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Chemical Structure| 20605-41-8 Chemical Structure| 20605-41-8

Structure of 20605-41-8

Chemical Structure| 20605-41-8

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Product Details of [ 20605-41-8 ]

CAS No. :20605-41-8
Formula : C3H8N2O2
M.W : 104.11
SMILES Code : O=C(NN)COC
MDL No. :MFCD02197887
InChI Key :XEPXDMNZXBUSOI-UHFFFAOYSA-N
Pubchem ID :2759532

Safety of [ 20605-41-8 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H228-H302-H315-H319-H335
Precautionary Statements:P210-P240-P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P330-P362-P370+P378-P403+P233-P501
Class:4.1
UN#:1325
Packing Group:

Computational Chemistry of [ 20605-41-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 7
Num. arom. heavy atoms 0
Fraction Csp3 0.67
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 2.0
Molar Refractivity 23.33
TPSA ?

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

64.35 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.47
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

-1.32
Log Po/w (WLOGP)?

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

-1.38
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.

-1.29
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

-1.3
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-0.97

Water Solubility

Log S (ESOL):?

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

0.54
Solubility 364.0 mg/ml ; 3.5 mol/l
Class?

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

Highly soluble
Log S (Ali)?

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

0.47
Solubility 305.0 mg/ml ; 2.93 mol/l
Class?

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

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

0.02
Solubility 109.0 mg/ml ; 1.04 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.

-7.87 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

2.0 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)

1.4

Application In Synthesis of [ 20605-41-8 ]

* 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 [ 20605-41-8 ]

[ 20605-41-8 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 2525-16-8 ]
  • [ 20605-41-8 ]
  • 3-methoxymethyl-6,7,8,9-tetrahydro-5<i>H</i>-[1,2,4]triazolo[4,3-<i>a</i>]azepine [ No CAS ]
  • 2
  • [ 39094-32-1 ]
  • [ 20605-41-8 ]
  • [ 109097-99-6 ]
  • 3
  • [ 75-44-5 ]
  • [ 20605-41-8 ]
  • [ 1711-90-6 ]
  • 5
  • [ 20605-41-8 ]
  • [ 2524-03-0 ]
  • [ 40402-87-7 ]
  • 6
  • [ 20605-41-8 ]
  • [ 2524-04-1 ]
  • [ 40402-96-8 ]
  • 9
  • [ 2142-68-9 ]
  • [ 20605-41-8 ]
  • [ 122432-95-5 ]
  • 10
  • [ 20605-41-8 ]
  • [ 77796-17-9 ]
  • [ 77796-11-3 ]
  • 11
  • [ 20605-41-8 ]
  • [ 89-98-5 ]
  • [ 133661-70-8 ]
  • 12
  • [ 20605-41-8 ]
  • [ 83-38-5 ]
  • [ 128153-79-7 ]
  • 15
  • [ 20605-41-8 ]
  • [ 220445-36-3 ]
  • [ 220445-35-2 ]
  • 16
  • [ 20605-41-8 ]
  • [ 246048-63-5 ]
  • N2-(methoxymethylcarbonyl)-4-aminofurazan-3-carboxamide hydrazone [ No CAS ]
  • 17
  • [ 108-30-5 ]
  • [ 20605-41-8 ]
  • succinic acid 2-(methoxyacetyl)hydrazide [ No CAS ]
  • 18
  • [ 108-31-6 ]
  • [ 20605-41-8 ]
  • (Z)-4-[N'-(2-Methoxy-acetyl)-hydrazino]-4-oxo-but-2-enoic acid [ No CAS ]
  • 19
  • [ 616-02-4 ]
  • [ 20605-41-8 ]
  • (Z)-4-[N'-(2-Methoxy-acetyl)-hydrazino]-2-methyl-4-oxo-but-2-enoic acid [ No CAS ]
  • 20
  • [ 20605-41-8 ]
  • [ 452973-87-4 ]
  • [ 452973-97-6 ]
  • 21
  • [ 20605-41-8 ]
  • [ 80109-86-0 ]
  • C18H20N6O4 [ No CAS ]
  • 22
  • [ 20605-41-8 ]
  • [ 122-51-0 ]
  • [ 440125-30-4 ]
YieldReaction ConditionsOperation in experiment
With toluene-4-sulfonic acid; at 140℃; for 8h; A mixture of above hydrazide (45 g), triethylorthoformate (146 mL) and p-toluenesulfonic acid (61mg) was heated at 140 °C for 8 h. Excess triethylorthoformate wasremoved under vacuum. The product was purified by silica gel column chromatography to yield4.6gof 2-methoxymethyl-l,3,4-oxadiazole.
toluene-4-sulfonic acid; at 140℃; for 8h; A mixture of above hydrazide (45 g), triethylorthoformate (146 mL) and p- toluenesulfonic acid (61mg) was heated at 140 C for 8 h. Excess triethylorthoformate was removed under vacuum. The product was purified by silica gel column chromatography to yield 4.6 g of2-methoxymethyl- [1. 3. 4] -oxadiazole.
With toluene-4-sulfonic acid; at 140℃; for 8h; Reference P Synthesis of [()-2-AMINO-1- (5-METHOXYMETHYL- [1,] 3,4] [OXADIAZOL-2-YL)-BUTAN-1-OL] Step 1 [(S)- (+)-2-AMINO-L-BUTANOL] (50 g, 561 mmol) in a mixture of water and dioxane (200 mL of water and: 200 mL) dioxane was cooled to [0 °C] and mixed with [NAOH] (26.9 g, 673 mmol) and di-tert-butyl-dicarbonate (146.96 g, 673 mmol). After the addition, the reaction was allowed to warm to room temperature. The reaction mixture was stirred for 2 h. After removing the dioxane, the residue was extracted with EtOAc, then washed with brine and dried with anhydrous [MGS04,] filtered and concentrated. Without further purification, the crude [(S)-2-BOC-AMINO-L-BUTANOL] (120 g) was used for next step reaction. Step 2 A solution of oxalyl chloride (40.39 g, 265 mmol) in [MECLZ] (700 mL) was stirred and cooled to-60 [°C.] Dimethylsulfoxide (51.7 g, 663 mmol) in [MECL2] (100 [ML)] was added dropwise. After 10 min. , a solution of [(S)-2-BOC-AMINO-L-BUTANOL] (50 g, 265 mmol) in [MECL2] (100 mL) was added dropwise [AT-70 °C.] The reaction mixture was allowed to warm to-40 °C for 10 min. and then cooled to-70 °C again. A solution of triethylamine (74.9 g, 742 mmol) in MeCl2 (100 mL) was added. The reaction mixture was allowed to warm to room temperature over 2 h. Saturated sodium dihydrogen phosphate (100 [ML)] was added, and then the organic layer was washed with brine and dried over [MGS04. THE] solvent was removed to yield 45g of [(S)-2-BOC-AMINO-BUTYRALDEHYDE (L-FORMYL-PROPYL)-CARBAMIC] acid [TERT-BUTYL] ester. Step 3 A mixture of methyl methoxyacetate (52 g, 500 mmol), hydrazine hydrate (30 mL) was heated to reflux for 8 h. Excess hydrazine and water were removed under vacuum. The residue was extracted with n-butanol, dried with [NA2SO4.] Excess n-butanol was removed to yield 45g of hydrazide. Step 4 A mixture of above hydrazide (45 g), [TRIETHYLORTHOFORMATE] (146 mL) and p- toluenesulfonic acid (61mg) was heated at [140 °C] for 8 h. Excess [TRIETHYLORTHOFORMATE] was removed under vacuum. The product was purified by silica gel column chromatography to yield 4.6g of 2-methoxymethyl-1, 3,4-oxadiazole. Step 5 To a stirred solution of 2-methoxymethyl-1, 3,4-oxadiazole (4.6 g, 40 mmol) in THF (100 mL) was added n-BuLi (1.6 M solution in 25.2 mL of hexane) dropwise under N2 at-78 [°C.] After 1 h, MgBr. Et2O (10.4 g, 40.3 mmol) was added and the reaction mixture was allowed to warm to-45 [°C] for 1 h before being treated with (S)-2-Boc-amino- propanylaldehyde butyraldehyde (5.28 g, 28.25 mmol) in THF (20 mL). The reaction mixture was stirred for 1 h, quenched with saturated [NH4C1,] and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgS04 and concentrated. The residue was purified by silica gel column chromatography to yield [(S)-2-BOC-AMINO-1- (5-] methoxymethyl-[1, 3, [4]-OXADIAZOLE-2-YL)-1-PROPANOL] butanol (500 mg). Step 6 [2-BOC-AMINO-1- (5-METHOXYMETHYL- [1,] 3, [4]-OXADIAZOLE-2-YL)-1-PROPANOL] butanol (500 mg, 1.66 mmol), and MeCl2 (5 mL) were mixed and TFA (0.5 mL) was added at room temperature. After stirring for 1 h, the solvent and excess TFA were removed under vacuum to produce [(S)-2-AMINO-L- (5-METHOXYMETHYL- [1,] 3,4] oxadiazol-2-yl)-butan-1-ol. TFA salt (340 mg).
With toluene-4-sulfonic acid; at 140℃; for 8h; Step 4 A mixture of above hydrazide (45 g), triethylorthoformate (146 ml) andp-toluene- sulfonic acid (61mg) was heated at 140 °C for 8 h. Excess triethylorthoformate was removed under vacuum. The product was purified by silica gel column chromatography to yield 2- methoxymethyl- [1, 3, 4]-oxadiazole (4.6 g).

  • 23
  • [ 6290-49-9 ]
  • [ 20605-41-8 ]
YieldReaction ConditionsOperation in experiment
95% With hydrazine; In methanol; at 70℃; for 18h; Preparation 5: 2-Methoxyacetylhydrazide Hydrazine monohydrate (9.85 mL, 202 mmol) was added to a solution of methyl methoxyacetate (10 mL, 101 mmol) in methanol (50 mL) and the mixture was heated at 70° C. for 18 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was azeotroped with toluene (.x.2) to give a white solid. The solid was triturated with diethyl ether and the resulting solid was dried under vacuum, at 50° C. for 30 minutes, to afford the title compound as a white solid in 95percent yield, 9.98 g. 1H NMR(400 MHz, DMSO-d6) delta: 3.26(s, 3H), 3.79(s, 2H), 4.22(bs, 2H), 8.97(bs, 1H)
With hydrazine; for 8h;Heating / reflux; A mixture of methyl methoxyacetate (52 g, 500 mmol), hydrazine hydrate (30 mL) washeated to reflux for 8 h. Excess hydrazine and water were removed under vacuum. The residuewas extracted with n-butanol, dried with NaaSC^. Excess w-butanol was removed to yield 45g ofhydrazide.
With hydrazine; for 8h;Heating / reflux; A mixture of methyl methoxyacetate (52 g, 500 mmol), hydrazine hydrate (30 mL) was heated to reflux for 8 h. Excess hydrazine and water were removed under vacuum. The residue was extracted with n-butanol, dried with Na2SO4. Excess n-butanol was removed to yield 45 g of hydrazide.
With hydrazine; In water; for 8h;Heating / reflux; Reference P Synthesis of [()-2-AMINO-1- (5-METHOXYMETHYL- [1,] 3,4] [OXADIAZOL-2-YL)-BUTAN-1-OL] Step 1 [(S)- (+)-2-AMINO-L-BUTANOL] (50 g, 561 mmol) in a mixture of water and dioxane (200 mL of water and: 200 mL) dioxane was cooled to [0 °C] and mixed with [NAOH] (26.9 g, 673 mmol) and di-tert-butyl-dicarbonate (146.96 g, 673 mmol). After the addition, the reaction was allowed to warm to room temperature. The reaction mixture was stirred for 2 h. After removing the dioxane, the residue was extracted with EtOAc, then washed with brine and dried with anhydrous [MGS04,] filtered and concentrated. Without further purification, the crude [(S)-2-BOC-AMINO-L-BUTANOL] (120 g) was used for next step reaction. Step 2 A solution of oxalyl chloride (40.39 g, 265 mmol) in [MECLZ] (700 mL) was stirred and cooled to-60 [°C.] Dimethylsulfoxide (51.7 g, 663 mmol) in [MECL2] (100 [ML)] was added dropwise. After 10 min. , a solution of [(S)-2-BOC-AMINO-L-BUTANOL] (50 g, 265 mmol) in [MECL2] (100 mL) was added dropwise [AT-70 °C.] The reaction mixture was allowed to warm to-40 °C for 10 min. and then cooled to-70 °C again. A solution of triethylamine (74.9 g, 742 mmol) in MeCl2 (100 mL) was added. The reaction mixture was allowed to warm to room temperature over 2 h. Saturated sodium dihydrogen phosphate (100 [ML)] was added, and then the organic layer was washed with brine and dried over [MGS04. THE] solvent was removed to yield 45g of [(S)-2-BOC-AMINO-BUTYRALDEHYDE (L-FORMYL-PROPYL)-CARBAMIC] acid [TERT-BUTYL] ester. Step 3 A mixture of methyl methoxyacetate (52 g, 500 mmol), hydrazine hydrate (30 mL) was heated to reflux for 8 h. Excess hydrazine and water were removed under vacuum. The residue was extracted with n-butanol, dried with [NA2SO4.] Excess n-butanol was removed to yield 45g of hydrazide. Step 4 A mixture of above hydrazide (45 g), [TRIETHYLORTHOFORMATE] (146 mL) and p- toluenesulfonic acid (61mg) was heated at [140 °C] for 8 h. Excess [TRIETHYLORTHOFORMATE] was removed under vacuum. The product was purified by silica gel column chromatography to yield 4.6g of 2-methoxymethyl-1, 3,4-oxadiazole. Step 5 To a stirred solution of 2-methoxymethyl-1, 3,4-oxadiazole (4.6 g, 40 mmol) in THF (100 mL) was added n-BuLi (1.6 M solution in 25.2 mL of hexane) dropwise under N2 at-78 [°C.] After 1 h, MgBr. Et2O (10.4 g, 40.3 mmol) was added and the reaction mixture was allowed to warm to-45 [°C] for 1 h before being treated with (S)-2-Boc-amino- propanylaldehyde butyraldehyde (5.28 g, 28.25 mmol) in THF (20 mL). The reaction mixture was stirred for 1 h, quenched with saturated [NH4C1,] and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgS04 and concentrated. The residue was purified by silica gel column chromatography to yield [(S)-2-BOC-AMINO-1- (5-] methoxymethyl-[1, 3, [4]-OXADIAZOLE-2-YL)-1-PROPANOL] butanol (500 mg). Step 6 [2-BOC-AMINO-1- (5-METHOXYMETHYL- [1,] 3, [4]-OXADIAZOLE-2-YL)-1-PROPANOL] butanol (500 mg, 1.66 mmol), and MeCl2 (5 mL) were mixed and TFA (0.5 mL) was added at room temperature. After stirring for 1 h, the solvent and excess TFA were removed under vacuum to produce [(S)-2-AMINO-L- (5-METHOXYMETHYL- [1,] 3,4] oxadiazol-2-yl)-butan-1-ol. TFA salt (340 mg).
With hydrazine; for 8h;Heating / reflux; Step 3 A mixture of methyl methoxyacetate (52 g, 500 mmol), hydrazine hydrate (30 ml) was heated to reflux for 8 h. Excess hydrazine and water were removed under vacuum. The residue was extracted with n-butanol, dried with Na2S04. Excess n-butanol was removed to yield hydrazide (45 g).

  • 24
  • C18H26ClN3O2S [ No CAS ]
  • [ 20605-41-8 ]
  • tert-butyl 4-[4-(4-chlorophenyl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl]-2-methylpiperazine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Methoxyacetic acid hydrazide (1.95 g, 18.75 mmol) was added to a solution of the compound of preparation 49 (4.80 g, 12.50 mmol) in tetrahydrofuran (200 mL) and the solution was stirred for 10 minutes. Trifluoroacetic acid (710 mg, 6.25 mmol) was added and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the crude product was purified by column chromatography using a silica gel cartridge and dichloromethane:methanol (100:0 to 90:10) as eluant, and repeated using ethyl acetate as eluant to afford the title compound as a foam, 1.84 g. 1H NMR (400 MHz, CDCl3): delta 0.98 (d, 3H), 1.42 (s, 9H), 2.82-3.05 (m, 4H), 3.24 (m, 1H), 3.34 (s, 3H), 3.80 (m, 1H), 4.18 (m, 1H), 4.34 (s, 2H), 7.40 (d, 2H), 7.64 (d, 2H); LCMS: m/z APCl+363 [MH]+
  • 25
  • [7-chloro-5-(2,3-dimethoxyphenyl)-2-thioxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetic acid ethyl ester [ No CAS ]
  • [7-chloro-5-(2,3-dimethoxyphenyl)-2-thioxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetic acid ethyl ester [ No CAS ]
  • [ 20605-41-8 ]
  • [8-chloro-6-(2,3-dimethoxyphenyl)-1-(methoxymethyl)-4H,6H-[1,2,4]triazolo[4,3-a][4,1]benzoxazepin-4-yl]acetic acid ethyl ester [ No CAS ]
  • 26
  • [ 868833-81-2 ]
  • [ 20605-41-8 ]
  • 2-({1-[4-(4-chlorophenyl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl]piperidin-4-yl}oxy)pyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With trifluoroacetic acid; In tetrahydrofuran; water; for 5h;Heating / reflux; Example 33; 2-({1-[4-(4-Chlorophenyl)-5-(methoxymethyl)-4H-1,2,4- triazol-3-yl]piperidin-4-yl)oxy)pyridine; A mixture of the product of preparation 13 (252g, 0.69mmol) methoxyacethydrazide (80mg, 0.77mmol) and trifluoroacetic acid (26pL, 0.35mmol) in tetrahydrofuran (15mL) was heated under reflux for 5 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol: 95: 5, to afford the title compound in 65percent yield, 180mg.
  • 27
  • [ 868833-92-5 ]
  • [ 20605-41-8 ]
  • 2-({1-[4-(4-chlorophenyl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl]piperidin-4-yl}oxy)pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% In butan-1-ol; at 140℃; for 18h; Example 48; 2-({1-[4-(4-Chlorophenyl)-5-(methoxymethyl)-4H1,2,4- triazol-3-yl] piperidin-4-yl}oxy)pyrimidine; A mixture of the product of preparation 31 (200mg, 0.55mmol) and methoxyacethydrazide (57mg, 0.55mmol) in nbutanol (2mL) was heated at 140°C for 18 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol: 0. 88 ammonia, 90: 10:1, to afford the title compound in 45percent yield, 100mg.
  • 28
  • [ 20605-41-8 ]
  • (5-(3-(3-(2-chloro-4-fluorophenoxy)azetidin-1-yl)-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl)-2-methoxypyridine) [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% EXAMPLE 112 5-[3-[3-(2-Chloro-4-fluorophenoxy)azetidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine Potassium tert-butoxide (4 g, 35.42 mmol) was added portionwise to an ice-cooled solution of the product of preparation 80 (10.86 g, 29.52 mmol) in tetrahydrofuran (100 mL) and the reaction was stirred at room temperature for 20 minutes. Methyl p-toluenesulfonate (51.4 mg, 0.28 mmol) was then added and the mixture was stirred for 40 minutes. The reaction mixture was then concentrated in vacuo and partitioned between ethyl acetate (150 mL) and water (50 mL). The organic layer was separated washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was re-dissolved in tetrahydrofuran (75 mL) and trifluoroacetic acid (1.2 mL), 2-methoxyacetylhydrazide (preparation 5, 6.15 g, 59.04 mmol) was added and the mixture was heated under reflux for 90 minutes. The reaction mixture was then concentrated in vacuo and re-dissolved in ethyl acetate. The organic solution was washed with sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to give an oil. The oil was then triturated with diethyl ether to afford the title compound as a solid in 52percent yield, 6.5 g. 1H NMR(400 MHz, CDCl3) delta: 3.29(s, 3H), 3.99(s, 3H), 4.05(dd, 2H), 4.18(m, 2H), 4.31(s, 2H), 4.92(m, 1H), 6.50(m, 1H), 6.85(m, 2H), 7.15(dd, 1H), 7.61(dd, 1H), 8.22(d, 1H); LRMS APCI m/z 420/422 [M+H]+
  • 29
  • [ 900512-30-3 ]
  • [ 20605-41-8 ]
  • [5-[3-(2-chloro-4-fluorophenoxy)azetidin-1-yl]-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
6% In butan-1-ol; for 18h;Heating / reflux; EXAMPLE 111 [5-[3-(2-chloro-4-fluorophenoxy)azetidin-1-yl]-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]methanol A mixture of the products of preparations 81 (300 mg, 0.8 mmol) and 80 (360 mg, 4 mmol) in butanol (5 mL) was heated under reflux for 18 hours. The reaction mixture was then cooled to room temperature concentrated in vacuo and the residue was purified by HPLC using a Phenomenex Luna C18 system, eluting with water/acetonitrile/trifluoroacetic acid (5:95:0.1):acetonitrile, 95:5 to 5:95, to afford the title compound as a clear oil in 6percent yield. LRMS ESI m/z 406 [M+H]+
  • 30
  • [ 900512-42-7 ]
  • [ 20605-41-8 ]
  • 5-[3-[(3S)-3-(2-Chlorophenoxy)pyrrolidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
25% EXAMPLE 160 5-[3-[(3S)-3-(2-Chlorophenoxy)pyrrolidin-1-yl]-5-(methoxymethyl)-4H-1,2,4-triazol-4-yl]-2-methoxypyridine 5-Isothiocyanato-2-methoxypyridine [(306 mg, 1.84 mmol), J. Org. Chem. (1980), 45, 4219] was added to a solution of the product of preparation 91 [(387 mg, 1.95 mmol) and N,N-diisopropylethylamine (0.32 mL, 1.84 mmol) in dichloromethane (5 mL) and the mixture was stirred for 1 hour at room temperature. The reaction mixture was then washed with water (5 mL), saturated citric acid solution (5 mL) and brine. The organic solution was dried over magnesium sulfate and concentrated in vacuo. Potassium tert-butoxide (217 mg, 1.93 mmol) was added to a solution of the residue in tetrahydrofuran (6 mL) and the reaction was stirred at room temperature for 15 minutes. Methyl p-toluenesulfonate (360 mg, 1.93 mmol) was then added and the mixture was stirred for 45 minutes at room temperature. The reaction mixture was concentrated in vacuo and re-dissolved in dichloromethane. The organic solution was washed with sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was re-dissolved in tetrahydrofuran (10 mL), trifluoroacetic acid (67 muL) and 2-methoxyacetylhydrazide (183 mg, 1.76 mmol) were added and the mixture was heated under reflux for 2 hours. The reaction mixture was then concentrated in vacuo and partitioned between ethyl acetate and water. The organic solution was separated, washed with sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluding with dichloromethane:methanol, 100:0 to 95:5, afforded the title compound in 25% yield, 191 mg. 1H NMR(400 MHz, CDCl3) delta: 2.00-2.10(m, 2H), 3.20-3.60(m, 7H), 3.98(s, 3H), 4.25(s, 2H), 4.85-4.90(m, 1H), 6.78-6.90(m, 3H), 7.10-7.18(m, 1H), 7.30-7.35(d, 1H), 7.55-7.60(d, 1H), 8.20(s, 1H); APCI m/z 416 [M+H]+
  • 31
  • methyl N-(6-methoxypyridin-3-yl)-3-[(methylsulfonyl)oxy]azetidine-1-carboximidothioate [ No CAS ]
  • [ 20605-41-8 ]
  • 1-[5-(methoxymethyl)-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]azetidin-3-yl methanesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% trifluoroacetic acid; In tetrahydrofuran; for 8h;Heating / reflux; Preparation 6: 1-[5-(Methoxymethyl)-4(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]azetidin-3-yl methanesulfonate A mixture of the product of preparation 3 (1 g, 3 mmol), the product of preparation 5 (629 mg, 6 mmol) and trifluoroacetic acid (3 drops) in tetrahydrofuran (20 mL) was heated under reflux for 8 hours. The cooled mixture was then diluted with a mixture of water and brine, 30:70, and extracted with ethyl acetate (3.x.30 mL). The combined organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 95:5, to afford the title compound as a pale brown oil in 72percent yield, 800 mg. 1H NMR(400 MHz, CDCl3) delta: 3.03(s, 3H), 3.27(s, 3H), 3.98(s, 3H), 4.06(m, 2H), 4.20(m, 2H), 4.32(s, 2H), 5.23(m, 1H), 6.84(d, 1H), 7.60(dd, 1H), 8.17(d, 1H); LRMS APCI m/z 370 [M+H]+
  • 32
  • C20H22FN3O2S [ No CAS ]
  • [ 20605-41-8 ]
  • 5-fluoro-1'-[5-(methoxymethyl)-4-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]-3H-spiro[1-benzofuran-2,4'-piperidine] [ No CAS ]
YieldReaction ConditionsOperation in experiment
56% In ethanol; at 75℃; for 144h; Example 37: 5-f luoro-1 '-r5-fmethoxymethyl)-4-(6-methoxypyridin-3-vn-4H-1.2.4-triazol-3-vpi- 3H-spirori-benzofuran-2.4'-piperidinel EPO <DP n="85"/>A mixture of the product of preparation 87 (147mg, 0.38mmol) and methoxy acetic acid hydrazide (156mg, 1.90mmol) in ethanol (2ml_) was heated at 750C for 6 days. The mixture was then cooled to room temperature, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel-, eluting with dichloromethane:methanol, 100:0 to 95:5, to afford the title compound in 56percent yield, 90mg.1HNMR (CDCI3, 400MHz) delta: 1.65-1.95(m, 6H), 2.50(m, 2H), 3.20(m, 2H), 3.50(s, 3H), 3.95(s, 3H), 4.30(s, 2H), 6.60-6.90(m, 4H), 7.65(m, 1 H), 8.20(m, 1 H). LRMS APCI m/z 426 [M+H]+
  • 33
  • methyl 4'-aminomethylbiphenyl-2-carboxylate hydrochloride [ No CAS ]
  • [ 20605-41-8 ]
  • [ 115-80-0 ]
  • [ 124806-71-9 ]
YieldReaction ConditionsOperation in experiment
With 1,8-diazabicyclo[5.4.0]undec-7-ene; Part A: 3-Ethyl-5-methoxymethyl-4-[(2'-carbomethoxy-biphenyl-4-yl)methyl]-1.2,,4-triazole This compound was prepared according to Example 67, Part B. From triethyl orthopropionate (2.86 g, 16.2 mmol), methoxyacetylhydrazide (1.7 g, 16.2 mmol), DBU (1.8 ml, 11.9 mmol) and methyl 4'-aminomethylbiphenyl-2-carboxylate hydrochloride (3.0 g, 10.8 mmol) in refluxing xylenes (50 ml) was obtained 2.4 g (60percent) of the title compound as a pale yellow oil following flash chromatography. NMR (200 MHz, CDCl3, TMS) delta: 7.88-7.05 (m,8H), 5.24 (s,2H), 4.58 (s,2H), 3.65 (s,3H), 3.35 (s,3H), 2.67 (q,J=7 Hz,2H), 1.32 (t,J=7 Hz,3H).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; Part A 3-Ethyl-5-methoxymethyl-4-[(2'-carbomethoxybiphenyl-4-yl)methyl]-1,2,4-triazole This compound was prepared according to Example 67, Part B. From triethyl orthopropionate (2.86 g, 16.2 mmol), methoxyacetylhydrazide (1.7 g, 16.2 mmol), DBU (1.8 ml, 11.9 mmol) and methyl 4'-aminomethylbiphenyl-2-carboxylate hydrochloride (3.0 g, 10.8 mmol) in refluxing xylenes (50 ml) was obtained 2.4 g (60percent) of the title compound as a pale yellow oil following flash chromatography. NMR (200 MHz,CDCl3,TMS)delta: 7.88-7.05(m,8H), 5.24(s,2H), 4.58(s,2H), 3.65(s,3H), 3.35(s,3H), 2.67(q,J=7 Hz,2H), 1.32(t,J=7 Hz,3H).
  • 34
  • methyl 4'-aminomethylbiphenyl-2-carboxylate hydrochloride [ No CAS ]
  • [ 24964-76-9 ]
  • [ 20605-41-8 ]
  • [ 124806-70-8 ]
YieldReaction ConditionsOperation in experiment
With 1,8-diazabicyclo[5.4.0]undec-7-ene; Part A: 3-Methoxymethyl-5-propyl-4-[(2'-carbomethoxy-biphenyl-4-yl)methyl]-1.2.4-triazole This compound was prepared according to the method described for Example 67, Part B. From triethyl orthobutyrate (3.1 g, 16.2 mmol) methoxyacetyl hydrazide (1.7 g, 16.2 mmol) DBU (1.8 ml, 11.9 mmol) and methyl 4'-aminomethylbiphenyl-2-carboxylate hydrochloride (3.0 g, 10.8 mmol) in refluxing xylenes (50 ml) was obtained 2.3 g (56percent) of the title compound as a colorless oil following flash chromatography. NMR (200 MHz;CDCl3, TMS) delta: 7.88-7.04 (m,8H), 5.25 (s,2H), 4.56 (s,2H), 3.65 (s,3H), 3.34 (s,3H), 2.66 (t,J=7 Hz,2H), 1.78 (m,2H), 0.98 (t,J=7 Hz,3H).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; Part A 3-Methoxymethyl-5-propyl-4-[(2'-carbomethoxybiphenyl-4-yl)methyl]-1,2,4-triazole This compound was prepared according to the method described for Example 67, Part B. From triethyl orthobutyrate (3.1 g, 16.2 mmol) methoxyacetyl hydrazide (1.7 g, 16.2 mmol) DBU (1.8 ml, 11.9 mmol) and methyl 4'-aminomethylbiphenyl-2-carboxylate hydrochloride (3.0 g, 10.8 mmol) in refluxing xylenes (50 ml) was obtained 2.3 g (56percent) of the title compound as a colorless oil following flash chromatography. NMR (200 MHz;CDCl3,TMS)delta: 7.88-7.04(m,8H), 5.25(s,2H), 4.56(s,2H), 3.65(s,3H), 3.34(s,3H), 2.66(t,J=7 Hz,2H), 1.78(m,2H), 0.98(t,J=7 Hz,3H).
  • 35
  • methyl 4'-aminomethylbiphenyl-2-carboxylate hydrochloride [ No CAS ]
  • [ 919-29-9 ]
  • [ 20605-41-8 ]
  • 3-Butyl-5-methoxymethyl-4-[(2'-carbomethoxy-biphenyl-4-yl)methyl]-1.2.4-triazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1,8-diazabicyclo[5.4.0]undec-7-ene; Part B: 3-Butyl-5-methoxymethyl-4-[(2'-carbomethoxy-biphenyl-4-yl)methyl]-1.2.4-triazole A solution of triethyl orthovalerate (3.3 g, 16.2 mmol), methoxyacetyl hydrazide (1.7 g, 16.2 mmol) and DBU (1.8 g, 11.9 mmol) in xylenes (50 ml) was refluxed for 2 hrs and cooled to room temperature, whereupon methyl 4'-aminomethylbiphenyl-2-carboxylate hydrochloride (3.0 g, 10.0 mmol) was added. The reaction was brought back to reflux for a further 24 h. After being cooled to room temperature, the mixture was diluted with ethyl acetate (150 ml) and washed with water (100 ml), saturated aqueous sodium chloride and dried (MgSO4). Filtration and evaporation of solvents gave 4.8 g of a yellow oil which was purified by flash chromatography on silica gel (150 g, 5-10percent EtOAc/hexane) to afford 3.4 g (78percent) of the title compound as a yellow viscous oil. NMR (200 MHz, CDCl3, TMS) delta: 7.87-7.05 (m,8H), 5.25 (s,2H), 4.56 (s,2H), 3.67 (s,3H), 3.37 (s,3H), 2.68 (t,J=8 Hz,2H), 1.73 (m,2H), 1.38 (m,2H), 0.90 (t, J=9 Hz, 3H).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; Part B 3-Butyl-5-methoxymethyl-4-[(2'-carbomethoxybiphenyl-4-yl)methyl]-1,2,4-triazole A solution of triethyl orthovalerate (3.3 g, 16.2 mmol), methoxyacetyl hydrazide (1.7 g, 16.2 mmol) and DBU (1.8 g, 11.9 mmol) in xylenes (50 ml) was refluxed for 2 hrs and cooled to room temperature, whereupon methyl 4'-aminomethylbiphenyl-2-carboxylate hydrochloride (3.0 g, 10.0 mmol) was added. The reaction was brought back to reflux for a further 24 h. After being cooled to room temperature, the mixture was diluted with ethyl acetate (150 ml) and washed with water (100 ml), saturated aqueous sodium chloride and dried (MgSO4). Filtration and evaporation of solvents gave 4.8 g of a yellow oil which was purified by flash chromatography on silica gel (150 g, 5-10percent EtOAc/hexane) to afford 3.4 g (78percent) of the title compound as a yellow viscous oil. NMR (200 MHz,CDCl3,TMS)delta: 7.87-7.05(m,8H), 5.25(s,2H), 4.56(s,2H), 3.67(s,3H), 3.37(s,3H), 2.68(t,J=8 Hz,2H), 1.73(m,2H), 1.38(m,2H), 0.90(t,J=9 Hz,3H).
 

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