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Chemical Structure| 75051-55-7

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Product Details of [ 75051-55-7 ]

CAS No. :75051-55-7
Formula : C7H16N2O3
M.W : 176.21
SMILES Code : O=C(OC(C)(C)C)NCCON
MDL No. :MFCD11934722
InChI Key :JRLJOAREDJOYLW-UHFFFAOYSA-N
Pubchem ID :15610443

Safety of [ 75051-55-7 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of [ 75051-55-7 ]

* 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.

  • Downstream synthetic route of [ 75051-55-7 ]

[ 75051-55-7 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 75051-55-7 ]
  • [ 871942-52-8 ]
  • [ 1007552-74-0 ]
YieldReaction ConditionsOperation in experiment
65% In ethanol; at 70℃; for 1.5h; A) Preparation of Compound 1 A mixture of 4-(3-bromophenyl)-4-[4-(trifluoromethoxy)phenyl]-1,3-thiazolidine-2,5-dithione (1.32 g, 2.84 mmol) and Boc-protected 2-(aminooxy)ethanamine (1.49 g, 8.53 mmol) in ethanol was stirred at 70 C. for 1.5 h, cooled to room temperature and concentrated under reduced pressure. The resultant residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification of this residue by flash chromatography ( silica, 1:4 ethyl acetate/hexanes) afforded compound 1 as a white solid, 1.12 g (65% yield), 1H NMR (500 MHz, CDCl3) δ 7.72 (bs, 1H), 7.56 (dt, J=4.1, 1.6 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.30 (m, 3H), 4.68 (bs, 1H), 4.21 (t, J=5.1 Hz, 2H), 3.37 (bs, 2H), 1.43 (s, 9H); ESI MS m/z 607 [C23H23BrF3N3O4S2+H]+.
  • 2
  • [ 75051-55-7 ]
  • 3-furyl(1H-pyrrolo[2, 3-c]pyridin-2-yl)methanone [ No CAS ]
  • tert-butyl 2-[[[(3-furyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% With hydrogenchloride; In diethyl ether; ethanol; for 12h;pH ~ 4;Heating / reflux; 3-Furyl(lH-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 137) (63 mg, 0.30 mmol) and tert-butyl [2- (aminooxy)ethyl]carbamate (55 mg, 0.31 mmol) were combined in ethanol (5 mL). The pH of the mixture was adjusted to ca. 4 using 1 M ethereal hydrogen chloride and the reaction mixture was refluxed for 12 h. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, and concentrated to a solid. Purification by Biotage chromatography (silica gel, 2 to 18% methanol in dichloromethane) produced tert-butyl 2-[[[(3-furyl) (lH- pyrrolo[3,3- c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate (50 mg, 45%) as a yellow solid.
  • 3
  • [ 75051-55-7 ]
  • (4-methylphenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone [ No CAS ]
  • tert-butyl 2-[[[(4-methylphenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate [ No CAS ]
  • tert-butyl 2-[[[(4-methylphenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In diethyl ether; ethanol;pH ~ 4; (4-Methylphenyl) (1H-pyrrolo [2, 3-c] pyridin-2-yl)me thanone (Example 100) (130 mg, 0.55 mmol) and tert-butyl' [2- (aminooxy)ethyl]carbamate (99 mg, 0.56 mmol) were combined in ethanol (8 mL). The pH of the mixture was adjusted to ca. 4 using 1 M ethereal hydrogen chloride and the reaction mixture was refluxed for 14 h. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed with. saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, and concentrated to a solid. Purification by column chromatography (silica gel, 75 to 100% ethyl acetate in hexanes) produced tert-butyl 2-[[[(4-methylphenyl)(1H- pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate (geometry of the oxime double bond undefined). Isomer A (22 mg, 10%) as a white solid: ¹H NMR (500 MHz CD30D) 8 1.41 (9H, s), 3.11 (3H, s), 3.51-3.53 (2H, m), 4.32-4 .34 (2H, m), 6.61 (1H, s), 7.20-7.22 (2H, m), 7.45-7.58 (3H, m), 8.08 (lH, d, J = 5.6 Hz), 8 . 93 (1H, br s). Isomer B (24 mg, 11%) as a clear oil : ¹H NMR (300 MHz CD30D) 8 1.40 (9H, s), 2.42 (3H, s), 3.40-3.43 (2H, m), 4.21-4.2 4 (2H, m) , 6.32 (1H, s), 7.28-7.52 (5H, m) , 8.03 (lH, d, J = 5.6 Hz), -(at):(at)h//(at)(at)r(at)4T?(at) " "It "" ""'I ...1' "it ... (at)I:I' 7 :.1 (at) ( T H'(at) I I tis Ir' .It'- III" III " "1(at)1 t Im;l(at) m (at)
  • 4
  • [ 75051-55-7 ]
  • (3,4-dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone [ No CAS ]
  • tert-butyl 2-[[[(3,4-dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With hydrogenchloride; In diethyl ether; ethanol; for 14h;pH ~ 4;Heating / reflux; 3,4-Dichlorophenyl) (1H-pyrrolo[2,3-c] pyridin-2- yl) methanone (Example 127) (92 mg, 0.32 mmol) and tert-butyl [2-(aminooxy)ethyl]carbamate (58 mg, 0.33 mmol) were combined in. ethanol (5 mL). The pH was adjusted to ca. 4 using 1 M ethereal hydrogen chloride and the reaction mixture was refluxed for 14 h. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and then brine, dried over sodium sulfate, and concentrated to a solid. Purification by Biotage chromatography (silica gel, 97: 3 CH2Cl2: CH3OH) produced tert- butyl 2-[[[(3,4-dichlorophenyl) (lH-pyrrolo [2, 3-c] pyridin-2- yl_ ) methylene ] amino ] oxy] ethylcarbamate (74 mg, 51%) as a yellow foam: ¹H NMR (300 MHz CD30D) No. 1.39 (9H, s), 3.50-3.54 (2H, m), 4.26-4.39 (2H, m), 6.35 (0.35H, s), 6.62 (0.65H, s), 7.38-7.77 (4H, m), 8.04-8.11 (lH, m), 8.72 (0.35H, s), 8.93 (0.65H, s); ESI MS m/z 449 [C21H22C12N403 + H]+.
  • 5
  • [ 87276-51-5 ]
  • [ 60-34-4 ]
  • [ 75051-55-7 ]
YieldReaction ConditionsOperation in experiment
100% In dichloromethane; at 20℃; for 72h; Step B: [2-(1,3-dioxo-1,3-dihydroisoindol-2-yloxy)-ethyl]-carbamic acid tert-butyl ester (0.842 g, 2.749 mmol) was dissolved in 20 ml of CH2Cl2 and methylhydrazine (150 μL, 2.776 mmol) was added at room temperature. As soon as methylhydrazine was added, a white precipitate was formed. The reaction was stirred at room temperature for 72 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide 0.496 g of a viscous oil (102% yield). The crude material was used without further purification
  • 6
  • [ 75051-55-7 ]
  • [ 753922-80-4 ]
  • {2-[(2,4-difluorophenyl)-(1-isobutyl-1H-indazol-5-yl)-methyleneaminooxy]-ethyl}-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
63.9% With hydrogenchloride; methanol; In pyridine; at 20℃; for 64h; Example 29 Preparation of {2-[(2,4-difluorophenyl)-(1-isobutyl-1H-indazol-5-yl)-methyleneaminooxy]-ethyl}-carbamic acid tert-butyl ester (7f-5) In this example, the synthesis of compound 7f-5 having the general Formula XII as shown in , where R1 is isobutyl, R2 is CH2CH2NHBoc, and Ar is 2,4-difluorophenyl is described.Compound 5f, where R1 is isobutyl and Ar is 2,4-difluorophenyl was prepared according to steps A-D of Example 27.A mixture of compound 5f (50 mg, 0.159 mmol), (2-aminooxyethyl)-carbamic acid tert-butyl ester prepared as described in Example 30 (112 mg, 0.636 mmol), pyridine (1.5 ML), and a drop of 6N HCl-MeOH (1:1 mixture of concentrated HCl and MeOH by volume) was stirred at room temperature for 64 hours.Excess pyridine was removed under reduced pressure and the residue was purified by chromatography with 1:2 ether/hexanes yielding 63.9% yield of compound 7f-5.
  • 7
  • [ 75051-55-7 ]
  • [ 753923-18-1 ]
  • {2-[(4-fluorophenyl)-(1-isobutyl-1H-indazol-5-yl)-methyleneaminooxy]-ethyl}-carbamic acid tert-butyl ester [ No CAS ]
  • {2-[(4-fluorophenyl)-(1-isobutyl-1H-indazol-5-yl)-methyleneaminooxy]-ethyl}-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; methanol; In pyridine; at 20℃; for 39h; Step E: A mixture of compound 5f-2, (2-aminooxyethyl)-carbamic acid tert-butyl ester prepared as described in Example 30 (120 mg, 0.675 mmol), pyridine (1.5 mL), and a drop of 6N HCl/MeOH (1:1 mixture of concentrated HCl and MeOH by volume) was stirred at room temperature for 39 h. Excess pyridine was removed under reduced pressure. The residue was purified by chromatography with 1:1 ether/hexanes to provide 65.6 mg (85.5% yield) of compound 7f-6 as pale yellow oil. 1H-NMR showed that compound 7f-6 was a 1:1.8 ratio of isomers.
  • 8
  • [ 75051-55-7 ]
  • [ 149876-78-8 ]
  • 7-t-Boc-amino-4-aza-3,3-dimethyl-1-(2-nitro-1H-imidazol-1-yl)-5-oxaheptan-2-one oxime [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In acetonitrile; Preparation of 7-t-Boc-amino-4-aza-3,3-dimethyl-1-(2-nitro-1H-imidazol-1-yl)-5-oxaheptan-2-one oxime 3-Chloro-3-methyl-2-nitroso-1-(2-nitro-1H-imidazol-1-yl)butane (2.46 g, 0.01 mol, Example 4(D)) was added to a solution of 2-(aminoxy)-1-t-Boc-aminoethane (1.76 g, 0.01 mol, Example 7(C)) and diisopropylethylamine (1.32 g, 0.0102 mol) in acetonitrile (30 mL), and the mixture was stirred at room temperature for 24 hrs. Acetonitrile was removed on a rotary evaporator and the thick viscous oil thus obtained was purified by column chromatography (hexane - ethyl acetate 7:3). UV visible fractions were collected and evaporated to give a thick viscous oil which solidified on standing to yield the title product. Yield 2.68 g (70%.). mp. 97-98 C. 1 H NMR (CDCl3) δ 1.24 [s, 6H, C(CH3)2 ], 1.45 [s, 9H, C(CH3)3 ], 1.91 (s, 3H, CH3), 3.22 (m, 2H, OCH2 CH2 NHtBoc), 3.51 (m, 2H, OCH2 CH2 NHtBoc), 4.70 (bs, 1H, NHtBoc), 5.34 (s, 2H, CH2 <N), 7.10 and 7.31 (s, 2H, imiH), 8.66 (bs, 1H, NOH).
  • 9
  • [ 75051-55-7 ]
  • [ 149876-83-5 ]
  • 8-t-Boc-amino-5-aza-4,4-dimethyl-1-(2-nitro-1H-imidazol-1-yl)-6-oxaoctan-3-one oxime [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In acetonitrile; B. Preparation of 8-t-Boc-amino-5-aza-4,4-dimethyl-1-(2-nitro-1H-imidazol-1-yl)-6-oxaoctan-3-one oxime To a suspension of 4-chloro-4-methyl-1-(2-nitro-1H-imidazol-1-yl)-3-nitrosopentane (2.6 g, 0.01 mole) in acetonitrile (50 mL) was added 2-(aminoxy)-1-t-Boc-aminoethane (1.76 g, 0.01 mole, Example 7(C)). To this mixture was added diisopropylethylamine (1.4 g, 0.011 mol), and the mixture was stirred for 48 hrs. The clear solution obtained was concentrated and the resulting greenish thick oil was purified by column chromatography (CH2 Cl2:CH3 OH, 95:5). U.V. visible fractions were collected, and the solvent was evaporated to give a yellow solid. Yield: 3.12 g (78%). It was recrystallized from hexane-ethyl acetate to give the title product. mp: 117-118 C. 1 H NMR (CDCl3) δ 1.22 (s, 9H, Boc-CH3), 1.41 and 1.45 [s, 6H, C(CH3)2 ], 2.92 (m, 2H, OCH2 CH2 NH-Boc)), 3.33 (m, 2H, CH2 CH2 C=NOH), 3.73 (m, 2H, OCH2 CH2 NH-Boc), 4.73 (t, 2H, CH2 CH2 C=NOH), 7.14 and 7.27 (s, 2H, imil-H), 8.78 (s, 1H, NH-Boc).
  • 10
  • [ 75051-55-7 ]
  • [ 161490-84-2 ]
  • [ 161490-85-3 ]
YieldReaction ConditionsOperation in experiment
0.62 g (85%) With N-ethyl-N,N-diisopropylamine; In acetonitrile; C. Preparation of N-[3-[[(t-Boc-amino)ethoxy]amino]-2-(hydroxyimino)-3-methylbutyl]-5-nitro-2-furancarboxamide 2-(Aminoxy)-1-t-Boc-aminoethane (0.4 g, 2.3 mmol, Example 7(C)) and N-(3-chloro-3-methyl-2-nitrosobutyl)-5-nitro-2-furancarboxamide (0.5 g, 1.7 mmol) were suspended in acetonitrile (10 mL). To the solution was added N,N-diisopropylethylamine and the reaction mixture was stirred under N2 at room temperature overnight. A clear solution was obtained. Solvent was evaporated and the residue was loaded on silica gel column and eluted with 50% ethyl acetate-hexane. Yield: 0.62 g (85%). MS m/z 430 (M+H)+, 374 (M->=)+. 1 H NMR CDCl3) δ1.26 [s, 6H, (CH3)2 C=], 1.38 (s, 9H, boc--CH3), 3.35 (m, 2H, CH2 NH), 3.68 (t, 2H, NHOCH2), 4.28 (d, 2H, CH2 NH), 5.15 (tb, 1H, NHBoc), 6.24 (s, 1H, ONH), 7.35 (s, 2H, furanyl-H), 7.72 (tb, 1H, NHCO), 8.54 (s, 1H, C=NOH).
  • 11
  • [ 87276-51-5 ]
  • [ 75051-55-7 ]
YieldReaction ConditionsOperation in experiment
99% With hydrazine hydrate; In ethanol; at 20℃; for 2h; To a solution of N-(2-tert-Boc-aminoethoxy)phthalimide (27a) (3.8 g, 12.4 mmol) in EtOH (38 mL) at room temperature was added hydrazine monohydrate (0.63 mL, 13.0 mmol). The reaction was stirred at room temperature for 2 h. The mixture was filtered and washed with ethyl acetate. The filtrate was concentrated and a white solid was formed. The white solid was removed by filtration and washed with ethyl acetate. This process was repeated three additional times. The combined filtrate was then concentrated to give the product (27b) as a yellow paste (2.16 g, yield 99%). 1H NMR (300 MHz, CDCl3): δ 5.46 (br s, 2H), 4.91 (br s, 1H), 3.70 (m, 2H), 3.35 (m, 2H), 1.44 (s, 9H).
80% With hydrazine; In ethanol; at 20℃; for 2h; General procedure: To a solution of 4a (or 4b-e, 5.8 mmol ) in EtOH (10 mL), was added hydrazine (187 uL, 5.97 mmol)in drop. The reaction mixture was stirred at rt. until the reaction was completed as judged by TLC. Themixture was filtered and the filtrate was concentrated and purified by column chromatography to givethe product 5a-e. 5a was obtained as a white solid (817 mg, 80%).
78% With hydrazine hydrate; In ethanol; The obtained compound 3 (1.78 g, 5.8 mmol) was dissolved in 10 mL of ethanol,Then hydrazine hydrate (187L, 5.97mmoL) was slowly added dropwise to the reaction system,White precipitate appeared in the system,The reaction was monitored by TLC until the substrate was consumed,filter,The filtrate was concentrated,Pass through the column to afford pure Compound 4 (800 mg, 78%).
55% With hydrazine hydrate; at 20℃; Hydrazine monohydrate (0.146 mL, 4.71 mmol, 1.03 eq.) at room temperatureAdd to a solution of compound MC-116-1 (1.4 g, 4.57 mol, 1.0 eq.) in ethanol (10 mL).The reaction was then allowed to react overnight at room temperature. Point plate detection reaction, after the reaction is over,The reaction solution was filtered, and the residue obtained by concentration of filtrate was chromatographed on silica gel.(ethyl acetate / petroleum ether = 1/2) purified to give a colorless oily compoundMC-116-2 (448 mg, 55%).
255 mg (71%) Step C: Preparation of (2-aminooxy-ethyl)-carbamic acid tert-butyl ester. The synthesis of the title compound was carried out according to Step D of Example 41 (i) using [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-ethyl]-carbamic acid tert-butyl ester as the starting material to provide 255 mg (71%) of the desired compound as a yellow liquid. 1H NMR (400 MHz, CDCl3) δ 5.50 (br s, 2H), 5.02 (br s, 1H), 3.71 (t, 2H), 3.36 (q, 2H), 1.45 (s, 9H).
With methylhydrazine; In dichloromethane; at 20℃; for 16h; INTERMEDIATE 37[2-(Aminooxy)ethyl"|carbamic acid tert-butyl ester; Intermediate 36 (1 g, 3.3 mmol) in DCM (20 mL) was treated with methyl- hydrazine (15 8 mg, 3.4 mmol) and the reaction mixture stirred at r.t. for 16 h. The solvent was removed, and the residue was suspended in diethyl ether, filtered and concentrated, to give the title compound. δH (DMSOd6) 6.74-6.65 (IH, br m), 5.99-5.88 (2H, br s), 3.47 (2H, t, J 5.8 Hz), 3.09 (2H, q, J5.8 Hz), 1.38 (9H, s). LCMS (ES") RT 1.93 minutes, 175 (M-H)'.
With methylamine; In methanol; dichloromethane; for 2h; Reference Example 9 tert-Butyl 2-(aminooxy)ethylcarbamate [0251] To a solution of tert-butyl (2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate (1.83 g, 6.00 mmol) described in Reference Example 7 in methylene chloride (11 mL) was gradually added 9.8M methylamine methanol solution (1.83 mL), followed by stirring for 2 hours. The reaction solution was filtered and the filtrate was distilled off under reduced pressure, followed by extracting with 0.5M hydrochloric acid (24 mL). To the resulting aqueous layer were added methylene chloride and 1M sodium hydroxide (18 mL), thereby the target was extracted with ethylene chloride. The resulting organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. 1.038 g of the title compound was afforded as the crude product (yield 98%). 1H NMR (400 MHz, CDCl3) δ 1.45 (m, 9H), 3.35-3.36 (m, 2H), 3.70-3.72 (m, 2H), 4.91 (br s, 1H), 5.47 (br s, 2H); MS m/z 177 [M+H]+.
28 g With hydrazine hydrate; In dichloromethane; at 0℃; for 2.75h; To a stirred solution of N-Boc-2-(2-aminoethoxy)isoindoline-1 ,3-dione (IX, 97 g, 0.3167 mol) in dichloromethane (970 ml) was added hydrazine hydrate (31.7 g, 0.6334 mol) , at 0C, drop wise, over a period of 45 minutes and the stifling continued further. After 2 hours, the reaction mass was filtered under suction. Filtrate was washed with water (485 ml), and the organic layer was diluted with an aq. solution of 10% potassium hydrogen sulfate (485 ml) and stined for 15 minutes. The aqueous layer was separated, neutralized with solid sodium hydrogen carbonate and extracted with dichloromethane (2 x 485 ml). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain colorless oil, this was used as such for further reaction immediately (28g, overall yield of step II and step III was 60%)Analysis:Mass: 177.2 (M+1) for Molecular Weight of 176.2 and Molecular Formula of C7H16N203.
With hydrazine; In ethanol; C. Preparation of 2-(Aminoxy)-1-t-Boc-aminoethane Hydrazine (98%, 2.1 g, 0.065 mol) was added to a solution of crude N-(2-t-Boc-aminoethoxy)phthalimide (20 g, 0.065 mol) in ethanol (50 mL) and the mixture was refluxed for 2 hrs. The solid which formed was removed by filtration and the filtrate was evaporated on a rotary evaporator. The residue thus obtained was triturated with ethyl acetate and the resultant precipitate was removed by filtration. The ethyl acetate solution was evaporated on a rotary evaporator to give the title product amine as an oil. Yield: 10 g. (83%). 1 H NMR (CDCl3) δ 1.48 [s, 9H, C(CH3)3 ], 3.42 (m, 2H, OCH2 CH2 NHtBoc), 4.21 (m, 2H, OCH2 CH2 NHtBoc), 5.68 (bs, 1H, NH), 7.7-7.82 (m, 4H, ArH).
With hydrazine hydrate; In ethanol; at 65℃; for 3h; Tert-butyl (2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl)carbamate (1.53 g, 5.000 mmol) prepared in step 1, hydrazine hydrate (2.5 g, 50.00 mmol) was dissolved in ethanol (30 ml) and then heated to 65C. Reaction 3h. After the reaction, the filtrate was concentrated, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.

  • 13
  • [ 75051-55-7 ]
  • [ 753923-18-1 ]
  • {2-[(4-fluorophenyl)-(1-isobutyl-1H-indazol-5-yl)-methyleneaminooxy]-ethyl}-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
85.5% With hydrogenchloride; In methanol; Step E: A mixture of compound 5f-2, (2-aminooxyethyl)-carbamic acid tert-butyl ester prepared as described in Example 30 (120 mg, 0.675 mmol), pyridine (1.5 mL), and a drop of 6N HCl/MeOH (1:1 mixture of concentrated HCl and MeOH by volume) was stirred at room temperature for 39 hours. Excess pyridine was removed under reduced pressure. The residue was purified by chromatography with 1:1 ether/hexanes to provide 65.6 mg (85.5% yield) of compound 7f-6 as pale yellow oil. 1H-NMR showed that compound 7f-6 was a 1:1.8 ratio of isomers.
  • 14
  • [ 75051-55-7 ]
  • [ 20055-01-0 ]
  • [ 530-62-1 ]
  • [ 689294-11-9 ]
YieldReaction ConditionsOperation in experiment
To a suspension of 1, 1'-CARBONYLDIIMIDAZOLE (973 mg) in methylene chloride (10 ml) was added 0- [2- (tert- butoxycarbonylamino) ethyl] hydroxylamine (1.11 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added N-ethyldiisopropylamine (1.28 g) and 4,5-diamino- 1-methylpyrazole sulfuric acid salt (1.05 g), and the mixture was stirred under reflux for 4 hours. The reaction mixture was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 10% methanol/chloroform to give 5-amino-4- (3- {2- [ (TERT-BUTOXYCARBONYL) amino] ethoxy} UREIDO)-1- methylpyrazole (255 mg) as a solid. H-NMR (DMSO-d6) 8 1.38 (9H, s), 3.19-3. 20 (2H, m), 3.51 (3H, s), 3.72 (2H, t, J=6Hz), 4.86 (2H, br), 6.95 (1H, br), 7.06 (1H, s), 8.02 (1H, brs), 9.15 (1H, brs)
  • 16
  • [ 75051-55-7 ]
  • [ 1452467-93-4 ]
  • 17
  • [ 75051-55-7 ]
  • [ 1174020-25-7 ]
  • [ 1452466-19-1 ]
YieldReaction ConditionsOperation in experiment
89% With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; Step 1. tert-Butyl {2-[([(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate (42) To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.150 g, 0.543 mmol, US 2005/20572 A1) in DCM (4.0 mL) was added tert-butyl[2-(aminooxy)ethyl]carbamate 41 (0.143 g, 0.814 mmol, US 2005/54701 A1), 1-hydroxybenzotriazole (0.110 g, 0.814 mmol), 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.156 g, 0.814 mmol) and DMAP (0.100 g, 0.814 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 42 (0.21 g, 89%) as a white foam. 1H NMR (400 MHz, CDCl3): δ 1.44 (9H, s), 1.65 (1H, m), 1.93 (2H, m), 2.31 (1H, m), 2.76 (1H, d, J=12 Hz), 3.04 (1H, d, J=11.2 Hz), 3.26 (2H, m), 3.38 (1H, m), 3.91 (2H, m), 3.98 (1H, d, J=12 Hz), 4.89 (1H, d, J=11.2 Hz), 5.07 (1H, d, J=11.2 Hz), 5.41 (1H, br s), 7.41 (5H, m), 9.30 (1H, br s). MS (ES+): m/z [M+H]+ calcd for C21H31N4O6: 435.22. Found: 435.02.
89% With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.1.50 g, 0.543 mmol, US 2005/20572 A1 ) in DCM (4.0 mL) was added tert-butyl [2-(aminooxy)ethyl]carbamate 41 (0.143 g, 0.814 mmol, US 2005/54701 A1 ), 1-hydroxybenzotriazole (0.1 10 g, 0.814 mmol), 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.156 g, 0.814 mmol) and DMAP (0.100 g, 0.814 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 42 (0.21 g, 89 %) as a white foam. 1H NMR (400 MHz, CDCl3): δ 1.44 (9H, s), 1.65 (1 H, m), 1.93 (2H, m), 2.31 (1 H, m), 2.76 (1 H, d, J = 12 Hz), 3.04 (1 H, d, J = 11.2 Hz), 3.26 (2H, m), 3.38 (1 H, m), 3.91 (2H, m), 3.98 (1 H, d, J = 12 Hz), 4.89 (1 H, d, J = 11.2 Hz), 5.07 (1 H, d, J = 1 1.2 Hz), 5.41 (1 H, br s), 7.41 (5H, m), 9.30 (1 H, br s). MS (ES+): m/z [M+H]+ calcd for C21H31N406: 435.22. Found: 435.02.
84% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; Step 1 tert-Butyl {2-[([(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate [0439] methylene chloride (35 mL) were added triethylamine (2.71 mL), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g), 1-hydroxybenzotriazole · monohydrate (1.15 g), and tert-butyl 2-(aminooxy)ethylcarbamate (1.12 g) described in Reference Example 9, followed by agitating at room temperature overnight. To the residue resulting from concentrating the reaction solution under reduced pressure was added water, followed by extracting with ethyl acetate. The resulting organic layer was washed with 0.1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtrated, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 8/2-0/10) to afford 1.77 g of the title compound (yield 84%). [α]D20 -0.08 (c 0.29, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 1.56-1.70 (m, 1H), 1.90-2.09 (m, 2H), 2.25-2.38 (m, 1H), 2.76 (d, J = 11.6 Hz, 1H), 3.03 (br d, J = 11.6 Hz, 1H), 3.24-3.47 (m, 3H), 3.84-4.01 (m, 3H), 4.90 (d, J = 11.6 Hz, 1H), 5.05 (d, J = 11.6 Hz, 1H), 5.44 (br s, 1H), 7.34-7.48 (m, 5H), 9.37 (br s, 1H); MS m/z 435 [M+H]+; enantiomeric excess 99.9% ee or more (CHIRALPAK AD-H, 4.6 x 150mm, hexane/ethanol = 2/1, UV 210 nm, flow rate 1 mL/min., retention time 4.95 min. (2R,5S), 6.70 min. (2S,5R).
79% With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (20a) (3.19 g, 11.6 mmol), <strong>[75051-55-7]tert-butyl (2-(aminooxy)ethyl)carbamate</strong> (27b) (2.06 g, 11.7 mmol) in DCM (20 mL) was added HATU (4.39 g, 11.6 mmol) and DIPEA (2.02 mL, 11.6 mmol). The reaction was stirred at room temperature overnight. The mixture was washed with saturated NH4Cl solution, water and brine. The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/ hexane (1:1 to 3:1) as an eluent to give the product (27c) as a white paste (4.0 g, yield 79%). 1H NMR (300 MHz, CDCl3): δ 9.46 (br, s, 1H), 7.26-7.43 (m, 5H), 5.46 (t, 1H), 4.80-5.10 (dd, 2H, J=11.1 Hz), 2.75-3.97 (m, 8H), 1.61-2.33 (m, 4H), 1.43 (t, 9H). MS (ESI) C21H30N4O6=435 (M+1)+.
76% 10335] A solution of (2S,5R)-6-(benzyloxy)-7-oxo- 1 ,6-di- azabicyclo[3.2. l]octane-2-carboxylic acid (4.80 kg, 17.373 mol) in dehydrated ethyl acetate (62 L) was cooled to -30 C., isobutyl chloroformate (2.52 kg) and triethylamine (1.85 kg) were sequentially added dropwise, followed by stirring at -30 C. for 15 minutes. To the reaction solution was added a solution of tert-butyl 2-(aminooxy)ethylcarbamate in dehydrated ethyl acetate (15 wt %, 23.45 kg) over 30 minutes (washed with 2 L of dehydrated ethyl acetate), and the temperature was elevated to 0 C. over 1 hour. The mixture was washed sequentially with 8% citric acid (65 L), 5% sodium bicarbonate (60 L), and water (60 L), and concentrated to 24 L. To the concentrate was added ethyl acetate (24 L), and the mixture was substitution-concentrated twice to 24 L. To the resulting concentrate was added ethyl acetate (29 L) and hexane (72 L), followed by stirring overnight. To the mixture was added dropwise hexane (82 L), followed by stirring for 2 hours. The precipitated crystals were filtered, washed with hexane, and dried in vacuo to afford 5.51 kg of the title compound (yield 76%). Instrumental data were consistent with those of ReferenceExample 5, Step 1.
76% A solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-carboxylic acid (4.80 kg, 17.373 mol) in dehydrated ethyl acetate (62 L) was cooled to -30 C., to which isobutyl chloroformate (2.52 kg) and then triethylamine (1.85 kg) were added dropwise, and was stirred at -30 C. for 15 minutes. To the reaction mixture was added a solution of tert-butyl 2-(aminooxy)ethylcarbamate in dehydrated ethyl acetate (15 wt %, 23.45 kg) over 30 minutes (the residue washed with 2 L of dehydrated ethyl acetate), and the temperature was raised to 0 C. over 1 hour. The mixture was washed sequentially with an 8% solution of citric acid (65 L), a 5% solution of sodium bicarbonate (60 L), and water (60 L), and concentrated to 24 L. A step of adding ethyl acetate (24 L) to the concentrated mixture, followed by concentration to 24 L for solvent displacement was performed twice, and to the resultant concentrated solution, ethyl acetate (29 L) and hexane (72 L) were added, and stirred overnight. To the mixture, hexane (82 L) was added dropwise and stirred tier 2 hours. The precipitated crystals were separated by filtration, washed with hexane, and vacuum-dried to give 5.51 kg of the title compound (yield 76%). HPLC:COSMOSIL 5C18 MS-II 4.6*150 mm, 33.3 mM phosphate buffer/MeCN=50/50, 1.0 mL/min, UV 210 nm, RT 4.4 min; 1H NMR (400 MHz, CDCl) δ 1.44 (s, 9H), 1.56-1.70 (m, 1H), 1.90-2.09 (m, 2H), 2.25-2.38 (m, 1H), 2.76 (d, J=11.6 Hz, 1H), 3.03 (br.d., J=11.6 Hz, 1H), 3.24-3.47 (m, 3H), 3.84-4.01 (m, 3H), 4.90 (d, J=11.6 Hz, 1H), 5.05 (d, J=11.6 Hz, 1H), 5.44 (br.s., 1H), 7.34-7.48 (m, 5H), 9.37 (br.s., 1H); MS m/z 435 [M+H]+.
74% A solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (4.30 g, 15.56 mmol) in dehydrated ethyl acetate (47 mL) was cooled to -30 C., and isobutyl chloroformate (2.17 g, washed with dehydrated ethyl acetate 1 mL) and triethylamine (1.61 g, washed with 1 mL of dehydrated ethyl acetate) were sequentially added dropwise at -30 C., followed by stirring for 1 hour. To the reaction solution was added a solution of tert-butyl 2-(aminooxy)ethylcarbamate (3.21 g) in dehydrated ethyl acetate (4 mL) (washed with 1 mL of dehydrated ethyl acetate), and the temperature of the mixture was elevated to 0 C. over 1.5 hours, followed by stirring overnight. The mixture was washed sequentially with 8% aqueous citric acid (56 mL), saturated sodium bicarbonate (40 mL), and saturated brine (40 mL), and dried over anhydrous magnesium sulfate. The mixture was then filtered, concentrated to 5 mL, and further substitution-concentrated with ethanol (10 mL) to 6 mL. To the resulting solution was added ethanol (3 mL) and hexane (8 mL), and the mixture was ice-cooled and seeded with crystals, followed by stirring for 15 minutes. To the mixture was added dropwise hexane (75 mL) over 2 hours, followed by stirring overnight. The crystalline material was filtered, washed with hexane, and dried in vacuo to afford 5.49 g of the title compound (net 4.98 g, yield 74%).
73% To a clear solution of sodium (2S,5R)-6-(benzyloxy)-7 -oxo- 1 ,6-diazabicyclo [3.2.1 ]octane-2- carboxylate (II, 42.67 g, 0.143 mol; prepared according to the procedure disclosed in hidian Patent Application No. 6991MUM/2013) in water (426 ml) was added EDC.HC1 (67.1 g, 0.349 mol) at 15Cunder stirring. After 10 minutes, a solution of tert-butyl-[2-(aminooxy) ethyl]carbamate (III, 28.Og, 0.159 mol; prepared as per the literature procedure depicted in Scheme 2) in dimethylformamide (56 ml) was added drop wise at 10C under continuous stirring. The temperature of the reaction mass was allowed to warm to 25C and then HOBt (21.5g, 0.159 mol) was added in small portions over a period of 15 minutes and the resulting mixture was further stirred at room temperature for 16 hours. The reaction was continuously monitored using thin layer chromatography using mixture of acetone and hexane (35:65) as solvent system. After completion of reaction, the resulting mixture was filtered and the residue was washed with water (130 ml). The obtained white residue was suspended in water (130 ml) and the mixture stined at 50C for 3 hours. The resulting suspension was filtered, the residue dried under reduced pressure to obtain 51 g of (2S ,5R)-N-(2-Boc-aminoethoxy)-6-(benzyloxy)-7-oxo- 1,6- diaza-bicyclo [3.2.1 ]octane-2-carboxamide (IV) as off white solid in 73% yield.Analysis:Mass: 433.4 (M-1); for Molecular Weight of 434.5 and Molecular Formula of C21H30N4061H-NMR (400MHz, CDC13): 5 9.32 (br s, 1H), 7.41-7.26(m,5H), 5.41(br s, 1H), 5.06-4.88(dd,2H), 3.98-3.96(d,1H), 3.91-3.90(m,2H), 3.39(m, 1H), 3.31-3.26(m, 2H), 3.04-3.01(d,1H), 2.77-2.74(d,1H), 2.33-2.28(m, 1H), 2.03-1.93(m, 2H), 1.67-1.64(m, 1H), 1.44(s, 9H); Purity as determined by HPLC: 99.4%.
The (2S, 5R) -6- (benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxylic acid (4.30g, 15.56mmol) dehydrated ethyl acetate (47mL) was cooled to -30 , successively added isobutylchloroformate (2.17g, dehydrated and washed with ethyl acetate 1mL), triethylamine (1.61g, dehydrated and washed with ethyl acetate 1mL), in stirred at -30 1 hour. Was added to the reaction mixture2- (aminooxy) ethylcarbamateTert-butyl ester (3.21 g) in dehydrated ethyl acetate (4mL) solution of (ethyl acetate, washed with dehydrated 1mL), spending 1.5 hours warmed to 0 , and further stirred overnight. The mixture was washed with 8% aqueous citric acid (56mL), saturated aqueous sodium bicarbonate solution (40 mL), saturated brine (40 mL) successively, dried over anhydrous magnesium sulfate, filtered, and concentrated to 5mL, further washed with ethanol (10 mL) replacement concentrate to 6mL. Was added ethanol (3mL) in the resulting solution, hexane (8mL), cooled on ice, seeded and stirred for 15 minutes. It takes two hours the mixture was added dropwise hexane (75mL), stirred overnight. Precipitated crystal was filtered out, washed with hexane, and dried in vacuo to give 5.49 g of the title compound (4.98g essence, yield 74%).

  • 20
  • [ 75051-55-7 ]
  • [ 391211-97-5 ]
  • tert-butyl-(2-((3,4-difluoro-2-(2-fluoro-4-iodobenzyl)benzamido)oxy)ethyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 20℃;Inert atmosphere; General procedure: To a stirring mixture comprised of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid(755 mg, 1.92 mmol), 5a (or 5b-e, 2 mmol) and diisopropylethylamine (0.7 mL, 4.23 mmol) in 40 mLof 1:1 (v/v) THF-DCM, was added directly the benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBOP) (1.04 g, 2 mmol). The reaction mixture was stirred at room temperatureunder argon atmosphere overnight. The mixture was concentrated to an oil under reduced pressure.The oil was partitioned between diethyl ether (60 mL) and 10% aqueous hydrochloric acid (45 mL).The organic phase was washed with saturated aqueous sodium bicarbonate (40 mL) and brine (45 mL),and then dried with MgSO4, concentrated in vacuo. The residue was purified through columnchromatography to give the product 6a-e.
  • 21
  • [ 75051-55-7 ]
  • [ 391211-97-5 ]
  • [ 1596369-01-5 ]
  • 22
  • [ 75051-55-7 ]
  • (1R,4S)-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1'-cyclopropane]-4-carboxylic acid [ No CAS ]
  • tert-butyl {2-[([(1R,4S)-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1'-cyclopropan]-4-yl]carbonyl}amino)oxy]ethyl}carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; Step 1 : (ferf-butyl {2-[([(1 R,4S)-7-(benzyloxy)-6-oxo-5,7- diazaspiro[bicyclo[3.2.1 joctane-2,1 '-cyclopropan]-4- yl]carbonyl}amino)oxy]ethyl}carbamate (3): To a mixture of (1 R,4S)-7-(benzyloxy)-6-oxo-5,7-diazaspiro[bicyclo[3.2.1 ]octane-2,1 '- cyclopropane]-4-carboxylic acid 1 (0.201 g, 0.665 mmol) in dichloromethane (15.0 ml_) were added ferf-butyl [2-(aminooxy)ethyl]carbamate 2 (0.176 g, 1 .0 mmol), 1 -hydroxybenzotriazole (0.135 g, 1 .0 mmol), and 1 -ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.192 g, 1.0 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM, washed with water, brine, dried over sodium sulfate and concentrated to provide a residue which was subjected to chromatography (silica gel, DCM: EtOAc: MeOH = 70: 27: 3) to give ferf-butyl {2-[([(1 R,4S)-7-(benzyloxy)-6-oxo-5,7- diazaspiro[bicyclo[3.2.1]octane-2,1'-cyclopropan]-4-yl]carbonyl}amino)oxy]ethyl}carbamate 3 (0.255 g, 83 %) as a white foam.1H NMR (400 MHz, CDCI3): δ 0.09 (1H, m), 0.42-0.62 (3H, m), 1.44 (9H, s), 1.80 (1H, d, J= 15.2 Hz), 2.27-2.32 (1H, m), 2.39 (1H, d, J=4.0 Hz), 2.92 (1H, d, J= 11.6 Hz), 3.07 (1H, m), 3.26-3.40 (2H, m), 3.92 (2H, m), 4.06 (1H, d, J= 7.6 Hz), 4.87 (1H, d, J= 11.2 Hz), 5.02 (1H, d, J= 11.6 Hz), 5.55 (1H, br s), 7.36-7.39 (5H, m), 9.69 (1H, br s). MS (ES) m/z: [M-H]" calcd for C16H26N406: 460.23. Found: 458.9.
  • 23
  • [ 75051-55-7 ]
  • (1R,2S,4R,5S)-8-(benzyloxy)-7-oxo-6,8-diazatricyclo[4.2.1.02,4]nonane-5-carboxylic acid [ No CAS ]
  • tert-butyl {2-[([(1R,2S,4R,5S)-8-(benzyloxy)-7-oxo-6,8-diazatricyclo[4.2.1.02,4]non-5-yl]carbonyl}amino)oxy]ethyl}carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; Step 8: fert-Butyl {2-[([(1S,2S,4/?,5/?)-8-(benzyloxy)-7-oxo-6,8- diazatricyclo[4.2.1.02'4]non-5-yl]carbonyl}amino)oxy]ethyl}carbamate (11): To a solution of (1 S,2S,4R,5R)-8-(benzyloxy)-7-oxo-6,8- diazatricyclo[4.2.1.02,4]nonane-5-carboxylic acid 9 (0.08 g, 0.28 mmol) in dry dichloromethane (15 mL) were added fert-butyl [2-(aminooxy)ethyl]carbamate 10 (0.084 g, 0.48 mmol), 1-hydroxybenzotriazole (0.057 g, 0.42 mmol), 1-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.08 g, 0.42 mmol) and 4- (dimethylamino)pyridine (0.05 g, 0.42 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give fert-butyl {2-[([(1 S^S^R.S^-S-ibenzyloxy)- 7-0X0-6, 8-diazatricyclo[4.2.1.02'4]non-5-yl]carbonyl}amino)oxy]ethyl}carbamate 11 (0.09 g, 72%) as a white solid.1H NMR (400 MHz, CDCI3): δ 0.89 (1H, m), 0.96 (1H, m), 1.36 (1H, m), 1.44 (10H, m), 2.70 (1H, d, J= 10.8 Hz), 3.03 (1H, m), 3.33 (2H, m), 3.64 (1H, m), 3.90 (2H, m), 4.19 (1H, s), 4.84 (1H, d, J= 12.0 Hz), 4.98 (1H, d, J = 11.6 Hz), 5.50 (1H, br s), 7.40 (5H, m), 9.57 (1H, brs).
  • 24
  • [ 75051-55-7 ]
  • [ 391212-00-3 ]
  • C20H21F3IN3O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Reagents and conditions: (a) 1. pentafluorophenyl trifluoroacetate, pyridine, DMF, rt; 2. NH2OCH2CH2NH(tBoc), DIPEA, DMF; (b) 1.0 M HCI, Et20, rt; (c) BrCOCH2Br, Et3N, DCM, 0 C; (d) compound MV3-46A, Nal, K2C03, CH3CN, reflux.
  • 25
  • [ 75051-55-7 ]
  • [ 1452466-19-1 ]
  • 27
  • [ 75051-55-7 ]
  • (2S,5R)-N-(2-tert-butoxycarbonylaminoethoxy)-5-(benzyloxyamino)piperidine-2-carboxamide [ No CAS ]
  • 28
  • [ 39684-80-5 ]
  • [ 75051-55-7 ]
  • 29
  • [ 75051-55-7 ]
  • (2S,5R)-5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylic acid [ No CAS ]
  • (2S,5R)-N-(2-tert-butoxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3h;Cooling with ice; Example 102 (2S,5R)-N-(2-tert-Butoxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxamide (IV-b2-Boc-059) [0621] (2S,5R)-5-(Benzyloxyamino)-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylic acid (0.879 g, 2.54 mmol) described in Example 98 and tert-butyl 2-(aminooxy)ethylcarbamate (0.559 g) of Reference Example 9 were dissolved in N,N-dimethylformamide (11 mL), and to which was added 1-hydroxybenzotriazole· monohydrate (0.489 g), followed by ice-cooling. To this was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.613 g), and the temperature was elevated to room temperature, followed by reacting for 3 h. Water was added to the reacted mixture, and extracted with ethyl acetate. After the organic layer was washed with 10% citric acid aqueous solution, water, 6.5% sodium bicarbonate aqueous solution and saturated brine sequentially, and then the solvent was distilled off under reduced pressure. The resulting oil residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 1/2) to afford 1.07 g of the title compound (yield 84%). 1H NMR (400 MHz, CDCl3) δ observed as a mixture of 2 rotamers (approx. 7:3). 1.26 (m, 0.3H), 1.44 (s, 9H), 1.70 (m, 0.7H), 1.81-2.12 (m, 3H), 3.10 (br. d, J = 14.4 Hz, 0.3H), 3.30 (m, 3H), 3.54 (br. d, J = 12.4 Hz, 0.7H), 3.87 (m, 2H), 4.15 (d, J=13.2 Hz, 0.7H), 4.58-4.79 (m, 2.6H), 4.90 (m, 0.7H), 4.97 (m, 0.3H), 5.11 (m, 0.7H), 5.33 (m, 1H), 7.26-7.38 (m, 5H), 9.75 (br. s, 0.7H), 10.48 (br. s, 0.3H); MS m/z 505 [M+H]+.
  • 30
  • [ 75051-55-7 ]
  • (2S,5R)-5-((benzyloxy)amino)-1-(2-trimethylsilylethoxycarbonyl)piperidine-2-carboxylic acid [ No CAS ]
  • (2S,5R)-N-(2-tert-butoxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-[2-(trimethylsilyl)ethyloxycarbonyl]piperidine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
54% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 5h;Cooling with ice; Example 104 (2S,5R)-N-(2-tert-Butoxycarbonylaminoethoxy)-5-(benzyloxyamino)-1-[2-(trimethylsilyl)ethyloxycarbonyl]piperidine-2-carboxamide (IV-b4-059) [0626] (2S,5R)-5-(Benzyloxyamino)-1-((2-(trimethylsilyl)ethoxy)carbonyl)piperidine-2-carboxylic acid (601 mg, 1.52 mmol) described in Example 101 and tert-butyl 2-(aminooxy)ethylcarbamate (303 mg, 1.72 mmol) of Reference Example 9 were dissolved in N,N-dimethylformamide (5.8 mL), to which was added 1-hydroxybenzotriazole· monohydrate (264 mg), followed by ice cooling. To this was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg), a temperature was elevated to room temperature, followed by reaction for 5 h. Water was added to the reaction mixture and extracted with ethyl acetate. After the organic layer was washed with 10% citric acid aqueous solution, water, 6.5% sodium bicarbonate aqueous solution and saturated brine sequentially, the organic layer was dehydrated over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting oil residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 1/2) to afford 450 mg of the title compound (yield 54%). 1H NMR (400 MHz, CDCl3) δ 0.01 (s, 9H), 0.98 (m, 2H), 1.42 (s, 9H), 1.58 (m, 1H), 1.84-1.96 (m, 3H), 3.04 (m, 1H), 3.18 (br. s, 1H), 3.28 (m, 1H), 3.35 (m, 1H), 3.85 (m, 2H), 4.16-4.35 (m, 3H), 4.63-4.75 (m, 3H), 5.32-5.70 (br. m, 2H), 4.26-4.33 (m, 5H), 9.44 (br. s, 1H); MS m/z 553 [M+H]+.
  • 31
  • [ 75051-55-7 ]
  • [ 1263182-81-5 ]
  • (1R,4aS,E)-6-bromo-9-((2-((tert-butoxycarbonyl)amino)ethoxy)imino)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
97% With pyridine; In ethanol; at 90℃; for 3h; A mixture of 18a (4.5 g, 0.011mol), pyridine (2.8 mL, 0.034 mol), and NH2OCH2CH2NHBoc (5.15 g, 0.034 mol) in EtOH (25 mL) was stirred at 90oC for 3 h, the whole was cooled, and the solvent was evaporated invacuum. The residue was purified by flash chromatography (n-hexane/AcOEt = 2:1) to afford 18b as yellow oil in 97% yield.1HNMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.42 (s, 1H), 6.58 (s, 1H),4.41 - 4.30 (m, 2H), 3.66 - 3.58 (m, 2H), 3.33 - 3.22 (m, 1H), 2.94 (dd, J= 17.9, 3.8 Hz, 1H), 2.46 (dd, J = 17.7, 13.9 Hz, 1H), 2.28 - 2.22 (m,2H), 1.77 (s, 4H), 1.59 - 1.53 (m, 1H), 1.34 (s, 3H), 1.25-1.22 (m, 15H), 1.16(s, 3H).
  • 32
  • [ 75051-55-7 ]
  • [ 18492-70-1 ]
  • (1R,4aS,E)-methyl 6-bromo-9-((2-((tert-butoxycarbonyl)amino)ethoxy)imino)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With pyridine; In ethanol; at 90℃; for 3h; General procedure: A mixture of the methylester 3 or 4 (0.015 mol), pyridine(3.6 mL), and the appropriate O-substituted hydroxylamines S-4 (0.045 mmol) in EtOH (25mL) was stirred at 90 oC for 3 h, the whole was cooled, and thesolvent was evaporated in vacuum. The residue was purified by flashchromatography (n-hexane/AcOEt = 8:1) to afford 5a-d and 6.
  • 33
  • [ 75051-55-7 ]
  • [ 17751-36-9 ]
  • (1R,4aS,E)-methyl 9-((2-((tert-butoxycarbonyl)amino)ethoxy)imino)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With pyridine; In ethanol; at 90℃; for 3h; General procedure: A mixture of the methylester 3 or 4 (0.015 mol), pyridine(3.6 mL), and the appropriate O-substituted hydroxylamines S-4 (0.045 mmol) in EtOH (25mL) was stirred at 90 oC for 3 h, the whole was cooled, and thesolvent was evaporated in vacuum. The residue was purified by flashchromatography (n-hexane/AcOEt = 8:1) to afford 5a-d and 6.
  • 34
  • [ 37718-11-9 ]
  • [ 75051-55-7 ]
  • C11H18N4O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
39% Under inert atmosphere <strong>[37718-11-9]1H-pyrazol-4-carboxylic acid</strong> (207 mg, 1 .87 mmol) was diluted in anhydrous DMF (19 mL). HOBt H20 (367 mg, 2.40 mmol) and EDC HCl (460 mg, 2.40 mmol) were successively added. The reaction mixture was stirred at rt for 10 min. tert- Butyl N-(2-aminoxyethyl)carbamate (325 mg, 1 .87 mmol) and DIPEA (420 muIota_, 2.40 mmol) were added. The reaction mixture was stirred at rt for 16h. The reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel (DCM/acetone: 100/0 to 20/80) to give intermediate (24a) (198 mg, 0.72 mmol, 39percent) as a white solid. MS m/z ([M+H]+) 271 . MS m/z ([M-H]") 269. 1 H NMR (400 MHz, CDCI3) delta 1 .42 (s, 9H), 3.38-3.41 (m, 2H), 3.92-3.95 (m, 2H), 5.56 (br s, 1 H), 8.02 (s, 2H), 10.52 (s, 1 H).
  • 35
  • [ 37718-11-9 ]
  • [ 75051-55-7 ]
  • tert-butyl N-[2-(1H-pyrazole-4-carbonylamino)ethyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
36% 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 50℃; <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (50 mg, 4.46 mmol) was dissolved in DMF (45 mL). Tert- butyl N-(2-aminoethyl)carbamate (1 .44 mL, 9.82 mmol), HATU (1 .87g, 4.91 mmol) and DIPEA (2.33 mL, 13.4 mmol) were added and mixture was stirred at 50°C overnight. After concentration, the residue was purified on silica gel (DCM/MeOH: 100/0 to 80/20) to provide intermediate (38a) (408 mg, 1 .61 mmol, 36percent).MS m/z ([M+H]+) 255.1H NMR (400 MHz, CD3OD): delta (ppm) 1 .42 (s, 9H), 3.25 (t, J= 6.1 Hz, 2H), 3.41 (t, J= 6.1 Hz, 2H), 8.04 (s, 2H).
 

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