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[ CAS No. 96517-92-9 ] {[proInfo.proName]}

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Chemical Structure| 96517-92-9
Chemical Structure| 96517-92-9
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Product Details of [ 96517-92-9 ]

CAS No. :96517-92-9 MDL No. :MFCD22056316
Formula : C10H18O7 Boiling Point : -
Linear Structure Formula :- InChI Key :WFLUHYUKINZPNZ-UHFFFAOYSA-N
M.W : 250.25 Pubchem ID :13225972
Synonyms :
Chemical Name :3,3'-((Oxybis(ethane-2,1-diyl))bis(oxy))dipropanoic acid

Safety of [ 96517-92-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P271-P280-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 96517-92-9 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 96517-92-9 ]

[ 96517-92-9 ] Synthesis Path-Downstream   1~48

  • 1
  • [ 22397-31-5 ]
  • [ 96517-92-9 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride at 70 - 100℃;
With hydrogenchloride for 0.0833333h; Heating;
20.9 g With hydrogenchloride at 70℃; 73.2 Step 2: 3.3'-(Yoxybisiethane-2. 1 -diyl ribistoxyridipropionic acid. A mixture of 3,3'-((oxybis(ethane-2,l-diyl))bis(oxy))dipropanenitrile (26 g, 123 mmol) and concentrated HC1 (140 mL) was stirred at 70 °C overnight. After cooled to room temperature, the solids were filtered out by filtration and the filtrate was concentrated under vacuum. The crude residue was purified by flash column chromatography with 30-100% ethyl acetate in petroleum ether to afford 3,3'-((oxybis(ethane-2,l-diyl))bis(oxy))dipropionic acid (20.9 g, 70% over 2 steps) as yellow oil. NMR (400 MHz, DMSO-r/d) d 12.16 (s, 2H), 3.61 - 3.57 (m, 4H), 3.51 - 3.47 (m, 8H), 2.44 (t, J= 6.3 Hz, 4H).
20.9 g With hydrogenchloride; water at 70℃; 2.M.2 Step 2: Synthesis of 3,3'-((oxybis(ethane-2,1-diyl))bis(oxy))dipropionic acid. A mixture of 3,3'-((oxybis(ethane-2,1-diyl))bis(oxy))dipropanenitrile (26 g, 123 mmol) and concentrated HCl (140 mL) was stirred at 70 C overnight. After cooled to room temperature, the solids were filtered out by filtration and the filtrate was concentrated under vacuum. The crude residue was purified by flash column chromatography with 30~100% ethyl acetate in petroleum ether to afford 3,3'-((oxybis(ethane-2,1-diyl))bis(oxy))dipropionic acid (20.9 g, 70% over 2 steps) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 2H), 3.61 - 3.57 (m, 4H), 3.51 - 3.47 (m, 8H), 2.44 (t, J = 6.3 Hz, 4H).

Reference： [1]Christian; Hixon [Journal of the American Chemical Society, 1948, vol. 70, p. 1334]
[2]Ashikaga, Kazuo; Ito, Shinzaburo; Yamamoto, Masahide; Nishijima, Yasunori [Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 7, p. 2443 - 2450]
[3]Current Patent Assignee: NURIX THERAPEUTICS INC - WO2020/81450, 2020, A1 Location in patent: Paragraph 0920; 0923; 0924
[4]Current Patent Assignee: NURIX THERAPEUTICS INC - WO2021/91575, 2021, A1 Location in patent: Paragraph 0625-0626
  • 2
  • [ 96517-92-9 ]
  • [ 93505-76-1 ]
YieldReaction ConditionsOperation in experiment
With thionyl chloride Umsetzen des Reaktionsprodukts mit konz.NH3;
Reference： [1]Christian; Hixon [Journal of the American Chemical Society, 1948, vol. 70, p. 1334]
  • 3
  • [ 96517-92-9 ]
  • [ 40976-91-8 ]
YieldReaction ConditionsOperation in experiment
With thionyl chloride at 50℃; for 1h;
Reference： [1]Ashikaga, Kazuo; Ito, Shinzaburo; Yamamoto, Masahide; Nishijima, Yasunori [Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 7, p. 2443 - 2450]
  • 4
  • [ 7647-01-0 ]
  • [ 22397-31-5 ]
  • [ 96517-92-9 ]
Reference： [1]Christian; Hixon [Journal of the American Chemical Society, 1948, vol. 70, p. 1334]
  • 5
  • [ 96517-92-9 ]
  • 1-Dibenzo[b,f]azepin-5-yl-3-{2-[2-(3-dibenzo[b,f]azepin-5-yl-3-oxo-propoxy)-ethoxy]-ethoxy}-propan-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: thionyl chloride / 1 h / 50 °C 2: benzene / 5 h / Heating
Reference： [1]Ashikaga, Kazuo; Ito, Shinzaburo; Yamamoto, Masahide; Nishijima, Yasunori [Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 7, p. 2443 - 2450]
  • 6
  • [ 96517-92-9 ]
  • C46H76N10O22Pol [ No CAS ]
  • [ 1204530-94-8 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3,3’-((oxybis(ethane-2,1-diyl))bis(oxy))dipropanoic acid; C46H76N10O22Pol With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; solid phase reaction; Stage #2: With chlorotriisopropylsilane; water; trifluoroacetic acid at 20℃; for 2h; solid phase reaction;
Reference： [1]Bach, Anders; Chi, Celestine N.; Pang, Gar F.; Olsen, Lars; Kristensen, Anders S.; Jemth, Per; Stromgaard, Kristian [Angewandte Chemie - International Edition, 2009, vol. 48, # 51, p. 9685 - 9689]
  • 7
  • [ 96517-92-9 ]
  • [ 99645-14-4 ]
  • monoaqua-κO-tris(µ-3,3'-{oxybis[2,1-ethanediylbis(oxy)]dipropanoato) 1κ4O1,O2,O3,O4:2κO1',O2',O5,O6:3κ4O3',O4',O5',O6'-dihydroxido-κ2O-di-µ3-oxido-1:2:3κ6O-triangulo-tritungsten(IV)(3W-W) [ No CAS ]
  • monoaqua-κO-bis(µ3-3,3'-{oxybis[2,1-ethanediylbis(oxy)]dipropanoato-1κO1: 2κO1',O2:3κO2')(µ3-3,3'-{oxybis[2,1-ethanediylbis(oxy)]dipropanoato)1κ2O1,O2: 2κ2O1',O2'-dihydroxido-κ2O-di-µ3-oxido-1:2:3κ6O-triangulo-tritungsten(IV)(3W-W) [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 37 mg 2: 7 mg In water at 140℃; for 0.25h; Microwave irradiation; 4.4b Monoaqua-κO-tris(μ-3,3'-{oxybis[2,1-ethanediylbis(oxy)]dipropanoato) 1κ4O1,O2,O3,O4:2κO1',O2',O5,O6:3κ4O3',O4',O5',O6'-dihydroxido-κ2O-di-μ3-oxido-1:2:3κ6O-triangulo-tritungsten(IV)(3 W-W) Example 4b Monoaqua-κO-tris(μ-3,3'-{oxybis[2,1-ethanediylbis(oxy)]dipropanoato) 1κ4O1,O2,O3,O4:2κO1',O2',O5,O6:3κ4O3',O4',O5',O6'-dihydroxido-κ2O-di-μ3-oxido-1:2:3κ6O-triangulo-tritungsten(IV)(3 W-W) A suspension of 3,3'-[oxybis(ethane-2,1-diyloxy)]dipropanoic acid (303 mg, 1.21 mmol) and hexacis(μ-acetato-κ2O)-monoaqua-κ2O)-dihydroxido-κO-di-μ3-oxido-1:2:3κ6O-triangulo-tritungsten(IV) (400 mg, 0.40 mmol) in water (30 mL) was irradiated in a micowave reactor for 15 minutes at 140°C. The reaction mixtures were filtrated and the fitrates was concentrated in vacuum. Separation on a preparative HPLC (acetonitrile water + acetic acid) yields 7 mg monoaqua-κO-tris(μ-3,3'-{oxybis[2,1-ethanediylbis (oxy)]dipropanoato)-1κ4O1,O2,O4:2κ4O1',O2',O2', O5, O6:3κ4O3',O4',O5',O6'-dihydroxido-κ2O-di-μ3-oxido-1:2:3κ6O-triangulo-tritungsten(IV)(3 W-W) and 37 mg of example 5. 1H-NMR (300 MHz, D2O) δ = 2.89 (t, 12 H), 3.62 - 3.69 (m, 12 H), 3.70 (m, 12 H), 3.88 (t, 12 H) ppm. LC/MS ES- m/z = 1379.21 (M-1).
Reference： [1]Current Patent Assignee: BAYER AG - EP2733148, 2014, A1 Location in patent: Paragraph 0053
  • 8
  • [ 96517-92-9 ]
  • [ 756525-95-8 ]
  • C21H39NO10 [ No CAS ]
YieldReaction ConditionsOperation in experiment
2 g With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0℃; for 1.5h; To the solution of compound 301 (1.0 g, 4.3 mmol) and compound 643 (1.6 g, 6.4 mmol) in DCM (15 mL) were added HATU (1.83 g, 4.83 mmol) and TEA (0.68 mL, 4.83 mmol) at 0 . The reaction mixture was allowed to stir at 0 for 90 min, then concentrated and purified by column chromatography (MeOH/DCM) to afford the title compound 681 (2.0 g, >100%yield, containing silica gel) . ESI m/z C21H40NO10[M+H]+: 466.26, found 466.23.
Reference： [1]Patent: WO2019/127607,2019,A1 .Location in patent: Page/Page column 13; 244
  • 9
  • [ 96517-92-9 ]
  • tert-butyl 1-amino-9-oxo-3,6,13,16-tetraoxa-10-azanonadecan-19-oate [ No CAS ]
  • 2,2-dimethyl-4,14,24-trioxo-3,7,10,17,20,27,30,33-octaoxa-13,23 -diazahexatriacontan-36-oic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃; for 1h; 252 Example 252. Synthesis of compound 644 To a solution of amine 630 (1.50 g, 3.82 mmol) and diacid 643 (1.90 g, 7.64 mmol) in DMF (10 mL) were added HATU (1.45 g, 3.82 mmol) and DIPEA (0.66 mL, 3.82 mmol) at 0 . The reaction mixture was warmed to r.t. and stirred for 1 h, then diluted with DCM (80 mL) , washed with water (10 mL) , dried over sodium sulfate, filtered, concentrated and purified by silica gel column chromatography to afford a colorless liquid (1.75 g, 75%yield) . ESI m/z calcd for C28H53N2O13[M+H]+: 625.35, found 625.35.
75% With 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 1h;
75% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl acetamide at 20℃; for 1h; 252 Example 252. Synthesis of compound 644 To a solution of amine 630 (1.50 g, 3.82 mmol) and diacid 643 (1.90 g, 7.64 mmol) in DMF (10 mL) at 0 °C. Add HATU (1.45 g, 3.82 mmol) and N,N'-diisopropylethylamine (0.66 mL, 3.82 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. It was then diluted with dichloromethane (80 mL), washed with water (10 mL), dried over sodium sulfate, filtered, concentrated and purified by silica gel column chromatography to obtain a colorless liquid (1.75 g, 75% yield).
75% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃; for 1h;

Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2019/127607, 2019, A1 Location in patent: Page/Page column 13; 233
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1 Location in patent: Page/Page column 263
[3]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - TW2020/41237, 2020, A Location in patent: Paragraph 000708; 000709
[4]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2021/212638, 2021, A1 Location in patent: Page/Page column 187
  • 10
  • di-tert-butyl 3,3’-((oxybis(ethane-2,1-diyl))bis(oxy))dipropanoate [ No CAS ]
  • [ 96517-92-9 ]
YieldReaction ConditionsOperation in experiment
With formic acid at 20℃; 251 Example 251. Synthesis of compound 643 Compound 642 (34 g, 0.093 mol) was dissolved in formic acid (100 mL) at room temperature and stirred overnight. The reaction was concentrated under vacuum to afford the title compound. ESI m/z calcd for C10H19O7[M+H]+: 251.11, found 251.11.
With formic acid at 20℃;
With formic acid at 20℃; 251 Example 251. Synthesis of Compound 643 Compound 642 (34 g, 0.093 mol) was dissolved in formic acid (100 mL) at room temperature and stirred overnight. The reaction was concentrated in vacuo to obtain the target compound.
With formic acid at 20℃;

Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2019/127607, 2019, A1 Location in patent: Page/Page column 13; 233
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1 Location in patent: Page/Page column 262-263
[3]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - TW2020/41237, 2020, A Location in patent: Paragraph 000706; 000707
[4]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2021/212638, 2021, A1 Location in patent: Page/Page column 186-187
  • 11
  • [ 96517-92-9 ]
  • 1-tert-butyl 33-(2,5-dioxopyrrolidin-1-yl) 11,21-dioxo-4,7,14,17,24,27,30-heptaoxa-10,20-diazatritriacontane-1,33-dioate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl acetamide / 1 h / 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2019/127607, 2019, A1
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - TW2020/41237, 2020, A
[3]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2021/212638, 2021, A1
  • 12
  • [ 96517-92-9 ]
  • (S)-42-(((benzyloxy)carbonyl)amino)-2,2-dimethyl-4,14,24,36-tetraoxo-3,7,10,17,20,27,30,33-octaoxa-13,23,37-triazatritetracontan-43-oic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C 3: sodium hydrogencarbonate / 1,4-dioxane; water / 1 h / 5 - 20 °C
Multi-step reaction with 3 steps 1: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C 3: sodium carbonate / 1,4-dioxane; water / 1 h / 5 - 20 °C
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl acetamide / 1 h / 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C 3: sodium hydrogencarbonate / 1,4-dioxane; water / 1 h / 5 - 20 °C
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C 3: sodium carbonate / water / 1 h / 5 - 20 °C

Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2019/127607, 2019, A1
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1
[3]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - TW2020/41237, 2020, A
[4]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2021/212638, 2021, A1
  • 13
  • [ 96517-92-9 ]
  • C67H109N7O21 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C 3: sodium hydrogencarbonate / 1,4-dioxane; water / 1 h / 5 - 20 °C 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1 h / 0 - 20 °C
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl acetamide / 1 h / 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C 3: sodium hydrogencarbonate / 1,4-dioxane; water / 1 h / 5 - 20 °C 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1 h / 0 - 20 °C
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2019/127607, 2019, A1
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - TW2020/41237, 2020, A
  • 14
  • [ 96517-92-9 ]
  • C59H103N7O19 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C 3: sodium hydrogencarbonate / 1,4-dioxane; water / 1 h / 5 - 20 °C 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1 h / 0 - 20 °C 5: palladium 10% on activated carbon; hydrogen / methanol / 760.05 Torr
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2019/127607, 2019, A1
  • 15
  • [ 96517-92-9 ]
  • C67H110N8O22 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C 3: sodium hydrogencarbonate / 1,4-dioxane; water / 1 h / 5 - 20 °C 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1 h / 0 - 20 °C 5: palladium 10% on activated carbon; hydrogen / methanol / 760.05 Torr 6: sodium dihydrogenphosphate / water; ethanol / 20 °C
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl acetamide / 1 h / 20 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C 3.1: sodium hydrogencarbonate / 1,4-dioxane; water / 1 h / 5 - 20 °C 4.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1 h / 0 - 20 °C 5.1: palladium 10% on activated carbon; hydrogen / methanol / 760.05 Torr 5.2: 20 °C
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2019/127607, 2019, A1
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - TW2020/41237, 2020, A
  • 16
  • [ 96517-92-9 ]
  • C28H45NO10 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1.5 h / 0 °C 2: potassium carbonate / N,N-dimethyl-formamide / 20 °C
Multi-step reaction with 2 steps 1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1.5 h / 0 °C 2: potassium carbonate / N,N-dimethyl-formamide / 20 °C
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2019/127607, 2019, A1
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - TW2020/41237, 2020, A
  • 17
  • [ 96517-92-9 ]
  • C38H55N3O13 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1.5 h / 0 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.2: 1 h / 0 - 20 °C
Multi-step reaction with 4 steps 1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1.5 h / 0 °C 2: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 4: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1 h / 0 - 20 °C
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2019/127607, 2019, A1
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - TW2020/41237, 2020, A
  • 18
  • [ 96517-92-9 ]
  • C63H94N6O18 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1.5 h / 0 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.2: 1 h / 0 - 20 °C 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 20 °C 4.2: 1 h / 0 °C
Multi-step reaction with 5 steps 1.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1.5 h / 0 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 4.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1 h / 0 - 20 °C 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 20 °C 5.2: 1 h / 0 °C
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2019/127607, 2019, A1
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - TW2020/41237, 2020, A
  • 19
  • [ 96517-92-9 ]
  • C48H82N6O16 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1.5 h / 0 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.2: 1 h / 0 - 20 °C 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 20 °C 4.2: 1 h / 0 °C 5.1: palladium 10% on activated carbon; hydrogen / methanol
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2019/127607, 2019, A1
  • 20
  • [ 96517-92-9 ]
  • C56H89N7O19 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1.5 h / 0 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.2: 1 h / 0 - 20 °C 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 20 °C 4.2: 1 h / 0 °C 5.1: palladium 10% on activated carbon; hydrogen / methanol 6.1: sodium dihydrogenphosphate / ethanol / 20 °C
Multi-step reaction with 6 steps 1.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1.5 h / 0 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 4.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1 h / 0 - 20 °C 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 20 °C 5.2: 1 h / 0 °C 6.1: palladium 10% on activated carbon; hydrogen / methanol 6.2: 20 °C
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2019/127607, 2019, A1
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - TW2020/41237, 2020, A
  • 21
  • [ 96517-92-9 ]
  • C62H88F5N7O19 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1.5 h / 0 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3.2: 1 h / 0 - 20 °C 4.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 20 °C 4.2: 1 h / 0 °C 5.1: palladium 10% on activated carbon; hydrogen / methanol 6.1: sodium dihydrogenphosphate / ethanol / 20 °C 7.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / ethyl acetate / 1 h / 20 °C
Multi-step reaction with 7 steps 1.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1.5 h / 0 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 4.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1 h / 0 - 20 °C 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 20 °C 5.2: 1 h / 0 °C 6.1: palladium 10% on activated carbon; hydrogen / methanol 6.2: 20 °C 7.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / ethyl acetate / 1 h / 20 °C
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2019/127607, 2019, A1
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - TW2020/41237, 2020, A
  • 22
  • [ 96517-92-9 ]
  • [ 1448297-52-6 ]
  • (S)-15-((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-16,16-dimethyl-13-oxo-4,7,10-trioxa-14-azaheptadecanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
59% With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 12h;Inert atmosphere; General procedure: To a stirred solution of succinic acid (680mg, 5.8mmol) in DMF (10mL) was added anhydrous DCM (150mL). Then the mixture was cooled to 0C, NMM (1.16g, 11.5mmol), VHL-1 (1.0g, 2.3mmol), HOAT (63mg, 0.46mmol) and EDCI.HCl (530mg, 2.8mmol) were added sequentially. The solution was purged and refilled with nitrogen. The resulting mixture was stirred at room temperature for 12h. The reaction mixture was quenched with water (1mL). After concentration, the residue was purified reverse phase ISCO (C18) to afford the desired compound s-4a (4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid) (s-4a) (0.82g, 65% yield) as a white solid.
Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 193
[2]Journal of Medicinal Chemistry,2020,vol. 63,p. 1216 - 1232
[3]Journal of Medicinal Chemistry,2019,vol. 62,p. 9281 - 9298
  • 23
  • [ 96517-92-9 ]
  • [ 1448297-52-6 ]
  • N-(2-chloro-6-methylphenyl)-2-((6-(4-((S)-15-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-16,16-dimethyl-13-oxo-4,7,10-trioxa-14-azaheptadecanoyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide; dichloromethane / 12 h / 0 - 25 °C / Inert atmosphere 2: 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 12 h / 25 °C
Reference： [1]Zhao, Quanju; Ren, Chaowei; Liu, Linyi; Chen, Jinju; Shao, Yubao; Sun, Ning; Sun, Renhong; Kong, Ying; Ding, Xinyu; Zhang, Xianfang; Xu, Youwei; Yang, Bei; Yin, Qianqian; Yang, Xiaobao; Jiang, Biao [Journal of Medicinal Chemistry, 2019, vol. 62, # 20, p. 9281 - 9298]
  • 24
  • [ 252881-74-6 ]
  • [ 96517-92-9 ]
  • 2,2-dimethyl-4,17-dioxo-3,7,10,13,20,23,26-heptaoxa-16-azanonacosan-29-oic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; In a solution of tert-butyl 3- (2- (2- (2-aminoethoxy) ethoxy) ethoxy) propanoate (6.00 g, 21.64 mmol) and 3, 3'- ( (oxybis (ethane-2, 1-diyl) ) bis (oxy) ) dipropanoic acid (21.01 g, 84.00 mmol) in DMA (200 ml) were added EDC (18.00 g, 93.75 mmol) and DIPEA (5.00 g, 38.75 mmol) . The mixture was stirred overnight, then concentrated and purified by SiO 2 column chromatography (MeOH: CH 2Cl 2 = 1: 12 to 1: 5) to give the title compound as a white oil (9.15 g, 86%yield) . ESI m/z: calcd for C 23H 44NO 11 [M+H] +: 510.28, found: 510.55.
Reference： [1]Patent: WO2020/6722,2020,A1 .Location in patent: Page/Page column 188
[2]Patent: WO2020/73345,2020,A1 .Location in patent: Page/Page column 196
  • 25
  • [ 96517-92-9 ]
  • [ 1448297-52-6 ]
  • (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / dimethyl sulfoxide / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / dimethyl sulfoxide / 12 h / 20 °C
Reference： [1]Cheng, Meng; Yu, Xufen; Lu, Kaylene; Xie, Ling; Wang, Li; Meng, Fanye; Han, Xiaoran; Chen, Xian; Liu, Jing; Xiong, Yue; Jin, Jian [Journal of Medicinal Chemistry, 2020, vol. 63, # 3, p. 1216 - 1232]
  • 26
  • [ 96517-92-9 ]
  • (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / N,N-dimethyl-formamide; dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere 2: 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / N,N-dimethyl-formamide; dichloromethane / 12 h / 20 °C / Inert atmosphere
Reference： [1]Chen, Jinju; Jiang, Biao; Kong, Ying; Li, Yan; Lin, Haifan; Qiu, Xing; Ren, Chaowei; Song, Xiaoling; Sun, Ning; Yang, Xiaobao; Zhang, Jianshui; Zhong, Hui; Zhou, Yuedong [European Journal of Medicinal Chemistry, 2020, vol. 193]
  • 27
  • [ 96517-92-9 ]
  • (2S,4R)-1-((S)-2-(tert-butyl)-16-((1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidine-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / N,N-dimethyl-formamide; dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere 2: 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / N,N-dimethyl-formamide; dichloromethane / 12 h / 20 °C / Inert atmosphere
Reference： [1]Chen, Jinju; Jiang, Biao; Kong, Ying; Li, Yan; Lin, Haifan; Qiu, Xing; Ren, Chaowei; Song, Xiaoling; Sun, Ning; Yang, Xiaobao; Zhang, Jianshui; Zhong, Hui; Zhou, Yuedong [European Journal of Medicinal Chemistry, 2020, vol. 193]
  • 28
  • [ 96517-92-9 ]
  • (2S,4R)-1-((S)-2-(tert-butyl)-16-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / N,N-dimethyl-formamide; dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere 2: 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / N,N-dimethyl-formamide; dichloromethane / 12 h / 20 °C / Inert atmosphere
Reference： [1]Chen, Jinju; Jiang, Biao; Kong, Ying; Li, Yan; Lin, Haifan; Qiu, Xing; Ren, Chaowei; Song, Xiaoling; Sun, Ning; Yang, Xiaobao; Zhang, Jianshui; Zhong, Hui; Zhou, Yuedong [European Journal of Medicinal Chemistry, 2020, vol. 193]
  • 29
  • [ 96517-92-9 ]
  • C19H22N3O4(1+)*Cl(1-) [ No CAS ]
  • C48H58N6O13(2+)*2Cl(1-) [ No CAS ]
YieldReaction ConditionsOperation in experiment
2.01 g Stage #1: 3,3’-((oxybis(ethane-2,1-diyl))bis(oxy))dipropanoic acid With thionyl chloride In dichloromethane for 6h; Inert atmosphere; Stage #2: C19H22N3O4(1+)*Cl(1-) With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; 1 Under nitrogen protection, add sulfoxide chloride (1.88 g, 15.8 mmol) dropwise to the dissolved Bis-Peg3-acid(Carboxy dipolyethylene glycol carboxy, compound IV) (1.32 g, 5.3 mmol) in 40 ml of anhydrous dichloromethane, after stirring for 6 hours,The above solution was concentrated to dryness and dissolved in anhydrous DMF (40 mL), then intermediate III (3.56 g, 10 mmol) and DIPEA (3.8 mL, 23.5 mmol) were added; then the whole solution was stirred at room temperature,TLC traced to the end of the reaction, developing agent: water: acetonitrile = 1: 9; then concentrated to dryness under reduced pressure and purified by silica gel column(The mobile phase is water/acetonitrile: 1/100 to 10/100) to obtain the final product dye compound, solid 2.01 g,
Reference： [1]Current Patent Assignee: SUZHOU UELANDY BIOTECHNOLOGY; US EVERBRIGHT - CN111117284, 2020, A Location in patent: Paragraph 0024; 0029-0030
  • 30
  • [ 96517-92-9 ]
  • [ 1613552-03-6 ]
  • 3-(2-(2-(3-(((3S,SS)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)amino)-3-oxopropoxy)ethoxy)ethoxy)propanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
15% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate; acetonitrile at 20℃; for 16h; Inert atmosphere; 73.3 Step 3: 3-(2-(2-(3-(((3S.5SVl-((S -2-((S -2-((tert- butoxycarbonvn(methvnamino)propanamido)-2-cvclohexylacetvn-5-(((R)-l.2.3.4- tetrahydronaphthalen- 1 -vDcarbamovDpynOlidin-3 -v0amino)-3 - oxopropoxy)ethoxy)ethoxy)propanoic acid. To a stirred solution of /ert-butyl ((S)-l-(((S)-2-((2S,4S)-4-amino-2-(((R)-l,2,3,4- tetrahydronaphthalen-l-yl)carbamoyl)pyrrolidin-l-yl)-l-cyclohexyl-2-oxoethyl)amino)-l- oxopropan-2-yl)(methyl)carbamate (1.0 g, 1.71 mmol), 3,3'-((oxybis(ethane-2,l- diyl))bis(oxy))dipropionic acid (1.15 g, 3.43 mmol) and DIEA (1.1 g, 8.57 mmol) in acetonitrile (20 mL), was added T3P (8.66 g, 6.86 mmol, 50% in EtOAc) under nitrogen. The resulting mixture was stirred at room temperature for 16 h. When the reaction was completed, the reaction was quenched by the addition of 50 mL H20. The aqueous solution was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated under vacuum. The residue was purified by pre-HPLC with the following conditions: [(Column: X Bridge Prep OBD C18 Column 30>Gradient: 28% B to 44% B in 7 min; 254/220 nm] to afford 3-(2-(2-(3-(((3S,5S)-l-((S)-2- ((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-5-(((R)- l,2,3,4-tetrahydronaphthalen-l-yl)carbamoyl)pyrrolidin-3-yl)amino)-3- oxopropoxy)ethoxy)ethoxy)propanoic acid (215.4 mg, 15%) as a white solid. 'H NMR (300 MHz, DMSO-i) d 8.39 (d, J= 8.7 Hz, 1H), 8.22 (d, J= 7.5 Hz, 1H), 7.80 - 7.70 (m, 1H), 7.32 (d, J= 7.2 Hz, 1H), 7.22 - 6.98 (m, 3H), 4.94 - 4.92 (m, 1H), 4.51 - 4.49 (m, 1H), 4.28 - 4.26 (m, 3H), 4.09 (t, J= 8.7 Hz, 1H), 3.60 - 3.58 (m, 4H), 3.49 (s, 8H), 2.75 - 2.73 (m, 5H), 2.35 - 2.31 (m, 5H), 1.99 - 1.50 (m, 11H), 1.40 (s, 9H), 1.30 - 0.82 (m, 9H). MS (ESI) calculated for (C42H65N5O11) [M+H]+, 816.5; found, 816.5.
15% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate; acetonitrile at 20℃; for 16h; Inert atmosphere; 2.M.3 Step 3: Synthesis of 3-(2-(2-(3-(((3S,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)amino)-3-oxopropoxy)ethoxy)ethoxy)propanoic acid. To a stirred solution of tert-butyl ((S)-1-(((S)-2-((2S,4S)-4-amino-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (1.0 g, 1.71 mmol), 3,3'-((oxybis(ethane-2,1-diyl))bis(oxy))dipropionic acid (1.15 g, 3.43 mmol) and DIEA (1.1 g, 8.57 mmol) in acetonitrile (20 mL) was added T3P (8.66 g, 6.86 mmol, 50% in EtOAc) under nitrogen. The resulting mixture was stirred at room temperature for 16 h. When the reaction was completed, the reaction was quenched by the addition of 50 mL H2O. The aqueous solution was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by pre-HPLC with the following conditions: [(Column: X Bridge Prep OBD C18 Column 30×150mm 5um; Mobile Phase A: Water(10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 44% B in 7 min; 254/220 nm] to afford 3-(2-(2-(3-(((3S,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-2-cyclohexylacetyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)amino)-3-oxopropoxy)ethoxy)ethoxy)propanoic acid (215.4 mg, 15%) as a white solid.1H NMR (300 MHz, DMSO-d6) δ 8.39 (d, J = 8.7 Hz, 1H), 8.22 (d, J = 7.5 Hz, 1H), 7.80 - 7.70 (m, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.22 - 6.98 (m, 3H), 4.94 - 4.92 (m, 1H), 4.51 - 4.49 (m, 1H), 4.28 - 4.26 (m, 3H), 4.09 (t, J = 8.7 Hz, 1H), 3.60 - 3.58 (m, 4H), 3.49 (s, 8H), 2.75 - 2.73 (m, 5H), 2.35 - 2.31 (m, 5H), 1.99 - 1.50 (m, 11H), 1.40 (s, 9H), 1.30 - 0.82 (m, 9H). MS (ESI) calculated for (C42H65N5O11) [M+H]+, 816.5; found, 816.5.
Reference： [1]Current Patent Assignee: NURIX THERAPEUTICS INC - WO2020/81450, 2020, A1 Location in patent: Paragraph 0920; 0925; 0926
[2]Current Patent Assignee: NURIX THERAPEUTICS INC - WO2021/91575, 2021, A1 Location in patent: Paragraph 0627-0628
  • 31
  • [ 96517-92-9 ]
  • 1-tert-butyl 33-(2,5-dioxopyrrolidin-1-yl)-11,21-dioxo-4,7,14,17,24,27,30-heptaoxa-10,20-diazatritriacontane-1,33-dioate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1
  • 32
  • [ 96517-92-9 ]
  • (S)-tert-butyl 5-((4-((5-((2R,4S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-methyl-5-oxopentyl)-2-hydroxyphenyl)amino)-4-oxobutyl)carbamoyl)-3,11,23,33-tetraoxo-1-phenyl-2,14,17,20,27,30,37,40-octaoxa-4,10,24,34-tetraazatritetracontan-43-oate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C 3: sodium carbonate / 1,4-dioxane; water / 1 h / 5 - 20 °C 4: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 - 20 °C
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1
  • 33
  • [ 96517-92-9 ]
  • (S)-tert-butyl 39-amino-45-((5-((2R,4S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-methyl-5-oxopentyl)-2-hydroxyphenyl)amino)-11,21,33,40,45-pentaoxo-4,7,14,17,24,27,30-heptaoxa-10,20,34,41-tetraazapentatetracontan-1-oate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C 3: sodium carbonate / 1,4-dioxane; water / 1 h / 5 - 20 °C 4: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 - 20 °C 5: palladium 10% on activated carbon; hydrogen / methanol / 760.05 Torr
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - WO2020/73345, 2020, A1
  • 34
  • [ 96517-92-9 ]
  • [ 82436-78-0 ]
  • C18H24N2O17S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3,3’-((oxybis(ethane-2,1-diyl))bis(oxy))dipropanoic acid With N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.0833333h; Stage #2: N-hydroxy-2,5-dioxopyrrolidine-3-sulfonic acid In dimethyl sulfoxide; N,N-dimethyl-formamide for 1h; 4 Example 4 SulfoSE-PEG3-SmTrip9 (693) (8134) PEG3 bis Sulfo-SE 3,3′-((oxybis(ethane-2,1-diyl))bis(oxy))dipropionic acid (55 mg, 0.22 mmol) was dissolved in anhydrous DMF, and then diisopropylethylamine (120 mg, 0.88 mmol) and HATU (176 mg, 0.45 mmol) added. The mixture was stirred for five minutes. Meanwhile, N-hydroxy-2,5-dioxopyrrolidine-3-sulfonic acid (90 mg, 0.46 mmol) was dissolve in 5 ml DMSO, and then added to the previous solution dropwise. The mixture was stirred for another hour until LC-MS shows disappearance of acid. The solution was directly used in the next step. Calculated: m/z=603.05 [M-]; measured (ESI): m/z=603.04 [M-].
Reference： [1]Current Patent Assignee: PROMEGA CORP - US2020/166460, 2020, A1 Location in patent: Paragraph 0157-0158
  • 35
  • [ 96517-92-9 ]
  • [ 1448297-52-6 ]
  • N-((S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((1-((S)-15-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-16,16-dimethyl-13-oxo-4,7,10-trioxa-14-azaheptadecanoyl)azetidin-3-yl)amino)pyrimidine-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / dichloromethane; N,N-dimethyl-formamide / 6 h / 0 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / dimethyl sulfoxide / 20 °C
Reference： [1]Shen, Yudao; Gao, Guozhen; Yu, Xufen; Kim, Huensuk; Wang, Li; Xie, Ling; Schwarz, Megan; Chen, Xian; Guccione, Ernesto; Liu, Jing; Bedford, Mark T.; Jin, Jian [Journal of Medicinal Chemistry, 2020, vol. 63, # 17, p. 9977 - 9989]
  • 36
  • [ 96517-92-9 ]
  • 4-(3-aminopropoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ No CAS ]
  • 17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-13-oxo-4,7,10-trioxa-14-azaheptadecanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3,3’-((oxybis(ethane-2,1-diyl))bis(oxy))dipropanoic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 0.25h; Stage #2: 4-(3-aminopropoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione In N,N-dimethyl-formamide at 0 - 20℃; for 16h; 9.4 Step 4 To a 2-mL vial with an ice-cold solution of 3,3'-((oxybis(ethane-2,l-diyl))bis(oxy))dipropionic acid (30.4 mg, 2 equiv., 121 pmol) and HATU (25.4 mg, 1.1 equiv., 66.8 pmol) in DMF (0.25 mL), was added DIPEA (31.4 mg, 42 pL, 4 equiv., 243 pmol), and the resultant solution was stirred for 15 min. Then, 4-(3-aminopropoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (20.1 mg, 1 equiv., 60.7 pmol) dissolved in DMF (0.25 mL) was added and the reaction mixture was stirred from 0 °C to RT for 16 h. LCMS showed product and di-amide compound. The crude material was directly purified by reverse phase preparative HPLC, and used in the next step.
Reference： [1]Current Patent Assignee: NORTHWESTERN UNIVERSITY (ILLINOIS) - WO2020/214555, 2020, A1 Location in patent: Paragraph 0136; 0138
  • 37
  • [ 96517-92-9 ]
  • C58H94N8O20 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl acetamide / 1 h / 20 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0 - 20 °C 3.1: sodium hydrogencarbonate / 1,4-dioxane; water / 1 h / 5 - 20 °C 4.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1 h / 0 - 20 °C 5.1: palladium 10% on activated carbon; hydrogen / methanol / 760.05 Torr 5.2: 20 °C 6.1: trifluoroacetic acid / dichloromethane / 2 h / 20 °C
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - TW2020/41237, 2020, A
  • 38
  • [ 96517-92-9 ]
  • C24H37NO10 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1.5 h / 0 °C 2: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - TW2020/41237, 2020, A
  • 39
  • [ 96517-92-9 ]
  • C47H73N7O17 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1.5 h / 0 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 4.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 1 h / 0 - 20 °C 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 20 °C 5.2: 1 h / 0 °C 6.1: palladium 10% on activated carbon; hydrogen / methanol 6.2: 20 °C 7.1: trifluoroacetic acid / dichloromethane / 0.5 h / 20 °C
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - TW2020/41237, 2020, A
  • 40
  • [ 96517-92-9 ]
  • 1-(cyanomethoxy)-1-oxo-3-phenylpropan-2-aminium [ No CAS ]
  • bis(cyanomethyl) (2R,18R)-2,18-dibenzyl-4,16-dioxo-7,10,13-trioxa-3,17-diazanonadecanedioate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine at 25℃;
Reference： [1]Lee, Joongoo; Schwarz, Kevin J.; Yu, Hao; Krüger, Antje; Anslyn, Eric V.; Ellington, Andrew D.; Moore, Jeffrey S.; Jewett, Michael C. [Chemical Communications, 2021, vol. 57, # 21, p. 2661 - 2664]
  • 41
  • [ 64-18-6 ]
  • [ 96517-92-9 ]
  • 1-cyclopropyl-6-fluoro-7-[2-(methylamino)ethoxy]-3-([(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one monohydrochloride [ No CAS ]
  • 3-[2-(2-{2-[(2-[1-cyclopropyl-6-fluoro-3-([(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]oxy}ethyl)(methyl)carbamoyl]ethoxy}ethoxy)ethoxy]propanoic acid formate [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% Stage #1: 3,3’-((oxybis(ethane-2,1-diyl))bis(oxy))dipropanoic acid; 1-cyclopropyl-6-fluoro-7-[2-(methylamino)ethoxy]-3-([(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one monohydrochloride With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; Stage #2: formic acid 11G Example 11G.3-[2-(2-{2-[(2-[1-cyclopropyl-6-fluoro-3-([(3S)-1-(6-methylpyridin-3-yl)piperidin- 3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]oxy}ethyl)(me- thyl)carbamoyl]ethoxy}ethoxy)ethoxy]propanoic acid formate Preparation of 3-[2-(2-{2-[(2-[1-cyclopropyl-6-fluoro-3-([(3S)-1-(6-methylpyridin-3-yl)piperidin-3- yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-4-oxo-1,4-dihydroquinolin-7-yl]oxy}ethyl)(me- thyl)carbamoyl]ethoxy}ethoxy)ethoxy]propanoic acid formate HATU (0.057 g, 1.3 eq.), DIPEA (0.061 ml, 3.0 eq.), 1-cyclopropyl-6-fluoro-7-[2-(methyla- mino)ethoxy]-3-([(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2-methylpyridin-4-yl)me- thyl]amino}methyl)-1,4-dihydroquinolin-4-one (Example 11) (0.07 g, 1.0 eq.) and 3-{2-[2-(2-car- boxyethoxy)ethoxy]ethoxy}propanoic acid (0.03 g, 1.0 eq.) were mixed in anh. DMF (1.5 mL). The reaction mixture were stirred overnight at RT. Solvent was concentrated under reduced pressure. The residue was dissolved in DCM and washed with water, brine, dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC (H2O:MeCN:FA) to give product as a formate salt (0.045 g, 45% yield) as a yellow oil. ESI-MS: 817.6 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.30 - 8.25 (m, 1H), 8.14 (s, 1H), 8.14 - 8.11 (m, 1H), 7.86 - 7.76 (m, 2H), 7.55 - 7.46 (m, 1H), 7.25 - 7.18 (m, 2H), 7.19 - 7.14 (m, 1H), 7.05 - 6.99 (m, 1H), 4.40 - 4.34 (m, 1H), 4.34 - 4.28 (m, 1H), 3.86 - 3.70 (m, 5H), 3.66 - 3.55 (m, 6H), 3.52 - 3.42 (m, 6H), 3.13 - 3.08 (m, 2H), 2.92 - 2.89 (m, 1H), 2.80 - 2.66 (m, 4H), 2.63 - 2.52 (m, 6H), 2.45 - 2.41 (m, 1H), 2.39 - 2.35 (m, 3H), 2.35 - 2.30 (m, 3H), 2.01 - 1.93 (m, 1H), 1.80 - 1.71 (m, 1H), 1.58 - 1.43 (m, 2H), 1.28 - 1.21 (m, 2H), 0.94 - 0.82 (m, 2H).
Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA - WO2021/116446, 2021, A1 Location in patent: Page/Page column 260; 261
  • 42
  • [ 96517-92-9 ]
  • (2R)-4-({2-[1-(1-hydroxy-6-oxopyridin-2-yl)-N-{2-[2-(2-{2-[3-(2-{2-[3-oxo-3-(2,3,5,6-tetrafluorophenoxy)propoxy]ethoxy}ethoxy)propanamido]ethoxy}ethoxy)ethoxy]ethyl}formamido]ethyl}carbamoyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]butanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide / 1,4-dioxane / 16 h / 20 °C / Cooling with ice 2: N-ethyl-N,N-diisopropylamine / acetonitrile; water / 0.17 h / 20 °C
Reference： [1]Current Patent Assignee: FUSION PHARMACEUTICALS INC - WO2021/142258, 2021, A1
  • 43
  • [ 96517-92-9 ]
  • (2R)-4-[2-(N-{2-[2-(2-{2-[3-(2-{2-[3-(2,6-Dichlorophenoxy)-3-oxopropoxy]ethoxy}ethoxy)propanamido]ethoxy}ethoxy)ethoxy]ethyl}-1-(1-hydroxy-6-oxopyridin-2-yl)formamido)ethyl]carbamoyl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]butanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide / 1,4-dioxane / 6.5 h / 20 °C / Cooling with ice 2: N-ethyl-N,N-diisopropylamine / acetonitrile; water / 0.67 h / 20 °C
Reference： [1]Current Patent Assignee: FUSION PHARMACEUTICALS INC - WO2021/142258, 2021, A1
  • 44
  • [ 96517-92-9 ]
  • 2,6-dichlorophenyl 3-[2-(2-{2-[(2-[4-({1,4,7,10-tetrakis[(1-hydroxy-6-oxopyridin-2-yl)methyl]-1,4,7,10-tetraazacyclododecan-2-yl}methyl)phenyl]carbamoyl}ethyl)carbamoyl]ethoxy}ethoxy)ethoxy]propanoate trifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dicyclohexyl-carbodiimide / 1,4-dioxane / 6.5 h / 20 °C / Cooling with ice 2.1: N-ethyl-N,N-diisopropylamine / acetonitrile; water / 1 h / 20 °C 2.2: 0.01 h / Cooling with ice
Reference： [1]Current Patent Assignee: FUSION PHARMACEUTICALS INC - WO2021/142258, 2021, A1
  • 45
  • [ 96517-92-9 ]
  • 2,6-dichlorophenyl 3-[2-(2-{3-oxo-3-[4,7,10-tris([1-(benzyloxy)-6-oxo-1,6-dihydropyridin-2-yl]methyl})-1,4,7,10-tetraazacyclododecan-1-yl]propoxy}ethoxy)ethoxy]propanoate trifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide / 1,4-dioxane / 6.5 h / 20 °C / Cooling with ice 2: potassium carbonate / acetonitrile / 23 h / 85 °C
Reference： [1]Current Patent Assignee: FUSION PHARMACEUTICALS INC - WO2021/142258, 2021, A1
  • 46
  • [ 96517-92-9 ]
  • 2,6-dichlorophenyl 3-{2-[2-(3-oxo-3-{4,7,10-tris[(1-hydroxy-6-oxopyridin-2-yl)methyl]-1,4,7,10-tetraazacyclododecan-1-yl}propoxy)ethoxy]ethoxy}propanoate trifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: dicyclohexyl-carbodiimide / 1,4-dioxane / 6.5 h / 20 °C / Cooling with ice 2: potassium carbonate / acetonitrile / 23 h / 85 °C 3: hydrogenchloride / 1,4-dioxane / 22 h / 20 - 25 °C / Sealed tube
Reference： [1]Current Patent Assignee: FUSION PHARMACEUTICALS INC - WO2021/142258, 2021, A1
  • 47
  • [ 96517-92-9 ]
  • [ 769-39-1 ]
  • 2,3,5,6-tetrafluorophenyl 3-(2-{2-[3-oxo-3-(2,3,5,6-tetrafluorophenoxy)propoxy]ethoxy}ethoxy)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With dicyclohexyl-carbodiimide In 1,4-dioxane at 20℃; for 16h; Cooling with ice; 14.1 Step 1: Synthesis of 2,3,5,6-Tetrafluorophenyl 3-(2-{2-[3-oxo-3-(2,3,5,6-tetrafluorophenoxy)propoxy]ethoxy}ethoxy)propanoate (Intermediate 13 - A) To a 20 mL scintillation vial containing 3-{2-[2-(2-carboxyethoxy)ethoxy]ethoxy}propanoic acid (Bis-PEG3-acid, 51 mg, 0.20 mmol) and a stir bar was added a solution of 2,3,5,6-tetraflurophenol (76 mg, 0.43 mmol in 1 mL of anhydrous 1,4-dioxanes). The reaction was then placed in an ice bath to stir and after ~5 min noticed was no longer fully soluble. Lastly, added N,N′-Dicyclohexylcarbodiimide (DCC, 90 mg, 0.43 mmol) in anhydrous 1,4-dioxanes (0.5 mL) in one portion and then removed the mixture from the ice bath to stir at room temperature for 16 h. The reaction was then monitored by HPLC-MS and worked up by dilution with MeCN (2 mL) and filtration through a fritted filter. The filtered solid was then washed with an additional MeCN (~5 mL) and the combined filtrate was concentrated under vacuum and purified on a preparative C18 HPLC column to afford Intermediate 13 - A (100 mg, 90%, 96% purity) as a clear oil.
Reference： [1]Current Patent Assignee: FUSION PHARMACEUTICALS INC - WO2021/142258, 2021, A1 Location in patent: Page/Page column 64-65
  • 48
  • [ 87-65-0 ]
  • [ 96517-92-9 ]
  • 2,6-dichlorophenyl 3-(2-{2-[3-(2,6-dichlorophenoxy)-3-oxopropoxy]ethoxy}ethoxy)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With dicyclohexyl-carbodiimide In 1,4-dioxane at 20℃; for 6.5h; Cooling with ice; 14.2 Step 2: Synthesis of 2,6-Dichlorophenyl 3-(2-{2-[3-(2,6-dichlorophenoxy)-3-oxopropoxy]ethoxy}ethoxy)propanoate (Intermediate 14 - A) To a 20 mL scintillation vial containing 3-{2-[2-(2-carboxyethoxy)ethoxy]ethoxy}propanoic acid (bis-PEG3-acid, 250 mg, 0.98 mmol) in 3 mL of anhydrous 1,4-dioxanes was added as stir bar and 2,6-dichlorophenol (365 mg, 2.15 mmol). The clear solution was then placed in an ice bath and stirred for 5 minutes. Lastly, N,N′-dicyclohexylcarbodiimide (DCC, 449 mg, 2.15 mmol) was added in 3 mL of anhydrous 1,4-dioxanes in one portion and then the reaction was removed from the ice bath to stir overnight at room temperature for 6.5 h during which time the reaction progress was monitored by HPLC-MS. Proceeded to add 1 mL of anhydrous DMF which did not fully solubilize the reaction contents and next added HBTU (557 mg, 1.42 mmol) and DIPEA (0.75 mL, 4.31 mmol) and stirred at room temperature for 65 h. The reaction was monitored by HPLC-MS and then worked up by concentration under vacuum to afford a brown oil. The residual DMF remaining was concentrated under an airstream to afford a thick brown oil. The reaction was purified on a preparative C18 HPLC column to afford Intermediate 14 - A (319 mg, 60%) as a pale yellow oil.1H NMR (600 MHz, CDCl3) = δ7.33 (d, J = 8.1 Hz, 2 H), 7.11 (t, J = 8.1 Hz, 2 H), 3.90 (t, J = 9.0 Hz, 4 H), 3.68-3.62 (m, 8 H), 2.95 (t, J = 6.0 Hz, 4 H).
Reference： [1]Current Patent Assignee: FUSION PHARMACEUTICALS INC - WO2021/142258, 2021, A1 Location in patent: Page/Page column 64-66
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