Article Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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A Practical Telescoped Three-Step Sequence for the Preparation of (1R,2R)‑2-(4-Bromobenzoyl)cyclohexanecarboxylic Acid: A Key Building Block Used in One of Our Drug Development Projects Staffan Karlsson,*,† Rolf Bergman,‡ Johan Broddefalk,‡ Christian Löfberg,‡ Peter R. Moore,§ Andrew Stark,§ and Hans Emtenas̈ *,† †
Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca R&D Gothenburg, SE-431 83 Mölndal, Sweden ‡ CVRM Medicinal Chemistry, Cardiovascular, Renal and Metabolic Diseases, IMED Biotech Unit, AstraZeneca R&D Gothenburg, SE-431 83 Mölndal, Sweden § Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca R&D Macclesfield, Macclesfield SK10 2NX, U.K. S Supporting Information *
ABSTRACT: A large-scale, robust telescoped process involving acid chloride generation and Friedel−Crafts acylation followed by hydrolysis of an ester was developed for the manufacture of a homochiral disubstituted cyclohexane. Chromatography was avoided, and instead, crystallization was employed to furnish the pure carboxylic acid. This acid was further used as a key building block for the synthesis of drug candidates via amide bond formation using various amines followed by a Suzuki coupling with a pyrazole pinacol ester. The total synthesis of one of the drug candidates on a multihundred gram scale is described.
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INTRODUCTION
Retrosynthesis disconnection of the amide bond and the aryl−heteroaryl bond of compound 1 (route (i)) furnished the three main building blocks A−C (Figure 1). We reasoned that both of these bonds should be easily formed via an amide coupling and an organometallic coupling such as a Suzuki reaction, respectively. The main focus was put on the central cyclohexane core, B, which constituted a common building block for most of the potent inhibitors investigated. The key building block B could potentially be obtained via an organometallic coupling of D with E (route (ii)). In the firstgeneration synthesis for medicinal chemistry needs, racemic building block B (LG = OH) was purchased from one supplier.2 Although the enantiomers were separable by chiral chromatography, the medicinal chemistry approach chose to separate the enantiomers at the API stage. The first-generation synthesis of 1 is depicted in Scheme 1. Starting from the racemic commercially available compound rac-2 and 1,3-dimethylpyrazol-4-amine, a standard amide coupling using TBTU gave compound rac-3, which was sequentially transformed into the corresponding boronate ester rac-4. A Suzuki coupling with bromide 5 gave the racemic API rac-6 in low yield, after which chiral chromatography gave the enantiomerically pure API 1. The first-generation synthesis of compound 1 was reliable and could also be used for the synthesis of an array of analogues to 1 for biological screening activities by varying the bromide used in the Suzuki coupling and the amine in the amide coupling. However, the firstgeneration synthesis was not suitable for large-scale synthesis for several reasons: (a) Starting from commercially available
In order to identify drug candidates, we needed hundreds of grams of compound 1 for preclinical studies (Figure 1).1 Various approaches were evaluated to identify a route that safely and with consistency could be used for the first scale-up campaign and potentially also for future manufacturing.
Figure 1. Retrosynthesis of compound 1. LG = leaving group; Y = boronate ester or halogen; X = halogen or H. © XXXX American Chemical Society
Received: March 1, 2018
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DOI: 10.1021/acs.oprd.8b00066 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
Scheme 1. First-Generation Synthesis of 1
rac-2 required dependence on one or a few suppliers at a high cost. (b) Starting from rac-2 demanded enantioseparation/ resolution, which was expected to be time-consuming and inefficient on a larger scale. (c) An alternative amide coupling reagent had to be identified because TBTU is known to be highly energetic and requires special handling.3 (d) The Suzuki coupling was low-yielding, and therefore, optimization was needed and alternative conditions/reagents would have to be evaluated. Given the short time frame for identifying a new large-scale route that could deliver large quantities of 1, we decided to put most of our efforts into finding an enantioselective route to building blocks of type B or alternatively finding suppliers of a suitable homochiral starting material.
of acid chloride 10 with a metalloorganic reagent obtained from 1,4-dihalobenzene or a Friedel−Crafts reaction with bromobenzene would potentially furnish compound 11 (Scheme 3). Scheme 3. Potential Routes To Obtain Compound 11
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RESULTS AND DISCUSSION The enantioselective synthesis of compounds of type D (Figure 1) can be performed using various methods such as enzymemediated desymmetrization of anhydrides and diesters4 or via other non-enzymatic methods.5 We believed that such an approach would be suitable also for large-scale purposes, and we began to investigate the opportunity to use such a strategy (Scheme 2). The advantage of using such a strategy is that
Thus, attempts were made to selectively transform 1,4dihalosubstituted benzenes into the corresponding monometalated species using metals such as Mg and Zn. This was followed by reaction with preformed acid chloride 10. However, incomplete transmetalation and/or nonselective reaction with acid chloride 10 was observed, resulting in a myriad of various byproducts, and it was clear that this approach was not suitable for scale-up. A literature survey showed that a Friedel−Crafts acylation strategy had previously been utilized for the synthesis of an analogous compound.6 We believed that a similar strategy to obtain 11 could be used, and initial small-scale attempts to react acid chloride 10 with bromobenzene in 1,2-dichloroethane mediated by AlCl3 were promising. However, before we were ready to scale up this reaction following this literature procedure, a few issues first had to be addressed: (i) Acid chloride 10 is a reactive and quite volatile compound, and consequently, isolation of this intermediate should be avoided. (ii) The use of environmentally hazardous 1,2-dichloroethane as the solvent for the Friedel−Crafts reaction was unfavorable, and alternative solvents had to be evaluated. To address these issues, we aimed for a telescoped process in which the isolation of acid chloride 10 was avoided and instead the generation of the acid chloride and the Friedel−Crafts acylation could be run in the same solvent. We also hoped to avoid chromatography and replace with crystallization of the crystalline carboxylic acid 2
Scheme 2. Desymmetrization of Anhydride 7 Mediated by Enzyme or Organocatalyst
potentially 100% of the symmetrical anhydride 7 can be converted to homochiral compound 9 via epimerization of ester 8. However, we soon realized that working with anhydride 7 was associated with risks since this compound is classified as a sensitizer and we also had a few in-house reports of allergic reactions. Thus, we chose to abandon this approach and identify another starting material. Fortunately, we found that homochiral compound 9 (>99% ee) was commercially available at a reasonable cost from a few suppliers. Although an investment in homochiral starting materials is associated with an extra cost, starting from 9 in which the chirality is already in place would give us some extra time to investigate the subsequent organometal coupling. We believed that a coupling B
DOI: 10.1021/acs.oprd.8b00066 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
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Scheme 4. Telescoped Acid Chloride Generation and Friedel−Crafts Acylation Followed by Hydrolysis To Give 2
(Scheme 4). A prerequisite was to find a good method to generate 10 that did not utilize an excess of reagent that would interfere in the next step or require postprocessing of the crude mixture. To avoid 1,2-dichloroethane as the solvent, which is frequently used in Friedel−Crafts reactions, we reasoned that since bromobenzene was used as reagent in the acylation reaction, it might also function as the solvent in both the Friedel−Crafts acylation and the acid chloride generation. Our initial attempts to prepare acid chloride 10 using SOCl2 as the chlorinating agent in rather concentrated suspension of 9 in bromobenzene (∼1.5 relative volume) resulted in slow conversions, and an impractical large-scale process was foreseen. However, upon the addition of a catalytic amount of pyridine,7 a rate enhancement was observed, resulting in full conversion to 10 within 1 h at 75 °C.8 Gratifyingly, only a small excess of SOCl2 was required to reach full conversion to 10. We believed that the HCl generated as a byproduct in the chlorination step and the pyridine catalyst would not interfere in the subsequent Friedel−Crafts acylation. We chose to add the crude solution of acid chloride 10 to a mixture of AlCl3 at rather high concentration in bromobenzene as the solvent and reagent at 0 °C. Fortunately, we found that the reaction took place, furnishing full conversion to compound 11 in 86% assayed yield after an extractive workup. Since high-boiling bromobenzene was used in large excess (∼4 relative volumes, ∼8 equiv) as both the solvent and reagent, product 11 was obtained, after an extractive workup, as a solution in bromobenzene after removal of all of the volatile components. We envisaged that excess bromobenzene could be removed in the subsequent extractive workup after the hydrolysis step. It was found that MeOH (1 relative volume) was required as a cosolvent in the hydrolysis step to obtain one homogeneous phase, which facilitated the hydrolysis. Thus, aqueous NaOH (10 M) was first added to ester 11 in bromobenzene, followed by the addition of MeOH (1 relative volume). After heating at 50 °C for 1 h, full conversion to carboxylic acid 2 was obtained. After removal of the MeOH, the addition of CH2Cl2 and water resulted in two clear phases. Fortunately, the aqueous one contained mainly carboxylic acid 2, and only a trace amount of bromobenzene was detected. After acidification of the aqueous layer and extraction with organic solvent, crude acid 2 was obtained. Fortunately, a single crystallization from MTBE/ EtOAc/heptane furnished pure acid 2 in 62% isolated yield over three steps with 99% ee.9 The reaction gave consistent results on a 50−100 g scale, but for further scale-up we were a bit concerned about the procedure for extraction of acid 2. The need to concentrate the above hydrolysis mixture to remove all of the methanol prior to extraction was time-consuming and demanded further tedious repeated extractions. Furthermore, we sometimes observed that incomplete removal of methanol resulted in a less efficient extraction. To address this issue, we
optimized the workup of carboxylic acid 2 and found that using more dilute aqueous NaOH (5 M), a direct simple acidification of the reaction mixture to pH 1, and addition of CH2Cl2 as the extraction solvent allowed the carboxylic acid to be efficiently extracted into the organic layer without the need to remove the methanol. After removal of the CH2Cl2, the addition of heptane effected crystallization of acid 2, and excess bromobenzene was left in the mother liquor. No erosion in stereoisomeric purity was observed, and with this simplified procedure in hand, we were able to synthesize compound 2 consistently in ∼74% overall yield from 9 on a multihundred gram scale.10 What remained to reach our target 1 were an amide coupling and a Suzuki coupling of 2. We chose to utilize a strategy similar to the first-generation synthesis, in which the Suzuki coupling was performed as the last step. Thus, a good procedure to couple acid 2 with the commercially available amine 1,3-dimethylpyrazole-4-amine was first sought in which hazardous coupling reagents such as TBTU used in the first-generation synthesis were avoided (Scheme 5). Scheme 5. T3P-Mediated Amide Coupling To Give 3
On a large scale, we have had good experiences with propylphosphonic anhydride (T3P) as a coupling reagent since the reaction often is high-yielding and the waste generated is easily removed by aqueous alkaline washes. Thus, we chose to employ T3P as the coupling reagent, which in this case fortunately gave the product 3 in good yield (78%) with acceptable purity. Because of the poor nucleophilicity of the aminopyrazole it was necessary to perform the coupling at elevated temperatures for several days to reach full conversion. The reaction was also performed with consistency on a multihundred gram scale. Amide 3 was obtained as a sticky amorphous solid, and all attempts to obtain a crystalline form failed. We reasoned that the quality of 3 was good enough to be used in the subsequent step, and we hoped to identify a crystalline form at a later stage. Thus, the crude mixture of 3 was dissolved in dioxane and used as such in the subsequent C
DOI: 10.1021/acs.oprd.8b00066 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
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Scheme 6. Synthesis of Boronic Ester 12 through Selective Lithiation of 14
Scheme 7. Synthesis of 1 via Suzuki Reaction Followed by Deprotection
step. What remained to be optimized in the synthesis of API 1 was the Suzuki coupling with pyrazole 5. In the first-generation synthesis, this was accomplished through transformation of rac3 to the corresponding boronate ester rac-4 followed by reaction with commercially available bromide 5 (Scheme 1). We reasoned that a more efficient and convergent approach would be to react bromide 3 with the boronate ester of the pyrazole instead. However, although many unprotected methylpyrazoles are commercially available as their boronic acids or esters, we observed that these performed poorly in the Suzuki coupling and had short shelf lives due to rapid competing protodeborylation. Therefore, we aimed for a good protecting group strategy instead. It was known in the literature that THP-protected pyrazoles can be selectively deprotonated α to the protected nitrogen using a strong base such as butyllithium.11 Quenching with triisopropylborate followed by treatment with pinacol and acetic acid, furnishes the corresponding pinacol ester. We found this method attractive and wanted to evaluate such an approach to obtain compound 12. Unfortunately, we found that protection of methylpyrazole 13 with dihydropyran (DHP) furnished a mixture of regioisomers 14 and 15 with low selectivity (75:25) as a viscous oil (Scheme 6). Even though these regioisomers could be separated by column chromatography, we instead focused on the removal of the undesired regioisomer at a later stage and investigated the possibility of using the 14/15 mixture as such in the subsequent steps. Since the undesired regioisomer 15 cannot be deprotonated by alkyllithium and thereby react with triisopropylborate, we envisaged a process in which the unreacted pyrazole 15 could be removed in the final stage through extractions after removal of the THP protecting group. To our delight, we found that selective deprotonation of 14 using either hexyllithium or butyllithium was possible, probably because of the neighboring THP oxygen, which facilitated
deprotonation through coordination to the lithium. After sequential treatment with triisopropylborate and pinacol followed by an extractive workup, the desired boronate 12 was obtained as a brown viscous oil in low assay purity (∼65% w/w), mainly due to the contaminant 15. The reaction was amenable to synthesis on a large scale and gave consistent results.10 Although an unfavorable noncrystalline form of 12 was obtained in low purity, the brown oil could easily be handled and charged to the reaction vessel in the subsequent step. Also, the product mixture was found to be stable even after long storage at 20 °C, and the impurities did not have a negative impact on the subsequent Suzuki coupling. Therefore, we were confident that the process as such was suitable for further scale-up of 12, and no time was spent identifying conditions for purification. What remained to complete the synthesis was to develop a good process for the Suzuki reaction followed by the deprotection of the THP group (Scheme 7). When the conditions for the first-generation synthesis were used with only small modifications, the Suzuki reaction of boronate 12 and bromide 3 was found to proceed with consistency in good assay yield (∼95% to 16) using a low catalyst loading (1.5 mol %). It was clear that the reverse type of Suzuki reaction compared with the first-generation synthesis was more successful. The final deprotection of the THP group of 16 is worth some attention. Since we did not identify a crystalline form of 16 and to save time, we aimed for a process in which the crude mixture of 16 could be used as such in the subsequent THP deprotection followed by a final purification of API 1 through crystallization. Thus, the solution of crude 16 in EtOAc was treated with MeOH and aqueous HCl, which resulted in removal of the THP protecting group. After an extractive workup by which the undesired pyrazole 13 obtained from 15 finally could be removed, API 1 was obtained as a nonfavorable amorphous solid, albeit in a good overall assay yield from 3. To D
DOI: 10.1021/acs.oprd.8b00066 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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Large-scale reactions were performed using glass reactors equipped with an overhead stirrer. IPCs were recorded either by HPLC or 1H NMR analysis of the crude reaction mixtures. Assays were determined by 1H NMR integration using benzyl benzoate as an internal standard. The enantiomeric purity of 1 was determined using HPLC [(S,S) Whelk-O1 column (4.6 mm × 250 mm), MeOH as the eluent]. The enantiomeric purity of 2 was determined using HPLC [Chiralpak IC column (4.6 mm × 250 mm), heptane/2-propanol/AcOH 80/20/0.1 as the eluent]. High-resolution mass spectrometry with a mass precision ±5 ppm was performed on a QTOF 6530 instrument (Agilent). NMR measurements were performed using a Bruker Avance III spectrometer. LC/MS analyses were recorded on a Waters ZMD with a Waters XTerra MS C8 LC column and detection with an HP 1100 MS diode array detector. (1R,2R)-2-(4-Bromobenzoyl)cyclohexanecarboxylic Acid (2). Acid Chloride Formation. A 20 L reactor equipped with an in-line scrubber containing caustic soda was charged with (1R,2R)-2-(methoxycarbonyl)cyclohexanecarboxylic acid (9) (643 g, 3.42 mol), bromobenzene (3.8 kg), and pyridine (27.4 g, 0.34 mol). Under a low-flow-rate nitrogen purge, the mixture was heated to 70 °C. Thionyl chloride (427 g, 3.59 mol) was slowly charged via subsurface addition during 1 h. This was followed by further stirring for 30 min and then cooling to 20 °C to give the intermediate (1R,2R)-methyl 2(chlorocarbonyl)cyclohexanecarboxylate (10) (4.68 kg, 14.3% w/w, 3.27 mol, 96% yield) as a solution in bromobenzene, which was used as such in the subsequent Friedel−Crafts acylation. Friedel−Crafts Acylation. A 20 L reactor was charged with granulated AlCl3 (1091 g, 8.18 mol) followed by purging with nitrogen. Bromobenzene (3.0 kg, 19.0 mol) was added, and the light-yellow slurry was cooled to +5 °C. A solution of 10 (4.68 kg, 14.3% w/w, 3.27 mol) in bromobenzene was added during 30 min while a reaction temperature of 500 g of 1 for the initial preclinical studies.
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CONCLUSION A robust telescoped three-step approach for the synthesis of key homochiral building block 2 was developed comprising acid chloride generation, Friedel−Crafts acylation, and hydrolysis. Furthermore, we have described the total synthesis of one candidate drug, 1, starting from this building block. As another key step, pyrazole borester 12 was prepared on a large scale via selective sequential deprotonation of THP-protected pyrazole 14 using butyllithium followed by quenching with triisopropyl borate and pinacol. Suzuki coupling followed by deprotection in situ resulted in the final API 1 in 53% overall yield from 9. With the exception of chromatography needed for API 1, all of the purifications were performed using extractions and/or crystallizations.
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EXPERIMENTAL SECTION All of the materials were purchased from commercial suppliers and used as such without further purification. All of the reactions were performed under an atmosphere of nitrogen. E
DOI: 10.1021/acs.oprd.8b00066 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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L × 3). The resulting solid was transferred to a high-vacuum oven for drying at 65 °C for 48 h to provide 1 (565 g, 98% w/ w, 1.37 mol, 92% yield) as a free-flowing light-golden amorphous solid. [Pd] = 24 ppm, 99.9% ee, [α]20 D +101° (c 1.0, CH3CN); 1H NMR (500 MHz, CDCl3) δ 1.28−1.44 (m, 2H), 1.45−1.56 (m, 1H), 1.74−1.84 (m, 1H), 1.85−1.94 (m, 2H), 2.03−2.12 (m, 2H), 2.14 (s, 3H), 2.37 (s, 3H), 2.85−2.95 (m, 1H), 3.70 (s, 3H), 3.73−3.81 (m, 1H), 6.43 (s, 1H), 7.22 (s, 1H), 7.66 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.5 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 10.9, 11.6, 25.4, 25.7, 29.6, 30.7, 38.8, 46.3, 47.7, 102.9, 118.2, 124.0, 125.8, 129.3, 135.0, 137.3, 138.9, 142.8, 149.4, 173.0, 203.6; HRMS (ESI) calcd for C23H28N5O2+ 406.2238 [M + H]+, found 406.2240. 3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12). THP Protection. 2,2,2-Trifluoroacetic acid (11.9 mL, 161 mmol) was added to a solution of 3-methyl-1H-pyrazole (13) (322 g, 3.92 mol) in toluene (450 mL) at 20 °C, and the resulting solution was heated to 90 °C. To this solution was added via syringe pump 3,4-dihydro-2H-pyran (366 mL, 4.01 mol) at a rate of 1 mL/min, and the reaction mixture was stirred at 90 °C for 16 h. More 3,4-dihydro-2H-pyran (7 mL, 77 mmol) was then added, and the reaction mixture was stirred for 5 min at 90 °C. The temperature was then ramped down to 40 °C during 1 h, and the reaction mixture was concentrated under reduced pressure to give a 75/25 mixture of 3-methyl-1-(tetrahydro-2H-pyran-2yl)-1H-pyrazole (14) and 5-methyl-1-(tetrahydro-2H-pyran-2yl)-1H-pyrazole (15) as an oil. The mixture containing 14 (741 g, 65% w/w, 71% yield) was used in the next step without further purification. Lithiation/Borylation. In a 10 L cryoreactor, a solution of the above mixture containing 14 (741 g, 65% w/w, 2.79 mmol) in THF (3 L) was cooled to −57 °C. Butyllithium (2.5 M in hexane, 800 mL, 2.0 mol) and hexyllithium (2.3 M in hexane, 500 mL, 1.15 mol) were added over 30 min while the temperature was maintained below −50 °C.13 Triisopropyl borate (778 mL, 3.31 mol) was then added over 25 min while the temperature was maintained below −40 °C. The solution was allowed to warm to 20 °C, and 2,3-dimethylbutane-2,3-diol (373 g, 3.16 mol) and HOAc (351 mL, 6.14 mol) were added. The mixture was aged at 20 °C for 17 h, and heptane (3.8 L) was added, followed by saturated aqueous NH4Cl (3 L). The phases were separated, and the organic phase was washed with saturated aqueous NaHCO3 (3 L), saturated aqueous NaCl (3 L), and finally water (1 L). The organic layer was concentrated under reduced pressure to give the title compound 12 (864 g, 79% w/w, 84% yield) as an oil. Data for 12 (crude): 1H NMR (500 MHz, CDCl3) δ 1.34 (s, 12H), 1.50−1.58 (m, 1H), 1.64− 1.80 (m, 2H), 1.89−1.99 (m, 1H), 2.01−2.11 (m, 1H), 2.30 (s, 3H), 2.39−2.52 (m, 1H), 3.63−3.71 (m, 1H), 4.04−4.13 (m, 1H), 5.77 (dd, J = 10.5, 2.2 Hz, 1H), 6.52 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 13.3, 23.2, 24.7, 24.9, 25.1, 30.1, 68.2, 84.0, 86.3, 116.1, 148.7; MS m/z 293.2 [M + H]+.
(c 1.0, CH3CN), 98.9% ee; 1H NMR (500 MHz, CDCl3) δ 1.16−1.29 (m, 1H), 1.29−1.53 (m, 3H), 1.77−1.93 (m, 2H), 1.94−2.03 (m, 1H), 2.18−2.28 (m, 1H), 2.86−2.96 (m, 1H), 3.4−3.5 (m, 1H), 7.60 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 11.48 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 25.4, 25.5, 29.0, 29.7, 44.2, 46.6, 128.1, 129.9, 131.9, 134.7, 181.2, 201.7; MS m/z 308.8 [M − H]−. (1R,2R)-2-(4-Bromobenzoyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)cyclohexanecarboxamide (3). A reactor was charged with 2 (850 g, 2.72 mol), 1,3-dimethyl-1H-pyrazol-4amine dihydrochloride (650 g, 3.53 mol), and EtOAc (6.5 L), followed by the addition of Et3N (1.65 kg, 16.4 mol). The mixture was heated to 50 °C, and a solution of T3P (50% in EtOAc, 3.05 kg, 4.77 mol) was added during 10 min while a reaction temperature of 99% ee. (10) A safety assessment for each operation was undertaken, and DSC and/or the Carius tube test was performed. The reaction is unlikely to pose a chemical hazard as long as efficient agitation/cooling can be secured and dose-controlled addition of reagents can be performed to control exotherms and/or gas evolution (see the Experimental Section for details). G
DOI: 10.1021/acs.oprd.8b00066 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
