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Chemical Structure| 17841-68-8 Chemical Structure| 17841-68-8

Structure of 17841-68-8

Chemical Structure| 17841-68-8

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Product Details of [ 17841-68-8 ]

CAS No. :17841-68-8
Formula : C9H12ClNO2
M.W : 201.65
SMILES Code : O=C(OC)C1=CC=CC(CN)=C1.[H]Cl
English Name :Methyl 3-(aminomethyl)benzoate hydrochloride
MDL No. :MFCD04039173
InChI Key :UOWRPTFJISFGPI-UHFFFAOYSA-N
Pubchem ID :2794825

Safety of [ 17841-68-8 ]

Computational Chemistry of [ 17841-68-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 6
Fraction Csp3 0.22
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 52.36
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

52.32 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

0.0
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.06
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.58
Log Po/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.

1.67
Log Po/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

1.31
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.32

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.53
Solubility 0.593 mg/ml ; 0.00294 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.79
Solubility 0.329 mg/ml ; 0.00163 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

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

-2.51
Solubility 0.622 mg/ml ; 0.00308 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

Yes
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.

-6.07 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.

0.55

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

0.0 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)

1.46

Application In Synthesis of [ 17841-68-8 ]

* 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 [ 17841-68-8 ]

[ 17841-68-8 ] Synthesis Path-Downstream   1~14

  • 1
  • [ 17841-68-8 ]
  • [ 903556-10-5 ]
YieldReaction ConditionsOperation in experiment
100% With ammonia; water at 90℃; for 20h; A; 2008.A Commercial available 3-aminomethyl-benzoic acid methyl ester hydrochloride (500 mg) was dissolved in aqeous ammonia (33%, 50 mL) and stirred at 90° C. in a sealed pressure tube for 20 h. The solvent was removed to afford the title compound as colorless solid (469 mg; quantitative). [M-Cl]+=151.
  • 2
  • [ 100-52-7 ]
  • [ 17841-68-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With acetic acid In 1,2-dichloro-ethane at 120℃; for 0.333333h; Microwave irradiation; 41 Suspendend 3-aminomethyl-benzoic acid methyl ester hydrochloride (100 mg. 0.99 mmol) in 3 mL of dichloroethane in a microwave tube and added 100 uL of AcOH. To this was added benzaldehyde (0.10 mL, 1.00 mmol). The mixture was sealed and heated at 120 0C for 20 minutes resulting in a homogeneous solution. 2 mL of MeOH was added and the mixture was treated with NaBH4 (56.8 mg, 1.50 mmol) resulting in gas evolution. The mixture stirred for 19 h. The mixture was quenched with careful addition of 5% HCl resulting in a bi-phasic mixture. The aqueous phase was removed and treated with 50X2- 200 Dowex acidic ion exchange resin. The product was liberated with 10% NH3 in MeOH and concentrated to give 197 mg of 3-(benzylamino-methyl)-benzoic acid methyl ester, partially contaminated with starting benzyl amine (15%).Dissolved 3-(benzylamino-methyl)-benzoic acid methyl ester (197 mg, 0.77 mmol) in 5 mL of DMF. To this was added 4-cyanophenyl isocyanate (112 mg, 0.78 mmol). The mixture stirred for 48. LC-MS analysis indicated the desired urea. The mixture was diluted with 100 mL EtOAc, washed with 3x50 mL of H2O and 1x20 mL of brine. The organic phase was dried with MgSO4, filtered and concentrated. The resulting residue was applied to a SiO2 prep plate and eluted with 50% EtOAc/hexanes to give two fractions-one clear band and a tail. LC-MS analysis indicated both band and tail were composed of the product. Both fractions were combined to give 105.7 mg of 3-[l-benzyl-3-(4-cyano- phenyl)-ureidomethyl] -benzoic acid methyl ester.Dissolved to 3-[l-benzyl-3-(4-cyano-phenyl)-ureidomethyl]-benzoic acid methyl ester (106 mg, 0.27 mmol) in 1 :1 mixture of THF/MeOH (4 mL). To this was added a 15% NaOH solution and the mixture stirred overnight at room temperature. LC-MS analysis indicated the desired carboxylic acid. Concentrated the mixture and the residue was suspended in 5 mL of H2O and made acidic by the addition of 5% HCl, resulting in a white ppt., which was filtered and dried to give 101.6 mg of 3-[l-benzyl-3-(4-cyano-phenyl)- ureidomethylj-benzoic acid.[210] 3-[ 1 -Benzyl-3-(4-cyano-phenyl)-ureidomethyl]-Λ/-(5-methyl-4,5,6,7-tetrahydro- thiazolo[5,4-c]pyridin-2-yl)-benzamide was prepared by the method described in Example 23. MS, electrospray, 537, (M+H).
  • 3
  • [ 93-07-2 ]
  • [ 17841-68-8 ]
  • [ 1038549-71-1 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 17h; 8 3,4-Dimethoxybenzoic acid (400.8 mg, 2.2 mmol), EDC (479 mg, 2.5 mmol) and HOBt (338 mg, 2.5 mmol) were combined in a reaction vial. DMF (2 mL) was added followed by Hunig's base (0.79 mL, 4.5 mmol). The resulting mixture was agitated for 1 hour. Subsequently, 3-methoxycarbonyl-benzyl-ammonium chloride (403.3 mg, 2 mmol) was added and the mixture was agitated 16 h. The reaction mixture was diluted with 10 mL dichloromethane, and the resulting mixture was washed with IN HCl (2 x 10 mL), NaHCO3 (satd. aq., 2 x 10 mL), and brine (1 x 10 mL), dried, and the solvents were evaporated to give 3-[(3,4-dimethoxy-benzoylamino)-methyl]-benzoic acid methyl ester (680 mg) as an oil which was used without purification. The ester was then dissolved in a mixture of methanol (6 mL) and DMF (1 mL) and treated with Amberlyst A26 (OH" form) (3730 mg, 5 mmol), and the resulting mixture was agitated for 36 h. The resin was then filtered and washed with 2 x 4 mL methanol, 1 x 4 mL DMF and 2 x 4 mL methanol. The product acid was eluted with a solution of 20% formic acid in methanol. The eluant solvents were evaporated, and the resulting solid was triturated in diethylether. 3-[(3,4- dimethoxy-benzoylamino)-methyl]-benzoic acid was isolated by filtration (386 mg, 61% - 2 steps) and carried forward. This intermediate (80 mg, 0.254 mmol) was combined with EDC (57.5 mg, 0.3 mmol) and HOBt (40.5 mg, 0.3 mmol) in a reaction vial, and N-methyl morpholine (0.034 mL, 0.3 mmol) was added. The resulting mixture was agitated for 30 min, after which time, 3-(2-amino-ethyl)-piperidine-l-carboxylic acid tert-butyl ester (64 mg, 0.28 mmol) was added and the resulting mixture was agitated overnight. The reaction mixture was diluted with 3 mL dichloromethane, and the resulting mixture was washed with IN HCl (2 x 1 mL), NaHCO3 (satd. aq., 2 x 1 mL), and brine (1 x 1 mL), dried, and the solvents were evaporated to 140 mg of the intermediate, 3-(2-{3-[(3,4-dimethoxy- benzoylamino)-methyl]-benzoylamino} -ethyl)-piperidine- 1 -carboxylic acid tert-butyi ester, which was redissolved in dichloromethane (2 mL). SCX (681 mg, 0.6 mmol) was added and the resulting mixture was agitated overnight. The reaction mixture was filtered and the solids were washed with dichloromethane (2 x 2 mL) and methanol (2 x 2 mL). The product was eluted with NH3 in methanol (7N, 3x1 mL). The solvents were evaporated to provide 80 mg (74.3% - 2 steps) of the title compound, MS analysis electrospray, 426 (M+H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide
  • 4
  • [ 40465-45-0 ]
  • [ 17841-68-8 ]
  • [ 1038548-33-2 ]
YieldReaction ConditionsOperation in experiment
91% Stage #1: p-cyanophenyl isocyanate; 3-aminomethyl-benzoic acid methyl ester hydrochloride With Si-dimethylamine In N,N-dimethyl-formamide Stage #2: With SCX In N,N-dimethyl-formamide for 0.5h; 1 3-Methoxycarbonyl-benzyl-ammonium chloride (605 mg, 3.0 mmol) was dissolved in 6 mL DMF in a reaction vial. Si-dimethylamine (silica-bound dimethylamine; 3.3g, 5 mmol) was added and the mixture was agitated for 1 hour. Subsequently, p- cyanophenylisocyanate (403.5 mg, 2.8 mmol) was added and the mixture was agitated overnight. SCX (strong cation exchanger; silica-bound benzenesulfonic acid; (568 mg, 0.5 mmol) was added and the mixture was agitated for 30 minutes. The solids were filtered, and the filtrate was evaporated to provide 843 mg (91% yield) of the desired urea, 3-[3-(4- cyano-phenyl)-ureidomethyl] -benzoic acid methyl ester, which was used directly. The intermediate urea was dissolved in 7 rnL THF. A solution of lithium hydroxide (410 mg, 10 mmol) in 3 mL water was added. The resulting mixture was heated at 50 0C for 2 hours then cooled to room temperature. The organic phase was evaporated, and the remaining aqueous solution was neutralized. 3-[3-(4-Cyano-phenyl)-ureidomethyl]-benzoic acid (118 mg, 0.4 mmol) was isolated as a white solid by filtration (710 mg; 93% yield) and was used directly. The intermediate acid (118 mg, 0.4 mmol), EDC (115 mg, 0.6 mmol), and HOBt (67.6 mg, 0.5 mmol) were combined in a reaction vial and DMF (1 mL) then N- methylmorpholine (0.066 mL, 0.6 mmol) were added. The reaction mixture was agitated for 1 h, then 7-amino-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester (104.3 mg, 0.42 mmol) was added. Shaking was continued overnight. The reaction mixture was diluted to 6 mL with dichloromethane, washed with IN HCl (3 x 2 mL), NaHCO3 (satd. aq., 3 x 2 mL), and brine (1 x 2 mL), dried, and the solvents were evaporated to give 220 mg of the intermediate 7-{3-[3-(4-cyano-phenyl)-ureidomethyl]- benzoylamino}-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyi ester, which was treated directly with a solution of TFA (0.6 mL) in dichloromethane (2 mL). The reaction mixture was stirred for 2 h, and then the solvents were evaporated. The residue was purified by preparative ΗPLC using an acetonitrile/water/formic acid gradient. The title compound was collected as a solid (137 mg, 77% - 2 steps) following evaporation of the solvent; MS analysis electrospray, 426 (M+Η).
91% Stage #1: 3-aminomethyl-benzoic acid methyl ester hydrochloride With Si-DMA In N,N-dimethyl-formamide for 1h; Stage #2: p-cyanophenyl isocyanate In N,N-dimethyl-formamide for 16h; Stage #3: With Bond Elut SCX In N,N-dimethyl-formamide for 0.5h;
  • 5
  • [ 472-15-1 ]
  • [ 17841-68-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 20h; A mixture of betulinic acid (200 mg, 0.438 mmol), 3- carbomethoxybenzylamine hydrochloride (107 mg, 1.2 equiv.), N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (101 mg, 1.2 equiv.), and 1- hydroxy-7-azabenzotriazole (30 mg, 0.5 equiv.) was dissolved in 2.2 mL of DMF (0.2 M) and then 4-methylmorpholine (0.23 mL, 4.5 equiv.) was added at room temperature. The mixture was stirred for 20 h at room temperature, then diluted with THF (2.2 mL) and water (2.2 mL), and then lithium hydroxide (105 mg, 10 equiv.) was added to the solution. The resulting solution was stirred for 16 h at room temperature. The mixture was cooled to 0 0C and then 2 N HCl solution (30 mL) was slowly added. The resulting white precipitate was collected on a sintered glass filter and dried with suction for 1 h to give the title compound 2 (230 mg, 89% yield).
  • 6
  • [ 24424-99-5 ]
  • [ 17841-68-8 ]
  • [ 180863-55-2 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydrogencarbonate In dichloromethane; water for 2h; 110 3-(tert-Butoxycarbonylamino-methyl)-benzoic acid methyl ester Preparation 110 3-(tert-Butoxycarbonylamino-methyl)-benzoic acid methyl ester Stir 3-aminomethyl-benzoic acid methyl ester hydrochloride (2.13 g, 10.6 mmol) in a mixture of dichloromethane (200 mL) and saturated aqueous sodium bicarbonate (100 mL). Add di-tert-butyl-dicarbonate (2.76 g, 12.7 mmol) and stir for 2 hrs. Separate the organic phase and dry over sodium sulfate. Filter and concentrate. Purify the residue by chromatography (silica get) eluding with 20-30% ethyl acetate/hexane to provide the title compound (2.8 g, 100%).
92% With sodium hydrogencarbonate In water; ethyl acetate for 1.16667h; V; 35.3 The crude product obtained in the previous step was diluted with water, basified (PH=8.0) with aq. Sodium bicarbonate. To this mixture a solution of Di-tert-butyl dicarbonate (0.79 mL, 3 40 mmol) in ethyl acetate (10 mL) was added drop wise over a period of 10 min and it was stirred over a period of 60 min. The reaction mixture was diluted with ethyl acetate (100 mL), washed water, brine and dried over sodium sulphate. Solvent was removed under reduced pressure to give 3-(tert-Butoxycarbonylamino-methyl)-benzoic acid methyl ester as a colourless solid (0.6 g, 92%).
With sodium hydrogencarbonate In water; ethyl acetate for 1.16667h; 35.3; V The crude product obtained in the previous step was diluted with water, basified (P =8.0) with aq. Sodium bicarbonate. To this mixture a solution of Di-tert-butyl dicarbonate (0.79 mL, 3.40 mmol) in ethyl acetate (10 mL) was added drop wise over a period of 10 min and it was stirred over a period of 60 min. The reaction mixture was diluted with ethyl acetate (100 mL), washed water, brine and dried over sodium sulphate. Solvent was removed under reduced pressure to give 3-(tert-Butoxycarbonylamino-methyl)-benzoic acid methyl ester as a colourless solid (0.6 g, 92 %).
  • 7
  • [ 1219089-32-3 ]
  • [ 17841-68-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; 281 Example 281; Preparation of rac 3-([(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid methyl ester To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.26 mmol) in methylene chloride (10 mL), HATU (Aldrich,177 mg, 0.46 mmol) was added followed by the addition of DIPEA(0.36 mL, 2.06 mmol) and 3-aminomethyl-benzoic acid methyl ester hydrochloride salt(Aldrich, 104 mg, 0.52 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/hexanes) to give a white solid. 118 mg.MS (ES+) m/z Calcd: [(M+H)+]: 614, found: 614
  • 8
  • [ 37527-66-5 ]
  • [ 17841-68-8 ]
  • [ 1203719-50-9 ]
YieldReaction ConditionsOperation in experiment
90% Stage #1: 3-aminomethyl-benzoic acid methyl ester hydrochloride With Si-DMA In N,N-dimethyl-formamide for 1h; Stage #2: 3,4-dimethoxyphenylisocyanate In N,N-dimethyl-formamide for 16h; Stage #3: With Bond Elut SCX In N,N-dimethyl-formamide for 0.25h;
  • 9
  • [ 99-04-7 ]
  • [ 17841-68-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-Bromosuccinimide / 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 3 h / 25 °C / Reflux 2: thionyl chloride / 1 h / 25 °C / Reflux 3: N,N-dimethyl-formamide / 12 h / 85 °C 4: hydrazine hydrate / methanol / 4 h / 25 °C / Reflux
Multi-step reaction with 4 steps 1: N-Bromosuccinimide / 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 3 h / 25 °C / Reflux 2: thionyl chloride / 1 h / 25 °C / Reflux 3: N,N-dimethyl-formamide / 12 h / 85 °C 4: hydrazine hydrate / methanol / 4 h / Reflux
  • 10
  • [ 781632-38-0 ]
  • [ 17841-68-8 ]
YieldReaction ConditionsOperation in experiment
Stage #1: methyl 3-((1,3-dioxoisoindolin-2-yl)methyl)benzoate With hydrazine hydrate In methanol at 25℃; for 4h; Reflux; Stage #2: With hydrogenchloride In water 35.2; V To a suspension of 3-(l ,3-Dioxo-l ,3-dihydro-isoindol-2-ylmethyl)-benzoic acid methyl ester ( 0.5 g, 1.70 mmol) in methanol (15 mL) was added hydrazine mono hydrate (0.08 mL) at 25 °C and the reaction mixture was refluxed over a period of 4 h and it was allowed to reach 25 °C. The white suspension formed was filtered and the filtrate was concentrated. The filtrate obtained was diluted with water (20 mL) and acidified with 1.5 N HCl and water was evaporated under reduced pressure to obtain (0.5 g) of the 3-Aminomethyl- benzoic acid methyl ester hydrochloride as a crude solid. The crude product obtained was used for next step without further purification.
Stage #1: methyl 3-((1,3-dioxoisoindolin-2-yl)methyl)benzoate With hydrazine hydrate In methanol for 4h; Reflux; Stage #2: With hydrogenchloride In methanol; water V; 35.2 To a suspension of 3-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoic acid methyl ester (0.5 g, 1.70 mmol) in methanol (15 mL) was added hydrazine mono hydrate (0.08 mL) at 25° C. and the reaction mixture was refluxed over a period of 4 h and it was allowed to reach 25° C. The white suspension formed was filtered and the filtrate was concentrated. The filtrate obtained was diluted with water (20 mL) and acidified with 1.5 N HCl and water was evaporated under reduced pressure to obtain 0.5 g) of the 3-Aminomethyl-benzoic acid methyl ester hydrochloride as a crude solid. The crude product obtained was used for next step without further purification.
  • 11
  • [ 135447-09-5 ]
  • [ 17841-68-8 ]
  • [ 1325217-54-6 ]
YieldReaction ConditionsOperation in experiment
63% With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In dichloromethane at 20℃; for 24h; Inert atmosphere;
  • 12
  • [ 1338778-47-4 ]
  • [ 17841-68-8 ]
  • [ 1354555-51-3 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 6-carbamoylimidazo[1,2-a]pyridine-2-carboxylic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 3-aminomethyl-benzoic acid methyl ester hydrochloride In N,N-dimethyl-formamide at 20℃; 8 Example 8: Synthesis of imidazo[l,2-a]pyridine-2,6-dicarboxylic acid 6-amide 2-[3-(5- methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-benzylamide] (Cpd 213, Table 1); To a solution of 6-carbamoyl-imidazo[l,2-a]pyridine-2-carboxylic acid (500 mg, 2.44 mmol) in DMF (10 mL), add Et3N (0.67 mL, 4.9 mmol) and TBTU (939 mg, 2.92 mmol) and stir at rt for 30 min. Add methyl 3 -aminomethyl -benzoic acid methyl ester hydrochloride (541 mg, 2.68 mmol). Stir the mixture at rt overnight. LCMS indicates desired product. Dilute the mixture with EtOAc, and pour into water to form a solid. Filter and set aside as crop 1. Extract the filtrate with EtOAc, dry the organic (Na2S04), concentrate and purify by silica gel chromatography to afford additional desired product. Combine and dry the crops to give 3-{ [(6-carbamoyl-imidazo[l,2-a]pyridine-2-carbonyl)- amino] -methyl} -benzoic acid methyl ester as a solid (722 mg, 2.05 mmol).
  • 13
  • [ 1159516-94-5 ]
  • [ 17841-68-8 ]
  • [ 1256969-22-8 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In acetonitrile for 2h; Reflux; 117.117.1 Working Example 117-1 Synthesis of 2-(2-(3-methoxycarbonylphenylmethyl)aminonitroTbenzen-5-yl)benzoxazole To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (250 mg, 0.968 mmol) in acetonitrile (5 mL) was added triethylamine (245 mg, 2.42 mmol) and 3-carbomethoxybenzylamine hydrochloride (215 mg, 1.07 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (365 mg, 94% yield). 1H-NMR (DMSO-d6) δ: 3.85 (3H, s), 4.82 (2H, d, J = 6.3 Hz), 7.14 (1H, d, J = 9.1 Hz), 7.37-7.40 (2H, m), 7.52 (1H t, J = 7.8 Hz), 7.68-7.77 (3H, m), 7.87 (1H, d, J = 7.8 Hz), 8.03 (1H, s), 8.15 (1H, dd, J = 9.1,2.1 Hz), 8.84 (1H, d, J = 2.1 Hz), 9.21 (1H, t, J = 6.5 Hz).
  • 14
  • [ 17841-68-8 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
90% Stage #1: monensin A With benzotriazol-1-ol In tetrahydrofuran at 5℃; for 0.5h; Stage #2: With dicyclohexyl-carbodiimide In tetrahydrofuran for 1h; Stage #3: 3-aminomethyl-benzoic acid methyl ester hydrochloride With 4-methyl-morpholine In tetrahydrofuran at 20℃; for 72h; 2 Compound (3c)-1-(3-methylbenzoate)methylene Amidomonensin; NMR 1H (400 MHz, CDCl3) ppm: 7.94 (1H, s), 7.89 (1H, d, J=7.80 Hz), 7.49 (1H, d, J=7.80 Hz), 7.38-7.33 (2H, m), 5.08 (1H, s), 4.63 (1H, d, J=7.52 Hz), 4.51-4.40 (2H, m), 4.30 (1H, m), 4.15 (1H, dd, J1=2 Hz, J2=7.80 Hz), 3.92-3.88 (6H, m), 3.71 (1H, s), 3.52 (1H, dd, J1=5.56 Hz, J2=10.08 Hz), 3.40-3.35 (6H, m), 2.56-2.53 (1H, m), 2.24-2.21 (2H, m), 2.03-1.97 (1H, m), 1.96-1.87 (3H, m), 1.84-1.64 (6H, m), 1.61-1.55 (1H, m), 1.54-1.35 (11H, m), 1.25 (3H, d, J=7.04 Hz), 1.01 (3H, d, J=6.80 Hz), 0.92-0.89 (6H, m), 0.83-0.75 (9H, m).NMR 13C (400 MHz, CDCl3) ppm: 176.50, 167.15, 139.83, 132.27, 130.39, 128.66, 128.37, 107.91, 97.64, 86.52, 85.97, 85.60, 83.22, 82.40, 76.62, 74.94, 71.25, 67.63, 67.50, 58.96, 52.17, 42.86, 42.38, 38.96, 37.50, 36.98, 36.60, 35.12, 34.70, 34.45, 33.36, 33.17, 32.70, 31.10, 30.44, 27.69, 26.77, 17.33, 16.31, 15.47, 14.11, 12.92, 10.95, 8.38.Exact mass: HR ESIMS: Calculated for C45H71O12NNa+=840.4874, found=840.4873.; A mixture of monensin acid (507.9 mg, 0.75 mmol, 1 eq) and HOBt (124.3 mg, 0.90 mmol, 1.2 eq) in THF (3 mL) was stirred at 5° C. for 30 min and then DCC (190.4 mg, 0.90 mmol, 1.2 eq) was added. After being stirred for 1 h, the reaction mixture was treated with a solution of methyl 3-(aminomethyl)benzoate hydrochloride (199.4 mg, 0.98 mmol, 1.3 eq) and N-methylmorpholine (110 μL, 0.98 mmol, 1.3 eq) in THF (2 mL), and stirring was maintained at room temperature during 3 days. The mixture was evaporated to dryness to give a powder, which was suspended in EtOAc (6 mL) and filtered off. The organic phase was washed with 10% citric acid solution (3 mL), saturated NaHCO3 (3 mL) and distilled water (3 mL), successively, dried over MgSO4 and evaporated to dryness to afford 549.2 mg (90%) of the desired amide.
 

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