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Adventures in Atropisomerism: Development of a Robust, Diastereoselective, Lithium-Catalyzed Atropisomer-Forming API Step Steven R. Wisniewski, Ronald Carrasquillo-Flores, Federico Lora gonzalez, Antonio Ramirez, Matthew Casey, Maxime C. Soumeillant, Thomas M. Razler, and Brendan Mack Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 11 Sep 2018 Downloaded from http://pubs.acs.org on September 11, 2018
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Organic Process Research & Development
Adventures in Atropisomerism: Development of a Robust, Diastereoselective, Lithium-Catalyzed Atropisomer-Forming API Step Steven R. Wisniewski,* Ronald Carrasquillo-Flores, Federico Lora Gonzalez, Antonio Ramirez, Matthew Casey, Maxime Soumeillant, Thomas M. Razler, Brendan Mack Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States
ABSTRACT: The final step in the route to BMS-986142, a reversible inhibitor of the BTK enzyme, involves the diastereoselective construction of an atropisomeric bond during the base-mediated cyclization of the quinazolinedione fragment. Optimization of the reaction to minimize formation of the undesired atropisomer led to the discovery that the amount of the base and nature of the counterion play a vital role in the diastereoselectivity of the reaction. The highest diastereoselectivities were observed with a catalytic amount of LiOt-Bu. Development of a crystallization to selectively purge the undesired atropisomer is reported. Interestingly, ripening of the crystalline API was observed and further investigated, leading to a significant increase in purity of the active pharmaceutical ingredient.
KEYWORDS: Atropisomer, Ripening, API-Step, Bruton’s Tyrosine Kinase, Chiral Axis
INTRODUCTION Developing a stereoselective route to prepare an active pharmaceutical ingredient (API) with multiple chiral axes can be challenging since atropisomer isomerization must be prevented during the reaction, work-up, isolation, and storage. BMS-9861421 (1A) is a reversible inhibitor of the BTK enzyme with two chiral axes and four interconvertible atropisomers by rotation about the CarylN bond (1B), the Caryl-Caryl bond (1C), or both bonds (1D) (Figure 1). In solution, the equilibrium concentration between all four atropisomers corresponds to a nearly statistical 1:1:1:1 distribution.
Figure 1. Structure and atropisomers of BMS-986142 (1A) with interconversion barriers calculated at the B3LYP/6-31G(d) level of theory.2 In the route to BMS-986142,3 the Caryl-Caryl chiral axis is formed through an asymmetric Suzuki coupling that affords the desired biaryl 3 in 87% yield and 14:1 dr (eq 1). The atropisomer isomerization of 3 is not observed under an array of reaction conditions and moderate temperatures (K was observed across a range of bases. Organic bases6 provided low levels of conversion or low levels of diastereoselectivity (i.e. DBU). Calculations of the tetrahedral intermediates suggest a preferred Li-F interaction in the path to the desired atropisomer.3
Figure 2. Temperature dependence of the isomerization of 1A to 1B. Rates were extrapolated from data collected over 24 h age times. The rates were observed to be independent of the concentration of 1A at all temperatures (0th order kinetics). RESULTS AND DISCUSSION Optimization of the API-forming step began by determining the effect of the leaving group on the diastereoselectivity of the reaction (Table 1). With stoichiometric KOt-Bu as a base at 20 °C, branched substitution had a detrimental effect as isopropyl and benzyl carbamates displayed low selectivity. Interestingly, cyclization of a phenyl carbamate inverts the selectivity such that the formation of 1B is favored (entry 5). A straight chain alkyl group provides the highest levels of selectivity (up to 6:1 dr, entry 6); increasing the length of the chain from methyl to n-ethyl to npropyl led us to target the n-propyl carbamate as the synthetic precursor. Table 1. Effect of the Leaving Group on the Diastereoselectivity of the API-Forming Reaction
Figure 3. Counterion effect on the diastereoselectivity of the APIforming reaction A study of eight different lithium bases was completed in MeTHF with 5 mol % base, further demonstrating that the counterion of the base is much more important than the pKa of the corresponding conjugated acids (Figure 4). Because the base is only catalytic, after the first 5 mol % conversion, the active base is presumably LiOn-Pr, leading to similar diastereoselectivities for each of the lithium bases tested.
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Organic Process Research & Development chosen as the optimized reaction conditions to conserve solvent. Based on the significant range in selectivity, we believe that these differences are attributed to the ability of organoltihium species to self-associate to form higher order aggregates. Therefore the desired selectivity is achieved by finding an addition order to prefer one type of aggregation of the lithium enolate.10
Table 2. Order of Addition Optimization
Figure 4. Diastereoselectivity of the API-forming reaction with various lithium bases (5 mol %) vs pKa values of the corresponding conjugated acids.7 As the lithium bases provided 1A in similar dr, LiOt-Bu was chosen for further optimization because of its low cost and stability in THF solution. A solvent screen with LiOt-Bu was completed (Figure 5), which showed dioxane as a superior solvent, closely followed by MeTHF. Under the optimized conditions, dioxane afforded 1A in ~40:1 dr. As this reaction was the API-forming step, the inherent toxicity associated with dioxane8 led us to choose MeTHF as the reaction solvent.
Figure 5. Diastereoselectivity of the API-forming reaction in various solvents with LiOt-Bu (5 mol %). Unoptimized reaction conditions: 10 vol, rt, 2 h. Optimized conditions: Dioxane (40 L/kg total) or MeTHF (25 L/kg total), reverse addition of substrate to base. Testing the various addition orders9 (Table 2) demonstrated the importance of the relative concentration of the reactants in controlling the level of 1B. Diastereoselectivities were greatly improved by slowly adding 3 as a solution in MeTHF to a solution of LiOt-Bu (entry 3) relative to having both reagents in the reactor (entry 1) or the addition of the base solution (entry 2). Further, higher dilution and slower addition times improved the dr values (entries 4-8). As the increase in selectivity from 25 to 40 L/kg was not significant, 25 L/kg with a 2 h addition time was
Entry
Pen Solution (L/kg)
LiOt-Bu Solution (L/kg)
Addition Time (h)
Addition Type
dr
1 2 3 4 5 6 7 8
10 10 10 17 3 3 3 3
10 10 10 3 17 17 22 40
N/A 1 1 1 1 2 2 2
One-pot Forward Reverse Reverse Reverse Reverse Reverse Reverse
13 13 20 19 23 24 25 28
The last variables analyzed were the amount of base and reaction temperature.11 Decreasing the reaction temperature increased the formation of 1B; however, increasing the temperature from 20 to 40 °C had no impact on the selectivity. At temperatures higher than 40 °C, diastereoselectivity was lowered presumably due to rotation about the C–N atropisomeric bond. The highest selectivity was observed with a base charge of 5-10 mol %; further increasing the amount of base led to an increase in the formation of 1B. Optimization of these variables led to a process where a solution of 3 (5 vol) was charged to a reaction containing LiOt-Bu (5 mol %) in MeTHF (20 vol) over 2 h at 25 °C, consistently affording 3.5-3.8 AP of 1B. We next turned our attention to the development of an isolation that would selectively crystallize the desired atropisomer 1A and avoid the use of chromatography. The critical impurity 1B had to be controlled in the isolated product, meaning a purge of at least 75% would be required to avoid a recrystallization. Based on the kinetic isomerization data,12 the temperature of the work-up and isolation is vital to prevent any additional formation of the undesired atropisomer 1B. Aging the reaction stream led to crystallization of the MeTHF solvate of 1A as a poorly filtered solid with little purge of the atropisomer. This solvate was isolated and recrystallized with an array of solvents to determine a path forward (Table 3).13 The crystallization solvents tested were based on solubility data of BMS-986142. The API formed a solvate with practically every solvent, and therefore the adequate choice of crystallization solvent was key to avoid a form conversion during the addition of the anti-solvent. Of the solvent combinations tested, an alcohol anti-solvent was required to form an easily filterable form of the API. Regardless of the main solvent (EtOAc, diethoxymethane [DEM], DMAc), the anti-solvent that provided the most purging during the crystallization was MeOH (entries 1-9). A solvent screen was then completed with MeOH as the antisolvent, which showed that acetone provided ~20% greater purge than any other solvent (entries 10-13). Switching to EtOH did not improve the purging of the atropisomer (entry 14). We therefore began investigating acetone/MeOH as the solvent system for isolation.
Table 3. Crystallization of the MeTHF Solvate of 1A
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Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Solvent
% Reduction of 1A a ML Conc b (wt%) Filterable?
EtOAc/IPA EtOAc/ACN EtOAc/MeOH DEM/IPA DEM/ACN DEM/MeOH DMAc/H2O DMAc/ACN DMAc/MeOH MeOAc/MeOH IPAc/MeOH MIBK/MeOH nBuOH/MeOH Acetone/MeOH Acetone/EtOH Acetone/IPA
4 14 57 17 23 41 25 32 36 57 40 25 55 76 49
1 2 0.5 1 2 0.4 2 2 0.7 1 0.7 1 0.7 0.8 0.5 Did not crystallize
Yes No Yes Yes No Yes No No Yes Yes Yes Yes Yes Yes Yes
a
Relative to 1A in MeTHF Solvate b Mother Liquor Concentration of 1A
Development of this crystallization quickly showed the importance of self-nucleation. At methanol concentrations below 30%, Form A of the API will crystallize (Figure 6, left). Further addition of methanol would cause a slurry-to-slurry form conversion to Form B (Figure 6, right), resulting in variable 67-80% purging of the atropisomer. However, simply increasing the crystallization temperature and charging 35% MeOH before cooling to initiate crystallization resulted in direct formation of the desired Form B along with a more controlled crystallization, with an increased 76-93% purge of the atropisomer. By performing the crystallization under these conditions, we mitigate the risk of Form A and do not require seeding the crystallization.
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consumed 40 L/kg of acetone. To improve cycle time and develop a greener process, we investigated the effect of a three solvent crystallization with MeTHF, acetone, and MeOH, and discovered that 4 L/kg MeTHF, 1.5 L/kg acetone, and 5.3 L/kg MeOH consistently provided ~75% purging (~2.8 AP) of atropisomer 1B. This solvent system did not require seeding with 1A to induce crystallization. The crystallization was performed by distilling the batch to 5 L/kg (in MeTHF), warming to 35 °C, and adding acetone and MeOH while keeping the batch above 30 °C to prevent crystallization of Form A. The batch was then cooled to 20 °C over 1 h to induce spontaneous nucleation of Form B. Interestingly, holding the batch at 20 °C overnight further purged atropisomer 1B by an additional 5-10% (Figure 7). This further reduction could be attributed to two phenomena: significant desaturation of the product overnight (which was confirmed experimentally to not be the case), or a ripening effect where impure material is dissolved into the bulk and pure material is deposited onto the solids.15 Because the nucleation of the Form B solids is spontaneous and rapid, and the solubility of 1B (16.5 wt %) is significantly higher than the solubility of 1A (3.3 wt %), we hypothesize that the majority of the impurity in the solids was entrapped during the initial nucleation event. Furthermore, it was found that repeated heat cycling (20-35-20 °C, 0.6 cycles/h, Figure 7, orange line) improves the rate and magnitude of this ripening effect, presumably from the increased solubility of Form B at elevated temperatures. At 35 °C, the increase in purging of the atropisomer outweighs the small amount of atropisomer that forms from isomerization during the hold at elevated temperatures. In a separate experiment, it was found that a slurry of the Form B in MeTHF/acetone/MeOH held over a long period of time (11 days) at 0°C, in a vial with a stir bar, completely purged the atropisomer from the solids (the measured purity of the product in the solid was >99.95 AP). This experiment further corroborates the hypothesis that entrapment is the key culprit to the impurity in the solid, and that ripening (in this case enhanced by a grinding effect) can aid the impurity purge. Based on this observation, the implementation of a wet mill further improved the rate and magnitude of the purge of 1B. The use of the wet mill (2500 RPM, IKA Works UTL-25 Turrax wet mill with fine configuration)16 led to the highest purging of the atropisomer in the shortest amount of time (Figure 7, gray line). Although this particular experiment was performed on a lab-scale (20 g), the same effect was observed in the pilot plant at 40 kg.
Figure 6. Form A (left) and Form B (right) of BMS-986142 (1A) To study the interconversion of the two forms, an experiment where seeds of 1A were added after 10% MeOH was monitored using an FBRM probe.14 Slow addition of MeOH caused desaturation until rapid conversion to the Form B. The final atropisomer level was 1.29 AP, a reduction of only 67%. Alternatively, seeding at 40% MeOH with 1A at an elevated temperature followed by cooling to 20°C resulted in crystallization of the desired Form B. After the remainder of the MeOH addition, the final atropisomer level was 0.43 AP, a reduction of 89%. We therefore sought a process to selectively crystallize Form B to maximize removal of the undesired atropisomer. Although effective in purging the undesired atropisomer 1B (see Table 3), the acetone/MeOH solvent system required a solvent swap from the reaction solvent MeTHF to acetone, which
Figure 7. Comparison of ripening by various methods
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Organic Process Research & Development A robust crystallization was developed with strict control of the atropisomer in the wet cake (
