And washed. MgSO 4_FourAnd the solvent was evaporated. Got The residue is substantially pure (by TLC), excluding some baseline material. Silica gel using hexane: EtOAc (9: 1) as eluent to remove Through a short pad of water. Evaporate the solvent, slightly yellow-orange 538 mg (92% yield) of an oil was obtained. Rf 0.75 (hexane: Et OAc (9: 1)), IR (raw) 2933, 2250 (CN), 1590 cm^-1 ;¹H NMR (CDCl_Three) Δ 6.70 (d, J = 16 Hz, 1H), 6.59 (D, J = 16.4 Hz, 1H), 5.09 (s (1H), 2.06 (s3H), 2.07 (t, J = 4.0 Hz, 2H), 1.75 (s, 3H), 1.62 (m, 2 H), 1.47 (m, 2H), 104 (s, 6H).        (2Z, 4E) -3-methyl-5- (2,6,6-trimethyl-    1-cyclohexen-1-yl) -2,4-pentadiennal (5):   (2Z, 4E) -2,4-pentane was added to a 25 mL flame-dried round bottom flask. Dienitrile-3-methyl-5- (2,6,6-trimethyl-1-cyclohexene -1-yl) (4) (94.2 mg, 0.438 mmol) and hexane (5.0 mL) and cooled to -78 ° C. Diisobutyl aluminum hydroxide (hexa 480 μL of a 1.0 M solution in water, 0.480 mmol) was added at an internal reaction temperature of -70. The solution was added dropwise at such a rate that the temperature did not exceed ° C. The mixture was stirred for 5 minutes, Chromatography (TLC) analysis (Hexane: EtOAc (9: 1)) revealed the reaction. Was completed (Rf 0.75 for starting material; 0.70 for product). B A saturated solution of shell salt (1.0 mL) was added and the mixture was warmed to room temperature. Et OAc (10 mL) was added, and the mixture was combined with water (2 × 10 mL) and brine (2 mL). × 10 mL). MgSO 4_FourAnd the solvent is evaporated. Fire Was. The residue obtained is substantially pure (by TLC), 90.5 mg, 9 5% yield; IR (neat) 2958, 2928, 2866, 1668 ( C = O), 1614 (C = C) cm^-1;¹H NMR (CDCl_Three; 400 MHz ) Δ (ppm): 10.16 (d, J = 8.0 Hz, CHO) 7.16 (d, J = 16.0 Hz, vinyl-CH, transformer), 6.63 (d, J = 16.0 Hz, Nil-CH, trans), 5.88 (d, J = 8.0 Hz, 1H, CH-CHO) , 2.69 (s, 2H, ring), 2.14 (s, 3H, -C- (CH_Three) = CH-C HO, cis), 1.80 (s, 3H, CH_Three, Ring), 1.11 (s, 6H, Jemi Null-2 × CH_Three).                  Ethyl-3,7-dimethyl-9- (2,6,6-             Trimethyl-1-cyclohexen-1-yl) -2-to Lance-4-trans-6-cis-8-trans-nonatetraenoate (6)   Diethyl-3-ethoxycarbonyl-2 dissolved in anhydrous THF (5.0 mL) -Methylprop-2-enylphosphonate (354 mg, 1.33 mmol) The solution was cooled to 0 ° C. and dissolved in anhydrous DMPU (0.5 mL) and hexane. -BuLi (0.56 mL of a 2.35 M solution, 1.33 mmol) was added. The The mixture was stirred at the same temperature for 20 minutes and then cooled to -78 ° C. THF (3.0m L) contains (2Z, 4E) -3-methyl-5- (2,6,6-trimethyl-1-cyclyl). (Rohexen-1-yl) -2,4-pentadiennal (5) (241 mg) 1. 115 mmol) was slowly added and the reaction mixture was cooled at -78 ° C. Stirred for an additional 60 minutes. When the reaction is complete as monitored by TLC The mixture was warmed to 0 ° C. Add saturated ammonium chloride solution (5 mL) The mixture was extracted using EtOAc (3 × 10 mL). The organic layer is treated with water ( 2 × 5 mL) and brine (10 mL), washed with MgSO_FourAnd concentrated did. The obtained residue is subjected to a short silica gel chromatography (sgc) column. Purified above, the 13-trans isomer in a １５15: 1 ratio of the 13-cis isomer 296 mg (78% yield) of the desired ester were obtained. IR (freshness): 2928 , 1709cm^-1;¹H NMR (CDCl_Three; 400 MHz) δ (ppm): 7. 0 8 (dd, J = 15, 11.3 Hz, 1H), 6.65 (d, J = 16 Hz, 1H) ), 6.29 (d, J = 15 Hz, 1H), 6.23 (d, J = 15 Hz, 1H) , 6.06 (d, J = 11.3 Hz, 1H), 4.17 (m, J = 7 Hz, 2H) , 2.7 (s, 2H), 2.33 (s, 3H), 2.03 (s, 3H), 1.82 ( s, 3H), 1.29 (t, J = 7 Hz, 3H), 1.1 (s, 6H).                     3,7-dimethyl-9- (2,6,6-             Trimethyl-1-cyclohexenyl) -2-trans-       4-trans-6-cis-8-trans-nona-tetraenoic acid (7)   Ethyl-3,7-dimethyl-9- (2,6,6-to) in ethanol (10 mL) Limethyl-1-cyclohexen-1-yl) -2-trans-4-trans-6 -Cis-8-trans-nonatetraenoate (6) (275 mg) 8.25 mi Solution) was treated with 1N KOH (10 mL) at 70 ° C. for 3 hours and allowed to reach room temperature. And acidified with 10% (vol: vol) HCl and EtOAc (2 × 20 mL). The organic layer was washed with water (2 × 5 mL) and brine (2 × 5 mL). Washed, MgSO_FourAnd the solvent was evaporated. The residue is ethanol: water By dissolving in a minimum volume of a 9: 1 mixture (〜20 ml / g of material) And recrystallized (twice). Thus, the desired 9-cis retinoic acid can be converted to very pure In the form (¹Obtained as a pale yellow solid (by 1 H NMR) in 85% yield; Point 188-190 ° C; IR (KBr, cm^-1) 2914, 1670, 1583;¹ H NMR (CDCl_Three; 400 MHz): δ (ppm) 7.20 (dd, J = 1) 5.0 Hz, 1 H), 6.65 (d, J = 16.0 Hz, 1 H), 6.28 (d, J) = 16.0 Hz, 1H), 6.25 (d, J = 15.0 Hz, 1H), 6.06 (d , J = 11.0 Hz, 1H), 5.80 (s, 1H), 2.35 (s, 3H), 2. 05 (t, J = 6.6 Hz, 2H), 2.01 (s, 3H), 1.75 (s, 3H) ), 1.64 (m, 2H), 1.49 (m, 2H), 1.04 (s, 6H).   Although the preferred embodiments and processing conditions have been described in accordance with the Patent Act, the scope of the present invention is not limited thereto. It is not limited by this. Various changes and modifications of the present invention are within the scope of the invention. It will be apparent to those skilled in the art without departing from the box. Therefore, the scope of the present invention is not considered. For a solution, reference is made to the following claims.

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, M C, NL, PT, SE), OA (BF, BJ, CF, CG , CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, MW, SD, SZ, UG), AM, AT, AU, BB, BG, BR, BY, CA, C H, CN, CZ, DE, DK, EE, ES, FI, GB , GE, HU, JP, KE, KG, KP, KR, KZ, LK, LR, LT, LU, LV, MD, MG, MN, M W, MX, NO, NZ, PL, PT, RO, RU, SD , SE, SI, SK, TJ, TT, UA, UZ, VN

Claims (1)

Claims 1. (a) Reduction of cyclohexenyl ketone in the presence of a base to produce cyclohexadienine of the following formula: (B) condensing the cyclohexadienine with an electrophilic nitrile source to produce cyclohexadienine nitrile; and (c) adding an alkyl, alkene, aryl or aralkyl group to the cyclohexadienine nitrile in a 1,4-conjugated manner. To form cyclohexatriene nitrile of the formula (D) reducing the cyclohexatriene nitrile to the corresponding cyclohexatriene aldehyde, and then (e) extending the cyclohexatriene aldehyde with a carbanion equivalent produced by adding a base to a phosphonate or phosphine salt. Produces a reaction product consisting of a mixture of retinoid ester stereoisomers having the general formula Wherein R ¹ and R ² may each independently represent hydrogen or lower linear or branched alkyl having 1 to 5 carbon atoms; R ³ has hydrogen or 1 to 6 carbon atoms R ⁴ and R ⁵ may each independently represent hydrogen or lower branched or straight chain alkyl, alkene, aryl or aralkyl having 1 to 12 carbon atoms. R ⁶ represents a low linear or branched alkyl, alkene or alkyne having 1 to 5 carbon atoms; the dashed line between carbons 11-12 and 13-14 in the structural formula represents trans or cis. A olefinic bond which may be in any of the configurations). 2. The method of claim 1, further comprising hydrolyzing the reaction product with an aqueous methanolic hydroxide to form a mixture of retinoid stereoisomers, further after the elongation step. 3. After the hydrolysis step, the following general formula: Wherein R ¹ -R ⁵ have the meaning specified in claim 1, R ⁷ represents hydrogen or a pharmaceutically acceptable salt, and the 11-12 and 13-14 olefinic bonds are in the trans configuration or 3. The method of claim 2, further comprising isolating a retinoid stereoisomer having any of the cis configurations. 4. The method according to claim 1, wherein the electrophilic nitrile source is phenyl cyanide or cyanogen bromide. 5. The method according to claim 1, wherein the phosphonate or phosphine salt is diethyl-3-ethoxycarbonyl-2-methylprop-2-enyl phosphonate. 6.9-cis retinoid is 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2-trans-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 acid and 3,7-dimethyl-9- The method according to claim 3, wherein the method is selected from the group consisting of (2,6,6-trimethyl-1-cyclohexenyl) -2-trans-4-cis-6-cis-8-trans-nonatetraenoic acid. 7. (a) reducing cyclohexenyl ketone in the presence of a base and an electrophilic nitrile to form a cyclohexadienine nitrile of the formula: (B) adding an alkyl, alkene, aryl or aralkyl group to the cyclohexadienine nitrile in a 1,4-conjugated manner to produce cyclohexatriene nitrile, and (c) converting the cyclohexatriene nitrile to the corresponding cyclohexatriene A mixture of retinoid ester stereoisomers having the general formula: (d) extending the cyclohexatriene aldehyde with a carbanion equivalent formed by adding a base to a phosphonate or phosphine salt, A reaction product consisting of Wherein R ¹ and R ² may each independently represent hydrogen or lower linear or branched alkyl having 1 to 5 carbon atoms; R ³ is hydrogen or lower having 1 to 6 carbon atoms. R ⁴ and R ⁵ may each independently represent hydrogen or lower branched or straight chain alkyl, alkene, aryl or aralkyl having 1 to 12 carbon atoms. R ⁶ represents lower linear or branched alkyl, alkene or alkyne having 1 to 5 carbon atoms; the dashed line between carbons 11-12 and 13-14 in the structural formulas is of trans or cis configuration A method for producing a 9-cis retinoid. 8. The method of claim 7, further comprising hydrolyzing the reaction product with an aqueous methanolic hydroxide to form a mixture of retinoid stereoisomers, further after the elongation step. 9. After the hydrolysis step, the following general formula: Wherein R ¹ -R ⁵ have the meaning specified in claim 7, R ⁷ represents hydrogen or a pharmaceutically acceptable salt, and the 11-12 and 13-14 olefinic bonds have the trans configuration or 9. The method of claim 8, further comprising isolating a retinoid stereoisomer having any of the cis configurations. 10.9-cis retinoid is 3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2-trans-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 acid and 3,7-dimethyl-9- The method according to claim 9, wherein the method is selected from the group consisting of (2,6,6-trimethyl-1-cyclohexenyl) -2-trans-4-cis-6-cis-8-trans-nonatetraenoic acid. 11. Cyclohexanyl ketone is reduced in the presence of a base and an electrophilic nitrile source to give the following formula: Wherein R ¹ and R ² may each independently represent hydrogen or lower linear or branched alkyl having 1 to 5 carbon atoms, and R ³ represents hydrogen or lower alkyl having 1 to 6 carbon atoms. A cyclohexadieninenitrile (which may represent a branched or straight-chain alkyl, alkene or alkyne). 12. (a) cyclohexadienin is condensed with an electrophilic nitrile source to produce cyclohexadienine nitrile; (b) an alkyl, alkene, aryl or aralkyl group is added to the cyclohexadienine nitrile in a 1,4-conjugated manner. With the following formula: Wherein R ¹ and R ² may each independently represent hydrogen or lower linear or branched alkyl having 1 to 5 carbon atoms, and R ³ has hydrogen or 1 to 6 carbon atoms R ⁴ represents hydrogen or lower branched or straight chain alkyl, alkene, aryl or aralkyl having 1 to 6 carbons, wherein 9-9 bond is cis; A process for producing a 9-cisalkylsilsoidonitrile of the above configuration). 13. 9-cis retinoid prepared according to the method of claim 1. 14.3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexenyl) -2-trans-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 acid and 3,7-dimethyl-9- (2,6,6 The 9-cis retinoid according to claim 13, which is selected from the group consisting of -trimethyl-1-cyclohexenyl) -2-trans-4-cis-6-cis-8-trans-tetraenoic acid. 15.5- (2,6,6-trimethyl-1-cyclohexen-1-yl) -pent-2-yn-4-ennitrile.