[ CAS No. 1333880-60-6 ]

Name: 1333880-60-6|tert-Butyl (2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)carbamate|95%
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{[proInfo.proName]} (Synonyms:Boc-NH-PEG3-propargyl) ,{[proInfo.pro_purity]}

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Quality Control of [ 1333880-60-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1333880-60-6 ]

CAS No. :	1333880-60-6	MDL No. :
Formula :	-	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IKRULGOPBBCYPJ-UHFFFAOYSA-N
M.W :	-	Pubchem ID :	126480465
Synonyms :	Boc-NH-PEG3-propargyl

Calculated chemistry of [ 1333880-60-6 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.79
Num. rotatable bonds :	13
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	75.34
TPSA :	66.02 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.63 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.88
Log Po/w (XLOGP3) :	0.6
Log Po/w (WLOGP) :	1.27
Log Po/w (MLOGP) :	0.61
Log Po/w (SILICOS-IT) :	2.09
Consensus Log Po/w :	1.69

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	1.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.14
Solubility :	20.7 mg/ml ; 0.0722 mol/l
Class :	Very soluble
Log S (Ali) :	-1.56
Solubility :	7.91 mg/ml ; 0.0275 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.96
Solubility :	0.312 mg/ml ; 0.00109 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.45

Safety of [ 1333880-60-6 ]

Signal Word:		Class:
Precautionary Statements:		UN#:
Hazard Statements:		Packing Group:

Application In Synthesis of [ 1333880-60-6 ]

* 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.

Downstream synthetic route of [ 1333880-60-6 ]

[ 1333880-60-6 ] Synthesis Path-Downstream 1~46

1
[ 1333880-60-6 ]
[ 1333880-63-9 ]

Reference： [1]Analytical Biochemistry,2011,vol. 417,p. 264 - 273

2
[ 1333880-60-6 ]
[ 1333880-67-3 ]

Reference： [1]Analytical Biochemistry,2011,vol. 417,p. 264 - 273

3
[ 1333880-60-6 ]
[ 1333880-69-5 ]

Reference： [1]Analytical Biochemistry,2011,vol. 417,p. 264 - 273

4
[ 1333880-60-6 ]
[ 35109-88-7 ]
[ 1333880-61-7 ]

Reference： [1]Analytical Biochemistry,2011,vol. 417,p. 264 - 273

5
[ 139115-92-7 ]
[ 106-96-7 ]
[ 1333880-60-6 ]

Yield	Reaction Conditions	Operation in experiment
72%	With tetra-(n-butyl)ammonium iodide; potassium iodide; potassium hydroxide; In tetrahydrofuran; at 25℃; for 16h;Inert atmosphere;	A mixture of <strong>[139115-92-7]tert-butyl N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate</strong> (3.00 g, 12.0 mmol), 3-bromoprop-1-yne (1.72 g, 14.4 mmol, 1.24 mL), TBAI (356 mg, 962 umol), KI (299 mg, 1.81 mmol) and KOH (675 mg, 12.0 mmol) in THF (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 C. for 16 hrs under N2 atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (2.50 g, 72% yield) as light yellow oil. 1H NMR (400 MHz, CDCl3) delta 5.05 (s, 1H), 4.22 (d, J=2.4 Hz, 2H), 3.76-3.60 (m, 8H), 3.55 (t, J=5.2 Hz, 2H), 3.35-3.27 (m, 2H), 2.44 (t, J=2.4 Hz, 1H), 1.47 (s, 9H).
	With sodium hydroxide; In dichloromethane; at 50℃;	To a stirred solution of <strong>[139115-92-7]tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate</strong> (0.854 g) in dichloromethane (20 mL) was added sodium hydroxide (0.5 g) and 3-bromoprop-1-yne (0.7 mL). The mixture was stirred at 50 C overnight, filtered through Celite and concentrated under reducedpressure to give the title compound.
	With sodium hydroxide; In dichloromethane; at 50℃;	To a stirred solution of <strong>[139115-92-7]tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate</strong> (0.854 g) in dichloromethane (20 mL) was added sodium hydroxide (0.5 g) and 3-bromoprop-1-yne (0.7 mL). The mixture was stirred at 50 C. overnight, filtered through Celite and concentrated under reduced pressure to give the title compound.

1.1 g

With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 5h;

To a stirred solution of <strong>[139115-92-7]tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate</strong> (1.0 g, 4.01 mmol, synthesized via Step 1 on Intermediate AC) in THF (50 ml) was added NaH (0.2 g, 4.81 mmol) at 0-5 C. 3-bromoprop-1-yne (0.9 ml, 6.02 mmol, CAS : 106-96-7) was added dropwise at 0-5 C. The reaction mixture was stirred at rt for 5 h. The resulting reaction mixture was poured into ice cold water (200 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford tert-butyl (2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)carbamate (1.1 g, 3.83 mmol). LCMS m/z (ES+): 188.2 (M-99)+.

Reference： [1]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 4042; 4043
[2]Analytical Biochemistry,2011,vol. 417,p. 264 - 273
[3]Patent: WO2017/214456,2017,A1 .Location in patent: Page/Page column 364
[4]Patent: US2019/153107,2019,A1 .Location in patent: Paragraph 1142
[5]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2985; 2986

6
[ 139115-92-7 ]
[ 1333880-60-6 ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,2016,vol. 80,p. 432 - 439
[2]MedChemComm,2019,vol. 10,p. 1037 - 1041

7
[ 107-19-7 ]
2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethyl bromide [ No CAS ]
[ 1333880-60-6 ]

Yield	Reaction Conditions	Operation in experiment
20%		10 mL of dry THF was added to a flask containing 2-propyn-1-ol (560 mg, 10 mmol) and NaH (480 mg, 20 mmol) and was stirred on ice for 20 min. After the addition of 6 (488 mg, 1.6 mmol) to the solution, it was stirred for an additional 2 h. An aqueous solution of NH4Cl was added to the reaction mixture to terminate the reaction, and the solution was then extracted with 60 mL of EtOAc. The organic layer was dried over Na2SO4. The resultant matter was purified by silica gel column chromatography (40 g, n-hexane-EtOAc 3/2) to yield 7 (90 mg, 0.31 mmol, 20%) as ayellow oil. 1H NMR (270 MHz, CDCl3): 5.00 (1H, br),4.18 (2H, d, J = 3.3 Hz), 3.70-3.66 (4H, m), 3.64-3.56 (4H, m), 3.50 (2H, t, J = 7.3 Hz), 3.28 (2H, t,J = 7.2 Hz), 2.40 (1H, t, J = 3.3 Hz), 1.41 (s, 9H); 13CNMR (67.8 MHz, CDCl3): 155.9, 79.5, 79.1, 74.5,70.4, 70.3, 70.19, 70.17, 69.0, 58.3, 40.3, 28.3; FD-MSm/z (rel.int.): 288 (100, [M + H]+), 287 (19.0, [M]+),69.0 (95.7), 57.0 (91.3); FD-HR-MS m/z: calcd. forC14H26NO5, 288.18110, found 288.18038.

Reference： [1]Bioscience, Biotechnology and Biochemistry,2016,vol. 80,p. 432 - 439

8
[ 1333880-60-6 ]
[ 932741-19-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With trifluoroacetic acid; In dichloromethane; at 0℃; for 2h;	Compound 7 (90 mg, 0.31 mmol) was dissolved in 50% TFA-CH2Cl2 (2 ml) and stirred at 0 C for 2 h. The reaction mixture was evaporated to yield 8 (58 mg, 0.31 mmol, 99%) as a yellow oil. 1H NMR (270 MHz,CD3OD): 4.80 (2H, s), 4.20 (2H, d, J = 3.1 Hz), 3.68-3.56 (8H, m), 3.30 (2H, t, J = 7.2 Hz), 2.95 (2H, t,J = 7.4 Hz), 2.85 (1H, t, J = 3.1 Hz); 13C NMR(67.8 MHz, CD3OD): 80.5, 76.0, 71.4, 71.25, 71.23,70.5, 70.0, 59.0, 41.3; FD-MS m/z (rel.int.): 188 (100,[M + H]+); FD-HR-MS m/z: calcd. for C9H18NO3,188.12867, found 188.12836.
	With hydrogenchloride; In diethyl ether; dichloromethane; at 20℃; for 2h;	To a stirred solution of Example 2.58.1 (0.986 g) in dichloromethane (20 mL) was added hydrochloric acid (20 mL, 2M in ether). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was suspended in dichloromethane (20 mL). Triethylamine (3 mL) and 9-fluorenylmethyl chloroformate (1.5 g) were added, and the reaction stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure. Ethyl acetate was added, and the suspension was filtered. The eluent was concentrated under reduced pressure and purified by silica gel chromatography, eluting with a gradient of 5% to 40% heptanes/ethyl acetate, to give the title compound. MS (ESI) m/e 410.0 (M+H)+.

Reference： [1]Bioscience, Biotechnology and Biochemistry,2016,vol. 80,p. 432 - 439
[2]Patent: US2019/153107,2019,A1 .Location in patent: Paragraph 1143
[3]MedChemComm,2019,vol. 10,p. 1037 - 1041

9
[ 1333880-60-6 ]
5-((3aS,4S,6aR)-2-oxohexahydrothieno[3,4-d]imidazol-4-yl)-pentanoic acid ((1S)-2-(4-benzoylphenyl)-1-{2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethylcarbamoyl}ethyl)amide [ No CAS ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,2016,vol. 80,p. 432 - 439

10
[ 1333880-60-6 ]
C₆₀H₇₉Cl₂N₉O₁₀S [ No CAS ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,2016,vol. 80,p. 432 - 439

11
[ 5197-62-6 ]
[ 1333880-60-6 ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,2016,vol. 80,p. 432 - 439

12
[ 86520-52-7 ]
[ 1333880-60-6 ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,2016,vol. 80,p. 432 - 439

13
[ 6338-55-2 ]
[ 1333880-60-6 ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,2016,vol. 80,p. 432 - 439
[2]Patent: US2019/192668,2019,A1

14
[ 1333880-60-6 ]
4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ No CAS ]
tert-butyl (2-(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethoxy)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; In dimethyl sulfoxide; at 120℃; for 0.5h;Microwave irradiation;	General procedure: A mixture of 19 (1.2 equiv.), 20 (1.0 equiv.), Pd(FPh3)4(0.1 equiv.), Cul (0.2 equiv.), and Et3N (4.8 equiv.) in DM SO was heated under mi crowave i rradi ation at 120 C for 30 mi n. The reacti on was cool ed to room temperature, poured into water and extracted with EtOAc. The organic layer was washed with waterχ2, brineχ1 , dried over anhydrous N a2S04, filtered, and evaporated to dryness. The crude product was purified by flash col umn chromatography usi ng EtOAc and DCM as el uents to afford the ti tl e compound.Preparation of terf-Butvl (2-(2-(2-((3-(2-(2,6-di oxopi peri di n-3-vl 1-1 ,3-dioxoi9oi ndol i n-4- vI)prop-2-yn- 1 -yl )oxv)ethoxv)ethoxv)ethyl lcarbamate (21a). Following general method, compound 21a was obtained from 19 and 20a. Yield 80%.1H NMR (600 MHz, CDCI3) δ 8.18 (s, 1H), 7.88 - 7.84 (m, 1H), 7.80 - 7.77 (m, 1H), 7.73 (t, J= 7.6 Hz, 1H), 5.07 (s, 1H),15 5.01 (dd, J= 12.5, 5.4 Hz, 1H), 4.55 (s, 2H), 3.91 - 3.86 (m, 2H), 3.79 - 3.75 (m, 2H), 3.71 - 3.66 (m, 4H), 3.59 - 3.54 (m, 2H), 3.39 - 3.30 (m, 2H), 2.98 - 2.75 (m, 3H), 2.21 - 2.14 (m, 1H), 1.46 (s, 9H) ppm. LC-MS (ESI): m/z 566.2 [M+Na]+.
18 mg	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; at 70℃; for 10h;Inert atmosphere;	EXAMPLE 11 Synthesis of 4-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propyl)-2-(2,6-dioxopiperidin-3- yl)isoindoline- 1 ,3-dione Step 1: Synthesis of S33 To a round-bottom flask, S30 (50 mg) and tert-butyl (2-(2-(2-(prop-2-yn-l- yloxy)ethoxy)ethoxy)ethyl)carbamate (60 mg) were added to a solution of Cul (6.3 mg) and Pd(PPh3)2Cl2 (11 mg) in THF (5 mL) and Et3N (2 mL). The mixture was stirred for 10 hours at 70 C under Ar and purified directly by flash column chromatography to yield S33 in 18 mg. ESI-MS calculated for C27H34N309 [M+H]+ = 544.2; Observed: 544.4.

Reference： [1]Patent: WO2021/146536,2021,A1 .Location in patent: Page/Page column 77-78
[2]Patent: WO2017/176958,2017,A1 .Location in patent: Paragraph 0886-0887

15
[ 1333880-60-6 ]
[ 142188-68-9 ]
C₃₄H₅₃N₅O₁₇ [ No CAS ]

Reference： [1]Chinese Chemical Letters,2018,vol. 29,p. 76 - 80

16
[ 1333880-60-6 ]
(2S,3R,4S,5S,6S)-2-(5-(1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13-tetraoxa-4-azahexadec-15-yn-16-yl)-2-formylphenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]

Reference： [1]Patent: WO2017/214456,2017,A1

17
[ 1333880-60-6 ]
(2S,3R,4S,5S,6S)-2-(5-(1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13-tetraoxa-4-azahexadecan-16-yl)-2-formylphenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]

Reference： [1]Patent: WO2017/214456,2017,A1

18
[ 1333880-60-6 ]
(2S,3R,4S,5S,6S)-2-(5-(1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13-tetraoxa-4-azahexadecan-16-yl)-2-(hydroxymethyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]

Reference： [1]Patent: WO2017/214456,2017,A1

19
[ 1333880-60-6 ]
(2S,3R,4S,5S,6S)-2-(5-(1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13-tetraoxa-4-azahexadecan-16-yl)-2-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]

Reference： [1]Patent: WO2017/214456,2017,A1

20
[ 1333880-60-6 ]
[ 28920-43-6 ]
(9H-fluoren-9-yl)methyl (2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of Example 2.5 8.1 (0.986 g) in dichloromethane (20 mL) was added hydrochloric acid (20 mL, 2M in ether). The mixture was stirred at room temperature for 2 hours and concentratedunder reduced pressure. The residue was suspended in dichloromethane (20 mL). Triethylamine (3 mL) and 9-fluorenylmethyl chloroformate (1.5 g) were added, and the reaction stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure. Ethyl acetate was added, and the suspension was filtered. The eluent was concentrated under reduced pressure and purified by silica gel chromatography, eluting with a gradient of 5% to 40% heptanes/ethyl acetate, togive the title compound. MS (ESI) mle 410.0 (M+H).

Reference： [1]Patent: WO2017/214456,2017,A1 .Location in patent: Page/Page column 364

21
[ 1333880-60-6 ]
3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ No CAS ]
tert-butyl N-[2-[2-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]prop-2-yn-1-yl]oxy)ethoxy]ethyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 110℃;Inert atmosphere;	A mixture of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (200 mg, 0.592 mmol), <strong>[1333880-60-6]tert-butyl (2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)carbamate</strong> (430 mg, 1.78 mmol), Pd(PPh3)2Cl2(34 mg, 0.0474 mmol), Cul (18 mg, 0.0947 mmol) and DMF (15 mL) was bubbled with N2for 10 min. Then to the mixture was added TEA (598 mg, 5.92 mmol) under N2. The mixture was heated to 110 C under N2and stirred for 3 h. To the mixture was added H20 (50 mL) and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2S04. The solid was filtered and the filtrate was concentrated, the residue was purified by column chromatography on silica gel (DCM/EA = 1/1 +1% THF) to give tert-butyl (2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate (100 mg, 34 % yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.20 (d, J= 8.3 Hz, 1H), 7.13 (s, 1H), 6.75 (d, 7= 8.2 Hz, 1H), 5.20 (dd, 7= 12.6, 5.4 Hz, 1H), 4.44 (s, 2H), 3.77-3.75 (m, 2H), 3.69-3.67 (m, 2H), 3.57 (t, 7= 5.2 Hz, 2H), 3.43 (s, 3H), 3.34 (d, J = 5.2 Hz, 2 H), 2.88-2.70 (m, 2H), 2.27-2.22 (m, 2H), 1.44 (s, 9H). LC-MS (ESI+): m/z 401.1 (M-Boc+H)+

Reference： [1]Patent: WO2019/60742,2019,A1 .Location in patent: Paragraph 00374; 00385; 00386

22
[ 1333880-60-6 ]
(9H-fluoren-9-yl)methyl (2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)carbamate [ No CAS ]

Reference： [1]Patent: US2019/153107,2019,A1

23
[ 1333880-60-6 ]
(2S,3R,4S,5S,6S)-2-(5-(1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13-tetraoxa-4-azahexadec-15-yn-16-yl)-2-formylphenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]

Reference： [1]Patent: US2019/153107,2019,A1

24
[ 1333880-60-6 ]
(2S,3R,4S,5S,6S)-2-(5-(1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13-tetraoxa-4-azahexadecan-16-yl)-2-formylphenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]

Reference： [1]Patent: US2019/153107,2019,A1

25
[ 1333880-60-6 ]
(2S,3R,4S,5S,6S)-2-(5-(1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13-tetraoxa-4-azahexadecan-16-yl)-2-(hydroxymethyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]

Reference： [1]Patent: US2019/153107,2019,A1

26
[ 1333880-60-6 ]
(2S,3R,4S,5S,6S)-2-(5-(1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13-tetraoxa-4-azahexadecan-16-yl)-2-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate [ No CAS ]

Reference： [1]Patent: US2019/153107,2019,A1

27
[ 24424-99-5 ]
[ 1333880-60-6 ]

Reference： [1]MedChemComm,2019,vol. 10,p. 1037 - 1041
[2]Patent: US2019/192668,2019,A1

28
[ 139115-91-6 ]
[ 1333880-60-6 ]

Reference： [1]MedChemComm,2019,vol. 10,p. 1037 - 1041

29
2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]acetic acid ethyl ester [ No CAS ]
[ 1333880-60-6 ]

Reference： [1]MedChemComm,2019,vol. 10,p. 1037 - 1041

30
[ 430430-57-2 ]
[ 107-19-7 ]
[ 1333880-60-6 ]

Reference： [1]MedChemComm,2019,vol. 10,p. 1037 - 1041

31
[ 1333880-60-6 ]
2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione [ No CAS ]

Reference： [1]MedChemComm,2019,vol. 10,p. 1037 - 1041

32
[ 1333880-60-6 ]
3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ No CAS ]
tert-butyl N-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxobenzimidazol-5-yl]prop-2-ynoxy]ethoxy]ethoxy]ethyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere;	A mixture of tert-butyl N-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethyl]carbamate (849 mg, 2.96 mmol, Intermediate VS), 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, Intermediate HN), Pd(PPh3)2Cl2 (311 mg, 443 umol), CuI (84 mg, 443 umol) and TEA (2.69 g, 26.6 mmol, 3.70 mL) in DMF (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 C. for 3 hrs under N2 atmosphere. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% FA) to give the title compound (400 mg, 49% yield) as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.33 (s, 1H), 7.21-7.12 (m, 2H), 6.77-6.71 (m, 1H), 5.39 (dd, J=5.2, 12.8 Hz, 1H), 4.40 (s, 2H), 3.68-3.62 (m, 2H), 3.61-3.56 (m, 2H), 3.55-3.47 (m, 6H), 3.35 (s, 3H), 3.07 (q, J=6.0 Hz, 2H), 2.96-2.80 (m, 1H), 2.72-2.58 (m, 2H), 2.08-1.99 (m, 1H), 1.37 (s, 9H).

Reference： [1]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 4044; 4045

33
[ 1333880-60-6 ]
3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ No CAS ]
tert-butyl N-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxobenzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethoxy]ethyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere;	A mixture of tert-butyl N-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethyl]carbamate (1.27 g, 4.44 mmol, Intermediate VS), 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, Intermediate HP), CuI (85 mg, 446 umol), Pd(PPh3)2Cl2 (311 mg, 443 umol) and Cs2CO3 (2.41 g, 7.39 mmol) in DMF (12 mL) was stirred at 80 C. for 2 hours under N2 atmosphere. On completion, after cooled to 25 C., the mixture was filtered through a pad of celite and the cake was washed with EA (50 mL). The filtrate and washing were combined, diluted with water (100 mL), and extracted with EA (3×40 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reversed phase chromatography (0.1% FA condition) to give the title compound (420 mg, 52% yield) as light yellow gum. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.10-7.15 (m, 1H), 7.00-7.06 (m, 1H), 5.39 (dd, J=12.4, 5.6 Hz, 1H), 4.46 (s, 2H), 3.61-3.69 (m, 5H), 3.55-3.60 (m, 2H), 3.46-3.55 (m, 6H), 3.05 (q, J=6.0 Hz, 2H), 2.83-2.93 (m, 1H), 2.58-2.76 (m, 3H), 2.04-2.02 (m, 1H), 1.36 (s, 9H)

Reference： [1]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 4048; 4049

34
[ 1333880-60-6 ]
3-(4-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione [ No CAS ]
tert-butyl (2-(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethoxy)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58.1%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere;	A mixture of 3-(4-bromo-l-oxo-2,3-dihydro-lH-isoindol-2-yl)piperidine- 2,6-dione (2.52 mmol), (PPh3)2PdCl2 (0.15 mmol), Cul (0.25 mmol), alkyne (5.04 mmol) were added to a vial. The vial was evacuated and backfilled with N2 5 times. DMF and triethylamine (30.3 mmol) were added and the mixture was allowed to stir at 90 C overnight. The mixture was filtered through celite, washing with MeOH and EtOAc. EtOAc and saturated aqueous NaCl were added. The organic layer was dried with MgS04, filtered, concentrated and purified by reverse phase MPLC (5-100% MeCN in H20 on C18 column) to afford the product.
0.5 g	With copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; triethylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 3.33333h;Inert atmosphere;	To a stirred solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.5 g, 1.55 mmol, Intermediate IR) in DMF (6.0 ml) was added <strong>[1333880-60-6]tert-butyl (2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)carbamate</strong> (0.6 g, 2.32 mmol, Intermediate IS) at rt. The reaction mixture was purged with N2 gas for 20 min. To the stirred reaction mixture were added CuI (0.014 g, 0.0776 mmol), TEA (5.5 ml, 37.26 mmol), PdCl2(PPh3)2 (0.054 g, 0.0776 mmol) and further purged with N2 gas for 20 min. The reaction mixture was heated at 80 C. for 3 h. On completion, the reaction mixture was poured into water (200 ml) and product was extracted with ethyl acetate (3×200 ml). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude material was purified by silica gel flash chromatography (eluting at 4% MeOH in MDC) to afford tert-butyl (2-(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethoxy)ethyl)carbamate (0.5 g, 1.0 mmol). LCMs m/z: (ES+) 528.4 (M-1)+.

Reference： [1]Patent: WO2020/81450,2020,A1 .Location in patent: Paragraph 0727; 0728; 0731
[2]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2837; 2838

35
[ 1333880-60-6 ]
tert-butyl (2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)ethoxy)ethyl)carbamate [ No CAS ]