Development of a Multikilogram Scale Synthesis of a TRPV1

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Development of a Multi-kilogram Scale Synthesis of a TRPV1 Antagonist Jeffrey T Kuethe, Michel Journet, zhihui Peng, Dalian Zhao, Arlene E McKeown, and Guy Humphrey Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00388 • Publication Date (Web): 13 Jan 2016 Downloaded from http://pubs.acs.org on January 21, 2016

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Organic Process Research & Development

Development of a Multi-kilogram Scale Synthesis of a TRPV1 Antagonist Jeffrey T. Kuethe,* Michel Journet, Zhihui Peng, Dalian Zhao, Arlene McKeown, and Guy R. Humphrey Department of Process Chemistry, Merck & Co., Inc., Rahway, New Jersey 08065 [email protected] TITLE RUNNING: Development of a Multikilogram-Scale Synthesis of a TRPV1 Antagonist

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ABSTRACT :


A highly efficient, regioselective 5 step synthesis of the TRPV1 antagonist 1 is

described. The coupling of piperazine 7 with dichloropyrimidine 8 proceeded via a regioselective Pdmediated amination affording product 11 in excellent yield. Conversion of the penultimate product 14 to 1 through formation of a magnesium ate complex and trapping with CO2 afforded 1.

Keywords:

TRPV1 antagonist, Suzuki-Miyaura coupling regioselective palladium-catalyzed

amination, magnesium ate complex



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Introduction Activated by a wide range of stimuli such as capsaicin, acid, or heat, the transient receptor potential vanilloid-1 (TRPV1) has been identified as a potential treatment for chronic pain.1 TRPV1 is a highly characterized member of the TRP cation channel family believed to be involved in a number of important biological roles and plays a role in the transmission of pain.2 TRPV1 activation inhibits the transition of pain signals from the periphery to the central nervous system (CNS) leading to the possible development of analgesic and anti-inflammatory agents. TRPV1 antagonists have also been evaluated in multiple clinical trials where hyperthermic effects seen preclinically are also observed in humans.3 Our interest in this area was prompted by the need to prepare multikilogram quantities of the TRPV1 antagonist 1 (Scheme 1).4 While the original synthesis4 was suitable for the preparation of gram quantities of 1, the synthesis was not practical for the production of kilogram quantities due to a low temperature metal-halogen exchange reaction, regioselectivity issues arising from amination of the core pyrimidine, and the need for chromatography at each step. Our retrosynthetic strategy mirrored the original route, and centered on the use of commercially available starting materials 2-5. Herein, we describe the development of a robust process for the manufacture of TRPV1 antagonist 1 on multikilogram scale.

Scheme 1. Retrosynthesis of TPRV1 Antagonist 1


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Results and Discussion The synthesis began by optimizing the aromatic nucleophilic substitution (SNAr) of 2,5-dibromo3-methylpyridine 2 with commercially available (R)-2-methylpiperazine 3 as well as identifying suitable conditions for isolation of 7 without the need for chromatography (Scheme 2).5,6 The reaction was investigated in terms of solvent, base, temperature, and number of equivalents of piperazine 3 needed to drive the reaction to completion. The reaction performed best in polar aprotic solvents at elevated temperatures (> 120 °C). Insufficient conversion or prolonged reaction times were required when attempting to conduct the reaction below 120 °C. Use of less than 1.35 equivalents of piperazine 3 resulted in an inferior reaction profile.

The optimal reaction conditions utilized 1.4 equivalents of

piperazine 3 in the presence of 2 equiv. of K2CO3 in dimethylacetamide (DMAc) at 130 °C for 24 h. This combination resulted in complete conversion to SNAr product 7 and provided an excellent end of reaction HPLC profile, with no detectable amounts of dimeric by-products, giving product 7 in 95% assay yield. After an aqueous workup and extraction into aqueous HCl, compound 7 was crystallized upon addition of aqueous NaOH and isolated in analytically pure form in 88% isolated yield. Scheme 2. Synthesis of Piperazinylpyridine 7.

The formation of intermediate 8 initially involved a 2 step protocol involving nucleophilic addition of 4-fluorophenyllithium to 2,4-dichloropyrimidine at -78 °C followed by DDQ oxidation. In order to avoid this sequence, we investigated the coupling of readily available 2,4,6-trichloropyrimidine 4 with boronic acid 5. It was rapidly discovered that the coupling could be carried out effectively by employing Pd(OAc)2 in combination with PPh3 under standard Suzuki-Miyaura cross coupling ACS Paragon Plus Environment


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conditions (1 M Na2CO3, THF, 60 °C, 3 h) in a highly regioselective manner.7 While complete conversion was observed, the formation of bis-arylated by-product 9 (up to 10%) needed to be suppressed. The reaction was further optimized in terms of stoichiometry of pyrimidine 4 utilized and the charge of Pd/ligand. Increasing the amount of pyrimidine 4 to 1.5 equivalents relative to boronic acid 5 minimized the formation of bis-adduct 9 to an acceptable level of ~ 4 LCAP which could be rejected in downstream chemistry. It was established that the coupling could be carried out with as low as 0.1 mol% Pd(OAc)2/0.2 mol% PPh3 without affecting the reaction rate and yield (92%). Interestingly, when a higher Pd loading (2 mol%) was employed, palladium complex 10 was isolated, and its identity was established earlier via single crystal X-ray analysis.8 This complex and its presence in the isolated solid at ~ 1.5 mol% proved to be critical for the next step (vide infra). The final conditions selected for scale up involved reaction of 1.5 equivalents of pyrimidine 4 with boronic acid 5 in the presence of 2 equivalents of 1M aqueous Na2CO3 in THF at 60 °C for 3 h and employed 2 mol% Pd(OAc)2/4 mol% PPh3. The product was isolated by crystallization from MTBE/heptane in 85% yield (corrected for 90 wt%). The product also contained ~1.5 mol% of complex 10.9


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Scheme 3. Palladium-Catalyzed Coupling of 4 and 5 F F Cl

Pd(OAc)2 (2 mol%) PPh3 (4 mol%)

N

+

N

N Cl

N

Cl

F

B(OH)2

N Cl

N

F

4 8

5

Cl

Cl 9

1 M Na2CO3, THF 60 °C, 3 h Cl Ph3P Pd PPh3 N Cl

N

Cl

10 X-ray structure of 10

The reaction between compounds 7 and 8 to afford the desired regioisomer 11 required a significant amount of investigation in the early stages of the program due to the formation of substantial amounts of the undesired regioisomer 12 (Scheme 4). The initial conditions involved reaction of compounds 7 and 8 in DMAc at 60 °C in the presence of K2CO3 and afforded a 3:1 mixture of regioisomers 11:12 where isomer 11 could be isolated in ~ 70% yield after silica gel chromatography (Scheme 4). The use of other solvents such as DMF, DMSO, and NMP provided similar levels of selectivity (~ 3:1) and the use of EtOH or THF gave lower selectivity’s (~2:1). We next turned our attention to the effect of base and solvent on the reaction and made a serendipitous discovery. Initially, reactions between compounds 7 and 8 were conducted with highly purified starting materials, typically involving chromatographically pure pyrimidine 8. When LiHMDS was investigated as a possible base employing chromatographically pure 8 in THF at room temperature, the ratio of 11:12 was ~ 3:1. However, when the reaction was repeated in THF at room temperature employing crystallized compound 8 that also contained ~ 1.5 mol% of complex 10 it was observed that the regioselectivity ACS Paragon Plus Environment


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jumped to 20:1.8 It was also observed that the desired regioisomer 11 was formed in 91% assay yield after only 0.5 h at room temperature.

Performing the reaction in the presence of complex 10

demonstrated that switching from an SNAR reaction to a palladium-catalyzed reaction had a profound effect on the product distribution.

This observation led to further reaction optimization in terms of

base and temperature (Table 1). For example, the reaction could be carried out with purified pyrimidine 8 utilizing PdCl2(PPh)3 at 0 °C in the presence of LiHMDS to give 96:4 of 11:12 (Table 1, entry 1). The use of other bases such as LDA, i-PrMgCl, Hünigs base, DBU, or NaOt-Bu lead to significant erosion is the regioisomeric ratio of 11:12 regardless of the temperature (Table 1, entries 2-6). The optimal conditions selected for scale up involved using crystallized 8 containing 1.5 mol% of complex 10 employing 1.1 equiv. of LiHMDS at -5 °C (Table 1, entry 7).10 The reaction was complete within 0.5 h at this temperature and afforded a 96:4 ratio of 11:12 in 92% assay yield. After an aqueous workup and treatment with Ecosorb C-941 to remove residual palladium, the product was crystallized from isopropanol to afford coupled product 11 in 85% isolated yield and with a 97:3 ratio of regioisomers 11:12.


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Scheme 4. Palladium-Catalyzed Coupling of 7 and 8.

F

F

F K2CO3, DMAc, 60 °C

N

Me

Me

N Cl

Me

+

N

N

Cl

N

N Cl

N Me

Cl

N Br

N

Br

~3:1

11

12

N 7 F

Me LiHMDS, THF

Me

8

-10 to -5 °C Cl Ph3P Pd PPh3

N

N

N

Br

N

11

92% assay: 96:4 11:12 85% isolated yield: 97:3 11:12

N Cl

N

Cl

N

7 + 1.5 mol% 10

N

Me

NH

8

N

Cl

10 active catalyst


Me N N

Br


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Table 1. Effect of Base and Temperature on Coupling of 7 and 8.

Entry

Pd cat.

Base

1

PdCl2(PPh3)2 2 mol%

LiHMDS

0 °C/0.5 h

100%a

96:4

2

PdCl2(PPh3)2 2 mol%

LDA

-30 °C/0.5h

100%a

5:1

3

PdCl2(PPh3)2 2 mol%

i-PrMgCl

0 °C/1 h

90%a

8:1

4

PdCl2(PPh3)2 2 mol%

DIPEA

rt/15h

20%a

1:1

5

PdCl2(PPh3)2 2 mol%

DBU

rt/20h

20%a

2:1

6

PdCl2(PPh3)2 2 mol%

NaOt-Bu

rt/5h

5%

1:1

7

10 (1.5 mol%) LiHMDS

-5 °C/0.5 h

100%

96:4

Temp °C/Time Conversion Ratio 11:12

a) Chromatographed 8 was utilized for these experiments.

The preparation of the penultimate compound 14 involved SNAr displacement of the chlorine atom of intermediate 11 with (R)-2-methylpyrrolidine 13. At the time, compound 13 was not commercially available in sufficient quantities and was prepared by a four step sequence we have previously disclosed.11 Reaction of piperazine 7 with 1.5 equivalents of the tartrate salt of 13 was successfully accomplished at 95 °C in DMAc in the presence of 4 equivalents of K2CO3 for 18 h. The optimal reaction temperature was found to be + 95 °C; however, this temperature was at the boiling point of the free base of pyrrolidine 13 and required an excess of pyrrolidine 13 to achieve complete conversion.12 This displacement reaction was found to be exceedingly clean providing penultimate compound 14 in 95% assay yield. After an aqueous workup and a solvent switch to


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THF, crude product 14 was obtained with sufficiently high purity that it was used in the next step without further purification or isolation. Scheme 5. Coupling of 11 and 13.

The final end game for the synthesis of TRPV1 antagonist 1 involved conversion of the bromopyridine to the corresponding carboxylic acid. It was reasoned that this could be accomplished in a single step by metal-halogen exchange followed by trapping with CO2.

Initial studies into the

feasibility of this approach were not encouraging. For example, treatment of penultimate 14 with nBuLi at -25 °C resulted in rapid metal-halogen exchange. Subsequent quenching of the lithiate by bubbling CO2 gas through the reaction mixture only afforded ~ 45% assay yield of product 1. The mass balance was observed to be the reduced compound 15 in up to 35% yield with the formation of a number of other unidentified reaction by-products. Inverse quench of the lithiate into a solution of CO2 did not enhance the reaction profile. Attempted metal-halogen exchange with i-PrMgCl under standard Knochel conditions13 simply resulted in no detectable reaction and the starting bromide was recovered unchanged. Finally, the use of a magnesium ate complex was examined.14 Treatment of a THF solution of compound 14 first with i-PrMgCl and then with BuLi at -25 °C resulted in clean metal-halogen exchange. Bubbling CO2 through the mixture resulted in the formation of compound 1 in up to 85% assay yield. Also observed in the crude reaction mixture were 3-5% of reaction impurity 15 and 5% of butyl ketone impurity 16 in addition to the ~3% process impurity 17 that was still present from a previous step. Further optimization of the reaction led to the discovery that reverse quenching the



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magnesium ate complex into CO2/THF solution at -10 °C improved the reaction profile and minimized the formation of 15 to < 2% and 16 to 0.5%. Compound 1 was obtained in 90% assay yield. An extractive workup effectively removed impurities 15 and 16 in the organic wash leaving compound 1 and 3% of process impurity 17. At this stage, elimination of 17 to acceptable levels was required. The free base of 1 was not crystalline but formed a number of various crystalline salts (HCl, MsOH, tosylate, CAS); however, these did not suppress the presence of 17 to acceptable levels. The fortuitous discovery that compound 1 formed a crystalline solvate with DMSO which completely rejected impurity 17 when isolated allowed for its implementation into the process.

After the extractive workup to remove

impurities 15 and 16, the aqueous layer was acidified, extracted into MTBE and solvent switched into DMSO. The resulting crystalline DMSO solvate of 1 was isolated in 95% yield and in > 98.5 LCAP. The mesylate salt was selected as the final form of 1 and conversion of the DMSO solvate to this salt involved dissolving the isolated solvate

in water/DMAc, addition of aqueous NaOH to effect

dissolution, and addition of MsOH. The mesylate salt crystallized from the reaction mixture and was isolated in 93% (98.5 LCAP) overall yield. Scheme 6. End Game F

1. DMSO 1. i-PrMgCl (1 equiv), n-BuLi (1.35 equiv) THF, -25 °C, 30 min 14

Me Me

N

N

N

93%

Me

Me

Me

N

H 15

1

N

HO2C

1 Mesylate

2. MsOH, DMAc/H2O

N

2. Reverse quench into CO2/THF 90% assay

N

N

Me Bu

N O

16

Reaction impurities


N

N 17

N

Me

process impurity

N

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Conclusion In conclusion, we have outlined a highly efficient synthesis of the TRPV1 antagonist 1 which proceeds in 5 linear steps and in 63% overall yield from commercially available starting materials. The process was successfully utilized to prepare > 6 kg of the mesylate salt of compound 1. Hallmarks of the synthesis include the highly regioselective coupling of intermediates 7 and 8 in the presence of palladium complex 10 to give intermediate 11 and the utilization of a magnesium ate complex to facilitate the metal-halogen exchange of bromide 14 leading to 1. In addition, the fortuitous discovery of a DMSO solvate of the API allowed for an efficient purity purge ultimately providing the mesylate salt of 1 in excellent yield and purity.

Experimental Section General. All solvents and reagents were used as received from commercial sources. Analytical samples were obtained by chromatography on silica gel using an ethyl acetate/hexane mixture as the eluent. The water content (KF) was determined by Karl Fisher titration. NMR data were obtained on a Bruker 500 MHz spectrometer. Analysis by HPLC was performed on a Hewlett-Packard Series 1100 system eluting with acetonitrile/0.1% aqueous H3PO4 using a Waters Symmetry column (250 X 4.6; 5 µm). All reported yields are corrected for weight percent purity based on analytical standards. Preparation of (R)-1-(5-Bromo-3-methylpyridin-2-yl)-3-methylpiperazine (7). Two batches were conducted at similar scale. In a 72 L round bottom flask was charged with 3.00 kg (11.96 moles) of 2,5-dibromo-3-methylpyridine 2, 1.68 kg (16.74 moles) of (R)-(-)-2-methylpiperazine 3, 3.30 kg (23.92 moles) of powdered K2CO3, and 13.5 L of dimethylacetamide. The resulting slurry was heated to an internal temperature of 130 oC for 24 h. The reaction mixture was cooled to 5 oC and 25 L of water was added over 30 min while keeping the internal temperature below 20 oC. The resulting mixture was transferred to a 100 L extractor and diluted with 27 L of isopropyl acetate. The layers were separated and the organic layer was washed with water (2 X 10 L). The organic layer was cooled to 10 oC and ACS Paragon Plus Environment


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13.2 L (13.2 moles) of 1N aqueous HCl was added over 15 min keeping the internal temperature < 25 o

C. The layers were separated and the aqueous layer transferred to a 50 L round bottom flask where the

residual isopropyl acetate was removed by distillation under reduced pressure. To the resulting solution was added 14.4 L (14.4 moles) of 1N aqueous NaOH over 1 h while maintaining the internal temperature < 25 oC. The resulting slurry was stirred at room temperature for 2 h and filtered. The wet cake was washed with 30 L of water and dried under vacuum/N2 sweep for 24 h to afford 2.83 kg (88%, 99 wt%, 99.3 A%, KF 1% H2O by mole) of 7 as an off white solid.1H NMR (CDCl3, 500 MHz) δ 1.61 (d, 3H, J = 6.4 Hz), 2.27 (s, 3H), 2.56 (dd, 1H, J = 10.2 and 12.2 Hz), 2.85 (dt, 1H, J = 3.2, 12.2, and 14.7 Hz), 3.03-3.09 (m, 3H), 3.31-3.34 (m, 2H), 7.53 (d, 1H, J = 2.4 Hz), 8.19 (d, 1H, J = 2.4 Hz); 13C NMR (CDCl3, 125 MHz) δ 19.2, 19.8, 45.9, 50.1, 50.5, 57.1, 112.9, 126.6, 141.3, 145.8, 160.4. Anal. Calcd. For C11H16BrN3: C, 48.90; H, 5.97; N, 15.55. Found: C, 48.80; H, 5.98; N, 15.59. Preparation of 2,4-Dichloro-6-(4-fluorophenyl)pyrimidine (8). Two batches were conducted at similar scale. A 50 L reactor was charged 2.77 kg (15.0 moles) of 2,4,6-trichloropyrimidine 4, 1.4 kg (10 moles) of 4-fluorophenyl boronic acid 5, 44.9 g (0.20 moles) of Pd(OAc)2, 104.9 g (0.4 moles) of PPh3, 10 L of THF and 20 L (20 moles) of a 1M solution of aqueous Na2CO3. The biphasic mixture was warmed to 60 oC and stirred for 3 h under nitrogen. The reaction mixture was cooled to room temperature and the layers separated. The organic layer was washed with 10 L of a 5% aqueous solution of NaCl. The organic layer was concentrated at atmospheric pressure to ~ 6 L and MTBE was added at a constant feed during the distillation until a total of 16 L was used keeping the volume at ~ 6 L during the course of the distillation. The resulting slurry was warmed to 55 oC for 1 h and 16 L of heptane was added at the same temperature over 1 h. The slurry was cooled to 5 oC, stirred for 1 h, and filtered. The wet cake was washed with cold heptane (5 oC, 9 L) and dried at 40 oC under vacuum for 24 h to give 2.29 kg (85%, 90 wt%) of 8 containing ~ 1.5 mol% 10. An analytical sample was obtained by silica gel chromatography.

1

H NMR (CDCl3, 500 MHz) δ 7.23 (m, 2H), 7.66 (s, 1H), 8.13 (m, 2H);

13

C NMR

(CDCl3, 125 MHz) δ 115.0, 116.4 (d, J = 22.7 Hz), 129.9 (d, J = 9.2 Hz), 130.2 (d, J = 2.9 Hz), 163.3 ACS Paragon Plus Environment

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(d, J = 255.7 Hz), 164.5, 166.5, 166.9;

19

F NMR (CDCl3, 470 MHz) δ - 106.3 Anal. Calcd. For

C10H5Cl2FN2: C, 49.42; H, 2.07; N, 11.53. Found: C, 49.23; H, 2.06; N, 11.49. Preparation of (R)-4-(4-(5-Bromo-3-methylpyridin-2-yl)-2-methylpiperazin-1-yl)-2-chloro6-(4-fluorophenyl)pyrimidine (11). Two batches were conducted at identical scale. A 50 L reactor was charged with 2.0 kg (8.23 mol by assay) of 8, 2.22 kg (8.23 mol) of piperidine 7 and 16 L of THF. The resulting solution was degassed 3X with vacuum/N2 cycles and cooled to ̶10 ºC and 9.05 L (9.05 mol) of a 1M solution of LiHMDS was added over 1 h while keeping the internal temperature between ̶10 ºC and ̶5 ºC. The reaction mixture was stirred at ̶5 ºC for 1 h and quenched with 15 L of a 15% aqueous solution of NaCl. The layers were separated and the organic layer was treated with 1.4 kg of Ecosorb C-941 at room temperature for 1 h and filtered through a pad of celluose. The filtrate was concentrated under reduced pressure with a constant feed of isopropanol keeping the volume at ~ 30 L during the course of the distillation. During the distillation the product crystallized. After the addition of ~ 30 L of isopropanol, the slurry was allowed to cool to room temperature, stirred for 2 h, and was filtered. The wet cake was washed with 6 L of isopropanol and dried at 40 ºC under vacuum for 48 h to afford 3.43 kg (85%, 96 wt%, 97:3 11:12) of 11 as a white solid. 1H NMR (CDCl3, 500 MHz) δ 1.46 (d, 3H, J = 7.0 Hz), 2.37 (s, 3H), 3.01 (dt, 1H, J = 12.6 and 3.6 Hz), 3.13 (dd, 1H, J = 12.6 and 3.6 Hz), 3.39 (dt, 1H, J = 12.6 and 2.1 Hz), 3.47 (m, 1H), 3.53 (m, 1H), 4.36 (br s, 1H), 4.71 (br s, 1H), 6,76 (s, 1H), 7.17 (m, 2H), 7.61 (d, 1H, J = 2.4 Hz), 7.99 (m, 2H), 8.23 (d, 1H, J = 2.4 Hz); 13C NMR (CDCl3, 125 MHz) δ 14.8, 18.2, 39.7, 48.0, 49.4, 53.9, 96.6, 114.1, 115.7 (d, J = 22.0 Hz), 127.0, 129.2 (d, J = 8.9 Hz), 133.0 (d, J = 3.0 Hz), 141.7, 146.1, 160.1, 161.1, 163.3, 162.2 (d, J = 291.0 Hz) 164.6, 165.4; 19

F NMR (CDCl3, 470 MHz) δ -110.0. Anal. Calcd. For C21H20BrClFN5: C, 52.90; H, 4.23; N, 14.69.

Found: C, 52.64; H, 4.06; N, 14.86.

Preparation of (R)-2-Methylpyrrolidine Tartrate Salt (13). Two batches were conducted at similar scale. To a 50 L reactor was added 2.54 kg (13.7 mol) of N-Boc-(R)-2-methylpryyolidine,11 13 L of



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EtOH, and 6.86 L (34.3 mol) of 5N aqueous HCl. The resulting solution was heated to 50 ºC for 1 h and then cooled to 5 ºC. To the cooled solution was added slowly 2.54 g of phenolphthalein and 10.2 L (27.3 mmol) of a 21 wt% solution of NaOEt in EtOH was added until the solution turned pale pink. The slurry was filtered with the receiving pot cooled in a dry ice/acetone bath. The wet cake (NaCl) was washed with 2 L of EtOH. The filtrate was transferred to a 50 L reactor and 2.26 kg (15.1 mol) of Ltartaric acid was added. The mixture was stirred at 50 ºC for 3 h and cooled to room temperature. The slurry was azeotropically concentrated under reduced pressure with addition of isopropylalcohol (at a constant total volume of ~ 30 L and a temperature of ~ 30 ºC; a total of ~ 38 L was needed). The slurry was cooled to room temperature, stirred for 2 h, and filtered.

The wet cake was washed with

isopropanol and dried at 40 ºC under vacuum for 48 h to give 2.87 kg (83 wt%, 3.38 kg assay, >99.6% ee) of 13 as an off-white solid: 1H NMR (CD3OD, 400 MHz), δ 1.37 (d, 3H, J =6.6 Hz), 1.62 (m, 1H), 2.02 (m, 2H), 2.17 (m, 1H), 3.27 (m, 2H), 3.63 (m, 1H), 4.38 (s, 2H); 13C NMR (CD3OD, 100 MHz) δ 16.2, 23.1, 31.4, 44.7, 55.9, 72.9, 175.8.

Preparation

of

4-((R)-4-(5-Bomo-3-methylpyridin-2-yl)-2-methylpiperazin-1-yl)-6-(4-

fluorophenyl)-2-((R)-2-methylpyrrolidin-1-yl)pyrimidine (14).

Two batches were conducted at

identical scale. In a 75 L reactor was charged 3.33 kg (6.98 mol) of 11, 2.57 kg (9.08 mol, 83 wt%, 2.14 kg by assay) of (R)-(-)-2-methylpyrrolidine tartrate 13, 4.83 kg (34.95 mol) of powdered K2CO3, and 28 L of dimethylacetamide. The resulting slurry was warmed to 95 °C for 18 h and then cooled to room temperature. The slurry was inversely quenched into a biphasic mixture of 20 L of MTBE and 35 L of water. The layers were separated and the organic layer was washed with water (2 X 28 L). The solvent was removed under reduced pressure while solvent switching to THF to a final volume of 16.7 L and a KF of ~225 ppm water (3.49 kg, 95% assay of 14) and used in the next step without further purification.

Preparation of 6-((R)-4-(6-(4-Fluorophenyl)-2-((R)-2-methylpyrrolidin-1-yl)pyrimidin-4yl)-3-methylpiperazin-1-yl)-5-methylnicotinic acid methanesulfonic acid salt (1). Two batches were ACS Paragon Plus Environment

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conducted at identical scale. To a 50 L reactor was added 3.46 kg (6.60 mol by assay) of 14 in 17.5 L of THF and the solution was cooled to -35 ºC. To the solution was added over 15 min 3.30 L (6.6 mol) of a 2M solution of i-PrMgCl in THF while maintaining the internal temperature < ̶ 25 ºC. To the mixture was added over 30 minutes 4.15 L (8.90 mol) of a 2.15 M solution of n-BuLi in hexanes while maintaining the internal temperature < ̶ 25 ºC. The resulting solution of the anion was stirred at the same temperature for 1 h. In a separate 50 L reactor was placed 9 L of THF and solution was cooled to 35 ºC and CO2 gas was bubbled into the THF for 20 min. The above solution of the anion was added to the solution of CO2/THF over 45 minutes while maintaining a constant bubbling of CO2 through the mixture.15 The mixture was allowed to warm to room temperature and quenched into a 100 L extraction vessel containing a biphasic mixture of 26 L of MTBE and 30 L of a 7.5% aqueous solution of KH2PO4 (2.25 kg of KH2PO4). The layers were separated and the organic layer was washed with water (2 X 20 L). To the organic layer was added 28.5 L of a 2:1 mixture of water/dimethylacetamide followed by 2.8 L (14.0 mol) of a 5N solution of aqueous NaOH to give a pH ~11. The layers were separated and the organic layer discarded. To the aqueous layer was added 25 L of MTBE and the biphasic mixture neutralized to pH ~6.0 by the addition of 750 mL of 85% H3PO4. The layers were separated and the organic layer was washed with water (2 X 13 L) to give 3.08 kg (95% by assay) of 1 in MTBE.

The two batches (5.78 kg by assay, 11.78 mol) of crude 1 were combined and concentrated under reduced pressure and solvent switched to a final volume of 47 L in DMSO. The solution was stirred at room temperature for 2 h to give a slurry of the DMSO solvate of 1. To the slurry was added 5.2 L of water over 30 min and the slurry was stirred at room temperature for 16 h, filtered, washed with 45 L of water, and dried for 3 h to give 9.8 kg (95%, 5.50 kg of 1 by assay, 65wt%). The DMSO solvate was added to a 100 L reactor containing 65 L of a 1.8:1 mixture of water/dimethylacetamide, 7.5 L of MTBE, and 2.25 L (11.3 mol) of a 5N aqueous solution of NaOH. The mixture was stirred at room temperature to completely dissolve the solids and then warmed to 45 ºC. To the solution was added 2.55 kg (26.6 mol) of MsOH over 30 minutes to give a slurry which was stirred at 50 ºC for 4 h. The ACS Paragon Plus Environment


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slurry was cooled to room temperature and filtered. The wet cake was washed with 55 L of water and dried at 65 ºC for 48 h under vacuum to give 6.30 kg (98%) of 1 was a white solid. 1H NMR (CD3OD, 400 MHz) δ 1.37 (d, 3H, J = 6.4 Hz), 1.48 (d, 3H, J =6.7 Hz), 1.84 (m, 1H), 2.09 (m, 1H), 2.17-2.25 (m, 2H), 2.42 (s, 3H), 2.66 (s, 3H), 3.10 (dt, 1H, J = 12.3 and 3.3 Hz), 3.28 (dd, 1H, J = 13.1 and 3.7 Hz), 3.65-3.72 (m, 3H), 3.78 (m, 1H), 3.87 (m, 1H), 4.49 (m, 1H), 4.63 (m, 3H), 4.96 (br m, 1H), 6.61 (s, 1H), 7.32 (m, 2H), 7.82 (m, 2H), 8.05 (m, 1H), 8.69 (d, 1H, J = 1.9 Hz); 13C NMR (CD3OD, 125 MHz) δ 19.4, 24.5, 33.5, 39.6, 41.5, 48.6, 50.0, 50.9, 54.1, 56.9, 94.8, 117.3 (d, J =22.5 Hz), 122.1, 125.0, 130.1 (d, J = 3.3 Hz), 131.8 (d, J =8.9 Hz), 142.1, 148.7, 153.1, 153.3, 162.4, 165.4, 166.4, (d, J = 251.3 Hz), 168.8;

19

F NMR (CD3OD, 470 MHz) δ -108.6. Anal. Calcd. For C28H35FN6O5S: C, 57.32; H,

6.01; N, 14.32. Found: C, 57.34; H, 6.13; N, 14.29.

Acknowledgment

The authors wish to thank Robert Reamer, Peter Dormer, and Lisa DiMichael of Merck & Co., Inc

for helpful NMR analysis of crude reaction mixtures to confirm structures of products and

impurities.

Note: The authors declare no competing financial interest. Supporting Information Available Full characterization data for all new compounds.

References

1

For recent reviews, see: (a) Szallasi, A.; Cortright, D. N.; Blum, C. A.; Eid, S. R. Nat. Rev. Drug

Discovery, 2007, 6, 357-372. (b) Broad, L. M.; Keding, S. J.; Blanco, M.-J.; Curr. Top. Med. Chem. 2008, 8, 1431-1441. (c) Khairatkar-Joshi, N.; Szallasi, A. Trends Mol. Med. 2009, 15, 14-22. (d) Vanilloid Receptor TRPV1 in Drug Discovery: Targeting Pain and Other Pathological Disorders; ACS Paragon Plus Environment

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Gomtsyan, A., Faltynek, C. R., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, 2010. (e) Luo, J.; Walters, E. T.; Carlton, S. M.; Hu, H. Curr. Neuropharm 2013, 11, 652-663. 2

(a) For leading references, see: (a) Julius, D. Annu. Rev. Cell Dev. Biol. 2013, 29, 355-384. (b)

Caterina, M. J.; Schumacher, M. A.; Tominaga, M.; Rosen, T. A.; Levine, J. D.; Julius, D. Nature 2007, 389, 816-824. (c) Szallasi, A.; Appendino, G. J. Med. Chem. 2004, 47, 2717-2723. 3

(a) Gavva, N. R.; Treanor, J. J.; Garami, A.; Fang, L.; Surapaneni, S.; Akrami, A.; Alvarez, F.; Bak,

A.; Darling, M.; Goer, A.; Jang, G. R.; Kesslak, J. P.; Ni, L.; Norman, M. H.; Palluconi, G.; Rose, M. J.; Salfi, M.; Tan, E.; Romanovsky, A. A.; Banfield, C.; Davar G. Pain 2008, 136, 202-210.

(b)

Gunthorpe, M. J.; Chizh, B. A. Drug Discovery Today 2009, 14, 56-67. (c) Krarup, A. L.; Ny, L.; Åstrand, M.; Bajor, A.; Hvid-Jensen, F.; Hansen, M. B.; Simrén, M.’ Funch-Jensen, P.p; Drews, A. M. Aliment. Pharmacol. Ther. 2001, 33, 1113-1122. (d) Rowbotham, M. C.; Nothaft, W.; Duan, W. R.; Wang, Y.; Faltynek, C.; McGaraughty, S.; Chu, K. L.; Svensson, P. Pain 2011, 152, 1192-1200. (e) Szallasi, A.; Sheta, M. Expert Opin. Invest. Drugs 2012, 21, 1351-1369. (f) De Petrocellis, L.; Moriello, A. S. Recent Pat. CNS Drug Discovery 2013, 8, 180—204. (g) Peppin, J. F.; Pappagallo, M. Ther. Adv. Neurol. Disord. 2014, 7, 22-32. (h) Voight, E. A.; Gomtsyan, A. R.; Daanen, J. F.; Perner, R. J.; Schmidt, R. G.; Bayburt, E. K.; DiDomenico, S.; McDonald, H. A.; Puttfarcken, P. S.; Chen, J.; Neelands, T. R.; Bianchi, B. R.; Han, P.; Reilly, R. M.; Franklin, P. H.; Segreti, J.A.; Nelson, R. A.; Su, Z.; King, A. J.; Polakowski, J. S.; Baker, S. J.; Gauvin, D. M.; Lewis, L. R.; Mikusa, J. P.; Joshi, S. K.; Faltynek, C. R.; Kym, P. R.; Kort, M. E. J. Med. Chem. 2014, 57, 7412-7424. 4

(a)

Blum, C. A.; Brielmann, H.; Chenard, B. L.; Zheng, X. Preparation of substituted biaryl

piperazinyl-pyridine analogues as capsaicin modulators. PCT Int. Appl. (2006), WO 2006026135 A2 20060309.

(b) Compound 1 was developed in collaboration with Neurogen Corporation, a Subsidiary

of Ligand Pharmaceuticals Inc., 11119 North Torrey Pines Road, Suite 200, La Jolla, CA 92037, USA.



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5

(R)-2-methylpiperazine 3 was purchased on kg scale from ChemPacific Corporation.

6

For a related SNAR displacement of 2,5-dibromo-3-methylpyridine with morpholine, see: Watterson,

S. H.; Chen, P.; Zhao, Y.; Dhar, T. G. M.; Xiao, Z.; Ballentine, S. K.; Shen, Z.; Fleener, C. A.; Rouleau, K. A.; Obermeier, M.; Yang, Z.; McIntyre, K. W.; Shuster, D. J.; Witmer, M.; Damback, D; Chao, S.; Mathur, A.; Chen, B.-C.; Barrish, J. C.; Robi, J. A.; Townsend, I. E. J. J. Med. Chem. 2007, 50, 37303742. 7

The conditions reported in this manuscript are slightly modified from the original conditions reported

in the literature, see: (a) Schomaker, J. M.; Delia, T. J. J. Org. Chem. 2001, 66, 7125-7128. (b) Delia, T. J.; Schomaker, J. M.; Kalinda, A. S.; J. Heterocyclic Chem. 2006, 43, 127-131. (c) Achelle, S.; Romondene, Y.; Marsais, F.; Ple, N. Eur. J. Org. Chem. 2008, 18, 3129-3140. 8

For an initial disclosure of our findings in this general area, see: Peng, Z.-H.; Journet, M. Humphrey,

G. Org. Lett. 2006, 3, 395-398. 9

The presence of 10 at ~1.5 mol% was established by quantitative HPLC analysis employing

analytically pure 10. 10

The decesion to utilize a higher catalyst charge for the Suzuki reaction discussed in Scheme 3 was

based on these highly optimized conditions with this level of advantatious catalyst 10 present. 11

(a) Zhao, D.; Kuethe, J. T.; Journet, M.; Peng, Z.; Humphrey, G. R. J. Org. Chem. 2006, 71, 4336-

4338. (b) Pu, Y.-M.; Grieme, T.; Gupta, A.; Plata, D.; Bhatia, A. V.; Cowart, M.; Ku, Y.-Y. Org. Process Res. and Dev. 2005, 9, 45-50. 12

The boiling point of (R)-2-methylpyrrolidine is 97-98 °C.


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13


For a leading reference, see: Knochel, P.; Dohle, W.; Gommermann, N., Kneisel, F. F.; Kopp, F.;

Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem. Int. Ed. 2003, 42, 4302-4320 and references cited therein. 14

For a leading reference on the formation and use of magnesium ate complexes, see: (a) Inoue, A.;

Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2001, 66, 4333-4339. (b) Tian, Q.; Cheng, Z.; Yajima, H. M.; Savage, S. J.; Green, K. L.; Humphries, T.; Teynolds, M. E.; Babu, S.; Gosselin, F.; Askin, D.; Kurimoto, I.; Hirata, N.; Iwasaki, M.; Shimasaki, Y.; Miki, T. Org. Process Res. Dev. 2013, 17, 97-107. 15

Commercially available lecture bottles of CO2 were employed. Continued bubbling of CO2 during

the addition of the anion insures saturation of CO2 in THF.


Development of a Multikilogram Scale Synthesis of a TRPV1

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