[ CAS No. 64987-85-5 ] {[proInfo.proName]}

Name: 64987-85-5|2,5-Dioxopyrrolidin-1-yl 4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexanecarboxylate|97%
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SKU: A104275
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Quality Control of [ 64987-85-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 64987-85-5 ]

SDS Specification

Alternatived Products of [ 64987-85-5 ]

Product Details of [ 64987-85-5 ]

CAS No. :	64987-85-5	MDL No. :	MFCD00009634
Formula :	C₁₆H₁₈N₂O₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JJAHTWIKCUJRDK-UHFFFAOYSA-N
M.W :	334.32	Pubchem ID :	125175
Synonyms :	NSC 344483;Succinimidyl-4-(N-maleimidomethyl cyclohexane)-1-carboxylate;SMCC crosslinker;SMCC, heterobifunctional cross-linker;Succinimidyl 4-(N-maleimidomethyl)cyclohexan-1-carboxylate	Chemical Name :	2,5-Dioxopyrrolidin-1-yl 4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexanecarboxylate

Calculated chemistry of [ 64987-85-5 ] Expand+

Physicochemical Properties

Num. heavy atoms :	24
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.56
Num. rotatable bonds :	5
Num. H-bond acceptors :	6.0
Num. H-bond donors :	0.0
Molar Refractivity :	87.92
TPSA :	101.06 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-8.4 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.15
Log Po/w (XLOGP3) :	-0.09
Log Po/w (WLOGP) :	-0.44
Log Po/w (MLOGP) :	0.81
Log Po/w (SILICOS-IT) :	0.43
Consensus Log Po/w :	0.57

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.53
Solubility :	9.96 mg/ml ; 0.0298 mol/l
Class :	Very soluble
Log S (Ali) :	-1.58
Solubility :	8.79 mg/ml ; 0.0263 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.13
Solubility :	24.8 mg/ml ; 0.0743 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.88

Safety of [ 64987-85-5 ]

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

Application In Synthesis of [ 64987-85-5 ]

* 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.

Upstream synthesis route of [ 64987-85-5 ]
Downstream synthetic route of [ 64987-85-5 ]

[ 64987-85-5 ] Synthesis Path-Upstream 1~2

1
[ 6066-82-6 ]
[ 64987-85-5 ]

Reference： [1] Journal of Pharmaceutical Sciences, 1986, vol. 75, # 7, p. 711 - 713

2
[ 64987-85-5 ]
[ 2450-71-7 ]
[ 1036847-90-1 ]

Reference： [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 21, p. 6916 - 6926

[ 64987-85-5 ] Synthesis Path-Downstream 1~84

1
[ 6066-82-6 ]
[ 64987-85-5 ]

Reference： [1]Journal of Pharmaceutical Sciences,1986,vol. 75,p. 711 - 713

2
[ 64987-85-5 ]
[ 20255-95-2 ]
dimyristoyl-N-<<4-(maleimidomethyl)cyclohexyl>carbonyl>phosphatidylethanolamine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1988,vol. 110,p. 7455 - 7459

3
[ 64987-85-5 ]
[ 124659-35-4 ]
{5,9-Bis-carboxymethyl-3-[4-([4-(2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl)-cyclohexanecarbonyl]-amino}-methyl)-benzyl]-1,5,9-triaza-cyclododec-1-yl}-acetic acid [ No CAS ]

Reference： [1]Journal of the Chemical Society. Chemical communications,1989,p. 794 - 796

4
[ 64987-85-5 ]
[ 62571-86-2 ]
(S)-1-((S)-3-{1-[4-(2,5-Dioxo-pyrrolidin-1-yloxycarbonyl)-cyclohexylmethyl]-2,5-dioxo-pyrrolidin-3-ylsulfanyl}-2-methyl-propionyl)-pyrrolidine-2-carboxylic acid [ No CAS ]

Reference： [1]Journal of Pharmaceutical Sciences,1986,vol. 75,p. 711 - 713

5
[ 64987-85-5 ]
[ 173415-05-9 ]
C₄₉H₇₈N₄O₂₆ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 509 - 514

6
[ 64987-85-5 ]
[ 167475-62-9 ]
C₄₉H₇₈N₄O₂₆ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 509 - 514

8
[ 64987-85-5 ]
5\-DAP-p-d(CAGTAAATATCTAGGA)-deg-U, DAP = 1,5-diaminopentane, deg = diethylene glycol linker [ No CAS ]
5\-MaM-DAP-p-d(CAGTAAATATCTAGGA)-deg-U, MaM = 4-(N-maleimidomethyl)cyclohexane-1-carbonyl, DAP = 1,5-diaminopentane, deg = diethylene glycol linker [ No CAS ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2003,vol. 22,p. 1715 - 1719

9
[ 64987-85-5 ]
5\-p-d(CAGTAAATATCTAGGA)-deg-U-Lys, deg = diethylene glycol linker [ No CAS ]
5\-p-d(CAGTAAATATCTAGGA)-deg-U-Lys-MaM, deg = diethylene glycol linker, MaM = 4-(N-maleimidomethyl)cyclohexane-1-carbonyl [ No CAS ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2003,vol. 22,p. 1715 - 1719

10
[ 64987-85-5 ]
[ 70-54-2 ]
[ 462-94-2 ]
5\-p-d(CAGTAAATATCTAGGA)-deg-U, deg = diethylene glycol linker [ No CAS ]
fluorescein isothiocyanate [ No CAS ]
5\-Flu-DAP-p-d(CAGTAAATATCTAGGA)-deg-U-Lys-MaM, Flu = fluorescein isothiocyanate, DAP = 1,5-diaminopentane, deg = diethylene glycol linker, MaM = 4-(N-maleimidomethyl)cyclohexane-1-carbonyl [ No CAS ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2003,vol. 22,p. 1715 - 1719

11
[ 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

12
[ 64987-85-5 ]
recombinant streptavidin [ No CAS ]
rSAv-SMCC [ No CAS ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2003,vol. 46,p. S387 - S387

13
[ 23214-92-8 ]
[ 64987-85-5 ]
[ 400647-59-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5071 - 5075

14
5-(2-aminoethyl)indole-3-acetic acid [ No CAS ]
[ 64987-85-5 ]
5-{2-[4-(maleimidomethyl)cyclohexane-1-carboxamido]ethyl}indole-3-acetic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 3229 - 3240

15
6-(2-aminoethyl)indole-3-acetic acid [ No CAS ]
[ 64987-85-5 ]
[6-(2-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl)-cyclohexanecarbonyl]-amino}-ethyl)-1H-indol-3-yl]-acetic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 3229 - 3240

16
[ 872854-10-9 ]
[ 64987-85-5 ]
[ 872854-12-1 ]

Reference： [1]European Journal of Medicinal Chemistry,2005,vol. 40,p. 1295 - 1306

17
[ 872854-06-3 ]
[ 64987-85-5 ]
[ 872854-08-5 ]

Reference： [1]European Journal of Medicinal Chemistry,2005,vol. 40,p. 1295 - 1306

18
[ 872854-03-0 ]
[ 64987-85-5 ]
[ 872854-01-8 ]

Reference： [1]European Journal of Medicinal Chemistry,2005,vol. 40,p. 1295 - 1306

19
[ 64987-85-5 ]
[ 77420-96-3 ]
[ 872854-14-3 ]

Reference： [1]European Journal of Medicinal Chemistry,2005,vol. 40,p. 1295 - 1306

20
[ 912816-65-0 ]
[ 64987-85-5 ]
4-(2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl)-cyclohexanecarboxylic acid (3-{2-methoxy-4-[5-(4-methyl-piperazin-1-yl)-1H,1'H-[2,5']bibenzoimidazolyl-2'-yl]-phenoxy}-propyl)-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 6444 - 6452

21
[ 64987-85-5 ]
[ 60-32-2 ]
[ 172100-40-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 420℃; for 4h;	DIEA (78 pL, 0.50 mmol) and 6-aminohexanoic acid (44 mg, 0.33 mmol) were added to a solution of succinimidyl-4-(N-maleimidomethyl)cyclohexane-1 -carboxylate (0.30 mmol) in DMF (5 mL) in a 40 mL vial, and the reaction mixture was stirred at rt for 4 h. Thereaction mixture was then purified by HPLC and lyophilized to give 76-(4-((2,5-dioxo-2,5- dihydro-1 H-pyrrol-1 -yl)methyl)cyclohexanecarboxam ido)hexanoic acid (i-2). MS (M+1) =351, 1H-NMR (MeOD, 400 MHz) O 7.79 (bs, 1H), 6.76 (s, 2H), 3.29 (d, 2H, J=4.4 Hz), 3.10 (m, 2H), 2.24 (t, 2H, J=7.2 Hz), 2.07 (m, 4H), 1.56(m, 3H) 1.43 (m, 3H), 1.33 (m, 3H), 0.97 (m, 2 H).
	In water; N,N-dimethyl-formamide; at 20℃; for 4.08333h;	A solution of succinimidyl 4-[N-maleimidomethyl]cyclohexane-l-carboxylate (PIERCE Ref: 22360) (25 mmol) in DMF (10OmL) was stirred for 5 min, and was added at room temperature to a solution of 6-aminohexanoic acid (50 mmol) (SIGMA Ref: A2504) in H2O(50 mL). The mixture was stirred for 4h at room temperature. Dichloromethane was added(100 mL) and the organic layer was washed with water (3x150 mL) and then with 5percent aqueous citric acid (3x150 mL) to remove 6-aminohexanoic acid excess. The organic layer was dried under vacuum and the resulting white powder was stored at -200C.

Reference： [1]Patent: WO2016/71856,2016,A1 .Location in patent: Page/Page column 113
[2]Patent: WO2007/113687,2007,A2 .Location in patent: Page/Page column 44

22
tranexamic acid [ No CAS ]
[ 64987-85-5 ]
4-[((N-maleimidomethyl)cyclohexanecarboxamido)methyl]cyclohexanecarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water; N,N-dimethyl-formamide; at 20℃; for 4.08333h;	A solution of succinimidyl 4-[N-maleimidomethyl]cyclohexane-l-carboxylate (PIERCE Ref: 22360) (25 mmol) in DMF (100 mL) was stirred for 5 min, and was added at room temperature to a solution of tralphapiji-4-(aminomethyl)cyclohexanecarboxylic acid (50 mmol) (SIGMA ref: 08455) in H2O (50 mL). The mixture was stirred for 4h at room temperature. Dichloromethane was added (100 mL) and the organic layer was washed with water (3x150 mL) and then with 5percent aqueous citric acid (3x150 mL) to remove trans-4- <n="46"/>(aminomethyl)cyclohexanecarboxylic acid excess. The organic layer was dried under vacuum and the resulting white powder was stored at -20°C.

Reference： [1]Patent: WO2007/113687,2007,A2 .Location in patent: Page/Page column 44-45

23
C₅₆H₉₆N₆O₁₃ [ No CAS ]
[ 64987-85-5 ]
C₆₈H₁₀₉N₇O₁₆ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 4759 - 4765

24
[ 64987-85-5 ]
C₄₁H₄₆N₂O₁₆S*C₈H₁₉N [ No CAS ]

Reference： [1]Synthetic Communications,2004,vol. 34,p. 2407 - 2414

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide;Aqueous phosphate buffer;Conversion of starting material;	A 20 mM solution of SMCC (6.69 mg/mL) was prepared in dimethylsulfoxide (DMSO). The solution was diluted 1/40 in Assay Buffer and the absorbance of the samples measured at 302 nm. The concentration of the stock solution was calculated using an extinction coefficient of 602 M-1cm-1.
	In dimethyl sulfoxide;Aqueous phosphate buffer;Conversion of starting material;	A 20 mM solution of SMCC (6.69 mg/mL) was prepared in DMSO. The solution was diluted 1/40 in Assay Buffer and the absorbance of the samples was measured at 302 nm. The concentration of the stock solution was calculated using a molar extinction coefficient of 602 M-1 cm-1.

26
[ 64987-85-5 ]
trastuzumab [ No CAS ]
Trastuzumab-SMCC [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Aqueous phosphate buffer;	Trastuzumab antibody was obtained from Genentech for conjugation to DM1 using the non-cleavable heterobifunctional cross-linking reagent SMCC. The antibody was buffer-exchanged from 50 mM potassium phosphate/2 mM EDTA, pH 6.0 into 50 mM potassium phosphate/50 mM sodium chloride/2 mM EDTA, pH 6.5 (Buffer A). The antibody was then reacted with 7.5-fold molar excess SMCC linker and purified by Sephadex G25 resin before it was conjugated with DM1. The final conjugate was again purified by Sephadex G25 resin. The resulting conjugate contained 3.1 moles of DM1 per mole of antibody.
	In dimethyl sulfoxide; at 20℃; for 2h;Aqueous phosphate buffer;	The antibody was modified using a 7.5-fold molar excess of SMCC at 20 mg/mL antibody. The reaction was carried out in Buffer A (95percent v/v) with DMSO (5percent v/v) for 2 hours at room temperature with stirring.

Reference： [1]Patent: US2005/169933,2005,A1 .Location in patent: Page 14
[2]Patent: US2005/169933,2005,A1 .Location in patent: Page 15

27
huC₂₄₂ [ No CAS ]
[ 64987-85-5 ]
huC₂₄₂-SMCC [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide; at 20℃; for 2h;Aqueous phosphate buffer;	The antibody was split into two samples; one was modified using a 7.5-fold molar excess of SMCC cross-linker, the other with a 8.5-fold molar excess of SMCC cross-linker. Samples were reacted at 8 mg/mL antibody. The reactions were carried out in Buffer A (95percent v/v) with DMSO (5percent v/v) for 2 hours at room temperature with stirring.

Reference： [1]Patent: US2005/169933,2005,A1 .Location in patent: Page 14

28
rituximab [ No CAS ]
[ 64987-85-5 ]
Rituximab crosslinked with [succinimidyl 4-(maleimidomethyl) cyclohexane-1-carboxylate] [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With edetate disodium; In water; dimethyl sulfoxide; at 20℃; for 1h;pH 7.5;	1. Derivatization with SMCC. Five mg of Rituximab at a concentration of 5 mg/mL in 0.05M phosphate buffer containing 3 mM Na2EDTA (PBE; pH 7.5) and 2.5 muL of SMCC (9.3 mg/mL in dimethyl sulfoxide) were incubated with continuous rotation at room temperature for 1 h using a SMCC/Rituximab molar ratio of 4.5. Conjugated protein was purified by chromatography on a PD-10 column in the same PBE buffer. 2. Derivatization with SATA. Five mg of Rituximab at a concentration of 5 mg/mL in PBE buffer was mixed with 2.5 muL of SATA (5.8 mg/mL in dimethyl sulfoxide) and incubated at room temperature for 1h using a SATA/Rituximab molar ratio of 4.0. The excess SATA was then removed by chromatography on a PD-10 column and the purified protein was deacetylated with 5 mg of hydroxylamine-HCl (Sigma) for 5 min at room temperature. Excess hydroxylamine-HCl was removed by chromatography on a PD-10 column. 3. Rituximab Homodimer Formation and Physical Characterization SMCC- and SATA-derived proteins were mixed together and incubated with continuous rotation at room temperature for 1-2 h. The preparation was dialyzed overnight in PBS at 4° C., sterilized by filtration through a 0.22 mum non-pyrogenic filter (Costar, Corning, N.Y.), and further fractionated on a Superose 6 Column (FPLC) using the Pharmacia AKTA described above at flow rate of 0.5 mL/min. In general, the polymer revealed a retention time of approximately 16 min while the dimer revealed a retention time of approximately 29 min by FPLC. The protein fractions from FPLC were further concentrated using a Centricon YM-100 (Millipore, Billerica, Mass.), filter sterilized, and analyzed by SDS/PAGE. The expected molecular weights of the Rituximab dimer was observed for the dimer preparation by non-reducing SDS-PAGE. A 2percent agarose gel was used with murine IgM as a standard (970 kDa) for sizing the polymer. By this method, one band was resolved for the Rituximab polymer which was slightly higher than that of IgM corresponding to the molecular weight of approximately 5 immunoglobulin molecules.

Reference： [1]Patent: US2005/214286,2005,A1 .Location in patent: Page/Page column 15

29
C₅₀H₈₄N₄O₂₆ [ No CAS ]
[ 64987-85-5 ]
C₆₂H₉₇N₅O₂₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%Spectr.	In dimethyl sulfoxide; at 20℃; for 3h;borate-buffered saline;	A solution containing 20 mg (60 mumoles) of N-hydroxysuccinimidyl 4-(N- methylmaleimido)cyclohexane-l-carboxylate (SMCC) in 400 muL of anhydrous DMSO was added to a buffered pH 8.6 solution containing 34 mg (~20 mumoles) of crude YE(ahLac)2 (10) in 10 mM borate-buffered saline. The mixture was stirred at room temperature for 3 h, then purified and desalted by size exclusion gel filtration (G- 10 Sephadex, 0.5 x 33 cm) using 20percent ethanol in H2O. Fractions were collected and those which corresponded to the product by 1H NMR spectroscopy was combined and concentrated under diminished pressure. HPLC analysis and purification of the residue was accomplished on an Rainin reversed phase Ci8 column (4.6 mm x 150 mm). The column was washed with a linear gradient system of 50 mM aqueous sodium phosphate (pH 5.8) containing increasing amounts OfCH3CN (0-20 min at a flow rate of 1.0 mL/min. The eluate was monitored at 277 nm; the product eluted at 9.4 min. The yield was determined by UV spectroscopy (A277 = 0.350/1 mL aliquot; 26 mL solution, 45percent)

Reference： [1]Patent: WO2006/104530,2006,A1 .Location in patent: Page/Page column 12; 3/5

30
[ 64987-85-5 ]
[ 153086-78-3 ]
C₂₃H₃₇N₃O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 0.333333h;	SMCC (0.334 g), monoprotected diamine reagent (0.248 g) and DIEA (0.17 mL) were dissolved in dichloromethane (20 mL), stirred at ambient temperature for 20 min. The product was purified by flash chromatography, and further reacted with TFA (2 mL) and anisole (0.5 mL) for 2 hours, and the final product was isolated after removal of TFA and anisole. The corresponding hydrochloride salt was prepared by dissolving in HCl and evaporating off HCl. Mass spectrum: M+H m/e 368. The process schematically shown in Scheme-6.

Reference： [1]Patent: US2008/171067,2008,A1 .Location in patent: Page/Page column 17

31
[ 64987-85-5 ]
[ 909000-59-5 ]
[ 909023-85-4 ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2007,vol. 26,p. 1471 - 1477

32
[ 64987-85-5 ]
acetylcholinesterase [ No CAS ]
acetylcholinesterase and succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate conjugate [ No CAS ]

Reference： [1]Carbohydrate Research,2008,vol. 343,p. 2101 - 2110

33
[ 64987-85-5 ]
[ 2450-71-7 ]
[ 1036847-90-1 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6916 - 6926

34
LMWH; N-deacetylated [ No CAS ]
[ 64987-85-5 ]
LMWH; maleimide and Alexa Fluor 350 functionalized [ No CAS ]

Reference： [1]Patent: US2006/240110,2006,A1 .Location in patent: Page/Page column 9

35
[ 64987-85-5 ]
C₄₈H₄₁N₉O [ No CAS ]
C₆₀H₅₄N₁₀O₄ [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2010,vol. 21,p. 302 - 312

36
[ 64987-85-5 ]
C₅₈H₆₁N₉O₈ [ No CAS ]
C₇₀H₇₄N₁₀O₁₁ [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2010,vol. 21,p. 302 - 312

37
[ 64987-85-5 ]
[ 1374749-52-6 ]
[ 1374847-68-3 ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2012,vol. 31,p. 432 - 444

38
[ 64987-85-5 ]
[ 1374847-87-6 ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2012,vol. 31,p. 432 - 444

39
[ 64987-85-5 ]
[ 1374847-75-2 ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2012,vol. 31,p. 432 - 444

40
[ 64987-85-5 ]
[ 1374847-77-4 ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2012,vol. 31,p. 432 - 444

41
[ 64987-85-5 ]
[ 1374847-79-6 ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2012,vol. 31,p. 432 - 444

42
[ 64987-85-5 ]
[ 1374847-89-8 ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2012,vol. 31,p. 432 - 444

43
[ 64987-85-5 ]
(S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)pentanedioic acid [ No CAS ]
[ 1374847-70-7 ]

Reference： [1]Nucleosides, nucleotides and nucleic acids,2012,vol. 31,p. 432 - 444

44
[ 64987-85-5 ]
[ 1375262-88-6 ]
[ 1426395-64-3 ]

Yield	Reaction Conditions	Operation in experiment
68%	With triethylamine; In N,N-dimethyl-formamide; at 50℃; for 24h;	To a solution of 4-amino-2-butyl-l-(2-hydroxy-2methylpropyl)-7-methoxycarbonyl-lH- imidazo[4,5-c]quinoline S7 (37 mg, 0.1 mmol, 1.0 equiv) and 2,5-dioxopyrrolidin-l-yl 4-[(2,5- dioxo-2,5-dihydro-lH-pyrrol-l-yl)methyl]cyclohexanecarboxylate (66 mg, 0.20 mmol, 2.0 equiv) in DMF (2.0 mL) at 25 °C was added NEt3 (40 iL, 0.30 mmol, 3.0 equiv) in one injection. The reaction was heated at 50 °C for 24 h. The solvent was then removed in vacuo and the solid was redissoved in 1 :9 MeOH/EtOAc (50 mL), washed successively with saturated NaHC03 solution (15 mL), H20 (15 mL) and saturated aqueous NaCl (15 mL) and the organic layer concentrated. TLC and MS analysis indicated existence of both the imidazoquinoline starting material and the desired product. Purification by flash column chromatography on silica gel (CH2Cl2-l/9 MeOH/CH2Cl2, gradient) afforded the title compound 550 (40 mg, 68percent) as a white solid: 1H NMR (CD3OD, 600 Hz) delta 1.04 (t, J= 7.2 Hz, 3H), 1.11-1.18 (m, 2H), 1.26 (br s, 6H), 1.51-1.66 (m, 4H), 1.68-1.85 (m, 3H), 1.91 (pent, J= 7.2 Hz, 2H), 3.13 (t, J= 7.2 Hz, 2H), 3.40 (d, J= 7.2 Hz, 2H), 6.83 (s, 2H), 7.98 (d, J= 9.0 Hz, 1H), 8.41 (d, J= 9.0 Hz, 1H), 8.66 (s, 1H); 13C NMR (CD3OD, 150 Hz) delta 12.9, 22.3, 27.2, 28.5, 28.7, 29.5, 29.6, 36.6, 43.1, 45.4, 51.4, 54.9, 71.1, 119.9, 121.4, 123.7, 126.5, 126.6, 126.6, 128.0, 128.8, 130.5, 133.9, 135.2, 142.5, 144.3, 158.2, 159.9, 160.0, 166.8, 171.4; MS (APCI+): calcd C32H40N5O6 [M + H]+ 590.3, found 590.3.

Reference： [1]Patent: WO2013/33345,2013,A1 .Location in patent: Page/Page column 22

45
[ 64987-85-5 ]
[ 941290-95-5 ]
C₁₁₈H₁₆₉N₃₅O₂₅ [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2013,vol. 24,p. 2015 - 2024

46
[ 64987-85-5 ]
[ 107-96-0 ]
MPr-SMCC [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-ethyl-N,N-diisopropylamine;	The drug-linker SMCC-MDC was prepared in the following reactions: (1) 3-mercaptopropanoic acid (MPr) was reacted with N-succinimidyl 4-(maleimidomethyl)cyclohexane-1-carboxylate (SMCC) in the presence of N,N-diisopropylethylamine (DIEA), giving the MPr-SMCC at a yield of over 95percent;
95%	With N-ethyl-N,N-diisopropylamine;	The drug-linker SMCC-MDC was prepared in the following reactions: (1) 3-mercaptopropanoic acid (MPr) was reacted with N-succinimidyl 4-(maleimidomethyl)cyclohexane-1-carboxylate (SMCC) in the presence of N,N-diisopropylethylamine (DIEA), giving the MPr-SMCC at a yield of over 95percent;
95%	With N-ethyl-N,N-diisopropylamine;	The drug-linker SMCC-MDC was prepared in the following reactions: (1) 3-mercaptopropanoic acid (MPr) was reacted with N-succinimidyl 4-(maleimidomethyl)cyclohexane-1-carboxylate (SMCC) in the presence of N,N-diisopropylethylamine (DIEA), giving the MPr-SMCC at a yield of over 95percent;

> 95%	With N-ethyl-N,N-diisopropylamine;	The drug-linker SMCC-MDC was prepared in the following reactions: (1) 3-mercaptopropanoic acid (MPr) was reacted with N-succinimidyl 4-(maleimidomethyl)cyclohexane-1-carboxylate (SMCC) in the presence of DIEA, giving the MPr-SMCC at a yield of over 95percent; Secondly, condensation of N-Me-L-Ala-MDC, which was prepared by deprotection of Fmoc-N-Me-Ala-MDC under a base piperidine in CH3CN, with MPr-SMCC under a coupling reagent EDC, giving the desired coupled product SMCC-MDC in 60-70percent yield over two steps. Antibody Bat0206 (Abu) was diluted to 2.5 mg/mL in solution A (50 mM potassium phosphate, 50 mM NaCl, and 2 mM EDTA, pH 6.5). SMCC-MDC was added to give a ratio of SMCC-MDC to antibody of 7:1 mole equivalent. Then DMA was added to 15percent (v/v) to the reaction and reaction was mixed by stirring for 4 h at ambient temperature. D-Lmcc-Bat0206 conjugate was purified from excess unreacted or hydrolyzed reagent and excess SMCC-MDC using a G25 gel filtration column equilibrated in pH 7.4 phosphate buffer (aqueous). The conjugate was then dialyzed overnight into pH 7.4 phosphate buffer (aqueous) and then filtered through a 0.22 mum filter for final storage. The number of SMCC-MDC molecule per Abu molecule in the final conjugate was measured by determining absorbance of the conjugate at 252 and 280 nm and using known extinction coefficients for SMCC-MDC and antibody at these two wavelengths. A ratio of maytansinoid compound to antibody of 3.5:1.0 was normally obtained.
95%	With triethylamine; In dichloromethane; at 20℃; for 2h;	In the solution of SMCC (3 g) in anhydrous CH2Cl2 (80 ml), mercaptoacetic acid (0.937 ml) and triethylamine (1.428 ml) wereadded. The mixture was stirred for 2 h at room temperature. After evaporation of the solvent under vacuum, the solid was purified by column chromatography (CH2Cl2:Methanol = 20:1) to yield compound 2(3.76 g, 95percent). The structure was identified by ESI-QTOF-MS, 1H and 13C NMR. (M + H)+ = 441.1591; (M + Na)+ = 463.1132. 1H NMR(400 MHz, DMSO-d6): delta 12.33 (s, 1H), 4.02 (1H,dd, J = 8.9, 3.8 Hz), 3.25(d,2H, J = 7.0 Hz), 3.22?3.13 (m, 1H), 2.94 (dd,1H,J = 13.5, 6.7 Hz),2.86 (dd,1H,J = 13.7, 6.7 Hz), 2.8 (s,3H), 2.69 (t,1H,J = 12.0 Hz), 2.62?2.44 (m, 4H), 2.00 (d,2H,J = 11.1 Hz), 1.69 (d,3H,J = 13.3 Hz), 1.48?1.27 (m, 2H), 1.05 (dd,2H,J = 23.6, 11.0 Hz). 13C NMR (100 MHz,DMSO-d6): delta 177.0, 175.3, 172.8, 170.8, 170.2, 43.7, 35.6, 34.9, 34.0, 28.5,27.8, 26.8, 25.4.

Reference： [1]Patent: US2014/178413,2014,A1 .Location in patent: Paragraph 158
[2]Patent: US2014/178412,2014,A1 .Location in patent: Paragraph 188
[3]Patent: US2014/178411,2014,A1 .Location in patent: Paragraph 160
[4]Patent: US2014/178415,2014,A1 .Location in patent: Paragraph 0453
[5]Journal of Controlled Release,2015,vol. 220,p. 5 - 17

47
[ 64987-85-5 ]
[ 1228105-51-8 ]

Reference： [1]Patent: US2014/178413,2014,A1
[2]Patent: US2014/178415,2014,A1

48
[ 64987-85-5 ]
Lys-MCC-MDC [ No CAS ]

Reference： [1]Patent: US2014/178412,2014,A1
[2]Patent: US2014/178415,2014,A1

49
[ 64987-85-5 ]
(S)-2,2',2''-(10-(2-((5,6-diamino-6-oxohexyl)amino)-(((gadolinium⁽³⁺⁾))-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) [ No CAS ]
SMCC-Lys(Gd-DOTA)-NH₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.0%	In aq. phosphate buffer; N,N-dimethyl-formamide; at 20℃; for 1.5h;	To a solution of (5) H-Lys(Gd-DOTA)-NH2 (24.00 mg, 3.49×10-2 mmol) dissolved in PBS buffer (1 mL) of pH 8.5, the SMCC linker (17.51 mg, 5.24×10-2 mmol) in DMF (2 mL) was added. The solution was stirred for 1.5 h at room temperature while using LC-MS method B: 20-100% to check the reaction progress every 0.5 h. Once the reaction was complete, the material was concentrated down. The product was purified through SPE method B: 10-50%. The product was found in fractions 15-25%. Yield: 19.0 mg (2.10×10-2 mmol, 60.0%); LC-MS=Calcd. for C34H52GdN8O11: 906.07 (m/z), found: 904.9 [M-H]-.

Reference： [1]Patent: US2015/38672,2015,A1 .Location in patent: Paragraph 0148

50
[ 64987-85-5 ]
H-Lys(Gd-DOTA)-Lys(Gd-DOTA)-NH2  [ No CAS ]
SMCC-Lys(Gd-DOTA)-Lys(Gd-DOTA)-NH2  [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.3%	In aq. phosphate buffer; N,N-dimethyl-formamide; at 20℃; for 1.5h;	To a solution of (28) H-Lys(Gd-DOTA)-Lys(Gd-DOTA)-NH2 (3.50 mg, 2.58×10?3 mmol) dissolved in PBS buffer (0.25 mL) of pH 8.5, the SMCC linker (2.20 mg, 6.45×10?3 mmol) in DMF (0.25 mL) was added. The solution was stirred for 1.5 h at room temperature while using LC-MS methanol B: 20-100percent to check the reaction progress every 0.5 h. Once the reaction was complete, the material was concentrated down. The product was purified through SPE method B: 10-50percent. The product was found in fractions 15-25percent. Yield: 4.0 mg (2.54×10?2 mmol, 98.3percent); LC-MS=Calcd. for C56H88Gd2N14O19: 1575.8 (m/z), found: 1573.8 [M?H]?. The mass spectra of this compound is shown in FIG. 3, displaying the di-Gd isotope pattern.

Reference： [1]Patent: US2015/38672,2015,A1 .Location in patent: Paragraph 0135

51
[ 64987-85-5 ]
H-DLys(Cy_5.5)-Lys(Gd-DOTA)-NH2  [ No CAS ]
SMCC-DLys(Cy_5.5)-Lys(Gd-DOTA)-NH2  [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.17%	In aq. phosphate buffer; N,N-dimethyl-formamide; at 20℃; for 1h;	To a solution of (36b) H-DLys(Cy5.5)-Lys(Gd-DOTA)-NH2 (24.00 mg, 3.49×10?2 mmol) dissolved in PBS buffer (1 mL) of pH 7.4, the SMCC linker (17.51 mg, 5.24×10?2 mmol) in DMF (2 mL) was added. The solution was stirred for 1 h at room temperature while using LC-MS methanol B: 20-100percent to check the reaction progress every 0.5 h. Once the reaction was complete, the material was concentrated down. The product was not purified; the residue was used directly in the next reaction. Yield: 4.1 mg (2.18×10?3 mmol, 88.17percent); LC-MS=Calcd. for C83H112GdN12O22S3: 1883.3 (m/z), found: 941.1 [M?H/2]?.

Reference： [1]Patent: US2015/38672,2015,A1 .Location in patent: Paragraph 0152

52
[ 64987-85-5 ]
(1R,3S,4S)-N-((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((S)-1-((4-(aminomethyl)phenyl)amino)-1-oxo-3-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)-2-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide [ No CAS ]
(1R,3S,4S)-N-((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((S)-1-((4-((4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexanecarboxamido)methyl)phenyl)amino)-1-oxo-3-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)-2-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;	Example 78: (1 R,3S,4S)-N-((S)-1 -(((3R,4S,5S)-1 -((S)-2-((1 R,2R)-3-(((S)-1 -((4-((4-((2,5- Dioxo-2,5-dihydro-1 H-pyrrol-1 -yl)methyl)cyclohexanecarboxamido)methyl)phenyl)amino)- 1 -oxo-3-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)-2-methyl- 2-azabicyclo[2.2.1 ]heptane-3-carboxamide (40)Step 6: (1 R,3S,4S)-N-((S)-1 -(((3R,4S,5S)-1 -((S)-2-((1 R,2R)-3-(((S)-1 -((4- (Aminomethyl)phenyl)amino)-1 -oxo-3-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)-2-methyl-2-azabicyclo[2.2.1 ]heptane-3-carboxamide (12 mg, 0.014 mmol) and 2,5-dioxopyrrolidin-1 -yl 4-((2,5-dioxo-2,5-dihydro-1 H-pyrrol-1 - yl)methyl)cyclohexanecarboxylate (5.6 mg, 0.017 mmol) were dissolved in DMF (1 ml_), and DIEA (10.8 mg, 0.084 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature. LCMS analysis indicated the completion of the reaction. The crude was purified by reverse phase HPLC using C18 column, eluted with 10-90percent acetonitrile- H20 containing 0.05percent TFA. The fractions containing the desired product were pooled and lyophilized to obtain compound 40, MS m/z 1079.5 (M+1 ). Retention time 1 .12 minutes.
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;	Step 6: (1 R,3 S,4S)-N-((S)- 1 -(((3R,4S,5 S)- 1 -((S)-2-((i R,2R)-3-(((S)- 1 -((4- (Aminomethyl)phenyl)amino)- 1 -oxo-3 -phenylpropan-2-yl)amino)- 1 -methoxy-2-methyl-3 - oxopropyl)pyrrolidin- i-yl)-3 -methoxy-5 -methyl-i -oxoheptan-4-yl)(methyl)amino)-3 -methyl-i -oxobutan2-yl)-2-methyl-2-azabicyclo [2.2.1 jheptane-3 -carboxamide (12 mg, 0.014 mmol) and 2,5 -dioxopyrrolidin5 1 -yl 4-((2,5 -dioxo-2,5 -dihydro- 1 H-pyrrol- 1 -yl)methyl)cyclohexanecarboxylate (5.6 mg, 0.017 mmol)were dissolved in DMF (1 mL), and DIEA (10.8 mg, 0.084 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature. LCMS analysis indicated the completion of the reaction. The crude was purified by reverse phase HPLC using Ci8 column, eluted with 10-90percent acetonitrile-H20 containing 0.05percent TFA. The fractions containing the desired product were pooled and lyophilized to obtaincompound 40, MS m/z 1079.5 (M+i). Retention time i.i2 minutes.

Reference： [1]Patent: WO2015/95301,2015,A2 .Location in patent: Page/Page column 146; 149
[2]Patent: WO2016/203432,2016,A1 .Location in patent: Paragraph 00569; 00575

53
[ 404858-60-2 ]
Paramax Wang resin [ No CAS ]
[ 64987-85-5 ]
[ 29022-11-5 ]
[ 104091-09-0 ]
[ 88574-06-5 ]
C₄₄H₆₄N₈O₂₂S [ No CAS ]