Communication pubs.acs.org/OPRD
Kiloscale Buchwald−Hartwig Amination: Optimized Coupling of Base-Sensitive 6‑Bromoisoquinoline-1-carbonitrile with (S)‑3-Amino2-methylpropan-1-ol Jeffrey B. Sperry,*,† Kristin E. Price Wiglesworth,† Ian Edmonds,‡ Phillip Fiore,‡ David C. Boyles,† David B. Damon,† Roberta L. Dorow,† Eugene L. Piatnitski Chekler,§ Jonathan Langille,§ and Jotham W. Coe§ †
Chemical Research and Development, Pfizer, Inc., 558 Eastern Point Road, Groton, Connecticut 06340, United States Bridge Organics, 311 West Washington Street, Vicksburg, Michigan 49097, United States § Pfizer Worldwide Medicinal Chemistry, Pfizer, Inc., 558 Eastern Point Road, Groton, Connecticut 06340, United States ‡
S Supporting Information *
repeatedly in the scale-up of pharmaceuticals.10 As with many transition-metal catalyzed transformations, the number of variables associated with this reaction guarantees a significant amount of development work will be required to optimize this reaction for any given substrate. In this communication, we describe the development and scale-up of a Buchwald−Hartwig coupling reaction between a heterocyclic aryl bromide and a chiral primary amine that limits the use of the costly chiral amine component as well as formation of biaryl byproducts.
ABSTRACT: This work describes the optimization and scale-up of a Buchwald−Hartwig amination reaction for the preparation of a pharmaceutical intermediate. This C− N bond formation is challenged by the use of a chiral primary amine, which both adds cost and favors formation of biaryl byproducts. In order to develop a scalable process, a number of factors had to be investigated including catalyst selection and stoichiometry of the chiral amine. These all needed to be optimized while maintaining low palladium levels in the isolated product. The reaction was found to be most effective using Pd(dba)2 with BINAP and Cs2CO3 in THF. When executed on 2.5 kg scale, these conditions provided 2.06 kg of the desired product in 80% yield with only 73 ppm residual palladium. To date, this process has been successfully executed to produce more than 12 kg of compound (S)-3.
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RESULTS AND DISCUSSION The conversion of 6-bromoisoquinoline-1-carbonitrile 1 to rac3 (Scheme 1) was explored as a first step to synthesize an active pharmaceutical ingredient in early development. This transformation could be facilitated by a Buchwald−Hartwig amination. The main catalytic cycle for the Buchwald−Hartwig amination reaction involves (a) insertion of the palladium into the Ar−Br bond, (b) formation of the Pd(II) amido complex via coordination with the amine, rac-2, and formal elimination of HBr, and (c) reductive elimination to regenerate Pd(0) and to release product (Scheme 1). In the case of a primary amine such as rac-2, a second undesired pathway is also available that involves coordination of aryl product (rac-3) in place of the primary amine (e) that will generate the biaryl product (rac-5) via steps (f) and (g). The relative rate of formation of the Pd(II) amido complex with the primary amine (rac-2) and with the secondary amine (rac-3) will be largely dependent on the catalyst, base, and solvent selected.6a If the rate-determining step, with a given catalyst/base pairing, is the deprotonation of the amine, the relatively low pKa of the secondary amine (rac3) could bias the reaction towards the undesired pathway. Beyond catalyst, base, and solvent choice, the reaction’s selectivity could also be biased by a large excess of primary amine, which, in this case, would only be practical using racemic material. When initially developed, chemists in Medicinal Chemistry employed a large excess of primary amine to bias the selectivity and a chelating ligand (Scheme 2). The coupling of 6-
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INTRODUCTION In 1983, Migita et al. first described the metal-catalyzed conversion of aryl halides to arylamines via a tributyltin amide.1 More than a decade later, in 1995, Buchwald2 and Hartwig3 concurrently published results on tin-free aminations of aryl halides. The Buchwald−Hartwig amination reaction provided a means to construct aryl amines from aryl halides and amines in the presence of a palladium catalyst and a base. This reaction provided an alternative, not only to Migita chemistry but also to traditional amination routes such as the Ullmann coupling,4 nitration, or benzyne chemistry.5 These methods require high temperatures, can involve highly reactive intermediates, and may lead to formation of the biaryl or isomeric byproducts that are typically avoided in the Buchwald−Hartwig chemistry. Since the disclosures by Buchwald and Hartwig in 1995, the transition-metal catalyzed C−N amination reaction has initiated myriad investigations6 including development of new catalysts7 to broaden the substrate scope and improve yields. Investigations have been carried out to elucidate the mechanism6b of this reaction as well as the roles of base8 and solvent.9 As a testament to the utility of this transformation, the Buchwald−Hartwig amination reaction has been performed © XXXX American Chemical Society
Received: July 11, 2014
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dx.doi.org/10.1021/op5002319 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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Scheme 1. Mechanism11 of Desired Buchwald−Hartwig Amination Reaction
Scheme 2. Medicinal Chemistry Conditions for Buchwald− Hartwig Amination Reaction
Scheme 3. Byproduct Formation from Nucleophilic Bases
bromoisoquinoline-1-carbonitrile (1) with racemic 3-amino-2methylpropan-1-ol (rac-2) (1.8 equiv) was performed with Pd2(dba)3 (10 mol %) as the precatalyst in the presence of 1 equiv of racemic BINAP and 2.5 equiv of K3PO4 in 100 volumes of DMSO at 80 °C. After an aqueous work-up and silica gel chromatography, the desired product was isolated in 23% yield. Although sufficient for generating small quantities of material, this reaction was far from optimal. The high-volume DMSO procedure would not only prove challenging to scale but also to work up. The high catalyst loading (20 mol % Pd) and ligand loading (100 mol %) are not cost-effective and could provide work-up issues in lieu of chromatography. In the end, the catalyst, ligand, base, solvent, and reaction temperature all had to be reexamined before scale-up could commence.12 Early development work also suggested the biaryl product (rac-5) was very difficult to purge and could continue to react in subsequent steps, generating potential genotoxic impurities (PGIs). Taken together, these observations demonstrated the need for a reproducibly selective and scalable Buchwald− Hartwig coupling reaction. Initial studies also revealed instability of the nitrile moiety in 1.13 Attempts to use stronger bases such at NaOt-Bu or LiHMDS, which are common in this type of amination reaction, resulted in the addition of base to the nitrile to generate impurities (6 and 7) (Scheme 3). This instability was also observed when 1 was exposed to aqueous base during
work-up, generating 8. This instability helped direct reaction conditions toward less nucleophilic bases and away from aqueous work-up conditions. A 2009 report14 from the Hartwig laboratories described the coupling of ammonia with aryl halides employing PdCl2[P(otol)3]2 together with Josiphos.15 When similar16 conditions were applied to the conversion of 1 to rac-3, a 41% yield was obtained after chromatography (Scheme 4). The major byproduct from this reaction was the diamination adduct rac5 (ca. 10%). Although this isolated yield was twice the isolated yield from the conditions shown in Figure 1 from Medicinal Chemistry, a significant amount of optimization would still be required to avoid the formation of rac-5. The low isolated yield, high level of rac-5, and need for chromatography precluded further development. In order to find conditions that increase the yield of the desired product (rac-3), control the formation of the biaryl impurity (rac-5), and limit the excess amine required (rac-2), broader reaction screening was employed.
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INITIAL SCREENING RESULTS There were three primary goals for the initial screening efforts. The first, minimize the equivalents of 2. Medicinal Chemistry utilized rac-2, which necessitated a chiral separation at the B
dx.doi.org/10.1021/op5002319 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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The first screen for this chemistry varied solvent, base, catalyst, and reaction time. Dioxane, t-amyl alcohol, and toluene were used as solvents on the first screen. These were chosen to represent solvent classes (ethereal, alcohol, and hydrocarbon) based on literature precedent.1−3 Cesium carbonate, potassium carbonate, potassium phosphate, and sodium pentoxide were selected as the four bases to be screened. Five catalysts, that had previously shown activity in amination reactions were selected: Pd(t-Bu3P)2,17 Pd[P(o-tol)3]2/Josiphos,14,18 BrettPhos Palladacycle,19,20 Pd[Xantphos]Cl2,21,22 and Pd[BINAP]Cl2.23,24 Each of the 60 reaction condition combinations was set up in duplicate so that the reaction could be quenched after 5 and 24 h. The results of the initial screen can be seen in Figure 1. Focus quickly centered around Pd[Xantphos]Cl2 and Pd[BINAP]Cl2. The Pd[Xantphos]Cl2 provided the best ratio of product to biaryl impurity as well as complete consumption of starting material, 1. The Pd[BINAP]Cl2 results were also promising, with very low levels of the biaryl impurity in spite of the reaction not reaching completion in the time allowed. Additional screening reactions (carried out as a follow up to this study) proved that other ethereal solvents (MeTHF or DME) were as effective as dioxane and could be used as substitutes, as these solvents are more readily scalable. In an attempt to drive the Pd[BINAP]Cl2 conditions to completion, a mixed solvent system of 2-MeTHF and toluene was first explored, while these additional screening efforts were underway. It is notable that the use of toluene (vide infra) lead to additional byproduct formation. It was also found that lower
Scheme 4. Application of Hartwig Josiphos Conditions
penultimate step. Sourcing efforts were underway to secure the desired enantiomer in order to avoid this challenging and lowyielding chromatographic purification. Without sufficient quantities of either enantiopure or racemic 2, the decision was made to perform the screening studies with 3-aminopropanol (9), an inexpensive, commercially available reagent. The second, minimize the formation of the diarylated impurity, in this case 11. As previously stated, this impurity is difficult to purge and continues to react in subsequent steps. Finally the third, reduce catalyst loading and cost.
Figure 1. Product distribution by UPLC peak area in screening reactions after 5 h of reaction time (white is starting material 1, blue is desired product 10, and black is biaryl product 11). All reactions were carried out using 40 μmol of 1, 1.2 equiv of 3-aminopropanol (9), 2.5 equiv base, 10 mol % catalyst,25 and 25 mL/g of solvent. The overall circle size is the sum of the peak areas of 1, 10, and 11.26 C
dx.doi.org/10.1021/op5002319 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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Table 1. Initial Scale-Up Efforts and Solvent Optimization for Coupling of 1 with rac-2
entry
scale (g)
solvent
temp (°C)
time (h)
rac-3 isolated yield (%)
rac-5 (UPLC A%)
1 2 3 4 5 6
5 15 37 95 0.93 9.3
2:1 Tol:2-MeTHF 2:1 Tol:2-MeTHF 2:1 Tol:2-MeTHF 2:1 Tol:2-MeTHF 2-MeTHF 2-MeTHF
85 85 85 85 75 75
17 17 17 17 3 3
70.3 73.1 72.3 50.4 72.7 89.0
5.4 7.5 7.4 7.7 7.6 4.2
the equivalents from 1.8 to 1.4 did not result in any significant decrease in efficiency. It was not until the number of equivalents was reduced to 1.2 that a significant reduction in reaction completion was observed. Development of Palladium Removal Protocol. Three procedures were explored to reduce the levels of residual palladium in the final product.28 The coupling was performed and the reaction split into 3 batches after filtration to remove solids (Scheme 5). Before any treatments, the typical residual
reaction temperatures and catalyst loadings could be employed.27
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PROCESS DEVELOPMENT As seen in Table 1, the conditions derived from the screening hit translated into a remarkable improvement in not only the yield (ca. 70%) but also minimized the formation of rac-5 (5− 7%). Entries 1−4 show the reaction was scaling nicely up to 95 g scale. Performing the 95 g scale reaction required a mechanical stirrer, in contrast to the previous trials that were mixed through standard magnetic stirring. During the course of these experiments, it was discovered that efficient mixing was critical for conversion to the desired product and avoiding decomposition. The solubility of rac-3 in 2-MeTHF (48 mg/ mL) is significantly higher than in toluene (
