Home Cart 0 Sign in  

[ CAS No. 1394238-92-6 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 1394238-92-6
Chemical Structure| 1394238-92-6
Structure of 1394238-92-6 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 1394238-92-6 ]

Related Doc. of [ 1394238-92-6 ]

Alternatived Products of [ 1394238-92-6 ]

Product Details of [ 1394238-92-6 ]

CAS No. :1394238-92-6 MDL No. :MFCD28557283
Formula : C37H36N4O9 Boiling Point : -
Linear Structure Formula :- InChI Key :ZJHZWBDLYYJQAV-WYOOIXGGSA-N
M.W : 680.70 Pubchem ID :100029276
Synonyms :

Safety of [ 1394238-92-6 ]

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 [ 1394238-92-6 ]

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

  • Downstream synthetic route of [ 1394238-92-6 ]

[ 1394238-92-6 ] Synthesis Path-Downstream   1~51

  • 1
  • [ 150114-97-9 ]
  • [ 1394238-92-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 48 h / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 48 h / 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / Inert atmosphere 2: pyridine / tetrahydrofuran / 1.5 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / tetrahydrofuran 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / 20 °C
Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 26 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / 20 °C
Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / 20 °C
Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 72 h / 20 °C / Darkness 2: pyridine / tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C

  • 3
  • [ 5070-13-3 ]
  • [ 1394238-91-5 ]
  • [ 1394238-92-6 ]
YieldReaction ConditionsOperation in experiment
92% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 4h; 6.6A.1 Step 1. Synthesis of (9H-Fluoren-9-yl)methyl ((S)-3-methyl-1 -(((S)-1 -((4- ((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1 -oxopropan-2-yl)amino)-1 - oxobutan-2-yl)carbamate ("Fmoc-VAP-PNC") Procedure: (9H-Fluoren-9-yl)methyl ((S)-1 -(((S)-1 -((4- (hydroxymethyl)phenyl)amino)-1 -oxopropan-2-yl)amino)-3-methyl-1 -oxobutan-2- yl)carbamate (21 ) (Fmoc-VAP-OH) (200 mg, 0.387 mmol) was dissolved in DMF (2 mL) and bis(4-nitrophenyl) carbonate (141 mg, 0.465 mmol) and DIPEA (200 mg, 1 .55 mmol) were added. The resulting solution was stirred for 4 h at room temperature. The reaction was concentrated under vacuum and purified by silica gel chromatography (DCM/EtOAc 0-100%). Concentration of the appropriate fractions gave (9H-fluoren-9-yl)methyl((S)-3-methyl-1 -(((S)-1 -((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1 -oxopropan-2-yl)amino)-1 - oxobutan-2-yl)carbamate (Fmoc-VAP-PNC) (22) (242 mg, 0.355 mmol, 92%). LC/MS 4.480 min (5-95% acetonitrile in water over 5 min), m/z 703.3 [M+Na].
74% With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere;
74% With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; 3.c Under a nitrogen atmosphere 4.2 mL N,N-diisopropylethylamine (DIPEA) (24.55 mmol, 3 eq) was added to a suspension of Fmoc-Val-Ala-PABOH 18 (4.22 g, 8.18 mmol, 1 eq) and bis-PNP carbonate (3.73 g, 12.28 mmol, 1.5 eq) in dry dichloromethane (84 mL). This yellow mixture was treated with 42 mL dry N,N-dimethylformamide (DMF) until a clear solution resulted and stirred over night at room temperature. Then, the solution was washed with water (60 mL) and the phases were separated. The aqueous layer was extracted four times with dichloromethane (a 30 mL) and the combined organic phases were dried and the solvent was removed under reduced pressure. The oily yellow residue was treated with diethyl ether (30 mL), sonicated and the precipitate was dried in vacuo to isolate product 19 as a white solid (4.1 g, 74%). 1H NMR (DMSO-d6): δ[ppm] 0.87 (d, 3H, J=6.8 Hz), 0.90 (d, 3H, J=6.7 Hz), 1.32 (d, 3H, J=7.0 Hz), 1.96-2.05 (m, 1H), 3.94 (t, 1H, J=7.3 Hz), 4.21-4.34 (m, 3H), 4.45 (p, 1H, J=7.0 Hz and 13.8 Hz), 5.25 (s, 2H), 7.31-7.47 (m, 7H), 7.55-7.77 (m, 6H), 7.89 (d, 2H, J=7.5 Hz), 8.21 (d, 1H, J=6.9 Hz), 8.30-8.33 (m, 2H), 10.10 (s, 1H). 13C NMR (DMSO-d6): δ[ppm] 18.4, 18.7, 19.6, 30.8, 47.1, 49.5, 60.4, 66.1, 70.7, 119.5, 120.5, 123.6, 125.8, 126.6, 127.5, 128.1, 129.9, 139.9, 141.1, 144.2, 144.3, 145.6, 152.4, 155.7, 156.6, 171.5, 171.7.
65% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;
7 g With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; 4 Example 4 21 g of compound 4 (41 mmol) was suspended in 500 mL of dichloromethane.DIPEA (16 g, 126 mmol) was added in sequence.Di(p-nitrophenyl)carbonate (18.5 g, 69 mmol),Finally DMF was added until the solution was clear and stirred at room temperature overnight.DMF was distilled off under reduced pressure, and the viscous solid was washed with a small amount of methanol.Recrystallized several times with petroleum ether and ethyl acetate (or methyl tert-butyl ether).7 g of pure compound 5 were obtained.
7 g With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; 4 Example 4 21g of compound 4 (41 mmol) was suspended in 500 mL of dichloromethane, DIPEA (16 g, 126 mmol), bis (p-nitrobenzene) carbonate (18.5 g, 69 mmol) were added sequentially, and finally DMF was added until the solution was clear and stirred at room temperature overnight. DMF was distilled off under reduced pressure. The viscous solid was first washed with a small amount of methanol, and then recrystallized several times with petroleum ether and ethyl acetate (or methyl tert-butyl ether) to obtain 7 g of pure compound 5.

  • 4
  • [ 1394238-92-6 ]
  • [ 1394238-94-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C
  • 5
  • [ 1394238-92-6 ]
  • [ 1394238-95-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3: triethylamine / dichloromethane; N,N-dimethyl-formamide / 18 h / 20 °C / Inert atmosphere
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3: triethylamine / dichloromethane; N,N-dimethyl-formamide / 18 h / 20 °C / Inert atmosphere
  • 6
  • [ 1394238-92-6 ]
  • C58H75N5O24P2S2*4H3N [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3: triethylamine / dichloromethane; N,N-dimethyl-formamide / 18 h / 20 °C / Inert atmosphere 4: ammonium bicarbonate / water / 0.25 h / 20 °C / pH 7.4
  • 7
  • [ 1394238-92-6 ]
  • [ 25316-40-9 ]
  • [ 1394238-93-7 ]
YieldReaction ConditionsOperation in experiment
78% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 5h; Weigh 690mg of <strong>[25316-40-9]doxorubicin hydrochloride</strong>,1.036 g of compound 5 in a round bottom flask,After the addition, 10 mL of DMF was added.0.21 mL of DIPEA was added with stirring, and reacted at room temperature for 5 h.After the reaction is completed, the reaction solution is slowly dropped into methyl tert-butyl ether.Centrifuge to obtain a crude product. It was dissolved in a small amount of DMF and subjected to a second recrystallization.Have a product of 1.076g,Yield = 78%.
78% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 5h; Weigh 690 mg of <strong>[25316-40-9]doxorubicin hydrochloride</strong> and 1.036 g of compound 5 into a round-bottomed flask. Add 0.21 mL of DIPEA with stirring, and react at room temperature for 5 h. After completion of the reaction, the reaction solution was slowly dropped into methyl tert-butyl ether and centrifuged to obtain a crude product. It was dissolved in a small amount of DMF and subjected to a second recrystallization. The product was obtained at 1.076 g, yield = 78%.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; Under a nitrogen atmosphere compound 19 (Fmoc-Val-Ala-PABC-PNP, 89 mg, 0.13 mmol, 1.1 eq), doxorubicin.HCl (69 mg, 0.12 mmol, 1 eq) and DIPEA (20 muL, 0.12 mmol, 1 eq) were dissolved in 2 mL DMF (abs.) and stirred over night at room temperature. The crude product was precipitated dropwise with a mixture of diethyl ether and hexane (5:1, 100 mL) over 5 min. The precipitate was centrifuged, washed twice with diethyl ether and dried in vacuo. This crude product 20 (130 mg) was used in the next step without further purification.
  • 8
  • [ 1394238-92-6 ]
  • C58H75N5O24P2S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3: triethylamine / dichloromethane; N,N-dimethyl-formamide / 18 h / 20 °C / Inert atmosphere 4: ammonium bicarbonate / dichloromethane; N,N-dimethyl-formamide / 0.33 h / 20 °C / pH 7.4
  • 9
  • [ 1394238-92-6 ]
  • monomethyl auristatin D trifluoroacetate [ No CAS ]
  • 4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl ((S)-1-(((S)-1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2-phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20℃; for 20h; 21; 61 Preparation of 4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl ((S)-1- (((S)-1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2- phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4- yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2- yl)(methyl)carbamate (H2N-Val-Ala-PABC-MMAD)(Figure 61) Preparation of 4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl ((S)-1- (((S)-1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2- phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4- yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2- yl)(methyl)carbamate (H2N-Val-Ala-PABC-MMAD)(Figure 61) To a dried scintillation vial containing a magnetic stir bar was added (9H-fluoren- 9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2- yl)carbamate (102 mg, 0.15 mmol), monomethyl auristatin D (TFA salt, 110 mg, 0.125 mmol), HOAt (14 mg, 0.01 mmol), DIPEA (65 μL, 0.37 mmol), and DMA (1 mL). The solution was stirred for 20 hours at room temperature. The MMAD was consumed as detected by HPLC. Piperidine (100 μL, 1 mmol) was added to the reaction mixture and the resulting solution was stirred for an additional 20 minutes at room temperature. The reaction mixture was directly purified by C18 flash chromatography (elute 5-100% MeCN/water) to yield the title compound as a light yellow solid (101 mg, 75% yield). ESI-MS calculated [MH]+: 1090.6; found 1090.6.
  • 10
  • [ 1394238-92-6 ]
  • (hemiglutarate)-Val-Ala-N-[4-[[[( N-(Boc)-N,N′-dimethylethylenediamine)carbonyl]oxy]methyl]phenyl] [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; 4-dimethylaminopyridine / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 0 - 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C
  • 11
  • [ 1394238-92-6 ]
  • cyclo[DKP-RGD]-Val-Ala-N-[4-[[[(N-(Boc)-N,N′-dimethylethylenediamine)carbonyl]oxy]methyl]phenyl] [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; dmap / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere 4: diisopropyl-carbodiimide / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere 5: sodium hydroxide / aq. phosphate buffer; acetonitrile / 0 - 20 °C / pH 7.3-7.6 / Inert atmosphere
  • 12
  • [ 1394238-92-6 ]
  • C34H50N6O11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; dmap / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere 4: diisopropyl-carbodiimide / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere
  • 13
  • [ 1394238-92-6 ]
  • C25H41N5O6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 0 - 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C
  • 14
  • [ 1394238-92-6 ]
  • C52H75N15O14*C2HF3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; dmap / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere 4: diisopropyl-carbodiimide / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere 5: sodium hydroxide / aq. phosphate buffer; acetonitrile / 0 - 20 °C / pH 7.3-7.6 / Inert atmosphere 6: dichloromethane / 1 h / 20 °C / Inert atmosphere
  • 16
  • [ 623-04-1 ]
  • [ 1394238-92-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / Inert atmosphere 2: pyridine / tetrahydrofuran / 1.5 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 26 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 72 h / 20 °C / Darkness 2: pyridine / tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C

  • 17
  • [ 1394238-91-5 ]
  • [ 7693-46-1 ]
  • [ 1394238-92-6 ]
YieldReaction ConditionsOperation in experiment
88% With pyridine In tetrahydrofuran at 0 - 20℃; for 1.5h; Inert atmosphere;
66% With pyridine In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere;
35% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 2h; Inert atmosphere; Compound 22: (9H-fluoren-9-yl)methyl ((S)-3-methyl-1 -(((S)-i -((4-((((4-nitrophenoxy)carbonyl)-oxy)methyl)phenyl)amino)-1 -oxopropan-2-yl)amino)-1 - oxobutan-2-yl )carbamate To a solution of compound 21 (1 .3 g, 2.52 mmol) in DMF (10 mL), was added, under Ar, DIEA (2.55 mL, 15.13 mmol), the solution was cooled down at 0°C before theaddition of 4-nitrophenyl chloroformate (1 .57 g, 7.56 mmol). The reaction medium was stirred for 2 h at RT. 20 mL of H20 were added and the medium was extracted twice with EtOAc (10 mL). The combined organic phases were washed with brine, dried over Mg504, filtered, concentrated in vacuo and purified by flash chromatography on 120 g of silica gel (gradient elution DCM/MeOH) to give 600 mgof compound 22 as a solid (35%).RMN 1H (400 MHz, ö in ppm, DMSO-d6): 0.86 (d, J = 7.0 Hz, 3 H); 0.89 (d, J =7.0 Hz, 3 H); 1 .31 (d, J = 7.0 Hz, 3 H); 1 .99 (m, 1 H); 3.91 (m, 1 H); 4.18 to 4.35 (m,3 H); 4.43 (m, 1 H); 5.24 (5, 2 H); 7.31 (t, J = 7.9 Hz, 2 H); 7.35 to 7.44 (m, 5 H); 7.56(d, J = 9.1 Hz, 2 H); 7.63 (d, J = 8.6 Hz, 2 H); 7.74 (m, 2 H); 7.88 (d, J = 7.9 Hz, 2 H);8.19 (d, J = 7.3 Hz, 1 H); 8.31 (d, J = 9.1 Hz, 2 H); 10.07 (5, 1 H).
5.6 g With pyridine In tetrahydrofuran; dichloromethane at 20℃; for 15h; 3.1 Step 1: [4-[[(2S)-2-[[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl- butanoyl]amino]propanoyl]amino]phenyl]methyl (4-nitrophenyl) carbonate To a solution of 9H-fluoren-9-ylmethyl N-[(1S)-1-[[(1S)-2-[4-(hydroxymethyl)anilino]- 1-methyl-2-oxo-ethyl]carbamoyl]-2-methyl-propyl]carbamate (5.0 g, 9.7 mmol) in THF (20 mL) and DCM (10 mL) were successively added paranitrophenyl chlorocarbonate (4.1 g, 20.1 mmol) and pyridine (1.65 mL, 20.4 mmol). The reaction was stirred at room temperature for 15 h. A 10% aqueous solution of citric acid was added and the reaction mixture was extracted twice with AcOEt. The organic layer was washed with brine and dried over MgSO4. After evaporation under vacuum the solid was dissolved in a minimum amount of AcOEt and ether was added to precipitate the desired compound (5.6 g, 8.22 mmol). IR: (ν cm-1) 3350-3200, 1760;1690;1670;1630, 1523;1290.1H NMR (400 MHz, dmso-d6) δ ppm 10.07 (m, 1 H), 8.31 (d, 2 H), 8.19 (d, 1 H), 7.89 (d, 2 H), 7.74 (t, 2 H), 7.64 (d, 2 H), 7.57 (d, 2 H), 7.41 (m, 2 H), 7.41 (d, 2 H), 7.4 (m, 1 H), 7.32 (t, 2 H), 5.24 (s, 2 H), 4.43 (m, 1 H), 4.36-4.19 (m, 3 H), 3.92 (dd, 1 H), 2 (m, 1 H), 1.32 (d, 3 H), 0.9/0.87 (2d, 6 H).
5.6 g With pyridine In tetrahydrofuran; dichloromethane at 20℃; for 15h; 3.1 Step 1: [4-[[(2S)-2-[[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl- butanoyl]amino]propanoyl]amino]phenyl]methyl (4-nitrophenyl) carbonate To a solution of 9H-fluoren-9-ylmethyl N-[(1S)-1-[[(1S)-2-[4-(hydroxymethyl)anilino]- 1-methyl-2-oxo-ethyl]carbamoyl]-2-methyl-propyl]carbamate (5.0 g, 9.7 mmol) in THF (20 mL) and DCM (10 mL) were successively added paranitrophenyl chlorocarbonate (4.1 g, 20.1 mmol) and pyridine (1.65 mL, 20.4 mmol). The reaction was stirred at room temperature for 15 h. A 10% aqueous solution of citric acid was added and the reaction mixture was extracted twice with AcOEt. The organic layer was washed with brine and dried over MgSO4. After evaporation under vacuum the solid was dissolved in a minimum amount of AcOEt and ether was added to precipitate the desired compound (5.6 g, 8.22 mmol). IR: (ν cm-1) 3350-3200, 1760;1690;1670;1630, 1523;1290.1H NMR (400 MHz, dmso-d6) δ ppm 10.07 (m, 1 H), 8.31 (d, 2 H), 8.19 (d, 1 H), 7.89 (d, 2 H), 7.74 (t, 2 H), 7.64 (d, 2 H), 7.57 (d, 2 H), 7.41 (m, 2 H), 7.41 (d, 2 H), 7.4 (m, 1 H), 7.32 (t, 2 H), 5.24 (s, 2 H), 4.43 (m, 1 H), 4.36-4.19 (m, 3 H), 3.92 (dd, 1 H), 2 (m, 1 H), 1.32 (d, 3 H), 0.9/0.87 (2d, 6 H).

  • 18
  • [ 1394238-92-6 ]
  • 3-(1-[3-(2-aminoethoxy)-5,7-dimethyltricyclo[3.3.1.13'7]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic acid trifluoroacetic acid salt [ No CAS ]
  • 3-(1-((3-(2-((((4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl)oxy)carbonyl)amino)ethoxy)-5,7-dimethyladamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate; 3-(1-[3-(2-aminoethoxy)-5,7-dimethyltricyclo[3.3.1.13'7]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic acid trifluoroacetic acid salt With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With diethylamine In N,N-dimethyl-formamide at 20℃; for 2h; 2.21.5 .21.5. 3-(l-((3-(2-((((4-((S)-2-((S)-2-amino-3- methylbutanamido) propanamido)benzyl)oxy)carbonyl)amino)ethoxy)-5,7- dimethyladamantan-l-yl)methyl)-5-methyl-lH-pyrazol-4-yl)-6- (8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin- 2(lH)-yl)picolinic acid solution of Example 1.3.7 (0.102 g), Example 2.21.4 (0.089 g) and N,N- diisopropylethylamine (0.104 mL) were stirred together in N,N-dimethylformamide ( 1 mL) at room temperature. After stirring overnight, diethylamine (0.062 mL) was added, and the reaction was stirred for an additional 2 hours. The reaction was diluted with water ( 1 mL), quenched with trifluoroacetic acid and was purified by Prep HPLC using a Gilson system, eluting with 10-85% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound
Stage #1: (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate; 3-(1-[3-(2-aminoethoxy)-5,7-dimethyltricyclo[3.3.1.13'7]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic acid trifluoroacetic acid salt With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; Stage #2: With diethylamine In N,N-dimethyl-formamide for 2h; 2.51.6 2.51.6. 3-(1-((3-(2-((((4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl)oxy)carbonyl)amino)ethoxy)-5,7-dimethyladamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acid A solution of the trifluoroacetic acid salt of Example 1.3.7 (0.102 g), Example 2.21.4 (0.089 g) and N,N-diisopropylethylarnine (0.104 rnL) were stirred in N,N-dimethylformamide (1 rnL) at room temperature for 16 hours. Diethylarnine (0.062 mL) was added, and the reaction was stirred for 2 hours at room temperature. The reaction was diluted with water (1 mL), quenched with trifluoroaceticacid (0.050 mL) and purified by reverse-phase HPLC using a Gilson system and a C18 column, eluting with 5-85% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The product fractions were lyophilized to give the title compound. MS (LC-MS) m/e 1066.5 (M+H).
  • 19
  • [ 1394238-92-6 ]
  • 4-(amino)-1,6-heptanediamide bis-AHX-DM1 trifluoroacetate [ No CAS ]
  • Fmoc-Val-Ala-PAB-amido-1,6-heptanediamide bis-AHX-DM1 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 18h; 9.1 A stock solution of hydroxybenzotriazole (HOBt, 6.6 mg) in DMF (200 μ) was prepared. To a stirred solution of cytotoxic payload 1A (10 mg) in DMF (500 μ) was added Fmoc- val-ala-PAB-PNP (3.7 mg) and an aliquot of HOBt stock solution (2 μ). The reaction solution was cooled to 0 °C before DIPEA (2.14 μ) was added. The reaction solution was then stirred at room temperature for 18 h before purification by reverse phase C18-column chromatography, eluting with buffer A (v/v): water: 0.05% trifluoroacetic acid and buffer B (v/v): acetonitrile:0.05% trifluoroacetic acid (100:0 v/v to 0: 100 v/v). The solvent was removed by lyophilisation to give Fmoc-val-ala-PAB-amido-l,6-heptanediamide bis-AFTX- DM1 reagent 17A.
  • 20
  • [ 1394238-92-6 ]
  • ((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; 1-hydroxy-7-aza-benzotriazole / N,N-dimethyl-formamide / 18 h / 20 °C 2: piperidine / N,N-dimethyl-formamide / 1 h / 20 °C
  • 21
  • [ 1394238-92-6 ]
  • 4-((S)-2-((S)-2-(6-(3,4-dibromo-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl ((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; 1-hydroxy-7-aza-benzotriazole / N,N-dimethyl-formamide / 18 h / 20 °C 2.1: piperidine / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; diisopropyl-carbodiimide / tetrahydrofuran / 1 h 3.2: 6 h
  • 22
  • [ 1394238-92-6 ]
  • [ 1359995-63-3 ]
  • 4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)propanamido)benzyl ((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18h; 6.6A.2 Step 2. Synthesis of 4-((S)-2-((S)-2-((((9H-Fluoren-9- yl)methoxy)carbonyl)amino)-3-methylbutanamido)propanamido)benzyl ((S)-1 -(((S)-1 - (((3R,4S,5S)-1 -((S)-2-((1 R,2R)-3-(((1 S,2R)-1 -hydroxy-1 -phenylpropan-2-yl)amino)-1 - methoxy-2-methyl-3-oxopropyl)pyrrolidin-1 -yl)-3-methoxy-5-methyl-1 -oxoheptan-4- yl)(methyl)amino)-3-methyl-1 -oxobutan-2-yl)amino)-3-methyl-1 -oxobutan-2- yl)(methyl)carbamate ("Fmoc-VAP-MMAE") Procedure: (9H-fluoren-9-yl)methyl ((S)-3-methyl-1 -(((S)-1 -((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1 -oxopropan-2-yl)amino)-1 - oxobutan-2-yl)carbamate (22) (Fmoc-VAP-PNC) (20 mg, 0.02938 mmol) was dissolved in DMF (0.5 mL) and MMAE.HCI (17 mg, 0.02351 mmol), HOAt (2 mg, 0.01469 mmol) and DIPEA (8 mg, 0.0587 mmol) were added. The resulting solution was stirred for 18 h at room temperature. The DMF was removed under vacuum and the residue was purified by silica gel chromatography (eluent methylene chlohde/methanol 0-20%). Concentration of the appropriate fractions gave 4-((S)-2- ((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- methylbutanamido)propanamido)benzyl ((S)-1 -(((S)-1 -(((3R4S,5S)-1 -((S)-2- ((1 R,2R)-3-(((1 S,2R)-1 -hydroxy-1 -phenylpropan-2-yl)amino)-1 -methoxy-2-methyl-3- oxopropyl)pyrrolidin-1 -yl)-3-methoxy-5-methyl-1 -oxoheptan-4-yl)(methyl)amino)-3- methyl-1 -oxobutan-2-yl)amino)-3-methyl-1 -oxobutan-2-yl)(methyl)carbamate (23) (Fmoc-VAP-MMAE) (32 mg, 0.025 mmol, 86%). LC/MS 4.649 min (5-95% acetonitrile in water over 5 min), m/z 1259.6 [M+H].
  • 23
  • (S)-tert-butyl 2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)propanoate [ No CAS ]
  • [ 1394238-92-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: trifluoroacetic acid / dichloromethane 2: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / tetrahydrofuran 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / 20 °C
  • 24
  • [ 1394238-92-6 ]
  • 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13'7]dec-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic acid [ No CAS ]
  • 3-(1-((3-(2-((((4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl)oxy)carbonyl)(2-sulfoethyl)amino)ethoxy)-5,7-dimethyladamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate; 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13'7]dec-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With diethylamine In N,N-dimethyl-formamide at 20℃; for 2h; 2.2.38.2.38.1 2.38.1. 3-(1-((3-(2-((((4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl)oxy)carbonyl)(2-sulfoethyl)amino)ethoxy)-5,7-dimethyladamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acid [000925] A solution of Example 1.2.9 (0.050 g), (9H-fluoren-9-yl)methyl ((S)-3-methyl-l-(((S)-l- ((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)- 1 -oxopropan-2-yl)amino)- 1 -oxobutan-2- yl)carbamate (0.039 g) and N,N-diisopropylethylamine (0.027 mL) in N,N-dimethylformamide (1 mL) was stirred at room temperature. After stirring overnight, diethylamine (0.027 mL) was added to the reaction, and stirring was continued for 2 hours. The reaction was quenched with trifluoroacetic acid, and the mixture was purified by reverse phase HPLC using a Gilson system, eluting with 5-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. MS (ESI) m/e 1499.5 (M+H)+.
Stage #1: (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate; 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13'7]dec-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With diethylamine In N,N-dimethyl-formamide for 2h; 2.2.38.2.38.1 2.38.1 3-(1-((3-(2-((((4-((S)-2-((S)-2-amino-3- methylbutanamido)propanamido)benzyl)oxy)carbonyl)(2- sulfoethyl)amino)ethoxy)-5,7-dimethyladamantan-1-yl)methyl)- 5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2- ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acid A solution of Example 1.2.9 (0.050 g), (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1- ((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2- yl)carbamate (0.039 g) and N,N-diisopropylethylamine (0.027 mL) in N,N-dimethylformamide (1 mL) was stirred at room temperature. After stirring overnight, diethylamine (0.027 mL) was added to the reaction, and stirring was continued for 2 hours. The reaction was quenched with trifluoroacetic acid, and the mixture was purified by reverse phase HPLC using a Gilson system, eluting with 5-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. MS (ESI) m/e 1499.5 (M+H)+.
Stage #1: (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate; 6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13'7]dec-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With diethylamine In N,N-dimethyl-formamide for 2h; 2.38.1 2.38.1 3-(1-((3-(2-((((4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl)oxy)carbonyl)(2-sulfoethyl)amino)ethoxy)-5,7-dimethyladamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acid A solution of Example 1.2.9 (0.050 g), (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate (0.039 g) and N,N-diisopropylethylamine (0.027 mL) in N,N-dimethylformamide (1 mL) was stirred at room temperature. After stirring overnight, diethylamine (0.027 mL) was added to the reaction, and stirring was continued for 2 hours. The reaction was quenched with trifluoroacetic acid, and the mixture was purified by reverse phase HPLC using a Gilson system, eluting with 5-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. MS (ESI) m/e 1499.5 (M+H)+.
  • 25
  • [ 1394238-92-6 ]
  • C70H102IN5O27S3 [ No CAS ]
  • C86H123IN8O31S3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
112 mg Stage #1: (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate; C70H102IN5O27S3 With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 1h; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.166667h; 1 Preparation of Compound 28 To compound 26 (140 mg, 84 μmol) in 3 mL of DMF was added compound 27 (69 mg, 101 μmol), HOBt (11 mg), and 43 μL of DIEA. The mixture was stirred for 1 h, then 150 μL of piperidine was added. After 10 min the mixture was purified by HPLC to give compound 28 (112 mg). MS m/z 1987.6 (M+H).
  • 26
  • [ 1394238-92-6 ]
  • C63H88IN5O26S4 [ No CAS ]
  • C79H109IN8O30S4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
22 mg Stage #1: (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate; C63H88IN5O26S4 With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 1h; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.166667h; 1 Preparation of Compound 45 To compound 42 (30 mg, 19 umol) in 2 mL of DMF was added compound 27 (16 mg, 23 μmol), HOBt (5 mg), and 13 μL of DIEA. The mixture was stirred for 1 h, then 40 μL of piperidine was added. After 10 min the mixture was purified by HPLC to give compound 45 (22 mg). MS m/z 1905.5 (M+H).
  • 27
  • [ 1260431-28-4 ]
  • [ 1394238-92-6 ]
  • 4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl 4-((2R,3R)-3-((S)-1-((3S,10R,16S,E)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-2,5,9,12-tetraoxo-1,4-dioxa-8,11-diazacyclohexadec-13-en-16-yl)ethyl)oxiran-2-yl)benzylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% Stage #1: (3S,10R,16S,E)-16-((S)-1-((2R,3R)-3-(4-(aminomethyl)phenyl)oxiran-2-yl)ethyl)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetraone; (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; Inert atmosphere; Stage #2: With piperidine In tetrahydrofuran at 20℃; for 1h; Compound 23: 4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl 4-((2R,3R)-3-((S)-1 -((3S,1 OR, 1 65,E)-1 O-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-2,5,9,1 2-tetraoxo-1 ,4-dioxa-8,1 1 -diazacyclohexadec-1 3-en-i 6-yl)ethyl)oxiran-2-yl)benzylcarbamate To a solution of (3S, 1 OR, 1 6S,E)-1 6-((S)-1 -((2R,3R)-3-(4-(aminomethyl)phenyl)oxiran- 2-yl)ethyl)-1 O-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-1 ,4-dioxa-8, 11- diazacyclohexadec-13-ene-2,5,9,12-tetraone (the synthesis of which was describedin W02011001052, compound 77, 100 mg, 143.2 pmol) in THE (5 mL), were added, under argon compound 22 (117 mg, 171.9 pmol) and DIEA (60.4 pL, 358 pmol). The reaction medium was stirred at RT under Ar overnight. Then piperidine (142.9 pL, 1.43 mmol) was added and the reaction medium stirred for 1 h at RT. After concentrating in vacuo, the crude medium was purified by flash chromatography on5 g of silica gel (gradient elution DCM/MeOH) to give 100 mg of compound 23 as a white solid (73%).
  • 28
  • [ 1394238-92-6 ]
  • 3-(1-[3-(2-aminoethoxy)-5,7-dimethyltricyclo[3.3.1.13,7]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic acid trifluoroacetate [ No CAS ]
  • 3-(1-((3-(2-((((4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl)oxy)carbonyl)amino)ethoxy)-5,7-dimethyladamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate; 3-(1-[3-(2-aminoethoxy)-5,7-dimethyltricyclo[3.3.1.13,7]dec-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridine-2-carboxylic acid trifluoroacetate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; Stage #2: With diethylamine In N,N-dimethyl-formamide at 20℃; for 2h; 2.21.5 2.21.5. 3-(1-((3-(2-((((4-((S)-2-((S)-2-amino-3-methylbutanamido) propanamido)benzyl)oxy)carbonyl)amino)ethoxy)-5,7-dimethyladamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic Acid A solution of Example 1.3.7 (0.102 g), Example 2.21.4 (0.089 g) and N,N-diisopropylethylamine (0.104 mL) were stirred together in N,N-dimethylformamide (1 mL) at room temperature. After stirring overnight, diethylamine (0.062 mL) was added, and the reaction was stirred for an additional 2 hours. The reaction was diluted with water (1 mL), quenched with trifluoroacetic acid and was purified by Prep HPLC using a Gilson system, eluting with 10-85% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound.
  • 29
  • [ 1394238-92-6 ]
  • C70H102IN5O27S3 [ No CAS ]
  • C101H133IN8O33S3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In N,N-dimethyl-formamide at 20℃; for 18.9167h; 5-13 To a solution of 151 (9.1 mg, 5.4 mitioI, 1.0 equiv.) in DMF (100 pL) was added a solution of 9-fluorenylmethyloxycarbonyl-valyl-alanyl-(4-aminobenzyl)-(4-nitrophenyl)carbonate (4.42 mg, 6.49 mitioI, 1 .20 equiv.) in DMF (48.6 pL). The resulting reaction mixture turned yellow and was left at rt for circa 30 minutes and then put in the freezer for 16h. The sample was then allowed to warm to rt and left for another 100 minutes and then additional 9-fluorenylmethyloxycarbonyl-valyl-alanyl-(4-aminobenzyl)-(4-nitrophenyl)carbonate(2.95 mg, 4.32 mitioI, 0.8 equiv.) in DMF (32.4 mI_) was added, followed by Et3N (1.89 mI_, 13.5 mmol, 2.0 equiv.). The mixture was stirred at rt for 45 minutes and then diluted with THF (900 mI_) and treated with diethylamine (100 mI_). The resulting yellow solution was left at rt for 72 minutes and was then cone in vacuo. The residue was purified by RP-HPLC (C18, 5% 95% MeCN (1 % AcOH) in H2O (1 % AcOH). The desired product was obtained as a brown oil (8.5 mg, 4.3 mitioI, 79%). LCMS (ESI+) calculated for C86Hi24lN803iS3+ (M+H+) 1987.66, found 1987.76.
  • 30
  • [ 1394238-92-6 ]
  • C34H56N2O9 [ No CAS ]
  • 1-(4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)propanamido)benzyl) 4-((2S,3S,6S,7R,10R,E)-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-(3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-7-methoxy-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl) piperazine-1,4-dicarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
27.9% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide 1.1.4.1.1.1 General procedure: Step 1 : Macrocycle payload (1.0 equiv.), DMF (0.1 M), (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate (1.5 equiv.; prepared using the procedure described in WO 2012/153193), and Hunig's base (3.0 equiv.) were combined and stirred overnight. The reaction mix was concentrated to dryness and chromatographed to afford fmocVal-Ala-pABC-payload.
  • 31
  • [ 1394238-92-6 ]
  • TFA*NH2-Val-Ala-PAB-P-Trigger-(NMeBoc) [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tetrahydrofuran / 2 h / 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C
  • 32
  • [ 1394238-92-6 ]
  • COOH-PEG9-Val-Ala-PAB-P-Trigger-(NMeBoc) [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tetrahydrofuran / 2 h / 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C 3: N-ethyl-N,N-diisopropylamine / acetonitrile / 16 h / 0 - 20 °C
  • 33
  • [ 1394238-92-6 ]
  • COOH-PEG9-Val-Ala-PAB-P-Trigger-(NMe*TFA) [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: tetrahydrofuran / 2 h / 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 1 h / 0 °C 3: N-ethyl-N,N-diisopropylamine / acetonitrile / 16 h / 0 - 20 °C 4: dichloromethane / 1 h / 0 - 20 °C
  • 34
  • [ 1394238-92-6 ]
  • [ 172477-91-7 ]
  • Fmoc-Val-Ala-PAB-P-Trigger-(NMeBoc) [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; 1a.1.32 1.32 Fmoc-Val-Ala-PAB-P-Trigger-(NMeBoc), Compound 59 The compound may be obtained as described in Dal Corso et. al Angew. Chem Int. Ed. 2020, 59, 4176-4181. It may also be prepared as follows. Fmoc-Val-Ala-PAB-O-oPNP ester (Iris Biotech, 127.0 mg, 0.186 mmol) and (S)-tert-butyl methyl(pyrrolidine-2- ylmethyl)carbamate (Ascension Chemical, 42.0 mg, 0.195 mmol) were taken in a round bottom flask followed by addition of THF (5 mL). The reaction mixture stirred at room temperature for 2h underinert atmosphere. LCMS analysis of the reaction mixture showed formation of the title compound. Solvent was removed under reduced pressure and the product obtained will be used in next reaction without purification. LCMS (philic method, TFA buffer), Rt = 6.60 min.ESIMS (Eve) 756 [M]+l; calc. m/z for C42H53N5O8[M]+1: 756]
  • 35
  • [ 1394238-92-6 ]
  • tert-butyl (4-((S)-2-((S)-3-methyl-2-(pent-4-ynamido)butanamido)propanamido)benzyl) ethane-1,2-diylbis(methylcarbamate) [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere
  • 36
  • [ 1394238-92-6 ]
  • C25H37N5O5*C2HF3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 4: dichloromethane / 2 h / 20 °C
  • 37
  • [ 1394238-92-6 ]
  • C35H43N5O6*C2HF3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: dichloromethane / 2 h / 20 °C
  • 38
  • [ 68858-20-8 ]
  • [ 1394238-92-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide / tetrahydrofuran / 16 h / 0 - 20 °C 1.2: 72 h / 20 °C 2.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 72 h / 20 °C / Darkness 3.1: pyridine / tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 4 steps 1: dicyclohexyl-carbodiimide / tetrahydrofuran / 20 °C 2: Sodium hydrogenocarbonate / water monomer; 1,2-dimethoxyethane / 20 °C 3: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane; methanol / 20 °C 4: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C
  • 39
  • [ 1394238-92-6 ]
  • (2S,3S,4E,6S,7R,10R)-7-acetyloxy-10-hydroxy-2-((2E,4E,6R)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl piperazine-1-carboxylate [ No CAS ]
  • 1-(4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)propanamido)benzyl) 4-((2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl)piperazine-1,4-dicarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 18 - 25℃; for 0.5h; 1.7.1 Step 1: 1-(4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- methylbutanamido)propanamido)benzyl) 4-((2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2- ((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6- methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl) piperazine-1,4- dicarboxylate. To a stirred solution of (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2- ((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta- 2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl piperazine-1-carboxylate (35 mg, 0.053 mmol) and (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2- yl)carbamate (43 mg, 0.06 mmol) in DMF (530 µL) was added DIPEA (28 µL, 0.16 mmol). The reaction mixture was stirred at RT for 30 min and then concentrated in vacuo and then dry loaded onto silica gel. The residue was purified by silica gel chromatography to afford 1-(4-((S)- 2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)propanamido)benzyl) 4-((2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)- 3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12- oxooxacyclododec-4-en-6-yl) piperazine-1,4-dicarboxylate. LC/MS (ESI, m/z), 1228.0 [M+Na]+.
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 18 - 25℃; for 0.5h; 1.7.1 Step 1: 1-(4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- methylbutanamido)propanamido)benzyl) 4-((2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2- ((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6- methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl) piperazine-1,4- dicarboxylate. To a stirred solution of (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2- ((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta- 2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl piperazine-1-carboxylate (35 mg, 0.053 mmol) and (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2- yl)carbamate (43 mg, 0.06 mmol) in DMF (530 µL) was added DIPEA (28 µL, 0.16 mmol). The reaction mixture was stirred at RT for 30 min and then concentrated in vacuo and then dry loaded onto silica gel. The residue was purified by silica gel chromatography to afford 1-(4-((S)- 2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)propanamido)benzyl) 4-((2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)- 3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12- oxooxacyclododec-4-en-6-yl) piperazine-1,4-dicarboxylate. LC/MS (ESI, m/z), 1228.0 [M+Na]+.
  • 40
  • [ 1394238-92-6 ]
  • C40H43FN6O8 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 h 2: piperidine / N,N-dimethyl-formamide / 5.5 h
  • 41
  • [ 1394238-92-6 ]
  • C59H59FN8O12 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 h 2: piperidine / N,N-dimethyl-formamide / 5.5 h 3: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1.83 h / 20 °C
  • 42
  • [ 1394238-92-6 ]
  • C44H49FN8O10 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 h 2: piperidine / N,N-dimethyl-formamide / 5.5 h 3: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1.83 h / 20 °C 4: triethylamine / N,N-dimethyl-formamide; lithium hydroxide monohydrate / 5 h / 20 °C
  • 43
  • [ 1394238-92-6 ]
  • C56H65FN8O15S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 h 2: piperidine / N,N-dimethyl-formamide / 5.5 h 3: triethylamine / N,N-dimethyl-formamide / 23 h / 20 °C
  • 44
  • [ 1394238-92-6 ]
  • C54H66FN7O13 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 h 2: piperidine / N,N-dimethyl-formamide / 5.5 h 3: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 0.58 h / 20 °C
  • 45
  • Exatecan mesylate [ No CAS ]
  • [ 1394238-92-6 ]
  • C55H53FN6O10 [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 20h; 3 Example 3. Preparation of compounds 9a and 9b Compound 8a (163 mg, 240 pmol) was added to a mixture of exatecan mesylate (125 mg, 235 pmol) and DIPEA (61 mg, 82 pL, 0.47 mmol) in dry DMF (0.9 mL). After 20 h, the reaction mixture was diluted to 9 mL DCM and purified by gradient column chromatography (0 -> 40% MeOH/DCM) to afford 9a (155 mg, 159 pmol, 68%). LCMS (ESI+) calculated for CSSHS+FNBOK/ (M+H)+977.39, found 977.72. In addition to 9a, free base of exatecan (82.4 mg, 189 pmol, 20%) was recovered. LCMS (ESI+) calculated for C24H23FN3C>4+(M+H)+436.46, found 436.54.
20% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 20h; 3 Example 3. Preparation of compounds 9a and 9b Compound 8a (163 mg, 240 pmol) was added to a mixture of exatecan mesylate (125 mg, 235 pmol) and DIPEA (61 mg, 82 pL, 0.47 mmol) in dry DMF (0.9 mL). After 20 h, the reaction mixture was diluted to 9 mL DCM and purified by gradient column chromatography (0 -> 40% MeOH/DCM) to afford 9a (155 mg, 159 pmol, 68%). LCMS (ESI+) calculated for CSSHS+FNBOK/ (M+H)+977.39, found 977.72. In addition to 9a, free base of exatecan (82.4 mg, 189 pmol, 20%) was recovered. LCMS (ESI+) calculated for C24H23FN3C>4+(M+H)+436.46, found 436.54.
  • 46
  • [ 1394238-92-6 ]
  • C43H50N4O14 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C
  • 47
  • [ 1394238-92-6 ]
  • C25H39N5O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / 0 - 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 4: trifluoroacetic acid / dichloromethane / 0.75 h / 20 °C
  • 48
  • [ 1394238-92-6 ]
  • C48H56N4O17 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: piperidine / N,N-dimethyl-formamide / 2 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C
  • 49
  • [ 1394238-92-6 ]
  • daunorubicin [ No CAS ]
  • C58H60N4O16 [ No CAS ]
YieldReaction ConditionsOperation in experiment
34% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
  • 50
  • [ 1394238-92-6 ]
  • 2-({6-[(1,3-benzothiazol-2-yl)amino]-5-methylpyridazin-3-yl}(methyl)amino)-5-(3-{2-fluoro-4-[3-(methylamino)prop-1-yn-1-yl]phenoxy}propyl)-1,3-thiazole-4-carboxylic acid [ No CAS ]
  • 2-[[6-(1,3-benzothiazol-2-ylamino)-5-methylpyridazin-3-yl]methylamino]-5-[3-[4-[3-[[4-[[(2S)-2-[[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methoxycarbonylmethylamino]prop-1-ynyl]-2-fluorophenoxy]propyl]thiazole-4-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
15.6 mg With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; 3.2 Step 2: 2-[[6-(1,3-benzothiazol-2-ylamino)-5-methyl-pyridazin-3-yl]-methyl-amino]-5-[3- [4-[3-[[4-[[(2S)-2-[[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl- butanoyl]amino]propanoyl]amino]phenyl]methoxycarbonyl-methyl-amino]prop-1- ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid To a solution of 2-[[6-(1,3-benzothiazol-2-ylamino)-5-methyl-pyridazin-3-yl]-methyl- amino]-5-[3-[2-fluoro-4-[3-(methylamino)prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid (P7) (366.0 mg, 559 mmol) in DMF (10 mL) were successively added the product from Step 1 (378 mg, 556 mmol) and DIPEA (368 µL, 2.22 mmol). The reaction mixture was stirred at room temperature for 16 h and then evaporated to dryness. The crude product was purified by silica gel chromatography (gradient of methanol in DCM) to afford the desired compound (15.6 mg, 9.64 µmol).
15.6 mg With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; 3.2 Step 2: 2-[[6-(1,3-benzothiazol-2-ylamino)-5-methyl-pyridazin-3-yl]-methyl-amino]-5-[3- [4-[3-[[4-[[(2S)-2-[[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl- butanoyl]amino]propanoyl]amino]phenyl]methoxycarbonyl-methyl-amino]prop-1- ynyl]-2-fluoro-phenoxy]propyl]thiazole-4-carboxylic acid To a solution of 2-[[6-(1,3-benzothiazol-2-ylamino)-5-methyl-pyridazin-3-yl]-methyl- amino]-5-[3-[2-fluoro-4-[3-(methylamino)prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid (P7) (366.0 mg, 559 mmol) in DMF (10 mL) were successively added the product from Step 1 (378 mg, 556 mmol) and DIPEA (368 µL, 2.22 mmol). The reaction mixture was stirred at room temperature for 16 h and then evaporated to dryness. The crude product was purified by silica gel chromatography (gradient of methanol in DCM) to afford the desired compound (15.6 mg, 9.64 µmol).
  • 51
  • [ 474645-27-7 ]
  • [ 1394238-92-6 ]
  • [ 1912408-92-4 ]
YieldReaction ConditionsOperation in experiment
74% Stage #1: MMAE; (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.5h; Preparation of4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl ((S)-1-(((S)-1- (((3R,4S,5S)-l-((S)-2-((lR,2R)-3-(((lS,2R)-l-hydroxy-l-phenylpropan-2-yl)amino)-l-methoxy-2- methyl-3-oxopropyl)pyrrolidin-l-yl)-3-methoxy-5-methyl-l-oxoheptan-4-yl)(methyl)amino)-3- methyl-l-oxobutan-2-yl)amino)-3-methyl-l-oxobutan-2-yl)(methyl)carbamate (177) To a mixture of PNP-carbonate 176 (100 mg, 0.15 mmol) and MMAE (106 mg, 147 pL) in anhydrous DMF (1 mL) were added HO At (20 mg, 0.15 mmol) and DIPEA (77 mE, 0.44 mmol). Reaction mixture was stirred overnight at room temperature until all the starting materials were consumed. Piperidine (290 pL, 2.94 mmol) was then added to the reaction mixture. After 30 minutes, reaction mixture was quenched with 1M HC1 to slightly acidic pH. The mixture was filtered and purified by reversed phase chromatography (Cl 8, 0-70% CH3CN- H2O with 0.05% TFA). The pure fractions were collected and lyophilized to obtain compound 177 as a yellow solid (113 mg, 109 pmol, 74% yield). LRMS (ESI): m/z 1037.7 [M+H]+, Calcd for CssHssNsOii m/z 1037.7.
74% Stage #1: MMAE; (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.5h; Preparation of4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl ((S)-1-(((S)-1- (((3R,4S,5S)-l-((S)-2-((lR,2R)-3-(((lS,2R)-l-hydroxy-l-phenylpropan-2-yl)amino)-l-methoxy-2- methyl-3-oxopropyl)pyrrolidin-l-yl)-3-methoxy-5-methyl-l-oxoheptan-4-yl)(methyl)amino)-3- methyl-l-oxobutan-2-yl)amino)-3-methyl-l-oxobutan-2-yl)(methyl)carbamate (177) To a mixture of PNP-carbonate 176 (100 mg, 0.15 mmol) and MMAE (106 mg, 147 pL) in anhydrous DMF (1 mL) were added HO At (20 mg, 0.15 mmol) and DIPEA (77 mE, 0.44 mmol). Reaction mixture was stirred overnight at room temperature until all the starting materials were consumed. Piperidine (290 pL, 2.94 mmol) was then added to the reaction mixture. After 30 minutes, reaction mixture was quenched with 1M HC1 to slightly acidic pH. The mixture was filtered and purified by reversed phase chromatography (Cl 8, 0-70% CH3CN- H2O with 0.05% TFA). The pure fractions were collected and lyophilized to obtain compound 177 as a yellow solid (113 mg, 109 pmol, 74% yield). LRMS (ESI): m/z 1037.7 [M+H]+, Calcd for CssHssNsOii m/z 1037.7.
Stage #1: MMAE; (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate With pyridine; benzotriazol-1-ol In N,N-dimethyl-formamide at 37℃; Stage #2: With piperidine at 20℃;
Same Skeleton Products
Historical Records