Process Development and Multikilogram-Scale Synthesis of a TRPV1

Nov 21, 2013 - ABSTRACT: The process development and multikilogram preparation of a TRPV1 antagonist, 1, is described. Pyrido[2,3- b]pyrazine 1 was ...
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Process Development and Multikilogram-Scale Synthesis of a TRPV1 Antagonist Ed Cleator,* Jeremy P. Scott,* Paulo Avalle, Matthew M. Bio, Sarah E. Brewer, Antony J. Davies, Andrew D. Gibb, Faye J. Sheen, Gavin W. Stewart, Debra J. Wallace, and Robert D. Wilson. Global Process Chemistry, Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, U.K. ABSTRACT: The process development and multikilogram preparation of a TRPV1 antagonist, 1, is described. Pyrido[2,3b]pyrazine 1 was prepared in a convergent manner by the coupling of two key fragments, glyoxal 2 and diamine 3. Glyoxal 2 was synthesized in six chemical steps in 20% overall yield, the key step being a challenging Grignard reaction to install the glyoxalate moiety. Diamine 3 was also prepared in six chemical steps in 46% overall yield, exploiting a regioselective nucleophilic aromatic substitution to obtain the key nitrodiamine intermediate 19.

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INTRODUCTION The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel which is activated by a wide range of stimuli, such as capsaicin, acid, or heat.1 Recently, selective antagonists of TRPV1 activation have been investigated in attempts to identify new treatments for pain.2 Our interest in this field instigated a multikilogram preparative campaign of pyrido[2,3-b]pyrazine 1.3 The original route for the preparation of 1 was sufficient for gram quantities but not scalable to the kilogram level. Because of the length of the synthesis and a number of challenging and/or low-yielding steps, we designed and implemented a new synthesis. Our synthetic strategy was based upon a disconnection approach giving two divergent fragments, glyoxal 2 and diamine 3 (Scheme 1), which could be coupled under acidic conditions at a late convergent stage of the synthesis. Herein we describe the process development and preparation of 1 on a pilot-plant scale.

unsuitable as elevated temperatures were required to drive the reaction to completion, which led to significant decomposition products. Alternatively, acetonitrile buffered with disodium hydrogen phosphate at 80 °C gave an acceptable reaction profile, but a white solid sublimed onto the nearest cool surface. The formation of this solid was attributed to the interaction of hydrogen bromide with acetonitrile. On scale, the reaction was performed in a closed system to prevent the blockage of plant vessel valves by this sublimation byproduct. The crude reaction mixture was cooled and filtered, and the solvent was switched to isopropyl alcohol to crystallize 7, which was isolated in 69% yield over the two steps. Conversion of bromide 7 to iodide 8 was necessary in order to improve the efficiency of the halogen−metal exchange reaction to form glyoxal fragment 2. Iodide 8 was stable under the conditions required to form 9, so a telescoped process from 7 to 9 was developed. Bromide 7 was converted to 8 using sodium iodide and acetic acid in acetonitrile at 65 °C. Iodide 8 was obtained in >95% assay yield, and after an aqueous workup, a solvent switch to toluene was performed. The solution of 8 was then treated with concentrated sulfuric acid and heated to 50 °C to hydrolyze the nitrile, affording amide 9. An extractive workup was developed, beginning with an inverse quench into a sodium hydroxide solution (1 M). Amide 9 was isolated in 85% yield over the two steps following extraction of the aqueous phase with methyl tert-butyl ether and a solvent switch to toluene. In order to complete the synthesis of glyoxal 2, several kilograms of electrophile 10 (Scheme 3) had to be prepared. Initially, during our development phase, the piperidine analogue of 10 was synthesized using a literature procedure.5 The preparation of the piperidine derivative was deemed unsatisfactory to be run on larger scale because of long reaction times, elevated temperatures, and the need for vacuum distillation to purify the product. A more attractive alternative for the synthesis of 10 was identified by using a literature

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RESULTS AND DISCUSSION Synthesis of Glyoxal Fragment 2. The synthesis of glyoxal fragment 2 began from commercially available 2hydroxy-3-(trifluoromethyl)pyridine (4) (Scheme 2). Iodination of 4 with N-iodosuccinimide (NIS) in acetic acid was complete in 5 h at 65 °C. The product could be crystallized directly from the reaction mixture by the addition of aqueous sodium thiosulfate followed by additional water, affording 5 in 86% yield. Rosenmund−von Braun cyanation4 of 5 with copper(I) cyanide in DMF gave 6, which was not isolated because of thermal stability concerns. After removal of the copper salts by filtration and aqueous washes with N-(2hydroxyethyl)ethylenediaminetriacetic acid and water to ensure complete removal of DMF, the crude stream was taken directly onto the bromination step to form 7. Phosphorous oxybromide was found to be the only reagent which could effectively brominate 6. Although the yields were high, several issues needed to be addressed before we could run the reaction on scale. The only compatible solvents were chlorobenzene and acetonitrile. Chlorobenzene was deemed © 2013 American Chemical Society

Received: October 24, 2013 Published: November 21, 2013 1561

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Scheme 1. Retrosynthetic Strategy for Target 1

Scheme 2. Synthesis of Glyoxal Fragment 2a

Reagents and conditions: (a) NIS, AcOH/MeCN, 65 °C, 86%; (b) CuCN, DMF, 120 °C, 85−88% by assay; (c) POBr3, MeCN, 80 °C, 69% isolated yield over two steps; (d) NaI, AcOH, 65 °C; (e) conc. H2SO4, toluene, 50 °C, 85% isolated yield over two steps; (f) NaH, THF, TMEDA, then 10 in THF, cool to T < −60 °C, then iPrMgCl, 39%.

a

Scheme 3. Preparation of Glyoxal Acetal Electrophile 10a

procedure for the formation of similar amides using Grignard reagents.6 This allowed us to substitute piperidine with diethylamine (Scheme 3). Thus, amide 11 was prepared from diethylamine by the addition of isopropylmagnesium chloride in tetrahydrofuran (THF) and subsequently added to ethyl acetal 12. Following a quench and aqueous extraction, the organic phase was concentrated in vacuo to give a 78% yield of 10 in suitable purity to be used directly in downstream chemistry. The coupling of 9 and 10 to prepare glyoxal 2 proceeded via halogen−metal exchange of 9 (Scheme 2), which proved challenging. There are several examples of acylation reactions of this type using organolithium reagents derived from 2bromopyridines. 7 , 8 The lithiation of 2-bromo-3(trifluoromethyl)pyridine9 and the magnesium−halogen exchange of 2-iodo-5-cyanopyridine10 are also outlined in the literature. When we applied these conditions to our system, we found that proton transfer from the amide was a significant issue, as only modest yields of 2 were observed. Optimisation of this reaction was demanding; treatment of 9 with sodium hydride prior to organometallic generation was found to inhibit proton transfer and increase the amount of desired 2 formed. The evaluation of a protecting group strategy for the amide moiety, which would obviate the need to use NaH, ultimately offered no advantage over the optimized sodium hydride conditions and would have increased the step count in the longest linear sequence. The results were further improved when isopropylmagnesium chloride was added to a mixture of deprotonated 9 and 10 to initiate the magnesium−halogen exchange in situ. Glyoxal 2 was then separated from the undesired deiodinated analogue of 9 by selective aqueous extraction with hydrochloric acid and subsequent crystallization, giving an isolated yield of 39%.

a

Reagents and conditions: (a) THF, T < 25 °C, 78%.

Synthesis of Diamine Fragment 3. The synthesis of diamine 3 (Scheme 4) was initiated from commercially available dihydroxypyridine 13. Selective nitration of 13 at the 3-position of the pyridine ring has been reported in the literature.11−13 Slight modifications to this protocol allowed the reaction to proceed efficiently using lower reagent volumes. The optimized conditions for the reaction at 0 °C, with three volumes of concentrated sulfuric acid and 1.6 equiv of fuming nitric acid, gave 14 in 98% yield. Dichlorination of 14 was initially explored as a one-pot process using phosphorus oxychloride;11 however, significant charring and high temperatures were observed, which required us to explore alternative reagents. A high-yielding, one-pot dichlorination was found to proceed with either phenyl dichlorophosphate or phenylphosphoric dichloride; however, because of extended lead times for these reagents, a two-step procedure was developed. Initial chlorination with freshly prepared Vilsmeier reagent in acetonitrile selectively chlorinated the 4-position of 14 at ambient temperature with assay yields greater than 90%. Isolation was achieved by a solvent switch into water, which provided 15 in 91% yield. The second chlorination required more strenuous conditions. Following a screen of reagents, neat phosphorus oxychloride at elevated temperatures proved the most effective. The rate of conversion to 16 was improved by charging lithium chloride and hydrochloric acid into the reaction mixture at 1562

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Scheme 4. Synthesis of Diamine 3 from Pyridine 13a

Reagents and conditions: (a) H2SO4/HNO3, 0 °C, 98%; (b) (COCl)2, DMF, MeCN, 20 °C, 91%; (c) POCl3, LiCl, HCl added portionwise, 105 °C, 88%; (d) NH3, 91 °C, 94%; (e) DMPU, NaOt-Bu, 55 °C, 68%; (f) Pd/C (5 wt %), EtOAc, H2 (50 psi) then AcOH, 91%.

a

Scheme 5. Coupling of Glyoxal Fragment 2 and Diamine Fragment 3a

a

Reagents and conditions: (a) NMP, 4 M HCl, 45−50 °C; (b) CDI, NH3, THF, 52 °C, 74% over two steps; (c) EtOH/water 4:1, 45 °C, 95%.

hourly intervals. It is proposed that these additives maintained the level of chloride ion in the reaction mixture, enabling the reaction to go to completion. At the end of the reaction, acetonitrile was added to homogenize the reaction mixture before a controlled quench with water. The acetonitrile was then removed by distillation, and 16 crystallized directly from the reaction mixture in 88% yield. Amination of dichloride 16 was achieved using aqueous ammonia in a sealed vessel at 91 °C (the internal pressure reached 4090 mbar during this reaction), and 17 could be simply filtered from the crude stream on cooling. This reaction gave diamine 17 in 94% yield. Development showed that the SNAr displacement of 18 was selective at the 4-position of 17 when performed in polar aprotic solvents.14 Deprotonation was required for the reaction to proceed, and screening several bases showed that sodium was a better counterion than potassium or cesium in these reactions. As a result, sodium tertbutoxide was chosen. Initial solvent screening showed that good conversion was observed when dimethyl sulfoxide

(DMSO) was used, although isolation of the product was troublesome. N,N-Dimethylacetamide (DMAc) and N,Ndimethylformamide (DMF) acylated the free amine at the 2position and were therefore unsuitable. N,N′-Dimethyl-N,Nisopropyleneurea (DMPU) gave reproducible results and was inert to the reaction conditions. A bis-substituted byproduct, 20, (Scheme 4) was observed as the major impurity formed under these conditions and proved difficult to reject at high levels. Further investigations showed that the formation 20 could be minimized by slow addition of the base. Under these conditions, the formation of 20 could be successfully reduced to less than 1 mol %. When the reaction was complete, 19 was crystallized from 1:1 ethanol/acetic acid in 68% isolated yield. Finally, reduction of the nitro group completed the synthesis of diamine 3. During the development phase of this reaction, although the assay yields were high, it became apparent that high levels of 3 (up to 20%) remained attached to the catalyst after the reaction, giving yields that were lower than anticipated. Using ethyl acetate as the solvent improved the recovery of 3, 1563

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followed by water (22 kg); the temperature was allowed to fall during the addition. The slurry was cooled to room temperature, filtered, and washed with water (8 kg). After overnight drying at 50 °C under vacuum, 5 was isolated as a pale-yellow solid (6.33 kg, 96.4 wt %, 96.3 A%) in 86% yield. 1 H NMR (400 MHz, CDCl3): δ 13.33 (br s, 1H), 7.98 (d, J = 2 Hz, 1H), δ 7.85 (d, J = 2 Hz, 1H). 13C NMR (400 MHz, CDCl3): δ 159.8, 147.8 (q, J = 5 Hz), 144.1, 121.8 (q, J = 32 Hz), 121.3 (q, J = 272 Hz), 62.8. HRMS (EI): calcd 289.9290 for C6H4F3INO (M + H), found 289.9294. Mp 195−196 °C. 6-Bromo-5-trifluoromethylnicotinonitrile (7). 2-Hydroxy-3trifluoromethyl-5-iodopyridine (5) (12.33 kg, 42.67 mol) and copper(I) cyanide (4.01 kg, 44.80 mol) were heated at 120 °C in DMF (52 kg) for 16 h. The batch was then cooled to ambient temperature and filtered through a closed filter to remove copper(I) iodide, and the cake was washed with DMF (11 kg). The filtrate and wash were stirred vigorously with N(2-hydroxyethyl)ethylenediaminetriacetic acid (55 kg of a 35 wt % solution in water) for 1 h, and the solution was acidified to a pH in the range 5.5 to 6 using 4 M HCl. Water was then added such that the total charge of water and 4 M HCl constituted 60 kg (5 mL/g w.r.t. 5). Isopropyl acetate (85 kg) was charged, and the phases were separated. The aqueous (lower) phase was back-extracted with isopropyl acetate (53 kg), and the combined organic layers were washed with lithium chloride (3 × 24.5 kg of a 5 wt % solution in water) and once with water (24.5 kg). The organic phase was then switched to acetonitrile (final volume ∼70 L) by vacuum distillation. HPLC assay of this layer showed 6.9 kg of 6 (86% assay yield). Disodium hydrogen phosphate (2.7 kg, 19.0 mol) was added to the acetonitrile solution of 6, followed by phosphorous oxybromide (12.1 kg, 42.4 mol). The mixture was heated to 80 °C for 16 h, with the vessel sealed apart from some venting during the heat up. The batch was cooled to ambient temperature and filtered, and the cake was washed with acetonitrile (22 L). The combined filtrate and wash were switched to 2-propanol (final volume 22−25 L) by vacuum distillation, the batch self-seeding upon cooling. Water (20 L) was added over 1 h, and the slurry was filtered and washed with 2:1 water/IPA (10 L). The solid was dried under vacuum to give 7 as a pale-pink solid (7.4 kg, 99.3 wt %, 99.1 A%) in 69% yield over the two steps. 1H NMR (400 MHz, CDCl3): δ 8.54 (d, J = 2 Hz, 1H), 7.95 (d, J = 2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 154.2, 143.8, 138.6 (q, J = 5 Hz), 128.5 (q, J = 34 Hz), 121.0 (q, J = 274 Hz), 114.2, 111.4. Anal. Calcd for C7H2BrF3N2: C, 33.5; H, 0.80; N, 11.16. Found: C, 33.39; H, 0.77; N, 10.97. Mp 71 °C. 6-Iodo-5-trifluoromethylnicotinamide (9). 6-Bromo-5-trifluoromethylnicotinonitrile (7) (7.2 kg, 29.08 mol) was dissolved in acetonitrile (34.4 kg), and sodium iodide (21.8 kg, 145.4 mol) and glacial acetic acid (8.73 kg, 145.4 mol) were added. The slurry was heated to 65 °C for 15 h and then cooled to ambient temperature. Sodium thiosulfate solution (1.1 kg in 22 L of water), K2CO3 solution (1.1 kg in 22 L of water), and toluene (19 kg) were added, and the phases were cut. The aqueous layer was back-extracted with toluene (19 kg), and the combined organic phases were washed with saturated NaHCO3 (2.2 kg in 22 L of water). The organic phase was reduced by vacuum distillation (T < 45 °C) to a volume of 15 L and warmed to 50 °C, and concentrated H2SO4 (40.8 kg) added over 30 min, keeping T < 60 °C. The mixture was aged for 2 h at 50 °C and then cooled to 40 °C and quenched into 1 M NaOH(aq) (110 L), keeping T < 25 °C and rinsing the batch in with water (20 L). The quenched batch was agitated for 30

as only 5% of the material was lost to the catalyst. The free base was found to be unstable, so a suitable salt was sought to facilitate the isolatation of 3. The monoacetate salt was identified, and the filtrate of the reaction mixture post palladium removal could be treated directly with acetic acid, allowing crystallisation of the salt from the crude reaction stream to give 3·AcOH in 91% isolated yield with a residual palladium level of 8 ppm. The nitro-reduced analogue of impurity 20 was found to be completely rejected in the liquors. Fragment 3 was therefore produced on scale in six steps from commercially available materials in 46% overall yield. Final Coupling and Isolation. The coupling of glyoxal 2 and diamine 3 proceeded under acidic conditions in a variety of solvents (Scheme 5). During the course of initial experimentation, significant quantities of acid 22 were produced in addition to deazadenine byproduct 21 (identified by high-resolution MS and subsequently confirmed by synthesis); therefore, our process development focused on reducing the formation of these byproducts in order to maximize the overall yield of 1. A screen of the reaction for improved conditions was initiated, and this highlighted that hydrochloric acid in Nmethylpyrrolidine (NMP) at 45 °C for 50 h was optimal. When applied, this protocol allowed the level of acid 22 to be lowered to 5%, and deazaadenine 21 was formed in only trace quantities. Separation of 22 from 1 was problematic, and the easiest solution was to convert 22 into 1 by treatment with 1,1carbonyldiimidazole (CDI) and ammonia. A purity upgrade of 1 from this two-step protocol was achieved using tetrahydrofuran (THF), and as a result, 1 could be crystallized as a THF solvate by the addition of water in 74% yield, containing 0.26 A% acid 22 by HPLC. The monohydrate of 1 had been identified as the desired crystalline form, and a process for its conversion from the THF solvate of 1 was developed. Thus, a suspension of the THF solvate of 1 in 20 mL/g of a 4:1 mixture of water and ethanol followed by heating of the mixture to 45 °C effected the desired turnover to the monohydrate of 1 in 95% isolated yield.

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CONCLUSION

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EXPERIMENTAL SECTION

In summary, we developed a new synthesis of the TPVR1 antagonist 1 which was implemented on multikilogram scale. Our new synthesis allows this target to be prepared in 14% overall yield with the longest linear sequence consisting of nine steps, including a form change to the desired monohydrate 1.

General. Starting materials were obtained from commercial suppliers and used without further purification. Melting points were obtained using a Stuart Scientific SMP3 capillary melting point apparatus and are uncorrected. NMR data were obtained using a Bruker 400 MHz instrument. HPLC analyses were performed on a Hewlett-Packard Series 1100 system eluting with acetonitrile/0.1% aqueous H3PO4 in varying gradients. Reported yields are corrected for weight percent purity based on analytical standards, unless otherwise noted. Syntheses. 2-Hydroxy-3-trifluoromethyl-5-iodopyridine (5). 2-Hydroxy-3-trifluoromethylpyridine (4) (4.0 kg, 24.52 mol) was slurried in acetonitrile (11 kg), and glacial acetic acid (1.55 kg, 25.75 mol) was added, followed by N-iodosuccinimide (6.62 kg, 29.43 mol). The resultant slurry was heated to 65 °C for 5 h. The slurry was cooled to 40 °C, and 10 wt % sodium thiosulfate solution (16 kg) was charged over 30 min, 1564

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MHz, CDCl3): δ 9.21 (d, J = 2 Hz, 1H), 8.56 (d, J = 2 Hz, 1H), 6.8 (br s, 1H), 6.6 (br s, 1H), 5.75 (s, 1H), 3.78 (m, 2H), 3.68 (m, 2H), 1.19 (t, J = 7 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 195.0, 165.6, 155.9 (q, J = 2 Hz), 149.9, 134.8 (q, J = 5 Hz), 130.2, 125.1 (q, J = 35 Hz), 122.4, (q, J = 273 Hz), 99.2, 63.3, 15.0. HRMS (EI): calcd 343.0882 for C13H15F3N2NaO4 (M + Na), found 343.0894. Mp 112−113 °C. 3-Nitropyridine-2,4-diol (14). 2,4-Dihydroxypyridine (13) (4.95 kg, 43.2 mol) was added portionwise to cooled (0−20 °C) concentrated sulfuric acid (15 L). The reaction was aged for 35 min. Fuming nitric acid (2 L) was added at a rate to maintain the internal temperature below 5 °C (addition time 4.5 h). Cold water (6 L) was added, keeping the internal temperature below 5 °C (addition time 2.6 h). The remaining 54 L of water was added at a rate which allowed the internal temperature to increase to 15 °C (addition time 1.25 h). The reaction was seeded with 50 g of 14, and a liquor assay was obtained. The slurry was cooled to 8 °C, and a second liquor assay was obtained. The batch was filtered (2 h) and washed with water (2 × 20 L). The solid was dried under nitrogen in a vacuum oven at 75 °C to give 14 (6.82 kg, 97.0 wt %, 100A%) in 98% yield. 1H NMR (400 MHz, DMSO-d6): δ 12.45 (br s, 1H), 11.91 (br s, 1H), 7.44 (d, J = 7.3 Hz, 1H), 6.04 (d, J = 7.3 Hz, 1H). Other data were consistent with those previously reported.11,12 4-Chloro-3-nitropyridin-2-ol (15). DMF (4.76 L) was charged into the vessel followed by acetonitrile (51 L). A solution of oxalyl chloride (8.3 kg, 65.3 mol) in acetonitile (10.3 L) was added to this solution over 1 h and aged for a further 10 min. 2,4-Dihydroxy-3-nitropyridine (14) (6.79 kg, 43.6 mol) was added, and the reaction was stirred for a further 30 min. HPLC analysis confirmed reaction completion. Water was charged (60.9 L), and the acetonitrile was evaporated under vacuum at 30 °C until the supernatant contained 3.6% of the product. Water (60.9 L) was added, and the slurry was filtered and washed with water (16.6 L). The solid was dried under vacuum at 55 °C to provide 15 (6.72 kg, 100 wt %, 99.3 A%) in 91% yield. 1H NMR (400 MHz, DMSO-d6): δ 13.12 (br s, 1H), 7.78 (d, J = 7.0 Hz, 1H), 6.60 (d, J = 7.0 Hz, 1H). Other data were consistent with those previously reported.11,13 2,4-Dichloro-3-nitropyridine (16). Phosphorus oxychloride (29.4 kg, 191.9 mol) was charged into a vessel, and 4-chloro-3nitropyridinyl-2-ol (15) (6.72 kg, 38.4 mol) was added, followed by lithium chloride (1.7 kg). The reaction mixture was heated to 105 °C for 2.5 h and then cooled to 89 °C, and a sample was analysed by HPLC assay. Hydrochloric acid (70 g, 37%) was added, and the reaction was reheated to 105 °C for 1 h. The reaction mixture was then cooled 88 °C, treated with hydrochloric acid (80 g, 37%), and then reheated to 105 °C and stirred for 1 h. Another 2 portions of hydrochloric acid were added to the batch in this way until