Exemplifying Prediction of Preferred Coupling Partners in Developing

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Exemplifying Prediction of Preferred Coupling Partners in Developing a Buchwald-Hartwig Coupling for the Synthesis of a c-Kit Inhibitor Quanbing Wu, Xin Xiong, Yudong Cao, Lijuan He, and ZhongBo Fei Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00043 • Publication Date (Web): 28 Mar 2018 Downloaded from http://pubs.acs.org on March 28, 2018

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Organic Process Research & Development

Exemplifying Prediction of Preferred Coupling Partners in Developing a Buchwald-Hartwig Coupling for the Synthesis of a c-Kit Inhibitor Quanbing Wu, Xin Xiong, Yudong Cao, Lijuan He, Zhongbo Fei* †Chemical and Analytical Development, Suzhou Novartis Pharma Technology Co. Ltd, Changshu, Jiangsu, China 215537 ABSTRACT

Two convergent syntheses for compound 1 are described applying the Buchwald-Hartwig coupling as the key steps. This development work provides a direct comparison of the coupling results from different coupling partners and illustrates that more efficiency can be achieved by selecting the right coupling partners.

INTRODUCTION Encoded from the KIT gene, tyrosine kinase protein (c-Kit) functions as the receptor for stem cell factor.1 Binding of SCT to c-Kit leads to the release of histamine that triggers the inflammatory response.2 Blocking c-Kit signaling pathway may be an effective therapeutic method in treating the inflammatory disease.3 Compound 1 is identified as a c-Kit inhibitor.4 Novartis was interested in developing compound 1 for treating respiratory diseases, in particular,

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asthma. Developing an efficient synthesis for compound 1 was needed to supply drug substance for preclinical and clinical studies. The medicinal synthesis of compound 1 is shown in Scheme 1. The linear synthesis sequentially incorporating aryl moieties and the piperidine ring prioritizes the chance for accessing analogues in the course of drug discovery, but is not efficient for producing the finally selected compound. We were keen on developing a convergent synthesis by employing the Buchwald-Hartwig coupling

5

to assemble two components of equal size6 as the key step, and

developing the synthesis into a scalable process. Here we report our results in achieving this objective. Scheme 1. The medicinal synthesis of 1

RESULTS AND DISCUSSION Our first plan was to use pyrimidine 5 and arylbromide 9 for the coupling as shown in Scheme 2. The synthesis of pyrimidine 5 started with the Miyaura borylation7 of 2 to afford boronate ester 3 in a 90% yield. The oily product was purified by high vacuum distillation to greater than 97% purity by HPLC area. The Suzuki-Miyaura coupling of 3 and 4-bromopyrimidine 4 using Pd(PPh3)4 as catalyst produced the desired pyrimidine 5 but also yielded ca 8% of impurity 6. The impurity was likely formed from a side pathway in the catalytic cycle, involving an aryl-aryl


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exchange between the aryl group (from 3) bound to the palladium center and the phenyl group of the phosphine ligand in the palladium (II) complex8, 9 followed by reductive elimination. We found that the impurity could be removed upon precipitation of 5 as a hydrochloride salt by adding aqueous hydrochloric acid to the reaction solution, and hence pursued no further efforts to change the catalyst for avoiding the impurity formation in view of tight project timeline. Scheme 2. The first generation synthesis

The arylbromide component 9 was synthesized via alkylation of piperidine derivative 8, thus setting us the stage for the key Buchwald-Hartwig coupling. We screened different bases, catalysts, ligands and solvents for obtaining a clean reaction profile, and the results are summarized in Table 1. Using potassium tert-butoxide as base complicated the reaction due to transesterification, and only afforded a trace amount of the coupled product (entry 1). Under conditions without such complication, the reaction generally suffered from low conversions. The ligand selection was found crucial; Xantphos was identified as the best ligand for the conversion and selected for further optimization (entry 2).


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Table 1. Conditions and conversion for C-N coupling of 5 and 9 a Entry

solvent

base

ligand

catalyst

conversion

1

toluene

KOtBu

Xantphos

Pd(OAc)2

messy

2

toluene

Cs2CO3

Xantphos

Pd(OAc)2

33%

3

dioxane

Cs2CO3

Xantphos

Pd(OAc)2

24%

4

toluene

K3PO4

Xantphos

Pd(OAc)2

14%

5

toluene

Cs2CO3

BINAP

Pd(OAc)2

0%

6

toluene

Cs2CO3

DPPE

Pd(OAc)2

0%

7

toluene

Cs2CO3

Xantphos

Pd2(dba)3

33%

8

toluene

Cs2CO3

Xantphos

Pd(OAc)2 b

33%

9

toluene

Cs2CO3

Xantphos c

Pd(OAc)2

100%

a. Reaction conditions in general: 1 equiv of 5, 2 equiv of 9, 3 mol % of catalyst, 3 mol % of ligand, 0.42 M substrate 5 in solvent at 85 °C for 12 h b. Additional 3 mol % Pd(OAc)2 was loaded when the reaction did not proceed c. Additional 3 mol % Xantphos was added at two-hour intervals, and total 27 mol % Xantphos was added The reaction under selected conditions always stopped at around 33% conversion. To improve the conversion, we charged additional 3 mol % catalyst when the reaction stopped, but it did not give any higher conversion (entry 8). Intriguingly, when charging additional 3 mol % ligand instead, we obtained some new but partial conversions. The complete conversion was eventually achieved by charging 3 mol % Xantphos every two hours and up to eight times in total (entry 9). This ligand effect was also observed with conditions of entry 3. But charging all 27 mol % Xantphos upfront did not give complete conversion either. One observation was the conversion of Xantphos to its mono phosphine oxide under reaction conditions based on LC-MS analysis, which might be the reason for the beneficial effect of charging additional Xantphos in the course


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of the reaction. Hydrolysis of 10 with aqueous LiOH solution provided target 1. By applying this synthesis, we successfully produced over one hundred grams of drug substance for preclinical studies. This synthesis is convergent but suffers from a sluggish Buchwald-Hartwig coupling that was only driven to completion by repeatedly charging expensive Xantphos. It is feasible for supplying a few hundred grams of drug substance but not practical for kilogram scales. A more efficient and scalable synthesis was needed to supply multi-kilogram drug substance for clinical studies. The sluggish coupling reaction was presumably due to unfavorable C–N-bond forming reductive elimination of complex I in the catalytic cycle (Figure 1); ligand oxidation thus prevailed. Mechanistic studies by Hartwig et al 11, 12 suggested that the key reductive elimination step is generally favored by increasing nucleophilicity of the amido and increasing electrophilicity of the aryl group in the formed palladium-amido aryl complex. In comparison, the coupling partners with switched polarity (Arylchloride 12 and aniline 15 in Scheme 3) would form a palladium-amido aryl complex II with higher nucleophilicity of the amido group and higher electrophilicity of the aryl group therefore favor the reductive elimination to produce the same product. With this hypothesis we developed the second generation synthesis. Figure 1. Two types of complex for C–N-bond forming reductive elimination


5


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Aryl chloride 12 was prepared via Suzuki-Miyaura coupling of bromopyrimidine 11 with the boronate ester 30 following the same conditions as for preparing 5 (Scheme 3). Comparably this reaction was more rapid and did not give the phosphine aryl exchange impurity analogous to 6. To simplify operational steps for scaling up, the two coupling steps were telescoped from 2; thus boronate ester 3 in DME solution was filtered to remove inorganic salts after the borylation reaction, and was used for the second coupling step by adding the catalyst and aqueous sodium carbonate solution. The streamlined process was scaled up to produce 9 kg of 12. Aniline 15 was synthesized by a two-step process starting with alkylation of 8 with para-nitrobenzyl bromide 13, followed by reduction of the nitro group. To avoid the potential reduction at the benzylic position of 14 under hydrogenation conditions, iron powder was selected for reduction of the nitro group, which gave a very clean reaction, even though portion-wise charging of iron powder was needed to avoid heat accumulation in the reaction. Scheme 3. The second generation synthesis

Consistent with the prediction, the new partners 12 and 15 underwent smooth coupling with complete conversion within two hours under catalysis of Pd(OAc)2/BINAP. DMF was selected as the reaction solvent because it allowed direct product precipitation upon addition of aqueous ammonium chloride solution. About 6% of by-product 16 was formed based on LC-MS analysis


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from the coupling of 12 with the desired product 10, and was removed in the workup process to give 10 in 69% isolated yield. The process requires neither expensive Xantphos nor repetitive addition of the ligand as required for using partners 5 and 9, and was demonstrated on a 100gram scale for the reproducibility.14 Without catalyst, the reaction did not proceed under otherwise identical conditions, ruling out the possibility of a direct SNAr pathway.15 Palladium residue was controlled at this point of synthesis. Treatment of product 10 from the coupling with 10 wt % of Smopex® 234 in hot toluene followed by crystallization in the same solvent reduced the palladium level to 25 ppm, which was sufficient to control the palladium level below 10 ppm in the drug substance after subject to the final hydrolysis process. Hydrolysis of 10 following the same conditions in the first generation synthesis afforded target 1.

CONCLUSION In summary, we have developed two convergent syntheses for c-kit inhibitor 1 to deliver the required amounts supporting the drug development. The first generation synthesis was scaled up to over one hundred grams, but suffered from a sluggish Buchwald-Hartwig reaction between 5 and 9, and was not suitable for multi-kilogram scale. This led us to explore the second generation synthesis by employing 12 and 15 as the coupling partners. Consistent with the general principle described by Hartwig,13 partners 12 and 15 form a palladium-amido aryl complex with a higher nucleophilicity of amido and higher electrophilicity of the aryl group comparing to that with 5 and 9, hence favor an efficient coupling reaction. To the best of our knowledge, this is the first report of applying the principle for solving C–N-bond forming problem in target-oriented synthesis. The study exemplifies a direction for retrosynthetic selection of coupling partners for the Buchwald-Hartwig reaction in synthesis design.


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EXPERIMENTAL SECTION NMR spectra were recorded on a Bruker 400 MHz spectrometer. HPLC analysis was performed using Agilent 1200, and the results were described as area %. LC-MS analysis was performed using Agilent 1200 and 6130 Quadrupole system. 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3). To a 2-L three-necked round-bottom flask was charged with bis(pinacolato)diborane (112.0 g, 0.44 mol, 1.1 eq), KOAc (83 g, 0.85 mol, 2.1 eq), 2 (90.0 g, 0.40 mol, 1.0 eq), Pd(PPh3)4 (13.9 g, 12.0 mmol, 0.03 eq), and 1,2-dimethoxyethane (400 mL) under nitrogen atmosphere. The hazy solution was heated to internal temperature at 88±3 °C and stirred at this temperature. The reaction was monitored by HPLC until completion (~ 6 h). Then the reaction suspension was cooled to 10±3 °C and filtered. The filter cake was washed with 1, 2-dimethoxyethane (280 mL). The combined filtrate was concentrated. The concentrated material was subject to high vacuum distillation to give the product as oil (98.0 g, 0.36 mol, 90% yield). 1H NMR (400 MHz, DMSOd6): δ 1.28 (s, 12 H), 7.17 (d, J = 8.53 Hz, 2 H), 7.72(d, J = 8.53 Hz, 2 H), 7.30 (t, J = 72 Hz, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 1`53.6, 136.5, 117.7, 116.1 (t, J = 256 Hz), 83.8, 24.6. 5-(4-(difluoromethoxy)phenyl)pyrimidin-2-amine (5). To a 1-L three-necked round bottom flask was charged 3 (51.7 g, 0.19 mol, 1.0 eq), 4 (43.8 g, 0.25 mol, 1.3 eq), sodium carbonate in H2O (1 M, 230 mL, 1.2 eq), Pd(PPh3)4 (8.6 g, 7.4 mmol, 0.039 eq) and THF (400 mL). The resulting yellow hazy solution was bubbled with nitrogen for 30 min, then heated to 83±3 °C and stirred for 16 h. After cooling to RT, to the solution was very slowly added aqueous HCl (3M, 300 mL) and stirred for 1 h. The precipitants were filtered. The filter cake was suspended in water ( 400 mL) followed by slow addition of aqueous NaOH until pH reached 7~8. The suspension was filtered. The filter cake was dried to give 5 (31.1 g, 0.13


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mol, 68.4% yield) as an off-white solid: mp 151.5~153.1 °C; 1H NMR (400 MHz, DMSO-d6): δ 6.87 (br s, 2 H), 7.00 - 7.45 (m, 3 H), 7.65 (br d, J = 8.56 Hz, 2 H), 8.32 - 9.03 (m, 2 H);

13

C

NMR (100 MHz, DMSO-d6): δ 162.8, 155.8, 150.0, 132.2, 126.6, 121.1, 119.3, 118.7, 116.1, 113.6; MS m/z = 238.0721 (M + H+). Methyl 1-(4-bromobenzyl)piperidine-4-carboxylate (9). To a suspension of 7 (25.0 g, 0.100 mol, 1.0 eq), K2CO3 (27.7 g, 0.20 mol, 2.0 eq) in acetone (310 mL) was added 8 (14.3 g, 0.10 mol, 1.0 eq) dropwise with stirring, and the internal temperature was kept below 20 °C. After addition, the suspension was warmed to 25 °C and stirred for 2 hr. The suspension was filtered and the filter cake was washed with acetone (10 mL x 2). The filtrate was concentrated under vacuum at 40 °C to give a crude product as light yellow oil. Heptane (110 mL) was added to the crude product and heated to 45 °C and stirred for 15 min. The resulting solution was cooled to -20 °C. The precipitates were filtered and dried to give the product (23.1 g, 0.074 mmol, 74.0% yield) as a white solid: mp 40.0~40.7 °C; 1H NMR (400 MHz, CDCl3): δ 1.64 - 1.80 (m, 2 H), 1.82 - 1.92 (m, 2 H), 2.00 (td, J = 11.37, 2.08 Hz, 2 H), 2.28 (tt, J = 11.13, 4.10 Hz, 1 H), 2.80 (br. d., J = 11.62 Hz, 2 H), 3.37 - 3.49 (m, 2 H), 3.58 3.75 (m, 3 H), 7.18 (d, J = 8.31 Hz, 2 H), 7.41 (d, J = 8.31 Hz, 2 H);

13

C NMR (100 MHz,

CDCl3): δ 175.5, 137.1, 131.1, 130.5, 120.5, 62.3, 52.6, 51.4, 40.9, 28.1; MS m/z = 312.0576 (M + H+) . Methyl

1-(4-((5-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)amino)benzyl)piperidine-4-

carboxylate (10). To a 250-mL flask was added 9 (39.5 g, 126.5 mmol, 1.99 eq), Pd(OAc)2 (425.9 mg, 1.90 mmol, 0.03 eq), Xantphos (1.1 g, 1.90 mmol, 0.03 eq), Cs2CO3 (41.2 g, 126.5 mmol, 1.99 eq) and toluene (150 mL). The hazy solution was bubbled with nitrogen gas while stirring for 10 min


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and then heated to 85 °C. The color of the reaction solution turned from yellow to dark brown. Substrate 5 (15.1 g, 63.7 mmol, 1.0 eq) was added to the hazy solution and stirred at 85±3 °C. Two hours later, additional Xantphos (1.1 g, 1.9 mmol, 0.03 eq) was added at every two-hour interval under nitrogen protection for 8 times in total until completion of the conversion. The reaction was cooled and filtered. The filtrate was concentrated and dissolved in THF (300 mL). The THF solution was washed with saturated NH4Cl (200 mL). The organic phase was concentrated until a 20 mL volume, to which was slowly added ethyl acetate (200 mL). The precipitants were filtered and dried to give the product (13.5 g, 28.8 mmol, 45.2% yield) as a white solid: mp 166.3~166.4 °C; 1H NMR (400 MHz, DMSO-d6): δ 1.55 (m, 2 H), 1.78 (d, J = 12 Hz, 2 H), 1.95 (t, J = 12 Hz, 2 H ), 2.29 (m, 1 H), 2.74 (br. s., 2 H), 3.37 (br. s., 2 H), 3.58 (s, 3 H), 7.19 (d, J = 8.53 Hz, 2 H), 7.27 (d, J = 12 Hz, 2 H), 7.29 (t, J = 148 Hz, 1 H), 7.77 (d, J = 8.78 Hz, 2 H), 7.72 (d, J = 8.53 Hz, 2 H), 8.81(s, 2 H), 9.77 (s, 1 H);

13

C NMR (100 MHz,

DMSO-d6): δ 174.9, 159.3, 155.7, 150.4, 139.1, 131.9, 131.4, 129.1, 127.3, 123.1, 119.4, 118.8, 116.3 (t, J = 256 Hz), 62.0, 52.2, 51.4, 40.3, 28.0; MS m/z = 469.2044 (M + H+). 1-(4-((5-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)amino)benzyl)piperidine-4carboxylic acid (1). A 2000-mL round-bottom flask was charged with 10 (213.0 g, 455 mmol, 1.0 eq), LiOH· H2O (76.4 g, 1.82 mol, 4.0 eq), THF (760 mL), methanol (500 mL) and water (254 mL) at room temperature. The reaction suspension was stirred at room temperature and monitored by HPLC until completion (~6 h). The reaction solution was concentrated and diluted with water (800 mL). The suspension was neutralized with 2 M HCl at 20 °C until pH = 6.3, stirred for 2 h and filtered. The filter cake was dried under vacuum at 80 °C overnight to give 1 (186 g, 0.41 mol, 90.0 % yield) as a white solid: mp 254.1–257.1°C; 1H NMR (400 MHz, DMSO-d6): δ 1.54 (m, 2H), 1.78


10

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(d, J = 12 Hz, 2 H), 1.95 (t, J = 12 Hz, 2 H), 2.18 (m, 1 H), 2.75 (br. s., 2 H), 3.37 (br. s., 2 H), 7.20 (d, J = 8.53 Hz, 2 H), 7.28 (d, J = 12 Hz 2 H), 7.30 (t, J = 148 Hz 1 H), 7.77 (d, J = 8.78 Hz, 2 H), 7.72 (d, J = 8.53 Hz, 2 H), 8.81(s, 2 H), 9.77 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): δ 176.2, 159.3, 155.7, 150.4, 139.1, 131.9, 131.4, 129.1, 127.3, 123.1, 119.4, 118.8, 116.4 (t, J = 257 Hz), 62.0, 52.3, 40.2, 28.1; MS m/z=455.1866 (M + H+). 2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine (12). To a reactor was charged with bis(pinacolato)diborane (10.52 kg, 41.43 mol, 1.1 eq), KOAc (7.76 kg, 79.07 mol, 2.1 eq), 2 (8.40 kg, 37.66 mol, 1.0 eq), Pd(PPh3)4 (1.3 kg, 1.13 mol, 0.03 eq), and 1, 2-dimethoxyethane (30.0 kg) under nitrogen atmosphere. The hazy solution was heated to the internal temperature at 88±3 °C and stirred at this temperature. The reaction was monitored by HPLC until completion (~ 6 h). Then the reaction suspension was cooled to 10±3 °C and filtered. The filter cake was washed with 1, 2-dimethoxyethane (10.0 kg). The combined organic layer containing 3 was carried to the next step without further purification. To a reactor was charged crude 3 solution from the previous step, 11 (8.74 kg, 45.18 mol, 1.2 eq), H2O (41.4 kg), Na2CO3(4.39 kg, 41.40 mol, 1.1 eq) and Pd(PPh3)4 (1.30 kg, 1.13 mol, 0.03 eq) under nitrogen atmosphere. The resulting solution was heated to the internal temperature at 88±3°C and stirred at this temperature. The reaction was monitored by HPLC until completion (~7 h). The reaction solution was concentrated under vacuum to afford a yellow suspension. The suspension was filtered and washed with water (30 kg) to afford a crude product. The crude product was then recrystallized in methanol (60 kg) to afford 12 (9.00 kg, 35.07 mol, 93.0% yield for two steps) as a white solid: mp 172.3–175.6 °C; 1H NMR (400 MHz, CDCl3): δ 6.59 (t, 1 H), 7.29 (d, J = 8.53 Hz, 2 H), 7.57 (d, J = 8.53 Hz, 2 H), 8.81 (t, J = 72 Hz, 2 H); 13C NMR


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(100 MHz, CDCl3): δ 160.5, 157.4, 132.2, 130.2, 128.6, 120.8, 115.6 (t, J = 259 Hz); MS m/z = 257.0271 (M + H+). Methyl 1-(4-nitrobenzyl)piperidine-4-carboxylate (14). A 1-L three-necked round-bottom flask was charged with 8 (31 g, 0.22 mol, 1.1 eq), acetone (400 mL), K2CO3 (55 g, 0.40 mol, 2.0 eq), and 13 (43 g, 0.20 mol, 1.0 eq). The reaction solution was stirred at room temperature and monitored by HPLC. After completion (~ 2 h), the reaction was filtered and washed with acetone (100 mL). The filtrate was concentrated under vacuum to give 14 as an oil (55 g, 0.20 mol, 99% yield). 1H NMR (400 MHz, CDCl3): δ 1.75 (t, J =10.42 Hz, 2 H), 1.84 (d, J = 3.51 Hz, 1 H), 1.88 (d, J = 3.51Hz, 1 H), 2.05 (td, J = 11.29, 2.51 Hz, 2 H), 2.29 (m, 1 H), 2.78 (d, J = 11.54 Hz, 2 H), 3.54 (s, 2 H), 3.65 (s, 3 H), 7.47 (d, J = 8.78 Hz, 2 H), 8.12 (d, J = 8.78 Hz, 2 H); 13C NMR (100 MHz, CDCl3): δ 175.5, 146.8, 129.3, 123.5, 62.3, 53.0, 51.7, 40.8, 28.3; MS m/z = 279.1327 (M + H+). Methyl 1-(4-aminobenzyl)piperidine-4-carboxylate (15). To a 1-L three-necked round-bottom flask was charged a solution of 14 (55 g, 0.20 mol, 1.0 eq) in methanol (500 mL) and aqueous HCl (5 M, 48 mL). The solution was heated to 60 °C, to which was added iron powder (100 µm) (39 g, 0.70 mol, 3.5 eq) in 4 equal portions at 5 minute intervals. The reaction was monitored by HPLC until completion (~3 h). The reaction was cooled to room temperature, filtered, and washed with methanol (200 mL). The filtrate was concentrated to a residue, which was partitioned between aqueous Na2CO3 solution (1 M, 300 mL) and IPAc (600 mL). The organic layer was washed with water (300 mL X 3) and concentrated to give 15 (42 g, 0.17 mol, 85% yield) as a waxy solid: mp 40.5–44.6°C; 1H NMR (400 MHz, DMSO-d6): δ 1.51 (dd, J = 12.30, 2.76 Hz, 2 H), 1.78 (br. s., 1 H), 1.76 (d, J = 10.54 Hz, 1 H), 1.90 (d, J = 1.76 Hz, 2 H), 2.26 (m, 1 H), 2.71 (d, J = 11.80 Hz, 2 H), 3.24 (s, 2 H), 3.58 (s, 3H), 6.48 (d, J =


12

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8.28 Hz, 2 H), 6.89 (d, J = 8.53 Hz, 2 H); 13C NMR (100 MHz, CDCl3): δ 175.8, 145.5, 130.4, 128.1, 115.0, 62.9, 52.8, 51.7, 41.3, 28.4; MS m/z = 249.1577 (M + H+). Methyl

1-(4-((5-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)amino)benzyl)piperidine-4-

carboxylate (10). A 2-L three-necked round-bottom flask was charged with 15 (183 g, 0.74 mol, 2.0 eq), Pd(OAc)2 (2.48 g, 11.1 mmol, 0.03 eq), Cs2CO3 ( 240 g, 0.74 mol, 2.0 eq), and DMF (1000 mL). The reaction hazy solution was heated to the internal temperature at 70±3 °C in a 10 min period and then BINAP (11.3 g, 18.2 mmol, 0.049 eq) was added. After 20 min, to the reaction hazy solution was added 12 (95.0 g, 0.37 mol, 1.0 eq). The reaction was stirred at 70±3 °C and monitored until completion (~1.5 h). The reaction hazy solution was cooled to RT, filtered and washed with DMF (100 mL). The filtrate was cooled to 10±3°C. To the solution was slowly added a half-saturated NH4Cl solution (1.1 L) while the internal temperature was kept below 30 °C. The obtained suspension was agitated for 30 min. The suspension was filtered, washed with water (100 mL) and toluene (600 mL), and dried under vacuum at 60 °C to afford 10 (120 g, 0.256 mol, 69.2 % yield). Removal of palladium residue in 10. To a 5-L three-necked round-bottom flask was added 10 (120 g, 800 ppm Pd level), Smopex® 234 (12 g) and toluene (2.4 L). The suspension was heated to reflux for 2 h and slowly cooled to 60±3°C, followed by hot filtration. The filtrate was distilled under vacuum until recovery of 1200 mL toluene. The concentrated solution was stirred at 10±3 °C for 2 h, followed by filtration. The filter cake was washed with toluene (100 mL) and dried under vacuum at 60 °C overnight to afford 10 (91 g, 21 ppm Pd level, 76 % yield).


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AUTHOR INFORMATION Corresponding Author *[email protected] ABBREVIATIONS DME,

dimethoxyethane;

RT,

room

temperature;

IPAc,

iso-propyl

acetate;

THF,

tetrahydrofuran; DMF, dimethylformamide. REFERENCES (1) Zsebo, K. M.; Williams, D. A.; Geissler, E. N.; Broudy, V. C.; Martin, F. H.; Atkins, H. L.; Hsu, R. Y.; Birkett, N. C.; Okino, K. H.; Murdock, D. C.; Jacobsen, F. W.; Langley, K. E.; Smith, K. A.; Takeishi, T.; Cattanach, B. M.; Galli, S. J.; Suggs, S.V. Cell 1990, 63, 213. (2) Reber, L.; Silva, C. A.; Frossard, N. Eur. J. Pharmacol. 2006, 533, 327. (3) Jensen, B. M.; Metcalfe, D. D.; Gilfillan, A. M. Inflammation Allergy: Drug Targets 2007, 6, 57. (4) Molteni, V.; Li, X.; Liu, X.; Chianelli, D.; Nabakka, J., Loren, J.; You, S. WO 2009/026276. (5) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609. (6) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem. 1995, 107, 1456; Angew. Chem. Int. Ed. 1995, 34, 1348. (7) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. (8) Kong, K. C.; Cheng, C. H. J. Am. Chem. Soc. 1991, 113, 6313. (9) O’Keefe, D. F.; Dannock, M. C.; Marcuccio S. M. Tetrahedron Lett. 1992, 33, 6679. (10) Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Org. Lett. 2002, 4, 3481. (11) Drive, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 8232.


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(12) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046. (13) Hartwig, J. F. Nature 2008, 455, 314. (14) Due to project status change, the production of this step was not executed. (15) No other SNAr conditions were investigated.


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Exemplifying Prediction of Preferred Coupling Partners in Developing

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