Development of an Efficient Asymmetric Synthesis of the Chiral

Chapter 5

Downloaded by COLUMBIA UNIV on December 12, 2016 | http://pubs.acs.org Publication Date (Web): December 9, 2016 | doi: 10.1021/bk-2016-1239.ch005

Development of an Efficient Asymmetric Synthesis of the Chiral Quaternary 5-Lipoxygenase Activating Protein Inhibitor Keith Fandrick,* Jason Mulder, Jean-Nicolas Desrosiers, Nitin Patel, Xingzhong Zeng, Daniel Fandrick, Carl A. Busacca, Jinhua J. Song, and Chris H. Senanayake Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06778, United States *E-mail: [email protected].

The rapid pace of the development program along the structurally complex 5-lipoxygenase activating protein (FLAP) inhibitor required a dual strategic approach within process development. In order to advance the program forward, the Discovery synthesis was rendered safe and scalable while eliminating the non-scalable chromatographic chiral separation. This approach allowed the advancement of the target while offering the necessary development time to discover an efficient asymmetric process for the synthesis of the challenging drug target. Multiple approaches were explored experimentally for an asymmetric synthesis; the ultimate route was derived from a dual boronate rearrangement process that was rendered robust and efficient for large-scale operations.

© 2016 American Chemical Society Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Introduction Process development resides at the interface between medicinal chemistry and manufacturing. In this capacity, process development is charged with two main tasks:

•


•

The delivery of high quality drug substance to advance the drug candidate through development. The development of a practical and economical process for manufacturing.

For the cases where a drug candidate is particularly synthetically challenging, process development teams invoke a strategy where they quickly modify and render safe the medicinal chemistry approach to supply the required drug substance to advance the candidate. This strategic approach provides the necessary time to devise innovative solutions that are required to develop an efficient chemical process or route for manufacturing. The complexity of compound 1, a 5-lipoxygenase activating protein (FLAP) inhibitor, necessitated such an approach. The compound represents a significant challenge for development (1–3) as it contains diverse functionalities and at its core is an all-carbon quaternary stereogenic center. Retrosynthetically the target can be reduced to the aryl-aldehyde 5 that contains the crucial quaternary sterogenic center (Figure 1). A classical approach to the synthesis of 5 involves the construction of the benzylic quaternary center via ionization of the tertiary alcohol followed by trapping with a suitable soft nucleophile (4). Due to the formation of the benzylic carbocation, the route is racemic and a chiral separation/resolution is required to produce the single enantiomer FLAP inhibitor. Unfortunately, this also sacrifices at least half of the overall yield. As highlighted in a recent review article (5), the stereoselective construction of all-carbon quaternary centers embedded in acyclic systems has proved to be particularly challenging. Although there are several asymmetric methodologies for the synthesis of acyclic all-carbon stereocenters in the literature (4, 6–14), these methods require cryogenic temperatures and/or have limited substrate scope. Thus the development of a new practical synthesis was required. The resolution approach was implemented initially to supply the necessary drug substance for development. We then explored the validity of three approaches (Figure 1) for the asymmetric synthesis of 5 including:

• • •

The nitro olefin approach employing the asymmetric copper catalyzed conjugate addition with a suitable nitro olefin substrate (15). A route employing the stereospecific pinacol rearrangement. A stereospecific boronate rearrangement approach (16, 17).

122 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 1. Racemic and Asymmetric Strategies Experimentally Explored.

Modified Discovery Route The synthesis of 5 presented significant challenges for large-scale operations and required two main objectives, (Scheme 1). The first was to eliminate the bottleneck and low yielding chiral SFC separation in the Discovery synthesis. A resolution strategy toward the quaternary center would avoid the chiral SFC separation and be amenable to large scale synthesis. Despite the aforementioned liabilities of the Discovery synthesis, nitrile 6 was a strategic intermediate as it could be readily converted to the corresponding carboxylic acid, which in turn could serve as an effective handle for resolution via diastereomeric salt formation (18). The second main objective was to render the conversion of nitrile 6 to the corresponding amidoxime safe for large scale operations. The highly convergent end-game required extensive optimization for both the optimal reaction sequence and the high catalyst loading Suzuki-Miyaura cross-coupling (19, 20). The overall objectives (Scheme 2) are to render the original discovery approach robust and safe in order to deliver the initial material needs for early development. 123

Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 1. Discovery Approach

Scheme 2. Resolution Strategy

Racemic Acid Synthesis A robust and efficient synthesis of the requisite tertiary alcohol 15 was targeted first. The Discovery route to 15 involved methyl Grignard addition to the relatively expensive ketone 7 (Scheme 1). Two alternative approaches were explored involving either the cyclopropyl Grignard (21) addition to an acetophenone precursor, or the aryl Grignard addition to cyclopropylmethyl ketone 21. Our efforts focused on optimization of the latter process (Scheme 3) as the starting materials were widely available. The requisite 4-bromophenyl Grignard reagent was generated in situ via metal halogen exchange of 1,4-dibromobenzene using the iPrMgCl-LiCl complex (22, 23). The aryl Grignard addition to the ketone proceeded in high yield to provide tertiary alcohol 15 that was used directly in the subsequent cyanation reaction. It was suspected that the low purity for nitrile 16 in the Discovery route was caused by prolonged holding of the mixture containing the tertiary alcohol and BF3•OEt2 before before the TMSCN addition, thus generating a number of impurities. It was found that the carbocation was very effectively trapped by premixing the tertiary alcohol 15 with excess TMSCN and slowly adding the BF3•OEt2 (24) reagent to the mixture at low temperature, thus improving the yield of 16 to nearly quantitative, with excellent purity. Compounds 15 and 16 were both oils making their isolation and purification challenging. Purification had to be postponed until isolation of a downstream solid could be achieved. Thus it was imperative that the two steps (to form 15 and 16) were high yielding and generated minimal impurities. 124



Scheme 3. Synthesis of 20-DCA Salt The racemic nitrile 16 was converted to acid 20 via hydrolysis with potassium hydroxide. A high concentration of potassium hydroxide in 1-propanol was required in order to drive the hydrolysis of the nitrile moiety fully to the carboxylic acid. In subsequent optimization, performing the chemistry in a pressure vessel (facilitating temperatures > 120 °C, compared to a reflux temperature of 107 °C at atmospheric pressure) reduced the reaction time by a factor of 2-3. Acid 20 could not be isolated as a solid directly, but the corresponding dicyclohexylammonium (DCA) salt was readily formed and provided for a clean isolation of 20-DCA.

Resolution of Racemic Acid 20 After screening an extensive library of chiral amines, a robust process was identified for the resolution using the chiral amine (1R,2R)-1,3-dihydroxy-1(4-nitrophenyl)propan-2-amine (DNP) utilizing a single solvent (IPA) system (Scheme 4). Consistent good overall yield (28-32%) and high enantiomeric purity (>99% ee) were achieved with good crystallization control through temperature cycling. In order to meet the >99% enantiomeric purity requirement, the process required two enrichments. Efforts to isolate the crude carboxylic acid directly after the hydrolysis as the 23-DNP salt (avoiding the intermediate DCA isolation) led to lower overall recoveries (20% overall yield).

Scheme 4. Resolution of 20

Amidoxime Formation With an efficient synthesis of the enantiomerically pure carboxylic acid, the conversion to the key chiral nitrile 6 was achieved via an efficient telescopic sequence (Scheme 5). The reaction sequence could be monitored by React-IRTM. The implementation of this process analytical technology (PAT) monitoring ultimately allowed the reduction of the reagent charge of thionyl chloride, since no change was observed during further excess addition (Figure 2), which ultimately simplified the processing and subsequent operations. 125 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 5. Formation of Nitrile 6

Figure 2. React-IRTM trace of acid chloride formation.

Conversion of this rather hindered nitrile to amidoxime 26 presented a significant safety challenge for large scale operations. In the Discovery route, this transformation was accomplished thermally from the corresponding nitrile and hydroxylamine. This approach required thermally unsafe refluxing conditions in ethanol and 20-30 fold excess of hydroxylamine. For large scale synthesis, the amidoxime synthesis was accomplished in a step-wise process via the oxime intermediate 25 (Scheme 6). A DIBAL-H reduction of nitrile 6 to the aldehyde was followed by oxime formation. A rapid exotherm was observed during the HCl quench with local hot spots, which led to the undesired reduction of oxime 25 to the corresponding primary amine. The presence of the amine complicated the work-up significantly by causing emulsions during the phase separations. A CeliteTM filtration resolved the immediate problem. The amidoxime was formed by a two-step one-pot process via chloro-oxime formation using NCS and catalytic acid (17), followed by ammonia treatment (25, 26). After recrystallization from a toluene and heptane mixture, amidoxime 26 was isolated in 75% yield based on the assay of crude 25, (98.9% purity, 97.3 wt%, 99.4 %ee) (overall yield from solid 23-DNP to solid 26 over 3 steps was 59%). 126


Scheme 6. Formation of Amidoxime 26


Oxadiazole Formation The oxadiazole 27 was formed via reaction of amidoxime 26 and the acyl imidazole derived from activation of acid 3 with CDI (Scheme 7). A higher reaction temperature (100 °C) was required to drive the final hydroxyl elimination forming the 1,2,4 oxadiazole. The charge of CDI was found to be optimal at 1.05 equivalents and the pyrazole-carboxylic acid 3 at 1.1 equivalents. Charging either of these materials in greater excess was detrimental to the reaction (vida infra). THF was used as a carrier solvent for reagent addition and was then removed by distillation until the reaction temperature reached 100 °C. As a result, only 2.5 volumes of DMF were used in the reaction obviating the need for any back extractions during work-up (27). Oxadiazole 27 was obtained as an oil (not isolated) in an average yield of 95% (assay corrected) and 90% purity.

Scheme 7. Synthesis of Oxadiazole 27 Significant inconsistencies were seen in initial Suzuki-Miyaura coupling studies using nitrile 6 (Discovery Route) since 6 could not be purified. In order to achieve a consistent and a practical palladium catalyst loading for the Suzuki-Miyaura coupling, it was advantageous to have a crystalline solid starting material to insure consistent quality. Fortunately oxadiazole 27 (Scheme 7), whose free base is non-crystalline, could be crystallized as its mesylate salt in 80% yield (95% purity, 99.3%ee). No other acids screened provided such a well-behaved, isolable salt. Several reaction intermediates were identified in the cyclization reaction in route to 27 (Scheme 8). The excess amount of (1H-imidazol-1-yl)(1Hpyrazol-4-yl)methanone C, formed from CDI and pyrazole acid, reacted with the intermediate amide A to form B which may inhibit the final dehydration to form the oxadiazole. Through the course of the reaction, intermediates A and B are converted to E, which is dehydrated to provide oxadiazole 27. Impurity D, apparently formed directly from a reaction of amidoxime 26 with excess CDI is a non-productive pathway. This impurity could be controlled via using an excess of acid 3 as compared to CDI. 127



Scheme 8. 1,2,4-Oxadiazole Mechanistic Insights

Initial Boronate Synthesis and Suzuki-Miyaura Cross-Coupling A palladium-catalyzed borylation protocol using di-t-butylphosphinoferrocene tetrafluoroborate (FcP(t-Bu)2-HBF4) (28) as the ligand was developed into an efficient process for the synthesis of highly pure boronate 4 (Scheme 9). Following the reaction, the mixture was diluted with THF, the inorganics were removed by filtration, and the solvent was switched to EtOH. The boronate was isolated as a white crystalline solid from EtOH directly after an activated carbon treatment of the solution, which was implemented to remove residual palladium species which could have a deleterious effect on the subsequent Suzuki-Miyaura coupling. The scale-up of the Suzuki-Miyaura coupling after preliminary optimization proceeded smoothly to provide 28 (Scheme 9). An activated carbon treatment of the EtOAc solution of the crude product was used to remove color and to reduce residual palladium level to < 10 ppm.

Scheme 9. Completion of the Synthesis of 1 128 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


The final alkylation step was modified from the initial solvents of THF/water to DMF to improve throughput and the reaction rate, most likely due to the improved solubility of the starting materials. In addition, an organic base (DBU) was used instead of poorly soluble K2CO3. After reaction completion, the crude API (1) was crystallized from the reaction mixture. The crude API contained 0.53% of an unexpected impurity which was not purged in the final crystallization. This impurity was identified as compound 29 resulting from the 1,4-addition of 27 to dibenzylideneacetone and subsequent alkylation analogous to the API (Figure 3). Extensive work to remove 29 resulted in two effective options: • •

Crystallization of HCl salt of the API / salt break. Anisole recrystallization.

However, since the dimethylamide moiety is sensitive to strong acid and base, resulting in partial amide hydrolysis, the anisole crystallization was chosen to remove the impurity. After a final crystallization from ethanol/water, 1 was obtained with < 0.20% of the impurity which met the acceptance criteria. This route was sufficient to provide the first early development batches of 1 up to 1.5 kg.

Figure 3. dba adduct impurity 29.

Alternative Suzuki-Miyaura Coupling The above process was effective to provide drug substance for early development work packages. However, there was a motivation to change the endgame to address the high Pd loading needed for the Suzuki-Miyaura coupling and to eliminate the potential of the formation of the dba (dibenzylideneacetone) adduct impurity altogether. A strategic decision was made to move the Suzuki-Miyaura coupling one step earlier in the synthetic sequence. This would change the Pd source to address the issues discussed above and provide more opportunities for palladium removal prior to isolation of the final API. The isolable solid amidoxime 26 was a viable alternative coupling partner (Scheme 10). The Suzuki-Miyaura coupling of 26 with boronate 4 was a clean and efficient reaction which could be run with low catalyst loadings of 0.05 to 0.2 mol% Pd(TFA)2 (29) with the FcP(t-Bu)2-HBF4 ligand. Upon reaction completion, N-acetylcysteine was added to the reaction mixture as a palladium scavenger. The product precipitated from the reaction mixture directly and was isolated in 95% yield with > 99A% (220 nm HPLC purity). The formation 129



of 1,2,4-oxadiazole 28 utilized a process analogous to that used for 27 (vide supra) yielding an ethyl acetate solution of 28. During our development work, a crystalline form of 28 free base or salt could not be found despite substantial effort, (regardless of material chemical purity or solvent composition). While in storage at room temperature for 6 months, a very concentrated IPA solution of 28 produced a few crystals. With some scoring of the flask, the entire 70 g sample crystallized. This fortuitous discovery provided an additional purity control point prior to isolation of the final API to remove organic and inorganic impurities. Using these crystalline seeds, 28 could be consistently isolated in high yield and purity as a crystalline solid. The palladium level in 28 was controlled to < 10 ppm with a carbon treatment/crystallization strategy. The final alkylation was conducted under conditions analogous to that shown above, heating the mixture of 28, 19, and DBU at 45 °C for 2 h. Following work-up, the crude 1 was isolated from IPAc, and a final recrystallization from ethanol/water provided the target compound 1 (83% for 2 steps, >99% purity) with < 5 ppm palladium.

Scheme 10. Second Generation Racemic Synthesis of 1

Asymmetric Pinacol Rearrangement Approach With the objective to develop an alternative robust and scalable enantioselective synthesis of the chiral quaternary aryl-aldehyde 5, we decided to explore the stereospecific pinacol rearrangement of a tri-substituted epoxide (Scheme 11) (30–32). Jung et al. reported the pinacol rearrangement of 2-aryl-3-ethynyloxiranes for the synthesis of ibuprofen (33). Similarly, Eisai demonstrated the efficiency of this methodology to synthesize biologically active emopamil (13). In this present case, such an approach would allow the formation of the all-carbon stereocenter via a Lewis acid-induced migration of the cyclopropyl substituent (34). Considering that multiple methodologies are known to provide tri-substituted enantioenriched epoxides (35–37), this strategy would alleviate the more challenging direct enantioselective synthesis of the quaternary stereocenter. 130



Scheme 11. Pinacol Rearrangement Approach

In order to study this route, E-trisubsituted alkene 11 was first prepared on 220 gram scale (Scheme 12). 4-Bromo-phenethylalcohol was brominated with PBr3 to provide the corresponding secondary bromide in 94% yield, which upon treatment with triphenylphosphine, provided access to the corresponding triphenylphosphonium bromide (38, 39). A subsequent Wittig olefination with cyclopropanecarboxaldehyde using LHMDS afforded the -tri-substituted alkene in a 6:1 E/Z ratio (40). The crystalline alkene was then enriched to 99.8:0.2 E/Z after a recrystallization from MeOH at 5 °C.

Scheme 12. Synthesis of E-Olefin 11

With alkene 11 in hand, the enantioselective epoxidation was explored. After screening of various enantioselective catalytic epoxidations, Shi’s methodology turned out to be the most promising system in terms of enantiomeric excess, yield, and affordability of the catalyst (Scheme 13) (14, 41, 42). After optimization of reaction conditions, an addition of OxoneTM (potassium peroxomonosulfate) (43, 44) and buffer over 4 h at 0 °C in acetonitrile provided the desired epoxide with 82% yield, over 99:1 dr and 92% ee on 15g scale. These reaction conditions are very reproducible and straightforward to scale-up (50 g) since an inert atmosphere or anhydrous conditions are not required.

Scheme 13. Asymmetric Pinacol Synthesis of Aldehyde 5 131 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


The stereospecific pinacol rearrangement to afford the quaternary stereocenter was studied. An extensive screening of a wide range of Lewis and Brønsted acids was performed. Strong Lewis acids, such as BF3•OEt2 led to complete epoxide opening (45), but with a significant amount of ketone originating from a [1,2]-shift of the aryl substituent instead of the cyclopropyl migration. The optimal reagent found was methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide) (MAD) which was formed in situ from Me3Al and BHT (46–50). Complete stereospecificity generated the desired aldehyde 5 with 94% yield and 92% ee. Overall, this route where the quaternary center is built through a stereospecific pinacol rearrangement can be achieved on multi-gram scale without the need of purification by flash chromatography. There are a number of limitations to this asymmetric approach that precluded its implementation on large scale, and these include:

• • • •

Lower level of enantioselectivity (92% ee). High volume of water required to solubilize Oxone.TM Limited availability of the catalyst’s enantiomer. High catalyst loading (30 mol%) needed to reach full conversion due to catalyst de-activation during the epoxidation.

Asymmetric Conjugate Addition Approach One of our strategies to generate the all-carbon quaternary stereogenic center was to utilize a Cu-catalyzed Asymmetric Conjugate Addition (ACA) of dimethylzinc to a (Z)-nitroalkene substrate (15). In the past 15 years, the Cu-catalyzed ACA of enones, nitroalkenes and Meldrum’s acid derivatives with organozinc, aluminum, magnesium or boronic acid reagents has attracted considerable attention owing to its capability to construct chiral molecules with all-carbon quaternary stereogenic centers in high enantioselectivity (51–58). Hoveyda’s system (6) is of particular interest due to organozinc reagents’ high reactivity, excellent enantioselectity and high yield observed on the challenging acyclic nitroalkene substrates. This renders this methodology particularly attractive for the targeted compound 1. However, under optimized Hoveyda conditions on our substrate, only moderate enantioselectivity (65%) was obtained initially in the ACA of Me2Zn to the (E)-nitroalkene catalyzed by (CuOTf)2•PhH - Hoveyda dipeptide ligand complex. After intensive research, it was found that Me2Zn’s relatively lower reactivity and nitroalkene isomerization, coupled with use of less reactive (E)-nitroalkene and use of (CuOTf)2•PhH as Cu-precatalyst, were the main reasons for the moderate enantioselectivity observed. To solve this problem, we modified the reaction to use the more reactive (Z)-nitroalkene under conditions that minimize the nitroalkene isomerization.

132 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 14. Asymmetric Conjugate Addition Approach (Z)-Nitroalkene 9 is a yellow crystalline solid, readily prepared from 4-bromobenzoic acid via a three-step protocol in 72% overall yield (Scheme 14). Thus, under our modified conditions, enantioselective conjugate addition of dimethylzinc to the (Z)-nitroalkene with 4% [(MeCN)4Cu]PF6 – Hoveyda ligand complex in toluene at -30 °C smoothly delivered the corresponding nitroalkane 8 in 91% yield and 95% ee. The crude nitroalkane was converted via a Nef reaction (59, 60) into enantiomerically enriched aldehyde 5, thus demonstrating this approach for the synthesis of the key quaternary intermediate. However, this approach was discontinued in preference to the boronate rearrangement approach described below.

Asymmetric Boronate Rearrangement Approach After evaluating several synthetic strategies for the construction of the key all-carbon stereocenter, Aggarwal’s approach was attractive with respect to both the availability of the key starting materials and overall cost. Aggarwal and co-workers reported a stereoretentive transformation of secondary carbonates to tertiary boronates (61–64). Furthermore, the authors demonstrated that the resulting boronic esters could then be utilized to introduce a formyl functionality and thus have an effectively asymmetric synthesis of all-carbon quaternary stereocenters (Scheme 15) (65, 66). The stereochemistry of the process was ultimately generated from a scalable asymmetric catalytic reduction of a prochiral ketone (67). The reported Aggarwal processes required cryogenic temperatures (both boronate rearrangements: -78 °C and -100 °C) and could lead to the accumulation of thermally unstable intermediates (Scheme 15). Although the cryogenic temperatures could be managed with specialized reactors, the accumulation of these unstable intermediates with long processing times (1 h or more) called for significant development work before this approach could be employed for large scale operations. As the chemistry was developed and optimized with the aryl bromide for the key Suzuki-Miyaura cross-coupling (20, 68–70), it was necessary to avoid the use of alkyl lithium bases which are incompatible with this halogen substitution. As this approach was short and all the reagents were relatively inexpensive, we undertook efforts to render the process safe, robust and amenable to large scale synthesis (17, 18). 133



Scheme 15. Aggarwal’s Approach for the Construction of Chiral Quaternary Stereocenters from Secondary Chiral Carbamates

The required chiral secondary alcohol 37 was prepared by a Noyori asymmetric transfer hydrogenation (71, 72) of bromoacetophenone 13 (91% ee, Figure 4). Purging of the reaction with dry nitrogen (73) allowed the catalyst loading to be reduced to 0.1 mol% by removing the by-product carbon dioxide that is generated in the reaction. The intermediate alcohol 37 (not isolated) was treated with carbamyl chloride 38 to form solid carbamate 39, whose enantiomeric purity could be enriched to 99.9% ee with a single recrystallization.

Figure 4. Synthesis of chiral benzylic carbamate 39.

The reported Aggarwal boronate rearrangement process (66–69) was shown to be quite general with respect to both the boranate substitution and the migratory group. The reported process is performed in three separate parts (Figure 5). The benzylic carbamate is initially deprotonated with an alkyl lithium base (74, 75) and the resulting lithiated carbamate is trapped with the boronic ester to form the unstable boronate complex. The key 1,2-alkyl rearrangement was promoted with the addition of a Lewis Acid to minimize racemization. On large scale, the unit operations would require considerable more time to complete, and thus the unstable lithiated carbamate 41 and the boronate complex 43 would be held for long periods rendering the current process unsuitable for large scale synthesis. If the deprotonation of the benzyl carbamate 40 is conducted in the presence of the boronic ester 42 the in situ formed lithiated carbamate 41 would be instantly trapped by the electrophile to form the boronate complex 43 (Figure 5). Thus, 134 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


the accumulation of the configurationally unstable lithiated carbamate 41 would be avoided and would allow the process to be conducted at non-cryogenic temperatures. In order to accomplish the in situ deprotonation a suitable base that is compatible with the electrophilic boronic ester needed to be found.

Figure 5. Boronate rearrangement mechanisms.

Attempts to perform the in situ deprotonation of benzylic carbamate 39 with the reported conditions (sec-butyllithium) provided no product. It was postulated that the alkyl lithium base traps the boronic ester at a much faster rate than the deprotonation of the benzylic carbamate. A base survey found that LDA (76) is compatible with the boronic ester in the in situ deprotonation and boronate formation. Furthermore, high conversion and low ee erosion were obtained for the desired system 39 even at -10 °C (Scheme 16) (77).

Scheme 16. First Generation Non-cryogenic Boronate Rearrangement

Further examination of the reaction variables revealed that the use of methanolic magnesium bromide was not needed as the desired tertiary boronate ester 12 was formed with this LDA process in near perfect yield (99%, Scheme 17 and high stereoretention (98.6% ee). The process was demonstrated to produce 24 kg of the chiral non-racemic tertiary boronate 12 in a single batch (99% yield, 98.6% ee). 135 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 17. Second Generation Non-cryogenic Boronate Rearrangement Based on the results in the in situ deprotonation, an identical strategy was employed with the deprotonation of DCM (78) for the enantiospecific conversion of the boronate 12 to the enantiomerically enriched aldehyde intermediate 5 containing the key all-carbon quaternary stereogenic center. It was postulated that the in situ deprotonation would avoid the problematic accumulation of the highly unstable lithiated DCM-species (76, 79). Attempts at the in situ deprotonation of DCM with LDA proved to be successful as high yields were obtained for the aldehyde product even at -15 °C (Figure 6). However, through a series of stress testing experiments it was found that at these elevated temperatures (-15 °C), the LDA base would need to be added at a fast rate (90%) and upon the hydrogen peroxide treatment any remaining tertiary boronic ester 12 would be converted to the tertiary alcohol 48 (Scheme 20). The residual tertiary alcohol 48 would then serve as an acid scavenger via ionization of the benzylic alcohol 48, thus inhibiting the acid-promoted chlorination of the oxime. This indeed proved to be the case as the addition of catalytic amounts of HCl at the onset of the chlorination was sufficient to eliminate the unpredictable exothermic induction period and rendered the process robust and reproducible. This modified process was demonstrated with the crude formylation product (90% molar conversion) which was directly processed to the solid amidoxime (10 kg scale) intermediate 26 in 99% ee and 52% overall yield for the entire sequence from boronic ester 12 (Scheme 21).

Scheme 19. Initial Investigation of the NCS Chlorination of Oxime 26 138 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 20. Formation of Tertiary Alcohol 48 from Incomplete Formylation of Boronic Ester 12

Scheme 21. Synthesis of Amidoxime 26 from Tertiary Boronate 12

Non-Precious Metal Borylation The literature protocol for the synthesis of the pinacol boronate ester 4 involved the Suzuki-Miyaura borylation of 2-amino-5-bromopyrimidine with bis(pinacolato)diboron in presence of palladium-based catalysts (84–86). Employing the known process from the literature using PdCl2(dppf)-CH2Cl2 (5 mol%) in the presence of potassium acetate (3 equiv) in 1,4-dioxane at 100 °C, inconsistent results were obtained due to difficulties in achieving complete conversion, and due to hydrolysis of the pinacol boronate ester 4 during the aqueous workup. After a catalyst screening was conducted, we discovered that the use of 0.1 mol% of Pd2(dba)3 and 0.2 mol% Fc(PtBu2)HBF4 in the presence of KOAc (2 equiv) in 2-MeTHF at 80 °C afforded the pinacol boronate ester 4 in 80% yield with high purity on a multi-kilogram scale (Figure 9).

Figure 9. Pilot Plant Synthesis of 4. 139 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


However, the use of expensive palladium metal coupled with the high cost and low atom economy associated with bis(pinacolato)diboron provided us the impetus to develop a more cost-effective and efficient process. Initial efforts on the formation of the target boronic acid 52 using 2-amino-5-bromopyrimidine and B(Oi-Pr)3 with n-BuLi/THF/-78 °C gave inconsistent and poor yields (11-40%). While boronic acid can be prepared from heteroaryl bromide containing an amino group utilizing an amine protection (87–96), most of those methods suffered from modest yields and required two or three isolation steps as well as a deprotection operation. Our attention turned to easily accessible and removable silyl based protecting groups such as tetramethyldisilylazacyclopentane (STABASE) (97–99) and trimethylsilyl chloride (TMSCl) (100, 101). Use of STABASE for the in-situ protection of the amino functionality followed by typical boronic acid synthesis and its purification (Figure 10) afforded (2-aminopyrimidin-5-yl) boronic acid 52 in 77% overall yield (102) in 85 wt% purity, with the remaining mass balance composed of water. While the STABASE process was suitable for the preparation of kilogram quantities of 52, it became apparent that the STABASE reagent was not economically viable on large scale.

Figure 10. Synthesis of 52 using STABASE group. To our delight, replacement of STABASE with the readily available TMSCl was successful using similar conditions (LiHMDS/toluene/0 °C) (Scheme 22). At this point, a screening was performed using different bases for the amine protection and NaH in presence of catalytic amount of 2-propanol (7 mol%) afforded bisTMS adduct 53 in quantitative yield. The crude bis-TMS adduct was subjected to n-BuLi/THF/-78 °C conditions in the presence of B(OiPr)3 to afford boronic acid 52 after aqueous acid treatment and workup. The crude boronic acid 52 was re-slurred in water at 85 °C to afford purified (2-aminopyrimidin-5-yl) boronic acid 52 in overall 80% yield in high purity (>99 area% and 90 wt% with the remainder being simply water).

Scheme 22. Optimized Route to Boronic Acid 52 140 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Asymmetric Synthesis of FLAP Inhibitor 1 With a safe and scalable processes established for the key quaternary stereocenter in >99% ee (amidoxime 26) and the achiral pinacol boronate ester 52 these intermediates were then in position to intercept the optimized key Suzuki-Miyaura cross coupling (19, 20, 103) and the end-game of the synthesis (Scheme 23). Although the cross-coupling could be performed with Pd2(dba)3 and the tetrafluoroborate salt of P(t-Bu)3 (1 mol% Pd), the catalyst loading could be reduced to 0.2 mol% (Pd) with the di-tert-butylphosphinoferrocene (t-Bu2PFc-HBF4) (104–106) ligand. The Suzuki-Miyaura product 2 precipitated directly from the reaction mixture in high yield and purity. Following the synthesis of the oxadiazole (107) from the CDI-activated carboxylic acid 3, a final alkylation of the pyrazole completed the synthesis. This sequence was employed to produce multi-kilogram quantities of the target compound 1 to support preclinical development.

Scheme 23. Synthesis of 1 from Amidoxime 26

Conclusion The FLAP program and subsequent development of the target compound 1 highlights the roles of both Discovery and Development in bringing a target compound from the initial discovery hit to the development of safe and robust scalable processes for the manufacture of the drug candidate. Once the compound transitions to the development phase, the process group is charged with the rapid delivery of high quality drug substance. Two main issues needed to be resolved quickly in the discovery approach. The first was the elimination of the bottleneck and low yielding chiral SFC separation that was accomplished by the strategic introduction of a carboxylic handle for a chiral base resolution. The second and most pertinent problem was rendering the conversion of the nitrile to the corresponding amidoxime safe for large scale operations. A two-step operation that avoided the thermal addition of hydroxylamine to the nitrile was accomplished by first reducing the nitrile to the corresponding aldehyde that could then be converted in situ to the oxime. Significant development was required 141



to derive the ambient conditions for the oxidation and amidooxime formation. Although the first generation process was longer than than the original discovery approach, it accomplished the two main task of a process group; which is to render the route safe and scalable to provide the necessary multikilogram of material that was required to advance the compound in development. This strategic approach offered the necessary development time to discover an efficient and economical asymmetric process for the synthesis of the challenging drug target. Multiple approaches were explored experimentally for an asymmetric synthesis. A pinacol rearrangement based approach was synthetically feasible for the synthesis of the challenging all carbon quaternary core of the compound, but due the limited availability of the epoxidation catalyst’s enantiomer coupled with high catalyst loading and lower enantioselectivity this approach was not pursued for further development. An improved process employing the Hoveyda asymmetric Cu-mediated conjugate addition to nitro-olefins was developed. Due to the low reactivity observed with the (E)-nitroalkenes, the reaction was modified to employ the more reactive (Z)-nitroalkenes with conditions that minimized the nitroalkene isomerization. The corresponding non-racemic chiral adduct was converted to the key quaternary aldehyde intermediate via a Nef reaction. The asymmetric conjugate addition approach was discontinued in preference to the third approach that was derived from a dual boronate rearrangement process which the asymmetry of the process was ultimately derived form a well precedented and scalable asymmetric catalytic reduction of a prochiral ketone. The discovery of the compatibility of hindered amide bases for both the benzylic carbamate and formylation deprotonations was instrumental in allowing both processes to be performed in situ and thus rendered robust and efficient for large scale operations. Overall, the Discovery and Process Development groups were able to accomplish the two aspects of producing new therapeutics: the initial discovery of the drug target and the subsequent development of an efficient, safe, economical and robust process for the synthesis of the drug candidate on large scale.

References 1.

2. 3.

4. 5.

Busacca, C. A.; Fandrick, D. R.; Song, J. J.; Senanayake, C. H. “Transition Metal Catalysis in the Pharmaceutical Industry. In Applications of Transition Metal Catalysis in Drug Discovery and Development an Industrial Perspective; Crawley, M. L, Trost, B. M., Eds.; Wiley: Hoboken, NJ, 2012. Anderson, N. G. Practical Process Research & Development; Academic Press: Waltham, MA, 2012. Practical Process Development: Current Chemical and Engineering Challenges; Blacker, J., Williams, M. T., Eds.; RSC Publishing: London, 2011; p 374. Hrdina, R.; Müller, C. E.; Wende, R. C.; Lippert, K. M.; Benassi, M.; Spengler, B.; Schreiner, P. R. J. Am. Chem. Soc. 2011, 133, 7624–7627. Marek, I.; Minko, Y.; Pasco, M.; Mejuch, T.; Gilboa, N.; Chechik, H.; Das, J. P. J. Am. Chem. Soc. 2014, 136, 2682–2694. 142


6. 7. 8.


9. 10. 11. 12. 13. 14. 15.

16.

17.

18. 19. 20. 21. 22. 23. 24. 25. 26.

27. 28.

29.

Wu, J.; Mampreian, D. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 4584–4585. Lee, K.-S.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 7182–7184. Martin, D.; Kehrli, S.; d’Augustin, M.; Clavier, H.; Mauduit, M.; Alexakis, A. J. Am. Chem. Soc. 2006, 128, 8416–8417. Fillion, E.; Wilsily, A. J. Am. Chem. Soc. 2006, 128, 2774–2775. Wilsily, A.; Fillion, E. Org. Lett. 2008, 10, 2801–2804. Wilsily, A.; Lou, T.; Fillion, E. Synthesis 2009, 12, 2066–2082. Wilsily, A.; Fillion, E. J. Org. Chem. 2009, 74, 8583–8594. Kimura, T.; Yamamoto, N.; Suzuki, Y.; Kawano, K.; Norimine, Y.; Ito, K.; Nagato, S.; Iimura, Y.; Yonaga, M. J. Org. Chem. 2002, 67, 6228–6231. Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224–11235. Zeng, X.; Gao, J. J.; Song, J. J.; Ma, S.; Desrosiers, J-N; Mulder, J.; Rodriguez, S.; Herbage, M.; Haddad, N.; Qu, B.; Fandrick, K. R.; Grinberg, N.; Lee, H.; Wei, X.; Yee, N. K.; Senanayake, C. H. Angew. Chem., Int. Ed. 2014, 53, 12153–12157. Fandrick, K. R.; Mulder, J. A.; Patel, N. D.; Gao, J.; Konrad, M.; Archer, E.; Buono, F. G.; Duran, A.; Schmid, R.; Daeubler, J.; Desrosiers, J.-N.; Zeng, X.; Rodriguez, S.; Ma, S.; Qu, B.; Li, Z.; Fandrick, D. R.; Grinberg, N.; Lee, H.; Bosanac, T.; Takahashi, H.; Chen, Z.; Bartolozzi, A.; Nemoto, P.; Busacca, C. A.; Song, J. J.; Yee, N. K.; Mahaney, P. E.; Senanayake, C. H. J. Org. Chem. 2015, 80, 1651–1660. Fandrick, K. R.; Patel, N. D.; Mulder, J. A.; Gao, J.; Konrad, M.; Archer, E.; Buono, F. G.; Duran, A.; Schmid, R.; Daeubler, J.; Fandrick, D. R.; Ma, S.; Grinberg, N.; Lee, H.; Busacca, C. A.; Song, J. J.; Yee, N. K.; Senanayake, C. H. Org. Lett. 2014, 16, 4360–4363. Porter, W. H. Pure Appl. Chem. 1991, 63, 1119–1122. Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437–3440. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483. Grignard, V. C. R. Acad. Sci. 1900, 130, 1322–1324. Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333–3336. Bao, R.; Zhao, R.; Shi, L. Chem. Commun. 2015, 51, 6884–6900. Rajagopal, G.; Kim, S.-S. Tetrahedron Lett. 2009, 65, 4351–4355. Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45, 3916–3918. Menzel, K.; Machrouhi, F.; Bodenstein, M.; Alorati, A.; Cowden, C.; Gibson, A.; Bishop, B.; Ikemoto, N.; Nelson, T. D.; Kress, M. H.; Frantz, D. E. Org. Process Res. Dev. 2009, 13, 519–524. No back-extractions were required; however, four water washes were needed to remove residual imidazole and DMF from the organic layer. Other ligands were effective including PdCl2(dppf); however, FcP(t-Bu)2HBF4 was the preferred ligand in the subsequent Suzuki coupling so it was also chosen for the boronate formation to avoid potential carry-over problems with a second ligand. 0.2 mol% was used for scale-up. 143


30. 31. 32. 33. 34. 35.


36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63.

Snape, T. J. Chem. Soc. Rev. 2007, 36, 1823–1842. Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523–7556. Wang, B.; Tu, Y. Q. Acc. Chem. Res. 2011, 44, 1207–1222. Jung, M. E.; Anderson, K. L. Tetrahedron Lett. 1997, 38, 2605–2608. Nakamura, K.; Osamura, Y. J. Am. Chem. Soc. 1993, 115, 9112–9120. Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Chem. Rev. 2005, 105, 1603–1662. McGarrigle, E. M.; Gilheany, D. Chem. Rev. 2005, 105, 1563–1602. Wong, O. A.; Shi, Y. Chem. Rev. 2008, 108, 3958–3987. Dauben, W.; Gerdes, J. M.; Bunce, R. A. J. Org. Chem. 1984, 49, 4293–4295. Schweizer, E. E.; Wehman, A. T. J. Chem. Soc., C 1971, 2, 343–346. Wang, S. C.; Troast, D. M.; Conda-Sheridan, M.; Zuo, G.; La Garde, D.; Louie, J.; Tantillo, D. J. J. Org. Chem. 2009, 74, 7822–7833. Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806–9807. Ager, D. J.; Anderson, K.; Oblinger, E.; Shi, Y.; VanderRoest, J. Org. Process Res. Dev. 2007, 11, 44–51. OxoneTM is a product of The Chemours Company FC, LLC. For an example of the use of OxoneTM in the epoxidation of olefins, see: Hasimoto, N.; Kanda, A. Org. Process Res. Dev. 2006, 6, 405–406. Neef, G.; Baesler, S.; Depke, G.; Vierhufe, H. Tetrahedron Lett. 1999, 40, 7969–7973. Yamamoto, H.; Yanagisawa, A.; Ishihara, K.; Saito, S. Pure Appl. Chem. 1998, 70, 1509–1512. Yamamoto, H.; Saito, S. Pure Appl. Chem. 1999, 71, 239–245. Saito, S.; Yamamoto, H. Chem. Commun. 1997, 1585–1592. Maruoka, K.; Saito, S.; Yamamoto, H. Synlett 1994, 439–440. Maruoka, K.; Sato, J.; Yamamoto, H. Tetrahedron 1992, 48, 3749–3762. Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829–2844. Hoveyda, A. H.; Hird, A. W.; Kacprzynski, M. A. Chem. Commun. 2004, 1779–1785. Alexakis, A.; Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez, M. Chem. Rev. 2008, 108, 2796–2823. Jerphagnon, T.; Pizzuti, M. G.; Minnaard, A. J.; Feringa, B. L. Chem. Soc. Rev. 2009, 38, 1039–1075. Thaler, T.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 645–648. Wencel, J.; Mauduit, M.; Hénon, H.; Kehrli, S.; Alexakis, A. Aldrichimica Acta 2009, 42, 43–50. Hawner, C.; Alexakis, A. Chem. Commun. 2010, 46, 7295–7306. Dumas, A. M.; Fillion, E. Acc. Chem. Res. 2010, 43, 440–454. Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017–1047. Ballini, R.; Petrini, M. Adv. Synth. Catal. 2015, 357, 2371–2402. Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008, 456, 778–782. Bagutski, V.; Ros, A.; Aggarwal, V. K. Tetrahedron 2009, 65, 9956–9960. Bagutski, V.; French, R. M.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2010, 49, 5142–5145. 144



64. Sonawane, R. P.; Jheengut, V.; Rabalakos, C.; Larouche-Gauthier, R.; Scott, H. K.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2011, 50, 3760–3763. 65. Rangaishenvi, M. V.; Singaram, B.; Brown, H. C. J. Org. Chem. 1991, 56, 3286–3294. 66. Scott, H. K.; Aggarwal, V. K. Chem Eur. J. 2011, 17, 13124–13132. 67. Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J. Chem. Rev. 2006, 106, 2734–2793. 68. Stanforth, S. P. Tetrahedron 1998, 54, 263–303. 69. Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633–9695. 70. Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 14, 2419–2440. 71. Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521–2522. 72. Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97–102. 73. Blacker, J. A.; Thompson, P. Scale-up Studies in Asymmetric Transfer Hydrogenation. In Asymmetric Catalysis on Industrial Scale, 2nd ed.;, Blaser, H.-U., Schmidt, E., Eds.; Wiley, Hoboken, NJ, 2010; pp 265−290. 74. Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem., Int. Ed. 1990, 29, 1422–1424. 75. Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. 1997, 36, 2282–2316. 76. Matteson, D. S.; Soundararajan, R.; Ho, O. C.; Gatzweiler, W. Organometallics 1996, 15, 152–163. 77. For general purpose large scale reactors the minimum preferred operational internal temperature is 0 °C to –40 °C. 78. Matteson, D. S.; Man, H.-W.; Ho, O. C. J. Am. Chem. Soc. 1996, 118, 4560–4566. 79. During the scaling of the DCM homologation, a similar process was reported: Pulis, A. P.; Aggarwal, V. K. J. Am. Chem. Soc. 2012, 134, 7570–7574. 80. Grabarnick, M.; Zamir, S. Org. Process Res. Dev. 2003, 7, 237–243. 81. Connolly, T. J.; Matchett, M.; McGarry, P.; Sukhtankar, S.; Zhu, J. Org. Process Res. Dev. 2006, 10, 391–397. 82. Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45, 3916–3918. 83. Hansen, E. C.; Levent, M.; Connolly, T. J. Org. Process Res. Dev. 2010, 14, 574–578. 84. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513–519. 85. Clapham, K. M.; Smith, A. E.; Batsanov, A. S.; McIntyre, L.; Pountney, A.; Bryce, M. R.; Tarbit, B. Eur. J. Org. Chem. 2007, 34, 5712–5716. 86. Burger, M. T.; Pecchi, S.; Wagman, A.; Ni, Z.-J.; Knapp, M.; Hendrickson, T.; Atallah, G.; Pfister, K.; Zhang, Y.; Bartulis, S.; Frazier, K.; Ng, S.; Smith, A.; Verhagen, J.; Haznedar, J.; Huh, K.; Iwanowicz, E.; Xin, X.; Menezes, D.; Merritt, H.; Lee, I.; Wiesmann, M.; Kaufman, S.; Crawford, K.; Chin, M.; Bussiere, D.; Shoemaker, K.; Zaror, I.; Maira, S.-M.; Voliva, C. F. ACS Med. Chem. Lett. 2011, 2, 774–779. 87. Srinivasan, B.; Zhigang, C.; Francis, G.; Pirmin, H.; Ursula, H.; Theresa, H.; Reinhard, R.; Qingping, T.; Herbert, Y. Process for Making Thienopyrimidine Compounds. U.S. Pat. Appl. US2014/0100366A1, 2014. 88. Zhao, J. J.; Wang, Q. Method of Inhibiting Hamartoma Tumor Cells. Int. Pat. Appl. WO2012/109423A1, 2012. 145



89. Li, J.; Zhang, S.; Wang, S.; Zhu, X.; Yang, M.; Wu. X. Synthesis Method of 2-Aminopyrimidine-5-Boric acid. Patent CN 102367260, 2012. 90. Lai, W.; Xu, J.; Gu. S.; Yang, B. Synthesis Method of 2-Amino-5-Pyrimidine Pinacol Borate. Patent CN 102399235, 2012. 91. Kressierer, J. C.; Lehnemann, B.; Jung, J. Preparation of Aminoaryl and Aminoheteroaryl Boronic Acids and Derivatives Thereof. U.S. Pat. Appl. US2008/0269523A1, 2008. 92. Pick, T.; Barsanti, P.; Iwanowicz, E.; Fantl, W.; Hendryckson, T.; Knapp, M.; Meritt, H.; Voliva, C.; Wiesmann, M.; Xin, X.; Burger, M.; Ni, Z.-J.; Pecchi, S.; Atallah, G.; Bartullis, S.; Frazier, K.; Smith, A.; Verhagen, J.; Zhang, Y.; Wagman, A.; Ng, S.; Pfister, K.; Poon, D.; Louie, A. Pyrimidine Derivatives Used as PI-3 Kinase Inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. Int. Pat. Appl. WO2007/084786A1, 2007. 93. Das, B.; Ahmed, S.; Yadav, A. S.; Ghosh, S.; Gujrati, A.; Sharma, P.; Rattan, A. Oxazolidinone Derivatives as Antimicrobials. Int. Pat. Appl. WO2006/ 038100A1, 2006. 94. Meudt, A.; Lehnemann, B.; Scherer, S.; Kalinin, A.; Snieckus, V. Process for the Preparation of Aniline Boronic Acids and their Derivatives. Patent EP2004/1479686A1, 2004. 95. Tian, Q.; Hoffmann, U.; Humphries, T.; Cheng, Z.; Hidber, P.; Yajima, H.; Guillemot-Plass, M.; Li, J.; Bromberger, U.; Babu, S.; Askin, D.; Gosselin, F. Org. Process Res. Dev. 2015, 19, 416–426. 96. Busch, T.; Nonnenmacher, M. Process for the Preparation of Boronic Acid Intermediates. U.S. Pat. Appl. US2014/0330008A1, 2014. 97. Magnus, P.; Djuric, S.; Venit, J. Tetrahedron Lett. 1981, 22, 1787–1790. 98. Rizzo, C. J.; Wang, Z. Org. Lett. 2001, 3, 565–568. 99. Rizzo, C. J.; Elmquist, C. E.; Stover, J. S.; Wang, Z. J. Am. Chem. Soc. 2004, 126, 11189–11201. 100. Asher, S. A.; Das, S.; Alexeev, V. L.; Sharma, A. C.; Geib, S. J. Tetrahedron Lett. 2003, 44, 7719–7722. 101. Chikhalia, H. K.; Patel, A. B.; Patel, R. V.; Kumari, P.; Rajani, D. P. Med. Chem. Res. 2013, 22, 367–381. 102. Patel, N. D; Zhang, Y.; Gao, J.; Sidhu, K.; Lorenz, J. C.; Fandrick, K. R.; Mulder, J. A.; Herbage, M. A.; Li, Z.; Ma, S.; Lee, H.; Grinberg, N.; Song, J. J.; Busacca, C. A.; Yee, N. K.; Senanayake, C. H. Org. Process Res. Dev., 20, 95–99. 103. Miyaura, N.; Suzuki, A. Chem. Commun. 1979, 19, 866–867. 104. Busacca, C. B.; Eriksson, M. C.; Haddad, N.; Han, Z. S.; Lorenz, J. C.; Qu, B.; Zheng, X.; Senanayake, C. H. Org. Synth. 2013, 90, 316–326. 105. Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 3224–3225. 106. Qu, B.; Haddad, N.; Han, Z. S.; Rodriguez, S.; Lorenz, J. C.; Grinberg, N.; Lee, H.; Busacca, C. A.; Krishnamurthy, D. K.; Senanayake, C. H. Tetrahedron Lett. 2009, 50, 6126–6129. 107. Kayukova, L. A. Pharm. Chem. J. 2005, 39, 539–547. 146


Development of an Efficient Asymmetric Synthesis of the Chiral

Recommend Documents