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[ CAS No. 28697-17-8 ]

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Chemical Structure| 28697-17-8
Chemical Structure| 28697-17-8
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CAS No. :28697-17-8 MDL No. :MFCD00237380
Formula : C11H19NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :N/A
M.W :229.27 g/mol Pubchem ID :688618
Synonyms :

1. Boc-D-HoPro-OH

Safety of [ 28697-17-8 ]

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 [ 28697-17-8 ]

  • Upstream synthesis route of [ 28697-17-8 ]
  • Downstream synthetic route of [ 28697-17-8 ]

[ 28697-17-8 ] Synthesis Path-Upstream   1~24

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YieldReaction ConditionsOperation in experiment
87.8% With sodium hydrogencarbonate In methanol at 20℃; for 24 h; To a 1000 mL round bottom flask, 2R-piperidine carboxylic acid (8.0 g, 0.062 mol), di-tert-butyl dicarbonate (14.8 g, 0.068 mol), sodium bicarbonate (26.04 g, 0.310 mol) and methanol (400 mL) were added, and stirred at room temperature for 24 hours. Thereafter, the reaction product was subjected to vacuum distillation for removal of methanol, dissolved with water, washed 3 times with ethyl ether, adjusted to pH = 2 with saturated potassium hydrogen sulfate, and extracted 3 times with dichloromethane. The extracts were combined, washed 3 times with saturated brine, concentrated, and separated through a silica gel column (eluent: petroleum ether/ethyl acetate/acetic acid), to give 12.48 g of a white product, yield 87.8percent. [0075] 1H-NMR (400 MHz, DMSO) δ ppm: 12.71 (1H, s), 4.61 (1H, d, J = 28.8 Hz), 3.82 (1H, d, J = 12 Hz), 2.93 (1H, m), 2.06 (1H, s), 1.62 (3H, m), 1.39(11H, m); EI-MS (m/z): 229.1[M]+.
87.8% With sodium hydrogencarbonate In methanol at 20℃; for 24 h; To a 1000 mL round bottom flask, 2R-piperidine carboxylic acid (8.0 g, 0.062 mol), di-tert-butyl dicarbonate (14.8 g, 0.068 mol), sodium bicarbonate (26.04 g, 0.310 mol) and methanol (400 mL) were added, and stirred at room temperature for 24 hours. Thereafter, the reaction product was subjected to vacuum distillation for removal of methanol, dissolved with water, washed 3 times with ethyl ether, adjusted to pH=2 with saturated potassium hydrogen sulfate, and extracted 3 times with dichloromethane. The extracts were combined, washed 3 times with saturated brine, concentrated, and separated through a silica gel column (eluent: petroleum ether/ethyl acetate/acetic acid), to give 12.48 g of a white product, yield 87.8percent.1H-NMR (400 MHz, DMSO) δ ppm: 12.71 (1H, s), 4.61 (1H, d, J=28.8 Hz), 3.82 (1H, d, J=12 Hz), 2.93 (1H, m), 2.06 (1H, s), 1.62 (3H, m), 1.39(11H, m); EI-MS (m/z): 229.1[M]+.
83% With triethylamine In 1,4-dioxane; water at 20℃; for 20 h; To a suspension of (R)-piperidine-2-carboxylic acid (12.5 g, 96.8 mmol) in water (88mL) and 1,4-dioxane (133 mL), were added di-tert-butyl dicarbonate (23.2 g, 106 mmol) andtriethylamine (13.5 mL, 96.8 mmol). The solution was stirred at room temperature for 20hours. The mixture was concentrated in vacuo, diluted with ethyl acetate (200 mL) and25 washed with 5percent aqueous HCl. The organic phase was separated, dried over anhydrousNa2S04, filtered, and concentrated to afford the compound as a white solid (18.5 g, 83percent).MS 130 (MH+- boc).
Reference: [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 4, p. 591 - 601
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 9, p. 1550 - 1557
[3] ChemMedChem, 2013, vol. 8, # 4, p. 577 - 581
[4] Patent: EP2805947, 2014, A1, . Location in patent: Paragraph 0074-0075
[5] Patent: US2015/126500, 2015, A1, . Location in patent: Paragraph 0127; 0128
[6] Patent: WO2014/25706, 2014, A1, . Location in patent: Page/Page column 73
[7] Journal of the American Chemical Society, 1995, vol. 117, # 32, p. 8488 - 8489
[8] Patent: US2004/198701, 2004, A1, . Location in patent: Page/Page column 10
[9] Patent: US2005/227969, 2005, A1, . Location in patent: Page/Page column 10
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Reference: [1] Patent: WO2012/117048, 2012, A1, . Location in patent: Page/Page column 52-53
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Reference: [1] Organic Preparations and Procedures International, 2007, vol. 39, # 5, p. 503 - 508
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 2, p. 184 - 187
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  • [ 58632-95-4 ]
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Reference: [1] European Journal of Medicinal Chemistry, 1998, vol. 33, # 1, p. 23 - 31
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Reference: [1] Journal of the American Chemical Society, 2010, vol. 132, # 35, p. 12216 - 12217
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Reference: [1] Journal of the American Chemical Society, 1995, vol. 117, # 32, p. 8488 - 8489
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Reference: [1] Organic Letters, 2012, vol. 14, # 19, p. 5006 - 5009
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Reference: [1] Journal of the American Chemical Society, 1997, vol. 119, # 4, p. 656 - 673
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Reference: [1] Organic Letters, 2012, vol. 14, # 19, p. 5006 - 5009
[2] Organic Letters, 2012, vol. 14, # 19, p. 5010 - 5013
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Reference: [1] Chemistry - A European Journal, 2010, vol. 16, # 13, p. 4082 - 4090
[2] Journal of the American Chemical Society, 2010, vol. 132, # 21, p. 7260 - 7261
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Reference: [1] Tetrahedron Asymmetry, 2003, vol. 14, # 12, p. 1685 - 1689
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Reference: [1] Tetrahedron Letters, 1994, vol. 35, # 2, p. 237 - 240
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Reference: [1] Tetrahedron Letters, 1994, vol. 35, # 2, p. 237 - 240
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Reference: [1] Tetrahedron Asymmetry, 2003, vol. 14, # 12, p. 1685 - 1689
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Reference: [1] Tetrahedron Asymmetry, 2003, vol. 14, # 12, p. 1685 - 1689
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 2, p. 184 - 187
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 9, p. 2711 - 2714
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 17, p. 2621 - 2624
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YieldReaction ConditionsOperation in experiment
99% With potassium carbonate In N,N-dimethyl-formamide at 20℃; Example 1.1; (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester; To (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.1 g, 22.2 mmol) in DMF (60 mL) were added K2CO3 (12.3 g, 88.8 mmol) and Mel (1.7 mL, 26.6 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water (6 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product (5.4 g, 99percent).1H NMR (300 MHz, CDCl3): δ 4.82 (m, 1H), 3.99 (m, 1H), 3.75 (s, 3H), 2.95 (m, 1H), 2.21 (m, 1H), 2.45 (m, 14H).
99% With potassium carbonate In N,N-dimethyl-formamide at 20℃; Example 1.1(R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester To (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.1 g, 22.2 mmol) in DMF (60 mL) were added K2CO3 (12.3 g, 88.8 mmol) and MeI (1.7 mL, 26.6 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The organic layer washed with water (6 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title product (5.4 g, 99percent).1H NMR (300 MHz, CDCl3): δ (ppm) 4.82 (m, 1H), 3.99 (m, 1H), 3.75 (s, 3H), 2.95 (m, 1H), 2.21 (m, 1H), 2.45 (m, 14H)
Reference: [1] Patent: US2007/259916, 2007, A1, . Location in patent: Page/Page column 9
[2] Patent: US2007/259862, 2007, A1, . Location in patent: Page/Page column 10
[3] Patent: US2004/198701, 2004, A1, . Location in patent: Page/Page column 10
[4] Patent: US2005/227969, 2005, A1, . Location in patent: Page/Page column 10
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Reference: [1] Organic Letters, 2012, vol. 14, # 19, p. 5006 - 5009
[2] Organic Letters, 2012, vol. 14, # 19, p. 5010 - 5013
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YieldReaction ConditionsOperation in experiment
100% With ammonium chloride; N-ethyl-N,N-diisopropylamine; HATU In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 18 h; Step B. tert-Butyl (2R)-2-(aminocarbonyl)piperidine-1-carboxylate; HATU (5.60 g, 14.7 mmol) was added to a mixture of the (2R)- 1 -(tert- butoxycarbonyl) piperidine-2-carboxylic acid (2.29 g, 10 mmol), ammonium chloride (3.21 g, 60 mmol) and DIPEA (3.88 g, 30 mmol) in DMF (70 mL) at 0 °C. The mixture was stirred for 18 h at room temperature, diluted with H20 (100 mL) and extracted with EtOAc (3x100 mL). The combined organic phases were washed with 10percent Na2C03 solution (2x30 mL), brine (2x30 mL) and dried with Na2S04. After filtration and concentration, the title compound was purified by MPLC on silica gel using hexane/EtOAc (1:1) g, 100 percent) as a white solid. (at)H NMR(400 MHz, CDCl3) No. 1.46 (s, 9 H), 1.63 (m, 2 H), 2.22 (m, 1 H), 2.91 (m, 1 H), 3.06 (m, 3 H), 4.01 (m, 1 H), 4.71 (m, 1 H), 6.46 (s broad, 2 H). MS (ESI) (M+H) (at)= 228.92
99%
Stage #1: With triethylamine; methyl chloroformate In tetrahydrofuran at 0℃;
Stage #2: With ammonia In tetrahydrofuran; water at 0 - 20℃; for 4 h;
a) 1, 1-Dimethylethyl (2/tO-2-(aminocarbonyI)-1-piporidinecarboxylalc. To a cold (0°C) solution of fe/iS-1-iUl, 1-dimethylethy^oxy]carbonyl]-2-piperidinecarboxylic acid(1.0 g, 4.36 mmol) in THF (20 ml) was added triethylamine (0.60 mL, 4,36 rnmol)followed by slow addition of methyl chloroform ate (0.34 mL, 4,36 rnmol). After a fewminutes a suspension had formed, To this mixture was added concentrated NI-LiOH(1.5 mL) and the solution was allowed to warm to rt as the bath warmed and stirredfor a total of 4 h. The mixture was concentrated in vacuo and the residue was takenup in EtOAc, The organic layer was washed with citric acid, bicard and then brine,dried over NasSO-i. Filtration and concentration gave 1, 1-dimethylethyl(2R)-2-(aminocarbonyl)-1-piperidinecarboxylate (3 .0 g, 99percent). 1H NMR (CDCl3) δ 6,03(br, 1 H), 5.45 (br, 1 H), 4.77 (br, 1 H), 4.06 (br, 1 H), 2.82 (m, 1 H), 2.29 (m, 1 H),1.67- 1.43 (m, 13 H),
89% With ammonium chloride; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20℃; for 1.5 h; Example 1; 1-{(R)-2-[4-(4-Chloro-phenyl)-thiazol-2-yl]-piperidin-1-yl}-2-phenoxy-ethanone; The title compound was prepared as illustrated in scheme 1, steps 1 to 5.; Step 1. A suspension of ammonium chloride (3.44 g, 64 mmol) in N,N-dimethylacetamide (150 mL) under argon was treated with diisopropylethylamine (13.44 g, 17.7 mL, 104 mmol). A solution of (R)-(+)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.10 g, 22 mmol) was added, followed by TBTU (10.11 g, 31 mmol). The mixture was stirred at room temperature for 1.5 h, then diluted with ethyl acetate (850 mL) and washed several times with water (5*50 mL) and finally with saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The resulting oil was purified by flash chromatography (heptane/ethyl acetate gradient) to yield (R)-2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (4.54 g, 89percent) as a white solid, MS (ISP): 229.0 (M+H)+..
Reference: [1] Patent: WO2005/115986, 2005, A1, . Location in patent: Page/Page column 103
[2] Patent: WO2006/116764, 2006, A1, . Location in patent: Page/Page column 121; 151
[3] Patent: US2008/300279, 2008, A1, . Location in patent: Page/Page column 9
[4] ACS Infectious Diseases, 2018, vol. 4, # 7, p. 1130 - 1145
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Reference: [1] Patent: WO2006/116764, 2006, A1,
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Reference: [1] Patent: WO2012/117048, 2012, A1,
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