Serotonin Receptor


Jan 10, 2013 - ABSTRACT: The evolution of a process for the preparation of a new heterocyclic dual NK1/serotonin receptor antagonist is described. The...
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Development of a Scalable Route to a Dual NK-1/Serotonin Receptor Antagonist Christina Risatti,* Kenneth J. Natalie, Jr.,* Zhongping Shi, and David A. Conlon Chemical Development, Research & Development, Bristol-Myers Squibb Co., One Squibb Drive, P.O. Box 191, New Brunswick, New Jersey 08903-0191, United States ABSTRACT: The evolution of a process for the preparation of a new heterocyclic dual NK1/serotonin receptor antagonist is described. The final synthesis features a telescoped sequence in which an iron(III)-catalyzed Grignard coupling is followed by a benzylic chlorination utilizing trichlorocyanuric acid to construct an unsymmetrical 2,4,6-trisubstituted pyridine. Etherification of a 4,4′-arylhydroxymethane substituted piperidine fragment completes the synthesis of the active pharmaceutical ingredient in 44% overall yield.



INTRODUCTION Substance P is a neuropeptide that functions as a neurotransmitter and a neuromodulator.1 The endogenous receptor for Substance P is the neurokinin 1 receptor (NK1-receptor).2 The binding of Substance P to the NK1 receptor has been associated with the transmission of pain, contraction of smooth muscles, and inflammation.3 NK1 receptor antagonists have been targeted for clinical development in the treatment of migraine and psychiatric disorders.4 Current treatments of psychiatric disorders utilize selective serotonin reuptake inhibitors (SSRI) which inhibit the reuptake of the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) into the presynaptic cell and, as a result, increase levels of 5-HT within the synaptic cleft.5 The combination of serotonin reuptake inhibition with the modulation of 5HT function via NK1 antagonism may lead to a new class of antidepressants with better efficacy.6 As part of a program to develop novel, dual-action therapeutic agents for the treatment of depression, 17 was identified as a development candidate. As part of the development process, a scaleable synthetic route for the preparation of 1 was needed. Key structural features of 1 include a piperidine ring with an aryl-substituted quaternary carbon connected via a methylene ether bridge to a 2,4,6trisubstituted pyridine. Initial Route.7 The initial approach to clinical candidate 1 (Scheme 1) was primarily designed to access a range of derivatives by functionalization of intermediates such as 5, 8, or 9. The initial synthesis constructed the piperidine ring of 5 via sequential alkylation of 4-fluorophenylacetonitrile (2) with protected 2,2′-dichlorodiethylamine (4).8 Hydrolysis with aqueous NaOH followed by borane reduction furnished alcohol 6. The preparation of pyridylbromide 8, from 2-chloro-6methyl-4-(trifluoromethyl)pyridine (7) using NBS in carbon tetrachloride was low yielding (33%) due to a product mixture consisting of desired 8, the geminal dibromide (25%), and unreacted 7. Subsequent coupling of benzylbromide 8 with piperidine alcohol 6 was also low yielding (25−50%) due to competitive nucleophilic aromatic substitution of the 2chloropyridine. Introduction of the cyclopropane moiety via Suzuki−Miyaura cross-coupling followed by Boc deprotection © 2013 American Chemical Society

and subsequent reductive amination with formaldehyde furnished active pharmaceutical ingredient (API) 1 as an oil. This route was used to prepare the first 100 g of 1 by the Discovery Chemical Synthesis. To deliver large quantities for toxicological evaluation, we sought a route with opportunities to avoid hazardous reagents, achieve high chemoselectivity, and intercept crystalline intermediates. The results of our development efforts are described below.



RESULTS AND DISCUSSION Chemical Development Strategy. Strategically, we sought to effect a late-stage coupling of fully functionalized pyridine 12 with piperidine 11, as shown in Scheme 2. In addition to being highly convergent, this approach was anticipated to afford a facile purification of the API, as the impurities would likely resemble starting materials rather than product. Incorporating the cyclopropane earlier in the sequence would eliminate competing nucleophilic aromatic substitution during the coupling which hindered the original approach. Preparation of the corresponding benzylic alcohol 12 would enable a more selective halogenation strategy since the existing hydroxyl group could be easily converted to a leaving group. The proposed starting material for preparation of 12, 2-chloro6-methyl-4-(trifluoromethyl)pyridine (7) is commercially available. We envisioned preparation of alcohol 11 by utilizing commercially available piperidine derivative 14. Preparation of Piperidine 11. An α-arylation approach was investigated to enable the rapid production of 11, Scheme 3. The optimized α-arylation sequence involved formation of lithium enolate 15 with lithium dicyclohexylamide followed by palladium-catalyzed coupling with 13 using tri-tert-butylphosphonium tetrafluoroborate as the ligand to give ester 16 (Scheme 3). This was then reduced with lithium aluminum hydride (LAH) to produce alcohol 6 in 77% chromatographic yield starting from 13.9,10 Alternatively, 16 could be directly hydrolyzed to crystalline acid 17 to facilitate isolation in 76−80% isolated yield. Received: November 8, 2012 Published: January 10, 2013 257

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Scheme 1. Initial route to NK-1/SERT API 1

Scheme 2. Retrosynthetic analysis: chemical development route

Scheme 3. α-Arylation approach to piperidine 11

Subsequent reduction of 17 was accomplished with BH3·DMS. Utilizing a biphasic system, the hydrolysis of the resulting trialkoxyborane to the desired alcohol with aqueous NaOH was slow, but was readily accomplished using ethanolic potassium hydroxide in hot water (70−75 °C) to afford alcohol 6 in 81% isolated yield.11 The N-Boc to N-methyl conversion was also accomplished by utilizing LAH. While workup with either citric acid or Rochelle’s salts produced emulsions and low yields, the

procedure described by Fieser12 provided filterable, granular aluminum salts. Using this protocol, 5 kg of 613 were successfully converted to 2.2 kg of 11 in seven batches in 78−82% yield and >99 LCAP14 purity. Preparation of Pyridine 12. The Boekelheide rearrangement15 is a valuable method for the conversion of 2-picoline derivatives to their corresponding hydroxy methyl analogues. We reasoned that the requisite benzyl alcohol 12 could arise from Boekelheide rearrangement of a suitably functionalized 258

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Scheme 4. Preparation of pyridine 12 via Boekelheide rearrangement

Scheme 5. Second Boekelheide approach to 12 and isolation as its BSA salt

pyridine N-oxide, Scheme 4. Oxidation of pyridine 7 with mCPBA provided N-oxide 18. The crude reaction mixture was treated with trifluoroacetic anhydride to give the desired rearranged product, benzyltrifluoroacetate 20. A competing SNAr reaction lead to moderate levels of 2-trifluoroacetoxypyridone 19 (2.3:1 mixture of 20:19 by 1H NMR). Methanolysis of the mixture afforded the desired benzylic alcohol 22, along with pyridone 21 derived from impurity 19. Fortunately, pyridone 21 was effectively removed from the product-rich organic stream via an aqueous sodium bicarbonate wash. Subsequent Suzuki−Miyaura coupling of 22 with cyclopropylboronic acid provided 12. The complications arising from the competing reactivity of the 2-chloro substituent in the Boekelheide rearrangement prompted a modified approach involving the installation of the 2-cyclopropyl substituent prior to rearrangement, Scheme 5. We were concerned by the possibility of potential cyclopropane fragmentation or competitive rearrangement to generate a tertiary alcohol, as this cyclopropane reactivity had been previously reported.16 In fact, there are only a few examples of Boekelheide rearrangements in which 2,6-dialkylsubstituted pyridine N-oxides have been utilized as substrates.17 Despite

the limited literature precedent we were intrigued by the brevity of the approach and the potential advantages that would accrue. Catalytic iron(III)-mediated coupling of cyclopropyl magnesium bromide with 7 in THF/NMP was shown to be an efficient method to synthesize 23.18−20 Following reaction completion,21 crude 23 was oxidized directly to prepare Noxide 24. We were pleased to find that oxidation of 23 was faster (18 h), required fewer equivalents of m-CPBA (1.5 equiv), and could be conducted at lower temperature (23 °C) as compared to electron-deficient pyridine 7 (Scheme 4). Residual m-chlorobenzoic acid and m-CPBA were removed by stirring with aqueous sodium carbonate and subsequent crystallization from n-heptane. The desired 2-cyclopropyl-6methyl-4-(trifluoromethyl)pyridine-N-oxide 24 was produced in 79% yield and good purity (95 LCAP). Exposure of 24 to TFAA induced rearrangement with remarkable selectivity for the methyl position with no trace of cyclopropane fragmentation or tertiary alcohol detected. However, N-oxide 24 was identified as a thermal hazard;22 therefore, a telescoped process was developed to avoid its isolation. Following oxidation with m-CPBA, the process stream was taken directly into the Boekelheide rearrangement. 259

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Scheme 6. Coupling of fully elaborated pyridine 25 with piperidine 11

charge of HCl at 50 °C. This telescoped process from 12·BSA afforded 1·HCl in 55% yield and excellent purity (99.6 LCAP). Final Process. The successful use of benzyl chloride 25 in the potassium tert-amylate-mediated coupling reaction with 11 to prepare 1 prompted us to explore an expedited approach to 25. Direct conversion of N-oxide 24 to the benzylic chloride 25 failed;24 the reactions were low yielding and produced numerous byproducts.25 We had been apprehensive toward benzylic halogenation as it had been previously shown that a mixture of products was formed during the bromination (Scheme 1); however, upon treatment with trichlorocyanuric acid (TCCA), pyridine 23 was converted to the requisite benzyl chloride 25 with minimal byproduct formation (Scheme 7).26 The heterogeneous reaction stalled at 93% completion but could be reinitiated by filtration to remove the byproduct, dichlorocyanuric acid, followed by a second charge of TCCA. The resulting benzyl chloride 25 was isolated as its ptoluenesulfonic acid (p-TSA) salt which completely purged other components from the reaction mixture including a dichloro impurity (5% LCAP) and residual starting material 23. Ultimately, the p-toluenesulfonic acid salt of 25 was prepared from 7 in 68% yield, utilizing only two synthetic transformations as compared to 54% overall yield for the four steps required in the Boekelheide approach. Etherification of the potassium alkoxide of 11 with the free base 25 was followed by conversion to the crystalline HCl salt of 1, which was isolated in 61−65% yield. Conclusions. A highly efficient route to 1·HCl that is amenable for multikilogram synthesis was developed. The highlights of the synthesis include a selective formation of the 2,4,6-trisubstituted pyridine coupling partner through an ironcatalyzed coupling, followed by chlorination with TCCA. Furthermore, the strategy to couple fully functionalized piperidine and pyridine fragments was highly convergent, avoided handling of noncrystalline intermediates, and required no chromatographic purifications.

An optimized workup protocol for the N-oxide process was developed in which the product-rich methylene chloride stream from the oxidation was quenched with an aqueous sodium thiosulfate solution followed by a sodium carbonate wash and a half-saturated brine wash. The solution was then concentrated by distillation23 and treated directly with TFAA to effect the rearrangement which provided, after methanolysis, 2-cyclopropyl-6-hydroxymethyl-4-(trifluoromethyl)pyridine (12) as an oil. A crystallization screening study revealed that 12 could be isolated as its benzenesulfonic acid salt 12·BSA. On scale this provided an excellent cleanup and high-quality material in 73% yield and >99% LCAP. Coupling. With pyridine 12·BSA and piperidine 11 in hand, a telescoped process was designed for the coupling to produce 1. Examination of activated derivatives of 12 including the corresponding sulfonates or ammonium salts with nucleophilic partner 11 gave, in addition to the desired 1, multiple byproducts arising from competing pathways. The corresponding chloride 25, readily prepared from 12 with thionyl chloride, was found to be an ideal electrophilic partner in the coupling with 11 to give 1 (Scheme 6). In preparation for the coupling, the free base 12 was obtained by partitioning of 12·BSA into aqueous sodium hydroxide and 2-methyltetrahydrofuran (2-MeTHF); subsequent azeotropic drying of the product-rich 2-MeTHF stream and treatment with thionyl chloride cleanly produced a solution of chloride 25 (Scheme 6). Following a wash with aqueous potassium phosphate (K3PO4) and azeotropic drying, the rich organic stream was directly carried into the coupling reaction. Coupling with 11 was promoted by potassium tert-amylate at room temperature. Minor impurities in the reaction mixture which were identified included pyridine dimer 27 and ether 26 (Figure 1). Fortunately, undesired alkylation at the piperidine



EXPERIMENTAL SECTION General. All reactions were performed under a nitrogen atmosphere using anhydrous techniques unless otherwise noted. Reagents were used as received, unless otherwise noted. Quoted yields are for isolated materials or calculated solution yields and have not been corrected for potency. NMR spectra were recorded on Bruker DRX-600 or DRX-500 instruments and are referenced to residual undeuterated solvent. The following abbreviations are used to explain multiplicities: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. High-resolution mass spectra (HRMS) were recorded on a Thermo Orbi-trap Discovery instrument. Preparation of 1-(tert-Butoxycarbonyl)-4-(4fluorophenyl)piperidine-4-carboxylic Acid 17. A solution of 2.5 M n-BuLi (21.2 mL, 53 mmol) was slowly added to a mixture of dicyclohexylamine (11.2 mL, 56.2 mmol) and 70 mL

Figure 1. Byproducts identified in coupling.

nitrogen was not a competitive reaction at room temperature as the resulting bis-alkylation product was only observed at elevated temperatures. Ultimately, the HCl salt of 1 could be isolated as a crystalline solid following aqueous work-up, azeotropic drying, polish filtration, and addition of anhydrous HCl in isopropanol. Throughout the course of our investigations, only two polymorphic forms of 1·HCl were detected. The desired polymorph was obtained reproducibly by seeding after a partial 260

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Scheme 7. Final process for preparation of 1·HCl

additional 2 h and then cooled to 10 °C for 30 min. The solid was collected by filtration and washing with 30 mL 1:8 MTBE− n-heptane. The wet cake was dried under vacuum at 55 °C for 1 d to give 3.88 g (81%, 99.5 LCAP) of 6. 1H NMR (CDCl3, 400 MHz) δ 7.29 (dd, 2H, J = 8.8, 5.2 Hz), 7.06 (t, 2H, J = 8.8 Hz), 3.72 (m, 2H), 3.2 (d, 2H, J = 6.3 Hz), 3.03 (m, 2H), 2.11 (m, 2H), 1.76 (ddd, 2H, J = 14.1, 10.3, 3.9 Hz), 1.42 (s, 9H), 1.31 (t, OH, J = 6.3 Hz). 13C NMR (CDCl3, 100 MHz) δ 161.6 (d, J = 246.0 Hz), 155.0, 137.8 (d, J = 3.1 Hz), 128.9 (d, 2C, J = 7.7 Hz), 115.7 (d, 2C, J = 21.5 Hz), 79.5, 71.9, 42.3 (2C), 40.1 (br d, J = 59.2 Hz), 31.8 (2C), 28.5 (3C). Elemental Analysis: Calcd for C17H24FNO3: C, 65.99; H, 7.81; N, 4.52; F, 6.14. Found: C, 65.99; H, 8.01; N, 4.58; F, 6.12. Preparation of (4-(4-Fluorophenyl)-1-methylpiperidin-4-yl)methanol 11. LAH/THF (1 M, 161.6 mL, 161.6 mmol) was added to a solution of 6 (25 g, 80.8 mmol) in THF (250 mL) at −5 to 0 °C. The mixture was slowly warmed to 20 °C, held at 20 °C for 30 min and then slowly heated to 60 °C and held at 60 °C overnight. Upon reaction completion as determined by HPLC evaluation of a worked-up aliquot, the reaction mixture was cooled to rt and then further cooled to 4 °C. Water (6.13 mL) was charged, and after 10 min the reaction mixture was treated sequentially with a solution of NaOH (15%, 6.13 mL) and then water (3 × 6.1 mL). The resulting mixture was allowed to stir at rt for 2 h and was then filtered to remove inorganic solids. The filtrate was concentrated, redissolved in methylene chloride (500 mL), and washed sequentially with water (150 mL) and brine (150 mL). The resulting rich methylene chloride stream was dried with Na2SO4, filtered, and concentrated to an oil. Trituration with methylene chloride (24 mL) overnight was followed by filtration. The cake was washed with methylene chloride (16 mL) and then dried in the vacuum oven to give 14 g (78%, 99.2 LCAP) of 11. 1H NMR (400 MHz, CDCl3) δ 7.28 (dd, 2 H, J = 8.8, 5.5 Hz), 7.02 (t, 2H, J = 8.8 Hz), 3.48 (d, 2H, J = 4.9 Hz), 2.45−2.55 (m, 2H), 2.38 (br s, 1 H), 2.13 (s, 3H), 2.05− 2.18 (m, 4H), 1.80−1.90 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 161.3 (d, J = 245.2), 139.1, 129.0 (d, 2C, J = 6.9), 115.4 (d, 2C, J = 20.7), 71.8, 51.8 (2C), 46.2, 41.4, 32.1 (2C). Elemental Analysis: Calcd for C13H18FNO: C, 69.92; H, 8.12; N, 6.27; F, 8.50. Found: C, 69.43; H, 8.18; N, 6.29; F, 8.08. Preparation of 2-Cyclopropyl-6-methyl-4(trifluoromethyl)pyridine 5. 2-Chloro-6-methyl-4-trifluoromethyl pyridine (40 g, 204.5 mmol) and iron tris-

toluene at −17 to −7 °C. After 15 min at −7 to −11 °C, a solution of ethyl N-Boc-piperidine-4-carboxylate (12.8 g) in 68 mL toluene was slowly added at −11 to −5 °C over ∼20 min. The mixture was then warmed to rt. p-Bromofluorobenzene (5.2 mL, 8.4 g) was added, followed by Pd2dba3-CHCl3 (0.46 g) and tri-tert-butylphosphonium tetrafluoroborate (0.62 g) at 20−30 °C. After stirring at 25 °C for 2 h, the mixture was treated with 120 mL n-heptane and 120 mL water. The organic layer was separated, washed with 15% citric acid twice (2 × 90 mL), and filtered on Celite which was then rinsed with toluene (25 mL). The organic layer was concentrated to 30 g. The mixture was treated with ethanol (70 mL) and 1 N NaOH (170 mL) at 75 °C for 16 h. The reaction mixture was treated with 80 mL n-heptane and filtered on Celite to remove black insoluble material. The aqueous layer was separated and washed with 2 × 70 mL 1:1 heptane−toluene. The aqueous solution was concentrated to 184 g and treated with 85 g 40% citric acid aqueous solution. The mixture was stirred at rt for 2 h to give a slurry. The solid was collected by filtration. The wet cake was washed with water (100 mL) followed by 20% ethyl acetate−n-heptane (80 mL). Drying the wet cake gave 12.2 g (76%, 98.4 LCAP) desired 17. 1H NMR (CDCl3, 400 MHz) δ 9.78 (br s, 1H), 7.35 (dd, 2H, J = 8.8, 5.2 Hz), 7.02 (t, 2H, J = 8.8 Hz), 3.89 (m, 2H), 3.05 (m, 2H), 2.46 (br d, 2H, J = 13.2 Hz), 1.42 (s, 9H). 13C NMR (CDCl3, 100 MHz) δ 179.4, 162.1 (d, J = 246.8 Hz), 155.0, 137.4 (d, J = 3.1 Hz), 127.8 (d, 2C, J = 7.7 Hz), 115.6 (d, 2C, J = 21.6 Hz), 80.0, 48.7 (2C), 41.4, 33.5 (2C), 28.5 (3C). Elemental Analysis: Calcd for C17H22FNO4: C, 63.14; H, 6.85; N, 4.33; F, 5.87. Found: C, 62.76; H, 6.94; N, 4.31; F, 5.98. Preparation of tert-Butyl 4-(4-Fluorophenyl)-4(hydroxymethyl)piperidine-1-carboxylate 6. BH3.SMe2 in DCM (1 M, 19.1 mL) was added to a solution of 5.1 g 17 in 21 mL THF at rt. After 1 h, the mixture was heated to 45 °C for 6 h. The mixture was cooled to rt and quenched with 1 mL 2 N KOH/water and stirred for 15 min. Cyclopentyl methyl ether (CPME) (20 mL) and 2 N KOH (14 mL) were added to the mixture which was stirred for 15 min. The organic layer was separated, washed with saturated brine (2 × 20 mL), and then filtered on Celite. The Celite was rinsed with CPME (10 mL). The filtrate was concentrated to 5.1 g which was then treated with 4 mL CPME and 20 mL n-heptane. Seeds of 6 were added to the mixture which was stirred at rt for 2 h. Additional nheptane (20 mL) was added, and the mixture was stirred for 261

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ature between 40 and 45 °C. The resulting slurry was held at this temperature for 1 h and then cooled to 20 °C. The slurry was held at this temperature overnight. The crystals were collected via filtration and washed with 50 mL of ethyl acetate. The cake was deliquored for 1 h and then dried under vacuum at 45−50 °C overnight to yield 45.5 g (59.2% for the five-step telescope from 2-chloro-6-methyl-4-(trifluoromethyl)pyridine 7): 1H NMR (400 MHz, d6-DMSO) δ 10.15 (br s, 2H), 7.67− 7.62 (m, 2H), 7.60 (s, 1H), 7.59 (s, 1H), 7.37−7.32 (m, 3H), 4.63 (s, 2H), 2.36−2.29 (m, 2H), 1.12−1.02 (m, 4H). 13C NMR (101 MHz, d6-DMSO) δ 162.4, 161.9, 146.8, 137.7 (q, J = 33 Hz), 128.1, 127.1, 124.8, 123.0 (q, J = 273 Hz), 114.7− 114.5.4 (m), 112.4−112.2(m), 63.0, 16.5, 11.2. HRMS (ESI): Calcd for C10H11F3NO (M+ + 1): 218.0787. Found: 218.07819. Preparation of 2-Chloromethyl-6-cyclopropyl-4(trifluoromethyl)pyridine p-Toluenesulfonic Acid Salt 25. 2-Cyclopropyl-6-methyl-4-(trifluoromethyl)pyridine 23 (71 g, 352.9 mmol), N,N-dimethylformamide (2.6 g, 2.8 mL, 35.3 mmol, 0.1 mol equiv), and dichloromethane (426 mL) were charged to a 1-L three-necked Morton flask fitted with a nitrogen inlet/outlet and an overhead stirrer. Then trichloroisocyanuric acid (93.0 g, 388.2 mmol, 1.1 mol equiv) was charged to the flask in portions over a 0.5 h period. Caution: This reagent, although not a respiratory dust hazard, has a pungent odor and should be handled in a hood. On scale a full-faced respirator should be used. The reaction mixture was warmed to reflux and held at this temperature for 24 h after which time HPLC analysis indicated that about 7 RAP of unreacted starting material remained. The reaction was heterogeneous throughout. The dichlorocyanuric acid byproduct was removed via filtration and the cake washed with 100 mL of methylene chloride. The filtrate and wash were charged back into the Morton flask and the volume was adjusted to about 500 mL. Then trichloroisocyanuric acid (10 g, 0.043 mol) was charged to the flask. The slurry was warmed to reflux and held overnight. HPLC analysis indicated that about 2 RAP of unreacted starting material remained with about 5 RAP of the bis-chloro impurity. The resulting thin slurry was filtered and the clear filtrate charged back into the reactor. Then 300 mL of saturated aqueous sodium bisulfate was charged to the reactor and the biphasic mixture agitated for 15 min. The apparent pH of the reaction mixture was 6. The biphasic stream was filtered through a Celite pad, and the layers were allowed to separate. The lower, rich organic stream was drawn off for further processing. The upper, spent aqueous stream was discarded. The methylene chloride stream was washed with 200 mL of half-saturated brine. The methylene chloride stream was solvent exchanged into isopropyl acetate, the volume was adjusted to 300 mL and charged to a 1-L reactor fitted with an overhead stirrer. In a separate reactor 67 g (0.353 mol, 1 mol equiv) of ptoluenesulfonic acid monohydrate was dissolved in 250 mL of isopropyl acetate, and this was charged to the free base solution in the 1-L reactor. The resulting slurry was stirred overnight at rt. The crystals were collected via filtration and washed with 100 mL of cold (0−5 °C) isopropyl acetate. The cake was deliquored for 1 h and then dried under vacuum at 50 °C to yield 111.5 g (74.0%) of a white crystalline solid. The salt formation step completely removed the bis-chloro impurity: 1H NMR (400 MHz, d6-DMSO) δ 7.69−7.60 (m, 4H), 7.39−7.33 (m, 3H), 4.67 (s, 2H), 2.39−2.31 (m, 1H), 1.16−1.05 (m, 4H), 13 C NMR (101 MHz, d6-DMSO) δ 163.4, 162.6, 147.5, 139.03 (q, J = 33 Hz), 129.0, 127.9, 125.6, 123.0 (q, J = 273 Hz), 115.6−115.4 (m), 113.4−113.2(m), 62.9 16.2, 11.2. HRMS

(acetylacetonate) (723 mg, 2.045 mmol, 0.01 mol equiv) were charged to a 1-L Morton flask fitted with an overhead stirrer and a nitrogen inlet/outlet. Then THF (600 mL) and Nmethylpyrrolidinone (64 mL) were charged to the flask, and the resulting slurry was cooled to −5 to 0 °C. To this was added 532 mL of a 0.5 M solution of cyclopropylmagnesium bromide (38.6 g, 265.9 mol, 1.3 mol equiv) over a 17 min period, maintaining the temperature below 12 °C with active cooling. The maximum temperature was 10 °C. After the addition was complete, the reaction mixture was warmed to 20 °C and held at this temperature for 0.5 h after which time HPLC analysis indicated that less than 1 rel. area % (RAP) of the starting material remained. The reaction mixture was cooled to −5 to 0 °C, and 400 mL of half-saturated ammonium chloride was charged over a 2 min period. There was a 15 °C exotherm during the addition. The biphasic mixture was warmed to 20 °C, and 50 mL of heptane was added to facilitate the phase split. Agitation was stopped, and the layers were allowed to separate. The upper, rich organic layer was concentrated under reduced pressure to a volume of about 100 mL with the bath temperature not exceeding 35 °C. The crude organic stream was polish filtered through silica gel and taken directly into the next reaction without further purification: 1H NMR (400 MHz, CDCl3) δ 7.09 (s, 1H), 7.08 (s, 1H), 2.53 (s, 3H), 2.03−2.10 (m, 1H), 1.08−0.98 (m, 4H). 13C NMR (101 MHz, d6-DMSO) δ 163.2, 158.6, 137.8 (q, J = 33 Hz), 122.8 (q, J = 271 Hz), 114.9 (q, J = 3 Hz), 113.2(q, J = 4 Hz), 24.9, 17.8, 10.7. Preparation of 2-Hydroxymethyl-6-cyclopropyl-4(trifluoromethyl)pyridine Benzenesulfonic Acid Salt 12. To 800 mL of a methylene chloride stream containing 2cyclopropyl-6-methyl-4(-trifluoromethyl)pyridine (40.0 g, 0.199 mol) was added m-CPBA (58.0 g, 0.238 mol based on a measured potency of 71%, 1.2 mol equiv), and the resulting solution was stirred at room temperature for 5 h after which time HPLC analysis indicated complete reaction. Then 400 mL of a 5 wt % solution of sodium thiosulfate was charged to the reaction mixture, and it was stirred for 15 min. Agitation was stopped, and the layers were allowed to separate. The lower, rich organic stream was drawn off for further processing. To the separated organic stream, 400 mL of saturated aqueous sodium carbonate was added, and the biphasic mixture was stirred until the m-chlorobenzoic acid was completely removed. The rich organic stream was washed with 400 mL of half-saturated brine. The methylene chloride solution was concentrated via rotoevaporation to a volume of 150 mL. Caution: The Noxide is thermally unstable, and the distillation was performed under vacuum to a concentration of ∼4 mL/g. The KF went from 0.12% to