Name: 16024-58-1|2-(2-(2-Methoxyethoxy)ethoxy)acetic acid|98%
Brand: Ambeed
SKU: A240373
Rating: 98 (40 reviews)

1
[ 16024-58-1 ]
[ 63881-16-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With oxalyl dichloride In toluene at 65℃; for 4h;
80%	With thionyl chloride	32.A Step A Step A Synthesis of 3,6,9-trioxadecanoyl chloride as an intermediate Thionyl chloride, 8.0 grams (0.112 mole) was stirred, and 10.0 grams (0.056 mole) of 3,6,9-trioxadecanoic acid was added dropwise during a 45 minute period. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred for 45 minutes. The reaction mixture was cooled, yielding 3,6,9-trioxadecanoyl chloride. An 80% yield of acid chloride was assumed.
	With thionyl chloride; benzene

	With phosphorus pentachloride In chloroform for 2h; Heating; Yield given;
	With Dichloromethyl methyl ether at 35℃; for 24h;
	With Dichloromethyl methyl ether; zinc(II) chloride for 1h; Heating;
	With oxalyl dichloride at 20℃;
	With thionyl chloride In dichloromethane for 12h; Heating;
	With thionyl chloride	5.1.1 In the synthesis of Compound I, 6.2 ml (0.085 mol) of thionyl chloride was placed through a dropping funnel into a two-neck flask equipped with a reflux condenser. The flask was heated gently on a water bath and anhydrous [2-(2-Methoxy-ethoxy)-ethoxy]-acetic acid (10 g, 0.056 mol) was added during the course of 40 min. When all acid had been introduced, the reaction mixture was heated on a water bath for 30 min and reaction mixture was stirred overnight at room temperature. Excess thionyl chloride was removed by aspiration pump and the product was distilled under the reduced pressure. The product was characterized using IR and NMR.
	With thionyl chloride In dichloromethane; N,N-dimethyl-formamide
	With thionyl chloride In 1-methyl-pyrrolidin-2-one
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 0.666667h;	24 Synthesis of the PEG-β-Lactamse Substrate Lacking a C2 Linker 2-[2-(2-Methoxyethoxy)ethoxy]acetic acid (67, 1.0 mL, 6.5 mmol) was dissolved in CH2Cl2 (10.0 mL). DMF (5 drops) was added and the solution was cooled to 0° C. Following the dropwise addition of oxalyl chloride (1.7 mL, 19 mmol), the reaction was stirred at 0° C. for 40 min. The volatiles were evaporated and the residue was re-evaporated from toluene one time. A 100% conversion to the acid chloride was assumed, and crude acid chloride 68 was used directly in the next reaction without further purification.
	With thionyl chloride In water at 20 - 70℃; for 2.5h;	4 2.3.3 Reaction of 6-azido-6-deoxycurdlan with 3,6,9-trioxadecanoyl chloride (TODCl) TODA (71.2g, 61.3mL, 0.4mol) was first weighed into a 250mL three-neck round-bottom flask equipped with a dropping funnel and a gas outlet connecting to a 5M NaHCO3 solution. Thionyl chloride (31.2mL, 0.44mol) was added dropwise into the flask with magnetic stirring at room temperature. It was stirred for 30min and then heated to 70°C for an additional 2h until gas release stopped. The unreacted thionyl chloride was removed by rotary evaporation. The residual liquid (TODCl) was used for subsequent esterification without further purification. (0014) Dry 6-azido-6-deoxycurdlan (0.5g, 2.67mmol) was dissolved in 25mL of DMAc in a 100mL flask. Pyridine (2.15mL, 10 eq per AGU) was injected all at once, then TODCl (4.6mL, 10 eq per AGU) was added dropwise from an addition funnel at room temperature. The mixture was heated to 80°C and stirred at that temperature for 24h. The homogeneous solution was cooled to room temperature and transferred to 3500g/mol MWCO dialysis tubing (prewet with water) that was placed in a large beaker containing deionized water. After five days of dialysis, the brown solution was then freeze-dried to yield 6-azido-6-deoxy-2,4-di-O-trioxadecanoyl-curdlan. 13C NMR (CDCl3): δ 169.1 (C=O), 100.1 (C-1), 72.9-67.2 (C-2∼5 and C-8∼14), 58.9 (C-16), 50.9 (C-6-N3). Yield: 78%.
	With thionyl chloride for 1h; Heating / reflux;	18 A solution of [2- (2-METHOXY-ETHOXY)-ETHOXY]-ACETIC acid (1 g, 5.6 mmol) and thionyl chloride (3 mL) was heated at reflux temperature for 1 hour. Excess thionyl chloride was removed by distillation at atmospheric pressure. The residue was purified by short path distillation under high vaccum to give 910 mg of acid chloride which was used in the next step without further purification.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃;	2 Preparation of 6-PEG oxycodone Oxycodone free base (0.316 g, 1 mmol) was mixed with LiN(TMS)2 (3 mmol) in anhydrous THF (20 ml) at -78°C for 30 minutes followed by stirring at room temperature for 30 minutes. The solution was re-chilled to -78°C and a solution of an acetyl chloride derivative, made by reacting 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (30 mg, 3 mmol) with 3 eq. of oxalyl chloride, was added to this reaction mixture. The reaction was let stir overnight and warm up slowly to room temperature. Based on LCMS, the conversion for the title compound was about 44%. The reaction mixture was rotary evaporated and re- dissolved in 20 ml of DCM. Saturated sodium bicarbonate solution was added until the aqueous layer was neutralized. After extracting the mixture with DCM (20 mL x 3 times), the combined organic layer was dried over MgS04 and concentrated under reduced pressure affording an amber oil 0.85 g. A portion of the residue was purified by preparatory HPLC to give 85% pure title product and 15% of oxycodone as impurity.

Reference： [1]Bailie; Malveau; Zhu; Kim; Ford [Macromolecules, 2003, vol. 36, # 3, p. 839 - 847]
[2]Current Patent Assignee: FMC CORP - US5534518, 1996, A
[3]Current Patent Assignee: CIBA PHARMACEUTICAL PRODUCTS, INC. - US2769838, 1954, A
[4]Heimann, Ulrich; Voegtle, Fritz [Liebigs Annalen der Chemie, 1980, # 6, p. 858 - 862]
[5]Pfammatter, Michael J.; Darbre, Tamis; Keese, Reinhart [Helvetica Chimica Acta, 1998, vol. 81, # 6, p. 1105 - 1116]
[6]Pfammatter, Michael J.; Siljegovic, Vuk; Darbre, Tamis; Keese, Reinhart [Helvetica Chimica Acta, 2001, vol. 84, # 3, p. 678 - 689]
[7]Panuganti, Sree D.; Penn, Jill M.; Moore, Kathleen H. [Journal of Biochemical and Molecular Toxicology, 2003, vol. 17, # 2, p. 76 - 85]
[8]Lafitte, Valerie G. H.; Aliev, Abu E.; Hailes, Helen C.; Bala, Kason; Golding, Peter [Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2701 - 2707]
[9]Current Patent Assignee: BIOCON LIMITED - US6713454, 2004, B1 Location in patent: Page/Page column 23
[10]Zhang, Jiahui; Wu, Xiangxiang; Yamato, Kazuhiro; Liu, Futao; Su, Tianyi; Zheng, Chong; He, Lan; Gong, Bing [Chemical Communications, 2010, vol. 46, # 7, p. 1062 - 1064]
[11]Gao, Yuan; De Jubera, Ana M. Saenz; Marinas, Benito J.; Moore, Jeffrey S. [Advanced Functional Materials, 2013, vol. 23, # 5, p. 598 - 607]
[12]Current Patent Assignee: THERMO FISHER SCIENTIFIC INC - US2016/139135, 2016, A1 Location in patent: Paragraph 0400-0401
[13]Zhang, Ruoran; Edgar, Kevin J. [Carbohydrate Polymers, 2015, vol. 122, p. 84 - 92]
[14]Current Patent Assignee: GILEAD SCIENCES INC - WO2005/25498, 2005, A2 Location in patent: Page/Page column 25
[15]Current Patent Assignee: PURDUE PHARMA L.P. - WO2019/165298, 2019, A1 Location in patent: Paragraph 0480

2
[ 112-35-6 ]
[ 16024-58-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hydrogencarbonate; sodium carbonate at 20℃; Electrochemical reaction;
99%	Stage #1: triethylene glucol monomethyl ether With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium carbonate at 20℃; for 2h; aq. buffer; Electroliysis; Stage #2: With Amberlite IR 120 for 0.5h; aq. buffer;
88%	Stage #1: triethylene glucol monomethyl ether With C₂₉H₄₄Cl₂N₂Ru; sodium hydroxide In water for 24h; Reflux; Stage #2: With hydrogenchloride In water

75%	With potassium hydroxide; potassium permanganate In water for 12h; Ambient temperature;
	With 4-(benzyloxycarbonyl)-2,2,6,6-tetramethylpiperidine-1-oxyl; acetylcholine chloride; sodium hydrogencarbonate; pyridinium hydrobromide perbromide In TETRAHYDROPYRANE; water at 20℃; for 2h;
	With Jones reagent In acetone at 20℃;
	With oxygen In water at 80℃; for 20h; Autoclave;

Reference： [1]Yoshida, Tomonori; Kuroboshi, Manabu; Oshitani, Jun; Gotoh, Kuniaki; Tanaka, Hideo [Synlett, 2007, # 17, p. 2691 - 2694]
[2]Location in patent: experimental part Kuroboshi, Manabu; Yoshida, Tomonori; Oshitani, Jun; Goto, Kuniaki; Tanaka, Hideo [Tetrahedron, 2009, vol. 65, # 34, p. 7177 - 7185]
[3]Malineni, Jagadeesh; Keul, Helmut; Möller, Martin [Dalton Transactions, 2015, vol. 44, # 39, p. 17409 - 17414]
[4]Heimann, Ulrich; Voegtle, Fritz [Liebigs Annalen der Chemie, 1980, # 6, p. 858 - 862]
[5]Location in patent: experimental part Mei, Zhen-Wu; Ma, Li-Jian; Kawafuchi, Hiroyuki; Okihara, Takumi; Inokuchi, Tsutomu [Bulletin of the Chemical Society of Japan, 2009, vol. 82, # 8, p. 1000 - 1002]
[6]Location in patent: experimental part Beneito-Cambra, Miriam; Bernabe-Zafon, Virginia; Simo-Alfonso, Ernesto F.; Ramis-Ramos, Guillermo [Rapid Communications in Mass Spectrometry, 2010, vol. 24, # 14, p. 2093 - 2100]
[7]Heidkamp, Katharina; Aytemir, Memet; Vorlop, Klaus-Dieter; Pruesse, Ulf [Catalysis science and technology, 2013, vol. 3, # 11, p. 2984 - 2992]

3
[ 16024-58-1 ]
[ 543-27-1 ]
C₁₂H₂₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine In N,N-dimethyl-formamide at -10℃; for 0.0833333h;
	With 4-methyl-morpholine In N,N-dimethyl-formamide at -15℃; for 0.0833333h;

Reference： [1]Walpole, Christopher S.J.; Wrigglesworth, Roger; Bevan, Stuart; Campbell, Elizabeth A.; Dray, Andy; et al. [Journal of Medicinal Chemistry, 1993, vol. 36, # 16, p. 2381 - 2389]
[2]Walpole, Christopher S.J.; Wrigglesworth, Roger; Bevan, Stuart; Campbell, Elizabeth A.; Dray, Andy; et al. [Journal of Medicinal Chemistry, 1993, vol. 36, # 16, p. 2381 - 2389]

4
[ 33657-49-7 ]
[ 16024-58-1 ]
Butyric acid 2-[2-(2-methoxy-ethoxy)-ethoxy]-acetoxymethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With triethylamine In acetone at 40℃;

Reference： [1]Nudelman, Abraham; Gnizi, Elisheva; Katz, Yifat; Azulai, Revital; Cohen-Ohana, Mirit; Zhuk, Regina; Sampson, Sanford R; Langzam, Leah; Fibach, Eitan; Prus, Eugenia; Pugach, Victoria; Rephaeli, Ada [European Journal of Medicinal Chemistry, 2001, vol. 36, # 1, p. 63 - 74]

5
[ 16024-58-1 ]
[ 625386-12-1 ]
[ 650609-88-4 ]

Yield	Reaction Conditions	Operation in experiment
53%	With 1-methyl-2-chloropyridinium chloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h;
	With 1-chloro-3-methylpyridinium iodide; N-ethyl-N,N-diisopropylamine In dichloromethane

Reference： [1]Rzepecki; Wehner; Molt; Zadmard; Harms; Schrader [Synthesis, 2003, # 12, p. 1815 - 1826]
[2]Rzepecki, Petra; Schrader, Thomas [Journal of the American Chemical Society, 2005, vol. 127, # 9, p. 3016 - 3025]

6
[ 6066-82-6 ]
[ 16024-58-1 ]
[ 260428-99-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With dicyclohexyl-carbodiimide In tetrahydrofuran for 16h; cooling;

Reference： [1]Bellomo, Enrico G.; Davidson, Patrick; Imperor-Clerc, Marianne; Deming, Timothy J. [Journal of the American Chemical Society, 2004, vol. 126, # 29, p. 9101 - 9105]

7
[ 16024-58-1 ]
[ 760174-14-9 ]
[ 862072-76-2 ]

Yield	Reaction Conditions	Operation in experiment
52%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 12h;

Reference： [1]Carlise, Joseph R.; Kriegel, Robert M.; Rees Jr., William S.; Weck, Marcus [Journal of Organic Chemistry, 2005, vol. 70, # 14, p. 5550 - 5560]

8
[ 16024-58-1 ]
[ 132806-44-1 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 4h;

Reference： [1]Wender, Paul A.; Baryza, Jeremy L. [Organic Letters, 2005, vol. 7, # 6, p. 1177 - 1180]

9
[ 16024-58-1 ]
[ 114459-62-0 ]
2-[2-(2-methoxyethoxy)ethoxy]acetamido-N²,N³,N⁴-tri(tert-butoxycarbonyl)spermine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In ethyl acetate at 20℃; for 48h;
	With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In dichloromethane

Reference： [1]Kostiainen, Mauri A.; Hardy, John G.; Smith, David K. [Angewandte Chemie - International Edition, 2005, vol. 44, # 17, p. 2556 - 2559]
[2]Hardy, John G.; Ashworth, Ian; Brennan, Colin; Smith, David K. [Organic and Biomolecular Chemistry, 2007, vol. 5, # 6, p. 900 - 906]

10
[ 229645-50-5 ]
[ 16024-58-1 ]
[ 881027-67-4 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: 2-[2-(2-methoxyethoxy)etoxy]acetic acid With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 1h; Stage #2: ethyl 14-amino-3,6,9,12-tetraoxatetradecanoate In dichloromethane at 20℃; for 0.5h;

Reference： [1]Bhosale, Sidhanath; Bhosale, Sheshanath; Wang, Tianyu; Kopaczynska, Marta; Fuhrhop, Jurgen-Hinrich [Journal of the American Chemical Society, 2006, vol. 128, # 7, p. 2156 - 2157]

11
[ 16024-58-1 ]
triglycine benzyl ester toluenesulfonic acid salt [ No CAS ]
[ 881027-70-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 2-[2-(2-methoxyethoxy)etoxy]acetic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Stage #2: triglycine benzyl ester toluenesulfonic acid salt With triethylamine In dichloromethane at 20℃;

Reference： [1]Bhosale, Sidhanath; Bhosale, Sheshanath; Wang, Tianyu; Kopaczynska, Marta; Fuhrhop, Jurgen-Hinrich [Journal of the American Chemical Society, 2006, vol. 128, # 7, p. 2156 - 2157]

12
[ 935761-46-9 ]
[ 16024-58-1 ]
[ 935761-47-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 48h;

Reference： [1]Hardy, John G.; Ashworth, Ian; Brennan, Colin; Smith, David K. [Organic and Biomolecular Chemistry, 2007, vol. 5, # 6, p. 900 - 906]

13
[4-({3-[2,6-bis-(2,6-diamino-hexanoylamino)-hexanoylamino]-propyl}-tert-butoxycarbonyl-amino)-butyl]-(3-tert-butoxycarbonylamino-propyl)-carbamic acid tert-butyl ester [ No CAS ]
[ 16024-58-1 ]
C₇₁H₁₃₄N₁₀O₂₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 48h;

Reference： [1]Hardy, John G.; Ashworth, Ian; Brennan, Colin; Smith, David K. [Organic and Biomolecular Chemistry, 2007, vol. 5, # 6, p. 900 - 906]

14
[ 208404-01-7 ]
[ 16024-58-1 ]
C₂₈H₂₈O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	In toluene for 5h; Heating / reflux;	10 Example 10 The preparation of ester VIII (structure V, R'-CH2OCH2CH2OCH2CH2OCH3) was carried out. Acetate III (3.9 g, 10 mmol) and 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (1.78 g, 10 mmol) were combined in about 15 mL of toluene and heated at reflux for 5 hours. The toluene was then distilled from the reaction mixture, replaced with fresh toluene, distilled, replaced with fresh toluene again, and distilled once more. The reaction mixture was then cooled, taken up in ether, and filtered to yield 4.13 g (81%) of compound VIII.

Reference： [1]Current Patent Assignee: GENERAL ELECTRIC CO - US6395922, 2002, B1 Location in patent: Page column 12

15
[ 16024-58-1 ]
cryptophycin 55 [ No CAS ]
cryptophycin 55 3,6,9-tioxadecanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.5h;	94 To a solution of 1' (18 mg, 0.026 mmol), 3,6,9-trioxadecanoic acid (7.8 μl, 0.051 mmol), and 4-dimethylamino pyridine (0.3 mg, 0.0026 mmol) in 100 μl of anhydrous methylene chloride at room temperature was added a solution of 1,3-dicyclohexylcarbodiimide (11 mg, 0.051 mmol) in 28 μl of methylene chloride. After stirring for 30 min, the cloudy white reaction mixture diluted with ethyl acetate-hexanes (3:1, 0.5 ml), stirred for 10 min, and filtered through a plug of celite, washing with ethyl acetate:hexanes (3:1). The filtrate and washings were concentrated in vacuo to an off-white oil. Chromatography (12 g of flash silica gel, 2% methanol in ethyl acetate) afforded 19 mg (86%) of the title compound as a white foam: 500 MHz, 1H NMR (CDCl3) δ 7.49-7.29 (m, 5H), 7.24 (d, 1H, J=1.8 Hz), 7.22-7.19 (m, 1H), 7.10 (dd, 1H, J=8.4, 1.8 Hz), 6.87 (d, 1H, J=8.4 Hz), 6.74 (ddd, 1H, J=15, 10, 4.5 Hz), 5.32-5.28 (m, 2H), 5.56 (d, 1H, J=9.7 Hz), 4.98-4.90 (m, 2H), 4.83 (d, 1H, J=9.7 Hz), 4.77-4.71 (m, 1H), 3.90 (s, 3H), 3.83 (d, 1H, J=17 Hz), 3.65-3.55 (m, 7H), 3.42-3.33 (m, 6H), 3.24-3.18 (m, 2H), 3.03 (dd, 1H, J=15, 8.1 Hz), 2.69-2.61 (m, 1H), 2.61-2.56 (m, 1H), 2.54-2.46 (m, 1H), 2.00-1.93 (m, 1H), 1.85-1.77 (m, 1H), 1.72-1.66 (m, 1H), 1.26 (s, 3H), 1.19 (s, 3H), 1.09 (d, 3H, J=7.0 Hz), 1.02 (d, 3H, J=6.6 Hz), 0.97 (d, 3H, J=6.5 Hz).

Reference： [1]Current Patent Assignee: UNIVERSITY OF HAWAI'I - US6680311, 2004, B1 Location in patent: Page/Page column 209-210

16
[ 16024-58-1 ]
[ 28230-32-2 ]
[ 844696-61-3 ]
[ 77464-05-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	With diisopropyl-carbodiimide In dichloromethane at 20℃;	35 3-Hydroxy-1 ,2,3-benzotriazin-4(3H)-one (10.0 g; 61 .3 mmol) and 2-[2-(2-methoxyethoxy)- ethoxy]acetic acid (10.9 g; 61 .3 mmol) was suspended in DCM (125 ml) and DIC (7,7 g; 61 .3 mmol) was added. The mixture was stirred under a dry atmosphere at ambient temperature over night. A precipitate of diisopropyl urea was formed, which was filtered off. The organic solution was washed extensively with aqueous saturated sodium hydrogen carbonate solution, then dried (Na2SO4) and evaporated in vacuo, to give the title product as a clear yellow oil. Yield was 16.15 g (81 %). 1H-NMR (CDCI3): δ = 3.39 ppm (s, 3H); 3.58 (t, 2H); 3.68 (t, 2H); 3.76 (t, 2H); 3.89 (t, 2H); 4.70 (s, 2H); 7.87 (t, 1 H); 8.03 (t, 1 H); 8.23 (d, 1 H); 8.37 (d, 1 H). 13C-NMR (CDCI3, selected peaks): δ = 57.16 ppm; 64.96; 68.71 ; 68.79; 69.59; 69.99; 120.32; 123.87; 127.17; 130.96; 133.63; 142.40; 148.22; 164.97.

Reference： [1]Current Patent Assignee: NOVO NORDISK A/S - WO2006/79641, 2006, A2 Location in patent: Page/Page column 72

17
[ 63881-16-3 ]
[ 16024-58-1 ]
[ 132806-44-1 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine In toluene	32.B Step B Step B Synthesis of 3,6,9-trioxadecanoic anhydride as an intermediate The cooled reaction mixture from Step A was stirred, diluted with 50 mL of toluene, and 7.1 grams (0.090 mole) of pyridine was added. To this was added dropwise 8.0 grams (0.045 mole) of 3,6,9-trioxadecanoic acid. Upon completion of addition, the reaction mixture was stirred at ambient temperature for one hour. The reaction mixture was then filtered to remove a precipitate. The filtrate was concentrated under reduced pressure, yielding 14.0 grams of 3,6,9-trioxadecanoic anhydride. The NMR spectrum was consistent with the proposed structure.

Reference： [1]Current Patent Assignee: FMC CORP - US5534518, 1996, A

18
CC-4 silica gel [ No CAS ]
[ 112-35-6 ]
[ 16024-58-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydrogencarbonate In water	18.A Part A Part A Preparation of 3,6,9-trioxadecanoic acid (23899IG-154) A 0.5 g quantity of platinum oxide is hydrogenated in 60 ml of water at 25° C. and atmospheric pressure until the uptake of hydrogen ceases. To the resultant mixture is added a mixture of 0.6 g (7.14 mmoles) of sodium bicarbonate and 1.0 g (6.1 mmoles) of triethylene glycol monomethyl ether dissolved in 20 mL of water. Air is bubbled through the above mixture for 4 hr following the consumption of staging material by TLC. The reaction is then filtered though Celite and the Celite washed with water. The combined washes are treated with 7.2 mL (7.2 mmoles) of 1N hydrochloric acid and the resultant solution freeze-dried. The residue is washed with acetone and filtered. The filtrate is evaporated to dryness under vacuum. The residual oil is chromatographed over 100 g of CC-4 silica gel eluted with (50-50)acetone-methylene chloride, collecting 20 mL fractions. Concentration of fractions 11-16 gives 0.92 g of the desired 3,6,9-trioxadecanoic acid. NMR (acetone-d6): δ 3.30 (s, 3H); 3.40-3.75 (m, 8H); 4.12 (s, 2H). TLC: Rf =0.13 in (40-60-2) acetone-hexane-acetic acid.

Reference： [1]Current Patent Assignee: PFIZER INC - US5739350, 1998, A

19
[ 16024-58-1 ]
[ 3282-30-2 ]
[ 883564-87-2 ]

Yield	Reaction Conditions	Operation in experiment
92%		9 Example 9; 4-[5-amino-l-(2,6-difluoro-benzoyl)-lH-[l,2,4]triazol-3- ylamino]-N-{2-[2-(2-methoxy-ethoxy)~ethoxy]-acetyl}- benzenesulfonamide (Cpd 9); 9a; Using the mixed anhydride formation procedure, 2.7 g (92 %) of Compound 9a was generated from 2-2-methoxyethoxyethoxy acetic acid (2.00 g) and pivaloyl chloride (1.49 g). 1H NMR (300 MHz, CDCl3) δ 4.27 (s, 2 H), 3.78 (t, J = 7.0 Hz, 2H), 3.69 (t, / = 6.9 Hz, 2 H), 3.66 (t, J = 7.0 Hz, 2 H), 3.58 (t, / = 7.0 Hz, 2 H), 3.37 (s, 3 H), 1.24 (s, 9 H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2006/42215, 2006, A1 Location in patent: Page/Page column 38

20
2-(1,1-dimethylheptyl)-5,6,7,8,9,9a-hexahydro-4bH-10-oxa-benzo[a]azulen-4,9-diol [ No CAS ]
[ 16024-58-1 ]
2-(2-methoxyethoxy)-ethoxyacetic acid mono-(2-(1,1-dimethylheptyl)-9-hydroxy-5,6,7,8,9,9a-hexahydro-4bH-10-oxa-benzo[a]azulen-4-yl) ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h;	10.K.f C7S-2 (0.15 g) was dissolved in dry DCM (30 ml) containing N5N-Dimethylaminopyridine (DMAP) (20 mg) and [2-(2-Methoxy-ethoxy)-ethoxy]-acetic acid(53 mg) the reaction mixture was stirred at RT under a N2 atmosphere until everything dissolved. A solution of l^-Dicyclohexylcarbodiimide (DCC, 167 mg) in DCM (5 ml) was then added to the mixture and stirring at RT continued for 24 hrs. Ethyl acetate (100 ml) and water were added to the mixture which was washed with NaHCO3, brine and water. The organic layer was dried over Na2SO4 (anh.)5 filtered and evaporated under reduced pressure. The compound was purified via CombiFlash chromatography as previously described and 10 mg of C7S-27 were obtained.

Reference： [1]Current Patent Assignee: PHARMOS CORPORATION - WO2006/129318, 2006, A2 Location in patent: Page/Page column 65

21
2-N-[1,4,7-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-L-lysine-[(1H,1H,2H,2H-perfluorodecyl)-methyl]-amide, Gd complex [ No CAS ]
[ 16024-58-1 ]
2-N-[1,4,7-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-6-N-{2-[2-(2-methoxyethoxy)-ethoxy]-acetyl}-L-lysine-[(1H,1H,2H,2H-perfluorodecyl)-methyl]-amide, Gd complex [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0 - 20℃; for 19h;	20.a 2.84 g (13.75 mmol) of dicyclohexylcarbodiimide is added at 0° C. to a solution of 12.75 g (10.0 mmol) of the title compound of Example 16b and 1.96 g (11.0 mmol) of [2-(2-methoxyethoxy)-ethoxy]-acetic acid (Aldrich) and 1.27 g (11.0 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide, it is stirred for 3 hours at 0° C. and then for 16 hours at room temperature. Precipitated urea is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in a little water, insoluble components are filtered out, and the filtrate is then purified by chromatography (RP-18; mobile solvent: gradient that consists of water/acetonitrile). Yield: 11.6 g (78% of theory) of a colorless solid Water content (Karl-Fischer): 7.0% Elementary Analysis (relative to the anhydrous substance): Cld.: C 37.50 H 4.39 N 8.14 F 23.45 Gd 11.42 Fnd.: C 37.66 H 4.42 N 8.10 F 23.42 Gd 11.33

Reference： [1]Current Patent Assignee: BAYER AG - US2007/20183, 2007, A1 Location in patent: Page/Page column 31

22
[ 16024-58-1 ]
[ 28230-32-2 ]
[ 844696-61-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	With diisopropyl-carbodiimide In dichloromethane at 20℃;	35 3-Hydroxy-1 ,2,3-benzotriazin-4(3H)-one (10.0 g; 61 .3 mmol) and 2-[2-(2- methoxyethoxy)ethoxy]acetic acid (10.9 g; 61.3 mmol) was suspended in DCM (125 ml) and DIC (7,7 g; 61 .3 mmol) was added. The mixture was stirred under a dry atmosphere at ambient temperature over night. A precipitate of diisopropyl urea was formed, which was filtered off. The organic solution was washed extensively with aqueous saturated sodium hydrogen carbonate solution, then dried (Na2SO4) and evaporated in vacuo, to give the title product as a clear yellow oil. Yield was 16.15 g (81 %). 1H-NMR (CDCI3): δ = 3.39 ppm (s, 3H); 3.58 (t, 2H); 3.68 (t, 2H); 3.76 (t, 2H); 3.89 (t, 2H); 4.70 (s, 2H); 7.87 (t, 1 H); 8.03 (t, 1 H); 8.23 (d, 1 H); 8.37 (d, 1 H). 13C-NMR (CDCI3, selected peaks): δ = 57.16 ppm; 64.96; 68.71 ; 68.79; 69.59; 69.99; 120.32; 123.87; 127.17; 130.96; 133.63; 142.40; 148.22; 164.97.

Reference： [1]Current Patent Assignee: NOVO NORDISK A/S - WO2006/87354, 2006, A2 Location in patent: Page/Page column 97

23
[ 16024-58-1 ]
[ 1020857-22-0 ]
[ 1020857-23-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0 - 20℃; for 19h;	9.c 3.34 g (16.18 mmol) of dicyclohexylcarbodiimide are added at 0° C. to a solution of 8 g (12.94 mmol) of the title compound from Example 9b and 2.31 g (12.94 mmol) of [2-(2-methoxyethoxy)ethoxy]acetic acid (Aldrich) and 1.49 g (12.94 mmol) of N-hydroxy-succinimide in 100 ml of dimethylformamide, and the mixture is stirred at 0° C. for 3 h and subsequently at room temperature for 16 h. It is filtered off from the precipitated urea, the filtrate is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane/methanol 20:1). Yield: 8.5 g (84% of theory) of a colourless viscous oil.

Reference： [1]Current Patent Assignee: BAYER AG - US2008/159954, 2008, A1 Location in patent: Page/Page column 27

24
[ 16024-58-1 ]
C₂₄H₂₈F₁₄N₂O₆ [ No CAS ]
N-[2-(benzyloxycarbonyl)aminoethyl]-N-(1H,1H,2H,2H,4H,4H-6,9,12,15-tetraoxa-8,11,14-trimethylperfluoropentadecyl)-2-[2-(2-methoxyethoxy)ethoxy]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0 - 20℃; for 19h;	10.c 2.52 g (12.24 mmol) of dicyclohexylcarbodiimide are added at 0° C. to a solution of 8.5 g (9.79 mmol) of the title compound from Example 10b and 1.74 g (9.79 mmol) of [2-(2-methoxyethoxy)ethoxy]acetic acid (Aldrich) and 1.13 g (9.79 mmol) of N-hydroxy-succinimide in 100 ml of dimethylformamide, and the mixture is stirred at 0° C. for 3 h and subsequently stirred at room temperature for 16 h. It is filtered from the precipitated urea, the filtrate is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane/methanol 20:1). Yield: 8.1 g (80% of theory) of a colourless viscous oil.

Reference： [1]Current Patent Assignee: BAYER AG - US2008/159954, 2008, A1 Location in patent: Page/Page column 28

25
[ 16024-58-1 ]
2-N-(2H,2H,4H,4H-3,6,9,12,-tetraoxa-5,8,11-trimethylperfluoropentadecanoyl)-L-lysine methyl ester [ No CAS ]
6-N-{2-[2-(2-methoxyethoxy)ethoxy]acetyl}-2-N-(2H,2H,4H,4H-3,6,9,12,-tetraoxa-5,8,11-trimethylperfluoropentadecanoyl)-L-lysine methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0 - 20℃; for 19h;	12.c 4.10 g (19.89 mmol) of dicyclohexylcarbodiimide are added at 0° C. to a solution of 13.5 g (15.91 mmol) of title compound from Example 12b, 2.83 g (15.91 mmol) of [2-(2-methoxyethoxy)ethoxy]acetic acid (Aldrich) and 1.83 g (15.91 mmol) of N-hydroxy-succinimide in 200 ml of dimethylformamide, the mixture is stirred at 0° C. for 3 h and subsequently at room temperature for 16 h. It is filtered off from the precipitated urea, the filtrate is evaporated to dryness in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane/methanol 20:1). Yield: 12.4 g (77% of theory) of a colourless viscous oil.

Reference： [1]Current Patent Assignee: BAYER AG - US2008/159954, 2008, A1 Location in patent: Page/Page column 30

26
[ 16024-58-1 ]
2-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-L-lysine[N-methyl-(1H,1H,2H,2H,4H,4H,-3,6,9,12-tetraoxaperfluorohexadecyl)]amide, Gd complex [ No CAS ]
2-N-[1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-10-N-(pentanoyl-3-aza-4-oxo-5-methyl-5-yl)]-6-N-{2-[2-(2-methoxyethoxy)ethoxy]acetyl}-L-lysine[N-methyl-(1H,1H,2H,2H,4H,4H,-3,6,9,12-tetraoxaperfluorohexadecyl)]-amide, Gd complex [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0 - 20℃; for 19h;	20.a 2.84 g (13.75 mmol) of dicyclohexylcarbodiimide are added at 0° C. to a solution of 14.31 g (10.0 mmol) of the title compound from Example 19b and 1.96 g (11.0 mmol) of [2-(2-methoxyethoxy)ethoxy]acetic acid (Aldrich) and 1.27 g (11.0 mmol) of N-hydroxysuccinimide in 100 ml of dimethylformamide, and the mixture is stirred at 0° C. for 3 h and subsequently at room temperature for 16 h. It is filtered off from the precipitated urea and the filtrate is evaporated to dryness in vacuo. The residue is taken up in a little water, filtered off from the insoluble constituents, and the filtrate is subsequently purified by chromatography (RP-18; eluent: gradient of water/acetonitrile). Yield 12.4 g (77% of theory) of a colourless solid Water content (Karl Fischer): 6.7%

Reference： [1]Current Patent Assignee: BAYER AG - US2008/159954, 2008, A1 Location in patent: Page/Page column 35-36

27
[ 16024-58-1 ]
[ 13956-29-1 ]
[ 1110598-75-8 ]
[ 1110598-77-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-[2-(2-methoxyethoxy)etoxy]acetic acid; CBD With dmap In dichloromethane at 20℃; for 0.0833333h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 5h;	2.4.6 Cannabidiol (105 mg, 0.00033 mol), 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (83.3 mg, 0.00047 mol), and DMAP (12.3 mg, 0.00011 mol) were combined in 1 mL dry dichloromethane. The solution was stirred for 5 min at ambient temperature. DCC (117 mg, 0.00056 mol) was added to the mixture. The mixture was allowed to stir for 5 h at ambient temperature. Hexane was added and precipitate removed by filtration. The solution was reduced to a small volume under nitrogen. ALL00140 and ALL00141 were separated and isolated using a semi-preparatory silica column with hexane: ethyl acetate gradient. The solvent from each collected fraction was removed under vacuum. The purified products appeared as transparent, viscous oil with light amber color.ALL00140 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 492.37 (M+18, 100%) and 475.37 (M+1, 35%).ALL00141 was analyzed by LC/MS in electrospray positive mode. Masses were observed at 652.51 (M+18, 100%) and 635.52 (M+1, 10%).

Reference： [1]Current Patent Assignee: ZYNERBA PHARMACEUTICALS, INC. - US2009/36523, 2009, A1 Location in patent: Page/Page column 20

28
[ 16024-58-1 ]
[ 1141776-83-1 ]
[ 1141777-76-5 ]

Yield	Reaction Conditions	Operation in experiment
50%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18h;	77 EXAMPLE 77PREPARATION OF N-(3-(3-(CYCLOHEXYLMETHOXY)PHENYL)-3-HYDROXYPROPYL)-2-(2-(2- METHOXYERHOXY)ETHOXY)ACETAMME[00701] iv"-(3-(3-(Cyclohexyknethoxy)phenyl)-3-hydroxypropyl)-2-(2-(2-methoxyethoxy)ethoxy)acetamide was prepared following the method shown in Scheme 26. SCHEME 26[00702] Step 1: To a mixture of 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (0.6 g, 3.34 mmol), TBTU (1.2 g, 4.0 mmol) and DIPEA (1.3 ml, 4.0 mmol) in DMF (20 ml) was added 3-amino-l-(3-(cyclohexylmethoxy)phenyl)propan-l-ol (1.0 g, 3.34 mmol). The resulting mixture was stirred for 18 hr at room temperature. The reaction mixture was then diluted with ethyl acetate (100 ml), washed with water (2x 100 ml), brine (100 ml), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave Example 77 as a colorless oil. Yield (0.7 g, 50%): 1H NMR (400 MHz, DMSO-cU) δ 7.65 (t, J = 5.6 Hz, IH), 7.17 (t, J = 7.6 Hz, IH), 6.82-6.85 (m, 2H), 6.72-6.75 (m, IH), 5.22 (d, J = 4.8 Hz, IH), 4.48-4.52 (m, IH), 3.82 (s, 2H), 3.72 (d, J = 6.4 Hz, 2H), 3.42-3.52 (m, 2H), 3.39-3.41 (m, 2H), 3.30 (s, 3H), 3.12-3.17 (m, 2H), 2.86 (s, 2H), 2.66 (s, 2H), 1.61-1.79 (m, 8H), 1.08-1.28 (m, 3H), 0.98-1.06 (m, 2H).

Reference： [1]Current Patent Assignee: KUBOTA PHARMACEUTICAL HOLDINGS CO LTD - WO2009/45479, 2009, A1 Location in patent: Page/Page column 212-213

29
[ 16024-58-1 ]
C₃₅H₃₄N₈O₈S [ No CAS ]
C₄₂H₄₆N₈O₁₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 8h;

Reference： [1]Location in patent: experimental part Hernández, Delia; Altuna, Marta; Cuevas, Carmen; Aligué, Rosa; Albericio, Fernando; Álvarez, Mercedes [Journal of Medicinal Chemistry, 2008, vol. 51, # 18, p. 5722 - 5730]

30
[ 632365-54-9 ]
[ 16024-58-1 ]
[ 1202657-33-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	With dicyclohexyl-carbodiimide In 1,4-dioxane at 20℃; for 40h;

Reference： [1]Location in patent: scheme or table Kusakiewicz-Dawid, Anna; Gorecki, Lukasz; Masiukiewicz, Elzbieta; Rzeszotarska, Barbara [Synthetic Communications, 2009, vol. 39, # 22, p. 4122 - 4132]

31
[ 16024-58-1 ]
[ 1232037-10-3 ]
C₃₃H₃₈N₆O₅*1.7ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	Stage #1: 2-[2-(2-methoxyethoxy)etoxy]acetic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: C₂₆H₂₆N₆O In N,N-dimethyl-formamide at 20℃; for 2h;	B.8.c HBTU (107 mg, 0.28 mmol) was added to a solution of [2-(2-methoxy-ethoxy)- ethoxy] -acetic acid (40 μl, 0.26 mmol) and DIPEA (57 μL, 0.32 mmol) in DMF (1 ml). After stirring for 10 min at r.t., compound 107 (95 mg, 0.22 mmol) was added to the mixture and the r.m. was stirred at r.t. for 2 h. The solvent was evaporated and the residue was dissolved in DCM. The organic layer was washed with H2O and with a sat. aq. Na2CO3 solution, was dried (MgSO4), filtered and concentrated in vacuo. The product was purified by flash column chromatography over silicagel (eluent: DCM/MeOH(NH3) from 100/0 to 98/2). The product fractions were collected and the solvent was evaporated. The resulting oil was dissolved in CH3CN and converted into the HCl salt by adding a 6 N HCl solution in 2-propanol. The precipitate was filtered off and dried in vacuo. Yield: 36 mg of compound 114 (23 %; .3H2O .1.7HCl).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2010/70008, 2010, A1 Location in patent: Page/Page column 74

32
[ 100-02-7 ]
[ 16024-58-1 ]
[ 1252661-82-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃;

Reference： [1]Location in patent: experimental part Ikeda, Hiroshi; Nishikawa, Satoshi; Yamamoto, Yukinori; Ueno, Akihiko [Journal of Molecular Catalysis A: Chemical, 2010, vol. 328, # 1-2, p. 1 - 7]

33
[ 16024-58-1 ]
[ 554-84-7 ]
[ 1252661-81-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	With dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃;

Reference： [1]Location in patent: experimental part Ikeda, Hiroshi; Nishikawa, Satoshi; Yamamoto, Yukinori; Ueno, Akihiko [Journal of Molecular Catalysis A: Chemical, 2010, vol. 328, # 1-2, p. 1 - 7]

34
[ 16024-58-1 ]
[ 10268-70-9 ]
[ 1220918-50-2 ]

Yield	Reaction Conditions	Operation in experiment
83%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃;

Reference： [1]Location in patent: experimental part Yoshino, Kazuo; Hachiman, Kotaro; Yokoyama, Akihiro; Yokozawa, Tsutomu [Journal of Polymer Science, Part A: Polymer Chemistry, 2010, vol. 48, # 6, p. 1357 - 1363]

35
[ 16024-58-1 ]
[ 619-45-4 ]
[ 1220918-49-9 ]

Yield	Reaction Conditions	Operation in experiment
54%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃;

Reference： [1]Location in patent: experimental part Yoshino, Kazuo; Hachiman, Kotaro; Yokoyama, Akihiro; Yokozawa, Tsutomu [Journal of Polymer Science, Part A: Polymer Chemistry, 2010, vol. 48, # 6, p. 1357 - 1363]

36
[ 16024-58-1 ]
[ 1314357-54-4 ]
[ 1314357-55-5 ]

Yield	Reaction Conditions	Operation in experiment
73%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane; ethyl acetate at 0℃; for 27.17h;

Reference： [1]Welsh, Daniel J.; Smith, David K. [Organic and Biomolecular Chemistry, 2011, vol. 9, # 13, p. 4795 - 4801]

37
[ 16024-58-1 ]
[ 29022-11-5 ]
[ 881027-71-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: N-(fluoren-9-ylmethoxycarbonyl)glycine With N-ethyl-N,N-diisopropylamine In dichloromethane solid phase reaction; Stage #2: With piperidine In N,N-dimethyl-formamide solid phase reaction; Stage #3: 2-[2-(2-methoxyethoxy)etoxy]acetic acid Further stages;

Reference： [1]Welsh, Daniel J.; Smith, David K. [Organic and Biomolecular Chemistry, 2011, vol. 9, # 13, p. 4795 - 4801]

38
[ 16024-58-1 ]
[ 501-53-1 ]
[ 1268444-33-2 ]

Yield	Reaction Conditions	Operation in experiment
79%	With dmap; triethylamine In dichloromethane at 0℃; for 0.5h;

Reference： [1]Location in patent: experimental part Yokoyama, Akihiro; Inagaki, Yuko; Ono, Tomomi; Yokozawa, Tsutomu [Journal of Polymer Science, Part A: Polymer Chemistry, 2011, vol. 49, # 6, p. 1387 - 1395]

39
[ 16024-58-1 ]
[ 1159995-72-8 ]
[ 1313494-77-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h;

Reference： [1]Location in patent: experimental part Mikami, Koichiro; Daikuhara, Hiroaki; Kasama, Jyunya; Yokoyama, Akihiro; Yokozawa, Tsutomu [Journal of Polymer Science, Part A: Polymer Chemistry, 2011, vol. 49, # 14, p. 3020 - 3029]

40
[ 16024-58-1 ]
[ 5159-59-1 ]
[ 1313494-73-3 ]

Reference： [1]Journal of Polymer Science, Part A: Polymer Chemistry,2011,vol. 49,p. 3020 - 3029

41
[ 16024-58-1 ]
[ 1391871-32-1 ]

Yield	Reaction Conditions	Operation in experiment
	With phosphorus(III) oxide; methanesulfonic acid at 30℃; for 2h;	3 Example 3In a three-necked round-bottom flask equipped with a mechanical stirrer, a thermometer, a condenser and a dropping funnel 31.36 g (176 mmol) 3,6,9- trioxadecanoic acid was mixed with 50 ml methanesulfonic acid. 9.68 g (44 mmol) P406 was added drop-wise at below 30 °C. After completed addition the reaction mixture was stirred for 2 h at 30 °C. During the addition and the reaction time the evolution of CO was observed. Then 25 ml H20 was added and the obtained liquid was analysed by 1 H- and 31 P-NMR spectroscopy. 2,5,8-TrioxanonyM-phosphonic acid was detected at 97.0 %w/w
	Stage #1: 2-[2-(2-methoxyethoxy)etoxy]acetic acid With methanesulfonic acid; phosphorus trichloride at 50℃; for 4h; Inert atmosphere; Stage #2: With water Inert atmosphere;	10 Example 10 In a three-necked round-bottom flask under nitrogen atmosphere equipped with a mechanical stirrer, a thermometer, a condenser and a dropping funnel and 13.73 g (0.1 mol) phosphorus trichloride was mixed with 15 ml methanesulfonic acid. Drop-wise 15.00 g (0.084 mol) 3,6,9- trioxadecanoic acid was added and the reaction mixture was heated to 50 °C for 4 h. During the addition and reaction time the evolution of CO was observed. The reaction mixture was allowed to cool down and 10 ml water was added. The solution was analyzed by 31P-NMR spectroscopy and 1- phosphono-2, 5, 8-trioxanonane was detected at 82.0 %w/w.
90.4 %Spectr.	With phosphonic Acid; trifluoroacetic anhydride at 50℃; for 6h;	26 Example 26.[0110] In a three-necked round-bottom flask equipped with a mechanical stirrer, a thermometer, a condenser and a dropping funnel 1.37 g (17 mmol) phosphorous acid and 10.5 g (50 mmol) trifluoracetic anhydride were mixed and stirred for 1 h. Then 3.03 g (17 mmol) 3,6,9-trioxadecanoic acid was added drop-wise and stirring was continued for 6 h at 50 °C. During the addition and the reaction time the evolution of CO was observed. Then 5 ml H2O was added and the obtained liquid was analysed by 31P-NMR spectroscopy. 2,5,8-Trioxanonyl-1-phosphonic acid was detected at 90.4 %w/w.

Stage #1: 2-[2-(2-methoxyethoxy)etoxy]acetic acid With trifluoroacetic anhydride for 1h; Stage #2: With phosphorus(III) oxide at 50℃; for 5h;

15 Example 15 Example 15.In a three-necked round-bottom flask equipped with a mechanical stirrer, a thermometer, a condenser and a dropping funnel 8.91 g (50 mmol) 3,6,9- trioxadecanoic acid was mixed with 10.50 g (50 mmol) trifluoroacetic anhydride and stirred for 1 h. 2.75 g (12.5 mmol) P406 was added drop-wise. After completed addition the reaction mixture was stirred for 5 h at 50 °C. During the addition and the reaction time the evolution of CO was observed. Then 5 ml H20 was added and the obtained liquid was analysed by 1H- and 31P-NMR spectroscopy. 2,5,8-Trioxanonyl-1 - phosphonic acid was detected at 22.5 %w/w.

Reference： [1]Current Patent Assignee: Monsanto (in: Bayer); BAYER AG - WO2012/98255, 2012, A1 Location in patent: Page/Page column 27
[2]Current Patent Assignee: BAYER AG; Monsanto (in: Bayer) - WO2013/17564, 2013, A2 Location in patent: Page/Page column 42
[3]Current Patent Assignee: BAYER AG; Monsanto (in: Bayer) - EP2567961, 2013, A1 Location in patent: Paragraph 110
[4]Current Patent Assignee: BAYER AG; Monsanto (in: Bayer) - WO2013/34730, 2013, A2 Location in patent: Page/Page column 40

42
[ 16024-58-1 ]
ethyl 2-(azetidin-3-yl((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)amino)acetate [ No CAS ]
[ 1429340-33-9 ]

Yield	Reaction Conditions	Operation in experiment
65 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine at 20℃; for 1h;	22.4 Step 4. Ethyl 2-((f6-(7-(4-(3-cvclopropylureidoV2-fluorophenoxy)thienor3.2- fclpyridin-2-yl^')pyridin-3-yl)methyl)(l -(2-(2-(2-methoxyethoxy)ethoxy^')acetYnazetidin-3- yl)amino)acetate (44) Step 4. Ethyl 2-((f6-(7-(4-(3-cvclopropylureidoV2-fluorophenoxy)thienor3.2- fclpyridin-2-yl')pyridin-3-yl)methyl)(l -(2-(2-(2-methoxyethoxy)ethoxy')acetYnazetidin-3- yl)amino)acetate (44)[000224) To a solution of 43 (0.136 mmol) in DMF (5 mL) were added 2-[2-(2- methoxyethoxy)ethoxy] acetic acid (49 mg, 0.272 mmol), EDC hydrochloride (52 mg, 0.272 mmol), HOBT monohydrate (31 mg, 0.204 mmol) and triethylamine (95 μί, 0.68 mmol) at RT and the reaction mixture was stirred at RT for 1 h. The mixture was then quenched with water and extracted with EtOAC/MeOH. The organic phase was collected, washed with brine, dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by Biotage (SNAP 10 g cartridge; MeOH/DCM: 0/100 to 20/80), to afford the title compound44 (65 mg, 64% yield, over 2 steps) as a beige solid. Ή NMR (400 MHz, DMSO-^6) δ (ppm) : 8.82 (s, 1 H), 8.55 (d, J = 1.6 Hz, 1 H), 8.52 (d, J = 5.6 Hz, 1 H), 8.35 (s, 1H), 8.25 (d, J = 8.4 Hz, 1 H), 7.89 (dd, J = 8.0, 2.0 Hz, 1 H), 7.73 (dd, J = 13.6, 2.4 Hz, 1 H), 7.38 (t, J = 9.0 Hz, 1 H), 7.24-7.18 (m, 1 H), 6.67 (bd, J = 2.4 Hz, 1 H), 6.65 (dd, J = 5.2, 0.8 Hz, 1 H), 4.27-4.20 (m, 1 H), 4.14-4.02 (m, 5H), 3.97 (s, 2H), 3.96-3.89 (m, 1 H), 3.54-3.46 (m, 6H), 3.43-3.37 (m, 2H), 3.22 (s, 3H), 2.59-2.51 (m, 1 H), 1.18 (t, J = 7.2 Hz, 3H), 0.68-0.62 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 751.61 (M+H).

Reference： [1]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - WO2013/44361, 2013, A1 Location in patent: Paragraph 000223; 000224

43
[ 67-56-1 ]
[ 16024-58-1 ]
[ 178924-05-5 ]
[ 29022-11-5 ]
C₃₆H₅₃N₈O₁₆PolS [ No CAS ]
[ 15462-45-0 ]
[ 188970-92-5 ]
C₇₂H₁₀₁N₁₆O₂₅PolS₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5587 - 5600

44
[ 67-56-1 ]
[ 16024-58-1 ]
[ 1001851-99-5 ]
[ 178924-05-5 ]
[ 29022-11-5 ]
[ 15462-45-0 ]
[ 1444301-79-4 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5587 - 5600

45
[ 16024-58-1 ]
[ 181954-34-7 ]
[ 1444302-35-5 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5587 - 5600

46
[ 16024-58-1 ]
[ 108-45-2 ]
N,N'-(1,3-phenylene)bis(2-(2-(2-methoxyethoxy)ethoxy)acetamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 12h;

Reference： [1]Hua, Yuran; Liu, Yun; Chen, Chun-Hsing; Flood, Amar H. [Journal of the American Chemical Society, 2013, vol. 135, # 38, p. 14401 - 14412]

47
[ 16024-58-1 ]
[ 161420-87-7 ]
[ 1444302-35-5 ]

Reference： [1]Molecules,2014,vol. 19,p. 3135 - 3148

48
[ 16024-58-1 ]
[ 1613334-62-5 ]
[ 1613334-98-7 ]

Yield	Reaction Conditions	Operation in experiment
33%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 18h;	73 Example 73 (Z)-3-(2-(5-bromo-l-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)-lH-indol-3-yl)-2- cyanovinyl)-4-methoxybenzonitrile Example 73 (Z)-3-(2-(5-bromo-l-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)-lH-indol-3-yl)-2- cyanovinyl)-4-methoxybenzonitrile (Z)-3-(2-(5-bromo-lH-indol-3-yl)-2-cyanovinyl)-4-methoxybenzonitrile (150mg), 2- (2-(2-methoxyethoxy)ethoxy)acetic acid (88mg), PyBOP (310mg), Triethylamine (0.11 ml), DMF (2ml). Reaction time 18 hours at RT. Poured in water and washed with acetonitrile. Aspect of the product: yellow solid. (Yield: 33%) APCI-MS: (M+H)+ = 538 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (d, J = 8.9 Hz, 1H), 8.33 - 8.23 (m, 2H), 8.18 (d, J = 1.7 Hz, 1H), 8.01 (dd, J = 8.7, 2.0 Hz, 1H), 7.94 (s, 1H), 7.65 (dd, J = 8.9, 1.8 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 4.93 (s, 2H), 3.98 (s, 3H), 3.81 - 3.68 (m, 2H), 3.60 (d, J = 5.0 Hz, 2H), 3.55 - 3.48 (m, 2H), 3.39 (d, J = 5.3 Hz, 2H), 3.19 (s, 3H).

Reference： [1]Current Patent Assignee: DIACCURATE SAS - WO2014/86964, 2014, A1 Location in patent: Page/Page column 94

49
[ 16024-58-1 ]
[ 213622-11-8 ]
[ 1610009-70-5 ]

Yield	Reaction Conditions	Operation in experiment
57%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 18h; Inert atmosphere;

Reference： [1]Bolag, Altan; Lopez-Andarias, Javier; Lascano, Santiago; Soleimanpour, Saeideh; Atienza, Carmen; Sakai, Naomi; Martin, Nazario; Matile, Stefan [Angewandte Chemie - International Edition, 2014, vol. 53, # 19, p. 4890 - 4895][Angew. Chem., 2014, vol. 126, # 19, p. 4990 - 4995,6]

50
[ 16024-58-1 ]
methyl-{(S)-1-[(S)-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester [ No CAS ]
{(S)-1-[(S)-5-{2-[2-(2-methoxyethoxy)ethoxy]acetyl}-1-(2-methylnaphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]ethyl}methylcarbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.040 g	With pyridine; trichlorophosphate at 0℃; for 1h;	13a.1 Step 1: To a solution of methyl- { (S)-i - [(S)-i -(2-methyl-naphthalen- 1 -ylmethyl)-2-oxo- 2,3,4,5 -tetrahydro- 1 H-benzo[bj [1 ,4ldiazepin-3-ylcarbamoyll -ethyl } -carbamic acid tert-butyl ester (0.052 g 0.1 mmol) and 2-[2-(2-methoxyethoxy)ethoxylacetic acid (0.023 mL 0.15 mmol) in 2 mL of pyridine at 0 °C was slowly added POC13 (0.028 mL 0.30 mmol). After 1 h at 0 °C, the mixture was diluted with H20 and EtOAc. The organic layer was washed with 1 M citric acid, brine, aq. Na2CO3, brine, dried over anhydr. Na2504, filtered and concentrated to give a material that was purified by silica gel chromatography to afford {(S)-i-[(S)-5-{2-[2-(2- methoxy-ethoxy)-ethoxyl -acetyl } -1 -(2-methyl-naphthalen- 1 -ylmethyl)-2-oxo-2,3 ,4,5 -tetrahydro-1 H-benzo [bI [1 ,4ldiazepin-3 -ylcarbamoyll -ethyl } -methyl-carbamic acid tert-butyl ester (0.040 g, white solid).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2015/71393, 2015, A1 Location in patent: Page/Page column 105; 106

51
[ 16024-58-1 ]
(S)-2,6-diamino-N-(3-oxo-3-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)propyl)hexanamide di-hydrochloride [ No CAS ]
(S)-N,N’-(6-oxo-6-(3-oxo-3-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)propylamino)hexane-1,5-diyl)bis(2-(2-(2-methoxyethoxy)ethoxy)acetamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37.9%	With pyridine; 1,1'-carbonyldiimidazole In tetrahydrofuran for 16h;	39 Example 33 (S)-N,N'-(6-Oxo-6-(3-oxo-3-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)propylamino)hexane-1,5-diyl)bis(2-(2-(2-methoxyethoxyl)ethoxy)acetamide) (63) Example 33 (S)-N,N'-(6-Oxo-6-(3-oxo-3-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)propylamino)hexane-1,5-diyl)bis(2-(2-(2-methoxyethoxyl)ethoxy)acetamide) (63) To a solution of 2-(2-(2-methoxyethoxyl)ethoxy)acetic acid (0.160 g, 0.900 mmol) in dry THF (10 mL) was added CDI (0.219 g, 1.350 mmol). The reaction mixture was stirred for 3 hours. The compound 14 (0.250 g mg, 0.450 mmol) was then added followed by the pyridine (0.218 mL, 2.70 mmol) and the combined mixture was stirred overnight (16 hrs). The solvent was partially evaporated, the remaining solution wass diluted with EtOAc and washed twice with a 5% KHSO4 solution, then brine. The organic phase was finally dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash column chromatography, eluient 6.4% MeOH in DCM followed by a second column purification using MeOH (10%) in EtOAc, and finally by a third purification eluting with MeOH (20%) in EtOAc. Title compound 63 (0.137 g, 37.9% yield) was obtained as a colorless honey-like material. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.02 (s, 1H), 8.29 (br. s, 1H), 7.65 (t, J=5.7 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.27-7.24 (m, 2H), 7.18-7.09 (m, 7H), 4.27-4.21 (m, 1H), 3.90 (s, 2H), 3.84 (s, 2H), 3.61-3.39 (m, 20H), 3.234 (s, 3H), 3.231 (s, 3H), 3.05 (q, J=6.8 Hz, 2H), 2.65-2.56 (m, 6H), 1.73-1.55 (m, 6H), 1.50-1.36 (m, 2H), 1.23-1.16 (m, 2H). LRMS (ESI): (calc.) 803.0 (found) 803.4 (MH)+
37.9%	Stage #1: 2-[2-(2-methoxyethoxy)etoxy]acetic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran for 3h; Stage #2: (S)-2,6-diamino-N-(3-oxo-3-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)propyl)hexanamide di-hydrochloride With pyridine In tetrahydrofuran	39 EXAMPLE 39 (S)-N,N’-(6-Oxo-6-(3-oxo-3-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)propylamino)hexane- 1 ,5-diyl) bis(2-(2-(2-methoxyethoxy)ethoxy)acetamide) (63) To a solution of 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (0.160 g, 0.900 mmol) in dry THF (10 mL) was added CDI (0.219 g, 1.3SOmmol). Thereactionmixturewas stirred for 3 hours. The compound 14 (0.250 g mg, 0.450 mmol)was then added followed by the pyridine (0.2 18 mL, 2.70mmol) and the combined mixture was stirred overnight (16 hrs). The solvent was partially evaporated, the remaining solution was diluted with EtOAc and washed twice with a 5% KHSO solution, then brine. The organic phase wasfinally dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash column chromatography, eluient 6.4% MeOH in DCM followed by a second column purification using MeOH (10%) in EtOAc, and finally by a third purification eluting with MeOH (20%) in EtOAc. Title compound 63 (0.137 g, 37.9% yield) was obtained as a colorless honey-like material. ‘H NMR (400 MHz, DMSO-d5) ö (ppm): 12.02 (s, 1H), 8.29 (br. s, 1H), 7.65 (t, J=5.7 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.27-7.24 (m, 2H), 7.18-7.09 (m, 7H), 4.27-4.21 (m, 1H), 3.90 (s, 2H),3.84 (s, 2H), 3.61-3.39 (m, 20H), 3.234 (s, 3H), 3.231 (s, 3H), 3.05 (q, J=6.8 Hz, 2H), 2.65-2.56 (m, 6H), 1.73-1.55 (m, 6H), 1.50-1.36 (m, 2H), 1.23-1.16(m, 2H). LRMS (ESI):(calc.) 803.0 (found) 803.4 (MH)+

Reference： [1]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US2015/203517, 2015, A1 Location in patent: Paragraph 0394
[2]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US9636298, 2017, B2 Location in patent: Page/Page column 93; 94; 95

52
[ 16024-58-1 ]
[ 771-61-9 ]
O-[2-(2-methoxyethoxy)-ethyl]glycolic acid pentafluorophenol ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 6h;
50%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 6h;	Synthesis of 12-(2-methoxyethoxy)ethoxy/acetic acid pentafluorophenyl ester (Peg 178 PFP ester): To a solution of [2-(2-methoxyethoxy)ethoxy]acetic acid (1 equivalent) and pentafluorophenol (1.2 equivalent) in dry dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 equivalent) and catalytic amount of 4-dimethylaminopyridine at 0 °C. The reaction mixture was stirred for 6 h at room temperature. The reaction mixture was washed with saturated NaHCO3 aqueous solution and then with brine. The organic solution was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. It was purified by column chromatography using silica gel as the stationary phase and mixture of ethyl acetate/hexane as eluent. Yield: 50%. 1H NMR (400MHz, CDCl3) δ: 4.54 (s, 2H), 3.83 (m, 2H), 3.74 (m, 2H), 3.65 (m, 2H), 3.57 (m, 2H), 3.38 (s, 3H). 19F NMR (300 MHz, CDCl3) δ: -152.5 (2F),-157.3 (1F), -161.9 (2F).

Reference： [1]Zhou, Zhuxian; Ma, Xinpeng; Murphy, Caitlin J.; Jin, Erlei; Sun, Qihang; Shen, Youqing; Vankirk, Edward A.; Murdoch, William J. [Angewandte Chemie - International Edition, 2014, vol. 53, # 41, p. 10949 - 10955][Angew. Chem., 2014, vol. 126, # 41, p. 11129 - 11135,7]
[2]Current Patent Assignee: UNIVERSITY OF MASSACHUSETTS - WO2015/105549, 2015, A3 Location in patent: Paragraph 00117

53
[ 16024-58-1 ]
[ 57260-71-6 ]
tert-butyl 4-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 24h;	52 Synthesis of tert-butyl 4-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperazine-l- carboxylate T-Boc-piperazine (1.5837 g, 8.50 mmol) and mPEG2-CM (1.55 mL, 10.10 mmol) were dissolved in dichloromethane (100 mL). Triethylamine (3.5 mL, 25.10 mmol) was added, followed by addition of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (3.0889 g, 16.11 mmol). The resulting mixture was stirred at room temperature for 24 h. The reaction was washed with brine and dried over anhydrous sodium sulfate. Solvent was removed by rotavap. The residue was purified with column chromatography on silica gel using 0-10% methanol/dichloromethane to afford product as oil (2.4095 g, Yield: 82%). NMR (500 MHz, Chloroform-;/) δ 4.20 (s, 2H), 3.69-3.64 (m, 4H), 3.62-3.61 (m, 2 H), 3.57-3.54 (m, 2H), 3.53-3.51 (m, 2H), 3.49-3.48 (m, 2H), 3.43-3.38 (m, 4H), 3.36 (s, 3H), 1.45 (s, 9H).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2015/92819, 2015, A2 Location in patent: Paragraph 0517; 0518

54
[ 16024-58-1 ]
(S)-2,6-diamino-N-methyl-N-(4-oxo-4-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)butyl)hexanamide dihydrochloride [ No CAS ]
(S)-N,N’-(6-(methyl(4-oxo-4-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)butyl)amino)-6-oxohexane-1,5-diyl)bis(2-(2-(2-methoxyethoxy)ethoxy)acetamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41.2%	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water; N,N-dimethyl-formamide at 20℃; for 4h;	40 Example 40 (S)-N,N'-(6-(Methyl(4-oxo-4-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)butyl)amino)-6-oxohexane-1,5-diyl)bis(2-(2-(2-methoxyethoxyl)ethoxy)acetamide) (64) Example 40 (S)-N,N'-(6-(Methyl(4-oxo-4-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)butyl)amino)-6-oxohexane-1,5-diyl)bis(2-(2-(2-methoxyethoxyl)ethoxy)acetamide) (64) To a suspension of (S)-2,6-diamino-N-methyl-N-(4-oxo-4-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)butyl)hexanamide dihydrochloride (65, 0.653 g, 1.119 mmol) in dry DMF (15 mL) were added 2-(2-(2-methoxyethoxyl)ethoxy)acetic acid (0.439 g, 2.462 mmol), HOBtH2O (0.377 g, 2.462 mmol), EDCHCl (0.858 g, 4.48 mmol) and pyridine (0.900 mL, 11.2 mmol). The reaction mixture turned into a solution and was stirred for 4 hours at RT, partitioned between EtOAc and acidified brine. The organic phase was separated, washed with brine and finally dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash column chromatography three times eluting with 10% MeOH in DCM (first time), 5% MeOH in DCM (second time) and finally, 4% MeOH in DCM (third time). The purified material was purified yet again by Biotage by a reverse phase chromatography (Snap 120 g cartridge KP-C18-HS, eluent 5 to 95% MeOH in water), to afford title compound 64 (0.383 g, 41.2% yield) as a colorless honey-like material. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.87 (s, 1H), 7.37 (br. d, 2H), 7.28-7.24 (m, 2H), 7.18-7.10 (m, 7H), 4.73-4.67 (m, 1H), 3.90 (d, 2H, rotamers), 3.84 (s, 2H), 3.61-3.52 (m, 12H), 3.46-3.42 (m, 6H), 3.40-3.26 (m, 4H), 3.24 (s, 3H), 3.23 (s, 3H), 3.10-3.04 (m, 2H), 2.81 (s, 2H), 2.61-2.53 (m, 4H), 2.40 (t, J=7.4 Hz, 2H), 1.88-1.23 (m, 13H). LRMS (ESI): (calc.) 831.0 (found) 831.6 (MH)+ and 853.5 (MNa)+;
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide	40 EXAMPLE 40 (S)-N,N’-(6-(Methyl(4-oxo-4-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)butyl)amino)-6-oxohexane-1,5-diyl)bis(2-(2-(2- methoxyethoxy)ethoxy)acetamide) (64) To a suspension of (S)-2,6-diamino-N-methyl-N-(4-oxo- 4-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)butyl)hexana- mide dihydrochioride (65, 0.653 g, 1.119 mmol) in dry DMF (15 mL) were added 2-(2-(2-methoxyethoxy)ethoxy)aceticacid (0.439 g, 2.462 mmol), HOI3TxH2O (0.377 g, 2.462mmol), EDCxHC1 (0.858 g, 4.48 mmol) and pyridine (0.900mL, 11.2 mmol). The reaction mixture turned into a solution like material. ‘H NMR (400 MHz, DMSO-d5) ö (ppm):11.87 (s, 1H), 7.37 (bt d, 2H), 7.28-7.24 (m, 2H), 7.18-7.10(m, 7H), 4.73-4.67 (m, 1H), 3.90 (d, 2H, rotamers), 3.84 (s,2H), 3.61-3.52 (m, 12H), 3.46-3.42 (m, 6H), 3.40-3.26 (m,4H), 3.24 (s, 3H), 3.23 (s, 3H), 3.10-3.04 (m, 2H), 2.81 (s,2H), 2.61-2.53 (m, 4H), 2.40 (t, J=7.4 Hz, 2H), 1.88-1.23(m,13H). LRMS (ESI): (calc.) 831.0 (found) 831.6 (MH) and853.5 (MNa).

Reference： [1]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US2015/203517, 2015, A1 Location in patent: Paragraph 0395
[2]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US9636298, 2017, B2 Location in patent: Page/Page column 95; 96

55
[ 16024-58-1 ]
(S)-2,6-diamino-N-((S)-2-methyl-3-oxo-3-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy) propyl)hexanamide dihydrochloride [ No CAS ]
N,N’-((S)-6-((S)-2-methyl-3-oxo-3-(2-(4-(4-phenylbutyl)phenyl)acetamido)oxypropylamino)-6-oxohexane-1,5-diyl) bis(2-(2-(2-methoxyethoxy)ethoxy)acetamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 3.5h;	59.3 Step 3.Step 3. N,N'-((S)-6-((S)-2-Methyl-3-oxo-3-(2-(4-(4-phenylbutyl)phenyl)acetamido oxy)propylamino)-6-oxohexane-1,5-diyl)bis(2-(2-(2-methoxyethoxyl)ethoxy)acetamide) (91) Step 3. N,N'-((S)-6-((S)-2-Methyl-3-oxo-3-(2-(4-(4-phenylbutyl)phenyl)acetamido oxy)propylamino)-6-oxohexane-1,5-diyl)bis(2-(2-(2-methoxyethoxyl)ethoxy)acetamide) (91) To a stirred solution at RT of compound 90 (0.066 mmol) in DMF (3 ml) under nitrogen were added 2-(2-(2-methoxyethoxyl)ethoxy)acetic acid (59 mg, 0.33 mmol), EDC x HCl (76 mg, 0.4 mmol) and pyridine (80 pi, 0.99 mmol). The reaction mixture was stirred at RT for 3.5 h, diluted with AcOEt, and successively washed with a mixture of 1N HCl/brine, brine (*2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by Biotage (Snap KP-Sil 10 g cartridge; MeOH/DCM: 0/100 to 5/95 over 50 CV, then 05/95 to 10/90 over 30 CV, 220 nm detection wavelength) to afford the desired product 91 (19 mg, 0.02 mmol, 35% yield) as a colorless sticky film/oil. 1H NMR (400 MHz, DMSO-d6) 6 (ppm): mixture of rotamers, 12.00 (bs, 1H), 8.50-8.05 (m, 1H), 7.68-7.55 (m, 2H), 7.30-7.06 (m, 9H), 4.29-4.19 (m, 1H), 3.89 (s, 2H), 3.84 (s, 2H), 3.63-3.36 (m, 18H), 3.23 (2s, 6H), 3.20-2.70 (m, 5H), 2.64-2.52 (m, 4H), 1.70-1.46 (m, 6H), 1.44-1.12 (m, 4H), 1.09 (d, J=7.0 Hz, 3H). MS (m/z): 817.48 [M+H]+. and 839.46 [M+Na]+.
35%	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 3.5h; Inert atmosphere;	59.3 Step 3. N,N’-((S)-6-((S)-2-Methyl-3-oxo-3-(2-(4-(4-phenyl-butyl)phenyl)acetamidooxy)propylamino)-6-oxohexane- 1,5-diyl) bis(2-(2-(2-methoxyethoxy)ethoxy)acetamide) (91) To a stirred solution at RT of compound 90 (0.066 mmol)in DMF (3 ml) under nitrogen were added 2-(2-(2-methoxy-ethoxy)ethoxy)acetic acid (59 mg, 0.33 mmol), EDCxHC1(76 mg, 0.4 mmol) and pyridine (80 jil, 0.99 mmol). Thereaction mixture was stirred at RT for 3.5 h, diluted withAcOEt, and successively washed with a mixture of iN HC1/brine, brine (x2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by l3iotage (Snap KP-Sil 10 g cartridge; MeOH/DCM:0/100 to 5/95 over 50 CV, then 05/95 to 10/90 over 30 CV, 220 nm detection wavelength) to afford the desired product91 (19 mg, 0.02 mmol, 35% yield) as a colorless sticky filmloil. ‘H NMR (400 MHz, DMSO-d5) ö (ppm): mixture of rotamers, 12.00 (bs, 1H), 8.50-8.05 (m, 1H), 7.68-7.55 (m, 2H), 7.30-7.06 (m, 9H), 4.29-4.19 (m, 1H), 3.89 (s, 2H), 3.84 (s, 2H), 3.63-3.36 (m, 18H), 3.23 (2s, 6H), 3.20-2.70 (m, 5H), 2.64-2.52 (m, 4H), 1.70-1.46 (m, 6H), 1.44-1.12 (m, 4H), 1.09 (d, J7.0 Hz, 3H). MS (mlz): 817.48 [M+H] and 839.46 [M+Na].

Reference： [1]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US2015/203517, 2015, A1 Location in patent: Paragraph 0413
[2]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US9636298, 2017, B2 Location in patent: Page/Page column 113; 114; 115

56
[ 16024-58-1 ]
(S)-2,6-diamino-N-(4-oxo-4-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)butyl)hexanamide dihydrochloride [ No CAS ]
(S)-N,N’-(6-oxo-6-(4-oxo-4-(2-(4-(4-phenylbutyl) phenyl)acetamidooxy)butylamino)hexane-1,5-diyl)bis(2-(2-(2-methoxyethoxy)ethoxy)acetamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48.9%	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 3h;	61.3 Step 3. (S)-N,N'-(6-Oxo-6-(4-oxo-4-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)butylamino)hexane-1,5-diyl)bis(2-(2-(2-methoxyethoxyl)ethoxy)acetamide) (99 Step 3. (S)-N,N'-(6-Oxo-6-(4-oxo-4-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)butylamino)hexane-1,5-diyl)bis(2-(2-(2-methoxyethoxyl)ethoxy)acetamide) (99) To a stirred solution at rt of compound 98 (2.2 g, 3.86 mmol) in DMF (15 mL) under nitrogen were added 2-(2-(2-methoxyethoxyl)ethoxy)acetic acid (1.78 ml, 11.59 mmol), HOBtH2O (1.18 g, 7.73 mmol), EDCHCl (2.96 g, 15.45 mmol) and pyridine (3.12 ml, 38.6 mmol). The reaction mixture was stirred at RT for 3 h, diluted with AcOEt, and successively washed with a mixture of 1N HCl/brine (*3), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified twice by Biotage (Snap KP-Sil 100 g cartridge KP-Sil; MeOH/DCM: 0/100 to 10/90 over 30 CV, and by reverse phase: Snap 120 g cartridge KP-C18-HS; MeOH/water: 20/80 to 95/5 over 40 CV, 40 ml/min, 220 nm detection wavelength) to afford the desired product 99 (1.544 g, 1.89 mmol, 48.9% yield) as a colorless gel. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.98-11.76 (m, 1H), 8.07 (t, J=5.5 Hz, 1H), 7.62 (t, J=6.0 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.30-7.06 (m, 9H), 4.24 (td, J=8.3, 5.5 Hz, 1H), 3.93 and 3.89 (2d, J=15.3 Hz, 2H), 3.84 (s, 2H), 3.65-3.37 (m, 18H), 3.24 and 3.23 (2s, 6H), 3.14-3.02 (m, 4H), 2.63-2.53 (m, 4H), 2.44 (t, J=7.4 Hz, 2H), 1.74-1.12 (m, 12H). MS (m/z): 817.6 [M+H]+. and 839.6 [M+Na]+.

Reference： [1]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US2015/203517, 2015, A1 Location in patent: Paragraph 0422

57
[ 16024-58-1 ]
N-α-Boc-lys-OMe*HCl [ No CAS ]
(S)-methyl 16-(tert-butoxycarbonylamino)-10-oxo-2,5,8-trioxa-11-azaheptadecan-17-oate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.7%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 60h;	91.1 Step 1. (S)-Methyl 16-(tert-butoxycarbonylamino)-10-oxo-2,5,8-trioxa-11-azaheptadecan-17-oate (137) Step 1. (S)-Methyl 16-(tert-butoxycarbonylamino)-10-oxo-2,5,8-trioxa-11-azaheptadecan-17-oate (137) To a stirred solution of N-α-Boc-lys-OMeHCl (3.0 g, 10.11 mmol) in DMF (30 mL) was added 2-[2-(2-methoxyethoxyl)ethoxy]acetic acid (1.98 g, 11.12 mmol), EDCHCl (2.71 g, 14.15 mmol), HOBt*H2O (2.16 g, 14.15 mmol) and NEt3 (2.82 mL, 20.22 mmol). The reaction mixture was stirred at RT for 2.5 days, diluted with AcOEt, water and a saturated NH4Cl solution, and successively washed water, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the desired product 137 (4.6 g, 94.7% yield), contaminated with HOBT) as colorless oil.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 60h;	91.1 Step 1. (S)-Methyl 1 6-(tert-butoxycarbonylamino)- 1 0-oxo- 2,5,8-trioxa-1 1 -azaheptadecan-1 7-oate (137) To a stirred solution of N-a-Soc-lys-OMexHC1 (3.010.11 mmol) in DMF (30 mL) was added 2-[2-(2-methoxy- ethoxy)ethoxy]acetic acid (1.98 g, 11.12 mmol), EDCxHC1 (2.71 g, 14.15 mmol), HOI3TxH2O (2.16 g, 14.15 mmol) and NEt3 (2.82 mL, 20.22 mmol). The reaction mixture was stirred at RT for 2.5 days, diluted with AcOEt, water andsaturated NH4C1 solution, and successively washed water, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the desired product 137 (4.694.7% yield), contaminated with HOST) as colorless oil.

Reference： [1]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US2015/203517, 2015, A1 Location in patent: Paragraph 0442
[2]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US9636298, 2017, B2 Location in patent: Page/Page column 143; 144; 145; 146

58
[ 16024-58-1 ]
N-((S)-1-((S)-2,6-diaminohexanoyl)pyrrolidine-2-carbonyloxy)-2-(4-(4-phenylbutyl)phenyl)acetamide dihydrochloride [ No CAS ]
N,N’-((S)-6-oxo-6-((S)-2-((2-(4-(4-phenylbutyl)phenyl)acetamidooxy)carbonyl)pyrrolidin-1-yl)hexane-1,5-diyl)bis(2-(2-(2-methoxyethoxy)ethoxy)acetamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;	66.a.n.d.67.3 Step 3. N,N’-((S)-6-Oxo-6-((S)-2-((2-(4-(4-phenyl- butyl)phenyl)acetamidooxy) carbonyl)pyrrolidin-yl)hexane- 1 ,5-diyl)bis(2-(2-(2-methoxyethoxy)ethoxy)acetamide (107) Step 3. N,N'-((S)-6-Oxo-6-((S)-2-((2-(4-(4-phenylbutyl)phenyl)acetamidooxy) carbonyl)pyrrolidin-1-yl)hexane-1,5-diyl)bis(2-(2-(2-methoxyethoxy)ethoxy)acetamide (107) To a stirred solution of compound 106 (160 mg, 0.275 mmol) in DMF (4 ml) at RT under nitrogen were added 2-(2-(2-methoxyethoxyl)ethoxy)acetic acid (147 mg, 0.83 mmol), HOBtH2O (42 mg, 0.275 mmol), EDCHCl (211 mg, 1.10 mmol) and pyridine (223 μl, 2.75 mmol). The reaction mixture was stirred at RT overnight, diluted with AcOEt, and successively washed with a mixture of 1N HCl/brine (2), brine (2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified twice by Biotage (Snap KP-Sil 25 g cartridge; MeOH/DCM: 0/100 to 10/90 over 40 CV, and by reverse phase: Snap 30 g cartridge KP-C18-HS; MeOH/water: 5/95 to 95/5 over 40 CV, 40 ml/min, 220 nm detection wavelength) afford the desired product 107 (57 mg, 0.07 mmol, 25% yield) as colorless gel. 1H NMR (400 MHz, DMSO-d6) 6 (ppm): mixture of rotamers, 12.26-11.96 (m, 1H), 7.74-7.58 (m, 2H), 7.32-7.04 (m, 9H), 4.68-4.20 (m, 2H), 3.97-3.80 (m, 4H), 3.76-3.66 (m, 1H), 3.64-3.36 (m, 19H), 3.24 (2s, 6H), 3.08 (q, J=6.89 Hz, 2H), 2.64-2.52 (m, 4H), 2.28-2.18 (m, 1H), 2.07-1.87 (m, 3H), 1.74-1.20 (m, 10H). MS (m/z): 829.6 [M+H]+. and 851.6 [M+Na]+. Compound 108 (example 68) was prepared in one step by coupling compound 106 with 2-(2-methoxyethoxyl)acetic acid similarly to compound 107 (scheme 20).
25%	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	66.3; 67.3 Step 3. N,N’-((S)-6-Oxo-6-((S)-2-((2-(4-(4-phenylbutyl)phenyl)acetamidooxy)carbonyl)pyrrolidin-1 -yl)hexane-1 ,5-diyl)bis(2-(2-(2-methoxyethoxy)ethoxy)acetamide) (107) To a stirred solution of compound 106 (160 mg, 0.275mmol) in DMF (4 ml) at RT under nitrogen were added2-(2-(2-methoxyethoxy)ethoxy)acetic acid (147 mg, 0.83mmol), HOBTxH2O (42 mg, 0.275 mmol), EDCxHC1 (211mg, 1.10 mmol) and pyridine (223 pi, 2.75 mmol). Thereaction mixture was stirred at RT overnight, diluted withAcOEt, and successively washed with a mixture of iN HC1/brine (x2), brine (x2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified twice by Biotage (Snap KP-Sil 25 g cartridge; MeOH/DCM:0/100 to 10/90 over 40 CV, and by reverse phase: Snap 30cartridge KP-C18-HS; MeOH/water: 5/95 to 95/5 over 40 CV, 40 ml/min, 220 nm detection wavelength) afford the desired product 107 (57 mg, 0.07 mmol, 25% yield) ascolorless gel. ‘H NMR (400 MHz, DMSO-d5) ö (ppm):mixture of rotamers, 12.26-11.96 (m, 1H), 7.74-7.58 (m, 2H), 7.32-7.04 (m, 9H), 4.68-4.20 (m, 2H), 3.97-3.80 (m, 4H), 3.76-3.66 (m, 1H), 3.64-3.36 (m, 19H), 3.24 (2s, 6H),3.08 (q, J=6.89 Hz, 2H), 2.64-2.52 (m, 4H), 2.28-2.18 (m,1H), 2.07-1.87 (m, 3H), 1.74-1.20 (m, 1OH). MS (mlz):829.6 [M+H] and 851.6 [M+Na].

Reference： [1]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US2015/203517, 2015, A1 Location in patent: Paragraph 0426
[2]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US9636298, 2017, B2 Location in patent: Page/Page column 125; 126; 128

59
[ 16024-58-1 ]
[ 1035264-81-3 ]
2-(2-(2-Methoxyethoxyl)ethoxy)-N-((1-((2-(4-(4-phenylbutyl)phenyl)acetamidooxy)carbonyl)cyclopropyl)methyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32.8%	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 50℃; for 24h;	33 Example 33 2-(2-(2-Methoxyethoxyl)ethoxy)-N-((1-((2-(4-(4-phenylbutyl)phenyl)acetamidooxy)carbonyl)cyclopropyl)methyl)acetamide (55) Example 33 2-(2-(2-Methoxyethoxyl)ethoxy)-N-((1-((2-(4-(4-phenylbutyl)phenyl)acetamidooxy)carbonyl)cyclopropyl)methyl)acetamide (55) To a solution of the 54 (0.240 g, 0.576 mmol) in DMF (5 mL) was added 2-(2-(2-methoxyethoxyl)ethoxy)acetic acid (0.205 g, 1.151 mmol) followed by HOBtH2O (0.176 g, 1.151 mmol), EDCHCl (0.331 g, 1.727 mmol) and pyridine (0.230 ml, 2.88 mmol). The reaction mixture was stirred for 24 hours at 50° C., cooled to RT and partitioned between the brine and EtOAc. The organic layer was collected, dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash column chromatography; eluent MeOH (5%) in DCM to form an oily material which was further purified using the same eluent. A third column purification (eluent 10% MeOH in EtOAc) afforded the title compound 55 (0.102 g, 32.8% yield) as honey-like colorless material which eventually has solidified. 1H NMR (DMSO-d6) δ (ppm): 12.02 (br. s, 1H), 7.74 (br. t, 1H), 7.28-7.24 (m, 2H), 7.18-7.10 (m, 7H), 3.88 (s, 2H), 3.56-3.40 (m, 12H), 3.33-3.20 (m, 4H), 3.23 (s, 3H), 2.60-2.54 (m, 4H), 1.57-1.55 (m, 4H), 1.18-1.15 (m, 2H), 1.08-1.04 (m, 2H). LRMS (ESI): (calc.) 540.7 (found) 541.3 (MH)+.
32.8%	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 50℃; for 24h;	33 EXAMPLE 33 2-(2-(2-Methoxyethoxy)ethoxy)-N-((l -((2-(4-(4- phenylbutyl)phenyl)acetamidooxy)carbonyl)cyclopropyl)methyl)acetamide (55) To a solution of the 54 (0.240 g, 0.576 mmol) in DMF (5 mL) was added 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (0.205 g, 1.151 mmol) followed by HOI3TxH2O (0.176 g, 1.151 mmol), EDCxHC1 (0.331 g, 1.727 mmol) and pyridine (0.230 ml, 2.88 mmol). The reaction mixture was stirred for 24 hours at 500 C., cooled to RT and partitioned between the brine and EtOAc. The organic layer was collected, dried over anhydrous Mg504, filtered and evaporated. The residue was purified by flash column chromatography; eluent MeOH (5%) in DCM to form an oily material which was thther purified using the same eluent. A third column purification (eluent 10% MeOH in EtOAc) affordedthe title compound 55 (0.102 g, 32.8% yield) as honey-likecolorless material which eventually has solidified. ‘H NMR(DMSO-d5) ö(ppm): 12.02 (bt s, 1H), 7.74 (bt t, 1H),7.28-7.24 (m, 2H), 7.18-7.10 (m, 7H), 3.88 (s, 2H), 3.56-3.40 (m, 12H), 3.33-3.20 (m, 4H), 3.23 (s, 3H), 2.60-2.54(m, 4H), 1.57-1.55 (m, 4H), 1.18-1.15 (m, 2H), 1.08-1.04(m, 2H). LRMS (ESI): (calc.) 540.7 (found) 541.3 (MH).

Reference： [1]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US2015/203517, 2015, A1 Location in patent: Paragraph 0391
[2]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US9636298, 2017, B2 Location in patent: Page/Page column 89; 90

60
[ 16024-58-1 ]
[ 935674-30-9 ]
C₁₁₂H₁₇₁N₂₅O₁₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: C₄₃H₅₅N₅O₉ With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine at 20℃; Stage #2: With piperidine In N,N-dimethyl-formamide at 20℃; Stage #3: 2-[2-(2-methoxyethoxy)etoxy]acetic acid Further stages;	General procedure for synthesis of peptide analogues General procedure: The peptide analogues were prepared as previously described [15]. In brief, Rink amide resin (loading: 0.70mmol/g) and Teflon reactors (10mL) were used for all compounds. Fmoc deprotection conditions: Excess 20% piperidine-DMF (2×10min under shaking at room temperature). Washing conditions: DMF, MeOH, and DCM (each 3×3min). Coupling conditions: Building block, PyBOP, and DIPEA (each 2.0 equiv. for loading; 2.5 equiv for coupling 1, and 2; 3.0 equiv for all subsequent couplings; in all cases: 2h coupling time under shaking at room temperature). Capping was applied after coupling 4: excess Ac2O-DIPEA-NMP 1:2:3 (10min at room temperature). Final Fmoc deprotection was followed by attachment of the N-terminal end groups. The corresponding carboxylic acid version of each moiety was added under conditions identical to those applied for the above coupling procedure used for the dimeric building blocks. Cleavage and simultaneous side chain deprotection: Excess TFA-water 95:5 (1h under shaking at room temperature). The filtrate was collected and the resin was eluted with DCM (2mL), MeOH (2mL), TFA-water 95:5 (2mL) and DCM (2mL). The combined filtrates were concentrated in vacuo, and then co-evaporated with toluene and MeOH (each 3×5mL). The crude product was purified by using preparative HPLC and concentrated in vacuo as previously described [7]. Finally, the product was dissolved in water (1mL) and lyophilized.

Reference： [1]Jahnsen, Rasmus O.; Sandberg-Schaal, Anne; Frimodt-Møller, Niels; Nielsen, Hanne Mørck; Franzyk, Henrik [European Journal of Pharmaceutics and Biopharmaceutics, 2015, vol. 95, p. 40 - 46]

61
[ 16024-58-1 ]
[ 303114-51-4 ]
C₄₄H₆₆O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With dmap In N,N-dimethyl-formamide for 4h; Reflux;	4.4 PEGylation of OA (I) and OA-Bn (III) Oleanolic acid (I) or 28-benzyl oleanolic acid (III) (0.44mmol), were separately dissolved in DMF (2mL). Then, DIPCDI (4mmol), DMAP (0.12mmol) and 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (VII, 4mmol), were added. The reaction mixture was maintained at reflux for 4h, and then was diluted with water and extracted three times with DCM. The organic layer was dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. Finally, the residue was purified by column chromatography using hexane/ethyl acetate as solvents, yielding compound 1 (95%) and 2 (94%), respectively.

Reference： [1]Medina-O'Donnell, Marta; Rivas, Francisco; Reyes-Zurita, Fernando J.; Martinez, Antonio; Martin-Fonseca, Samuel; Garcia-Granados, Andres; Ferrer-Martín, Rosa M.; Lupiañez, Jose A.; Parra, Andres [European Journal of Medicinal Chemistry, 2016, vol. 118, p. 64 - 78]

62
[ 16024-58-1 ]
[ 508-02-1 ]
C₃₇H₆₀O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With dmap In N,N-dimethyl-formamide for 4h; Reflux;	4.4 PEGylation of OA (I) and OA-Bn (III) Oleanolic acid (I) or 28-benzyl oleanolic acid (III) (0.44mmol), were separately dissolved in DMF (2mL). Then, DIPCDI (4mmol), DMAP (0.12mmol) and 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (VII, 4mmol), were added. The reaction mixture was maintained at reflux for 4h, and then was diluted with water and extracted three times with DCM. The organic layer was dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. Finally, the residue was purified by column chromatography using hexane/ethyl acetate as solvents, yielding compound 1 (95%) and 2 (94%), respectively. 4.4.1 Compound 1 (0037) White solid, mp 120-122°C; [α]25D+58 (c 1 in MeOH); IR νmax(KBr)/cm-1 2938, 1749, 1728, 1691, 1205, 1107, 1010 and 969; δH (CDCl3, 300MHz): 5.26 (dd, 1H, J1=J2=3.5Hz, H-12), 4.59 (dd, 1H, J1=J2=7.8Hz, H-3), 4.13 (collapsed AB system, 2H, CH2CO PEG group), 3.76-3.56 (m, 8H, CH2O PEG group), 3.39 (s, 3H, CH3O PEG group), 2.81 (dd, 1H, J1=3.2, J2=13.4Hz, H-18), 1.12, 0.92, 0.92, 0.89, 0.85, 0.83, 0.74 (s, 3H each, methyl groups); δC (CDCl3, 75MHz) see TableS1 (Supplementary material); ESI-HRMS m/z calcd for C37H60O7Na [M+Na]+ 639.4237, found 639.4238.

Reference： [1]Medina-O'Donnell, Marta; Rivas, Francisco; Reyes-Zurita, Fernando J.; Martinez, Antonio; Martin-Fonseca, Samuel; Garcia-Granados, Andres; Ferrer-Martín, Rosa M.; Lupiañez, Jose A.; Parra, Andres [European Journal of Medicinal Chemistry, 2016, vol. 118, p. 64 - 78]

63
[ 16024-58-1 ]
maslinic acid [ No CAS ]
C₄₄H₇₂O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap In N,N-dimethyl-formamide for 4h; Reflux;	4.4 PEGylation of OA (I) and OA-Bn (III) General procedure: Oleanolic acid (I) or 28-benzyl oleanolic acid (III) (0.44mmol), were separately dissolved in DMF (2mL). Then, DIPCDI (4mmol), DMAP (0.12mmol) and 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (VII, 4mmol), were added. The reaction mixture was maintained at reflux for 4h, and then was diluted with water and extracted three times with DCM. The organic layer was dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. Finally, the residue was purified by column chromatography using hexane/ethyl acetate as solvents, yielding compound 1 (95%) and 2 (94%), respectively.

Reference： [1]Medina-O'Donnell, Marta; Rivas, Francisco; Reyes-Zurita, Fernando J.; Martinez, Antonio; Martin-Fonseca, Samuel; Garcia-Granados, Andres; Ferrer-Martín, Rosa M.; Lupiañez, Jose A.; Parra, Andres [European Journal of Medicinal Chemistry, 2016, vol. 118, p. 64 - 78]

64
[ 16024-58-1 ]
[ 464876-77-5 ]
C₅₁H₇₈O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With dmap In N,N-dimethyl-formamide for 4h; Reflux;	4.4 PEGylation of OA (I) and OA-Bn (III) General procedure: Oleanolic acid (I) or 28-benzyl oleanolic acid (III) (0.44mmol), were separately dissolved in DMF (2mL). Then, DIPCDI (4mmol), DMAP (0.12mmol) and 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (VII, 4mmol), were added. The reaction mixture was maintained at reflux for 4h, and then was diluted with water and extracted three times with DCM. The organic layer was dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. Finally, the residue was purified by column chromatography using hexane/ethyl acetate as solvents, yielding compound 1 (95%) and 2 (94%), respectively.

Reference： [1]Medina-O'Donnell, Marta; Rivas, Francisco; Reyes-Zurita, Fernando J.; Martinez, Antonio; Martin-Fonseca, Samuel; Garcia-Granados, Andres; Ferrer-Martín, Rosa M.; Lupiañez, Jose A.; Parra, Andres [European Journal of Medicinal Chemistry, 2016, vol. 118, p. 64 - 78]

65
[ 16024-58-1 ]
[ 2450-71-7 ]
2-(2-(2-methoxyethoxy)ethoxy)-N-(prop-2-yn-1-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.53%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 1.5h;	Preparation of 2- (2-(2 -met hoxy ci’ hoxy) ethoxy)-N- (prop-2-yn-1-yl)acetamide To a solution of 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (1.53 g, 8.59 mmol) in THF (28.6 ml) was added prop-2-yn-1-amine (0.660 ml, 10.30 mmol) and DIPEA (3.00 ml, 17.17 mmol). HBTU (3.91 g, 10.30 mmol) was then added, and the mixture stirred at rt. After 1.5 h, LC/MS indicated that the reaction had advanced tonear-completion. The solvent was decanted from the white precipitate, and was concentrated in vacuo. The residue was taken up in EtOAc, then extracted with NaHCO3 to remove any unreacted acid. The organic layer was then extracted twice with 0.1 M HC1 to remove excess base. The organic extracts were then dried over MgSO4, filtered, and concentrated in vacuo. The residue was applied to silica gel(40g) and eluted with CH2C12 (60 mL), then a gradient to 25% acetone CH2C12 over600 mL, and finally a hold at 25% acetone CH2C12 for 300 mL. The appropriate fractions were combined to obtain 2-(2-(2-methoxyethoxy)ethoxy)-N-(prop-2-yn- 1- yl)acetamide (102.2 mg, 0.475 mmol, 5.53 % yield). ‘H NMR (500MHz, CHLOROFORM-d) ö 7.41 (br. s., 1H), 4.11 (dd, J=5.6, 2.6 Hz, 2H), 4.05 (s, 2H),3.74 - 3.67 (m, 6H), 3.63 - 3.60 (m, 2H), 3.43 (s, 3H), 2.23 (t, J=2.5 Hz, 1H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2016/77518, 2016, A1 Location in patent: Page/Page column 469

66
[ 16024-58-1 ]
[ 148759-41-5 ]
N-(5-azidopentyl)-2-(2-(2-methoxyethoxy)ethoxy)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 1.5h;	Preparation of N-(5-azidopentyl)-2- (2- (2-methoxyethoxy) ethoxy)acetamide To a solution of 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (400 mg, 2.245 mmol) in THF (7483 tl) was added 5-azidopentan-1-amine (317 mg, 2.469 mmol)and DIPEA (784 tl, 4.49 mmol). HBTU (936 mg, 2.469 mmol) was then added, and the mixture stirred at rt. After 1.5 h, LC/MS indicated that the reaction had advanced to near-completion. The solvent was decanted from the white precipitate, and was concentrated in vacuo. The residue was taken up in EtOAc, then extracted with NaHCO3 to remove any unreacted acid. The organic layer was then extractedtwice with 0.1 M HC1 to remove excess base. The organic extracts were then dried over MgSO4, filtered, and concentrated in vacuo. The material was used as-is for further chemistry. LC/MS: (M+H) = 289.15.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2016/77518, 2016, A1 Location in patent: Page/Page column 470

67
[ 16024-58-1 ]
C₂₆H₂₉N₂O₃P [ No CAS ]
C₄₀H₅₃N₂O₁₁P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	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 1,2-dichloro-ethane at 20℃; for 48h;	4 Synthesis of A-4 140 mg (0.31 mmol) of B-4 was taken in an eggplant flask and dissolved in 5 ml of 1,2-dichloroethane under shade. 265 μl (1.56 mmol) of N, N-diisopropylethylamine, 120 μl (0.78 mmol) of methoxyethoxyethoxyacetic acid, and O- (7-azabenzotriazol-1-yl) -1,1,3,3- Tetramethyluronium hexafluorophosphate (263 mg, 0.69 mmol) was added thereto, and the mixture was stirred at room temperature for 24 hours.Thereafter, 260 μl (1.5 mmol) of N, N-diisopropylethylamine, 240 μl (1.60 mmol) of methoxyethoxyethoxyacetic acid,And 500 mg (1.30 mmol) of O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate were added and stirred for 24 hours. The obtained reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 80 mg (0.10 mmol, yield 32%) of A-4.

Reference： [1]Current Patent Assignee: KURARAY CO LTD - JP5688939, 2015, B2 Location in patent: Paragraph 0152-0154

68
[ 16024-58-1 ]
MCL 187 [ No CAS ]
2-[2-(2-methoxyethoxy)ethoxy]-N-[(4aR,5R,11bR)-14-methyl-2,3,4,4a,5,6-hexahydro-1H-5,11b-(epiminoethano)phenanthro[3,2-d][1,3]thiazol-9-yl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With triethylamine; HATU In dichloromethane at 20℃;	68 Example 68 Preparation of 2- [2-(2-methoxyethoxy)ethoxy] -N- [(4aR,5R,l lbR)-14-methyl- 2,3,4,4a,5,6-hexahydro-lH-5,llb-(epiminoethano)phenanthro[3,2-d] [l,3]thiazol-9- yl]acetamide (68), hydrochloride salt Example 68 Preparation of 2- [2-(2-methoxyethoxy)ethoxy] -N- [(4aR,5R,l lbR)-14-methyl- 2,3,4,4a,5,6-hexahydro-lH-5,llb-(epiminoethano)phenanthro[3,2-d] [l,3]thiazol-9- yl]acetamide (68), hydrochloride salt To a solution of 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (39.1 mg, 0.220 mmol), 0-(7-azabenzotnazol-l-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (104 mg, 0.543 mmol) and triethylamine (0.034 mL, 0.439 mmol) in 3 mL of dichloromethane, (4aR,5R,l lbR)-14-methyl-2,3,4,4a,5,6-hexahydro-lH-5,l lb- (epiminoethano)phenanthro[3,2-d] [l,3]thiazol-9-arnine [Zhang et al. (2004) J. Med. Chem. 47(8): 1886-1888] (45.9 mg, 0.146 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was then taken up in 10 mL of dichloromethane and was sequentially washed with saturated sodium bicarbonate (10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate, was filtered and was concentrated. The residue was purified on flash silica gel column to give desired product (68) as the free base (1 .4 mg, 28%). MS (EI) for C25H35N3O4S: 474.2 (MH+). 1H NMR (500 MHz, Methanol-d4) δ 7.79 (d, 7.1 Hz, 2H), 4.34 (s, 2H), 3.82 (dd, J = 5.6, 2.9 Hz, 2H), 3.80 - 3.60 (m, 7H), 3.46 - 3.29 5H), 3.15 - 3.07 (m, 1H), 2.93 (s, 3H), 2.74 - 2.61 (m, 2H), 2.13 (dt, J = 12.5, 3.2 Hz, 1H), 2.01 (td, J = 13.8, 4.6 Hz, 1H), 1.75 (dt J = 12.9, 3.4 Hz, 1H), 1.69 - 1.43 (m, 5H), 1.43 - 1.26 (m, 2H), 1.19 (qd, J = 12.8, 3.9 Hz, 1H).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2016/182840, 2016, A1 Location in patent: Paragraph 00378

69
[ 16024-58-1 ]
(+)-3-amino-17-methylmorphinan [ No CAS ]
2-[2-(2-methoxyethoxy)ethoxy]-N-(17-methylmorphinan-3-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.2%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h;	33 Example 33 Preparation of 2-[2-(2-methoxyethoxy)ethoxy]-N-(17-methylmorphinan-3-yl)acetamide (33), hydrochloride salt Example 33 Preparation of 2-[2-(2-methoxyethoxy)ethoxy]-N-(17-methylmorphinan-3-yl)acetamide (33), hydrochloride salt To a solution of 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (0.083 mL, 0.543 mmol), EDC (104 mg, 0.543 mmol) and DIPEA (0.126 mL, 0.724 mmol) in 3 mL of dichloromethane were added 17-methylmorphinan-3-amine (92.8, 0.362 mmol). The reaction was stirred at room temperature for two hours. The reaction was then taken up in 10 mL of dichloromethane and sequentially washed with 10 mL of brine/lN HCl (1 : 1), saturated sodium bicarbonatelO mL and brine 10 mL. The organic layer was dried over sodium sulfate, was filtered and was concentrated. The residue was purified on flash silica gel column to give desired product (33) as free base (89.2 mg, 59.2%). MS (EI) for C24H36 2O4: 417.2 (MH+). NMR (500 MHz, DMSO-c) δ 9.42 (s, 1H), 7.49 - 7.39 (m, 2H), 7.04 (d, J = 8.3 Hz, 1H), 4.02 (s, 2H), 3.67 - 3.50 (m, 6H), 3.47 - 3.39 (m, 2H), 3.22 (s, 3H), 2.92 (d, J = 18.4 Hz, 1H), 2.69 (dd, J = 5.6, 3.1 Hz, 1H), 2.49 (dd, J = 18.6, 5.5 Hz, 1H), 2.33 - 2.22 (m, 5H), 1.90 (td, J = 12.1, 3.2 Hz, 1H), 1.71 (dt, J = 13.0, 3.2 Hz, 1H), 1.66 - 1.54 (m, 2H), 1.52 - 1.43 (m, 1H), 1.39 - 1.09 (m, 6H), 0.98 (qd, J= 12.8, 4.0 Hz, 1H).

Reference： [1]Current Patent Assignee: NEKTAR THERAPEUTICS - WO2016/182840, 2016, A1 Location in patent: Paragraph 00301

70
[ 16024-58-1 ]
C₁₇H₂₅NO₇ [ No CAS ]
2-(2-(2-methoxyethoxy)ethoxy)ethyl 3-(1,3-dioxolan-2-yl)-4-(2-(2-(2-methoxyethoxyethoxy)acetamido)benzoate) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: 2-[2-(2-methoxyethoxy)etoxy]acetic acid With dmap; 2-chloro-1-methyl-pyridinium iodide In dichloromethane at 45℃; for 0.5h; Inert atmosphere; Stage #2: C₁₇H₂₅NO₇ In dichloromethane at 45℃; for 20h; Inert atmosphere;

Reference： [1]Busschaert, Nathalie; Thompson, Sam; Hamilton, Andrew D. [Chemical Communications, 2017, vol. 53, # 2, p. 313 - 316]

71
[ 16024-58-1 ]
C₂₇H₃₄N₂O₁₀ [ No CAS ]
2-(2-(2-methoxyethoxy)ethoxy)ethyl 4-(3-(1,3-dioxolan-2-yl)-4-(2-(2-(2-methoxyethoxy)ethoxy)acetamido)benzamido)-3-(1,3-dioxolan-2-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: 2-[2-(2-methoxyethoxy)etoxy]acetic acid With 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine In dichloromethane at 45℃; for 0.5h; Inert atmosphere; Stage #2: C₂₇H₃₄N₂O₁₀ In dichloromethane at 45℃; for 48h; Inert atmosphere;

Reference： [1]Busschaert, Nathalie; Thompson, Sam; Hamilton, Andrew D. [Chemical Communications, 2017, vol. 53, # 2, p. 313 - 316]

72
[ 16024-58-1 ]
(S)-2,6-diamino-N-(4-oxo-4-(2-(4-(4-phenylbutyl)phenyl)acetamidooxy)butyl)hexanamide dihydrochloride [ No CAS ]
(S)-N,N’-(6-oxo-6-(4-oxo-4-(2-(4-(4-phenylbutyl) phenyl)acetamidooxy)butylamino)hexane-1,5-diyl)bis(2-(2-(2-methoxyethoxy)ethoxy)acetamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48.9%	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere;	61.3 Step 3. (S)-N,N’-(6-Oxo-6-(4-oxo-4-(2-(4-(4-phenylbutyl) phenyl)acetamidooxy)butylamino)hexane-1 ,5-diyl)bis(2-(2-(2- methoxyethoxy)ethoxy)acetamide) (99) To a stirred solution at rt of compound 98 (2.2 g, 3.86 mmol) in DMF (15 mL) under nitrogen were added 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (1.78 ml, 11.59 mmol), HOI3TxH2O (1.18 g, 7.73 mmol), EDCxHC1 (2.96 g, 15.45 mmol) and pyridine (3.12 ml, 38.6 mmol). The reaction mixture was stirred at RT for 3 h, diluted with AcOEt, and successively washed with a mixture of iNHC1/brine (x3), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified twice by l3iotage (Snap KP-Sil 100 g cartridge KP-Sil; MeOH/ 121DCM: 0/100 to 10/90 over 30 CV, and by reverse phase:Snap 120 g cartridge KP-C1 8-HS; MeOH/water: 20/80 to95/5 over 40 CV, 40 mi/mm, 220 nm detection wavelength)to afford the desired product 99 (1.544 g, 1.89 mmol, 48.9%yield) as a colorless gel. ‘H NMR (400 MHz, DMSO-d5) ö(ppm): 11.98-11.76 (m, 1H), 8.07 (t, J=5.5 Hz, 1H), 7.62 (t,J=6.0 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.30-7.06 (m, 9H),4.24 (td, J=8.3, 5.5 Hz, 1H), 3.93 and 3.89 (2d, J=15.3 Hz,2H), 3.84 (s, 2H), 3.65-3.37 (m, 18H), 3.24 and 3.23 (2s,6H), 3.14-3.02 (m, 4H), 2.63-2.53 (m, 4H), 2.44 (t, J=7.4

Reference： [1]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US9636298, 2017, B2 Location in patent: Page/Page column 117; 118; 119; 120; 121; 122

73
[ 5333-42-6 ]
[ 16024-58-1 ]
2-octyldodecyl 2-(2-(2-methoxyethoxy)ethoxy)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With p-toluenesulfonic acid monohydrate	13 Preparation of 2-octyldodecyl 2-(2-(2-methoxyethoxy)ethoxy)acetate Example 13 Preparation of 2-octyldodecyl 2-(2-(2-methoxyethoxy)ethoxy)acetate To a 3-neck 1000 ml round-bottomed flask was added 2-octyl-1-dodecanol (220.00 g, 736.89 mmol, 1.0 equiv.), 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (170.693 g, 957.95 mmol, 1.30 equiv.), toluene (200 ml) and p-toluenesulfonic acid monohydrate (1.4017 g, 7.3688 mmol, 0.010 equiv.) at room temperature. The resulting mixture was heated at reflux with stirring in an oil bath at 134° C. under a nitrogen atmosphere for 6 hours. The water produced in the reaction was collected in a Dean-Stark trap. The cooled mixture was diluted with diethyl ether, washed with dilute aqueous Na2CO3 solution, water, brine, dried (MgSO4), filtered, and concentrated in vacuo to afford a crude product. Excess solvent was further removed by heating the crude product with stirring in an oil bath under high vacuum for 2 hours to afford a clear light yellow liquid (319.67 g, 94%).

Reference： [1]Current Patent Assignee: EXXON MOBIL CORP - US2017/183595, 2017, A1

74
[ 16024-58-1 ]
N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)pyridin-4-amine [ No CAS ]
2-(2-(2-methoxyethoxy)ethoxy)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-N-(pyridin-4-yl) acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With dicyclohexyl-carbodiimide In chloroform at 0℃; Reflux;

Reference： [1]Carrara, Serena; Aliprandi, Alessandro; Hogan, Conor F.; De Cola, Luisa [Journal of the American Chemical Society, 2017, vol. 139, # 41, p. 14605 - 14610]

75
[ 504-24-5 ]
[ 16024-58-1 ]
N-(4-pyridyl)2-[2-(2-methoxyethoxy)ethoxy]acetic acid amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: 4-aminopyridine; 2-[2-(2-methoxyethoxy)etoxy]acetic acid With dicyclohexyl-carbodiimide In chloroform at 20℃; for 1h; Stage #2: In chloroform for 4h; Reflux;

Reference： [1]Carrara, Serena; Aliprandi, Alessandro; Hogan, Conor F.; De Cola, Luisa [Journal of the American Chemical Society, 2017, vol. 139, # 41, p. 14605 - 14610]

76
[ 16024-58-1 ]
C₃₃H₅₆N₂O₂ [ No CAS ]
C₄₀H₆₈N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	In tetrahydrofuran at 20℃; for 4h;	4.4 PEGylation reaction on the free amino group of the OA- or MA-diamine conjugates General procedure: DIPCDI (4mmol each) and 3,6,9-trioxadecanoic acid (PEG-COOH, 4mmol each) were added to six solutions of compounds 1, 3, 5, 7, 9, or 11 (1mmol of each) in THF (20mL each). The reaction mixtures were stirred at rt for 4h, and then filtered and diluted with CH2Cl2. These organic layers were separately washed several times with water, treated with dry Na2SO4, and the solvent removed under reduced pressure. Finally, each residue was purified on a chromatography column using CH2Cl2/acetone as eluent, isolating the following PEGylated-diamine conjugates of OA or MA: 13 (91%), 14 (88%), 15 (89%), 16 (91%), 17 (94%), and 18 (89%).

Reference： [1]Medina-O'Donnell, Marta; Rivas, Francisco; Reyes-Zurita, Fernando J.; Martinez, Antonio; Lupiañez, Jose A.; Parra, Andres [European Journal of Medicinal Chemistry, 2018, vol. 148, p. 325 - 336]

77
[ 16024-58-1 ]
C₃₃H₅₆N₂O₃ [ No CAS ]
C₄₀H₆₈N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	In tetrahydrofuran at 20℃; for 4h;	4.4 PEGylation reaction on the free amino group of the OA- or MA-diamine conjugates General procedure: DIPCDI (4mmol each) and 3,6,9-trioxadecanoic acid (PEG-COOH, 4mmol each) were added to six solutions of compounds 1, 3, 5, 7, 9, or 11 (1mmol of each) in THF (20mL each). The reaction mixtures were stirred at rt for 4h, and then filtered and diluted with CH2Cl2. These organic layers were separately washed several times with water, treated with dry Na2SO4, and the solvent removed under reduced pressure. Finally, each residue was purified on a chromatography column using CH2Cl2/acetone as eluent, isolating the following PEGylated-diamine conjugates of OA or MA: 13 (91%), 14 (88%), 15 (89%), 16 (91%), 17 (94%), and 18 (89%).

Reference： [1]Medina-O'Donnell, Marta; Rivas, Francisco; Reyes-Zurita, Fernando J.; Martinez, Antonio; Lupiañez, Jose A.; Parra, Andres [European Journal of Medicinal Chemistry, 2018, vol. 148, p. 325 - 336]

78
[ 16024-58-1 ]
C₃₆H₆₂N₂O₂ [ No CAS ]
C₄₃H₇₄N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	In tetrahydrofuran at 20℃; for 4h;	4.4 PEGylation reaction on the free amino group of the OA- or MA-diamine conjugates General procedure: DIPCDI (4mmol each) and 3,6,9-trioxadecanoic acid (PEG-COOH, 4mmol each) were added to six solutions of compounds 1, 3, 5, 7, 9, or 11 (1mmol of each) in THF (20mL each). The reaction mixtures were stirred at rt for 4h, and then filtered and diluted with CH2Cl2. These organic layers were separately washed several times with water, treated with dry Na2SO4, and the solvent removed under reduced pressure. Finally, each residue was purified on a chromatography column using CH2Cl2/acetone as eluent, isolating the following PEGylated-diamine conjugates of OA or MA: 13 (91%), 14 (88%), 15 (89%), 16 (91%), 17 (94%), and 18 (89%).

Reference： [1]Medina-O'Donnell, Marta; Rivas, Francisco; Reyes-Zurita, Fernando J.; Martinez, Antonio; Lupiañez, Jose A.; Parra, Andres [European Journal of Medicinal Chemistry, 2018, vol. 148, p. 325 - 336]

79
[ 16024-58-1 ]
C₃₆H₆₂N₂O₃ [ No CAS ]
C₄₃H₇₄N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	In tetrahydrofuran at 20℃; for 4h;	4.4 PEGylation reaction on the free amino group of the OA- or MA-diamine conjugates General procedure: DIPCDI (4mmol each) and 3,6,9-trioxadecanoic acid (PEG-COOH, 4mmol each) were added to six solutions of compounds 1, 3, 5, 7, 9, or 11 (1mmol of each) in THF (20mL each). The reaction mixtures were stirred at rt for 4h, and then filtered and diluted with CH2Cl2. These organic layers were separately washed several times with water, treated with dry Na2SO4, and the solvent removed under reduced pressure. Finally, each residue was purified on a chromatography column using CH2Cl2/acetone as eluent, isolating the following PEGylated-diamine conjugates of OA or MA: 13 (91%), 14 (88%), 15 (89%), 16 (91%), 17 (94%), and 18 (89%).

Reference： [1]Medina-O'Donnell, Marta; Rivas, Francisco; Reyes-Zurita, Fernando J.; Martinez, Antonio; Lupiañez, Jose A.; Parra, Andres [European Journal of Medicinal Chemistry, 2018, vol. 148, p. 325 - 336]

80
[ 16024-58-1 ]
C₄₀H₇₀N₂O₂ [ No CAS ]
C₄₇H₈₂N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	In tetrahydrofuran at 20℃; for 4h;	4.4 PEGylation reaction on the free amino group of the OA- or MA-diamine conjugates General procedure: DIPCDI (4mmol each) and 3,6,9-trioxadecanoic acid (PEG-COOH, 4mmol each) were added to six solutions of compounds 1, 3, 5, 7, 9, or 11 (1mmol of each) in THF (20mL each). The reaction mixtures were stirred at rt for 4h, and then filtered and diluted with CH2Cl2. These organic layers were separately washed several times with water, treated with dry Na2SO4, and the solvent removed under reduced pressure. Finally, each residue was purified on a chromatography column using CH2Cl2/acetone as eluent, isolating the following PEGylated-diamine conjugates of OA or MA: 13 (91%), 14 (88%), 15 (89%), 16 (91%), 17 (94%), and 18 (89%).

Reference： [1]Medina-O'Donnell, Marta; Rivas, Francisco; Reyes-Zurita, Fernando J.; Martinez, Antonio; Lupiañez, Jose A.; Parra, Andres [European Journal of Medicinal Chemistry, 2018, vol. 148, p. 325 - 336]

81
[ 16024-58-1 ]
C₄₀H₇₀N₂O₃ [ No CAS ]
C₄₇H₈₂N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	In tetrahydrofuran at 20℃; for 4h;	4.4 PEGylation reaction on the free amino group of the OA- or MA-diamine conjugates General procedure: DIPCDI (4mmol each) and 3,6,9-trioxadecanoic acid (PEG-COOH, 4mmol each) were added to six solutions of compounds 1, 3, 5, 7, 9, or 11 (1mmol of each) in THF (20mL each). The reaction mixtures were stirred at rt for 4h, and then filtered and diluted with CH2Cl2. These organic layers were separately washed several times with water, treated with dry Na2SO4, and the solvent removed under reduced pressure. Finally, each residue was purified on a chromatography column using CH2Cl2/acetone as eluent, isolating the following PEGylated-diamine conjugates of OA or MA: 13 (91%), 14 (88%), 15 (89%), 16 (91%), 17 (94%), and 18 (89%).

Reference： [1]Medina-O'Donnell, Marta; Rivas, Francisco; Reyes-Zurita, Fernando J.; Martinez, Antonio; Lupiañez, Jose A.; Parra, Andres [European Journal of Medicinal Chemistry, 2018, vol. 148, p. 325 - 336]

82
C₁₁H₂₂O₅ [ No CAS ]
[ 16024-58-1 ]

Yield	Reaction Conditions	Operation in experiment
	With methoxybenzene; trifluoroacetic acid In dichloromethane at 20℃; for 5h;	2.1 (1) Synthesis of Compound 2a (n= 2) diethylene Glycol Monomethyl Ether - tert-butyl acetate derivative [ or MPEG2 - tert-butyl acetate] (1.80 g, 7.68 mmol) was dissolved in dichloromethane (30 mL), then trifluoroacetic acid (14.2 mL, 192.00 mmol) and anisole (0.96 ml, 8.83 mmol) were added, stirred at room temperature for 5 h and then dried to give the corresponding acid. Under a nitrogen atmosphere, a solution of the acid obtained in the above step and 4-dimethyl amino pyridine (0.47 g, 3.84 mmol) in dichloromethane (50 mL) was added dicyclohexylcarbodiimide (1.90 g, 9.22 mmol), after stirring for 10 minutes, propofol (2.05 g, 11.52 mmol) was dissolved in dichloromethane (10 mL) and thenslowly added dropwise to the reaction mixture. After the addition was completed, the mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was suction filtered, and the filtrate was washed twice with dilute hydrochloric acid, and the organic phase was spin-dried and purified by column chromatography to afford compound 2a (1.47 g, 57%).
	With methoxybenzene; trifluoroacetic acid In dichloromethane at 20℃; for 5h;	General procedure: (Using the synthesis of ester 3a as an example). Trifluoroacetic acid (14.3 mL, 192.5 mmol) was added to a stirring solution of tert-butyl ester 20 (1.8 g, 7.7 mmol) and anisole (1.0 mL, 8.8 mmol) in CH2Cl2 (20 mL), and the resulting solution was stirred at rt for 5 h. The reaction mixture was evaporated to dryness under vacuum to give the acid as a reddish oil which was used in the next step without further purification. Then, under the atmosphere of N2, to a solution of the acid (1.4 g, 7.7 mmol), DMAP (473 mg, 3.8 mmol) and DCC (1.9 g, 9.2 mmol) in CH2Cl2 (50 mL) was added Propofol 12 (2.1 g, 11.5 mmol). After stirred for 16 h at rt, the resulting mixture was filtered and the filtrate was diluted with EtOAc (150 mL), washed with HCl (1 N aq, 2 × 150 mL) and then washed with NaHCO3 (1 N aq, 2 × 150 mL). The organic layer was collected, concentrated under vacuum to give a residue which was purified by column chromatography on silica gel (CH2Cl2/MeOH = 20/1) to give ester 3a as clear oil (1.5 g, 57% yield, 99.9% pure (HPLC), Fig. 2).
400 mg	With trifluoroacetic acid In dichloromethane at 20℃;	79.2 Step 4 General procedure: To a 100 mL round-bottom flask were added Compound 53-4 (510 mg, 0.872 mmol), 10 mL of dichloromethane and 1 mL of trifluoroacetic acid, and the mixture was stirred at room temperature overnight. The reaction was monitored by LC-MS until completion. The reaction solution was washed with saturated sodium bicarbonate and brine, and the organic layer was dried and concentrated to give 440 mg of Compound 53-5 as a yellow solid.

Reference： [1]Current Patent Assignee: WUHAN UNIVERSITY - CN108164419, 2018, A Location in patent: Paragraph 0042-0045
[2]Deng, Tao; Mao, Xianglan; Li, Yu; Bo, Shaowei; Yang, Zhigang; Jiang, Zhong-Xing [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 22, p. 3502 - 3505]
[3]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - US2019/161468, 2019, A1 Location in patent: Paragraph 0348; 0352; 0450; 0452

83
[ 16024-58-1 ]
[ 2078-54-8 ]
C₁₉H₃₀O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.47 g	Stage #1: 2-[2-(2-methoxyethoxy)etoxy]acetic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane for 0.166667h; Inert atmosphere; Stage #2: 2,6-diisopropylphenol In dichloromethane at 20℃; for 16h; Inert atmosphere;	2.1 (1) Synthesis of Compound 2a (n = 2) diethylene Glycol Monomethyl Ether - tert-butyl acetate derivative [ or MPEG2 - tert-butyl acetate] (1.80 g, 7.68 mmol) was dissolved in dichloromethane (30 mL), then trifluoroacetic acid (14.2 mL, 192.00 mmol) and anisole (0.96 ml, 8.83 mmol) were added, stirred at room temperature for 5 h and then dried to give the corresponding acid. Under a nitrogen atmosphere, a solution of the acid obtained in the above step and 4-dimethyl amino pyridine (0.47 g, 3.84 mmol) in dichloromethane (50 mL) was added dicyclohexylcarbodiimide (1.90 g, 9.22 mmol), after stirring for 10 minutes, propofol (2.05 g, 11.52 mmol) was dissolved in dichloromethane (10 mL) and thenslowly added dropwise to the reaction mixture. After the addition was completed, the mixture was stirred at room temperature for 16 h. After completion of the reaction, the mixture was suction filtered, and the filtrate was washed twice with dilute hydrochloric acid, and the organic phase was spin-dried and purified by column chromatography to afford compound 2a (1.47 g, 57%).
1.5 g	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 16h; Inert atmosphere;	General procedure for the synthesis of esters 3a-3f (Using the synthesis of ester 3a as an example). Trifluoroacetic acid (14.3 mL, 192.5 mmol) was added to a stirring solution of tert-butyl ester 20 (1.8 g, 7.7 mmol) and anisole (1.0 mL, 8.8 mmol) in CH2Cl2 (20 mL), and the resulting solution was stirred at rt for 5 h. The reaction mixture was evaporated to dryness under vacuum to give the acid as a reddish oil which was used in the next step without further purification. Then, under the atmosphere of N2, to a solution of the acid (1.4 g, 7.7 mmol), DMAP (473 mg, 3.8 mmol) and DCC (1.9 g, 9.2 mmol) in CH2Cl2 (50 mL) was added Propofol 12 (2.1 g, 11.5 mmol). After stirred for 16 h at rt, the resulting mixture was filtered and the filtrate was diluted with EtOAc (150 mL), washed with HCl (1 N aq, 2 × 150 mL) and then washed with NaHCO3 (1 N aq, 2 × 150 mL). The organic layer was collected, concentrated under vacuum to give a residue which was purified by column chromatography on silica gel (CH2Cl2/MeOH = 20/1) to give ester 3a as clear oil (1.5 g, 57% yield, 99.9% pure (HPLC), Fig. 2). 1H NMR (400 MHz, CDCl3) δ 7.25-7.15 (m, 3H), 4.50 (s, 2H), 3.88-3.83 (m, 2H), 3.78-3.73 (m, 2H), 3.71-3.66 (m, 2H), 3.60-3.55 (m, 2H), 3.39 (s, 3H), 2.94-2.82 (m, 2H), 1.19 (d, J = 6.9 Hz, 12H). 13C NMR (100 MHz, CDCl3) δ 169.2, 145.0, 140.3, 126.7, 124.0, 71.9, 71.1, 70.7, 70.6, 68.4, 59.1, 27.6, 23.3. HRMS (ESI) calcd for C19H30NaO5+ ([M+Na]+), 361.1985; found, 361.1981.

Reference： [1]Current Patent Assignee: WUHAN UNIVERSITY - CN108164419, 2018, A Location in patent: Paragraph 0042-0045
[2]Deng, Tao; Mao, Xianglan; Li, Yu; Bo, Shaowei; Yang, Zhigang; Jiang, Zhong-Xing [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 22, p. 3502 - 3505]

84
[ 16024-58-1 ]
2-(2-chloro-5-aminophenyl)-4,5-diphenyl-1H-imidazole [ No CAS ]
C₂₈H₂₈ClN₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	Stage #1: 2-[2-(2-methoxyethoxy)etoxy]acetic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl acetamide at 20℃; for 1h; Stage #2: 2-(2-chloro-5-aminophenyl)-4,5-diphenyl-1H-imidazole In N,N-dimethyl acetamide at 20℃; for 48h;	4 Coupling with 2- [2- (2 -methoxyethoxy) ethoxy] acetic acid 2.69 g (15.1 mmol) 2 - [2 - (2 -methoxyethoxy) ethoxy] acetic acid was dissolved in 30 ml dimethyl acetamide. 3.0 g (18.7 mmol) carbodiimidazole was added and the reaction was allowed to continue for 1 hour at room temperature. 5.0 g (14.4 mmol) 2- (2-chloro-5- amino-phenyl) -4 , 5-diphenyl-lH-imidazole was added and the reaction was allowed to continue for 48 hours at room temperature. The solvent was removed under reduced pressure and the ethoxylated triaryl imidazole was isolated by preparative column chromatography on a Grace Resolve RS80 column, using a gradient elution from methylene chloride to methylene chloride/ethyl acetate 50/50. The isolated compound was redissolved in 10 ml methylene chloride and crystallized by the addition of hexane . 2.69 g (y : 37 %) of the ethoxylated triaryl imidazole was isolated (TLC analysis on TLC Silicagel 60 F254, supplied by Merck, eluent methylene chloride/ethyl acetate 50/50, Rf : 0.27).

Reference： [1]Current Patent Assignee: AGFA-GEVAERT - WO2018/192932, 2018, A1 Location in patent: Page/Page column 41

85
[ 16024-58-1 ]
[ 125-73-5 ]
C₂₄H₃₅NO₅*ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-[2-(2-methoxyethoxy)etoxy]acetic acid; (+)-dextrorphan With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; trimethylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With hydrogenchloride In 1,4-dioxane at 20℃;	3-(Methoxy-PEGp-CHpC(O))-dextrorphan 49: [0176] To a solution of dextrorphan 1, 2-[2-2-methoxyethoxy)ethoxy] acetic acid 47, HOBt and trimethylamine in DMF is added a solution of HBTU in DMF. The reaction mixture is stirred at room temperature. The reaction is quenched with water and the solvent is evaporated under reduced pressure. The residue is partitioned between CH2CI2 and 5% aq. NaHCO3. The aqueous part is extracted with CH2CI2. The combined organic part is finished with brine, is dried over anhydrous Na2SO4 and is evaporated to dryness. The purified product is dissolved in 2N HCI in dioxane, is stirred at room temperature and is then evaporated under reduced pressure to give the hydrochloride salt 49 .

Reference： [1]Current Patent Assignee: KEMPHARM INC - WO2018/191477, 2018, A1 Location in patent: Paragraph 0176

86
[ 16024-58-1 ]
Levorphanol [ No CAS ]
C₂₄H₃₅NO₅*ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 2-[2-(2-methoxyethoxy)etoxy]acetic acid; Levorphanol With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide; butan-1-ol at 20℃; Stage #2: With hydrogenchloride In 1,4-dioxane at 20℃; for 0.0833333h;	3-(Methoxy-PEG2-CH2C(O))-levorhanol 49: To a solution of levorphanol 1 (0.09 g, 0.35 mmol), 2-[2-(2-methoxyethoxy)ethoxy] acetic acid 47 (0.065 mL, 0.42 mmol), HOBt (0.052 g,0.39 mmol) and trimethylamine (0.15 mL, 1.05 mmol) in DMF ( 6mL) was added a solution of HBTU (0.146 g, 0.385 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (1 mL) and the solvent was evaporated under reduced pressure. The residue was partitioned between CH2CI2 (50 mL) and 5% aq. NaHCO3 (50 mL). The aqueous part was extracted with CH2CI2 (50 mL). The combined organic part was washed with brine (60 mL), dried over anhydrous Na2SO4 and evaporated to dryness. The crude product was purified by preparative HPLC. The purified product was dissolved in 2N HCI in dioxane (4 mL), stirred at room temperature for 5 mm. and then evaporated under reduced pressure to give the hydrochloride salt 49 (0.125 g, 78%) as an oil.

Reference： [1]Current Patent Assignee: KEMPHARM INC - WO2018/191472, 2018, A1 Location in patent: Paragraph 0179

87
[ 16024-58-1 ]
[ 19245-95-5 ]
L-asparagine 1,1-dimethylethyl ester monohydrochloride [ No CAS ]
N-[2-(2-methoxyethoxy)ethoxy]acetyl}-L-alanyl-D-alanyl-L-asparagine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N-[(benzyloxy)carbonyl]-L-alanyl-D-alanine; L-asparagine 1,1-dimethylethyl ester monohydrochloride 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 Stage #2: With palladium 10% on activated carbon In methanol Stage #3: 2-[2-(2-methoxyethoxy)etoxy]acetic acid Further stages;	N-[2-(2-Methoxyethoxy)ethoxy]acetyl}-L-alanyl-D-alanyl-L-asparagine N-[2-(2-Methoxyethoxy)ethoxy]acetyl}-L-alanyl-D-alanyl-L-asparagine The title compound was prepared by conventional methods of peptide chemistry by HATU coupling, in the presence of N,N-diisopropylethylamine and of N-[(benzyloxy)carbonyl]-L-alanyl-D-alanine, to tert-butyl L-asparaginate hydrochloride, followed by hydrogenolytic detachment of the Z protecting group over 10% palladium/activated carbon in methanol, then another HATU coupling to [2-(2-methoxyethoxy)ethoxy]acetic acid and subsequent cleavage of the tert-butyl ester with TFA. LC-MS (Method 1): Rt=0.6 min; MS (ESIpos): m/z=491 (M+H)+.

Reference： [1]Current Patent Assignee: BAYER AG - US2019/77752, 2019, A1 Location in patent: Paragraph 2287-2289

88
[ 16024-58-1 ]
[ 76-42-6 ]
6,14-bis-PEG-oxycodone [ No CAS ]
14-PEG-oxycodone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In chloroform Reflux;	10 Preparation and Isolation of 6,l4-bis-PEG-Oxycodone (as a PEG-acid salt) After the above reaction, the crude product was further purified by flash column using 80 g silica gel cartridge and 5% MeOH in EtOAc. Two batches of product were isolated. A purer fraction contains 82 mg of 88% pure 6,14-bis-PEG-Oxycodone 2-[2-(2- methoxyethoxy)ethoxy]acetic acid salt and 12% of mono-PEG-Oxycodone with no Oxycodone. A less pure fraction contains about 251 mg of 81% pure 6,l4-bis-PEG- Oxycodone 2-[2-(2-nethoxyethoxy)ethoxy]acetic acid salt, 18% of mono-PEG- Oxycodone, and 1% of Oxycodone as an impurity.

Reference： [1]Current Patent Assignee: PURDUE PHARMA L.P. - WO2019/165298, 2019, A1 Location in patent: Paragraph 0512; 0513

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	16024-58-1	MDL No. :	MFCD00044098
Formula :	C₇H₁₄O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YHBWXWLDOKIVCJ-UHFFFAOYSA-N
M.W :	178.18	Pubchem ID :	85241
Synonyms :

Num. heavy atoms :	12
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.86
Num. rotatable bonds :	8
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	40.79
TPSA :	64.99 Å²

GI absorption :	High
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) :	-7.83 cm/s

[ CAS No. 16024-58-1 ] {[proInfo.proName]}

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[ 16024-58-1 ] Synthesis Path-Downstream 1~88

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[ 16024-58-1 ]

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Log Po/w (iLOGP) :	1.81
Log Po/w (XLOGP3) :	-0.62
Log Po/w (WLOGP) :	-0.25
Log Po/w (MLOGP) :	-0.93
Log Po/w (SILICOS-IT) :	0.25
Consensus Log Po/w :	0.05

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.85

Log S (ESOL) :	-0.03
Solubility :	168.0 mg/ml ; 0.942 mol/l
Class :	Very soluble
Log S (Ali) :	-0.27
Solubility :	95.1 mg/ml ; 0.534 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.89
Solubility :	23.2 mg/ml ; 0.13 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	2.26

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338	UN#:	3265
Hazard Statements:	H318	Packing Group:	Ⅲ
GHS Pictogram:

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P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
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P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
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P401
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[ CAS No. 16024-58-1 ] {[proInfo.proName]}

Quality Control of [ 16024-58-1 ]

Related Doc. of [ 16024-58-1 ]

Product Details of [ 16024-58-1 ]

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[ 16024-58-1 ] Synthesis Path-Downstream 1~88

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Ethers

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Related Functional Groups of
[ 16024-58-1 ]