Tetrahydropyranyl-4-acetic acid

white to light yellow crystal powder

A solution of sodium hydroxide (15.9 g, 44.06 mmol) in water (150 ml) was added dropwise to a solution of ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate (15 g, 8.81 mmol) in methanol (150 ml) at a temperature of 0 °C or below, and the mixture was stirred at room temperature for 15 hr. The solvent of the reaction mixture was removed by distillation under reduced pressure, and the water layer was adjusted to pH 3 by the addition of 1 M hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give a corresponding acid as a colorless solid (12.0 g, 94percent). This compound was used in the next step without further purification. Benzyl bromide (14.3 g, 83.33 mmol) was added dropwise to a suspension of this compound (10.0 g, 69.44 mmol) and anhydrous potassium carbonate (28.8 g, 208.3 mmol) in acetonitrile (100 ml) at room temperature, and the mixture was refluxed for 48 hr. The solvent of the mixture was removed by distillation under reduced pressure, the residue was diluted with water and was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on silica gel column (hexane:ethyl acetate = 9:1) to give the tile compound as an oil (12.0 g, yield 75percent). 1H-NMR (400 MHz, CDClGeneral procedure: Lithium hydroxide monohydrate (151.7 mmol), as a solution indistilled water (79.5 mL, 1.9 M), was added to a solution of the ester (7.59 mmol) in THF (79.5 mL, 0.1 M) at room temperature in air and stirred at 60 C for 90 min. The mixture was cooled to room temperature, acidified to pH 0 with 1M HCl and partitioned with EtOAc (20 mL). The aqueous layer was extracted with EtOAc (20 mL) and the organic layer was washed with brine (20 mL), dried (MgSO4), filtered, and concentrated under vacuum to give the desired compound, which was taken forward without purification.A solution of tetrahydropyran-4-yl acetic acid (Combi-Blocks, Inc., 0.18 g, 1.2 mmol) in thionyl chloride (7 mL, 96 mmol, excess) was refluxed for 1 h then was cooled to ambient temperature and concentrated under reduced pressure. The residue was azeotroped twice with 10 mL of benzene to remove any remaining thionyl chloride. The resulting acid chloride was used without further purificationTo a solution of (tetrahydropyran-4-yl)acetic acid (500mg, 3.47mmol) in thionyl chloride (1OmL) was added DMF (1 drop). The reaction was heated to reflux for Ih, cooled to rt and the solvent removed in vacuo. The residue was redissolved in THF (5mL) and added dropwise to a solution of methylamine hydrochloride (2.34g, 34.7mmol) and NaOH (1.1 Ig, 27.7mmol) in water. The solution was stirred for 30min and EtOAc (10OmL) added. The mixture was extracted with EtOAc (5 x 10OmL) and the combined organic phase dried (MgSOzi). Solvent was removed in vacuo to give the title compound: delta' (CDCl5) 1.14-1.33 (2H, m), 1.48-1.63 (3H, m), 1.97-2.07 (2H, m), 2.74 (3H, s), 3.26-3.41 (2H, m), 3.87 (2H, dd), 5.34 (IH, bs).To a solution OF TETRAHYDROPYRAN-4-YLACETIC acid (5 g, 35 MMOL) in DCM (70 ML) was added oxalyl chloride (4.6 ML, 52.5 MMOL) dropwise followed by DMF (2 drops) and the mixture was stirred at room temperature for 3h. After this time the reaction was concentrated in vacuo and the residue was dissolved in THF (25 ml) then added to a suspension of compound (F) (5.67 g, 25 MMOL) in THF (50 mi) and pyridine (4 ML, 50 MMOL). The reaction was heated at 50C for 4h then concentrated in vacuo. A mixture of a saturated aqueous solution of NAHCO3 (150 ml) followed by ethyl acetate (150 ml) was added to the residue, which resulted in the formation of a solid. The solid was collected by filtration, which was washed with ethyl acetate to give the desired product as an off white solid (4.81 g, 55%). ON (250 MHz, DMSO) 1.30-1. 36 (m, 2H), 1.60-1. 66 (m, 2H), 1.97- 2.03 (m, 1H), 2.29 (s, 3H), 2.39 (d, J 7.5, 2H), 3.26-3. 31 (m, 2H), 3.81- 3.87 (m, 2H), 8.32 (d, J 1.2 1H), 8.77 (d, J 1.2, 1H), 10.11 (s, 1H); M/Z (APCI) 353 (M+) ; HPLC 99%.Oxalyl chloride (5 mi) and DMF (1 drop) were added to a solution of Intermediate 28 (10 g) in DCM (100 ML). The mixture was stirred for 3 h, then EVAPORATED IN VACUO and thoroughly azeotroped with toluene. The residue was dissolved in THF (30 ml) and added dropwise to a solution of (R)- BENZYLOXAZOLIDINONE (12.1 g) and nBuLi (2.5M in hexanes, 30 ml) in THF (200 mi) AT-78C. The solution was stirred for 2 h, then quenched with saturated aqueous ammonium chloride (100 ml) and evaporated in vacuo. The mixture was extracted with EtOAc (100 ML), solvent washed with water (100 ML) and brine, dried (MGS04) and evaporated to give the title compound as a colourless solid (14 g). MS 304 (M + H)N-[6-(4-Morpholinyl)-3-pyridinyl]-2-(tetrahydro-2H-pyran-4-yl)-N-[(1-(at)[4- (trifluoromethyl)phenyl]methyl)-4-piperidinyl)methyl]acetamide; Oxalyl chloride (0.27ml, 3.05mmol) was added to a stirred solution of tetrahydro-2H- pyran-4-ylacetic acid (0.2g, 1.38mmol) in DCM (10ml). DMF (1 drop) was added and the reaction mixture stirred at room temperature for 1.5h then evaporated in vacuo to afford a colourless oil (1.17g). The crude acid chloride was dissolved in DCM (10ml) and added to a stirred solution of 6-(4-morpholinyl)-N-[(1-{[4-(trifluoromethyl)phenyl]methyl)-4- piperidinyl) methyl]-3-pyridinamine D5 (0.45g, 1.03mmol) and triethylamine (0.58ml, 4.12mmol) in DCM (10ml). After 24h the mixture was washed with saturated sodium hydrogen carbonate, the organic layer separated by passage through a phase separation cartridge and evaporated in vacuo. Chromatography on silica gel eluting with 50-100% ethyl acetate in pentane gradient afforded the title compound as an orange gum (0.47g). A 70mg portion was dissolved in 1:1 DMSO/MeCN (0.9ml) and purified by mass directed autoprep hplc on a Waters C18 5muM column 8(id 19 x 100mm) eluting with 5 - 99% MeCN in water gradient containing 0.1 % formic acid. Fractions containing the desired material were passed through a 2g SCX column, the column washed with methanol (30ml) and eluted with 1 N ammonia in methanol to afford the title compound as a colourless gum (0.05g). Mass Spectrum (AP+): Found 561 (MH+). C30H39F3N403 requires 560.Oxalyl chloride (1.33ml, 15.3mmol) was added to a stirred solution of The starting materials are prepared as follows:; a) N-{2-[(2S, 5R)-5-[4-(3-Methoxypropyn-3, 4-dihvdro-2H-benzo[1 , 4loxazin-6- ylmethoxyl-1 -(toluene-4-sulphonyl)piperidin-2-yll-1 , 1 -dimethylethyl)-2- (tetrahydropyran-4-yl)acetamide; A solution of 0.511 mmol of tetrahydropyranyl-4-acetic acid [85064-61-5] in 5 ml of dichloromethane is treated with 1.023 mmol of 1-chloro-N, N-2-trimethylpropenyl- amine. The reaction mixture is stirred at room temperature for 1.5 hours. In a second flask, a solution of 0.341 mmol of 2-[(2S, 5R)-5-[4-(3-methoxypropyl)-3, 4-dihydro-2H- benzo[1 , 4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-1 , 1 -dimethyl- ethylamine in 10 ml of dichloromethane are treated with 1.023 mmol of triethylamine, and cooled to 00C. The solution of acid chloride is added dropwise to this second flask, and the reaction mixture is stirred at room temperature for 2 hours. Water is added, and the aqueous phase is extracted with dichloromethane (3X). The combined organic extracts are dried over sodium sulphate, concentrated and purified by flash chromatography (Sitheta2 60F) to afford the title compound as a dark yellow resin. Rf = 0.20 (dichloromethane-methanol-conc ammonia); Rt = 4.94 (gradient I).General procedure: To a solution of 8 (0.2 mmol, 1 equiv) in CH2Cl2 (2 mL) were added TEA (0.6 mmol, 3 equiv), N, N, N?, N?-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU, 0.26 mmol, 1.3 equiv) and the appropriate carboxylic acid (1.25 equiv). The reaction was stirred overnight and then concentrated. Flash chromatography, using a silicagel column with a gradient of 0'100percent EtOAc/hexanes, provided the purified amide.A mixture of (rac)-ethyl 4, 5-dimethyl-17-[3-(naphthalen-1-yloxy)propyl]-7, 8, 9, 14-tetrahydro-5H- indolo[1 , 7-bc]pyrazolo[4, 3-e][2, 8]benzodiazacycloundecine-16-carboxylate (see intermediate 31, 150 mg, 251 mihoI), (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (143 mg, 276 pmol), General procedure: Step 5a: The mixture of the crude compound 11a (1.0 eq) orcompound 11b (1.0 eq), HATU (1.5 eq), different acid (1.1 eq) andDIPEA (3.0 eq) in DCM was stirred at room temperature overnightunder N2 atmosphere. When the starting material wasconsumed completely, the mixture was washed with saturatedNaHCO3 solution and water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reducedpressure to afford the crude product, which was purified bycolumn chromatography to afford the target compounds (2a, 2d, 3a-3d, 4a-4d, 5a, 5b, 5e-5h and 6a-6f). Enantiomers (S)-5c and(R)-5d were obtained by chiral HPLC separation of 5b.General procedure: Step 5a: The mixture of the crude compound 11a (1.0 eq) orcompound 11b (1.0 eq), HATU (1.5 eq), different acid (1.1 eq) andDIPEA (3.0 eq) in DCM was stirred at room temperature overnightunder N2 atmosphere. When the starting material wasconsumed completely, the mixture was washed with saturatedNaHCO3 solution and water, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reducedpressure to afford the crude product, which was purified bycolumn chromatography to afford the target compounds (2a, 2d, 3a-3d, 4a-4d, 5a, 5b, 5e-5h and 6a-6f). Enantiomers (S)-5c and(R)-5d were obtained by chiral HPLC separation of 5b.At room temperature, to the containing 1-(3-(3-amino-5-chloro-2-methylbenzyl)-3, 8-diazabicyclo[3.2.1]octan-8-yl)-2-cyclobutylethan-1-one (150.0 mg, 0 . 42 mmol) in dichloromethane solution, adding N, N - diisopropyl ethylamine (160.8 mg, 1 . 25 mmol) and At room temperature, to the containing N-(3-((3, 8-diazabicyclo[3.2.1]octan-3-yl)methyl)-5-chloro-2-methoxyphenyl)-6-methylnicotinamide (100 mg, 0 . 26 mmol) in dichloromethane solution, adding N, N - diisopropyl ethylamine (100.6 mg, 0 . 78 mmol), added to clarify the solution 0 °C lower, comprising the

Molecular Weight:144.17
XLogP3:0.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:144.078644241
Monoisotopic Mass:144.078644241
Topological Polar Surface Area:46.5
Heavy Atom Count:10
Complexity:116
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes