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DOI: 10.1055/s-0043-1773542
Development of an Efficient Synthesis toward a 4,4-Difluoropiperidine Intermediate Bearing a Pyridine N-Oxide Motif at the Carbon Stereocenter
Abstract
The synthesis of a 4,4-difluoropiperidine intermediate, a key component of an MRGPRX2 antagonist, is challenging due to the presence of a gem-difluoro moiety adjacent to a stereocenter which also bears a reactive pyridine N-oxide motif. The initial discovery chemistry route required chiral supercritical fluid chromatography (SFC) at the end of the synthesis to provide enantiopure product. XtalFluor-E was used for deoxyfluorination on a ketone adjacent to a p-pyridylmethyl position, resulting in very low yields due to the elimination of HF. After several unsuccessful attempts for a de novo asymmetric synthesis, we focused our attention on the process development for a more practical synthesis than the existing route. A much higher yielding deoxyfluorination was enabled by SF4 and HF. Furthermore, the chiral SFC was replaced by an efficient classical resolution at a much earlier stage of the synthesis, taking advantage of the basicity of the pyridine moiety before oxidation to the pyridine N-oxide. Although not all stages have been scaled up in the plant scale, the new synthesis is much more practical and has improved the overall yield from 12% to 23% for this challenging molecule.
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Key words
pyridine N-oxides - gem-difluoropiperidine synthesis - classical resolution - deoxyfluorination of ketone - MRGPRX2 antagonistNitrogen-containing heterocycles and fluorine-substituted rings are two essential structural features in bioactive compounds. For instance, chiral piperidine is known as one of the most prevalent scaffolds present in many natural products and pharmaceutical drugs.[1] In addition, heterocyclic N-oxides have become an important moiety in many compounds that exhibit anticancer, antibacterial, anti-HIV and anti-inflammatory properties.[2] The pyridine N-oxide motif is also known to be the bioisosteric replacement for pyridone due to enhanced solubility and metabolic properties.[3] Introduction of fluorine in pharmaceutical compounds is also known to increase permeability,[4a] metabolic stability[4a] and many other applications.[4b] [c] Due to these essential biological properties, herein we present the synthesis of compound 1 which is comprised of a 4,4-difluoropiperidine that contains a pyridine N-oxide motif at the C-3 carbon stereocenter (Figure [1]). Compound 1 is also a key intermediate for the synthesis of MRGPRX2 antagonist 2 at GSK.[5]
The discovery chemistry route to 1 was a racemic synthesis that started from Pd-catalyzed C–H arylation of Boc-protected 4-piperidinone 3 with 4-bromopyridine (4) to give racemic ketone 5 (Scheme [1]).[6] Ketone 5 was then subjected to deoxyfluorination using XtalFluor-E to provide gem-difluoro product 6. However, up to 13% (by HPLC) of 7 was produced as the major side product from dehydrofluorination due to the acidity of the adjacent proton at the carbon stereocenter. This impurity was very difficult to remove, even with column chromatography. As a result, the mixture of 6 and 7 was treated with KMnO4, which selectively oxidized impurity 7 to diol 8 while maintaining the integrity of desired 6. The high water solubility of 8 facilitated its removal in a subsequent aqueous extraction to give an overall 38% yield of 6 from 5. The nitrogen atom in pyridine 6 was subsequently oxidized using Oxone to provide N-oxide intermediate 9, which was followed by Boc deprotection to provide 10. The final step was chiral purification via supercritical fluid chromatography (SFC) to afford enantiomerically pure 1.[6]
The major drawbacks in the discovery chemistry route were the low yield in the deoxyfluorination and the column chromatography needed. In addition, the chiral resolution by chiral SFC at the end of the synthesis also contributed to the overall low efficiency. This prompted us to investigate asymmetric syntheses that would take advantage of commercially available starting materials that already contain a gem-difluoro moiety, however, none were successful. Ultimately, we turned our attention to the optimization of the discovery chemistry route which we believed would be more attractive if better deoxyfluorination conditions for 5 could be achieved and/or a classical resolution could be implemented at a much earlier point of the synthesis to replace the SFC at the last stage (Scheme [2]). Herein, we report our progress on these efforts which ultimately led to a much improved synthesis of 1.
The deoxyfluorination of ketones with XtalFluor-E is well precedented in the literature.[7] However, we only found one report with an example of a cyclic ketone that contains an α-substituted arene and the isolated yield was 56%.[8] Although the authors did not comment, we perceived the activation of methine proton by neighboring aryl groups could lead to formation of HF to form olefin impurity such as 7 which contributed to the lower yield. A recent report of deoxyfluorination of β-keto esters using SF4 in combination with HF by Trofymchuk and co-workers[9] demonstrated that these conditions had the potential to suppress the HF elimination resulting from the acidic proton adjacent to the gem-difluoro moiety. In these deoxyfluorination conditions, low temperature and the use of HF in the reaction were crucial to suppress the undesired dehydrofluorination side product. Therefore, we envisioned that 5, with activation of the α-proton by the pyridine ring, would benefit from similar conditions with SF4 and HF.
We conducted a screening of the deoxyfluorination of 5 using SF4 and HF in an autoclave following the procedure as described by Trofymchuk and co-workers,[9] and the results are summarized in Table [1]. Typically, the reaction was set up by precooling the autoclave to –65 °C to introduce SF4 via condensation from a gas cylinder. Then, the autoclave was warmed to the reaction temperature for the deoxyfluorination. In a combination of 5 equivalents of SF4 with 10 equivalents of HF, the deoxyfluorination proceeded at 0 °C; however, the Boc group under acidic reaction conditions was cleaved from the gem-difluoro product 11. After aqueous workup and extraction into ethyl acetate, 11 was subjected to Boc protection conditions to provide 6 in 62% yield (entry 1). More importantly, a significantly lower level of dehydrofluorination side product 7 was observed compared to using XtalFluor-E (~3% vs 13% by HPLC, respectively). As a result, we were able to isolate 6 by silica gel chromatography without the need of KMnO4 oxidation to purge 7. When the deoxyfluorination was run at –30 °C, the ratio between 6 and 7 did not change and the yield remain the same (entry 2). Next, we evaluated the impact of HF in these new deoxyfluorination conditions at 0 °C. In the absence of HF, only 17% of 6 was isolated due to formation of a high level of 7 (entry 3) and several other unknown impurities. Increasing the stoichiometry of HF to 20 equivalents had no impact on the yield of 6 compared to 10 equivalents (entry 4 vs 1). Next, the amount of SF4 was also evaluated in combination with 10 equivalents of HF. The yield of 6 was further increased to 69% with 3 equivalents of SF4, accompanied with only slight increase of 7 (entry 5). Reducing the stoichiometry of SF4 to 1 equivalent led to decreased yield of 6 and no impact on the level of 7 (entry 6 vs 5). Therefore, 10 equivalents of HF and 3 equivalents of SF4 were selected as the optimum conditions. This procedure has been demonstrated on 20-gram scale to provide 66% yield of 6 (entry 7) compared to the 38% yield from the discovery route and avoided KMnO4 oxidation. The amount of 7 generated in this 20-gram reaction was lower than the 2-gram reaction (entry 7 vs 5) and 6 was isolated via just column purification.
a Reaction conditions: 5 (2 g, 1.0 equiv), 8 h; aq Na2CO3 and extraction into EtOAc; Na2CO3 (2.5 equiv), Boc2O (1.05 equiv), 10–20 °C, 12 h.
b Determined by HPLC at the end of reaction based on area% ratio between 6 and 7.
c Isolated yield.
d After introduction of HF and SF4 at –65 °C, the autoclave was warmed to –30 °C.
e The column purification could not separate the high level of 7 from 6.
f Performed on 20-gram scale.
We next investigated classical resolution to replace chiral SFC separation of racemic 1. When utilized early in a synthetic sequence, a classical resolution can be a practical solution if an asymmetric synthesis is unavailable. Unfortunately, ketone 5 was not a good substrate for classical resolution as the chiral center adjacent to the carbonyl and the pyridine group was prone to racemization under a variety of conditions. Compound 6 on the other hand was a more suitable candidate for a classical resolution. A 72-vial high-throughput screening (HTS) was carried out with eight chiral acids and nine solvents.[10] The representative results are summarized in Table [2] for those combinations with some degree of success in the reactive crystallization.[11] We found camphorsulfonic acid ((+)-CSA) favored the crystallization of the undesired enantiomer 12 in four of the solvents and no solid was formed in other solvents attempted. The enantiomeric purity of 12 from the crystallization in 2-MeTHF was only 60% ee (entry 1). Switching the solvent to ethyl acetate did not improve the ee of 12 (entry 2). Both 2-propanol and methyl ethyl ketone (MEK) afforded 12 in 80–85% ee but the recovery was lower (entries 3 and 4). In pursuing a system that would provide high enantiomeric purity and good recovery, other combinations of chiral acids and solvents were explored. However, only di-p-toluoyl-d-tartaric acid (d-DTTA) in acetonitrile had success in crystallization of the diastereomeric salt. We were pleased to find that this combination favored the crystallization of the desired enantiomer 13 in 90% ee and 42% yield in acetonitrile (entry 5, theoretical maximum yield 50%). Further upgrade of the enantiomeric purity of 13 downstream via recrystallization proved promising as well. Eventually, we were able to recrystallize 13 in MeOH/water to provide the final solid in 99.6% ee and 41% overall yield from 6 (Scheme [3]). This process is highly reproducible and has been performed in multiple kilogram-scale batches.
a Reaction conditions: 6 (20 mg, 0.067 mmol), chiral acid (0.067 mmol), solvent (25 vol), 25–50 °C.
b Analyzed by chiral HPLC.
c Based on 50% maximum yield.
d Repeated on 1-gram scale.
The new deoxyfluorination and classical resolution enabled us to efficiently synthesize 13 from 4 (Scheme [4]). Then, salt break of 13 in DCM using aqueous NaHCO3 afforded (S)-6 which was oxidized with Oxone to give (S)-9. After workup and concentration, (S)-9 was used directly without further purification. Boc deprotection with HCl provided 99% yield of (S)-10 as the HCl salt over two steps from (S)-6. Free basing of (S)-10 was necessary due to the incompatibility of chloride anion in downstream chemistry.[12] However, this free basing process was more difficult than expected. In the discovery chemistry route, racemic 10 was free based upon chiral SFC purification with a mobile phase containing triethylamine as an additive. An alternative approach was needed since the chiral SFC was no longer implemented at the end of the synthesis. The high solubility of 1 in water ruled out a typical aqueous salt break and subsequent extraction of the free base into an organic solvent. In addition, 1 was also highly hygroscopic and was prone to formation of a sticky gel. To counter this issue, we implemented a non-aqueous protocol to free base (S)-10 in MeOH solution using a basic anion resin which afforded 1 in 93% yield and 99.2% ee.
In summary, a new synthesis of the chiral difluoropiperidine 1 was enabled by a SF4–HF mediated deoxyfluorination and a classical resolution. The resolution at a much earlier point of the synthesis, as well as the high-yielding downstream chemistry, led to the synthesis of 1 in 23% overall yield compared to 12% yield in the previous synthesis. It is noteworthy that the SF4–HF process, which also eliminated the need of KMnO4 oxidation to remove an olefin impurity, has not been scaled up beyond 20-gram scale. Flow chemistry[13] or process specific equipment is needed for manufacturing in a pilot plant.
All reactions were run under nitrogen. Unless otherwise specified, concentration by rotary evaporation or distillation was carried out under house vacuum of 12–50 Torr. Heating was provided by a steam-heated silicone heat transfer fluid in a pilot plant for all the reactions on kilogram scale. All other reactions were heated with an oil bath or a Huber unit connected to an EasyMax reactor. Melting points were measured with a Mettler Toledo MP 90 Melting Point System, and the results are not corrected. Optical rotations were recorded on a JASCO P-2000 polarimeter. All NMR spectra were acquired at ambient temperature on a Bruker 400 MHz spectrometer. Solvents and frequencies for specific data acquisitions are noted for each case. Chemical shifts were calibrated relative to residual protio solvent (1H and 13C). Data were processed using ACD Spectrus software. HPLC analysis was performed on Agilent 1260 or 1290 Series instruments with diode array detectors, though analysis was typically done with traces from a single wavelength. Unless otherwise mentioned, all reaction monitoring and product purity was obtained by HPLC and chiral HPLC analysis. HRMS (m/z) was measured using a Thermo Scientific Orbitrap Eclipse mass spectrometer equipped with a heated electrospray ionization ion source.
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tert-Butyl 4-Oxo-3-(pyridin-4-yl)piperidine-1-carboxylate (5)
To a solution of NaOtBu (42.0 kg, 437.0 mol) in 1,4-dioxane (630.0 L) was added 4 (21.0 kg, 108.0 mol) under N2. Then, 3 (29.4 kg, 147.6 mol), X-Phos (4.2 kg, 8.8 mol) and Pd(OAc)2 (0.84 kg, 3.7 mol) were added sequentially. The mixture was stirred at 45 °C for 23 h and then poured into aq NH4Cl (630.0 L). The layers were separated and the aqueous layer was extracted with EtOAc (210.0 L). The combined organic layers were washed with brine (168.0 L) and concentrated under vacuum at 45 °C to give the crude product. The crude product was dissolved in EtOAc (63.0 L), filtered and concentrated. The resulting residue was triturated with a mixture of MTBE and heptane (1:2, 94.5 L) and dried under vacuum to give intermediate 5 (31.0 kg, 97% yield, adjusted for 93.1 area%) as a yellow solid; mp 87.0–91.5 °C.
1H NMR (400 MHz, CDCl3): δ = 8.66–8.53 (m, 2 H), 7.20–7.08 (m, 2 H), 4.40–4.13 (m, 2 H), 3.74–3.65 (m, 1 H), 3.63–3.45 (m, 2 H), 2.66–2.48 (m, 2 H), 1.51 (s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 205.25, 154.20, 149.73, 144.38, 123.84, 81.02, 55.56, 55.50, 40.60, 40.60, 28.31.
HRMS (ESI): m/z [M + H]+ calcd for C15H21N2O3: 277.1547; found: 277.1539.
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tert-Butyl 4,4-Difluoro-3-(pyridin-4-yl)piperidine-1-carboxylate (6)
To an autoclave was added 5 (20.0 g, 72.4 mmol) and then cooled to –65 °C prior to introduction of anhydrous HF (14.5 g, 724 mmol) and SF4 (23.5 g, 217 mmol). (Note: SF4 was condensed into the autoclave from a gas cylinder. The gas cylinder was tared with a balance in order to control the amount of SF4 added to the reaction system.) Then, the autoclave was warmed to 0 °C and stirring was undertaken for 8 h before quenching with sat. aq Na2CO3 (1.00 L). EtOAc (500 mL), Na2CO3 (19.2 g, 181 mmol) and Boc2O (16.6 g, 76.0 mmol) were added. The mixture was stirred at 10–20 °C for 12 h. The mixture was extracted into EtOAc (3 × 500 mL), dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography (silica gel; petroleum ether/EtOAc, 1:0 to 0:1) to give 6 (14.7 g, 66% yield, adjusted for 97.6 area%) as a yellow solid; mp 108.4–109.7 °C.
1H NMR (400 MHz, DMSO-d 6): δ = 8.55 (m, 2 H), 7.36 (m, 2 H), 4.14–3.88 (m, 2 H), 3.32–3.25 (m, 2 H), 3.18–2.97 (m, 1 H), 2.22–1.90 (m, 2 H), 1.41 (s, 9 H).
13C NMR (101 MHz, DMSO-d 6): δ = 153.45, 149.54, 143.27, 124.65, 122.02 (t, J = 245.6 Hz, 1 C), 79.64, 47.06 (t, J = 20.4 Hz, 1 C), 44.55, 33.16, 32.94, 27.93.
19F{1H} NMR (376 MHz, DMSO-d 6): δ = –94.26 (d, J = 236.2 Hz, 1 F), –111.07 to –112.27 (m, 1 F).
HRMS (ESI): m/z [M + H]+ calcd for C15H21F2N2O2: 299.1566; found: 299.1566.
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tert-Butyl 4,4-Difluoro-3-(pyridin-4-yl)piperidine-1-carboxylate d-DTTA Salt (13)
The classical resolution was performed in 8 × 1.56 kg batches. A solution of intermediate 6 (1.56 kg, 5.2 mol) in MeCN (31.0 L) was treated with d-DTTA (1.01 kg, 2.6 mol) at 20 °C. The mixture was then heated to 55 °C until the solid dissolved completely. Then, a solution of d-DTTA (0.41 kg, 1.1 mol) in MeCN (3.0 L) was added to the mixture at 55 °C. The resultant white suspension was stirred for 0.5 h at 55 °C. Additional d-DTTA (0.61 kg, 1.6 mol) in MeCN (4.5 L) was added. The resulting slurry was cooled to 25 °C over 3 h and then aged for 2 h. The slurry was filtered, and the cake was washed with MeCN (2 × 3.0 L) and dried under vacuum to provide the crude 13.
The crude intermediate 13 was dissolved in MeOH (12.5 L) at 25–30 °C, followed by slow addition of water (3.1 L). After the formation of white solid, additional water (9.4 L) was added over 1 h and the slurry was aged at 25 °C for 3 h. The slurry was filtered, and the cake was washed with a mixture of MeOH and water (1:1, 2 × 3.1 L). The filter cake was dried under vacuum to provide 13 (11.7 kg combined, from total input of 12.5 kg of 6, 41% yield; 99.6% ee) as a yellow solid; mp 99.0–102.0 °C.
[α]D 22 +46.3 (c 1.00, MeOH).
1H NMR (400 MHz, DMSO-d 6): δ = 13.88 (br s, 2 H), 8.56 (d, J = 5.9 Hz, 2 H), 7.91 (d, J = 1.0 Hz, 4 H), 7.48–7.32 (m, 6 H), 5.84 (s, 2 H), 4.16–3.91 (m, 2 H), 3.52–3.28 (m, 2 H), 3.15–2.99 (m, 1 H), 2.41 (s, 6 H), 2.27–1.88 (m, 2 H), 1.41 (s, 9 H).
13C NMR (101 MHz, DMSO-d 6): δ = 167.29, 164.69, 153.51, 149.47, 144.60, 143.45, 129.59, 129.49, 125.83, 124.73, 121.68 (t, J = 246.5 Hz, 1 C), 79.71, 71.38, 47.13 (t, J = 20.2 Hz, 1 C), 44.52, 33.29, 32.93, 27.97, 21.28.
19F{1H} NMR (376 MHz, DMSO-d 6): δ = –93.98 (d, J = 236.7 Hz, 1 F), –111.10 to –112.29 (m, 1 F).
HRMS (ESI): m/z [M + H]+ calcd for C15H21F2N2O2: 299.1566; found: 299.1566.
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tert-Butyl (S)-4,4-Difluoro-3-(pyridin-4-yl)piperidine-1-carboxylate [(S)-6]
The salt break of 13 was performed in 6 × 2.03 kg batches. A mixture of 13 (2.03 kg, 3.00 mol), DCM (10.2 L) and H2O (10.2 L) was treated with NaHCO3 (2.29 kg, 27.3 mol) at <10 °C until the pH value of the aqueous layer was 8. The mixture was stirred for an additional 0.5 h at 10 °C before separation of the layers. The aqueous layer was extracted with DCM (2 × 10.2 L). The combined organic layers were washed with sat. brine (5.08 L) and concentrated under vacuum at 45 °C to give (S)-6 (5.00 kg combined, from total input of 12.2 kg of 13, 96% yield, adjusted for 99.5 area%) as a yellow solid; mp 128.0 °C.
[α]D 20 –44.7 (c 0.917, MeOH).
1H NMR (400 MHz, DMSO-d 6): δ = 8.59–8.52 (m, 2 H), 7.41–7.30 (m, 2 H), 4.17–3.89 (m, 2 H), 3.44–3.36 (m, 2 H), 3.17–3.01 (m, 1 H), 2.23–1.88 (m, 2 H), 1.42 (br s, 9 H).
13C NMR (101 MHz, DMSO-d 6): δ = 153.46, 149.54, 143.27, 124.65, 121.96 (t, J = 248.3 Hz, 1 C), 79.65, 47.05 (t, J = 20.5 Hz, 1 C), 44.66, 33.20, 33.11, 27.94.
19F{1H} NMR (376 MHz, DMSO-d 6): δ = –93.98 (d, J = 236.2 Hz, 1 F), –111.11 to –112.30 (m, 1 F).
HRMS (ESI): m/z [M + H]+ calcd for C15H21F2N2O2: 299.1566; found: 299.1566.
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(S)-4-(4,4-Difluoropiperidin-3-yl)pyridine 1-Oxide HCl Salt [(S)-10]
A solution of (S)-6 (5.00 kg, 16.8 mol) in acetone (25.0 L) and H2O (25.0 L) was treated with K2CO3 (7.40 kg, 53.5 mol) at 20 °C. Oxone (25.5 kg, 83.0 mol) was added into the mixture in portions at such a rate that the internal temperature was kept between 5 to 10 °C. The mixture was stirred for 17 h, followed by filtration through a pad of Celite. The filter cake was washed with DCM (2 × 10.0 L). Layers in the filtrate were separated and the aqueous layer was extracted with DCM (2 × 10.0 L). The combined organic layers were washed successively with sat. aq Na2SO3 (25.0 L) and sat. brine (12.5 L), dried over Na2SO4 and concentrated under vacuum at 30 °C to give (S)-9 (99.2 area%) as a yellow oil.
A solution of (S)-9 in MeOH (7.5 L) was treated with 4 M HCl/MeOH (30.0 L, 120 mol) at 25 ± 5 °C. The mixture was stirred for 12 h and then concentrated under vacuum at 40 °C. The residue was treated with MeOH (5.00 L) and concentrated under vacuum. This was repeated twice to give (S)-10 [4.18 kg, 99% yield from (S)-6, adjusted for 99.5 area%] as a white solid.
[α]D 20 –18.0 (c 1.02, MeOH).
1H NMR (400 MHz, DMSO-d 6): δ = 10.02 (br s, 2 H), 8.60–8.52 (m, 2 H), 7.71–7.62 (m, 2 H), 4.10–3.86 (m, 1 H), 3.66–3.44 (m, 2 H), 3.14–3.04 (m, 1 H), 2.61–2.49 (m, 2 H), 2.48–2.39 (m, 1 H).
13C NMR (101 MHz, DMSO-d 6): δ = 139.05, 135.85, 128.15, 119.68 (t, J = 246.4 Hz, 1 C), 43.84 (t, J = 23.3 Hz, 1 C), 43.44 (d, J = 6.5 Hz, 1 C), 40.80 (d, J = 10.7 Hz, 1 C), 30.62 (t, J = 24.8 Hz, 1 C).
19F{1H} NMR (376 MHz, DMSO-d 6): δ = –96.38 (d, J = 243.6 Hz, 1 F), –111.73 (d, J = 240.6 Hz, 1 F).
HRMS (ESI): m/z [M + H]+ calcd for C10H13F2N2O: 215.0990; found: 215.1000.
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(S)-4-(4,4-Difluoropiperidin-3-yl)pyridine 1-Oxide (1)
The free basing of (S)-10 using anion resin was performed in 62 × 50 g batches. Prior to the free basing, the anion exchange resin (LX-D201C) in the hydroxide (OH) form was pretreated with deionized water (150 mL) twice, filtered and washed with deionized water (250 mL) until the pH became 7–8. The resin was further treated with MeOH (150 mL) twice until no impurity was observed in the MeOH solution by 1H NMR.
To a solution of (S)-10 (50 g, 0.2 mol) in MeOH (150 mL) at 5 ± 5 °C was added the pretreated anion exchange resin (LX-D201C) (250 g, 5.0 wt) in portions. The resulting suspension was stirred at 20 ± 5 °C for 12 h until NMR analysis showed completed consumption of (S)-10. The suspension was filtered and the filtrate was concentrated at 40 °C to give 1 as a yellow oil. The product was azeotropically dried with anhydrous i-PrOAc (100 mL) at 40 °C to remove residual water and provide 1 [2.50 kg combined, from total input of 3.10 kg of (S)-10, 93% yield, adjusted for 98.8 area%; 99.2% ee] as a light yellow solid which required storage under nitrogen; mp 110.0–119.0 °C.
[α]D 22 –44.1 (c 1.00, MeOH).
1H NMR (400 MHz, DMSO-d 6): δ = 8.18 (d, J = 6.6 Hz, 2 H), 7.35 (d, J = 6.4 Hz, 2 H), 3.24–2.97 (m, 3 H), 2.97–2.82 (m, 2 H), 2.70 (t, J = 11.6 Hz, 1 H), 2.09–1.98 (m, 1 H), 1.98–1.77 (m, 1 H).
13C NMR (101 MHz, DMSO-d 6): δ = 138.22, 133.53, 127.23, 122.66 (t, J = 246.1 Hz, 1 C), 48.43–48.09 (m, 1 C), 42.95 (d, J = 9.5 Hz, 1 C), 34.78 (d, J = 18.3 Hz, 1 C), 34.55 (d, J = 19.1 Hz, 1 C).
19F{1H} NMR (376 MHz, DMSO-d 6): δ = –96.38 (d, J = 234.9 Hz, 1 F), –111.73 (d, J = 241.9 Hz, 1 F).
HRMS (ESI): m/z [M + H]+ calcd for C10H13F2N2O: 215.0990; found: 215.0984.
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Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
We are grateful to the plant staff and the analytical group at WuXi for their support; to Ed Carenzo (GSK) for acquiring HRMS; to Mark Mellinger (GSK) for acquiring optical rotations; and to Laura Adduci (GSK) for helpful discussion on NMR spectra.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0043-1773542.
- Supporting Information
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- 11 Unsuccessful combinations did not yield solids in the reactive crystallization. See the Supporting Information for a full list of chiral acids and solvents.
- 12 The Boc deprotection with various sulfonic acids was successful for isolation of 1 as a crystalline salt of the sulfonic acids. However, those salts did not perform as efficiently as the free base 1 in the downstream chemistr
- 13 For an example of deoxyfluorination using SF4 in flow chemistry, see: Polterauer D, Wagschal S, Bersier M, Bovino C, Roberge DM, Hone CA, Kappe CO. Org. Process Res. Dev. 2024; 28: 2919
For reviews, see:
Corresponding Authors
Publication History
Received: 18 February 2025
Accepted after revision: 01 April 2025
Article published online:
17 April 2025
© 2025. Thieme. All rights reserved
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- 11 Unsuccessful combinations did not yield solids in the reactive crystallization. See the Supporting Information for a full list of chiral acids and solvents.
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For reviews, see:
