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[ CAS No. 5337-03-1 ]

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Chemical Structure| 5337-03-1
Chemical Structure| 5337-03-1
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CAS No. :5337-03-1 MDL No. :MFCD00031016
Formula : C6H10O3 Boiling Point : 264.5°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :130.14 g/mol Pubchem ID :219302
Synonyms :

Safety of [ 5337-03-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 5337-03-1 ]

  • Upstream synthesis route of [ 5337-03-1 ]
  • Downstream synthetic route of [ 5337-03-1 ]

[ 5337-03-1 ] Synthesis Path-Upstream   1~20

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  • [ 38041-19-9 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1938, vol. 535, p. 37,45
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  • [ 7732-18-5 ]
  • [ 2081-44-9 ]
  • [ 4677-17-2 ]
Reference: [1] Journal of the Chemical Society, 1952, p. 2268,2271
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  • [ 5337-03-1 ]
  • [ 14774-37-9 ]
YieldReaction ConditionsOperation in experiment
54%
Stage #1: With borane In tetrahydrofuran at 0℃; for 1 h;
Stage #2: With water In tetrahydrofuran at 20℃; for 0.166667 h;
EXAMPLE 77A
4-(Hydroxymethyl)tetrahydropyran
To an ice-cooled solution of 2.60 g (20.0 mmol) of tetrahydropyran-4-carboxylic acid in 8 mL of THF was added 21 mL (21 mmol) of 1.0M borane in THF.
The reaction was stirred at 0 C for 1 h, then quenched by dropwise addition of 2 mL of water.
After stirring for 10 min at ambient temperature, solid K2CO3 was added and swirled until free flowing.
The salts were filtered, and the supernatant was concentrated to 1.25 g (54percent) of 4-(hydroxymethyl)tetrahydropyran as a colorless oil.
54% With borane; water In tetrahydrofuran at 0℃; for 1 h; To an ice-cooled solution of 2.60 g (20.0 mmol) of tetrahydropyran-4-carboxylic acid in 8 mL of THF was added 21 mL (21 mmol) of 1.0M borane in THF.
The reaction was stirred at 0 C for 1 h, then quenched by dropwise addition of 2 mL of water.
After stirring for 10 min at ambient temperature, solid K2CO3 was added and swirled until free flowing.
The salts were filtered, and the supernatant was concentrated to 1.25 g (54percent) of 4-(hydroxymethyl)tetrahydropyran as a colorless oil.
98.9 %Chromat. at 199.84℃; for 10 h; Autoclave General procedure: The hydrogenation of carboxylic acids or other substrates was performed in a high-pressure stainless-steel autoclave (Xinyuan Chemical Machinery, Series CJK, 300 mL) with a maximum stirring rate of 1500 r/min. In a typical experiment, 0.2 g of catalyst (or without catalyst for the control experiment), 3 mmol of the substrate, and 100 mL alkane solvent (n-hexane, n-heptane, i-octane, or n-dodecane) were well mixed in the autoclave and purged with pure nitrogen at room temperature. The gas supply and discharge were carried out manually through needle valves. The autoclave was rapidly heated to the desired temperature and hydrogen was introduced at 2 MPa to initiate the reaction. The reaction pressure was kept at 2 MPa with a small negative deviation (∼0.2 MPa) owing to the consumption of hydrogen. Samples of the liquid phase were continuously taken through a sampling tube with a filter at certain intervals. The stirring rate was kept at 750 r/min during the reaction.
Reference: [1] Helvetica Chimica Acta, 2003, vol. 86, # 3, p. 865 - 893
[2] Patent: US2005/70712, 2005, A1, . Location in patent: Page/Page column 40
[3] Patent: US2005/171131, 2005, A1, . Location in patent: Page/Page column 39
[4] Journal of the American Chemical Society, 1950, vol. 72, p. 5512,5514
[5] Journal of the American Chemical Society, 1993, vol. 115, # 18, p. 8401 - 8408
[6] Patent: US5852195, 1998, A,
[7] Angewandte Chemie - International Edition, 2015, vol. 54, # 36, p. 10596 - 10599[8] Angew. Chem., 2015, vol. 127, p. 10742 - 10745,4
[9] ACS Catalysis, 2018, vol. 8, # 2, p. 785 - 789
[10] Chinese Journal of Catalysis, 2018, vol. 39, # 2, p. 250 - 257
[11] Patent: CN108314680, 2018, A, . Location in patent: Paragraph 0691-0695
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  • [ 125552-89-8 ]
Reference: [1] Journal of the American Chemical Society, 1993, vol. 115, # 18, p. 8401 - 8408
[2] Journal of the American Chemical Society, 1950, vol. 72, p. 5512,5514
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  • [ 50675-18-8 ]
Reference: [1] Helvetica Chimica Acta, 2003, vol. 86, # 3, p. 865 - 893
[2] Patent: US2007/117797, 2007, A1, . Location in patent: Page/Page column 29
[3] Patent: CN108314680, 2018, A,
  • 6
  • [ 5337-03-1 ]
  • [ 137052-08-5 ]
Reference: [1] Patent: WO2011/50016, 2011, A1,
[2] Patent: WO2011/50016, 2011, A1,
[3] Patent: EP2485920, 2016, B1,
  • 7
  • [ 5337-03-1 ]
  • [ 344329-76-6 ]
YieldReaction ConditionsOperation in experiment
91%
Stage #1: With triethylamine; isobutyl chloroformate In chloroform at 0℃; for 2 h; Inert atmosphere
Stage #2: With ammonia In chloroform for 0.25 h; Inert atmosphere
Intermediate 30 oxane-4-carboxamide To a stirred solution of oxane-4-carboxylic acid (800 mg, 6.15 mmol) in chloroform (5 mL) were added triethylamine (1.28 mL, 9.22 mmol) and isobutyl chloro formate (884 μ, 7.37 mmol) dropwise at 0°C under argon. The reaction mixture was stirred at 0°C for 2 h and then ammonia gas was passed through the solution for 15 min. The reaction mixture was concentrated. The residue was dissolved in propan-2-ol/chloroform (1 :4, 25 mL) and washed with water, 5percent aHC03(aq) and then 1M HCl(aq). The organic phase was dried (Na2SC>4), filtered and concentrated. The crude product was purified by trituration in DCM to afford the title compound as a white solid (1.20 g, 91percent); FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-i/6) δ 1.44 - 1.63 (m, 4H), 2.23 - 2.34 (m, 1H), 3.27 (td, 2H), 3.82 (ddd, 2H), 6.75 (s, 1H), 7.22 (s, 1H).
46%
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 0℃; for 1 h; Inert atmosphere
Stage #2: With ammonium hydroxide In acetonitrile at 20℃;
Example B5
A 0° C. solution of tetrahydro-2H-pyran-4-carboxylic acid (0.5 g, 3.84 mmol) in MeCN (15 mL) was treated with EDC (0.884 g, 4.61 mmol) and HOBT (0.706 g, 4.61 mmol) under an argon atmosphere and stirred at 0° C. for 1 h.
Ammonium hydroxide (˜15M, 0.512 mL, 7.68 mmol) was added slowly and the mixture was warmed to RT and stirred overnight.
The mixture was treated with water, saturated with solid NaCl and the aqueous layer was extracted with THF (2*).
The combined organics were washed with brine, dried over Na2SO4 and concentrated to afford tetrahydro-2H-pyran-4-carboxamide (0.23 g, 46percent) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.20 (s, 1H), 6.73 (s, 1H), 3.82-3.81 (m, 2H), 3.30-3.21 (m, 2H), 2.30-2.27 (m, 1H), 1.60-1.46 (m, 4H).
46%
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 0℃; for 1 h; Inert atmosphere
Stage #2: With ammonium hydroxide In acetonitrile at 20℃;
Example B5
A 0° C. solution of tetrahydro-2H-pyran-4-carboxylic acid (0.5 g, 3.84 mmol) in MeCN (15 mL) was treated with EDC (0.884 g, 4.61 mmol) and HOBT (0.706 g, 4.61 mmol) under an argon atmosphere and stirred at 0° C. for 1 h.
Ammonium hydroxide (˜15M, 0.512 mL, 7.68 mmol) was added slowly and the mixture was warmed to RT and stirred overnight.
The mixture was treated with water, saturated with solid NaCl and the aqueous layer was extracted with THF (2*).
The combined organics were washed with brine, dried over Na2SO4 and concentrated to afford tetrahydro-2H-pyran-4-carboxamide (0.23 g, 46percent) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.20 (s, 1H), 6.73 (s, 1H), 3.82-3.81 (m, 2H), 3.30-3.21 (m, 2H), 2.30-2.27 (m, 1H), 1.60-1.46 (m, 4H).
Reference: [1] Patent: WO2015/177367, 2015, A1, . Location in patent: Page/Page column 71; 72
[2] Patent: US2014/275016, 2014, A1, . Location in patent: Paragraph 0254
[3] Patent: US2014/275080, 2014, A1, . Location in patent: Paragraph 0358
[4] Journal of the Chemical Society, 1930, p. 2525,2529
[5] Journal of the Chemical Society, 1930, p. 2525,2529
[6] Patent: WO2015/62486, 2015, A1,
[7] Patent: CN108003122, 2018, A, . Location in patent: Paragraph 0020; 0028; 0034; 0035; 0036; 0044; 0052
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  • [ 40191-32-0 ]
YieldReaction ConditionsOperation in experiment
100% With thionyl chloride In toluene at 80℃; for 1.5 h; Example 5; Synthesis of tetrahydropyran-4-carboxylic acid chlorideIn a vessel made of a glass, having an inner volume of 50 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 6.85 g (52.6 mmol) of tetrahydropyran-4-carboxylic acid, 9.79 g (82.3 mmol) of thionyl chloride and 10 ml of toluene, and the mixture was reacted at 80° C. for 1.5 hours under stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 7.81 g (Isolation yield; 100percent) of tetrahydropyran-4-carboxylic acid chloride as pale brownish liquid.Physical properties of the tetrahydropyran-4-carboxylic acid chloride were as follows.1H-NMR (CDCl3, δ (ppm)); 1.79 to 1.93 (2H, m), 1.99 to 2.06 (2H, m), 2.91 to 3.00 (1H, m), 3.40 to 3.49 (2H, m), 3.97 to 4.03 (2H, m)CI-MS (m/e); 131 (M+1)
95% for 2.5 h; Heating / reflux Tetrahydropyran-4-carnboxylic acid (0.92g, 7.07 mmol) was dissolved in thionyl chloride (5.7 mL, 77.8 mmol) and refluxed for 2.5 h. After this time the mixture <n="13"/>was cooled to room temperature and evaporated to dryness. Toluene (50 ml_) was added and the resulting oil and the mixture was evaporated to dryness to give tetrahydropyran-4-carbonyl chloride as a brown oil. This material was used without any further purification (1 g, 95percent). 1H NMR (400 MHz, CDCI3) 1.85 - 1.90 (2H, m), 1.91 - 2.0 (2H, m), 2.94 - 2.96 (1 H, m), 3.42 - 3.43 (2H, m) 3.97 - 4.00 (2H, s).
0.6 g With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 1 h; 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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[2] Patent: WO2008/71948, 2008, A2, . Location in patent: Page/Page column 11-12
[3] Helvetica Chimica Acta, 1997, vol. 80, # 5, p. 1528 - 1551
[4] Journal of the Chemical Society, 1930, p. 2525,2529
[5] Chemical and Pharmaceutical Bulletin, 1987, vol. 35, # 6, p. 2426 - 2436
[6] Journal of Medicinal Chemistry, 1994, vol. 37, # 26, p. 4538 - 4553
[7] Organic Letters, 2003, vol. 5, # 13, p. 2343 - 2346
[8] Journal of Medicinal Chemistry, 2003, vol. 46, # 25, p. 5512 - 5532
[9] Journal of Organic Chemistry, 2006, vol. 71, # 18, p. 7035 - 7044
[10] Journal of Medicinal Chemistry, 2007, vol. 50, # 20, p. 4793 - 4807
[11] Patent: WO2005/85170, 2005, A1, . Location in patent: Page/Page column 10
[12] Patent: US2005/277671, 2005, A1, . Location in patent: Page/Page column 38
[13] Patent: WO2007/67836, 2007, A2, . Location in patent: Page/Page column 156-157
[14] Patent: EP1894925, 2008, A1, . Location in patent: Page/Page column 34
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[18] Patent: WO2004/52880, 2004, A1, . Location in patent: Page 60-61
[19] Patent: WO2005/3123, 2005, A1, . Location in patent: Page 27-28
[20] Patent: WO2005/105770, 2005, A2, . Location in patent: Page/Page column 140
[21] Patent: US2010/9964, 2010, A1, . Location in patent: Page/Page column 14
[22] Patent: WO2010/67130, 2010, A1, . Location in patent: Page/Page column 41
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[24] Patent: US2011/9390, 2011, A1, . Location in patent: Page/Page column 14
[25] Patent: EP2511265, 2012, A1, . Location in patent: Page/Page column 27
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[28] Patent: EP2612848, 2013, A1, . Location in patent: Paragraph 0298; 0299; 0300
[29] Patent: WO2014/13076, 2014, A1, . Location in patent: Page/Page column 100
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[32] Patent: WO2014/151142, 2014, A1, . Location in patent: Paragraph 00106
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[39] Patent: CN106565706, 2017, A, . Location in patent: Paragraph 0248; 0249
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  • [ 77-78-1 ]
  • [ 110238-91-0 ]
YieldReaction ConditionsOperation in experiment
99% With potassium carbonate In acetone for 3 h; Heating / reflux Tetrahydro-2H-pyran-4-carboxylic acid (1.00 g, 7.68 mmol) was slowly added to a stirred suspension of anhydrous potassium carbonate (1.17 g, 8.45 mmol) in acetone (40 mL), followed by dimethyl sulfate (0.8 mL, 8.45 mmol). The mixture was stirred and heated for 3 h. The inorganic salts were then removed by filtration and washed with acetone, and the filtrate was dried and concentrated to give methyl tetrahydro-2H-pyran-4-carboxylate (1.1 g, 99percent), which was used in the next step without further purification. GC-MS m/z 145 (MH+); 1H NMR (300 MHz, CDCl3) δ 11.70-1.80 (m, 4H), 2.47-2.52 (m, 1H), 3.34-3.43 (m, 2H), 3.65 (s, 3H), 3.88-3.95 (m, 2H).
Reference: [1] Patent: US2004/224997, 2004, A1, . Location in patent: Page 18
[2] Journal of the American Chemical Society, 1993, vol. 115, # 18, p. 8401 - 8408
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  • [ 110238-91-0 ]
Reference: [1] Patent: WO2015/62486, 2015, A1, . Location in patent: Paragraph 00324
[2] Patent: WO2013/66729, 2013, A1, . Location in patent: Page/Page column 184; 185
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  • [ 110238-91-0 ]
Reference: [1] Journal of the Chemical Society, 1930, p. 2525,2529
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  • [ 64-17-5 ]
  • [ 96835-17-5 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1932, vol. 4, p. 259,263
[2] Patent: WO2016/138532, 2016, A1, . Location in patent: Paragraph 0474
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  • [ 96835-17-5 ]
Reference: [1] Journal of the Chemical Society, 1930, p. 2525,2529
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  • [ 33024-60-1 ]
Reference: [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 30, p. 9501 - 9504[2] Angew. Chem., 2018, vol. 130, # 30, p. 9645 - 9648,4
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  • [ 74-88-4 ]
  • [ 233276-38-5 ]
YieldReaction ConditionsOperation in experiment
53%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at 0 - 50℃; for 3.41667 h;
Stage #2: at 0 - 20℃;
Stage #3: With water; citric acid In tetrahydrofuran; hexane
Description 9. 4-methyltetrahydro-2H-pyran-4-carboxylic acid. (D9); Diisopropylamine (6.37 ml_, 44.7 mmol) in THF (50 ml.) was cooled to 0 0C under argon. N-Butyllithium (16.7 ml_, 2.5 M in hexane, 41.7 mmol) was added dropwise over 10 min. The reaction mixture was left to stir for 15 min at 0 0C. A solution of tetrahydro-2H-pyran- 4-carboxylic acid (D8) (1.94 g, 14.9 mmol) in THF (1OmL) was added and a white precipitate was formed. The resulting mixture was then heated at 50 0C for 3 h. The reaction mixture was cooled to 0 0C and methyl iodide (2.80 ml_, 44.7 mmol) was added dropwise. The reaction was then allowed to warm to rt and left to stir overnight. 10percent aqueous citric acid solution (40 ml.) was then added and the THF was removed by rotary evaporation. The residual aqueous mixture was extracted with Et2O (2x). The organics were combined, dried (Na2SO4) and concentrated by rotary evaporation to give the title compound (D9) (1.26 g, 53percent) as a yellow solid.
1.05 g
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at 50℃; for 3 h; Inert atmosphere; Cooling with ice
Stage #2: at 20℃; for 19 h; Inert atmosphere; Cooling with ice
(1) To a solution of Compound 1 (1.3 g) in tetrahydrofuran (20 mL) was added dropwise a solution of lithiumdiisopropylamide-tetrahydrofuran (2 mol/mL, 14 mL) under nitrogen atmosphere under ice-cooling, and then the mixture was stirred at 50°C for 3 hours. To the reaction mixture was added dropwise methyl iodide (1.87 mL) under ice-cooling, and the mixture was stirred at room temperature for 19 hours. To the reaction mixture was added a 10percent aqueous solution of citric acid (20 mL), stirred, then tetrahydrofuran was evaporated under reduced pressure, and extracted with ethyl acetate. The organic layer was dried, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=80:20-50:50) to give Compound 2 (1.05 g) as a pale brown powder. To a solution of Compound 2 (896 mg) in toluene (37 mL) were added triethylamine (1.12 mL) and Compound 3 (1.39 mL), and the mixture was stirred under nitrogen atmosphere at 85°C for 17 hours. To the reaction solution was added dropwise an aqueous solution of sodium hydroxide (1 mol/mL, 27 mL) under ice-cooling, ethyl acetate and water were added thereto, and then the organic layer was separated. The resultant organic layer was dried, and concentrated under reduced pressure to give a crude material of Compound 4 (671 mg) as a brown viscous material. To a solution of Compound 4 (665 mg) in tetrahydrofuran (55 mL) was added a mixed solution of concentrated hydrochloric acid (3.05 mL) and water (5.5mL), and the mixture was stirred at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure to give a crude material of Compound 5 (558 mg) as a pale brown powder. MS (ESI): m/z 116 [M+H]+
Reference: [1] Patent: WO2009/37293, 2009, A1, . Location in patent: Page/Page column 53
[2] Patent: EP3150578, 2017, A1, . Location in patent: Paragraph 0581
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  • [ 233276-38-5 ]
Reference: [1] Patent: WO2015/5901, 2015, A1,
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  • [ 6638-79-5 ]
  • [ 156353-01-4 ]
YieldReaction ConditionsOperation in experiment
96% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane; water at 0 - 20℃; for 2 h; N,N- diisopropylethylamine (8.1 mL, 46 mmol) was slowly added to a cold (0 °C) solution of tetrahydro-2H-pyran-4-carboxylic acid (2 g, 15 mmol) and O,N-Dimethyl-hydroxylamine hydrochloride (2.25 g, 23.05 mmol) in DCM (20 mL). To the above solution was added 2,4,6- tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (11 mL, 50 percentw/w; 18.4 mmol) slowly while at 0 °C. The mixture was warmed to rt and allowed to stir for 2 h. The reaction mixture was quenched with ice cubes then diluted with water (10 mL) and extracted with DCM (2 X 30 mL). The organic fractions were combined, washed with aq. sodium bicaronate solution, dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the title compound as an oily liquid (2.56 g, 96percent). 1H NMR (400MHz, CD3OD) ^ = 3.96 (ddd, J = 1.7, 4.0, 11.5 Hz, 2H), 3.75 (s, 3H), 3.49 (dt, J = 2.4, 11.7 Hz, 2H), 3.19 (s, 3H), 3.10 - 2.92, (m, 1H), 1.83 - 1.60 (m, 4H); [M+H] = 174.2.
89%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 2 h;
Stage #2: at 20℃;
In a 1 L RB flask, a solution of tetrahydro-2H-pyran-4-carboxylic acid (46.0 g, 353 mmol) in dichloromethane (250 mL) was treated with 1,1′-carbonyldiimidazole (63.0 g, 389 mmol) portion-wise—caution bubbling. After the addition was complete the mixture was stirred at room temperature for 2 h and then treated portion wise with N,O-dimethylhydroxylamine, HCl (37.9 g, 389 mmol) and then stirred overnight at room temperature. Washed with water and brine, dried over MgSO4, filtered, and concentrated to give N-methoxy-N-methyloxane-4-carboxamide (55.0 g, 302 mmol, 85percent) as light amber oil. 1H NMR (400 MHz, CDCl3) δ 4.02 (ddd, J=11.4, 4.2, 2.1 Hz, 2H), 3.71 (s, 3H), 3.46 (td, J=11.8, 2.2 Hz, 2H), 3.19 (s, 3H), 1.93-1.80 (m, 2H), 1.69-1.62 (m, 2H).
81% With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 18 h; [0239] To a solution of tetrahydro-2H-pyran-4-carboxylic acid 1 (4.0 g, 31 mmol) in DCM (65 mL) was added sequentiallyN,O-dimethylhydroxylamine hydrochloride (3.3 g, 34 mmol), 4-methylmorpholine (7.4 mL, 68 mmol), and N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (6.5 g, 34 mmol). The resulting mixture was stirred at RT for 18 h. Atthat time, the reaction was diluted with 1 N HCl and EtOAc and stirred vigorously until both phases cleared. The phases were separated, and the aqueous layer was extracted with EtOAc. The organic portions were combined, washed withbrine, dried over MgSO4, filtered, and concentrated. The crude residue was subjected to column chromatography (120g silica, 80 mL/min, 0percent to 100percent EtOAc/hexanes) to give N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide 2(4.3 g, 24.8 mmol, 81percent). LCMS for 2 (conditions D): tR = 1.12 min, m/e = 174.3 (M+H, base).
73.3% With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 16 h; The racemate of the methyl ester of the title compound was prepared according the literature using the scheme described above (US 2016/0176864). [00237] Methyl 3-(3,5-dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)- 5H-pyrido[3,2-b]indole-7-carboxylate (0.22 g, prepared according to literature and the synthetic route above) was separated by chiral HPLC to give (R)-methyl 3-(3,5- dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7- carboxylate (0.095 g) and (S)-methyl 3-(3,5-dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H- pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate (0.090 g) as a yellow solid. H NMR (racemate) (400 MHz, CDC13) δ 0.98-1.02 (IH, m), 1.32-1.36 (2H, m), 1.95 (IH, s), 2.15 (3H, s), 2.31 (3H, s), 3.00-3.08 (IH, m), 3.24-3.31 (IH, m), 3.45-3.51 (IH, m), 3.76-3.80 (IH, m), 3.96 (3H, s), 4.00-4.01 (IH, m), 5.52 (IH, d, J = 10.8 Hz), 7.22-7.29 (3H, m), 7.38-7.40 (2H, m), 7.51 (IH, d, J = 1.6 Hz), 7.99 (IH, dd, / = 8.0, 1.2 Hz), 8.36 (IH, d, J = 8.0 Hz), 8.39 (2H, s); LC/MS 496.3 [M+H]+. [00238] The chiral material ester was hydrolyzed under basic condition (aq. NaOH in MeOH) to provide (R)-PTM-3-l-A and (S)-PTM-3-l-B.
831 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 10 - 35℃; A)
N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide
To a solution of tetrahydro-2H-pyran-4-carboxylic acid (800 mg) in N,N-dimethylformamide (60.0 mL) were added 1-hydroxybenzotriazole monohydrate (1.17 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g), N,O-dimethylhydroxylamine hydrochloride (600 mg) and triethylamine (1.73 mL).
The reaction mixture was stirred overnight at room temperature, water was added thereto, and the mixture was extracted with ethyl acetate.
The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (831 mg).
MS (API+): [M+H]+174.3.

Reference: [1] Patent: WO2016/73424, 2016, A1, . Location in patent: Page/Page column 63
[2] Patent: US2016/176864, 2016, A1, . Location in patent: Paragraph 0491; 0492; 0775
[3] Patent: EP2485920, 2016, B1, . Location in patent: Paragraph 0238-0239
[4] Patent: WO2017/30814, 2017, A1, . Location in patent: Paragraph 00236-00237
[5] Patent: WO2011/50016, 2011, A1, . Location in patent: Page/Page column 100
[6] Patent: EP2848618, 2015, A1, . Location in patent: Paragraph 1039
[7] Patent: US2015/105366, 2015, A1, . Location in patent: Paragraph 0183; 0184
[8] Patent: WO2015/57205, 2015, A1, . Location in patent: Page/Page column 58; 59
[9] Patent: US2015/111870, 2015, A1, . Location in patent: Paragraph 0533; 0534
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YieldReaction ConditionsOperation in experiment
89%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 2 h;
Stage #2: at 20℃; for 16 h;
Step 1: N-Methoxy-N-methyloxane-4-carboxamideTo a 500 mL round bottom flask containing a solution of oxane-4-carboxylic acid (8.00 g, 61.5 mmol) in CH2C12 (100 mL), 1,1’-carbonyldiimidazole (12.0 g, 73.8 mmol)was added in portions. The reaction solution was stirred at room temperature for 2 h. N,O-Dimethylhydroxylamine hydrochloride (6.60 g, 67.6 mmol) then was added in one portion. The reaction was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aq. ammonium chloride and separated. The organic layer was washed with saturated aq. NaHCO3, dried with sodium sulfate, filtered, and concentratedto give the title compound (9.50 g, 89 percent), which was used as without purification. ‘H NMR(400MHz, CD3OD)ö 3.99 (ddd,J11.5, 4.2, 2.1 Hz, 2H), 3.77 (s, 3H), 3.51 (td, J=1 1.8, 2.4 Hz, 2H), 1.7 Hz, 1H), 3.21 (s, 3H), 3.06 (br. s., 1H), 1.88-1.52 (m, 4H); LCMS (M+H) = 174.2; HPLC RT = 1.39 mm (Column: Waters Sunfire C18, 2.1 x 50mm, 3.5-tim particles; Mobile Phase A: 10:90 MeOH:water with 0.1percent TFA; Mobile Phase B: 90:10 MeOH:water with 0.1percent TFA; Temperature: 40°C; Gradient: 0-100percent B over 4 mm, then a 1.00 mm hold at 100percent B; Flow: 4 mL/min; Detection: UV at 220 nm).
Reference: [1] Patent: WO2015/100282, 2015, A1, . Location in patent: Page/Page column 269; 270
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  • [ 811842-25-8 ]
Reference: [1] Patent: US2016/319312, 2016, A1,
  • 20
  • [ 5337-03-1 ]
  • [ 1131912-76-9 ]
Reference: [1] Science, 2017, vol. 357, # 6348, p. 283 - 286
[2] ACS Catalysis, 2018, vol. 8, # 10, p. 9537 - 9542
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