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Chemical Structure| 104711-65-1 Chemical Structure| 104711-65-1
Chemical Structure| 104711-65-1

4-Chloro-6-methylpicolinonitrile

CAS No.: 104711-65-1

4.5 *For Research Use Only !

Cat. No.: A242575 Purity: 98%

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Product Details of [ 104711-65-1 ]

CAS No. :104711-65-1
Formula : C6H4ClN3
M.W : 153.57
SMILES Code : N#CC1=NC(C)=CC(Cl)=C1
MDL No. :MFCD09607719
InChI Key :VLNYLEMSSXHBPF-UHFFFAOYSA-N
Pubchem ID :18505249

Safety of [ 104711-65-1 ]

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

Calculated chemistry of [ 104711-65-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 38.93
TPSA ?

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

36.68 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.79
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

1.93
Log Po/w (WLOGP)?

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

1.92
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.

0.73
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

2.4
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.75

Water Solubility

Log S (ESOL):?

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

-2.45
Solubility 0.547 mg/ml ; 0.00358 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-2.32
Solubility 0.723 mg/ml ; 0.00474 mol/l
Class?

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

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-3.1
Solubility 0.122 mg/ml ; 0.0008 mol/l
Class?

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

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
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.

-5.86 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)

1.67

Application In Synthesis of [ 104711-65-1 ]

* 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 [ 104711-65-1 ]

[ 104711-65-1 ] Synthesis Path-Downstream   1~29

  • 1
  • 3M-methyl magnesium bromide [ No CAS ]
  • [ 104711-65-1 ]
  • [ 339586-00-4 ]
YieldReaction ConditionsOperation in experiment
With ammonium chloride; In diethyl ether; ii) Production of 1-(4-chloro-6-methyl-2-pyridinyl)ethanone 10 g (66 mmol) of <strong>[104711-65-1]4-chloro-2-cyano-6-methylpyridine</strong> was dissolved in 100 ml of anhydrous diethyl ether. The resultant solution was cooled to maintain the temperature thereof at 5 C., and was then fed dropwise with 262 ml (87 mmol) of diethyl ether solution of 3M-methyl magnesium bromide (manufactured by Aldrich) at the same temperature in a manner of spending 15 min. At that time, the inner temperature of the mixture had elevated to 20 C. due to heat generated by the reaction. The mixture was stirred for 2.5 hours, then cooled down to 5 C. and added with aqueous solution of ammonium chloride to discontinue the reaction. The reacted mixture was extracted with diethyl ether, and the resultant nonaqueous layer was washed with water, then dried with anhydrous magnesium sulfate and condensed under reduced pressure to thereby obtain a crude product. The obtained crude product was purified by means of silica gel column chromatography (elude; hexane:ethyl acetate=4:1 (v/v)) to obtain the target compound in an amount of 3.8 g. 1H-NMR (CDCl3, TMS, delta ppm) data; 2.61 (s, 3H), 2.70 (s, 3H), 7.32 (d, 1H), 7.83 (d, 1H).
  • 2
  • [ 696-08-2 ]
  • sodium hydrogen atomcarbonate [ No CAS ]
  • trimethyl silylanilide [ No CAS ]
  • [ 79-44-7 ]
  • [ 104711-65-1 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; i) Production of 4-chloro-2-cyano-6-methylpyridine 32 g (223 mmol) of 4-chloro-2-methylpyridine-1-oxide was dissolved in 250 ml of methylene chloride. The resultant solution was added with 24. 6 g (248 mmol) of trimethyl silylanilide at a room temperature in a manner of spending 5 min. The mixture was stirred for 10 min. and then added with 23. 5 g (219 mmol) of dimethylcarbamoyl chloride at the same temperature in a manner of spending 5 min. At that time, the inner temperature of the mixture had elevated to the reflux temperature thereof due to heat generated by the reaction. While stirring the mixture, the mixture was naturally cooled until the time that the inner temperature of the mixture falls to reach a room temperature. After stirring the mixture for 4 days, the reacted solution was cooled so as to maintain the temperature thereof at 5 C. and was added with 300 ml of 10% aqueous solution of sodium hydrogen atomcarbonate. The organic layer of the mixture was separated, and the aqueous layer was extracted with chloroform. The obtained chloroform layer was unified with the separated organic layer, and the unified mixture was dried with anhydrous magnesium sulfate and then condensed under reduced pressure to obtain a crude product. The obtained crude product was then purified by means of silica gel column chromatography (elude; hexane:ethyl acetate=4:1 (v/v)) to obtain the target compound in an amount of 10 g. 1H-NMR (CDCl3, TMS, delta ppm) data; 2.60 (s, 3H), 7.40 (d, 1H), 7.53 (d, 1H).
  • 3
  • [ 104711-65-1 ]
  • [ 374-01-6 ]
  • [ 1156542-46-9 ]
YieldReaction ConditionsOperation in experiment
<Reference Production Example 30> Into 6 ml of N,N-dimethylformamide was suspended 0.18 g of sodium hydride(60% oily), and 0.44 g of l,l,l-trifluoro-2-propanol was added at 10C. After stirring for 10 minutes, 0.49 g of <strong>[104711-65-1]4-chloro-6-methylpyridine-2-carbonitrile</strong> was added, the mixture was stirred for 1 hour, and the reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert- butyl=methyl=ether. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.72 g of 6-methyl-4-(2,2,2-trifluoro-l-methylethoxy)pyridine-2-carbonitrile. 6-Methyl-4-(2,2,2-trifluoro-l-methylethoxy)pyridine-2-carbonitrile <n="135"/>1H-NMR: 1.56 (d, 3H), 2.57 (s, 3H), 4.76-4.82 (m, IH), 6.91 (d, IH), 7.10 (d, IH)
  • 4
  • [ 104711-65-1 ]
  • [ 75-89-8 ]
  • [ 1156542-44-7 ]
YieldReaction ConditionsOperation in experiment
<Reference Production Example 28>Into 8 ml of N,N-dimethylformamide was suspended 0.22 g of sodium hydride (60% oily), and 0.47 g of trifluoroethyl alcohol was added at 100C. After stirring for 10 minutes, 0.6 g of <strong>[104711-65-1]4-chloro-6-methylpyridine-2-carbonitrile</strong> was added at 0C, the mixture was stirred for 1 hour, and the reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert- butyl=methyl=ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.79 g of 6-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile. 6-Methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile1H-NMR: 2.59 (s, 3H), 4.43 (q, 2H), 6.91 (d, IH), 7.12 (d, IH)
  • 5
  • [ 5470-66-6 ]
  • [ 7677-24-9 ]
  • [ 104711-65-1 ]
  • 6
  • [ 104711-65-1 ]
  • [ 118-92-3 ]
  • [ 1375798-58-5 ]
YieldReaction ConditionsOperation in experiment
c) To a solution of 4-chloro-6-methyl-pyridine-2-carbonitrile (0.460 g, 3.02 mmol) in anhydrous methanol (1 ml) was added sodium methoxide (30% wt, 0.201 ml, 1.055 mmol). The reaction mixture was stirred at RT for 1 h before a solution of anthranilic acid (0.517 g, 3.77 mmol) in dry methanol (6 mL) was added. The resulting yellow solution was stirred at RT for an additional 45 min and then heated under reflux overnight. The reaction mixture was then cooled to 0 C and kept at this temperature for 1 h. The resulting yellow precipitate was filtered to afford 2-(4-chloro-6-methyl-pyridin-2-yl)-3/-/-quinazolin-4-one. The product was used in the next step without further purification.LCMS: 1.87 min; method A; [M+H]+ = 272
  • 7
  • [ 696-08-2 ]
  • [ 7677-24-9 ]
  • [ 104711-65-1 ]
YieldReaction ConditionsOperation in experiment
84% With triethylamine; at 20℃; for 44h;Reflux; To a solution of intermediate 1A (128.0 g, 889 mmol) and triethylamine (260 ml) in propionitrile (1.5 1) was added trimethylsilyl cyanide (334 ml, 2.67 mol). The mixture was stirred at reflux for26 h then left to stand at room temperature for 18 h. The reaction was quenched by the addition of30% aqueous potassium carbonate solution and the layers were separated. The organic layer was washed with 10% aqueous potassium carbonate solution, brine, dried over magnesium sulfate, filtered and concentrated. The resulting dark solid was recrystallized from hot isopropanol (150 ml) and water (300 ml) to give intermediate 2A (114.3 g, 84%).
75% c. PREPARATION OF 4-CHLORO-6-METHYLPICOLINONITRILE.[00398] 4-chloro-2-methylpyridine-N-oxide (8.97g, 62.5 mmol, 1 .00 eq) was dissolved in CH2C12 and dried over MgSO^. The solution was added to a flame-dried round-bottom flask and CH2C12 was added to give a total volume of 188 mL. TMS-cyanide (10 mL, 75 mmol, 1.2 eq) was added and the reaction stirred for 1 5 minutes. Dimethylcarbamyl chloride (6.9 mL, 75 mmol, 1.2 eq) was added dropwise over 20 minutes, and the reaction was stirred for 24 hours. An additional one equivalent each of TMS-cyanide and dimethylcarbamyl chloride were added and the reaction was stirred for another 72 hours. The reaction was made basic with 10% K2C03 and extraxcted with CH2C12 (3 ). The combined organics were dried (MgS04), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 7.2 g (75%) of the title compound as a white solid. NMR (400 MHz, OMSO-d6) delta 8.13 (d, J= 1 .6 Hz, 1), 7.82 (d, J= 1.7 Hz, 1H), 2.52 (s, 3H); ES-MS [M+l ]+:
75% With magnesium sulfate; N,N-Dimethylcarbamoyl chloride; In dichloromethane; for 96.5833h; b. SYNTHESIS OF 4-CHLORO-6-METHYLPICOLINONITRILE (COMPOUND 2)Compound 1 (8.97 g, 62.5 mmol, 1.00 eq) was dissolved in CH2Cl2 and dried over MgSO4. The solution was added to a flame-dried round-bottom flask and CH2Cl2 was added to give a total volume of 188 mL. TMS-cyanide (10 mL, 75 mmol, 1.2 eq) was added and the reaction stirred for 15 minutes. Dimethylcarbamoyl chloride (6.9 mL, 75 mmol, 1.2 eq) was added dropwise over 20 minutes, and the reaction was stirred for 24 hours. An additional one equivalent each of TMS-cyanide and Dimethylcarbamoyl chloride was added and the reaction was stirred for another 72 hours. The reaction was made basic with 10% K2CO3 and extracted with CH2Cl2 (3x). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 7.2 g (75%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) delta 8.13 (d, J = 1.6 Hz, 1H), 7.82 (d, J = 1.7 Hz, 1 H), 2.52 (s, 3H); ES-MS [M+1]+: 153.2.
51% To a solution of 4-chloro-2-methylpyridine-N-oxide(7, 4.3 kg, 29.94 mol) in dichloromethane (64.5 L, 15 V) was added trimethylsilyl cyanide (9.76 L, 77.83 mol) at 25-30 C over a period of 30 min and furtherstirred for 15 min. Reaction mass was cooled to 0-5 C. N,NDimethylcarbamoylchloride (7.17 L, 77.83 mol) was added drop wise over aperiod of 1 h. The reaction mass was slowly warmed to 25-30 C and stirred for36 h. Reaction was monitored by HPLC [7 NMT 1.0%]. The reaction mass wascooled to 0-5 C. The reaction was quenched with 10% aqueous potassiumcarbonate solution until the pH of aqueous layer was about 9-10. Thetemperature of reaction mass was allowed to attain 25-30 C and the layerswere separated. The aqueous layer was extracted with dichloromethane (8.6 L,2 V). The combined organic layer was washed with 0.5 N HCl solution (21.5 L,5 V) followed by brine solution (21.5 L, 5 V), dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was chased twice with nheptane(2 17.2 L). The crude product was diluted with 2% ethyl acetate[Ashok alco-chem limited, Purity (area%) by GC - 100%] in hexanes (43 L, 10 V)and filtered through silica plug (21.5 kg, 5% w/w on SM, 230-400 mesh) andsilica plug was washed with 10% ethyl acetate in hexanes till the product was completely eluted (300 L, 69 V). Combined fractions were concentrated andresidue was chased twice with n-heptane (2 17.2 L). Resulting mass wasstirred in n-heptane (21.5 L, 5 V) at 0-5 C for 1 h and filtered. Solid waswashed with cold n-heptane (4.3 L, 1 V) and dried to get 8 as off white solid(2.32 kg, 51%).. 1H NMR (400 MHz, DMSO-d6) d 8.13 (d, J = 1.6 Hz, 1H), 7.82 (d,J = 1.7 Hz, 1H), 2.52 (s, 3H); 13C NMR (100 MHz, DMSO-d6) d = 161.99, 144.13,133.01, 127.65, 126.40, 116.60, 23.57 ppm; LCMS (Method 1): RT = 0.715 min,m/z = 153.2 [M + H]+; HRMS, calc?d for C7H5ClN2 [M], 152.0141; found152.0139.
With triethylamine; In acetonitrile;Reflux; b) To a solution of 4-chloro-2-methyl-pyridine 1 -oxide (2.250 g, 15.67 mmol) in acetonitrile (50 ml) was added Et3N (6.55 ml, 47.0 mmol,) and TMSCN (1 1.76 ml, 94.03 mmol). The resulting brown solution was heated overnight under reflux and then quenched with 60 mL of sat. aqueous NaHC03. The aqueous phase was extracted with CH2CI2 and the combined organic layers were washed with water and brine, dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography (cyclohexane/AcOEt; 100/0 to 0/100) to afford 4-chloro-6-methyl-pyridine-2-carbonitrile as a light orange powder.LCMS: 1.35 min; method A; [M+H]+ = 153

  • 9
  • [ 104711-65-1 ]
  • [ 1375338-67-2 ]
  • 10
  • [ 104711-65-1 ]
  • [ 1375798-60-9 ]
  • 11
  • [ 104711-65-1 ]
  • [ 1375324-82-5 ]
  • 12
  • [ 104711-65-1 ]
  • [ 1375320-24-3 ]
  • 15
  • [ 26456-59-7 ]
  • [ 104711-65-1 ]
  • [ 1396337-93-1 ]
YieldReaction ConditionsOperation in experiment
82.1% With potassium carbonate; In N,N-dimethyl-formamide; at 25 - 80℃; for 36h;Large scale; To a solution of 5-hydroxypyrimidine (9, 1.73 kg, 18.08 mol) in DMF (23.0 L,10 V), potassium carbonate (6.25 kg, 45.21 mol) was added followed by <strong>[104711-65-1]4-chloro-6-methylpicolinonitrile</strong> (8, 2.3 kg, 15.07 mol) at 25-30 C. The reactionmass was heated at 75-80 C for 36 h. The reaction was monitored by HPLC 8NMT 2.0% by HPLC). Reaction mass was cooled to 25-30 C. The solid wasfiltered and washed the solid with DMF (4.6 L, 2.0 V). The filtrate was cooled to0-5 C and purified water (27.6 L, 12 V) was added drop wise over a period of1 h. The solid precipitated was filtered and washed with purified water (2.3 L,10 V) to afford 10 as off white solid (2.62 kg, 82.1%). 1H NMR (400 MHz, DMSOd6)d 9.17 (s, 1H), 8.85 (s, 2H), 7.74 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H),2.48 (s, 3H); 13C NMR (100 MHz, DMSO-d6) d = 164.04, 162.28, 155.51, 150.02,148.75, 133.54, 117.05, 115.59, 115.04, 23.82 ppm; LCMS (Method 1):RT = 0.535 min, m/z = 213.2 [M+H]+; HRMS, calc?d for C11H8N4O [M],212.0698; found 212.0697.
77% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; d. PREPARATION OF 6-METHYL-4-(PYRIMIDIN-5-YLOXY)PICOLINONITRILE.[00399] <strong>[104711-65-1]4-chloro-6-methylpicolinonitrile</strong> (4.0 g, 26 mmol, 1.0 eq), 5-hydroxypyrimidine (5.56 g, 57.9 mmol, 2.20 eq), K2C03 (7.24 mg, 52.4 mmol, 2.0 eq) and DMF (66 mL) were added to a reaction vessel and heated at 80 C for 16 hours. The reaction was filtered and concentrated on silica gel (25 g). The silica gel was loaded on top of a fresh bed of silica gel and washed with 50% ethyl acetate/hexane. The solvents were removed in vacuo and the crude solid was purified by flash chromatography on silica gel to afford 4.31 g (77%) of the title compound as a pale-yellow solid. NMR (400 MHz, DMSO-<¾) delta 9.1 7 (s, 1 H), 8.85 (s, 2H), 7.74 (d, J = 2.4 Hz, 1 H), 7.32 (d, J = 2.3 Hz, 1 H), 2.48 (s, 3H); ES-MS [M+l ]+: 213.2.
  • 17
  • [ 104711-65-1 ]
  • [ 86087-24-3 ]
  • (R)-6-methyl-4-((tetrahydrofuran-3-yl)oxy)-picolinonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% With sodium hydride; In N,N-dimethyl-formamide; for 18h; c. SYNTHESIS OF (R)-6-METHYL-4-((TETRAHYDROFURAN-3- YL)OXY)PICOLINONITRILE (COMPOUND 3)To a solution of (R)-tetrahydrofuran-3-ol (693 mg, 7.86 mmol, 2.0 eq) and sodium hydride (199 mg, 7.86 mmol, 2.0 eq) in DMF (20 mL) was added compound 2 (600 mg, 3.93 mmol, 1.0 eq). After 18 hours, the reaction was diluted with EtOAc and washed with water and brine twice. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 325 mg (40%) of the title compound: 1H NMR (400 MHz, , DMSO-d6) delta 7.52 (d, J = 2.28 Hz, 1H), 7.18 (d, J = 2.28 Hz, 1H), 5.22-5.19 (m, 1H), 3.91-3.33 (m, 4H), 2.46 (s, 3H), 2.34-2.25 (m, 1H), 2.00-1.93 (m, 1H); ES-MS [M+1]+: 205.2.
  • 18
  • [ 104711-65-1 ]
  • (R)-6-methyl-4-((tetrahydrofuran-3-yl)oxy)picolinic acid [ No CAS ]
  • 19
  • [ 104711-65-1 ]
  • (R)-N-(4-(fluoromethyl)thiazol-2-yl)-6-methyl-4-((tetrahydrofuran-3-yl)oxy)picolinamide [ No CAS ]
  • 20
  • [ 104711-65-1 ]
  • [ 1068-55-9 ]
  • rac-1-(4-chloro-6-methylpyridin-2-yl)-2-methylpropan-1-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
53% To a solution of intermediate 2A (114 g, 745 mmol) in tetrahydrofuran (1.5 1) was added isopropyl magnesium chloride (2M, 0.48 1, 968 mmol) dropwise, at -78 C. After the addition was complete the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was then cooled to 0 C and methanol (0.5 1) was added over a period of 10 mm. The mixture was thenwarmed to room temperature and sodium borohydride (16.9 g, 447 mmol) was added portionwise over a period of 30 mm. The mixture was then stirred at room temperature for 18 h and the reaction was then stopped by the addition of ice. The mixture was concentrated; then, dichloromethane was added followed by celite. The mixture was filtered, washed with dichloromethane and the layers separated. The organic layer was dried and concentrated. The residue was purified by flash chromatography (0-15% methanol in ethyl acetate) to give intermediate 3A (78.5 g, 53%) as a black oil.?H NMR (400 MHz, CDC13) oe [ppm] = 7.07 (d, 1H), 7.00 (d, 1H), 3.64 (d, 1H), 2.47 (s, 3H), 2.02 (sept, 1H), 1.68 (bs, 2H), 0.91 (d, 3H), 0.82 (d, 3H).
  • 21
  • [ 104711-65-1 ]
  • [ 15366-08-2 ]
  • 1-(4-chloro-6-methylpyridin-2-yl)-2-methylbutan-1-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
<strong>[104711-65-1]4-chloro-6-methylpyridine-2-carbonitrile</strong> (CAS 104711-65-1, 45 g, 295 mmol) was dissolved in tetrahydrofuran (700 ml). The mixture was cooled to -60C and isobutyl magnesium chloride solution (25% w/w in THF, 180 g, 384 mmol) was added dropwise. The mixture was stirred fortwo hours at room temperature. The mixture was adjusted to 0 C and methanol (230 ml) was added dropwise. Sodium borohydride (7 g, 177 mmol) was added to the mixture portionwise. The solution was stirred one hour at 0 C. The solution was poured into an ice/water mixture (1.3 1) and the mixture was stirred overnight at room temperature. Dichloromethane (1.5 1) was added and the resulting emulsion was filtered over Celite. The aqueous layer was extracted with dichloromethane.The organic layer was dried over magnesium sulfate, filtered and concentrated to give a black oil (62.2 g). The crude product was purified by column chromatography to give several batches of the expected product as in a combined yield of 50% as a mixture of diastereomers.?H NMR (300 MHz, CDC13) oe [ppm] = 7.28 (s, 1H), 7.03 (s, 1H), 3.85 (isomer 1) and 3.73 (isomer 2) (d, 1H), 2.51 (s., 3H), 1.70 - 1.90 (isomer 1) and 1.11 - 1.29 (isomer 2) (m, 2H), 1.52 - 1.67(isomer 2) and 1.33 - 1.49 (isomer 1) (m, 1 H), 0.80 - 1.01 (m, 3H), 0.74 -0.88 (m, 3H).
  • 22
  • [ 104711-65-1 ]
  • [ 32916-51-1 ]
  • rac-1-(4-chloro-6-methylpyridin-2-yl)-1-cyclopentylmethanamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% 4-Chloro-6-methylpyridine-2-carbonitrile (CAS 104711-65-1, 43.6 g, 286 mmol) was dissolved in tetrahydrofuran (840 ml). The mixture was cooled to -60C and cyclopentyl magnesium chloride solution (2M in diethyl ether, 185 mL, 370 mmol) was added dropwise. The mixture was stirred for two hours at room temperature. The mixture was adjusted to 0C and methanol (284 ml) was addeddropwise. Sodium borohydride (6.5 g, 171 mmol) was added to the mixture portionwise. The solution was stirred two hours at 0C. The solution was poured into an ice/water mixture (1.3 1) and the mixture was stirred overnight at room temperature. Dichloromethane (1.5 1) was added and the layers were separated. The aqueous layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated to give a crude product. The productwas mixed with hydrochloric acid solution (400 ml, 2M in ether). The resulting precipitate was filtered and rinsed with tetrahydrofuran. The combined filtrates were concentrated and treated a second time with a hydrochloric acid solution (400 ml, 2M in ether). Diisopropyl ether was added to the resulting suspension and the solid was filtered. The combined solids where re-dissolved into water and the aqueous layer was made basic using a saturated aqueous sodium hydrogen carbonatesolution. The product was extracted three times using dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give an impure product that was purified using column chromatography on silica gel eluting with ethyl acetate, giving the expected product (41.8 g, 65%).
  • 23
  • [ 1768-64-5 ]
  • [ 104711-65-1 ]
  • rac-(4-chloro-6-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
44% Preparation of the Grignard (carried out in flame dried glassware under argon) - Magnesium turnings 3.00 g (125 mmol) were stirred in tetrahydrofuran 75 mL, one flake of iodine was added. The mixture was stirred for 2 hours until the colour had dissipated. 4-Chlorotetrahydropyran (2.00g) was added and the mixture was heated to 60 C, and one drop of methyl iodide was added. The mixture turned cloudy and an exothermia was observed. A further portion of 4- chlorotetrahydropyran 8.00 g was added and the mixture was stirred at 60 C for 2 hours. To a solution of <strong>[104711-65-1]4-chloro-6-methylpicolinonitrile</strong> (intermediate 2A, 8.50 g, 56.0 mmol) in tetrahydrofuran 400 mL was added the Grignard solution drop-wise, at -78 C, under argon. After the addition was complete the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was then cooled to 5 C and methanol 150 mL was added drop-wise followed by sodium borohydride 1.50 g (0.40 mmol) which was added portion-wise. After the addition was complete the mixture was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of water and ethyl acetate. The phases were separated and the aqueous phase was extracted again with ethyl acetate. The organic phases were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness. The residue waspurified by dry flash chromatography (silica gel, eluent: ethyl acetate/methanol 9:1 to 4:1) to yield5.90 g (44%) of (4-chloro-6-methylpyridin-2-yl)(tetrahydro-2H-pyran-4-yl)methanamine.?H-NMR (400 MHz, CDC13): oe [ppm] = 1.14-1.45 (m, 4H), 1.83-1.93 (m, 1H), 2.51 (s, 3H), 3.33 (m, 2H), 3.61 (d, 1H), 3.90 (dd, 1H), 4.01 (dd, 1H), 7.02 (s, 1H), 7.04 (s, 1H).
  • 24
  • [ 104711-65-1 ]
  • rac-N-[1-(4-chloro-6-methylpyridin-2-yl)-2-methylpropyl]formamide [ No CAS ]
  • 25
  • [ 104711-65-1 ]
  • 7-chloro-5-methyl-1-(propan-2-yl)imidazo[1,5-a]pyridine [ No CAS ]
  • 26
  • [ 104711-65-1 ]
  • 7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-1-isopropylimidazo[1,5-a]pyridine-5-carboxamide [ No CAS ]
  • 27
  • [ 104711-65-1 ]
  • 7-chloro-1-isopropyl-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl]imidazo[1,5-a]pyridine-5-carboxamide [ No CAS ]
  • 28
  • [ 104711-65-1 ]
  • rac-1-sec-butyl-7-chloro-N-[(4-ethoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]imidazo[1,5-a]pyridine-5-carboxamide [ No CAS ]
  • 29
  • [ 104711-65-1 ]
  • 7-chloro-1-cyclopentyl-N-[(4-ethoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]imidazo[1,5-a]pyridine-5-carboxamide [ No CAS ]
 

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Technical Information

Categories

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[ 104711-65-1 ]

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