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Chemical Structure| 5325-64-4 Chemical Structure| 5325-64-4

Structure of H-Sar-NH2.HCl
CAS No.: 5325-64-4

Chemical Structure| 5325-64-4

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Product Details of [ 5325-64-4 ]

CAS No. :5325-64-4
Formula : C3H9ClN2O
M.W : 124.57
SMILES Code : Cl.CNCC(N)=O
MDL No. :MFCD00058283
InChI Key :VVIXOTCTYAILNP-UHFFFAOYSA-N
Pubchem ID :13892956

Safety of [ 5325-64-4 ]

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

Computational Chemistry of [ 5325-64-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 7
Num. arom. heavy atoms 0
Fraction Csp3 0.67
Num. rotatable bonds 2
Num. H-bond acceptors 2.0
Num. H-bond donors 2.0
Molar Refractivity 29.21
TPSA ?

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

55.12 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

-0.46
Log Po/w (WLOGP)?

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

-0.51
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.

-0.8
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

-1.04
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-0.56

Water Solubility

Log S (ESOL):?

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

-0.19
Solubility 80.3 mg/ml ; 0.645 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.

-0.23
Solubility 73.1 mg/ml ; 0.587 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

-0.21
Solubility 76.5 mg/ml ; 0.614 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.

-7.39 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

2.0
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)

1.0

Application In Synthesis of [ 5325-64-4 ]

* 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 [ 5325-64-4 ]

[ 5325-64-4 ] Synthesis Path-Downstream   1~28

  • 1
  • [ 88-88-0 ]
  • [ 5325-64-4 ]
  • [ 118745-04-3 ]
  • 2
  • [ 54150-57-1 ]
  • [ 5325-64-4 ]
  • [ 106231-62-3 ]
  • 3
  • [ 590-28-3 ]
  • [ 5325-64-4 ]
  • [ 111184-52-2 ]
  • 4
  • [ 5325-64-4 ]
  • [ 103-71-9 ]
  • [ 111184-56-6 ]
  • 5
  • [ 5325-64-4 ]
  • [ 624-83-9 ]
  • [ 111184-54-4 ]
  • 6
  • [ 50329-91-4 ]
  • [ 5325-64-4 ]
  • 2-[(3-formyl-2-oxo-2<i>H</i>-chromen-4-yl)-methyl-amino]-acetamide [ No CAS ]
  • 7
  • (2S,4S,5S)-1-[(benzyloxy)carbonyl]-4-(dimethylcarbamoyl)-5-methyl-2-pyrrolidinecarboxylic acid [ No CAS ]
  • [ 5325-64-4 ]
  • benzyl (2S,3S,5S)-5-[(2-amino-2-oxoethyl)(methyl)carbamoyl]-3-(dimethylcarbamoyl)-2-methyl-1-pyrrolidinecarboxylate [ No CAS ]
  • 8
  • [ 5325-64-4 ]
  • (+/-) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl} benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% To a solution of 3- [5-BROMO-4- [ (2, 4-difluorobenzyl) oxy]- 2-methyl-6-oxopyrimidin-1 (6H)-YL]-4-METHYLBENZOIC acid (1.0 g, 0.022 mol) in dimethylacetamide (10.0 mL) at-20 oC was added isobutylchloroformate (0.36 g, 0.0028 mol), followed by dropwise addition of N-METHYLMORPHOLINE (0.30 G, 0.003 mol) and stirred for 10 min under nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 20 min, cooled to 0 oC, and added N-methylmorpholine (0.30 g, 0.003 mol) followed by the addition of N-methylglycine amide hydrochloride (0.35 G, 0.0028 mol) and DMAP (0.025 g). The reaction mixture was stirred at room temperature for 4 h, and concentrated IN VACUO. The resulting the residue was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z = 535) were combined, and freeze-dried to give a white solid. This was dissolved in dichloromethane (25 mL), washed successively with 5% sodium bicarbonate (2 x 20 mL), water (2 x 20 mL), dried (NA2SO4), and concentrated to dryness to afford the racemic title compound (0.75 g, 65%) as a white amorphous substance : 1H NMR (CD30D/400 MHz) 5 7.96 (dd 1H, J = 1.6 Hz, 8.0 Hz), 7.72 (d, 1H, J = 1.6 Hz), 7.62 (m, 1H), 7.56 (d, 1H, J = 8.0 Hz), 7.01 (m, 2H), 5.55 (abq, 2H), 3.99 (s, 2H), 2.74 (s, 3H), 2.18 (s, 3H), and 2.14 (s, 3H); ES-HRMS M/Z 535.0792 (M+H calcd for C23H22N404F2 Br requires 535. 0787). 19F NMR (CD3OD/ 400 MHz) -111. 85 (m) and - 115. 91 (m).
  • 9
  • [ 5325-64-4 ]
  • [ 79-04-9 ]
  • [ 114665-31-5 ]
YieldReaction ConditionsOperation in experiment
8.5 g (52%) With sodium hydrogencarbonate; In water; benzene; A solution of chloroacetyl chloride (0.1 mole, 11.3 g) in benzene (40 ml) was added over 30 min to a mixture of <strong>[5325-64-4]sarcosinamide hydrochloride</strong> (0.1 mole, 12.45 g) and sodium bicarbonate (0.25 mole, 20.0 g) in 40 ml of water. The mixture was vigorously stirred for 3 h at room temperature. The aqueous phase was acidified with 5M hydrochloric acid to pH 5 and extracted with ethyl acetate (3*400 ml). The combined extracts were dried over anhydrous sodium sulphate and evaporated in vacuo. The solid residue obtained was recrystallized from ethanol-ether to give 8.5 g (52%) of the title compound. Mp 85-86 C.
  • 10
  • [ 79-07-2 ]
  • [ 5325-64-4 ]
YieldReaction ConditionsOperation in experiment
With methylamine; EXAMPLE 87 PREPARATION OF alpha-CHLOROACETYLSARCOSINAMIDE Sarcosinamide hydrochloride was prepared by reacting methylamine with 2-chloroacetamide as described by Marvel et al. (1946). The compound was recrystallized from ethanol. Mp 160-161 C.
YieldReaction ConditionsOperation in experiment
75% To a solution of carbamoylmethyl-methyl-carbamic acid t-butyl ester (848 mg, 4.50 mmol) (obtained as described in Reference Example 44(1)) in 1,4-dioxane (8.50 ml) was added a solution of 4N hydrogen chloride in 1,4-dioxane (8.50 ml) in an ice bath, and the mixture was stirred at room temperature for 2.5 hours. After checking the completion of the reaction, diethyl ether was added thereto, and the reaction mixture was stirred for 30 minutes. The resulting reaction mixture was filtered, and the obtained residue was washed with diethyl ether and dried to give 2-methylaminoacetamide hydrochloride (421 mg, yield 75%).
  • 12
  • [ 928149-87-5 ]
  • [ 5325-64-4 ]
  • 7-chloro-1-(tetrahydropyran-4-yl)methyl-3-(4-[N-(carboxamido)methyl-N-methylamino]methyl}-[1,3]-thiazol-2-yl)-1H-indole [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; sodium iodide; In N,N-dimethyl-formamide; at 160℃; for 0.0833333h;Microwave irradiation; Example 16A 7-Chloro-1-(tetrahvdropyran-4-yl)methyl-3-(4-[Lambda/-(carboxamido)methyl-Lambda/- methylaminolmethylHI ,3l-thiazol-2-yl)-1 /-/-indole A mixture of 7-chloro-3-[4-(chloromethyl)thiazol-2-yl]-1-(tetrahydropyran-4- yl)methyl-1 /-/-indole (prepared as described in Example 16, using toluene-4-sulfonic acid tetrahydropyran-4-ylmethyl ester instead of cyclohexylmethyl bromide) (40 mg, 0.10 mmol), Lambda/-methyl glycine amide hydrochloride (18.4 mg, 0.15 mmol), di- isopropylethylamine (35 mul, 0.21 mmol) and sodium iodide (16 mg, 0.10 mmol) in dimethylformamide (2 ml) was subjected to microwave irradiation for 5 min at 160 C. The reaction mixture was filtered through a 5 g Strata SCX giga tube. The tube was washed with dichloromethane and then eluted with 10% (2 M ammonia in methanol) in dichloromethane. The product was purified by column chromatography eluting with 3:97 (v/v) (2M ammonia in methanol): dichloromethane to give the title compound (39 mg, 0.09 mmol). EsIMS: m/z 433.5, 435.4 [M+H]+.
With N-ethyl-N,N-diisopropylamine; sodium iodide; In N,N-dimethyl-formamide; at 160℃; for 0.0833333h;Microwave irradiation; EXAMPLE 16A 7-Chloro-1-(tetrahydropyran-4-yl)methyl-3-(4-[N-(carboxamido)methyl-N-methylamino]methyl}-[1,3]-thiazol-2-yl)-1H-indole A mixture of 7-chloro-3-[4-(chloromethyl)thiazol-2-yl]-1-(tetrahydropyran-4-yl)methyl-1H-indole (prepared as described in Example 16, using toluene4-sulfonic acid tetrahydropyran4-ylmethyl ester instead of cyclohexylmethyl bromide) (40 mg, 0.10 mmol), N-methyl glycine amide hydrochloride (18.4 mg, 0.15 mmol), di-isopropylethylamine (35 mul, 0.21 mmol) and sodium iodide (16 mg, 0.10 mmol) in dimethylformamide (2 ml) was subjected to microwave irradiation for 5 min at 160 C. The reaction mixture was filtered through a 5 g Strata SCX giga tube. The tube was washed with dichloromethane and then eluted with 10% (2 M ammonia in methanol) in dichloromethane. The product was purified by column chromatography eluding with 3:97 (v/v) (2M ammonia in methanol): dichloromethane to give the title compound (39 mg, 0.09 mmol). EsIMS: m/z 433.5, 435.4 [M+H]+.
  • 13
  • [ 928150-02-1 ]
  • [ 5325-64-4 ]
  • 7-chloro-3-[5-[N-(carboxamido-methyl)-N-methyl-amino]methyl}-[1,2,4]oxadiazol-3-yl]-1-(tetrahydropyran-4-yl)methyl-1H-indole [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20℃; for 18h; Example 20 7-Chloro-3-[(5-[Lambda/-(carboxamido)methyl1-Lambda/-methylamino)methyl)-([1 ,2,41oxadiazol-3- vDI-1 -(tetrahydropyran-4-yl)methyl-1 /-/-indole, hydrochloride salt To a solution of 7-chloro-3-[(5-chloromethyl)-([1 ,2,4]oxadiazol-3-yl)]-1-(tetra- hydropyran-4-yl)methyl-1 /-/-indole (Example 19; Step C; 1.5 g, 4.09 mmol) in 1- methyl-2-pyrrolidinone (5 ml) was added Lambda/-methyl glycine amide hydrochloride (1.0 g, 8.19 mmol) and potassium carbonate (3.4 g, 24.6 mmol). The reaction was stirred at room temperature for 18 h before being diluted with dichloromethane (10 ml) and filtered through a 20 g Strata SCX giga tube. The tube was washed with methanol and then eluted with 2 M ammonia in methanol. The methanolic ammonia solution was evaporated to dryness. This was re-dissolved in dichloromethane, washed with water and brine, dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography eluting with 2% (v/v) ethanol in dichloromethane. The solid was dissolved in dichloromethane and hydrogen chloride (2M solution in diethyl ether) was added. The resultant EPO <DP n="39"/>hydrochloride salt was crystallised from acetone to afford the title compound as a 1 :1 hydrochloride salt (1.24 g, 2.73 mmol). EsIMS: m/z 418.3 [M+H]+
  • 14
  • [ 928149-33-1 ]
  • [ 5325-64-4 ]
  • 7-methoxy-3-(5-[N-(carboxamido-methyl)-N-methyl-amino]methyl}-[1,2,4]thiadiazol-3-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In acetonitrile; at 150℃; for 0.5h;Microwave irradiation; Example 5 7-Methoxy-3-[(5-[(Lambda/-carboxamido)methyl1methylamino)methyl)-([1 ,2,41-thiadiazol-3- yl)1-1-(tetrahvdropyran-4-yl) methyl-1 /-/-indole, trifluoroacetic acid salt. Methanesulfonic acid 3-(1 -tetrahydropyran-4-yl)methyl-7-methoxy-indol-3-yl)- ([1 ,2,4]thiadiazol-5-ylmethyl ester (106 mg, 0.25 mmol), prepared according to the method of Example 1 using 7-methoxyindole instead of 7-chloroindole, was dissolved in acetonitrile (2 ml) and transferred into a microwave vial. Lambda/-methyl glycine amide hydrochloride (53 mg, 1.26 mmol) and potassium carbonate (174 mg, 1.26 mmol) were added and the reaction mixture subjected to microwave irradiation at 150 C for 30 mins using an Emrys Optimizer EXP. The free base was purified by semi-prep. HPLC (Method i) to afford the title compound as a 1 :1 trifluoroacetic acid salt (17.4 mg, 0.03 mmol). EsIMS: m/z 452.1 [M+Na]+, 429.8 [M+H]+
  • 15
  • [ 928149-43-3 ]
  • [ 5325-64-4 ]
  • 7-ethyl-3-(5-[{N-(carboxamido-methyl)-N-methyl-amino}methyl]-[1,2,4]thiadiazol-3-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In dichloromethane; at 100℃; for 0.05h;Microwave irradiation; Example 9 7-Ethyl-3-r(5-{r/V-(carboxamido)methyll-/V-methylamino>methyl)-(ri ,2,41-thiadiazol-3- yl)1-1-(tetrahvdropyran-4-yl)methyl-1 H-indole, hydrochloride acid salt Methanesulfonic acid 3-(1 -tetrahydropyran-4-yl)methyl-7-ethyl-1 H-indol-3-yl)- ([1 ,2,4]thiadiazol-5-ylmethyl ester (30 mg, 0.07 mmol) prepared according to Example 1 , using 7-ethylindole instead of 7-chloroindole, was dissolved in dry dichloromethane (1 ml) in a 5 ml microwave vial and potassium carbonate was added (70 mg, 0.51 mmol) followed by Lambda/-methyl glycine amide hydrochloride (26 mg, 0.21 mmol). The mixture is heated in a microwave oven at 100 0C for 3 mins. After cooling down to room temperature, the mixture was partitioned between water and dichloromethane. The organic phase was separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. The crude oil was prepurified on a 2 g SCX column and on a 2 g Si-based lsolute column eluting with 50%-100% (v/v) ethyl acetate in n-heptane. The free base was converted into its hydrochloride salt by dissolving it in dry dichloromethane and adding a 2M solution of HCI in ether to afford the title compound: (7.9 mg, 0.017 mmol). EsIMS: m/z 428.1 [M+H]+.
  • 16
  • [ 928149-43-3 ]
  • [ 5325-64-4 ]
  • 7-ethyl-3-[(5-[N-(carboxamido)methyl]-N-methylamino}methyl)-([1,2,4]-thiadiazol-3-yl)]-1-(tetrahydropyran-4-yl)methyl-1H-indole, hydrochloride acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 9 7-Ethyl-3-[(5-[N-(carboxamido)methyl]-N-methylamino}methyl)-([1,2,4]-thiadiazol-3-yl)]-1-(tetrahydropyran-4-yl)methyl-1H-indole, hydrochloride acid salt Methanesulfonic acid 3-(1-tetrahydropyran-4-yl)methyl-7-ethyl-1H-indol-3-yl)-([1,2,4]thiadiazol-5-ylmethyl ester (30 mg, 0.07 mmol) prepared according to Example 1, using 7-ethylindole instead of 7-chloroindole, was dissolved in dry dichloromethane (1 ml) in a 5 ml microwave vial and potassium carbonate was added (70 mg, 0.51 mmol) followed by N-methyl glycine amide hydrochloride (26 mg, 0.21 mmol). The mixture is heated in a microwave oven at 100 C. for 3 mins. After cooling down to room temperature, the mixture was partitioned between water and dichloromethane. The organic phase was separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. The crude oil was prepurified on a 2 g SCX column and on a 2 g Si-based Isolute column eluding with 50%-100% (v/v) ethyl acetate in n-heptane. The free base was converted into its hydrochloride salt by dissolving it in dry dichloromethane and adding a 2M solution of HCl in ether to afford the title compound: (7.9 mg, 0.017 mmol). EsIMS: m/z 428.1 [M+H]+.
  • 17
  • 7-chloro-3-[(5-chloromethyl)-([1,2,4]oxadiazol-3-yl)]-1-(tetrahydropyran-4-yl)methyl-1H-indole [ No CAS ]
  • [ 5325-64-4 ]
  • 7-chloro-3-[(5-[N-(carboxamido)methyl]-N-methylamino}methyl)-([1,2,4]oxadiazol-3-yl)]-1-(tetrahydropyran-4-yl)methyl-1H-indole, hydrochloride salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 20 7-Chloro-3-[(5-[N-(carboxamido)methyl]-N-methylamino]methyl)-([1,2,4]oxadiazol-3-yl)]-1-(tetrahydropyran-4-yl)methyl-1H-indole, hydrochloride salt To a solution of 7-chloro-3-[(5-chloromethyl)-([1,2,4]oxadiazol-3-yl)]-1-(tetrahydropyran-4-yl)methyl-1H-indole (Example 19; Step C; 1.5 g, 4.09 mmol) in 1-methyl-2-pyrrolidinone (5 ml) was added N-methyl glycine amide hydrochloride (1.0 g, 8.19 mmol) and potassium carbonate (3.4 g, 24.6 mmol). The reaction was stirred at room temperature for 18 h before being diluted with dichloromethane (10 ml) and filtered through a 20 g Strata SCX giga tube. The tube was washed with methanol and then eluted with 2 M ammonia in methanol. The methanolic ammonia solution was evaporated to dryness. This was re-dissolved in dichloromethane, washed with water and brine, dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography eluding with 2% (v/v) ethanol in dichloromethane. The solid was dissolved in dichloromethane and hydrogen chloride (2M solution in diethyl ether) was added. The resultant hydrochloride salt was crystallized from acetone to afford the title compound as a 1:1 hydrochloride salt (1.24 g, 2.73 mmol). EsIMS: m/z 418.3 [M+H]+.
  • 18
  • [ 928149-33-1 ]
  • [ 5325-64-4 ]
  • [ 76-05-1 ]
  • 7-methoxy-3-[(5-[(N-carboxamido)methyl]methylamino}methyl)-([1,2,4]-thiadiazol-3-yl)]-1-(tetrahydropyran-4-yl) methyl-1H-indole, trifluoroacetic acid salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 5 7-Methoxy-3-[(5-[(N-carboxamido)methyl]methylamino}methyl)-([1,2,4]-thiadiazol-3-yl)]-1-(tetrahydropyran-4-yl) methyl-1H-indole, trifluoroacetic acid salt Methanesulfonic acid 3-(1-tetrahydropyran-4-yl)methyl-7-methoxy-indol-3-yl)-([1,2,4]thiadiazol-5-ylmethyl ester (106 mg, 0.25 mmol), prepared according to the method of Example 1 using 7-methoxyindole instead of 7-chloroindole, was dissolved in acetonitrile (2 ml) and transferred into a microwave vial. N-methyl glycine amide hydrochloride (53 mg, 1.26 mmol) and potassium carbonate (174 mg, 1.26 mmol) were added and the reaction mixture subjected to microwave irradiation at 150 C. for 30 mins using an Emrys Optimizer EXP. The free base was purified by semi-prep. HPLC (Method i) to afford the title compound as a 1:1 trifluoroacetic acid salt (17.4 mg, 0.03 mmol). EsIMS: m/z 452.1 [M+Na]+, 429.8 [M+H]+
  • 19
  • [ 5325-64-4 ]
  • [ 287731-68-4 ]
  • [ 1217886-80-0 ]
  • 20
  • [ 1443616-54-3 ]
  • [ 5325-64-4 ]
  • [ 1443616-71-4 ]
YieldReaction ConditionsOperation in experiment
10% With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; at 60℃; for 16h; A solution of Intermediate 13A (50 mg, 148 muiotaetaomicron) in THF (2 ml) was treated with N-methyl- glycinamide hydrochloride (92 mg, 739 muiotaetaomicron), sodium triacetoxyborohydride (157 mg, 739 muiotaetaomicron) and acetic acid (17 mu, 296 muiotaetaomicron), and the mixture was stirred at 60C for 16 h. After this, the reaction mixture was directly separated by preparative RP-HPLC (Reprosil CI 8, gradient 20-40% acetonitrile/0.2%) aq. TFA). The product fractions were combined and evaporated to dryness, and the residue was dissolved in methanol and filtered through an anion exchange cartridge (StratoSpheres SPE, PL-HCO3 MP -resin). The cartridge was eluted with methanol, and the filtrate was evaporated yielding 7 mg (10%> of th.) of the title compound. LC-MS (method 4): Rt = 0.58 min; MS (ESIpos): m/z = 411 (M+H)+ -NMR (400 MHz, DMSO-de): inter al. delta = 7.91 (s, 1H), 7.9 (br. s, 1H), 7.83 (s, 1H), 7.60-7.66 (m, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 6.84 (s, 1H), 5.7 (br. s, 1H), 3.95 (s, 3H), 3.65 (d, 2H), 3.04 (d, 2H), 2.45 (s, 3H) ppm.
  • 21
  • [ 1443616-54-3 ]
  • [ 5325-64-4 ]
  • [ 1443616-72-5 ]
YieldReaction ConditionsOperation in experiment
6% With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; at 60℃; for 16h; A solution of Intermediate 13A (48 mg, 142 muiotaetaomicron) in THF (2 ml) was treated with N2-methyl- glycinamide hydrochloride (88 mg, 709 muiotaetaomicron), sodium triacetoxyborohydride (150 mg, 709 muiotaetaomicron) and acetic acid (16 mu, 284 muiotaetaomicron), and the mixture was stirred at 60C for 16 h. After this, the reaction mixture was directly separated by preparative RP-HPLC (Reprosil CI 8, gradient 30-50% acetonitrile/0.2%) aq. formic acid). The product fractions were combined, neutralized with 1 M aq. ammonia and concentrated under vacuum. The remaining aqueous solution was diluted 1 : 1 with 1 ,4- dioxane and lyophilized. The product thus obtained was dissolved in ethyl acetate and washed with brine. The organic layer was dried with magnesium sulfate, filtered and evaporated to dryness. The residue was purified by preparative TLC (silica gel, dichloromethane/7 M ammonia in methanol 20:1) yielding 4 mg (6%> of th.) of the title compound. LC-MS (method 4): Rt = 0.58 min; MS (ESIpos): m/z = 411 (M+H)+ -NMR (400 MHz, DMSO-de): delta = 7.92-7.94 (m, 2H), 7.36 (s, 1H), 7.30 (s, 1H), 7.09-7.14 (m, 1H), 7.04-7.09 (m, 1H), 6.84 (s, 1H), 5.7 (br. s, 1H), 3.94-3.96 (m, 5H), 3.57 (s, 2H), 2.83 (s, 2H), 2.45 (s, 3H), 2.15 (s, 3H) ppm.
  • 22
  • 3-(5-((1R,2S)-2-(2,2-difluoropropanamido)-1-(2,3-dihydrobenzo-[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoic acid [ No CAS ]
  • [ 5325-64-4 ]
  • N-(2-amino-2-oxo-ethyl)-3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-methylbenzamide [ No CAS ]
  • 23
  • 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid [ No CAS ]
  • [ 5325-64-4 ]
  • N-(2-amino-2-oxoethyl)-N, 4-dimethyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
2.00 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 17.5h; General procedure: Example 23 N-(2-amino-2-oxoethyl)-N, 4-dimethyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide (racemate) 4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid (racemate: 20.0 mg) was dissolved into methylene chloride (1.5 mL), thereto were added 1-hydroxybenzotriazole (13.4 mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (19.0 mg), and <strong>[5325-64-4]N-methylglycinamide hydrochloride</strong> (12.4 mg), and the reaction mixture was stirred at room temperature for 17.5 hours. After the reaction solution was added with water and extracted with methylene chloride, the organic phase was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated saline in sequence, and then dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated with a reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography (chloroform/methanol=10/1) to thus obtain the title compound (2.00 mg) as a white solid. 1H-NMR (400 MHz, CDCl3) delta7.84-7.44 (m, 2H), 7.19-6.76 (m, 4H), 7.11 (dd, J=8.2, 2.0 Hz, 1H), 6.60 (d, J=7.4 Hz, 1H), 6.27-6.19 (m, 1H), 5.56 (brs, 1H), 5.33 (brs, 1H), 4.96-4.82 (m, 1H), 4.56-4.49 (m, 1H), 4.18-3.94 (m, 2H), 3.61-3.15 (m, 5H), 2.93-2.88 (m, 1H), 2.52-2.33 (m, 6H), 1.95-1.89 (m, 1H), 1.56 (brs, 2H), 1.26 (brs, 1H). ESI/MS (m/z) 474 (M+H)+, 472 (M-H)-.
2 mg With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 17.5h; 4-Methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzylidene]-2,3,4,5-tetrahydro-1H- Benzo[b]azepine-4-carboxylic acid (racemic: 20.0 mg) was dissolved in dichloromethane (1.5 mL).Add 1-hydroxybenzotriazole (13.4 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.0 mg), and N-methylglycineamine hydrochloride (12.4 mg),Stir at room temperature for 17.5 hours. After adding water and extracting with dichloromethane, the organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate.After filtration, the filtrate was concentrated under reduced pressure.Using thin layer gelatin chromatography (chloroform / methanol = 10/1)Purifying the residue obtained,The title compound (2.00 mg) was obtained as a white solid.
  • 24
  • 1-(5-(5-ethyl-2-fluorophenyl)pyrimidin-2-yl)-3-(1-hydroxyethyl)-1H-indole-6-carboxylic acid [ No CAS ]
  • [ 5325-64-4 ]
  • N-(2-amino-2-oxoethyl)-1-(5-(5-ethyl-2-fluorophenyl)pyrimidin-2-yl)-3-(1-hydroxyethyl)-N-methyl-1H-indole-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
28% With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; at 20℃; for 16h;Cooling with ice; [1238] N-methylmorpholine (0.107 mL, 0.986 mmol),TBTU (0.191 g, 0.592 mmol) and 2-(methylamino)acetamidehydrochloride (0.123 g, 0.986 mmol) were added to anice-cooled suspension of331e) (0.2 g, 0.493 mmol) in DMF( 4 mL ). The reaction mixture was stirred at room temperaturefor 16 h and then diluted with ice-cold water. A precipitatewas filtered off and dissolved in dichloromethane. Theorganic phase was washed with sodium hydrogen carbonatesolution (20 mL) and brine (20 mL ), dried over sodium sulfateand evaporated. The renmant was purified by flash columnchromatography [silica gel; dichloromethane with 4% methano]followed by preparative HPLC. White solid. Yield: 65 mg(28% of theory)[1239] HPLC-MS (method 5): R,=3.13 min; m/z [M+Ht=476.2[1240] 1H NMR (400 MHz, DMSO-d6, 100 C., o ppm):9.05 (s, 2H), 8.86 (s, lH), 8.26 (s, lH), 7.81 (d, lH, 1=8.0 Hz),7.56 (d, lH, 1=7.6 Hz), 7.32-7.24 (m, 3H), 6.92 (bs, 2H),5.13-5.1 (m, lH), 4.88 (bs, lH), 4.0 (s, 2H), 3.03 (s, 3H),2.74-2.69 (m, 2H), 1.58 (d, 3H, 1=6.0 Hz), 1.27 (t, 3H, 1=7.2Hz).
  • 25
  • 2-amino-2-oxo-1-phenylethyl methanesulfonate [ No CAS ]
  • [ 5325-64-4 ]
  • [ 18520-07-5 ]
  • 2-((6-((2-amino-2-oxoethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% To a suspension of 2,6-dichloro-4-ethylpyridine-3,5-dicarbonitrile (synthesis described in example 3, step 2, 1.7 g, 7.52 mmol) in ethanol (30 mL) mechanically stirring at -20 C was added a solution of 2-(methylamino)acetamide, Hydrochloride (1.0 g, 8.03 mmol) and Et3N (2.17 mL, 15.57 mmol) in ethanol (30 mL). The reaction mixture was then stirred at -20 C for 45 minutes. To the reaction mixture was then added potassium ethanethioate (1.3 g, 11.38 mmol) and Et3N (2.62 mL, 18.80 mmol). The heterogeneous reaction mixture was then warmed to 40 C and stirred at the same temperature. After stirring overnight at 40 C, the reaction mixture was cooled to room temperature. To the room temperature reaction mixture was added 2-amino-2-oxo-1-phenylethyl methanesulfonate (synthesis described in example 3, step 5, 2.6 g, 11.34 mmol). The reaction was warmed to 40 C and stirred at the same temperature for 3.5 hours. The reaction mixture cooled to 20 C and then was filtered. The solid was then washed with 300 mL of EtOH, followed by 300 mL of water. The resulting white solid was then again washed with EtOH (200 mL) followed by 100 mL of Et2O. The solid was then dried in the vacuum oven overnight to obtain 2-((6-((2-amino-2- oxoethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide (1.53 g, 3.75 mmol, 50% yield) as a white solid. LCMS m/z = 409.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.83 (s, 1H), 7.62 (s, 1H), 7.47-7.53 (m, 2H), 7.32-7.42 (m, 5H), 5.59 (s, 1H), 4.52 (d, J=17.49 Hz, 1H), 4.29 (d, J=17.24 Hz, 1H), 3.39 (s, 3H), 2.77 (q, J=7.60 Hz, 2H), 1.21 (t, J=7.48 Hz, 3H)
  • 26
  • 2,6-dichloro-4-cyclopropylpyridine-3,5-dicarbonitrile [ No CAS ]
  • [ 5325-64-4 ]
  • 2-((6-chloro-3,5-dicyano-4-cyclopropylpyridin-2-yl)(methyl)amino)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
32 g With triethylamine; In dichloromethane; at 20℃; for 1h; To a stirred solution of 2-(methylamin (20.41 g, 164 mmol) in dichloromethane (1000 mL) was added triethylamine (54.6 mL, 378 mmol) followed by 2,6- dichloro-4-cyclopropylpyridine-3,5-dicarbonitrile (synthesis described in example 4 step 2, 30 g, 126 mmol). The reaction mixture was stirred at room temperature for 1 hour. Water (1000 mL) was added and the mixture extracted with DCM (2 x 1000 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude material. Purification of the crude material by silica gel chromatography (60-120 mesh; 10% MeOH/EtOAc as eluent) afforded 2-((6-chloro-3,5-dicyano-4- cyclopropylpyridin-2-yl)(methyl)amino)acetamide (32 g). LCMS m/z = 290.4 [M+H]+.
  • 27
  • 5'-(cis-3-cycloheptyl-4-oxo-3,4,4a,5,8,8a-hexahydrophthalazin-1-yl)-2'-methoxy-[1,1'-biphenyl]-4-carboxylic acid [ No CAS ]
  • [ 5325-64-4 ]
  • N-(2-amino-2-oxoethyl)-5'-(cis-3-cycloheptyl-4-oxo-3,4,4a,5,8,8a-hexahydrophthalazin-1-yl)-2'-methoxy-N-methyl-[1,1'-biphenyl]-4-carboxamide [ No CAS ]
  • 28
  • 2-(5-{1-[(6,7-dimethoxy-2-methylquinazolin-4-yl)amino]ethyl}-2-thienyl)benzaldehyde [ No CAS ]
  • [ 5325-64-4 ]
  • 2-[2-(5-{1-[(6,7-dimethoxy-2-methylquinazolin-4-yl)amino]ethyl}thiophen-2-yl)benzyl]-N-methylglycinamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% A solution of 2-(5-{1 -[(6,7-dimethoxy-2-methylquinazolin-4-yl)amino]ethyl}thiophen-2- yl)benzaldehyde (described in example 179a; 50.0 mg, 1 15 muetaetaomicronIota) and <strong>[5325-64-4]N-methylglycinamide hydrochloride</strong> (1 :1) (14.4 mg, 1 15 muetaetaomicronIota) in MeOH (1.2 mL) was stirred at room temperature during 5 hours. NaBH(OAc)3 (48.9 mg, 231 muetaetaomicronIota) was added and the solution stirred at room temperature during 15mn. The reaction was quenched with aqueous NaOH (1.0 M, 1.0 mL), the mixture extracted with DCM and the solvent removed in vacuo. Purification by column chromatography (silica gel, MeOH/EtOAc 0-50% then MeOH) followed by preparative HPLC (basic conditions) gave the title compound as a white solid (26.0 mg, 45%). 1H-NMR (400 MHz, DMSO-de): delta [ppm] = 8.15 (d, 1H), 7.67 (br d, 1H), 7.64 (s, 1H), 7.55 (d, 1H), 7.35-7.29 (m, 2H), 7.29-7.24 (m, 1H), 7.10 (d, 1H), 7.08 (dd, 1H), 7.05 (s, 1H), 5.96 (quin, 1H), 3.87 (s, 6H), 3.70 (s, 2H), 3.04 (s, 2H), 2.56 (d, 3H), 2.43 (s, 3H), 1.71 (d, 3H). LC-MS (method 7): m/z: [M+H]+ = 506, Rt = 0.56 min.
 

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