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Maleimido-tri(ethylene glycol)-propionic acid
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[ CAS No. 518044-40-1 ] {[proInfo.proName]}

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Product Details of [ 518044-40-1 ]

CAS No. :518044-40-1 MDL No. :MFCD23103943
Formula : C13H19NO7 Boiling Point : -
Linear Structure Formula :- InChI Key :YSFOTVPQFVYTQX-UHFFFAOYSA-N
M.W : 301.29 Pubchem ID :70980870
Synonyms :
Mal-PEG3-acid

Safety of [ 518044-40-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 518044-40-1 ]

* 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 [ 518044-40-1 ]

[ 518044-40-1 ] Synthesis Path-Downstream   1~25

  • 1
  • [ 55750-48-6 ]
  • [ 1404072-05-4 ]
  • [ 518044-40-1 ]
YieldReaction ConditionsOperation in experiment
75% With sodium hydrogencarbonate at 0 - 20℃; for 1.66667h; 3-(2-{2-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy]ethoxy}ethoxy)propanoic acid 186 mg (555 μmol) of 3-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}propanoic acid trifluoroacetate were dissolved in 2.6 ml of saturated sodium hydrogencarbonate solution and admixed at 0° C. with 86 mg (555 μmol) of N-methoxycarbonylmaleimide. The reaction mixture was stirred at 0° C. for 40 min and at RT for 1 h, then cooled again to 0° C., adjusted to pH 3 with sulphuric acid and extracted 3× with 25 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. [1548] 126 mg (75% of theory) of the title compound were obtained. [1549] LC-MS (Method 1): Rt=0.53 min; m/z=302 (M+H)+
75% With sodium hydrogencarbonate at 0 - 20℃; for 1.66667h; 42 3-(2-{ 2-[2-(2,5-dioxo-2,5-dihydro-1 H -pyrrol-1-yl)ethoxy ]ethoxy }ethoxy)propanoic acid [3921] 186 mg (555 f.tmol) of 3-{2-[2-(2-aminoethoxyl)ethoxy ]ethoxy }propanoic acid trifluoroacetate were dissolvedin 2.6 ml of saturated sodiumhydrogencarbonate solutionand admixed at oo C. with 86 mg (555 f.tmol) ofN-methoxycarbonylmaleimide. The reaction mixture wasstirred at oo C. for 40 min and at RT for 1 h, then cooled againto oo C., adjusted to pH 3 with sulphuric acid and extracted 3xwith 25 ml of ethyl acetate. The combined organic phaseswere dried over magnesium sulphate and concentrated. 126mg (75% of theory) of the title compound were obtained.[3922] LC-MS (Method 1): R,=0.53 min; m/z=302(M+Ht.
3-(2-{2-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy]ethoxy}ethoxy)propanoic acid 3-(2-{2-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy]ethoxy}ethoxy)propanoic acid 186 mg (555 μmol) of 3-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}propanoic acid trifluoroacetate were dissolved in 2.6 ml of saturated sodium hydrogencarbonate solution and admixed at 0° C. with 86 mg (555 μmol) of N-methoxycarbonylmaleimide. The reaction mixture was stirred at 0° C. for 40 min and at RT for 1 h, then cooled again to 0° C., adjusted to pH 3 with sulphuric acid and extracted 3* with 25 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. 126 mg (75% of theory) of the title compound were obtained. LC-MS (Method 1): Rt=0.53 min; m/z=302 (M+H)+.
Reference： [1]Current Patent Assignee: SEAGEN INC - US2015/23989, 2015, A1 Location in patent: Paragraph 1547-1549
[2]Current Patent Assignee: SEAGEN INC - US2015/246136, 2015, A1 Location in patent: Paragraph 3920-3922
[3]Current Patent Assignee: SEAGEN INC - US2013/66055, 2013, A1 Location in patent: Page/Page column Current Patent Assignee: SEAGEN INC - US2014/127240, 2014, A1 Location in patent: Page/Page column
  • 2
  • [ 518044-40-1 ]
  • [ 543-27-1 ]
  • [ 1404072-06-5 ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine In tetrahydrofuran tert-butyl 15-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-oxo-7,10,13-trioxa-2,3-diazapentadecan-1-oate tert-butyl 15-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-oxo-7,10,13-trioxa-2,3-diazapentadecan-1-oate 125 mg (417 μmol) of 3-(2-{2-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy]ethoxy}ethoxy) propanoic acid were dissolved at 0° C. in 2.1 ml of THF and admixed with 46 μl (417 mmol) of 4-methylmorpholine and 54.5 μl (417 μmol) of isobutyl chloroformate. The ice bath was removed and the reaction mixture was stirred at RT for 30 min. Subsequently, at 0° C., 55 mg (417 μmol) of tert-butyloxycarbonyl hydrazide were added. The reaction mixture was warmed to RT overnight, concentrated and purified by preparative HPLC. 60 mg (33% of theory) of the title compound were obtained. LC-MS (Method 1): Rt=0.66 min; m/z=416 (M+H)+.
With 4-methyl-morpholine In tetrahydrofuran tert-butyl-15-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-oxo-7,10,13-trioxa-2,3-diazapentadecan-1-oate tert-butyl-15-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-oxo-7,10,13-trioxa-2,3-diazapentadecan-1-oate 125 mg (417 μmol) of 3-(2-{2-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy]ethoxy}ethoxy)propanoic acid were dissolved at 0° C. in 2.1 ml of THF and admixed with 46 μl (417 mmol) of 4-methylmorpholine and 54.5 μl (417 μmol) of isobutyl chloroformate. The ice bath was removed, and the reaction mixture was stirred at RT for 30 min. Subsequently, at 0° C., 55 mg (417 μmol) of tert-butyloxycarbonyl hydrazide were added. The reaction mixture was warmed to RT overnight, concentrated and purified via preparative HPLC. 60 mg (33% of theory) of the title compound were obtained. LC-MS (Method 1): Rt=0.66 min; m/z=416 (M+H)+.
Reference： [1]Current Patent Assignee: SEAGEN INC - US2013/66055, 2013, A1 Location in patent: Page/Page column
[2]Current Patent Assignee: SEAGEN INC - US2014/127240, 2014, A1 Location in patent: Page/Page column
  • 3
  • [ 252881-74-6 ]
  • [ 518044-40-1 ]
Reference： [1]Patent: US2013/66055,2013,A1
[2]Patent: US2015/23989,2015,A1
[3]Patent: US2015/246136,2015,A1
  • 4
  • [ 518044-40-1 ]
  • [ 1404072-08-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 4-methyl-morpholine / tetrahydrofuran 2: trifluoroacetic acid / dichloromethane
Multi-step reaction with 2 steps 1.1: 4-methyl-morpholine; isobutyl chloroformate / tetrahydrofuran / 0.5 h / 0 - 20 °C 1.2: 0 - 20 °C 2.1: dichloromethane / 0.5 h / 20 °C
Reference： [1]Current Patent Assignee: SEAGEN INC - US2013/66055, 2013, A1 Current Patent Assignee: SEAGEN INC - US2014/127240, 2014, A1
[2]Current Patent Assignee: SEAGEN INC - US2015/246136, 2015, A1
  • 5
  • [ 518044-40-1 ]
  • 3-(2-{2-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy]ethoxy}ethoxy)propanehydrazide trifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 4-methyl-morpholine; isobutyl chloroformate / tetrahydrofuran / 0 - 20 °C 2: dichloromethane / 0.5 h / 20 °C
Reference： [1]Current Patent Assignee: SEAGEN INC - US2015/23989, 2015, A1
  • 6
  • [ 518044-40-1 ]
  • N-[1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-12,15-dioxo-3,6,9-trioxa-13,14-diazaoctadecan-18-yl]-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-[(2S)-1-(1,2-oxazinan-2-yl)-1-oxo-3-phenylpropan-2-yl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 4-methyl-morpholine; isobutyl chloroformate / tetrahydrofuran / 0 - 20 °C 2: dichloromethane / 0.5 h / 20 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C
Multi-step reaction with 3 steps 1.1: 4-methyl-morpholine; isobutyl chloroformate / tetrahydrofuran / 0.5 h / 0 - 20 °C 1.2: 0 - 20 °C 2.1: dichloromethane / 0.5 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C
Reference： [1]Current Patent Assignee: SEAGEN INC - US2015/23989, 2015, A1
[2]Current Patent Assignee: SEAGEN INC - US2015/246136, 2015, A1
  • 7
  • [ 870-46-2 ]
  • [ 518044-40-1 ]
  • [ 1404072-06-5 ]
YieldReaction ConditionsOperation in experiment
33% With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 0 - 20℃; tert-butyl 15-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4-oxo-7,10,13-trioxa-2,3-diazapentadecan-1-oate 125 mg (417 μmol) of 3-(2-{2-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy]ethoxy}ethoxy) propanoic acid were dissolved at 0° C. in 2.1 ml of THF and admixed with 46 μl (417 mmol) of 4-methylmorpholine and 54.5 μl (417 μmol) of isobutyl chloroformate. The ice bath was removed and the reaction mixture was stirred at RT for 30 min Subsequently, at 0° C., 55 mg (417 μmol) of tert-butyloxycarbonyl hydrazide were added. The reaction mixture was warmed to RT overnight, concentrated and purified by preparative HPLC. [1552] 60 mg (33% of theory) of the title compound were obtained. [1553] LC-MS (Method 1): Rt=0.66 min; m/z=416 (M+H)+
33% Stage #1: 3-(2-{2-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy]ethoxy}ethoxy)propanoic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: t-butoxycarbonylhydrazine In tetrahydrofuran at 0 - 20℃; 43 tert-butyl-15-(2,5-dioxo-2,5-dihydro-lH -pyrrol-1-yl)-4-oxo-7, 10, 13-trioxa-2,3-diazapentadecan-1-oate [3924] 125 mg (417 flillOl) of 3-(2-{2-[2-(2,5-dioxo-2,5-dihydro-18 -pyrrol-1-yl)ethoxy ]ethoxy }ethoxy) propanoicacid were dissolved at oo C. in 2.1 ml ofTHF and admixedwith 46 fll (417 mmol) of 4-methylmorpholine and 54.5 fll(417 flillOl) of isobutyl chloroformate. The ice bath wasremoved, and the reaction mixture was stirred at RT for 30min. Subsequently, at oo C., 55 mg (417 f.tmol) oftert-butyloxycarbonylhydrazide were added. The reaction mixturewas warmed to RT overnight, concentrated and purified viapreparative HPLC.[3925] 60 mg (33% of theory) of the title compound wereobtained.[3926] LC-MS (Method 1): R,=0.66 min; m/z=416(M+Ht.
Reference： [1]Current Patent Assignee: SEAGEN INC - US2015/23989, 2015, A1 Location in patent: Paragraph 1551-1553
[2]Current Patent Assignee: SEAGEN INC - US2015/246136, 2015, A1 Location in patent: Paragraph 3923-3926
  • 8
  • [ 918827-51-7 ]
  • [ 518044-40-1 ]
  • N-(21-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-10-oxo-3,6,13,16,19-pentaoxa-9-azahenicosyl)-5-(1,2-dithiolan-3-yl)pentanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 3h;
Reference： [1]García-Astrain; Ahmed; Kendziora; Guaresti; Eceiza; Fruk; Corcuera; Gabilondo [RSC Advances, 2015, vol. 5, # 62, p. 50268 - 50277]
  • 9
  • [ 518044-35-4 ]
  • [ 518044-40-1 ]
YieldReaction ConditionsOperation in experiment
With trifluoroacetic acid In dichloromethane at 20℃; for 2h;
Reference： [1]García-Astrain; Ahmed; Kendziora; Guaresti; Eceiza; Fruk; Corcuera; Gabilondo [RSC Advances, 2015, vol. 5, # 62, p. 50268 - 50277]
  • 10
  • [ 518044-40-1 ]
  • (R)-N-((2S,3S)-1-(((S,E)-6-(4-((14S,17S)-1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-14-isopropyl-12,15-dioxo-17-(3-ureidopropyl)-3,6,9-trioxa-13,16-diazaoctadecanamido)phenylsulfonamido)-2,5-dimethyl-6-oxohex-4-en-3-yl)(methyl)amino)-3-methyl-1-oxopentan-2-yl)-1-methylpiperidine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: dicyclohexyl-carbodiimide / ethyl acetate; 1,4-dioxane / 36 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 16 h 3: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; benzotriazol-1-ol; copper dichloride / dichloromethane; N,N-dimethyl-formamide / 20 °C
Reference： [1]Current Patent Assignee: ZYMEWORKS INC - WO2015/95953, 2015, A1
  • 11
  • [ 518044-40-1 ]
  • (14R,17R)-1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-14-isopropyl-12,15-dioxo-17-(3-ureidopropyl)-3,6,9-trioxa-13,16-diazaoctadecan-18-oic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide / ethyl acetate; 1,4-dioxane / 36 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 16 h
Reference： [1]Current Patent Assignee: ZYMEWORKS INC - WO2015/95953, 2015, A1
  • 12
  • [ 6066-82-6 ]
  • [ 518044-40-1 ]
  • 2,5-dioxopyrrolidin-1-yl 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
9% With dicyclohexyl-carbodiimide In 1,4-dioxane; ethyl acetate at 20℃; for 36h; 1.14 Example 1.14: MT-NHS: 2,5-Dioxopyrrolidin-1-yl 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol- 1-yl)ethoxy)ethoxy)ethoxy)propanoate. MT-OH (2.6 g, 8.6 mmol, 1.0 eq) was treated with dicyclohexylcarbodiimide (1.87 g, 9.06mmol, 1.05 eq), and N-hydroxysuccinimide (1.04 g, 6.06 mmol, 1.05 eq) in 30 mL of 5:1EtOAc/dioxane at ft. After 36 h, the mixture was filtered, washing with EtOAc, and the residue was purified by flash chromatography to yield the title compound (309 mg, 9.0%) as a clear oil along with starting material (1.31 g, 50% recovered).‘H NMR (400 MHz, Chloroform-d) ö 6.72 (s, 2H), 3.87 (t, J = 6.4 Hz, 2H), 3.74 (t, J = 5.6 25 Hz, 2H), 3.70 - 3.58 (m, 1OH), 2.93 (t, J = 6.4 Hz, 2H), 2.86 (s, 4H), 1.32 - 1.19 (m, 2H). m/z calcd.for C,7H22N209 = 398.13. Found [M+H] = 399.15, [M+Na] = 421.14. Rf= 0.59 (10% (5% AcOH/MeOH)/1 0% Hex/CH2C12).
With dicyclohexyl-carbodiimide In 1,4-dioxane; ethyl acetate at 20℃; for 36h; Compound 9: MT-NHS: 2,5-Dioxopyrrolidin-l-yl3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-lH-pyrroI-l-yI)ethoxy)ethoxy)ethoxy)propanoate. MT-OH (2.6 g, 8.6 mmol, 1.0 eq) was treated with dicyclohexylcarbodiimide (1.87 g, 9.06 mmol, 1.05 eq), and N-hydroxysuccinimide (1.04 g, 6.06 mmol, 1.05 eq) in 30 mL of 5: 1 EtOAc/dioxane at rt. After 36 h, the mixture was filtered, washing with EtOAc, and the residue was purified by flash chromatography to yield the title compound (309 mg, 9.0%) as a clear oil along with starting material (1.31 g, 50% recovered). NMR (400 MHz, Chloroform- d) δ 6.72 (s, 2H), 3.87 (t, J= 6.4 Hz, 2H), 3.74 (t, J= 5.6 Hz, 2H), 3.70 - 3.58 (m, 10H), 2.93 (t, J = 6.4 Hz, 2H), 2.86 (s, 4H), 1.32 - 1.19 (m, 2H). m/z calcd. for C17H22N209 = 398.13. Found [M+H]+ = 399.15, [M+Na]+ = 421.14. Rf = 0.59 (10% (5% AcOH/MeOH)/10% Hex/CH2C12).
Reference： [1]Current Patent Assignee: ZYMEWORKS INC - WO2016/41082, 2016, A1 Location in patent: Page/Page column 98
[2]Current Patent Assignee: ZYMEWORKS INC - WO2015/95953, 2015, A1 Location in patent: Page/Page column 119
  • 13
  • [ 518044-40-1 ]
  • (S,E)-N-((4-((R)-2-((R)-2-Amino-3-methylbutanamido)-5-ureidopentanamido)benzyl)sulfonyl)-2,5-dimethyl-4-((S)-N,3,3-trimethyl-2-((S)-3-methyl-2-((tert-butoxycarbonyl)(methyl)amino)-3-phenylbutanamido)butanamido)hex-2-enamide [ No CAS ]
  • C63H96N10O16S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 2-chloro-1-methyl-pyridinium iodide; triethylamine In dichloromethane for 3.5h; Example 6 Compound F-1 To a stirred solution of Compound E-4 (40.0 mg, 0.040 mmol, 1.0 eq) in CH2CI2 (0.5 mE) was added MT-OH (18.1 mg, 0.060 mmol, 1.5 eq). Next, triethylamine (0.017 mE, 0.120 mmol, 3.0 eq) then Mukiyama’s reagent (15.4 mg, 0.060 mmol, 1.5 eq) were added. After 3 h, approximately one equivalent of acid, triethylarnine, and Mukiyama’s reagent wasadded, and after 30 more mm, HPLC indicated consumption of starting material Compound E4. The reaction mixture was diluted with 0.25 mL hexanes and loaded directly onto flash chromatography to yield the title compound (29.3 mg, 57%) as a clear yellow film.C63H96N100)6S calcd. rn/z = 1280.67. Found [M+H] = 1281.94, [M+Naj = 1303.91, [M-Boc+2H] = 1181.86. Rf= 0.45 (10% (5% AcOHIMeOH)/10% Hex/CH2C12).
Reference： [1]Current Patent Assignee: ZYMEWORKS INC - WO2015/95953, 2015, A1 Location in patent: Page/Page column 136; 137
  • 14
  • [ 771-61-9 ]
  • [ 518044-40-1 ]
  • perfluorophenyl 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane 1.31 Example 1.31: Perfluorophenyl 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propanoate. To a stirred solution of 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro- 1H-pyrrol- 1-yl)ethoxy)ethoxy)ethoxy)propanoic acid, (Example 1.13) (2.28g, 7.57 mmol) in dichloromethane (100mL) was added 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.59 g, 1.1 equiv)and pentafluorophenol (1.53 g, 1.1 equiv). The reaction was allowed to stir overnight at which time 30 HPLC-MS indicated no remaining starting material (Rt = 5.30 mm, 490.4 m/z, full gradient). Thecrude reaction mixture was diluted with saturated sodium bicarbonate (-20 mL) and the mixture was transferred to a separatory funnel. The organic phase was washed with brine (-50 mL), dried overMgSO4, filtered and concentrated to give a slightly yellow oil. The oil was dissolved in a minimal amount of dichloromethane and loaded on to a 100 g silica gel column for purification (Isolera, 10- 100% EtOAc in hexanes over 12 column volumes). Fractions containing the desired material were pooled and concentrated under reduced pressure to give a colorless oil (3.32 g, 94%).
44% With dicyclohexyl-carbodiimide In ethyl acetate at 0 - 20℃; 6 Synthesis of perfluorophenyl 3-(2-(2-(2-(2, 5-dioxo-2, 5-dihydro- lH-pyrrol-1- y)ethoxy)ethoxy)ethoxy)propanoate 58.4 The acid (340 n g, 1.13 mmol) was combined with pentafluorophenoi (207 mg, 1.13 mmol) and dissolved in EtOAc (5 mL). The resulting mixture was cooled to 0 °C and a solution of DCC (233 mg, 1.13 mmol) in EtOAc (.3 mL) was added dropwise. The reaction mixture was stirred for 2 hours at 0 °C, then allowed to warm to room temperature overnight. The mixture was evaporated to dryness and the residue was purified by flash silica gel chromatography to give 230 mg a semi solid for a 44% yield.
Reference： [1]Current Patent Assignee: ZYMEWORKS INC - WO2016/41082, 2016, A1 Location in patent: Page/Page column 104; 105
[2]Current Patent Assignee: IL 2RX - WO2020/14541, 2020, A2 Location in patent: Paragraph 0577; 0579-0580
  • 15
  • [ 518044-40-1 ]
  • (S)-N-(1-(4-(N-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanoyl)sulfamoyl)phenyl)cyclopropyl)-2-((S)-1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-14-isopropyl-12-oxo-3,6,9-trioxa-13-azapentadecan-15-amido)-5-ureidopentanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide / 1,4-dioxane; ethyl acetate / 36 h / 20 °C 2: 1-hydroxy-pyrrolidine-2,5-dione / N,N-dimethyl-formamide
Reference： [1]Current Patent Assignee: ZYMEWORKS INC - WO2016/41082, 2016, A1
  • 16
  • [ 518044-40-1 ]
  • C36H55N5O5S [ No CAS ]
  • (1S,2R)-2-((2-((1R,3R)-1-(acetyloxy)-3-((2S,3S)-N,3-dimethyl-2-(((R)-1-methylpiperidine-2-yl)formamido)pentanamido)-4-methylpentyl)-1,3-thiazol-4-yl)formamido)-1-phenylpropyl 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With dmap; dicyclohexyl-carbodiimide In dichloromethane 48 EXAMPLE 48(1 S,2R)-2-(2-((1R,3R)-1 -acetoxy-3-((2S,3S)-N,3-dimethyl-2-((R)- 1 -methylpiperidine-2-carboxamido)pentanamido)-4-methylpentyl)thiazole-4-carbox-amido)-1 -phenyl-propyl 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro- 1H-pyrrol- 1 -yl)ethoxy)ethoxy)ethoxy)propanoate (211) Compound 208a (95 mg, 0.141 mmol) and 3-(2- (2-(2-(2,5-dioxo-2,5-dihydro- 1 H-pyrrol- 1 -yl)ethoxy) ethoxy)ethoxy)propanoic acid (55 mg, 0.182 mmol) in CH2C12 (5 ml) were added DCC (122 mg, 0.591 mmol) and DMAP (25 mg, 0.204 mmol) and the mixture was stirred overnight, evaporated and purified with Si02 chromatography (EtOAc/CH2C12, 1:3) to afford the title compound (95.1 mg, 71%). MS ESI: mlz+: [M+Na], calcd for C48H70NaN5O12S, 977.47, Found, 977.47.
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - US2017/157262, 2017, A1 Location in patent: Paragraph 0294; 0295
  • 17
  • [ 769-39-1 ]
  • [ 518044-40-1 ]
  • 2,3,5,6-tetrafluorophenyl 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h; Intermediate 5: <strong>[769-39-1]2,3,5,6-tetrafluorophenyl</strong> 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)ethoxy)ethoxy)ethoxy)propanoate (MT-<strong>[769-39-1]TFP</strong>) (0703) (0704) [00426] To a stirred solution of MT-OH (0.520 g, 1.73 mmol, 1 eq) in dichloromethane (10 mL) was added 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (0.301 g, 1.81 mmol, 1.05 eq), followed by N-(3- dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.348 g, 1.81 mmol, 1.05 eq). The reaction was stirred at room temperature. After 18hr, the reaction solvent was evaporated under reduced pressure and the resulting residue was purified by flash chromatography to yield the title compound (0.323 g, 42% yield). NMR (400 MHz, Chloroform- ) delta 7.02 (tt, J = 9.9, 7.1 Hz, 1H), 6.71 (s, 2H), 3.90 (t, J= 6.3 Hz, 2H), 3.75 (td, J = 5.6, 0.9 Hz, 2H), 3.70 - 3.64 (m, 6H), 3.63 (s, 4H), 2.98 (t, J = 6.3 Hz, 2H). m/z calc'd for G9H19F4NO7 449.11. Found [M+H]+ = 450.48, [M+Na]+ = 472.48
Reference： [1]Patent: WO2017/54080,2017,A1 .Location in patent: Paragraph 00426
  • 18
  • [ 518044-40-1 ]
  • C35H53N5O6S [ No CAS ]
  • (1S,2R)-2-((2-((1R,3R)-1-(acetyloxy)-3-((2S,3S)-N,3-dimethyl-2-(((R)-1-methylpiperidine-2-yl)formamido)pentanamido)-4-methylpentyl)-1,3-thiazol-4-yl)formamido)-1-phenylpropyl 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With dmap; dicyclohexyl-carbodiimide In dichloromethane 48 Compound 208a (95 mg, 0.141 mmol)3-(2-(2 - (2 - (2,5 - dioxo - 2,5 - dihydro - 1 H - pyrrol - 1 - yl) ethoxy) ethoxy) ethoxy)Propionic acid(55 mg, 0.182 mmol)Dichloromethane(5 ml)To the solution, dicyclohexylcarbodiimide (122 mg, 0.591 mmol)And 2,2-dimethylolpropionic acid (25 mg, 0.204 mmol) were added thereto,The mixture was stirred overnight, then concentrated and separated by column chromatography (EtOAc / CH 2 Cl 2 = 1: 3) to give the target compound 211 (95.1 mg, 71%).
71% With dmap; dicyclohexyl-carbodiimide In dichloromethane 48 Example 48. (1 S,2R)-2-(2-((i R,3R)-i -acetoxy-3-((2S,3S)-N,3-dimethyl-2-((R)- 1 -methylpiperidine2-carboxamido)pentanamido)-4-methylpentyl)thiaz-ole-4-carboxamido)-i -phenyl-propyl 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro- 1 H-pyrrol- 1 -yl)ethoxy)ethoxy)ethoxy)-propanoate (211) Compound 208a (95 mg, 0.141 mmol) and 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propanoic acid (55 mg, 0.182 mmol) in CH2Cl2 (5 ml) were added DCC (122 mg, 0.591 mmol) and DMAP (25 mg, 0.204 mmol) and the mixture was stirred overnight, evaporated and purified with SiO2 chromatography (EtOAc/CH2Cl2, 1:3) to afford the title compound (95.1 mg, 71%). MS ESI: m/z+: [M+Na]+, calcd for C48H70NaN6O12S, 977.47, Found, 977.47.
71% With dmap; dicyclohexyl-carbodiimide In dichloromethane 48 Example 48. (1S, 2R) -2- (2-((1R, 3R) -1-acetoxy-3-((2S, 3S) -N, 3-dimethyl-2-((R) -1-methylpiperidine-2-carboxamido) valeramido) -4-methylpentyl) thiazole-4-carboxamido) -1-phenylpropyl-3- (2- (2- (2- (2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl) ethoxy) ethoxy) ethoxy) -ethyl propionate (211) Compound 208a (95 mg, 0.141 mmol) and 3- (2- (2- (2- (2- (2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl) ethoxy) ethyl To a solution of (oxy) ethoxy) propionic acid (55 mg, 0.182 mmol) in dichloromethane (5 ml) was added dicyclohexylcarbodiimide (122 mg, 0.591 mmol) and 2,2-dimethylolpropionic acid ( 25 mg, 0.204 mmol), the mixture was stirred overnight, then concentrated, and column chromatography (EtOAc / CH2Cl2 = 1: 3) to give the target compound 211 (95.1 mg, 71%).
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - JP2017/160205, 2017, A Location in patent: Paragraph 0305; 0306
[2]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - US2017/296663, 2017, A1 Location in patent: Paragraph 0287; 0288
[3]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - CN110279872, 2019, A Location in patent: Paragraph 0052; 0438-0440
  • 19
  • [ 518044-40-1 ]
  • (1R,3R)-3-[(2S,3S)-N-methyl-3-methyl-2-[(2R)-1-methylpiperidin-2-yl]formamido}pentanamido]-4-methyl-1-(4-[1-oxo-1-phenylpropan-2-yl]carbamoyl}-1,3-thiazol-2-yl)pentyl acetate [ No CAS ]
  • (1R,3R)-3-((2S,3S)-N,3-dimethyl-2-(((R)-1-methylpiperidine-2-yl)formamido)pentanoylamido)-1-(4-(((R)-1((3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-ethoxy)ethoxy)ethoxy)propanamido)imino)-1-phenylpropan-2-yl)carbamoyl)-1,3-thiazol-2-yl)-4-methylpentyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With acetic acid In methanol 47 Compound 205 (75 mg, 0.112 mmol)In methanol (5 ml) was added compound 12(50 mg HCl salt, 0.126 mmol) and acetic acid (3 ul, 0.052 mmol)After reacting the mixture overnight, N, N'-diisopropylethylamine (23 ul, 0.132 mmol) was added and neutralized, Concentrated and separated by column chromatography (EtOAc / CH 2 Cl 2 = 1: 4 - 1: 3) to obtain the target compound 206 (79.3 mg, 70%).
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - JP2017/160205, 2017, A Location in patent: Paragraph 0303; 0304
  • 20
  • [ 518044-40-1 ]
  • C148H247N33O46 [ No CAS ]
  • C161H264N34O52 [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% 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 20℃; for 0.5h;
76% 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 20℃; for 0.5h; 4.e Step e. Preparation of Deca Boc lnt-4 A solution of Step d product (0.135 g, 0.042 mmol), 3-(2-{2-[2-(2,5-dioxo-2,5-dihydro-1 H-pyrrol-1 - yl)ethoxy]ethoxy}ethoxy)propanoic acid (0.015 g, 0.050 mmol), and DIEA (0.026 ml_, 0.150 mmol), in DMF (1 ml_), were treated with HATU (0.01 9 g, 0.050 mmol), while stirring at room temperature. After 30 minutes, the product was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% methanol and water, using no modifier. Yield 0.1 12 g, 76% yield lon(s) found by LCMS: [(M-3Boc)/3]+H+ = 1069.6, [(M-4Boc)/3]+H+ = 1036.3, [(M-5Boc)/3]+H+ = 1003.0.
Reference： [1]Current Patent Assignee: CIDARA THERAPEUTICS INC - WO2017/218922, 2017, A2 Location in patent: Page/Page column 162; 163
[2]Current Patent Assignee: CIDARA THERAPEUTICS INC - WO2019/126341, 2019, A2 Location in patent: Page/Page column 372; 375
  • 21
  • [ 518044-40-1 ]
  • [ 76-05-1 ]
YieldReaction ConditionsOperation in experiment
With Zinc chloride Trifluoroacetic Acid/(2S)-2-amino-4-[{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}(glycoloyl)amino]-N-[1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-12-oxo-3,6,9-trioxa-13-azapentadecan-15-yl]butanamide (1:1) Trifluoroacetic Acid/(2S)-2-amino-4-[{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}(glycoloyl)amino]-N-[1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-12-oxo-3,6,9-trioxa-13-azapentadecan-15-yl]butanamide (1:1) The title compound was prepared by coupling of 5 mg (0.006 mmol) of Intermediate C64 with 2 mg (0.007 mmol) of 3-(2-{2-[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy]ethoxy}ethoxy)propanoic acid, the preparation of which is described under Intermediate L15, in the presence of 3.5 mg (0.009 mmol) of HATU and 4 μl of N,N-diisopropylethylamine and subsequent deprotection with zinc chloride in trifluoroethanol as described for Intermediate F119. Purification by preparative HPLC gave 2 mg (35% of theory over 2 steps) of the title compound. LC-MS (Method 1): Rt=0.86 min; MS (EIpos): m/z=839 [M+H]+.
Reference： [1]Current Patent Assignee: BAYER AG - US2018/169256, 2018, A1
  • 22
  • [ 518044-40-1 ]
  • C148H247N33O46 [ No CAS ]
  • C161H264N34O52 [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% 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 20℃; for 0.5h; 5.e Step e. Preparation of Deca Boc Int-4 A solution of Step d product (0.135 g, 0.042 mmol), 3-(2-{2-[2-(2,5-dioxo-2,5-dihydro-1 H-pyrrol-1 - yl)ethoxy]ethoxy}ethoxy)propanoic acid (0.015 g, 0.050 mmol), and DIEA (0.026 mL, 0.150 mmol), inDMF (1 mL), were treated with HATU (0.01 9 g, 0.050 mmol), while stirring at room temperature. After 30 minutes, the product was purified by RPLC using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% methanol and water, using no modifier. Yield 0.112 g, 76% yield. Ion(s) found by LCMS:[(M-3Boc)/3]+H+ 1069.6, [(M-4Boc)/3]+H+ 1036.3, [(M-5Boc)/3]+H+ 1003.0.
Reference： [1]Current Patent Assignee: CIDARA THERAPEUTICS INC - WO2018/128826, 2018, A1 Location in patent: Page/Page column 219; 222
  • 23
  • [ 518044-40-1 ]
  • N-(8-amino-4-(3-(methyl(2-(methylamino)ethyl)amino)acryloyl)pyrrolo[4,3,2-de]quinolin-6-yl)isobutyramide [ No CAS ]
  • N-(2-((3-(8-amino-6-isobutyramidopyrrolo[4,3,2-de]quinolin-4-yl)-3-oxoprop-1-en-1-yl)(methyl)amino)ethyl)-3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)-N-methylpropanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2.5h; N-(2-((3-(8-Amino-6-isobutyramidopyrrolo[4,3,2-de]quinolin-4-yl)-3-oxoprop-1-en-1-yl)(methyl)amino)ethyl)-3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)-ethoxy)-N-methylpropanamide (11) To a solution of compound 10 (5 mg, 0.01 mmol) and mc-peg3-propanoic acid (2.7 mg, 0.01 mmol) in DMF was added HATU (3.6 mg, 0.01 mmol) followed by Hunig's base (3.5 mg, 0.025 mmol) at room temperature. The reaction was allowed to stir at room temperature for 2.5 h. Then the reaction mixture was loaded on silica column and purified by ISCO (12 g, 0-5% methanol in methylene chloride plus 0.1 mL Et3N in 500 mL solvent), removed solvents to afford 5.2 mg (85%) of the desired product 11 as a red solid. 1H NMR (400 MHz, METHANOL-d4) d 8.67 (m, 1H), 8.33 (m, 1H), 8.18 (m, 1H), 8.12 (m, 1H), 7.87 (d, J = 12.30 Hz, 1H), 6.72 (s, 2H), 6.53 (d, J = 12.10 Hz, 1H), 3.11 - 3.71 (m, 22H), 2.94 (m, 2H), 2.94 (m, 2H), 2.60 (m, 2H), 2.44 (m, 1H), 1.29 (m, 6H). Purity: HPLC 210 nM > 95% and 254 nM > 95%. HRMS: calcd for C34H43N7O8 + H+, 678.3251; found (ESI, [M + H]+), 678.3247.
Reference： [1]Zhou, Dahui; Casavant, Jeffrey; Graziani, Edmund I.; He, Haiyin; Janso, Jeffrey; Loganzo, Frank; Musto, Sylvia; Tumey, Nathan; O'Donnell, Christopher J.; Dushin, Russell [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 7, p. 943 - 947]
  • 24
  • [ 518044-40-1 ]
  • (4R)-tert-butyl 5-(3-amino-4-hydroxyphenyl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoate [ No CAS ]
  • (4R)-tert-butyl 4-((tert-butoxycarbonyl)amino)-5-(3-(3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propanamido)-4-((3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propanoyl)oxy)phenyl)-2-methylpentanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With triethylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate In dichloromethane at 20℃; 194 Example 194. (4R) -4- (tert-butoxycarbonyl) amino) -5- (3- (3- (2- (2- (2- (2,5-dioxo-2,5-di Hydrogen-1H-)-tert-butyl-4-tert-butyl ester pyrrol-1-yl) ethoxy) ethoxy) ethoxy) propionamido) -4-((3- (2- (2- (2- (2,5-dioxo-2,5-dihydro-1H-pyrrole-1-ylethoxy) ethoxy) ethoxy) propoxy) propionyl) oxy) phenyl ) Synthesis of tert-butyl-2-methylvalerate (4R) -5- (3-amino-4-hydroxyphenyl) -4-((tert-butoxycarbonyl) amino) -2-methylvaleric acid tert-butyl ester (100 mg, 0.25 mmol),3- (2- (2- (2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl) ethoxy) ethoxy) ethoxy) propionic acid (75mg, 0.25 mmol) and HATU (190 mg, 0.5 mmol) were dissolved in dichloromethane (50 mL), then TEA (73 ul, 0.5 mmol) was added.The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure and purified on a silica gel column, eluting with ethyl acetate / dichloromethane (1: 3) to give the title product (180.1 mg, 75%).
Reference： [1]Current Patent Assignee: HANGZHOU DAC BIOTECH CO LTD - CN110621673, 2019, A Location in patent: Paragraph 1035-1037
  • 25
  • [ 108-31-6 ]
  • 3-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}propanoic acid [ No CAS ]
  • [ 518044-40-1 ]
YieldReaction ConditionsOperation in experiment
With acetic acid at 105℃; 6 Synthesis of 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)ethoxy)ethoxy)ethoxy)propanoic acid 57A Maleic anhydride (11 1 nig, 1.13 mmol, R is H) was combined with 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoic acid (250 mg, 1.13 mmol) and AcOH (5 ml.) was added. The resulting solution was heated to 105 °C overnight. The reaction was allowed to cool to room temperature and the solvent was evaporated to dryness. Toluene (5 niL) was added and the mixture was evaporated to dryness 2 more times. The reaction product was very pure and used in the next reaction without purification
Reference： [1]Current Patent Assignee: IL 2RX - WO2020/14541, 2020, A2 Location in patent: Paragraph 0577; 0579
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