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With thionyl chloride; at 60℃; for 1h; |
Step 1. Benzyl tetrahydropyran-4-yl-carboxylate A mixture of tetrahydropyran-4-yl-carboxylic acid (910 mg, 6.99 mmol) and SOCl2 (5.0 mL) was stirred for 1 h at 60 C. and concentrated in vacuo. To the residue were added benzyl alcohol (1.52 g, 14.1 mmol) and tetrahydrofuran (5.0 mL) at ambient temperature. The resulting mixture was stirred for 13 h at ambient temperature and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (silica gel, eluding with hexane/ethyl acetate (2:1)) to give 1.08 g (70%) of the title compound as a pale yellow oil. 1H NMR (CDCl3) delta 7.45-7.25 (5H, m), 5.13 (2H, s), 3.95 (2H, m), 3.42 (2H, m), 2.59 (1H, m), 1.94-1.68 (4H, m). |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; for 1h; |
Example 24; Tetrahydro-pyran-4-carboxylic acid [6-(3-pyridin-3-yl-5- trifluoromethyl-pyrazol-l -yl)-pyridin-3-yl]-amide; Step a; Tetrahydro-pyran-4-carboxylic acid (175 rng, 1.3 mmol) is dissolved in dichloromethane (7 mL) and oxalyl chloride (0.23 mL, 2.6 mmol), and catalytic amounts of dimethylformamide are added. The solution is stirred for one hour after which all volatiles are evaporated. The residue is dried under high vacuum for three hours and the resulting product, tctrahydro-pyran-4-carbonyl chloride (192 mg, 100%), is used without further purification. |
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With thionyl chloride; at 20℃; for 1h; |
0.13 g (10 mmole) tetrahydropyran-4-yl-carboxylic acid and 5.1 ml (70 mmole) thionylchloride were stirred at RT for 1 h. Thereafter, thionylchloride was removed under vacuum and the oily residue was dissolved in 2 ml dichloromethane. 358 mg (10 mmole) 4-[5-(4-fluoro-phenyl)-3-(2-methoxy-ethyl)-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-ylamine were dissolved in 10 ml pyridine and cooled to 0-5C in an icebath. The dichloromethane solution containing tetrahydropyran-4-yl-carboxylic acid chloride was added dropwise, the mixture was kept at 0-5C. After 2 h, the solvent was removed, the residue dissolved in ethyl acetate, washed with water, dried over sodium sulfate and concentrated under vacuum. The product was purified by chromatography on silica (Methanol / Ethyl acetate 2.5/97.5). |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0℃; for 1h; |
Step A: To an ice-cold suspension of tetrahydro-2H-pyran-4-carboxylic acid (0.65 g, 5.0 mmol) in dichloromethane (20 mL) was added oxalyl chloride (0.47 mL, 5.0 mmol) dropwise followed by a few drops of anhydrous DMF. After the ice-water bath was removed, the mixture was stirred for 1 h. To the above solution was added 2-amino-3-hydroxybenzoic acid hydrobromide (1.17 g, 5.0 mmol) followed by triethylamine (2.09 mL, 15.0 mmol). The resulting reaction mixture was stirred at room temperature for 17 h. The reaction was quenched with 1 N HCl (20 mL) and extracted with dichloromethane. The aqueous phase was further extracted with dichloromethane (2×200 mL). The combined organic phase was washed with water (2×100 mL), dried (Na2SO4), filtered and concentrated to afford a light yellow solid. The crude solid was dissolved in toluene (10 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (1.42 g, 7.46 mmol). The reaction mixture was then heated to reflux under nitrogen for 10 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate (2×250 mL). The organic phase was separated, washed with water, brine, dried (Na2SO4), filtered and concentrated to afford the 2-(tetrahydro-2H-pyran-4-yl)benzoxazole-4-carboxylic acid (590 mg, 49%) as a light brown solid: 1H NMR (500 MHz, DMSO-d6) delta 12.90 (br s, 1H), 7.93 (dd, J=7.9, 1.0 Hz, 1H), 7.86 (dd, J=7.9, 1.0 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 3.97-3.92 (m, 2H), 3.55-3.48 (m, 2H), 3.38-3.30 (m, 1H), 2.07-2.02 (m, 2H), 1.92-1.82 (m, 2H); MS (ESI+) m/z 248 (M+H). |
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With thionyl chloride; In dichloromethane; at 0 - 20℃; for 23h; |
Method 2: Synthesis of [4-(6-Methyl-benzothiazol-2-yl)-[l,4]diazepan-l-yl]-(tetrahydro- pyran-4-yl)-methanone <n="33"/>Step 1: Synthesis of 4-(Tetrahydro-pyran-4-carbonyl)-[l,4]diazepane-l-carboxylic acid tert-butyl ester; To a solution of 5 g (38.5 mmol) of tetrahydro-pyran-4-carboxylic acid in anhydrous dichloromethane (50 rnL) at 0 0C is added 7 rnL (96.2 mmol) of thionyl chloride dropwise. The reaction mixture is stirred at room temperature for 23 h. The reaction is concentrated under reduced pressure, dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to 0 0C. To this cooled solution 7.17 mL (36.9 mmol) of [l,4]diazepane-l-carboxylic acid tert-butyl ester and 25.5 mL (231 mmol) of triethylamine in anhydrous tetrahydrofuran (50 mL) are added dropwise over 15 min. The reaction mixture is stirred at room temperature for 18 h. The reaction is concentrated under reduced pressure and the residue is dissolved in dichloromethane (100 mL). The organic layer is washed with saturated aqueous ammonium chloride solution (100 mL), saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL). The organic layer is dried (Na2SO4), filtered and the filtrate is concentrated <n="34"/>under reduced pressure to afford 8.58 g of 4-(tetrahydro-pyran-4-carbonyl)-[l,4]diazepane-l- carboxylic acid tert-butyl ester. ES MS m/z 313 (M+H). |
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With thionyl chloride; at 80℃; for 1h; |
To compound 64A (3.Og, 23.1mmol) was added SOCb (SmL) and the solution was stirred and heated to 800C for 1 hour. Reaction was concentrated under vacuum. Crude product was added to a suspension of AICI3 (5.84g, 43.8mmol) in benzene (2OmL) and the <n="166"/>solution was stirred and heated to 75C for 1 hour. Allowed to cool, poured into ice water, extracted with CH2CI2, dried (MgSO*), filtered and concentrated. Crude residue was purified by flash column chromatography using silica gel (20%EtOAc/hexanes) to yield compound 64B (3.4g, 78%). |
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With thionyl chloride; at 20℃; for 0.5h; |
TETRAHYDRO-2H-PYRAN-4-CARBOXYLIC acid (83 mg, 0.64 mmol) was dissolved in 4 mL of thionyl chloride and the solution was stirred for 30 min at room temperature. The solvent was removed under vacuum and the resulting oil was dissolved in 1 mL dichloromethane. This solution was added dropwise to a solution of N-phenyl-4, 4'-bipyridine-2,2'-diamine (160 mg, 0.61 mmol) in 10 ML of pyridine. After lh stirring, the solvent was removed under vacuum and the crude product was purified by HPLC: column: Terra) prep MSCS, gradient 20-80% B, 20mL/min, 40C, (A-0. 1M NH40Ac in 0. 1 % CH3CN aqueous solution, B-CH3CN). Yield: 48% (110 mg). 1H NMR (400 MHz, CDCl3) : 8 8.49 (s, 1 H), 8. 32 (d, J=6. 1 Hz, 1 H), 8.28 (d, J=4. 5 Hz, 1 H), 8.05 (s, 1 H), 7.42-7. 33 (m, 4 H), 7.23- 7.19 (m, 1 H), 7.09-7. 03 (m, 2 H), 6.99 (d, J=5. 6 Hz, 1 H), 6.71 (s, 1 H), 4.10-4. 02 (m, 2 H), 3.51-3. 41 (m, 2 H), 2.59-2. 49 (m, 1 H), 1.95-1. 84 (m, 4 H). 13C NMR (101 MHz, CDCl3) : 8 172.97 (s, 1 C), 156.66 (s, 1 C), 152.05 (s, 1 C), 149.20 (s, 1 C), 148.43 (s, 1 C), 147.38 (s, 1 C), 140.17 (s, 1 C), 129.38 (s, 2 C), 123.07 (s, 1 C), 120.35 (s, 2 C), 117.82 (s, 1 C), 113.24 (s, 1 C), 111.70 (s, 1 C), 106.29 (s, 1 C), 67.07 (s, 2 C), 43.26 (s, 1 C), 29.01 (s, 2 C). MS (TSP) 7N/Z (M+1) : 375.; TETRAHYDRO-2H-PYRAN-4-CARBOXYLIC acid (97.5 mg, 0.75 mmol) was dissolved in 5 ML of thionyl chloride and the solution stirred for 30 min at room temperature. The solvent was removed under vacuum and the resulting oil was dissolved in 2 mL dichloromethane. This solution was added dropwise to a solution of N- (4-FLUOROPHENYL)-4, 4'-bipyridine-2,2'- diamine (70 mg, 0.25 mmol) in 10 mL of pyridine. After LH STIRRING, the solvent was removed under vacuum and the crude product was purified by HPLC column: XTERRA (E prep MSCS, gradient 20-80% B, 20ML/MIN, 40C, (A-0. 1M NH40AC in 0.1% CH3CN aqueous solution, B-CH3CN). Yield: 47% (130 MG).'H NMR (400 MHz, DMSO-D6) : 8 10.63 (s, 1 H), 9.31 (s, 1H), 8.49 (s, 1 H), 8.43 (d, J=5. 1 Hz, 1 H), 8.25 (d, J=5. 6 Hz, 1 H), 7.76-7. 69 (m, 2 H), 7.45-7. 40 (m, 1 H), 7.14-7. 06 (m, 4 H), 3.94-3. 87 (m, 2 H), 2.83- 2.73 (m, 1 H), 1.74-1. 64 (m, 4 H). MS (TSP) M/Z (M+1) : 393. |
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With thionyl chloride; for 1h; |
Methyl 3-ANILINO-5- {2-[(TERT-BUTOXYCARBONYL) AMINO] PYRIDIN-4-YL LBENZOATE (from examplel) (1.28 g, 3.05 mmol) was treated with trifluoroacetic acid (5 mL) in dichloromethane (10 mL) for 3h at room temperature. The solvent was evaporated under vacuum. The resulting material was dissolved in an aqueous solution of potassium carbonate (20 ML) and extracted with dichloromethane. The organic layer was dried over potassium carbonate, filtered and evaporated under vacuum to give the deprotected 2- aminopyridine derivative. Tetrahydro-2H-pyran-4-carboxylic acid (390 mg, 3.0 mmol) was dissolved in 15 mL thionyl chloride and this solution was stirred for 1h. After evaporation of the solvent the resulting oil was dissolved in dichloromethane (2 mL). This solution was added dropwise to a solution of the deprotected 2-aminopyridine derivative in pyridine (30 mL) at 0C under nitrogen atmosphere. After lh stirring, the solvent were removed under vacuum and the crude compound purified by flash chromatography (ethyl acetate/DME: 2/1). Yield: 64% (850 mg). 1H NMR (400 MHz, CDCl3) : B 8.49 (s, 1 H), 8.29 (d, J=6. 1 Hz, 1 H), 8.10 (s, 1 H), 7.80 (s, 2 H), 7.46 (m, 1 H), 7.34 (m, 3 H), 7.29-7. 25 (m, 1 H), 7.13 (d, J=7. 6 Hz, 3 H), 7.02 (t, J=7. 6 Hz, 2 H), 5.92 (s, 1H), 4.06 (m, 2H), 3.92 (s, 3H), 3.47 (td, J= 11.1/3. 1 Hz, 2H), 2.55 (m, 1H), 1.96-1. 85 (m, 4H). MS (TSP) m/z (M+1) : 432. |
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With thionyl chloride; In tetrahydrofuran; |
Example 260 Tetra hyd ro-pyra n-4-ca rboxyl ic acid (3-f4-(3-morpholin-4-yl-3-oxo-propenLrl -2,3- bis-trifiuoromethvi-phenvisuifanv.]-phenyi}-amide; [0527] Product of Example 4 was reacted with potassium carbonate and tetrahydro-pyran-4-carbonyl chloride ( prepared from tetrahydro-pyran-4- carboxylic acid and thionyl chloride in tetrahydrofuran) to afford the crude product that was purified by trituration with methanol to afford the final product. MS ESI (+) m/z 589 (M+H+). |
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With thionyl chloride; In dichloromethane; at 0 - 20℃;Inert atmosphere; |
Example 11; Synthesis of 4-(Tetrahydro-pyran-4-carbonyl)-[1,4]diazepane-1-carboxylic acid (4,5-dimethyl-isoxazol-3-yl)-amide (Compound 233 in Table 1, Method L); To a solution of 6 g (46.1 mmol) of tetrahydro-pyran-4-carboxylic acid in anhydrous DCM (60 mL) were added dropwise 8.4 mL (115.3 mmol) of thionyl chloride at 0 C. under a nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred for 18 h. The solvent was removed under reduced pressure to give the crude acid chloride, which was dissolved in anhydrous THF (60 mL). |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃;Inert atmosphere; |
Example 2: Lambda/-(4-(4-(3-(3-terf-Butyl-1 -p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1 -yloxy) pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamideTo a suspension of tetrahydro-2/-/-pyran-4-carboxylic acid (38.5 mg, 0.296 mmol) in dry DCM (3.0 mL) under nitrogen at 00C was added oxalyl chloride (29.2 mul, 0.345 mmol) followed by DMF (1 drop) and the mixture maintained at 00C for 20 min and then warmed to RT. After 1 hr the mixture was cooled to 00C, and Intermediate A1 (50 mg, 0.099 mmol) and DIPEA (86 mul, 0.493 mmol) were added. The reaction mixture was kept at 00C for 30 min and was then warmed to RT and after 2.25 hr was quenched by the addition of a solution of 1% NH3 in MeOH (2.0 mL). After a further 30 min the resulting mixture was evaporated in vacuo and the residue was subjected to SCX capture and release. The crude product so obtained was purified by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-85%, gradient elution) to afford the title compound, Example 2, as a white solid (25 mg, 41%); R' 2.43 min (Method 2); m/z 619 (M+H)+ (ES+); 1H NMR (400MHz, DMSO-d6) delta: 1 .29 (9H, s), 1.48-1.64 (4H, overlapping m), 2.40 (3H, s), 2.68 (1 H, m), 3.27 (2H, dt), 3.84 (2H, m), 6.41 (1 H, s), 6.71 (1 H, dd), 7.33 (1 H, d), 7.38 (2H, d) 7.47 (2H, d), 7.57 (1 H, m), 7.65 (1 H, m), 7.67 (1 H, d), 7.84 (1 H, dd), 7.97 (1 H, d), 8.09 (1 H, d), 8.18 (1 H, d), 8.62 (1 H, br s), 9.14 (1 H, br s), 10.49 (1 H, br s). |
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With thionyl chloride; at 10 - 20℃; |
Reference Example 5; 2-bromo-1-(tetrahydro-pyran-4-yl)-ethanone; Thionyl chloride (2 mL, 27 mmol) was added to tetrahydro-pyran-4-carboxylic acid (1.1 g, 8.4 mmol) at 10 C. The mixture was warmed to ambient temperature and stirred for 2 h. Excess thionyl chloride was evaporated and the residue co-distilled with toluene to remove the traces of thionyl chloride. The resulting crude acid chloride was dissolved in dry acetonitrile (3 mL) and cooled to 0 C. Trimethylsilyl diazomethane (12.6 mL, 25.3 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. It was then cooled to -10 C. and a solution of 15% HBr in acetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 h then quenched with saturated sodium bicarbonate solution and extracted with ether (3×20) mL). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-bromo-1-(tetrahydro-pyran-4-yl)-ethanone (620 mg, 35%) as an oil. |
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With oxalyl dichloride; In tetrahydrofuran; methanol; dichloromethane; N,N-dimethyl-formamide; at 20℃; for 2h;Product distribution / selectivity; |
A mixture of tetrahydro-2H-pyran-4-carboxylic acid (200 mg), oxalyl chloride (0.13 mL), DMF (0.010 mL), and dichloromethane (0.85 mL) was stirred at room temperature for 2 hours. To the reaction mixture were added methyl 3-[acetyl(cyclopropylmethyl)amino]-5-({5-[(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)benzoate (170 mg) and 4-dimethylaminopyridine (101 mg), followed by stirring at room temperature for 4 hours. To the reaction mixture was added hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80) to obtain a light yellow oily substance. A mixture of the obtained oily substance, a 1 M aqueous sodium hydroxide solution (1 mL), methanol (1 mL), and tetrahydrofuran (1 mL) was stirred at room temperature for 2 hours. To the reaction mixture was added 1 M hydrochloric acid to adjust the pH to 4, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 3-[acetyl(cyclopropylmethyl)amino]-5-({5-[(cyclopropylmethyl)(tetrahydro-2H-pyran-4-ylcarbonyl)amino]pyrazin-2-yl}oxy)benzoic acid (175 mg) as a white amorphous substance. |
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With thionyl chloride; at 85℃; for 1h; |
SOCl2 (8 mL) was added to tetrahydro-2H-pyran-4-carboxylic acid (3.0 g, 23.1 mmol) and the resulting mixture was heated at 85 C (oil temp.) for 1 h and cooled to rt. Removal of volatile materials gave crude acid chloride as pale yellow liquid.It was diluted with benzene (12 mL) and added slowly to a suspension of A1C13 (5.84 g, 43.8 mmol) in benzene (12 mL). After addition, the resulting mixture was heated at 75 C for 1 h, cooled to rt, poured onto ice/H20, extracted with DCM and purified by flash chromatography (EtOAc/hex 20 %) to give phenyl(tetrahydro-2H-pyran-4-yl)methanone (light yellow solid, 3.15 g, 72 %). ? NMR (400 MHz, CDCl3) delta 7.64 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 2H), 4.07 (tt, J = 1 1.6 Hz, 2.8 Hz, 2H), 3.58 (dt, J = 1 1.6 Hz, 2.5 Hz, 2H), 3.54-3.48 (m, 1H), 1.96-1.84 (m, 2H), 1.83-1.77 (m, 2H). |
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With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 3h;Cooling with ice; |
To an ice-cooled mixture of Compound I (1.0 g) and methylene chloride (15 mL) were added dropwise DMF (10 muL) and thionyl chloride (1.17 mL), and then the mixture was stirred at room temperature for 3 hours, and the reaction mixture was concentrated under reduced pressure. To the resulting residue was added methylene chloride (10 mL), and the mixture was ice-cooled, and then thereto was added aluminum chloride (1.23 g). The mixture was stirred for 1 hour, and then thereto was added dropwise a solution of 2-bromo-3-methylthiophene (860 muL) in methylene chloride (5.0 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 80/20 to 60/40) to give Compound II (550 mg). |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; |
Tetrahydro-2H-pyran-4-carboxylic acid (3 g, 23.052 mmol) was dissolved in dry DCM (20 mL) and one drop of DMF added. The reaction mixture was cooled to 0C before Oxalyl chloride (2.212 ml, 25.357 mmol) was added dropwise and the reaction mixture stirred at rt under nitrogen for 2 hours. Solvent was removed in vacuo after this time, before the residue was redissolved in DCM (20 mL) and the resulting solution was added dropwise to a solution of Trimethylsilyldiazomethane (20.75 ml, 41.493 mmol) (2M in hexane) at -10C. The reaction mixture was stirred at rt overnight. The reaction mixture was cooled to -10C again after this time before aqueous Hydrobromic acid(2.4 ml, .00 mmol) (48% in water) was added dropwise. The reaction mixture was allowed to stir at rt for 1 h before being diluted with sat. NaHC03 (aq) and brine. The layers were separated and the aqueous extracted a further 2 times with DCM. The combined organics were dried over MgS04, filtered and solvent removed in vacuo to afford crude material as a brown oil. Crude material was purified by column chromatography (normal phase, 50g, Biotage SNAP cartridge KP-Sil, 50mL per min, gradient 0% to 60% EtOAc in n-hexane 10CV) to afford the title compound (3.413 g, 16.48 mmol, 71.5 % yield) as yellow crystals. |
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With thionyl chloride; at 0℃; for 2h; |
Tetrahydro-2H-pyran-4-carboxylic acid (10 g,76.84 mmol) was added into a flask and thionyl chloride (20 mL, 275.7 mmol) was added drop wise at 0 C. The mixture was stir at this temp for 2 h and then the volatiles were removed under vacuum to afford the acid chloride which was directly dissolved in dichloromethane (5 mL) and (trimethylsilyl)diazomethane (22.8g, 0.2 mol) was added drop wise at C The mixture was stirred for 2 h affording the solution was used directly in the next step. |
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With thionyl chloride; for 2.5h;Reflux; |
A mixture of tetrahydro-2H-pyran-4-carboxylic acid (1.36 g, 10.45 mmol) and thionyl chloride (7.63 mL, 105 mmol) was heated to gentle reflux for 2.5 h. The mixture was then cooled to room temperature and evaporated in vacuo. To a solution of this tetrahydro-2H-pyran-4-carbonyl chloride in DCM (15 mL) was added Et3N (4.36 mL, 31.4 mmol) and benzyl alcohol (1.622 mL, 15.68 mmol) dropwise while cooled with an ice bath. The formed solurry was stirred with cooling for 30 min, and then at rt 30 min. The mixture was then washed in turn with water, 5% citric acid and saturated aqueous sodium chloride solution. The organic solution was dried over MgS04, and then, concentrated under reduced pressure. The resulting residue was purified by column chromatography (5% to 30% EtOAc-hexane) to give Cap W-22 Step A (1.83 g) as colorless oil.XH NMR (500MHz, CDC13) delta 7.52 - 7.31 (m, 5H), 5.16 (s, 2H), 3.99 (dt, J=l 1.5, 3.6 Hz, 2H), 3.45 (td, J=11.2, 2.9 Hz, 2H), 2.69 - 2.49 (m, 1H), 2.03 - 1.73 (m, 4H). |
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With oxalyl dichloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h; |
To a stirred solution of tetrahydro-2H-pyran-4-carboxylic acid (1.5 g, 0.01 mmol) in CH2Cl2 (10 mL) was added oxalyl chloride (1.6 g, 0.01 mmol) and DMF (1 drop) at 0 oC. The reaction mixture was warmed to room temperature and stirred for 2 h. After consumption of acid (monitored by TLC), the mixture was concentrated in vacuo. The crude material was dissolved in ether and cooled to -10 oC. A solution of CH2N2 in ether (20 mL) was added and the reaction mixture was warmed to room temperature and stirred for 16 h. After consumption of the starting material (monitored by TLC), the mixture was concentrated in vacuo. To a stirred solution of the crude material in CH2Cl2 (20 mL) was added a solution of 48% aq HBr (5 mL) at -10 oC. The reaction mixture was warmed to room temperature and stirred for 1 h. After consumption of the starting material (monitored by TLC), the reaction was quenched with a sodium bicarbonate solution (50 mL) and extracted with CH2Cl2 (2 x 50 mL). The combined organic extracts were washed successively with a sodium bicarbonate solution (20 mL) and water (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-bromo-1-(tetrahydro-2H-pyran-4-yl) ethan-1- one (2 g) as a yellow solid. 1H-NMR (DMSO-d6, 500 MHz): delta 4.49 (s, 2H), 3.83 (d, 2H), 3.33 (t, 2H), 2.90-2.80 (m, 1H), 1.80-1.70 (m, 2H), 1.57-1.44 (m, 2H); TLC: 30% EtOAc:hexanes (Rf: 0.7). |
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With oxalyl dichloride; In dichloromethane; at 20℃; for 2h; |
Tetrahydro -2H- oxalyl chloride (762muL) and DMF (1 drop) in methylene chloride solution (2.00 mL) of pyran-4-carboxylic acid (585 mg) was added, and the reaction mixture was stirred for 2 hours at room temperature.The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride (1.00mL), under ice-cooling to a methylene chloride solution (3.00mL) of the compound obtained in Reference Example 136 (500mg) and triethylamine (697muL) dropwise and stirred for 30 minutes at room temperature.Water was added to the reaction mixture, the mixture was extracted twice with chloroform.The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated.The residue was purified by silica gel column chromatography, and purified by (solvent: hexane / ethyl acetate = 70 / 30-20 / 80) to give the title compound (555 mg). |
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With oxalyl dichloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 1h;Cooling with ice; |
Synthesis of 732-0. To a solution of SM2 (230 mg, 1.8 mmol) and a catalytic amount of DMF in THF (15mL) was added (COCl) 2 (0.2 mL, 2.7 mmol) dropwise under ice bath. The resulting mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to afford 732-0 (240 mg, 90 %) as a yellow oil, which was used directly to next step without further purification. |
| 0.6 g |
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 1h; |
The starting tetrahydropyran-4-carboxylic acid (0.5 g, 4 mmol, 1.0 eq) was added to 10 mL of DCM and a catalytic amount ofDMF, and then 0.4 mL of thionyl chloride was added dropwise at 0 C. Dropping at room temperature for 1 h. The solvent and excess of thionyl chloride were vacuum dried to give 0.6 g of a colorless liquid which was used directly in the next step. |
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With thionyl chloride; at 90℃; for 1h; |
A mixture of compound 29 (1 g, 7.69 mmoL) and SOC12 (10 mL) was refluxed at 90C for 1 h. The progress of reaction was monitored by TLC. After completion, the reactionmixture was concentrated in vacuo, the residue obtained was dissolved in DCM (10 mL), A1C13 (1.02 g, 7.69 mmol) was added at 0 C and stirred for 5 mm. To this solution compound 26 (1.13 g, 7.69 mmol) was added portion wise at 0 C and the resulting reaction mixture was heated at 70 C for 2 h. The progress of reaction was monitored by TLC. After completion, the reactionmixture was quenched with ice cold water; basified with sat. aq. NaHCO3 solution and extracted with DCM (3 X 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude compound was purified by silica gel column chromatography using 15% EtOAc/ hexane to afford the title compound 31 (0.9 g, 41%) as white semi-solid. TLC: 30% EtOAc/ hexanes (Rf: 0.4); ?H NMR (400 MHz,DMSO-d6): oe 12.32 (s, 1H), 8.65 (s, 1H), 8.28 (d, J= 8.8 Hz, 1H), 8.09 (s, 1H), 7.79 (d, J= 8.8 Hz, 1H), 3.92 - 3.91 (m, 2H), 3.90 (s, 3H), 3.52 - 3.44 (m, 2H), 1.76 - 1.67 (m, 5H). LCMS Calculated for C,6H,7N04: 287.12; LCMS Observed (m/z): 288 (M+1). |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃;Inert atmosphere; |
To tetrahydro-2H-pyran-4-carboxylic acid (0.690 g, 5.3 mmol) in DCM (10 mL) was added, under nitrogen, at 0C, DMF (0.041 mL, 0.530 mmol), and dropwise, oxalyl chloride (1.180 mL, 7.9 mmol). The ice bath was removed and the mixture was stirred for 45 minutes. The volatiles were removed on the rotovap, the crude oil diluted with lOmL of DCM and the evaporation repeated. To a RBF (round-bottomed flask) was added 2-amino-4-bromophenol (1097 mg, 5.83 mmol) in DCM (20 mL) along with pyridine (0.429 mL, 5.30 mmol). The mixture was stirred for 15minutes under nitrogen. In a second RBF containing the above mentioned freshly synthesized tetrahydro-2H-pyran-4-carbonyl chloride (788 mg, 5.30 mmol) was added, at room temperature, 2 mL of DCM followed by the above mixture containing 2-amino-4-bromophenol/pyridine in DCM. The combined pink heterogeneous mixture was stirred overnight at room temperature under nitrogen. The crude product mixture was washed with water, brine, dried over sodium sulfate, filtered and evaporated. The isolated crude product was triturated with 4: 1 ice cold diethyl ether/hexane to give 1.512g of N-(5-bromo-2-hydroxyphenyl)tetrahydro-2H-pyran-4-carboxamide (88% yield) as a pink solid. The LC/MS data was obtained on a Shimadzu analytical LCMS (ESI+) at 220nm using the following set of conditions: Waters Aquity BEH 1.7muiotaeta CI 8, 2.1 x 50mm column, with a gradient of 0-100%B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water / 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute. LCMS Rt = 1.190 mia, m/z 300.15, 302.15 (M + H), 90% purity. NMR (500MHz, CDCh) delta 8.37 (br. s., 1H), 7.58 (br. s., 1H), 7.39 (d, J=2.4 Hz, 1H), 7.20 (dd, J=8.7, 2.4 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 4.09 (m, 2H), 3.47 (m, 2H), 2.62 (m, 1H), 1.98 - 1.77 (m, 4H). |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1.5h; |
To a stirred suspension of a tetrahydro-pyran-4-carboxylic acid (55.4 mg, 0.43 mmol) in CH2Cl2 (5 ml) were added DMF (2 drops) followed by oxalyl chloride (0.10 ml, 1.06 mmol) and the resultant mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure and the acid chloride was dried in vacuo for 45 minutes. To the acid chloride was added a solution of [3-(4-benzylamino-piperidin-l-yl)- butyl]-carbamic acid tert-butyl ester (0.10 g, 0.27 mmol) and triethylamine (0.10 ml, 0.66 mmol) in THF (5 ml) and the mixture was stirred at 50 0C for 16 hours. The mixture was concentrated under reduced pressure and then diluted with CH2Cl2 (30 ml) and 10 ml saturated aqueous NaHCO3. The phases were separated and the aqueous layer was extracted with CH2Cl2 (5 x 30 ml). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. EPO <DP n="117"/>The crude material was purified by flash column chromatography on silica gel (96:3:1, CH2Cl2/MeOH/NH4OH) to generate (R)-(3-{4-[(4-methyl-pyridin-3-ylmethyl)-(tetrahydro- pyran-4-carbonyl)-amino]-piperidin-l-yl}-butyl)-carbamic acid tert-butyl ester as a crude yellow oil (0.10 g). |
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With thionyl chloride; N,N-dimethyl-formamide; at 0 - 70℃; for 5h; |
Sulfoxide chloride (50 mL) and DMF (0.1 mL) were successively added dropwise to tetrahydropyran-4-carboxylic acid (10.00 g, 0.077 mol) at 0C. After the addition was completed, the resulting mixture was slowly heated to 70C to react for 5h. After the reaction was completed, a corresponding acyl chloride (11g) was obtained by concentration. Benzene (100 mL) was added to the acyl chloride at 0C, and then anhydrous AlCl3 (30 g, 0.22 mol) was added in batches. After the addition was completed, the system was stirred for additional 15 min, and heated to reflux for 5h. After the reaction was completed, the resulting mixture was cooled, ice water and a saturated ammonium chloride aqueous solution were successively added, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phases were combined, washed with a saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, and concentrated to obtain a black residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=6:1) to obtain a white solid product (8.5 g, 60%). 1H NMR (400 MHz, CDCl3) delta 7.96-7.99 (m, 2H), 7.59-7.62 (m, 1H), 7.49-7.53 (m, 2H), 4.06-4.11 (m, 2H), 3.55-3.62 (m, 2H), 3.49-3.54 (m, 1H), 1.86-1.97 (m, 2H), 1.80-1.85 (m, 2H). |
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