pubs.acs.org/joc
A Practical Synthesis of Renin Inhibitor MK-1597 (ACT-178882) via Catalytic Enantioselective Hydrogenation and Epimerization of Piperidine Intermediate Carmela Molinaro,*,† Scott Shultz,‡ Amelie Roy,† Stephen Lau,† Thao Trinh,† Remy Angelaud,† Paul D. O’Shea,† Stefan Abele,§ Mark Cameron,‡ Ed Corley,‡ Jacques-Alexis Funel,§ Dietrich Steinhuebel,‡ Mark Weisel,‡ and Shane Krska‡ †
Department of Process Research, Merck, 16711 Autoroute Transcanadienne, Kirkland, Qu ebec, Canada H9H 3L1, ‡Department of Process Research, Merck, P.O. Box 2000, Rahway, New Jersey 07065, United States, and §Department of Process Research Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, 4123 Allschwil, Switzerland
[email protected] Received October 19, 2010
A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treatment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester, a highly efficient epimerization/saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2.
Introduction The renin-angiotensin aldosterone system (RAAS),1 is known to play a key role in the regulation of blood pressure through several seminal studies culminating with the discovery (1) (a) MacGregor, G. A.; Markandu, N. D.; Roulston, J. E.; Jones, J. C.; Morton, J. J. Nature 1981, 291, 329. (b) Weber, M. A. Am. J. Hypertens. 1999, 12, 189S. (c) Weir, M. R.; Dzau, V. J. Am. J. Hypertens. 1999, 12, 205S. (d) Brewster, U. C.; Perazella, M. A. Am. J. Med. 2004, 116, 263. (e) Chen, A.; Bayly, C.; Bezenc- on, O.; Richard-Bildstein, S.; Dube, D.; Dube, L.; Gagne, S.; Gallant, M.; Gaudreault, M.; Grimm, E.; Houle, R.; Lacombe, L.; Laliberte, S.; Levesque, J.-F.; Liu, S.; MacDonald, D.; Mackay, B.; Martin, D.; McKay, D.; Powell, D.; Reme n, L.; Soisson, S.; Toulmond, S. Bioorg. Med. Chem. Lett. 2010, 20, 2204.
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of the angiotensin converting enzyme (ACE) inhibitors2 and angiotensin II receptor blockers (ARBs).3 Several antagonists of the RAAS pathway have emerged as effective treatments for hypertension.4 A collaboration between Actelion5 and our discovery efforts at Merck1e identified MK-15976 as a potent, selective inhibitor of the renin receptor and a promising lead in (2) (a) Patchett, A. A.; Cordes, E. H. Adv. Enzymol. Relat. Areas Mol. Biol. 1985, 57, 1. (b) Fyhrquist, F. Drugs 1986, 32 (Suppl. 5), 33. (3) (a) Ruilope, L. M.; Rosei, E. A.; Bakris, G. L.; Mancia, G.; Poulter, N. R.; Taddei, S.; Unger, T.; Volpe, M.; Waeber, B.; Zanna, F. Blood Pressure 2005, 14, 196. (b) Oparil, S.; Yarows, S. A.; Patel, S.; Fang, H.; Zhang, J.; Satlin, A. Lancet 2007, 370, 221.
Published on Web 01/20/2011
DOI: 10.1021/jo102070e r 2011 American Chemical Society
JOC Article
Molinaro et al. SCHEME 1.
Retrosynthetic Approach to Renin Inhibitor MK-1597 (1)
the treatment of hypertension. In order to support the development of this compound, we sought to develop a scalable synthesis of MK-1597. We describe herein a practical, chromatography-free, enantioselective synthesis of MK-1597 that has been performed on multikilogram scale. Our retrosynthetic analysis of MK-1597 is shown in Scheme 1. We envisioned that MK-1597 could be assembled by a coupling between piperidine carboxylic acid 3 and cyclopropylamine fragment 2. The two stereocenters of carboxylic acid 3 could be installed via a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester 4 followed by an epimerization/saponification sequence. Ene-ester 4 in turn can be prepared from commercially available ethyl 4-oxopiperidine-3-carboxylate (8), 2,5-dibromopyridine (9) and p-cresol (7). Results/Discussion Preparation of Amine Side Chain 2. Amine 2 was prepared in five steps from cheap and readily available 5-bromo-2chlorobenzoic acid (5) (Scheme 2). The synthesis started with a Bouveault reaction.7 Thus, bromide 5 was converted to aldehyde 10 in 65% yield via Knochel’s magnesium-halogen (4) (a) Kasani, A.; Subedi, R.; Stier, M.; Holsworth, D. D.; Maiti, S. N. Heterocycles 2007, 73, 47. (b) Fisher, N. D. L.; Hollenberg, N. K. J. Am. Soc. Nephrol. 2005, 16, 592. (c) Amin Zaman, M.; Oparil, S.; Calhoun, D. A. Nat. Rev. Drug. Discovery 2002, 1, 621. (d) Rahuel, J.; Rasetti, V.; Maibaum, J.; Rueger, H.; Goschke, R.; Cohen, N.-C.; Stutz, S.; Cumin, F.; Fuhrer, W.; Wood, J. M.; Gruetter, M. G. Chem. Biol. 2000, 7, 493. (e) Wood, J. M.; Stanton, J. L.; Hofbauer, K. G. J. Enzyme Inhib. 1987, 1, 169. (f) Rahuel, J.; Priestle, J. P.; Gruetter, M. G. J. Struct. Biol. 1991, 107, 227. (5) (a) Corminboeuf, O.; Bezenc-on, O.; Grisostomi, C.; Reme n, L.; Richard-Bildstein, S.; Bur, D.; Prade, L.; Hess, P.; Strickner, P.; Fischli, W.; Steiner, B.; Treiber, A. Bioorg. Med. Chem. Lett. 2010, 20, 6286. (b) Corminboeuf, O.; Bezenc-on, O.; Reme n, L.; Grisostomi, C.; RichardBildstein, S.; Bur, D.; Prade, L.; Strickner, P.; Hess, P.; Fischli, W.; Steiner, B.; Treiber, A. Bioorg. Med. Chem. Lett. 2010, 20, 6291. (6) Also known as ACT-178882. (7) (a) Bouveault, L. Bull. Soc. Chim. Fr. 1904, 31, 1306. (b) Bouveault, L. Bull. Soc. Chim. Fr. 1904, 31, 13C22. (8) (a) Boymond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed. 1998, 37, 1701. (b) Abarbri, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett. 1999, 40, 7449. (c) Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Vu, V. A.; Knochel, P. Synthesis 2002, 4, 565. (d) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302.
SCHEME 2.
Synthesis of Amine Side Chain 2a
a Conditions: (a) 1. iPrMgCl, THF, -30 °C, 80%; 2. DMF, 0 °C; 3. HCl, 80%. (b) NaH, MeOCH2PPh3, THF, 50 °C, 86%. (c) H2 (45 psi), Pd(OH)2/C, EtOAc, 96%. (d) 1. CDI, CH3CN; 2. cyclopropylamine, 30 °C, 86%. (e) NaBH4, BF3 3 THF, 36 °C, 99%.
exchange protocol8 followed by a DMF quench. Aldehyde 10 was subsequently reacted with NaH and MeOCH2PPh3 to furnish a 1:1 mixture of E- and Z-vinyl methyl ethers 11.9 The mixture of olefins was submitted to hydrogenation conditions using Pearlman’s catalyst, providing carboxylic acid 12 in 96% yield and 94 A%.10,11 CDI-mediated coupling of carboxylic acid 12 with cyclopropylamine in CH3CN afforded amide 13 in 86% yield. In order to meet the purity criteria for amine 2 (>95 A%), a recrystallization of amide 13 using hot iPAc/hexanes was performed resulting in an 83% recovery and a purity upgrade from 95 A% to 98 A%. Finally, a largescale BH3 3 THF reduction12 at 36 °C afforded 4.54 kg of crude amine 2 in 99% assay yield and 96 A%. (9) (a) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635. (b) Coffman, D. D.; Marvel, C. S. J. Am. Chem. Soc. 1929, 51, 3496. (c) Wittig, G.; Geissler, G. Ann. 1953, 580, 44. (d) Wittig, G.; Schollkopf, U. Chem. Ber. 1954, 97, 1318. (e) Wittig, G.; Haag, W. Chem. Ber. 1955, 88, 1654. (f) Horner, L.; Hoffmann, H. M. R.; Wippel, H. G. Ber. 1958, 91, 61. (g) Horner, L.; Hoffmann, H. M. R.; Wippel, H. G.; Klahre, G. Ber. 1959, 92, 2499. (h) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733. (10) A% = HPLC area percent monitored at 220 nm. (11) Other Pt- and Rh-based metals were also tested; however, much lower reactivities and/or purity profiles were observed. (12) For the large-scale in situ preparation of BH3 3 THF see: Kanth, J. V. B.; Brown, H. C. Inorg. Chem. 2000, 39, 1795 and references therein.
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JOC Article SCHEME 3.
Synthesis of Hydrogenation Precursor 4aa
a
Conditions: (a) NaOCl, CH3CN, 89%. (b) 1. Ethylene carbonate, 1-methylimidazole, DMAc 110 °C; 2. KOH, dibromopyridine, 77%. (c) Bis(pinacolato)diboron, PdCl2(dppf), KOAc, DMAc, 80 °C, 71%. (d) Pd(PPh3)4, Na2CO3, water, DME, 50 °C, 99%.
Preparation of Hydrogenation Precursor 4a. Ene-ester 4a was prepared in 49% yield and four steps starting from pcresol (7) (Scheme 3). Dichlorination of p-cresol (7) using commercial bleach cleanly provided 14 in 89% yield. Alkylation of phenol 14 with ethylene carbonate followed by SNAr reaction on dibromopyridine 9 provided pyridine bromide 15. Aryl boronate 16 was prepared using bis(pinacolato)diboron and a palladium catalyst (PdCl2(dppf)) in 71% yield.13 Finally, Suzuki coupling between the aryl boronate 16 and the Boc-protected piperidine triflate 17a14 provided 99% yield of the tetrasubstituted ene-ester 4a. Asymmetric Hydrogenation. During the course of development we screened the tetrasubstituted ene-ester 4a under microscale hydrogenation conditions15 using H2 (500 psi), a metal precursor and ligand (1: 1.05 ratio) in a solvent at 50 °C for 18 h, as a first pass approach.16 Ru-, Ir-, and Rh-based metal precursors were tested using over 384 combinations of metal precursors, ligands, and solvents. While a few Rh catalysts did give some level of enantioselectivity, it is notable that Rh catalysts derived from representative ubiquitous ligand families such as BINAP and DuPhos gave no conversion.17 In general, the reactivity was very poor, and only a small selection of conditions gave reasonable conversions. During our screen, we were pleased to find that Ru metal pre(13) (a) Ishiyama, T.; Matsuda, N.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (14) Petersen, M. D.; Boye, S. V.; Nielsen, E. H.; Willumsen, J.; Sinning, S.; Wiborg, O.; Bols, M. Bioorg. Med. Chem. 2007, 15, 4159. (15) For a description of the microscale screening conditions utilized in this study see: Shultz, C. S.; Krska, S. Acc. Chem. Res. 2007, 40, 1320. (16) Previous approaches to this class of intermediates include: (1) racemic hydrogenation followed by HPLC chiral separation: (a) Patane, M. A.; DiPardo, R. M.; Price, R. P.; Chang, R. S. L.; Ransom, R. W.; O’Malley, S. S.; Di Salvo, J.; Bock, M. G. Bioorg. Med. Chem. Lett. 1998, 8, 2495. (b) Bachmann, S.; Scalone, M. Schnider, P. Process for the preparation of enantiomerically enriched cyclic β-aryl or heteroaryl carboxylic acids. U.S. Pat. Appl. 2007/0232653 A1, 2007; (2) resolution of the racemic carboxylic acid: ref 16a; (3) asymmetric hydrogenation on the carboxylic acid: ref 16b. (17) Other ligands tested: (S)-xyl-BINAP, (R,R)-Me-DuPhos, (R,R,S,S)Tangphos, W006-1, Catasium I, J004-1 and J212-1 (structures are available in the Supporting Information)
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Molinaro et al. TABLE 1.
Resultsa
Selected Microscale Asymmetric Hydrogenation Screening
entry
mol % of metal precursor
temperature (°C)
HBF4 3 OEt2 (equiv)
1 2 3 4 5 6 7c
15 2.7 2.7 2.7 2.7 2.7 2.7
50 r.t. r.t. r.t. r.t. r.t. r.t.
0 0 0.09 0.37 0.64 0.9 0.9
conv.b % (%) ee 30 29 37 65 87 96 84d
91 99 98 98 98 99 99
a Reaction conditions: (COD)Ru(Me-allyl)2: SL-J212-1(1: 1.05), 500 psi H2, 18 h. bConversion is defined as the HPLC area % product/(starting material þ product) observed at 210 nm. c1.89 kg scale. dIsolated yield.
cursor (COD)Ru(Me-allyl)2 and Josiphos ligand SL-J212-1 gave >90% ee albeit in low yield 30% (Table 1, entry 1). Further optimization revealed that a lower catalyst loading with a concurrent lower reaction temperature resulted in an increase in enantioselectivity from 91% ee to 99% ee while maintaining the yield to ∼30% (entry 1 vs 2). At this stage we believed that the pyridine moiety was likely a catalyst inhibitor and that the addition of a Brønsted acid might help. However, the potential lability of the Boc group gave us concern with that approach. Nevertheless, HBF4 3 OEt2 was found to provide a considerable boost in reactivity from 36 to 96% conversion (entries 3-6 vs 2) while maintaining the enantioselectivities at 98-99%ee. The use of 0.9 equiv of HBF4 3 OEt2 resulted in a reasonably robust procedure and after Darco treatment18 on scale provided 2.3 kg of 6a in 84% isolated yield and 99% ee (entry 7). Epimerization/Saponification Sequence. A study of the epimerization of the ester carbon center of piperidine 6a is reported in Table 2. We were surprised and pleased to find that depending on the source of NaOEt tested (solid NaOEt in EtOH, a commercially available solution of 21 wt % NaOEt/ EtOH in EtOH or 2 N NaOH in EtOH) different results were obtained (entries 1-3). The best trans/cis ratio (14:1) of the ester substrate 18 was obtained with the commercially available solution of 21 wt % NaOEt/EtOH (entry 2).19 A direct epimerization/saponification using 5 equiv of 2 N NaOH in (18) The Darco treatment is necessary to reduce the metal content in the product. Before treatment the levels are >20000 ppm. (19) Isolation of the product and resubjecting the esters to the same epimerization conditions did not change the trans/cis ratio observed.
JOC Article
Molinaro et al. TABLE 2.
Epimerization/Saponification Sequencea
entry
conditions
18 trans/cis ratio
1 2 3 4 5 6c
solid NaOEt, EtOH 21 wt % NaOEt/EtOH, EtOH 70 °C 1 equiv 2 N NaOH, EtOH, 70 °C 5 equiv 2 N NaOH, EtOH, 70 °C 5 equiv 2 N NaOH, dioxane, 70 °C 1) 5 equiv 21 wt % NaOEt/EtOH, EtOH, 70 °C 2) 5 equiv 2 N NaOH 1) 5 equiv 21 wt % NaOEt/EtOH, EtOH 2) 5 equiv 2 N NaOH
only cis 14:1 1:1 n.a. n.a.
7d a
3 trans/cis ratio
10:1 n.a.
yield (%)b n.d. n.d. n.d. n.d. no rx
14:1
99:1
83
14:1
>120:1
84
Unless otherwise stated, the reactions were run on 100-mg scale in 0.5 mL of solvent. bIsolated yield of 3. c40-g scale. d4.8-kg scale.
EtOH and dioxane was also tested (entries 4-5).20 A 10:1 ratio of trans-/cis-carboxylic acid substrate 3 was obtained (entry 4). Although promising, we knew that we would be unable to meet final purity criteria for MK-1597 (>97 A%) with this ratio. A purity upgrade after this stage would be difficult without a flash chromatography since we were unable to reject the diastereomer with subsequent crystallizations. Gratifyingly, a sequential epimerization with a solution of 21 wt % NaOEt/EtOH followed by an in situ saponification with 5 equiv of 2 N NaOH resulted in a 99:1 ratio of trans/cis of carboxylic acid 3 (entries 6). Presumably, under these conditions, the trans-ester 17 converts to the trans-carboxylic acid 3 faster than the cis-somer, and in parallel, the cis ester 6 would still equilibrate to the thermodynamically stable trans-isomer, providing a final trans/cis ratio of 99:1 for the carboxylic acid 3. We were able to reproduce these results on 4.8 kg scale of 6a providing 3.8 kg of carboxylic acid 3 in 84% yield, trans/cis ratio >120:1 and 98.9 A%. Alternative Synthesis of Carboxylic Acid 3. Although the asymmetric hydrogenation with a Boc protecting group was viable on ∼2.5 kg scale, for even larger-scale campaigns a more robust procedure was necessary to address the lability of the Boc-substrates 4a and 6a under acidic conditions. We subsequently tested the TFA ene-ester 4b because of its ability to tolerate the acidic hydrogenation reaction conditions (Scheme 4). We were pleased to find that the (COD)Ru(Meallyl)2 catalyst provided 92% yield and 99% ee of 6b under the same conditions. We have run preliminary experiments in order to determine the mechanism by which the reduction occurs. Substrate 4b was subjected to D2 under the same reaction conditions. Analysis of the reaction at partial conversion (∼35%) revealed that the major product had incorporated three deuterium atoms in the molecule. The unreacted olefin 4b, however, showed no evidence of deuterium incorporation. These results suggest that a rearrangement step may be involved in the process and is enantioselective.21 (20) The rate of dissolution or solubility of different NaOEt sources in ethanol may explain the different results observed. (21) A full mechanism analysis is underway and will be reported in due course.
SCHEME 4.
Alternative Synthesis of Carboxylic acid 3a
Conditions: (a) 1. Pd(dppf)Cl2, KHCO3, water, 2-MeTHF, 60 °C; 2. 4 N HCl, dioxane; 3. aqueous NaHCO3, 80%. (b) SL-J212-1, Ru(cod)(methallyl)2, HBF4 3 OEt2, 2-MeTHF, 1000 psi H2, 23 °C, 92%, 99%ee. (c) 1. 21 wt % NaOEt/EtOH; 2. water; 3. Boc2O; 4. 2 N NaOH, 70 °C, 88%. a
Similar conditions were used to convert the TFA protected piperidine 6b to carboxylic acid 3. Thus a one-pot in situ TFA deprotection, Boc protection, epimerization and hydrolysis sequence allowed the preparation of 3.9 kg of 3 in 88% yield and >100:1 trans/cis ratio. Amidation. A series of coupling conditions for carboxylic acid 3 with amine fragment 2 have been explored (Table 3). Although, HATU coupling was the highest yielding and cleanest reaction to provide 19 (96% yield and 97.7 A%), the cost of this reagent is prohibitive on scale. After a screen J. Org. Chem. Vol. 76, No. 4, 2011
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JOC Article TABLE 3.
Molinaro et al.
heptane was added. The slurry was filtered and dried. MK1597 3 AcOH was isolated as a white crystalline salt (Ru = 5 ppm, Pd = < 1 ppm, 2.94 kg, 83% yield, 98.6 A%).
Amidation
Conclusion
entry
coupling reagent
yield (%)
purity (A%)
1 2 3 4 5 6 7
oxalyl chloride CDI EDC-HCl, HOBt HATU MsCl, 1-methylimidazole TsCl, 4-methylmorpholine TsCl, 1-methylimidazole
50 0 85 96 21 70 94
nd nd 65 97.7 nd nd 86
SCHEME 5.
End Game
Conditions: (a) 1. H3PO4, 70 °C, 95%. 2. D-tartaric acid, 90 °C, 90%. 3. NaOH, MTBE, 99%. (b) AcOH, MTBE, Heptane, 83%.
of coupling agents, we opted for a cheaper mixed anhydride approach using TsCl/1-methylimidazole activation/amidation. This reagent gave a similar yield (94%) to HATU, albeit in a lower purity profile (86 A%). The low purity profile can be further upgraded during the subsequent salt formations. End Game. Completion of the synthesis for MK-1597 is outlined in Scheme 5. H3PO422 was used to cleave the Boc protecting group and provided 3.91 kg of MK-1597 in 93% yield and 91.8 A%. Rejection of impurities was possible during the work up through a pH swing with aqueous MsOH. Thus, the organic layer was treated with aqueous MsOH, which formed a water-soluble salt with MK-1597. This layer was washed with MTBE to remove impurities and then basified with NaOH and re-extracted to recover MK-1597. This process allowed us a slight increase in purity profile from 86 A% for the amidation to 91.8 A% for the Boc deprotection and a reduction of the metal content of the final compound MK-1597 (Ru = from 17 to 11 ppm and Pd = from 56 to 2 ppm). At this stage the purity of MK-1597 was further upgraded to 98.6 A% with a bis-D-tartrate salt formation/ salt break. Finally, MK-1597 3 AcOH was identified as a crystalline and bioavailable form for development. Therefore, MK-1597 was dissolved in MTBE and a solution of AcOH in (22) Alternatively 10 equiv of TFA can be used with carefull monitoring of the KF.
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In conclusion, a practical large-scale chromatography free synthesis of renin inhibitor MK-1597, a potential new treatment for hypertension, was developed. The synthetic route provided MK-1597, as its acetate salt, in 9 steps (isolated intermediates) and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester and a highly efficient epimerization/ saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2. This approach was used to successfully produce 2.94 kg of MK-1597 acetate salt. Experimental Section 2-Chloro-5-formylbenzoic Acid (10). A 100-L reactor equipped with an overhead stirrer, a nitrogen inlet, and a temperature probe was charged with THF (15 L, predegassed by bubbling nitrogen for 30 min) followed by 5-bromo-2-chlorobenzoic acid (5) (5027.3 g, 21.35 mol). The solution was degassed by bubbling nitrogen for 15 min then cooled to -30 °C. iPrMgCl (2.0 M/ THF, 27.8 L, 55.5 mol) was slowly added via an addition funnel. The rate of addition was controlled such that for the first equivalent of iPrMgCl (10.7 L), the temperature stayed below 0 °C and for the second equivalent it stayed below -20 °C. The slurry was aged O/N from -20 °C to rt (>99% conversion). The reaction mixture was cooled to 0 °C, and a solution of DMF (4.15 L, 53.4 mol) in THF (16 L) was slowly added with vigorous stirring. The rate of addition was controlled in order to keep the temperature below 25 °C. The thick slurry was aged at 10-15 °C for 1 h at which point 4 N HCl (23.5 L, 93.9 mol) was added slowly. The reaction mixture was stirred at rt for 30 min until all solids dissolved. The batch was transferred to a 150-L extractor, and the two layers were cut. The organic layer was successively washed with 10 wt %/wt aqueous LiCl, (15 L), 1 M Na2CO3 (32 L) and 1 M Na2CO3 (21 L). The combined Na2CO3 layers were washed with MTBE (25 L), cooled to 0 °C, and acidified with 6 N HCl (15.9 L). The resulting slurry was filtered through a filter pot. The solid obtained was washed with water (32 L) and heptane (40 L) and dried under vacuum with a flow of nitrogen until KF analysis showed 10. The rate of addition of 50 wt/wt aqueous NaOH was such that internal temperature was maintained below 26 °C. The batch was extracted with 2 MTBE (2 45 L), and the combined organic layer was washed with water (20 L), dried over Na2SO4 (8 kg), filtered, and concentrated, yielding the desired amine 2: 6448 g (70.4 wt %, 95.85 A%, 99% yield). 1H NMR (500 MHz, CDCl3) δ 7.27 (d, 1H, J = 8.2 Hz), 7.21 (d, 1H, J = 2.0 Hz), 7.06 (dd, 1H, J1 = 2.1 Hz, J2 = 8.1 Hz), 3.90 (s, 2H), 3.57 (t, 2H, J = 6.9 Hz), 3.34 (s, 3H), 2.84 (t, 2H, J = 6.9 Hz), 2.11 (m, 1H), 1.93 (br, 2H), 0.47-0.40 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 137.7, 137.4, 131.4, 130.8, 129.2, 128.6, 73.1, 58.5, 51.1, 35.4, 29.7, 6.4; IR 3314, 3083, 2925, 2866, 2826, 1648, 1470, 1374, 1107, 1039, 1014, 811, 752 cm-1; HRMS (ESI) (m/z): [M þ H]þ calcd for C13H19ClNO, 240.1150; found 240.1148. 2,6-Dichloro-4-methylphenol (14).23 A 400 L reactor equipped with an overhead stirrer, a nitrogen inlet and an addition funnel was charged with p-cresol (7) (8000 g, 74 mol) and acetonitrile (40 L). The solution was cooled to 0 °C and 10% aqueous sodium hypochlorite solution (127 kg, 169 mol) was added over 2 h keeping the temperature
