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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 870-46-2 * 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] Chemistry of Natural Compounds, 1982, vol. 18, # 3, p. 322 - 327[2] Khimiya Prirodnykh Soedinenii, 1982, # 3, p. 349 - 354
3
[ 870-46-2 ]
[ 36016-38-3 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 955
4
[ 24424-99-5 ]
[ 870-46-2 ]
Yield
Reaction Conditions
Operation in experiment
97%
With hydrazine hydrate In isopropyl alcohol at 0℃; for 2 h;
Hydrazine hydrate (113 mg, 2.26 mmol, 2.26 equiv) was dissolved in IPA (5 mL) and cooled down to 0 °C. Di-tert-butyl carbonate (174 mg, 1 mmol, 1 equiv) in IPA (1 mL) was added drop-wise and the mixture was stirred for 2 h. The solvent was then evaporated and the residue was dissolved in DCM, dried over MgSO4, and filtered. Evaporation of the solvent gave tert-butyl hydrazinecarboxylate 10 as a white semi-solid (128 mg, 97percent). 1H NMR (300 MHz, CDCl3) δ 6.73(s, 1H), 3.83 (s, 2H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 158.2, 80.1, 28.2.21
93%
With potassium carbonate; hydrazine hydrate In 1,4-dioxane; water at 20℃; for 12 h;
A solution of di-tert-butyl dicarbonate (2.91 g, 13.3 mmol) in dioxane(50 mL) was dropwise added to a solution of K2CO3 (7.35 g,53.2 mmol) and hydrazine hydrate (2.58 mL, 53.2 mmol) in water(50 mL), and the mixture was stirred at r.t. for 12 h. Two phaseswere formed, separated, and then the aqueous phase was washedwith ethyl ether (2 × 25 mL). The ether phase was added to the dioxanephase, and the total organic solution was evaporated. The colorlessoil obtained was distilled under vacuum, and the pure productwas obtained as the sublimated white crystals (1.64 g, 93percent yield),m.p. 38–39 °C. 1H NMR (CDCl3) δ (ppm): 5.83 (bs, 1H, NHBoc), 3.67(d, J = 3.0 Hz, 2H, NH2), 1.45 (s, 9H, t-BuH); m/z (ESI MS): 155.0(M + Na)+.
90%
With hydrazine hydrate; toluene-4-sulfonic acid In water at -5 - 0℃; for 1.5 h;
Add 500ml of water and 50g of hydrazine hydrate (0.8mol) with a mass concentration of 80percent to a 5L reaction flask, and start stirring.Controlled temperature -5 ~ 0 °C batchwise addition of monohydrate p-toluene sulfonic acid 152g (0.8mol), plus complete the next -5 ~ 0 °C reaction 0.5 hours, then addBOC anhydride (di-tert-butyl dicarbonate) 174 g (0.8 mol), stir at -5 to 0°C for 1 hour, add 400 ml of dichloromethane,Liquid caustic soda was added dropwise to pH=11-12, and the organic phase was concentrated to dryness under reduced pressure. 200 g of petroleum ether was added and stirred for 0.5 hours.After suction filtration, the solid product was dried and used as the target product BOC-; the resulting solid had a weight of 95 g, a purity of 99.9percent, and a yield of 90percent.
80%
With hydrazine hydrate In isopropyl alcohol at 0 - 10℃; for 0.5 h; Cooling with ice
With the stirrer in three-opening reaction bottle 30 g of hydrazine hydrate and the isopropanol added 150 ml, ice water bath cooling by the addition of BOC anhydride 111.6 g isopropanol solution of 120 ml, 0 - 10 °C degrees stirring 0.5h to the reaction is complete, concentrated to solution is clarified, dichloromethane 100 ml by adding, dried with anhydrous sodium sulfate, concentrated under reduced pressure to obtain white solid. The resulting crude product using petroleum ether 200 ml of beating, the decompression to obtain white solid 35.7 g, LC purity 55percent or more, the yield is 80percent.
70%
With hydrazine hydrate In tetrahydrofuran at 0℃; for 1 h;
To a round bottom flask equipped with a stir bar, 25 mmol of hydrazine monohydrate was dissolved in THF at 0 °C. Added drop-wise to this was a solution of Boc2O in THF. The reaction was allowed to mix at 0 °C for an additional hour. The reaction was then diluted with ethyl acetate and washed with water (2.x.). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. 3.53 mmol of desired product was collected (70percent yield). LCMS: tR = 7.23 min. m/z = 133.2 (M+H).
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 33 - 41
[2] Tetrahedron Letters, 2015, vol. 56, # 48, p. 6653 - 6655
[3] Journal of Inorganic Biochemistry, 2013, vol. 127, p. 188 - 202
[4] Organic and Biomolecular Chemistry, 2017, vol. 15, # 43, p. 9071 - 9076
[5] Journal of Materials Chemistry B, 2017, vol. 5, # 19, p. 3565 - 3571
[6] Patent: CN108003062, 2018, A, . Location in patent: Paragraph 0022; 0023
[7] Organic and Biomolecular Chemistry, 2016, vol. 14, # 5, p. 1579 - 1583
[8] Patent: CN106565531, 2017, A, . Location in patent: Paragraph 0036; 0039-0042
[9] Journal of the American Chemical Society, 2004, vol. 126, # 21, p. 6759 - 6764
[10] Chemistry - An Asian Journal, 2018, vol. 13, # 19, p. 2854 - 2867
[11] Tetrahedron, 2008, vol. 64, # 28, p. 6788 - 6793
[12] Chemical Communications, 2012, vol. 48, # 65, p. 8129 - 8131
[13] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 1, p. 487 - 497
[14] Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8255 - 8281
[15] Journal of Organic Chemistry USSR (English Translation), 1977, vol. 13, # 12, p. 2352 - 2355[16] Zhurnal Organicheskoi Khimii, 1977, vol. 13, # 12, p. 2531 - 2535
[17] Chemistry of Natural Compounds, 1982, vol. 18, # 3, p. 322 - 327[18] Khimiya Prirodnykh Soedinenii, 1982, # 3, p. 349 - 354
[19] Molecular Pharmaceutics, 2010, vol. 7, # 4, p. 953 - 962
[20] Patent: WO2015/139263, 2015, A1, . Location in patent: Page/Page column 6; 7
[21] Green Chemistry, 2018, vol. 20, # 21, p. 4859 - 4864
5
[ 51300-90-4 ]
[ 870-46-2 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 96, p. 330 - 339
6
[ 6627-89-0 ]
[ 870-46-2 ]
Reference：
[1] Tetrahedron Letters, 1991, vol. 32, # 26, p. 3079 - 3082
[2] Journal of the American Chemical Society, 1957, vol. 79, p. 98,100
[3] Org. Synth. Coll. Vol. V <1973> 168,
7
[ 1860-21-5 ]
[ 870-46-2 ]
Reference：
[1] Journal of the American Chemical Society, 1960, vol. 82, p. 2725 - 2727
8
[ 29518-83-0 ]
[ 870-46-2 ]
Reference：
[1] Org. Synth. Coll. Vol. V <1973> 166,
[2] Journal of the American Chemical Society, 1960, vol. 82, p. 2725 - 2727
9
[ 99969-78-5 ]
[ 870-46-2 ]
Reference：
[1] Journal of the American Chemical Society, 1960, vol. 82, p. 2725 - 2727
Reference：
[1] Dalton Transactions, 2018, vol. 47, # 14, p. 4785 - 4789
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 20, p. 4789 - 4792
25
[ 870-46-2 ]
[ 16689-35-3 ]
Reference：
[1] Journal of the American Chemical Society, 2004, vol. 126, # 21, p. 6759 - 6764
[2] Polish Journal of Chemistry, 2002, vol. 76, # 12, p. 1693 - 1697
[3] Journal of the Chemical Society. Perkin transactions 1, 1975, # 17, p. 1712 - 1720
[4] Journal of the American Chemical Society, 1963, vol. 85, p. 4040 - 4041
[5] Organic and Biomolecular Chemistry, 2012, vol. 10, # 12, p. 2439 - 2446
[6] Journal of Organic Chemistry, 2013, vol. 78, # 8, p. 3541 - 3552
[7] Patent: WO2014/140073, 2014, A1,
[8] Patent: US2015/191473, 2015, A1,
[9] Patent: CN104628771, 2016, B,
[10] Patent: US2017/291901, 2017, A1,
[11] European Journal of Inorganic Chemistry, 2018, vol. 2018, # 3, p. 517 - 524
[12] Chemistry - A European Journal, 2018, vol. 24, # 33, p. 8325 - 8330
[13] New Journal of Chemistry, 2018, vol. 42, # 20, p. 17062 - 17072
[14] Patent: WO2007/135417, 2007, A1,
26
[ 870-46-2 ]
[ 100-52-7 ]
[ 24469-50-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 0.123333 h; Flow reactor
General procedure: General procedure for the continuous-flow hydrazone synthesis (products 3a-j) Following initiation of the control script, using the apparatus shown in Figure 3, the system was primed with dichloromethane and the aqueous extraction solvent for several minutes until there were no air gaps in the flow path. The aldehyde (0.20 M) and pyridinium paratoluenesulfonate (PPTS) (0.10 M) in dichloromethane (7.5 mL) were loaded in to the corresponding 7.5 mL injection loop. tert-Butyl carbazate (0.4 M) in dichloromethane (10.0 mL) was loaded into the 10.0 mL injection loop. The tert-butyl carbazate loop was injected into the system 30 seconds prior to the substrate loop. Organic solution exiting the system was collected for 40 minutes. The solvent was then removed under reduced pressure to afford a solid.
Reference：
[1] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 5, p. 462 - 467
[2] Chemistry - A European Journal, 2018, vol. 24, # 33, p. 8325 - 8330
[3] Journal of Heterocyclic Chemistry, 1986, vol. 23, p. 945 - 949
[4] Journal of Organic Chemistry, 1981, vol. 46, # 26, p. 5413 - 5414
[5] Journal of the American Chemical Society, [6] Journal of the American Chemical Society, 2008, vol. 130, p. 12907 - 12911
[7] Tetrahedron Letters, 2016, vol. 57, # 47, p. 5188 - 5191
[8] Canadian Journal of Chemistry, 2012, vol. 90, # 11, p. 985 - 993
[9] Journal of the American Chemical Society, 2004, vol. 126, # 21, p. 6759 - 6764
[10] Organic and Biomolecular Chemistry, 2016, vol. 14, # 5, p. 1579 - 1583
[11] Polish Journal of Chemistry, 2002, vol. 76, # 12, p. 1693 - 1697
[12] Journal of the Chemical Society. Perkin transactions 1, 1975, # 17, p. 1712 - 1720
[13] Journal of the American Chemical Society, 1960, vol. 82, p. 2728 - 2731
[14] Journal of the American Chemical Society, 1957, vol. 79, p. 98,100
[15] Journal of the Chemical Society, Chemical Communications, 1993, # 13, p. 1052 - 1053
[16] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 3, p. 315 - 320
[17] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 22, p. 2955 - 2958
[18] Patent: EP1184370, 2002, A2, . Location in patent: Example 19
[19] ACS Combinatorial Science, 2012, vol. 14, # 5, p. 323 - 334
[20] Tetrahedron Letters, 2013, vol. 54, # 8, p. 896 - 899
[21] Journal of Organic Chemistry, 2013, vol. 78, # 8, p. 3541 - 3552
[22] Organic Process Research and Development, 2007, vol. 11, # 3, p. 431 - 440
[23] Angewandte Chemie - International Edition, 2013, vol. 52, # 48, p. 12705 - 12708[24] Angew. Chem., 2013, vol. 125, # 48, p. 12937 - 12940,4
[25] Molecules, 2015, vol. 20, # 5, p. 9229 - 9241
[26] Organic and Biomolecular Chemistry, 2017, vol. 15, # 40, p. 8648 - 8654
[27] New Journal of Chemistry, 2018, vol. 42, # 20, p. 17062 - 17072
27
[ 870-46-2 ]
[ 24469-50-9 ]
Reference：
[1] Journal of Organic Chemistry, 1975, vol. 40, p. 3450 - 3452
Reference：
[1] Journal of the American Chemical Society, 2004, vol. 126, # 21, p. 6759 - 6764
30
[ 870-46-2 ]
[ 501-53-1 ]
[ 57699-88-4 ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: at 0 - 20℃; Stage #2: With sodium hydrogencarbonate In dichloromethane; water
To a solution of fe/t-butyl carbazate (75 g, 567 mmol) in methylene chloride (2.0 L) at 0°C was added benzyl chloroformate over -45 minutes. After the addition was complete the reaction was stirred overnight coming to rt as the ice bath was depleted. The reaction was carefully poured into saturated sodium bicarbonate (1L) and extracted. The organic layer was washed with water, and dried over sodium sulfate. Removal of the solvent in vacuo gave the desired product (148 g, 556 mmol, 98percent crude yield) as a viscous oil. The material was judged to be of satisfactory purity without further purification.
85%
With sodium carbonate In dichloromethane at -78 - 20℃;
tert-Butyl hydrazinecarboxylate 10 (132 mg, 1 mmol) was dissolved in dry DCM and cooled down to -78 °C. Benzyl chloroformate (20.5 mg 1.2 mmol) was added drop-wise followed by Na2CO3 (106 mg, 1 mmol). The reaction mixture was allowed to rt and stirred overnight. Filtration, evaporation of solvents, and recrystallization from hexanes/EtOAc 50:1 gave 1-benzyl 2-(tert-butyl)hydrazine-1,2-dicarboxylate 11 as a white solid (226 mg, 85percent), mp 75.0–77.0 °C, lit. 72–74 °C. 1H NMR (300 MHz, CDCl3) δ 7.34 (s, 5H), 6.80 (s, 1H), 6.49 (s, 1H), 5.16 (s, 2H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 156.9, 155.9, 135.8, 128.7, 128.5, 128.4, 81.9, 67.8, 28.3.22
13.8 g
With 4-methyl-morpholine In tetrahydrofuran at 0℃;
To a cold solution (0° C) of tert-butyl hydrazinecarboxylate hydrochloride (7.1 g, 53.8 mmol) in and N-methylmorpholine (17.7 mL, 161 mmol) in tetrahydrofuran (100 mL) added benzyl chloroformate (7.7 g, 53.8 mmol) and slowly brings to room temperature stirred for 10 h. Tetrahydrofuran was removed under reduced pressure and the resulting viscous solution was diluted with water (40 mL) and thoroughly extracted with ethyl acetate (50x3 mL). The combined organic extracts were washed with 1 N HCl (25 mL), saturated aqueous sodium bicarbonate (NaHCO3) (25 mL) and dried over anhydrous sodium sulphate (Na2SO4) and concentrated to give a residue, which was purified by by silica gel column chromatography (EtOAc : Hexane – 2:5) as a white solid (13.8 g, yield: 96percent). 1H NMR (400 MHz, CDCl3) d ppm: 7.44 - 7.27 (m, 5 H), 6.48 (bs, 1 H), 6.29 (bs, 1 H), 5.18 (s, 1H), 1.46 (bs, 9 H). MS (ESI): found: [M + Na]+, 289.2.
Reference：
[1] Patent: WO2008/65500, 2008, A2, . Location in patent: Page/Page column 67
[2] Tetrahedron, 2010, vol. 66, # 49, p. 9538 - 9544
[3] Tetrahedron Letters, 1992, vol. 33, # 36, p. 5209 - 5212
[4] Tetrahedron Letters, 2007, vol. 48, # 33, p. 5767 - 5770
[5] Journal of the American Chemical Society, 2004, vol. 126, # 21, p. 6759 - 6764
[6] Journal of the American Chemical Society, 2003, vol. 125, # 5, p. 1221 - 1235
[7] Tetrahedron Letters, 2015, vol. 56, # 48, p. 6653 - 6655
[8] Heterocycles, 2009, vol. 78, # 11, p. 2755 - 2768
[9] Patent: WO2017/189920, 2017, A1, . Location in patent: Sheet 4/7
[10] Tetrahedron, 1977, vol. 33, p. 739 - 743
[11] Journal of the Chemical Society. Perkin transactions 1, 1975, # 17, p. 1712 - 1720
[12] Tetrahedron Letters, 2001, vol. 42, # 30, p. 5009 - 5012
[13] Patent: US2010/204214, 2010, A1, . Location in patent: Page/Page column 115
[14] Patent: US2011/65694, 2011, A1, . Location in patent: Page/Page column 73
[15] Patent: WO2015/58163, 2015, A2, . Location in patent: Paragraph 410
[16] European Journal of Medicinal Chemistry, 2018, vol. 149, p. 193 - 210
31
[ 870-46-2 ]
[ 21075-83-2 ]
Reference：
[1] Journal of Organic Chemistry, 2000, vol. 65, # 14, p. 4370 - 4374
[2] ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694
With sodium cyanoborohydride; acetic acid In methanol at 25℃; for 16 h;
Step I: To a solution of dihydro-2H-pyran-4(3H)-one (5 g, 0.05 mol) in MeOH (60 mL) was added tert-butyl tert-butyl hydrazinecarboxylate (7.92 g, 0.06 mol), AcOH (500 uL) and NaBH3CN (6.3 g, 0.1 mol). The mixture was stirred at 25 °C for 16 hours, then concentrated. The residue was dissolved in DCM (100 mL), washed with water (80 mL), dried over anhydrous Na2SO4, concentrated. The crude residue was purified by silical gel chromatography (PE : EA = 5:1 to 1:1) to give tert-butyl tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (10 g, 92percent) as a white solid.
88%
Stage #1: at 20℃; for 3 h; Stage #2: at 20℃; for 60 h;
Intermediate 221,1-Dimethylethyl 2-(tetrah dro-2H-pyran-4-yl)hydrazinecarboxylateTetrahydro-4H-pyran-4-one (9.69 g, 97 mmol) was added to a solution of 1,1- dimethylethyl hydrazinecarboxylate (14.07 g, 106 mmol) in methanol (100 mL) and stirred at room temperature for 3 h. The solvent was removed in vacuo, and the crude residue was suspended in acetic acid (140 mL). Next added sodium cyanoborohydride (6.69 g, 106 mmol) in portions over 3 minutes. The contents were stirred at room temperature for 60 h. The solvent was removed in vacuo, and the crude residue was suspended in DCM (100 mL). The reaction mixture was adjusted to pH 7 with 6N NaOH. The layers were separated, and the aq. layer extracted with DCM. The combined organic layers were washed with saturated NaHC03, and brine. The organic layer was dried over MgS04, filtered, and concentrated in vacuo to afford the product as a solid, 18.4 g (88percent). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (m, 2 H), 1.39 (s, 9 H), 1.43 - 1.48 (m, 1 H), 1.59 - 1.69 (m, 2 H), 2.82 - 2.98 (m, 1 H), 3.20 - 3.32 (m, 2 H), 3.80 (d, J=l 1.62 Hz, 2 H), 4.36 (br. s., 1 H), 8.07 - 8.34 (m, 1 H).
88%
Stage #1: at 20℃; for 2 h; Stage #2: at 20℃;
10 g (100 mmol) of tetrahydropyran-4-one was dissolved in 100 ml_ methanol and 14.5 g (110 mmol) tert-butylcarbazate was added. The reaction mixture was stirred at room temperature for 2h. The solvent was evaporated by reduced pressure. The residue was mixed with 140 ml_ acetic acid (50 percent), 6.9 g (110 mmol) sodium cyanoborohydride was added and the mixture was stirred at room temperature over night. The reaction mixture was neutralized with 4M NaOH and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. <n="175"/>The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under reduced pressure. 19 g (88 percent) of the product were obtained as a white solid.MS ( ESI pos ): m/z = 217 (IvRH)+
64%
Stage #1: With sodium cyanoborohydride; acetic acid In ethanol; water at 20℃; for 2.5 h; Stage #2: With potassium carbonate In ethanol; water; ethyl acetate
A mixture of tetrahydro-4H-pyran-4-one (31.7mL, 0.34mol) and tert-butylcarbazate (47.7g, 0.36mol) in EtOH (50OmL) was stirred at ambient temperature overnight. The reaction mixture was evapotrated and the reisdue suspended in HOAc-H2O (1:1 / 50OmL). NaCNBH3 (22.64g,0.36mol) was added and the mixture was stirred at ambient temperature for 2.5hr. The reaction mixture was suspended in EtOAc-10percent K2CO3 (2:1 / 75OmL). The organic layer was separated, washed with brine (2 x 40OmL) and dried (MgSO4). Filtration and evaporation of the solvent and trituration of the residue with hexane afforded the product as a white amorphous solid(47.5g, 64percent). 1H NMR (CDCl3) 6.10 (IH, br s), 3.99-3.35 (5H, m), 3.06 (IH, m), 1.79-1.35(4H, m), 1.46 (9H, s)
2.34 g
Stage #1: at 10 - 35℃; for 1 h; Stage #2: With sodium tetrahydroborate; acetic acid In tetrahydrofuran at 0℃; for 1 h;
A) tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate [0431] A solution of tetrahydro-4H-pyran-4-one (2.50 g) and tert-butyl hydrazinecarboxylate (3.47 g) in methanol (10 mL) was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in THF (25 mL), acetic acid (4.3 mL) and sodium borohydride (0.525 g) were added thereto, and the mixture was stirred at 0°C for 1 hr. To the reaction mixture was added 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.34 g). 1H NMR (300 MHz, CDCl3) δ 1.35-1.54 (11H, m), 1.77 (2H, dd, J = 12.1 Hz, 2.3 Hz), 2.98-3.15 (1H, m), 3.40 (2H, td, J = 11.3 Hz, 2.3 Hz), 3.96 (3H, dt, J = 11.5 Hz, 3.7 Hz), 6.03 (1H, brs).
To a solution of tetrahydropyran-4-one (71.6 g, 715 mmol) in methanol (2 L) was added tert-butylcarbazate (100 g, 758 mmol) at ambient temp. The mixture was stirred at ambient temp for 20 h. The reaction mixture was concentrated under reduced pressure to dryness to afford a white solid (154 g). To a suspension of the white solid (154 g, 715 mmol) in water (1 L) was added acetic acid (500 mL, 8.73 mol) and the mixture was stirred for 30 min to get a clear solution. To this solution, solid NaCNBH3 (44.5 g, 708 mmol) was added portion-wise. The mixture was stirred at ambient temp for 2 h. The mixture was then transferred to a 12 L flask, cooled to 0° C., and quenched with 1N NaOH (8.73 L, 8.73 mol). The mixture was extracted with CH2Cl2 (3*3 L) and dried over Na2SO4. The organic layer was filtered and concentrated to afford a white solid (164 g, contains ~15percent of N-acetyl-N'-Boc-hydrazine derivative). Chromatography [silica, ethyl acetate/MeOH (95:5] gave 94 g of 90percent pure boc-hydrazine. A solution of boc-hydrazine (50 g, 231 mmol) in methanol (500 mL) was added a solution of HCl in dioxane (462 mL, 1.85 mol, 4.0 M). The mixture was stirred at ambient temp overnight. Concentration of the reaction mixture under reduced pressure afforded the title compound as a white solid (43 g, 98percent). 400 MHz 1H NMR (DMSO) δ 3.85-3.82 (m, 2H), 3.27-3.21 (m, 2H), 3.13-3.05 (m, 1H), 1.88-1.84 (m, 2H), 1.48-1.38 (m, 2H). MS: (M+H m/z=117.2).
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 21, p. 9045 - 9054
45
[ 127406-56-8 ]
[ 870-46-2 ]
[ 198904-84-6 ]
Yield
Reaction Conditions
Operation in experiment
91.1%
for 4 h; Heating / reflux
Synthesis of tert-butyl 2-(4-(pyridin-2-yl)benzylidene)hydrazinecarboxylate (XII, Y1a = H).; A mixture of 4-(pyridin-2-yl)benzaldehyde X (17.7 g, 96.6 mmol) and tert-butyl carbazate (12.2 g, 92.3 mmol) in ethanol (125 mL) was kept at reflux under nitrogen for 4 hours (hrs). The reaction mixture was cooled to 40°C and ice (60 g) was added, The resulting mixture was stirred for 20 minutes (min). The precipitate was collected by filtration, washed with water and dried in a vacuum oven (60 °C) to give the product XII, wherein Y1a = H (25.0 g, 91.1 percent).
Reference：
[1] Patent: EP2003120, 2008, A1, . Location in patent: Page/Page column 33
[2] Organic and Biomolecular Chemistry, 2013, vol. 11, # 39, p. 6806 - 6813
[3] Organic Process Research and Development, 2002, vol. 6, # 3, p. 323 - 328
[4] Patent: US6765097, 2004, B1, . Location in patent: Page column 14-15
[5] Patent: WO2010/149356, 2010, A1, . Location in patent: Page/Page column 14; 15
[6] Molecules, 2015, vol. 20, # 5, p. 9229 - 9241
[7] Patent: CN106543073, 2017, A, . Location in patent: Paragraph 0040; 0041
To a solution of fe/t-butyl carbazate (75 g, 567 mmol) in methylene chloride (2.0 L) at 0°C was added benzyl chloroformate over -45 minutes. After the addition was complete the reaction was stirred overnight coming to rt as the ice bath was depleted. The reaction was carefully poured into saturated sodium bicarbonate (1L) and extracted. The organic layer was washed with water, and dried over sodium sulfate. Removal of the solvent in vacuo gave the desired product (148 g, 556 mmol, 98percent crude yield) as a viscous oil. The material was judged to be of satisfactory purity without further purification.
85%
With sodium carbonate; In dichloromethane; at -78 - 20℃;
tert-Butyl hydrazinecarboxylate 10 (132 mg, 1 mmol) was dissolved in dry DCM and cooled down to -78 °C. Benzyl chloroformate (20.5 mg 1.2 mmol) was added drop-wise followed by Na2CO3 (106 mg, 1 mmol). The reaction mixture was allowed to rt and stirred overnight. Filtration, evaporation of solvents, and recrystallization from hexanes/EtOAc 50:1 gave 1-benzyl 2-(tert-butyl)hydrazine-1,2-dicarboxylate 11 as a white solid (226 mg, 85percent), mp 75.0?77.0 °C, lit. 72?74 °C. 1H NMR (300 MHz, CDCl3) delta 7.34 (s, 5H), 6.80 (s, 1H), 6.49 (s, 1H), 5.16 (s, 2H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl3) delta 156.9, 155.9, 135.8, 128.7, 128.5, 128.4, 81.9, 67.8, 28.3.22
In dichloromethane; at 20℃;
To a solution of intermediate I-86 (20 g, 150 mmol, 1 eq) in dichloromethane (400 mL) was added drop wise neat CbzCl (28 g, 166 mmol, 1.1 eq) over the period of 20 minutes and the reaction mixture was stirred at room temperature overnight. Excess solvent was removed by evaporation and the residue was diluted with water and extracted with ether. pH of the aqueous layer was adjusted to 8 and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration. The filtrate was concentrated to give intermediate I-87 (38 g, 94percent) that was used in the following step without further purification. MS (ESI): m/z 167 (M+H+).
In dichloromethane; at 20℃;
Intermediate I-78 (1-benzyl 2-tert-butyl hydrazine-1,2-dicarboxylate)To a solution of intermediate I-77 (20g, 150 mmol, 1 eq) in dichloromethane (400 mL) was added drop wise neat CbzCl (28 g, 166 mmol, 1.1 eq) over the period of 20 minutes, and the reaction mixture was stirred at room temperature overnight. Excess solvent was removed by evaporation, and the residue was diluted with water and extracted with ether. pH of the aqueous layer was adjusted to 8, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4, and the solids were removed by filtration. The filtrate was concentrated to give intermediate I-78 (38 g, 94percent) that was used in the following step without further purification. MS (ESI): m/z 167 (M+H+).
In dichloromethane; at 0 - 20℃;
1-benzyl 2-tert-butyl hydrazine-1,2-dicarboxylateTo a stirred solution of tert-butyl hydrazinecarboxylate (50 g, 0.38 mol) in DCM (500 mL) was added benzyl carbonochloridate (64.54 g, 0.38 mol) dropwise over 30 min at 0 °C. After theaddition, the mixture was stirred at rt overnight. The mixture was poured into NaHC03 solution. The organic layers were separated and washed with brine, dried over Na2S04, evaporated and purified by column to afford the title compound (25 g, purity: 90percent on TLC).
13.8 g
With 4-methyl-morpholine; In tetrahydrofuran; at 0℃;
To a cold solution (0° C) of tert-butyl hydrazinecarboxylate hydrochloride (7.1 g, 53.8 mmol) in and N-methylmorpholine (17.7 mL, 161 mmol) in tetrahydrofuran (100 mL) added benzyl chloroformate (7.7 g, 53.8 mmol) and slowly brings to room temperature stirred for 10 h. Tetrahydrofuran was removed under reduced pressure and the resulting viscous solution was diluted with water (40 mL) and thoroughly extracted with ethyl acetate (50x3 mL). The combined organic extracts were washed with 1 N HCl (25 mL), saturated aqueous sodium bicarbonate (NaHCO3) (25 mL) and dried over anhydrous sodium sulphate (Na2SO4) and concentrated to give a residue, which was purified by by silica gel column chromatography (EtOAc : Hexane ? 2:5) as a white solid (13.8 g, yield: 96percent). 1H NMR (400 MHz, CDCl3) d ppm: 7.44 - 7.27 (m, 5 H), 6.48 (bs, 1 H), 6.29 (bs, 1 H), 5.18 (s, 1H), 1.46 (bs, 9 H). MS (ESI): found: [M + Na]+, 289.2.
<i>N</i>'-[(benzyl-<i>tert</i>-butoxycarbonyl-amino)-(4-methoxy-phenyl)-acetyl]-<i>N</i>'-[1-(2,6-dimethyl-phenylcarbamoyl)-3-methyl-butyl]-hydrazinecarboxylic acid <i>tert</i>-butyl ester[ No CAS ]
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
Compound 26.1 (5.72 g, 35.3 mmol), l-(3-Dimethylarninopropyl)-3- ethylcarbodiimide hydride (6.77 g, 35.3 mmol) and 1-hydroxybenzotriazole hydrate (5.4 g, 35.3 mmol) were suspended in 90 ml DMF. Then tert-bvAyl carbazate (4.67 g, 35.3 mmol) was added followed by diisopropylethylamine (12.3 ml, 70.6 mmol). The reaction was stirred overnight at <n="76"/>room temperature. Then the solvent was removed under vacuum and the residue was flooded with ethyl acetate, rinsed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered, and evaporated to dryness. This was purified using flash chromatography to give Compound 26.2 (4.06 g, 42percent) as a white solid. ES (+) MS m/e = 277 (M+l).
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 1h;
To a solution of l-[(benzyloxy)carbonyl]azetidine-3-carboxylic acid (6.00 g, 25.5 mmol) in DMF (150 ml) were added ter/-butyl carbazate (4.05 g, 30.6 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (7.34 g, 38.3 mmol), l-hydroxy-7-azabenzotriazole (3.47 g, 25.5 mmol), and diisopropylethylamine (6.66 ml, 38.3 mmol). The reaction was allowed to stir for 1 h. The product was extracted with EtOAc, washed with 3M lithium chloride (3x), dilute HCl, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography (silica, 60percent EtOAc/hexanes isocratic) to afford the Boc protected product as a white foam. A solution of the protected material in EtOAc was cooled to O0C, saturated with HCl gas, and allowed to stir for 8 h. The reaction was concentrated in vacuo, and the residue was dissolved in EtOAc, washed with IN sodium hydroxide, dried over sodium sulfate, filtered, and concentrated in vacuo to yield benzyl 3- (hydrazinocarbonyl)azetidine- 1 -carboxylate (75percent).
With sodium cyanoborohydride; acetic acid; In methanol; at 25℃; for 16h;
Step I: To a solution of dihydro-2H-pyran-4(3H)-one (5 g, 0.05 mol) in MeOH (60 mL) was added tert-butyl tert-butyl hydrazinecarboxylate (7.92 g, 0.06 mol), AcOH (500 uL) and NaBH3CN (6.3 g, 0.1 mol). The mixture was stirred at 25 C for 16 hours, then concentrated. The residue was dissolved in DCM (100 mL), washed with water (80 mL), dried over anhydrous Na2SO4, concentrated. The crude residue was purified by silical gel chromatography (PE : EA = 5:1 to 1:1) to give tert-butyl tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (10 g, 92%) as a white solid.
88%
Intermediate 221,1-Dimethylethyl 2-(tetrah dro-2H-pyran-4-yl)hydrazinecarboxylateTetrahydro-4H-pyran-4-one (9.69 g, 97 mmol) was added to a solution of 1,1- dimethylethyl hydrazinecarboxylate (14.07 g, 106 mmol) in methanol (100 mL) and stirred at room temperature for 3 h. The solvent was removed in vacuo, and the crude residue was suspended in acetic acid (140 mL). Next added sodium cyanoborohydride (6.69 g, 106 mmol) in portions over 3 minutes. The contents were stirred at room temperature for 60 h. The solvent was removed in vacuo, and the crude residue was suspended in DCM (100 mL). The reaction mixture was adjusted to pH 7 with 6N NaOH. The layers were separated, and the aq. layer extracted with DCM. The combined organic layers were washed with saturated NaHC03, and brine. The organic layer was dried over MgS04, filtered, and concentrated in vacuo to afford the product as a solid, 18.4 g (88%). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.22 (m, 2 H), 1.39 (s, 9 H), 1.43 - 1.48 (m, 1 H), 1.59 - 1.69 (m, 2 H), 2.82 - 2.98 (m, 1 H), 3.20 - 3.32 (m, 2 H), 3.80 (d, J=l 1.62 Hz, 2 H), 4.36 (br. s., 1 H), 8.07 - 8.34 (m, 1 H).
88%
10 g (100 mmol) of tetrahydropyran-4-one was dissolved in 100 ml_ methanol and 14.5 g (110 mmol) tert-butylcarbazate was added. The reaction mixture was stirred at room temperature for 2h. The solvent was evaporated by reduced pressure. The residue was mixed with 140 ml_ acetic acid (50 %), 6.9 g (110 mmol) sodium cyanoborohydride was added and the mixture was stirred at room temperature over night. The reaction mixture was neutralized with 4M NaOH and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. <n="175"/>The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under reduced pressure. 19 g (88 %) of the product were obtained as a white solid.MS ( ESI pos ): m/z = 217 (IvRH)+
64%
A mixture of tetrahydro-4H-pyran-4-one (31.7mL, 0.34mol) and tert-butylcarbazate (47.7g, 0.36mol) in EtOH (50OmL) was stirred at ambient temperature overnight. The reaction mixture was evapotrated and the reisdue suspended in HOAc-H2O (1:1 / 50OmL). NaCNBH3 (22.64g,0.36mol) was added and the mixture was stirred at ambient temperature for 2.5hr. The reaction mixture was suspended in EtOAc-10% K2CO3 (2:1 / 75OmL). The organic layer was separated, washed with brine (2 x 40OmL) and dried (MgSO4). Filtration and evaporation of the solvent and trituration of the residue with hexane afforded the product as a white amorphous solid(47.5g, 64%). 1H NMR (CDCl3) 6.10 (IH, br s), 3.99-3.35 (5H, m), 3.06 (IH, m), 1.79-1.35(4H, m), 1.46 (9H, s)
Intermediate 26: 1,1-Dimethylethyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate. [Show Image] To a solution of tert-butyl carbazate (FLUKA, 4.6 g, 34.6 mmol) in MeOH (124 mL), tetrahydro-4H-pyran-4-one (ALDRICH, 3.47 g, 34.6 mmol), sodium cyanoborohydride (ALDRICH, 3.3 g, 52 mmol) and glacial acetic acid (10 mL) were added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralised with 2N NaOH solution (20 mL) and concentrated in vacuo. Product was extracted with DCM and the organic layer was washed with brine, dried over anhydrous MgSO4 and the solvent evaporated under reduced pressure to give the title compound. 1H NMR (300 MHz, DMSO-d6) delta ppm: 8.19 (br.s, 1H), 4.47- 4.21 (br.s, 1H), 3.82- 3.75 (dt, 2H), 3.29- 3.21 (td, 2H), 2.94- 2.81 (m, 1H), 1.68-1.55 (m, 2H), 1.37 (s, 9H), 1.31-1.11 (m, 2H).
Intermediate 12: tetrahydro-2H-pyran-4-ylhydrazine, trifluoroacetate; Tetrahydro-4H-pyran-4-one (Apollo; 924 muL; 10.0 mmol) and te/f-butyl carbazate (1 .39 g; 10.50 mmol) were dissolved in ethanol (10 mL) and stirred at room temperature overnight. The solvent was removed in vacuo and the residue was redissolved in 1 :1 wate?acetic acid (10 mL) and sodium cyanoborohydride (660 mg; 10.50 mmol) added. The mixture was stirred at room temperature for 3 hours and then 2:1 ethyl acetate: 10% aqueous potassium carbonate (50 mL) added. The organic layer was separated, washed with brine, passed through a hydrophobic frit and the solvent removed in vacuo. The residue was redissolved in DCM (10 mL) and trifluoroacetic acid (1 mL) added and the mixture stirred overnight. The solvent was removed in vacuo to yield Intermediate 12 as a semi-solid slurry which was used directly without any purification. 1H NMR: (DMSOd6, 400MHz) delta 4.08-3.76 (2 H, m), 3.41 -3.27 (2 H, m), 3.23-3.14 (1 H, m), 1 .99-1.83 (2 H, m), 1 .59-1.43 (2 H, m). LC/MS: 1 17 (M+H)+.
2.34 g
A) tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate [0431] A solution of tetrahydro-4H-pyran-4-one (2.50 g) and tert-butyl hydrazinecarboxylate (3.47 g) in methanol (10 mL) was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in THF (25 mL), acetic acid (4.3 mL) and sodium borohydride (0.525 g) were added thereto, and the mixture was stirred at 0C for 1 hr. To the reaction mixture was added 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.34 g). 1H NMR (300 MHz, CDCl3) delta 1.35-1.54 (11H, m), 1.77 (2H, dd, J = 12.1 Hz, 2.3 Hz), 2.98-3.15 (1H, m), 3.40 (2H, td, J = 11.3 Hz, 2.3 Hz), 3.96 (3H, dt, J = 11.5 Hz, 3.7 Hz), 6.03 (1H, brs).
With sodium cyanoborohydride; acetic acid; In methanol; at 0 - 20℃; for 0.5h;
To the stirred solution of tetrahydro-4H-pyran-4-one (2 g, 9.33 mmol), tert-butoxycarbonyl hydrazide (1.8 g, 13.99 mmol) in AcOH: MeOH (1 :1 , 10 mL), NaCNBH3 (0.52 g, 8.4 mmol) was added portion wise at 0 C and the reaction mixture was stirred at RT for 30 min. Completion of the reaction was monitored by TLC; the reaction mixture was then concentrated under vacuum. The resulting mixture was suspended with 10% NaHC03 (20 mL) and was extracted with DCM (2 x 15 ml_). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2S04 and concentrated under vacuum to afford the title compound. Yield: 99% (crude) (2 g, off white solid). 1H NMR (400 MHz, DMSO-d6): delta 8.20 (s, 1 H), 4.34 (s, 1 H), 3.82-3.81 (m, 2H), 3.29-3.26 (m, 2H), 2.89-2.88 (m, 1 H), 1.63 (t, J = 2.0 Hz, 2H), 1.38 (s, 9H), 1.24 (t, J = 4.0 Hz, 2H). LCMS: (Method A) 1 17.2 (M-Boc), Rt. 1.2 min, 99.7%.
With sodium hydrogencarbonate;sodium iodide; In acetonitrile; for 18h;Heating / reflux;
To a solution of intermediate 1. 1 (3.5 g, 14.4 mmol) and t-butyl carbazate (2.09 g, 17.3 mmol), commercially available from Acros, in ACETONITRILE (75 mL) was added sodium bicarbonate (1.45 g, 17.3 mmol) and catalytic amount of sodium iodide and the reaction mixture was refluxed for 18 h. The salt was then filtered and the solvent was removed. The resulting solution was diluted with EtOAc and washed with brine. The organic solution was dried over sodium sulfate, concentrated IN VACUO and purified by flash chromatography using EtOAc/DCM as eluent to afford intermediate 1. 2 (2.34 g, 56% yield) as white solid. RF0. 5 (EtOAc/DCM 1 : 2) ;'H NMR (CD3) 8 1.45 (s, 9H), 2.82 (t, J=7. 32 Hz, 2H), 3.13 (t, J=7. 32 Hz, 2H), 3.90 (s, 3H), 7.27 (D,. --8. 04 Hz, 2H), 7.95 (d, J=8. 04 HZ, 2H).
With sodium hydrogencarbonate; sodium iodide; In acetonitrile; for 24h;Heating / reflux;
Synthesis of t-butyl 2-{2-[(4-methoxycarbonyl)phenyl]ethyl}hydrazinecarboxylate (Intermediate ia-02) (Preparation method ia-2) A solution of Intermediate ia-01 (4.28 g) in acetonitrile (50 ml) was added with t-butyl carbazate (11.64 g, WAKO), sodium hydrogencarbonate (7.40 g), and sodium iodide (700 mg), and the mixture was refluxed for 24 hours by heating. The insoluble solid was removed by filtration, and then the filtrate was concentrated under reduced pressure. The residue was added with ethyl acetate (150 ml), and washed successively with purified water (75 ml), and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Flash, hexane:ethyl acetate=5:1) to obtain the title compound (Intermediate ia-02, 3.67 g).
N'-(tert-butyloxycarbonyl)-5-chloro-1H-pyrrolo[2,3-c]picolinic acid hydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 12h;
EXAMPLE 25; 5-Chloro-1H-pyrrolo [2, 3-c] pyridine-2-carboxylic acid N'- (tertbutyloxycarbonyl) hydrazide; To a solution of 5-chloro-lH-pyrrolo [2,3-c] pyridine-2-carboxylic acid (Preparation 8, 2. 05g, 10. 4mmol) in DMF (30mL), tert-butyl carbazate (1.38g, 10. 4mmol), DIPEA (3. 5mL, 20. 4mmol), HOBt (1.58g, 10. 3mmol) and EDCI (2.54g, 13. 3mmol) were added successively. The resulting solution was stirred for 12h at rt before adding water and brine (1: 1, 200mL). The solution was extracted with ethyl acetate (4 x 50mL) and the combined organic layers were washed with dilute hydrochloric acid (1N, 50mL), dilute sodium hydroxide solution (1N, 50mL) and brine. The organic layer was dried (MgSO4) and concentrated in vacuo to give a solid residue, which was purified by flash chromatography on silica gel (hexane/ethyl acetate, 1: 3) to give the title compound. aH (CDC13) : 1.42 (9H, s), 7.19 (1H, s), 7.78 (1H, s), 8.60 (1H, s), 9.28 (1H, br s).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 3h;
To a solution of 5.Og (31.6 mmol) of <strong>[2991-28-8]2,5-difluorobenzoic acid</strong> (1-1) in 2OmL of 1: 1 THF/DMF was added 4.39g (33.2 mmol) of t-butylcarbazate, 6.67g (34.8 mmol) of EDCI, and 50 mg of DMAP. After stirring for 3h at room temperature, the reaction was dumped into ice water and extracted three times with ether. The combined organic phases were washed two times with 10percent citric acid, two times with saturated NaHCO3, once with water, once with brine, and then dried over MgSO4. Concentration by rotary evaporation provided the BOC-protected acyl hydrazine as a white solid. To a solution of 1.5g (5.5 mmol) of this material in 20 mL of CH2Cl2, cooled to 00C, was added 10 mL of trifluoroacetic acid, and the resultant mixture was allowed to stir for 2 h at that temperature. The volatiles were removed by rotary evaporation, the residue was partitioned between EtOAc and aqueous NaHCO3, the layers were separated, and the aqueous phase was extracted two more times with EtOAc. The combined organic phases were washed twice with saturated NaHCO3, brine, dried over Na2SO4, and concentrated to provide 663mg (3.85 mmol) of 2,5-difluorobenzohydrazide (1-2) as a white solid. This material was dissolved in 30 mL of EtOH, and then 1.5 mL of HOAc was added, followed by 390 muL (3.85 mmol) of benzaldehyde. After stirring for Ih at room temperature, the solvents were removed by rotary evaporation, and the residue was triturated with Et2O to provide the imine as a white powder. A portion of this imine (225mg, 0.86 mmol) was dissolved in 3 mL of acetic anhydride and heated at 125 0C for 2h After cooling to room temperature, the volatiles were removed by rotary evaporation, the residue was dissolve in EtOAc, washed twice with saturated NaHCO3, water, dried over Na2SO4, and concentrated. The residue was then purified by column chromatography with a gradient of EtOAc in hexanes to provide (1-3) as a white solid. IH NMR (500 MHz, CDC13): delta 7.6 -7.4 (m, 6H), 7.2 (m, 2H), 7.1 (s, IH), 2.4 (s, 3H) ppm. HRMS (ES) calc'd M + H for C16H12F2N2O2: 303.0940; found 303.0926.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In tetrahydrofuran; N,N-dimethyl-formamide; for 16h;
Step B: Preparation of <strong>[2991-28-8]2,5-difluorobenzoic acid</strong> hydrazide: To a solution of<strong>[2991-28-8]2,5-difluorobenzoic acid</strong> (3.5 g, 22 mmol) in THF/DMF (20 mL/20 mL) was added EDCI (4.7 g, 24 mmol), DMAP (50 mg) and NH2NHBoC (3.07 g, 23.2 mmol). After stirring for 16 hours, the reaction was quenched with water (30 mL) and diluted with EtOAc (30 mL). The organic layer was then washed with HCl (0.5 M, 20 mL), saturated NaHCO3 (20 mL), and brine (20 mL). The organic layer was then dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude Boc-protected product, which was then dissolved in DCM (60 mL) at 0 °C. TFA (50 mL) was added to the above DCM solution. After stirring for 2 hours, the reaction mixture was concentrated and the residue was dissolved in DCM (60 mL). The solution was washed with saturated NaHCO3 (40 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired crude product.
Example 1 [6-(2,4-Difluoro-phenoxy-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-isopropyl-amine The synthetic procedure of Example 1 is shown in Scheme G. Step 1 N'-(5-Cyano-2-methylsulfanyl-pyrimidin-4-yl)-hydrazinecarboxvlic acid tert-butyl ester 4-Chloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (prepared as described in US2003158218, 0.509 g, 2.74 mmol), tert-butyl carbazate (tert-butoxycarbonyl hydrazine, 0.403 g, 3.05 mmol) and triethylamine (0.57 mL, 4.1 mmol) were added to 25 mL THF. The reaction mixture was stirred 22 hours, and then 25 mL diethyl ether was added and the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and the resulting oil was chromatographed through silica (0%-33% EtOAc in hexanes) to give 0.64 g of N'-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-hydrazinecarboxylic acid tert-butyl ester. Step 2 N'-F 5-Cyano-2-(2,4-difluoro-phenoxy)-pyrimidin-4-yll-hydrazinecarboxylic acid tert-butyl ester
Trifluoromethanesulfonic anhydride (29.7 mL, 176 mmol) was added dropwise to a 0 0C solution of 4-hydroxy-6-methyl-3-nitropyridin-2(lH)-one (15.0 g, 88.0 mmol) and triethylamine (36.9 mL, 265 mmol) in dichloromethane (450 mL). The solution was allowed to warm to room temperature and was stirred for two hours before tert-butyl carbazate (12.8 g, 97.0 mmol) was added. The solution was allowed to stir overnight, then was transferred to a separatory funnel and washed with water (200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 30% ethyl acetate in hexanes) to provide 16.2 g of tert-butyl 2-(6-methyl-3-nitro-2- [(trifluoromethyl)sulfonyl]oxy}pyridin-4-yl)hydrazinecarboxylate as a light orange solid.
N-(3,5 dichlorobenzyl)hydrazine carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With potassium carbonate; In ethyl acetate; acetonitrile;
3,5 Dichlorobenzyl bromide (10 g, 41.7 mmol) was dissolved in 200 mL of acetonitrile and K2CO3 (11.0 g, 83.36 mmol) and hydrazine carboxylic acid tert-butyl ester (11.0 g, 83.36 mmol) were added. The resulting mixture was warmed to reflux for 3 hours. The reaction mixture was then cooled to room temperature, concentrated in vacuo, and diluted with water and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give a yellow oil. Purification by column chromatography (SiO2, 5-10% EtOAc/Hex eluent) provided 6.4 g of N-(3,5 dichlorobenzyl)hydrazine carboxylic acid tert-butyl ester as a white solid (53% yield).
With HBTU; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 22℃; for 2h;
A solution of Fmoc-Amb-OH (1.00 g, 2.68 mmol) in dry DMF (10.0 mL) at 22 C was treated with HBTU (1.22 g, 3.22 mmol) followed by /-Pr2NEt (2.30 mL, 13.2 mmol) and tert-butyl carbazate (354 mg, 2.68 mmol). After 2 hours of reaction time, all volatiles were removed in vacuo. The resulting oil was taken up in ethyl acetate (50 mL), washed with saturated solutions OfNaHCO3 (2 x 15 mL) and NaCl EPO <DP n="79"/>(1 x 15 mL) then dried over MgSO4, filtered through a plug of silica and concentrated in vacuo to a pale yellow crystalline solid (1.2Og, 2.46 mmol, 91.9%). This material was used directly in the subsequent step. 1H NMR (CDCl3, 600 MHz): delta 9.50 (IH, br s), 7.71 (IH, br s), 7.40 (2H, br d, J= 6.6 Hz), 7.31 (2H, d, J= 7.5 Hz), 7.20 (2H, d, J = 7.4 Hz), 6.94 (2H, t, J= 7.4 Hz), 6.90 (IH, t, J= 5.9 Hz), 6.86-6.84 (4H, m), 3.97 (2H, d, J= 6.8 Hz), 3.87 (2H, d, J= 6.0 Hz), 3.77 (IH, t, J= 6.6 Hz), 1.02 (9H, s). MS (ESI): 875.3 (100, 2M-Boc). 388.2 (90, M-Boc).
87%
A solution of Fmoc-Amb-OH (2.50 g, 6.7 mmol), HOBt (1.11 g, 7.3 mmol), HBTU (2.77 g, 7.3 mmol) and diisopropylethylamine (3 ML, 17.2 mmol) in anhydrous N, N-dimethylformamide (10 mL) was stirred at ambient temperatures under nitrogen for 20 minutes, and treated with t-butyl carbazate (0.74 g, 5.6 mmol). After an additional 2 hours, the reaction was diluted with ethyl acetate (50 mL), washed consecutively with 0.1 N HC1 (3 x 30 mL), 0.1 N NaOH (30 ML), water (30 mL), dried over MgS04 and evaporated to dryness. The resulting yellow solid was recrystallized from ethyl acetate/hexanes to give the title compound as a colorless solid (2.37 g, 87%)
With dmap; diisopropyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 16h;
DMAP (0.1 equiv, 14.8 mmol, 1.81 g) and DIPC (1.5 equiv., 222.3 mmol, 34.5 ml_) were added under nitrogen atmosphere slowly at 00C to a solution of Cbz-Glu-OtBu (1 equiv., 148.2 mmol, 50 g) and tetrt.butyl-carbazate (1.5 equiv., 222.3 mmol, 29.4 g) in dry DCM (100 mL). The mixture was stirred then at RT for 16 h. The solid was removed by suction filtration and washed with DCM. The organic layer was extracted with 0.1 M HCI (10 x 100 mL). The organic phase was then extracted with brine, water, dried and the solvent was removed under reduced pressure to give Cbz-Glu-NH-NH-BOC as a white solid (66.6 g) 60 g Cbz-Glu-NH-NH-BOC was dissolved under nitrogen in dry methanol (200 mL). Pd/C (10percent, 2.5 g) was added and a hydrogen balloon was applied to the flask. The reaction mixture was stirred au RT for 4 d during which the balloons were exchanged with new ones. The suspension was then diluted with methanol, filtered over celite and the solvent was removed under reduced pressure. The oily rest was purified by FC on silica eluting with CHCI3ZMeOH 20:1 to give H-GIu-NH-NH- BOC as a white solid (42 g). The 6-maleimidocaproic acid chloride was prepared from maleimidocaproic acid (82.78 mmol, 17.35 g) and oxalic acid chloride (1.0 equiv, 82.78 mmol, 9.93 mL) in dry DCM (180 mL). Then dry trietylamine (82.8 mmol, 1 1.47 mL) was added at RT under nitrogen atmosphere to a solution of H- GIu-NH-NH-BOC (82.8 mmol, 26.36 g) in dry DCM (300 mL) followed by slowly adding the solution of the 6-maleimidocaproic acid chloride. The reaction solution was stirred at RT for 18 h. The solvent was removed under reduced pressure. The oily residue was purified by flash chromatography on silica eluting with EE/hexane (i) 1 :1 , (i) 2:1 , (i) 4:1 to give EMC-Glu-NH-NH-BOC as a white solid (36 g, 76 percent).
With dmap; bis-2-propyl carbonate; In dichloromethane; at 0 - 20℃; for 16h;
DMAP (0.1 equiv, 14.8 mmol, 1.81 g) and DIPC (1.5 equiv, 222.3 mmol, 34.5 ml_) were added under nitrogen atmosphere slowly at 00C to a solution of Cbz-Glu-OtBu (148.2 mmol, 50 g) and tert.-butyl carbazate (1.5 equiv, 222.3 mmol, 29.4 g) in dry DCM (100 ml_). The mixture was stirred at RT for 16 h. The solid was removed by suction filtration and washed with DCM. The organic layer was extracted with 0.1 M HCI (10 x 100 ml_). The organic phase was then extracted with brine, water, dried and the solvent was removed under reduced pressure to give 1 as a white solid (66.6 g). C22H33N3O7, Exact Mass: 451.23, MS (ESI): m/e 474.0 (M + Na)+. 1 (60 g) was dissolved under nitrogen in dry methanol (200 ml_). Pd/C (10percent, 2.5 g) was added and a hydrogen balloon was applied to the flask. The reaction mixture was stirred at RT for 4 d during which the balloons were exchanged with new ones. The solution was then <n="22"/>diluted with methanol, filtered over celite and the solvent was removed under reduced pressure. The oily rest was purified by flash chromatography on silica with CHCI3ZMeOH 20:1 to give 2 as a white solid (42 g, 50percent). CuH27N3O5, Exact Mass: 317.2, MS (ESI): m/e 318.0 (M + H)+, m/e 340.0 (M + Na)+. The 6- maleimidocaproic acid chloride was prepared from maleimidocaproic acid (82.78 mmol, 17.35 g) and oxalic acid chloride (1.0 equiv, 82.78 mmol, 9.93 ml_) in dry DCM (180 ml_). Dry triethylamine (82.78 mmol, 11.47 mL) was added at RT under nitrogen atmosphere to a solution of 2 (82.78 mmol, 26.36 g) in dry DCM (300 mL) followed by slow addition of the solution of 6-maleimidocaproic acid chloride. The reaction solution was stirred at RT for 18 h. The solvent was removed under reduced pressure. The oily residue was purified by flash chromatography on silica elu- ting with EE/hexane (i) 1 :1 , (i) 2:1 , (i) 4:1 to give 3 as a white solid (36 g, 76 percent). C24H38N4O8, Exact Mass: 510.27, (ESI): m/e 533.1 (M + H)+. A solution of 3 (32.4 g) and TFA (165 mL) in CH2CI2 (165 mL) was stirred at RT for 80 min. The product was precipitated with diethyl ether (4 L) as a TFA-salt. 4 was then collected by suction filtration, washed with ether and dried (20 g, 68 percent). Ci5H22N4O6, Exact Mass: 354.15, (ESI): m/e 355.1 (M + H)+. A stirred suspension of 4 (11 mmol, 5 g,) in dry DCM (50 mL) under nitrogen atmosphere at RT was treated with trimethyl- silyl chloride (2.1 equiv, 23.1 mmol, 3mL) and DIEA (1.05 equiv, 11.55 mmol, 1.9 mL). The mixture was heated at reflux for 1 h, and then cooled to 0 0C. DIEA (3.1 equiv, 63.8 mmol, 5.8 mL) was added, followed by 4-metyltrityl chloride (1.05 equiv, 11.55 mmol, 3.41 g). The reaction was stirred at RT for 16 h. Methanol (50 mL) was added and the solution was stirred for 5 min. The solvent was evaporated at 30 0C, and the residue was partitioned between DCM and pH 5 buffer (acetate). The organic phase was washed with pH 5 buffer, water, and brine, dried and the solvent was evaporated. The oily residue was purified by flash chromatography on silica eluting with CHCI3ZCH3OH (10:1 ) to give 5 as pale yellow foam (4.5 g, 83percent). C35H38N4O6, Exact Mass: 610.28, (ESI): m/e 633.1 (M + Na)+. 13 C NMR (100.61 MHz, CDCI3): delta = 21 (-, CH3), 25, 26, 28, 37, 39, 41 , 44 (-, 7 x CH2), 55 (+, CONHCH), 72 (+, Ar3C), 135 (+, CHCH), 127, 128, 129, 130 (-, Ar), 138, 141 , 144 (-, Ar), 170, 171 , 174 (-, HOCO, 4 x NCO). A stirred solution of 5 (6.22 mmol, 3.8 g) and HOSu (1.05 equiv, 6.60 mmol, 755 mg) in dry THF (25 mL) at 0 <n="23"/>0C was treated with DCC (1.05 equiv, 6.60 mmol, 1.36 g). After 20 min, the mixture was allowed to warm to RT and was stirred for 16 h. The solid by-product was filtered off, washed with dry THF, and the solvent was evaporated. The residue was purified by flash chromatography on diol, eluting with THF/hexane (1 :1 ) to furnish 6 as a white solid (2.70 g, 62percent). C39H41N5O8, Exact Mass: 707.30, (ESI): m/e 730.2 (M + Na)+.
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 100℃; for 3h;
<strong>[143879-80-5]2,3,4-<strong>[143879-80-5]trifluorobenzonitrile</strong></strong> (3 g, 19 mmol), tert-butyl carbazate (4 g, 30 mmol) and Hunig's base were dissolved in dioxane (10 mL) and heated at 100° C. for 3 d. The mixture was concentrated and then partitioned between toluene (25 mL) and water (29 mL). The toluene layer was added to a column and chromatographed (silica gel, 10 to 40percent ethyl acetate in hexanes) to give product as an oil. Recrystallization from ethyl acetate/hexanes gave N'-(4-cyano-2,3-difluoro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (1.16 g, 22percent) as a white powder. A second crop (0.5 g, 10percent) was obtained as a slightly pinkish powder. LCMS (m/z): M+H=170.1 (loss of BOC).
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 120.16h;
To a solution of <strong>[96606-37-0]2,4,6-trifluorobenzonitrile</strong> (5.62 g, 34.7 mmol) and tert-butylcarbazate (4.68 g, 34.7 mmol) in DMSO (70.0 mL) was added DIPEA (6.65 mL, 38.2 mmol) over 10 min. The resulting mixture was stirred at room temperature for 5 days. The mixture obtained was poured into brine solution and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (3×30 mL), dried over Na2SO4, filtered and concentrated at reduced pressure to dryness. The residue obtained was purified by column chromatography (silica gel, 80:20 hexanes/ethyl acetate) to afford tert-butyl 2-(4-cyano-3,5-difluorophenyl)hydrazinecarboxylate (5.74 g, 61%) as a light yellow solid: ESI MS m/z=270 [M+H]+.
To a solution of tetrahydropyran-4-one (71.6 g, 715 mmol) in methanol (2 L) was added tert-butylcarbazate (100 g, 758 mmol) at ambient temp. The mixture was stirred at ambient temp for 20 h. The reaction mixture was concentrated under reduced pressure to dryness to afford a white solid (154 g). To a suspension of the white solid (154 g, 715 mmol) in water (1 L) was added acetic acid (500 mL, 8.73 mol) and the mixture was stirred for 30 min to get a clear solution. To this solution, solid NaCNBH3 (44.5 g, 708 mmol) was added portion-wise. The mixture was stirred at ambient temp for 2 h. The mixture was then transferred to a 12 L flask, cooled to 0 C., and quenched with 1N NaOH (8.73 L, 8.73 mol). The mixture was extracted with CH2Cl2 (3*3 L) and dried over Na2SO4. The organic layer was filtered and concentrated to afford a white solid (164 g, contains ~15% of N-acetyl-N'-Boc-hydrazine derivative). Chromatography [silica, ethyl acetate/MeOH (95:5] gave 94 g of 90% pure boc-hydrazine. A solution of boc-hydrazine (50 g, 231 mmol) in methanol (500 mL) was added a solution of HCl in dioxane (462 mL, 1.85 mol, 4.0 M). The mixture was stirred at ambient temp overnight. Concentration of the reaction mixture under reduced pressure afforded the title compound as a white solid (43 g, 98%). 400 MHz 1H NMR (DMSO) delta 3.85-3.82 (m, 2H), 3.27-3.21 (m, 2H), 3.13-3.05 (m, 1H), 1.88-1.84 (m, 2H), 1.48-1.38 (m, 2H). MS: (M+H m/z=117.2).
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1.5h;
Part A:1,1 -Dimethylethyl 2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)hydrazinecarboxylate. 2,4,6-Trichloro-5-fluoropyrimidine (20.92 g, 104.1 mmol) was dissolved in THF (300 ml.) at room temperature and stirred. To this stirring solution was added f-butyl carbazate (13.74 g, 104.1 mmol), followed by diisopropylethylamine (19.0 ml_, 109.3 mmol). The reaction mixture turned light yellow, and after several minutes a precipitate formed. The reaction appeared complete after 1.5 h, as monitored by TLC (10% EtOAc/Hex). The reaction mixture was concentrated in vacuo to remove most of the THF, and the residue was dissolved in CH2CI2 (-400 ml_). The solution was washed with -400 ml. of sat. aq. NH4CI. The organics were dried and concentrated to give a pale yellow solid (31.37 g). LCMS: (M+H+2Na-Boc) +: 241.
31.37 g
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1.5h;Inert atmosphere;
Part A: 1 ,1 -Dimethylethyl 2-(2,6-dichloro-5-fluoro-4- py ri m id i ny I )hyd razi neca rboxy I ate 2,4,6-Trichloro-5-fluoropyrimidine (20.92 g, 104.1 mmol) was dissolved in THF (300 ml.) at room temperature and stirred. To this stirring solution was added f-butyl carbazate (13.74 g, 104.1 mmol), followed by diisopropylethylamine (19.0 ml_, 109.3 mmol). The reaction mixture turned light yellow, and after several minutes a precipitate formed. The reaction appeared complete after 1 .5 h, as monitored by TLC (10% EtOAc/Hex). The reaction mixture was concentrated in vacuo to remove most of the THF, and the residue was dissolved in CH2CI2 (-400 ml_). The solution was washed with -400 ml. of sat. aq. NH4CI. The organics were dried and concentrated to give a pale yellow solid (31 .37 g). LCMS: (M+H+2Na-Boc) +: 241 .
To a solution of 1-benzoylamino-cyclopropanecarboxylic acid (5.0 g, 21.3 mmol) in DMF (5 mL) was added Et3N (2.94 mL, 21.3 mmol) and HATU (8.08 g, 21.3 mmol). The reaction mixture was allowed to stir for 10 min then hydrazinecarboxylic acid tert- butyl ester (2.81 g, 21.3 mmol) was added. The reaction was allowed to stir at room temperature overnight. The mixture was diluted with water and extracted with EtOAc (3 x 50 mL). The combined extracts were washed with saturated NaHCO3, 2N HCl, brine and dried with MgSO4. The mixture was filtered, concentrated in vacuo, and purified by silica gel chromatography (25-100% EtOAc in hexanes) to give the lambdaT-(1-benzyloxy- <n="109"/>carbonylamino-cyclopropyl)-hydrazinecarboxylic acid tert-butyl ester (6.2 g, 17.7 mmol) as a white solid, m/z 250.6 [M-IOl]+.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 1h;
4-Pyridin-4-yl benzoic acid (250mug, 1.25mmol), EDAC (288mug, 1.51 mmol), HOBt (227mug), and 1 ,1-dimethylethyl hydrazinecarboxylate (199mug), in DMF were stirred at <n="29"/>room temperature for 1 h. The reaction mixture was diluted with water (20mul), extracted with ethyl acetate (30mul x 3), the organic phase washed with bicarbonate, dried over magnesium sulfate and evaporated to give an oil, 520mg. This was used without further purification.
In dimethyl sulfoxide; at 100℃; for 0.166667h;Microwave irradiation;
Stage 1: tert-butyl N-(2-methyl-6-nitro-phenyl)-hydrazino-carboxylate To 250 mg of 2-fluoro-3-methyl-nitrobenzene in 5 mL of DMSO are added 1.065 g of commercial tert-butoxycarbonylhydrazine (5 equivalents). The whole is brought to 100° C. for 10 min under microwave heating. The medium is hydrolyzed and then extracted with ethyl acetate several times. The organic phases are collected, dried on magnesium sulfate, filtered and evaporated under reduced pressure leading to a residue which is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 80/20). 342 mg of product corresponding to the expected product are obtained. Yield: 80percent 1H NMR (CDCl3, 250 MHz) delta (ppm): 7.86 (d, 1H), 7.35 (d, 1H), 6.97 (t, 1H), 6.40 (s broad, 1H), 1.34 (s broad, 9H)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 5℃;
In a 4L round bottomed flask, 1 ,1-dimethylethyl hydrazinecarboxylate (45g, 334 mmol) was dissolved in dry DMF (1 L) followed by slow addition of DIPEA (0.059 L, 334 mmol); the system was cooled down until intrenal temperature was 50C, then a solution of 2- bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (105 g, 350 mmol) in dry DMF (0.100 L) was added dropwise. After 2 hours at O0C, the mixture was poured in to 2 L of water and extracted with diethyl ether (2x1 L); combined organics were washed with water (2x0.5L), dried on sodium sulphate and evaporated under reduced pressure (bath set at 250C) to obtain 140.6 g of 1 ,1-dimethylethyl 2-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2- oxoethyl}hydrazinecarboxylate (140.6 g, 264 mmol, 79 % yield) as crude material (pale yellow solid) used quickly without further purifications in the next step.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 12h;
Step 1:900 mg of <strong>[171050-06-9]3-cyano-4-fluorobenzoic acid</strong>, 727 mg of tert-butyl carbazate and 1342 mg of DAPECI are stirred for 12 hours in 10 ml of DMF. The reaction mixture is poured into about 40 ml of a 10% sodium hydrogencarbonate solution, the precipitated solid is filtered off with suction and dried, giving 1140 mg of tert-butyl N'-(3-cyano-4-fluorobenzoyl)hydrazinecarboxylate (75%) as colourless solid; MS-FAB (M+H+-BOC)=180.3; Rf (polar method): 1.23 min.
To theta-bromo-I H-indazole^-carboxylic acid (5 g, 20.74 mmol) in Lambda/,Lambda/-dimethylformamide (20 ml) was added O-(7-azabenzotriazol-1-yl)-/V,/V,/V7V-tetramethyluronium hexafluorophosphate (8.68 g, 22.82 mmol) followed by Lambda/,Lambda/-diisopropyethylamine (5.42 ml, 31.1 mmol), and the clear solution was stirred for IOmins at 2O0C. To this was added t-butylcarbazate (3.29 g, 24.89 mmol) and the heterogeneous reaction was stirred for 24h at 2O0C under nitrogen. The mixture was left to stand for 7 days. Dichloromethane (200ml) and saturated aqueous sodium hydrogen carbonate (50ml) were added. Ethyl acetate (100ml) added and the mono-phasic mixture was left to stand for 30mins then the mixture was filtered through a filter paper under vacuum to give a biphasic filtrate. The organic phase was separated, passed through a hydrophobic frit, then evaporated to dryness to give a yellow liquid containing Lambda/,Lambda/-dimethylformamide. The solid collected on the filter paper was dried in air to give a beige solid (6g) which was treated with methanol (75ml) and chloroform (75ml) and the mixture stirred at room temperature for 2h. The mixture was left to stand for IOmins, then the supernatant was decanted off and loaded directly onto an aminopropyl (7Og) cartridge which had been pre-eluted with methanol. A further quantity of methanol (30ml) and chloroform (30ml) was added to the remaining slurry, stirred for IOmins and heated for a couple of minutes with a heat gun. The mixture was left to stand for IOmins and the supernatant added to the cartridge. The cartridge was then eluted with methanol, and the eluant evaporated to give the title compound as a yellow solid (3.47g).LCMS (Method B): Rt 2.78mins, MH+355.The aqueous was further extracted with dichloromethane (2x100ml), the combined organics were passed through a hydrophobic frit, then evaporated to dryness to give light yellow liquid containing Lambda/,Lambda/-dimethylformamide. The two liquids from above were combined and loaded equally onto silica (2x10Og) cartridges which had been pre-eluted with cyclohexane. The cartridges were eluted with 0-100% ethyl acetate/cyhexane over 40mins using the Flashmaster Il to give further quantities of the title compound as a beige solid (0.693g). LCMS (Method B): Rt 2.78mins, MH+355.
4.163 g
1,1-Dimethylethyl 2-[(6-bromo-1H-indazol-4-yl)carbonyl]hydrazinecarboxylate To <strong>[885523-08-0]6-bromo-1H-indazole-4-carboxylic acid</strong> (5 g, 20.74 mmol) in N,N-dimethylformamide (20 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate (8.68 g, 22.82 mmol) followed by N,N-diisopropyethylamine (5.42 ml, 31.1 mmol), and the clear solution was stirred for 10 mins at 20 C. To this was added t-butylcarbazate (3.29 g, 24.89 mmol) and the heterogeneous reaction was stirred for 24 h at 20 C. under nitrogen. The mixture was left to stand for 7 days. Dichloromethane (200 ml) and saturated aqueous sodium hydrogen carbonate (50 ml) were added. Ethyl acetate (100 ml) added and the mono-phasic mixture was left to stand for 30 mins then the mixture was filtered through a filter paper under vacuum to give a biphasic filtrate. The organic phase was separated, passed through a hydrophobic frit, then evaporated to dryness to give a yellow liquid containing N,N-dimethylformamide. The solid collected on the filter paper was dried in air to give a beige solid (6 g) which was treated with methanol (75 ml) and chloroform (75 ml) and the mixture stirred at room temperature for 2 h. The mixture was left to stand for 10 mins, then the supernatant was decanted off and loaded directly onto an aminopropyl (70 g) cartridge which had been pre-eluted with methanol. A further quantity of methanol (30 ml) and chloroform (30 ml) was added to the remaining slurry, stirred for 10 mins and heated for a couple of minutes with a heat gun. The mixture was left to stand for 10 mins and the supernatant added to the cartridge. The cartridge was then eluted with methanol, and the eluant evaporated to give the title compound as a yellow solid (3.47 g). LCMS (Method B): Rt 2.78 mins, MH+ 355.The aqueous was further extracted with dichloromethane(2x100 ml), the combined organics were passed through ahydrophobic frit, then evaporated to dryness to give lightyellow liquid containing N,N-dimethylformamide. The two liquids from above were combined and loaded equally onto silica (2x 100 g) cartridges which had been pre-eluted with cyclohexane. The cartridges were eluted with 0-100% ethyl acetate/cyhexane over 40 mins using the Flashmaster II to give further quantities of the title compound as a beige solid (0.693 g).LCMS (Method B): Rt 2.78 mins, MH+ 355.
To a solution of <strong>[86-59-9]8-quinolinecarboxylic acid</strong> (750 mg, 4.33 mmol, commercially available from e.g. Sigma-AIdrich, Acros or Apollo) and oxalyl chloride (0.417 ml, 4.76 mmol) in dichloromethane (50 ml) stirred under argon at 00C was added neat DMF (34 mul, 0.439 mmol). The reaction mixture was stirred at 0 0C for 18 hr, then evaporated in vacuo and azeotroped with toluene (2 x 5 ml). The residue was dissolved in dichloromethane (50 ml), and to this were added DIPEA (0.908 ml, 5.20 mmol) and t-butyl carbazate (1259 mg, 9.53 mmol). The reaction mixture was stirred at room temp for 6 hr. The reaction mixture was partitioned between dichloromethane (~ 50 ml) and saturated sodium bicarbonate solution (~ 25 ml). The aqueous phase was extracted with dichloromethane (2 x 50 ml) and the combined organic extracts washed with saturated sodium bicarbonate solution (~ 50 ml), dried over sodium sulphate and evaporated in vacuo to give the crude product as a burgundy gum. This was purified via Biotage (5:1 DCM/MeOH; 40+M Biotage column; flow rate 20 ml/min) to afford impure product as a burgundy foam. This was further purified via Biotage (1 :1 Hex/EtOAc; 40+M Biotage column) and dried overnight in a vacuum oven at 40 0C to afford the required product as a fine, pale yellow powder in 947.8 mg.LCMS: 2 minute run in MeOH. MH+ m/z = 288.12; RT = 0.84-0.86 min.
1 ,3-thiazole-4-carboxylic acid (0.775 g, 6 mmol, commercially available from e.g. Sigma-AIdrich, Apollo or Fluorochem) was dissolved in dichloromethane (DCM) (50 ml_), and the solution was cooled to 0 0C. To this was added oxalyl chloride (0.578 ml_, 6.60 mmol) and 5 drops of DMF (cat.) and the solution was stirred, under argon, for 3 hours. The solvent was then removed in vacuo, and the remaining residue was redissolved in dichloromethane (DCM) (50 ml_), before 1 ,1-dimethylethyl hydrazinecarboxylate (0.872 g, 6.60 mmol) and DIPEA (1.258 ml_, 7.20 mmol) were added. The solution was stirred under argon for 2 hours, LCMS and TLC confirmed product formation, thus the solvent was evaporated in vacuo. The remaining residue was then partitioned between ethyl acetate (30 mL) and saturated sodium bicarbonate solution (20 ml). The aqueous phase was then further extracted with ethyl acetate (2 x 30 mL) and the combined extracts were washed with brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was then evaporated in vacuo to yield the product in 1.308 g.
A solution of 5-methyl-1 ,3-thiazole-4-carboxylic acid (500 mg, 3.49 mmol) in dry dichloromethane (DCM) (17.500 ml) was stirred at room temperature under an atmosphere of argon. EDC (736 mg, 3.84 mmol) and HOBt (267 mg, 1.746 mmol) were added to the stirred solution and the resulting solution was stirred at room temperature for 1/2 hour. After this time, 1 ,1-dimethylethyl hydrazinecarboxylate (554 mg, 4.19 mmol) was added and the solution was stirred for a further 16 hours (overnight) at room temperature. The solution was diluted with DCM (approx. 50 ml) and washed with water (2 x approx. 25 ml). The organics were dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow coloured oily solid. The residue was chromatographed [SiO2, MeOH in DCM 0-5%] to give a pale yellow coloured solid of desired material in 544mg.
EDC (742 mg, 3.87 mmol) and HOBt (593 mg, 3.87 mmol) were added to a suspension of 1 ,3-<strong>[14190-59-1]thiazole-2-carboxylic acid</strong> (500 mg, 3.87 mmol) in dry Dichloromethane (DCM) (19 ml) - solution became clear after the addition of EDC. The mixture was stirred at room temperature for 30 mins. 1 ,1-dimethylethyl hydrazinecarboxylate (512 mg, 3.87 mmol) was added and the resulting mixture was stirred at room temperature 1 day. The reaction mixture was diluted in DCM (150 mL) and washed with sat. NaHCOo (2 x 25 mL) and brine (25 mL). The resulting organic layer was dried over MgSpsi4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (10percent MeOH in DCM / DCM - 10CV) to afford desired product in 432.9 mg as an orange oil. LCMS m/z 243.9 [M+H] (at) 0.66 min (2 min run)
A solution of <strong>[3209-71-0]3-<strong>[3209-71-0]isoxazolecarboxylic acid</strong></strong> (500 mg, 4.42 mmol, commercially available from e.g. Manchester Organics, Bio-Farma or APAC) in dry dichloromethane (DCM) (14.700 ml) was stirred at room temeprature under an atmosphere of argon. EDC (1017 mg, 5.31 mmol) and HOBt (339 mg, 2.21 1 mmol) were added to the stirred soltuion and the resulting solution was stirred for 3/4 hour. After this time, 1 ,1- dimethylethyl hydrazinecarboxylate (701 mg, 5.31 mmol) was added to the stirred solution and strring continued for a further 18 hours at room temperature (overnight). The reaction mixture was partitioned between DCM (~ 20 ml) and saturated sodium bicarbonate solution (~ 20 ml). The aqueous phase was extracted with DCM (2 x 20 ml) and the combined organic extracts washed with saturated brine (~ 50 ml), dried over sodium sulphate, evaporated in vacuo and dried (vacuum oven, 40 0C, 72 hr) to afford the crude product as a brown oil. This was purified via Biotage SP4 (2-20 % MeOH/DCM; 100g SNAP Biotage column; 12 CV) to afford the required product as an orange oil in 510.6 mg, which was used without further purification in the next step. LCMS: [M-Boc+H]+ m/z = 128.0; RT. = 0.62-0.63 min.
6-Fluoro-2-pyridinecarboxylic acid (2.83 g, 20.06 mmol, CAS[402-69-7], commercially available e.g. from Sigma-Aldrich or Apollo Scientific) was dissolved inDichloromethane (DCM) (100 ml.) at 0 0C. Oxalyl chloride (2.107 ml_, 24.07 mmol) and a drop of Lambda/,Lambda/-dimethylformamide (DMF) was added and the mixture was stirred for 2 hours. The solvents were removed in vacuo and azeotroped with toluene (3x20ml). The residue was dissolved in dichloromethane (DCM) (100 ml) whereupon 1 ,1-dimethylethyl hydrazinecarboxylate (2.92 g, 22.06 mmol) and Lambda/,Lambda/-diisopropylethylamine (DIPEA) (7.71 ml_, 44.1 mmol) were added. The mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and saturated sodium bicarbonate solution (50 ml). The aqueous phase was extracted with ethyl acetate (3x100ml), the combined organic extracts were washed with brine (50 ml), were dried over anhydrous sodium sulphate and were concentrated in vacuo. The residue was purified by flash chromatography (Biotage SP4, 40+M, 0-100percent ethyl acetate/iso- hexane) to afford 1 ,1-dimethylethyl 2-[(6-fluoro-2- pyridinyl)carbonyl]hydrazinecarboxylate (5.04 g, 19.75 mmol).LC/MS = 156 (M+H-BOC)+, retention time = 0.81 minutes (2 minute method).
A solution of <strong>[21169-71-1]5-isoxazolecarboxylic acid</strong> (500 mg, 4.42 mmol, commercially available from e.g. Sigma-Aldrich, Maybridge or Apollo) in dry dichloromethane (DCM) (14.700 ml) was stirred at room temperature under an atmosphere of argon. EDC (1017 mg, 5.31 mmol) and HOBt (339 mg, 2.21 1 mmol) were added to the solution and stirring was continued at room temperature for 1/2 hour. After this time, 1 ,1-dimethylethyl hydrazinecarboxylate (701 mg, 5.31 mmol) was added to the reaction mixture and stirring was continued for a further 18 hours at room temperature (overnight). The solution was diluted with DCM (approx 30 ml) and washed with water (2 x 20 ml). The organics were dried over MgSO4, filtered and concentrated under reduced pressure to give a colourless oil. The oil was chromatographed [Sitheta2, EtOAc/Hexane 0-100%] to give a colourless, thick oil in 321 mg. The oil was used directly in the next step. LCMS [M-H] 226.22 and [M+H- BOC]+ 128.07 (at) 0.60 min (2 min run).
A solution of <strong>[10271-85-9]5-isothiazolecarboxylic acid</strong> (500 mg, 3.87 mmol, commercially available from e.g. Fluorochem or Astatech) in dry Dichloromethane (DCM) (12.9 ml) was stirred at room temperature under an atmosphere of argon. EDC (891 mg, 4.65 mmol) and HOBt (296 mg, 1.936 mmol) were added to the stirred solution. The resulting solution was stirred at room temperature under an atmosphere of argon for 1/2 hour. After this time, 1 ,1-dimethylethyl hydrazinecarboxylate (614 mg, 4.65 mmol) was added and the solution was stirred for a further 18 hours at room temperature (overnight). The solution was diluted with DCM (approx 30 ml) and washed with water (2 x 20ml). The organics were dried over MgSO4, filtered and concentrated under reduced pressure to give a brown coloured oil. The oil was chromatographed [Sitheta2, EtOAc/Hexane 0-100%] to give a thick, yellow-coloured oil which solidified on standing to afford the product in 480 mg. The residue was used directly in the next step. LCMS [M+H]+ 244.14 (at) 0.66 min (2 min run).
A solution of <strong>[26893-73-2]6-(methyloxy)-2-pyridinecarboxylic acid</strong> (1.00 g, 6.53 mmol) in dichloromethane (DCM) (13.52 ml) was stirred and cooled to 0 0C. Oxalyl chloride (0.686 ml, 7.84 mmol) was added dropwise followed by DMF (5.06 mul, 0.065 mmol). The solution immediately turned yellow and the reaction was followed by LCMS. LCMS after circa 1 hour showed the methyl ester of the acid chloride to be present. The solvent was removed under reduced pressure and the residue was azeotroped with toluene. The residue was dissolved in dichloromethane (DCM) (27.0 ml) and cooled to O 0C. DIPEA (1.71 1 ml, 9.80 mmol) was added dropwise followed by 1 ,1- dimethylethyl hydrazinecarboxylate (0.949 g, 7.18 mmol) and the solution was left to stir at 20 0C, under an argon atmosphere for 18 hours. A dark brown solution formed and LCMS showed the desired compound to be present. The solvent was removed under reduced pressure and the residue was diluted with dichloromethane and washed with saturated sodium bicarbonate, saturated ammonium chloride, water and brine. The organic extracts were dried over magnesium sulfate and the solvent was removed under vacuum to yield the desired product in 1.685 g. LCMS m/z 268.16 [M+H] (at)0.83 min ( 2 min run)
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 150℃; for 0.5h;sealed vial; microwave irradiation;
A 5 mL microwave vial was charged with Intermediate C (150 mg,0.56 mmol), tert-butyl hydrazinecarboxylate (1-195, 222 mg, 1.68 mmol), Pd2(dba)3 (1 10 mg, 0.12 mmol), BetaGammaNuAlphaRho (150 mg, 0.24 mmol), Cs2C03 (546 mg, 1.68 mmol), and 4 mL of dioxane. The vial was sealed and heated in a microwave to 150 C for 0.5h. Upon cooling to 23 C, the reaction mix was diluted with EtOAc, and rinsed sequentially with saturated, aqueous solutions of ammonium chloride, sodium bicarbonate, and brine. The resulting organic liquid was dried over sodium sulfate and decanted into a 250 mL round bottom flask. After concentration of the product under reduced pressure, the resulting residue was purified by MPLC (0 to 100% EtOAc/hexanes) to give 140 mg of the desired intermediate, half of which was taken directly (2 mL of DCM solution) into 4 N HC1 in dioxane. After lh, the solution was concentrated under reduced pressure to give the HC1 salt (compound 11-195).
A solution of <strong>[22929-52-8]dihydrofuran-3(2H)-one</strong> (5.0 g, 58 mmol) and tert-butyl hydrazinecarboxylate (7.68 g, 58.08 mmol) in MeOH (50 mL) was stirred at 15° C. for 2 hours. The mixture was concentrated to remove MeOH and afford tert-butyl 2-(dihydrofuran-3(2H)-ylidene)hydrazine-1-carboxylate (11 g, 55 mmol, 95percent yield). 1H NMR (MeOD 400 MHz): delta4.19 (s, 2H), 4.03 (t, J=6.8 Hz, 2H), 2.53 (t, J=7.2 Hz, 2H), 1.50 (s, 9H).
85%
In methanol; at 20℃; for 2h;
General procedure: A 100 mL 3-neck flask with inert gas valve and septum was charged with (6.50 g, 49.04 mmol) tert-butylhydrazinecarboxylate and 30 mL MeOH. (4.91 g, 49.04 mmol) dihydro-2H-pyran-3(4H)-one was syringed into the flask. The mixture was stirred at rt for 2 h to observe the disappearance of tert-butylhydrazinecarboxylate monitored by LC-MS. The mixture was then dried over Na2SO4 and the solution was filtered and the solvent removed under reduced pressure to yield 10.4 g of white solid (99percent yield). The compound was further purified by passing through a short silica pad using 50percent EtOAc in hexanes.
27.3 g
In methanol; at 10 - 35℃; for 12h;
(1) Synthesis of t-butyl 2-[dihydrofuran-3(2H)-ylidene]hydrazinecarboxylate 3-oxotetrahydrofuran (10.38 g) was dissolved in methanol (200 mL), and t-butyl carbazate (17.53 g) was added to the solution. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to give the title compound (27.3 g). 1H-NMR (400 MHz, CDCl3) delta (ppm): 1.52 (s, 9H), 2.46 (t, J=6.9 Hz, al), 4.10 (t, J=6.9 Hz, 2H), 4.33 (s, 2H).
1.95 mmol
In ethanol;Reflux;
To a solution of dihydro(3(2H)-furanone (1 .95 mmol) in ethanol(2 mL) was added tert-butyl carbazate (2.35 mmol) and the reaction was heated to reflux and stirred overnight. Volatiles were removed under reduced pressure to give the titled compound (1.95 mmol) as a white solid. 1H NMR (400 MHz,CDCI3, 3, mixture of isomers): 7.25 (5, 0.75H), 7.12 (5, 0.25 H), 4.34 (t, J= 1.2 Hz, i.5H), 4.24 (t, J=1.2 Hz, 0.5H), 4.12 (t, J = 6.9 Hz, 1 .5H), 4.02 (t, J = 6.9 Hz, 0.5H), 2.78 (td, J = 6.9, 1.2 Hz, 0.5H), 2.48 (td, J = 6.9, 1.2 Hz, 1 .5H), 1.54 (5, 7.5H), 1.53 (5, 1 .5H).
General procedure: To 292 mg (4 mmol) of isobutyraldehyde in 4 ml of MeOH, 530 mg (4 mmol)of tert-butylcarbazatare added and the mixture is stirred at rt for 2 h. Then 1011 mg (4 mmol) of o-iodobenzoic acid and 339 mg (4 mmol) of tert-butylisocyanidare added and the reaction mixture is stirred overnight at rt. After evaporation of the solvent the crude product is purified by column chromatography on silica gel (chloroform/methanol = 99.5/0.5-->90/10, Rf = 0.20 [chloroform/methanol = 99.5/0.5]) to yield 1.52 g of the title compound (white solid, 73percent).
5-Bromo- 1 f-benzoimidazole-2-carboxylic acid (5 g, 20.743 mmol) was stirred in DCM (200 mL) and DIPEA (10.7 mL, 62.229 mmol) and HBTU (9.44 g, 24.892 mmol) were added. The r.m. was stirred at r.t. for 1 h, then tert-butylcarbazate (3.016 mmol, 22.817 mmol) dissolved in 20 mL of DCM was added drop wise and the r.m. was stirred at r.t. for 20 h. The r.m. was then washed with a sol. of Na2CC>3. The o.l. was dried (MgS04), filtered and evaporated. The residue was purified by flash column chromatography (silica; eluent: DCM/MeOH from 98/2 to 97/3). The fractions containing the product were collected, concentrated, the residue stirred in Et20, the precipitate filtered off and dried in vacuo at 60 C. Yield: 7 g of intermediate 83 (95% yield).
t-butyl 2-[(3RS,4SR)-4-hydroxytetrahydrofuran-3-yl]hydrazinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.78 g
In isopropyl alcohol; at 90℃; for 120h;
(1) Synthesis of t-butyl 2-[(3RS,4SR)-4-hydroxytetrahydrofuran-3-yl]hydrazinecarboxylate <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> (3.33 mL) and t-butyl carbazate (6.14 g) were dissolved in 2-propanol (15 mL), and the solution was heated to 90° C. After three days, t-butyl carbazate (6.3 g) was further added. After heating with stirring for further two days, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Xylene was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was partitioned by adding chloroform and brine. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 50percent to 100percent) to give the title compound (5.78 g). ESI-MS m/z 241 [M+Na]+
Step 1: Formation of N?-(2-Oxo-1-aza-spiro[4.5ldec-8-yl)-hydrazinecarboxylic acid tert10 butyl ester A solution of 1-Aza-spiro[4.5]decane-2,8-dione (Chembridge corporation, 800 mg; 4.78mmol; 1.0 eq.) and hydrazinecarboxylic acid tert-butyl ester (309 mg; 2.34 mmol; 1.1 eq.)in AcOH (5 mL) was stirred at RT for 5 mm. Sodium cyanoborohydride (133 mg; 2.13mmol; 1.0 eq.) was then added and the reaction mixture was stirred 0/N at RT. It wasthen diluted with water and basified to pH 9 by addition of a SN solution of NaOH. During the addition, the reaction mixture was maintained at 20 C by addition of crushed ice. It was extracted with DCM and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as ayellow oil (1.0 g, 98%) which was used without further purification.
Step 6: preparation of 3-(tert-butoxycarbonyl-hydrazono)-piperid me-i -carboxylic acid benzyl ester. To a solution of <strong>[61995-20-8]3-oxo-piperidine-1-carboxylic acid benzyl ester</strong> (150 g, 0.64 mol) in tetrahydrofuran (1.5 L) was added tert-butyl hydrazinecarboxylate (85 g, 0.64 mol). The solution was heated to reflux for 2 h, after which it was cooled to ambienttemperature and concentrated in vacuo to afford the title compound. MS (M+H) m/z348. 1H-NMR (CDCI3) 67.56 (s, 1H), 7.28-7.41 (m, 5H), 5.14-5.16 (d, 2H), 4.13-4.25 (d,2H), 3.73-3.78 (m, 0.6 H), 3.53-3.61 (m, 1.4H), 2.51-2.56 (t, 0.7H), 2.33-2.37 (t, 1.3H),1.82-1.91 (m, 2H), 1.52 (s, 9H)
148 g
With sodium sulfate; In methanol; at 28℃; for 4h;
100 g (1.0 eq.) of XlV-Cbz and 56.66 g (1.0 eq.) Boc-NHNH2 was dissolved in 500 mL solvent (methanol, 5.0 V), Na2S04 was added and the mixture was stirred for 4h at 28C. The solvent was evaporated by reduce pressure to get 148g of XV-Cbz as a 0 yellow oil. MS (ESI):m/z =370 (M+23(Na))
benzyl 3-[2-(tert-butoxycarbonyl)hydrazino]pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
Step 3: preparation of benzyl 3-[2-(tert-butoxycarbonyl)hydrazino]pyrrolid me-i -carboxylate. To a solution of <strong>[130312-02-6]benzyl 3-oxopyrrolidine-1-carboxylate</strong> (3.0 g, 13.7 mmol)in tetrahydrofuran (30 mL) was added tert-butyl hydrazinecarboxylate (1.81 g, 13.7mmol). The mixture was heated to reflux for 24h, then cooled to 15C, after whichsodium cyanoborohydride (0.86 g, 13.7 mmol) was added, followed by drop wiseaddition of para-toluene sulfonic acid (2.6 g, 15.1 mmol) in tetrahydrofuran (15 mL). The reaction mixture was allowed to stir at ambient temperature for an additional 16 h, then concentrated in vacuo. The resulting residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated, thenadded to 30 mL of 1 N aqueous sodium hydroxide and allowed to stir for 30 mm. The aqueous layer was removed and the organic washed with water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a clear oil (4.4 g, 97%).
N'-(4-benzyloxycarbonylamino-cyclohexylidene)hydrazinecarboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16.4 g
In methanol; at 20℃; for 4h;
Step 1: N?-(4-l3enzyloxycarbonylaminocyclo- hexylidene)hydrazinecarboxylic acid tert-butyl ester0(I)10185] 11.3 g (44.3 mmol) of benzyl (4-oxocyclohexyl) carbamate and 6.6 g (48.7 mmol) of tert-butyl carbazate are stirred in 140 ml of methanol at AT for 4 h. The reaction medium is evaporated to dryness. The solid residue is trim- rated with iso ether, and the precipitate is filtered off and then oven-dried under vacuum to give 16.4 g of expected product in the form of a pinkish powdet10186] Quantitative yield.10187] ?H NMR: DMSO-d5 (400 MHz): oe (ppm): 9.54 (1H, br); 7.43-7.24 (6H, m); 5.01 (2H, s); 3.60 (2H, m); 2.74 (1H, m); 2.35-2.11 (2H, m); 2.01-1.76 (2H, m); 1.47-1.25 (11H,m).
tert-butyl 2-(4-benzamidobenzoyl)hydrazinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 18h;
The p-benzamido-benzoic acid (0.325 g, 1.3 mmol, 1.0 equiv.) and tert-butyl carbazate (0.160 g, 1.2 mmol, 0.9 equiv.) were dissolved in 6 ml of 1:1 DMF:THF at room temperature. The EDCI (0.284 g, 1.5 mmol, 1.1 equiv.) was added followed by catalytic amount of DMAP. The reaction was stirred for 18 hrs. The reaction was poured into saturated bicarb and the aqueous solution was extracted with EtOAc (3x). The combined organic layers were washed with H2O, 10percent HCl, H2O, brine, dried over Na2SO4 and concentrated in vacuo. tert-butyl 2-(4-benzamidobenzoyl) hydrazinecarboxylate (0.465 g, 1.31 mmol) was obtained as an off-white in 97percent yield.1H-NMR (400 MHz; DMSO-d6): delta 10.48 (s, 1H), 10.10 (s, 1H), 8.86 (s, 1H), 7.96 (dd, J = 8.3, 1.4 Hz, 2H), 7.90-7.85 (m, 4H), 7.63-7.59 (m, 1H), 7.56-7.53 (m, 2H), 1.43 (s, 9H); 13C NMR (101 MHz; DMSO-d6): delta 165.9, 165.4, 155.6, 142.2, 134.7, 131.8, 128.4, 128.1, 127.7, 119.5, 79.1, 28.10, 28.07; LC/MS (APCI) m/z calcd. for C19H20N3O4 [M?H]?: 354.2, found: 354.0
tert-butyl 2-(5-bromo-3-fluoropicolinoyl)hydrazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h;
To an oven-dried flask, <strong>[669066-91-5]5-bromo-3-fluoropicolinic acid</strong> (1.0 g, 4.54 mmol) was dissolved in DMF (10 mL). To the stirring flask, tert-butyl carbazate (1.2 g, 9.09 mmol), DIPEA (1 mL) and HATU (3.45 g, 9.09 mmol) was added sequentially. The reaction mixture was stirred for one hour at room temperature and then diluted with water. The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the product as a white solid (1.4 g, 4.2 mmol, 92%). ESI-MS m/z: 356.15 [M+Na]+.
83%
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h;
A solution of <strong>[669066-91-5]5-bromo-3-fluoropicolinic acid</strong> (1.0 g, 4.57 mmol) was dissolved in DMF (15 mL) and BocNH1?H2 (1.2 g, 9.14 mmol) was added. HATU (1.8 g, 4.80 mmol) and Et3N (5mL) was added. The mixture was stirred at rt for 1 hour. Water (20 mL) was added and the mixture was extracted with EA (25 mLx3). The combined organic phase was dried overanhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (PE/EA=3/1) to give the desired product as a white solid (1.3 g, 83%).
83%
With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h;
A solution of <strong>[669066-91-5]5-bromo-3-fluoropicolinic acid</strong> (1.0 g, 4.57 mmol) was dissolved in DMF (15 mL) and BocNHNH2 (1.2 g, 9.14 mmol) was added. HATU (1.8 g, 4.80 mmol) and Et3N (5 mL) was added. The mixture was stirred at rt for 1 hour. Water (20 mL) was added and the mixture was extracted with EA (25 mL3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (PE/EA=3/1) to give the desired product as a white solid (1.3 g, 83%).
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 6h;
<strong>[160233-76-1]6-bromoquinoline-4-carboxylic acid</strong> (502 mg, 2.0 mmol), tert-butyl hydrazinecarboxylate (528 mg, 4.0 mmol), HATU (836 mg, 2.2 mmol), DIPEA (774mg, 6.0 mmol) in DMF (5 mL) was stirred for 6 hours at rt. The solution was quenched with water, extracted with EA (x3), washed with brine (x2), the organic layer was dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to give the desired compound as yellow solid(680 mg, 93%). ESI MS m/z = 367.9 [M+Hjt
93%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 6h;
<strong>[160233-76-1]6-bromoquinoline-4-carboxylic acid</strong> (502 mg, 2.0 mmol), tert-butyl hydrazinecarboxylate (528 mg, 4.0 mmol), HATU (836 mg, 2.2 mmol), DIPEA (774 mg, 6.0 mmol) in DMF (5 mL) was stirred for 6 hours at rt. The solution was quenched with water, extracted with EA (x3), washed with brine (x2), the organic layer was dried, concentrated. The crude product was purified via silica gel chromatography (PE-EA) to give the desired compound as yellow solid (680 mg, 93%). ESI MS m/z = 367.9 [M+H]+.
tert-butyl 2-(4,4,4-trifluorobutanoyl)hydrazinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
Example 20 Preparation of tert-butyl 2-(4,4,4-trifluorobutanoyl)hydrazinecarboxylate (C56) 4-Methylmorpholine (1.6 g, 16 mmol) was added to solution of <strong>[406-93-9]4,4,4-trifluorobutanoic acid</strong> (1.5 g, 11 mmol) in dichloromethane (20 mL) at -78 C. and stirred for 5 minutes. Isobutyl carbonochloridate (1.7 g, 13 mmol) was added to the mixture and stirred for another 10 minutes. tert-Butyl N-amino carbamate (1.7 g, 13 mmol) was added, and the reaction was warmed to room temperature for 2 hours. The reaction mixture was diluted with dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography using 30% ethyl acetate/petroleum ether as eluent provided the title compound as an off-white solid (1.5 g, 52%): mp 95-98 C.; 1H NMR (400 MHz, CDCl3) delta 7.19 (br s, 1H), 6.42 (s, 1H), 2.60-2.48 (m, 4H), 1.49 (s, 9H); ESIMS m/z 156 ([M-tert butyl CO]+).
N'-[4-(2,5-dioxo-2,5-dihydropyrrol-1-yl)benzoyl]hydrazine carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
A cooled suspension (0 C) of molecule 3 (211 mg, 0.97 mmol) in methylene chloride (4.5 mL) was treated with triethylamine (190 mu, 1.36 mmol) and isobutyl chloroformate (175 mu, 1.34 mmol). The mixture was stirrred for 1 h at 0C and at room temperature (22 C) for about 1 h. Afterwards, tert-butyl carbazate (128 mg, 0.97 mmol) dissolved in methylene chloride (0.8 mL) was added dropwise to the mixture and stirred for an additional 12 h at 22C. The reaction mixture was diluted with ethyl acetate (55 mL) and methylene chloride (20 mL) and washed twice with saturated NaHC03(2 x 50 mL), twice with 0.1 N HCl (2 x 50 mL), twice with saturated NaCl (2 x 50 mL), and finally with H20 (50 mL). The organic phase was dried (MgS04) and evaporated to give crude derivative 4. The product was purified by flash chromatography, using a mixture of hexanes / acetone (3/2), to yield 173 mg (54%) of 4. The spectral data of this derivative correspond to those reported in the literature.10IR (v, cm"1): 3360-3240 (NH), 3087 (C=C), 2988 (CH, aliphatic), 1733 (C=0), 1706 (C=0); 1H NMR (acetone-d6, delta ppm): 9.05 (s, 1H, NH), 8.02 and 7.53 (2 x d, J=8.6 Hz, 4H, aromatic), 7.07 (s, 2H, maleimide), 2.84 (br s, 1H, NH), 1.45 (s, 9H, 3 x CH3);13C NMR (acetone-d6, delta ppm): 169.3 (2), 166.0, 155.7, 135.1, 134.6 (2), 131.6, 127.9 (2), 125.9 (2), 79.6, 27.5 (3); ESI+HRMS: (M+Na)+ calculated for C16H17N3NaO5 = 354.1060; found = 354.1072; (M -2-methylpropene +H)+ calculated for C12H11N3O5= 276.0620; found = 276.0627.
tert-butyl 2-(2,2-difluorocyclopropanecarbonyl)hydrazinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 19h;Cooling with ice;
A flask containing 2,2-difluorocyclopropanecarboxylic acid (1.01 g, 8.2 mmol) (commercially available from Alfa Aesar, a Johnson Mathey Company) in anhydrous DCM (16.5 mL) was cooled in an ice bath. After 20 mins, 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (1.62 g, 8.5 mmol) and then tert-butyl carbazate (1.14 g, 8.6 mmol) were carefully added in portions to the homogeneous solution. Upon complete addition of tert-butyl carbazate, the solution was allowed to warm to RT. After 19 h, the reaction was carefully quenched with water and then extracted three times with DCM. The organic layers were pooled and then washed once with brine. The organic layer was dried over anhydrous magnesium sulfate and was then filtered and concentrated in vacuo. The colorless film was identified as tert-butyl 2-(2,2-difluorocyclopropanecarbonyl) hydrazinecarboxylate, Example 100.1 (1.95 g, 8.2 mmol, 100 % yield), and was used without purification. 1H NMR (400MHz, CD2C12) oe = 8.02 - 7.81 (m, 1H), 6.72 - 6.53 (m, 1H), 2.44 - 2.34 (m, 1H), 2.15 -2.08 (m, 1H), 1.80 - 1.73 (m, 1H), 1.46 (s, 9H
tert-butyl 2-(imidazo[1,2-a]pyrazin-8-yl)hydrazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With sodium hydride; In tetrahydrofuran; at 30℃; for 16h;
8-Chloroimidazo[1,2-a]pyrazine (400 mg, 2.6 mmol) and tert-butyl hydrazinecarboxylate (516.4 g, 3.9 mmol) were dissolved in THF (8 mL), sodium hydride (312.5 mg, 7.8 mmol) was added, and the mixture stirred at 30 C. for 16 h. Saturated aqueous NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (10 mL*2). The combined organic layers were dried over Na2SO4, filtered, and the filtrates concentrated under reduced pressure to afford a crude product as a black oil. The crude product was purified by flash column chromatography over silica gel (petroleum ether/ethyl acetate from 100/0 to 30/70). The solvent was concentrated under reduced pressure to afford compound 65a as a yellow solid (220 mg, 28%). LCMS (ESI): m/z 250.1 [M+H]+.
(E)-tert-butyl 2-((6-(trifluoromethyl)pyridin-3-yl)methylene)hydrazinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid; In ethanol; at 20℃; for 1h;
A round bottom flask was charged with 6-(trifluoromethyl)nicotinaldehyde (10 g, 57.1 mmol) in ethanol (200 mE), followed by the addition of tert-butyl hydrazinecarboxylate (8.30 g, 62.8 mmol) and acetic acid (1.144 ml, 19.99 mmol). The mixture was stirred at ambient temperature for 1 h and the reaction mixture was concentrated under reduced pressure to afford the title compound. 1H NMR (400 MHz, DMSO-d6): delta 11.31 (s, 1H), 8.94 (s, 1H), 8.29-8.26 (m, 1H), 8.12 (s, 1H), 7.94 (d, J=11.20 Hz, 1H), 1.49 (s, 9H). LCMS (ES, mlz): 290 [M+H].
tert-butyl 2-(4-amino-2-fluorobenzoyl)hydrazinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With 4-methyl-morpholine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In tetrahydrofuran; ethyl acetate; at 20℃; for 16h;
To a solution of <strong>[446-31-1]4-amino-2-fluorobenzoic acid</strong> (8.1 g, 52.22 mmol), tert-butyl carbazate (8.28 g, 62.66 mmol) and N-methylmorpholine (14.35 ml, 130.54 mmol) in tetrahydrofuran (25 ml) and EtOAc 7(5 ml), 1.67 M T3P (50% in ethyl acetate, 40.65 ml) was dropwise added via a funnel. The mixture was stirred at RT for 16 h. Water was added and the organic layer was washed with saturated KHCO3 and water, dried over MgSO4, filtered and concentrated in vacuo. The crude product was triturated in MTBE, filtered and dried in vacuo to give 9.7 g (69%) of tert-butyl 2-(4-amino-2-fluorobenzoyl)hydrazinecarboxylate as a white solid. Chemical Formula: C12H16FN3O3, calculated [M-H]+: 268.11, found [M-H]+: 268.00. To a solution of tert-butyl 2-(4-amino-2-fluorobenzoyl)hydrazinecarboxylate (9.68 g, 35.94 mmol), 6-maleimidohexanoic acid (6.6 g, 31.25 mmol) and N-methylmorpholine (8.59 ml, 0.08 mol) in tetrahydrofuran (40 ml) and EtOAc (120 ml), 1.67M T3P (50% in ethyl acetate, 24.32 ml) was added and the mixture was stirred at 60 C. for 48 h. Water and EtOAc were added, and the organic layer was washed with saturated KHCO3, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by chromatography column using n-hexane:EtOAc 1:1 to 1:2 as an eluent. The obtained solid was triturated in MTBE to provide 7.5 g (51.9%, purity >98%) of N-Boc-O-fluorolinker as a white solid. Chemical Formula: C22H27FN4O6, calculated [M-H]+: 461.18, found [M-H]+: 461.00. To a suspension of N-Boc-O-fluorolinker (7 g, 15.14 mmol) in dichloromethane (40 ml) at 0 C., TFA (40.54 ml, 0.53 mol) was added. The mixture was stirred at 0 C. for 15 min and at RT for 15 min. The solvent was removed in vacuo at 0 C. The crude product was triturated in MTBE/DCM 7:1. The solid was filtered and dried in vacuo to give 6.5 g (90.1%) of O-Fluor maleimide linker as a white solid. Purity HPLC 96.8% (220 nm). Chemical Formula: C17H18FN4O4, calculated [M-H]+: 361.13, found [M-H]+: 361.10.
tert-butyl 2-(4-amino-2-nitrobenzoyl)hydrazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; for 26h;Cooling with ice;
<strong>[610-36-6]4-amino-2-nitrobenzoic acid</strong> (4.62 g, 25.36 mmol) was stirred with tert-butyl carbazate (5.04 g, 38.14 mmol), HOBt hydrate (5.297 g, 34.6 mmol) and EDC (4.84 g, 25.25 mmol) in 120 mL of a 1:2-mixture dimethylformamide/dichloromethane in an ice-bath for 15 min then at room temperature overnight. TLC (CHCl3/methanol, 9:1) shows completion of the reaction after 26 h. The crude product was purified by column chromatography on silica yielding the pure compound as a yellow foam (6.2 g, 82%). In a 250 mL flask, 4-amino-2-nitro carbazate (2.827 g, 9.54 mmol) was dissolved in 80 mL tetrahydrofuran. To the stirring solution, 6-maleimidocaproic acid chloride (2.41 g, 10.5 mmol), dissolved in 30 mL tetrahydrofuran, was added. Triethylamine (1.455 mL, 10.5 mmol), mixed with 40 mL THF, was added dropwise to the mixture over 1 h using a dropping funnel. The resulting light brown suspension was stirred at room temperature for 15 h. TLC (CHCl3/methanol, 9:1) showed completion of the reaction. The crude product was purified by silica gel flash chromatography (CHCl3/methanol, 9:1), yielding the pure product as a yellow solid (3 g, 64%). The product (3 g, 6.13 mmol) was suspended in 10 mL dichloromethane and cooled in an ice-bath. 10 mL trifluoroacetic acid were added dropwise over 30 min using a dropping funnel to the cooled, stirring mixture. TLC (CHCl3/methanol, 9:1) of the yellow solution after 3 h shows complete cleavage of the BOC group. All solvents were removed by under reduced pressure and the residue dried under high vacuum overnight. The residue was dissolved in a minimum amount of tetrahydrofuran and precipitated in a 1:1-mixture of diisopropyl ether and n-hexane, then stored at 5 C. overnight. The cream-colored precipitate was isolated by centrifugation, washed with diethyl ether and dried under high vacuum to yield 2.5 g (81%) of linker A as a beige solid.
(Z)-tert-butyl 2-(1-(2-chloropyrimidin-5-yl)ethylidene)hydrazinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid; In ethanol; at 20℃; for 1h;
To a solution of <strong>[110100-00-0]1-(2-chloropyrimidin-5-yl)ethanone</strong> (5.00 g, 31.9 mmol), tert-butyl hydrazinecarboxylate (4.22 g, 31.9 mmol) in EtOR (2 mE) was added AcOR (0.64 mE, 11.18 mmol) at room temperature. The reaction solution was stirred for 1 h. The reaction was concentrated under vacuum to afford (Z)-tert-butyl 2-(i-(2- chioropyrimidin-5-yl)ethylidene)-hydrazinecarboxylate.The crude product was used for next step directly. (ES, mlz):271.1 [M+H].
tertbutyl 2-(5-methoxypicolinoyl)hydrazinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 16h;
To a solution of <strong>[29082-92-6]5-methoxypicolinic acid</strong> (300 mg,2.0 mmol) in DCM (10 mL) was added DIPEA (516 mg, 4.0 mmol), B0cNHNH2 (397 mg, 3.0 mmol) and HATU (912 mg, 2.4 mmol). The resulting solution was stirred for 16 h at room temperature. After concentration, the residue was purified by column chromatography on silica gel eluted with PE/EA (1/1) to afford desired product tertbutyl 2-(5-methoxypicolinoyl)hydrazinecarboxylate (500 mg, 93%). LC-MS [M+Hj268
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 120h;
To a stirred solution of <strong>[60629-92-7]1-cyclopropylcyclopropanecarboxylic acid</strong> (9.63 g, 76.3 mmol), and HATU (32.3 g, 83.2 mmol) in DMF (300 mL) is added tert-butyl carbazate (5.00 g, 37.8 mmol) followed by DIPEA (14.5 mL, 83.1 mmol), and the reaction is stirred at room temperature for 5 d. The reaction mixture is diluted with ethyl acetate, washed with 1.0 N hydrochloric acid, saturated NaHC03, and water. The organics are then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. 1,4-Dioxane (50 mL) is added to the residue, hydrochloric acid (4 mol/L) in 1,4-dioxane (100 mL, 400 mmol) is added over 20 min and the reaction is stirred at room temperature for 1 h. The solution is filtered, the filter cake is washed with MTBE, and dried under reduced pressure to give the title compound, (8.01 g, 58.7%). MS (m/z): 141 (M+H)
tert-butyl 2-(2,5-dichloro-3-fluorophenyl)hydrazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19.5%
With palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 110℃; for 1h;Inert atmosphere; Microwave irradiation;
A mixture of <strong>[202865-57-4]1-bromo-2,5-dichloro-3-fluorobenzene</strong> (0.50 g, 2.050 mmol), tert-butyl (0564) hydrazinecarboxylate (0.325 g, 2.460 mmol), palladium(II) acetate (9.21 mg, 0.041 mmol), xantphos (0.024 g, 0.041 mmol) and sodium tert-butoxide (0.296 g, 3.08 mmol) in toluene (4 mL) was degassed and then heated under microwave irridiation at 110 C for 1 h. The reaction mixture was loaded onto a silica gel flash column via a solid cartridge, eluting with 0-30% EtOAc in hexane to afford tert-butyl 2-(2,5-dichloro-3- fluorophenyl)hydrazine-1-carboxylate (118 mg, 0.400 mmol, 19.50 % yield) as a tan solid. MS (ESI) m/z: 238.8 [M-C4H9+H]+; 1H NMR (400 MHz, chloroform-d) delta 6.74-6.78 (m, 1H), 6.70 (dd, J=2.31, 8.47 Hz, 1H), 6.42 (br s, 1H), 6.30 (s, 1H), 1.48 (br s, 9H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In toluene; at 105℃; for 2h;Inert atmosphere;
To a stirred solution of 5.0 g (24 mmol) of <strong>[884494-81-9]3-bromo-5-fluoro-2-methoxypyridine</strong> in 35 mL of toluene were added 3.2 g (24 mmol) of (tert-butoxy)carbohydrazide, 1 .0 g (1 .4 mmol) of Pd(dppf)CI2and 4.0 g (12 mmol) of Cs2C03. The mixture was stirred at 105 C for 2 h under nitrogen atmosphere and cooled to rt. The mixture was concentrated to afford a residue, which was purified by silica gel column chromatography eluting with 0 to 10 % gradient of ethyl acetate in petroleum ether to afford compound 2-1 . LC-MS: m/e = 258 [M+H]+.
tert-butyl 2-[trans-4(trifluoromethyl)cyclohexyl]carbonyl}hydrazine carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 36h;
2.13 g (10.9 mmol) of fra/?s-4-(trifluoromethyi)cyclohexanecarboxyiic acid (Manchester Organics Ltd) was dissolved in 50 mL of DMF. 1.44 g (10.9 mmol) of tert- butyhydrazine carboxylate, 4.75 mL (27.3 mmol) of DIPEA, 2.00 g (13.10 mmol) of HOBt and 2.51 g (13.1 mmol) of EDC was added to the solution. The reaction mixture was stirred at room temperature for 36 hours, and then concentrated. 40 mL of saturated NaHC03 solution was added to the residue and after a short stirring the precipitate was filtered, washed with water and dried in a vacuum oven over phosphorus pentoxide. Thus, 3.35 g (99%) of the title product was obtained as white powder. GC-MS (El) m/z 310.1.
methyl 6-[1-(tert-butoxycarbonyl)hydrazino]pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In toluene; at 100℃;Inert atmosphere;
Methyl 6-[1-(tert-butoxycarbonyl)hydrazino]pyridine-2-carboxylate Methyl 6-chloropyridine-2-carboxylate (32.5 g, 189 mmol), tert-butyl hydrazinecarboxylate (25.0 g, 189 mmol) and caesium carbonate (61.6 g, 189 mmol) in toluene (325 ml) were degassed with argon, before [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.9 g, 10 mmol) was added. The reaction mixture was stirred at 100 C. overnight. The reaction mixture was diluted with dichloromethane and filtered through kieselguhr. The filtrate was concentrated under reduced pressure and the residue was purified via column chromatography (silica gel, eluent: methanol/dichloromethane 4/96). The product-containing fractions were concentrated under reduced pressure and stirred with methyl tert-butyl ether. 28.8 g (57% of theory) of the title compound were obtained. LC-MS (Method 5): Rt=3.45 min; MS (ESIpos): m/z=268 [M+H]+
With sodium cyanoborohydride; acetic acid; at 20℃; for 8h;
The solution of tert-butyl 3,3-difluoro-4-oxo-piperidine-l-carboxylate 32-1 (200 mg, 850.24 umol) and tert-butyl N-aminocarbamate 32-2 (449.48 mg, 3.40 mmol, 165.29 uL) in acetic acid (3 mL) was stirred at room temperature for 10 minutes followed by the addition of sodium cyanoboranuide (349.64 mg, 850 24 umol). The reaction was stirred for 8 hours and then was diluted with DCM (20 mL) and quenched with saturated sodium bicarbonate solution. The organic portion was separated and washed with water and brine. After separation, the organic phase ws dried over sodium sulfate and concentrated to obtain crude tert-butyl 4-(2-tert- butoxyearbonylhydrazino)~3,3-difluoro~piperidine-l-carboxylate 32-3 (250 mg, 71 1.46 umol, 83.68% yield) used as crude for the next step.
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