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DOI: 10.1055/s-0040-1707859
Practical Early Development Synthesis of Nav1.7 Inhibitor GDC-0310
Publication History
Received: 18 April 2020
Accepted after revision: 12 May 2020
Publication Date:
22 June 2020 (online)
Published as part of the Special Topic Synthesis in Industry
Abstract
The concise early development route to the Nav1.7 inhibitor GDC-0310 is described. The active pharmaceutical ingredient (API) contains one stereocenter, which was obtained with high enantiomeric excess (>99:1) by using an SN2 displacement approach to connect two intermediates: a chiral benzyl alcohol and a piperidine. The synthesis of the piperidine building block proceeded via a regioselective SNAr reaction on 1-chloro-2,4-difluorobenzene by N-Boc-4-piperidinemethanol, followed by installation of the methyl ester group by electrophilic aromatic bromination and a palladium-catalyzed alkoxycarbonylation. A subsequent Suzuki–Miyaura cross-coupling reaction was then telescoped directly into cleavage of the Boc group to provide the advanced piperidine intermediate. The key feature of the synthesis is the highly selective SN2 displacement of the chiral mesylate of (R)-1-(3,5-dichlorophenyl)ethan-1-ol with the piperidine intermediate, followed by a chiral purity upgrade via the corresponding (1S)-(+)-camphorsulfonic acid salt. After standard hydrolysis of the methyl ester and CDI mediated amidation to couple the resulting acid with methanesulfonamide, enantiomerically pure GDC-0310 was obtained in high overall yield (37%) on a 6.5 kilogram scale.
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Key words
Nav1.7 inhibitor - nucleophilic substitutions - Suzuki–Miyaura cross-coupling - palladium catalysis - alkoxycarbonylationThe voltage gated sodium ion channel Nav1.7 is a membrane protein found in nerve C-fibers that senses voltage differentials between the inside and outside of the cell membrane, triggered by painful external stimuli. The channel opens above a critical threshold and initiates an action potential that allows the pain signal to propagate through neighboring cells into the spinal cord.[1] Selective inhibition of Nav1.7 has been shown to interrupt the transmission of pain signals and become a valuable therapeutic strategy for the treatment of pain.[2] The development of novel therapies in the area of pain has recently gained traction because of unwanted side effects exhibited by existing medications, such as opioid addiction.[3]
GDC-0310 was developed in our laboratories as a selective small molecule inhibitor of Nav1.7 to potentially treat pain. In an effort to support human clinical studies, we were tasked to develop an efficient and safe manufacturing process to produce kilogram amounts of this active pharmaceutical ingredient (API).
The retrosynthesis of GDC-0310 is shown in Scheme [1]. We envisioned synthesizing GDC-0310 by amidation of 1 with methanesulfonamide, preceded by a key SN2 carbon–nitrogen bond formation between piperidine benzoate 3 and the chiral mesylate 2, and successive ester hydrolysis. The installation of the ester group in 3 would be accomplished by alkoxycarbonylation of aryl bromide 4, followed by Suzuki–Miyaura coupling with cyclopropylboronic acid. Aryl bromide 4 would be accessed by a regioselective SNAr reaction of the commercially available 1-chloro-2,4-difluorobenzene with N-Boc-4-piperidinemethanol, and subsequent regioselective bromination.
We commenced our endeavour with the SNAr alkoxylation reaction of 1-chloro-2,4-difluorobenzene and 4-piperidinemethanol (Scheme [2]). It has been previously demonstrated that a highly regioselective displacement of a fluorine substituent on polyhalogenated difluorobenzenes with alkoxides can be achieved at the fluorine next to a chlorine substituent by using potassium tert-butoxide (t-BuOK) in THF.[4] [5] We surmised that this methodology could also be applied to the SNAr reaction of 1-chloro-2,4-difluorobenzene with 4-piperidinemethanol.
The SNAr reaction was thus investigated using different bases (DIPEA, NaH, KOH, t-BuOK) and solvents (NMP, DMF, DMSO, THF) (Scheme [2]). Most of these bases resulted in consumption of starting material and 73–98% conversion to desired product 5 regardless of the solvent, but also produced significant amounts of undesired regioisomer 6 (up to 10A% as determined by HPLC analysis). Gratifyingly, the reaction with t-BuOK (220 mol%) in THF at 15 °C proceeded with complete conversion and the highest selectivity (<2A% of 6 as determined by HPLC analysis), resulting in the best reaction profile. All attempts to directly isolate 5 from the THF reaction mixture by adding water as antisolvent failed due to the product oiling out. Alternatively, a solvent swap from THF to methanol, followed by addition of water and crystallization produced compound 5 as a white solid in 89% yield and >99A% HPLC purity.
a Reaction conditions: 5 (550 mg, 1.6 mmol), base, solvent (5.5 mL), heating/cooling to the indicated temperature; then addition of brominating agent, 2 h.
b A% = the percentage area at 254 nm determined by HPLC analysis after 2 h reaction time.
c DBH added in 5 portions over 30 min, 4.5 h reaction time.
d H2O (0.165 mL, 500 mol%) added.
Next, the regioselective bromination of 5 with various brominating agents was investigated (Table [1]).[6] Examining the reaction of 5 with Br2 in various solvents, we observed that the conversion to 4 was fastest in MeCN with K3PO4 as base to avoid formation of des-Boc 7 as a side product, but required a large excess of Br2 (400 mol%) to consume all starting material (entry 1). Considering process safety, we subsequently explored the less hazardous N-bromosuccinimide (NBS) and 1,3-dibromo-5,5-dimethylhydantoin (DBH) as the brominating reagent. Bromination of 5 with NBS or DBH in MeCN and/or DMF proceeded very sluggishly, and gave only trace amounts of 4 even when heating to 50 °C (entries 2 and 3). Interestingly, a 50% conversion was observed with DBH (70 mol%) when using sodium acetate (NaOAc) as the base in acetic acid (entry 4). The conversion was increased to >99% by co-mixing a small amount of water (500 mol%),[7] [8] and slowly adding portions of DBH over 30 min[9] (entry 5). The reaction impurity profile could be further improved by excluding light, and subsequently quenching the mixture with aqueous sodium disulfite to minimize the generation of side products. Product 4 was then extracted with cyclohexane, followed by solvent swap from cyclohexane to MeOH and isolated by crystallization in MeOH/water as a pale yellow solid in 90% isolated yield (99.8A% by HPLC analysis).
With access to bromide 4 established, we next focused on the installation of the carbonyl group in 8 (Scheme [3]) by exploring the Pd-catalyzed alkoxycarbonylation of 4, which based on previous experience had provided good results when PdCl2(dppf) was employed as the catalyst.[5] [10] Performing the carbonylation of 4 in an autoclave under CO pressure (5 bar) at 125 °C, with MeOH/toluene (37 mL/g, 5:1) as the reaction solvent, Et3N as base, and PdCl2(dppf) as the catalyst, the reaction readily afforded complete conversion, however, with varying quantities of the bis-carbonylated impurity 9 (0.5–1.5A% as determined by HPLC analysis), indicating that the CO insertion reaction also took place at the chloro substituent (Scheme [3]). After further optimization of the solvent volume of MeOH/toluene (6 mL/g, 5:1), complete conversion of 4 to 8 was achieved with only 0.3 mol% catalyst loading, but this had no major impact on the chemoselectivity. Treatment of the reaction mixture with activated carbon[11] was implemented to mitigate the risk of catalyst poisoning in the subsequent Suzuki–Miyaura coupling. Product 8 was isolated directly by crystallization from MeOH/toluene (99:1) in 88% yield (98.5A% by HPLC analysis), with bis-carbonylated impurity 9 being controlled to ~0.5A% (by HPLC).
Next, the Suzuki–Miyaura cross-coupling of 8 with cyclopropylboronic acid was investigated, using different combinations of Pd catalyst/monodentate phosphine ligand in toluene/water and with potassium phosphate (K3PO4) as the base (Table [2], entries 1–6). The Buchwald second-generation palladium precatalyst XPhos Pd G2/XPhos (1:1) was identified as the best catalyst system (entry 4).[5] [12] The catalyst loading could be lowered to 1 mol% from 3 mol% without compromising the reaction conversion and purity profile (entries 3 and 4), but required an excess of cyclopropylboronic acid (140 mol%). Although the Pd(OAc)2/PCy3 catalyst system performed equally well in terms of conversion, it exhibited a slightly worse impurity profile (entry 6), and was therefore not selected for further development.
a Reaction conditions: 8 (1 g, 2.5 mmol), cyclopropylboronic acid (300 mg, 3.5 mmol, 140 mol%), toluene (7 mL); then K3PO4 (1.016 g, 7.5 mmol, 300 mol%) in H2O (2.4 mL); then catalyst/ligand (1:1), r.t., evacuating and backfilling with N2; then 75 °C, 3 h.
b No conversion was observed with Pd2dba3 as precatalyst.
c No conversion was observed with P(t-Bu)3 and PPh3 as ligands.
d Conversion determined by HPLC analysis at 220 nm.
e A% = the percentage area at 220 nm determined by HPLC analysis after 3 h.
f XPhos = 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.
g XPhos Pd G2 = chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II).
To control the residual Pd to <10 ppm level, the crude mixture of 10 in toluene/water was treated successively with silica gel, activated carbon,[11] and aqueous N-acetylcysteine. The treated toluene solution of 10 was directly telescoped to the subsequent Boc deprotection step (Scheme [4]).
Various acids, for example, p-TsOH, HCl, methanesulfonic acid (MSA), and (1S)-(+)-camphorsulfonic acid (CSA) were investigated for the Boc deprotection of 10. Although an HCl salt of 3 could be isolated, ultimately, MSA provided the best reactivity and cleanest reaction profile. Adding a small amount of MeOH (0.5 mL/g) prior to addition of MSA (100 mol%) at 55 °C afforded complete conversion in 3 h. The MSA salt of 3 crystallized in the reaction mixture and was isolated by simple filtration as a white solid in 85% yield over 2 steps (98.6A% by HPLC analysis).
a Conversion determined based on the percentage area at 254 nm by HPLC analysis of the product versus starting material after 2 h reaction time.
b On 500 mg (2.6 mmol) scale.
c On 10 g (52.3 mmol) scale.
a Relative to piperidine 3 (100 mol%).
b Conversion determined based on the percentage area at 254 nm of the product versus starting material by HPLC analysis.
c Determined by chiral HPLC analysis.
d Piperidine 3·HCl was used.
e Reaction run for 32 h instead of 16 h.
f Reaction performed on 200 g (0.743 mol) scale.
g Reaction performed at 80 °C instead of 60 °C.
h Isolated yield 85%.
With an optimized procedure in place to access key piperidine intermediate 3·MSA, we then turned our focus to the late-stage chemistry towards the GDC-0310 API. To generate an appropriate electrophile for the planned SN2 reaction with 3, the activation of commercially available chiral alcohol 11 (100:0 er) via sulfonylation was thus investigated (Table [3]). Initially, tosylation of 11 was tested using different equivalents of p-toluenesulfonic anhydride along with various bases in CH2Cl2, but conversion to the tosylate product was limited to ≤90%, even when using a 120 mol% excess of p-toluenesulfonic anhydride. Switching instead to methanesulfonic anhydride (Ms2O) in the presence of Et3N afforded complete and clean conversion to mesylate 2 in various solvents, and with only a small excess of either reagent (entries 1–7). Methyl isobutyl ketone (MIBK) was ultimately selected as the solvent for the mesylation due to promising results in the subsequent SN2 and enantiomeric purity upgrade (vide infra). Using a larger excess of reagent and base, the reaction in MIBK provided high conversion to mesylate 2 on multigram (entry 8) and, subsequently, kilogram scale (Scheme [5]).[9]
With the preparation of mesylate 2 demonstrated, its reaction with piperidine 3 in the SN2 step was next optimized (Table [4]). Initially, piperidine 3 was used as its HCl salt (vide supra) and the reaction was performed at 60 °C. However, in both 1,4-dioxane and DMF, this led to low conversion and erosion of stereochemical purity (entries 1 and 2). This is presumably due to both the presence of chloride, which can erode our stereocenter through an undesired background SN2, and also more competing SN1 pathway due to the possible stabilization of the benzylic carbocation in polar solvents such as DMF and 1,4-dioxane. In contrast, a base and solvent screen using the free base of 3 (prepared from freebasing of 3·HCl using 120 mol% NaOH in 10 mL/g MIBK and subsequent organic layer concentration) showed a significant improvement in both conversion and er (entries 3–6). Further improvement was observed when biphasic conditions (toluene or MIBK with water) were implemented for K2CO3 (entries 7–8). These biphasic conditions to access intermediate 12 proved robust, and the reaction in MIBK/water was scaled to 200 g, generating 98% conversion, 85% isolated yield of 12, and conserving the integrity of the chiral center (99:1 er) (entry 9).
As an additional safeguard to ensure a reproducibly high enantiomeric ratio of the API and its penultimate intermediates before scale-up, a diastereomeric salt upgrade was developed for SN2 product 12. (1S)-(+)-Camphorsulfonic acid (CSA) showed great promise after being tested to form salt 13 in various solvents (MIBK, 1,4-dioxane, toluene, THF, EtOAc, MTBE, Me-THF), and subsequently the undesired stereoisomer was completely purged away (with high recovery of 13) using MIBK (>90% yield, Scheme [5]). The following one-pot salt break and saponification sequence was effective using LiOH as both base (110 mol%) and reagent (190 mol%), before treatment with HCl (190 mol%) to form acid 1 in high yield. Lastly, sulfonamide formation to GDC-0310 was achieved using 1,1′-carbonyldiimidazole (CDI, 170 mol%) as an activating agent with methanesulfonamide (150 mol%), K2CO3 as base (200 mol%), and EtOAc as solvent. Multiple other solvents (DCM, MIBK, MeCN, EtOAc, NMP), bases (DIPEA, DBU), and charges of CDI (120–170 mol%) and methanesulfonamide (130–170 mol%) were evaluated, but none were superior to the conditions described.
The optimized steps were then implemented in an early development manufacturing synthesis of GDC-0310, which was performed on a 6.5 kg scale (Scheme [5]). During the scale-up, a one-pot four-step sequence was performed to generate free base 3 from its MSA salt for the SN2 reaction and then to obtain the (1S)-(+)-camphorsulfonic acid (CSA) intermediate salt 13 in 90% yield with undetectable amounts of the undesired enantiomer of 12 by HPLC. The following salt break and saponification steps using LiOH afforded acid 1 in 90% yield. Finally, GDC-0310 was formed via amide coupling with methanesulfonamide using the optimized conditions to afford the API in 76% yield and 99.8A% purity (by chiral HPLC) after crystallization in EtOAc.
In summary, a large-scale synthesis of the Nav1.7 channel inhibitor GDC-0310 via a ten-step synthetic sequence from commercially available 1-chloro-2,4-difluorobenzene was developed. The new route features a highly regioselective SNAr fluoride displacement on 1-chloro-2,4-difluorobenzene by N-Boc-4-piperidinemethanol (regioselectivity >98:2), followed by installation of the carbonyl group via bromination, and subsequent palladium-catalyzed methoxycarbonylation of aryl bromide 4 to afford the corresponding methyl ester 8. This intermediate was then subjected to a Suzuki–Miyaura cross-coupling with cyclopropylboronic acid to give 10, and telescoped into the cleavage of the Boc group to give the mesylate salt piperidine 3. The key transformation of the synthesis was the SN2 displacement of the chiral mesylate of (R)-1-(3,5-dichlorophenyl)ethan-1-ol with the piperidine intermediate 3, followed by hydrolysis to acid 1, and CDI activated amidation with methanesulfonamide to give 6.5 kg of GDC-0310 in excellent purity and in 37% overall yield.
Unless otherwise noted, all reactions were run under a nitrogen atmosphere and solvents and reagents were used without further purification. 1H (300 MHz, 400 MHz, and 500 MHz) and 13C NMR (125 MHz) spectra were recorded on a Bruker Avance 3 spectrometer. Chemical shifts are reported relative to internal TMS or residual CHCl3. (R)-1-(3,5-Dichlorophenyl)ethan-1-ol (CAS No. 1629065-91-3) and 1-chloro-2,4-difluorobenzene (CAS No. 1435-44-5) are commercially available. In process method (IPC) for analysis of 1, 12, and GDC-0310: diluent: MeCN; mobile phase A: 0.05% TFA/H2O; mobile phase B: 0.05% TFA/MeCN; column: Ace 3 C18 HL column, 3 × 50 mm, 3.0 μm; column temperature: 35 °C; detector wavelength: 220 nm; signal 220 nm; bandwidth 4 nm, reference off; injection volume: 2 μL; flow rate: 1.0 mL/min; sample concentration: 0.5–1.0 mg/mL in 75% MeCN/H2O; program: 0.0 min 30.0% B, 0.67 min 30.0% B, 4.0 min 60.0% B, 4.33 min 90% B, 4.67 min 90.0% B, 5.0 min 30.0% B, 6.5 min 30.0% B; typical retention times: 1 (2.59 min), 10 (3.35 min), GDC-0310 (2.68 min). Method for analysis of 1-chloro-2,4-difluorobenzene, 3, 4, 5, 8, 10: diluent: MeCN; mobile phase: MeCN/H2O (phosphate buffer, pH 6.01) isocratic; run time: 29 min; column: Zorbax SB-C18, 3.0 × 50 mm, 1.8 μm; column temperature: 30 °C; detector wavelength: 220 nm; bandwidth 4 nm; reference off; injection volume: 2 μL; flow rate: 1.0 mL/min; sample concentration: 0.5–1.0 mg/mL in 75% MeCN/H2O; typical retention times: 1-chloro-2,4-difluorobenzene (4.4 min), 3 (3.41 min), 4 (11.64 min), 5 (8.73 min), 9 (7.63 min), 10 (8.62 min). Method for analysis of 1, 2, 3, 11, 12, and GDC-0310: diluent: MeCN; mobile phase A: 0.05% TFA/H2O; mobile phase B: 0.05% TFA/MeCN; column: ACE 3 C18-HL, 3.0 × 50 mm, 3 μm; column temperature: 35 °C; detector wavelength: 220 nm; bandwidth 4 nm, reference off; injection volume: 2 μL; flow rate: 1.0 mL/min; sample concentration: 0.5–1.0 mg/mL in 75% MeCN/H2O; program: 0.0 min 30.0% B, 0.67 min 30.0% B, 4.0 min 60.0% B, 4.33 min 90.0%, 4.67 min 30.0%, 6.5 min 30.0%; typical retention times: 1 (2.56 min), 2 (2.34 min), 3 (3.89 min), 11 (1.05min), 12 (3.35 min), GDC-0310 (2.69 min); injection volume 2 μL. Chiral HPLC method for analysis of 12, 13, and GDC-0310: diluent: MeCN; mobile phase A: 0.1% NH4OH/H2O; mobile phase B: 0.1% NH4OH/MeCN; isocratic 30:70 A/B; run time: 20 min; column: Chiralpak AD-RH, 4.6 × 150 mm, 5 μm; column temperature: 35 °C; detector wavelength: 225 nm; signal 225 nm; bandwidth 4 nm, reference off; injection volume: 20 μL; flow rate: 1.0 mL/min; typical retention times: GDC-0310 (12.52 min), enantiomer of GDC-0310 (14.13 min). HRMS data were collected on an Agilent 6530C qTOF equipped with an ESI source in positive ionization mode. The samples were introduced into the mass spectrometer using an Agilent 1290 UPLC with an Agilent Extend C18 (1.8 μm, 2.1 × 50 mm) column with 0.1% TFA in the aqueous (A) and MeCN (B) mobile phases at a flow rate of 0.5 mL/min. Gradient conditions are listed below: 0 min 5% B, 0–4.8 min 90% B, 4.8–5.3 min 90% B, 5.3–5.8 min 95% B, 5.8–7.0 min 5% B.
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tert-Butyl 4-[(2-Chloro-5-fluorophenoxy)methyl]piperidine-1-carboxylate (5)
In a 1500 mL glass vessel, 1-chloro-2,4-difluorobenzene (28.0 g, 188.5 mmol) and N-Boc-4-(hydroxymethyl)piperidine (42.7 g, 198.3 mmol, 105 mol%) were suspended in THF (73 mL). Then, t-BuOK (20% w/w in THF, 233.0 g, 415.2 mmol, 220 mol%) was dosed at 15 °C over 1 h and then the mixture was stirred at that temperature for another 1 h. H2O (122 mL) was added and the phases were separated. The crude mixture was then concentrated under reduced pressure to minimum volume at 35 °C and MeOH was added in two portions (140 and 84 mL). The temperature was increased to 60 °C and H2O (40 mL) was added over 45 min and the batch was seeded (0.1 g seeding crystals and stirring for at least 30 min). The suspension was cooled to 15 °C over 2 h and stirred at this temperature for 1 h. The suspension was filtered and the wet filter cake was washed with MeOH/H2O (120 mL, 1:1), followed by H2O (112 mL). The wet product was dried at 50 °C under reduced pressure for at least 12 h to afford 5.
Yield: 57.6 g (90%); off white solid; 99.3A% purity by HPLC.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.23 (m, 1 H), 6.71–6.52 (m, 2 H), 4.19 (d, J = 13.5 Hz, 2 H), 3.85 (d, J = 6.4 Hz, 2 H), 2.78 (t, J = 12.9 Hz, 2 H), 2.10–2.01 (m, 1 H), 1.91–1.84 (m, 2 H), 1.49 (s, 8 H), 1.39–1.26 (m, 2 H).
13C NMR (126 MHz, CDCl3): δ = 161.9 (d, J = 245.8 Hz), 155.2 (d, J = 10.2 Hz), 154.9, 130.5 (d, J = 9.7 Hz), 117.9 (d, J = 3.8 Hz), 107.7 (d, J = 23.0 Hz), 101.4 (d, J = 24.1 Hz), 79.5, 73.5, 43.5 (2 C), 36.1, 28.8 (2 C), 28.5 (3 C).
HRMS (ESI): m/z [M + H]+ calcd for C17H23ClFNO5: 344.1428; found: 344.1423.
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tert-Butyl 4-[(4-Bromo-2-chloro-5-fluorophenoxy)methyl]piperidine-1-carboxylate (4)
In a 2000 mL glass vessel, 5 (80.0 g, 232.7 mmol) and NaOAc (28.6 g, 348.7 mmol, 150 mol%) were dissolved in AcOH (800 mL) and H2O (20.9 mL). After the mixture was heated to 50 °C, DBH (46.6 g, 163.0 mmol, 70 mol%) was added in 5 portions over 30 min. The resulting red solution was stirred at 50 °C for at least 2 h under light exclusion. The solution was cooled to 25 °C and H2O (400 mL) was added and sodium disulfite was added slowly. Cyclohexane (480 mL) was added and the phases were separated. The aqueous phase was again extracted with cyclohexane (240 mL). The combined organic phases were washed successively with aq NaOH (240 mL, 5% w/w), aq NaHCO3 (240 mL, 5% w/w), and H2O (240 mL). The solution was then heated to 50 °C and concentrated under reduced pressure to remove 560 mL of distillate. MeOH (400 mL) was then added. The solution was then heated to 40 °C and concentrated under reduced pressure to remove 267 mL of distillate. H2O was then added (20 mL) and dosed over 15 min and the solution was seeded (0.11 g seed crystals and stirring for 30 min). H2O (20 mL) was then added over 15 min. The suspension was cooled to 0 °C over 3 h and filtered. The filter cake was washed with MeOH/H2O (80 mL, 1:1), followed by H2O (80 mL).The product was dried at 50 °C under reduced pressure for at least 12 h to afford 4.
Yield: 88.9 g (90%); pale yellow solid; 99.8A% purity by HPLC.
1H NMR (500 MHz, CDCl3): δ = 7.54 (d, J = 7.1 Hz, 1 H), 6.72 (d, J = 9.9 Hz, 1 H), 4.19 (d, J = 13.2 Hz, 2 H), 3.83 (d, J = 6.4 Hz, 2 H), 2.78 (t, J = 12.8 Hz, 2 H), 2.11–1.99 (m, 1 H), 1.89–1.82 (m, 2 H), 1.48 (s, 9 H), 1.36–1.27 (m, 2 H).
13C NMR (126 MHz, CDCl3): δ = 158.1 (d, J = 246.7 Hz), 154.8, 154.6 (d, J = 8.9 Hz), 133.2, 118.9 (d, J = 3.9 Hz), 102.05 (dd, J = 27.3, 2.8 Hz), 98.9 (d, J = 22.7 Hz), 79.5, 73.8, 43.5 (2 C), 36.0, 28.7 (2 C), 28.5 (3 C).
HRMS (ESI): m/z [M + H – C5H9O2]+ calcd for C17H22BrClFNO3: 322.0003; found: 322.0004.
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tert-Butyl 4-{[2-Chloro-5-fluoro-4-(methoxycarbonyl)phenoxy]-methyl}piperidine-1-carboxylate (8)
A 500 mL glass vessel was charged with 4 (24.0 g, 56.8 mmol), MeOH (107 mL), and toluene (27 mL). Then, Et3N (6.8 g, 67.2 mmol, 118 mol%) was added. The solution was transferred to an autoclave under nitrogen, before [Pd(dppf)Cl2] (0.166 g, 0.2 mmol, 0.3 mol%) dissolved in MeOH (6 mL) was transferred to the autoclave. The autoclave was closed and degassed with N2 (3×), followed by CO (3×). The solution was heated to 130 °C with stirring. CO pressure (5 bar) was applied and the reaction mixture was stirred for 3 h. The mixture was then cooled to 30 °C and vented. The autoclave was well purged with N2 (3×). The solution was then filtered at 30 °C and the filter cake was rinsed with MeOH (12 mL). Activated charcoal (2.2 g, Norit® CAP Super-WJ) was added to the solution and the mixture was stirred at 30 °C. After 40 min, the suspension was filtered and the vessel was rinsed with MeOH (75 mL), which was added to the filter cake. The solution was then concentrated under reduced pressure at 100 °C until 190 mL of distillate was obtained. MeOH (113 mL) was added again and another 100 mL of distillate was removed. The solution was then cooled to 20 °C and the product began to crystallize. The solution was further cooled to 5 °C and stirred at this temperature for 3 h. The suspension was then filtered and the wet filter cake was washed with MeOH/H2O (50 mL, 1:2), followed by MeOH (50 mL). The resulting product was dried at 60 °C under reduced pressure for at least 4 h to afford 8.
Yield: 20.1 g (88%); off white solid; 98.5A% purity by HPLC.
1H NMR (500 MHz, CDCl3): δ = 7.98 (d, J = 7.5 Hz, 1 H), 6.67 (d, J = 12.0 Hz, 1 H), 4.20 (d, J = 13.2 Hz, 2 H), 3.92 (s, 3 H), 3.90 (d, J = 6.3 Hz, 2 H), 2.78 (t, J = 12.8 Hz, 2 H), 2.12–2.03 (m, 1 H), 1.92–1.82 (m, 2 H), 1.48 (s, 9 H), 1.37–1.29 (m, 2 H).
13C NMR (126 MHz, CDCl3): δ = 163.6 (d, J = 4.4 Hz), 161.8 (d, J = 260.9 Hz), 158.8 (d, J = 10.8 Hz), 154.8, 132.8, 118.1 (d, J = 3.3 Hz), 111.0 (d, J = 10.8 Hz), 101.6 (d, J = 24.9 Hz), 79.5, 73.8, 52.3 (d, J = 5.5 Hz), 43.5 (2 C), 35.9, 28.7 (2 C), 28.5 (3 C).
HRMS (ESI): m/z [M + Na]+ calcd for C19H25ClFNNaO5: 424.1297; found: 424.1303.
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Methyl 5-Cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)-benzoate–Methanesulfonic Acid Complex (3·MSA)
A 1000 mL glass flask was charged with toluene (441 mL), H2O (151 mL), 8 (63 g, 157 mmol), cyclopropylboronic acid (18.99 g, 221 mmol, 146 mol%), Xphos (0.75 g, 1.57 mmol, 1 mol%), and XPhos Pd G2 (1.23 g, 1.56 mmol, 1 mol%). After an inert atmosphere was created through full vacuum to N2 cycles (3×), K3PO4 (99.8 g, 470 mmol, 299 mol%) was added as solids in portions, and the mixture was subjected again to full vacuum to N2 cycles (3×), and then heated to 75 °C for 3 h (until HPLC showed ≤1.0A% 8). The biphasic mixture was cooled to 55 °C, silica gel (31.5 g) was added, and the mixture was stirred for 60 min at 55 °C. After filtration of the silica gel and rinsing with toluene (2 × 63 mL), the phases were separated at 40 °C. Activated carbon (3.15 g, Norit® CAP Super-WJ) was added at 55 °C and the mixture was stirred at this temperature for 60 min. Subsequently, the suspension was filtered and rinsed with toluene (2 × 63 mL). A solution of aq N-acetylcysteine (252 mL, 4 wt%, pH 9) was added and the mixture was stirred at 55 °C for 60 min. After phase separation, the organic phase was concentrated by distillation (7.5 mL/g) at 55 °C (100–300 mbar). After addition of MeOH (12.6 mL), MSA (15.1 g, 157 mmol, 100 mol%) was added over 30 min at 55 °C and the mixture was stirred for 3 h (IPC, conversion control with HPLC: ≤0.5A% 8). The suspension was cooled over 1 h to 20 °C and filtered, and the wet filter cake was washed with toluene (63 mL). The wet product was dried at 60 °C under vacuum for 12 h to give 3·MSA.
Yield: 53 g (85% yield); off-white solid; 98.6A% purity.
1H NMR (500 MHz, DMSO-d 6): δ = 8.79 (d, J = 9.3 Hz, 1 H), 8.55 (d, J = 12.1 Hz, 1 H), 7.33 (d, J = 8.2 Hz, 1 H), 6.98 (d, J = 13.0 Hz, 1 H), 4.01 (d, J = 5.8 Hz, 2 H), 3.80 (s, 2 H), 3.34 (d, J = 12.3 Hz, 2 H), 2.94 (q, J = 11.8 Hz, 2 H), 2.18–2.08 (m, 1 H), 2.03 (td, J = 8.5, 4.3 Hz, 1 H), 1.98–1.89 (m, 2 H), 1.62–1.50 (m, 2 H), 0.95–0.88 (m, 2 H), 0.64–0.57 (m, 2 H).
13C NMR (126 MHz, DMSO-d 6): δ = 164.29 (d, J = 3.71 Hz), 162.30 (d, J = 4.16 Hz), 161.32 (d, J = 270.34 Hz), 128.08 (d, J = 2.32 Hz), 127.89(d, J = 1.57 Hz), 109.49 (d, J = 9.92 Hz), 101.04 (d, J = 27.07 Hz), 72.47, 52.39 (d, J = 4.92 Hz), 43.24(2 C), 33.41, 25.55 (2 C), 9.39, 7.72 (2 C).
HRMS (ESI): m/z [M + Na]+ calcd for CHClFNNaO: 308.1656; found: 308.1648.
#
Methyl (S)-5-Cyclopropyl-4-({1-[1-(3,5-dichlorophenyl)ethyl]-piperidin-4-yl}methoxy)-2-fluorobenzoate–(1S)-(+)-10-Camphorsulfonic Acid Complex (13·CSA)
A 250 L reactor was charged with (R)-11 (4.1 kg, 21.5 mol), Ms2O (5.7 kg, 32.7 mol), and MIBK (18.1 kg); the mixture was stirred for 30 min at 20 °C until all solids dissolved, and then cooled to 2 °C. Et3N (3.6 kg, 35.6 mol) was added to the mixture, which was held at that temperature for 30 min. A solution of NH4Cl (6.3 kg) in H2O (35 kg) was added to the reaction mixture at <20 °C; the mixture was agitated for 10 min and then the aqueous layer was drained to waste. The same extraction was repeated with NH4Cl (6.3 kg) in H2O (35 kg), followed by two extractions with H2O (42 kg and 42 kg). A second 250 L reactor was charged with 3·HCl (7 kg, 20.3 mol), MIBK (24 kg), aq NaOH (3.4 kg of 28% aq NaOH in 22 kg H2O, 24.4 mol) and agitated for 20 min at 20 °C. The aqueous layer was drained to waste and the reaction mixture was extracted once more with H2O (14 kg). Due to emulsion formation, NaCl (0.5 kg) was added and the solution was stirred for 5 min. After phase separation and removal of the aqueous layer, the organic layer was then transferred to the first reactor. A third 250 L reactor was charged with aq K2CO3 (5.4 kg dissolved in 8 kg H2O, 38.6 mol), the reaction mixture from the first reactor, and MIBK (8 kg) and was heated to 70 °C and then held at this temperature for 12 h before being heated to 80 °C, and held at this temperature for another 7 h. The reaction mixture was cooled to 20 °C, H2O (7 kg) and MIBK (12 kg) were added, and the mixture was stirred for 10 min. The aqueous layer was drained to waste. The reaction mixture was then extracted two more times with H2O (21 kg and 21 kg). Then, the reactor was charged with MIBK (9 kg), a solution of (1S)-(+)-10-camphorsulfonic acid (4.74 kg, 20.3 mol) in MIBK (75 kg) and heated to 100 °C until all solids dissolved. The reaction mixture was then cooled to 20 °C over 14 h and filtered over a filter dryer, and the cake was washed with MIBK (32 kg). After no more filtrate could be collected from the filter, the cake was dried on the filter at ≤50 °C under vacuum (<19 mbar) for 16 h to give 13·CSA.
Yield: 13.1 kg (90% yield); off-white solid; 98.1A% purity by HPLC and 100A% chiral purity by HPLC.
1H NMR (400 MHz, DMSO-d 6): δ = 9.40 (s, 1 H), 7.75 (s, 1 H), 7.67 (s, 2 H), 7.32 (d, J = 8.3 Hz, 1 H), 6.96 (d, J = 13.0 Hz, 1 H), 4.57 (t, J = 6.4 Hz, 1 H), 3.98 (d, J = 5.8 Hz, 2 H), 3.79 (s, 3 H), 3.77–3.63 (m, 1 H), 2.88 (m, 3 H), 2.77–2.58 (m, 1 H), 2.40 (d, J = 14.7 Hz, 1 H), 2.24 (m, J = 18.1, 4.0 Hz, 1 H), 2.12–1.72 (m, 6 H), 1.74–1.45 (m, 5 H), 1.43–1.14 (m, 2 H), 1.05 (s, 3 H), 0.95–0.83 (m, 2 H), 0.75 (s, 3 H), 0.60 (d, J = 5.3 Hz, 2 H).
13C NMR (101 MHz, DMSO-d 6): δ = 216.71, 164.27 (d, J = 4.2 Hz), 162.23 (d, J = 10.4 Hz), 161.23 (d, J = 256.2 Hz), 138.94, 135.02, 129.77, 128.79, 128.09 (d, J = 3.3 Hz), 127.90, 109.58 (d, J = 9.6 Hz), 101.09 (d, J = 26.7 Hz), 72.29, 64.15, 58.69, 52.41, 50.63 (2 C), 49.24, 47.52, 47.20, 42.72, 42.61, 33.15 (2 C), 26.87, 26.26, 24.63, 20.60, 20.02 (2 C), 16.38, 9.39, 7.77 (2 C).
HRMS (ESI): m/z [M + H]+ calcd for C24H28Cl2FNO3: 480.1508; found: 480.1511.
#
(S)-5-Cyclopropyl-4-({1-[1-(3,5-dichlorophenyl)ethyl]piperidin-4-yl}methoxy)-2-fluorobenzoic Acid (1)
A 250 L reactor was charged with methyl (S)-13·CSA (12.9 kg, 18.1 mol), MIBK (62 kg), H2O (6.75 kg), and a solution of LiOH (0.87 kg, 19.9 mol) in H2O (42 kg) and the mixture was agitated for 10 min until all solids dissolved. The aqueous layer was drained to waste (IPC pH 14, by pH electrode measurement), and the organic layer was extracted one more time with H2O (32 kg). After phase separation, MIBK (10 kg) was added and the reaction mixture was distilled (52 °C internal temperature) under vacuum (50 mbar) until a volume of 13 L was obtained. The reactor was charged with THF (28 kg) and a solution of LiOH·H2O (1.44 kg, 34.4 mol) in H2O (18 kg) and heated for 17 h at 60 °C. H2O (55 kg) was added to the reaction mixture, which was distilled (<50 °C internal temperature) under vacuum (225 mbar) until a volume of 32 L was obtained. 2-Methyltetrahydrofuran (MeTHF, 50 kg) was added to the reaction mixture, which was then cooled to 20 °C, diluted with H2O (17 kg), and slowly acidified with 25% aq HCl (5.1 kg, 34.4 mol) to pH 4.3. The aqueous layer was drained to waste and the organic layer was extracted with a solution of NaCl (0.4 kg) in H2O (32 kg). The aqueous phase was drained to waste and MeTHF (15 kg) was added. The reaction mixture was distilled (<50 °C internal temperature) under vacuum (200 mbar) until a volume of 34 L was obtained. EtOAc (50 kg) was added and the reaction mixture was distilled (<50 °C internal temperature) under vacuum (150 mbar) while EtOAc (126 kg) was added continuously at a fixed volume. The reaction mixture was cooled to 22 °C over 120 min and stirred at this temperature for 16 h. The mixture was filtered through a filter dryer and the cake was washed with EtOAc (29 kg). After no more filtrate could be collected from the filter, the cake was dried in the filter dryer at 50 °C (jacket temperature) under vacuum (1 mbar) for 20 h to give 1.
Yield: 7.63 kg (90% yield); off-white solid; 98.9A% purity by HPLC.
1H NMR (400 MHz, methanol-d 4): δ = 7.45 (d, J = 8.2 Hz, 1 H), 6.78 (d, J = 12.6 Hz, 1 H), 4.49 (q, J = 6.9 Hz, 1 H), 4.01 (d, J = 5.5 Hz, 2 H), 3.77 (d, J = 12.2 Hz, 1 H), 3.42 (d, J = 12.8 Hz, 1 H), 3.11–2.82 (m, 2 H), 2.36–1.96 (m, 5 H), 1.96–1.70 (m, 5 H), 0.94 (dd, J = 8.5, 1.9 Hz, 2 H), 0.63 (dd, J = 6.2, 4.3 Hz, 2 H).
13C NMR (101 MHz, methanol-d 4): δ = 166.20, 162.09 (d, J = 10.1 Hz), 161.75 (d, J = 257.2 Hz), 138.63, 135.77 (2 C), 129.64, 128.26 (d, J = 2.6 Hz), 127.82 (d, J = 3.0 Hz), 127.48 (2 C), 110.13 (d, J = 9.7 Hz), 99.64 (d, J = 27.2 Hz), 71.31, 64.96, 50.54, 49.90, 33.41, 25.88 (2 C), 15.65, 8.65, 6.26, 6.21 (2 C).
HRMS (ESI): m/z [M + H]+ calcd for C24H26Cl2FNO3: 466.1352; found: 466.1360.
#
(S)-5-Cyclopropyl-4-({1-[1-(3,5-dichlorophenyl)ethyl]piperidin-4-yl}methoxy)-2-fluoro-N-(methylsulfonyl)benzamide (GDC-0310)
A 250 L reactor was charged with (S)-1 (7.3 kg, 13.4 mol), CDI (3.66 kg, 22.6 mol), and EtOAc (66 kg) and heated to 35 °C for 2 h. MsNH2 (2.29 kg, 20.1 mol) and K2CO3 (4.33 kg, 26.8 mol) were added and the reaction mixture was heated to 70 °C for 20 h. The reaction mixture was cooled to 20 °C and filtered through a polish filter into another reactor and the filter was washed with EtOAc (14 kg). EtOAc (46 kg) was added to the reaction mixture and the reactor contents were heated to 62 °C; then H2O (42 kg) and AcOH (5.5 kg) were added and the mixture was agitated for 10 min at 62 °C. The aqueous layer was drained to waste, and the organic layer was extracted once more with H2O (42 kg) at 62 °C. After phase separation, EtOAc (20 kg) was added to the reactor and the reaction mixture was distilled (<65 °C internal temperature, 650 mbar) until a volume of 9 L was obtained. The contents of the reactor were cooled to 22 °C over 2 h, held at that temperature for 10 h, cooled to 8 °C, aged at this temperature for 1 h, and filtered over a filter dryer; the cake was washed with EtOAc (27 kg). After no more filtrate could be collected from the filter, the cake was dried on the filter at 80 °C (jacket temperature) under vacuum (14–0 mbar) for 21 h to give GDC-0310.
Yield: 6.5 kg (76% yield); off-white solid; 99.7A% purity by HPLC and 99.8A% chiral purity by HPLC.
1H NMR (400 MHz, DMSO-d 6): δ = 11.23 (s, 1 H), 7.54 (s, 1 H), 7.44 (d, J = 2.1 Hz, 2 H), 7.16 (d, J = 8.4 Hz, 1 H), 6.87 (d, J = 12.8 Hz, 1 H), 3.92 (d, J = 5.7 Hz, 2 H), 3.82 (d, J = 7.1 Hz, 1 H), 3.19 (s, 3 H), 3.11 (d, J = 11.2 Hz, 1 H), 2.93 (d, J = 11.3 Hz, 1 H), 2.19 (q, J = 11.2 Hz, 2 H), 2.00 (m, J = 8.5, 4.4 Hz, 1 H), 1.89–1.69 (m, 3 H), 1.57–1.14 (m, 5 H), 0.87 (m, 2 H), 0.73–0.51 (m, 2 H).
13C NMR (101 MHz, DMSO-d 6): δ = 165.25, 161.11 (d, J = 10.1 Hz), 160.03 (d, J = 252.3 Hz), 134.48 (2 C), 127.58, 127.40 (d, J = 3.1 Hz), 127.16 (2 C), 127.03 (d, J = 3.4 Hz), 114.69, 100.55 (d, J = 26.6 Hz), 72.93, 63.17, 49.85, 49.68, 41.52, 35.14, 28.31 (2 C), 18.00, 9.39, 7.75 (2 C).
HRMS (ESI): m/z [M + H]+ calcd for C25H29Cl2FN2O4S: 543.1287; found: 543.1294.
#
#
Acknowledgment
The authors would like to thank the following Genentech colleagues: Chris Crittenden for high-resolution spectrometry results, Dr. Nathaniel Seagraves for NMR analysis, and Dr. Haiming Zhang and Dr. Lauren Sirois for helpful suggestions on the manuscript. Dr. Markus Stöckli and Dr. Roland Weixler (Dottikon Exclusive Synthesis) are thanked for technical support.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0040-1707859.
- Supporting Information
-
References
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- 5 Stumpf A, Cheng ZK, Beaudry D, Angelaud R, Gosselin F. Org. Process Res. Dev. 2019; 23: 1829
- 6a
Grillo M,
Li A.-R,
Liu J,
Medina JC,
Su Y,
Wang Y,
Jona J,
Allgeier A,
Milne J,
Murry J,
Payack JF,
Storz T.
International Patent No. WO200085277A1, 2009
- 6b Kromann JC, Jensen JH, Kruszyk M, Jessing M, Jorgensen M. Chem. Sci. 2018; 9: 660 ; Predict Regioselectivity of electrophilic aromatic substitution reactions in heteroaromatic systems; http://regiosqm.org/ (accessed June 4, 2020)
- 7 Addition of a trace amount of water has been shown to improve conversion in the bromination of alkenes using DBH in MeCN; see: Yin Q, You SL. Org. Lett. 2012; 14: 3526
- 8 A mechanism for the bromination of alkenes using DBH in water has been proposed, such that it is plausible that DBH reacts with water to form HBrO which is the active bromination species; see: Xu S, Wu P, Zhang W. Org. Biomol. Chem. 2016; 14: 11389
- 9 DBH was added in portions to avoid accumulation of the reagent in the reaction mixture
and subsequent increase in the amount of side products.
- 10a Beller M, Wu X.-F. Transition Metal Catalyzed Carbonylation Reactions: Carbonylative Activation. Springer; Heidelberg: 2013
- 10b Barnard CF. J. Organometallics 2008; 27: 5402
- 10c Martinelli JR, Watson DA, Freckmann DM. M, Barder TE, Buchwald SL. J. Org. Chem. 2008; 73: 7102
- 10d Natte K, Dumrath A, Neumann H, Beller M. Angew. Chem. Int. Ed. 2014; 53: 10090
- 10e Almeida AM, Andersen TL, Linhardt AT, Almeida MV, Skrydstrup T. J. Org. Chem. 2015; 80: 1920
- 11 Norit® CAP Super-WJ.
- 12 Kinzel T, Zhang Y, Buchwald SL. J. Am. Chem. Soc. 2010; 132: 14073
-
References
- 1a Wood JN, Boorman JP, Okuse K, Baker MD. J. Neurobiol. 2004; 61: 55
- 1b Gold MS, Gebhart GF. Nat. Rev. Med. 2010; 16: 1248
- 2a Emery EC, Luiz AP, Wood JN. Expert Opin. Ther. Targets 2016; 20: 975
- 2b Weiss MM, Dineen TA, Marx IE, Altmann S, Boezio A, Bregman H, Chu-Moyer M, DiMauro EF, Bojic EF, Foti RS, Gao H, Graceffa R, Gunaydin H, Guzman-Perez A, Huang H, Huang L, Jarosh M, Kornecook T, Kreiman CR, Ligutti J, La DS, Lin M.-HJ, Liu D, Moyer BD, Nguyen HN, Peterson EA, Rose PE, Taborn K, Youngblood BD, Yu V, Fremeau RT. J. Med. Chem. 2017; 60: 5969
- 2c Graceffa RF, Boezio AA, Able J, Altmann SM, Berry L, Boezio C, Butler JR, Chu-Moyer M, Cooke M, DiMauro EF, Dineen TA, Bojic EF, Foti RS, Fremeau RT, Guzman-Perez A, Gao H, Gunaydin H, Huang H, Huang L, Ilch C, Jarosh M, Kornecook T, Kreiman CR, La DS, Ligutti J, Milgram BC, Lin M.-HJ, Marx IE, Nguyen HN, Peterson EA, Rescourio G, Roberts J, Schenkel L, Shimanovich R, Sparling BA, Stellwagen J, Taborn K, Vaida KR, Wang J, Yeoman J, Yu V, Zhu D, Moyer BD, Weiss MM. J. Med. Chem. 2017; 60: 5990
- 2d McKerrall AJ, Nguyen T, Lai KW, Bergeron P, Deng L, DiPasquale A, Chang JH, Chen J, Chernov-Rogan T, Hackos DH, Maher J, Ortwine DF, Pang J, Payandeh J, Proctor WR, Shields SD, Vogt J, Ji P, Liu W, Ballini E, Schumann L, Tarozzo G, Bankar G, Chowdhury S, Hasan A, Johnson Jr JP, Khakh K, Lin S, Cohen CJ, Dehnhardt CM, Safina BS, Sutherlin DP. J. Med. Chem. 2019; 62: 4091
- 2e On Nav1.7 inhibitors for the treatment of chronic pain, see: McKerrall SJ, Sutherlin DP. Bioorg. Med. Chem. Lett. 2018; 28: 3141
- 2f Chernov-Rogan T, Li T, Lu G, Verschoof H, Khakh K, Jones SW, Beresini MH, Liu C, Ortwine DF, McKerrall SJ, Hackos DH, Sutherlin DP, Cohen CJ, Chen J. Proc. Natl. Acad. Sci. U.S.A. 2018; 115: E792
- 2g King GF, Vetter I. ACS Chem. Neurosci. 2014; 5: 749
- 2h Browne L, Lidster K, Al-Izki S, Clutterbuck L, Posada C, Chan AW. E, Riddall D, Garthwaite J, Baker D, Selwood DL. J. Med. Chem. 2014; 57: 2942
- 2i Swain NA, Batchelor D, Beaudoin S, Bechle BM, Bradley PA, Brown AD, Brown B, Butcher KJ, Butt RP, Chapman ML, Denton S, Ellis D, Galan SR. G, Gaulier SM, Greener BS, de Groot MJ, Glossop MS, Gurrell IK, Hannam JM. S, Lin Z, Markworth CJ, Marron BE, Millan DS, Nakagawa S, Pike A, Printzenhoff D, Rawson DJ, Ransley SJ, Reister SM, Sasaki K, Storer RI, Stupple PA, West CW. J. Med. Chem. 2017; 60: 7029
- 2j Bagal SK, Brown AD, Cox PJ, Omoto K, Owen RM, Pryde DC, Sidders B, Skerratt SE, Stevens EB, Storer RI, Swain NA. J. Med. Chem. 2013; 56: 593
- 2k Blass BE. ACS Med. Chem. Lett. 2018; 9: 161
- 2l Ali SR, Liu Z, Nenov MN, Folorunso O, Singh A, Scala F, Chen H, James TF, Alshammari M, Panova-Elektronova NI, White MA, Zhou J, Laezza F. ACS Chem. Neurosci. 2018; 9: 976
- 2m de Lera Ruiz M, Kraus RL. J. Med. Chem. 2015; 58: 7093
- 3a Gaskin DJ, Richard P. J. Pain 2012; 13: 715
- 3b https://injuryfacts.nsc.org/all-injuries/preventable-death-overview/odds-of-dying/ (accessed March 28, 2020).
- 4 Ouellet SG, Bernardi A, Angelaud R, O’Shea PD. Tetrahedron Lett. 2009; 50: 3776
- 5 Stumpf A, Cheng ZK, Beaudry D, Angelaud R, Gosselin F. Org. Process Res. Dev. 2019; 23: 1829
- 6a
Grillo M,
Li A.-R,
Liu J,
Medina JC,
Su Y,
Wang Y,
Jona J,
Allgeier A,
Milne J,
Murry J,
Payack JF,
Storz T.
International Patent No. WO200085277A1, 2009
- 6b Kromann JC, Jensen JH, Kruszyk M, Jessing M, Jorgensen M. Chem. Sci. 2018; 9: 660 ; Predict Regioselectivity of electrophilic aromatic substitution reactions in heteroaromatic systems; http://regiosqm.org/ (accessed June 4, 2020)
- 7 Addition of a trace amount of water has been shown to improve conversion in the bromination of alkenes using DBH in MeCN; see: Yin Q, You SL. Org. Lett. 2012; 14: 3526
- 8 A mechanism for the bromination of alkenes using DBH in water has been proposed, such that it is plausible that DBH reacts with water to form HBrO which is the active bromination species; see: Xu S, Wu P, Zhang W. Org. Biomol. Chem. 2016; 14: 11389
- 9 DBH was added in portions to avoid accumulation of the reagent in the reaction mixture
and subsequent increase in the amount of side products.
- 10a Beller M, Wu X.-F. Transition Metal Catalyzed Carbonylation Reactions: Carbonylative Activation. Springer; Heidelberg: 2013
- 10b Barnard CF. J. Organometallics 2008; 27: 5402
- 10c Martinelli JR, Watson DA, Freckmann DM. M, Barder TE, Buchwald SL. J. Org. Chem. 2008; 73: 7102
- 10d Natte K, Dumrath A, Neumann H, Beller M. Angew. Chem. Int. Ed. 2014; 53: 10090
- 10e Almeida AM, Andersen TL, Linhardt AT, Almeida MV, Skrydstrup T. J. Org. Chem. 2015; 80: 1920
- 11 Norit® CAP Super-WJ.
- 12 Kinzel T, Zhang Y, Buchwald SL. J. Am. Chem. Soc. 2010; 132: 14073
