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HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
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Structure of 1824-81-3 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 4152
[2] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
2
[ 1824-81-3 ]
[ 28279-41-6 ]
Reference：
[1] Russian Journal of Applied Chemistry, 2005, vol. 78, # 5, p. 787 - 790
3
[ 1824-81-3 ]
[ 56057-19-3 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[2] Patent: EP2366691, 2011, A1,
4
[ 1824-81-3 ]
[ 21901-29-1 ]
Yield
Reaction Conditions
Operation in experiment
29%
Stage #1: at 0℃; for 12 h; Stage #2: Cooling with ice
Example 7: Synthesis of the 6-(1-ethyleneimine)-2-carbamoyl-3-nitropyridine (compound V) [Show Image] The reagents used was ( i ) HNO3/H2SO4; (ii) NaNO2; (iii) POCl3; (iv) Na2Cr2O7; (v) SOCl2, followed by NH4OH; (vi) aziridine.Synthesis of the compound 24 A concentrated sulphuric acid (100 mL) was cooled in an ice bath, the starting material compound 23 (30 g, 0.28 mol) was slowly added and cooled to 0°C, 42 mL of a mixture in volumetric ratio of 1:1 of a concentrated sulphuric acid (98percent) and a concentrated nitric acid (72percent) was slowly added, and the reaction was run at 0°C for 1h and left standing for 12 h. The reaction liquid was poured into 2 L of ice-water mixture, adjusted to pH=7 by adding strong aqua, and filtered. The filter cake was dried, yielding 54 g of the crude product. The above mixture was subject to wet distillation, resulting in a bright yellow liquid, and it was extracted with ethyl acetate and recrystallized in ethanol to obtain 12.5 g of the compound 24 with a melting point of 156.5-158.5°C (ethyl acetate) and a yield of 29percent.
22%
Stage #1: at -15 - 20℃; for 2 h; Stage #2: With sodium hydroxide In water
25.0 g (231 mmol) of 2-amino-6-picoline was cooled to -15(C, and dissolved very carefully in concentrated sulfuric acid (100 ml). This solution was cooled to 0(C, and 22.0 ml (60 percent, d = 1.42, 347 mmol) of nitric acid was added dropwise thereto. After the addition, the ice-water bath was removed, and after the heat generation was stopped, the reaction mixture was stirred at room temperature for 2 hours. Thereactionmixture was poured into ice (400 g), and the mixture was controlled to have pH of from 4 to 5 with aqueous 4 N sodium hydroxide solution added thereto. The precipitate formed was taken out through filtration, and washed with hot water. This was dried, and applied to a silica gel column chromatography. From the eluate with chloroform/methanol (50/1, v/v), 7.60 g (22 percent) of the entitled compound was obtained as a yellow solid.1H-NMR(DMSO-d6)δ: 2.37(3H, s), 6.61(1H, d, J=8.7Hz), 7.86(2H, brs), 8.24(1H, d, J=8.7Hz).
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 6, p. 1331 - 1338
[2] Patent: EP2366691, 2011, A1, . Location in patent: Page/Page column 11
[3] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 22, p. 3171 - 3176
[4] Patent: EP1479681, 2004, A1, . Location in patent: Page 122
[5] Patent: US2002/32187, 2002, A1,
5
[ 1824-81-3 ]
[ 21901-29-1 ]
Reference：
[1] Patent: US5977101, 1999, A,
6
[ 1824-81-3 ]
[ 22280-62-2 ]
[ 21901-29-1 ]
Reference：
[1] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[2] Archiv der Pharmazie, 1995, vol. 328, # 3, p. 247 - 255
[3] Archiv der Pharmazie, 1995, vol. 328, # 3, p. 247 - 255
[4] Yakugaku Zasshi, 1952, vol. 72, p. 434[5] Chem.Abstr., 1953, p. 6404
[6] Journal of the American Chemical Society, 1955, vol. 77, p. 3154
[7] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[8] Journal of Molecular Structure, 2013, vol. 1043, p. 15 - 27
7
[ 1824-81-3 ]
[ 22280-62-2 ]
[ 25864-34-0 ]
[ 21901-29-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 2987 - 2991
8
[ 5315-25-3 ]
[ 1824-81-3 ]
Yield
Reaction Conditions
Operation in experiment
75%
With ammonium hydroxide; copper(I) iodide; 1-ethylacetoacetate-3-methyl imidazolium hydroxide In acetonitrile at 80℃; for 12 h; Inert atmosphere
General procedure: An oven-dried flask was charged with aryl halide (1.0 mmol), aqueous NH3 (28percent, 1.5 mmol), CuI nanoparticles (0.02 mmol), 4a (3.0 mmol) and acetonitrile (2 mL). The contents were stirred under argon atmosphere at rt for 12 h. After completion of the reaction as monitored by TLC, the product was extracted with diethyl ether (5×5 mL). The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. Purification was done on silica gel column, and elution with ethyl acetate–hexane mixture afforded the aminated products. All products obtained herein are known compounds, and were confirmed by 1H NMR, 13C NMR and mass spectroscopic analysis, see Supplementary data for full details.
Reference：
[1] Chemical Communications, 2010, vol. 46, # 6, p. 925 - 927
[2] Tetrahedron, 2013, vol. 69, # 25, p. 5092 - 5097
[3] Tetrahedron Letters, 2008, vol. 49, # 21, p. 3471 - 3474
9
[ 62674-71-9 ]
[ 1824-81-3 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2009, vol. 351, # 11-12, p. 1722 - 1726
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, p. 2801 - 2807
[2] Journal of the Chemical Society, Chemical Communications, 1982, # 14, p. 800 - 801
15
[ 5327-33-3 ]
[ 1824-81-3 ]
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 4, p. 887 - 891
16
[ 76809-21-7 ]
[ 1824-81-3 ]
[ 69-72-7 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 10, p. 3020 - 3028
17
[ 931-19-1 ]
[ 1824-81-3 ]
Reference：
[1] Bioorganic and medicinal chemistry letters, 2000, vol. 10, # 17, p. 1975 - 1978
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1914, vol. 46, p. 1232[2] Chem. Zentralbl., 1915, vol. 86, # I, p. 1065
23
[ 109-06-8 ]
[ 108-88-3 ]
[ 1824-81-3 ]
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1914, vol. 46, p. 1232[2] Chem. Zentralbl., 1915, vol. 86, # I, p. 1065
[3] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 536[4] Chem. Zentralbl., 1923, vol. 94, # III, p. 1022
24
[ 7647-01-0 ]
[ 1824-81-3 ]
[ 102753-94-6 ]
[ 106-47-8 ]
Reference：
[1] Chemische Berichte, 1958, vol. 91, p. 247,253
25
[ 1824-81-3 ]
[ 3279-76-3 ]
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 536[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1022
[3] Organic Syntheses, 2002, vol. 78, p. 51 - 51
26
[ 1824-81-3 ]
[ 407-22-7 ]
Reference：
[1] Tetrahedron, 1996, vol. 52, # 1, p. 23 - 36
[2] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[3] Journal of the American Chemical Society, 1949, vol. 71, p. 4152
[4] Journal of Fluorine Chemistry, 1988, vol. 38, p. 435 - 438
27
[ 1824-81-3 ]
[ 18368-63-3 ]
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 536[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1022
[3] Patent: US4614833, 1986, A,
28
[ 1824-81-3 ]
[ 5315-25-3 ]
Yield
Reaction Conditions
Operation in experiment
93.1%
Stage #1: at 60 - 62℃; for 1 h; Stage #2: at -5 - -3℃; for 3 h; Stage #3: With sodium nitrite In water for 3 h;
under stirring conditions, the mass concentration in the reaction tank 46percent the hydrobromidum 756g, 2-amino-6-methyl pyridine 108g, heating to 60-62 °C and thermal insulation 1h, then cool to-5 - - 3°C, keep the range of the temperature is dropping 640g bromine Br2, re-insulation 3h; in the range of the temperature is dropping mass concentration of 30percent sodium nitrite aqueous solution 920g, completion of the dropping, without the control of the reaction temperature the stirring reaction 3h; end of the reaction, the reaction solution when the temperature is reduced to 15 °C rear, used for quality concentration 30percent sodium hydroxide aqueous solution to regulate the pH=11, then through steam distillation to obtain 2-bromo-6-methylpyridine 150g, vapor content is 99.4percent, yield of 93.1percent;
80%
With hydrogen bromide; bromine; sodium nitrite In water at -20 - 30℃;
Example 31; 2-bromopicoline (104); 2-amino-picoline (37.35 g, 0.346 mol) is added to a mechanically-stirred round-bottom flask in several stages, in a hydrobromic acid solution (48percent in water, 187 mL) at a temperature maintained between 20 and 30° C. After entire dissolution of the reagent, the reaction medium is cooled to 20° C. during the dropwise addition of dibromine (49 mL, 0.966 mol), for 30 min. The temperature of the solution is maintained at -20° C. for 90 minutes. In sodium nitrite solution (63.5 g, 6 mol) in water (100 mL) is added dropwise. The temperature of the solution is then brought to 15° C. in an hour and stirred for 45 minutes at that temperature. The medium is cooled to -20° C. and treated with a sodium solution (249 g, 400 mL H2O) at a temperature maintained at below -10° C. during the adding. After return to room temperature, the solution is stirred for an hour and then extracted with AcOEt. The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is distilled under vacuum and the 2-bromopicoline (104) is obtained in the form of a colourless oil with a yield of 80percent.bp 129-132° C. (2.6 mbar).1H RMN (CDCl3) δ (ppm): 2.49 (s, 3H, H7), 7.08 (d, J=7.6, 1H, H5), 7.24 (d, J 7.6, 1H, H3), 7.41 (t, 1H, H4).
72%
Stage #1: at 0℃; for 1.5 h; Stage #2: With sodium nitrite In water at 10℃; for 2 h;
An alkali trap, an equal pressure dropping funnel, a thermometer, and a mechanical stirrer were attached to a 1000 mL four-necked round bottom flask. (A) 2-amino-6-picoline (27.0 g 0.25 mol) and 48percent HBr (125 mL 2.31 mol) were placed in this reaction vessel. The reaction vessel was immersed in an ice bath and cooled to 0 ° C. Br2 (37.5 mL 0.72 mol) was transferred to an equal pressure dropping funnel, The temperature of the reaction solution was kept at 0 ° C. and slowly dropped into the reaction vessel over 90 minutes while vigorously stirring with a mechanical stirrer. NaNO 2 (42.5 g 0.62 mol) was weighed and dissolved in about 100 mL of distilled water. This was transferred to an equal pressure dropping funnel,While stirring vigorously with a stirrer, it dripped over about 2 hours. At this time, care was taken that the temperature of the reaction solution did not exceed 10 ° C. In order to complete the reaction, NaNO 2 (2.50 g 0.036 mol) was dissolved in about 10 mL of distilled water and added, It was confirmed that nitrogen gas was not generated from the reaction vessel. While cooling in an ice bath, NaOH (95.0 g, 2.4 mol) was dissolved in about 300 mL of distilled water, after cooling sufficiently, it was gradually added to the solution for neutralization. At this time, care was taken that the temperature of the reaction solution did not exceed 20 ° C. The reaction mixture was extracted with Et 2 O (200 mL × 4) and the organic layer was collected. Anhydrous Na 2 SO 4 was added and dried, Upon concentration, a brown oily substance was obtained. This oily substance was distilled under reduced pressure in a rectifying tube, fractionated at 55 ° C. to 60 ° C. at a reduced pressure degree of 7.00 mmHg, A yellow oily substance was obtained. This material was stored at -40 ° C. Yield: 72percent (32.0 g)
66%
Stage #1: at -10 - 0℃; for 2 h; Stage #2: With sodium nitrite In water for 3 h;
1000 ml Four-neck reaction vessel was equipped with a mechanical stirrer,Alkaline trap,Two 200 ml isobaric dropping funnels were attached,(J) 2-amino-6-picoline (27.0 g 0.25 mol) was added,Was dissolved in 48percent HBr (125 ml 2.31 mol)The mixture was vigorously stirred with a mechanical stirrer.The reaction vessel was immersed in an ice bath containing saline,It was cooled to -10 ° C.The procedure up to neutralization below was done in an ice bath.Br2 (37.5 ml 0.72 mol) was transferred to an isobaric dropping funnel with vigorous stirring with a mechanical stirrer,And slowly added dropwise to the reaction vessel over about 2 hours while maintaining the temperature of the reaction solution at 0 ° C.The solution turned from light yellow to orange to brown.Weigh out NaNO 2 (42.5 g 0.615 mol)It was dissolved in about 100 ml distilled water.This was added dropwise from an isobaric dropping funnel over about 3 hours.At this time,Care was taken that the temperature of the reaction solution did not exceed 10 ° C.In order to complete the reaction,Further, NaNO 2 (2.50 g 0.036 mol) was dissolved in about 10 ml of distilled water and added, and it was confirmed that no bubbles were generated from the reaction solution.While keeping the solution at a low temperature in an ice bath,NaOH (95 g 2.35 mol) was dissolved in about 300 ml of distilled water,After cooling sufficiently,Was added to the solution little by little using an isobaric dropping funnel to neutralize.At this time,Care was taken that the temperature of the reaction solution did not exceed 20 ° C.When the pH became neutral, the color of the solution turned into fluorescent yellow.After checking that the pH reached around 8 with pH test paper, stop the addition, transfer the reaction solution to a separating funnel, extract with Et 2 O (300 ml × 5), collect the organic layer, dry with Na 2 SO 4, Upon concentration, a brown oily substance was obtained.This oily substance was subjected to distillation under reduced pressure (oil bath temperature 55 ° C.) using a distillation apparatus equipped with a rectifying tube to obtain 28.4 g of a transparent yellow oil substance.This material was degassed and purged with nitrogen and then stored at -40 ° C.Yield: 66percent
Reference：
[1] Patent: CN105384684, 2016, A, . Location in patent: Paragraph 0028; 0029
[2] Organic Letters, 2000, vol. 2, # 21, p. 3373 - 3376
[3] Phosphorus, Sulfur and Silicon and the Related Elements, 2002, vol. 177, # 11, p. 2579 - 2587
[4] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[5] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 19, p. 3151 - 3155
[6] Patent: US2010/4443, 2010, A1, . Location in patent: Page/Page column 33
[7] Tetrahedron Letters, 2006, vol. 47, # 11, p. 1793 - 1796
[8] Inorganic Chemistry, 2018, vol. 57, # 9, p. 5486 - 5498
[9] Dalton Transactions, 2007, # 33, p. 3676 - 3683
[10] Phosphorus, Sulfur and Silicon and the Related Elements, 2008, vol. 183, # 9, p. 2237 - 2247
[11] Tetrahedron, 2009, vol. 65, # 36, p. 7673 - 7686
[12] Patent: JP2017/197451, 2017, A, . Location in patent: Paragraph 0029
[13] Patent: JP2017/57177, 2017, A, . Location in patent: Page/Page column 9; 13
[14] Journal of the Chemical Society, 1954, p. 2693,2697
[15] Journal of the American Chemical Society, 1954, vol. 76, p. 3168,3171
[16] Journal of the American Chemical Society, 1951, vol. 73, p. 2109,2112
[17] Chemische Berichte, 1990, vol. 123, # 11, p. 2181 - 2185
[18] Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999), 1995, # 9, p. 1511 - 1518
[19] Acta Chemica Scandinavica, 1997, vol. 51, # 4, p. 462 - 469
[20] Tetrahedron Letters, 2001, vol. 42, # 35, p. 6113 - 6115
[21] Journal of the American Chemical Society, 2004, vol. 126, # 15, p. 4888 - 4896
[22] Tetrahedron Letters, 2005, vol. 46, # 36, p. 6033 - 6036
[23] Patent: US4338326, 1982, A,
[24] Helvetica Chimica Acta, 2008, vol. 91, # 11, p. 2089 - 2096
[25] European Journal of Inorganic Chemistry, 2014, vol. 2014, # 34, p. 5838 - 5848
[26] Main Group Metal Chemistry, 2015, vol. 38, # 5-6, p. 145 - 150
[27] Asian Journal of Chemistry, 2015, vol. 27, # 11, p. 4141 - 4144
29
[ 1824-81-3 ]
[ 3430-10-2 ]
Reference：
[1] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
30
[ 1824-81-3 ]
[ 63071-03-4 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 19, p. 3151 - 3155
[2] Journal of the Chemical Society, 1954, p. 2693,2697
31
[ 1824-81-3 ]
[ 67-66-3 ]
[ 3222-48-8 ]
[ 17566-03-9 ]
[ 2237-30-1 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 12, p. 4935 - 4953
32
[ 1824-81-3 ]
[ 67-66-3 ]
[ 3222-48-8 ]
[ 2237-30-1 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 12, p. 4935 - 4953
33
[ 1824-81-3 ]
[ 39745-40-9 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
34
[ 1824-81-3 ]
[ 164666-68-6 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
35
[ 1824-81-3 ]
[ 54923-31-8 ]
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 1186,1191
36
[ 1824-81-3 ]
[ 42753-71-9 ]
Yield
Reaction Conditions
Operation in experiment
85%
With dihydrogen peroxide; 1-butylpyridinium bromide; toluene-4-sulfonic acid In 1,2-dimethoxyethane at 80℃; for 24 h; Schlenk technique; Inert atmosphere; Green chemistry
General procedure: To a mixture of 2-aminopyridine (0.5 mmol, 1 equiv), p-TSA (0.4 mmol,0.8 equiv), 1-butylpyridinium bromide (1.5 mmol, 3 equiv) in a 50 mL Schlenk tube were added 1,2-dimethoxyethane (2 mL) under air. Then H2O2 (1.2 mmol, 2.4 equiv) was added. The mixture was stirred at 80°C for 24 h. And then the mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the products.
84%
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In dichloromethane at -10 - 20℃; for 2 - 3 h;
To a 2L flask was added 2-amino-6-methylpyridine (50 g, 0.462 mole) and DCM (1.0 L) and the solution was cooled to -5 0C. A/,ΛT-Dibromo-4,4,-dimethylhydantom (DBH, 66.1 g, 0.231 mol) was added portionwise (6 portions) during a Ih period while maintaining the pot temperature below -5 0C. The reaction was stirred at -5 0C for 1 h after addition, and an aliquot NMR showed about 7percent starting material left. Additional DBH was added based on the NMR integration of the remaining starting material. After stirring for another 1 h the mixture was quenched with cold 30percent Na2SO3 (100 mL) and brine (200 mL). The layers were separated and the aqueous was extracted with CH2Cl2 (2 x 100 mL). The combined organic layers were concentrated to dryness and CH2Cl2 (200 mL) was added to the residue followed by hexanes (500 mL). The slurry was agitated for 20 min at rt, then cooled in an ice- water bath for 30 min. The solid was filtered and washed with hexanes to afford 2-arnino-6-methyl- 5-bromopyridine as white dense crystals (75.22 g, 87percent).; To a solution of 2-amino-6-methylpyridine (10.0 g, 92.5 mmol) in CH2Cl2 (200 mL), cooled to -10 0C, was added l,3-dibromo-5,5-dimethylhydantoin (13.2 g, 46.2 mmol) portion-wise. After addition the mixture was brought to room temperature and stirred for 2 h. A saturated aqueous solution OfNa2S2O3 (10 mL) and brine (50 mL) were then added and the organic layer was collected. The aqueous layer was extracted with CH2Cl2 (4 X 100 mL). The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by recrystallization from EtOAc/hexanes or by flash chromatography on silica gel (EtOAc/hexanes, 2:3 in v/v) to afford a pale yellow solid (14.5 g, 84percent). 1H NMR (CDCl3) δ 2.48 (s, 3H), 4.47 (br s, 2H), 6.23 (d, IH, J= 8.4 Hz), 7.47 (d, IH, J= 8.4 Hz).
55%
With sulfuric acid; bromine In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water
Step 1 Preparation of 6-amino-3-bromo-2-picoline 32.4 g(0.3 mole) of 6-aminopicoline was dissolved in a mixture of 28 g of conc. sulfuric acid and 120 ml of water and the resulting solution was cooled in ice water. 52.8 g(0.33 mole) of bromine was added dropwise to the solution over 30 minutes at 0° C. The reaction solution was stirred for 20 minutes at room temperature and neutralized with cold aqueous NaOH solution. The resultant was filtered and purified by column chromatography using methylene chloride and ethyl acetate as an eluent to obtain 31 g of the title compound(yield 55percent).
42.8%
With bromine In acetic acid at 25℃; for 16 h;
The 6-Methylpyridin-2-amine (1.08g, 10mmol) dissolved in glacial acetic acid (20 ml) in, bromine is added for (1.6g, 10mmol), 25 °C reaction 16 hours. Water (50 ml), ethyl acetate extraction (150 ml × 2), combined organic phase, saturated salt water washing, dry anhydrous sodium sulfate, concentrated under vacuum, the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) purification, to obtain the title compound (800 mg, yield 42.8percent).
34.7%
With N-Bromosuccinimide In methanol at 0 - 20℃; for 17 h; Inert atmosphere
A solution of 6-methylpyridin-2-amine (5 g 46.2 mmol) in MeOH (20 mL) stirred under N2at 0 . NBS (8.23 g 46.2 mmol) was added to the solution slowly the reaction mixture was stirred at 0 for 1 h. The reaction mixture was stirred at rt for 16 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3solution. The combined organic extract was washed with brine dried over MgSO4 filtered and concentrated. The residue was purified by silica column chromatography to give 5-bromo-6-methylpyridin-2-amine (3 g 16.04 mmol 34.7yield) .1HNMR(400 MHz CD3OD) δ 7.49 (d J8.8 Hz 1H) 6.33 (d J8.8 Hz 1H) 2.39 (s 3H) ES-LCMS m/z 188.9 (M+H)
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4889 - 4905
[2] Tetrahedron Letters, 2014, vol. 55, # 36, p. 5058 - 5061
[3] Patent: WO2007/22371, 2007, A2, . Location in patent: Page/Page column 49-50
[4] Patent: US5849753, 1998, A,
[5] Patent: CN105541792, 2016, A, . Location in patent: Paragraph 0271; 0272; 0273
[6] Patent: WO2016/37578, 2016, A1, . Location in patent: Page/Page column 123; 124
[7] Journal of the American Chemical Society, 1949, vol. 71, p. 1186,1191
37
[ 1824-81-3 ]
[ 42753-71-9 ]
[ 91872-10-5 ]
Reference：
[1] Heterocycles, 1994, vol. 38, # 3, p. 529 - 540
[2] Russian Journal of Applied Chemistry, 2005, vol. 78, # 5, p. 787 - 790
Reference：
[1] Advanced Synthesis and Catalysis, 1997, vol. 339, # 4, p. 335 - 339
[2] Organic Letters, 2012, vol. 14, # 21, p. 5618 - 5620
40
[ 1824-81-3 ]
[ 23628-31-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 11, p. 2741 - 2748
[2] Journal of Carbohydrate Chemistry, 1994, vol. 13, # 5, p. 715 - 736
41
[ 1824-81-3 ]
[ 21190-87-4 ]
Reference：
[1] Tetrahedron Letters, 2001, vol. 42, # 35, p. 6113 - 6115
[2] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
42
[ 1824-81-3 ]
[ 91872-10-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 2987 - 2991
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 20, p. 5533 - 5539
[3] Journal of the American Chemical Society, 1949, vol. 71, p. 1186,1191
43
[ 1824-81-3 ]
[ 42753-71-9 ]
[ 91872-10-5 ]
Reference：
[1] Heterocycles, 1994, vol. 38, # 3, p. 529 - 540
[2] Russian Journal of Applied Chemistry, 2005, vol. 78, # 5, p. 787 - 790
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 4152
48
[ 1824-81-3 ]
[ 69142-64-9 ]
Reference：
[1] Journal of Carbohydrate Chemistry, 1994, vol. 13, # 5, p. 715 - 736
[2] European Journal of Inorganic Chemistry, 2010, # 13, p. 1913 - 1928
49
[ 1824-81-3 ]
[ 22280-60-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 2, p. 727 - 739
[2] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[3] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[4] Patent: CN105906621, 2016, A,
[5] Patent: WO2005/42464, 2005, A1,
50
[ 1824-81-3 ]
[ 28489-45-4 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[2] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[3] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[4] Patent: CN105906621, 2016, A,
[5] Patent: WO2005/42464, 2005, A1,
51
[ 1824-81-3 ]
[ 22280-62-2 ]
Yield
Reaction Conditions
Operation in experiment
75%
at -1 - 50℃; for 11.5 h;
10 mL of concentrated sulfuric acid was cooled at 0-1 ° C, slowly adding raw material 1 (20 g), cooled to 0 ° C, slowly added 110 mL of nitric acid at a volume ratio of 1: 1, stirred at -1 ° C and stirred at room temperature for 30 min. Reaction was carried out at 50 ° C for 11 h. The reaction solution was extracted with EA. The EA layer was washed with aqueous ammonia and the aqueous ammonia was concentrated. The solid layer 2 (18 g) was precipitated and the yield was 75percent.
48%
at 0 - 100℃;
Example 8 2-Methyl-2- (6-methyl-5-nitro-pyridin-2-ylamino)-propan-1-ol (a) Conc. H2S04 (140 ml) was cooled in an ice-salt bath and molten 6-amino-2-picoline (30 g, 0.277 mol) was added in portions with good stirring. To this brown, viscous solution which was maintained at 0°C was added a cooled (0°C) mixture of conc. H2SO4 (21 ml) and conc. HNO3 (21 ml) drop wise over a period of approx. 1.5 hrs. The red- orange reaction mixture was stirred for an additional hour at 0°C and then allowed to warm slowly to room temperature over night. The brown solution was heated at 60° C (oil bath) for 1 hr followed by lhr at 100°C (carefully controlled temperature). The reaction mixture was cooled to 0°C (ice bath), poured over cracked ice and neutralised by addition of a concentrated aqueous NaOH solution. The yellow precipitate was filtered and washed well with ice-water. (The filtrate was put in the refrigerator, additional product was precipitated together with the salts. ) The yellow product was suspended in water and divided into two portions, each of them subjected to steam distillation in turn. The yellow reaction mixture became more"transparent'after some hrs, but the collected steam, containing 4-amino-3-nitro-2-picoline, was still yellow after 6 hrs. The steam distillation was stopped after 8 hrs, the residual part of the reaction mixture was filtered and evaporated to dryness. 1HNMR (D2O) showed a mixture of 2-3 compounds. The mixture was washed with; CHCI ;, EtOH (x 2) and CHC leaving 20.4 g (48percent) of pure 6-amino- 3-nitro-2-picoline.
36%
at -6 - 20℃; for 7.5 h;
The 6-methylpyridin-2-amine (20g, 185mmol) was dissolved in 98percent H2SO4 (91mL). A mixture of fuming HNO3 (9mL) and 98percent H2SO4 (9mL) was added dropwise to the vigorously stirring solution over 30min at −6°C. The mixture was stirred for 2h at 0°C and slowly warmed to 10°C over 1h and kept stirring for an additional hour. Afterwards, the solution was warmed to 20°C over 1h and stirred for 2h. The reaction mixture was poured onto ice and basified with ammonium hydroxide (pH∼9). The precipitated solid was collected by filtration and purified by steam distillation to afford compound 9 (9.99g). Yellow solid (36percent), mp: 189–191°C. 1H NMR (500MHz, DMSO-d6) δ 7.77 (d, 1H, J=9.2Hz), 6.09 (d, 1H, J=9.2Hz), 6.11 (s, 2H), 2.36 (s, 3H). ESI-MS: m/z=154 [M+1]+.
Reference：
[1] Patent: CN105906621, 2016, A, . Location in patent: Paragraph 0019
[2] Patent: WO2005/42464, 2005, A1, . Location in patent: Page/Page column 32-33
[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 8, p. 1858 - 1868
[4] Patent: WO2009/30725, 2009, A2, . Location in patent: Page/Page column 58
[5] Patent: EP1857444, 2007, A1, . Location in patent: Page/Page column 20
52
[ 1824-81-3 ]
[ 22280-62-2 ]
[ 21901-29-1 ]
Reference：
[1] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[2] Archiv der Pharmazie, 1995, vol. 328, # 3, p. 247 - 255
[3] Archiv der Pharmazie, 1995, vol. 328, # 3, p. 247 - 255
[4] Yakugaku Zasshi, 1952, vol. 72, p. 434[5] Chem.Abstr., 1953, p. 6404
[6] Journal of the American Chemical Society, 1955, vol. 77, p. 3154
[7] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[8] Journal of Molecular Structure, 2013, vol. 1043, p. 15 - 27
53
[ 1824-81-3 ]
[ 22280-62-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 2, p. 727 - 739
54
[ 1824-81-3 ]
[ 22280-62-2 ]
[ 25864-34-0 ]
[ 21901-29-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 2987 - 2991
55
[ 1824-81-3 ]
[ 39745-39-6 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
[2] Patent: EP2366691, 2011, A1,
56
[ 1824-81-3 ]
[ 856834-95-2 ]
Reference：
[1] Journal of the American Chemical Society, 1947, vol. 69, p. 63,66
57
[ 1824-81-3 ]
[ 2980-33-8 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 2, p. 585 - 590
58
[ 1824-81-3 ]
[ 68957-50-6 ]
Reference：
[1] Russian Journal of Applied Chemistry, 2005, vol. 78, # 5, p. 787 - 790
With ferrous(II) sulfate heptahydrate; sulfuric acid; boric acid In water; glycerol at 0 - 135℃; for 4 h;
Sodium-3-nitrobenzenesulfonate (17.5 g, 77.7 mmol), boric acid (2.4 g, 38.8 mmol), and ferrous sulfate heptahydrate (1.4 g, 0.5 mmol) were added to 23.1 mL of 98percent sulfuric acid. After cooling to 0 °C, glycerol (12.5 mL), 2-amino-6-methylpyridine (4.3 g, 40.0 mmol), and hot water (50 °C, 22.5 mL) were slowly added to above mixture. The reaction solution was refluxed for 4 h at 135 °C and cooled to room temperature. 40percent water solution of NaOH was used to mediate pH to 7 and chloroform was used to extract the product. The organic phase was concentrated in vacuum to give the crude product and the final product was obtained by column chromatography (200-300 mesh, 3/1 ethyl acetate/petroleum ether) (3.0 g, 25.9percent yield). Characterization of 2-methyl-1,8-naphthyridine: HRMS (EI) m/z: calcd for C9H9N2 [M+H]+, 145.0766; found, 145.0768. 1H NMR (400 MHz; CDCl3; TMS) 9.08 (d, 1H), 8.13-8.16 (m, 1H), 8.08 (d, 1H), 7.43-7.45 (m, 1H), 7.28 (d, H), 2.82 (s, 3H). 13C NMR: δC (100 MHz, CDCl3): 163.1, 160.0, 153.3, 136.9, 136.7, 123.0, 121.4, 120.8, 25.7.
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 19, p. 3151 - 3155
72
[ 1824-81-3 ]
[ 131747-53-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
73
[ 1824-81-3 ]
[ 131747-42-7 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
74
[ 1824-81-3 ]
[ 532-55-8 ]
[ 96938-51-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
for 3 h; Reflux
To the solution of benzylisothiocyanate (83.0 g, 509.3 mmol) in acetone (700mL) was added compound 6-methylpyridin-2 -amine (50 g, 463.0mmol) in acetone (600 ml) dropwise, then the reaction mixture was stirred at reflux for 3h. The reaction mixture was poured on to crushed ice, then filtered and washed with water, water/MeOH (1 : 1) and MeOH to give l-benzoyl-3-(6- methylpyridin-2-yl)thiourea as a yellow solid (100.1 g, yield 80percent). To a solution of 1-benzoyl-3-(6-methylpyridin-2-yl)thiourea (60 g,221.4 mmol) in THF ( 1000 ml) was added 2N NaOH (243.5ml), then heated at reflux for 3 h. Cooled to RT and filtered to give (6-methylpyridin-2- yl)thiourea as a white solid (34.1 g, yield 92percent). A mixture of (6-methylpyridin-2-yl)thiourea (13.2 g, 79.16 mmol) and 2-bromo-l-(4-bromophenyl)ethan-l-one (22 g, 79.16 mmol) in ethanol (300 mL) was stirred at reflux for 3h, then concentrated and purified with silica gel column to give N-[4-(4-bromophenyl)-l,3-thiazol-2-yl]-6-methylpyridin-2-amine as a yellow solid (14.3 g,53percent). A solution of N-[4-(4-bromophenyl)-l,3-thiazol-2-yl]-6-methylpyridin-2-amine (5 g. 14.5mmol), Bis(pinacolato)diboron (4.8 g, 18.8mmol), Pd(dppf)2Ci2 (1.2 mg, 1.5mmol) and AcOK (4.3 g, 43.3mmol) in dioxane (100ml) was heated to 80 under 2 overnight. The mixture was evaporated to give (6-methyl-N-{4-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-l,3-thiazol-2-yl}pyridin-2-amine). Coupling (200mg) with 2-dimethylamino-4- bromopyridine under standard conditions gave 33 mg from 200 mg of, yellow solid, 17 percent yield.
Reference：
[1] Patent: WO2013/33037, 2013, A2, . Location in patent: Paragraph 0752
[2] Journal of Heterocyclic Chemistry, 1985, vol. 22, # 1, p. 137 - 140
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 12, p. 3081 - 3085
[4] Patent: WO2005/95345, 2005, A2, . Location in patent: Page/Page column 41
[5] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 2, p. 634 - 639
[6] ChemMedChem, 2013, vol. 8, # 5, p. 847 - 857
[7] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6385 - 6397
[8] Phosphorus, Sulfur and Silicon and the Related Elements, 2015, vol. 190, # 8, p. 1366 - 1377
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 1, p. 156 - 167
77
[ 1824-81-3 ]
[ 137778-18-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4889 - 4905
78
[ 1824-81-3 ]
[ 39919-65-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4889 - 4905
79
[ 1824-81-3 ]
[ 79651-64-2 ]
Reference：
[1] European Journal of Inorganic Chemistry, 2010, # 13, p. 1913 - 1928
[2] Patent: EP3018125, 2016, A1,
80
[ 1824-81-3 ]
[ 126325-46-0 ]
Yield
Reaction Conditions
Operation in experiment
55%
With sulfuric acid; bromine In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water
Step 1 Preparation of 6-amino-5-bromo-picoline 32.4 g (0.3 mole) of 6-aminopicoline was dissolved in a mixture of 28 g of conc. sulfuric acid and 120 ml of water and the resulting solution was cooled in ice water. 52.8 g (0.33 mole) of bromine was added dropwise to the solution over 30 minutes at 0° C. The reaction solution was stirred for 20 minutes at room temperature and neutralized with cold aqueous NaOH solution. The resultant was filtered and the solid was purified with column chromatography using methylene chloride and ethyl acetate as an eluent to obtain 31 g of the title compound (yield 55percent).
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 14, p. 4623 - 4633
87
[ 1824-81-3 ]
[ 208110-81-0 ]
Reference：
[1] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
88
[ 1824-81-3 ]
[ 75073-11-9 ]
Yield
Reaction Conditions
Operation in experiment
77%
With sulfuric acid; iodine; acetic acid; periodic acid In water at 80℃; for 6 h;
To a stirred solution of 6-methyl-pyridin-2-ylamine (30g, 278mmol, 1 eq) in acetic acid (167ml_) was added periodic acid (12.7g, 55.6mmol, 0.2eq) followed by addition of sulphuric acid (4.8ml_, 90.8mmol, 0.34eq), water (33ml_) and iodine (28.7g, 1 1 1 mmol, 0.4eq) at room temperature. Resulting reaction mixture was heated at 80°C for 6 hours. After complete consumption of starting material, reaction mixture was cooled and poured into sodium thiosulfate solution (200ml_), reddish oil was settled down at the bottom. Reaction mixture was decanted from reddish oil, and filtrate was basified with 50percent sodium hydroxide solution (100ml_), yellow colored solid was formed. Resulting solid was extracted with diethyl ether (2 x 200ml_) and dried over sodium sulfate. Organic layer was concentrated under reduced pressure to afford brown semi solid (60g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 15percent EtOAc in hexane to get title compound as faint brown solid (50g, 77percent). H NMR (400 MHz, CDCI3)8: 2.52 (s, 3H), 4.43(bs, 2H), 6.09 (d, J = 8.4 Hz, 1 H), 7.65 (d, J = 8.44 Hz, 1 H). LC-MS (m/z): 235.3 (M+H).
38%
With sulfuric acid; iodine; acetic acid In water
PREPARATION 2 2-amino-5-iodo-6-picoline A mixture of 2-amino-6-picoline (5.40 g), periodic acid (2.28 g), and iodine (5.00 g) is heated in a solution of acetic acid (30 mL), water (6 mL), and sulfuric acid (0.9 mL) at 80° C. for 3 h. The reaction is cooled to room temperature and poured into 100 mL 10percent aqueous sodium bisulfite. The aqueous solution is extracted with diethyl ether (3*100 mL). The combined organics are washed with 10percent NaOH, then dried over Na2SO4, filtered, and concentrated. Purification by chromatography (eluent EtOAc) affords a yellow liquid. The liquid is further dried on the vacuum pump where it crystallizes to afford 2-amino-5-iodo-6-picoline (4.48 g, 38percent). Physical characteristics are as follows: 1H NMR (300 MHz, DMSO-d6) δ 7.60, 6.09, 6.05, 2.38.
7.5 g
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃;
(A) 5-iodo-6-methylpyridin-2-amine (0307) To a solution of 6-methylpyridin-2-amine (10 g, 0.092 mol) in DMF (50 mL) was added N-iodosuccinimide (15 g, 0.13 mol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (200 mL), and the precipitated solid was collected by filtration and washed with ethyl acetate to give the title compound (7.5 g). MS: [M+H]+ 235.0
With sulfuric acid; dihydrogen peroxide; bromine; In tetrahydrofuran; at 65℃; for 8h;
(1) 10.81 g (0.1 mol) of 2-amino-6-methylpyridine was added to 200 ml of tetrahydrofuran, and 2 g of sulfuric acid was added and stirred. Add 100 ml of 35 wt% hydrogen peroxide, stir well, then add 15.98 g (0.1 mol) of bromine. The reaction was stirred at 65 C for 8 h to give the intermediate 2-amino-3,5-dibromo-6-methylpyridine;
A mixture of 2-amino-6-methylpyridine (10.00 g, 92.47 mmol), ethyl 4-chloro- acetoacetate (16.24 mL, 120.2 mmol), and polyphosphoric acid (50.00 g) was stirred at 125 0C. After 5.5 h, the mixture was removed from the heat. To the cooled mixture was added ice-water (200 mL) and neutralized with 2 N NaOH (400 mL) to pH 6-7. The resulting precipitate was collected by filtration, washed with water (~ 400 mL), and dried to give 2-(chloromethyl)-6-methyl-4H-pyrido- [l,2-a]pyrimidin-4-one as a dark brown solid: 1H NMR (400 MHz, DMSO-d6) delta ppm 7.68 (1 H, dd, J=9.0, 7.0 Hz), 7.40 (1 H, dd, J=9.0, 0.8 Hz), 6.93 (1 H, d, J=6.7 Hz), 6.36 (1 H, s), 4.58 (2 H, s), 2.93 (3 H, s); Mass Spectrum (ESI) m/e = 208.9 (M + 1).
With sulfuric acid; iodine; acetic acid; periodic acid; In water; at 80℃; for 6h;
To a stirred solution of 6-methyl-pyridin-2-ylamine (30g, 278mmol, 1 eq) in acetic acid (167ml_) was added periodic acid (12.7g, 55.6mmol, 0.2eq) followed by addition of sulphuric acid (4.8ml_, 90.8mmol, 0.34eq), water (33ml_) and iodine (28.7g, 1 1 1 mmol, 0.4eq) at room temperature. Resulting reaction mixture was heated at 80C for 6 hours. After complete consumption of starting material, reaction mixture was cooled and poured into sodium thiosulfate solution (200ml_), reddish oil was settled down at the bottom. Reaction mixture was decanted from reddish oil, and filtrate was basified with 50% sodium hydroxide solution (100ml_), yellow colored solid was formed. Resulting solid was extracted with diethyl ether (2 x 200ml_) and dried over sodium sulfate. Organic layer was concentrated under reduced pressure to afford brown semi solid (60g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 15% EtOAc in hexane to get title compound as faint brown solid (50g, 77%). H NMR (400 MHz, CDCI3)8: 2.52 (s, 3H), 4.43(bs, 2H), 6.09 (d, J = 8.4 Hz, 1 H), 7.65 (d, J = 8.44 Hz, 1 H). LC-MS (m/z): 235.3 (M+H).
38%
With sulfuric acid; iodine; acetic acid; In water;
PREPARATION 2 2-amino-5-iodo-6-picoline A mixture of 2-amino-6-picoline (5.40 g), periodic acid (2.28 g), and iodine (5.00 g) is heated in a solution of acetic acid (30 mL), water (6 mL), and sulfuric acid (0.9 mL) at 80 C. for 3 h. The reaction is cooled to room temperature and poured into 100 mL 10% aqueous sodium bisulfite. The aqueous solution is extracted with diethyl ether (3*100 mL). The combined organics are washed with 10% NaOH, then dried over Na2SO4, filtered, and concentrated. Purification by chromatography (eluent EtOAc) affords a yellow liquid. The liquid is further dried on the vacuum pump where it crystallizes to afford 2-amino-5-iodo-6-picoline (4.48 g, 38%). Physical characteristics are as follows: 1H NMR (300 MHz, DMSO-d6) delta 7.60, 6.09, 6.05, 2.38.
7.5 g
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃;
(A) 5-iodo-6-methylpyridin-2-amine (0307) To a solution of 6-methylpyridin-2-amine (10 g, 0.092 mol) in DMF (50 mL) was added N-iodosuccinimide (15 g, 0.13 mol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (200 mL), and the precipitated solid was collected by filtration and washed with ethyl acetate to give the title compound (7.5 g). MS: [M+H]+ 235.0
12.2 g
With N-iodo-succinimide; In acetonitrile; at 20℃; for 3h;
2. Dissolve 10.80 g of 2-amino-6-methylpyridine (Compound 9) in 500 mL of acetonitrile, add 33.7 g of N-iodosuccinimide, and react at room temperature for 3 h. The precipitate was filtered, washed with 200 mL of cold acetonitrile, and dried under vacuum to obtain 12.2 g (compound 10) as an off-white solid with a yield of about 52%.
With sulfuric acid; nitric acid; at -1 - 50℃; for 11.5h;
10 mL of concentrated sulfuric acid was cooled at 0-1 C, slowly adding raw material 1 (20 g), cooled to 0 C, slowly added 110 mL of nitric acid at a volume ratio of 1: 1, stirred at -1 C and stirred at room temperature for 30 min. Reaction was carried out at 50 C for 11 h. The reaction solution was extracted with EA. The EA layer was washed with aqueous ammonia and the aqueous ammonia was concentrated. The solid layer 2 (18 g) was precipitated and the yield was 75%.
48%
With sulfuric acid; nitric acid; at 0 - 100℃;
Example 8 2-Methyl-2- (6-methyl-5-nitro-pyridin-2-ylamino)-propan-1-ol (a) Conc. H2S04 (140 ml) was cooled in an ice-salt bath and molten 6-amino-2-picoline (30 g, 0.277 mol) was added in portions with good stirring. To this brown, viscous solution which was maintained at 0C was added a cooled (0C) mixture of conc. H2SO4 (21 ml) and conc. HNO3 (21 ml) drop wise over a period of approx. 1.5 hrs. The red- orange reaction mixture was stirred for an additional hour at 0C and then allowed to warm slowly to room temperature over night. The brown solution was heated at 60 C (oil bath) for 1 hr followed by lhr at 100C (carefully controlled temperature). The reaction mixture was cooled to 0C (ice bath), poured over cracked ice and neutralised by addition of a concentrated aqueous NaOH solution. The yellow precipitate was filtered and washed well with ice-water. (The filtrate was put in the refrigerator, additional product was precipitated together with the salts. ) The yellow product was suspended in water and divided into two portions, each of them subjected to steam distillation in turn. The yellow reaction mixture became more"transparent'after some hrs, but the collected steam, containing 4-amino-3-nitro-2-picoline, was still yellow after 6 hrs. The steam distillation was stopped after 8 hrs, the residual part of the reaction mixture was filtered and evaporated to dryness. 1HNMR (D2O) showed a mixture of 2-3 compounds. The mixture was washed with; CHCI ;, EtOH (x 2) and CHC leaving 20.4 g (48%) of pure 6-amino- 3-nitro-2-picoline.
36%
With sulfuric acid; nitric acid; at -6 - 20℃; for 7.5h;
The 6-methylpyridin-2-amine (20g, 185mmol) was dissolved in 98% H2SO4 (91mL). A mixture of fuming HNO3 (9mL) and 98% H2SO4 (9mL) was added dropwise to the vigorously stirring solution over 30min at -6C. The mixture was stirred for 2h at 0C and slowly warmed to 10C over 1h and kept stirring for an additional hour. Afterwards, the solution was warmed to 20C over 1h and stirred for 2h. The reaction mixture was poured onto ice and basified with ammonium hydroxide (pH?9). The precipitated solid was collected by filtration and purified by steam distillation to afford compound 9 (9.99g). Yellow solid (36%), mp: 189-191C. 1H NMR (500MHz, DMSO-d6) delta 7.77 (d, 1H, J=9.2Hz), 6.09 (d, 1H, J=9.2Hz), 6.11 (s, 2H), 2.36 (s, 3H). ESI-MS: m/z=154 [M+1]+.
1 a) 6-Methyl-5-nitropyridin-2-ylamine; A solution of 211 g of 6-amino-2-picoline in 994 ml of concentrated sulfuric acid is admixed dropwise at 00C with a cooled mixture of 145 ml of concentrated nitric acid and 145 ml of concentrated sulfuric acid. The reaction mixture is stirred at 00C for one hour and then at 25C for 16 hours. Subsequently it is heated at 600C for one hour and finally at 1000C for one hour. The reaction mixture is then poured cautiously onto ice and adjusted to a pH of 5 to 6 with a concentrated sodium hydroxide solution. The resultant solid is filtered off and washed with ethanol. The resulting crude product is prepuhfied by column chromatography on silica gel with chloroform/0 - 50% methanol. The material is then partly dissolved in 100 ml of 1 N hydrochloric acid, the precipitate is removed by filtration, and the solution is admixed with sodium carbonate. The resulting solid is recovered by filtration. Drying gives 33 g of the title compound as a yellow-orange solid.NMR (300 MHz, DMSO-d6): delta = 2.60 (3H), 6.37(1 H), 7.35 (2H), 8.09 (1 H).
According to the method described in Tetrahedron Lett., 24, 2211-2212 (1971), the title compound was synthesized by means of the following. To concentrated sulfuric acid (75 mL) was added 2-amino-6-methylpyridine (19.3 g) to be dissolved at 20C or below, a solution of fuming nitric acid (8.0 mL) in concentrated sulfuric acid (8 mL) was added dropwise at 5C or below over 15 min, and the mixture was further stirred at the same temperature for 2 hr. The reaction mixture was poured into ice water (1.4 L), pH of the mixture was adjusted to 10 with aqueous ammonia (300 mL), and the precipitate was collected by filtration. The precipitate was dissolved in ethyl acetate (600 mL), and the solution was washed successively with 10% aqueous ammonia and saturated brine, and dried over sodium sulfate. Then, ethyl acetate was evaporated under reduced pressure to give a powder (22.5 g). Toluene (200 mL) was added to this powder, and the mixture was refluxed for 1 hr and allowed to cool. The obtained powder was collected by filtration. The obtained powder was washed with methylene chloride (100 mL) and collected by filtration to give the title compound as a powder (14.5 g). IR nu (Nujol) cm-1; 1662, 1594, 1404, 1287, 1076. 1H-NMR (DMSO-d6) delta (ppm); 2.62 (3H, s), 6.38 (1H, d, J=9.3 Hz), 7.34 (2H, br-s), 8.09 (1H, d, J=9.3 Hz).
Step 1 Preparation of 2-amino-6-methyl-3,5-dinitropyridine To a stirred solution of 2-amino-6-methylpyridine (38 g, 352 mmol) in conc. H2 SO4 (70 mL) at 0 C. was added HNO3 (16.5 mL, d=1.49) drop-wise over 30 min. The mixture was warmed stirred an additional 1 h at 0 C. then poured into 500 g of ice. This heterogeneous mixture was stirred for 1 h at r.t., filtered, washed with 50 mL H2 O and the residue was briefly dried to give 58 g of crude moist 6-methyl-2-nitraminopyridine. This solid was carefully added in 1-2 g portions to stirred H2 SO4 (70 mL) at 40 C. After complete addition, the reaction mixture was stirred 1 h at 40 C., cooled and poured into 500 g of ice. The resulting precipitate was filtered, washed with 50 mL of H2 O, and air dried to give a yellow solid. 8.5 g of this mixture of 2-amino-6-methyl-3-nitropyridine and 2-amino-6-methyl-5-nitropyridine was dissolved in H2 SO4 (100 mL) at 0 C. and HNO3 (2.74 mL, d=1.49) was added drop-wise over 10 min. After complete addition, the mixture was warmed to 50 C. for 90 min., cooled, then poured onto 200 g of ice. The residue was collected by filtration and washed with cold H2 O (2*50 mL) to give 2-amino-6-methyl-3,5-dinitropyridine as a yellow solid.
With N-chloro-succinimide; In hexane; N,N-dimethyl-formamide;
2-Amino-5-chloro-6-methylpyridine (45) To a stirred solution of 2-amino-6-methylpyridine (10.80 g, 100.0 mmol) in dry DMF (50 mL) was added dropwise a solution of NCS (13.35 g, 100.0 mmol) in dry DMF (60 mL) at 0 C. over 20 min. The resulting brown yellow solution was stirred at 0 C. for 1 h, and at room temperature for 3 h, then poured into ice-water (about 300 mL). The resulting mixture was extracted with EtOAc (4*100 mL). The extracts were combined, washed with brine (6*50 mL), dried (MgSO4), and rota-evaporated. To the residual viscous black oil was added hexane (200 mL) and it was heated to boiling with stirring. The hot hexane solution was decanted carefully, concentrated to about 60 ml, then allowed to stand at room temperature overnight. The resulting crystals were filtered and dried at room temperature in vacuo, giving 6.06 g (42%) of 45 as orange-colored long needles, mp 74-5 C. (lit. 73-4 C., Cress et al., J. Org. Chem. 93-6 (1976)). 1 H NMR (CDCl3) delta2.439 (s, 3H), 4.376 (bs, 2H), 6.302 (d, 1H, J=8.5), 7.340 (d, 1H, J=8.5).
With sulfuric acid; bromine; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water;
Step 1 Preparation of 6-amino-5-bromo-picoline 32.4 g (0.3 mole) of 6-aminopicoline was dissolved in a mixture of 28 g of conc. sulfuric acid and 120 ml of water and the resulting solution was cooled in ice water. 52.8 g (0.33 mole) of bromine was added dropwise to the solution over 30 minutes at 0 C. The reaction solution was stirred for 20 minutes at room temperature and neutralized with cold aqueous NaOH solution. The resultant was filtered and the solid was purified with column chromatography using methylene chloride and ethyl acetate as an eluent to obtain 31 g of the title compound (yield 55%).
EXAMPLE 11 2 g of 4-methyl-6-cyclohexyl-2-pyrone and 1 g of hydroxylamine were dissolved in a mixture of 1.5 g of 2-aminopyridine and 4.5 g of 2-amino-6-methylpyridine and stored for 9 days at room temperature. After the usual working up, there were obtained 0.79 g (37 %) of 1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone melting at 143 C.
To 2.25 g (9.6 mM) of the phenyl carbamate 8 in 10 ml of anhydrous DMF was added 1.04 g (9.6 mM) of 2-amino-6-methylpyridine. After stirring the mixture for 4 hrs. at 50 C., it was filtered to separate a solid which was recrystallized from methanol to give 1.4 g of 1-(6-methyl-2-pyridinyl)-3-(tetrahydro-1-methyl-4-oxo-1H-imidazol-2-ylidene) urea 9 as a white solid, m.p. 202-203 C. (dec.). Anal. calcd. for C11 H13 N5 O2: C, 53.44; H, 5.30; N, 28.32. Found: C, 53.23; H, 5.11; N, 28.23.
General procedure: The appropriate (hetero) aromatic amine (1.0 mmol) and 2',6'-/3',5'-dihalo-substituted (hetero/aromatic) aldehyde (1.5 mmol) were stirred in dry toluene under reflux condition followed by addition of mercaptoaceticacid (2.0 mmol). The reaction mixture was refluxed with a Dean-Stark trap for 24-48 h until the complete consumption of (hetero) aromatic amine. The reaction mixture was concentrated to dryness under reduced pressure and the residue was taken up in ethyl acetate. The organic layer was successively washed with 5% aq citric acid, water, 5% aq sodium hydrogen carbonate, and then finally with brine. The organic layer was dried over sodium sulfate and solvent was removed under reduced pressure to get a crude product that was purified by column chromatography on silica-gel (230-400 mesh) using hexane-ethyl acetate as eluent. The structures of synthesized compounds were characterized by means of TLC, IR, ESI-MS, 1H NMR, 13C NMR, elemental analyses and HRMS.
With 1,4-diaza-bicyclo[2.2.2]octane; In water; at 60 - 70℃; for 3h;Green chemistry;
General procedure: The mixture of phenacyl bromide (1 mmol), 2-aminopyridine (1 mmol) and DABCO (10 mol %) was stirred in water (5 mL) at 60-70 C for 1 h. The reaction was monitored by TLC. After the completion of the reaction, it was extracted with ethyl acetate (3 × 5 mL). The combined organic layer washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude products were purified by silica gel column chromatography (ethyl acetate/hexane, 1:10). All compounds were characterized by mp, NMR, mass, HRMS and IR spectral data
With ferrous(II) sulfate heptahydrate; sulfuric acid; boric acid; In water; glycerol; at 0 - 135℃; for 4h;
Sodium-3-nitrobenzenesulfonate (17.5 g, 77.7 mmol), boric acid (2.4 g, 38.8 mmol), and ferrous sulfate heptahydrate (1.4 g, 0.5 mmol) were added to 23.1 mL of 98percent sulfuric acid. After cooling to 0 °C, glycerol (12.5 mL), 2-amino-6-methylpyridine (4.3 g, 40.0 mmol), and hot water (50 °C, 22.5 mL) were slowly added to above mixture. The reaction solution was refluxed for 4 h at 135 °C and cooled to room temperature. 40percent water solution of NaOH was used to mediate pH to 7 and chloroform was used to extract the product. The organic phase was concentrated in vacuum to give the crude product and the final product was obtained by column chromatography (200-300 mesh, 3/1 ethyl acetate/petroleum ether) (3.0 g, 25.9percent yield). Characterization of 2-methyl-1,8-naphthyridine: HRMS (EI) m/z: calcd for C9H9N2 [M+H]+, 145.0766; found, 145.0768. 1H NMR (400 MHz; CDCl3; TMS) 9.08 (d, 1H), 8.13-8.16 (m, 1H), 8.08 (d, 1H), 7.43-7.45 (m, 1H), 7.28 (d, H), 2.82 (s, 3H). 13C NMR: deltaC (100 MHz, CDCl3): 163.1, 160.0, 153.3, 136.9, 136.7, 123.0, 121.4, 120.8, 25.7.
4-methyl-N-(6-methylpyridin-2-yl)thiazole-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
A solution of <strong>[14542-16-6]4-methylthiazole-2-carboxylic acid</strong> (50.0 mg, 0.349 mmol) and CDI (84.9 mg,0.524 mmol) in THF (5.0 mL) was stirred at room temperature for 1 h, 2-amino-6-methylpyridine (37.7 mg, 0.349 mmol) was added. The mixture was stirred at room temperature for 2 h. The subsequent mixture was concentrated under reduced pressure and extracted with H2O/ethyl acetate. The combined organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography on silica gel (hexane/ethyl acetate = 10:1) to afford the title compound 6ae (55 mg, 57 %) as white solid; 1H-NMR (400MHz, CDCl3) delta 9.61(s, 1H), 8.12 (d, J = 8 Hz, 1H), 7.63(t, J = 8 Hz, 1H), 7.18 (d, J = 0.8, 1H), 6.93 (d, J = 7.2, 1H), 2.49 (d, J = 1.2, 1H). 13C-NMR (100MHz, CDCl3) delta 162.0, 157.7, 157.2, 154.4, 150.0, 138.7,120.4, 119.6, 110.9, 24.1, 17.0. LC/MS (ESI-) 234.1 (M+H)+.
57%
To 5.0 mL of tetrahydrofuran (THF) was added <strong>[14542-16-6]4-methylthiazole-2-carboxylic acid</strong> (50.0 mg, 0.349 mmol) andCarbonyldiimidazole (CDI; 84.9 mg, 0.524 mmol)After stirring at room temperature for 1 hour, 2-Amino-6-methylpyridine(37.7 mg, 0.349 mmol) was added and the mixture was stirred at room temperature for 2 hours. After adding water, the reaction mixture was extracted with ethyl acetate,Layer. The organic layer was dried over anhydrous Na2SO4 and purified by column chromatography to obtain the desired compound (55 mg, yield57%).
[02991 A mixture of 2-amino-6-picoline (324 mg, 3.0 rnrnol) and ethyl chloroacetate (594 rng, 3.60 mmol) in polyphosphoric acid (10 mL) was heated at 110 C for 5 hrs. After cooling to room temperature, the mixture was quenched with water (50 mL). The pH value was adjusted to 6-7 with aqueous K2C03. Then the new mixture was extracted with EA (50 mL x3).the organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuum to give 2-chloromethyl-6-methyl-pyrido[1,2-ajpyrimidin- 4-one (360 rng, yield: 58%) as yellow solid. [03001 ?H NMR (400 MHz, DMSO-d6): cS 7.68 (dd, J- 4.0, 1.2 Hz, 1H), 7.40 (d, J= 7.6 Hz, IH), 6.93 (d, J 6.8 Hz, 1H), 6.36 (s, 1H), 4.58 (s, 21-1), 2.93 (s, 3H).
With hydrazine hydrate; In tetrahydrofuran; for 2.0h;
General procedure: Into a 2 dram vial was placed 5-nitro-8-hydroxyquinonline (63 mg, 0.33 mmol), Ru/PS nanoparticle catalyst (8.0 mg, 0.477 mmol Ru/gram catalyst, 1.2 mol%), and hydrazine monohydrate (42 muL, 2.5 equiv) in 4 ml of THF. The reaction mixture was stirred for 2 hr, at which point the solvent was removed under reduced pressure. The product was extracted from the solid mixture with 3x 2 ml EtOH. The combined ethanol extracts were then passed through a short silica plug in a pipet and the silica plug was washed 2 times with 1 ml ethanol. The EtOH was then removed on a rotary evaporator under reduced pressure. The product 5-(hydroxyamino)quinolin-8-ol was isolated as an orange solid (51 mg, 0.29 mmol, 87% yield). For some of the more complex substrates, the reaction results are highly temperature sensitive, the reactions can be forced to completion by adding extra equivalents of hydrazine, and by raising the temperature to 27 C.
tert-butyl (S)-2-((6-methylpyridin-2-yl)carbaraoyl)azetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 170 (1 equiv) in DCM (10 vol) at 0 °C under nitrogen atmosphere was added Ghosez's reagent. The reaction mixture was stiixed at same temperature for 3 h and then 6-methylpyridin-2-amine (1 equiv), DIPEA (3 equiv) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was quenched with water (30 vol). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2S04, filtered and then concentrated. The residue was purified by column chromatography on silica gel using Hexane/ EtOAc to give compound 171.
To a solution of (S)-l-(fert-butoxycarbonyl)azetidine-2-carboxylic acid (1 equiv) in DCM (10 vol) at 0 °C under nitrogen atmosphere was added Ghosez's reagent, The reaction mixture was stirred at same temperature for 3 h and then 6-methylpyridin-2~amine (1 equiv), DIPEA (3 equiv) was added to the reaction mixture and the reaction mixture was stirred a room temperature for 16 h. After completion of the reaction, the reaction mixture was quenched with water (30 vol). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous NaiSCH, filtered and then concentrated. The residue was purified by column chromatography on silica gel using Hexane/ EtOAc to give compound ieri-butyl (S)- 2-((6-methylpyridin-2-yi)carbaraoyl)azeiidine-l-carboxylate
[0559] To a solution of (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (1 equiv) in DCM (10 vol) at 0 °C under nitrogen atmosphere was added Ghosez?s reagent. The reaction mixture was stirred at same temperature for 3 h and then 6-methylpyridin-2-amine (1 equiv), DIPEA (3 equiv) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was quenched with water (30 vol). The resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and then concentrated. The residue was purified by column chromatography on silica gel using Hexane/ EtOAc to give compound tert-butyl (S)-2- ((6-methylpyridin-2-yl)carbamoyl)azetidine-1-carboxylate. To a solution of compound tert-butyl (S)-2-((6-methylpyridin-2-yl)carbamoyl)azetidine-1-carboxylate (1 equiv) in 1,4-dioxane (3 vol) at 0 °C under nitrogen atmosphere was added 4 N HCl in 1,4-dioxane (10 vol) and stirred at room temperature for 3 h and then concentrated. The residue was taken in MTBE and stirred for 30 min. The resultant solid was filtered and dried to give (S)-N-(6-methylpyridin-2-yl)azetidine-2- carboxamide hydrochloride (99).
With ferrous(II) sulfate heptahydrate; sulfuric acid; boric acid; sodium 3-nitrobenzenesulfonate; In water; at 50 - 135℃;Cooling with ice; Reflux;
Ice bath under conditions of 250 mLOf the three bottles by adding concentrated H2SO441 g (22 mL),Stir by addingSodium nitrobenzene sulfonate17.5 g (78 mmol),Boric acid2.4 g (39 mmol),FeSO4 · 7H2O 1.4 g (5 mmol)Glycerol 12.5 mL,2-amino-6-methylpyridine (4.3 g, 40 mmol)Mixed evenly after adding 22.5mL 50 warm water,in135 ° CUnder reflux2-3h,After cooling; with 50percent NaOH solution transferred to alkaline, filter,The aqueous solution was extracted three times with chloroform and the organic layer was dried over anhydrous MgSO4,The solvent was removed by rotary distillation to give the crude product which was recrystallized from cyclohexane to give 2-methylnaphthyridine,Ie probe reagent;The concentrated sulfuric acid concentration is 95-98percent;
To a thermometer,Reflux condenser,Constant pressure dropping funnel and a mechanical stirrer 500mL four-necked flask,250 mL (3 mol) of 36percent hydrochloric acid was added,54 g (0.5 mol) of 2-amino-6-methylpyridine,12.7 g (0.05 mol) of iodine,30 g (0.5 mol) acetic acid.Turn on stirring and heatingMaintain the reaction bottle temperature 95-100 ,96.3 g (0.55 mol) of acrolein was evenly added dropwise over 3 hours,After the reaction was continued dropping 5h.Cooled to room temperature, carefully neutralized with 40percent aqueous sodium hydroxide to pH = 8,The aqueous phase was extracted with ethyl acetate and concentrated under reduced pressure to remove the solvent. The residue was distilled under reduced pressure to give 2-methyl-1,8-naphthyridine as a white crystal.
7-((3-fluoro-5-(trifluoromethyl)phenyl)(6-methylpyridin-2-ylamino)methyl)quinolin-8-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With formic acid; In acetonitrile; at 75℃;
General procedure: To a solution of 1 mmol aldehyde, 3 volume of acetonitrile and 1 equivalent volume of aminewere added to 0.6 equivalent of quinoline derivatives and 1% (v/v) formic acid. The reaction mixturewas stirred at higher temperature (75 C). The reaction was monitored by TLC (eluent: hexaneisomeric mixture:acetone). If the product precipitated, it was filtered, washed with hexane, and dried.If the reaction mixture was homogeneous, it was evaporated to dryness and was purified by columnchromatography (eluent: hexane:acetone from 20:1 to 4:1, v/v). The crude product was crystallizedfrom hexane/ethyl-acetate. The molecular structures were determined by means of 1D and 2D-NMRtechnologies (see Supplementary Materials)
7-((4-fluoro-3-(trifluoromethyl)phenyl)(6-methylpyridin-2-ylamino)methyl)quinolin-8-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With formic acid; In acetonitrile; at 75℃;
General procedure: To a solution of 1 mmol aldehyde, 3 volume of acetonitrile and 1 equivalent volume of aminewere added to 0.6 equivalent of quinoline derivatives and 1% (v/v) formic acid. The reaction mixturewas stirred at higher temperature (75 C). The reaction was monitored by TLC (eluent: hexaneisomeric mixture:acetone). If the product precipitated, it was filtered, washed with hexane, and dried.If the reaction mixture was homogeneous, it was evaporated to dryness and was purified by columnchromatography (eluent: hexane:acetone from 20:1 to 4:1, v/v). The crude product was crystallizedfrom hexane/ethyl-acetate. The molecular structures were determined by means of 1D and 2D-NMRtechnologies (see Supplementary Materials)
7-((2,4-bis(trifluoromethyl)phenyl)(6-methylpyridin-2-ylamino)methyl)quinolin-8-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
With formic acid; In acetonitrile; at 75℃;
General procedure: To a solution of 1 mmol aldehyde, 3 volume of acetonitrile and 1 equivalent volume of aminewere added to 0.6 equivalent of quinoline derivatives and 1percent (v/v) formic acid. The reaction mixturewas stirred at higher temperature (75 C). The reaction was monitored by TLC (eluent: hexaneisomeric mixture:acetone). If the product precipitated, it was filtered, washed with hexane, and dried.If the reaction mixture was homogeneous, it was evaporated to dryness and was purified by columnchromatography (eluent: hexane:acetone from 20:1 to 4:1, v/v). The crude product was crystallizedfrom hexane/ethyl-acetate. The molecular structures were determined by means of 1D and 2D-NMRtechnologies (see Supplementary Materials)
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