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Chemical Structure| 1903-91-9 Chemical Structure| 1903-91-9

Structure of 1903-91-9

Chemical Structure| 1903-91-9

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Product Details of [ 1903-91-9 ]

CAS No. :1903-91-9
Formula : C3H9ClN2O
M.W : 124.57
SMILES Code : N=C(N)COC.[H]Cl
MDL No. :MFCD08752294
InChI Key :JIQYMVXNVNFXIP-UHFFFAOYSA-N
Pubchem ID :13548602

Safety of [ 1903-91-9 ]

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

Computational Chemistry of [ 1903-91-9 ] 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 30.88
TPSA ?

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

59.1 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

-0.09
Log Po/w (WLOGP)?

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

0.37
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.

-0.39
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

-0.59
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-0.14

Water Solubility

Log S (ESOL):?

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

-0.42
Solubility 47.0 mg/ml ; 0.377 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.

-0.7
Solubility 24.9 mg/ml ; 0.2 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

-0.04
Solubility 112.0 mg/ml ; 0.902 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.

-7.12 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)

1.69

Application In Synthesis of [ 1903-91-9 ]

* 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 [ 1903-91-9 ]

[ 1903-91-9 ] Synthesis Path-Downstream   1~31

  • 1
  • [ 1903-91-9 ]
  • [ 123-06-8 ]
  • [ 76574-34-0 ]
  • 2
  • [ 1903-91-9 ]
  • [ 137860-26-5 ]
  • [ 148475-76-7 ]
  • 3
  • [ 141-97-9 ]
  • [ 1903-91-9 ]
  • [ 3122-74-5 ]
  • 4
  • [ 42945-65-3 ]
  • [ 1903-91-9 ]
YieldReaction ConditionsOperation in experiment
96% With ammonia; In ethanol; at -15 - 20℃; Description 79; 2-Methoxvethanimidamide hvdrochloride; Ethanol (500 ml) was cooled to-15C and anhydrous ammonia gas passed through until the mixture was saturated. Description 78 (90 g, 585 mmol) was added and the mixture stirred at room temperature overnight. The mixture was recooled to-15C and a small amount of solid removed by filtration. The filtrate was evaporated to dryness and the residue crystallised on standing to give the title compound (70 g, 96%). 1H NMR (360 MHz, DMSO-d6) 3.35 (3 H, s), 4.24 (2 H, s), 8.85 (4 H, br s).
88% With ammonia; In ethanol; at -10 - 20℃; for 17h; Step 2. Ammonia gas is bubbled through a solution of 2-methoxy-acetimidic acid ethyl ester hydrochloride (49.3 g, 0.32 mol) in EtOH (240 mL), which is chilled to -1O0C for twenty minutes. The reaction vessel is capped and stirred for 17 hours at ambient temperature. The mixture is concentrated in vacuo to afford 2-Methoxy-acetamidine hydrochloride (35 g, 88%) as a solid.
88% With ammonia; In ethanol; at -10℃; for 0.333333h; Ammonia gas is bubbled through a solution of 2-methoxy-acetimidic acid ethyl ester hydrochloride (49.3 g, 0.32 mol) in EtOH (240 mL), which is chilled to -1O0C for twenty minutes. The reaction vessel is capped and stirred for 17 hours at ambient temperature. The mixture is concentrated in vacuo to afford 2-Methoxy-acetamidine hydrochloride (35 g, 88%) as a solid.
  • 5
  • [ 1903-91-9 ]
  • methyl 2-{(3,4-difluorophenyl)methylene}-3-oxobutyrate [ No CAS ]
  • [ 200052-17-1 ]
  • 6
  • [ 41051-15-4 ]
  • [ 1903-91-9 ]
  • [ 3122-77-8 ]
  • 7
  • [ 506-68-3 ]
  • [ 1903-91-9 ]
  • 2-methoxy-N-cyano-acetamidine [ No CAS ]
  • 8
  • [ 506-68-3 ]
  • [ 1903-91-9 ]
  • 2-Methoxy-N-cyano-acetamidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In ethanol; water; acetonitrile; Step 3 2-Methoxy-N-cyano-acetamidine To an ice-cold solution of <strong>[1903-91-9]2-<strong>[1903-91-9]methoxyacetamidine hydrochloride</strong></strong> (0.1 mol) in ethanol (100 mL) and triethyl amine (0.2 mol, 27.8 mL) was added dropwise a solution of cyanogen bromide in acetonitrile. After 1 hr the solvents and the excess triethylamine were removed by evaporation and water (100 mL) was added to the resulting residue. It was then extracted with EtOAc (2*100 mL). The EtOAc extract was collected, dried, filtered and the filtrate was evaporated to obtain a light yellow solid, the title product of Step 3 (72%, 8.2 g); mp 101-103 C.
  • 9
  • [ 1903-91-9 ]
  • [ 105-53-3 ]
  • [ 1903-90-8 ]
YieldReaction ConditionsOperation in experiment
80% With sodium hydride; In ethanol; for 16h;Heating / reflux; Step 3. To a solution of <strong>[1903-91-9]2-methoxy-acetamidine hydrochloride</strong> (20.18 g, 0.16 mol) and diethylmalonate (24.6 mL, 0.16 mol) in EtOH (150 mL) is added 60% dispersion of sodium hydride in oil (14.3 g, 0.36 mol). The mixture is heated to reflux and stirred for 16 hours. The mixture is concentrated in vacuo and the residue is diluted with water (100 mL) and extracted with EtOAc (75 mL). The aqueous layer is acidified to pH 3 with HCl and extracted thrice with EtOAc (75 mL). The organic extracts from acidic solution are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-methoxymethyl-pyrimidine-4.6-diol (20 g, 80%)as an oil.
80% With sodium hydride; In ethanol; for 16h;Heating / reflux; To a solution of <strong>[1903-91-9]2-methoxy-acetamidine hydrochloride</strong> (20.18 g, 0.16 mol) and diethylmalonate (24.6 mL, 0.16 mol) in EtOH (150 mL) is added 60% dispersion of sodium hydride in oil (14.3 g, 0.36 mol). The mixture is heated to reflux and stirred for 16 hours. The mixture is concentrated in vacuo and the residue is diluted with water (100 mL) and extracted with EtOAc (75 mL). The aqueous layer is acidified to pH 3 with HCl and extracted thrice with EtOAc (75 mL). The organic extracts from acidic solution are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-methoxymethyl-pyrimidine-4,6-diol (20 g, 80%)as an oil.
With sodium methylate; In methanol; for 24h;Heating / reflux; Reflux the mixture of malonic acid diethyl ester (7. 96 g, 50 MMOL), 2-methoxy- acetamidine hydrochloride (6. 2 g, 50 mmol), and NaOMe methanol solution (4. 37 M, 22. 7 mL, 100 mmol) in MEOH (30 mL) for 24 hours. Concentrate, dilute with H20 (50 mL), wash with EtOAc, and concentrate the aqueous layer. Extract the solid with MEOH and concentrate to afford 2-methoxymethyl-pyrimidine-4, 6-diol.
With sodium methylate; In methanol; for 24h;Heating / reflux; Reflux a mixture of malonic acid diethyl ester (7. 96 g, 50 mmol), 2-methoxy- acetamidine hydrochloride (6. 2 g, 50 mmol), and NaOMe MeOH solution (4. 37 M, 22. 7 mL, 100 mmol) in MeOH (30 mL) for 24 hours. Concentrate, dilute with HA0 (50 mL), wash with EtOAc, and concentrate the aqueous layer. Extract with MeOH and concentrate to yield 2-methoxymethyl-pyrimidine-4, 6-diol.

  • 10
  • [ 1738-36-9 ]
  • [ 1903-91-9 ]
YieldReaction ConditionsOperation in experiment
75% Example 112 (S)-2-[4-(2-Chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid(3-methoxymethyl-[1,2,4]thiadiazol-5-yl)-amide To a stirred suspension of aluminum chloride (4.81 g, 0.090 mol) in toluene (33.5 mL) at 0 C. under argon was slowly added a solution of 2M trimethylaluminum in toluene (42 mL, 0.030 mol) maintaining a temperature below 10 C. The resulting mixture was allowed to stir at room temperature for 2 h before a solution of 3-methoxyacetonitrile (5.56 g, 0.050 mol) in toluene (16.5 mL) was added. A fine light yellow precipitate formed and the resulting mixture was warmed to 80 C. and allowed to stand for 20 h. The reaction mixture was cooled to room temperature and then slowly poured on to a cooled suspension of silica gel (40 g) in dichloromethane (100 mL). The resulting mixture was stirred for 15 min, filtered and the silica gel pad washed well with methanol. The filtrate was evaporated and the residue was redissolved in a solution of dichloromethane/methanol, filtered and evaporated which afforded a solid. The solid was suspended in a 3N hydrogen chloride solution in methanol (20 mL) and stirred vigorously while diethyl ether (500 mL) was added dropwise. The resulting mixture was stirred at room temperature (30 min) decanted, washed with diethyl ether (250 mL) decanted and dried under vacuum which afforded 2-methoxy-acetamidine hydrochloride (4.66 g, 75%) as a light yellow semisolid.
Example 42; 3,4-Dichloro-N-(2-methoxymethyl-pyrimidin-4-yl)-benzenesulfonamide; Step A]: 2-Methoxymethyl-pyrimidin-4-ylamine; 2-Methoxymethyl-pyrimidin-4-ylamine (which has been described in the patent literature earlier in BE641253, 1964, Ciba Ltd.) was made according to example 2, step A] via the alternative method from known 2-methoxy-acetamidine hydrochloride (0.3 g, obtained from 2-methoxyacetonitrile in analogy to Synth. Commun. 12 (13), 1982, 989-993 and Tetrahedron Lett. 31 (14), 1990, 1969-1972) and 2-chloro-acrylonitrile (0.2 mL). 2-Methoxymethyl-pyrimidin-4-ylamine was obtained as an off-white solid (0.1 g): 1H NMR (delta, CDCl3): 8.22 (d, 1H), 6.32 (d, 1H), 4.98 (br s, 2H), 4.49 (s, 2H), 3.50 (s, 3H). MS (ESI): 140.3 (MH+).
With ammonium chloride; sodium methylate; In methanol; acetone; Reference Example 3 Methoxyacetamidine hydrochloride Sodium methylate (1.62 g, 0.03 mole) was added all at once to a solution of methoxyacetonitrile (21.3 g, 0.3 mole) in methanol (100 ml) at room temperature with stirring, and the mixture was stirred at room temperature for 1 hour. Thereafter, ammonium chloride (16.1 g, 0.3 mole) was added all at once to the reaction solution, and after stirring at 35 to 40 C. for 2 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a colorless, transparent oily product. The product was suspended in acetone, and the suspension was rapidly cooled to obtain 33.5 g of methoxyacetamidine hydrochloride as white crystals (m.p. 44-45 C.).
Compound 4.7. 2-Methoxyacetimidamide hydrochloride. Into a 250-mL round- bottom flask, was placed a solution of 2-methoxyacetonitrile (6.00 g, 84.4 mmol) in methanol (60 mL). Sodium methoxide (860 mg, 15.9 mmol) was added and the mixture was stirred at room temperature for 40 h. Ammonium chloride (4.52 g, 84.5 mmol) was then added and the mixture was stirred at 40 C for 12 h then concentrated under reduced pressure. The residue was diluted with H20 (20 mL) and washed with ethyl acetate (2 x 20 mL). The aqueous was concentrated under reduced pressure to yield the title compound as a yellow solid (5 g, crude), which was used in the next ste
Compound 4.7. 2-Methoxyacetimidamide hydrochloride. Into a 250-mL round- bottom flask, was placed a solution of 2-methoxyacetonitrile (6.00 g, 84.4 mmol) in methanol (60 mL). Sodium methoxide (860 mg, 15.9 mmol) was added and the mixture was stirred at room temperature for 40 h. Ammonium chloride (4.52 g, 84.5 mmol) was then added and the mixture was stirred at 40 C for 12 h then concentrated under reduced pressure. The residue was diluted with H20 (20 mL) and washed with ethyl acetate (2 x 20 mL). The aqueous was concentrated under reduced pressure to yield the title compound as a yellow solid (5 g, crude), which was used in the next step without further purification.
73.36 g With sodium methylate; at 20℃; for 3h; To a solution of 2-methoxyacetonitrile (47.9 g) in methanol (240 ml), sodium methoxide (3.64 g) was added, and the mixture was stirred at room temperature for 3 hours. Ammonium chloride (36.1 g) was added to the reaction solution, and the mixture was stirred overnight at 40C. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue obtained was dissolved in 2-propanol (50 ml). Acetone (200 ml) was added to the solution, and the mixture was stirred at room temperature for 3.5 hours. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (73.35 g). 1H-NMR (DMSO-d6) delta: 3.35 (3H, s), 4.25 (2H, s), 9.06 (4H, br s).

  • 11
  • [ 1501-06-0 ]
  • [ 1903-91-9 ]
  • [ 159237-69-1 ]
YieldReaction ConditionsOperation in experiment
4.6 g (42%) With NaOEt; In ethanol; water; Step 1 Ethyl 3-(6-Methyl-2-methoxymethyl-3H-pyrimidin-4-on-5-yl)propionate A mixture of NaOEt (0.088 mol) in EtOH (prepared from 2.0 g of Na and 70 mL of EtOH), <strong>[1903-91-9]methoxyacetamidine hydrochloride</strong> (5.4 g, 0.044 mol), and diethyl acetylglutarate (10.0 g, 0.044 mol) was heated under reflux for 24 h. The mixture was concentrated, taken up in water, acidified to pH 4 with conc. HCl, and extracted with CH2 Cl2. The extracts were washed with brine, dried (MgSO4), and concentrated. Trituration with ether gave 4.6 g (42%) of product as an off-white solid, mp 87-90 C. 1 H NMR (DMSO-d6) delta1.15 (t, J=7.2 Hz, 3H), 2.22 (s, 3H), 2.45 (s, 3H), 2.63 (t, J=7.8 Hz, 2H), 3.30 (s, 3H), 4.08 (q, J=7.2 Hz, 2H), 4.18 (s, 2H), 12.40 (br s, 1H).
  • 12
  • [ 1903-91-9 ]
  • [ 5472-38-8 ]
  • ethyl 2-methoxymethyl-4-hydroxypyrimidine-5-acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% In ethanol; Step 1, ethyl 2-methoxymethyl-4-hydroxypyrimidine-5-acetate Sodium metal (0.754 mol) was dissolved in absolute ethanol (100 ml) and the resulting solution was added dropwise to a solution of <strong>[1903-91-9]methoxyacetamidine hydrochloride</strong> (0.703 mol) in ethanol (100 ml). After 15 minutes the reaction mixture was filtered and the filtrate was added to a solution of diethyl formylsuccinate (0.703 mol), which was prepared according to H. Nakao et al. Ann. Sankyo Res. Lab., 18, 33-37 (1966). The reaction was refluxed for 15 hours, cooled to room temperature and was then concentrated to obtain a crude solid. This solid was crystallized from isopropanol to obtain the title compound (43% yield), m.p. 142-143 C. 1 H NMR (CDCl3): 7.85 (s, 1H), 4.4 (s, 2H), 4.2 (q, J=7.5 Hz, 2H), 3.5 (s, 3H), 3.4 (s, 2H), 1.2 (t, J=7.5 Hz, 3H).
  • 13
  • [ 151510-02-0 ]
  • [ 1903-91-9 ]
  • [ 911388-93-7 ]
YieldReaction ConditionsOperation in experiment
86% With sodium methylate; In ethanol; for 8h;Heating / reflux; Preparation of 2-methoxymethyl-4-hydroxy-5-ethylpyrimidine; 111 ml of a 30% strength sodium methoxide solution are added to a solution of 44.7 g (261 mmol) of ethyl 2-[(dimethylamino)methylene]butanoate and 42.2 g (339 mmol) of methoxyacetamidinium hydrochloride in 680 ml of ethanol, and this reaction mixture is stirred under reflux for 8 h. The reaction mixture is then allowed to stand at RT for 72 h and subsequently concentrated under reduced pressure. The residue is dissolved in H2O, adjusted to pH 5 using concentrated HCl and extracted repeatedly with CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel using EA/ethanol (7:3) gives 37.7 g (86%) of product. 1H-NMR: delta [CDCl3]1.20 (t, 3H), 2.50 (q, 2H), 3.52 (s, 3H), 4.38 (s, 2H), 7.75 (s, 1H).
  • 14
  • ethyl formylacetate sodium salt [ No CAS ]
  • [ 1903-91-9 ]
  • [ 34274-23-2 ]
YieldReaction ConditionsOperation in experiment
In water; (a) A mixture of 120 g of <strong>[1903-91-9]methoxyacetamidine hydrochloride</strong> and 300 g of ethyl formylacetate sodium salt in 1.5 1 of water was stirred at room temperature for 3 days. The reaction solution was concentrated and then acidified with hydrochloric acid and extracted with hydrochloric acid and extracted with dichloromethane. Purification by column chromatography resulted in 100 g of 2-methoxymethyl-4-pyrimidone (melting point 126 C.).
  • 15
  • ethyl formyl acetate sodium salt [ No CAS ]
  • [ 1903-91-9 ]
  • [ 34274-23-2 ]
YieldReaction ConditionsOperation in experiment
In water; (i) A mixture of <strong>[1903-91-9]methoxyacetamidine hydrochloride</strong> (57 g) and ethyl formyl acetate sodium salt (150.5 g) in water (670 ml) were stirred at room temperature for 3 days. The volume was reduced and the solution acidified, saturated with sodium chloride and extracted with chloroform. After drying (MgSO4), the extracts were stripped to a solid which was triturated with ether to give 2-methoxymethyl-4-pyrimidone (53.5 g) m.p. 125-7.
  • 16
  • [ 638-07-3 ]
  • [ 1903-91-9 ]
  • 6-(Chloromethyl)-4-hydroxy-2-(methoxymethyl)-pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium methylate; In methanol; water; EXAMPLE 5 6-(Chloromethyl)-4-hydroxy-2-(methoxymethyl)-pyrimidine Sodium methylate (11.90 g, 0.22 mole) was added to a solution of <strong>[1903-91-9]methoxyacetamidine hydrochloride</strong> (12.45 g, 0.1 mole) and ethyl 4-chloroacetoacetate (16.50 g, 0.1 mole) in methanol (50 ml) at 5 to 10 C. with stirring. The resulting orange reaction mixture was stirred at 5 to 10 C. for 2 hours and then at 20 C. for 3 hours, and neutralized with conc. hydrochloric acid. The precipitate was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue which was then dissolved in water (300 ml). The aqueous solution was extracted with chloroform, and the chloroform extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crystalline residue. The residue was suspended in ether and then filtered to obtain 17.8 g of 6-(chloromethyl)-4-hydroxy-2-(methoxymethyl)pyrimidine as pale brown needle-like crystals (m.p. 124.0-125.5 C.).
  • 17
  • [ 1903-91-9 ]
  • [ 179482-24-7 ]
  • [ 200052-17-1 ]
YieldReaction ConditionsOperation in experiment
44% With potassium tert-butylate; p-toluenesulfonic acid monohydrate; In N,N-dimethyl-formamide; a) 6-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2-methoxy-methyl-4-methylpyrimidine. To a solution of <strong>[1903-91-9]2-<strong>[1903-91-9]methoxyacetamidine hydrochloride</strong></strong> (1.4 g, 11.2 mmol.) in DMF (6 mL) were added a solution of potassium tert-butoxide (0.69 g, 6.1 mmol.) in DMF (6 mL) and a solution of methyl {2-(3,4-difluorophenyl)methylene}-3-oxobutanoate (1.4 g, 5.8 mmol.) in DMF (6 mL) at 0 C. After the mixture was stirred for 0.5 hr at 0 C., p-toluenesulfonic acid monohydrate (2.2 g, 11.6 mmol.) was added. The mixture was heated at 100-120 C. for 2.5 hrs. The mixture was cooled to room temperature, quenched with aqueous NaOH solution (2N, 30 mL), and extracted with ether. The organic layer was dried over Na2SO4 and evaporated. The residue was flash chromatographed over silica gel (eluent:ethyl acetate) to give the product in 44% yield (0.8 g) as a yellow oil.
  • 18
  • [ 30414-53-0 ]
  • [ 1903-91-9 ]
  • [ 911388-92-6 ]
YieldReaction ConditionsOperation in experiment
Preparation of 2-methoxymethyl-4-hydroxy-6-ethylpyrimidine; 116 ml of a 30% strength sodium methoxide solution are diluted with 100 ml of methanol and, with ice-cooling, a solution of 26 g (208.7 mmol) of methoxy-acetamidinium hydrochloride in 200 ml of methanol is added dropwise. After the dropwise addition, the mixture is stirred for 1 h, and a solution of 27.1 g (208.7 mmol) of methyl propionyl acetate in 100 ml of methanol is then added dropwise at RT. The reaction mixture is stirred at RT for 96 h. For work-up, the reaction mixture is concentrated, the residue is taken up in 100 ml of H2O and the aqueous mixture is adjusted to pH 6 using concentrated HCl. The mixture is then concentrated and the residue is taken up in 30 ml of methanol. The solid is filtered off with suction, and concentration of the mother liquor gives 38.5 g of product. 1H-NMR: delta [CDCl3] 1.20 (t, 3H), 2.50 (q, 2H), 3.42 (s, 3H), 4.35 (s, 2H), 6.04 (s, 1H).
  • 19
  • [ 333-20-0 ]
  • [ 1903-91-9 ]
  • [ 115443-55-5 ]
YieldReaction ConditionsOperation in experiment
60% To a solution of <strong>[1903-91-9]2-methoxy-acetamidine hydrochloride</strong> (4.66 g, 0.037 mol) in methanol (20 mL) at 0 C. under vigorous stirring was added dropwise bromine (1.90 mL, 0.037 mol) and a 5.4M sodium methylate solution in methanol (13.7 mL, 0.037 mol) simultaneously over 30 min maintaining a slight bromine excess by color. To the resulting nearly colorless suspension was added dropwise a solution of potassium thiocyanate (3.64 g, 0.037 mol) in methanol (20 mL) over 10 min at 0-10 C. The resulting mixture was stirred for 2 h at 0-10 C. and filtered. The isolated material was washed with methanol and dried which afforded a brown solid which was purified by flash chromatography (silica gel 60, 5% methanol/diethyl ether) and crystallized from diethyl ether/hexanes which afforded 3-methoxymethyl-[1,2,4]thiadiazol-5-ylamine (3.25 g, 60%) as a light yellow solid.
  • 20
  • [ 1903-91-9 ]
  • [ 1077-96-9 ]
  • C11H11FN4O2 [ No CAS ]
  • 21
  • [ 1903-91-9 ]
  • [ 535-80-8 ]
  • C10H11ClN2O2 [ No CAS ]
  • 22
  • [ 1533440-62-8 ]
  • [ 1903-91-9 ]
  • [ 1533440-63-9 ]
YieldReaction ConditionsOperation in experiment
50 mg With potassium carbonate; In acetonitrile; at 80℃; for 12h;Inert atmosphere; Compound 27.3. Methyl 3-(2-(methoxymethyl)-lH-imidazol-5-yl)-4- methylbenzoate. Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(2-bromoacetyl)-4- methylbenzoate (compound 27.2, 281 mg, 1.04 mmol) in ACN (5 mL). 2- Methoxyacetimidamide (compound 4.7, 194 mg, 1.56 mmol) and potassium carbonate (434 mg, 3.14 mmol) were added and the resulting mixture was stirred for 12 hours at 80 C, then concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (3 x 50 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 : 1) as the eluent to yield 50 mg (19%) of the title compound as a brown solid.
50 mg With potassium carbonate; In acetonitrile; at 80℃; for 12h;Inert atmosphere; Compound 27.3. Methyl 3-(2-(methoxymethyl)-lH-imidazol-5-yl)-4- methylbenzoate. Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(2-bromoacetyl)-4- methylbenzoate (compound 27.2, 281 mg, 1.04 mmol) in ACN (5 mL). 2- Methoxyacetimidamide (compound 4.7, 194 mg, 1.56 mmol) and potassium carbonate (434 mg, 3.14 mmol) were added and the resulting mixture was stirred for 12 hours at 80 C, then concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (3 x 50 mL), dried ( a2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether ( 1 : 1 ) as olid.
  • 23
  • [ 1533440-31-1 ]
  • [ 1903-91-9 ]
  • [ 1533440-34-4 ]
  • [ 1533442-83-9 ]
YieldReaction ConditionsOperation in experiment
19%; 52% With potassium carbonate; In acetonitrile; at 80℃; Compounds 2.1 and 2.2. Methyl 5-(2-(methoxymethyl)-4-methyl-lH-imidazol-5- yl)-2,4-dimethylbenzoate and methyl 5-(2-(methoxymethyl)-4-methyloxazol-5-yl)-2,4- dimethylbenzoate. Into a 100-mL round-bottom flask, was placed a mixture of methyl 5-(2- bromopropanoyl)-2,4-dimethylbenzoate (compound 1.6, 600 mg, 2.01 mmol), 2- methoxyethanimidamide hydrochloride (510 mg, 4.09 mmol), potassium carbonate (840 mg, 6.08 mmol) and acetonitrile (30 mL). The resulting mixture was stirred at 80 C overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with H20 (50 mL) and extracted with ethyl acetate (100 mL). The organics was washed brine (2 x 50 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1 :2) as the eluent to yield methyl 5-(2-(methoxymethyl)-4-methyl-lH-imidazol-5-yl)-2,4- dimethylbenzoate (compound 2.1) (0.1 1 g, 19%) and methyl 5-(2-(methoxymethyl)-4- methyloxazol-5-yl)-2,4-dimethylbenzoate (compound 2.2) (0.30 g, 52%), both as a yellow oils.
19%; 52% With potassium carbonate; In acetonitrile; at 80℃; Compounds 2.1 and 2.2. Methyl 5-(2-(methoxymethyl)-4-methyl-lH-imidazol-5- yl)-2,4-dimethylbenzoate and methyl 5-(2-(methoxymethyl)-4-methyloxazol-5-yl)-2,4- dimethylbenzoate. Into a 100-mL round-bottom flask, was placed a mixture of methyl 5-(2- bromopropanoyl)-2,4-dimethylbenzoate (compound 1.6, 600 mg, 2.01 mmol), 2- methoxyethanimidamide hydrochloride (510 mg, 4.09 mmol), potassium carbonate (840 mg, 6.08 mmol) and acetonitrile (30 mL). The resulting mixture was stirred at 80 C overnight, then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with 0 (50 mL) and extracted with ethyl acetate (100 mL). The organics was washed brine (2 x 50 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1 :2) as the eluent to yield methyl 5-(2-(methoxymethyl)-4-methyl-lH-imidazol-5-yl)-2,4- dimethylbenzoate (compound 2.1) (0.1 1 g, 19%) and methyl 5-(2-(methoxymethyl)-4- methyloxazol-5-yl)-2,4-dimethylbenzoate (compound 2.2) (0.30 g, 52%), both as a yellow oils.
  • 24
  • [ 1533440-40-2 ]
  • [ 1903-91-9 ]
  • [ 1533440-41-3 ]
  • [ 1533442-84-0 ]
YieldReaction ConditionsOperation in experiment
30 mg; 60 mg With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere; Compound 4.8 and compound 4.9. Methyl 3-(4-cyclopropyl-2-(methoxymethyl)- lH-imidazol-5-yl)-4-methylbenzoate and methyl 3-(4-cyclopropyl-2- (methoxymethyl)oxazol-5-yl)-4-methylbenzoate. Into a 100-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-(2- bromo-2-cyclopropylacetyl)-4-methylbenzoate (compound 4.6, 150 mg, 0.48 mmol), 2- methoxyacetimidamide hydrochloride (compound 4.7, 90 mg, 0.72 mmol), potassium carbonate (200 mg, 1.44 mmol), and N,N-dimethylformamide (15 mL). The resulting mixture was stirred at 80 C for 3 h, then diluted with ethyl acetate (100 mL). The mixture was washed with brine (3 x 30 mL) and water (3 x 30 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1 :2) as the eluent to yield methyl 3-(4-cyclopropyl-2- (methoxymethyl)-lH-imidazol-5-yl)-4-methylbenzoate (compound 4.8) (30 mg, 21%) and methyl 3-(4-cyclopropyl-2-(methoxymethyl)oxazol-5-yl)-4-methylbenzoate (compound 4.9) (60 mg, 41 %), both as a yellow oils.
30 mg; 60 mg With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere; Compound 4.8 and compound 4.9. Methyl 3-(4-cyclopropyl-2-(methoxymethyl)- lH-imidazol-5-yl)-4-methylbenzoate and methyl 3-(4-cyclopropyl-2- (methoxymethyl)oxazol-5-yl)-4-methylbenzoate. Into a 100-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-(2- bromo-2-cyclopropylacetyl)-4-methylbenzoate (compound 4.6, 150 mg, 0.48 mmol), 2- methoxyacetimidamide hydrochloride (compound 4.7, 90 mg, 0.72 mmol), potassium carbonate (200 mg, 1.44 mmol), and N,N-dimethylformamide (15 mL). The resulting mixture was stirred at 80 C for 3 h, then diluted with ethyl acetate (100 mL). The mixture was washed with brine (3 x 30 mL) and water (3 x 30 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1 :2) as the eluent to yield methyl 3-(4-cyclopropyl-2- (methoxymethyl)-lH-imidazol-5-yl)-4-methylbenzoate (compound 4.8) (30 mg, 21%) and methyl 3-(4-cyclopropyl-2-(methoxymethyl)oxazol-5-yl)-4-methylbenzoate (compound 4.9) (60 mg, 41%), both as a yellow oils.
YieldReaction ConditionsOperation in experiment
Step 1: 2-(Methoxymethyl)-6-methylpyrimidin-4(3H)-one A mixture of sodium (1.84 g, 80.0 mmol) in ethanol (80 mL) was stirred until sodium disappeared under an inert atmosphere of nitrogen. Into the resulting mixture was added ethyl 3-oxobutanoate (5.20 g, 40.0 mmol) and 2-methoxyethanimidamide hydrochloride (5.00 g, 40.1 mmol). The resulting solution was stirred for 18 h at 80 C. and was then concentrated in vacuo. The residue was diluted with water and the pH was adjusted to 5 with concentrated hydrochloric acid (37%, 12 M) and extracted with ethyl acetate.
  • 26
  • [ 1903-91-9 ]
  • [ 87-13-8 ]
  • [ 69731-52-8 ]
YieldReaction ConditionsOperation in experiment
81% With ethanol; sodium ethanolate; at 90℃; for 17h; A mixture of diethyl 2-(ethoxymethylene)malonate (5 g, 23.2 mmol), <strong>[1903-91-9]2-methoxyacetimidamide hydrochloride</strong> (2.88 g, 23.2 mmol) and sodium ethoxide (3.15 g, 46.3 mmol) in anhydrous ethanol (200 mL) was stirred at 90 C for 17 h. The reaction mixture was concentrated, to give ethyl 4-hydroxy-2-(methoxymethyl)pyrimidine-5-carboxylate (4 g, 18.8 mmol, 81 %) as a white solid. LCMS (ESI) m/z: 213.1 [M+H]+
  • 27
  • methyl (±)-(3R,3aR,8bR)-8b-hydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-3-phenyl-1-(tosyloxy)-3a,8b-dihydro-3H-cyclopenta[b]benzofuran-2-carboxylate [ No CAS ]
  • [ 1903-91-9 ]
  • methyl (±)-(3aR,4R,5S,5aR,10bR)-3a-hydroxy-8,10-dimethoxy-2-(methoxymethyl)-5a-(4-methoxyphenyl)-5-phenyl-3a,4,5,5a-tetrahydro-1H-benzofuro[3',2':1,5]cyclopenta[1,2-d]imidazole-4-carboxylate [ No CAS ]
  • 28
  • 5-(2,4-dichlorobenzyl)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid hydrochloride [ No CAS ]
  • [ 1903-91-9 ]
  • 5-(2,4-dichlorobenzyl)-2-(methoxymethyl)-6-methylpyrimidin-4(3H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
4.53 g With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 70℃; for 7h;Microwave irradiation; To a solution of the compound (3.96 g) obtained in step 1 above in N,N-dimethylformamide (8 ml), the compound (4.4 g) obtained in step 1 of Reference Example 1 and 1,8-diazabicyclo[5.4.0]undec-7-ene (9 ml) were added, and the mixture was stirred at 70C for 7 hours under microwave irradiation. After cooling, the reaction solution was diluted with ice water. Ammonium chloride (7 g) was added to the aqueous solution, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration, washed with water, and then dried under reduced pressure to obtain the title compound (4.53 g). 1H-NMR (CDCl3) delta: 2.21 (3H, s), 3.52 (3H, s), 3.95 (2H, s), 4.38 (2H, s), 6.96 (1H, d, J = 8.3 Hz), 7.11 (1H, dd, J = 8.3, 2.1 Hz), 7.38 (1H, d, J = 2.1 Hz), 9.75 (1H, br s) . MS (m/z) : 313 (M+H)+.
  • 29
  • [ 4755-81-1 ]
  • [ 1903-91-9 ]
  • [ 120-83-2 ]
  • 5-(2,4-dichlorophenoxy)-2-(methoxymethyl)-6-methylpyrimidin-4(3H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.69 g To a suspension of 2,4-dichlorophenol (3.0 g) and cesium carbonate (6.0 g) in acetone (20 ml), methyl 2-chloro-3-oxobutanoate (2.2 ml) was added, and the mixture was heated to reflux for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue obtained was diluted with water. The aqueous solution was rendered acidic with 6 M hydrochloric acid, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (n-hexane/chloroform) to obtain the title compounds (4.54 g) as a tautomeric mixture. 1H-NMR (CDCl3) delta: 1.99 (3H, s) , 2.47 (1.5 H, s), 3.74 (3H, s), 3.83 (1.5 H, s), 5.02 (0.5 H, s), 6.70 (1H, d, J = 8.8 Hz), 6.78 (0.5 H, d, J = 8.9 Hz), 7.13 (1H, dd, J = 8.8, 2.4 Hz), 7.15-7.20 (0.5 H, m), 7.41 (1H, d, J = 2.4 Hz), 7.43 (0.5 H, d, J = 2.5 Hz), 11.29 (1H, s). [Step 2] 5-(2,4-Dichlorophenoxy)-2-(methoxymethyl)-6-methylpyrimidin-4(3H)-one (0170) To a solution of the compound (1.66 g) obtained in step 1 above and the compound (0.746 g) obtained in step 1 of Reference Example 1 in N,N-dimethylformamide (3 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.8 ml) was added, and the mixture was stirred at 70C for 16 hours. After cooling, the reaction solution was diluted with water, and 2 M hydrochloric acid (3.3 ml) was added to the aqueous solution, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (1.69 g). 1H-NMR (CDCl3) delta: 2.28 (3H, s), 3.52 (3H, s), 4.40 (2H, s), 6.62 (1H, d, J = 8.8 Hz), 7.09 (1H, dd, J = 8.8, 2.5 Hz), 7.43 (1H, d, J = 2.5 Hz), 10.03 (1H, br s). MS (m/z) : 315 (M+H)+.
  • 30
  • [ 1903-91-9 ]
  • [ 105-45-3 ]
  • [ 3122-74-5 ]
YieldReaction ConditionsOperation in experiment
7.38 g With sodium ethanolate; In ethanol; at 20℃; for 72h;Reflux; To a suspension of sodium ethoxide (11.3 g) in ethanol (25.0 ml), methyl 3-oxobutanoate (7.41 ml) and the compound (8.58 g) obtained in step 1 of Reference Example 1 were added at room temperature, and the mixture was heated to reflux for 3 days. After cooling, the reaction solution was concentrated under reduced pressure, and the residue obtained was dissolved in water. The pH of the aqueous solution was adjusted to 5.5 by the addition of 6 M hydrochloric acid, followed by extraction with dichloromethane and ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (7.38 g). 1H-NMR (CDCl3) delta: 2.28 (3H, s), 3.51 (3H, s), 4.38 (2H, s), 6.17 (1H, s). MS (m/z) : 155 (M+H)+.
  • 31
  • methyl 2-(2,4-dichlorobenzyl)-4-methyl-3-oxopentanoate [ No CAS ]
  • [ 1903-91-9 ]
  • 5-(2,4-dichlorobenzyl)-6-isopropyl-2-(methoxymethyl)pyrimidin-4(3H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 120℃; for 2h;Microwave irradiation; A solution of the compound (938 mg) obtained in step 1 above, the compound (578 mg) obtained in step 1 of Reference Example 1, and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.40 ml) in N,N-dimethylformamide (8 ml) were stirred at 120C for 1 hour under microwave irradiation. After cooling, the reaction solution was stirred again at 120C for 1 hour under microwave irradiation. After cooling, water and a saturated aqueous solution of ammonium chloride were added to the reaction solution, followed by extraction with chloroform. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (637 mg) . 1H-NMR (CDCl3) delta: 1.06 (6H, d, J = 6.7 Hz), 2.90 (1H, spt, J = 6.7 Hz), 3.52 (3H, s), 3.96 (2H, s), 4.41 (2H, s), 6.89 (1H, d, J = 8.3 Hz), 7.09 (1H, dd, J = 8.4, 2.1 Hz), 7.38 (1H, d, J = 2.1 Hz), 9.80 (1H, br s). MS (m/z) : 341 (M+H)+.
 

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