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Chemical Structure| 89531-58-8 Chemical Structure| 89531-58-8

Structure of 89531-58-8

Chemical Structure| 89531-58-8

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Product Details of [ 89531-58-8 ]

CAS No. :89531-58-8
Formula : C6H12ClNO3
M.W : 181.62
SMILES Code : O=C(O)CN1CCOCC1.[H]Cl
MDL No. :MFCD03540888
InChI Key :ICGYBJNONRDZOP-UHFFFAOYSA-N
Pubchem ID :17750946

Safety of [ 89531-58-8 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H319
Precautionary Statements:P305+P351+P338

Computational Chemistry of [ 89531-58-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 0
Fraction Csp3 0.83
Num. rotatable bonds 2
Num. H-bond acceptors 4.0
Num. H-bond donors 1.0
Molar Refractivity 45.47
TPSA ?

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

49.77 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

-1.99
Log Po/w (WLOGP)?

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

-0.18
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.

-0.5
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

0.05
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-0.52

Water Solubility

Log S (ESOL):?

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

0.42
Solubility 477.0 mg/ml ; 2.63 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.

1.47
Solubility 5340.0 mg/ml ; 29.4 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

0.18
Solubility 274.0 mg/ml ; 1.51 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.

-8.82 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

1.0
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)

1.66

Application In Synthesis of [ 89531-58-8 ]

* 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 [ 89531-58-8 ]

[ 89531-58-8 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 1055308-35-4 ]
  • [ 89531-58-8 ]
  • [ 108211-64-9 ]
  • [ 120385-29-7 ]
  • [ 120385-30-0 ]
  • 2
  • [ 89531-58-8 ]
  • [ 105535-42-0 ]
  • [ 120385-32-2 ]
  • 3
  • [ 3235-82-3 ]
  • [ 89531-58-8 ]
YieldReaction ConditionsOperation in experiment
91.7% With hydrogenchloride; In water; at 20℃; for 24h;Heating / reflux; Ethyl 4-morpholinoacetate (1.1 g, 6.3 mmol) was added to 3M hydrochloric acid solution (35 ml), refluxed for 2 hours, stirred for 1 day at a room temperature, and then concentrated under a reduced pressure. The resulting residue was dissolved in methanol and reconcentrated. The resulting solid was suspended in ethylether, filtered and dried under a reduced pressure to give 1.05 g of the titled compound. (Yield 91.7%) NMR (DMSO-d6): 3.3(s, 4H), 3.9(s, 4H), 4.2(s, 2H).
With sodium hydroxide; In ethanol; water; The morpholinoacetic acid used in Example 183.a. was prepared as follows: Ethyl morpholinoacetate (5.0 g) in ethanol (115 mL) was added to a solution of sodium hydroxide (1.27 g) in water (12 mL) and the mixture was allowed to stir for 1 h. The mixture was evaporated, dissolved in water (125 mL), and extracted with ethyl acetate. The aqueous phase was acidified with 10% hydrochloric acid (pH 2) and lyophilized to give a brown oil. The oil was dried under vacuum to yield morpholinoacetic acid hydrochloride, which was used directly for the acylation above.
  • 4
  • [ 89531-58-8 ]
  • [ 112924-45-5 ]
  • 7-O-[2-(4-morpholino)acetyl]dexanabinol [ No CAS ]
  • 5
  • potassium 2-(N-morpholinyl)acetate [ No CAS ]
  • [ 89531-58-8 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In ethanol; 28.5 ml of ethyl bromoacetate (MW = 167.0; d = 1.51 g/ml; 258 mmol) were added slowly to a solution of 45 g of morpholine (MW = 87; d = 0.995 g/ml; 517 mmol) in 200 ml of diethyl ether. After stirring the mixture for 2 hours at room temperature, the solid formed was removed by filtration.The solution thus obtained was concentrated under reduced <n="7"/>pressure. The residue obtained was treated with a solution of 18 g of KOH (MW = 56.1 ; 321 mmol) in 180 ml of ethanol for 4 hours at room temperature. The mixture was then made acid by adding a solution of 6N hydrochloric acid in ethanol (about 100 ml) and the solid product formed was then removed by filtration and washed with ethanol.This solid was the morpholin-4-yl acetic acid hydrochloride (48 g), which was used in subsequent reactions without further purification.LC/MS (M+H)+ = 146; 100 (base peak).
  • 6
  • [ 89531-58-8 ]
  • 4-[3-(1,1-dimethyl-heptyl)-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6<i>H</i>-benzo[<i>c</i>]chromen-9-ylmethoxycarbonylmethyl]-4-methyl-morpholin-4-ium; iodide [ No CAS ]
  • 7
  • [ 89531-58-8 ]
  • [ 108211-64-9 ]
  • 8
  • [ 89531-58-8 ]
  • [ 120385-31-1 ]
  • 9
  • [ 214540-40-6 ]
  • [ 89531-58-8 ]
  • C28H32FN5O3*ClH [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; The same procudures as in Example 167 were repeated using 5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrinidine(50 mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol), 4-morpholineacetic acid hydrochloride(28.8 mg, 0.158 mmol), and triethylamine(46 mul, 0.330 mmol) to afford the titled compound. NMR(CDCl3): 1.6(d, 3H), 2.2(s, 3H), 2.8(m, 1H), 3.2(m, 5H), 3.5(m, 1H), 3.8(s, 4H), 4.1(s, 2H), 4.2(m, 1H), 5.2(m, 3H), 7.0(m, 6H), 7.5(m, 2H), 11.0(s, 31H).
  • 10
  • 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine [ No CAS ]
  • [ 89531-58-8 ]
  • C28H32FN5O3*ClH [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; The same procudures as in Example 167 were repeated using 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50 mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol), 4-morpholineacetic acid hydrochloride(28.8 mg, 0.158 mmol), and triethylamine(46 mul, 0.330 mmol) to afford the titled compound. NMR(CDCl3): 1.6(d, 3H), 2.2(s, 3H), 2.4(s, 3H), 2.8(m, 1H), 3.0(s, 4H), 3.2(m, 1H), 3.5(m, 1H), 3.7(m, 4H), 3.9(m, 4H), 4.2(m, 1H), 5.3(m, 1H), 7.0(m, 5H), 7.5(m, 2H), 10.2(s, 1H).
  • 11
  • 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl}pyrimidine [ No CAS ]
  • [ 89531-58-8 ]
  • C28H32FN5O3*ClH [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; The same procudures as in Example 167 were repeated using 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50 mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol), 4-morpholineacetic acid hydrochloride (28.8 mg, 0.158 mmol), and triethylamine (46 mul, 0.330 mmol) to afford the titled compound. NMR(CDCl3): 1.6(d, 3H), 2.2(s, 3H), 2.4(s, 3H), 2.7(m, 4H), 2.8(m, 1H) 3.2(m, 1H), 3.5(m, 3H), 3.8(m, 4H), 4.2(m, 1H), 5.3(m, 1H), 7.0(m, 5H), 7.5(m, 2H), 10.6(s, 1H), 14(bs, 1H).
  • 12
  • 2-(4-fluorobenzyl)-9-hydroxy-7-(piperidin-4-yl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione monotrifluoroacetate [ No CAS ]
  • [ 89531-58-8 ]
  • 2-(4-fluorobenzyl)-9-hydroxy-7-[1-(morpholin-4-ylacetyl)piperidin-4-yl]-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); EXAMPLE 15 2-(4-Fluorobenzyl)-9-hydroxy-7-[1-(morpholin-4-ylacetyl) piperidin-4-yl] -3,4-dihydro-2H-pyrazino [1, 2-c] pyrimidine-1, 6,8 (7H) -trione To 2- (4-Fluorobenzyl)-8, 9-dihydroxy-7- (piperidin-4-ylmethyl)-3, 4-dihydro-2H- pyrido [1, 2-a] pyrazine-1, 6-dione mono TFA salt (50 mg, 0.10 mmol, Example 12) in DMF (1 mL) was added 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol), 1- hydroxybenzotriazole hydrate (23 mg, 0.15 mmol), triethylamine (31 AL, 0.22 mmol), and 2- morpholinoacetic acid HC1 (22 mg, 0.12 mmol). The reaction was stirred overnight and then purified by prep HPLC on a C18 stationary phase and eluting with a water/acetonitrile/TFA gradient. The TFA salt of the title compound was obtained as a white solid after lyophilizing from dioxane. tH NMR (400 MHz, d6 DMSO) 8 11.81 (s, 1H), 10.03 (bs, 1H), 7.39 (dd, 2H, J = 5.7, 8.4 Hz), 7.21 (t, 2H, J = 8.8 Hz), 4.98 (m, 1H), 4.69 (s, 2H), 4.47 (m, 2H), 4.36 (m, 1H), 3.90-4. 02 (m, 4H), 3. 80 (m, 2H), 3.64 (m, 2H), 3.57 (m, 3H), 3.44 (m, 2H), 3.18 (m, 2H), 2.78 (m, 1H), 2.39 (m, 1H), and 1.65 (m, 2H). HRMS (FT-ICR C25H30FN506+H) = 516. 2261 ; calculated 516.2253.
  • 13
  • ethereal HCl [ No CAS ]
  • [ 172409-77-7 ]
  • [ 89531-58-8 ]
  • [ 530-62-1 ]
  • 8-fluoro-5-methyl-3-(5-morpholin-4-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-formamide; acetonitrile; b) 0.38 ml (2.2 mmol) of N-ethyldiisopropylamine was added to a suspension of 0.4 g (2.2 mmol) of morpholin-4-yl-acetic acid hydrochloride in 4 ml of DMF. 390 mg (2.4 mmol) of 1,1'- carbonyldiimidazole were added portionwise at room temperature, whereupon the solution was stirred at 50° for 30 min. and then treated at room temperature with 0.58 g (2.0 mmol) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime. The reaction mixture was heated to 90° for 20 hrs. The solvent was removed in a vacuum, the residue was taken up in 15 ml of water and the solution was extracted several times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography on silica gel (methylene chloride/methanol 19:1). The solvent was removed in a vacuum, the residue was dissolved in 5 ml of acetonitrile and the solution was made acid by the addition of ethereal HCl solution. The white crystals were filtered off under suction and recrystallized from acetonitrile. There was obtained 0.5 g (54percent) of 8-fluoro-5-methyl-3-(5-morpholin-4-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (3:5) of m.p. 198°-205° (dec.).
  • 14
  • 4-[(E)-2-(2-Chlorophenyl)-1-ethenyl]piperidine [ No CAS ]
  • [ 89531-58-8 ]
  • 4-(2-{4-[(E)-2-(2-chlorophenyl)vinyl]piperidin-1-yl}-2-oxoethyl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 48h; (Example 1) To 10.0 ml of an N,N-dimethylformamide solution containing 0.45 g of 4-[(E)-2-(2-chlorophenyl)vinyl]piperidine were added 0.37 g of morpholin-4-yl-acetic acid mono-hydrochloride, 0.39 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide mono-hydrochloride, 0.27 g of 1-hydroxybenztriazole mono-hydrate and 0.28 ml of triethylamine. The mixture was stirred at room temperature for 2 days for reaction. The resulting reaction mixture was poured into a 10percent aqueous potassium carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate) to obtain 0.56 g of 4-(2-{4-[(E)-2-(2-chlorophenyl)vinyl]piperidin-1-yl}-2-oxoethyl)morpholine as pale yellow crystals. These crystals were made into a solution of 3.0 ml of ethanol and 1.0 ml of tetrahydrofuran. Thereto was added 2.0 ml of an ethanol solution containing 0.14 g of oxalic acid. The resulting crystals were collected by filtration and recrystallized from ethanol to obtain 0.52 g of 4-(2-{4-[(E)-2-(2-chlorophenyl)vinyl]piperidin-1-yl}-2-oxoethyl)morpholine oxalate as colorless powdery crystals.
  • 15
  • [ 1095823-03-2 ]
  • [ 89531-58-8 ]
  • [ 1095823-09-8 ]
YieldReaction ConditionsOperation in experiment
20% Synthesis of Compound 22.1. A mixture of oxalyl chloride (87 uL, 1.0 mmol) was added to a mixture of <strong>[89531-58-8]2-morpholinoacetic acid hydrochloride</strong> (93 mg, 0.51 mmol), TEA (70 uL, 0.5 mmol), and DMF (1 drop) in acetonitrile (1 mL) was stirred. After 1 hr, the solvent was removed in vacuo. The acid chloride was redissolved in acetonitrile (1 mL) and added to a solution of compound 21.1 (80 mg, 0.4 mmol) in pyridine (300 uL, 4 mmol). The solvent was removed in vacuo. MS m/z 324 [M+1]+. A solution of residue in acetic acid (1 mL) was heated at 130° C. in a microwave for 10 min. The solvent was removed in vacuo to afford compound 22.1 (20 mg, 20percent) MS m/z 306 [M+1]+.
  • 16
  • [ 110-91-8 ]
  • [ 105-36-2 ]
  • [ 89531-58-8 ]
YieldReaction ConditionsOperation in experiment
28.5 ml of ethyl bromoacetate (MW=167.0; d=1.51 g/ml; 258 mmol) were added slowly to a solution of 45 g of morpholine (MW=87; d=0.995 g/ml; 517 mmol) in 200 ml of diethyl ether. After stirring the mixture for 2 hours at room temperature, the solid formed was removed by filtration.The solution thus obtained was concentrated under reduced pressure. The residue obtained was treated with a solution of 18 g of KOH (MW=56.1; 321 mmol) in 180 ml of ethanol for 4 hours at room temperature. The mixture was then made acid by adding a solution of 6N hydrochloric acid in ethanol (about 100 ml) and the solid product formed was then removed by filtration and washed with ethanol.This solid was the morpholin-4-yl acetic acid hydrochloride (48 g), which was used in subsequent reactions without further purification.LC/MS (M+H)+=146; 100 (base peak).
  • 17
  • [ 15980-22-0 ]
  • [ 89531-58-8 ]
  • [ 956011-64-6 ]
YieldReaction ConditionsOperation in experiment
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 24h; To a suspension of 34.5 g of morpholin-4-yl acetic acid hydrochloride from Example 1a) (MW=181.6; 190 mmol) in 500 ml of dichloro-methane were added 42 g of 4-dimethylaminopyridine (MW=122.17; 344 mmol) and, after a few minutes, 71 g of N,N'-dicyclohexylcarbo-diimide (MW=206.33, 344 mmol).23.3 g of 4-amino-2,6-dimethylphenol from Example 1b) (MW=137.18; 170 mmol) were added to the stirred mixture under a nitrogen atmosphere and at room temperature.The mixture was stirred for 24 hours, after which the solid formed was removed by filtration. The solution was then concentrated under reduced pressure. The residue was taken up with a hexane/ethyl acetate 1:1 mixture and filtered again through a layer of silica.The resulting solution was concentrated under reduced pressure and the residue was purified by flash chromatography on silica, using a chloroform/methanol 9:1 mixture as eluent.The solid residue thus obtained was N-(4-hydroxy-3,5-dimethyl-phenyl)-2-morpholin-4-yl acetamide, which was crystallized twice from ethyl acetate and then used in the subsequent reactions without further purification.
  • 18
  • [ 38875-53-5 ]
  • [ 89531-58-8 ]
  • [ 1207624-01-8 ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; 2,3-Diamino-5-bromopyridine (2.00 g) and <strong>[89531-58-8]morpholin-4-ylacetic acid hydrochloride</strong> obtained by the method described in U.S. Pat. No. 6,352,993 (1.34 g) were dissolved in acetonitrile (15 ml). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.22 g), 1-hydroxybenzotriazole (0.98 g) and N-methylmorpholine (1.29 ml) were added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with chloroform and washed with brine. The organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The resulting solid was washed with diethyl ether to give the title compound (1.40 g) as a pale yellow solid.MS (ESI) m/z: 315 (M+H)+.1H-NMR (DMSO-d6) delta: 2.52 (4H, t, J=4.6 Hz), 3.62 (4H, t, J=4.6 Hz), 6.01 (2H, s), 7.84 (1H, d, J=2.2 Hz), 7.87 (1H, d, J=2.2 Hz), 9.20 (1H, s).
  • 19
  • [ 38875-53-5 ]
  • [ 89531-58-8 ]
  • [ 1207624-02-9 ]
  • 20
  • [ 103-90-2 ]
  • [ 89531-58-8 ]
  • 4-acetamidophenyl 2-morpholinoacetate [ No CAS ]
  • 21
  • [ 103-90-2 ]
  • [ 89531-58-8 ]
  • [ 20682-30-8 ]
YieldReaction ConditionsOperation in experiment
70% With pyridine; dicyclohexyl-carbodiimide; at 20℃; General procedure: Equimolar quantities of APAP, dialkylaminocarboxylic acid hydrochloride (3a-3k) and DCC in 35-40 ml dry pyridine were stirred at room temperature for 24-48 h after which the suspension was triturated with about 75 ml dichloromethane and 25 ml diethyl ether for 1 h. Then, the suspension was filtered and the solid obtained was washed thoroughly with dichloromethane till no smell of pyridine remained. The filtered solid was dried under vacuum for a few hours and then was refluxed with 150-200 ml chloroform for 4 h. The resulting suspension was filtered while hot to yield 4a-4k as white solids, while the dicyclohexyl urea remained in the filtrate. This step yields the prodrugs as hydrochlorides in excellent yields and purity. The hydrochloride salts of DAAC prodrugs of APAP were treated with 5-10 ml ice cold saturated aqueous sodium bicarbonate solution and the aqueous layer was subsequently extracted with 200-250 ml methylene chloride once. The organic layer was dried over sodium sulfate for 1 h and filtered. The solvent was evaporated on a rotary evaporator to yield compounds 5a-5k as colorless solids.
  • 22
  • 7-oxa-10,13,17,18,21-pentaazatetracyclo[12.5.2.1^{2,6}.0^{17,20}]docosa-1(20),2,4,6(22),14(21),15,18-heptaene hydrochloride [ No CAS ]
  • [ 89531-58-8 ]
  • [ 1429323-02-3 ]
YieldReaction ConditionsOperation in experiment
75% With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 2h; <strong>[89531-58-8]2-morpholinoacetic acid hydrochloride</strong> (90 mg, 0.497 mmol) and N,N-diisopropylethylamine (384 muIota, 2.26 mmol) were dissolved in N,N-dimethylformamide (1.80 ml). O-(Benzotriazol-l -yl)- Nu,Nu,Nu',Nu'-tetramethyluronium hexafluorophosphate (HBTU) (205 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and methanol was added. The precipitate was filtered and dried under reduced pressure. The product was taken up in dichloromethane/methanol (4:1 , 100 ml) and 4N HCI in 1 ,4-dioxane (90 muIota, 0.36 mmol) was added. The reaction mixture was stirred at room temperature for 90 minutes. The solvent was removed under reduced pressure and the compound was triturated with diethyl ether, filtered and dried under reduced pressure.Yield: 155 mg of example 23 (75percent)LCMS method 2: MH+ = 423, RT = 1.942 min
  • 23
  • (R)-N-[(1S,2R)-2-hydroxyindan-1-yl]-3-[(2S,3S)-3-((4-amino-2,6-dimethylphenoxyacetyl)amino)-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide hydrochloride [ No CAS ]
  • [ 89531-58-8 ]
  • [ 1595091-97-6 ]
  • 24
  • [ 88217-68-9 ]
  • [ 89531-58-8 ]
YieldReaction ConditionsOperation in experiment
99% With hydrogenchloride; In 1,4-dioxane; at 20℃; for 12h; A mixture of the product of the previous step (7-1) (300 g, 1.49 mol) in 3 M HCl in dioxane (2.0 L) was stirred at 20° C. for 12 h and concentrated to give the HCl salt of the title compound (270 g, 99percent yield) as a pale solid, which was used directly in the next step 1H NMR (400 MHz, MeOD) delta 4.13 (s, 2H), 3.93 (br. s, 4H), 3.64 (br. s, 4H).
80% With hydrogenchloride; In 1,4-dioxane; at 20 - 60℃; Tert-butyl 2-morpholinoacetate (11 g, 54.7 mmol) was stirred with HCl, 4M in dioxane (54 mL), giving a white precipitate (a mild exotherm was observed) which slowly dissolved with stirring at room temperature. Ten minutes after complete dissolution, the mixture solidified. Then the mixture was warmed to 60° C. and the thick suspension was stirred vigorously overnight. The mixture was then cooled to room temperature, diluted with diethyl ether (60 mL) and filtered to collect the title compound (8 g, 80percent) as a white solid. 1H NMR (CD3OD, 400 MHz): delta (ppm) 4.13 (s, 2H), 3.94 (brm, 4H), 3.41 (brm, 4H).
With hydrogenchloride; In 1,4-dioxane; (f) Preparation of 2-morpholinoacetic acid hydrochloride salt Tert-butyl 2-morpholinoacetate (11 g, 54.7 mmol) was stirred with HCl, 4M in dioxane (54 mL), giving a white precipitate (a mild exotherm was observed) which slowly dissolved with stirring at room temperature. Ten minutes after complete dissolution the mixture solidified. Then the mixture was warmed to 60° C. and the thick suspension was stirred vigorously overnight. The mixture was then cooled to room temperature, diluted with diethyl ether (60 mL) and filtered to collect the title compound (8 g, 80percent) as a white solid. 1H NMR (CD3OD, 400 MHz): delta (ppm) 4.13, s, 2H), 3.94 (brm, 4H), 3.41 (brm, 4H).
  • 25
  • [ 1616388-12-5 ]
  • [ 89531-58-8 ]
  • [ 1616385-60-4 ]
YieldReaction ConditionsOperation in experiment
15% To a solution of 2- morpholinoacetic acid hydrochloride 61 (0.02 g, 0.1 1 mmol) in dimethylacetamide (2 ml) was added benzotriazol- l -yl-oxytripyrrolidinophosphonium hexafluorophosphate (55.69 mg, 0.1 1 mmol). The mixture was stirred at room temperature for 40 minutes, then added 3,4-dimethyl-N-[2-(l , 2,3,6- tetrahydropyridin-4-yl)- lH-pyrrolo[2, 3-Z7]pyridin-5-yl]- lH-pyrazole-5-carboxamide 60 (0.02 g, 0.07 mmol) and N,N-diisopropylethylamine (0.02 ml, 0.14 mmol). The reaction mixture was stirred at room temperature for two hours. After the reaction was completed as evidenced by LCMS, the reaction mixture was filtered and purified by preparative HPLC to provide compounds (P-2073) (5 mg, 15percent). MS (ESI) [M+H]+ = 464.6. The data from the lH NMR spectrum were consistent with the structure of the compound.
  • 26
  • 3-amino-4-(cyclopropyloxy)-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzamide [ No CAS ]
  • [ 89531-58-8 ]
  • 4-(cyclopropyloxy)-3-[(morpholin-4-ylacetyl)amino]-N-(5-phenyl-1,3,4-thiadiazol-2-yl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
12% With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; 100 mg (0.28 mmol) of 3-amino-4-(cyclopropyloxy)-N-(5-phenyl-l,3,4-thiadiazol-2-yl)benzamide (intermediate 132) were dissolved in 2 mL of anh DMF. 0.20 mL (1.14 mmol) of N-ethyl-N- isopropylpropan-2-amine, 74 mg (0.41 mmol) of <strong>[89531-58-8]morpholin-4-ylacetic acid hydrochloride</strong> and 177 mg (0.34 mmol) of PYBOP were added. It was stirred overnight at rt. The precipitate was filtered off and washed once with methanol. It was dried at 45 °C under vacuum affording 17 mg (12percent) of the title compound. 1H-NM (300 MHz, DMSO-d6): delta [ppm]= 0.73 - 0.98 (m, 4H), 2.52 - 2.58 (m, 4H), 3.16 (s, 2H), 3.61 - 3.71 (m, 4H), 4.08 - 4.17 (m, 1H), 7.44 - 7.59 (m, 4H), 7.93 - 8.04 (m, 3H), 8.94 (d, 1H), 9.71 (s, 1H), 12.98 - 13.23 (m, 1H). LC-MS (method 3): Rt = 0.78 min; MS (ESIpos): m/z = 480 [M+H]+.
  • 27
  • 5-methyl-N4-(5-pyridin-4-yloxazol-2-yl)benzene-1,2,4-triamine [ No CAS ]
  • [ 89531-58-8 ]
  • (6-methyl-2-morpholin-4-ylmethyl-3H-benzoimidazol-5-yl)-(5-pyridin-4-yloxazol-2-yl)amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% Preparation of (6-methyl-2-morpholin-4-ylmethyl-3/- -benzoimidazol-5-yl)-(5-pyridin-4-yl- oxazol-2-yl)-amine 055 A mixture of dianiline IV-d (40 mg, 0.14 mmol), morpholin-4-yl-acetic acid hydrochloride (28 mg, 0.15 mmol), 1 -hydroxybenzotriazole hydrate (21 mg, 0.16 mmol), N-(3- dimethylaminopropyl)-/V-ethylcarbodiimide hydrochloride (30 mg, 0.16 mmol) and triethylamine (40 muIota_, 0.32 mmol) in DMF (2 mL) was stirred at room temperature overnight. The reaction mixture was then evaporated, diluted with ethyl acetate, washed with water, dried over MgS04, and concentrated. The residue was dissolved in AcOH (1 mL) and heated at 130^ for 15 min. After cooling, a saturated solution of NaHC03 (10 mL) and AcOEt (10 mL) were added and the organic layer was washed with water, then with a saturated solution of NaCI, dried over MgS04 and concentrated. The crude product was purified by silica gel chromatography using 5percent EtOH in DCM as eluent to give compound 055 as a yellow solid (17 mg, 31 percent). H NMR (400 MHz, DMSO-d6) delta 12.25 {br s, 1 H), 9.48 (s, 1 H), 8.55 (d, J = 6.0 Hz, 2H), 7.82 (s, 1 H), 7.74 (s, 1 H), 7.46 (d, J = 6.1 Hz, 2H), 7.36 (s, 1 H), 3.72 (s, 2H), 3.67 - 3.52 (m, 4H), 2.50 - 2.43 (m, 4H), 2.36 (s, 3H). LCMS : (ESI-) m/z 389 (M-H)~, Retention time = 1 .17 mins.
  • 28
  • C23H24O6 [ No CAS ]
  • [ 89531-58-8 ]
  • C29H33NO8 [ No CAS ]
  • 29
  • [ 89531-58-8 ]
  • [ 543-27-1 ]
  • benzyl(2S)-3-(difluoromethoxy)-2-[[(2S)-2-[[(2S)-3-(difluoromethoxy)-2-[(2-morpholinoacetyl)amino]propanoyl]amino]-4-methyl-pentanoyl]amino]propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate; In water; (g) Preparation of benzyl(2S)-3-(difluoromethoxy)-2-[[(2S)-2-[[(2S)-3-(difluoromethoxy)-2-[(2-morpholinoacetyl)amino]propanoyl]amino]-4-methyl-pentanoyl]amino]propanoate (XIX(a)) To a stirred solution of <strong>[89531-58-8]2-morpholinoacetic acid hydrochloride</strong> (317 mg, 1.74 mmol) in DCM (5 mL) and N-methylmorpholine (369 muL, 3.34 mmol) cooled to 0° C. was added isobutyl chloroformate (209 muL, 1.59 mmol), dropwise. The resulting mixture was stirred for 10 min then treated with the compound of Formula XVIII(a) as a solution in DCM (5 mL), followed by DIPEA, dropwise, then warmed to room temperature and stirred for a further 20 min. The mixture was diluted with ethyl acetate (50 mL) and washed with sat. NaHCO3 (2*75 mL), water (50 mL) and brine (50 mL). The organic phase was concentrated in vacuo and triturated with hexanes. The resulting white solid was collected via vacuum filtration giving the compound of Formula XIX(a) (811 mg, 89percent). 1H NMR (CDCl3, 400 MHz): delta (ppm) 7.86 (d, J=8 Hz, 1H), 7.42-7.31 (m, 5H), 6.76 (d, J=8 Hz, 1H), 6.65 (d, J=8 Hz, 1H), 6.24 (t, J=74 Hz, 1H), 6.15 (t, J=74 Hz, 1H), 5.26-5.16 (m, 2H), 4.87-4.78 (m, 1H), 4.72-4.65 (m, 1H), 4.51-4.42 (m, 1H), 4.32-4.21 (m, 2H), 4.16-4.09 (m, 1H), 4.05-3.99 (m, 1H), 3.77-3.67 (m, 4H), 3.06 (s, 2H), 2.57-2.49 (m, 4H), 1.75-1.66 (m, 1H), 1.61-1.49 (m, 2H), 0.95-0.86 (m, 6H).
  • 30
  • 4-N-octanoyl-3'-O-tetrahydropyranyl-2',2'-difluorodeoxycytidine [ No CAS ]
  • [ 89531-58-8 ]
  • C28H42F2N4O8 [ No CAS ]
  • 31
  • 4-N-octanoyl-3'-O-tetrahydropyranyl-2',2'-difluorodeoxycytidine [ No CAS ]
  • [ 89531-58-8 ]
  • 5'-O-(2-morpholinoacetoyl)-4-N-octanoyl-2',2'-difluorodeoxycytidine [ No CAS ]
  • 32
  • [ 89531-58-8 ]
  • (2S)-2-[[(2S)-3-(difluoromethoxy)-2-[(2-morpholinoacetyl)amino]propanoyl]amino]-3-phenylpropanoic acid [ No CAS ]
  • 33
  • [ 89531-58-8 ]
  • (2S)-2-[[(2S)-3-(difluoromethoxy)-2-[(2-morpholinoacetyl)amino]propanoyl]amino]-N-[(1S)-3-methyl-1-[(2R)-2-methyloxirane-2-carbonyl]butyl]-3-phenylpropanamide [ No CAS ]
  • 34
  • benzyl (2S)-2-[[(2S)-2-amino-3-(difluoromethoxy)propanoyl]amino]-3-phenylpropanoate hydrochloride [ No CAS ]
  • [ 89531-58-8 ]
  • benzyl (2S)-2-[[(2S)-3-(difluoromethoxy)-2-[(2-morpholinoacetyl)amino]propanoyl]amino]-3-phenylpropanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; To a stirred solution of benzyl (2S)-2-[[(2S)-2-amino-3-(difluoromethoxy)propanoyl]amino]-3-phenyl-propanoate hydrochloride (1.65 g, 3.84 mmol), <strong>[89531-58-8]2-morpholinoacetic acid hydrochloride</strong> (768 mg, 4.23 mmol) and HOBt hydrate (648 mg, 4.23 mmol) in DCM (20 mL) was added EDC hydrochloride (811 mg, 4.23 mmol). The resulting mixture was cooled to 0° C. and treated with DIPEA (0.736 mL, 4.23 mmoL), dropwise, warmed to room temperature and stirred overnight. The mixture was diluted with DCM (30 mL) and washed with saturated sodium bicarbonate (2*50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo then chromatographed on silica gel eluting with 0percent-100percent ethyl acetate in hexanes. The product-containing fractions were concentrated in vacuo giving the compound of Formula XVII(a) (1.54 g, 77percent) as a white solid. 1H NMR (CDCl3, 400 MHz): delta (ppm) 7.72 (m, 1H), 7.35-6.90 (m, 10H), 6.12 (t, J=74 Hz, 1H), 5.14-5.04 (m, 2H), 4.81-4.75 (m, 1H), 4.65-4.55 (m, 1H), 4.26-4.20 (m, 1H), 3.93-3.87 (m, 1H), 3.65-3.50 (m, 4H), 3.15-2.90 (m, 4H), 2.45-2.35 (m, 4H).
  • 35
  • (S)-methyl 2-((S)-2-((S)-2-amino-4-phenyIbutanamido)-4-methylpentanamido)-3-phenylpropanoate hydrochloride [ No CAS ]
  • [ 89531-58-8 ]
  • C32H44N4O6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 30℃; for 2h;Inert atmosphere; Hydroxybenzotriazole (4.1 gm) and N-methylmorpholine (31 gm) were added to a pre-cooled mixture of (S)-methyl 2-((S)-2-((S)-2-amino-4-phenylbutanamido)-4- methylpentanamido)-3-phenylpropanoate hydrochloride compound of formula- 12a (75 gm),. <strong>[89531-58-8]2-morpholinoacetic acid hydrochloride</strong> compound of formula- 13a (30.4 gm) and dichloromethane (525 ml) at 0-5°C under nitrogen atmosphere. A solution of dicyclohexylcarbodiimide (37.9 gm) in dichloromethane (225 ml) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the reaction mixture, cooled the filtrate to 10-15°C and washed with aqueous sodium bicarbonate solution followed by with aqueous hydrochloric acid solution and then with water. Distilled off the solvent completely from the reaction mixture under reduced pressure. Tetrahydrofuran (750 ml) and water (375 ml) were added to the obtained solid at 25-30°C. Cooled the reaction mixture to 10-15°C and aqueous LiOH.H20 solution (12.8 gm of LiOH.H20 dissolved in 75 ml of water) was added. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Water and dichloromethane were added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was washed with dichloromethane. Acidified the aqueous layer using aq.hydrochloric acid solution at 25-30°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the precipitated solid and washed with water. Methanol (450 ml) was added to the obtained solid at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 min at the same temperature. Ethanol (225 ml) was added to the reaction mixture at 55-60°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with methanol and then dried the material to get the title compound. Yield: 48.0 gm; M.R: 208-215°C.
 

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