Article pubs.acs.org/OPRD
The Manufacture of a Homochiral 4‑Silyloxycyclopentenone Intermediate for the Synthesis of Prostaglandin Analogues Julian P. Henschke,*,† Yuanlian Liu,‡ Xiaohong Huang,‡ Yungfa Chen,† Dechao Meng,‡ Lizhen Xia,‡ Xiuqiong Wei,‡ Aiping Xie,‡ Danhong Li,‡ Qiang Huang,‡ Ting Sun,‡ Juan Wang,‡ Xuebin Gu,‡ Xinyan Huang,‡ Longhu Wang,† Jun Xiao,‡ and Shenhai Qiu‡ †
ScinoPharm Taiwan, Ltd., 1 Nan-Ke Eighth Road, Tainan Science Industrial Park, Shan-Hua, Tainan, Taiwan 74144 ScinoPharm (Changshu) Pharmaceutical, Ltd., 16 Dong Zhou Road, Economic Development Zone, Changshu, Jiangsu Province, China 215513
‡
S Supporting Information *
ABSTRACT: A process is described for the synthesis of kilogram quantities of homochiral 4-silyloxycyclopentenone (R)-1, a key intermediate useful for the synthesis of a plurality of prostaglandin analogue drugs. Cyclopentenone (R)-1 was synthesized in 14 isolated steps from furfural. Key steps in the synthesis include a Wittig reaction, Piancatelli rearrangement, and an enzymatic resolution featuring in situ recycling of the undesired enantiomer furnishing the desired homochiral alcohol in ≥99.5% ee. As a retort to the unsatisfactory coformation of about 8% at best of the trans-olefin in the Wittig reaction, a change to the order of several steps and the identification of a recrystallisable, amine salt derivative, 2, allowed the unwanted isomer to be controlled to as low as 0.2%.
■
INTRODUCTION Prostaglandins (PGs) are naturally occurring, bioactive, polyunsaturated, fatty acid derivatives composed of 20 carbon atoms. Despite being highly potent and playing important roles in animal and human physiology, therapeutic applications of prostaglandins and their synthetic analogues as active pharmaceutical ingredients (APIs) have been surprisingly limited, in spite of extensive research efforts in both academia and industry beginning in the 1960s.1 In contrast to typical small-molecule drugs, prostaglandins and their synthetic analogues are stereochemically complex, their syntheses are long, their intermediates are typically oils (rather than crystallisable solids), and they can be chemically unstable. Notwithstanding this, there are a variety of synthetic prostaglandin analogues on the market available for the treatment of a range of conditions including peptic ulcer, hypertension, and fertility control in humans, and veterinary uses.1 PGF2α analogues, such as latanoprost2 (Xalatan), bimatoprost3a (Lumigan), and travoprost4 (Travatan) have achieved success as first-line topical treatments of glaucoma. More recently tafluprost5 (Zioptan) was also introduced into the glaucoma market, whilst bimatoprost (Latisse) was additionally approved for cosmetic use.3b Lubiprostone,6 a bicyclic PGE1 derivative, is the active drug substance in Amitiza, a gastrointestinal drug used for the treatment of chronic idiopathic constipation in adults. It was envisioned that all of these APIs could be accessed from the single, common intermediate, 4-silyloxycyclopentenone (R)-17 (Figure 1). As part of the original platform technology design, the isopropyl ester functionality of this intermediate would act not only as part of the final molecular structure of APIs, such as travoprost and tafluprost, but also as a carboxyl protecting group that could be deprotected at a late © 2012 American Chemical Society
stage in the synthesis of APIs, such as bimatoprost and lubiprostone. The advantages of the use of a single feedstock for a plurality of products is obvious and includes significant time and cost savings during the research and development stage as well as a lowering of manufacturing costs.8 Although the production volumes of these prostaglandin analogues would be small due to their extreme potency (a single dose of each of these drugs is in the order of micrograms), the upstream steps used to make the key diverging (R)-1 intermediate needed to be robust. Because of working on kilograms to tens of kilograms, it was preferable to avoid particularly low or high temperatures, the use of air- and moisture-sensitive reagents, or specialised equipment. Further, the common intermediate had to be of high chemical and stereochemical purity as to be able to provide the downstream APIs with high stereochemical purity to meet the demands of regulatory authorities. This was particularly important given that the single chiral centre of 4-silyloxycyclopentenone (R)-1 was responsible, through chiral induction, for the stereochemistry of up to three chiral centres formed in the subsequent synthetic steps. Of the three main approaches (Corey’s9 lactone approach, the two-component approach,10 and the three-component11 approach) used for prostaglandin and analogue synthesis,12 we favored the two-component approach, as this strategy would provide the degree of divergence that we required. The twocomponent approach comprises installation of the ω-side chain via a 1,4-addition of a vinyl cuprate to a cyclopentenone system already possessing the α-side chain (Figure 1). In this contribution we report our first-generation process for this Received: July 15, 2012 Published: November 15, 2012 1905
dx.doi.org/10.1021/op300188x | Org. Process Res. Dev. 2012, 16, 1905−1916
Organic Process Research & Development
Article
Figure 1. Use of cyclopentenone (R)-1 as a common intermediate in prostaglandin analogue synthesis.
Scheme 1. Retrosynthetic analysis of cyclopentenone (R)-1
Scheme 2. Synthesis of aldehyde 4a
key intermediate, with a focus on the Wittig reaction and how the required levels of geometric and stereochemical purity were achieved.
■
RESULTS AND DISCUSSION Attempted Synthesis of Cyclopentenone (R)-1, via Aldehyde 3. Although a significant number of syntheses of 4hydroxy-2-cyclopenten-1-ones with α-side chains useful for prostaglandin synthesis have been published,7,13 the first approach to the requisite cyclopentenone intermediate (R)-1 that we investigated was based on our retrosynthetic analysis shown in Scheme 1 (top pathway). This approach would rely upon the Piancatelli rearrangement14 of 2-furylcarbinols to 2substituted 4-hydroxy-2-cyclopenten-1-ones, a cis-selective Wittig reaction using the potentially labile aldehyde 3,15 and the enzymatic resolution of 2-substituted 4-hydroxy-2-cyclopenten-1-ones.16 Despite examining different solvents, temperatures, and concentrations and testing normal and reverse addition modes of the ylide and aldehyde, we were unable to convert aldehyde 3 into the desired olefin using the Wittig reaction. Multiple, unidentifiable products were formed due to the instability of aldehyde 3 under basic conditions.17 Synthesis of Aldehyde 4. We envisioned that this problem could be circumvented by exploiting the base-stable nature of the furan ring of aldehyde 4, using it as a latent form of the sensitive 4-silyloxycyclopent-2-enone ring system. This would delay the Piancatelli rearrangement until after the α-side chain had been installed by Wittig reaction (Scheme 1, bottom pathway). To this end silyl ether 5 was prepared from furfural in one pot by reaction with in situ formed allyl zinc bromide followed by trapping of the resultant zinc alkoxide with TBSCl
Reagents and conditions: (a) (i) Allylbromide, Zn, THF, 60−68 °C; (ii) TBSCl, imidazole, 1:1 DMF/THF, r.t., 70−77%; (b) NMO, K2OsO2(OH)4, (DHQ)2PHAL, acetone, H2O, 87%; (c) NalO4, acetone, H2O, r.t., 92−95%. a
(Scheme 2). Dihydroxylation of olefin 5 using NMO in the presence of catalytic K2OsO2(OH)4 and (DHQ)2PHAL,18 affording diol 6, was followed by oxidative cleavage with NaIO4 in aqueous acetone at ambient temperature to give desired aldehyde 4 in about 80% yield over two steps. Preliminary tests suggest that more expedient routes to aldehyde 4 exist.19 On a 3-kg scale, furfural was converted to silyl ether 5 in one reactor in 70−77% yield with 93−96% GC purity after fractional distillation. Nineteen kilograms of olefin 5 was dihydroxylated in a single batch, providing diol 6 (20.1 kg) in 87% yield that was then used without purification. Oxidative cleavage of diol 6 proceeded smoothly on a 0.2−0.6 kg scale, supplying oily aldehyde 4 in 92−95% yield (91−95% GC purity), following rapid flushing through a plug of silica gel. Aldehyde 4 was dissolved in THF under an inert atmosphere and used directly to avoid oxidation.20 A 20.1-kg-scale run 1906
dx.doi.org/10.1021/op300188x | Org. Process Res. Dev. 2012, 16, 1905−1916
Organic Process Research & Development
Article
absence of crystalline intermediates in our original process. Although the trans-isomer eluted slightly faster than cis-isomer, 9, column chromatography did not present a viable method for enrichment of the cis-isomer.24 With an immediate need to demonstrate the platform technology depicted in Figure 1 and to allow development of the GMP steps (i.e., (R)-1 through to the APIs) to begin, the process was moved to scale-up, albeit with the intention to return for a more thorough investigation of the Wittig reaction to reduce the levels of trans-isomer (see below). The first lot of ester 8 (10.1 kg; 14 batches of Wittig reaction and 3 batches of esterification) was prepared by a contractor. The Wittig reaction was conducted at −25 to −30 °C in THF using NaHMDS as the base, followed by esterification (i-PrI, K2CO3 at 55 °C in acetone25) and column chromatography, providing purified product 8 (91−95% GC purity). Desilylation (TBAF in THF) of a sample of silyl ether 8 gave alcohol 14 that upon HPLC analysis revealed that this lot of Wittig reaction product contained 12.2 mol% (relative to the mixture of cis- and transisomers) of the undesired trans-isomer.26 Investigations were resumed with a cosolvent study of the Wittig reaction step in THF at −15 °C, generating ylide 10b using NaHMDS as the base (Table 1, entry 1).27 The best improvement in cis-/trans-selectivity was observed when phosphoramide cosolvents HMPA and tripyrrolidinophosphoric acid triamide (TPPA) were used (entries 4−9).28 Due to its toxicity, HMPA was replaced with the pyrrolidine analogue, TPPA.30 When the amount of TPPA in THF was increased from 5 to 50% (entries 5 to 9) the trans-isomer steadily decreased from 10.2 to 7.7 mol%, albeit with a large drop in both the yield (from 75% down to 14%) and purity of olefin 8 along with a significant increase of diene side product 15. The use of other polar additives in THF (entries 10−15) provided no overall improvement and were inferior to the two phosphoramide solvents tested. Using 10% TPPA in THF and NaHMDS, a study of the influence of temperature (−20 to −78 °C) on the yield and cis-/trans-selectivity (entries 16−19) suggested that the best temperature was around −20 to −35 °C. Demonstration of these conditions (0.4 kg scale of 4 based on entry 17) in our kilo laboratory, followed by conversion of analytical test samples to ester 14 (entries 20 and 21), showed that about 8.0−8.3 mol% trans-isomer had formed (70−74% yield of 8 over two steps from 4), consistent with laboratoryscale runs.29 As a result of this study, the original conditions (LiHMDS in THF) were improved such that the level of undesired transisomer could be reduced from ∼20 mol% down to ∼8 mol%, whilst maintaining the purity of the product, without necessitating the use of dedicated cryogenic equipment.26 Although ostensibly small and falling short of our goal of ≤3%, the improvement in selectivity had a significant impact on the downstream API syntheses through reduced burden placed on the API and API precursor purification operations. As will be discussed below, this improvement was later operated together with a process modification that ultimately allowed levels of less than 1% of the trans-isomer to be achieved. Deprotection of Silyl Ether 8 and Piancatelli Rearrangement. Silyl ether 8 was treated with 1 equiv of TBAF in THF at 35−40 °C to furnish alcohol 14 (Scheme 3) in a quantitative yield on a 6.5 kg scale (77% GC purity). This material was used as is in the next step without further purification.
provided about 18 kg of crude aldehyde 4 with 93% purity by GC. Wittig Reaction of Aldehyde 4. Owing to the failure of the Wittig reaction of aldehyde 4 and putative ester ylide 7 (Figure 2; instead yielding 3-(furan-2-yl)prop-2-enal and
Figure 2. Miscellaneous compounds and Wittig reaction side products.
cyclopentenone) a two-step approach for the synthesis of ester 8 involving the Wittig reaction followed by esterification of the resulting carboxylic acid 9 was required (Scheme 3). A study of the Wittig reaction was initiated with a base screen. Scheme 3. Synthesis of ester 8a
a
Reagents and conditions: (a) PPh3, PhMe, 87%; (b) (i) LiHMDS, NaH, NaHMDS, t-BuOK, or KHMDS/THF, THF, 0−10 °C; (ii) 4, THF, 98% GC purity) using neat vinyl acetate at 38−42 °C and the free enzyme, Lipase PS “Amano” SD.39 The reaction was terminated at 33 h when 2.7% of (R)-alcohol (R)-16 remained. Once filtration and concentration were complete, a mixture of (R)-acetate (R)-17 with 96.7% ee and unreacted (S)-alcohol (S)-16 with 89.6% ee were obtained. As per Spur et al.’s adapted protocol,33a a Mitsunobu inversion of the (R)acetate (R)-17/(S)-alcohol (S)-16 mixture with formic acid was conducted directly, without prior chromatographic separation, and the resulting 1:1 mixture of the (R)-acetate and (R)formate (18) was purified and then treated with guanidine in MeOH at 0−10 °C to provide 94% GC pure (R)-alcohol (R)16 with 91% ee in 92% yield (based on racemic alcohol rac-16). An enantiopurity upgrade was then accomplished by enzymatic reprocessing, but this time the resolution step was followed by column chromatography to remove the undesired (S)-alcohol, providing 4.34 kg of 98% GC pure (R)-acetate (R)-17 with 99.9% ee.40 Finally, guanidinolysis supplied 3.38 kg (87% yield) of 94% GC pure (R)-alcohol (R)-16 in which its (S)enantiomer was not detected. Thus, over the double enzymatic resolution, Mitsunobu inversion and guanidinolysis steps a 72% yield of high stereochemical purity (R)-alcohol (R)-16 was obtained calculated on the basis of both enantiomorphs of the racemic alcohol input. Finally, protection41 of about 3.4 kg of (R)-16 with TBSCl in DMF in the presence of imidazole at 20−25 °C furnished key intermediate (R)-1 with 99.5% ee, 98% GC purity in 82% yield following column chromatography (Scheme 5). HPLC analysis
Scheme 6. Improved process for the synthesis of 14 and (R)1a
a
Reagents and conditions: (a) (i) TBAF, MTBE, reflux; (ii) 0.5 M HCl, 80−90%; (b) (i) MeOC6H4CH2NH2, MeCN, r.t., then 50 °C to recrystallise, 92%; (ii) Optionally recrystallize, 93%; (c) i-PrI, Cs2CO3, acetone, reflux, quantitative; (d) As per original process. 1909
dx.doi.org/10.1021/op300188x | Org. Process Res. Dev. 2012, 16, 1905−1916
Organic Process Research & Development
Article
chromatography steps might be eliminated by identification of new crystalline derivatives of intermediates. Finally, it is worth commenting on the choice of the isopropyl ester of cyclopentenone (R)-1 that was integral to our original strategy depicted in Figure 1. As we have disclosed elsewhere,7b,48 this ester is not end-product or structure limiting in that it serves as both a carboxyl protecting group and as part of the final drug structure for some products (i.e., for travoprost7b) or as a protecting group that can be converted downstream to an amide by aminolysis (i.e., for bimatoprost7b) or to the parent carboxylic acid (i.e., for lubiprostone48) by enzymatic hydrolysis. Further, this ester proved to be resistant to hydrolysis in the Piancatelli rearrangement and transesterification in the enzymatic resolution steps.
methoxybenzylamine in EtOAc, the three others were initially obtained as sticky solids. Due to the significant rate of background aminolysis of EtOAc,45 further solvent screening (MTBE, MIBK, MeCN) was required. MeCN was identified as the most preferred solvent for recrystallisation of 4-methoxybenzylamine salt 2, supplying a high yield (94%) and high enrichment of the cis-isomer. With these results in hand, a scalable process to convert crude, trans-isomer-contaminated Wittig reaction carboxylic acid 9 into pure ester cis-14 was now in sight. On laboratory-tokilogram scales, desilylation of crude Wittig reaction product 946 with >70% potency assay and 80% HPLC purity with TBAF in MTBE followed by a 0.5 M HCl quench provided hydroxycarboxylic acid 19 with 62−65% potency assay in 80− 93% assay yield. Recrystallisation of the crude acid as its 4methoxybenzylamine salt from hot MeCN with seeding gave 83−92% assay yields of 4-methoxybenzylamine salt 2 with 98.0−98.5% HPLC purity. This salt was contaminated with less than 1 mol% of the trans-isomer, demonstrating the utility of the new process. Although this was low enough for our requirements, if necessary the trans-isomer could be reduced down to 0.2 mol% by a second recrystallisation of the salt from MeCN, as was demonstrated on about half-kilogram scales (92−97% yield). Direct esterification of recrystallised salt 2, without a saltbreaking step, was demonstrated on a 0.7-kg scale by treatment with isopropyl iodide in the presence of Cs2CO347 under reflux in acetone. Isopropyl ester 14, which was an intermediate in the original process, was acquired as an oil in an almost quantitative yield with ≥98% HPLC purity without purification. The unalkylated amine was recovered from the aqueous phase of the acid wash step for recycling. Using the redesigned process described above, one chromatography step was eliminated from the original process, and with a single recrystallization of the salt intermediate 2 on a 1.0-kg scale, an overall yield of about 70% based on crude 9 was achieved with the trans-isomer lowered to 0.7% by HPLC. Conversion of this through the remaining steps of the synthetic route provided the cyclopentenone (R)-1 with 99.8% ee and only 0.62% of the trans-isomer, demonstrating good control of chiral purity and adequate control of the geometric isomer.
■
EXPERIMENTAL SECTION General. HPLC analyses were conducted using Agilent 1100 and 1200 HPLC systems. GC analyses were conducted using Agilent 6890 and 7890 GC systems. HPLC and GC purity is reported by area%. 1H and 13C NMR spectra were acquired using a Varian, Mercury Plus 300 MHz spectrometer. EIMS data were acquired using an Agilent 7890 GC system with a 5975C MSD. ESI data was acquired using an Agilent 1200 HPLC system coupled with a 6120 MSD. HRMS data was acquired using a Bruker APEX III 7.0 FTMS system. IR data was acquired using a Nicolet Avatar 360 FT-IR system. The specific rotation was calculated from data obtained using a Rudolph Autopol III polarimeter. Melting points were measured using Shanghai Jingke Scientific Instrument Co., Ltd.’s WRR melting point apparatus. The enzymatic resolution of rac-16 was monitored throughout (both enantiomorphs and cis- and trans-geometric isomers of both the alcohol ((R)-16, (S)-16, trans-(R)-16, trans-(S)-16 elute at about 49.0, 52.5, 55.3, 67.0 min, respectively) and the acetate esters ((R)-17, (S)-17, trans-(R)-17, trans-(S)-17 elute at about 25.0, 29.6, 31.7, 35.0 min, respectively) are separated) using an Agilent HPLC system (as above) monitoring at 216 nm equipped with a Chiralcel OJ-H column (250 mm × 4.6 mm, 5 μm) maintained at 25 °C using a 100:2 n-hexane/isopropanol mobile phase (isocratic) with a flow rate of 1.2 mL/min. The ee of (R)-1 ((R)-1 and (S)-1 elute at about 20.4 and 24.8 min, respectively) was determined using an Agilent HPLC system (as above) monitoring at 220 nm equipped with a Chiralcel OD-3 column (150 mm × 4.6 mm, 3 μm) maintained at 20 °C using a 99:1 n-hexane/isopropanol mobile phase (isocratic) with a flow rate of 0.2 mL/min. The cis- and trans-geometric isomer ratio of (R)-1 and trans-(R)-1 was determined using the same HPLC system ((R)-1 and trans-(R)-1 elute at about 20.4 and 21.6 min, respectively). The cis- and trans-geometric isomer ratio of 2 (cis-2 and trans-2 elute at 10.1 and 11.6 min, respectively) was determined using an Agilent HPLC system (as above) monitoring at 215 nm equipped with a Zorbax SBC18 column (150 mm × 4.6 mm, 5 μm) maintained at 30 °C using a 90:10 10 mM K2HPO4 (pH = 6.0)/MeCN for 0−11 min (isocratic), then 90 to 50:10 to 50 10 mM K2HPO4 (pH = 6.0)/MeCN (linear gradient) from 11 to 15 min, then 50 to 20:50 to 80 10 mM K2HPO4 (pH = 6.0)/MeCN (linear gradient) for 15−20 min, then 20:80 10 mM K2HPO4 (pH = 6.0)/MeCN (isocratic) for 20−28 min as the mobile phase with a flow rate of 1.5 mL/min. The cis- and trans-geometric isomer ratio of 14 (cis-14 and trans-14 elute at 14.6 and 15.3 min, respectively) was determined using an Agilent HPLC system (as above) monitoring at 215 nm equipped with a
■
CONCLUSION In summary, a robust and scalable process for the manufacture of the homochiral key intermediate cyclopentenone (R)-1, which is useful as an intermediate for the synthesis of prostaglandin analogues, has been developed. Cyclopentenone (R)-1 was produced on multikilogram scales with a high chemical and chiral purity in 14 steps, starting with furfural. Controlling the level of the undesired trans-isomer formed in the Wittig reaction that tracked through to the APIs was later addressed by development of improved Wittig reaction conditions followed by recrystallisation of an amine salt derivative of hydroxycarboxylic acid intermediate 19. The high enantiopurity of cyclopentenone (R)-1 was achieved through a double enzymatic resolution protocol adapted from reported procedures, making use of both enantiomers of the original racemate, in good yield. Improvements in process efficiency are still required, and these, with a particular focus on the Piancatelli rearrangement, will be addressed in future process development. A more expedient synthesis of aldehyde 4 is sought, and telescoping of reaction steps would provide much benefit. Further, additional 1910
dx.doi.org/10.1021/op300188x | Org. Process Res. Dev. 2012, 16, 1905−1916
Organic Process Research & Development
Article
Zorbax SB-C18 column (150 mm × 4.6 mm, 5 μm) maintained at 30 °C using a 80 to 60:20 to 40 10 mM KH2PO4 (pH = 3.0)/MeCN for 0−5 min (linear gradient), then 60:40 10 mM KH2PO4 (pH = 3.0)/MeCN (isocratic) from 5 to 18 min, then 60 to 20:40 to 80 10 mM KH2PO4 (pH = 3.0)/MeCN (linear gradient) for 18−20 min, then 20:80 10 mM KH2PO4 (pH = 3.0)/MeCN (isocratic) for 20−28 min as the mobile phase with a flow rate of 1.5 mL/min. Synthesis of 4-(tert-Butyldimethylsilyloxy)-4-(furan-2yl)-butene (5). To a stirred mixture of zinc (2.475 kg, 38.08 mol) and anhydrous THF (5.874 kg) at 60−65 °C in a 20-L reactor was added a 4% portion of allyl bromide (4.587 kg, 38 mol) and furfural (3.3 kg, 34.38 mol) in anhydrous THF (2.937 kg). The mixture was stirred at 60−65 °C until the reaction had initiated (as indicated by reflux); then the remaining 96% of the mixture was added dropwise without any heating. After the addition was complete (3 h), the mixture was heated again until the reaction was complete (GC analysis). The mixture was cooled to
