Development of a Scalable Synthesis for the Potent Kinase Inhibitor

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Development of a Scalable Synthesis for the Potent Kinase Inhibitor, BMS-986236; 1-(5-(4-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4(isopropylamino) pyridin-2-yl)-1H-pyrazolo[3,4-b] pyridine-5-carbonitrile Pirama Nayagam Arunachalam, Prakasam Kuppusamy, Sivakumar Ganesan, Suresh Krishnamoorthy, Roshan Y Nimje, Lokesh Babu Jarugu, Nanjundaswamy Kanikahalli Chikkananjaiah, China Anki Reddy, Prakash Anjanappa, Murali Botlagunta, Sridhar Vanteru, Nageswararao Maddala, Muniyappa Shankar, Satheesh Nair, John Hynes, Joseph B Santella, Percy H Carter, Richard A. Rampulla, Muthalagu Vetrichelvan, Anuradha Gupta, Arun Kumar Gupta, and Arvind Mathur Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00023 • Publication Date (Web): 27 Mar 2019 Downloaded from http://pubs.acs.org on March 27, 2019

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Organic Process Research & Development

ACS Paragon Plus Environment

Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 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

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Development of a Scalable Synthesis for the Potent Kinase Inhibitor, BMS-986236; 1-(5-(4-(3-hydroxy3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4(isopropylamino) pyridin-2-yl)-1H-pyrazolo[3,4-b] pyridine-5-carbonitrile Pirama Nayagam Arunachalam,† Prakasam Kuppusamy,† Sivakumar Ganesan,† Suresh Krishnamoorthy,† Roshan Y. Nimje,† Lokesh Babu Jarugu,† Nanjundaswamy Kanikahalli Chikkananjaiah,† China Anki Reddy,† Prakash Anjanappa,† Murali Botlagunta,† Sridhar Vanteru,† Nageswararao Maddala,† Muniyappa Shankar,† Satheesh Nair,† John Hynes, Jr,

‡

Joseph B.

Santella, III,‡ Percy H. Carter‡, Richard Rampulla‡, Muthalagu Vetrichelvan,†* Anuradha Gupta,† Arun Kumar Gupta,† and Arvind Mathur‡ †Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Center, Biocon Park, Bommasandra IV phase, Jigani Link Road, Bangalore-560 099, India ‡Discovery Chemistry, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 085434000, United States.


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Graphic for TOC only

First Generation Synthesis Overall Yield - 18% Hazardous reagents HO

B

N N N

C

A

NH O 2N

NH N

N 7

Cl

N

C

N N 1(BMS-986236)

B A

Second Generation Synthesis Overall Yield - 41% Less Hazardous reagents Scalable Scheme Cost efficient

CN

A - Azide formation B - Click chemistry C - Buchwald coupling


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ABSTRACT: A scalable route to 1-(5-(4-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4(isopropylamino) pyridin-2-yl)-1H-pyrazolo[3,4-b] pyridine-5-carbonitrile, 1 (BMS-986236) was developed by incorporating an alternate azide intermediate following safety driven processes. The newly developed process involved mitigating safety hazards and eliminating the column chromatography purification. The issue of trace metal contamination in the final API observed to the first generation synthesis has been overcome.

KEYWORDS: kinase inhibitor, scalable synthesis, DSC studies, azide, triazole, 1H-pyrazolo[3,4b]pyridine derivative.


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INTRODUCTION Recently 1,2,3-triazole derivatives have been successfully exploited in the discovery of a number of privileged scaffolds due to its bioisostere nature in medicinal chemistry.1 1-(5-(4-(3hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4-(isopropylamino) pyridin-2-yl)-1Hpyrazolo[3,4-b] pyridine-5-carbonitrile (1, BMS-986236) (Figure 1) is identified as a kinase inhibitor which is under investigation for a potential drug candidate for one of our discovery programs. As part of a developmental program, a safe and scalable process to synthesize large quantities of 1 was required. HO

N N N

NH N N

CN

N N

Figure 1. Structure of 1 (BMS-986236) In the first generation synthesis, 12 was synthesized in 5 steps starting from 2,4-dichloro5-nitropyridine, 2 with an overall yield of 18% (Scheme 1). While this approach worked well to provide material for the early medicinal chemistry efforts, there were some limitations in its scaling up such as; (i) it involved a high energy azide intermediate 5 (ii) low yield in the final Buchwald coupling (38%) and (iii) use of palladium catalyst in the final Buchwald coupling required rework to reduce the residual levels of Pd. Thus the existing route was not suitable for scale-up and long term supply of API 1. Reworking on retrosynthesis led to a change in the sequence of reactions to make it more practical and scalable. An early institution of Buchwald coupling followed by the introduction of a safer azide reagent was thought to be a better way to circumvent some of these issues, which led to the development of an alternate route.


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Scheme 1. First Generation Synthesis of 1 Cl

iPrNH2/CH3CN 40 oC, 12 h

O 2N N 2

Cl

NH

H2, PtO2 EtOAc, 25 oC, 4 h

O 2N N 3

91%

Cl

NH

N 4

90%

OH 6 CuSO4, Sodium ascorbate aq. t-BuOH, 50 oC, 10 h 82%

ADMP, DMAP, CH3CN, 40 oC, 12 h

H 2N

Cl

NH N3 Cl

N 5

73%

CN HO

N N N

7

HO

N N H

NH

N

Cl

N 8

N N N

Me4-di-t-Bu-XPhos,Pd2(dba)3, K3PO4, Dioxane, 100 oC, 12 h 38%

NH N N

1

CN

N N

RESULTS AND DISCUSSION First Generation Synthesis. Medicinal chemistry approach to the designed triazole active pharmaceutical intermediate (API) 1 (BMS-986236) involved five steps starting from 2,4dichloro-5-nitro pyridine (2) as shown in Scheme 1. The SNAr reaction on intermediate 2 with isopropyl amine3 underwent regio-selective substitution at the 4th position to afford the compound 3 and the nitro reduction of 3 with platinum oxide gave 6-chloro-N4isopropylpyridine-3,4-diamine (4) as reported earlier.2 Further, the amine 4 converted to the azide 5 in 73% yield using the reagent 2-azido-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium hexafluorophosphate (ADMP).4 The resulted azide 5 reacted with hexyn-2-ol 65 to provide the triazole derivative 7 with 82% yield. The final step Buchwald reaction with 1H-pyrazolo[3,4b]pyridine-5-carbonitrile 86 resulted in the required API 1 in 38% yield. The azide intermediate 5 of the 1st generation synthesis was found to be an energetic, as revealed by its differential scanning calorimeter thermogram (DSC) (Figure 2); displayed an onset of an exotherm at ~75 oC with an exothermic release of 1111 J / g. Further, intermediate 5 was suspected of being shock sensitive based on the Yoshida-Bodman correlation,7 and thus presented an explosion risk. These factors flagged a critical challenge for the scaling up this reaction.


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Figure 2. DSC data of an azide intermediate 5

As shown in Scheme 2, initially, it was decided to synthesize precursor 7 to avoid the above safety issues. Following click chemistry, three component one pot in situ azide-alkyne cycloaddition of intermediate 11 and alkyne 6 in the presence of sodium azide was carried out. It avoided isolation of the thermally labile azide intermediate 5.8 Intermediate 11 was synthesized in two steps, starting from 4-chloro-5-iodopyridine-2-amine (9) following diazotization using tert-butyl nitrite/ triethyl benzylammonium chloride (TEBAC) to provide the 2,4-dichloro-5-iodo pyridine (10) in 46% yield. Though the reagent tert-butyl nitrite is shock sensitive and explosive nature, thought to replace this reagent while going for the scale-up. Following the original procedure2 compound 10 was converted to intermediate 11 using isopropyl amine in DMA in


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75% yield. It was taken for in-situ click chemistry with alkyne 6 to provide the triazole intermediate 7 in 69% yield.10 Scheme 2. Alternate synthesis of triazole derivative 7 OH

Cl I N

O

N

O

TEBAC, DCM, RT, 10 h NH2

NH2

Cl I

46%

DMA, 100 oC, 16 h I N 10

9

Cl

75%

HN

N

HO 6 Sodium ascorbate, aq.DMSO, NaN3, 80 oC, 16 h Cl

11

N N N

HN

69% 7

N

Cl

Though Scheme 2 circumvented the isolation of azide intermediate (5), it had scalability issues since Buchwald coupling at the final step required pressure tube condition in first generation synthesis. Additionally, the issue of Pd contamination of API at the final step warranted repeat treatment with silica-supported scavenger SiliaMetS thiol11 to reduce the residual Pd content to below 50 ppm. Hence we were in search for an alternate scheme which circumvents these issues. Second Generation Synthesis. Based on retro-synthesis, there can be two disconnection approaches A and B to synthesize BMS-986236 (1) as shown in Scheme 3. First generation synthesis based on Approach-A and second-generation synthesis was based on Approach-B. In Approach-B, API, 1 could be synthesized from azide 12 using click chemistry. Azide 12 could be synthesized from its corresponding nitro intermediate 13 in two steps through azide transfer and reduction. Intermediate 13 was synthesized from the same starting material, 2 as first generation synthesis via Buchwald coupling using two steps. The main difference between these two approaches was the sequence of Buchwald coupling and click chemistry. In Approach-A the first step was the click chemistry followed by Buchwald coupling, and in Approach-B the first


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step was Buchwald coupling followed by the click chemistry reaction. For larger scale synthesis of BMS-986236, the later appeared more convenient.

Scheme 3. Retrosynthetic Approach to 1 (BMS-986236) HO

N N N

NH N

CN

N N

N 1(BMS-986236)

Approach A Buchwald coupling

HO

N N N

+ N Cl

N

N H

Approach B

NH

CN

NH

7

Click chemistry

N3

N

N N

8

OH

Click chemistry

CN

N 12 N Azide transfer Reduction

6 Reduction

NH

Azide transfer

N3 N

Buchwald Coupling O N 2 8

NH O 2N

NH N

Cl 3

5

N

CN

N N

N Cl 13

Cl O 2N N 2

Cl

Approach-B appeared appropriate, keeping the above issues in mind. Increasing the bulkiness of the key azide intermediate by increasing C/N ratio12 might increase the thermal stability of the azide intermediate and mitigate the hazard involved. Thus, flipping the original sequence of the reaction, with Buchwald as the first step, followed by the reduction of nitro and conversion to


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azide intermediate 12 through azide transfer4 followed by click chemistry would give the desired API 1 (Scheme 4).

Scheme 4. Improved final scalable synthesis of 1 (Second Generation Synthesis) CN N N N H 8 Xantphos,Pd2(dba)3, K2CO3 Dioxane, 100 oC, 12 h

NH O 2N N 3

Cl

NH

O 2N

N N

84%

13

CN

N2H4.H2O, 10% Pd/C 1:1 THF:EtOAc, 60 oC, 3 h

N N

ADMP, DMAP, CH3CN, RT, 12 h 83%

N3

N N

12

N N

CN

N

CN

N N

N

88%

14

OH HO

NH

NH

H 2N

6 CuSO4, Sodium ascorbate, Acetone:H2O, RT, 12 h 73%

N N N

NH N N

1

CN

N N

Once the sequence was finalized the reaction conditions for each step were optimized. The first Buchwald coupling between 3 and 8 attempted using Me4-di-t-Bu-Xphos, in a pressure tube as in first generation synthesis and resulted a moderate yield (50%). When the reaction was tried using the ligand Xantphos in a conventional method, the yield was increased significantly to 84%. About 1.1 kg of intermediate 13 was synthesized by following this procedure, in a maximum batch size of 200 g in an average yield of 84%. Also, the cost was reduced 1/10th to the original cost by selecting Xantphos over Me4-di-t-Bu-XPhos. For the next conversion 13 to 14, the reduction of the nitro group in 13 was screened using various reducing agents (Table 1). Among these, tin chloride in methanol gave a good yield of the corresponding amine 14 (Table 1, entry 1). However, considering the toxicity involved and difficulty associated with the tin removal process, other options were reviewed. The low conversions were obtained using standard reducing agents like sodium hydro sulfite,


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Fe/CaCl2, and Zn/NH4Cl. Use of hydrazine hydrate13/Pd-C in ethyl acetate/methanol mixed solvent gave promising results with a yield of 75% (Table 1, entry 5). Changing the solvent system from ethyl acetate/methanol to ethyl acetate/THF improved the yield further to furnish amine 14 (Table 1, entry 6) in 88% yield. About 600 g of the intermediate 14 was synthesized using this procedure with the maximum batch of 100 g. Table 1. Optimization of the Reduction Reaction HN

HN O2N N N

13

N N

Conditions

H 2N

CN

N N

CN

N N

14

Entry

Reagent

Temp. / h

Solvent

Conversion (%)

1

SnCl2

60 / 12

MeOH

79a

2

Na2O4S2

24 / 12

THF:H2O (1:1)

20b

3

Fe / CaCl2 · 2H2O

65 / 16

MeOH

25b

4

Zn / NH4Cl

24 / 12

THF:H2O (1:1)

45b

5

Pd/C, NH2NH2

65 / 4

Ethyl acetate:MeOH (1:5)

75a

6

Pd/C, NH2NH2

65 / 4

Ethyl acetate:THF (1:1)

88a

a

Isolated yield, b Monitored by LCMS

Our next attention was on the azide transfer reaction for the conversion of amine 14 to 12. Though 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP) used in the first generation synthesis, due to the limited commercial supply and lower shelf life of ADMP, initial attempts were made with most conventional reagent systems, such as NaNO2/NaN3, 2,4,6trimethylbenzenesulfonyl azide, isoamyl nitrite / TMS-N3, and DMAP/p-toluene sulfonyl azide. ACS Paragon Plus Environment

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Unfortunately, none of the reactions were successful which led us to re-consider ADMP, and the conversion yielded 83% of 12. It was clear that ADMP was the best option for our chemistry though there was an issue with limited shelf life4 as well as large scale supply of the reagent. Considering its limited shelf life, in-house synthesis of this reagent planned as reported earlier,4 which not only mitigated a steady supply but also had an advantage of making it on demand. ADMP was synthesized by following a literature protocol4a with all mentioned safety precautions. According to DSC data,4c the exothermic decomposition of ADMP was from 200 oC,

and it could be used preferably under 100 oC with sufficient margin.4c Accordingly the

reaction was tried at room temperature and was successful. About 700 g of ADMP was made insitu in various batches with 200 g batch scale as the upper limit for the batch size. ADMP was used immediately to synthesize azide 12 in excellent and reproducible yields. About 550 g of the azide 12 was synthesized using in-house synthesized ADMP reagent. Routine DSC analysis of an azide intermediate 12 (Figure 3) showed the higher onset of exotherm (125–138 oC) which significantly lowered the decomposition energy (645.9 J/g) compared to azide 5 of the first generation synthesis. However, the sharpness of the peak did indicate a rapid onset of decomposition; and it warranted further risk analysis for its shock sensitivity. Yoshida/Bodman calculation involving the onset of the exotherm and the heat evolved confirmed that the bulkier azide 12 was indeed safer and did not have shock sensitivity.7 The DSC study proved the hypothesis that increasing the bulkiness of the thermally labile intermediate could reduce the associated process safety hazard during the scale-up.


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Figure 3. DSC data for bulky azide 12 The final click chemistry between the intermediates 12 and 6 to construct the triazole moiety went smoothly under standard conditions14 using DMF / water (9:1) with a moderate yield of the desired API (1). It ran into an issue of the bulk removal of DMF which was found to be difficult. It led to a routine solvent screening, and acetone / H2O (8:2) was found to give a comparable yield from 69 to 72%. Following this improvement, ~475 g of the API, BMS-986236 was made with a maximum scale-up batch of 100 g of intermediate 12.


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CONCLUSION In summary, a scalable and fit for purpose process for the synthesis of 1-(5-(4-(3hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4-(isopropylamino)-pyridine-2-yl)-1H-pyrazolo[3,4-b]- pyridine-5-carbonitrile 1 (BMS-986236) was developed by judicious interchange of sequence of steps. The new route also included a critical manipulation of the highly energetic azide intermediate. All major safety and quality issues with the early phase route addressed and the thermal stability issue of the azide 5 circumvented by increasing the bulkiness of the azide 12. Based on these changes, the second-generation synthesis shows significant improvement relative to the first-generation route with the overall yield of 41% in five steps and has been demonstrated on ~100 g scale multiple times to produce 475 g of API with excellent purity.

EXPERIMENTAL SECTION All starting materials, reagents, and solvents were purchased from commercial suppliers and used without further purification. All reactions were performed under a nitrogen atmosphere unless otherwise specified. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were measured, and chemical shifts were reported in ppm using TMS or the residual solvent peak as a reference. The high-resolution mass spectra (HRMS) were recorded on Thermo Scientific LTQ orbitrap velos using direct infusion modes. LC-MS analyses were done using Agilent 6140 quadrupole LCMS using C18 columns (see Supporting Information for more details on the respective spectra). 1-(4-(isopropylamino)-5-nitropyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5- carbonitrile (13). A 5 L three-necked flask was charged with 2-chloro-N-isopropyl-5-nitropyridin-4-amine 3 (150 g, 0.70 mol), 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile 8 (100.5 g, 0.70 mol), 1,4-Dioxane (3


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L), K2CO3 (240 g, 1.74 mol) and Xantphos (80.4 g, 0.14 mol). The resultant reaction mixture was purged with nitrogen for 30 min and then added bis(dibenzlidineacetone)Pd(0) (79.8 g, 0.14 mol) and again purged with nitrogen for 30 min. The mixture was heated to 100 °C for 12 h. Then the reaction mixture was filtered through celite bed and washed with dichloromethane until product disappears in the celite bed (about 5 L) (Checked by TLC for the last drop), concentrated the solvent to one and half volume (1 L). The resulted reaction mixture was poured into 1,4dioxane: water (1:5) (5 volume), stirred for 1h, and the precipitate formed was collected by filtration and dried. This solid was slurried with dichloromethane (1 L), and added to 2L of petroleum ether, stirred for 30 min and the precipitate formed was collected by filtration, washed with water, and then dried at 35 °C in vacuum to give the title compound 13 (189 g, 84% yield, purity by HPLC: 98.4%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ = 9.14 (s, 1H), 9.10 (d, J = 2.27 Hz, 1H), 9.00-9.05 (m, 1H), 8.71 (s, 1H), 8.16 (d, J = 7.55 Hz, 1H), 7.74 (s, 1H), 4.00 (dq, J = 13.46, 6.47 Hz, 1H), 1.35 (d, J = 6.42 Hz, 6H). 13C NMR (300 MHz, DMSO-d6) δ = 152.51, 151.96, 150.19, 148.88, 148.58, 137.53, 136.99, 128.28, 117.39, 116.78, 103.50, 98.98, 44.38, 21.59. HRMS [M + H]+ calcd for C15H13N7O2 324.1203; found 324.1199. 1-(5-amino-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (14). A 10 L auto clave was charged with 1-(4-(isopropylamino)-5-nitropyridin-2-yl)-1Hpyrazolo[3,4-b]pyridine-5-carbonitrile 13 (150 g, 0.46 mmol), THF (3 L), ethyl acetate (3 L), Pd/C (30 g, 0.28 mol) and hydrazine hydrate (300 mL, 4.63 mol). The reaction mixture was heated to 60 °C for 3 h. Then the resulting mixture was filtered through celite bed to remove palladium residue, washed with 1.5 L of methanol. The combined organic layer was concentrated to obtained crude residue. The resultant residue was treated with 4.0 L of water, stirred for 15 min, and the precipitate formed was collected by filtration, washed with water, and then dried for


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overnight. The crude product was triturated with methyl tertiary butyl ether (1 L) and filtered to get the title product 14 as pale yellow solid (120 g, 88 % yield, purity by HPLC: 97.3%). 1H NMR (300 MHz, DMSO-d6) δ = 9.11 - 8.82 (m, 2H), 8.49 (s, 1H), 7.62 (s, 1H), 6.79 (s, 1H), 5.43 (d, J=7.2 Hz, 1H), 4.95 (s, 2H), 3.66 (dq, J=13.1, 6.5 Hz, 1H), 1.33 - 1.06 (m, 6H). 13C NMR (100 MHz, DMSO) δ = ppm 151.5, 149.8, 142.6, 142.3, 136.9, 135.0, 132.1, 131.6, 118.3, 115.5, 102.4, 99.5, 43.5, 22.5. HRMS [M + H]+ calcd for C15H15N7 294.1462; found 294.1462. 1-(5-azido-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (12). A 5 L three-necked flask was charged with 1-(5-amino-4-(isopropylamino)pyridin-2-yl)-1Hpyrazolo[3,4-b]pyridine-5-carbonitrile 14 (115 g, 0.39 mol), DMAP (62.3 g, 0.51 mol), acetonitrile (3 L) and then solution of (2-Azido-1,3-dimethylimidazolinium hexafluorophosphate (146 g, 0.51 mol) in acetonitrile (700 mL) was added drop wise and stirred at 24 °C for 12 h. The resulting mixture was concentrated to obtain the crude solid. The resultant solid was treated with water (3.0 L), stirred for 15 min, and the precipitate formed was collected by filtration, washed with water, and then dried at 35 °C in vacuum to obtain the crude solid. The crude was dissolved with 1.5 L acetone and treated with 10 g charcoal for 30 min. at 55 °C, filtered the reaction mass and washed with 300 mL of acetone. The filtrate was concentrated to obtain the solid and the crude product was triturated with pet ether : methyl tertiary butyl ether (1:1) (500 mL) and filtered to get the title product 12 (100 g, 80% yield, purity by HPLC: 99.3%) as light brown solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.16 - 8.83 (m, 2H), 8.59 (s, 1H), 8.19 (s, 1H), 7.14 (s, 1H), 6.02 (d, J=8.0 Hz, 1H), 3.72 (d, J=7.5 Hz, 1H), 1.21 (d, J=6.5 Hz, 6H). 13C NMR (100MHz, DMSO) δ = ppm 151.9, 150.0, 148.7, 146.1, 138.6, 137.1, 136.2, 121.2, 118.1, 116.2, 103.0, 98.8, 43.8, 22.1. HRMS [M + H]+ calcd for C15H13N9 320.1367; found 320.1362.


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Caution: Although we have never had any issue with ADMP, it is potentially explosive.4 The safe operation temperature was at RT was maintained.4c 1-(5-(4-(3-hydroxy-3-methylbutyl)-1H-1,2,3-triazol-1-yl)-4-(isopropylamino)pyridin-2-yl)1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (1). A 5 L three-necked flask was charged with 1(5-azido-4-(isopropylamino)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile 12 (92 g, 288 mmol), 2-methylhex-5-yn-2-ol 6 (35.5 g, 317 mmol), acetone (3 L), Sodium ascorbate (22.83 g, 115 mmol) and then added solution of copper(II) sulfate pentahydrate (14.39 g, 57.6 mmol) in water (250 mL) with stirring and purged nitrogen for about 15 min. Then the reaction mixture was stirred at 25 oC overnight. The resulting mixture was filtered through celite bed, washed with acetone (750 mL). Filtrate was concentrated to obtain the crude residue, which was dissolved in dichloromethane (3 L). The organic layer was washed with aq. ammonia solution (3 × 1 L), water (3 × 1 L), brine (2 × 1 L), dried over sodium sulfate and concentrated under vacuum to obtained the title compound as a pale yellow solid. The crude was dissolved in acetone (2 L) and treated with 10 g charcoal for 30 min at 55 °C, the reaction mass was filtered through celite bed and washed the bed with acetone (500 mL). The combined organic layer was concentrated to half of the volume (~ 1.5 L) at 50 °C and the water (1.5 L) was added slowly until the reaction mass became clear solution. The solution was concentrated again at 50 °C to remove acetone (~1 L) to obtained precipitation. The mixture was diluted with water (1.5 L) at same temperature and stirred for 15 min to obtained free solid. The mixture was filtered and the solid was washed with water (1 L) and dried in vacuum oven to obtained title product 1 (92.5 g, 73 % yield, purity by HPLC: 99.5%) as a cream colour solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.21 - 8.86 (m, 2H), 8.66 (s, 1H), 8.45 - 8.24 (m, 2H), 7.49 (s, 1H), 6.57 (d, J=7.5 Hz, 1H), 4.33 (s, 1H), 3.83 (d, J=7.0 Hz, 1H), 2.91 - 2.72 (m, 2H), 1.97 - 1.68 (m, 2H), 1.24 (d, J=6.5 Hz,


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12H). 13C NMR (100 MHz, DMSO) δ = ppm 151.7, 150.8, 149.8, 147.9, 147.7, 143.7, 136.8, 136.3, 122.9, 118.9, 117.6, 116.0, 102.8, 99.4, 68.4, 43.6, 42.7, 29.2, 21.7, 20.2. HRMS [M + H]+ calcd for C22H25N9O 432.2255; found 432.2259. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the web The following are available at supporting information: (i) synthetic scheme and procedures to make the intermediate 7 by alternate approach (ii) 1H NMR, 13C NMR, HRMS, LCMS and HPLC spectra for the compounds 13, 14, 12 and 1. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS The authors are thankful to Discovery Analytical Department, Biocon Bristol-Myers Squibb Research Centre (BBRC), Bangalore (India) for Analytical support and Chemical Development and API supply (CDAS, BBRC) for DSC support. DEDICATION: This research publication is dedicated to the memory of Joseph B. Santella- III, who inspired many chemists. REFERENCES 1.

(a) Bonandi, E.; Christodoulou, M. S.; Fumagalli, G.; Perdicchia, D.; Ratelli, G.; Passarella, D. The 1,2,3-triazole ring as a bioisostere in medicinal chemistry. Drug. Disc.


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Today. 2017, 22, 1572. (b) Divya, D.; Virender, S.; Ravi, S. Medicinal attributes of 1,2,3-triazoles: Current developments. Bioorg. Chem. 2017, 71, 30 and refs. therein. (c) Zhou, C. –H.; Wang, Y. Recent Researches in Triazole Compounds as Medicinal Drugs. Curr. Med. Chem. 2012, 19, 239. (d) Röhrig, U. F.; Majjigapu, S. M.; Caldelari, D.; Dilek, N.; Reichenbach, P.; Ascencao, K.; Irving, M.; Coukos, G.; Vogel, P.; Zoete, V.; Michielin, O. 1,2,3-Triazoles as inhibitors of indoleamine 2,3-dioxygenase 2 (IDO2). Bioorg. Med. Chem. Lett. 2016, 26, 4330. (e) Röhrig, U. F.; Majjigapu, S. M.; Grosdidier, A. L.; Bron, S.; Stroobant, V.; Pilotte, L.; Colau, D.; Vogel, P.; Van den Eynde, B. J.; Zoete, V.; Michielin, O. Rational Design of 4-Aryl-1,2,3-Triazoles for Indoleamine 2,3Dioxygenase 1 Inhibition. J. Med. Chem. 2012, 55, 5270. (f) Weide, T.; Saldanha, S. A.; Minond, D.; Spicer, T. P.; Fotsing, J. R.; Spaargaren, M.; Frère, J. M.; Bebrone, C.; Sharpless, K. B.; Hodder, P. S.; Fokin, V. V. NH-1,2,3-Triazole Inhibitors of the VIM-2 Metallo-β-Lactamase. ACS Med. Chem. Lett. 2010, 1, 150. 2. Gardner, D. S.; Santella, J. B.; Paidi, V. R.; Wu, H.; Duncia, J. V.; Nair, S. K.; Hynes, J. Heteroaryl Substituted Aminopyridine Compounds (BMS, USA). PCT Int. Appl. WO/2016/210034 A1. 2016. 3. Hanan, E. J.; Eigenbrot, C.; Bryan, M. C.; Burdick, D. J.; Chan, B. K.; Chen, Y.; Dotson, J.; Heald, R. A.; Jackson, P. S.; La, H.; Lainchbury, M. D.; Malek, S.; Purkey, H. E.; Schaefer, G.; Schmidt, S.; Seward, E. M.; Sideris, S.; Tam, C.; Wang, S.; Yeap, S. K.; Yen, I.; Yin, J.; Yu, C.; Zilberleyb, I.; Heffron, T. P. Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation. J. Med. Chem., 2014, 57, 10176.


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4. (a) Kitamura, M.; Kato, S.; Yano, M.; Tashiro, N.; Shiratake,Y.; Sando, M.; Okauchi, T. A reagent for safe and efficient diazo-transfer to primary amines: 2-azido-1,3dimethylimidazolinium hexafluorophosphate. Org. Biomol. Chem. 2014, 12, 4397. (b) Kitamura, M.; Miyagawa, S.; Okauchi, T. Synthesis of α, α-diarylacetamides from benzyl aryl ketones using 2-azido-1,3-dimethylimidazolinium Hexafluorophosphate. Tetrahedron Lett. 2011, 52, 3158. (c) Kitamura, M.; Yano, M.; Tashiro, N.; Miyagawa, S.; Sando, M.; Okauchi, T. Direct Synthesis of Organic Azides from Primary Amines with 2-Azido-1,3-dimethylimidazolinium Hexafluorophosphate. Eur. J. Org. 2011, 3, 458. 5. Aponick, A.; Li, C. Y.; Palmes, J. A. Au-Catalyzed Cyclization of Monopropargylic Triols: An Expedient Synthesis of Monounsaturated Spiroketals. Org. Lett. 2009, 11, 121. 6. Ayothiraman, R.; Rangaswamy, S.; Maity, P.; Simmons, E. M.; Beutner, G. L.; Janey, J.; Treitler, D. S.; Eastgaste, M. D.; Vaidyanathan, R. Zinc Acetate-Promoted Buchwald−Hartwig Couplings of Heteroaromatic Amines. J. Org. Chem. 2017, 82, 7420. 7. (a) Oxley, J. C.; Smith, J. L.; Marimaganti, K. Developing small-scale tests to predict explosivity. J. Therm. Analysis and Calorimetry. 2010, 102, 597. (b) Likhite, N.; Lakshminarasimhan, T.; Ramana Rao, M. H. V.; Shekarappa, V.; Sidar, S.; Subramanian, V.; Fraunhoffer, K. J.; Leung, S.; Vaidyanathan, R. A Scalable Synthesis of 2‑(1,2,4-Oxadiazol-3-yl)propan-2-amine Hydrobromide Using a Process Safety-Driven Protecting Group Strategy. Org. Process Res. Dev. 2016, 20, 1328. 8. (a) Feldman, A. K.; Colasson, B.; Fokin, V. V. One-Pot Synthesis of 1,4-Disubstituted 1,2,3-Triazoles from In Situ Generated Azides. Org. Lett. 2014, 6, 3897. (b) Buckley, B.


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R.; Figuerers, M. M. P.; Khan, A. N.; Heaney, H. A New Simplified Protocol for Copper(I) Alkyne–Azide Cycloaddition Reactions Using Low Substoichiometric Amounts of Copper(II) Precatalysts in Methanol. Synlett 2016, 27, 51. 9. Heffron, T. P.; Heald, R. A.; Ndubaku, C.; Wei, B.; Augistin, M.; Do, S.; Edgar, K.; Eigenbrot, C.; Friedman, L.; Gancia, E.; Jackson, P. S.; Jones, G.; Kolesnikov, A.; Lee, L. B.; Lesnick, J. D.; Lewis, C.; McLean, N.; Mörtl, M.; Nonomiya, J.; Pang, J.; Price, S.; Prior, W. W.; Salphati, L.; Sideris, S.; Staben, S. T.; Steinbacher, S.; Tsui, V.; Wallin, J.; Sampath, D.; Olivero, A. G. The Rational Design of Selective Benzoxazepin Inhibitors of the α-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326). J. Med. Chem. 2016, 59, 985. 10. Anderson, J.; Bolvig, S.; Liang, X. Efficient One-Pot Synthesis of 1-Aryl 1,2,3-Triazoles from Aryl Halides and Terminal Alkynes in the Presence of Sodium Azide. Synlett 2005, 19, 2941. 11. (a) Ravn, M. W.; Wagaw, S. H.; Engstrom, K. M.; Mei, J.; Kotechi, B.; Souers, A. J.; Kym, P. R.; Judd, A. S.; Zhao, G. Process Development of a Diacyl Glycerolacyltransferase-1 inhibitor. Org. Process Res. Dev. 2010, 14, 417. (b) Houpis, I. N.; Shilds, D.; Nettekoven, U.; Schnyder, A.; Bappert, A.; Weerts, K.; Canters, M.; Vermuelen, W. Utilization of Sequential Palladium-Catalyzed Cross-Coupling Reactions in the Stereospecific Synthesis of Trisubstituted Olefins. Org. Process Res. Dev. 2009, 13, 598. 12. Brase, S.; Gil, S.; Knepper, K.; Zimmermann, V. Organic Azides: An Exploding Diversity of a Unique Class of Compounds. Angew. Chem. Int. Ed., 2005, 44, 5188.


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Development of a Scalable Synthesis for the Potent Kinase Inhibitor

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