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Chemical Structure| 4045-25-4 Chemical Structure| 4045-25-4

Structure of 4045-25-4

Chemical Structure| 4045-25-4

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Product Details of [ 4045-25-4 ]

CAS No. :4045-25-4
Formula : C6H14ClNO
M.W : 151.63
SMILES Code : COC1CCNCC1.[H]Cl
MDL No. :MFCD06800959
InChI Key :DMFJRRMECZFOKR-UHFFFAOYSA-N
Pubchem ID :11542813

Safety of [ 4045-25-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 4045-25-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 0
Fraction Csp3 1.0
Num. rotatable bonds 1
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 43.61
TPSA ?

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

21.26 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

1.0
Log Po/w (WLOGP)?

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

0.81
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.

0.57
Log Po/w (SILICOS-IT)?

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

1.1
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.7

Water Solubility

Log S (ESOL):?

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

-1.34
Solubility 6.87 mg/ml ; 0.0453 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.

-1.04
Solubility 14.0 mg/ml ; 0.0922 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

-1.16
Solubility 10.5 mg/ml ; 0.069 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

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.

-6.51 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)

1.01

Application In Synthesis of [ 4045-25-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 4045-25-4 ]

[ 4045-25-4 ] Synthesis Path-Downstream   1~36

  • 1
  • [ 856669-30-2 ]
  • [ 4045-25-4 ]
  • 2-phenylamino-9-{4-[1-(4-methoxy)piperidyl]butyl}-6-oxopurine [ No CAS ]
  • 2
  • [ 960391-21-3 ]
  • [ 4045-25-4 ]
  • 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-5-[(4-methoxypiperidin-1-yl)carbonyl]-1H-benzimidazole trifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; Example 15; 2-tert-Butyl-l-[(4,4-difluorocyclohexyl)methyl]-5-[(4-methoxypiperidin-l-yI)carbonyl]- 1/f-benzimidazole; <n="45"/>To a mixture of 2-?err-butyl-l-[(4,4-difluorocyclohexyl)methyl]-lH-benzimidazole-5- carboxylic acid (for preparation see Example 1) (0.050 g, 0.143 mmol), DIPEA (0.063 mL, 0.358 mmol) and DMF (5 mL) were added etaATU (0.065 g, 0.172 mmol) and 4- methoxypiperidine hydrochloride (0.026 g, 0.172 mmol). The mixture was stirred at room temperature for Ih. The solvent was removed under reduced pressure. CH2Ck was added to the resulting residue and the organic layer was washed once with a saturated aqueous NaHCO3 solution, once with brine and dried over anhydrous Na2SO4. CH2Cl2 was removed under reduced pressure. The resulting residue was purified by reversed-phase HPLC using 20-50% CH3CN/H2O and lyophilized to afford the title compound as the corresponding TFA salt. Yield: 80 mg (99%); 1H NMR (400 MHz, METHANOL-D4) delta 1.49 - 1.63 (m, 4 H), 1.66 - 1.69 (m, 10 H), 1.71 - 1.86 (m, 5 H), 1.97 - 2.11 (m, 3 H), 2.21 - 2.32 (m, 1 H), 3.36 (s, 3 H), 3.49 - 3.60 (m, 3 H), 4.02 (s, 1 H), 4.57 (d, J=7.62 Hz, 2 H), 7.61 (dd, J=8.69, 1.46 Hz, 1 H), 7.78 (d, 7=0.78 Hz, 1 H), 7.99 (d, J=8.79 Hz, 1 H); MS (ESI) (M+H)+ 448.3; Anal. Calcd for C25H35N3O2F2 + 1.7 TFA + 0.5 H2O: C, 52.45; H, 5.84; N, 6.46. Found: C, 52.37; H, 5.80; N, 6.60.
  • 3
  • [ 65340-70-7 ]
  • [ 4045-25-4 ]
  • [ 474707-27-2 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In DMF (N,N-dimethyl-formamide); at 130℃; for 8h; Production Example 82 1-(6-Bromo-4-quinolyl)-4-piperidyl methyl ether A mixture of 500 mg 6-bromo-4-chloroquinoline, 330 mg <strong>[4045-25-4]4-methoxypiperidine monohydrochloride</strong>, 0.57 ML triethylamine and 10 ML N,N-dimethylformamide was stirred at 130C for 8 hours.. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated.. The organic layer was washed with water and brine and dried over sodium sulfate, and the solvent was evaporated.. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 516mg of the title compound as a pale yellow oil.1H-NMR (CDCl3) delta: 1.85-1.98(m, 2H), 2.08-2.20(m, 2H), 2.97-3.08(m, 2H), 3.38-3.55(m, 6H), 6.85(d, J=5.0Hz, 1H), 7.70(d, J=8.6Hz, 1H), 7.90(d, J=8.6Hz, 1H), 8.12(s, 1H), 8.69(d, J=5.0Hz, 1H)
  • 4
  • [ 188622-27-7 ]
  • [ 4045-25-4 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride; In ethanol; ethyl acetate; at 20 - 30℃; for 2h;Inert atmosphere; Compound 442 tert-butyl 4-methoxypiperidine-1-carboxylate 48b (242 mg, 1.12 mmol) was dissolved in 37 ethyl acetate (12 mL) and added with a solution of hydrochloride in 21 ethanol (33%, 3 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give the target 444 product 4-methoxypiperidine 48c (hydrochloride salt, 180 mg, brown solid). Yield: 100%. MS m/z (ESI): 116[M+1]
> 99% With hydrogenchloride; In 1,4-dioxane; at 0 - 23℃; for 2h; Step-3: Preparation of intermediate-41a; To a stirred solution of intermediate 40a (810 mg, 3.76 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (8 mL) at 0 C. The reaction mass was stirred for 2 h at 23 C. The organics were evaporated off under reduced pressured. The residue was washed with dry ether and dried under vacuum to afford intermediate 41a (430 mg, >99%) as its HCl salt.
53% With hydrogenchloride; methanol; isopropyl alcohol; The 4-methoxypirhoeridine used as starting material was prepared as follows: EPO <DP n="140"/>iV-tert-butyloxycarbonyl-4-hydroxypiperidme (5.0 g, 24.8 mmol) was dissolved inDMF (25 ml) and sodium hydride (60%, 1.49 g, 37.3 mmol) was added portion-wise. After 15 minutes at room temperature, iodomethane (3.1 ml, 49.8 mmol) was added drop-wise and the mixture was stirred for 1 hour. Water was then added (50 ml), the mixture acidified (pH= 2-3) with IN HCl and extracted with ether. The organic layer was dried and evaporated. The resulting N-tert-butyloxycarbonyl -4-methoxypiperidine was dissolved in methanol (15 ml), a saturated solution of HCl in isopropanol (15 ml) was then added and the mixture was stirred overnight. After removal of the solvent, the residue was taken in ether to precipitate 4- methoxy-piperidine as a hydrochloride salt, which was filtered and dried under vacuum to give 4-methoxypiperidine (HCl salt, 2.0 g, 53%); NuMR Spectrum: 1.68 (m, 2H), 1.96 (m, 2H), 2.92 (br s, 2H), 3.10 (br s, 2H), 3.25 (s, 3H), 3.42-3.45 (m, IH), 9.12 (br d, 2H).
With hydrogenchloride; In ethyl acetate; at 0 - 20℃; for 13h; Ethyl acetate (200 mL) was added to the residue, and the mixture was cooled to 0 C. and stirred. A 4N solution of hydrogen chloride in ethyl acetate (100 mL) was then gradually added over 10 minutes, and the temperature was slowly raised to room temperature. After stirring for 13 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a small amount of dichloromethane. An excess of ethyl acetate was then added and the precipitated solid was filtered out and dried under reduced pressure to give 17.0 g of the title compound as colorless crystals. 1H-NMR (400 MHz, CDCl3) delta: 1.95-2.02 (m, 2H), 2.05-2.15 (m, 2H), 3.14-3.30 (m, 4H), 3.32 (s, 3H), 3.52-3.57 (m, 1H). The 1H of NH could not be identified.
With hydrogenchloride; In methanol; This compound was cooled at 0 C. and 30 mL of 3N hydrochloric acid in methanol was added. After stirring for 19 hours at room temperature the reaction mixture was concentrated to give 2.4 g of 4-methoxypiperidine hydrochloride. 1H-NMR 200 MHz (CD3OD) delta: 1.76-2.12 (4H, m), 3.03-3.61 (5H, m), 3.36 (3H, s).
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 1h; 4N HCl-Dioxane (10 mL) was added to a solution of the above 4-methoxypiperidine-1-carboxylic acid tert-butyl ester (5.34 g) in 1,4-dioxane (10 mL) at room temperature, and the mixture was stirred for 30 minutes. 4N HCl-Dioxane (20 mL) was further added thereto, and the resultant mixture was stirred for 30 minutes. The reaction solvent was removed under reduced pressure, and the obtained solid was washed with ethyl acetate, to thereby give the title compound (3.55 g) . 1H-NMR (400MHz, DMSO-d6) delta: 1.68 (2H,m), 1.93 (2H,m), 2.91 (2H, m), 3.08(2H,m), 3.23(3H,s), 3.42 (1H, q, J=3. 90Hz).
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 1h; [Referential Example 27] 4-Methoxypiperidine hydrochloride 4-Methoxypiperidine-1-carboxylic acid tert-butyl ester (5.34 g) obtained in step 1) of Referential Example 11 was dissolved in 1,4-dioxane (10 mL), and 4N HCl-dioxane (10 mL) was added to the solution at room temperature, followed by stirring for 30 minutes. 4N HC1-dioxane (20 mL) was added to the reaction mixture, and the resultant mixture was stirred for 30 minutes. The reaction solvent was evaporated under reduced pressure, and the resultant solid was collected through filtration by use of ethyl acetate, to thereby give the title compound (3.55 g). 1H-NMR(400MHz,DMSO-d6)delta:1.68(2H,m), 1.93(2H,m), 2.91(2H,m), 3.08(2H,m), 3.23(3H,s), 3.42(1H,q,J=3.90Hz).
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 1h; [Reference Example 23] 4-Methoxypiperidine hydrochloride [Show Image] A 4 N hydrochloric acid-dioxane solution (10 mL) was added to a solution of 4-methoxypiperidine-1-carboxylic acid tert-butyl ester (5.34 g) of Reference Example 17-(1) in 1, 4-dioxane (10 mL) at room temperature, and the resultant mixture was stirred for 30 minutes. Further, a 4 N hydrochloric acid-dioxane solution (20 mL) was added to the mixture, which was then stirred for 30 minutes. The reaction solvent was evaporated under reduced pressure, and the solid thus obtained was filtered with ethyl acetate, to obtain the title compound (3.55 g). 1H-NMR(400MHz, DMSO-d6)delta: 1.68(2H, m), 1.93(2H, m), 2.91(2H, m), 3.08(2H, m), 3.23(3H, s), 3.42(1H, q, J=3.90Hz).
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 0.5h; 2) Title compound A 4 mol/L hydrochloric acid-dioxane solution (10 mL) was added to a solution of the 4-methoxypiperidine-1-carboxylic acid tert-butyl ester (5.34 g) thus obtained in 1,4-dioxane (10 mL) at room temperature, and the resultant mixture was stirred for 30 minutes. A 4 mol/L hydrochloric acid-dioxane solution (20 mL) was further added thereto, and the mixture was stirred for 30 minutes. The reaction solvent was evaporated under reduced pressure, and the solid thus obtained was washed with ethyl acetate, to obtain the title compound (3.55 g). 1H-NMR (400MHz, DMSO-d6) delta: 1.68 (2H, m), 1.93 (2H, m), 2.91 (2H, m), 3.08 (2H, m), 3.23 (3H, s), 3.42 (1H, q, J=3.90Hz).
With hydrogenchloride; In 1,4-dioxane; methanol; at 20℃; for 3h; To a solution OF 4-METHOXYPIPERIDINE-1-CARBOXYLIC acid tert-butyl ester (Preparation 67, 1. 58G, 7. 34MMOL) in methanol (20ML) was added hydrochloric acid in 1,4-dioxane (4M, lOmL) and the mixture stirred for 3H at rt. Concentration III VACUO gave an oil which was redissolved in water (LOOML). The aqueous layer was washed with ethyl acetate (2X30ML) and concentrated to give the title compound as colourless solid. ON (D2O): 1.80, 2.14 (4H, 2m), 3.13 (2H, m), 3.38 (2H, m), 3.40 (3H, s), 3.68 (m, 1H).
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 96h; 4-Methoxypiperidine (286). A mixture of terf-butyl 4-hydroxy-1-piperidinecarboxylate (284) (Dailewicz, J. C; et al., J. Med. Chem. 2002, 45, 2432-2453) (19.7 g, 98 mmol), crushed KOH (11.0 g, 196 mmol) and MeI (7.3 mL, 118 mmol) in DMSO (100 mL) was stirred at20 0C for 16 h under N2. The mixture was poured into water (500 mL) and extracted with Et2O (2 x 150 mL). The combined organic fraction was washed with water (2 x 50 mL), dried and the solvent evaporated to give methyl ether 285 (19.1 g, 91%) as a white solid: 1H NMR delta 3.71-3.78 (m, 2 H, CH2N), 3.31-3.39 (m, 4 H, CHO, OCH3), 3.06-3.12 (m, 2 H, CH2N), 1.80-1.85 (m, 2 H, CH2), 1.45-1.54 (m, 2 H, CH2), 1.43 [s, 9 H, C(CH3)3]. A solution of HCI in dioxane (4 M, 67 mL, 266 mmol) was added to a stirred solution of methyl ether 285 (19.1 g, 88.7 mmol) in dioxane (100 mL) and the mixture stirred at 20 0C for 96 h.The solvent was evaporated and the residue dried to give the amine hydrochoride 286 as a white solid: 1H NMR [(CD3)2SO] delta 8.99 (br s, 2 H, NH.HCI), 3.40-3.46 (m, 1 H, CHO), 3.25 (s, 3 H, OCH3), 3.07-3.12 (m, 2 H, CH2N)1 2.88-2.94 (m, 2 H, CH2N), 1.91- 1.99 (m, 2 H, CH2), 1.63-1.74 (m, 2 H, CH2). The hydrochloride was dissolved in water (50 mL), the pH adjusted to 10 with CNH3 and the mixture extracted with CHCI3 (4 x 50 mL) to give the free base, which was used without further purification.
1.42 g With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20℃; for 5h;Cooling with ice; The compound 486 tert-butyl 4-hydroxypiperidin-1-carboxylate (2.01 g, 10.0 mmol) was dissolved in 22 THF (10 mL), cooled in ice-water bath and 473 NaH (60%, 288 mg, 12.0 mmol) was added in portions, and stirred in the ice-water bath for 30 minutes. 154 Methyl iodide (0.65 mL, 10.5 mmol) was added in one portion, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 10 mL EA and 10 mL brine were added, the layers were separated, the water phase was extracted with ethyl acetate (10 mL×3), the organic phase was combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford a colorless oily liquid (2.12 g). The oily liquid obtained above (2.12 g) was dissolved in 402 DCM (10 mL), 4M 51 HCl in 113 dioxane (10 mL) was added in ice-water bath, and stirred at room temperature for 5 hours. The reaction mixture was concentrated to afford a white 492 solid (1.42 g).

  • 5
  • [ 800400-48-0 ]
  • [ 4045-25-4 ]
  • 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [1-(S)-(4-fluorobenzyl)-2-(4-methoxypiperidin-1-yl)-2-oxoethyl]amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 12h; To a solution OF 2-(2-[(5-CHLORO-LH-PYRROLO [2N3-C] PYRIDINE-2- carbonyl) amino] -3-phenylpropionic acid (EXAMPLE 42,150mg, 0. 42MMOL) and 4- methoxypiperidine hydrochloride (Preparation 68,86mg, 0. 57MMOL) in DMF (5ML) was added HOBt (66mg, 0. 43MMOL), DIPEA (0.23mL, 1. 34MMOL) and EDCI (102mg, 0. 53MMOL). After stirring at rt for 12h the mixture was added to diluted brine (100mL, WATER/BRINE : 1/1). Extraction with ethyl acetate (4 x 25mL), washing of the combined extracts with brine (50mL) and drying (MGS04) gave, after concentration, a residue which was purified by recrystallisation from methanol to give the title compound as a colourless solid. m/z (ES+) = 459.38 [M+ H]+ ; RT = 3. 40MIN.
  • 7
  • [ 446-36-6 ]
  • [ 4045-25-4 ]
  • [ 859217-96-2 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In DMF (N,N-dimethyl-formamide); at 80℃; for 3.5h; A mixture of <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> (9.10 g, 60.01 mmol) prepared in Example (7a), 5-fluoro-2-nitrophenol (6.91 g, 43.98 mmol) and dimethylformamide (12 mL) was stirred under a nitrogen atmosphere. Triethylamine (15.24 mL, 109.95 mmol) was added to the reaction mixture and the mixture was stirred at an external temperature of 80 C. for 3 hours and 30 minutes. After the reaction, saturated aqueous ammonium chloride and a mixed solvent of ethyl acetate-diethyl ether was added to the reaction mixture. The organic layer was separated off, and the aqueous layer was extracted with diethyl ether. The obtained organic layers were combined and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 37.36 g of the title compound as orange crystals. 1H-NMR (400 MHz, CDCl3) delta: 1.60-1.68 (m, 2H), 1.83-1.90 (m, 2H), 3.26 (ddd, J=13.2, 8.0, 3.6 Hz, 2H), 3.32 (s, 3H), 3.42-3.47(m, 1H), 3.62 (ddd, J=13.2, 7.6, 3.6 Hz, 2H), 6.24 (d, J=2.8 Hz, 1H), 6.36 (dd, J=10.0, 2.8 Hz, 1H), 7.87 (d, J=10.0 Hz, 1H). The 1H of OH could not be identified.
  • 8
  • ammoniacal methanol [ No CAS ]
  • [ 4045-25-4 ]
  • [ 39891-12-8 ]
  • 1-[(5-Bromo-3-pyridinyl)acetyl]-4-methoxypiperidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With diphenylphosphoranyl azide; triethylamine; In dichloromethane; N,N-dimethyl-formamide; a) 1-[(5-Bromo-3-pyridinyl)acetyl]-4-methoxypiperidine A mixture of the 5-bromo-3-pyridine acetic acid (428 mg), <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> (300 mg), triethylamine (826 mul), diphenylphosphoryl azide (640 mul), and DMF (10 ml) was stirred at +23 for 5 h. The mixture was evaporated, and the residual yellow oil was purified by column chromatography over silica gel eluding with a mixture of 5% ammoniacal methanol and dichloromethane (5:95) to give the product as a colourless gum.
  • 9
  • [ 4045-25-4 ]
  • [ 1133-42-2 ]
  • [ 155849-43-7 ]
YieldReaction ConditionsOperation in experiment
a 1,2-Dihydro-5-(4-methoxypiperidin-1-yl)-3H-1-methyl-1,4-benzodiazepin-2-one Prepared as described in Example 4c), from 1-methyl-1,2,3,4-tetrahydro-3H-1,4-benzodiazepin-2,5-dione (4.5 g) and <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> (3.6 g). 1 H NMR (360 MHz, CDCl3) delta1.43-1.86 (3H, m), 1.98-2.08 (1H, m), 2.91-3.18 (2H, m), 3.33-3.60 (9H, m), 3.63-3.75 (1H, m), 4.25-4.31 (1H, m), 7.20-7.32 (2H, m), 7.47-7.53 (2H, m). MS (CI) m/e 288 [MH]+.
  • 10
  • [ 4045-25-4 ]
  • [ 4045-24-3 ]
YieldReaction ConditionsOperation in experiment
With ammonia; In water;pH 10.0; 4-Methoxypiperidine (286). A mixture of terf-butyl 4-hydroxy-1-piperidinecarboxylate (284) (Dailewicz, J. C; et al., J. Med. Chem. 2002, 45, 2432-2453) (19.7 g, 98 mmol), crushed KOH (11.0 g, 196 mmol) and MeI (7.3 mL, 118 mmol) in DMSO (100 mL) was stirred at20 0C for 16 h under N2. The mixture was poured into water (500 mL) and extracted with Et2O (2 x 150 mL). The combined organic fraction was washed with water (2 x 50 mL), dried and the solvent evaporated to give methyl ether 285 (19.1 g, 91%) as a white solid: 1H NMR delta 3.71-3.78 (m, 2 H, CH2N), 3.31-3.39 (m, 4 H, CHO, OCH3), 3.06-3.12 (m, 2 H, CH2N), 1.80-1.85 (m, 2 H, CH2), 1.45-1.54 (m, 2 H, CH2), 1.43 [s, 9 H, C(CH3)3]. A solution of HCI in dioxane (4 M, 67 mL, 266 mmol) was added to a stirred solution of methyl ether 285 (19.1 g, 88.7 mmol) in dioxane (100 mL) and the mixture stirred at 20 0C for 96 h.The solvent was evaporated and the residue dried to give the amine hydrochoride 286 as a white solid: 1H NMR [(CD3)2SO] delta 8.99 (br s, 2 H, NH.HCI), 3.40-3.46 (m, 1 H, CHO), 3.25 (s, 3 H, OCH3), 3.07-3.12 (m, 2 H, CH2N)1 2.88-2.94 (m, 2 H, CH2N), 1.91- 1.99 (m, 2 H, CH2), 1.63-1.74 (m, 2 H, CH2). The hydrochloride was dissolved in water (50 mL), the pH adjusted to 10 with CNH3 and the mixture extracted with CHCI3 (4 x 50 mL) to give the free base, which was used without further purification.
  • 11
  • [ 188622-27-7 ]
  • hydrogen chloride ethyl acetate [ No CAS ]
  • [ 4045-25-4 ]
YieldReaction ConditionsOperation in experiment
In ethyl acetate; Reference example 5 4-Methoxypiperidine hydrochloride To 220ml of 9 % hydrogen chloride ethyl acetate solution, a solution of 43.9 g of N-tert-butoxycarbonyl-4-methoxypiperidine in 220 ml of ethyl acetate was added under ice-cooling and with stirring, and the mixture was stirred under ice-cooling for 2.5 hours. After the reaction, the precipitated crystals were collected by filtration to obtain 29.1 g of colorless crystals. NMR spectrum (CDCl3) delta ppm: 1.95-2.05(2H,m),2.10-2.20(2H,m),3.15-3.30(4H,m),3.33(3H,s),3.50-3.60(1H,m) IR spectrum nu (liq.) cm-1: 3448 Mass spectrum (m/z): 115(M+)
  • 12
  • [ 369-34-6 ]
  • [ 4045-25-4 ]
  • [ 221198-18-1 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; N-ethyl-N,N-diisopropylamine; In water; acetonitrile; Reference example 7 3-Fluoro-4-(4-methoxypiperidin-1-yl)nitrobenzene To a solution of 15.0 g of 3,4-difluoronitrobenzene and 41 ml of N,N-diisopropylethylamine in 150 ml of dried acetonitrile, 15.8 g of <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> was added, and the mixture was heated under reflux for 5 hours. The solvent was evaporated under reduced pressure, the residue was added with water and 10% aqueous sodium hydroxide, and the resulting alkaline mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain 24.1 g of a yellowish brown liquid. NMR spectrum (DMSO-d6) delta ppm: 1.54-1.62(2H,m),1.92-2.00(2H,m),3.08-3.16(2H,m),3.28(3H,s),3.38-3.46(1H,m),3.49-3.5 7(2H,m),7.16(1H,t,J=8.5Hz),7.95(1H,dd,J=14,3Hz),7.97(1H,dd,J=8.5,3Hz) IR spectrum nu (liq.) cm-1: 1336,1518 Mass spectrum (m/z): 254(M+)
  • 13
  • [ 916225-31-5 ]
  • [ 4045-25-4 ]
  • N-{5-[2-bromo-5-(4-methoxy-piperidine-1-sulfonyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With triethylamine; In dichloromethane; at 20℃; for 0.5h; 4-[2-(acetylamino)^-methyl-l ,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The reaction is put under nitrogen. Triethylamine (0.5 ml; 3.61 mmol; 5 eq) and 4-methoxy-piperidine hydrochloride (314.3 mg; 3.61 mmol; 5 eq) are added successively and the reaction mixture is stirred for 30 minutes at room temperature. It is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (250 mg; 60%). M (ESI): 494.15; M+(ESI): 495.5. HPLC (method A), Rt: 2.98 min (purity: 62.8%).
  • 14
  • (1-methyl-1H-pyrrol-3-yl)-1-(3-pyridyl)-1H-pyrazole-3-carboxylic acid [ No CAS ]
  • [ 4045-25-4 ]
  • 1-[5-(1-methyl-1H-pyrrol-3-yl)-1-(3-pyridyl)-1H-pyrazole-3-carbonyl]-4-methoxypiperidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 23h; [Example 56] 1-[5-(1-Methyl-1H-pyrrol-3-yl)-1-(3-pyridyl)-1H-pyrazole-3-carbonyl]-4-methoxypiperidine [Show Image] 1-Hydroxybenzotriazole (84 mg), <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> (123 mg) obtained from Referential Example 27, and triethylamine (0.3 mL) were added at room temperature to a solution of (1-methyl-1H-pyrrol-3-yl)-1-(3-pyridyl)-1H-pyrazole-3-carboxylic acid (165 mg) obtained from Referential Example 38 in dichloromethane (10 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (178 mg) was added to the reaction mixture, followed by stirring at room temperature for 23 hours. The reaction mixture was partitioned between water and chloroform, and the organic layer was dried over magnesium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (chloroform - methanol), to thereby give the title compound as an oily product. 1H-NMR(400MHz,CDCl3)delta:1.66(2H,br), 1.94(2H,br), 3.38(3H,s), 3.50(2H,m), 3.61(3H,s), 3.72(1H,br), 4.10(1H,br) 4.29(1H,br), 5.87(1H,t,J=1.95Hz), 6.51(2H,m), 6.74(1H,s), 7.36(1H,dd,J=8.18,4.76Hz), 7.79(1H,dt,J=8.18,1.9Hz), 8.61 (1H, dd, J=4.76,1.09Hz), 8.72(1H, d, J=2.32Hz). FAB-MS m/z:366(M+H)+.
  • 15
  • [ 858599-50-5 ]
  • [ 4045-25-4 ]
  • 1-[5-(5-methyl-2-pyridyl)-1-(2-pyrazinyl)-1H-pyrazole-3-carbonyl]-4-methoxypiperidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
44% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 22h; [Example 18] 1-[5-(5-Methyl-2-pyridyl)-1-(2-pyrazinyl)-1H-pyrazole-3-carbonyl]-4-methoxypiperidine; [Show Image] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.374 g), 1-hydroxybenzotriazole (0.139 g), <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> (0.216 g) obtained from Referential Example 27, and triethylamine (0.565 mL) were added at room temperature to a solution of 5-(5-methyl-2-pyridyl)-1-(2-pyrazinyl)-1H-pyrazole-3-carboxylic acid (0.253 g) obtained from Referential Example 35 in dichloromethane (8 mL), and the mixture was stirred for 22 hours. The reaction mixture was partitioned between water and chloroform, and the aqueous layer was further extracted with chloroform. The organic layers were combined, and the combined organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol - chloroform), to thereby give the title compound (0.149 g, 44%) as a solid product. 1H-NMR(400MHz,CDCl3)delta:1.55-1.78(2H,m), 1.87-2.04(2H,m), 2.35(3H,s), 3.38(3H,s), 3.47-3.63(2H,m), 3.72-3.84(1H,m), 4.02-4.13(1H,m), 4.20-4.32(1H,m), 7.05(1H,s), 7.45(1H,d,J=7.8Hz), 7.56(1H,dd,J=7.8,2.0Hz), 8.20-8.30(2H,m), 8.51(1H,d,J=2.5Hz), 8.97(1H,d,J=1.4Hz). ESI-MS m/z:379(M+H)+.
  • 16
  • [ 32315-10-9 ]
  • [ 4045-25-4 ]
  • [ 1032707-93-9 ]
YieldReaction ConditionsOperation in experiment
With pyridine; In dichloromethane; at 0℃; 4-Methoxy-piperidine-1-carbonyl chloride To a stirred solution of triphosgene (7.4 g, 0.025 mmol) in dichloromethane (200 ml) at ice bath was added dropwise a solution of <strong>[4045-25-4]4-methoxy-piperidine hydrochloride salt</strong> (10 g, 0.066 mmol) and pyridine (10.9 g, 0.139 mmol) in dichloromethane (100 ml). The mixture was stirred over night and filtered through a silica pad, eluding with dichloromethane and evaporated. After trituration with diisopropyl ether, the mixture was used without purification.
With pyridine; In dichloromethane; at 0℃; 4-Methoxy-piperidine-1-carbonyl chloride To a stirred solution of triphosgene (7.4 g, 0.025 mmol) in dichloromethane (200 mL) at 0 C. was added dropwise a solution of <strong>[4045-25-4]4-methoxy-piperidine hydrochloride salt</strong> (10 g, 0.066 mmol) and pyridine (10.9 g, 0.139 mmol) in dichloromethane (100 mL). The mixture was stirred over night and filtered through a silica pad, eluted with dichloromethane and evaporated. After trituration with diisopropyl ether, the mixture was used without purification.
  • 17
  • [ 1061750-08-0 ]
  • [ 4045-25-4 ]
  • [ 76-05-1 ]
  • [ 1061747-75-8 ]
  • [ 1061747-73-6 ]
YieldReaction ConditionsOperation in experiment
Compounds 1-3 and 1-4: N-[2-(3,5-Dimethyl-pyrazol-l-ylV6-(4-methoxy-3,4,5,6- tetrahvdro-2H-[l,2']bipyridinyl-6'-yl)-pyrimidin-4-yl1-acetamide and 2-(3,5-Dimethyl- pyrazol-l-yl)-6-(4-methoxy-3,4,5,6-tetrahvdro-2H-fL2'lbipyridinyl-6'-ylVpyrimidin-4- ylamine; A mixture of Intermediate 3 (60 mg, 0.17 mmol), <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> (128 mg, 0.84 mmol), triethylamine (0.12 ml, 0.86 mmol), and NMP (0.45 ml) was heated in a microwave reactor at 160 0C for 80 min. The reaction mixture was diluted with methanol, filtered, and purified by HPLC using 15-75% acetonitrile in water (0.05% TFA) to provide Compounds 1-3 and 1-4 as TFA salts.
  • 18
  • [ 1061750-08-0 ]
  • [ 4045-25-4 ]
  • [ 1061747-72-5 ]
  • 19
  • [ 19099-93-5 ]
  • [ 4045-25-4 ]
  • [ 1192122-31-8 ]
YieldReaction ConditionsOperation in experiment
To a solution of <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> QSl.1 mg) in a MeOH - THF mixed solvent (1/2, 6 mL) were added benzyl 4-oxo-l-piperazinecarboxylate (549.6 mg) and acetic acid (0.1 mL) at room temperature. The mixture was warmed to 45 Deg for 30 Min.To the mixture was slowly added sodium triacetoxyborohydride (1.65 g) for 4.5 hrs. After 2 hrs stirring, the reaction was quenched by addition of l.OM aqueous sodium hydroxyde (the <n="86"/>pH was adjusted to 9), then extracted with AcOEt (x 3). The combined organic layer was washed with water and brine, dried over magnesium sulfate, then concentrated. The residual dark red oil was purified by amine-capped silica gel column chromatography (hexane / AcOEt = 90/10 to 80/20) to give benzyl 4-methoxy-l,4'-birhoiperidine-l'-carboxylate (137 mg).
  • 20
  • 4-{1-(5-chloro-2-(trifluoromethyl)-benzyl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}benzoic acid [ No CAS ]
  • [ 4045-25-4 ]
  • {1-[5-chloro-2-(trifluoromethyl)-benzyl]-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}-(4-methoxy-piperidin-1-yl)-methanone [ No CAS ]
  • 21
  • [ 763114-26-7 ]
  • [ 4045-25-4 ]
  • [ 1174043-16-3 ]
YieldReaction ConditionsOperation in experiment
72.9% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20 - 23℃;Product distribution / selectivity; Example 1; 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (231 g, 1206.97 mmol) was added to <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> (183 g, 1206.97 mmol), 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (300 g, 1005.80 mmol) and 4-dimethylaminopyridine (30.7 g, 251.45 mmol) in DCM (4 L) at 23 C. The resulting suspension was stirred at room temperature over night. The reaction mixture was washed with 2M HCl (5 L) and 50% saturated sodium carbonate (3 L) before being dried over MgSO4, filtered and reduced in-vacuo to give the crude product. This was then slurried in 750 ml of ethyl acetate for 5 days, and then filtered and dried at 45 C. for 5 hours to afford 4-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (compound 1)(290 g, 72.9%).1H NMR (400.132 MHz, DMSO) delta 1.26-1.35 (1H, m), 1.40-1.49 (1H, m), 1.69-1.73 (1H, m), 1.84-1.89 (1H, m), 2.99-3.07 (1H, m), 3.25 (3H, s), 3.27-3.34 (2H, m), 3.39-3.44 (1H, m), 3.86-3.95 (1H, m), 4.33 (2H, s), 7.19-7.24 (1H, m), 7.33-7.35 (1H, m), 7.39-7.43 (1H, m), 7.81-7.91 (2H, m), 7.97 (1H, d), 8.27 (1H, d), 12.57 (1H, s); m/z (ES+) (M+H)+=396.31; HPLC tR=1.90 min.FIG. 1 shows the powder XRD pattern of the material produced, which is in Form C.FIG. 2 shows the DSC analysis of the material produced.
  • 23
  • [ 79099-07-3 ]
  • [ 4045-25-4 ]
  • 24
  • [ 4045-25-4 ]
  • [ 1152986-56-5 ]
  • 25
  • [ 4045-25-4 ]
  • [ 1351089-37-6 ]
  • 26
  • [ 1041598-53-1 ]
  • [ 4045-25-4 ]
  • [ 1351094-54-6 ]
YieldReaction ConditionsOperation in experiment
78% With triethylamine; at 110℃; for 20h;Sealed vessel; b) A/-methyl-4-[4-(methyloxy)-1 -piperidinyl]-3-nitrobenzenesulfonamideTo a solution of 4-fluoro-/V-methyl-3-nitrobenzenesulfonamide (300 mg, 1 .281 mmol) and Et3N (3.84 mmol) was added <strong>[4045-25-4]4-(methyloxy)piperidine hydrochloride</strong> (194 mg, 1.281 mmol). The reaction vessel was sealed and heated at 1 10 C for 20 h. The mixture was concentrated and purified by flash column chromatography (5-80% EtOAc/hexanes) to afford the title compound (227.4, 54%) as a yellow oil. LCMS (ES) m/z 330 (M+H)+; 1H NMR (400 MHz, DMSO-d6) delta ppm 1.51 - 1.61 (m, 2 H) 1.89 - 1.97 (m, 2 H) 2.41 (d, J=4.80 Hz, 3 H) 2.98 - 3.08 (m, 2 H) 3.26 - 3.32 (m, 5 H) 3.40 - 3.48 (m, 1 H) 7.44 (d, J=8.84 Hz, 1 H) 7.49 (d, J=5.05 Hz, 1 H) 7.80 (dd, J=8.84, 2.27 Hz, 1 H) 8.12 (d, J=2.27 Hz, 1 H).
  • 27
  • [ 5382-16-1 ]
  • [ 74-88-4 ]
  • [ 4045-25-4 ]
YieldReaction ConditionsOperation in experiment
33% EXAMPLE 93A/-methyl-4-[4-(methyloxy)-1 -piperidinyl]-3-(1 /-/-purin-6-ylamino)benzenesulfonamidea) 4-(methyloxy)piperidine hydrochlori To a solution of 4-piperidinol (500 mg, 4.94 mmol) in CH3CN (20 mL) was added Boc20 (1.15 mL, 4.94 mmol). The mixture was stirred for 20 h and concentrated to afford a colorless oil, which was dissolved in anhydrous THF (20 mL). The solution was cooled to 0 C and treated with NaH (60% dispersion in oil, 29 mg, 7.41 mmol). The mixture was gradually warmed to rt. After stirring at rt for 0.5 h, iodomethane (1403 mg, 9.89 mmol) was added. The mixture was stirred at 25 C for 20 h. The solution was concentrated and purified by flash column chromatography (0-70% EtOAc/hexanes) to afford a colorless oil which was dissolved in CH2CI2 (20 mL) and treated with a 2 M solution of HCI in 1 ,4- dioxane (12.4 mL, 24.72 mmol). After stirring at 25 C for 20 h, the solution was concentrated and azeotropically dried with toluene to afford the title compound (260.8 mg, 33%) as a white solid. LCMS (ES) m/z 152 (M+H)+; 1 H NMR (400 MHz, DMSO-d6) delta ppm 1.59 - 1.80 (m, 2 H) 1 .90 - 2.04 (m, 2 H) 2.92 (br. s, 2 H) 3.09 (br. s, 2 H) 3.23 - 3.30 (m, 3 H) 3.40-3.41 (m, 1 H) 9.03 (d, J=3.03 Hz, 2 H).
  • 28
  • [ 7461-50-9 ]
  • [ 4045-25-4 ]
  • [ 1602075-12-6 ]
YieldReaction ConditionsOperation in experiment
87% With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 18h; 2-Chloropyrimidin-4-ylamine (3.5 g, 27.0 mmol), <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> (4.09 g, 27.0 mmol) and Cs2C03 (26.4 g, 81.0 mmol) were suspended in DMF (60 mL) and heated at 120 C for 18 h. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was washed with EtOAc (x 2) and the combined organic phases were washed with brine, dried (MgSO i), and concentrated in vacuo affording the title compound as a solid (2.5 g). The aqueous phase was concentrated in vacuo and the slurry was extracted with EtOAc. The volatiles were removed in vacuo and the resulting residue was purified by chromatography (Si-PCC, gradient 0- 100% EtOAc in cyclohexane) and then triturated with cyclohexane affording a second batch of the title compound (2.38 g, 87% combining the two batches). lH NMR (400 MHz, CDC13) delta: 7.94 (1H, d, J=5.60 Hz), 5.74 (1H, d, J=5.60 Hz), 4.53 (2H s), 4.33-4.24 (2H, m), 3.47-3.37 (4H, m), 3.33-3.24 (2H, m), 1.98-1.87 (2H, m), 1.60-1.47 (2H, m).
87% With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 18h; 2-Chloropyrimidin-4-ylamine (3.5 g, 27.0 mmol), <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> (4.09 g, 27.0 mmol) and cesium carbonate (26.4 g, 81.0 mmol) were suspended in NN-dimethylformamide (60 mL) and heated at 120 C for 18 h. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous phase was washed with EtOAc (x 2) and the combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo affording the title compound as a solid (2.5 g). The aqueous phase was concentrated in vacuo and the slurry was extracted with EtOAc. The volatiles were removed in vacuo and the resulting residue was purified via flash chromatography on silica gel (solvent gradient: 0%-100% EtOAc in cyclohexane) and then triturated with cyclohexane affording a second batch of 2-(4-methoxypiperidin-l -yl)pyrimidin-4-amine (2.38 g, 87% combined yield). LCMS (ESI): [M+H]+ = 209.2; lH NMR (400 MHz, CDC13) delta: 7.94 (1H, d, J=5.60 Hz), 5.74 (1H, d, J=5.60 Hz), 4.53 (2H s), 4.33-4.24 (2H, m), 3.47-3.37 (4H, m), 3.33-3.24 (2H, m), 1.98-1.87 (2H, m), 1.60-1.47 (2H, m).
  • 29
  • tert-butyl [(3S,5R)-1-{3-[({2-[(tert-butoxycarbonyl)amino]-6-formylfuro[3,2-b]pyridin-3-yl}carbonyl)amino]pyridin-4-yl}-5-(trifluoromethyl)piperidin-3-yl]carbamate [ No CAS ]
  • [ 4045-25-4 ]
  • tert-butyl [(3S,5R)-1-{3-[({2-[(tert-butoxycarbonyl)amino]-6-[(4-methoxypiperidin-1-yl)methyl]furo[3,2-b]pyridin-3-yl}carbonyl)amino]pyridin-4-yl}-5-(trifluoromethyl)piperidin-3-yl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20 - 30℃; for 2h; Step 1. tert-Butyl [(3S,5R)-1-{3-[({2-[(tert-butoxycarbonyl)amino]-6-[(4-methoxypiperidin-1-yl)methyl]furo[3,2-b]pyridin-3-yl}carbonyl)amino]pyridin-4-yl}-5-(trifluoromethyl)piperidin-3-yl]carbamate A mixture of <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> (2.1 mg, 0.014 mmol) and tert-butyl [(3S,5R)-1-{3-[({2-[(tert-butoxycarbonyl)amino]-6-formylfuro[3,2-b]pyridin-3-yl}carbonyl)amino]pyridin-4-yl}-5-(trifluoromethyl)piperidin-3-yl]carbamate (8.0 mg, 0.01 mmol) (prepared in Example 99, step 4) in dry 1,2-dichloroethane (0.10 mL, 1.3 mmol) was treated with sodium triacetoxyborohydride resin (5.2 mg, 0.025 mmol) and stirred at room temperature for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product, which was used directly in the next step. LCMS calc. for C36H49F3N7O7 (M+H)+: m/z=748.4. Found: 748.4.
  • 30
  • [ 39856-50-3 ]
  • [ 4045-25-4 ]
  • 5-(4-methoxypiperidin-1-yl)-2-nitropyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.6 mmol With tetra-(n-butyl)ammonium iodide; potassium carbonate; In dimethyl sulfoxide; at 80℃; for 15h; Step a. A solution of 5-bromo-2-nitro-pyridine (2.0 mmol) and 4-methoxypiperidine HCl (4.0 mmol) in DMSO (10 ml) was stirred at rt for 5 min. K2C03 (4.0 mmol) and TBAI (0.2 mmol) were then added to the reaction mixture at rt. The reaction mixture was stirred at 80C for 15 h. The resulting reaction mixture was poured into water (200 ml) and extracted with EtOAc (2 x 150 ml). The combined organic phase was collected, dried over Na2SC>4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (15% EtOAc in hexane) yielding 5-(4-methoxypiperidin-l-yl)-2- nitropyridine (1.6 mmol). MS: ES+ 238.35; XH NMR (400 MHz, DMSO-d6) delta ppm 8.27 (d, J=3.05 Hz, 1 H), 8.14 (d, J=9.16 Hz, 1 H), 7.49 (dd, J=9.16, 3.05 Hz, 1 H), 3.75 - 3.84 (m, 2 H), 3.46 - 3.48 (m, 1 H), 3.30 - 3.35 (m, 2 H), 3.28 (s, 3 H), 1.90 - 1.95 (m, 2 H), 1.48 - 1.53 (m, 2 H).
  • 31
  • [ 39856-50-3 ]
  • [ 4045-25-4 ]
  • [ 866620-43-1 ]
  • 32
  • 8-bromo-4-methyl-2-(2-trifluoromethyl-pyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one [ No CAS ]
  • [ 4045-25-4 ]
  • 8-(4-methoxy-piperidin-1-yl)-4-methyl-2-(2-trifluoromethylpyridin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; lithium hexamethyldisilazane; In tetrahydrofuran; 1,2-dimethoxyethane; at 60℃; for 3h;Inert atmosphere; Sealed tube; General procedure: General procedure X: Amine introduction via Buchwald, Ullmann or nucleophilic substition Method (v): Method (iii): Under inert atmosphere, in a seal tube, a mixture of halide (1.0 equiv.), amine (1.2 equiv.), a solution of LiHMDS in THE (1.0 N; 2.4 equiv.) and BrettPhos precatalyst (0.1equiv.) were suspended in DME (C=0.1 molL1) and warmed for 2 hours at 60C. The reaction mixture was hydrolysed with a saturated aqueous NH4CI solution. The solid was collected, washed with water, dried under reduced pressure and purified to afford the product:_Example 62 was obtained according to general procedureX(iii) starting from example 58 in presence of 4- methoxypiperidine HCI. The reaction was performed with 3.0 O equiv of LiHMDS. The reaction mixture was heated for 2 hours, then 4-methoxypiperidine HCI (1.2 equiv.), LiHMDS (iN in THE; 3.0 equiv.) and BrettPhos precatalyst (0.1 equiv.) were added. The reactionmixture was further heated for one hour at 60C. Purification by flash-chromatography (MeOH in DCM, 0 to 3%) afforded example 62 as a beige solid in 48% yield.1H-NMR (400 MHz, DMSO): 1.51-1.59 (m, 2H, 2 CHaHb); 1.95-1.99 (m, 2H, 2 CHaHb); 3.23-3.30 (m, 5H, OCH3 + 2 NCHaHb); 3.45-3.51 (m, 4H, NCH3 +OCH); 3.45-3.51 (m, 2H, 2 NCHaHb); 7.08 (s, 1H, Ar); 7.11 (dd, J9.0 Hz, 2.4 Hz, 1H, Ar); 7.45 (d, 2.4 Hz, 1H, Ar); 7.93 (d,J9.0 Hz, 1H, Ar); 8.25-8.27 (m, 1H, Ar); 8.37 (bs, 1H, Ar); 8.86 (d, J5.1 Hz, 1H, Ar). MZ (M+H) = 458.2.MP: >250C.
  • 33
  • C20H18BrN3O3S [ No CAS ]
  • [ 4045-25-4 ]
  • 4-[({4-[(4-methoxy-1-piperidinyl)methyl]phenyl}sulfonyl)amino]methyl}-N-(3-pyridinyl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
16% at 20℃; for 2.5h; Reaction of amine salt 6 (340 mg, 0.87 mmol) and 4-(bromomethyl)benzenesulfonyl chloride(283 mg, 1.1 mmol) gave the intermediate bromide. 4-Methoxypiperidinehydrochloride (266 mg, 1.8 mmol) was added and the mixture waswarmed to 20 C. and stirred for a further 150 mins. The solvent was evaporated, H2O (30 mL) added to the residue and the resulting precipitate filtered. The aqueous layer was extracted with DCM (2×20 mL) and combined withthe crude solid. The solvent was evaporated and the crude solid purified bycolumn chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to givebenzamide 93 (67 mg, 16%).
  • 34
  • [ 19230-27-4 ]
  • [ 4045-25-4 ]
  • 1-(3-bromo-2-chlorophenyl)-4-methoxypiperidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 140℃; for 1h;Microwave irradiation; Inert atmosphere; Step A: 1 A souUon of I 3dbromo2 chorobenzene (300 mg, 1.1 mmo), 4methoxypperdne hydrochorde (168 mg, 1.1 mmoD, sodium tertbutoxde (160 mg, 1.7 mmoD, BNAP (35 mg, 0.05 mmo), and Pd2(dba)3 (20 mg, 0.02 mmo) n touene (3.0 mL) was degassed w[th nitrogen for 10minutes. The reacfion mixture was heated at 140 C n microwave for lh. After coohng to rt, water was added and the aqueous ayer was extracted wth EtOAc (x2), The combined organic extracts were dried over Na2SO4 and concentrated n vacuo, PurflcaUon (FCC, SO2; 0-50% EtOAc/hexanes) provded the tWe compound as an oH (168 mg, 50% yed). 1H NMR (400 MHz, DMS&-d6) oe 742 (dd, J = 7.7, 1.7 Hz, IH),7.28 7.14 (m, 2H), 339 3.33 (m, I H), 3.28 (5, 3H), 314 (dt, J = 105, 4.5 Hz, 2H),2.77 (ddd, J = 12.0, 92, 3.0 Hz, 2H), 204 1.91 (m, 2H), 1.61 (dtd, J = 12.2, 8.8, 3.4Hz, 2H).
  • 35
  • [ 4045-25-4 ]
  • [ 911300-69-1 ]
  • 36
  • [ 4045-25-4 ]
  • N-[2-(4-methoxy-1-piperidinyl)ethyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1-oxide [ No CAS ]
 

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