Chapter 5
Downloaded by STANFORD UNIV GREEN LIBR on July 18, 2012 | http://pubs.acs.org Publication Date: November 25, 2003 | doi: 10.1021/bk-2004-0870.ch005
Synthetic Approaches to the Retinoids Margaret M . Faul Lilly Research Laboratories, A Division of Eli Lilly and Company, Chemical Process Research and Development Division, Indianapolis, IN 46285-4813
Methods for the synthesis of retinoids (Acitretin, Etretinate, Isotretinoin, Tretinoin and Alitretinoin) derived from the tetraenoic acid platform via Wittig-Horner-Emmons reactions and photochemistry are described. Chemistry employed for synthesis of the more novel aryl/heteroaryl receptor selective retinoids (Bexarotene, Differin® and Zorac®) platforms is also reported.
Introduction Retinoids, natural and synthetic analogs of retinol (vitamin A), play an important role in cell differentiation and vertebrate development, which appears to account for their therapeutic or preventative effects in acne, psoriasis, photoaging, cancer and other diseases.(Z) Their activity is believed to be mediated through two classes of retinoid receptors:(2,3) the retinoic acid receptors (RAR) and the retinoid X receptors (RXR).(4) The RARs have a high affinity for both all-^ra«5-retinoic acid and its isomer 9-cw-retinoic acid, the latter is also the natural ligand of the RXRs (Figure 1). Other retinoids having the 9,10-0/5 olefin geometry have been found to selectively activate the retinoid X receptor. The RXRs serve as ligand-dependent transcription factors and as heterodimerization partners for other members of the nuclear receptor ,
© 2004 American Chemical Society In Chemical Process Research; Abdel-Magid, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.
71
Downloaded by STANFORD UNIV GREEN LIBR on July 18, 2012 | http://pubs.acs.org Publication Date: November 25, 2003 | doi: 10.1021/bk-2004-0870.ch005
72 superfamily including the RARs, the thyroid receptor (TR), the peroxisome proliferator-activated receptors (PPARs) and the vitamin D receptor (VDR). Due to their range of biological activities, the retinoids have demonstrated a large potential for inducing unwanted side effects including mucocutaneous toxicity, hypertriglyceridemia and teratogenesis.(J) Although retinoids have shown promise in dermatological and oncological indications, these adverse effects have hampered or restricted their use, particularly as preventive agents for chronic administration. Therefore one of the primary goals of retinoid research has been to design novel retinoids that have more favorable therapeutic indices with reduced risk of adverse effects and teratogenesis, and these efforts have been the subject of multiple reviews.(tf--cis isomers. Saponification of 9 yielded 9-cw-RA in 75% yield (Scheme 3). This process via 1 completed a 6 step synthesis of 9-cw-RA in 50% yield, while the Reformatsky reaction sequence proceeded in 5 steps starting with 5 to give 30% overall yield. Both processes have been reported on kilogram scale.
In Chemical Process Research; Abdel-Magid, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.
75
Downloaded by STANFORD UNIV GREEN LIBR on July 18, 2012 | http://pubs.acs.org Publication Date: November 25, 2003 | doi: 10.1021/bk-2004-0870.ch005
Scheme 3
(a) n-BuLi, DMPU, THF, -40 °C; (b) KOH, EtOH, 70 °C.
Photochemical isomerization of all-trans-RA in acetonitrile using a tungsten filament lamp afforded material that contained 14% 9-cw-RA at equilibrium.(2i,22) Recrystallization from EtOH provided 9-ew-RA in 5% yield (Scheme 4). Recycling of the mother liquor through photolytic re-equilibrium generated additional quantities of product (5% yield/cycle). Application of this chemistry to manufacturing scale was limited since the retinoic acids are not very soluble in organic solvents and the reaction needed to be performed at high dilution. Approaches to overcome these problems have been developed (vide infra).(23-25) Scheme 4
C0 H 2
(a) hv, CH CN 3
Alternative synthetic approaches to 9-cw-RA have been published, although their application to commercial scale has not been demonstrated.(/5,26~29)
In Chemical Process Research; Abdel-Magid, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.
76
Downloaded by STANFORD UNIV GREEN LIBR on July 18, 2012 | http://pubs.acs.org Publication Date: November 25, 2003 | doi: 10.1021/bk-2004-0870.ch005
Bexarotene (Targretin®) Bexarotene is an RXR-selective retinoid marketed by Ligand Pharmaceuticals Inc., for treatment of refractory advanced-stage cutaneous Tcell lymphoma. Bexarotene is orally administered, safe and side effects are reversible.(JO) The synthesis of Bexarotene starts with tetrahydronaphthalene 11, prepared in 91% yield by Friedel-Crafts alkylation of toluene with 2,5dichloro-2,5-dimethylhexane 10 (Scheme 5).(5/-55) Friedel-Crafts acylation of 11 with chloromethylterphthalate 12 afforded ester 13 in 72% yield. Scheme 5 o
Bexarotene
15
(a) Toluene (solvent), A1C1 ; (b) A1C1 , CH C1 ; (c) MePPh Br, NaNH , THF; (d) MeOH, KOH (aq), HC1. 3
3
2
2
3
2
Completion of the synthesis was achieved either (i) by olefmation of 12 with methyltriphenylphosphonium bromide/NaNH followed by saponification in 68% overall yield; or, (ii) by saponification of 13 to acid 14, treatment with MeMgCl and dehydration with cone. HC1 in 80% overall yield. The latter approach, which proved optimal, completed a 4 step synthesis of Bexarotene in 52% yield. Improvements to this process, involving catalytic Friedel-Crafts acylation chemistry have recently been reported.(54) 2
Tretinoin (Retin A,® Vesanoid®, Renova®, aIRrans-RA) The most general method to prepare all-*rara,y-RA is by Wittig reaction of Cis-phosphonium salt 17, prepared in two steps and 74% yield from
In Chemical Process Research; Abdel-Magid, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.
77 commercially available P-ionone 1, with methyl i?-3-formylcrotonate (Scheme 6).(23,35) An alternative approach via the acetate has also been reported.(Jd)
Downloaded by STANFORD UNIV GREEN LIBR on July 18, 2012 | http://pubs.acs.org Publication Date: November 25, 2003 | doi: 10.1021/bk-2004-0870.ch005
Scheme 6
aU-trans-RA
(a) Vinyl-MgBr,THF; (b)PPh HBr,MeOH; (c)(i)«-BuLi,hexanes,methyl E-3formylcrotonate; (ii) KOH, EtOH. 3
Tazarotene (Zorac®) Tazarotene is an RAR selective retinoid, currently marketed by Allergan Inc., for the topical treatment of acne and psoriasis.(37-39) Two approaches to its synthesis have been reported (Scheme 7). Thiophenol 18 or 19 was treated with NaOH in the presence of l-bromo-3-methyl-2-butene to afford the corresponding l-arylthio-3-methyl-2-butene 20 or 21, that upon cyclization with P 0 and H3PO4 yielded benzothiopyran 22 or 23. SnCl catalyzed acylation of 22 with acetyl chloride afforded the 6-acetyl derivative, that upon dehydration with lithium diisopropylamide and diethyl chlorophosphate was converted into ethynyl benzothiopyran 24. Alternatively 24 was prepared by Sonogishira coupling of bromobenzopyran 23 with TMS-acetylene, followed by removal of the TMS-protecting group. Completion of the synthesis was achieved by deprotonation of 24 with /i-BuLi and reaction with ethyl 6-chloropyridine-3carboxylate. Tazarotene was also prepared by palladium-catalyzed coupling of ethyl 6-chloropyridine-3-carboxylate with the organozincate derived from acetylene 24. The process via acetylation is preferred on commercial scale since it eliminated the use of transition metals that contaminate the final product. No yield for either process has been reported in the literature. 2
5
4
In Chemical Process Research; Abdel-Magid, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.
Downloaded by STANFORD UNIV GREEN LIBR on July 18, 2012 | http://pubs.acs.org Publication Date: November 25, 2003 | doi: 10.1021/bk-2004-0870.ch005
78
Scheme 7
Tazarotene (a) l-Bromo-3-methyl-2-butene, NaOH, acetone; (b) P 0 , H P0 , benzene; (c) (i) SnCl , acetyl chloride, benzene; (ii) LDA, THF, diethylchlorophosphate; (d) (i) Et N, TMS-acetylene, Cul, (PPh ) Pd Cl ; (ii) i-PrOH, 1 N NaOH; (e) w-BuLi, THF, ethyl 6-chloronicotinate; (f) w-BuLi, ZnCl , Pd(PPh ) , ethyl 6-chloronicotinate. 2
5
3
4
4
3
3 2
2
2
3 4
In Chemical Process Research; Abdel-Magid, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.
Scheme 8
a
C0 H
H
Me OLi
A M o L i 11
2
O C0 H Downloaded by STANFORD UNIV GREEN LIBR on July 18, 2012 | http://pubs.acs.org Publication Date: November 25, 2003 | doi: 10.1021/bk-2004-0870.ch005
2
39%
MeO
MeO'
25 .C0 H
b
2
MeO'
94%
Acitretin +
(a) LDA, THF; (b) H , I . 2
Acitretin (Soriatane®) The major active metabolite of etretinate, is a second generation monoaromatic retinoid for use in the treatment of severe psoriasis and other dermatoses.(40) It is currently marketed by Roche Holding AG. Two syntheses have been published. The first approach involved regioselective addition of lithium trienediolate 27 (prepared, in situ, by treatment of (2£,4J^-3-methylhexa-2,4-dienoic acid 26 with LDA in THF) to the 90% yield of product that contained 10-30% ll-trans/13cis-RA and 70-90% of the ll-cis/13-cis isomeric?) Upon treatment of this mixture with palladium or rhodium in an inert solvent, the 11-cis double bond selectively isomerized to the corresponding trans double bond without affecting the 13-cis double bond. However, application of this process to commercial scale was limited due to potential contamination of product with traces of the transition metal, potentially causing stability and toxcity issues with the polyene. It has been reported that by performing the Wittig reaction in a polar aprotic solvent e.g. JV,iV-dimethylacetamide in the presence of triethylamine and magnesium chloride as Lewis acid, 13-c/s-RA can be obtained in high selectivity (>98%). Unfortunately yields for this reaction were not reported.(^P)
In Chemical Process Research; Abdel-Magid, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.
Downloaded by STANFORD UNIV GREEN LIBR on July 18, 2012 | http://pubs.acs.org Publication Date: November 25, 2003 | doi: 10.1021/bk-2004-0870.ch005
82 Photochemical isomerization of the mixture of isomers obtained from the Wittig reaction has been reported. Although this process avoids the use of transition metals, the retinoic acids are not very soluble in organic solvents and the reactions need to be performed at high dilution. However, using of the potassium or sodium salt of the retinoic acid and performing the reaction with a photoactivator, such as rose bengal, eliminated some of these issues and allowed the reaction to be carried out at shorter wavelengths (330 nM) than possible in organic solvents (353 nM).(23-25) In addition the alkaline salts of ll-cis and 13-cis-RA are more stable in aqueous solution than the corresponding acids allowing the reactions to be performed at higher concentrations. Thus photochemical isomerization of an isomeric mixture of retinoic acids composed of 23% 13-cw-RA, 64% ll-cw/13-cw-RA and 13% ll-trans/13-trans-RA, using the above protocol (KOH, H 0 , rose bengal) for 2 hr affords a mixture of 66% 13-cis-RA, 24% I Ucis/13-cis-RA and 10% I l-trans/13-trans-RA. After acidification and recrystallization from EtOAc a 53% yield of 13-ds-RA was obatined in >99% purity.(25) A novel process for selective formation of the 13-cis double bond, by condensation of the dienolate of methyl 3-methyl-2-butenoate with P-ionylidene acetaldehyde 36 (9-trans content - 80%), has been reported (Scheme 12).(50) This reaction proceeded by formation of the intermediate lactone 37, which was not isolated. Lactonization resulted in release of a methoxide ion that in turn opened the lactone to afford 13-cis-RA as the carboxylate salt. Acidic work-up, followed by recrystallization from MeOH produced 13-cis-RA in 32% yield, >99% purity (
