[ CAS No. 133803-81-3 ] {[proInfo.proName]}

Name: 133803-81-3|tert-Butyl 3-(2-(2-hydroxyethoxy)ethoxy)propanoate|95%
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Quality Control of [ 133803-81-3 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 133803-81-3 ]

CAS No. :	133803-81-3	MDL No. :	MFCD20926380
Formula :	C₁₁H₂₂O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OKOWESVURLUVMD-UHFFFAOYSA-N
M.W :	234.29	Pubchem ID :	14833137
Synonyms :

Safety of [ 133803-81-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H312-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 133803-81-3 ]

* 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 [ 133803-81-3 ]
Downstream synthetic route of [ 133803-81-3 ]

[ 133803-81-3 ] Synthesis Path-Upstream 1~2

1
[ 1663-39-4 ]
[ 111-46-6 ]
[ 133803-81-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium In tetrahydrofuran at 20℃; for 20 h;	Example 1: tert-Butyl 3-(2-(2-hydroxyethoxy)ethoxy)propanoate (84) To 350 mL of anhydrous THF was added 80 mg (0.0025 mol) of sodium metal and diethylene glycol 83 (150.1 g, 1.41 mol) with stirring. After the sodium had completely dissolved, tert-butyl acrylate (24 mL, 0.33 mol) was added. The solution was stirred for 20 h at room temperature and neutralized with 8 mL of 1.0 M HC1. The solvent was removed in vacuo and the residue was suspended in brine (250 mL) and extracted with ethyl acetate(3 x 125 mL). The combined organic layers were washed with brine (100 mL) then water (100 mL), dried over sodium sulfate, and the solvent was removed. The resulting colorless oil was dried under vacuum to give 60.27 g (78percent yields) of product 84. ‘H NMR: 1.41 (s, 9H), 2.49 (t, 2H, 1=6.4 Hz), 3.59-3.72 (m, 1OH). ESI MS mlz- C,,H2,05 (M-H), cacld.233.15, found 233.40.
49.4%	Stage #1: With sodium In tetrahydrofuran	To a solution of 2,2'-oxydiethanol (19.7 mL, 206.7 mmol, 3.0 eq.) in anhydrous THF (100 mL) was added sodium (0.1 g). The mixture was stirred until Na disappeared and then tert-butyl acrylate (10.0 mL, 68.9 mmol, 1.0 eq.) was added dropwise. The mixture was stirred overnight, and brine (200 mL) was added and extracted with EtOAc (3 × 100 mL). The organic layers were washed with brine (3 × 300 mL), dried over anhydrous Na₂SO₄, filtered, concentrated and purified by SiO₂ column chromatography (1:1 hexanes/ EtOAc) to give to a colorless oil (8.10 g, 49.4percent yield). MS ESI m/z calcd for C₁₁H₂₃O₅ [M +H]⁺ 235.1467, found 235.1667.
40%	Stage #1: With sodium hydride In tetrahydrofuran for 1 h; Stage #2: for 48 h;	Metal sodium (64 mg, 0.03 eq) was added to a solution of diethylene glycol (29.5 g, 0.278 mmol) in THF (100 mL). The mixture was stirred for 1 hour to dissolve the sodium, then ie/ -butyl acrylate (12.4 g, 97 mmol) was added. The resulting mixture was stirred for 2 days, then concentrated under reduced pressure and the residue purified by silica chromatography (hexane:EtOAc = 1: 1) to give the title compound (9.1 g, 40percent) as a colorless oil. 1H NMR (400 MHz, CDC1₃): δ 3.75 (m, 4H), 3.64 (m, 6H), 2.53 (t, 2H), 2.40 (s, 1H), 1.45 (s, 9H).

Reference： [1] Synthesis (Germany), 2014, vol. 46, # 10, p. 1399 - 1406
[2] Patent: WO2015/155753, 2015, A2, . Location in patent: Page/Page column 84
[3] Journal of the American Chemical Society, 2011, vol. 133, # 10, p. 3230 - 3233
[4] Synthetic Communications, 2004, vol. 34, # 13, p. 2425 - 2432
[5] Patent: WO2018/2902, 2018, A1, . Location in patent: Page/Page column 46
[6] European Journal of Organic Chemistry, 2013, # 24, p. 5303 - 5314
[7] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2004, vol. 59, # 7, p. 802 - 806
[8] Patent: WO2016/59622, 2016, A2, . Location in patent: Page/Page column 104
[9] Patent: WO2018/86139, 2018, A1, . Location in patent: Page/Page column 152; 153
[10] Journal of the American Chemical Society, 2005, vol. 127, # 10, p. 3400 - 3405
[11] Journal of the American Chemical Society, 2018, vol. 140, # 48, p. 16428 - 16432
[12] Chemistry - A European Journal, 2017, vol. 23, # 72, p. 18216 - 18224
[13] Patent: WO2018/85247, 2018, A1, . Location in patent: Paragraph 00327
[14] Chemistry - A European Journal, 2012, vol. 18, # 19, p. 5880 - 5888
[15] Synthetic Communications, 2007, vol. 37, # 11, p. 1899 - 1915

2
[ 133803-81-3 ]
[ 756525-95-8 ]

Reference： [1] Synthesis (Germany), 2014, vol. 46, # 10, p. 1399 - 1406
[2] Patent: WO2016/59622, 2016, A2,
[3] Patent: WO2018/86139, 2018, A1,

[ 133803-81-3 ] Synthesis Path-Downstream 1~87

1
[ 821-06-7 ]
[ 133803-81-3 ]
[ 780761-84-4 ]

Reference： [1]Zeitschrift fur Naturforschung, B: Chemical Sciences,2004,vol. 59,p. 802 - 806

2
[ 822-06-0 ]
[ 133803-81-3 ]
[ 945867-56-1 ]

Reference： [1]Synthetic Communications,2007,vol. 37,p. 1899 - 1915

3
[ 133803-81-3 ]
[ 945867-58-3 ]

Reference： [1]Synthetic Communications,2007,vol. 37,p. 1899 - 1915

4
[ 133803-81-3 ]
[ 945867-61-8 ]

Reference： [1]Synthetic Communications,2007,vol. 37,p. 1899 - 1915

5
[ 133803-81-3 ]
[ 945867-64-1 ]

Reference： [1]Synthetic Communications,2007,vol. 37,p. 1899 - 1915

6
[ 133803-81-3 ]
[ 945867-67-4 ]

Reference： [1]Synthetic Communications,2007,vol. 37,p. 1899 - 1915

7
[ 133803-81-3 ]
(E)-14-bromo-4,7,10-trioxatetradec-12-enoic acid [ No CAS ]

Reference： [1]Zeitschrift fur Naturforschung, B: Chemical Sciences,2004,vol. 59,p. 802 - 806

8
[ 133803-81-3 ]
(E)-14-(2'-amino-6'-benzyloxypurine-7'-yl)-4,7,10-trioxatetradec-12-enoic acid tert-butyl ester [ No CAS ]

Reference： [1]Zeitschrift fur Naturforschung, B: Chemical Sciences,2004,vol. 59,p. 802 - 806

9
[ 133803-81-3 ]
(E)-14-(2'-amino-6'-benzyloxypurine-9'-yl)-4,7,10-trioxatetradec-12-enoic acid tert-butyl ester [ No CAS ]

Reference： [1]Zeitschrift fur Naturforschung, B: Chemical Sciences,2004,vol. 59,p. 802 - 806

10
[ 133803-81-3 ]
[ 796062-74-3 ]

Reference： [1]Journal of the American Chemical Society,2005,vol. 127,p. 3400 - 3405

11
[ 133803-81-3 ]
[ 850090-14-1 ]

Reference： [1]Journal of the American Chemical Society,2005,vol. 127,p. 3400 - 3405

12
[ 133803-81-3 ]
3-{2-[2-(4-{2-[2-(2-carboxy-ethoxy)-ethoxy]-ethoxy}-2,5-bis-<i>p</i>-tolylethynyl-phenoxy)-ethoxy]-ethoxy}-propionic acid [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2005,vol. 127,p. 3400 - 3405

13
[ 133803-81-3 ]
[ 1271728-79-0 ]

Reference： [1]Journal of the American Chemical Society,2011,vol. 133,p. 3230 - 3233
[2]European Journal of Organic Chemistry,2013,p. 5303 - 5314
[3]Patent: WO2015/155753,2015,A2
[4]Patent: WO2016/59622,2016,A2
[5]Patent: WO2018/2902,2018,A1
[6]Patent: WO2018/86139,2018,A1
[7]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 767 - 772
[8]Patent: WO2020/6722,2020,A1
[9]Patent: CN110621673,2019,A

14
[ 133803-81-3 ]
[ 1271728-80-3 ]

Reference： [1]Journal of the American Chemical Society,2011,vol. 133,p. 3230 - 3233

15
[ 133803-81-3 ]
[ 1271728-76-7 ]

Reference： [1]Journal of the American Chemical Society,2011,vol. 133,p. 3230 - 3233

16
[ 133803-81-3 ]
[ 1312309-63-9 ]

Reference： [1]Journal of the American Chemical Society,2011,vol. 133,p. 3230 - 3233
[2]European Journal of Organic Chemistry,2013,p. 5303 - 5314
[3]Patent: WO2015/155753,2015,A2
[4]Patent: WO2016/59622,2016,A2
[5]Patent: WO2018/86139,2018,A1
[6]Patent: WO2020/6722,2020,A1
[7]Patent: CN110621673,2019,A

17
[ 64-17-5 ]
[ 133803-81-3 ]
[ 1379649-80-5 ]

Reference： [1]Chemistry - A European Journal,2012,vol. 18,p. 5880 - 5888

18
[ 133803-81-3 ]
[ 1379649-81-6 ]

Reference： [1]Chemistry - A European Journal,2012,vol. 18,p. 5880 - 5888

19
[ 133803-81-3 ]
[ 1379649-82-7 ]

Reference： [1]Chemistry - A European Journal,2012,vol. 18,p. 5880 - 5888

20
[ 133803-81-3 ]
[ 1379649-73-6 ]

Reference： [1]Chemistry - A European Journal,2012,vol. 18,p. 5880 - 5888

21
[ 133803-81-3 ]
[ 1453118-14-3 ]

Reference： [1]European Journal of Organic Chemistry,2013,p. 5303 - 5314

22
[ 133803-81-3 ]
[ 1453118-21-2 ]

Reference： [1]European Journal of Organic Chemistry,2013,p. 5303 - 5314

23
[ 133803-81-3 ]
[ 1453118-13-2 ]

Reference： [1]European Journal of Organic Chemistry,2013,p. 5303 - 5314

24
[ 133803-81-3 ]
[ 1491136-22-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With pyridine; Dess-Martin periodane; In dichloromethane; for 3h;	Synthesis of 3-Methyl Pyrazalinone Compounds [00380] 3-Methyl pyrazalinone compounds were synthesized as illustrated in general reaction Scheme 4, below: Scheme 4 NHBoc 190 200 210 240 [00381] General reaction Scheme 4 was performed according to the reactions described in greater detail as follows: [00382] tert-Butyl 3-(2-(2-oxoethoxy)ethoxy)propanoate: To an oven-dried 20mL vial charged with 1.67 mmol (707mg) of Dess-Martin Periodinane was added 3.34 mmol (270mu) pyridine followed by 2mL DCM and sonicated until homogeneous. To this solution was added 1.39 mmol tert-Butyl 3-(2-(2-hydroxyethoxy)ethoxy)propanoate dissolved in 3mL DCM and stirred for 3h, after which 5mL DCM, 5mL 10% aqueous Na2S203, and 5mL saturated aqueous NaHC03 was added. This solution was stirred for 5min, then extracted lx5mL saturated aqueous NaHC03 followed by lx5mL Brine. The organic layer was dried over MgS04, concentrated by rotary evaporation and chromatographed on silica gel using a 10-100% Ethyl Acetate: Hexanes gradient to yield 291.4 mg of desired product in 90%> yield. 0 BocNHN h . . O
48%	With pyridine; Dess-Martin periodane; In dichloromethane; at 0 - 20℃; for 16h;	ferf-Butyl 3 (2 (2- hydroxyethoxy)ethoxy)propanoate (8.6 g, 37 mmol) was added to a suspension of Dess- Martin periodinane (DMP, 18.8 g, 44 mmol) and pyridine (7.0 g, 88 mmol) in DCM (150 mL) at 0C. The resulting mixture was stirred at room temperature for 16 hours, then filtered, washed with DCM (3 x 50 mL). The filtrate and washings were combined and washed with saturated NaHC03 solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica chromatography (hexane:EtOAc = 10: 1 to 3: 1) to give the title compound (4.1 g, 48%) as a yellow oil. 1H NMR (400 MHz, CDC13): delta 9.76 (s, 1H), 4.16 (s, 2H), 3.50-3.80 (m, 6H), 2.53(t, 2H), 1.46 (s, 9H).
48%	With pyridine; Dess-Martin periodane; In dichloromethane; at 0 - 20℃; for 16h;	/ -Butyl 3-(2-(2-hydroxyethoxy)ethoxy)propanoate (8.6 g, 37 mmol) was added to a suspension of Dess-Martin periodinane (DMP) (18.8 g, 44 mmol) and pyridine (7.0 g, 88 mmol) in DCM (150 mL) at 0C. The resulting mixture was stirred at room temperature for 16 hours, then filtered, and washed with DCM (3 x 50 mL). The filtrate and washings were combined and washed with saturated NaHCCb solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica chromatography (10: 1-3 : 1 hexane:EtOAc) to give the title compound (4.1 g, 48%) as a yellow oil. (0319) [00141] NMR (400 MHz, CDCb): d 9.76 (s, 1H), 4.16 (s, 2H), 3.50-3.80 (m, 6H), 2.53(t, (0320) 2H), 1.46 (s, 9H).

Reference： [1]Patent: WO2014/74218,2014,A1 .Location in patent: Paragraph 00380-00382
[2]Patent: WO2018/85247,2018,A1 .Location in patent: Paragraph 00328
[3]Patent: WO2020/69105,2020,A1 .Location in patent: Paragraph 00140-00141

25
[ 133803-81-3 ]
[ 1609643-79-9 ]

Reference： [1]Patent: WO2014/74218,2014,A1

26
[ 133803-81-3 ]
[ 1609643-80-2 ]

Reference： [1]Patent: WO2014/74218,2014,A1

27
[ 133803-81-3 ]
3-(2-(2-hydrazinylethoxy)ethoxy)propanoic acid trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2014/74218,2014,A1

28
[ 133803-81-3 ]
[ 1609643-82-4 ]

Reference： [1]Patent: WO2014/74218,2014,A1

29
[ 133803-81-3 ]
[ 1609643-83-5 ]

Reference： [1]Patent: WO2014/74218,2014,A1

30
[ 133803-81-3 ]
[ 756525-95-8 ]

Reference： [1]Synthesis,2014,vol. 46,p. 1399 - 1406
[2]Patent: WO2016/59622,2016,A2
[3]Patent: WO2018/86139,2018,A1
[4]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 767 - 772
[5]Patent: WO2020/6722,2020,A1
[6]Patent: CN110621673,2019,A

31
[ 133803-81-3 ]
tert-butyl 3-(2-{2-[3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido]ethoxy}ethoxy)propanoate [ No CAS ]

Reference： [1]Synthesis,2014,vol. 46,p. 1399 - 1406
[2]Synthesis,2014,vol. 46,p. 1399 - 1406

32
[ 133803-81-3 ]
[ 756525-98-1 ]

Reference： [1]Synthesis,2014,vol. 46,p. 1399 - 1406
[2]Synthesis,2014,vol. 46,p. 1399 - 1406

33
[ 133803-81-3 ]
[ 1037589-69-7 ]

Reference： [1]Synthesis,2014,vol. 46,p. 1399 - 1406
[2]Synthesis,2014,vol. 46,p. 1399 - 1406

34
[ 133803-81-3 ]
[ 1629676-51-2 ]

Reference： [1]Synthesis,2014,vol. 46,p. 1399 - 1406

35
[ 7145-49-5 ]
[ 133803-81-3 ]
tert-butyl 3-(2-(2-(3-methoxy-5-nitrophenoxy)ethoxy)ethoxy)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.13 g	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; 2-Methylpentane; ethyl acetate; at 0 - 20℃;	DIAD (730 muL, 3.60 mmol) was added dropwise to a stirred solution of 3-methoxy-5-nitrophenol (510 mg, 2.99 mmol), <strong>[133803-81-3]tert-butyl 3-(2-(2-hydroxyethoxy)ethoxy)propanoate</strong> (700 mg, 2.99 mmol) and triphenylphosphine (950 mg, 3.59 mmol) in THF (4 mL) at 0-5 C. The reaction was allowed to warm to rt and stirred at this temperature overnight. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g column, 0-100% EtOAc in isohexane) to afford the sub-title compound (1.13 g) as a yellow oil, which solidified on standing. The product was used in the next without further purification. 1H NMR (400 MHz, DMSO-d6) delta: 7.34-7.32 (m, 2H), 6.98 (t, 1H), 4.21-4.19 (m, 2H), 3.85 (s, 3H), 3.76-3.74 (m, 2H), 3.60-3.56 (m, 4H), 3.52-3.50 (m, 2H), 2.40 (t, 2H), 1.38 (s, 9H).
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;	DIAD (730 pL, 3.60 mmol) was added dropwise to a stirred solution of 3-methoxy-5- nitrophenol (510 mg, 2.99 mmol), tert-butyl 3-(2-(2-hydroxyethoxy)ethoxy) propanoate (700 mg, 2.99 mmol) and triphenylphosphine (950 mg, 3.59 mmol) in THF (4 mL) at 0-5 00 Thereaction was allowed to warm to rt and stirred at this temperature overnight. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g column, 0-100% EtOAc in isohexane) to afford the sub-title compound (1.13 g) as a yellow oil, which solidified on standing. The product was used in the next without further purification.1H NMR (400 MHz, DMSO-d6) O: 7.34-7.32 (m, 2H), 6.98 (t, 1H), 4.21-4.19 (m, 2H), 3.85 (5,3H), 3.76-3.74 (m, 2H), 3.60-3.56 (m, 4H), 3.52-3.50 (m, 2H), 2.40 (t, 2H), 1.38 (5, 9H).42wt% Hydrazine by-product present

Reference： [1]Patent: US2014/296208,2014,A1 .Location in patent: Paragraph 0894; 0895
[2]Patent: WO2014/162126,2014,A1 .Location in patent: Page/Page column 92

36
[ 133803-81-3 ]
(S)-8-((5-(((S)-10-(3-(2-(2-azidoethoxy)ethoxy)propanoyl)-7-methoxy-2-methylene-5-oxo-2,3,5,10,11,11a-hexahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)pentyl)oxy)-7-methoxy-2-methylene-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one [ No CAS ]

Reference： [1]Patent: WO2015/155753,2015,A2
[2]Patent: WO2016/59622,2016,A2
[3]Patent: WO2018/86139,2018,A1
[4]Patent: WO2020/6722,2020,A1

37
[ 133803-81-3 ]
(S)-8-((5-(((S)-10-(3-(2-(2-aminoethoxy)ethoxy)propanoyl)-7-methoxy-2-methylene-5-oxo-2,3,5,10,11,11a-hexahydro-1H-benzo[e]pyrrolo[ 1,2-a][1,4]diazepin-8-yl)oxy)pentyl)oxy)-7-methoxy-2-methylene-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one [ No CAS ]

Reference： [1]Patent: WO2015/155753,2015,A2
[2]Patent: WO2016/59622,2016,A2
[3]Patent: WO2018/86139,2018,A1
[4]Patent: WO2020/6722,2020,A1

38
[ 133803-81-3 ]
(2S)-2-((2R,3R)-3-((2S)-1-((11S,14S,17S)-1-azido-17-((R)-sec-butyl)-11,14-diisopropyl-18-methoxy-10,16-dimethyl-9,12,15-trioxo-3,6-dioxa-10,13,16-triazaicosan-20-oyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid [ No CAS ]

Reference： [1]Patent: WO2015/155753,2015,A2

39
[ 133803-81-3 ]
(2S)-2-((2R,3R)-3-((2S)-1-((11S,14S,17S)-1-amino-17-((R)-sec-butyl)-11,14-diisopropyl-18-methoxy-10,16-dimethyl-9,12,15-trioxo-3,6-dioxa-10,13,16-triazaicosan-20-oyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoicacid [ No CAS ]

Reference： [1]Patent: WO2015/155753,2015,A2

40
[ 133803-81-3 ]
2,3-dibromo-4-((2-(2-(3-((S)-7-methoxy-8-((5-(((S)-7-methoxy-2-methylene-5-oxo-2,3,5,11a-tetrahydro-1H-benzo [e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)pentyl)oxy)-2-methylene-5-oxo-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10(5H)-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-4-oxobutanoic acid [ No CAS ]

Reference： [1]Patent: WO2015/155753,2015,A2
[2]Patent: WO2016/59622,2016,A2

41
[ 133803-81-3 ]
2,5-dioxopyrrolidin-1-yl-2,3-dibromo-4-((2-(2-(3-((S)-7-methoxy-8-((5-(((S)-7-methoxy-2-methylene-5-oxo-2,3,5,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]-diazepin-8-yl)oxy)pentyl)oxy)-2-methylene-5-oxo-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10(5H)-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-4-oxobutanoate [ No CAS ]

Reference： [1]Patent: WO2015/155753,2015,A2
[2]Patent: WO2016/59622,2016,A2

42
[ 133803-81-3 ]
2,5-dioxopyrrolidin-1-yl-3 (2-(2-azidoethoxy)ethoxy)propanoate [ No CAS ]

Reference： [1]Patent: WO2015/155753,2015,A2
[2]Patent: WO2016/59622,2016,A2
[3]Patent: WO2018/86139,2018,A1
[4]Patent: WO2020/6722,2020,A1
[5]Patent: CN110621673,2019,A

43
[ 133803-81-3 ]
(4R)-4-(2-((1R,3R)-1-acetoxy-3-((2S,3S)-N,3-dimethyl-2-((R)-1-methylpiperidine-2-carboxamido)pentanamido)-4-methylpentyl)thiazole-4-carboxamido)-5-(3-(3-(2-(2-azidoethoxy)ethoxy)propanamido)-4-hydroxyphenyl)-2-methylpentanoic acid [ No CAS ]

Reference： [1]Patent: WO2015/155753,2015,A2
[2]Patent: WO2016/59622,2016,A2
[3]Patent: WO2018/86139,2018,A1

44
[ 133803-81-3 ]
(4R)-4-(2-((1R,3R)-1-acetoxy-3-((2S,3S)-N, 3-dimethyl-2-((R)-1-methyl-piperidine-2-carboxamido)pentanamido)-4-methylpentyl)thiazole-4-carboxamido)-5-(3-(3-(2-(2-aminoethoxy)ethoxy)propanamido)-4-hydroxyphenyl)-2-methylpentanoic acid [ No CAS ]

Reference： [1]Patent: WO2015/155753,2015,A2
[2]Patent: WO2016/59622,2016,A2
[3]Patent: WO2018/86139,2018,A1

45
[ 124-63-0 ]
[ 133803-81-3 ]
tert-butyl 3-[2-[2-(methanesulfonyloxy)ethoxy]ethoxy]propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With pyridine; In dichloromethane; for 5.5h;	Example 2. tert-Butyl 3-(2-(2-(tosyloxy)ethoxy)ethoxy)propanoate (85) A solution of 84 (10.0 g, 42.70 mmol) in dichloromethane (50.0 mL) was treated with pyridine (20.0 mL). A solution of methanesulfonyl chloride (7.50 g, 65.81 mmol) in 50 mL dichloromethane was added dropwise via an addition funnel over 30 minutes. After 5h TLC analysis revealed that the reaction was complete. The pyridine hydrochloride that had formed was filtered off and the solvent was removed. The residue was purified on silica gel by eluting from with 20% ethyl acetate in hexane to with neat ethyl acetate to give 10.39 g (76% yield) of compound 85. ?H NMR: 1.40 (s, 9H), 3.23 (s, 3H), 2.45 (t, 2H, 1=6.4 Hz), 3.54-3.70 (m, 1OH); ESI MS mlz+ C,2H25075 (M+H), cacld. 313.10, found313.30.
	With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;	To a solution of tert- butyl 3-[2-(2-hydroxyethoxy)ethoxy]propanoate (350 mg, 1.49 mmol) in DCM (15 ml) was added TEA (0.62 ml, 4.48 mmol), then the reaction mixture was cooled to 0 C (water ice/acetone bath) and Mesyl chloride (0.14 ml, 1.79 mmol) was added dropwise. The reaction mixture was stirred for 1 h at room temperature. By TLC no starting material (Hex:AcOEt, 3:7). Reaction mixture was poured into an aqueous solution of NaHC03 (20 mL) and product extracted with DCM (20mL, 2x), the organic extracts were combined, dried (Na2S04), and evaporated under vacuum. The crude product (mesylate) was used in the next step without any further purification (>95% pure by NMR): 1H NMR (500 MHz, Chloroform-d) delta 4.44 - 4.28 (m, 2H), 3.76 (dd, J = 5.2, 3.8 Hz, 2H), 3.70 (t, J = 6.4 Hz, 2H), 3.68 - 3.57 (m, 4H), 3.07 (s, 3H), 2.49 (t, J = 6.4 Hz, 2H), 1.45 (s, 9H). [00400] Crude mixture from previous step was diluted in Acetonitrile (5 ml) and Nal (335.88 mg, 2.24 mmol) was added, the reaction mixture was stirred at 70 C for 12 h (overnight). By TLC no starting material (Hex:AcOEt, 7:3), the reaction was poured into an aqueous solution of Na2S203 (10%, 50 mL) and product was extracted with DCM (2x50 mL). Organic extracts were combined, dried (Na2S04) and evaporated under vacuum. Crude product was purified by flash chromatography (SiO2-40g, grad. Hex:AcOEt, 2 to 40% in 15 min), to give 413 mg of product as an oil (80% yield). 1H NMR (500 MHz, Chloroform-d) delta 3.73 (dt, J = 13.5, 6.6 Hz, 4H), 3.68 - 3.54 (m, 4H), 3.24 (t, J = 6.9 Hz, 2H), 2.50 (t, J = 6.5 Hz, 2H), 1.44 (s, 9H). 13C NMR (151 MHz, cdcl3) delta 171.00, 80.69, 72.11, 70.50, 70.27, 67.09, 36.39, 28.25, 3.02. LC- MS ESI); m/z: [M+Na]+ Calcd. for CnH2iI04Na, 367.0382. Found 367.0943.

Reference： [1]Patent: WO2015/155753,2015,A2 .Location in patent: Page/Page column 84
[2]Patent: WO2018/226542,2018,A1 .Location in patent: Paragraph 00398-00401

46
C₁₃H₁₇N₂O₈PolS [ No CAS ]
[ 133803-81-3 ]
C₂₄H₃₇N₂O₁₂PolS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; for 1h;Inert atmosphere;	For the synthesis of Ns-NPEG4-diacid-linkerA (3; Scheme 1) 2-chlorotrityl chloride resin (3 mmol, 1.90 g) was washed and swelled (20 min) in DMF. Fmoc-NH-PEG2-CH2CH2COOH (1, Scheme 1; Biomatrik Inc., Jiaxing, China) was loaded onto the resin by adding 1 (2 mmol, 800 mg) in DMF (8 mL) to the drained resin followed by DIPEA (10 mmol, 1.75 mL). After shaking for 60 min, methanol (1 mL, 25 mmol) was added, and shaking was continued for another 5 min. The loaded resin was drained and washed thoroughly with DMF (10-15 flow washes, each of 10 mL), and the Fmoc group was de-protected with 20% piperidine in DMF for 5 min and 15 min with a DMF wash in between, followed by a DMF and THF wash. The resin was swelled in DIPEA (12 mmol, 2.1 mL) and THF (8 mL) for 15 min, and ortho-nitrobenzenesulfonyl chloride (NsCl, 8 mmol, 1.78 g) in DCM (5 mL) was added slowly while gently stirring the resin. After 4 hours, the resin was drained and washed consecutively with THF, MeOH, DCM, and THF. The resin-attached free amino group was alkylated with the alcohol HO-PEG2-CH2CH2COOtBu (2, Scheme 1; Biomatrik Inc., Jiaxing, China) starting by evacuating the reaction vessel and adding a nitrogen balloon. The resin (1 eq., 2 mmol) was treated with triphenylphosphine (PPh3, 10 mmol, 2625 mg) in THF (5 mL) and 2 (10 mmol, 2.34 g) in THF (5 mL). Diisopropyl azodicarboxylate (DIAD) (10 mmol, 2.02 g, 1.97 mL) was added dropwise, and the balloon was removed before shaking for 1 hour. The resin was thoroughly washed with THF and DCM, dried in vacuo and treated with TFA/triisopropylsilane/H2O (90/5/5, 20 mL) for 2.5 hours. The TFA-mixture was collected and the resin was washed with TFA and DCM before the combined TFA/DCM fractions were evaporated and co-evaporated with ether (2×30 mL). The resulting material was dissolved in water/MeCN (75/25, 100 mL) and lyophilized to get Ns-NPEG4-diacid-linkerA (3, Scheme 1) as an orange oil, which was used directly in the synthesis of dimeric NPEG4 ligands. Yield: 80%. m/z (ESI) 540.1 (22%), 523.1 (M++H, 100), 505.1 (11), 433.0 (7.3), 365.2 (7.4).

Reference： [1]Patent: US9139615,2015,B2 .Location in patent: Page/Page column 20

47
[ 133803-81-3 ]
(E)-methyl 13-bromo-1-((5-((2R)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-methyl-5-oxopentyl)-2-((tert-butyldimethylsilyl)oxy)phenyl)-amino)-1,11,14-trioxo-4,7-dioxa-10,15-diazaoctadec-12-en-18-oate [ No CAS ]