Home Cart 0 Sign in  

[ CAS No. 474645-27-7 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type HazMat fee for 500 gram (Estimated)
Excepted Quantity USD 0.00
Limited Quantity USD 15-60
Inaccessible (Haz class 6.1), Domestic USD 80+
Inaccessible (Haz class 6.1), International USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic USD 100+
Accessible (Haz class 3, 4, 5 or 8), International USD 200+
Chemical Structure| 474645-27-7
Chemical Structure| 474645-27-7
Structure of 474645-27-7 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 474645-27-7 ]

Related Doc. of [ 474645-27-7 ]

Alternatived Products of [ 474645-27-7 ]

Product Details of [ 474645-27-7 ]

CAS No. :474645-27-7 MDL No. :
Formula : C39H67N5O7 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 717.98 Pubchem ID :-
Synonyms :
MMAE;Vedotin;Brentuximab vedotin;SGD-1010

Safety of [ 474645-27-7 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P261-P264-P270-P271-P280-P302+P352-P304+P340-P310-P330-P361-P403+P233-P405-P501 UN#:2811
Hazard Statements:H301-H311-H331 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 474645-27-7 ]

* 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 [ 474645-27-7 ]

[ 474645-27-7 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 474645-27-7 ]
  • C31H30N2O17 [ No CAS ]
  • C64H92N6O21 [ No CAS ]
  • 2
  • [ 474645-27-7 ]
  • [ 148580-01-2 ]
  • C60H88N6O21 [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;Inert atmosphere; MMAE (25mg, 0.035mmol) and carbonate 4 (23mg, 0.035mmol) were dissolved in dry DMF (800muL) and pyridine (200muL). HOBt (4.7mg, 0.035mmol) and DIPEA (7.3muL, 0.042mmol) were added. The mixture was stirred at room temperature. After 48h, solvents were removed under reduced pressure and the crude material was purified by preparative TLC over silica gel (CH2Cl2/MeOH, 97/3) to afford 5 (29mg, 68percent) as a white solid (retention time=22.6min for HPLC analysis (method A)).
  • 3
  • C53H80N6O18 [ No CAS ]
  • [ 474645-27-7 ]
  • [ 41833-13-0 ]
YieldReaction ConditionsOperation in experiment
With Escherichia coli beta-glucuronidase; In aq. phosphate buffer; at 37℃;pH 7.0;Enzymatic reaction;Mechanism; Enzymatic hydrolysis was carried out with commercially available beta-glucuronidase from Escherichia coli (purchased from Sigma?Aldrich reference: G8162). Prodrug 1 (0.1mgmL?1) was incubated with beta-glucuronidase (133UmL?1) in phosphate buffer (0.02M, pH7) at 37°C. Aliquots of 20muL were taken at indicated time and analyzed by HPLC using Method B. Retention time for compounds 1, 3 and MMAE are 20.7, 5.1 and 6.0min respectively.
  • 4
  • [ 474645-27-7 ]
  • [ 1497404-31-5 ]
  • [ 1497404-33-7 ]
YieldReaction ConditionsOperation in experiment
25% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; The titled <strong>[474645-27-7]N-<strong>[474645-27-7]monomethyl auristatin E</strong></strong>-linker conjugate was prepared following the procedures shown in Example 12 from 4-pentenoic amide of Val-Cit-PABC-PNP (0.1 g, 0.16 mmol), <strong>[474645-27-7]N-<strong>[474645-27-7]monomethyl auristatin E</strong></strong> (MMAE) (0.11 g, 0.16 mmol) which was prepared according to the literature method with modifications (Pettit G R, et al. Anti-Cancer Drug Design 1998, 13, 243-277), and N,N-diisopropylethylamine (DIPEA) (0.21 g, 0.16 mmol) were mixed and stirred in 1-methyl-2-pyrrolidinone (NMP) (10 mL) at room temperature over the weekend to furnish 48 mg (0.04 mmol, 25percent yield) of white solid. MS (m/e): 1206, M+1; 1228, M+Na).
  • 5
  • [ 474645-27-7 ]
  • C45H44N6O10 [ No CAS ]
  • C78H106N10O14 [ No CAS ]
  • 6
  • [ 474645-27-7 ]
  • C51H48N6O11 [ No CAS ]
  • C84H110N10O15 [ No CAS ]
  • 7
  • N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide [ No CAS ]
  • [ 37577-28-9 ]
  • [ 474645-27-7 ]
  • 8
  • C44H75N5O9 [ No CAS ]
  • [ 474645-27-7 ]
YieldReaction ConditionsOperation in experiment
52% With trifluoroacetic acid; In dichloromethane; 50 mg (70 mumol) of Intermediate 26 and 11 mg (70 mumol) of (1S,2R)-2-amino-1-phenylpropan-1-ol in 10 ml of DMF were admixed with 42 mg (0.11 mumol) of O-(7-azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate and 25 mul of N,N-diisopropylethylamine, and the reaction mixture was stirred at RT for 5 min. This was followed by concentration and purification of the residue by means of preparative HPLC. After combining the corresponding fractions, concentrating and drying under high vacuum, 49 mg (81percent) of the protected intermediate were obtained. Subsequently, the Boc group was detached by known conditions with trifluoroacetic acid in dichloromethane. Concentration was followed by the purification of the title compound by preparative HPLC, and 26 mg (52percent) of the title compound were obtained. [1540] HPLC (Method 12): Rt=1.65 min; [1541] LC-MS (Method 1): Rt=0.77 min; MS (ESIpos): m/z=718 (M+H)+.
  • 12
  • N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(2R,3S,4S)-1-carboxy-2-methoxy-4-methylhexan-3-yl]-N-methyl-L-valinamide [ No CAS ]
  • [ 474645-27-7 ]
  • 13
  • [ 474645-22-2 ]
  • [ 474645-27-7 ]
  • 14
  • [ 1149-26-4 ]
  • [ 474645-27-7 ]
  • 15
  • [ 149606-97-3 ]
  • [ 474645-27-7 ]
  • 16
  • [ 1369426-98-1 ]
  • [ 474645-27-7 ]
  • 17
  • N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-(benzyloxy)-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide [ No CAS ]
  • [ 474645-27-7 ]
  • 18
  • [ 120205-52-9 ]
  • [ 474645-27-7 ]
  • 19
  • [ 159857-81-5 ]
  • [ 474645-27-7 ]
  • 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)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
71% With pyridine; benzotriazol-1-ol; In N,N-dimethyl-formamide; at 20℃; for 24h; Example 29 Synthesis of N-alkyl maleimido-Val-Cit-PAB-MMAE mc-ValCit-PAB-OH PNP Carbonate "N-alkyl maleimide Val-Cit-PAB-MMAE" Maleimidocaproyl-valine-citrulline-/7-aminobenzylcarbonyl-mono- methyl-Auristatin-E (mc- ValCit-PABC-MMAE) was prepared according to the literature method with modifications.1 Thus, a mixture of mc-Val-Cit-p-aminobenzyl alcohol p-nitrophenylcarbonate (8) freshly prepared according to literature method2 (265 mg, 0.36 mmol, 1.5 eq.), MMAE (9) (169 mg, 0.24 mmol, 1 eq.) and N-hydroxybenzotriazole (HOBt) (6.48 mg, 0.048 mmol, 0.2 eq.) were stirred in DMF (5 mL) at r.t. for 2 min., followed by addition of pyridine (38 mg, 0.48 mmol, 2 eq.). After stirring for 24 h, volatile organics were removed under vacuum. The residue obtained was triturated with ethyl acetate and methanol (1L) to afford mc-Val-Cit-PAB- MMAE (10) as a white powder (220 mg, 0.17 mmol, 71 % yield) that was usually >95% pure by RP-HPLC analysis. If necessary, further purification can be carried out by C18 reversed- phase preparative HPLC or size exclusive column chromatography. Electrospray (ES)-MS m/z 1339 (M+Na, base peak), 1317 (M + 1).
65% With 2,6-dimethylpyridine; benzotriazol-1-ol; In N,N-dimethyl acetamide; at 40℃; A compound of the following formula (1 eq.): and mc-Val-Cit-PABC-PNP (1.18 eq.) were solubilized in N,N-dimethylacetamide (7.87 vol.). l-Hydroxybenzotriazole (HOBt) hydrate (8.95 wt%) and 2,6-lutidine (2.315 vol.) were then added and the reaction mixture was stirred at 40C for 12-16 hours until reaction was complete. The reaction mixture was cooled to 20C and added into tert-Butyl methyl ether (168 vol.). The resultant slurry was stirred for 3-5 hours and filtered, washed and dried under vacuum. Crude product was purified by column purification and product-containing fractions were concentrated to dryness and slurried in Ethyl acetate (20 vol.) before being isolated by filtration, washed and dried (65% yield). MS: m/e 1317 (MH)+, 1339 (M+Na)+.
Ca. 42% 20 mg mc-vc-PAB-PNP (1.5 eq) and 3 mg HOBT were added to 2 ml DMF.After stirring for a while at room temperature,Add 13mg MMAE,0.5ml pyridine,25ulDIEA.The reaction was stirred at room temperature for 2 days.After the reaction is completed,The reaction solution is directly purified using a preparative column.Collect the required ingredients and lyophilize them after concentrationGet about 10mg product,The yield is about 42%.
Ca. 42% With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 48h; 20mg of mc-vc-PAB-PNP (1.5 eq) and 3 mg of HOBT were added to 2 ml of DMF. After stirring for a while at room temperature,Add 13 mg MMAE, 0.5 ml pyridine,25ulDIEA. The reaction solution was stirred at room temperature for 2d.. After the reaction is completed, the reaction solution is directly purified by a preparative column.The desired components are collected and concentrated and lyophilized to obtain about 10 mg of the product.The yield is about 42%.
With pyridine; benzotriazol-1-ol; In N,N-dimethyl-formamide; for 24h; Preparation Method of Compound 20-10: MMAE (100.5 mg, 0.14 mmol, 1 eq. ) , Compound 20-9 (110.6 mg, 0.15 mmol, 1.1 eq. ) and HPBt (19 mg, 0.14 mmol, 1.0eq. ) were diluted with DMF (2 mL) . After 2 minutes, pyridine (0.5 mL) was added and the reaction was monitored by reverse-phase HPLC. The reaction was complete after about 24 hours. The mixture was concentrated and the resulting residue was purified using reverse phase preparative-HPLC (Varian Dynamax column 21.4 mm×25 cm, 5mu,through gradient elution of MeCN and Et3N-CO2 (pH 7) at 20 mL/minutes from 10 to 100 for 40 minutes. The relevant fractions were pooled and concentrated to give an off-white solid intermediate, i.e., Compound 20-10. MS [M] +: 1, 315.78.
10.7 g MMAE (7.18g. lOmmol) was measured and added into a 250m1 three-neck flask, dissolved in anhydrous DMF, and stirred till clear at room temperature under N2 protection. Mc-Val-Cit-PAB-PNP (7.37g) and HOAt (72mg, 2mmol) were added into the solution and reacted for 5 mm, and then DIEA (3.5m1, 2Ommol) was added drop-wise, the reaction was continued for 30 mm at roomtemperature, and then the temperature was increased to 40?SOC and reacted for 20h, during which HPLC was used to monitor the reaction. DMF was removed by drying in vacuo, and the product Mc-Val-Cit-PAB-MMAE (10.7g. purity: 99.3%) was obtained by further HPLC purification.
With pyridine; benzotriazol-1-ol; In N,N-dimethyl-formamide; at 20℃; MC-VC-PAB-PNP (93 mg, 0.125 mmol) and MMAE (60 mg, 0.083 mmol) were dissolved in 4 mL DMF.Add HoBt (10 mg, 0.074 mmol) and 0.5 mL of pyridine in sequence.The reaction was stirred at room temperature overnight.The reaction product is isolated and purified using a preparative liquid phase.The chromatographic conditions were as follows: phase A H2O + 0.08% TFA, phase B acetonitrile + 0.08% TFA. 0-35min B phase 65% isocratic elution,The pure product was collected and the reaction product was lyophilized.

  • 20
  • N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide [ No CAS ]
  • [ 474645-27-7 ]
  • 21
  • C44H75N5O9 [ No CAS ]
  • [ 76-05-1 ]
  • [ 474645-27-7 ]
YieldReaction ConditionsOperation in experiment
52% In dichloromethane; [3914] 50 mg (70 f.tmol) of Intermediate 26 and 11 mg (70f.tmol) of (1S,2R)-2-amino-1-phenylpropan-1-ol in 10 ml ofDMF were admixed with42 mg (0.11 flillOl) of0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphateand 25 fll ofN,N-diisopropylethylamine, and thereaction mixture was stirred at RT for 5 min. This was followedby concentration and purification of the residue bymeans of preparative HPLC. After combining the correspondingfractions, concentrating and drying under highvacuum, 49 mg (81percent) of the protected intermediate wereobtained. Subsequently, the Boc group was cleaved usingknown conditions with trifluoroacetic acid in dichloromethane.Concentration was followed by the purification ofthe title compound via preparative HPLC, and 26 mg (52percent)of the title compound were obtained.[3915] HPLC (Method 12): R,=l.65 min;[3916] LC-MS (Method 1): R,=0.77 min; MS (ESipos):rnlz=718 (M+Hr.
  • 22
  • C21H41N3O5 [ No CAS ]
  • [ 474645-27-7 ]
  • 23
  • C14H25NO5*C12H23N [ No CAS ]
  • [ 474645-27-7 ]
  • 24
  • [ 474645-27-7 ]
  • C47H42N4O24 [ No CAS ]
  • C113H166N12O32 [ No CAS ]
  • 25
  • [ 474645-27-7 ]
  • C40H38N8O13 [ No CAS ]
  • C73H100N12O17 [ No CAS ]
YieldReaction ConditionsOperation in experiment
12 mg With pyridine; benzotriazol-1-ol; In N,N-dimethyl-formamide; at 20℃; for 0.5h; Compound 12 (35 mg, 42 mmol), MMAE (30 mg, 42 mmol; US 6884869) and N-hydroxybenzotriazole (HOBt,1.2 mg, 8.0 mmol) was added successively to dry DMF (2 mL) and pyridine (0.4 mL). The reaction mixture was stirredat room temperature for 30 min, and solvent was removed in vacuo. The residue was purified by preparative HPLC togive white powder (12 mg). LC-MS m/z (ES+), 1417.7 (M+H)+.
  • 26
  • [ 474645-27-7 ]
  • C39H40N6O11 [ No CAS ]
  • 4-((S)-2-((S)-2-(6-(3-(4-cyanophenoxy)-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
15% With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 6h; Procedure: CPM-Val-Ala-PAB-NPC (26) (28 mg), (S)-N-((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)-N,3- dimethyl-2-((S)-3-methyl-2-(methylamino)butanamido)butanamide (MMAE, 20 mg), DIPEA (6.2 mg), and HoAt (0.5 mg) were dissolved in 0.2 mL dimethylformamide. After 6 h at room temperature the reaction was purified via preparative HPLC and the appropriate fractions were lyophilized. A second purification via silica gel chromatography was required to give the purified product 4-((S)-2-((S)-2-(6-(3-(4- cyanophenoxy)-2,5-dioxo-2,5-dihydro-1 H-pyrrol-1 -yl)hexanamido)-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 (27) (CPM(C6)-Val-Ala-PAB-MMAE) (5 mg, 15percent). LC/MS 2.01 min (5-95percent acetonitrile/water + 0.1 percent formic acid over 2 min, hold at 95percent for 0.5 min, then 95-5percent over 0.1 min, and hold at 5percent for 0.4 min. Column used was Waters BEH C18 1 .7 muiotatauiota, 2.1 x 50 mm, flowrate was 0.8 mL/min.), m/z 1369.86 [M+Na]+.
  • 27
  • [ 474645-27-7 ]
  • C45H43N3O18 [ No CAS ]
  • C78H105N7O22 [ No CAS ]
  • 28
  • [ 55750-53-3 ]
  • [ 474645-27-7 ]
  • [ 863971-24-8 ]
YieldReaction ConditionsOperation in experiment
36% With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 12h;Inert atmosphere; To a suspension of MMAE (0.05 g, 0.0694 mmol) in freshly distilled dry DCM (2 ml), 6-maleimidocaproic acid (0.0221 g, 0.104 mmol) was added followed by diethylcyanophosphonate (21 muIota, 0.139 mmol) and DIPEA (37 muIota, 0.208 mmol). On addition of DIPEA, the reaction mixture became clear and was stirred at room temperature under nitrogen for 12 h, TLC [silica gel: 5percent MeOH/DCM, Rf 0.31]. The reaction mixture was diluted with DCM (30 ml) and washed with 10percent citric acid (2 X 20 ml), water (20 ml), brine (20 ml) and concentrated to dryness. The crude was purified by flash column chromatography [silica gel: 5percent MeOH/DCM] to give 6- Maleimidocaproyl-MMAE 37 as a white solid 0.023 g (36percent). MS (m/z) found 911.58 (M+1) calculated for C49H79N6O10
  • 29
  • [ 159857-81-5 ]
  • [ 474645-27-7 ]
  • C68H105N11O15 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With pyridine; benzotriazol-1-ol; In N,N-dimethyl-formamide; for 24h; The activated linker 39 (50 mg, 0.068 mmol), MMAE (32.6 mg, 0.045 mmol) and N-hydroxybenzotriazole (1.4 mg, 0.0091 mmol) are stirred in dry DMF (1 ml) for 2 min. after which a drop of pyridine is added and the reaction stirred for 24 h. The solvent is then removed by high vacuum and the residue purified by reverse-phase preparative HPLC togive the desired product 40 after lyopholisation as a white powder; MS (m/z) 1316.7 (M+H).
  • 30
  • [ 474645-27-7 ]
  • C33H39NO17Si [ No CAS ]
  • C66H101N5O21Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere; 10300] After Compound 2d (229 mg, 0.30 mmol) was dissolved in DMF (2 mE) at room temperature under nitrogen atmosphere, MMAE (1.34 g, 1.80 mmol) was added thereto, and then, the resultant was treated with HOI3T (8.2 mg, 0.06 mmol), pyridine (0.8 mE), and DIPEA (56 uL, 0.29 mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was completed, ethylacetate (100 mE) and distilled water (100 mE) were added thereto. The organic layer obtained as described above was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography, thereby obtaining Compound 6a (239 mg, 65percent).
  • 31
  • [ 474645-27-7 ]
  • 6-azido-6-deoxy-D-galactopyranose [ No CAS ]
  • C45H78N8O11 [ No CAS ]
  • 32
  • [ 474645-27-7 ]
  • 6-O-prop-2-yn-1-yl-D-galactopyranose [ No CAS ]
  • C48H81N5O12 [ No CAS ]
  • 33
  • [ 403518-14-9 ]
  • [ 474645-27-7 ]
  • C43H73N5O8S2 [ No CAS ]
  • 34
  • [ 474645-27-7 ]
  • C33H39NO17Si [ No CAS ]
  • C66H101N5O21Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere; Compound 2d (229mg, O.3Ommol) was dissolved in DMF (2mL) at room temperature under nitrogen atmosphere, and then MMAE (1 .34g, 1 .8Ommol) was addedthereto. The resultant composition was treated with HOBT (8.2mg, 0.O6mmol), pyridine (0.8mL), and DIPEA (56uL, 0.29mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was completed, ethylacetate (lOOmL) and distilled water (lOOmL) were added thereto. The organic layer obtained as described above was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography, thereby obtaining Compound 6a (23 9mg, 65percent). El-MS m/z: 1328(M+)
  • 35
  • [ 474645-27-7 ]
  • C15H13N3O7S2 [ No CAS ]
  • C48H75N7O11S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
70.3% With pyridine; benzotriazol-1-ol; In N,N-dimethyl-formamide; at 15℃; for 48h; To a solution of MMAE (100.0 mg, 0.140 mmol) in anhydrous DMF (5.0 mL) was added compound 2 (68.76 mg, 0.170 mmol), 1-HOBt (3.76 mg, 0.030 mmol), and pyridine(110.17 mg, 1.39 mmol). The solution was stirred at 15 °C for 2 days. The solution was concentrated in vacuo, and the residue was purified by prep-TLC (5percent MeOH in DCM, Rf = 0.5) to afford compound 3 (100 mg, 0.098 mmol, 70.3percent yield) as a white solid. LCMS (5- 95AB/1.Smin): RT = 0.996 mm, [M+Hj + 990.6.
  • 36
  • [ 474645-27-7 ]
  • C15H13N3O7S2 [ No CAS ]
  • C48H75N7O11S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
83.7% With pyridine; benzotriazol-1-ol; In N,N-dimethyl-formamide; at 30℃; for 8h; A mixture of MMAE (30.0 mg, 0.04 mmol) and compound 2 (60.0 mg, 0.15 mmol) in DMF (3.0 mL) was added pyridine (33.05 mg, 0.42 mmol) and HOBt (0.56 mg, 0.Olmmol).The reaction mixture was stirred at 30 °C for 8 h. The mixture was concentrated in vacuo and purified by prep-TLC (5percent MeOH in DCM) to give Compound 3 (35 mg, 0.035 mmol, 83.7 percent yield) as a white solid. LCMS (5-95AB11 .5mm): RT = 0.994 mm, [M+Hj 990.5.
  • 37
  • [ 474645-27-7 ]
  • 4-nitrophenyl 2-((5-nitropyridin-2-yl)disulfanyl)ethyl carbonate [ No CAS ]
  • C48H74N6O11S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With pyridine; benzotriazol-1-ol; In N,N-dimethyl-formamide; at 20 - 22℃; for 16h; To a stirred solution of compound 4 (30 mg, 0.0756 mmol), were added MMAE (49 mg, 0.068 mmol), HOBt (2.0 mg, 0.0 15 mmol) in DMF (3.0 mL) and pyridine (60 mg, 0.756 mmol) at 22 °C. After the mixture was stirred at 20 °C for 16 h, it was purified by prep-HPLC (FA) togive compound B (60.0 mg, yield: 80percent). LCMS: (5-95, AB, 1.5 mm), 1.007 mm, MS =998.6[M+231b; ?H NMR (400 MHz, DM50-cl6) 5 9.23 (s, 1 H), 8.53 (d, J= 7.6 Hz, 1 H), 7.44 ?8.02 (d, J= 8.0 Hz, 1 H), 7.58 (s, 1 H), 7.35 - 7.18 (m, 7 H), 5.10 (s, 1 H), 4.70 - 4.45 (m, 2 H),4.31 (s, 2 H), 4.18 (s, 1 H), 4.03 (s, 2 H), 3.80 (s, 1 H), 3.46 (s, 1 H), 3.40 - 3.18 (m, 12 H), 2.84(d, J 6.0 Hz, 3 H), 2.41 (s, 2 H), 2.18 (s, 2 H), 1.81 (s, 3 H), 1.74 - 1.50 (m, 2 H), 1.37 (s, 1 H),1.04-0.78 (m, 28 H). The molecular weight determined by NMR was 975.48.
  • 38
  • [ 474645-27-7 ]
  • C15H13N3O7S2 [ No CAS ]
  • C48H75N7O11S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With pyridine; benzotriazol-1-ol; In N,N-dimethyl-formamide; at 27℃; for 12h; To a stirred solution of MMAE (30 mg, 0.042 mmol) and compound 2 (34 mg, 0.084 mmol) in dry DMF (2.0 mL) was added HOBt (1.0 mg, 0.0042 mmol) and pyridine (33 mg, 0.42 mmol). The mixture was stirred at 27 °C for 12 h and purified by prep-HPLC (FA) to give compound C (23 mg, yield: 55percent) as a white solid. ?H NMR (400 MHz, MeOH-d4) 5 ppm 9.24 (br. s., 1H), 8.54 (dd, J 8.9, 2.6 Hz, 1H), 8.07 (dd, J= 9.0, 2.0 Hz, 1H), 7.53 - 7.09 (m, 5 H),4.73 - 4.56 (m, 5H), 4.36 - 4.15 (m, 5H), 3.92 - 3.51 (m, 1H), 3.49 - 3.37 (m, 2H), 3.35 (s, 5H),3.25 - 3.09 (m, 2H), 3.02 - 2.86 (m, 3H), 2.56 - 2.39 (m, 2H), 2.32 - 1.51 (m, 2H), 1.38 (dd, J=6.8, 2.8 Hz, 4H), 1.23 - 1.09 (m, 6H), 1.06 - 0.77 (m, 19H). The molecular weight determined byNMRwas 989.50.
  • 39
  • [ 474645-27-7 ]
  • C31H31NO17 [ No CAS ]
  • C64H93N5O21 [ No CAS ]
YieldReaction ConditionsOperation in experiment
67% With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 24h;Inert atmosphere; Preparation of Compound lh Compound lg (528 mg, 0.77 mmol), MMAE (500 mg, 0.7 mmol) and anhydrous HOBt (19 mg, 0.14 mmol) were dissolved in DMF (3 mL) at 0 °C. Then pyridine (0.7 mL) and DIPEA (0.24 mL, 1.39 mmol) were added. After stirring at room temperature for 24 hours under N2, the reaction mixture was diluted with H2O/saturated aqueous H4C1 solution (100 mL/50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by column chromatography to produce the compound lh (600 mg, 67 percent). EI-MS m/z: [M+H]+ 1269.5, [M+Na]+ 1291.5.
  • 40
  • [ 474645-27-7 ]
  • C16H18N4O5S2 [ No CAS ]
  • C49H80N8O9S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
41.1% With pyridine; benzotriazol-1-ol; In N,N-dimethyl-formamide; at 20℃; for 18h; A mixture of HOBt (1.65 mg, 0.010 mmol) and MMAE (78.6 mg, 0.110 mmol) in DMF (5.0 mL) was added pyridine (0.10 mL, 1.22 mmol) and compound 7 (50.0 mg, 0.120 mmol). After the reaction mixture was stirred at 20 °C for 18 h, it was concentrated in vacuo and purified prep-HPLC (acetonitrile 50-75/0.225percent FA in water) to give compound BB (50 mg, 0.050 mmol, 41.1percent yield) as a white solid. LCMS (5-95AB/1.Smin): RT = 0.795 mi [M+Hj989.4. HPLC (10-8OAB/8min): RT= 5.11 mm.
  • 41
  • [ 474645-27-7 ]
  • C17H19N2O5S2(1+) [ No CAS ]
  • C50H81N6O9S2(1+) [ No CAS ]
YieldReaction ConditionsOperation in experiment
48.6% With pyridine; benzotriazol-1-ol; In N,N-dimethyl-formamide; at 35℃; for 12h;Inert atmosphere; To a mixture of compound 9 (24.79 mg, 0.060 mmol) in DMF (5.0 mL) was addedMMAE (15.0 mg, 0.020 mmol), pyridine (16.53 mg, 0.210 mmol) and HOBt (1.41 mg, 0.010mmol). The mixture was stirred at 35 °C for 12 h under N2. The mixture was filtered and purified by prep-HPLC (Column : Phenomenex Synergi C18 250*21.2mm*4um, Condition:water (0.05percentHC1)-ACN) to give compound CC (10.3 mg, 0.0101 mmol, 48.6percent yield) as a white solid. LCMS (5-95_i .5mm): RT (220/254nm) = 0.708 mi [M+Hj 974.0.
  • 42
  • [ 474645-27-7 ]
  • C16H15N3O7S2 [ No CAS ]
  • C49H77N7O11S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% With pyridine; benzotriazol-1-ol; In d7-N,N-dimethylformamide; at 30℃; for 8h; To a mixture of compound 2 (100.0 mg, 0.240 mmol) and pyridine (186 mg, 2.35 mmol)in DMF (10 mL) was added MMAE (107 mg, 0.210 mmol) and HOBt (3.18 mg, 0.020 mmol).The reaction mixture was stirred at 30 °C for 8 h. The mixture was concentrated in vacuo and purified prep-TLC (5percent MeOH in DCM) to give compound D (110 mg, 46percent) as a white solid. LCMS (5-95AB/1.Smin): RT=0.899 mi [M+Naj1026.3. ?HNMR(400 MHz,CDC13) 5 9.18 (s, 1H), 8.30 (d, J 8.4 Hz, 1H), 7.88 (d, J= 12.8 Hz, 1H), 7.32-7.19 (m, 4H), 6.42 (d, J=9.2 Hz, 1H), 4.88 (s, 1H) , 4.72-4.60 (m, 1H), 4.25-4.20 (m, 1H), 4.14-3.94 (m, 5H), 3.78 (d, J=5.6, 1H), 3.44 (m,1H), 3.35-3.3 1 (m, 4H), 3.24 (s, 3H), 3.04 (s, 1H), 2.84-3.00 (m, 2H), 2.44-2.34 (m, 3H), 2.34-2.30 (m, 1H), 1.88-2.05 (m, 3), 1.84-1.75 (m, 3H), 1.30 (s, 7H), 1.20 (m, 3H)1.00-0.75 (m, 24H). The molecularweight determined by NMRwas 1003.51.
  • 43
  • [ 474645-27-7 ]
  • C30H28N2O17 [ No CAS ]
  • C63H90N6O21 [ No CAS ]
YieldReaction ConditionsOperation in experiment
66% With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 36h; Compound 4 (57.5 mg; 0.0835 mmol) and MMAE (60 mg; 1 eq.) are dissolved in 2 ml of a DMF/pyridine mixture (8/2). 11.3 mg of HOBt (0.0835 mmol; 1 eq.) and 17 mul of DIPEA (0.1 mmol; 1.2 eq.) are added. The stirring is maintained for 36 h at ambient temperature. The solvent is removed under vacuum and the residue is purified by flash chromatography (Eluant: DCM/MeOH 3percent-5percent). 70 mg of compound 5 are obtained (0.05 5 mmol; 66percent) in the form of a white solid.
  • 44
  • [ 474645-27-7 ]
  • 4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl)carbonate [ No CAS ]
  • 4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-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 ]
  • 45
  • [ 474645-27-7 ]
  • 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate [ No CAS ]
  • 4-((S)-2-((S)-2-(6-(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 ]
  • 46
  • [ 474645-27-7 ]
  • C53H80N6O18 [ No CAS ]
  • 47
  • [ 913168-10-2 ]
  • [ 474645-27-7 ]
  • C47H74N6O9S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 1.5h; MMAE (100 mg, 139 umol) was dissolved in DMF (2 mL), then 5A (72.8 mg, 209 umol) was added as a solution in DMF (1 mL), followed by diisopropylethylamine (54 mg, 418 umol, 73 uL). After 1.5 h, crude was purified on Combiflash by reverse phase chromatography (10-90percent MeCN/water, 0.1percent acetic acid). Pure fractions were pooled, frozen and lyophilized. 95 mg (73percent) of white lyophilized powder was obtained (4.79 mins, M+H = 932).
72% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; A solution of 2-(2-pyridinyldithio)ethanol HOBt carbonate (18.0 mg, 51.7 Pmol) in DMF (1.0 mL) was added to <strong>[474645-27-7]monomethyl auristatin E</strong> (12.5 mg, 17.4 Pmol). Diisopropylethylamine (50 PL) was added, and the reaction stirred at room temperature for 18 h. The reaction mixture was purified by preparative HPLC (5percent to 95percent acetonitrile in water with 0.1percent TFA) to give 5? (11.7 mg, 12.6 Pmol, 72percent yield). LCMS M/Z = 931.5 [M + 1].
  • 48
  • [ 474645-27-7 ]
  • C30H28N2O17 [ No CAS ]
  • C63H90N6O21 [ No CAS ]
  • 49
  • [ 474645-27-7 ]
  • 6-(4-(10,15,20-tris(4-(methoxycarbonyl)phenyl)porphyrin-5-yl)benzamido)hexanoic acid [ No CAS ]
  • trimethyl 4,4',4''-(20-(4-(((3R,4S,7S,10S)-4-((S)-sec-butyl)-3-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-7,10-diisopropyl-5,11-dimethyl-6,9,12-trioxo-2-oxa-5,8,11-triazaheptadecan-17-yl)carbamoyl)phenyl)porphyrin-5,10,15-triyl)tribenzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Preparation trimethyl 4,4',4''-(20-(4-(((3R,4S,7S,10S)-4-((S)-sec-butyl)-3-(2- ((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3- oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-7,10-diisopropyl-5,11-dimethyl-6,9,12-trioxo-2-oxa- 5,8,11-triazaheptadecan-17-yl)carbamoyl)phenyl)porphyrin-5,10,15-triyl)tribenzoate (OS035). To a mixture of 4 (21 mg, 0.022 mmol), HATU (20.2 mg, 0.053 mmol) and DIPEA (31 muL, 0.177 mmol) in DMF (2 mL) was stirred for 10 min at room temperature. To the above mixture was added <strong>[474645-27-7]monomethyl auristatin E</strong> (5, 17.5 mg, 0.024 mmol) followed by HOBt (3.3 mg, 0.024 mmol) and the resultant mixture was stirred at room temperature for 16 h. The mixture was diluted with CH2Cl2 and washed with water (3 x 10 mL). The organic layer was dried over Na2SO4, and evaporated. The residue was purified by normal phase chromatography with 0?10 percent MeOH- CH2Cl2 to get the desired target compound OS035 (12 mg, 33percent).
  • 50
  • [ 474645-27-7 ]
  • trimethyl 4,4',4''-(20-(4-((2-(((4-nitrophenoxy)carbonyl)oxy)ethyl)carbamoyl)phenyl)porphyrin-5,10,15-triyl)tribenzoate [ No CAS ]
  • trimethyl 4,4',4''-(20-(4-(((3R,4S,7S,10S)-4-((S)-sec-butyl)-3-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-2-oxoethyl)-7,10-diisopropyl-5,11-dimethyl-6,9,12-trioxo-2,13-dioxa-5,8,11-triazapentadecan-15-yl)carbamoyl)phenyl)porphyrin-5,10,15-triyl)tribenzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; Preparation of trimethyl 4,4',4''-(20-(4-(((3R,4S,7S,10S)-4-((S)-sec-butyl)-3- (2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2- methyl-3-oxopropyl) pyrrolidin-1-yl)-2-oxoethyl)-7,10-diisopropyl-5,11-dimethyl-6,9,12- trioxo-2,13-dioxa-5,8,11-triazapentadecan-15-yl)carbamoyl)phenyl)porphyrin-5,10,15- triyl)tribenzoate (OS0032). To a mixture of 6 (20 mg, 0.019 mmol) and <strong>[474645-27-7]monomethyl auristatin E</strong> 7 (15.1 mg, 0.021 mmol) in DMF (0.8 mL) was added DIPEA (27 muL g, 0.153 mmol) at room temperature. The resultant mixture was stirred for 16 at ambient temperature. The mixture was diluted with CH2Cl2 (5 mL), washed with water (2 x 10 mL), dried over Na2SO4, and evaporated. The crude residue was purified by normal phase chromatography with 0?10percent MeOH - CH2Cl2 to give the desired target OS0032 (15 mg, 77percent).1H-NMR (300 MHz, CDCl3): ^ 8.85 (s, 8H), 8.43 (d, 6H, J=8), 8.18-8.33 (m, 10H), 7.21-7.31 (m, 5H), 6.43 (m, 1H), 3.80-4.89 (m, 17H), 3.75 (d, 1H, J=7), 3.19-3.34 (m, 9H), 2.97 (m, 6H), 2.31-2.42 (m, 4H), 1.97-2.18 (m, 3H), 1.60- 1.75 (M, 3h), 1.17-1.38 (M, 5H), 0.68-0.97 (m, 26H).
  • 51
  • [ 474645-27-7 ]
  • C15H10ClNO7 [ No CAS ]
  • C54H76N6O14 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 0.166667h; MMAE (15.1, 287 mg, 0.4 mmol) was added to the PNP-PABC-chloroformate derivative (0.4mmol; Ref. 8; used previously for the synthesis of 3.31) in THF (5 niL), followed by DIPEA (0.21 niL, 1.2 mmol). The reaction was stirred at room temperature for 10 min and then diluted with EtOAc (100 mL) and the mixture was washed with IN hydrochloric acid (30 mL) and water (30 mL). The organic layer was dried (over anhydrous Na2S04, 1 h) and concentrated to dryness. The crude compound 15.2 was dissolved in anhydrous DMF (5 mL). Compound 3.30 (0.37 mmol) was added, followed by DIPEA (0.28 mL, 1.6 mmol). The mixture was stirred at room temperature for 16 h. and purified directly by reverse phase preparative HPLC to give compound 15.3 as a red solid after lyophilization (224 mg, 0.18 mmol). MS m/z : 1124.8 (M+H)+
  • 52
  • [ 474645-27-7 ]
  • C15H10ClNO7 [ No CAS ]
  • C59H85N11O11 [ No CAS ]
  • 53
  • [ 474645-27-7 ]
  • tert-butyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate [ No CAS ]
  • ((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 ]
  • 54
  • [ 474645-27-7 ]
  • tert-butyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)carbamate [ No CAS ]
  • C68H102N10O16 [ No CAS ]
  • 55
  • [ 159857-81-5 ]
  • [ 474645-27-7 ]
  • 4-((R)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl ((2S)-1-(((2S)-1-(((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 ]
  • 56
  • [ 474645-27-7 ]
  • (S)-4-(2-(1-(5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentylcarbamoyl)cyclobutanecarboxamido)-5-ureidopentanamido)benzyl 4-nitrophenyl carbonate [ No CAS ]
  • 4-((S)-2-(1-((5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentyl)carbamoyl)cyclobutane-1-carboxamido)-5-ureidopentanamido)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 ]
  • 57
  • [ 474645-27-7 ]
  • (S)-4-(2-(1-(5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentylcarbamoyl)cyclobutanecarboxamido)-5-ureidopentanamido)benzyl4-nitrophenyl carbonate [ No CAS ]
  • 4-((R)-2-(1-((3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentyl)carbamoyl)cyclobutane-1-carboxamido)-5-ureidopentanamido)benzyl ((2S)-1-(((2S)-1-(((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 ]
  • 58
  • [ 474645-27-7 ]
  • 4-((2R,5S,Z)-5-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-4-fluoro-6-methyl-2-(3-ureidopropyl)hept-3-enamido)benzyl 4-nitrophenyl carbonate [ No CAS ]
  • 4-((2R,5S,Z)-5-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-4-fluoro-6-methyl-2-(3-ureidopropyl)hept-3-enamido)benzyl ((2S)-1-(((2S)-1-(((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 ]
  • 59
  • [ 474645-27-7 ]
  • 4-((S)-2-(4-((S)-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-2-methylpropyl)-1H-1,2,3-triazol-1-yl)-5-ureidopentanamido)benzyl 4-nitrophenyl carbonate [ No CAS ]
  • 4-((S)-2-(4-((S)-1-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-2-methylpropyl)-1H-1,2,3-triazol-1-yl)-5-ureidopentanamido)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 ]
  • 60
  • [ 474645-27-7 ]
  • C42H51N3O21 [ No CAS ]
  • C75H113N7O25 [ No CAS ]
YieldReaction ConditionsOperation in experiment
59% With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 18h; MMAE (30 mg, 0.043 mmol) was dissolved in a mixture of THF (2.0 mL) and pyridine (0.5 mL) followed by the addition of DIPEA (80 muL), HOBt (1.5 mg, 0.01 mmol) and 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OpNP-PAB-succinate-alkynyl-PEG4 13 (40 mg, 0.043 mmol). After 48 hours the solvent was removed and the reaction mixture was then purified by silica gel chromatography eluting with CH2Cl2 (100percent), then 7.5percent MeOH/CH2Cl2 to give 38.4 mg (59percent) of 2,3,4-tri-Ac-6-methy 1-Glucuranate-2?-MMAE-PAB-succinate-alkynyl-PEG4 14. 1H NMR (400 MHz, CDCl3) delta 9.0 (m, 1H), 7.67-7.25 (m, 6H), 7.24-6.9 (m, 3H), 6.81 (s, 1H), 6.7-6.45 (m, 2H), 5.42-5.29 (m, 4H), 5.29-4.88 (m, 4H), 4.8-4.55 (m, 2H), 4.22 (bs, 1H), 4.15 (s, 3H), 4.12-4.0 (m, 3H), 3.85-3.23 (m, 33H), 3.1-2.75 (m, 6H), 2.73-2.5 (m, 5H), 2.42 (d, J=2.0 Hz, 1H), 2.4-2.3 (m, 4H), 2.3-2.16 (m, 2H), 2.15-2.07 (m, 5H), 2.06 (s, 9H), 1.8-1.0 (m, 33H). ESI-TOF m/z: 1408.7366 [M+Na]+.
  • 61
  • [ 474645-27-7 ]
  • C21H40N2O9 [ No CAS ]
  • C60H105N7O15 [ No CAS ]
YieldReaction ConditionsOperation in experiment
52.6 mg With N-ethyl-N,N-diisopropylamine; diethyl dicarbonate; at 0 - 20℃; for 16h; DEPC (0.31 g, 0.181 mmole) and DIPEA (0.03 mL, 0.181 mmol) were added sequentially to a solution of compounds 21 (30 mg, 0.0646 mmol) and MMAE (35.5 mg, 0.0494 mmol) in DMF (2 mL) at 0° C., and the mixture was stirred at 0° C. to room temperature for 16 h. The reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 6-10percent MeOH in CH2Cl2) to afford the product as an oil 22 (52.6 mg, 0.0452 mmole); HRMS (ESI-TOF, MNa+) calculated for C21H40N2O9Na 1186.7561. found 1186.7567.
  • 62
  • [ 474645-27-7 ]
  • C38H52N6O14 [ No CAS ]
  • C71H114N10O18 [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 48h; The obtained compound 27 and alkynyl-PEG4-COOH 28 (58 mg, 0.2 mmol) were suspended in anhydrous CH2Cl2 (2.0 mL) followed by the addition of HOBt (2.7 mg, 0.02 mmol) and EDCI (57 mg, 0.3 mmol). After 12 hours the solvent was removed and purified by silica gel chromatography eluting with CH2Cl2 (100percent), then 10percent MeOH/CH2Cl2 to give 80.8 mg (62percent) of alkynyl-PEG4-Val-Cit-PAB-OH 29. Then compound 29 (80 mg, 0.12 mmol) was suspended in anhydrous DMF (2 mL), followed by the addition of pyridine (58 muL, 0.72 mmol) and 4-nitrobenzoyl chloride (66.8 mg, 0.36 mmol). After 2 hours the solvent was removed and purified by silica gel chromatography eluting with CH2Cl2 (100percent), then 5percent MeOH/CH2Cl2 to give 63.7 mg (65percent) of alkynyl-PEG4-Val-Cit-PAB-OpNP 30. Next, MMAE (33.4 mg, 0.047 mmol) was dissolved in a mixture of DMF (1.5 mL) and pyridine (0.5 mL) followed by the addition of DIPEA (72 muL), HOBt (2 mg, 0.014 mmol) and alkynyl-PEG4-Val-Cit-PAB-OpNP 30 (38 mg, 0.047 mmol). After 48 hours the solvent was removed and the reaction mixture was then purified by silica gel chromatography eluting with CH2Cl2 (100percent), then 15percent MeOH/CH2Cl to give 30 mg (45percent) of alkynyl-PEG4-Val-Cit-PAB-MMAE 31. 1H NMR (400 MHz, MeOD) delta 7.48 (d, J=7.88 Hz, 2H), 7.3-7.05 (m, 7H), 5.14-4.9 (m, 2H), 4.6-4.37 (m, 3H), 4.19 (dd, J=2.76 Hz, 7.12 Hz, 1H), 4.15-4.09 (m, 2H), 4.07 (d, J=2.36 Hz, 2H), 3.78 (s, 2H), 3.64-3.57 (m, 5H), 3.56-3.53 (m, 8H), 3.51 (s, 4H), 3.3 (t, J=10.8 Hz, 1H), 2.45 (d, J=3.32 Hz, 1H), 3.17 (s, 1H), 3.15-2.95 (m, 3H), 2.85-2.8 (m, 3H), 2.75 (t, J=2.36 Hz, 1H), 2.45-2.35 (m, 2H), 2.15-1.57 (m, 11H), 1.45 (m, 4H), 1.35-1.13 (m, 9H), 1.07 (q, 3H), 1.03 (t, J=7.08 Hz, 3H), 1.0-0.55 (m, 25H). ESI-TOF m/z: 1417.8368 [M+Na]+.
  • 63
  • [ 474645-27-7 ]
  • C15H25NO7 [ No CAS ]
  • C54H90N6O13 [ No CAS ]
YieldReaction ConditionsOperation in experiment
25.9 mg With N-ethyl-N,N-diisopropylamine; diethyl dicarbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; DEPC (0.014 g, 0.0863 mmole) and DIPEA (0.021 mL, 0.127 mmol) were added sequentially to a solution of compounds 34 (24.5 mg, 0.0739 mmol) and MMAE (30 mg, 0.0418 mmol) in DMF (2.75 mL) at 0° C., and the mixture was stirred at 0° C. to room temperature for 16 h. The reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 4-7percent MeOH in CH2Cl2) to afford the product as an oil 35 (25.9 mg, 0.0251 mmole); HRMS (ESI-TOF, MNa+) calculated for C54H90N6O13Na 1053.6458. found 1053.6604.
  • 64
  • [ 474645-27-7 ]
  • [ 1429934-37-1 ]
  • C52H87N5O13 [ No CAS ]
YieldReaction ConditionsOperation in experiment
49.2 mg With N-ethyl-N,N-diisopropylamine; diethyl dicarbonate; at 0 - 20℃; for 16h; DEPC (0.0334 g, 0.206 mmole) and DIPEA (0.034 mL, 0.206 mmol) were added sequentially to a solution of compounds 37 (38.8 mg, 0.1337 mmol) and MMAE (51 mg, 0.071 mmol) in DMF (4 mL) at 0° C., and the mixture was stirred at 0° C. to room temperature for 16 h. The reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 4-6percent MeOH in CH2Cl2) to afford the product as an oil 38 (49.2 mg, 0.0497 mmole); HRMS (ESI-TOF, MNa+) calculated for C52H87N5O13Na 1012.6193. found 1012.6186.
  • 65
  • [ 474645-27-7 ]
  • C59H66N4O22 [ No CAS ]
  • C92H128N8O26 [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 48h; 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OH-PAB-PEG4-DBCO 41 (50 mg, 0.049 mmol) was suspended in anhydrous CH2Cl2 (1 mL), followed by the addition of pyridine (40 muL, 0.49 mmol) and 4-nitrobenzoyl chloride (41.4 mg, 0.197 mmol). After 2 hours the solvent was removed and purified by silica gel chromatography eluting with 20percent EA/hexane, then 60percent EA/hexane to give 36.3 mg (62.2percent) of 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OpNP-PAB-PEG4-DBCO 42. Then MMAE (25.3 mg, 0.035 mmol) was dissolved in a mixture of THF (1.6 mL) and pyridine (0.4 mL) followed by the addition of DIPEA (48 muL), HOBt (2 mg, 0.014 mmol) and 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OpNP-PAB-PEG4-DBCO 42 (36 mg, 0.03 mmol). After 48 hours the solvent was removed and the reaction mixture was then purified by silica gel chromatography eluting with CH2Cl2 (100percent), then 5percent MeOH/CH2Cl2 to give 29 mg (55percent) of 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-MMAE-PAB-PEG4-DBCO 43. 1H NMR (400 MHz, CDCl3) delta 8.8 (m, 1H), 7.7-7.18 (m, 14H), 7.17-6.87 (m, 1H), 6.66-6.3 (m, 2H), 5.5-5.2 (m, 4H), 5.5-4.88 (m, 2H), 4.87-4.59 (m, 2H), 4.35-3.95 (m, 6H), 3.85 (d, J=9.2 Hz, 1H), 3.79-3.68 (m, 7H), 3.68-3.47 (m, 16H), 3.44 (t, J=5.16 Hz, 2H), 3.37 (s, 3H), 3.36-3.3 (m, 2H), 3.27 (s, 3H), 2.98 (s, 2H), 2.88 (s, 2H), 2.67-2.02 (m, 18H), 2.01 (s, 9H), 1.92 (bs, 2H), 1.81 (bs, 2H), 1.77-1.59 (m, 3H), 1.5-1.15 (m, 11H), 1.14-0.76 (m, 20H), 0.65 (d, J=3.34 Hz, 1H). ESI-TOF m/z: 1784.8878 [M+Na]+.
  • 66
  • [ 474645-27-7 ]
  • C50H62N4O22 [ No CAS ]
  • C83H124N8O26 [ No CAS ]
YieldReaction ConditionsOperation in experiment
34.4% With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 48h; 2,3,4-tri-Ac-6-methyl-Glucuranate-2-OH-PAB-succinate-PEG4-BCN 47 (100 mg, 0.11 mmol) was suspended in anhydrous CH2Cl2 (3.24 mL), followed by the addition of pyridine (89.6 muL, 1.1 mmol) and 4-nitrobenzoyl chloride (92.7 mg, 0.45 mmol). After 2 hours the solvent was removed and purified by silica gel chromatography eluting with CH2Cl2 (100percent), then 5percent MeOH/CH2Cl2 to give 82.3 mg (69.8percent) of 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OpNP-PAB-succinate-PEG4-BCN 48. Then, MMAE (63.3 mg, 0.088 mmol) was dissolved in a mixture of THF (4.0 mL) and pyridine (1.0 mL) followed by the addition of DIPEA (120 muL), HOBt (3 mg, 0.021 mmol) and 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OpNP-PAB-succinate-PEG4-BCN 48 (82.3 mg, 0.0768 mmol). After 48 hours the solvent was removed and the reaction mixture was then purified by silica gel chromatography eluting with CH2Cl2 (100percent), then 7.5percent MeOH/CH2Cl2 to give 50 mg (34.4percent) of 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-MMAE-PAB-succinate-PEG4-BCN 49. 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-MMAE-PAB-succinate-PEG4-BCN 49 (50 mg, 0.03 mmol) was dissolved MeOH (1.2 mL), then Na2CO3 (10 mg, 0.095 mmol) was added. After 1 hour, H2O (60 muL) was added to the reaction mixture and the reaction was kept stirring for another 1 hour. Then the reaction was neutralized by IR-120, after filtered, the crude was evaporated and purified by C18 column eluting with 100percent H2O, then 35percent acetonitrile/H2O to give 14.2 mg (31.4percent) of Glucuranate-2?-MMAE-PAB-succinate-PEG4-BCN 50
  • 67
  • [ 474645-27-7 ]
  • C15H29NO9 [ No CAS ]
  • C54H94N6O15 [ No CAS ]
YieldReaction ConditionsOperation in experiment
48.6 mg With N-ethyl-N,N-diisopropylamine; diethyl dicarbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; DEPC (30.6 mg, 0.189 mmole) and DIPEA (0.030 mL, 0.182 mmol) were added sequentially to a solution of compounds 52 (44.8 mg, 0.1219 mmol) and MMAE (46.5 mg, 0.065 mmol) in DMF (2.7 mL) at 0° C., and the mixture was stirred at 0° C. to room temperature for 16 h. The reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 3-6percent MeOH in CH2Cl2) to afford the product as an oil 53 (48.6 mg, 0.0455 mmole); HRMS (ESI-TOF, MNa+) calculated for C54H94N6O15Na 1089.6669. found 1089.6660.
  • 68
  • [ 870487-10-8 ]
  • [ 474645-27-7 ]
  • C63H102N10O14 [ No CAS ]
YieldReaction ConditionsOperation in experiment
59% General procedure: One batch of reaction was carried out as following: a solution of compound 4 (1.2 g, 1.68 mmol) in DMF (10 mL) was added DIEA (1.22 mL, 6.98 mmol,) under nitrogen atmosphere, the solution was stirred at 0 °C for 10 mm, then HOBt (226 mg, 1.68 mmol) and MMAE (1.00 g, 1.40 mmol) were added thereto, the mixture was degassed and purged with N2 for 3 times, which was stirred at 35 °Cfor 16 hr. LC-MS (ES8396-1-P1A1, product: RI = 1.19 mm) showed compound 4 was consumed completely and one main peak with desired mass was detected. The resulting reaction mixture of five batches was combined in 1 L of beaker and 500 mL water was added, then a precipitate was formed and filtered to collect. The precipitate was triturated with EtOAc overnight. Compound 5 (5 g, 59percent yield) was obtained as a white solid.
45% With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 48h; Boc-Val-Cit-PAB-OH 26 (100 mg, 0.2 mmol) was suspended in a mixture of anhydrous DMF (1 mL), THF (2 mL) and CH2Cl2 (1 mL), followed by the addition of pyridine (97 muL, 1.2 mmol) and 4-nitrobenzoyl chloride (115 mg, 0.62 mmol). After 2 hours the solvent was removed and purified by silica gel chromatography eluting with CH2Cl2 (100percent), then 5percent MeOH/CH2Cl2 to give 89 mg (69percent) of Boc-Val-Cit-PAB-OpNP 55. Then, MMAE (88.6 mg, 0.123 mmol) was dissolved in a mixture of THF (2.8 mL) and pyridine (0.7 mL) followed by the addition of DIPEA (212 muL), HOBt (5.6 mg, 0.039 mmol) and Boc-Val-Cit-PAB-OpNP 55 (89 mg, 0.138 mmol). After 48 hours the solvent was removed and the reaction mixture was then purified by silica gel chromatography eluting with CH2Cl2 (100percent/o), then 15percent MeOH/CH2Cl2 to give 30 mg (45percent) of Boc-Val-Cit-PAB-MMAE 56. . 1H NMR (400 MHz, CDCl3) delta 7.49 (t, J=7.2 Hz, 2H), 7.29-7.08 (m, 11H), 5.13-4.94 (m, 2H), 4.69-4.4 (m, 5H), 4.2-4.05 (m, 4H), 4.97 (bs, 1H), 3.81 (dd, J=2.5 Hz, 6.56 Hz, 1H), 3.77 (dt, J=9.2 Hz, 1.8 Hz, 1H), 3.63-3.55 (m, 2H), 3.44 (m, 1H), 3.35-3.15 (m, 20H), 3.14-3.04 (m, 2H), 3.5-2.95 (m, 3H), 2.9-2.75 (m, 4H), 2.41-2.34 (m, 3H), 2.45 (s, 1H), 2.21 (s, 1H), 2.16-1.55 (m, 16H), 1.54-1.39 (m, 4H), 1.34 (s, 9H), 1.3 (bs, 2H), 1.11-0.95 (m, 11H), 0.9-0.6 (m, 42H).
40.63% A mixture of Compound 4 (1.10 g, 1.71 mmol, 1.00 eq) and DffiA (2.21 g, 17.06 mmol, 2.98 mL, 10.00 eq) in DMF (10.00 mL) was stirred under nitrogen at 0 °C for 30 mins. MMAE (900.00 mg, 1.25 mmol, 0.73 eq) and HOBt (230.56 mg, 1.71 mmol, 1.00 eq) was added to the mixture and the resulting reaction mixture was stirred under nitrogen at 0 °C for 10 min and at 30 °C for additional 18 hr. LC-MS showed Compound 4 was consumed completely and one main peak with desired MS was detected. The reaction mixture was purified by flash CI 8 gel chromatography (ISCO®; 120 g SepaFlash® CI 8 Flash Column, Eluent of 0-50percent MeCN/H20 85 mL/min). Compound 5 (850.00 mg, 694.71 umol, 40.63percent yield) was obtained as a white solid.
  • 69
  • [ 474645-27-7 ]
  • C40H50N4O21 [ No CAS ]
  • C73H112N8O25 [ No CAS ]
YieldReaction ConditionsOperation in experiment
57.4% With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 48h; Azido-diethylene glycol hydroxylamie-Boc 73 (168.5 mg, 0.684 mmol) was dissolved in a mixture of methanol (0.68 mL) and EA (6.2 mL) then the solution was degassed by N2(g). Pd(OH)2 (59 mg) was added and purged with H2(g) for 5 min, then the reaction was reacted for 2 hours under the same condition. After completion, the crude was filtered through a pad of celite then concentrated to dryness to give 145 mg (96.2percent) of amino-diethylene glycol hydroxylamie-Boc 74 without further purification. Then, 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OTBS-PAB-succinic acid 3 (322.6 mg, 0.482 mmol) and the above compound 74 (127.3 mg, 0.578 mmol) was dissolved in CH2Cl2 (5 mL) followed by the addition of EDCI (138.5 mg, 0.723 mmol), HOBt (74 mg, 0.48 mmol). After 8 hours, the solvent was removed and the reaction mixture was then purified by silica gel chromatography eluting with 15percent EA/hexane, then 60percent EA/hexane to give 312.2 mg (74percent) of 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OTBS-PAB-succinate-PEG2-hydroxylamie-Boc 75. The obtained compound 75 was dissolved in a mixture of pyridine (2.7 mL) and acetic acid (1.8 mL) followed by the addition of TBAF (0.3 mL, 1 M in THF). After 12 hours, the solvent was removed and the reaction mixture was then purified by silica gel chromatography eluting with CH2Cl2 (100percent), then 5percent MeOH/CH2Cl2 to give 218.1 mg (80.4percent) of 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OH-PAB-succinate-PEG2-hydroxylamie-Boc 76. 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OH-PAB-succinate-PEG2-hydroxylamie-Boc 76 (218.1 mg, 0.288 mmol) was suspended in anhydrous CH2Cl2 (5.5 mL), followed by the addition of pyridine (240 muL, 2.95 mmol) and 4-nitrobenzoyl chloride (260 mg, 1.26 mmol). After 2 hours the solvent was removed and purified by silica gel chromatography eluting with CH2Cl2 (100percent), then 5percent MeOH/CH2Cl2 to give 155.6 mg (58.7percent) of 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OpNP-PAB-succinate-PEG2-hydroxylamie-Boc 77. Then, MMAE (108.3 mg, 0.15 mmol) was dissolved in a mixture of THF (3.45 mL) and pyridine (0.86 mL) followed by the addition of DIPEA (260 muL), HOBt (6.9 mg, 0.048 mmol) and 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OpNP-PAB-succinate-PEG2-hydroxylamie-Boc 77 (155.6 mg, 0.169 mmol). After 48 hours the solvent was removed and the reaction mixture was then purified by silica gel chromatography eluting with CH2Cl2 (100percent), then 7.5percent MeOH/CH2Cl2 to give 145.7 mg (57.4percent) of 2,3,4-tri-Ac-6-methyl-Glucuranate-2?-MMAE-PAB-succinate-PEG2-hydroxylamie-Boc 78. 1H NMR (400 MHz, CDCl3) delta 9.22 (s, 1H), 8.2-7.95 (m, 2H), 7.6-6.5 (m, 12H), 5.4-5.15 (m, 5H), 5.15-4.92 (m, 3H), 4.85 (d, J=2.48 Hz, 1H), 4.82-4.5 (m, 3H), 4.49-3.98 (m, 7H), 3.95-3.17 (m, 27H), 3.14-2.46 (m, 13H), 2.45-1.45 (m, 24H), 1.39 (s, 9H), 1.17 (d, J=7.2 Hz, 1H), 1.05-0.45 (m, 30H).
  • 70
  • [ 474645-27-7 ]
  • C64H69N5O34 [ No CAS ]
  • C130H193N13O42 [ No CAS ]
YieldReaction ConditionsOperation in experiment
51.6% With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 48h; Di-(2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OH-PAB)-glutamic-N-Boc 102 (160 mg, 0.143 mmol) was suspended in anhydrous CH2Cl2 (2.5 mL), followed by the addition of pyridine (200 muL, 2.86 mmol) and 4-nitrobenzoyl chloride (230 mg, 1.14 mmol). After 2 hours the solvent was removed and purified by silica gel chromatography eluting with CH2Cl2 (100percent), then 4percent MeOH/CH2Cl2 to give 131.4 mg (63percent) of Di-(2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OpNP-PAB)-glutamic-N-Boc 103. Then, MMAE (162 mg, 0.225 mmol) was dissolved in a mixture of THF (4.0 mL) and pyridine (1.0 mL) followed by the addition of DIPEA (280 muL), HOBt (6.0 mg, 0.042 mmol) and Di-(2,3,4-tri-Ac-6-methyl-Glucuranate-2?-OpNP-PAB)-glutamic-N-Boc 103 (131 mg, 0.09 mmol). After 48 hours the solvent was removed and the reaction mixture was then purified by silica gel chromatography eluting with CH2Cl2 (100percent), then 9percent MeOH/CH2Cl2 to give 119.3 mg (51.6percent) of Di-(2,3,4-tri-Ac-6-methyl-Glucuranate-2?-MMAE-PAB)-glutamic-N-Boc 104. 1H NMR (400 MHz, CDCl3) delta 9.5-8.8 (m, 2H), 8.2-6.3 (m, 22H), 5.4-5.28 (m, 8H), 5.16-4.49 (m, 12H), 4.48-3.88 (m, 15H), 3.7 (d, J=2.87 Hz, 2H), 3.74-3.6 (m, 8H), 3.45 (s, 2H), 3.4-3.15 (m, 17H), 3.09 (s, 1H), 3.02-2.88 (m, 6H), 2.88-2.74 (m, 6H), 2.73-2.52 (m, 4H), 2.5-2.24 (m, 8H), 2.24-1.85 (m, 38H), 1.84-1.45 (m, 8H), 1.45-1.23 (m, 12H), 1.2-1.05 (m, 10H), 1.03-0.4 (m, 60H).
  • 71
  • [ 474645-27-7 ]
  • C40H48N6O22 [ No CAS ]
  • C73H110N10O26 [ No CAS ]
YieldReaction ConditionsOperation in experiment
79 mg With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72h; To a Dimethylformamide (7 mL) solution of compound 116 (100 mg, 0.107 mmole), MMAE (69 mg, 0.096 mmole), DIPEA (0.173 mL, 0.995 mmole), HOBT (12 mg, 0.092 mmole), and pyridine (2.5 mL) was stirred. After stirring for 72 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography (silica gel, 7percent MeOH in CH2Cl2) to afford the product as a solid 118 (79 mg, 0.051 mmole); HRMS (ESI-TOF, MNa+) calculated for C73H110N10O26Na 1565.7485. found 1565.7471.
  • 72
  • [ 474645-27-7 ]
  • C39H49N5O22S [ No CAS ]
  • C72H111N9O26S [ No CAS ]
YieldReaction ConditionsOperation in experiment
50 mg With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 48h; To a Dichloromethane (20 mL) solution of 123 (0.2 g, 0.25 mmole), 4-Nitrophenylchloroformate (151 mg, 0.75 mmole), and pyridine (0.103 mL, 1.25 mmole) was stirred. After stirring for 12 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography to afford the product as a solid (220 mg, 0.206 mmole). To a Dimethylformamide (6 mL) solution of compound (100 mg, 0.103 mmole) obtained above, MMAE (81.3 mg, 0.1133 mmole), DIPEA (66.6 mg, 0.515 mmole), HOBT (15.3 mg, 0.1133 mmole), and pyridine (81.5 mg, 1.03 mmole) was stirred. After stirring for 48 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography to afford the product as a solid 124 (50 mg, 0.032 mmole); HRMS (ESI-TOF, MNa+) calculated for C72H111N9O26SNa 1572.7253. found 1572.7324. To a Methyl alcohol (2 mL) solution of compound 124 (50 mg, 0.032 mmole), K2CO3 (25 mg, 0.182 mmole), and H2O (0.3 mL) was stirred. After stirring for 6 hr at room temperature, the solution was quenched with AcOH and then concentrated. The residue was purified by C18 column to afford the product as a solid. And then, TFA (0.35 mL) was slowly added into a solution of compound (44 mg, 0.0333 mmol) obtained above in DCM (0.65 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 h, and concentrated. Purification of the crude material using C18 column to afforded the product 125 as an oil.
  • 73
  • [ 474645-27-7 ]
  • C38H45N5O21 [ No CAS ]
  • C71H107N9O25 [ No CAS ]
YieldReaction ConditionsOperation in experiment
81 mg With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72h; To a Dimethylformamide (8 mL) solution of compound 128 (6 mg, 0.128 mmole), MMAE (83 mg, 0.116 mmole), DIPEA (0.203 mL, 1.167 mmole), HOBT (18 mg, 0.131 mmole), and pyridine (0.8 mL) was stirred. After stirring for 72 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography (silica gel, 8percent MeOH in CH2Cl2) to afford the product as a solid 129 (81 mg, 0.054 mmole); HRMS (ESI-TOF, MNa+) calculated for C71H107N9O25Na 1508.7270. found 1508.7298.
  • 74
  • [ 474645-27-7 ]
  • [ 1422540-81-5 ]
  • C51H85N5O13 [ No CAS ]
YieldReaction ConditionsOperation in experiment
47 mg With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; diethyl dicarbonate; In N,N-dimethyl-formamide; at 20℃; for 72h; To a Dichloromethane (5.00 mL) solution of compound 24 (46.4 mg, 0.150 mmole), 4-Nitrophenylchloroformate (150 mg, 0.744 mmole), and pyridine (0.12 mL, 1.497 mmole) was stirred. After stirring for 2 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography (silica gel, 35percent Ethyl acetate in Hexane) to afford the product as a solid (53 mg, 0.112 mmole); 1H NMR (400 MHz, CDCl3) 8.28-8.24 (m, 2H), 7.39-7.35 (m, 2H), 4.43-4.41 (m, 2H), 4.18 (d, J=2.4 Hz, 2H), 3.80-3.78 (m, 2H), 3.67-3.64 (m, 12H), 2.40 (t, J=2.4 Hz, 1H). To a Dimethylformamide (7.5 mL) solution of compound (28 mg, 0.0705 mmole) obtained above, MMAE (50 mg, 0.0696 mmole), DIPEA (0.110 mL, 0.631 mmole), HOBT (9.5 mg, 0.0703 mmole), and pyridine (2.0 mL) was stirred. After stirring for 72 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography (silica gel, 4percent MeOH in CH2Cl2) to afford the product as a solid 60 (47 mg, 0.0481 mmole); HRMS (ESI-TOF, MNa+) calculated for C51H85N5O13Na 998.6036. found 998.6051.
  • 75
  • [ 474645-27-7 ]
  • C42H55N3O23 [ No CAS ]
  • C75H117N7O27 [ No CAS ]
YieldReaction ConditionsOperation in experiment
70 mg With triethylamine; In tetrahydrofuran; at 20℃; for 48h; Compound 62 (220.0 mg, 0.27 mmol) was dissolved in 8 mL of CH2Cl2 and cooled to 0° C. Pyridine (0.20 mL) and PNP Chloroformate were added and the mixture was stirred in rt for 3 h. The solution was evaporated. The crude product was purified by column to give compound (80.0 mg, 0.082 mmol) for next step. A solution of compound from last step (80.0 mg, 0.082 mmol) and MMAE (60.0 mg, 0.082 mmol) in 5 mL of THF was treated with TEA (0.1 mL). The resulting mixture was stirred at rt for 48 h. After the reaction was completed, 35 mL of EA and 20 mL of 0.5N HCl solution were added. The organic layer extraction was dried by MgSO4 and concentrated. The crude product was purified by column to give compound 63 as yellow oil (70.0 mg, 0.05 mmol). ESI-TOF m/z: 1570.7932 [M+Na+].
  • 76
  • [ 474645-27-7 ]
  • C52H74N4O27 [ No CAS ]
  • C85H136N8O31 [ No CAS ]
YieldReaction ConditionsOperation in experiment
40 mg With pyridine; triethylamine; In dichloromethane; at 20℃; for 48h; Compound 66 (176.0 mg, 0.17 mmol) was dissolved in 5 mL of CH2Cl2 and cooled to 0° C. Pyridine (27 uL) and PNP Chloroformate (52 mg, 0.26 mmol) were added and the mixture was stirred in rt for 3 h. The resulting mixture was diluted with CH2Cl2 and washed with 1 N HCl, saturated aqueous NaHCO3 and brine. The organic layer extraction was dried by MgSO4 and concentrated. The crude product was purified by column to give compound for next step. A solution of compound from last step (128.0 mg, 0.108 mmol) and MMAE (78.0 mg, 0.108 mmol) in 4 mL of DMF was treated with TEA (100 uL) and pyridine (87 uL). The resulting mixture was stirred at rt for 48 h. The solution was evaporated. The crude product was purified by column to give compound 67 as yellow oil (40.0 mg, 0.02 mmol). ESI-TOF m/z: 1787.9224 [M+Na+].
  • 77
  • [ 474645-27-7 ]
  • C40H51N3O19 [ No CAS ]
  • C73H113N7O23 [ No CAS ]
YieldReaction ConditionsOperation in experiment
95 mg With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 48h; To a Dichloromethane (10 mL) solution of compound 84 (180 mg, 0.253 mmole), 4-Nitrophenylchloroformate (76 mg, 0.379 mmole), and pyridine (0.04 mL, 0.506 mmole) was stirred for 12 hr at room temperature. The solution was concentrated and the residue was purified by flash column chromatography to get the product as a solid (162 mg, 0.185 mmole) for next step. To a Dimethylformamide (6 mL) solution of compound (70.8 mg, 0.080 mmole) obtained above, MMAE (146 mg, 0.203 mmole), DIPEA (0.185 mL, 0.925 mmole), HOBT (9.65 mg, 0.0714 mmole), and pyridine (0.146 mL) was stirred. After stirring for 48 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography to afford the product as a solid 85 (95 mg, 0.065 mmole); HRMS (ESI-TOF, MNa+) calculated for C73H113N7O23Na 1478.7780. found 1478.7828.
  • 78
  • [ 474645-27-7 ]
  • C38H47N3O21 [ No CAS ]
  • C71H109N7O25 [ No CAS ]
YieldReaction ConditionsOperation in experiment
75 mg With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; To a solution of compound 88 (0.4676 g, 0.562 mmole), TBAF (0.56 mL, 0.56 mmole), AcOH (3.4 mL), and pyridine (5.5 mL) was stirred. After stirring for 12 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography (silica gel, Ethyl acetate) to afford the product as a solid (0.36 g, 0.5 mmole); 1H NMR (400 MHz, CDCl3) 8.81 (s, 1H), 7.95 (s, 1H), 7.82-7.79 (m, 1H), 7.33 (d, J=2.8 Hz, 11H), 6.95 (d, J=8.8 Hz, 1H), 5.35-5.23 (m, 3H), 5.03 (d, J=7.2 Hz, 1H), 4.74 (d, J=13.2 Hz, 1H), 4.41 (d, J=12.8 Hz, 1H), 4.11-4.02 (m, 7H), 3.77-3.68 (m, 8H), 2.07 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.41 (s, 9H). To a Dichloromethane (9 mL) solution of compound (90 mg, 0.126 mmole) obtained above, 4-Nitrophenylchloroformate (100 mg, 0.495 mmole), and pyridine (0.11 mL, 1.423 mmole) was stirred. After stirring for 2 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography (silica gel, 35percent Ethyl acetate in Hexane) to afford the product as a solid (70.8 mg, 0.080 mmole). To a Dimethylformamide (6 mL) solution of compound (70.8 mg, 0.080 mmole) obtained above, MMAE (58 mg, 0.08 mmole), DIPEA (0.125 mL, 0.7175 mmole), HOBT (9.65 mg, 0.0714 mmole), and pyridine (2.0 mL) was stirred. After stirring for 72 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography (silica gel, 4percent MeOH in CH2Cl2) to afford the product as a solid 89 (75 mg, 0.051 mmole); HRMS (ESI-TOF, MNa+) calculated for C71H109N7O25 Na 1482.7365. found 1482.7334.
  • 79
  • [ 474645-27-7 ]
  • C50H70N2O28 [ No CAS ]
  • C83H133N7O31 [ No CAS ]
YieldReaction ConditionsOperation in experiment
80 mg With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 72h; EDCI (0.18 g, 1.16 mmole) and HOBT (0.114 g, 0.843 mmol) were added sequentially to a solution of compounds 92 (0.46 g, 0.846 mmol) and compound I (0.683 g, 1.2 mmol) in Dichloromethane (0.51 mL), and the mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 5percent MeOH in CH2Cl2) to afford the product as an oil (0.51 g, 0.465 mmole); 1H NMR (400 MHz, CDCl3) 8.67 (s, 1H), 7.70 (s, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.48 (dd, J=2.0, 8.8 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 5.30-5.25 (m, 3H), 5.04 (d, J=6.8 Hz, 1H), 4.70 (d, J=15.2 Hz, 1H), 4.59 (d, J=15.2 Hz, 1H), 4.13-4.08 (m, 3H), 3.99-3.97 (m, 2H), 3.73-3.55 (m, 33H), 2.03 (s, 3H), 2.01 (s, 3H), 2.01 (s, 3H), 1.44 (s, 9H), 0.92 (s, 9H), 0.08 (s, 6H). To a solution of compound (0.51 g, 0.465 mmole) obtained above, TBAF (0.49 mL, 0.49 mmole), AcOH (3 mL), and pyridine (5 mL) was stirred. After stirring for 12 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography (silica gel, 5percent MeOH in CH2Cl2) to afford the product as a solid (0.49 g, 0.499 mmole); 1H NMR (400 MHz, CDCl3) 8.91 (s, 1H), 7.81 (s, 1H), 7.48 (dd, J=2.4, 8.8 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 5.32-5.23 (m, 3H), 5.05 (d, J=7.6 Hz, 1H), 4.69 (d, J=13.2 Hz, 1H), 4.43 (d, J=13.2 Hz, 1H), 4.10-4.07 (m, 3H), 3.98-3.96 (m, 2H), 3.72-3.56 (m, 33H), 3.44 (s, 1H), 2.07 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.43 (s, 9H). To a Dichloromethane (24 mL) solution of compound (122.5 mg, 0.125 mmole) obtained above, 4-Nitrophenylchloroformate (100 mg, 0.495 mmole), and pyridine (0.11 mL, 1.423 mmole) was stirred. After stirring for 2 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography (silica gel, 35percent Ethyl acetate in Hexane) to afford the product as a solid (59 mg, 0.051 mmole); 1H NMR (400 MHz, CDCl3) 8.90 (s, 1H), 8.26-8.23 (m, 2H), 7.74 (s, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.60 (dd, J=2.4, 9.2 Hz, 1H), 7.41-7.38 (m, 2H), 7.04 (d, J=9.2 Hz, 1H), 5.32-5.26 (nm, 4H), 5.19-5.10 (m, 2H), 4.16 (d, J=9.2 Hz, 1H), 4.08 (s, 2H), 3.99-3.96 (m, 2H), 3.73-3.56 (m, 33H), 2.04 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.43 (s, 9H). To a Dimethylformamide (6 mL) solution of compound (90 mg, 0.0785 mmole) obtained above, MMAE (60 mg, 0.084 mmole), DIPEA (0.14 mL, 0.8037 mmole), HOBT (22 mg, 0.163 mmole), and pyridine (2.0 mL) was stirred. After stirring for 72 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography (silica gel, 3percent MeOH in CH2Cl2) to afford the product as a solid 93 (80 mg, 0.046 mmole); HRMS (ESI-TOF, M2Na+) calculated for C83H133N7O31 Na2 884.9415. found 884.9360.
  • 80
  • [ 474645-27-7 ]
  • C34H39N3O19 [ No CAS ]
  • C67H101N7O23 [ No CAS ]
YieldReaction ConditionsOperation in experiment
85 mg With pyridine; triethylamine; at 20℃; for 48h; Compound 97 (275.0 mg, 0.27 mmol) was dissolved in 8 mL of CH2Cl2 and cooled to 0° C. Pyridine (0.50 mL) and PNP Chloroformate (176.0 mg, 0.87 mmol) were added and the mixture was stirred in rt for 3 h. The solution was evaporated. The crude product was purified by column to give compound (120.0 mg, 0.15 mmol) for next step. A solution of compound from last step (120.0 mg, 0.15 mmol) and MMAE (120.0 mg, 0.16 mmol) in 5 mL of THF was treated with TEA (0.5 mL). The resulting mixture was stirred at rt for 48 h. After the reaction was completed, 50 mL of EA and 30 mL of 0.5 N HCl were added. The organic layer extraction was dried by MgSO4 and concentrated. The crude product was purified by column to give compound 98 as yellow oil (85.0 mg, 0.062 mmol). ESI-TOF m/z: 1587.8759 [M-H]?.
  • 81
  • [ 474645-27-7 ]
  • C39H48N4O20S [ No CAS ]
  • C72H110N8O24S [ No CAS ]
YieldReaction ConditionsOperation in experiment
52 mg With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72h; To a solution of compound 112 (0.39 g, 0.447 mmole), TBAF (0.5 mL, 0.5 mmole), AcOH (3 mL), and pyridine (4.5 mL) was stirred. After stirring for 12 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography to afford the product as a solid (0.29 g, 0.382 mmole). To a Dichloromethane (20 mL) solution of compound (0.29 g, 0.382 mmole) obtained above, 4-Nitrophenylchloroformate (231 mg, 1.146 mmole), and pyridine (0.155 mL, 1.91 mmole) was stirred. After stirring for 12 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography to afford the product as a solid (110 mg, 0.12 mmole). To a Dimethylformamide (10 mL) solution of compound (110 mg, 0.12 mmole) obtained above, MMAE (94 mg, 0.131 mmole), DIPEA (0.104 mL, 0.595 mmole), HOBT (18 mg, 0.131 mmole), and pyridine (94 mg, 1.19 mmole) was stirred. After stirring for 72 hr at room temperature, the solution was concentrated and the residue was purified by flash column chromatography to afford the product as a solid 113 (52 mg, 0.035 mmole); HRMS (ESI-TOF, MNa+) calculated for C72H110N8O24SNa 1525.7246. found 1525.7189.
  • 82
  • [ 474645-27-7 ]
  • C44H58N4O23 [ No CAS ]
  • C77H120N8O27 [ No CAS ]
YieldReaction ConditionsOperation in experiment
98 mg With pyridine; triethylamine; In dichloromethane; at 20℃; for 48h; Compound 6 (100.0 mg, 0.12 mmol) was dissolved in 5 mL of CH2Cl2 and cooled to 0° C. TEA (24.0 mg, 0.24 mmol), DMAP (14.7 mg, 0.12 mmol), PNP Chloroformate (47.7 mg, 0.24 mmol) were added and the mixture was stirred in rt for 3 h. The resulting mixture was diluted with CH2Cl2 and washed with 1 N HCl, saturated aqueous NaHCO3 and brine. The organic layer extraction was dried by MgSO4 and concentrated. The crude product was purified by column to give compound A01-6 for next step. A solution of A01-6 (95.0 mg, 0.094 mmol) and MMAE (67.5 mg, 0.094 mmol) in 4 mL of THF was treated with TEA (19.0 mg, 0.188 mmol). The resulting mixture was stirred at RT for 48 h. After the reaction was completed, 35 mL of EA and 20 mL of 0.5N HCl solution were added. The organic layer extraction was dried by MgSO4 and concentrated. The crude product was purified by column to give compound 7 as yellow oil (98.0 mg, 0.06 mmol). ESI-TOF m/z: 1587.8759 [M-H]?.
  • 83
  • [ 474645-27-7 ]
  • [ 1341156-62-4 ]
  • C50H85N5O11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
10 mg With sodium cyanoborohydride; acetic acid; In dichloromethane; at 20℃; for 2h; To a solution of compound 24 (920 mg, 3.96 mmol) in 70 mL of dichloromethane was added Dess-Martin Periodinane (2.25 g, 5.30 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with the solution of sodium bisulfite in 60 mL of saturated sodium bicarbonate. The mixture was separated. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give compound (0.54 g, 2.345 mmole); 1H NMR (400 MHz, CDCl3) 9.69 (s, 1H), 4.16-4.13 (m, 2H), 3.71-3.62 (m, 14H), 2.40 (t, J=2.4 Hz, 1H). To a solution of MMAE (10 mg, 0.0139 mmol) in 0.286 mL of N,N-Dimethylformamide (DMF) was added compound obtained above (12.8 mg, 0.0556 mmol) and 16 muL of acetic acid, followed by addition of 2 mg of sodium cyanoborohydride. The resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated and purified by flash column chromatography to give compound 25 (10 mg, 0.0107 mmole); HRMS (ESI-TOF, MNa+) calculated for C50H85N5O11Na 954.6138. found 954.6303.
  • 84
  • [ 474645-27-7 ]
  • C24H31NO10 [ No CAS ]
  • C57H93N5O14 [ No CAS ]
  • 85
  • [ 474645-27-7 ]
  • [ 894095-98-8 ]
  • (3S,4S,6S)-6-[2-(3-aminopropanoylamino)-4-[[[(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]methylcarbamoyl]-2-methylpropyl]carbamoyl]-2-methylpropyl]methylcarbamoyl]oxymethyl]phenoxy]-3,4,5-trihydroxytetrahydropyran-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
64% Dissolve methyl (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-[2-[3-(9H-fluoren-9- ylmethoxycarbonylamino)propanoylamino]-4-[(4- nitrophenoxy)carbonyloxymethyl]phenoxy]tetrahydropyran-2-carboxylate (155mg, 0.17mmol) and (2S)-N-[(l S)-l-[[(l S,2R)-4-[(2S)-2-[(lR,2R)-3-[[(lR,2S)-2-hydroxy-l- methyl-2-phenyl-ethyl]amino]- 1 -methoxy-2-methyl-3-oxo-propyl]pyrrolidin- 1 -yl]-2- methoxy-l-[(l S)-l-methylpropyl]-4-oxo-butyl]-methyl-carbamoyl]-2-methyl-propyl]-3- methyl-2-(methylamino)butanamide (MMAE) (146 mg, 0.17 mmol) into DMF (2 mL) and add DIPEA (36 mu, 0.21 mmol) and HOBt (8 mg, 0.059 mmol) to the solution. Stir at room temperature overnight. Add MeOH (1 mL) and IN LiOH (1 mL). Concentrate and purify by HPLC (Column; Phenomenex Luna 5 muiotaeta CI 8 AXIA packed 30 x 75 mm column, Mobile phase; A: 0.1percent TFA in water, B: 0.1percent TFA in Acetonitrile, Monitored; 214 nm, Flow rate; 85 mL/min., Gradient; 10-38percent, Gradient time; 8 min.). Dry the collected fractions by lyophilizer to give the desired product, (3S,4S,6S)-6-[2-(3- aminopropanoylamino)-4-[[[(l S)-l-[[(l S)-l-[[(l S,2R)-4-[(2S)-2-[(lR,2R)-3-[[(lR,2S)-2- hydroxy- 1 -methyl -2-phenyl-ethyl]amino]-l -methoxy-2-methyl -3-oxo-propyl]pyrrolidin- l-yl]-2-methoxy-l-[(l S)-l-methylpropyl]-4-oxo-butyl]-methyl-carbamoyl]-2-methyl- propyl]carbamoyl]-2-methyl-propyl]-methyl-carbamoyl]oxymethyl]phenoxy]-3,4,5- trihydroxy-tetrahydropyran-2-carboxylic acid (NFb-P-Glucn-MMAE) (122 mg, Yield 64percent). MS m/z 1130 (M+H).
Same Skeleton Products
Historical Records

Similar Product of
[ 474645-27-7 ]

Chemical Structure| 2070009-72-0

A724771[ 2070009-72-0 ]

D8-mmae

Reason: Stable Isotope