Name: 25316-40-9|(8S,10S)-10-(((2R,4S,5S,6S)-4-Amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione hydrochloride|99+%
Brand: Ambeed
SKU: A130952
Rating: 90 (30 reviews)

1
[ 997-55-7 ]
[ 25316-40-9 ]
3'-N-[(N-acetyl)-β-aspartyl]-doxorubicin [ No CAS ]

Reference： [1]Synthetic Communications,2002,vol. 32,p. 1961 - 1975

2
[ 997-55-7 ]
[ 25316-40-9 ]
3'-N,14-bis[(N-acetyl)-β-aspartyl]-doxorubicin [ No CAS ]

Reference： [1]Synthetic Communications,2002,vol. 32,p. 1961 - 1975

3
[ 64987-85-5 ]
[ 25316-40-9 ]
[ 400647-59-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide; at 20℃;pH Ca. 8;Darkness;	To produce the maleimide-functionalized doxorubicin, SMCC was dissolved in DMF with the addition of triethylamine (TEA) to adjust the solution pH to approximately 8, measured roughly with pH paper. To this, 1.1 equivalents of doxorubicin HC1 was added. The mixture was allowed to mix in the dark overnight at room temperature before purification by HPLC using a gradient of 30-90% acetonitrile against 0.1% trifluoroacetic acid over 40 minutes. Retention time for unreacted doxorubicin was 13 minutes, unreacted SMCC was 23.5 minutes, and the product SMCC-Dox was 24.5 minutes.

Reference： [1]Synthetic Communications,2004,vol. 34,p. 2407 - 2414
[2]Biomacromolecules,2014,vol. 15,p. 715 - 725
[3]Journal of Controlled Release,2015,vol. 212,p. 94 - 102
[4]Patent: WO2019/183633,2019,A1 .Location in patent: Paragraph 00118

4
[ 55750-63-5 ]
[ 25316-40-9 ]
[ 932045-57-3 ]

Yield	Reaction Conditions	Operation in experiment
60%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.666667h;	The mixture of Doxorubicin (hydrochloride salt) (38.4 mg, 0.065 mmol), (2)(30 mg, 0.08 mmol), diisopropylethylamine (28 muL, 0.16 mmol) and DMF (1 mL) was prepared and stirred at room temperature (Figure 4B), while progress of the reaction was monitored by TLC (chloroform : methanol : ammonia = 85 : 15 : 2). After 40 min, the reaction was completed. The reaction mixture was diluted with dichloromethane (2 mL) and precipitated with hexanes (50 mL). The obtained solid was separated from solvents by centrifugation. The product was separated by column chromatography (SilicaGel 60, Merck) using chloroform, chloroform : methanol 98 : 2, 95 : 5 as eluents. Fractions containing WP936 were pooled together, evaporated to dryness, dissolved in chloroform (1 mL) and precipitated with hexanes (25 mL). The obtained solid was dried under vacuum to give 24 mg of WP936 (yield 60percent). The 1H NMR spectrum was obtained for WP936 and was in agreement with the proposed structure.[0108] 1H NMR (CDCl3, delta) ppm: 14.0, 13.25 (2s, IH ea, 6,11-OH), 8.04 (dd, IH, J =7.6 Hz, J = 0.7 Hz, H-I), 7.72 (dd, IH, J = J = 8.4 Hz, H-2), 7.4 (d, IH, J = 8.1 Hz, H-3), 6.67 (s, 2H, CH maleimid), 5.82 (d, IH, J = 8.6 Hz, NH), 5.50 (d, IH, J = 3.5 Hz, H-I '), 5.38 (bs, IH, H-7), 4.76 (s, 2H, 14-CH2), 4.56 (s, IH, 9-OH), 4.16 (q, IH, J = 6.1 Hz, H-5'), 4.08 (s, 3H, OMe), 3.63 (bs, IH, H-4), 3.49 (t, 2H, J = 7.1 Hz, CH2-linker), 3.28 (dd, IH, J = 18.8 <n="37"/>Hz, J = 1.8 Hz, H-IO), 3.24 (d, IH, J = 18.8 Hz, H-IO), 3.02 (m, IH, H-3'), 2.34 (d, IH, J = 14.7 Hz, H-8), 2.17 (dd, IH, J = 14.7 Hz, J = 4.1 Hz, H-8), 2.12 (dd, 2H, J = 7.2 Hz, J = 2.4 Hz, CH2 from linker), 1.83 (dd, IH, J = 12.7 Hz, J = 5.5 Hz, H-2'e), 1.78 (ddd, IH, J = J = 12.7 Hz, J = 4.1 Hz, H-2'a), 1.63 - 1.55 (m, 4H, CH2 from linker), 1.29 (d, 3H, J = 6.1 Hz, H-6'), 1,30 - 1.25 (m, 2H, CH2 from linker).[0109] Anal. Elem. For C37H40N2Oi4 x 2H2O Calc.C, 57.51; H, 5.74; N, 3.63, Found:C, 57.90; H, 5.42; N, 3.60

Reference： [1]Biochemical Pharmacology,2007,vol. 73,p. 620 - 631
[2]Patent: WO2007/90094,2007,A2 .Location in patent: Page/Page column 35; 4/9

5
[ 109425-49-2 ]
[ 25316-40-9 ]
[ 791111-74-5 ]

Yield	Reaction Conditions	Operation in experiment
45%	With N-ethyl-N,N-diisopropylamine; HATU; In dimethyl sulfoxide; at 20℃;	A solution of Fmoc-Val-Pro-OH and DOXORUBICIN. HCI (50 mg, 0,08 MMOL) in DMSO (4 mL), was successively treated at room temperature with N- [(DIMETHYLAMINO) 1 H-1, 2, 3-triazolo [4, 5-B] pyridino-1-ylmethylene]-N- methylmethanaminium HEXAFLUOROPHOSPHATE N-oxide (HATU) (36,0 mg, 0,09 MMOL) and diisopropylethylamine (DIEA) (29,5 AL, 0,17 MMOL). The reaction mixture was stirred at room temperature overnight. Then, the solvent was LYOPHILIZED and the residue was dissolved in ethyl acetate and washed with citric acid (10%), NaHCOs (10%) and brine. The organic layer was dried (NA2SO4) and evaporated to dryness to give F (45% yield).

Reference： [1]Patent: WO2004/98644,2004,A1 .Location in patent: Page/Page column 59-60
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 559 - 572

6
[ 25316-40-9 ]
[ 606967-53-7 ]

Yield	Reaction Conditions	Operation in experiment
75%		N-(-t-Butoxycarbonyl-L-alanyl-L-alanyl-L-asparaginyl-L-leucyl)doxorubicin (SEQ ID NO:7) was synthesized as follows. To cold (0 C.) solution of t-Butoxycarbonyl-L-alanyl-L-alanyl-L-asparaginyl-L-leucine (43 mg, 95 mumol) and 4-Methylmorpholine (20 muL, 200 mumol) in 5 mL DMF was added O-Benzotriazol-1-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) (54 mg, 142.5 mumol). After 10 min, <strong>[25316-40-9]doxorubicin hydrochloride</strong> (50 mg, 86 mumol) was added and the mixture was stirred for 2 h at room temperature in the dark. The solution was diluted with 30 mL of EtOAc and washed with water. The solvent was evaporated, and solids were dried over MgSO4 and purified over silica gel using CHCl3/MeOH (90/10) while protected from light to yield 65 mg of compound 1 (75% yield). 1H NMR (600 MHz, CD3OD, delta): 0.82 (d, 3H, J=6.1), 0.88 (d, 3H, J=6.6), 1.28-1.35 (m, 9H), 1.43 (s, 9H), 1.59-1.74 (m, 4H), 2.05 (m, 1H), 2.17 (m, 1H), 2.36 (d, 1H, J=14.5), 2.67 (m, 1H), 2.79 (m, 1H), 2.91 (d, 1H, J=18.0), 3.04 (d, 1H, J=18.0), 3.62 (m, 1H), 4.01-4.04 (m, 4H), 4.11 (m, 1H), 4.22-4.32 (m, 3H), 4.59 (dd, 1H, J=5.9, 7.2), 4.74 (d, 2H, J=4.4), 5.08 (s, 1H), 5.39 (d, 1H, J=3.1), 7.51 (d, 1H, J=8.8), 7.78 (dd, 1H, J=7.9, 7.9), 7.86 (d, 1H, J=7.5). Preparation HRMS (MALDI) calculated for C48H64N6O18 [M+Na]+ is 1035.4169, and found is 1035.4234. The compounds were purified by semi-preparative HPLC.

Reference： [1]Patent: US2006/135410,2006,A1 .Location in patent: Page/Page column 24

7
[ 25316-40-9 ]
[ 23214-92-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	With 4 A molecular sieves;Aqueous carbonate buffer;	The original syntheses of DoxF and its congeners, Daunoform and Epidoxoform (EpiF), were all performed by reaction of the respective clinical drug as its hydrochloride salt with formalin, an aqueous methanolic solution of formaldehyde, in acetate buffer at pH 6. The dimeric conjugates were extracted into chloroform as they were formed.Doxorubicin hydrochloride (40 mg, 69 mumol) formulated with lactose (clinical sample) was dissolved in 100 mL of saturated sodium carbonate/sodium bicarbonate buffer, pH 8.5. The aqueous solution was then extracted three times with 250 mL of chloroform. The chloroform extracts were combined, dried over sodium sulfate, filtered, and the chloroform was removed by rotary evaporation yielding doxorubicin as the free base. Doxorubicin free base (30 mg, 55 mumol) was dissolved in 17 mL of deuteriochloroform (3.7 mM) that had been dried over 4 A molecular sieves for at least 24 h, and the solution was degassed with argon. To this solution, 10 mg of paraformaldehyde (30% by weight of doxorubicin) was added and the solution was allowed to stir in the dark at ambient temperature (25 to 28 0C). Progress of the reaction was followed by 1H NMR and additional paraformaldehyde (10 mg) was added at 2 and 4 days if further progress was not observed. After 7 days, the reaction was complete as determined by observation of appearance of oxazolidine doublets at 4.31 ppm and 4.68 ppm and shift of the peak for the 5'- methyl from 1.36 ppm to 1.34 ppm. The reaction mixture was filtered to remove excess paraformaldehyde and solvent removed by rotary evaporation to dryness followed by evacuation (approx. 0.05 Torr) for 30 min to give 22 mg of Doxaz (40 mumol, 73% from doxorubicin free base) isolated as a red film. Product was characterized and analyzed for purity by 500 MHz fH NMR in chloroform-d (>90% pure). Positive ion electrospray mass spectrometry of a solution in THF showed a doubly-charged ion at m/z 278.8 ((M+2H+)/2, 100% rel. intensity, calc 278.8). HPLC shows a peak for Doxaz at 6.6 min (Doxorubicin elutes at 4.7 min); HPLC was not reliable for product purity because of some hydrolysis to Doxorubicin during elution.In contrast, reaction of Doxorubicin free-base in chloroform-d solvent with larger amounts of paraformaldehyde, the polymer of formaldehyde, with monitoring by 1H NMR, showed formation of Doxaz followed by formation of DoxF. Doxaz was isolated 90% pure (73% yield) by stopping the reaction at an intermediate time with the only impurities being traces of Doxorubicin and DoxF. Correspondingly, DoxF was isolated in greater than 90% purity (79% yield) by allowing the reaction to continue, again with the only impurity being Doxaz. The structure of Doxaz was established from an intense, doubly-charged molecular ion at m/z 278.8 in the electrospray mass spectrum and from the high resolution 1H NMR data with all of the J-couplings assigned in comparison with data for DoxF. Of particular note in the NMR spectrum of Doxaz is the absence of the singlet peak for the methylene connecting the two oxazolidine rings of DoxF and the characteristic small geminal coupling constant for the methylene protons of the oxazolidine.
	In water;pH 10;	DOX hydrochloride was neutralized by the following procedure.Briefly, 10 mg of DOX hydrochloride was dissolved in 2 ml of deionizedwater. Then the pH value was adjusted to about 10 to remove the hydrochloridesalt. The solution was extracted with dichloromethane.Then dichloromethanewas removed by rotary evaporator to yield DOX.
	With triethylamine; In dimethyl sulfoxide;	Preparation ofDOX-Loaded Micelles and Microemulsions Micelles: Doxorubicin-HCl ("DOX-HCl") is converted into the DOX base by incubation with triethylamine in dimethylsulfoxide ("DMSO"). DOX-loaded PEG2000-PLLA2000 copolymer micelles were produced using a solvent exchange technique. The joint solution in DMSO of copolymer and DOX base was dialyzed EPO <DP n="21"/>against PBS using a 2 kDa cut-off dialysis membrane (SpectraPor, Spectrum MedicalIndustries, CA, US). The amount of entrapped DOX was determined by HPLC. About 90-95% of the introduced DOX was encapsulated.Microemulsions: Aliquots of perfluoropentane FLUORINERT Fluid PFP- 5050 (3M, St. Paul, MN) were added to DOX-loaded PEG2000-PLLA2000 orPEG2000-PCL2000 micelles. The micelles were then exposed to 20 kHz ultrasound for 15 - 30 second (Sonics & Materials, Inc., Newton, CT) to prepare DOX-loaded microemulsions formed in micellar solutions of PEG/PLLA copolymers. PFP concentration in PEG-PLLA micellar solutions may be varied in the range of 0.1% to 5% (v/v) to obtain varying droplet sizes and microbubble sizes. This is necessary for optimizing the echogenic properties for various applications, for instance, syringe needle positioning, blood pool imaging, and acoustic activation of drug delivery.

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 10762 - 10769
[2]Patent: WO2007/102888,2007,A2 .Location in patent: Page/Page column 16
[3]Toxicology Letters,2008,vol. 178,p. 197 - 201
[4]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2579 - 2584
[5]European Journal of Pharmaceutical Sciences,2010,vol. 39,p. 152 - 163
[6]Pharmazie,2011,vol. 66,p. 496 - 505
[7]Molecular Pharmaceutics,2012,vol. 9,p. 2469 - 2478
[8]Chemical Communications,2013,vol. 49,p. 801 - 803
[9]Journal of Controlled Release,2014,vol. 185,p. 99 - 108
[10]Macromolecular Bioscience,2013,vol. 13,p. 623 - 632
[11]Molecular Pharmaceutics,2015,vol. 12,p. 1193 - 1202
[12]Molecular Pharmaceutics,2014,vol. 11,p. 4164 - 4178
[13]Journal of Controlled Release,2016,vol. 225,p. 170 - 182
[14]Colloids and Surfaces B: Biointerfaces,2018,vol. 161,p. 449 - 456
[15]Journal of the American Chemical Society,2018,vol. 140,p. 1235 - 1238
[16]ACS Biomaterials Science and Engineering,2018,vol. 4,p. 1696 - 1707
[17]Small,2018,vol. 14
[18]Patent: WO2006/127953,2006,A2 .Location in patent: Page/Page column 19; 20
[19]Journal of Medicinal Chemistry,2019,vol. 62,p. 1959 - 1970

8
[ 894096-04-9 ]
[ 25316-40-9 ]
[ 894096-05-0 ]

Yield	Reaction Conditions	Operation in experiment
41%	With sodium cyanoborohydride; In tetrahydrofuran; water; acetonitrile; at 0℃; for 2h;	To the aldehyde 14 (36 mg, 0.04 mmol) in a mix of acetonitrile and water (2:1 ; 4.5 ml_ total) at 00C was added doxorubicin-HCI (15) followed by stirring until all the solids were dissolved. The mixture was treated with a solution of sodium cyanoborohydride (1.0M solution in THF; 20 muL, 0.02 mmol)). The reaction mixture was stirred for 2 h and the mixture was poured into water and extracted repeatedly with dichloromethane (5 x 50 ml_). The combined organics were washed with water and brine and were concentrated under reduced pressure. The resulting residue was dissolved in 5% methanol in dichloromethane and was aspirated directly onto a 1 mm radial Chromatotron plate and eluted with 20% methanol in dichloromethane. The first major band was collected to give 23.6 mg (41%) of 16: 1H NMR (d6-DMSO); £1.14 (d, 3H, J = 6.5 Hz), 1.36-1.60 (b, 2H), 1.62-1.78 (b, 2H), 1.97-1.99 (m, 9H), 2.14 (b, 3H), 2.95 (s, 3H), 3.18-3.32 (m, 2H), 3.52 (b, 1 H), 3.60 (s, 3H)1 3.75 (q, 1H, J = 6.8 Hz), 4.95 (bs, 1H), 3.96 (s, 3H), 4.09 (b, 1H), 4.17 (t, 1 H, J = 6.5 Hz), 4.25 (d, 2H, J = 6.1 Hz)1 4.54 (d, 2H, J = 6.3 Hz), 4.70 (d, 1 H, J = 10.0 Hz), 4.86 (t, 1H, J = 5.9 hz), 4.92-5.07 (m, 3H), 5.15 (t, EPO <DP n="101"/>I H, J = 8.2 Hz), 5.25 (bs, 1H), 5.04 (d, 1H, J = 2.0 Hz), 5.48 (t, 1 H, J = 10.0 Hz), 5.55 (d, 1H1 J = 8.0 Hz), 7.0-7.11 (m, 2H), 7.28 (m, 2H), 7.37 (t, 3H, J = 7.3 Hz), 7.65 (d, 3H, J = 7.0 Hz), 7.85 (d, 2H, J = 7.6 Hz), 8.75 (b, 1 H); LC-MS m/z (ES"), 1428.9 (M-H)", 7.9 min.

Reference： [1]Patent: WO2018/175994,2018,A1 .Location in patent: Paragraph 0768-0769
[2]Patent: WO2007/11968,2007,A2 .Location in patent: Page/Page column 98-99; 102

9
Fmoc-Phe-Lys(MMT)-PABC-PNP [ No CAS ]
[ 25316-40-9 ]
[ 847871-55-0 ]

Yield	Reaction Conditions	Operation in experiment
99.6%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 20℃;	To a stirred solution of Fmoc-Phe-Lys(MMT)-PABC-PNP (0.6414 g, 0.6061 mmol, 1.0 eq) and <strong>[25316-40-9]doxorubicin hydrochloride</strong> (0.3465 g, 0.5974 mmol, 1.0 eq) in N-methylpyrrolindinone (15 ml) was added DIEA (0.12 ml, 0.6889 mmol, 1.15 eq). The red solution was stirred in the dark (wrapped with aluminum foil) at room temperature overnight. The reaction mixture was diluted with ethyl acetate (150 ml), washed with water (100 ml×1, 50 ml×2), brine (50 ml×1), dried over MgSO4. After removal of solvent, the residue was purified by silica column (2.4×19 cm), eluting with 5% methanol in methylene chloride, giving 0.8700 g (99.6%) of red glassy solid.

Reference： [1]Patent: US2005/54607,2005,A1 .Location in patent: Page/Page column 18

10
[ 50-00-0 ]
[ 25316-40-9 ]
doxoform [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		A clinical sample containing <strong>[25316-40-9]doxorubicin hydrochloride</strong> and lactose was used as the starting material. Most of the lactose was removed by extraction with chloroform. A doxorubicin/lactose mixture containing 40 mg of doxorubicin was dissolved in 75 mL of pH 8, 0.1 M potassium chloride, 40 mM tris(hydroxymethyl)aminomethane (Tris), 100 mM ethylenediaminetetraacetic acid (EDTA) buffer. To this was added 100 mL of chloroform, and the mixture was stirred vigorously for 30 min. The chloroform layer was then removed and a second extraction using 50 mL of chloroform performed. The chloroform extracts were combined and the chloroform removed by rotary evaporation yielding doxorubicin as the free base A solution of 1 mM doxorubicin and 50 mM formaldehyde in 68 mL of pH 6, tyiethylammonium acetate (20 mM)/acetic acid buffer was allowed to react in the dark at 25 C. for 15 h. The buffer was then removed by high-vacuum (0.1 Torr) rotary evaporation for 5 h. The product was dissolved in chloroform and placed in a 15 mL centrifuge tube. The solvent was removed by rotary evaporation and the dry sample was washed with 3×10 mL portions of water by centrifugation at 1550 rpm. After the final wash, the sample was again dried under vacuum at 0.02 Torr for 15 h. The 1H NMR spectrum in deuteriochloroform solvent established that the product was pure and together with the MS spectrum of crystalline material, indicated that it had the structure, bis-(3'-N-(3'-N,4'-O-methylenedoxorubicinyl))methane. (the dimeric formaldehyde conjugate of doxorubicin) (Scheme III). The isolated yield was determined to be 70% by visible absorption at 480 nm of a chloroform solution as described above for the dimeric formaldehyde conjugate of daunorubicin.

Reference： [1]Patent: US6677309,2004,B1 .Location in patent: Page/Page column 17; 18; 55

11
poly(17-(1,5-dimethyl-hexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl ester of 6-(2-methacryloylamino)hexanoic acid-co-N₁-(6-hydrazino-6-oxohexyl)-2-methylacrylamide-co-N-(2-hydroxypropyl)methacrylamide) [ No CAS ]
[ 25316-40-9 ]
PHPMA-AH-NH-N=DOX-co-MA-AH-chol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	acetic acid; In methanol; at 25℃; for 22h;	Copolymers with DOX bound to a PHPMA carrier by a hydrolytically cleavable hydrazone linkage containing a hydrophobic substituent were prepared by reaction of polymeric precursors containing hydrazide and hydrophobic groups (an aliphatic substituent, an ester and <n="11"/>hydrazide of cholesterol or cholic acid) with DOX.HC1 in methanol under catalysis of acetic acid.A solution of 15.384 g of the poly(HPMA-co-MA-AH-NHNH2-co-MA-AH-chol) copolymer in 92.1 ml of methanol (167 mg polymer/ml) was put into a thermostated cell, in which 2.5 g of D0X.HC1 (4.3 mmol) had been placed. The non-homogeneous suspension was stirred in dark at 25 0C and 1 minute later, 4.9 ml of acetic acid was added (total volume 116 ml). In the course of the reaction, dissolution of the suspension slowly occurred; after reacting for 22 hours, the polymeric product was isolated from the homogenous solution by precipitation with 1 1 of ethyl acetate, the precipitate of the polymeric drug was isolated by filtration with S4 sintered glass, washed with 150 ml of ethyl acetate and dried until the constant weight. The content of total DOX was determined spectrally. Mw and Mn were determined using liquid chromatography (LC AKTA) with light dispersion detection (Multiangel detector DAWN DSP, Wyatt). Characterization of the polymeric drug: Total yield of the drug-binding reaction: 17.2 g (96 %), content of the total DOX 11.3 w. %, content of free DOX 1.52 % of the total content of DOX. The procedure for binding doxorubicin to polymeric precursors through the hydrazone linkage was the same for all types of precurs

Reference： [1]Patent: WO2007/110003,2007,A2 .Location in patent: Page/Page column 9-10

12
[ 25316-40-9 ]
[ 15664-29-6 ]
pheophorbide-α-doxorubicin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 4h;	EDC (50.0 mg, 0.25 mmol), HOBt (23.0 mg, 0.17 mmol), and TEA (25.0 muL, 0.17 mmol) were add to Pa (1, 50.0 mg, 0.08 mmol) in DCM (3 mL). Then, <strong>[25316-40-9]doxorubicin hydrochloride</strong> (2, 60.0 mg, 0.10 mmol) in DMF was added to the resulting solution and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was added to NaHCO3 (aq) (30 mL) and extracted with chloroform (2 × 30 mL). The combined organic layers were dried over MgSO4, concentrated and purified by silica gel column chromatography (chloroform:methanol = 50:1) to give 6 as a brown sticky solid (50.0 mg). Yield: 53%; 1H NMR (400 MHz, CDCl3) delta (ppm) 9.22 (s, 1H), 9.17 (s, 1H), 8.43 (s, 1H), 7.91 (m, 1H), 7.54 (m, 1H), 7.39 (m, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.14 (m, 3H), 5.90 (s, 1H, -OH), 4.90 (s, 2H), 4.62 (s, 2H), 4.41 (m, 1H), 4.21 (m, 2H), 4.12 (m, 1H), 4.04 (m, 1H), 3.85 (m, 3H), 3.72 (s, 3H), 3.52 (m, 2H), 3.38 (s, 1H, -OH), 3.23 (s, 6H), 3.14 (s, 3H), 3.02 (m, 1H), 2.86 (d, J = 18.0 Hz, 1H), 2.60 (m, 2H), 2.36 (m, 2H), 2.04 (m, 2H), 2.01 (m, 1H), 1.85 (d, J = 14.0 Hz, 1H), 1.69 (d, J = 7.2 Hz, 3H), 1.62 (t, J = 7.6 Hz, 3H), 1.09 (d, J = 6.0 Hz, 3H); ESI [M+H] = 1118.4; HRMS (FAB) (C62H63N5O15): calcd 1118.4399, found 1118.4403.
53%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 4h;	1.2. Procedure for the Synthesis of Pheophorbide-alpha-Doxorubicin (6) EDC (50.0 mg, 0.25 mmol), HOBt (23.0 mg, 0.17 mmol), and TEA (25.0 IL, 0.17 mmol) were add to Pa (1, 50.0 mg, 0.08 mmol) in DCM (3 mL). Then, <strong>[25316-40-9]doxorubicin hydrochloride</strong> (2, 60.0 mg, 0.10 mmol) in DMF was added to the resulting solution and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was added to NaHCO3 (aq) (30 mL) and extracted with chloroform (2*30 mL). The combined organic layers weredried over MgSO4, concentrated and purified by silica gel column chromatography (chloroform:methanol=50:1) to give 6 as a brown sticky solid (50.0 mg). Yield: 53%; 1H NMR (400 MHz, CDCl3) d (ppm) 9.22 (s, 1H), 9.17 (s, 1H), 8.43 (s, 1H), 7.91 (m, 1H), 7.54 (m, 1H), 7.39 (m, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.14 (m, 3H), 5.90 (s, 1H, -OH), 4.90 (s, 2H), 4.62 (s, 2H), 4.41 (m, 1H), 4.21 (m, 2H), 4.12 (m, 1H), 4.04 (m, 1H), 3.85 (m, 3H), 3.72 (s, 3H), 3.52 (m, 2H), 3.38 (s, 1H, -OH), 3.23 (s, 6H), 3.14 (s, 3H), 3.02 (m, 1H), 2.86 (d, J=18.0 Hz, 1H), 2.60 (m, 2H), 2.36 (m, 2H), 2.04 (m, 2H), 2.01 (m, 1H), 1.85 (d, J=14.0 Hz, 1H), 1.69 (d, J=7.2 Hz, 3H), 1.62 (t, J=7.6 Hz, 3H), 1.09 (d, J=6.0 Hz, 3H); ESI [M+H]=1118.4; HRMS (FAB) (C62H63N5O15): calcd 1118.4399, found 1118.4403.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 5383 - 5391
[2]Patent: US2013/210756,2013,A1 .Location in patent: Paragraph 0051

13
[ 25316-40-9 ]
[ 104-15-4 ]
doxorubicin tosylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%		Example 33. Synthesis, Purification and Characterization of Doxorubicin TosylateIn a 250-mL round-bottom flask equipped with a magnetic bar and a thermocouple, doxorubicin»HCl (NetQem, 1.43 g, 2.46 mmol) was suspended in anhydrous THF (143 mL, 100 vol). The mixture was evacuated for 15 seconds while being stirred and filled up with nitrogen (1 atm). 1 M potassium tert-butoxide (KOtBu)/THF solution (2.7 mL, 2.70 mmol) was added dropwise with stirring within 10 min. The solution turned a purple color and a slight exotherm was observed. The reaction temperature rose from 19C to 21.7C within 15 min and then slightly climbed up to a maximum of 22.4C in half hour. The mixture was stirred for another hour at 22.4C and then p-Toluenesulfonic acid (p-TSA, 0.70 g, 3.96 mmol) was added in one portion. The solution immediately turned a red color along with the precipitation of fine particles. The mixture was stirred for an additional half hour at ambient temperature and then cooled to 5 C and stirred for 1 h. The resulting red suspension was filtered under nitrogen. The filter cake was washed with THF (3 x 10 mL) and dried under vacuum at 25C for 16 h to produce doxorubicin tosylate [1.73 g, 97% yield)]. HPLC analysis indicated a 97% purity (AUC, 480 nm). To remove the excess p-TSA, the product was slurried in 5: 1 MTBE/MeOH (60 mL) at ambient temperature for 3 h. The filtered solid was dried under vacuum at 25C for 16 h to afford 1.32 g of product. HPLC analysis indicated 99% purity (AUC, 4801nm); however, the H NMR analysis showed that the equivalents of p-TSA were still -1.2. DSC analysis of doxorubicin tosylate showed a sharp peak with a melting range of 188.5-196.5C.

Reference： [1]Patent: WO2012/44832,2012,A1 .Location in patent: Page/Page column 458-459

14
[ 5324-84-5 ]
[ 25316-40-9 ]
[ 114370-94-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	In water; at 20℃; for 2.5h;	Example 34. Synthesis and Characterization of Doxorubicin OctanesulfonateIn a 250 mL round-bottom flask equipped with a magnetic stirrer, 1- <strong>[5324-84-5]octanesulfonic acid sodium salt</strong> monohydrate (0.44 g, 1.86 mmol) was dissolved in water (50 mL). The mixture was stirred for 10 min to afford a clear solution, to which doxorubicin'HCl (1.08 g, 1.86 mmol) was added in one portion. The solution became a dark red color after being stirred for a few minutes. After about 30 min, an orange powder formed. The mixture was stirred at ambient temperature for 2 h. The suspension was stored in fridge for 16 h and filtered through a Sharkskin filter paper. The filtrate had a slightly red color and contained trace amounts of doxorubicin as evidenced by HPLC analysis. The presence of chloride in the filtrate was confirmed by the silver nitrate test. The filter cake was dried under vacuum at 28C for 16 h to afford doxorubicin octanesulfonate [1.16 g, yield: 85%] as an orange powder. The ]H NMR analysis indicated the desired product and HPLC analysis indicated >99.5% purity. DSC analysis of doxorubicin octanesulfonate showed a sharp peak with a melting range of 198.7 - 202.0C.

Reference： [1]Patent: WO2012/44832,2012,A1 .Location in patent: Page/Page column 459

15
[ 120-18-3 ]
[ 25316-40-9 ]
[ 1246449-86-4 ]

Yield	Reaction Conditions	Operation in experiment
100%		Example 35. Synthesis, Purification and Characterization of Doxorubicin Naphthalene-2-SulfonateA 250-mL round-bottom flask equipped with a magnetic bar and athermocouple was charged with doxorubicin»HCl (NetQem, 1.47 g, 2.53 mmol) and anhydrous THF (150 mL, 100 vol). The suspension was evacuated for 15 seconds with stirring and filled up with nitrogen (1 atm). 1 M (KOtBu)/THF solution (2.7 mL, 2.70 mmol) was added dropwise with stirring over 10 min. The mixture turned a purple color and a slight exotherm was observed, causing the reaction temperature to rise from 20.2 C to 21.4 C within 15 min. The solution was stirred at 21.1 C for one hour and 2-naphthalenesulfonic acid (0.63 g, 3.04 mmol) was added in one portion. The mixture immediately turned to a red color and the precipitation of fine particles was observed. The solution was stirred for an hour at ambient temperature and then filtered under nitrogen. The filtration was slow and took about 1 h. The filter cake was washed with THF (3 x 10 mL) and dried under vacuum at 25 C for 16 h to afford 2.1 g of doxorubicin naphthalene-2-sulfonate as a dark red solid [yield:>100%]. HPLC analysis indicated a 98% purity (AUC, 480 nm). The H NMR analysis showed that the ratio of 2-naphthalenesulfonic acid to doxorubicin was -1.08.To remove residual 2-naphthalenesulfonic acid, the doxorubicin naphthalene- 2-sulfonate was slurried in 5:1 MTBE/MeOH (60 mL) for 3 h. The suspension was filtered and the filter cake was dried under vacuum at 25 C for 24 h to afford 1.90 g1of the product as a fine red powder [yield: 100%]. The H NMR analysis indicated a clean product with a 1 : 1 ratio of doxorubicin to 2-naphthalenesulfonic acid. HPLC analysis showed >98% purity (AUC, 480 nm). The physical appearance of the product was similar to doxorubicin»HCl. DSC analysis of doxorubicin naphthalene-2- sulfonate showed a sharp peak with a melting range of 203.1 - 207.4 C.

Reference： [1]Patent: WO2012/44832,2012,A1 .Location in patent: Page/Page column 459-460

16
[ 1244966-81-1 ]
[ 25316-40-9 ]
[ 1244966-82-2 ]

Yield	Reaction Conditions	Operation in experiment
59.6%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 21h;Inert atmosphere;	N,N'-Diisopropylethylamine was added to a suspension of Doxorubicin HCl (1.50 g, 2.59 mmol) in dry DMF (30 ml) followed by the addition of EDC:HCl (555 mg, 2.90 mmol), 1-hydroxybenzotriazole (390 mg, 2.89 mmol), and OOC-GABA (1.033 g) in dry DMF (5 ml) under argon. The reaction mixture was stirred at room temperature for 21 h. Solvent was removed under high vacuum and the residue was purified by silica gel column chromatography using EtOAc to 1% MeOH/EtOAc to afford pure red title compound (1 g, purity=99.42%, 0.425 g purity=93%, yield: 1.425 g (1.00 g+0.425 g) 59.6%). Chemical Formula: C50H70N2O14 Exact Mass: 922.48 Molecular Weight: 923.10 LC-MS (negative ion): [M-H]-=921.5121, [M+H]+=923.5213. 1H NMR (400 MHz, CDCl3): delta 0.88 (t, J=8.0 Hz, 3H), 1.26-1.34 (m, 24H), 1.50-1.95 (m, 7H), 1.96-2.07 (m, 4H), 2.13-2.20 (m, 3H), 2.35 (d, J=16 Hz, 1H), 2.94-3.30 (m, 6H), 3.71 (d, J=8.0 Hz, 1H), 3.99-4.06 (m, 2H), 4.06 (s, 3H), 4.11-4.15 (m, 2H), 4.61 (s, 1H), 4.77 (s, d, J=4 Hz, 2H), 4.90 (m, 1H), 5.26 (s, 1H), 5.31-5.40 (m, 2H), 5.51 (s, 1H), 6.14-6.16 (m, 1H), 7.37 (d, J=8 Hz, 1H), 7.77 (t, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 13.19 (m, 1H), 13.94 (s, 1H).

Reference： [1]Patent: US2012/148595,2012,A1 .Location in patent: Page/Page column 17-18

17
[ 1394238-92-6 ]
[ 25316-40-9 ]
[ 1394238-93-7 ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Patent: CN110152013,2019,A .Location in patent: Paragraph 0043; 044; 0045
[2]Patent: CN110418653,2019,A .Location in patent: Paragraph 0043-0045
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 7502 - 7515
[4]Patent: US2014/51623,2014,A1 .Location in patent: Paragraph 0063; 0071

18
[ 1039044-92-2 ]
[ 25316-40-9 ]
C₃₃H₄₀N₆O₁₁*ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.4%	With acetic acid; sodium sulfate; In methanol; at 65℃; for 24h;Darkness;	6-Azidohexanohydrazide (102.0 mg, 0.60 mmol), DOX ? HCl (115.9 mg, 0.20 mmol) and anhydrous Na2SO4 (103 mg, 0.73 mmol) were weighed into a round bottom flask with a reflux condenser , Dissolved in 30 mL of anhydrous methanol (CH3OH). Then add 3 drops of glacial acetic acid, stir well, dark reaction at 65 C oil bath for 24 h. After the reaction was completed, the mixture was filtered through cotton and the Na2SO4 in the reaction solution was removed. After removing the solvent, the precipitate was precipitated three times in ice-ethyl ether. Finally, the following precipitate was obtained by centrifugation, which was placed in a vacuum oven and dried for 24 h to give the product as a red powderN3-hyd-DOX ? HCl (93.5 mg, yield: 62.4%).
62.4%	With acetic acid; sodium sulfate; In methanol; at 65℃; for 24h;	6-azido hexanohydrazide (102.0 mg, 0.60 mmol), DOX*HCl (115.9 mg, 0.20 mmol) and anhydrous Na2SO4 (103 mg, 0.73 mmol) were weighed, respectively.Add to a round-bottomed flask with a reflux condenser and dissolve with 30 mL of anhydrous methanol.Then add 3 drops of glacial acetic acid, stir evenly and then react in the oil bath at 65 C for 24 h. After the reaction is completed, filter with cotton to remove Na2SO4 from the reaction solution.The solvent was removed and precipitated three times in ice ether. Finally, the following precipitate was obtained by centrifugation and placed in a vacuum drying oven for 24 h to obtain a red powder product.That is, N3-hyd-DOX×HCl (93.5 mg, yield: 62.4%).
	With acetic acid; In methanol;	Methyl 6-bromohexanoate was reacted with sodium azide to give methyl 6-azidohexanoate, then converted to the corresponding hydrazide using hydrazine hydrate. The linker compound 6-azidohexanehydrazide was conjugated with DOX hydrochloride in dry methanol, with a drop of acetic acid, forming the desired DOX-azide compound. The one-pot method polymerization/click method shown in the scheme was used to synthesize the new DOX-polyMPC copolymer. The polymer was characterized with NMR spectroscopy and GPC, while drug weight percent was measured using a UV method.

Reference： [1]Bioconjugate Chemistry,2012,vol. 23,p. 1753 - 1763,11
[2]Patent: CN107233309,2017,A .Location in patent: Paragraph 0041
[3]Patent: CN107141323,2017,A .Location in patent: Paragraph 0026
[4]Patent: US2016/346400,2016,A1 .Location in patent: Paragraph 0097

19
[ 25316-40-9 ]
[ 89889-52-1 ]
[ 1401539-59-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With pyridine; dmap; at 20℃; for 16h;	To a solution of DOX hydrochloride (5.4 mg, 9.3 mumol) in pyridine (2 mL) was added biotinamidohexanoic acid N-hydroxysuccinimide ester (3) (4.8 mg, 11 mumol) and 4-(N,N-dimethylamino)pyridine (0.9 mg, 7.4 mumol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed by evaporation in vacuo and the residue was purified on silica gel flash column chromatography (chloroform/methanol = 4:1) to afford N3?-[biotynyl-6-aminohexanoyl]-DOX (4) as a red waxy amorphous solid (8.1 mg, 98%). HRMS (ESI) m/z calcd for C43H54N4O14NaS [M+Na]+ 905.3249, found 905.3251 (error: 0.17 ppm); 1H NMR (600 MHz, CD3OD) delta 7.96 (1H, d, J = 8.0 Hz), 7.83 (1H, t, J = 8.1, 8.0 Hz), 7.56 (1H, d, J = 8.0 Hz), 5.41 (1H, d, J = 3.5 Hz), 5.14 (1H, s), 4.76 (1H, d, J = 19.9 Hz), 4.70 (1H, d, J = 19.9 Hz), 4.47-4.44 (1H, m), 4.28-4.24 (2H, m), 4.14-4.11 (1H, m), 4.02 (3H, s), 3.58 (1H, s), 3.15-3.08 (5H, m), 2.88 (1H, dd, J = 5.04, 12.7 Hz), 2.67 (1H, d, J = 12.7 Hz), 2.36 (1H, s), 2.20-2.11 (5H, m), 1.99-1.94 (1H, m), 1.69-1.64 (1H, m), 1.60-1.52 (6H, m), 1.48-1.43 (2H, m), 1.38-1.34 (2H, m), 1.32-1.28 (2H, m), 1.25 (3H, d, J = 6.5 Hz).

Reference： [1]Bioorganic and medicinal chemistry,2012,vol. 20,p. 6248 - 6255,8

20
[ 151038-94-7 ]
[ 25316-40-9 ]
[ 151038-96-9 ]

Yield	Reaction Conditions	Operation in experiment
58%	With pyridine; In methanol; at 20℃;	The synthesis of DOXO-EMCH was accomplished using the procedure reported by Willner et al, with several changes to improve the yield (Willner, D., et al.,Bioconjugate Chem., 4:521-27, 1993). DOX'HCl (20 mg, 34 muiotaetaomicron) was dissolved in 6 mL of methanol. Pyridine (12.53 mu) was added to the solution, followed by 35.4 mgEMCH'TFA. The reaction was stirred at room temperature overnight. By HPLC, the reaction was 90% complete. The solvent was evaporated to dryness by rotary evaporation. A minimal amount of methanol was used to dissolve the solid, and six volumes of acetonitrile at 4 C were added to the solution. The resulting solution was allowed to sit undisturbed at 4 C for 48 h for crystallization. The precipitate was collected, and the crystallization method was repeated 4 times. The resulting solids were combined and washed three times with 1 : 10 methanokacetonitrile. The final yield of DOXO-EMCH was 11.59 mg, 58%. HPLC Method 1.1 was used. NMR spectra corresponded to those previously given by Willner (Bioconjugate Chem. 4:521-27. 1993).

Reference： [1]Patent: WO2012/167255,2012,A1 .Location in patent: Page/Page column 32

21
[ 68181-17-9 ]
[ 25316-40-9 ]
doxorubicin-SPDP [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dimethyl sulfoxide; at 50℃; for 6h;	DOX-SS-Pyr was synthesized according to the published procedures(41,42) with minor modification. Briefly, to the mixtureof DOX·HCl (17.4mg, 30 mumol) and SPDP (11.2mg, 36 mumol)inDMSO (5 mL) was added dropwise TEA (6.25 muL, 45 mumol).The reaction mixture was stirred at 50C and the progress ofthe reaction was monitored by thin-layer chromatography(TLC) with dichloromethane: methanol (13: 1, v: v) as developingsolvents. After stirred for 6 h, the product of DOX-SS-Pyrwas purified by column chromatography on silica gels (dichloromethane:methanol = 20: 1, v: v) and characterized by analyticalRP-HPLC, ESI MS and 1HNMR spectra.
	With triethylamine; In dimethyl sulfoxide; at 50℃; for 6h;	With reference to Yoon S, Kim WJ, Yoo HS. Dual-responsive breakdown of nanostructures with high doxorubicin payload for apoptoticanticancertherapy. Small. 2013, 9 (2): 284-293, DOX · HCl (17.4mg, 30mumol) and SPDP (11.2 mg, 36 mumol), dissolved in DMSO (5 mL), then added TEA (6.25 muL, 45 mumol), stirred the reaction at 50 C, and monitored by thin layer chromatography (developing solvent: DCM: methanol, 13: 1, v: v) The reaction progressed. After 6 hours of reaction, the target product DOX-SS-Pyr was separated and purified by silica gel column chromatography (mobile phase: DCM: methanol, 20: 1, v: v), and characterized by RP-HPLC and ESI-MS.The purity by RP-HPLC analysis was 95.7%;

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 9691 - 9697
[2]Small,2013,vol. 9,p. 284 - 293
[3]Pharmaceutical Research,2019,vol. 36
[4]Patent: CN110478494,2019,A .Location in patent: Paragraph 0021; 0059-0060

22
[ 1451073-54-3 ]
[ 25316-40-9 ]
[ 1451073-56-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 72h;Darkness;	A solution of p-(diphenylthiolmaleimide)-benzyl 4-nitrophenyl carbonate 13 (9.8 mg, 0.017 mmol) and DOX HCl (10 mg, 0.018 mmol) in MP (0.3 mL) at room temperature were treated with Et3N (0.0025 mL, 0.018 mmol). The mixture was allowed to stand in the dark for 3 days and then it was diluted with 10% i- propanol/EtOAc and was washed with H20 and brine, dried over MgS04, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to give the title product as yellow oil (16.4 mg, 0.0166 mmol, 99%). Rf 0.35 (5% MeOH/DCM); [a] D = +91.3 (c 1.1, CHC13); vmax (cm"1) 3481, 3080, 1716, 1580, 1517, 1383, 1286, 1073, 987; deltaEta (CDC13, 600MHz) 13.96 (1H, s , DOX), 13.22 (1H, s, DOX), 8.02 (1H, d, J= 8.2 Hz, DOX), 7.77 (1H, d, J= 8.2 Hz), 7.38 (2H, d, J = 8.2 Hz, DOX), 7.34 (2H, d, J= 8.2 Hz, ArHCH2), 7.31-7.22 (12H, m, ArHCH2 (2) and ArHS (10)), 5.49 (1H, br s, DOX), 5.27 (1H, br s, DOX), 5.18 (1H, d, J= 8.6 Hz, DOX), 5.03-4.98 (2H, m, DOX), 4.75 (2H, s, C0), 4.14-4.10 (1H, m, DOX), 4.07 (3H, s, DOX), 3.86-3.82 (1H, m, DOX), 3.65 (1H, s, DOX), 3.25 (1H, d, J= 18.7 Hz, DOX), 2.98 (1H, d, J= 18.7 Hz), 2.32 (1H, d, J= 14.6 Hz, DOX), 2.16 (1H, dd, J = 14.6 and 4.0 Hz, DOX), 1.86 (1H, dd, J= 13.4 and 4.9 Hz, DOX), 1.79-1.76 (1H, m, DOX), 1.27 (3H, d, J= 6.6 Hz, DOX); 6C (CDC13, 150 MHz) 214.0, 187.2, 186.8, 165.7, 161.1, 156.3, 155.7, 155.5, 136.1, 135.9, 135.7, 135.6, 133.7, 132.2, 131.2, 129.2, 129.2, 128.9, 128.9, 128.7, 125.9, 120.9, 120.0, 118.6, 111.7, 111.5, 100.8, 76.7, 69.7, 69.6, 67.4, 66.1, 65.7, 56.8, 47.1, 35.7, 34.1, 30.2, 17.0; Mass calculated for C5iH44N2Oi5NaS2: 1011.2081, observed: 1011.2122.

Reference： [1]Chemical Communications,2013,vol. 49,p. 8187 - 8189
[2]Patent: WO2013/121175,2013,A1 .Location in patent: Paragraph 47; 48

23
[ 6318-55-4 ]
[ 25316-40-9 ]
[ 1425615-40-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide;	The overall synthetic route was shown in Figure 1.The concrete steps were as follows: 0.3 g of dextranwas dissolved in 12 mL of DMSO/pyridine (v/v, 1/1),4-nitrophenyl chloroformate (PNC, 93 mg), 4-dimethylaminopyridine(DMAP, 11.28 mg) were added and reactedfor 4 h in ice-bath. The 4-Nitrophenyl chloroformateactivation of dextran (DEX-PNC) was isolated by precipitationin excess ethanol/diethyl ether (v/v, 1/1), centrifugation,collection and vacuum drying. The PNCcontent in DEX-PNC was determined by UV-Vis aspreviously reported.6 The product (DEX-PNC, 50 mg)obtained was dissolved in 40 mL of distilled water,then was added dropwise into 10 mL of PEI (0.6 g)aqueous solution with stirring, and continuing overnight,after which the reactant was dialyzed against distilledwater in dialysis membrane (MWCO: 3500 KDa) for 3 days, then freeze-dried in order to get DEX-PEIpolymer.To obtain pH-sensitive DOX-loaded conjugates, DOX·HCl (15 mg) was stirred with excess triethylamine and cisaconiticanhydride (4.5 mg) in anhydrous DMF overnightto obtain DOX cis-aconitic anhydride derivative, then EDC(39.6 mg) and NHS (23.76 mg) were added and reactedfor another 4 h to form the active ester of DOX cisaconiticanhydride derivative. Secondly, freeze-dried DEXPEI(75 mg) were dissolved in 12.5 mL of DMF/water(v/v, 1/1), then the DOX cis-aconitic anhydride derivativesolution was added and reacted overnight at room temperaturein dark, the reaction mixture was dialyzed againstdistilled water (pH 8.5) to remove DMF and small molecularsubstances, and allow the conjugates self-assemble intonanoparticles. Finally, the obtained nanoparticles solutionwas filtered through a 0.45 m filter and stored at 4 C indark.
	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;Darkness; Inert atmosphere;	Example 2: Preparation method of LGC12 modified doxorubicin (Doxorubicin)1 modified the original drug R (R = doxorubicin DOX) with cis aconitic anhydride (CA),Hereinafter, it is referred to as CAR, and is synthesized by a ring-opening reaction between R and CA using triethylamine as a catalyst. The original drug R (0.4 mmol) and CA (0.44 mmol) were dissolved in 20.0 mL of anhydrous DMF in a completely dried flask, and then 67.0 muL of triethylamine was added. The mixture was placed in the dark at room temperature and stirred under a nitrogen (N 2 ) atmosphere for 24 hours. Next, the solution was mixed with 200.0 mL of cold ethyl acetate, washed first with a saturated sodium chloride solution of pH 2-3, and then with a saturated solution of pH 7.4. The obtained organic layer was dried over anhydrous sodium sulfate for 12 hr. Finally, the solid CAR was isolated by filtration and dried under vacuum at room temperature to give the product.

Reference： [1]Biochemistry (Moscow),2013,vol. 78,p. 884 - 894
Biokhimiya (Moscow),2013,vol. 78,p. 1128 - 1140,13
[2]Macromolecular Bioscience,2013,vol. 13,p. 1300 - 1307
[3]Journal of Nanoscience and Nanotechnology,2015,vol. 15,p. 2613 - 2618
[4]Small,2015,vol. 11,p. 4321 - 4333
[5]Patent: CN109568599,2019,A .Location in patent: Paragraph 0051; 0052; 0054

24
C₂₇H₃₂N₄O₆ [ No CAS ]
[ 25316-40-9 ]
ethyl-5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-(((2S,3S,4S,6R)-3-hydroxy-2-methyl-6-(((1S,3S)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl)oxy) tetrahydro-2H-pyran-4-yl)carbamoyl)piperidin-1-yl)methyl)phenyl)-4H-1,2,4-triazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;Inert atmosphere;	[00662] To a solution of Hsp90 inhibitor fragment 1 (102mg, 0.2mmol) in anhydrous DMF (6 mL) was added HATU (78mg, 0.2mmol) under nitrogen at 0C, followed by diisopropylamine (78mg, 0.6mmol). The reaction mixture was stirred at 0C for 15 mm, followed by the addition of <strong>[25316-40-9]doxorubicin hydrochloride</strong> 2 (135mg, 0.25mmol), and stuffing was continued for 18h at room temperature. The reaction mixture was diluted with methylene chloride and washed with water and brine. The organic phase was dried with sodium sulfate, filtered and concentrated, leaving a dark red residue. The product was isolated using column chromatography (95:5 dichloromethane /methanol) to give SDC-TRAP-0 142 (ethyl-5-(2,4-dihydroxy-5-isopropylphenyl)-4- (4-((4-(((2S,3S,4S,6R)-3-hydroxy-2-methyl-6-((( 1 S ,3S)-3 ,5 , 12-trihydroxy-3- (2-hydroxyacetyl)- 1 0-methoxy-6, 11 -dioxo- 1,2,3,4,6,11 -hexahydrotetracen- 1 -yl)oxy) tetrahydro-2H-pyran-4-yl)carbamoyl)piperidin- 1 -yl)methyl)phenyl)-4H- 1 ,2,4-triazol e-3-carboxylate, 115mg, 55%) as a red solid.[00663] 1H NMR (400 MHz, DMSO-d6) delta 14.02 (s, 1H), 13.27 (s, 1H), 10.62 (s, 1H), 9.76 (s, 1H), 8.93 (t, J= 5.9 Hz, 1H), 7.90 (d, J= 4.8 Hz, 2H), 7.64 (p, J= 3.8 Hz, 1H), 7.44 (d, J= 8.1 Hz, 1H), 7.35 (d, J= 8.0 Hz, 2H), 7.27 (d, J= 8.0 Hz, 2H), 6.55 (s, 1H), 6.33 (s, 1H), 5.44 (s, 1H), 5.22 (d, J = 3.4 Hz, 1H), 4.94 (t, J = 4.4 Hz, 1H), 4.85 (t, J= 5.9 Hz, 1H), 4.72 (d, J= 5.8 Hz, 1H), 4.57 (d, J= 5.9 Hz, 2H), 4.16 (q, J= 6.7 Hz, 1H), 4.08 -3.93 (m, 3H), 3.41 (d, J= 17.4 Hz, 3H), 3.15 (p, J= 7.0 Hz, 2H), 3.05-2.77 (m, 5H), 2.24- 2.06 (m, 3H), 1.95 - 1.79 (m, 3H), 1.60 - 1.36 (m, 5H), 1.15 (dd, J= 23.9, 6.7 Hz, 2H), 1.02 (t, J= 7.1 Hz, 3H), 0.77 (d, J= 6.8 Hz, 6H). ESMS calculated for C54H59N50,6: 1033.40; Found: 1033.8 (M+H).
55%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;Inert atmosphere;	To a solution of Hsp90 inhibitor fragment 1 (102mg, 0.2mmol) in anhydrous DMF (6 mL) was added HATU (78mg, 0.2mmol) under nitrogen at 0C, followed by diisopropylamine (78mg, 0.6mmol). The reaction mixture was stirred at 0C for 15 min, followed by the addition of <strong>[25316-40-9]doxorubicin hydrochloride</strong> 2 (135mg, 0.25mmol), and stirring was continued for 18h at room temperature. The reaction mixture was diluted with methylene chloride and washed with water and brine. The organic phase was dried with sodium sulfate, filtered and concentrated, leaving a dark red residue. The product was isolated using column chromatography (95:5 dichloromethane /methanol) to give SDC-TRAP-0142 (ethyl-5-(2,4-dihydroxy-5-isopropylphenyl)-4- (4-((4-(((2S,3S,4S,6R)-3-hydroxy-2-methyl-6-(((lS,3S)-3,5,12-trihydroxy-3- (2-hydroxyacetyl)- lO-methoxy-6, 11-dioxo- 1,2,3,4,6, 11-hexahydrotetracen- l-yl)oxy) tetrahydro-2H-pyran-4-yl)carbamoyl)piperidin- 1 -yl)methyl)phenyl)-4H- 1 ,2,4-triazole-3-carb oxylate, 115mg, 55%) as a red solid. [00714] 1H NMR (400 MHz, DMSO-J6) delta 14.02 (s, 1H), 13.27 (s, 1H), 10.62 (s, 1H), 9.76 (s, 1H), 8.93 (t, J= 5.9 Hz, 1H), 7.90 (d, / = 4.8 Hz, 2H), 7.64 (p, / = 3.8 Hz, 1H), 7.44 (d, / = 8.1 Hz, 1H), 7.35 (d, / = 8.0 Hz, 2H), 7.27 (d, / = 8.0 Hz, 2H), 6.55 (s, 1H), 6.33 (s, 1H), 5.44 (s, 1H), 5.22 (d, / = 3.4 Hz, 1H), 4.94 (t, / = 4.4 Hz, 1H), 4.85 (t, 7 = 5.9 Hz, 1H), 4.72 (d, / = 5.8 Hz, 1H), 4.57 (d, 7 = 5.9 Hz, 2H), 4.16 (q, / = 6.7 Hz, 1H), 4.08 - 3.93 (m, 3H), 3.41 (d, / = 17.4 Hz, 3H), 3.15 (p, / = 7.0 Hz, 2H), 3.05 - 2.77 (m, 5H), 2.24 - 2.06 (m, 3H), 1.95 - 1.79 (m, 3H), 1.60 - 1.36 (m, 5H), 1.15 (dd, / = 23.9, 6.7 Hz, 2H), 1.02 (t, / = 7.1 Hz, 3H), 0.77 (d, / = 6.8 Hz, 6H). ESMS calculated for C54H59N5O16: 1033.40; Found: 1033.8 (M+H)+.
55%		To a solution of Hsp9O inhibitor fragment 1 (102mg, 0.2mmol) in anhydrous DMF (6 mL) was added HATU (78mg, 0.2mmol) under nitrogen at 0C, followed by diisopropylamine (78mg, 0.6mmol). The reaction mixture was stirred at 0C for 15 mm, followed by the addition of <strong>[25316-40-9]doxorubicin hydrochloride</strong> 2 (135mg, 0.25mmol), and stirring was continued for 1 8h at room temperature. The reaction mixture was diluted with methylene chloride and washed with water and brine. The organic phase was dried with sodium sulfate, filtered and concentrated, leaving a dark red residue. The product was isolated using column chromatography (95:5 dichloromethane /methanol) to give SDC-TRAP-0 142 (ethyl-5-(2,4-dihydroxy-5-isopropylphenyl)-4- (4-((4-(((2S,3S,4S,6R)-3-hydroxy-2-methyl-6-(((l S,3S)-3,5, 12-trihydroxy-3- (2-hydroxyacetyl)- 10-methoxy-6, 1 1-dioxo- 1,2,3,4,6,1 1-hexahydrotetracen- 1-yl)oxy) tetrahydro-2H-pyran-4-yl)carbamoyl)piperidin-1-yl)methyl)phenyl)-4H- 1 ,2,4-triazol e-3-carboxylate, 115mg, 55%) as a red solid. 1H NMR (400 MHz, DMSO-d6) 6 14.02 (s, 1H), 13.27 (s, 1H), 10.62 (s, 1H), 9.76 (s, 1H), 8.93 (t, J = 5.9 Hz, 1H), 7.90 (d, J= 4.8 Hz, 2H), 7.64 (p, J= 3.8 Hz, 1H), 7.44 (d, J= 8.1 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.27 (d, J= 8.0 Hz, 2H), 6.55 (s, 1H), 6.33 (s, 1H), 5.44 (s, 1H), 5.22 (d, J = 3.4 Hz, 1H), 4.94 (t, J = 4.4 Hz, 1H), 4.85 (t, J = 5.9 Hz, 1H), 4.72 (d, J = 5.8 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 4.16 (q, J = 6.7 Hz, 1H), 4.08-3.93 (m, 3H), 3.41 (d, J = 17.4 Hz, 3H), 3.15 (p, J = 7.0 Hz, 2H), 3.05-2.77 (m, 5H), 2.24-2.06 (m, 3H), 1.95 - 1.79 (m, 3H), 1.60- 1.36 (m, 5H), 1.15 (dd, J = 23.9, 6.7 Hz, 2H), 1.02 (t, J = 7.1 Hz, 3H), 0.77 (d, J = 6.8 Hz, 6H). ESMS calculated for C54H59N50,6: 1033.40; Found: 1033.8 (M+H)t

Reference： [1]Patent: WO2013/158644,2013,A2 .Location in patent: Paragraph 00661; 00662; 00663
[2]Patent: WO2015/38649,2015,A1 .Location in patent: Paragraph 00713; 00714
[3]Patent: WO2015/143004,2015,A1 .Location in patent: Paragraph 001010; 001011; 001012; 001013

25
Ac-Lys(OAloc)-Gly-Asp(OAll)-Glu(OAll)-Val-Asp(OAll)-OH [ No CAS ]
[ 25316-40-9 ]
Ac-Lys(OAloc)-Gly-Asp(OAll)-Glu(OAll)-Val-Asp(OAll)-OH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	4. Ac-Lys(OAloc)-Gly-Asp(OAll)-Glu(OAll)-Val-Asp(OAll)-PABC-DOX (19) [0096] Ac-Lys(OAloc)-Gly-Asp(OAll)-Glu(OAll)-Val-Asp(OAll)-PABC (77 mg, 0.065 mmol) and <strong>[25316-40-9]doxorubicin hydrochloride</strong> (1.2 eq) were dissolved in anhydrous DMF (8 mL), and then DIEA (5.4 eq) was added, and the flask was wrapped with foil to block light, followed by stirring at room temperature for 16 hours. The solvent was removed under reduced pressure, and then prep. HPLC was performed to separate Ac-Lys(OAloc)-Gly-Asp(OAll)-Glu(OAll)-Val-Asp(OAll)-PABC-DOX (non-crystalline orange-red solid, 76 mg, 74%) as Compound 19. [0097] [HPLC separation conditions: C-18 reverse-phase 22 mm i.d.×250 mm column; flow-rate 10 mL/min; 20100% (acetonitrile) in (water+0.1% TFA) linear gradient elution over 50 min.; retention time 34 min], ESI-MS: [M+Na+]=1605.06

Reference： [1]Patent: US2013/338422,2013,A1 .Location in patent: Paragraph 0095; 0096; 0097

26
[ 1596412-91-7 ]
[ 25316-40-9 ]
[ 1596412-92-8 ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	Doxorubicin hydrochloride (70.6 mg, 0.000122 moles) was dissolved DMF (1.5 mL), followed by addition of N,N-diisopropylethylamine (DIPEA) (0.021 mL, 0.000122 moles) and b5 (48 mg, 0.000116 moles). The solution was stirred at room temperature overnight, diluted with ethyl acetate (75 mL), and washed twice with water (50 mL each) and brine (50 mL). The organic layer was dried with anhydrous magnesium sulfate, which was removed by filtration. The filtrate was concentrated, and the residue was subject to silica gel chromatography using a gradient of 100% dichloromethane to 10% methanol in dichloromethane. The fractions containing the product were collected, and volatiles were removed by rotary evaporation. The resulting residue was dried overnight to yield DOX-N3 as a red solid (yield 92%). 1H NMR (400 MHz, CD2Cl2) delta 13.94 (s, 1H), 13.10 (s, 1H), 8.09 (d, J=9.1 Hz, 1H), 7.91 (dd, J=7.7, 1.1 Hz, 2H), 7.74 (t, J=8.1 Hz, 1H), 7.35 (dd, J=8.5, 1.1 Hz, 1H), 7.03-6.97 (m, 1H), 6.86-6.81 (m, 1H), 5.54 (d, J=8.6 Hz, 1H), 5.51-5.47 (m, 1H), 5.40 (dd, 24.6, 15.7, 1H), 5.24-5.19 (m, 1H), 4.74 (s, 2H), 4.60 (s, 1H), 4.19-4.11 (m, 1H), 4.09 (t, J=6.0 Hz, 2H) 3.99 (s, 3H), 3.89-3.82 (m, 1H), 3.68 (s, 1H), 3.48 (t, J=6.5 Hz, 2H), 3.22-3.12 (m, 1H), 2.94-2.87 (m, 1H), 2.50 (s, 1H), 2.34 (d, J=14.7 Hz, 1H), 2.13 (dd, J=14.6, 4.1 Hz, 1H), 2.02 (p, J=6.3 Hz, 2H), 1.91-1.80 (m, 2H), 1.29 (d, J=6.5 Hz, 3H). 13C-NMR (100 MHz, CD2Cl2) delta 214.52, 187.20, 163.64, 161.60, 156.56, 155.90, 155.49, 140.54, 136.24, 135.77, 134.17, 133.96, 128.32, 120.00, 119.21, 114.20, 113.48, 112.02, 111.87, 101.11, 77.18, 69.96, 67.96, 66.08, 66.03, 63.99, 57.03, 48.57, 47.48, 36.09, 34.40, 30.61, 28.97, 17.15 HRMS m/z: calculated for C38H39N5O16 [M+Na]+, 844.2284. found, 844.2271. Observed DMF, but does not interfere with the next step: 1H NMR (400 MHz, CD2Cl2) delta 7.96 (s), 2.91 (s), 2.82 (s); 13C-NMR (100 MHz, CD2Cl2) delta 162.89, 36.79, 31.61. **Pseudo-pentet

Reference： [1]Patent: US2014/308234,2014,A1 .Location in patent: Paragraph 0269; 0270
[2]Journal of the American Chemical Society,2014,vol. 136,p. 5896 - 5899

27
(E)-2,5-dioxopyrrolidin-1-yl 5-((((2, 5-dioxopyrrolidin-1-yl)oxy)carbonyl)oxy)-1-methylcyclooct-3-enecarboxylate [ No CAS ]
[ 25316-40-9 ]
doxorubicin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;	Doxorubicin hydrochloride(133mg; 2.3010-4 mol) were dissolved in DMF (5 mL), and DIPEA (148 mg; 1.15 10~3 mol) was added. The solution was stirred under an atmosphere of argon at 20C for 18 h. Acetonitrile (6.5 mL), formic acid (0.2 mL), and water (6.5 mL), were added and the suspension was filtered. The filtrate was purified by preparative RP-HPLC (50 v% acetonitrile in water, containing 0.1 v% formic acid). The product was isolated by lyophilization, dissolved in chloroform (3 mL), and precipitated in diethyl ether (20 mL), to yield 134 mg of an orange powder (68%). 1H-NMR (CDC13): delta - 13.97 (s, 1H), 13.22 (s, 1H), 8.03 (d, 7=7.9 Hz, 1H), 7.78 (t, 7=8.0 Hz, 1H), 7.38 (d, 7=8.6 Hz, 1H), 5.85 (m, 1H), 5.59 (m, 1H), 5.51 (s, 1H), 5.29 (s, 1H). 5.16 (d, 7=8.4 Hz, 1H), 5.12 (s, 1H), 4.75 (d, 7=4.8 Hz, 2 H), 4.52 (d, 7=5.8 Hz, 1H), 4.15 (q, 7=6.5 Hz, 1H), 4.08 (d, 7=3.6 Hz, 3H), 3.87 (m, 1H), 3.69 (m, 1H), 3.26 (d, 7=18.8 Hz, 1H), 3.00 (m, 2H), 2.81 (s, 4H), 2.4 - 1.7 (br. m, 13H), 1.62 (s, 2H), 1.30 (d, 7=6.5 Hz, 3H), 1.23 (s, 3H) ppm. 13C-NMR (CDCI3): delta = 213.89, 187.07, 186.68, 174.30, 169.27, 161.03, 156.15, 155.64, 154.66, 135.73, 135.49, 133.58, 131.70, 131.10, 120.88, 119.83, 118.43, 111.58, 111.40, 100.73, 72.09, 69.65, 67.28, 65.54, 56.67, 46.87, 44.38, 35.75, 34.00, 30.49, 30.39, 30.20, 25.61, 17.92, 16.84 ppm. LC-MS: m/z = +873.42 [M+Na]+ , - 849.58 [M-H]" (calcd 850.28 for C42H46N2O17).
68%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;	Doxorubicin hydrochloride (133 mg; 2.30* 10"4 mol) and TCO-2 (97.0 mg; 2.30* 10"4 mol) were dissolved in DMF (5 niL), and DIPEA (148 mg; 1.15* 10 3 mol) was added. The solution was stirred under an atmosphere of argon at 20C for 18 h. Acetonitrile (6.5 mL), formic acid (0.2 mL), and water (6.5 mL), were added and the suspension was filtered. The filtrate was purified by preparative RP-HPLC (50 v% acetonitrile in water, containing 0.1 v% formic acid). The product was isolated by lyophilization, dissolved in chloroform (3 mL), and precipitated in diethyl ether (20 mL), to yield 134 mg of an orange powder (68%). 1H-NMR (CDC13): delta = 13.97 (s, 1H), 13.22 (s, 1H), 8.03 (d, =7.9 Hz, 1H), 7.78 (t, =8.0 Hz, 1H), 7.38 (d, =8.6 Hz, 1H), 5.85 (m, 1H), 5.59 (m, 1H), 5.51 (s, 1H), 5.29 (s, 1H). 5.16 (d, =8.4 Hz, 1H), 5.12 (s, 1H), 4.75 (d, =4.8 Hz, 2 H), 4.52 (d, =5.8 Hz, 1H), 4.15 (q, =6.5 Hz, 1H), 4.08 (d, =3.6 Hz, 3H), 3.87 (m, 1H), 3.69 (m, 1H), 3.26 (d, =18.8 Hz, 1H), 3.00 (m, 2H), 2.81 (s, 4H), 2.4 - 1.7 (br. m, 13H), 1.62 (s, 2H), 1.30 (d, =6.5 Hz, 3H), 1.23 (s, 3H) ppm. 13C-NMR (CDCI3): delta = 213.89, 187.07, 186.68, 174.30, 169.27, 161.03, 156.15, 155.64, 154.66, 135.73, 135.49, 133.58, 131.70, 131.10, 120.88, 119.83, 118.43, 111.58, 111.40, 100.73, 72.09, 69.65, 67.28, 65.54, 56.67, 46.87, 44.38, 35.75, 34.00, 30.49, 30.39, 30.20, 25.61, 17.92, 16.84 ppm. LC-MS: m/z = +873.42 [M+Na]+ , - 849.58 [Mu-EtaGamma (calcd 850.28 for C^H^NiOn).

Reference： [1]Patent: WO2014/81300,2014,A1 .Location in patent: Page/Page column 110
[2]Patent: WO2014/81299,2014,A1 .Location in patent: Page/Page column 126; 127

28
[ 874302-76-8 ]
[ 25316-40-9 ]
[ 1058725-05-5 ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 12h;Darkness;	To an oven dried round bottom flask under nitrogen at room temperature equipped with a stir bar was added 2?-aldnthiol (6.4 g, 29.0 mmol) in 25 mL methanol purged withnitrogen. To this mixture was added 2-mercaptoethanol dropwise (757 mg, 9.78 mmol). The solution turned yellow and was allowed to stir for three hours. The solvent was then removed in vacuo and the cmde material was purified by column chromatography (Si02, DCM:EtOAc = 4: 1). The excess amount of the 2?-aldnthiol was eluted first with strong 280 nm wavelength absorption, followed by the desired product and then 2-mercaptopyridine. Theproduct was a yellow oil (5.05 g, 27.0 mmol, 93% yield). LCMS (M+1) = 188.274. NMR was consistent with the reported number. 2-(2-pyndyldithio)ethanol (121) (3 g, 16 mmol) and Et3N (4.5 mL, 32 mmol) were dissolved in DCM (60 mL) at 0 C. 4-Nitrophenyl chloroformate (3.55 g, 17.6 mmol) was added to the above solution at the same temperature. The resulting light yellow solution was allowed to warm up to room temperature and stirredfor another 4 hours. LCMS analysis for the above mixture after 4 hours stirring indicated complete consumption of the starting material. The light yellow reaction mixture was washed with water (2x50 mL) to remove the precipitated Et3N hydrochloride. The organic layer was dried with Na2SO4, filtered, and concentrated under vacuum. Crude product (122) was purified by column chromatography (Si02, Hexane: EtOAc = 1: 1) as a light yellow oil(5.08 g, 14.4 mmol, 90%). NMR was consistent with the published data. Compound (122) (1.34 g, 3.79 mmol) and Et3N (0.72 mL, 5.17 mmol) were dissolved in DCM/DMF (1:1, 12 mL, for the poor solubility of doxombicin hydrochloride in DCM). Doxombicin hydrochloride (2 g, 3.45 mmol) was then added to the above solution and the overall reaction mixture was stirred at room temperature under dark for 12 hours. LCMS analysis for theabove mixture after 12 hours stirring indicated complete consumption of compound (122). The solvent was removed under vacuum and the cmde material was re-dissolved in DCM and purified by column chromatography (Si02, DCM: MeOH = 20: 1) to afford product (123) as a red solid (2.27 g, 30.0 mmol, 87%).2 ?H NMR (500 MI-Tz, DMSO-d6) 13.88 (s, 1H), 13.11 (s, 1H), 8.56-8.16 (m, 1H), 7.99-7.61 (m, 4H), 7.49 (d,J= 8.4 Hz, 1H), 7.25-7.02 (m, 1H),6.80 (d, J= 8.0 Hz, 1H), 5.34 (s, 1H), 5.27-5.08 (m, 1H), 4.86 (t, J 5.9 Hz, 1H), 4.83-4.79(m, 1H), 4.70 (d, J= 5.7 Hz, 1H), 4.57 (d, J= 5.9 Hz, 3H), 4.34-4.00 (m, 3H), 3.90 (s, 3H),3.68 (d, J 13.4 Hz, 1H), 3.42 (dd, J 6.0, 2.6 Hz, 1H), 3.12-2.71 (m, 4H), 2.48 (t, J= 1.9Hz, 1H), 2.18 (d,J= 14.1 Hz, 1H), 2.03 (dd,J= 14.2, 5.5 Hz, 1H), 1.92-1.73 (m, 1H), 1.46(d, J 11.1 Hz, 1H), 1.12 (d, J 6.3 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) 214.33,186.56, 186.44, 161.04, 159.38, 156.48, 155.41, 154.87, 149.92, 138.19, 136.45, 135.70,134.77, 134.32, 121.60, 120.09, 119.90, 119.62, 119.23, 110.94, 110.81, 100.81, 75.31,70.20, 68.39, 67.06, 64.20, 61.85, 56.89, 47.58, 37.79, 36.76, 32.39, 30.24, 17.47.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 82,p. 355 - 362
[2]Patent: WO2019/23621,2019,A1 .Location in patent: Page/Page column 63

29
[ 124243-00-1 ]
[ 25316-40-9 ]
C₅₂H₅₁NO₁₇S₂ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2015,vol. 21,p. 228 - 238

30
[ 4781-83-3 ]
[ 25316-40-9 ]
C₃₁H₃₆N₂O₁₁S*ClH [ No CAS ]

Reference： [1]Journal of Controlled Release,2015,vol. 217,p. 64 - 73

31
[ 64987-85-5 ]
[ 25316-40-9 ]
C₃₉H₄₄N₂O₁₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 6435 - 6447

32
[ 55750-61-3 ]
[ 25316-40-9 ]
C₃₃H₃₄N₂O₁₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 6435 - 6447

33
[ 863971-53-3 ]
[ 25316-40-9 ]
C₆₁H₆₆N₆O₁₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	To a suspension of Dox.HCI (25 mg, 0.043 mmol) and Fmoc-Val-Cit-PNP 13 (30 mg, 0.039 mmol) in dry DMF (1 ml) DIPEA (7.5 muIota, 0.043 mmol) was added, resulting in a dark-red solution. This was stirred at toom temperature under nitrogen for 24 h after which the solvent was evaporated under high vacuum and the residue triturated with dry diethyl ether to give a red solid Rf 0.22 [silica gel: 10% MeOH/DCM]. Purification by flash chromatography [silica gel: 5% MeOH/DCM] gave the desired product 14 as a red solid 25.2 mg (55 %); HRMS (m/z) calculated for C61H67N6O18[M + H] 1 171.4512 found: 1 171.4534

Reference： [1]Patent: WO2016/46574,2016,A1 .Location in patent: Page/Page column 65

34
[ 863971-53-3 ]
[ 25316-40-9 ]
[ 1022094-34-3 ]

Reference： [1]Patent: WO2016/46574,2016,A1

35
[ 25316-40-9 ]
[ 546-43-0 ]
C₄₂H₄₉NO₁₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With sodium hydrogencarbonate; In methanol; water; at 20℃; for 144h;	Doxorubicin hydrochloride (250 mg, 0.431 mmol), <strong>[546-43-0]alantolactone</strong> (2, 100.1 mg, 0.431 mmol), andNaHCO3 (72 mg, 0.862 mmol) were dissolved in MeOH (3 mL) and H2O (0.1 mL) and left for 6 d at room temperature. Thecourse of the reaction was monitored by TLC on Silufol plates using CHCl3-MeOH (4:1, Rf of 3b, 0.75). The mixture wasevaporated at reduced pressure and purified by column chromatography over silica gel (20 g) with elution first by CHCl3 andthen by mixtures with added MeOH (10% and 20%). Evaporation afforded the product (144 mg, 43%, 0.186 mmol) as redplate-like crystals, mp 214-220, found: m/z 776.3244 [ + H]+. C42H49NO13. Calcd: 776.3277 [M + H]+. 1 NMR spectrum(CDCl3, , ppm, J/Hz): 0.90 (3H, d, J = 7.4, H-42), 0.9 (1, m, H-34), 1.00 (3H, s, H-41), 1.15 (3H, d, J = 6.5, H-27), 1.21 (1H,m, H-35), 1.32 (2H, m, H-32 + H-36), 1.40 (1H, m, H-34), 1.63 (3H, m, H-23 + H-35), 1.89 (1H, dd, J1 = 14.8, J2 = 2.9,H-32), 1.98 (1H, dd, J1 = 14.9, J2 = 4.2, H-12), 2.20 (1H, d, J = 14.9, H-12), 2.24 (1H, m, H-37), 2.54 (1H, m, H-28), 2.69(1H, m, H-24), 2.79 (3H, m, H-10 + H-28 + H-29), 2.96 (1H, m, H-30), 3.02 (1H, d, J = 18.0, H-10), 3.52 (1H, br.s, H-25),3.89 (4H, m, H-21 + H-26), 4.59 (3H, m, H-20 + H-31), 4.89 (1H, d, J = 2.5, H-39), 5.07 (1H, br.s, H-13), 5.32 (1H, br.s,H-22), 7.26 (1H, m, H-2), 7.62 (1H, t, J = 8.2, H-3), 7.80 (1H, d, J = 8.2, H-4). 13C NMR spectrum (CDCl3, , ppm): 16.5(C-35), 16.6 (C-27), 22.6 (C-42), 28.3 (C-41), 30.0 (C-23), 32.6 (C-36), 32.8 (C-33), 33.4 (C-10), 35.4 (C-12), 37.5 (C-30),38.3 (C-37), 42.0 (C-34), 42.1 (C-28), 42.4 (C-32), 45.7 (C-29), 52.7 (C-24), 56.4 (C-21), 64.9 (C-20), 66.8 (C-25), 67.3(C-26), 69.5 (C-13), 77.3 (C-31), 100.9 (C-22), 114.4 (C-39), 118.6 (C-2), 119.6 (C-4), 135.8 (C-3).
43%	With triethylamine; In methanol; chloroform; at 20℃; for 168h;	General procedure: The corresponding lactone (I)-(VI)(0.431 mmol) was dissolved in the mixture of methanol(1.5 mL) and chloroform (1.5 mL). Doxorubicinhydrochloride (250 mg) and triethylamine (120 muL,2 equivalents) were added. The reaction mixture waskept seven days at room temperature. The reaction wasmonitored by TLC in the CHCl3-MeOH chromatographicsystem (9 : 1). The product Rf ? 0.5. The reactionmixture was evaporated at a reduced pressure andpurified by column chromatography on silica gel. Thecolumn was eluted with CHCl3 and then with 20%MeOH in chloroform. The product was eluted fromthe column as a narrow zone.

Reference： [1]Chemistry of Natural Compounds,2016,vol. 52,p. 695 - 696
Khim. Prir. Soedin.,2016,p. 597 - 598,2
[2]Russian Journal of Bioorganic Chemistry,2018,vol. 44,p. 538 - 546
Bioorg. Khim.,2018,vol. 44,p. 538 - 546,9

36
[ 874302-76-8 ]
[ 25316-40-9 ]
DOX-S-S-Pyr [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;	To a solution of compound 2 (10 mg, 0.028 mmol) and doxorubicin hydrochloride (12 mg, 0.020 mmol) in DMF (1 mL) under N2, DIPEA (8 jiL, 0.028 mmol) is added at room temperature and stirred for 16 h. Then, the solvent is evaporated and the residue is purified by flash chromatography (eluent: CH2C12/MeOH 20:1) to obtain compound 3(Figure 3) as red solid in 90% yield; 1H NMR (500 MHz, CDC13) oe 13.94 (s, 1H), 13.18(s, 1H), 8.40 (d, J= 3.8 Hz, 1H), 8.00 (d, J 7.6 Hz, 1H), 7.76 (t, J 8.0 Hz, 1H), 7.70(d, J 7.5 Hz, 1H), 7.63 (t, J 7.4 Hz, 1H), 7.37 (d, J= 8.5 Hz, 1H), 7.07 (t, J= 1H),5.50 b(s, 1H), 5.26 (dd, J= 3.7, 2.0 Hz, 1H), 5.15 (d, J= 8.8 Hz, 1H), 4.74 b(s, J 21.4Hz, 2H), 4.56 (bs, 1H), 4.42 - 4.34 (m, 1H), 4.21 - 4.08 (m, 2H), 4.06 (s, 3H), 3.81 (m,1H), 3.62 (bs, 1H), 3.22 (dd, J= 18.8, 1.5 Hz, 1H), 3.14-2.86 (m, 5H), 2.33 (d, J14.6 Hz, 1H), 2.15 (dd, J= 15.0, 3.6 Hz, 1H), 1.81 (m, 2H), 1.48 - 1.42 (m, 2H), 1.29(d, J 6.5 Hz, 3H); 13C NMR (126 MHz, CDC13) oe 213.9, 187.0, 186.6, 161.0, 160.1,156.2, 155.6, 155.2, 149.8, 149.4, 137.3, 135.7, 135.4, 133.6, 133.6, 120.9, 120.8,119.9, 119.8, 118.4, 111.5, 111.4, 100.9, 69.7, 69.0, 67.4, 65.6, 63.5, 56.7, 53.4, 47.0,37.5, 35.6, 33.9, 30.0, 29.7, 28.3, 17.0; MS (ESI): mlz (%)757(100), (figures 13 and14).

Reference： [1]Patent: WO2016/150521,2016,A1 .Location in patent: Paragraph 32

37
[ 1151989-04-6 ]
[ 25316-40-9 ]
C₅₁H₅₁N₃O₁₄S₂ [ No CAS ]

Reference： [1]Journal of Materials Chemistry B,2017,vol. 5,p. 2644 - 2654

38
[ 1151989-04-6 ]
[ 25316-40-9 ]
C₄₀H₃₈N₂O₁₃S₂ [ No CAS ]

Reference： [1]Journal of Materials Chemistry B,2017,vol. 5,p. 2644 - 2654

39
[ 55750-62-4 ]
[ 25316-40-9 ]
[ 273216-93-6 ]

Reference： [1]Journal of Peptide Science,2019,vol. 25
[2]Chemical Biology and Drug Design,2020,vol. 95,p. 58 - 65

40
[ 1151989-04-6 ]
[ 25316-40-9 ]
C₄₀H₃₈N₂O₁₃S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%		Synthesis of Compound 9:Doxorubicin hydrochloride in the dark at room temperature (DOX·HCl, 127 mg, 0.22 mmol, 1 eq)Dissolved into dry dimethylformamide (4 mL),Triethylamine (34 mg, 46 muL, 0.33 mmol, 1.5 eq) was added slowly.The reaction solution was stirred at room temperature for 0.5 hour.Compound 8 (95 mg, 0.23 mmol, 1.05 eq) was added slowly,A solution of traces of 4-dimethylaminopyridine in dimethylformamide (2 mL).The reaction was carried out in the dark at room temperature and poured directly into water. The precipitated solid was filtered, washed with purified water and dried under vacuum.The crude product was further purified by rapid preparative column chromatography (methanol: dichloromethane, 1:50 to 1:10 v/v)Obtained as a dark red solid (61 mg, 34%).

Reference： [1]ChemMedChem,2019,vol. 14,p. 1196 - 1203
[2]Patent: CN109846824,2019,A .Location in patent: Paragraph 0068-0070

41
[ 1151989-04-6 ]
[ 25316-40-9 ]
doxorubicin [ No CAS ]

Reference： [1]Patent: CN109846824,2019,A

42
[ 463-40-1 ]
[ 25316-40-9 ]
[ 1116566-29-0 ]

Yield	Reaction Conditions	Operation in experiment
68%		General procedure: A solution of carboxylic acid (1 eqv, 0.34mmol) andN,N?-dicyclohexylcarbodiimide (DCC) (1.5 eqv, 106.8mg,0.52mmol) in dry CH2Cl2/DMF (9:1, 28mL) was stirred for15min at 22 C. Then, DMAP (1.1 eqv, 46.4mg, 0.38mmol)and DOX·HCl (1 eqv, 200mg, 0.34mmol) were added andthe red suspension was stirred for 20 h at 22-23 C in thedark. Then reaction mixture was filtered, solid was washedwith CH2Cl2 (2 × 20mL), and next the combined organicphases was washed with 1.5% HCl water solution (2 ×15mL). The organic layer was dried over MgSO4 and afterevaporation of the solvent under reduced pressure the productwas isolated using column chromatography on silica gel andCH2Cl2:MeOH mixture (0-2% MeOH) as an eluent.

Reference： [1]Medicinal Chemistry Research,2019,vol. 28,p. 2153 - 2164

43
[ 463-40-1 ]
[ 25316-40-9 ]
C₆₃H₈₅NO₁₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		General procedure: A solution of carboxylic acid (2 eqv, 0.34 mmol) andN,N?-dicyclohexylcarbodiimide (DCC) (2.5 eqv, 89.0 mg,0.43 mmol) in dry CH2Cl2/DMF (9:1, 14 mL) was stirredfor 15 min at 22 C. Then, DMAP (1.1 eqv, 23.2 mg,0.19 mmol) and DOX·HCl (1 eqv, 100 mg, 0.17 mmol)were added and the red suspension was stirred for 20 h at22-23 C in the dark. Then reaction mixture was filtered,solid was washed with CH2Cl2 (2 × 10 mL), and next thecombined organic phases were washed with 1.5% HClwater solution (2 × 10 mL). The organic layer was driedover MgSO4 and after evaporation of the solvent underreduced pressure the product was isolated using columnchromatography on silica gel and CH2Cl2:MeOH mixture(0-1% MeOH) as an eluent.

Reference： [1]Medicinal Chemistry Research,2019,vol. 28,p. 2153 - 2164

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	25316-40-9	MDL No. :	MFCD00077757
Formula :	C₂₇H₃₀ClNO₁₁	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	579.98 g/mol	Pubchem ID :	-
Synonyms :

Num. heavy atoms :	40
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.44
Num. rotatable bonds :	5
Num. H-bond acceptors :	12.0
Num. H-bond donors :	6.0
Molar Refractivity :	139.63
TPSA :	206.07 Å²

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-8.37 cm/s

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.07
Log Po/w (WLOGP) :	0.48
Log Po/w (MLOGP) :	-1.9
Log Po/w (SILICOS-IT) :	1.17
Consensus Log Po/w :	0.36

[ CAS No. 25316-40-9 ]

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[ 25316-40-9 ] Synthesis Path-Upstream 1~2

[ 25316-40-9 ] Synthesis Path-Downstream 1~43

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[ 25316-40-9 ]

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Inquiry

Lipinski :	3.0
Ghose :	None
Veber :	1.0
Egan :	1.0
Muegge :	3.0
Bioavailability Score :	0.17

Log S (ESOL) :	-4.63
Solubility :	0.0135 mg/ml ; 0.0000233 mol/l
Class :	Moderately soluble
Log S (Ali) :	-6.03
Solubility :	0.000545 mg/ml ; 0.00000094 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-3.46
Solubility :	0.2 mg/ml ; 0.000344 mol/l
Class :	Soluble

PAINS :	1.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	5.88

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335-H351-H361	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
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P285	In case of inadequate ventilation wear respiratory protection.
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P342	If experiencing respiratory symptoms:
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P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
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P401
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P411 + P235	Keep cool.
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P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling