Article Cite This: Org. Process Res. Dev. 2018, 22, 1276−1281
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Process Optimization for the Large-Scale Preparation of (2S,3aR,7aS)-tert-Butyl Hexahydro-2,5methanopyrrolo[3,2‑c]pyridine-1(4H)‑carboxylate, an Intermediate for Nicotinic Acetylcholine Receptor Agonists Lokesh Babu Jarugu,† China Anki Reddy,† Nanjundaswamy Kanikahalli Chikkananjunda,† Suresh Krishnamoorthy,† Pon Sarvanakumar,† Ulaganathan Sankar,† Pirama Nayagam Arunachalam,† Ivar M. McDonald,‡ Richard E. Olson,‡ Richard Rampulla,‡ Arvind Mathur,‡ and Anuradha Gupta*,† Org. Process Res. Dev. 2018.22:1276-1281. Downloaded from pubs.acs.org by IOWA STATE UNIV on 01/27/19. For personal use only.
†
Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru-560099, India ‡ Bristol Myers Squibb Company, P.O Box 4000, Princeton, New Jersey 08543-4000, United States S Supporting Information *
ABSTRACT: An optimized large-scale synthesis of (2S,3aR,7aS)-tert-butyl hexahydro-2,5-methanopyrrolo[3,2-c]pyridine1(4H)-carboxylate (1A), an important intermediate for nicotinic acetylcholine receptor agonists, is described. The key feature of the synthesis involves three transformations in a one-pot process, including debenzylation and ring hydrogenation of two fused bicyclic rings. Multihundred gram quantities of 1A were prepared. KEYWORDS: iodination, Sonogashira coupling, debenzylation, hydrogenation
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INTRODUCTION (2S,3aR,7aS)-tert-Butyl hexahydro-2,5-methanopyrrolo[3,2-c]pyridine-1(4H)-carboxylate (1A) is a key intermediate for tricyclic compounds identified as potent α7 nicotinic acetylcholine receptor ligands (Figure 1), which may be useful for the treatment of various disorders of the central nervous system that are potentially neurodegenerative disorders, such as schizophrenia.1,2
the debenzylation and ring reduction, and (3) use of expensive PtO2 for this conversion. This led to the optimization of the original route to a more scalable and economical process. The current article describes the streamlined large-scale synthesis of 1A featuring a more efficient one-step debenzylation and reduction of pyrrolo[3,2-c]pyridine 8, which is the key step leading to 1A.
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RESULTS AND DISCUSSION Synthesis and Optimization of 5 and 15. Because of an aggressive timeline and long lead time for both the starting material 5 and 15, it was decided to scale up in-house to jumpstart the synthesis. Compound 5 was synthesized from inexpensive and readily available 4-aminopyridine (2) following a known literature procedure3 (Scheme 2). Iodination of 2 with iodine gave a mixture of undesired 3,5diiodo-4-aminopyridine (3) and 3-iodo-4-aminopyridine (4) in a ratio of 6:4 as expected. Compound 4 was obtained in only 34% yield after a tedious chromatographic separation. This procedure was not conducive to scale-up because of the low yield and selectivity. Iodine monochloride (ICl) in acetic acid is reported4 to give higher selectivity and yield, but the reaction required over 10 days for completion at a temperature of around 40−45 °C. It was envisioned that the reaction time could be shortened by using a combination of higher temperature and a nonreactive acid instead of acetic acid, which potentially could react with the amine to form the corresponding acetamide. Initial attempts using iodine monchloride and a catalytic amount of
Figure 1. Intermediate 1A and general structure of α7 nicotinic receptor agonists.
The medicinal chemistry route1,2 to compound 1A consisted of 10 steps, including a chiral supercritical fluid chromatography (SFC) separation starting from tert-butyl (3-iodopyridin4-yl)carbamate (5) (Scheme 1). To support the preparation of a drug candidate, 200 g of the advanced intermediate 1A was required. On the basis of the reported yields, the calculations indicated that >14 kg of intermediate 5, 7 kg of intermediate 8, 2 kg of PtO2, and 1.5 kg of Pd(OH)2 would be needed. The original route was used for synthesizing a few hundred milligrams to a gram of 1A for initial studies. However, synthesizing multihundred gram samples following the original route posed some challenges: (1) expensive and not readily available starting materials such as 5 (>$100/g) and ((prop-2yn-1-yloxy)methyl)benzene (15), (2) low reproducibility of © 2018 American Chemical Society
Received: June 26, 2018 Published: August 28, 2018 1276
DOI: 10.1021/acs.oprd.8b00208 Org. Process Res. Dev. 2018, 22, 1276−1281
Organic Process Research & Development
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Scheme 1. Medicinal Chemistry Route to 1A
Scheme 2. Optimization of the Iodination
hydrochloric acid or sulfuric acid at 27 °C yielded negligible amounts of product. However, when the reaction mixture was heated to higher temperatures (100 °C) using 4 equiv of methanesulfonic acid, the reaction went to completion within 12 h giving almost exclusively monoiodinated product 4. On a 100 g scale, the reaction yielded the desired monoiodo compound 4 in 75% yield with the formation of the diiodo product 3 in 1.6% yield. Reducing the amount of methanesulfonic acid to 2 equiv resulted in a prolonged reaction time (24 h) with no apparent change in yield. The optimized procedure for large-scale iodination of 2 was performed using iodine monochloride and methanesulfonic acid at 100 °C for 12 h. Up to 600 g of 2 was converted in a single batch, and the product 4 was isolated in 75% yield with 96% purity after trituration in petroleum ether. Intermediate 4 was converted to the corresponding Boc derivative in 85% isolated yield after flash chromatography. This procedure was reproduced for a number of large batches, and >9 kg of intermediate 5 was synthesized in high yields. ((Prop-2-yn-1-yloxy)methyl)benzene (15) was synthesized from propargyl alcohol and benzyl bromide following a literature procedure 5 using sodium hydride in DMF. Compound 15 was obtained in moderate yield, and the procedure involved a tedious workup and column chromatography to isolate the desired compound. This seemed to be not scalable for safety reasons as well as the issue with isolation. NaH in DMF can result in a thermal runaway reaction, especially on larger scales, as is well-known in the literature. Following another literature procedure6a,b using KOH and
DMSO, compound 15 was synthesized in almost quantitative yield. This reaction workup gave quantitative conversion and was easier to handle, requiring a simple filtration through a silica gel pad/column, making it better-suited for scale-up operations. With these modifications, >5 kg of 15 was synthesized in excellent yield (Scheme 3). Scheme 3. Synthesis of Benzyl Propargyl Ether (15)
Optimization of the Sonogashira Coupling and Subsequent Cyclization. After the successful synthesis of both intermediates in-house, the focus turned to the synthesis of azaindole 8 (Scheme 4). This involved an intermolecular Sonogashira coupling of 5 with 15 in a pressure tube to get intermediate 8 in good yield (Scheme 1). From the initial route it was obvious that the use of a pressure tube was not amenable for scaling up to hundreds of grams in several batches. In view of this limitation, it was decided to use thermal conditions to ease out the scalability issue of this step. Scheme 4 describes the optimization efforts for the Sonogashira reaction. Following the medicinal chemistry procedure, an early attempt using reflux conditions led to the formation of an uncyclized intermediate, tert-butyl (3-(3(benzyloxy)prop-1-yn-1-yl)pyridin-4-yl)carbamate (6), after 1277
DOI: 10.1021/acs.oprd.8b00208 Org. Process Res. Dev. 2018, 22, 1276−1281
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Scheme 4. Optimization of the Sonogashira Coupling for the Synthesis of Intermediate 8
Table 1. Optimization Effort for Conversion of 8 to 9C with Variable Catalyst Loading and Hydrogen Pressure
entry
step
temp (°C)
solvent
1
8−9A to 9B
25
EtOH
2
9B to 9C
3 4
9B to 9C 9B to 9C
25 60 25 25
catalyst
cat.a
EtOH + AcOH
Pd(OH)2 Pd(OH)2 PtO2
2 2 1
AcOH AcOH
PtO2 PtO2
1 2.2
H2 (psi)
time (h)
conversion as per LCMS
99
48 48 24 48 72 1
33% 9A, 64% 9B 100% 9B no reaction no reaction 53% 9C 93% 9C
142 214 71 71
a
Pd(OH)2 20% w/w (50% wet).
original experimental procedure were found to be very confusing and inconsistent in terms of the conversion rate in going from compound 9A to 9C via 9B as well as the time taken for each batch. A pilot reaction on 10 g (0.03 mol) of compound 8 and 8.23 g of 20% w/w Pd(OH)2 (on activated carbon, 50% wet, 0.06 mol) at ambient temperature in EtOH in an autoclave for 48 h gave 9A in 33% yield and 9B in 64% yield and did not progress any further as a function of time. A recharge (filtration of the reaction mixture and concentration) of the reaction mixture with fresh solvent and the same amount of Pd(OH)2 took another 48 h for the complete conversion to 9B (Table 1, entry 1). Surprisingly, reductive hydrogenation of the crude product 9B using 6.58 g of PtO2 (0.03 mol, 1 equiv) in a mixture of EtOH and AcOH at a pressure of 214 psi did not proceed even at 60 °C (Table 1, entry 2). In further reactions, when AcOH alone was used as the solvent, a 53% yield of product 9C was observed over 72 h at a pressure of 71 psi (Table 1, entry 3) by LCMS. Notably, an improved yield was observed when 14.48 g of PtO2 (2.2 equiv) was used. The procedure provided a 93% yield of the product by LCMS (Table 1, entry 4). It was concluded that the conversion from 8 to 9C was not reproducible in terms of time taken and yield of the product and hence required further optimization (Table 1). Another undesirable aspect of this reduction procedure was also an extremely high catalyst loading. For example, over a few batches it was observed that every 1 g of compound 8 required
12 h under reflux conditions. Attempts to cyclize compound 6 with DBU in a mixture of MeOH and H2O at 60 °C resulted in loss of the Boc protecting group to form 7, which further required Boc protection to give intermediate 8. This was realized to be a handicap for the scale-up and led to further investigation. When the reaction mixture was heated to 65 °C using a round-bottom flask, LCMS showed the absence of starting material 5 along with 25% formation of intermediate 6 and 70% formation of the desired intermediate 8 after 12 h. Further heating for another 12 h led to complete conversion to the desired intermediate 8. Thus, a fine balance of lowering the reaction temperature to 65 °C and increasing the reaction time to 24 h led to complete conversion to 8 in excellent yields. Thus, the optimized conditions for the Sonogashira coupling7 involved heating intermediate 5 at 65 °C in the presence of CuI, Pd(PPh3)2Cl2, and TEA in DMF for 24 h to afford intermediate 8 in 97% yield. The reaction was scaled up to >2 kg in a single batch with reproducible yields, and a total of 8 kg was synthesized following the modified procedure. Optimization of the Debenzylation and Ring Reduction. The most challenging step, and the key step in the synthesis of 1A, was the tandem debenzylation and reduction of intermediate 8 to afford the completely saturated bicyclic core 9C. The original procedure for reduction of intermediate 8 to 9C involved use of Pd(OH)2 for debenzylation and double-bond reduction followed by the use of PtO2 for complete ring reduction. The initial pilot batches following the 1278
DOI: 10.1021/acs.oprd.8b00208 Org. Process Res. Dev. 2018, 22, 1276−1281
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Table 2. Further Optimization of the Hydrogenation Step Using Pd/C
entry
time (h)
9Aa
9Ba
9Ca
1
16 30 54 75 90 16 60 100 130 50 110
85 79 − − − 78 15 − − − −
10 18 76 29 − − 76 14 5 54 −
− − 26 70 98.5 − − 83 92.5 39 96
2
3b
remarks
yield (%) 52.8
first recharge here − second recharge here first recharge second recharge third recharge − one recharge after HCl treatment −
58
90
a
% LCMS monitoring. bThe reaction vessel was treated with HCl prior to the reaction (see the text).
Scheme 5. Synthesis of Compounds 11A and 11B
improvement after 30 h. At this point, the reaction mass was filtered and recharged with the same quantity of fresh catalyst. The reaction seemed to progress steadily, giving predominantly 9B and 9C over a period of 75 h. A second filtration at this point and recharge using same quantity of Pd/C led to complete conversion to 9C by 90 h with a crude yield of 53%. These batches upon further scale-up were found to be inconsistent in terms of reaction time and conversion from 8 to 9A, 9B, and 9C (Table 2, entry 2). It was concluded that a contaminant in the reaction vessel might be causing catalyst poisoning.8 As predicted, it was found that pretreating the reactor with 1 N HCl followed by washing with water and MeOH and complete drying greatly improved the conversion rate to 9C from intermediate 8. Following the pretreatment procedure, the hydrogenation required only one recharge and a total 5 days of reaction time for complete conversion to 9C (Table 2, entry 3). This telescopic process consistently led to the desired intermediate 9C from intermediate 8, requiring only one filtration and one recharge of the catalyst. Following this procedure, >4 kg of intermediate 9C was synthesized with a maximum batch size of 500 g in an average yield of 90%. The crude 9C, which was obtained as a mixture of cis and trans diastereomers, was used for the next step without further purification. Endgame for Intermediate 1A. Compound 9C was converted to the corresponding diastereomeric mixture of NCbz-protected intermediates, which could be separated by flash chromatography to give the desired racemic intermediate 10(±) in 49% yield (Scheme 5). At this stage, the diastereomeric ratio was found to be 1:1.5, with the major
0.6 mol of 20% w/w Pd(OH)2 and 2 g of PtO2, which indicated that >1.5 kg of Pd(OH)2 and ∼2 kg of PtO2 would be required to obtain ∼100 g of intermediate 1A with the above conversion. With this significant cost concern in mind, it was decided to invest in a cheaper catalyst system such as Pd/C. During initial optimization using Pd/C (10% w/w, dry-based), it was observed that reduction of the five-membered ring occurred first, followed by debenzylation to give intermediate 9B, and as the reaction progressed, significant amounts of 9B were converted to 9C. This looked promising, and it was decided to use Pd/C exclusively for the entire three-step reduction process. One of the optimization attempts involved a reaction batch of 17 g of 8 (0.05 mol) with 32 g of Pd/C (10% w/w, dry-based) at a pressure of 214 psi in ethanol at 60 °C. The batch needed two recharges each after 48 h and a total of 7 days of reaction time to give the required intermediate 9C in 46.6% yield, indicating the need for further optimization. Similarly, weighing and handling a large quantity of dry Pd/C was also a major concern, especially for scale-up batches. At this point, it was decided to use wet Pd/C as a safer alternative to dry Pd/C. Fortunately, pilot runs using 5% w/w Pd/C (50% wet) gave the same reaction pattern as dry Pd/C in terms of time taken with slightly higher yields. Further discussion explains the attempts to optimize the conversion of intermediate 8 to 9C via 9A and 9B by varying the catalyst loading, temperature, and time (Table 2). When 5% w/w Pd/ C (50% wet) was used at 60 °C in an autoclave under a pressure of 214 psi (Table 2, entry 1), formation of 9A (85%) and 9B (10%) was observed after 16 h with no significant 1279
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Scheme 6. Synthesis of Compounds 1A and 1B
methyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (8) (350 g, 1.03 mol) in ethanol (5.5 L) was added 5% w/w palladium on carbon (50% wet) (700 g, 3.29 mol) under a nitrogen atmosphere at room temperature. The reaction mixture was stirred at 60 °C under hydrogen at a pressure of 214 psi for 50 h. After 50 h, LC−MS indicated ∼39% yield of intermediate 9C and 54% yield of intermediate 9B. At this point, the reaction mixture was unloaded and filtered through a Celite bed. The Celite bed was washed with 500 mL of 5% triethylamine in methanol, and the combined filtrate was concentrated. The residue (265 g) was dissolved in ethanol (5.5 L) and recharged with 5% w/w palladium on carbon (50% wet) (700 g, 3.29 mol) under a nitrogen atmosphere at room temperature. The reaction mixture was stirred at 60 °C under hydrogen at a pressure of 214 psi for 48 h with periodic monitoring for the full conversion to 9C. The reaction mixture was filtered through a Celite bed and washed with 500 mL of 5% triethylamine in methanol repeatedly. The filtrate was concentrated to give the crude product (242 g, 90% yield) as a light-brown viscous liquid, which was moved to next step as such. LCMS (ES-APCI) for C13H24N2O3 [M + H]+ calcd 256.18, found 257. 5-Benzyl 1-(tert-Butyl) (2S,3aR,7aS)-2(hydroxymethyl)hexahydro-1H-pyrrolo[3,2-c]pyridine1,5(4H)-dicarboxylate (11A). To a stirred solution of 9C (380 g, 1.48 mol) in THF (5.03 L) was added 10% potassium carbonate (0.67 kg, 48.47 mol, 6.7 L) and benzyl chloroformate (444 mL, 3.11 mol) in a 10 L autoclave. After 3 h, the reaction mixture was filtered through Celite, concentrated, and extracted with ethyl acetate (3 × 2 L). The total organic layer was washed with water (2 L) followed by brine solution (2 L). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The diastereomeric mixture was purified by flash column chromatography using EtOAc as the eluent. The less polar diastereomer fractions were concentrated to get 288 g of the desired diastereomer of 10, which was separated by SFC to give the desired enantiomer 11A (124 g, 21.6% yield ) as a pale 1 viscous liquid. [α]25 D +20.6 (c 0.56, MeOH); H NMR (300 MHz, DMSO-d6) δ 7.28−7.42 (m, 5H), 5.08 (s, 2H), 4.71− 4.79 (m, 1H), 3.34−3.98 (m, 6H), 3.1−3.3 (m, 1H), 2.6−2.9 (m, 1H), 2.1−2.3 (m, 1H), 1.70−1.93 (m, 3H), 1.43−1.62 (m,
diastereomer bearing the cis configuration of the hydroxymethyl group with the piperidine ring. This single diastereomer of 10 was further subjected to chiral SFC resolution to give the desired enantiomer 5-benzyl 1-(tertbutyl) (2S,3aR,7aS)-2-(hydroxymethyl)hexahydro-1H-pyrrolo[3,2-c]pyridine-1,5(4H)-dicarboxylate (11A) in 21% overall yield from 9C. The pure enantiomer 11A thus obtained was treated with tosyl chloride and pyridine to provide tosylated the intermediate 5-benzyl 1-(tert-butyl) (2S,3aR,7aS)-2((tosyloxy)methyl)hexahydro-1H-pyrrolo[3,2-c]pyridine1,5(4H)-dicarboxylate (12A) in 92% yield. Intermediate 12A was deprotected with 10% w/w Pd/C (50% wet), followed by cyclization with K2CO3 under reflux conditions to give the final compound, (2S,3aR,7aS)-tert-butyl hexahydro-2,5methanopyrrolo[3,2-c]pyridine-1(4H)-carboxylate (1A), in 78% yield (Scheme 6). Approximately 250 g of the desired isomer 1A was prepared over multiple batches. Similarly, the other enantiomer 11B obtained during the SFC separation of compound 10 was converted to tosyl intermediate 12B followed by 1B, which was used as a reference.
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CONCLUSION An improved large-scale synthesis of (2S,3aR,7aS)-tert-butyl hexahydro-2,5-methanopyrrolo[3,2-c]pyridine-1(4H)-carboxylate (1A) was demonstrated starting from the readily available and inexpensive starting material 4-aminopyridine (2) over 10 steps in an overall yield of 14% for single enantiomer 1A. The optimized synthesis involved a high-yielding and selective monoiodination of 2, a scalable preparation of benzyl propargyl ether (15), and an improved one-pot Sonogashira coupling and cyclization to form pyrrolo[3,2-c]pyridine 8. We also identified a safer and a scalable hydrogenation sequence for the transformation of 8 to debenzylated tert-butyl 2(hydroxymethyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (9C).
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EXPERIMENTAL SECTION tert-Butyl 2-(Hydroxymethyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (9C). In a 10 L autoclave reactor, to a stirred solution of tert-butyl 2-((benzyloxy)1280
DOI: 10.1021/acs.oprd.8b00208 Org. Process Res. Dev. 2018, 22, 1276−1281
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1H), 1.39 (s, 9H); LCMS (ES-APCI) for C21H30N2O5 [M − H]− calcd 390.22, found 389; chiral purity >99%, RT 3.39 (method: ethanol, Chiralpak AD-H (250 × 4.6) mm, 5 μm). 5-Benzyl 1-(tert-Butyl) (2S,3aR,7aS)-2-((Tosyloxy)methyl)hexahydro-1H-pyrrolo[3,2-c]pyridine-1,5(4H)dicarboxylate (12A). To a stirred solution of 11A (70 g, 0.18 mol) in pyridine (0.84 L) in a 3 L multineck round-bottom flask equipped with a nitrogen outlet was added tosyl chloride (75 g, 0.39 mol) portionwise at room temperature. The reaction mixture was stirred overnight and then concentrated completely under reduced pressure. The residue was dissolved in water (800 mL) and extracted with ethyl acetate (3 × 500 mL). The organic layer was washed with 1.5 N HCl solution (2 × 500 mL) followed by brine solution (500 mL) and dried over sodium sulfate. This was filtered, concentrated under reduced pressure, and purified by flash column chromatography using EtOAc/petroleum ether as the eluent to yield compound 12A (91.5 g, 92%) as a pale viscous liquid. 1H NMR (400 MHz, DMSO-d6) δ 7.71−7.77 (m, 2H), 7.44−7.49 (m, 2H), 7.31−7.41 (m, 5H), 5.04−5.15 (m, 2H), 4.00−4.14 (m, 2H), 3.76−3.93 (m, 4H), 3.1−3.2 (m, 1H), 2.64−2.69 (m, 1H), 2.38−2.42 (m, 3H), 2.2 (m, 1H), 1.82−1.96 (m, 1H), 1.52−1.82 (m, 2H), 1.23−1.41 (m, 10H); LCMS (ES-APCI) for C28H36N2O7S [M + H]+ −100 (-Boc)calcd 544.22; found, 445. (2S,3aR,7aS)-tert-Butyl Hexahydro-2,5methanopyrrolo[3,2-c]pyridine-1(4H)-carboxylate (1A). To a stirred solution of 12A (128 g, 0.23 mol) in dry ethanol (3 L) in a 10 L autoclave was added 10% w/w palladium on carbon (42.5 g, 0.04 mol, 50% wet) under a nitrogen atmosphere. The reaction mass was stirred at room temperature at a hydrogen pressure of 57 psi. After 3 h, the reaction mixture was filtered through Celite and washed with dry ethanol. To the filtrate was added potassium carbonate (162 g, 1.17 mol), and the mixture was heated to 75 °C for 12 h, around which time the reaction was found to be complete on the basis of LCMS monitoring. The reaction mass was concentrated, diluted with water (300 mL), and extracted with dichloromethane (3 × 200 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to give compound 1A (44 g, 78% yield) as an off-white solid. 1 [α]25 D +42.6 (c 1.00, MeOH); H NMR (400 MHz, DMSO-d6) δ 3.98−4.06 (m, 1H), 3.87−3.97 (m, 1H), 3.11−3.21 (m, 1H), 2.87 (m, 1H), 2.59 (m, 4H), 2.22−2.35 (m, 1H), 1.91−2.13 (m, 1H), 1.45−1.79 (m, 3H), 1.36−1.43 (m, 9H); GCMS (ESI) for C13H22N2O2 [M + H]+ calcd 238.17, found 238; chiral purity 100%, RT 5.73 min (method: 0.2% NH4OH in methanol, Chiralpak IC (250 × 4.6) mm, 5 μm).
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are extremely grateful to Dr. Jianqing Li (BMS) for his valuable suggestions and proofreading of the manuscript. The authors are also thankful to the Discovery Analytical Department, Biocon Bristol-Myers Squibb Research Centre (BBRC), Syngene, Bangalore, India, for analytical support.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.8b00208. Experimental and analytical data for intermediates 4, 5, 15, 8, 11B, 12B, and 1B and analytical data for compounds 9C, 11A, 12A, and 1A (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Anuradha Gupta: 0000-0002-4211-1441 1281
DOI: 10.1021/acs.oprd.8b00208 Org. Process Res. Dev. 2018, 22, 1276−1281
