69907-67-1|trans-4-((2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexanecarboxylic acid| Ambeed

CAS No. :	69907-67-1
Formula :	C₁₂H₁₅NO₄
M.W :	237.25
SMILES Code :	O=C([C@H]1CC[C@H](CN2C(C=CC2=O)=O)CC1)O
MDL No. :	MFCD11519178
InChI Key :	LQILVUYCDHSGEU-UHFFFAOYSA-N
Pubchem ID :	11548799

Safety of [ 69907-67-1 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Calculated chemistry of [ 69907-67-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	17
Num. arom. heavy atoms	0
Fraction Csp3	0.58
Num. rotatable bonds	3
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	64.08
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	74.68 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.57
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.47
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.42
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.72
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.67
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.77

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.41
Solubility	9.25 mg/ml ; 0.039 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.61
Solubility	5.86 mg/ml ; 0.0247 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.63
Solubility	56.0 mg/ml ; 0.236 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.41 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.07

Application In Synthesis of [ 69907-67-1 ]

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

Downstream synthetic route of [ 69907-67-1 ]

[ 69907-67-1 ] Synthesis Path-Downstream 1~28

1
[ 108-31-6 ]
[ 1197-18-8 ]
[ 69907-67-1 ]

References: [1]Organic Preparations and Procedures International,1993,vol. 25,p. 592 - 594.
[2]Organic and Biomolecular Chemistry,2014,vol. 12,p. 6624 - 6633.
[3]Journal of the American Chemical Society,2019,vol. 141,p. 12274 - 12279.

2
[ 69907-67-1 ]
[ 14533-84-7 ]
pentafluorophenyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate [ No CAS ]

References: [1]Organic Preparations and Procedures International,1993,vol. 25,p. 592 - 594.

4
[ 69907-68-2 ]
[ 69907-67-1 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid;Reflux;	Trans-4-(aminomethyl)-cyclohexanecarboxylic acid (500 mg, 3.18 mmol) was dissolved in 3 ml of glacial acetic acid, maleic anhydride (31 1 mg, 3.18 mmol) was added and the mixture stirred at room temperature until a white precipitate of trans-4-([(2Z)-3-carboxyprop-2-enoyl]amino}methyl)cyclohexanecarboxylic acid was formed. The mixture was then heated under reflux to complete the cyclization of the trans-4-(N-maleimidemethyl)cyclohexane-1 -carboxylic acid, and the mixture is concentrated under reduced pressure to remove acetic acid. The crude product was purified by flash column chromatography (S1O2- CHCU/MeOH, eluting with gradient 99: 1 -> 90: 10. The product was obtained as a cream solid, yield 435 mg (58%), ESI-ITMS: m/z (%): 236 (M - H)-.

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3749 - 3753.
[2]Patent: WO2014/141094,2014,A1 .Location in patent: Page/Page column 63.

5
[ 69907-67-1 ]
[ 919-30-2 ]
N-(3-triethoxysilylpropyl)-4-(N'-maleimidylmethyl)cyclohexanecarboxamide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3749 - 3753.

6
[ 1197-18-8 ]
[ 69907-67-1 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3749 - 3753.
[2]Patent: WO2014/141094,2014,A1 .
[3]Patent: WO2015/31396,2015,A1 .

7
[ 69907-67-1 ]
[ 753-73-1 ]
(CH₃)2Sn(OCOC₆H₁₀CH₂N(CHCO)2)2 [ No CAS ]

References: [1]Bulletin of the Chemical Society of Japan,2006,vol. 79,p. 1054 - 1059.

8
[ 69907-67-1 ]
[ 866-55-7 ]
(CH₃CH₂)2Sn(OCOC₆H₁₀CH₂N(CHCO)2)2 [ No CAS ]

References: [1]Bulletin of the Chemical Society of Japan,2006,vol. 79,p. 1054 - 1059.

9
[ 69907-67-1 ]
[ 683-18-1 ]
(CH₃(CH₂)3)2Sn(OCOC₆H₁₀CH₂N(CHCO)2)2 [ No CAS ]

References: [1]Bulletin of the Chemical Society of Japan,2006,vol. 79,p. 1054 - 1059.

10
[ 69907-67-1 ]
[ 1135-99-5 ]
(C₆H₅)2Sn(OCOC₆H₁₀CH₂N(CHCO)2)2 [ No CAS ]

References: [1]Bulletin of the Chemical Society of Japan,2006,vol. 79,p. 1054 - 1059.

11
[ 69907-67-1 ]
[ 3002-01-5 ]
(C₆H₅CH₂)2Sn(OCOC₆H₁₀CH₂N(CHCO)2)2 [ No CAS ]

References: [1]Bulletin of the Chemical Society of Japan,2006,vol. 79,p. 1054 - 1059.

12
[ 6066-82-6 ]
[ 69907-67-1 ]
[ 71875-81-5 ]

Yield	Reaction Conditions	Operation in experiment
39%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;Inert atmosphere;	The product of the preceding step B (10.0 g, 42.1 mmol) was dissolved in dichioromethane (50 mL) under Ar, treated with N-hydroxysuccinimide (7.27 g, 63.2 mmol) and 1 -(3 -dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (EDAC, 12.4 g, 64.5 mmol), and the reaction was stirred at ambient temperature overnight. The resulting brown solution was diluted with dichloromethane, washed with water and brine, dried over Na2SO4, filtered over a sintered glass funnel, and the filtrate concentrated and dried in vacuo. This product was then dissolved in hot ethyl acetate, treated with activated charcoal (1.5 g), filtered, and the filtrate cooled. Filtration of the crystalline product, washing with cold ethyl acetate, and suction drying then gave the title compound as a tan solid (5.52 g, 39%). 1H NMR (300 MHz, CDC13) 5 6.72 (s, 2H), 3.42 (m, 2H), 2.85 (br s, 4H), 2.56 (tt, 1H, J= 12Hz, 4Hz), 2.18 (m, 2H), 1.80 (m, 2H),1.70 (m, 1H), 1.56 (m, 2H), 1.09 (m, 2H).
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4h;	To a solution of 6 (0.387 g, 1.60 mmol) and N-hydroxysuccinimide (HOSu) (0.562 g, 4.90 mmol) in 19.6 mL of DCM was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI·HCl) (0.939 g, 4.90 mmol) at room temperature and stirred for 4 h. The solvent was removed and the residue was dissolved in ethyl acetate. The solution was washed with 10% citric acid (three times), satd NaHCO3 (three times) and brine, dried over MgSO4 and concentrated to afford crude product 7 which was used without further purification. To a solution of c(RGDfK)·2TFA (50 mg, 0.06 mmol) and 7 (13.4 mg, 0.04 mmol) in 2 mL of DMF was added DIPEA (34.8 muL, 0.20 mmol) and the solution was stirred at room temperature. After 9 h, the solvent was removed in vacuo. Purification of the crude product by preparative RP-HPLC afforded 8 (19.1 mg, 40% for two-steps) as trifluoroacetate salt of colorless freeze-dried amorphous. HRMS (FAB) m/z: calcd for C39H55N10O10+ [M+H]+ 823.4097, found 823.4091.

References: [1]Patent: WO2015/31396,2015,A1 .Location in patent: Paragraph 00104.
[2]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 1721 - 1728.
[3]Organic and Biomolecular Chemistry,2014,vol. 12,p. 6624 - 6633.

13
[ 69907-67-1 ]
(S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-[3-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]propanoyl]piperazine-1-carboxylate [ No CAS ]
(S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(1-((1R,4R)-4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexyl)-1-oxo-5,8,11,14-tetraoxa-2-azaheptadeca-17-oyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 24h;	he compound of Formula 8, obtained as described above, is dissolved in dry methylene chloride, cooled in an ice bath and trifluoroacetic acid (0.3 ml) is added with stirring. The mixture is stirred for 5 hours, the volatile components are evaporated and the residue dissolved in dry methylene chloride (10 ml). To the resulting solution of (S)-4, 1 1 -diethyl-4-hydroxy-3, 14-dioxo-3,4, 12, 14-tetrahydro- 1 H-pyrano[3',4':6,7]indolizino[1 ,2-b]quinolin-9-yl 4-[3- [2- [2- [2-(2-aminoethoxy)- ethoxy]ethoxy]ethoxy]propanoyl]piperazine- 1 -carboxylate triethylamine (0.062 ml, 0.45 mmol) and trans-4-((2,5-dioxo-2,5-dihydro-pyrrol- 1 -ylo)methyl)cyclo- hexanecarboxyl chloride (38 mg, 0.15 mmol) are added. The mixture is stirred at room temperature for 4 hours, The solvent is evaporated and the residue purified on a silica gel column eluting with ethyl acetate - methanol 5 : 2, to obtain (S)- 4, 1 1 -diethyl-4-hydroxy-3, 14-dioxo-3,4, 12, 14-tetrahydro-1 H-pyrano[3',4':6,7] - indolizino[1 ,2-b]quinolin-9-yl 4-(1 -((1 R,4R)-4-((2,5-dioxo-2,5-dihydro- 1 H-pyrrol- 1 -ilo)methyl)cyclohexyl)-1 -oxo-5,8, 1 1 , 14-tetraoxa-2-azaheptadeca-17-oyl)- piperazine-1 -carboxylate (Formula 9), yield 90 mg (82%). MS: 993.33 (M+23)

References: [1]Patent: WO2014/141094,2014,A1 .Location in patent: Page/Page column 61.

14
[ 69907-67-1 ]
[ 150-13-0 ]
4-[({trans-4-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl]cyclohexyl}carbonyl)amino]benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%		trans-4-(N-maleimidemethyl)cyclohexane-1 -carboxylic acid (435 mg, 1 .83 mmol) was dissolved in 5 ml of dry DMF and cooled to -20C, then N- methylmorpholine (0.202 ml, 1 .83 mmol), followed by ethyl chloroformate (0.174 ml, 1 .83 mmol) were added. After 5 min, 4-aminobenzoic acid (264 mg, 1 .92 mmol) was added, and after further 5 minutes the cooling bath was removed and the reaction mixture was allowed to reach room temperature over 1 hour. Then, the mixture was concentrated under reduced pressure to remove DMF. The crude product was purified by flash column chromatography (SiC^-CHCU/MeOH, eluting with gradient 99: 1 -> 90: 10. 4-[({trans-4-[(2,5-Dioxo-2,5-dihydro-1 H-pyrrol-1 - yl)methyl]cyclohexyl}carbonyl)amino]benzoic acid was obtained as a white solid, yield 312 mg (48%), ESI-ITMS: m/z (%): 355 (M - H)-, 357 (M + H)+.

References: [1]Patent: WO2014/141094,2014,A1 .Location in patent: Page/Page column 63; 64.

15
[ 69907-67-1 ]
4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl (S)-4-(aminomethyl)cyclohexanecarboxylate [ No CAS ]
4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl (S)-4-(((1R,4R)-4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexanecarboxamide)methyl)cyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 24h;	4, 1 1 -Diethyl-4-hydroxy-3, 14-dioxo-3,4, 12, 14-tetrahydro-1 H-pyrano[3',4':6,7]- indolizino[1 ,2-b]quinolin-9-yl (1 R,4S)-(S)-4-(aminomethyl)cyclohexane- carboxylate (Formula 2) (59 mg, 0.25 mmol) is dissolved in dry methylene chloride (10 ml), and trans-4-((2,5-dioxo)-2H-pyrrol-1 (5H)-yl)methyl)cyclohexane- carboxylic acid (59 mg, 0.25 mmol) and (benzotriazol-l -yloxy)tris(dimethyl- amino)phosphonium hexafluorophosphate (BOP) (1 10 mg, 0.25 mmol) and triethylamine (0.07 ml) are added, with stirring. The mixture is stirred at room temperature for 24 hours, then the solvent is evaporated, and the residue is purified on a silica gel column eluting with ethyl acetate - methanol 10 : 1 to obtain 4, 1 1 -diethyl-4-hydroxy-3, 14-dioxo-3,4, 12, 14-tetrahydro-1 H-pyrano- [3',4':6,7]indolizino[1 ,2-b]quinolin-9-yl (1 R,4S)-(S)-4-(((1 R,4R)-4-((2,5-dioxo-2,5- dihydro-1 H-pyrrol-1 -ylo)methyl)cyclohexanecarboxamide)methyl)cyclohexane- carboxylate (L3-Z1 ) .23 (M+23).

References: [1]Patent: WO2014/141094,2014,A1 .Location in patent: Page/Page column 58.

16
[ 69907-67-1 ]
(S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(17-amino-3-oxo-6,9,12,15-tetraoxa-2-azaheptadecyl)cyclohexanecarboxylate [ No CAS ]
(S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-(1-((1R,4R)-4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexyl)-1,17-dioxo-5,8,11,14-tetraoxa-2,18-diazanonadekan-19-yl)cyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 24h;	The resulting product is dissolved in dry methylene chloride (10 ml), to the stirred solution trans-4-((2, 5-dioxo-2,5dihydro-pyrrol-1 -yl)methyl)cyclohexanecarboxylic acid (0.62 mg, 0.26 mmol), (benzotriazol-1 -yloxy)tris(dimethylamino)phosphor- nium hexafluorophosphate (BOP) (1 10 mg, 0.26 mmol) and triethylamine (0.06 ml) are added. The mixture is stirred at room temperature for 24 hours, then the solvent is evaporated, and the residue is purified on a silica gel column eluting with ethyl acetate - methanol 5 : 1 , to obtain (S)-4, 1 1 -diethyl-4-hydroxy-3, 14- dioxo-3,4, 12, 14-tetrahydro-1 H-pyrano[3',4':6,7]indolizino[1 ,2-b]quinolin-9-yl (1 R,4S)-4-(1 -((1 R,4R)-4-((2,5-dioxo-2,5-dihydro-1 H-pyrrol-1 -yl)methyl)cyclo- hexyl)-1 , 17-dioxo-5,8, 1 1 , 14-tetraoxa-2, 18-diazanonadekan-19-yl)cyclohexane- carboxylate L4-Z1 (Formula 6), yield 1 10 mg (42%). MS: 1020.37 (M+23).

References: [1]Patent: WO2014/141094,2014,A1 .Location in patent: Page/Page column 59.

17
[ 953817-12-4 ]
[ 69907-67-1 ]

Yield	Reaction Conditions	Operation in experiment
7 g	With sodium acetate; acetic anhydride; at 120℃; for 3h;Sealed tube;	Step B: The maleamic acid from Step A (36.8 g, 144 mmol) and sodium acetate (13.6 g, 165 mmol) were dissolved in acetic anhydride (368 mL), sealed in a glass reaction vessel, and heated to 120C for 3 hours. The cooled reaction mixture (a black syrup) was poured onto water (3 L), stirred, and extracted with dichloromethane. The organic layer was dried over Na2504, filtered over a sintered glass funnel, and the clear filtrate evaporated and dried under high vacuum giving the title compound as a yellow solid (7.00 g, 20%). 1H NMR (300 MHz, CDC13) 3 6.73 (s, 2H), 3.40 (d, 2H, J = 7 Hz), 2.28 (m, 1H), 2.06 (m, 2H), 1.75 (m, 3H), 1.42 (m, 2H), 1.03 (m, 2H).

References: [1]Patent: WO2015/31396,2015,A1 .Location in patent: Paragraph 00103.

18
[ 69907-67-1 ]
(R)-maytansin-3N-methyl-L-alaninepropanamidyl-3-thio-3-succinimidyl-N-methylcyclohexyl-4-trans-carboxylic acid [ No CAS ]

References: [1]Patent: WO2015/31396,2015,A1 .

19
[ 69907-67-1 ]
(S)-maytansin-3N-methyl-L-alaninepropanamidyl-3-thio-3-succinimidyl-N-methylcyclohexyl-4-trans-carboxylic acid [ No CAS ]

References: [1]Patent: WO2015/31396,2015,A1 .

20
maytansin-3N-methyl-L-alaninepropanamide-3-thiol [ No CAS ]
[ 69907-67-1 ]
maytansin-3N-methyl-L-alaninepropanamidyl-3-thio-3-succinimidyl-N-methylcyclohexyl-4-trans-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With sodium hydrogencarbonate; In 1,2-dimethoxyethane; at 20℃;pH 7.5;	A solution of trans-1,4- (maleimidomethyl) cyclohexane-1-carboxylic acid 7 (167 mg, 0.701 mmol) in 1, 2- dimethoxyethane (8 mL) was added to a solution of 4 (340 mg, 0.46 1 mmol) in 1, 2- dimethoxyethane (15 mL). The mixture was then treated with pH 7.5 buffer (20 mL) and a few drops of saturated aqueous NaHCO3 to maintain the pH. The reaction mixture was stirred overnight at room temperature under argon and then concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography using a Cl 8 column, 20-40 micron column (100 g), eluting with a gradient (10 95% over 25 mins) of acetonitrile (0.1% AcOH) in water (0.1% AcOH), and lyophilized to give 8 (330 mg, 0.338 mmol, 73% yield) as a white solid. MS m/z: 977.2 [MH+j, 957.2 [M-181, 999.2 [M+ Nal; Purity: >98% (by LC/MS).

References: [1]Patent: WO2015/31396,2015,A1 .Location in patent: Paragraph 00108.

21
[ 69907-67-1 ]
maytansin-3-N-methyl-L-alaninepropanamidyl-3-thio-3-succinimidyl-N-methylcyclohexyl-4-trans-carboxysuccinate [ No CAS ]

References: [1]Patent: WO2015/31396,2015,A1 .
[2]Patent: WO2015/31396,2015,A1 .

22
[ 69907-67-1 ]
(R)-maytansin-3N-methyl-L-alaninepropanamidyl-3-thio-3-succinimidyl-N-methylcyclohexyl-4-trans-carboxylic acid [ No CAS ]

References: [1]Patent: WO2015/31396,2015,A1 .

23
[ 69907-67-1 ]
1-[(4-[({7-amino-3-(2-hydroxy-2-methylpropyl)-3.5.8-triazatricyclo[7.4.0.02,6]trideca-1⁽⁹⁾,2⁽⁶⁾,4,7,10,12-hexaen-4-yl}methyl)-N-ethylamino]carbonyl}cyclohexyl)methyl]-1H-pyrrole-2,5-dione [ No CAS ]

References: [1]Patent: WO2018/140831,2018,A2 .

24
[ 69907-67-1 ]
C₁₂H₁₄ClNO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-chloro-1-(dimethylamino)-2-methyl-1-propene; In dichloromethane; at 0℃; for 1h;	To an ice-cold solution of (lr,4r)-4-((2,5-dioxo-2,5-dthydro- 1H-pyrrol- 1- yl)methyl)cyclohexane-1-carboxylic acid (82 mg, 0.346 mmol) in DCM (1728 tl) was added 1- chloro-N,N,2-trimethylprop-1-en-1-amine (50.3 iL, 0.380 mmol) dropwise. This was stirred at 0C for lh then added to an ice-cold mixture of 1-(4-amino-2-((ethylamino)methyl)-1H- imidazo [4,5-cjquinolin- 1 -yl)-2-methylpropan-2-ol (100 mg, 0.319 mmol) and triethylamine (133 tl, 0.957 mmol) in 1.6 mL of DCM. The mixture became a yellow solution as it stirred overnight to room temp. The reaction was concentrated to dryness, redissolved in MeOH/CH2C12, silica gel was added, then the solvents evaporated. Chromatography (12 g Gold silica, DCM to 20% MeOH/DCM, dry load) gave a solid which was dissolved in CH3CN, frozen and lyophilized to afford 170 mg of N-((4-(( i-(dimethylamino)-2-methylprop- 1-en-i -yl)amino)- 1 -(2-(( 1- (dimethylamino)-2-methyl-prop- i-en-i -yl)oxy)-2-methylpropyl)- 1 H-imidazo [4,5-cj quinolin-2- yl)methyl)-4-((2,5-dioxo-2,5-dthydro- 1 H-pyrrol- 1 -yl)methyl)-N-ethylcyclohexane- 1- carboxamide which was subsequently dissolved in 50% aqueous MeCN containing 0. i%TFA and heated in a microwave reactor at 150C for 60 mm. The reaction mixture was cooled and the solvents were evaporated and chromatographed to give ATAC34 (72 mg) as a white solid. ?HNMR (400 MHz, (DMSO-d6) oe 13.3 (s, 1H), 8.70- 8.50 (m, 3H), 7.83-7.79 (m, 1H), 7.7 1-7.65 (m, 1H), 7.55-7.48 (m, 1H), 7.00 (s, 1H), 6.98 (s, 1H), 5.13 (bs, 1H), 4.83 (bs, 1H), 3.65 (q, 1=7.0 Hz, 2H), 3.38 (m, 1H),3.25 and 3.18 (d, 1=6.5 Hz, 2H), 1.69-1.52 (m, 5H), 1.45-0.88 (m, 13H). ?9F NMR (DMSO-d6) oe -73.7. LCMS [M + Hj = 533.1.
	With thionyl chloride; N,N-dimethyl-formamide; In toluene; for 4h;Reflux;	S1, 23.7 g of maleimido tranexamic acid was added to 80 ml of toluene,Then add 15.2g of thionyl chloride,Add a drop of DMF and connect to the bubbler to observe the reaction gas.The reaction solution was heated to reflux reaction for 4 h until the bubbler had no gas, and the reaction was stopped.The reaction solution was concentrated to dryness, and then concentrated, and then concentrated.Obtaining a viscous liquid without post-treatment, directly proceeding to the next reaction;

References: [1]Patent: WO2018/140831,2018,A2 .Location in patent: Paragraph 0640; 0641.
[2]Patent: CN109535058,2019,A .Location in patent: Paragraph 0013.

25
[ 69907-67-1 ]
N-((4-((1-(dimethylamino)-2-methylprop-1-en-1-yl)amino)-1-(2-((1-(dimethylamino)-2-methylprop-1-en-1-yl)oxy)-2-methylpropyl)-1H-imidazo [4,5-c]quinolin-2-yl)methyl)-4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-N-ethylcyclohexane- 1-carboxamide [ No CAS ]

References: [1]Patent: WO2018/140831,2018,A2 .

26
[ 69907-67-1 ]
C₂₆H₃₃N₃O₆ [ No CAS ]

References: [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 7124 - 7128.

27
[ 69907-67-1 ]
C₃₁H₄₂N₄O₉S [ No CAS ]

References: [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 7124 - 7128.

28
[ 69907-67-1 ]
cesium (1R,4R)-4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexanecarboxylate [ No CAS ]

References: [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 7124 - 7128.

Historical Records

Technical Information

• Acyl Group Substitution • Arndt-Eistert Homologation • Chan-Lam Coupling Reaction • Complex Metal Hydride Reductions • Heat of Combustion • Hunsdiecker-Borodin Reaction • Hydride Reductions • Lawesson's Reagent • Passerini Reaction • Preparation of Amines • Preparation of Carboxylic Acids • Reactions of Amines • Reactions of Carboxylic Acids • Schmidt Reaction • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Specialized Acylation Reagents-Ketenes • Ugi Reaction

Related Functional Groups of
[ 69907-67-1 ]

Amides

A214596 [57079-01-3]

11-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)undecanoic acid

Similarity: 0.88

A245802 [57078-99-6]

5-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentanoic acid

Similarity: 0.88

A103872 [1036847-90-1]

4-((2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-N-(prop-2-yn-1-yl)cyclohexanecarboxamide

Similarity: 0.82

A455159 [104239-97-6]

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-Dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxylic acid

Similarity: 0.77

A114517 [7423-55-4]

3-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid

Similarity: 0.76

Carboxylic Acids

A214596 [57079-01-3]

11-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)undecanoic acid

Similarity: 0.88

A245802 [57078-99-6]

5-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentanoic acid

Similarity: 0.88

A455159 [104239-97-6]

(4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-Dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxylic acid

Similarity: 0.77

A114517 [7423-55-4]

3-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid

Similarity: 0.76

A104256 [5274-99-7]

1-Benzoylpiperidine-4-carboxylic acid

Similarity: 0.72

Related Parent Nucleus of
[ 69907-67-1 ]

Pyrrolines

A214596 [57079-01-3]

11-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)undecanoic acid

Similarity: 0.88

A245802 [57078-99-6]

5-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentanoic acid

Similarity: 0.88

A103872 [1036847-90-1]

4-((2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-N-(prop-2-yn-1-yl)cyclohexanecarboxamide

Similarity: 0.82

A114517 [7423-55-4]

3-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid

Similarity: 0.76

A104275 [64987-85-5]

2,5-Dioxopyrrolidin-1-yl 4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexanecarboxylate

Similarity: 0.73

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