Home Cart 0 Sign in  

[ CAS No. 2687-43-6 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 2687-43-6
Chemical Structure| 2687-43-6
Structure of 2687-43-6 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 2687-43-6 ]

Related Doc. of [ 2687-43-6 ]

Alternatived Products of [ 2687-43-6 ]

Product Details of [ 2687-43-6 ]

CAS No. :2687-43-6 MDL No. :MFCD00012952
Formula : C7H10ClNO Boiling Point : -
Linear Structure Formula :- InChI Key :HYDZPXNVHXJHBG-UHFFFAOYSA-N
M.W :159.61 Pubchem ID :102312
Synonyms :

Calculated chemistry of [ 2687-43-6 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 41.05
TPSA : 35.25 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.87 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 1.97
Log Po/w (WLOGP) : -1.96
Log Po/w (MLOGP) : 1.76
Log Po/w (SILICOS-IT) : 0.99
Consensus Log Po/w : 0.55

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.38
Solubility : 0.661 mg/ml ; 0.00414 mol/l
Class : Soluble
Log S (Ali) : -2.34
Solubility : 0.737 mg/ml ; 0.00462 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.14
Solubility : 1.16 mg/ml ; 0.00728 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.28

Safety of [ 2687-43-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P271-P280-P261-P264-P302+P352-P304+P340-P305+P351+P338-P312-P362+P364-P403+P233-P501 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 2687-43-6 ]

* 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.

  • Upstream synthesis route of [ 2687-43-6 ]
  • Downstream synthetic route of [ 2687-43-6 ]

[ 2687-43-6 ] Synthesis Path-Upstream   1~17

  • 1
  • [ 2687-43-6 ]
  • [ 51677-09-9 ]
Reference: [1] Tetrahedron, 2011, vol. 67, # 25, p. 4612 - 4615
  • 2
  • [ 16653-19-3 ]
  • [ 2687-43-6 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: With methylhydrazine In dichloromethane at 0 - 20℃; for 2 h;
Stage #2: With hydrogenchloride In 1,4-dioxane at 0℃;
After 500 mg of pregnenolone (TCI) was dissolved in 13 ml of tetrahydrofurane under argon flow, 215 mg of tri-O-acetyl-D-glucan (Aldrich) and 0.2 ml of borontrifluoride diethyl etherate (Aldrich) were added at 0° C., followed by stirring at room temperature for 6 hours. The reaction liquid was diluted by adding 50 ml of diethyl ether and washed with an aqueous sodium hydrogen carbonate solution, followed by drying over magnesium sulfate and filtering. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (1:10) as an eluent to obtain SAC-0906(250 mg, yield: 60percent). After 500 mg of hydroxyphthalimide (Aldrich) was dissolved in 5 ml of dimethylformamide under argon flow, 0.4 ml of benzyl bromide (Aldrich) was added, and 0.5 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (Aldrich) was slowly added. After the mixture was stirred at 60° C. for 2 hours, the temperature was again lowered to room temperature, and then the reaction was stopped by adding a 2 N hydrochloric acid solution. The reaction liquid was diluted by adding 20 ml of ethyl acetate, followed by drying over magnesium sulfate and then filtering. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography using a mixed eluent of ethyl acetate/hexane (1:5) and then dried to obtain 338 mg of a white solid (yield: 50percent). The white solid was dissolved in 5 ml of dichloromethane, and 0.11 ml of methyl hydrazine (TCI) was slowly added at 0° C. After the reaction liquid was stirred at room temperature for 2 hours, the temperature was again lowered to 0° C. The generated solid was then filtered out, and 1 ml of a 4 M-hydrochloric acid dioxane solution (Aldrich) was added to the residual filtrate, followed by filtration and drying, to obtain 171 mg of a solid (yield: 70percent). 21 mg of the obtained solid and 59 mg of SAC-0906 obtained as obtained above were dissolved in 1 ml of pyridine (Aldrich) under argon flow, followed by stirring at 80° C. for 4 hours. After the temperature was lowered to room temperature, the reaction liquid was acidified by adding a 2 N hydrochloric acid solution, followed by extraction with 20 ml of diethyl ether, drying over magnesium sulfate, and filtering. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography using a mixed eluent of ethyl acetate/hexane (1:5) to obtain the target compound SAC-1009 (57 mg, yield: 81percent). 1H-NMR (300 MHz, CDCl3) δ7.307.17 (m, 5H), 5.88-5.72 (m, 2H), 5.30-5.28 (m, 1H), 5.24-5.21 (m, 1H), 5.10 (m, 1H), 5.01 (s, 2H), 4.24-4.01 (m, 3H), 3.59-3.44 (m, 1H), 2.38-0.51 (m, 35H)
Reference: [1] Journal of Organic Chemistry, 1997, vol. 62, # 26, p. 9177 - 9181
[2] Patent: US2014/378399, 2014, A1, . Location in patent: Paragraph 0092
[3] Journal of Pharmacology and Experimental Therapeutics, 1999, vol. 288, # 2, p. 490 - 501
[4] Synthetic Communications, 1997, vol. 27, # 7, p. 1143 - 1147
[5] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 10, p. 3233 - 3241
[6] ChemMedChem, 2012, vol. 7, # 9, p. 1587 - 1593,7
[7] Synlett, 2014, vol. 25, # 13, p. 1873 - 1878
[8] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5182 - 5186
[9] Arkivoc, 2018, vol. 2018, # 4, p. 139 - 148
[10] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3064 - 3066
  • 3
  • [ 16115-53-0 ]
  • [ 2687-43-6 ]
YieldReaction ConditionsOperation in experiment
83% With hydrogenchloride In water at 110℃; for 2.5 h; Ethyl O-benzylacetohydroxamate (211.3g, 0.911mol, 1eq) was added into a solution of 3 mol/L hydrochloric acid (607mL, 1.822mol, 2.0eq) for reflux reaction, at same time magnetic stirring, and heated at 110 ° C and carry on reaction for 2.5h, the reaction solution was concentrated with a water pump and precipitated as a white solid, the white solid was pulverized with methanol and dried and obtained 120.7g of white crystals, melting point is 2238.1 ° C, the titration purity is 99.3percent, and the yield is 83percent
Reference: [1] Patent: CN108530315, 2018, A, . Location in patent: Paragraph 0079; 0082; 0083
  • 4
  • [ 142654-28-2 ]
  • [ 2687-43-6 ]
Reference: [1] Synthetic Communications, 2014, vol. 44, # 16, p. 2344 - 2347
  • 5
  • [ 681856-02-0 ]
  • [ 2687-43-6 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 2, p. 658 - 661
  • 6
  • [ 3532-25-0 ]
  • [ 2687-43-6 ]
Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1982, vol. 21, # 4, p. 361 - 363
[2] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 8, p. 1655 - 1663
  • 7
  • [ 622-33-3 ]
  • [ 2687-43-6 ]
Reference: [1] Journal of Agricultural and Food Chemistry, 2007, vol. 55, # 26, p. 10857 - 10863
  • 8
  • [ 3376-36-1 ]
  • [ 2687-43-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 16, p. 4499 - 4502
  • 9
  • [ 100-39-0 ]
  • [ 2687-43-6 ]
Reference: [1] Patent: US2014/378399, 2014, A1,
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5182 - 5186
[3] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3064 - 3066
[4] Patent: CN108530315, 2018, A,
  • 10
  • [ 100-44-7 ]
  • [ 2687-43-6 ]
Reference: [1] Synlett, 2014, vol. 25, # 13, p. 1873 - 1878
[2] Arkivoc, 2018, vol. 2018, # 4, p. 139 - 148
  • 11
  • [ 3528-17-4 ]
  • [ 2687-43-6 ]
Reference: [1] Tetrahedron Letters, 1991, vol. 32, # 6, p. 711 - 714
  • 12
  • [ 133341-70-5 ]
  • [ 2687-43-6 ]
  • [ 133341-71-6 ]
Reference: [1] Tetrahedron Letters, 1991, vol. 32, # 6, p. 711 - 714
  • 13
  • [ 63593-23-7 ]
  • [ 2687-43-6 ]
Reference: [1] Chemistry of Heterocyclic Compounds, 2005, vol. 41, # 6, p. 718 - 721
  • 14
  • [ 24424-99-5 ]
  • [ 2687-43-6 ]
  • [ 79722-21-7 ]
YieldReaction ConditionsOperation in experiment
69%
Stage #1: With sodium carbonate In dichloromethane for 1 h;
Stage #2: at 0 - 25℃; for 17 h;
Intermediate 153: tert-butyl benzyloxycarbamate To a solution of O-benzylhydroxylamine hydrochloride (225 g, 1.44 mol) in dichloromethane (300 mL) was added a solution of sodium bicarbonate (261 g, 3.11 mol, 300ml). After 1 hour the di-tert-butyl dicarbonate (375 g, 1.72 mol) was added at 0 °C. The resulting solution was stirred for 60 min at 0 °C in a water/ice bath and then the reaction was stirred for 16 h at room temperature. The reaction was then quenched by the addition of 300 mL of aqueous sodium bicarbonate. The aqueous phase was extracted with 3 x 500 mL of dichloromethane and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. Flash chromatograph on silica gel (PE: EA=10: 1) afforded 220 g (69percent) of the title compound as a yellow oil. 1H MR (300MHz. COCh) δ: 1.43 (9H, s), 4.85 (2H, s), 7.19-7.21 (1H, brs), 7.30-7.40 (5H, m).
50% With dmap; triethylamine In dichloromethane at 20℃; O-Benzyl-hydroxylamine hydrochloride (300 mg, 1.89 mmol) was dissolved in DCM (5 mL).
Triethylamine (1.05 mL, 7.56 mmol), DMAP (catalytic amount) and di-tert-butyldicarbonate (617 mg, 2.83 mmol) were added and the mixture was stirred at room temperature overnight.
Water and DCM were then added.
The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure.
The crude material was purified by preparative TLC on silica gel (DCM/MeOH 99/1) to give compound (116a) (210 mg, 0.94 mmol, 50percent).
91% With triethanolamine In tetrahydrofuran; water; ethyl acetate Nα -tert-Butyloxycarbonyl-O-benzylhydroxylamine (28)
O-Benzyl hydroxylamine hydrochloride (15.9 g, 100 mmol) was suspended in THF (150 ml) and water (50 ml) mixture.
To this stirred mixture was added TEA (15.15 g, 150 mmol) followed by di-tert-butyldicarbonate (23.98 g, 110 mmol).
The reaction mixture was stirred at room temperature for 12 h and evaporated to dryness.
The residue was partitioned between EtOAc (250 ml) and water (200 ml), and extracted in EtOAc.
The EtOAc extract was washed with potassium hydrogen sulfate (100 ml) and brine (100 ml), dried and evaporated to dryness to give 15 g (91percent) of clear oil.
Reference: [1] Journal of Organic Chemistry, 1997, vol. 62, # 26, p. 9148 - 9159
[2] Archiv der Pharmazie, 2016, vol. 349, # 5, p. 373 - 382
[3] Journal of Organic Chemistry, 1983, vol. 48, p. 24
[4] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 24, p. 8549 - 8555
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 19, p. 8847 - 8858
[6] Dalton Transactions, 2015, vol. 44, # 48, p. 20850 - 20858
[7] Patent: WO2013/150296, 2013, A1, . Location in patent: Page/Page column 150; 151
[8] Patent: EP2913330, 2015, A1, . Location in patent: Paragraph 0409
[9] Journal of Medicinal Chemistry, 2016, vol. 59, # 7, p. 3183 - 3203
[10] Patent: US6310095, 2001, B1,
[11] Patent: US5969135, 1999, A,
[12] Patent: WO2004/18466, 2004, A2, . Location in patent: Page 10; 7
[13] Organic and Biomolecular Chemistry, 2012, vol. 10, # 17, p. 3519 - 3530
[14] Patent: WO2016/27262, 2016, A1, . Location in patent: Page/Page column 63
  • 15
  • [ 34619-03-9 ]
  • [ 2687-43-6 ]
  • [ 79722-21-7 ]
Reference: [1] Journal of the American Chemical Society, 2008, vol. 130, # 32, p. 10458 - 10459
  • 16
  • [ 24424-99-5 ]
  • [ 2687-43-6 ]
  • [ 497-19-8 ]
  • [ 79722-21-7 ]
Reference: [1] Patent: US5066658, 1991, A,
  • 17
  • [ 2687-43-6 ]
  • [ 1694-92-4 ]
  • [ 77925-80-5 ]
YieldReaction ConditionsOperation in experiment
62.6% With pyridine In tetrahydrofuran at 0 - 20℃; for 1 h; A solution of 2-nitrobenzene-1-sulfonyl chloride (500 g, 2.26 mol) in pyridine (1500 mL) was added dropwise to a solution of O-benzylhydroxylamine hydrochloride (400 g, 2.51 mol) in pyridine (1500 mL) at 0° C.
The reaction mixture was then stirred at 20° C. overnight.
The mixture was concentrated in vacuum, diluted with DCM and washed with HCl (10percent) three times.
The combined organic layer was concentrated in vacuum and re-crystallized with DCM to afford N-(benzyloxy)-2-nitrobenzenesulfonamide (485 g, 62.6percent) as a yellow solid
62.6% at 0 - 20℃; [0232] A solution of 2-nitrobenzene-1-sulfonyl chloride (500 g, 2.26 mol) in pyridine (1500 mL) was added dropwise to a solution of O-benzylhydroxylamine hydrochloride (400 g, 2.51 mol) in pyridine (1500 mL) at 0° C. The reaction mixture was then stirred at 20° C. overnight. The mixture was concentrated in vacuum, diluted with DCM and washed with HCl (10percent) three times. The combined organic layer was concentrated in vacuum and re-crystallized with DCM to afford N-(benzyloxy)-2-nitrobenzenesulfonamide (485 g, 62.6percent) as a yellow solid. [0233] To a solution of N-(benzyloxy)-2-nitrobenzenesulfonamide (212 g, 0.69 mol) in THF (1000 mL) was added (2S,5S)-1-tert-butyl 2-ethyl 5-hydroxypiperidine-1,2-dicarboxylate (171 g, 0.63 mol) and PPh3 (275 g, 1.05 mol), followed by dropwise addition of a solution of DEAD (195 g, 1.12 mol) in THF (500 mL). The mixture was then stirred at 20° C. overnight. The reaction mixture was then concentrated in vacuum and purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to afford (2S,5R)-1-tert-butyl 2-ethyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)piperidine-1,2-dicarboxylate (283.8 g, 80percent) as a yellow oil.
62.6% at 0 - 20℃; Example 1: Synthesis of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1 loctane-2- carbox late (Intermediate Compound 1 ) 1 Step 1: Synthesis of (S)-l-tert-butyl 2-ethyl 5-oxopiperidine-l ,2 -dicarboxylate Method A: Boc Boc O Boc O ~ .N TMSCHN2 N^ HIL ,JL R 2(OAc)4 A OEt ~ ubt o "^ J n-BuLi (600 mL, 1.5 mol) was added dropwise to a solution of TMSCHN2 (690 mL, 1.38 mol ) in dry THF (3 L) at -78 °C, and the mixture was stirred at -78 °C for 30 minutes. The mixture was then transferred to a solution of (5')-l-ieri-butyl 2-ethyl 5-oxopyrrolidine-l ,2- dicarboxylate (300 g, 1.17 mol) in dry THF (3 L) via cannula, and the mixture was stirred at - 78 °C for 30 minutes. The reaction mixture was then quenched with sat. NH4CI solution, and extracted with DCM (3x). The combined organic layer was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (3 : 1 petroleum ether/EtOAc ) to afford (5')-ethyl 2-((ieri-butoxycarbonyl)amino)-6-diazo-5- oxohexanoate (262 g, 75 percent) as a yellow solid. A solution of (S^-ethyl 2-((ieri-butoxycarbonyl)amino)-6-diazo-5-oxohexanoate (350 g, 1.18 mol ) in DCM (1500 mL) was added to a 0 °C solution of Rh2(OAc)4 (3.5 g, 7.9 mmol ) in DCM (750 mL). The reaction mixture was then stirred at 20 °C overnight and then concentrated under reduced pressure. The crude sample was purified by silica gel column chromatography (5:1 petroleum ether/EtOAc) to afford (5')-l-ieri-butyl 2-ethyl 5- oxopiperidine- 1 ,2-dicarboxylate (175.9 g, 55percent) as a yellow oil. Method B: DMSO i-BuOK (330 g, 2.9 mol) was added to a solution of trimethylsulfoxonium iodide (750 g, 3.5mol) in dry DMSO (3 L) and the mixture was stirred at rt for 1 h. (S)-l-tert- Butyl 2-ethyl 5-oxopyrrolidine-l,2-dicarboxylate (900 g, 3.5 mol) was added and the mixture was stirred at rt for 2-3 hrs. Water was added to quench the reaction and the mixture was extracted with EtOAc (5x). The combined organic layer was concentrated under reduced pressure and the crude sample was purified by silica gel column chromatography (1 :1 petroleum ether/EtOAc then 1 :10 MeOH/DCM) to afford sulfoxonium ylide intermediate (977 g, 80percent) as a white solid. A solution of sulfoxonium ylide intermediate (156 g, 0.446 mol) and [Ir(COD)Cl]2 (3 g, 4.46 mmol) in toluene (4 L) was degassed by bubbling nitrogen through the solution for 10 minutes. The reaction mixture was heated to 80-90 °C for 2-3 hrs and then cooled to 20 °C. The toluene was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (10:1 to 3 :lgradient elution petroleum ether/EtOAc) to afford (5)-l-ieri-butyl 2-ethyl 5-oxopiperidine-l,2-dicarboxylate (140 g, 57.8percent) as a yellow oil. Step 2: Synthesis of (2S,5S)-1 -tert-butyl 2-ethyl 5-hydroxypiperidine-l,2-dicarboxylate NaBRt (36 g, 1.0 mol) was added in portions to a -40 °C solution of (5)-l-ieri-butyl 2-ethyl 5-oxopiperidine-l,2-dicarboxylate (250 g, 0.92 mol) in EtOH (1500 mL). The reaction mixture was then stirred at -40 °C for 0.5 hr then quenched with 10percent HO Ac solution. After diluting with water, the mixture was extracted with DCM (3x). The combined organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (1 : 1 petroleum ether/EtOAc) to afford (25,55')- 1 -tert-butyl 2-ethyl 5-hydroxypiperidine-l ,2- dicarboxylate (205 g, 80percent) as a yellow oil. Step 3: Synthesis of (2S,5R)-1 -tert-butyl 2-ethyl 5-(N-(benzyloxy)-2- nitrophenylsulfonamido)piperidine-l,2-dicarboxylate A solution of 2-nitrobenzene-l-sulfonyl chloride (500 g, 2.26 mol) in pyridine (1500 mL) was added dropwise to a 0 °C solution of 0-benzylhydroxylamine hydrochloride (400 g, 2.51 mol) in pyridine (1500 mL). The reaction mixture was allowed to warm to room temperature then was stirred at 20 °C overnight. The mixture was concentrated under reduced pressure, diluted with DCM and washed with HC1 (10percent, 3x). The combined organic layer was concentrated under reduced pressure and re-crystallized with DCM to afford N-(benzyloxy)- 2-nitrobenzenesulfonamide (485 g, 62.6percent) as a yellow solid. To a solution of N-(benzyloxy)-2-nitrobenzenesulfonamide (212 g, 0.69 mol) in THF (1000 mL) was added (25,55)- 1-ieri-butyl 2-ethyl 5-hydroxypiperidine-l,2-dicarboxylate (171 g, 0.63 mol) and PP1 (275 g, 1.05 mol), followed by dropwise addition of a solution of DEAD (195 g, 1.12 mol) in THF (500 mL). The mixture was then stirred at 20 °C overnight. The reaction mixture was then concentrated under reduced pressure and purified by silica gel column chromatography (3: 1 petroleum ether/EtOAc) to afford (25,5 ?)-l-ieri-butyl 2-ethyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)piperidine-l,2-dicarboxylate (283.8 g, 80percent) as a yellow oil. Step 4: Synthesis of (2S,5R)-l-tert-butyl 2-ethyl 5-((benzyloxy)amino)piperidine-l,2- dicarboxylate LiOH'H20 (95 g, 2.3 mol) and 2-mercaptoacetic acid (124 g, 1.3 mol) were added to a solution of (2S,5R)-l-tert-buty\ 2-ethyl 5-(N-(benzyloxy)-2- nitrophenylsulfonamido)piperidine-l ,2-dicarboxylate (251 g, 0.45 mol) in DMF (1200 mL) . The reaction mixture was then stirred at 20 °C overnight. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic layer was washed with saturated sodium chloride (3x), concentrated under reduced pressure and purified by silica gel column chromatography (3: 1 petroleum ether/EtOAc) to afford (25',5 ?)-l-ieri-butyl 2-ethyl 5-((benzyloxy)amino)piperidine-l ,2-dicarboxylate (122.9 g, 85percent) as a yellow solid. Synthesis of (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2-carboxylate TFA (600 mL) was added to a solution of (2S,5R)-l-tert-buty\ 2-ethyl 5- ((benzyloxy)amino)piperidine-l,2-dicarboxylate (263 g, 0.7 mol) in DCM (600 mL) at 20 °C. The mixture was stirred at rt overnight and then concentrated under reduced pressure. The crude product was adjusted to pH 10 with sat. NaHCC>3 solution then extracted with DCM (3x). The combined organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (20: 1 DCM/MeOH) to afford (2S,5R)-ethyl 5- ((benzyloxy)amino)piperidine-2-carboxylate (184.9 g, 95percent) as a yellow oil. Step 6: Synthesis of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1 ]octane-2- carboxylate Triphosgene (21.3 g, 72 mmol) was added in portions to a 0 °C solution of (25',5 ?)-ethyl 5- ((benzyloxy)amino)piperidine-2-carboxylate (50 g, 0.18 mol) and DIPEA (128 mL, 0.72 mol) in DCM (2000 mL). The reaction mixture was allowed to warm to rt. After stirring at rt overnight, the reaction mixture was washed with H3PO4 (10percent), sat. NaHCC>3 and saturated NaCl. The combined organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (3 :1 petroleum ether/EtOAc) to afford (25',5 ?)-ethyl 6- (benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylate (27.4 g, 50percent) as a yellow solid. lH NMR (400Mz, CDC13): δ 7.43-7.36 (m, 5H), 5.06 (d, / = 11.4 Hz, 1H), 4.90 (d, / = 11.4 Hz, 1H), 4.24 (q, 7 = 7.1 Hz, 2H), 4.11-4.08 (m, 1H), 3.32-3.31 (m, 1H), 3.08-3.05 (m, 1H), 2.93 (d, / = 11.9 Hz, 1H), 2.14-2.05 (m, 2H), 2.05-2.00 (m, 1H), 1.71-1.63 (m, 1H), 1.29 (t, 7 = 7.1 Hz, 3H).
62.6% at 0 - 20℃; Example 1: Synthesis of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1 loctane-2- carboxylate (Intermediate Compound 1 ) 1 Synthesis of (S)-l-tert-butyl 2-ethyl 5-oxopiperidine-l ,2-dicarboxylate Method A: Boc Boc O Boc N TMSCHN2 Ν,^ ΗΝ. ,J R 2(OAc)4 N "OEt X J ± J O' n-BuLi was added dropwise to a solution of TMSCHN2 (690 mL, 1.38 mol ) in dry THF (3 L) (600 mL, 1.5 mol ) at -78 °C, and the mixture was stirred at -78 °C for 30 minutes. The mixture was then transferred to a solution of (5')-l-tert-butyl 2-ethyl 5-oxopyrrolidine-l,2- dicarboxylate (300 g, 1.17 mol) in dry THF (3 L) via cannula, and the mixture was stirred at - 78 °C for 30 minutes. The reaction mixture was then quenched with sat. NH4CI solution, and extracted with DCM three times. The combined organic layer was concentrated in vacuum and the crude product was purified by silica gel column chromatography (3 : 1 petroleum ether :EtOAc ) to afford (5')-ethyl 2-((tert-butoxycarbonyl)amino)-6-diazo-5-oxohexanoate (262 g, 75 percent) as a yellow solid. A solution of (S^-ethyl 2-((ieri-butoxycarbonyl)amino)-6-diazo-5-oxohexanoate (350 g, 1.18 mol ) in DCM (1500 rriL) was added to a solution of Rh2(OAc)4 (3.5 g, 7.9 mmol ) in DCM (750 mL) at 0 °C. The reaction was then stirred at 20 °C overnight and then concentrated in vacuum. The crude sample was purified by silica gel column chromatography (5:1 petroleum ether/EtOAc) to afford (^-l-tert-butyl 2-ethyl 5-oxopiperidine-l,2-dicarboxylate (175.9 g, 55percent) as a yellow oil. Method B DMSO t-BuOK (330 g, 2.9 mol) was added to a solution of trimethylsulfoxonium iodide (750 g, 3.5mol) in dry DMSO (3 L) and the mixture was stirred at rt for 1 h. (^-l-tert-Butyl 2-ethyl 5-oxopyrrolidine-l,2-dicarboxylate (900 g, 3.5 mol) was added and the mixture was stirred at rt for 2-3 hrs. Water was added to quench the reaction and the mixture was extracted with EtOAc 5 times. The combined organic layer was concentrated in vacuum and the crude sample was purified by silica gel column chromatography (l:lpetroleum ether/EtOAc then 1:10 MeOH/DCM) to afford sulfoxonium ylide intermediate (977 g, 80percent) as a white solid. A solution of sulfoxonium ylide intermediate (156 g, 0.446 mol) and [Ir(COD)Cl]2 (3 g, 4.46 mmol) in toluene(4 L) was degassed by bubbling nitrogen through the solution for 10 minutes. The reaction mixture was heated to 80-90 °C for 2-3 hrs and then cooled to 20 °C. Then toluene was concentrated in vacuum, the residue was purified by silica gel column chromatography (10:1 to 3:1 gradient petroleum ether/EtOA) to afford (^-l-tert-butyl 2-ethyl 5-oxopiperidine-l,2-dicarboxylate (140 g, 57.8percent) as a yellow oil. Step 2: Synthesis of (2S,5S)-1 -tert-butyl 2-ethyl 5-hydroxypiperidine-l,2-dicarboxylate NaB (36 g, 1.0 mol) was added in portions to a solution of (5)- 1-tert-butyl 2-ethyl 5- oxopiperidine-l ,2-dicarboxylate (250 g, 0.92 mol) in EtOH (1500 mL) at -40 °C. The reaction mixture was then stirred at -40 °C for 0.5 hr then quenched with 10percent HOAc solution. After diluting with water, the mixture was extracted with DCM three times. The combined organic layer was concentrated in vacuum and purified by silica gel column chromatography (1 :1 petroleum ether/EtOAc) to afford (25,55)- 1-tert-butyl 2-ethyl 5- hydroxypiperidine-l,2-dicarboxylate (205 g, 80percent) as a yellow oil. Step 3: Synthesis of (2S,5R)-l-tert-butyl 2-ethyl 5-(N-(benzyloxy)-2- nitrophenylsulfonamido)piperidine-l,2-dicarboxylate A solution of 2-nitrobenzene-l-sulfonyl chloride (500 g, 2.26 mol) in pyridine (1500 mL) was added dropwise to a solution of 0-benzylhydroxylamine hydrochloride (400 g, 2.51 mol) in pyridine (1500 mL) at 0 °C. The reaction mixture was then stirred at 20 °C overnight. The mixture was concentrated in vacuum, diluted with DCM and washed with HC1 (10percent) three times. The combined organic layer was concentrated in vacuum and re-crystallized with DCM to afford N-(benzyloxy)-2-nitrobenzenesulfonamide (485 g, 62.6percent) as a yellow solid. To a solution of N-(benzyloxy)-2-nitrobenzenesulfonamide (212 g, 0.69 mol) in THF (1000 mL) was added (25,55)- 1-tert-butyl 2-ethyl 5-hydroxypiperidine-l,2-dicarboxylate (171 g, 0.63 mol) and PP1 (275 g, 1.05 mol), followed by dropwise addition of a solution of DEAD (195 g, 1.12 mol) in THF (500 mL). The mixture was then stirred at 20 °C overnight. The reaction mixture was then concentrated in vacuum and purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to afford (25,5 ?)-l-tert-butyl 2-ethyl 5-(N- (benzyloxy)-2-nitrophenylsulfonamido)piperidine-l,2-dicarboxylate (283.8 g, 80percent) as a yellow oil. Step 4: Synthesis of (2S,5R)-l-tert-butyl 2-ethyl 5-((benzyloxy)amino)piperidine-l,2- dicarboxylate LiOH'H20 (95 g, 2.3 mol) and 2-mercaptoacetic acid (124 g, 1.3 mol) were added to a solution of (2S,5fl)-l-tert-butyl 2-ethyl 5-(N-(benzyloxy)-2- nitrophenylsulfonamido)piperidine-l ,2-dicarboxylate (251 g, 0.45 mol) in DMF (1200 mL) . The reaction mixture was then stirred at 20 °C overnight. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic layer was washed with brine (3x), concentrated in vacuum and purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to afford (2S,5fl)-l-tert-butyl 2-ethyl 5- ((benzyloxy)amino)piperidine-l,2-dicarboxylate (122.9 g, 85percent) as a yellow solid. Step 5: Synthesis of (2S,5R)-ethyl 5-((benzyloxy)amino)piperidine-2-carboxylate TFA (600 mL) was added to a solution of (2S,5fl)-l-tert-butyl 2-ethyl 5- ((benzyloxy)amino)piperidine-l,2-dicarboxylate (263 g, 0.7 mol) in DCM (600 mL) at 20 °C. The mixture was stirred at rt overnight and then concentrated in vacuum. The crude product was adjusted to pH 10 with sat. NaHCC>3 solution, and then extracted with DCM three times. The combined organic layer was concentrated in vacuum and purified by silica gel column chromatography (20:1 DCM/MeOH) to afford (25,5R)-ethyl 5- ((benzyloxy)amino)piperidine-2-carboxylate (184.9 g, 95percent) as a yellow oil. Step 6: Synthesis of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1 ]octane-2- carboxylate Triphosgene (21.3 g, 72 mmol) was added in portions to a solution of (2S ,5R)-ethyl 5- ((benzyloxy)amino)piperidine-2-carboxylate (50 g, 0.18 mol) and DIPEA (128 mL, 0.72 mol) in DCM (2000 mL) at 0 °C . After stirring at 20 °C overnight, the reaction mixture was washed with H3PO4 (10percent), sat. NaHCC>3 and saturated NaCl. The combined organic layer was concentrated in vacuum and purified by silica gel column chromatography (3 : 1 petroleum ether/EtOAc) to afford (2S,5R)-ethy\ 6-(benzyloxy)-7-oxo-l,6- diazabicyclo[3.2.1]octane-2-carboxylate (27.4 g, 50percent) as a yellow solid. 1H NMR (400Mz, CDCI3): δ 7.43-7.36 (m, 5H), 5.06 (d, / = 11.4 Hz, 1H), 4.90 (d, / = 11.4 Hz, 1H), 4.24 (q, / = 7.1 Hz, 2H), 4.11-4.08 (m, 1H), 3.32-3.31 (m, 1H), 3.08-3.05 (m, 1H), 2.93 (d, / = 11.9 Hz, 1H), 2.14-2.05 (m, 2H), 2.05-2.00 (m, 1H), 1.71-1.63 (m, 1H), 1.29 (t, / = 7.1 Hz, 3H).
62.6% With pyridine In tetrahydrofuran at 0 - 20℃; Step 3:
Synthesis of (2S,5R)-1-tert-butyl 2-ethyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)piperidine-1,2-dicarboxylate
A solution of 2-nitrobenzene-1-sulfonyl chloride (500 g, 2.26 mol) in pyridine (1500 mL) was added dropwise to a solution of O-benzylhydroxylamine hydrochloride (400 g, 2.51 mol) in pyridine (1500 mL) at 0° C.
The reaction mixture was then stirred at 20° C. overnight.
The mixture was concentrated in vacuum, diluted with DCM and washed with HCl (10percent) three times.
The combined organic layer was concentrated under reduced pressure and re-crystallized with DCM to afford N-(benzyloxy)-2-nitrobenzenesulfonamide (485 g, 62.6percent) as a yellow solid

Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8081 - 8086
[2] Synthesis, 2001, # 7, p. 1086 - 1092
[3] Journal of Organic Chemistry, 2015, vol. 80, # 12, p. 6076 - 6082
[4] Patent: US2013/289012, 2013, A1, . Location in patent: Paragraph 0199; 0200
[5] Patent: US2013/296555, 2013, A1, . Location in patent: Paragraph 0231; 0232
[6] Patent: WO2013/149136, 2013, A1, . Location in patent: Page/Page column 50; 51; 52
[7] Patent: WO2013/149121, 2013, A1, . Location in patent: Page/Page column 63
[8] Patent: US2014/275001, 2014, A1, . Location in patent: Paragraph 0111
Same Skeleton Products
Historical Records

Related Functional Groups of
[ 2687-43-6 ]

Aryls

Chemical Structure| 622-33-3

[ 622-33-3 ]

O-Benzylhydroxylamine

Similarity: 0.96

Chemical Structure| 589-18-4

[ 589-18-4 ]

p-Tolylmethanol

Similarity: 0.75

Chemical Structure| 100-51-6

[ 100-51-6 ]

Phenylmethanol

Similarity: 0.75

Chemical Structure| 4464-18-0

[ 4464-18-0 ]

Benzene-1,3,5-triyltrimethanol

Similarity: 0.75

Chemical Structure| 626-18-6

[ 626-18-6 ]

1,3-Benzenedimethanol

Similarity: 0.75

Amines

Chemical Structure| 622-33-3

[ 622-33-3 ]

O-Benzylhydroxylamine

Similarity: 0.96

Chemical Structure| 876-33-5

[ 876-33-5 ]

O-(4-Methoxybenzyl)hydroxylamine hydrochloride

Similarity: 0.74

Chemical Structure| 51572-89-5

[ 51572-89-5 ]

O-(4-Fluorobenzyl)hydroxylamine hydrochloride

Similarity: 0.74

Chemical Structure| 31938-11-1

[ 31938-11-1 ]

O-Tritylhydroxylamine

Similarity: 0.71

Chemical Structure| 40896-62-6

[ 40896-62-6 ]

(3-(Aminomethyl)phenyl)methanol hydrochloride

Similarity: 0.71