MK ? NGD?

MK 2295; NGD 8243 may be???????

CAS 878811-00-8 FREE FORM

6-[(3R)-4-[6-(4-fluorophenyl)-2-[(2R)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]-3-methylpiperazin-1-yl]-5-methylpyridine-3-carboxylic acid

6-{4-[6-(4-Fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinic acid

3-​Pyridinecarboxylic acid, 6-​[(3R)​-​4-​[6-​(4-​fluorophenyl)​-​2-​[(2R)​-​2-​methyl-​1-​pyrrolidinyl]​-​4-​pyrimidinyl]​-​3-​methyl-​1-​piperazinyl]​-​5-​methyl-

Neurogen Corp  INNOVATOR

MESYLATE

CAS 1855897-95-8

6-((R)-4-(6-(4-Fluorophenyl)-2-((R)-2-methylpyrrolidin-1-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)-5-methylnicotinic acid methanesulfonic acid salt

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;

¹⁹F 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.

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.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.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

PATENT

http://www.google.com.na/patents/US20110003813

6-{4-[6-(4-Fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinic acid 1. 1-(5-Bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine

• Heat a solution of 2,5-dibromo-3-methyl-pyridine (Chontech Inc., Waterford, Conn.) (2.0 g, 7.97 mmol), (R)-2-methyl-piperazine (ChemPacific Corp., Baltimore, Md.; 3.2 g, 31.9 mmol) in DMA at 130° C. for 16 h. Partition the reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na₂SO₄) and concentrate under reduced pressure to give 1-(5-bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine as a solid.

2. 2,4-dichloro-6-(4-fluorophenyl)pyrimidine

• Dissolve 4-fluorobromobenzene (8.75 g, 0.05 moles) in anhydrous ether (80 mL) under nitrogen atmosphere and cool to −78° C. Add dropwise 1.6 M n-BuLi (34 mL, 0.055 moles) and stir at −78° C. for 45 min. Dissolve 2,4-dichloropyrimidine (7.45 g, 0.05 moles) in Et₂O (100 mL) and add dropwise to the reaction mixture. Warm the reaction mixture to −30° C. and stir at this temperature for 30 min followed by 0° C. for 30 min. Quench the reaction mixture with AcOH (3.15 mL, 0.055 moles) and water (0.5 mL, 0.027 moles) dissolved in THF (5.0 mL). Add dropwise a THF (40 mL) solution of DDQ (11.9 g, 0.053 moles) to the reaction mixture. Bring the reaction mixture to room temperature and stir at room temperature for 30 min. Cool the reaction mixture to 0° C., add 3.0 N aq. NaOH (35 mL) and stir for 30 min. Decant the organic layer from the reaction mixture and wash the brown solid with Et₂O (3×100 mL). Combine the organic layers, wash several times with saturated NaCl solution and dry with MgSO₄. Filter and evaporate under vacuum to afford a brown colored solid. Purify by flash column chromatography using 5% EtOAc/hexane to afford the title product as a white solid.

3. 4-[4-(5-Bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-2-chloro-6-(4-fluoro-phenyl)-pyrimidine

• Heat a mixture of 2,4-dichloro-6-(4-fluoro-phenyl)-pyrimidine (6.0 g, 24.7 mmol), 1-(5-bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine (7.0 g, 25.9 mmol) and K₂CO₃ (6.8 g, 49.4 mmol) in DMA at 60° C. for 16 h. Partition the mixture between EtOAc and water, dry (Na₂SO₄) the organic layer and concentrate under reduced pressure. Purify with flash silica gel column eluting with 15% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound.

4. 4-[4-(5-Bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-6-(4-fluoro-phenyl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidine

• Heat a mixture of 4-[4-(5-bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-2-chloro-6-(4-fluoro-phenyl)-pyrimidine (7.7 g, 16.2 mmol), (R)-2-methylpyrrolidine hydrobromide [prepared essentially as described by Nijhuis et. al. (1989) J. Org. Chem. 54(1):209] (3.5 g, 21.1 mmol) and K₂CO₃ (5.1 g, 37.3 mmol) in DMA at 110° C. for 16 h. Partition the mixture between EtOAc and water, dry (Na₂SO₄) the organic layer and concentrate under reduced pressure. Purify with flash silica gel column eluting with 10% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound.
• 5. 6-{4-[6-(4-Fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinonitrile
• To a mixture of 4-[4-(5-bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine (700 mg, 1.33 mmol) and Zn(CN)₂ (94 mg, 0.799 mmol) in DMF, add Pd(PPh₃)₄ (77 mg, 0.067 mmol). Purge the reaction mixture for 10 min with dry N₂. Heat the stirring reaction mixture overnight at 80° C., cool to room temperature and partition between water and EtOAc. Dry the solution (Na₂SO₄), concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:1) to afford the title compound as a white solid.
• 6. 6-{4-[6-(4-Fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinic acid
• Heat a solution of 6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-nicotinonitrile (100 mg, 0.212 mmol) in 12 M HCl for 3 hours at 90° C. Concentrate the mixture under reduced pressure. Add a small amount of water, adjust the pH to 6-7, and collect the resulting white precipitate to afford the title compound as a off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 1.24 (m, 6H, 2×CH₃))_; 1.61 (m, 1H,); 1.84 (m, 1H); 1.98 (m, 2H); 2.34 (s, 3H, Ar—CH₃); 2.91 (m, 1H); 3.08 (m, 1H); 3.26 (m, 2H); 3.56 (m, 2H); 3.74 (m, 1H); 4.21 (m, 1H); 4.35 (m, 1H); 4.74 (m, 1H); 6.57 (s, 1H); 7.26 (m, 2H); 7.91 (d, 1H, J=3 Hz); 8.15 (m, 2H); 8.60 (d, 1H, J=3 Hz).

END…………………

MESYLATE NMR

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;

¹⁹F NMR (CD₃OD, 470 MHz) δ −108.6.

PATENT

http://www.google.ga/patents/WO2006026135

Scheme 1

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Scheme 10

Scheme 14

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Scheme 17

Scheme 18

Scheme 19

Scheme 20

In

6-{4-[6~(4-Fluoro-phenyl)-2-(2~methyl-pyrrolidin-l-yl)-pyrimidin-4-yl]-3-(R)-met}τyl- piperazin-l-yl}-5-methyl-nicotinic acid

Heat a solution of 6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-l-yl)-pyrimidin-4-yl]- 3-(R)-methyl-piperazin-l-yl}-5-methyl-nicotinonitrile (100 mg, 0.212 mmol) in 12 M HCl for 3 hours at 9O⁰C. Concentrate the mixture under reduced pressure. Add a small amount of water, adjust the pH to 6-7, and collect the resulting white precipitate to afford the title compound as a off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 1.24 (m, 6H, 2xCH₃)); 1.61 (m, 1Η,); 1.84 (m, 1Η); 1.98 (m, 2Η); 2.34 (s, 3H, Ar-CH₃); 2.91 (m, 1Η); 3.08 (m, 1Η); 3.26 (m, 2Η); 3.56 (m, 2H); 3.74 (m, IH); 4.21 (m, IH); 4.35 (m, IH); 4.74 (m, IH); 6.57 (s, IH); 7.26 (m, 2H); 7.91 (d, IH, J = 3Hz); 8.15 (m, 2H); 8.60 (d, IH, J = 3Hz).

PAPER

Development of a Multikilogram Scale Synthesis of a TRPV1 Antagonist

Abstract

A highly efficient, regioselective five-step synthesis of the TRPV1 antagonist 1 is described. The coupling of piperazine 7 with dichloropyrimidine 8 proceeded via a regioselective Pd-mediated amination affording product 11 in excellent yield. Conversion of the penultimate product 14 afforded 1 through formation of a magnesium ate complex and trapping with CO₂.

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.5b00388

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.5b00388/suppl_file/op5b00388_si_001.pdf

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n1c(nc(cc1c2ccc(cc2)F)N3CCN(C[C@H]3C)c4ncc(cc4C)C(=O)O)N5CCC[C@H]5C