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Chemical Structure| 84025-81-0 Chemical Structure| 84025-81-0

Structure of 84025-81-0

Chemical Structure| 84025-81-0

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Product Details of [ 84025-81-0 ]

CAS No. :84025-81-0
Formula : C6H13NO
M.W : 115.18
SMILES Code : COC[C@@H]1NCCC1
English Name :(R)-2-(Methoxymethyl)pyrrolidine
MDL No. :MFCD00066219
InChI Key :CHPRFKYDQRKRRK-ZCFIWIBFSA-N
Pubchem ID :671216

Safety of [ 84025-81-0 ]

Computational Chemistry of [ 84025-81-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 8
Num. arom. heavy atoms 0
Fraction Csp3 1.0
Num. rotatable bonds 2
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 36.64
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.

1.84
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

0.2
Log Po/w (WLOGP)?

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

0.0
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.

0.21
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

0.67

Water Solubility

Log S (ESOL):?

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

-0.55
Solubility 32.6 mg/ml ; 0.283 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.

-0.21
Solubility 71.8 mg/ml ; 0.623 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

-1.29
Solubility 5.95 mg/ml ; 0.0516 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

Low
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.

-6.86 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)

1.69

Application In Synthesis of [ 84025-81-0 ]

* 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 [ 84025-81-0 ]

[ 84025-81-0 ] Synthesis Path-Downstream   1~14

  • 1
  • [ 63126-47-6 ]
  • [ 132898-96-5 ]
  • [ 220509-85-3 ]
YieldReaction ConditionsOperation in experiment
63.8% With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; chloroform; at 0℃; for 2.5h; Step 1: 5-[(2R)-2-(Methoxymethyl)pyrrolidin-1-yl]sulfonyl}-1H-indole-2,3-dione To a stirred cold suspension of 2,3-dioxo-2,3-dihydro-1H-indol-5-sulfonyl chloride (5.00 g, 20.4 mmol) in a 1:1 mixture of THF: CHCl3 (140 mL) was added dropwise, via syringe pump, a solution of N,N-diisopropylethylamine (7.11 mL, 40.8 mmol, 2 eq) and (R)-2-(Methoxymethyl)pyrrolidine (3.27 mL, 26.5 mmol, 1.3 eq) in CHCl3 (60 mL) over a period of 1.5 hours with cooling in an ice bath. After stirring an additional 1 h, the reaction was concentrated. The crude product was purified on Biotage KP silica gel eluding with 95/5 CH2Cl2/CH3OH followed by a second chromatography on silica gel eluding with EtOAc to give 4.21 g (63.8%) of the title compound. NMR (400 MHz, DMSO-d6): consistent.
  • 2
  • [ 84025-81-0 ]
  • [ 67714-53-8 ]
  • [ 697767-81-0 ]
YieldReaction ConditionsOperation in experiment
85% With 2-bicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl; sodium t-butanolate In toluene at 95℃; for 18h; 5.1 Step 1; 2, 5-DIETHYL-3-[(2R)-2-(METHOXYMETHYL) PYRROLIDIN-1-YL] PYRAZINE. A 20 ml telflon capped vial was charged with 3-chloro-2,5-diethylpyrazine (0.533 g, 3.13 mmol) and (R)-2- (methoxymethyl) pyrrolidine (0.300 g, 2.60 mmol) and 3 ML toluene under N2. PD2 (dba) 3 (0.095 g, 0.104 mmol), 2-dicyclohexylphosphino-2'- (N, N- dimethylamino) -biphenyl (0.082 g, 0.208 mmol), and NaOtBu (0.349 g, 3.64 mmol) were added and the solution was heated for 18 h at 95 °C. The reaction mixture was partitioned between saturated aqueous NAHC03 and CH2C12 and separated. The combined organic layers were dried with MGS04, filtered, and concentrated to give a residue, which was purified by flash chromatography (1/3: EtOAc/heptane) to provide 0.544 g (85%) of 2,5- diethyl-3- [ (2R)-2 (methoxymethyl) pyrrolidin-l-yl] pyrazine as an OIL. 1H NMR (400 MHz, CDC13) 8 7.80 (s, 1 H), 4.59 (m, 1 H), 3.73 (m, 1 H), 3.60 (dd, 1 H), 3.28 (s, 3 H), 3.26 (m, 2 H), 2.83 (q, 2 H), 2.67 (q, 2 H), 2.17 (m, 1 H), 1.99 (m, 1 H), 1.88 (m, 1 H), 1.27 (m, 6 H); MS (ESI+) for C14H23N30 MLZ 250.1912 (M+H) +.
  • 3
  • [ 70258-18-3 ]
  • [ 84025-81-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
82% With potassium carbonate In acetonitrile at 55℃; for 20h; 62 Example 62; (7R, 9aS)-trans-2-Benzo[d]isoxazol-3-yl-7-[5-(2-methoxymethyl-pyrrolidin-1-ylmethyl)-pyridin-2-yloxymethyl]-octahydro-pyrido[1.2-a]pyrazine To a solution of 2-chloro-5- (chloromethyl) pyridine (369 mg, 2.28 mmole) in 5 mL of dry acetonitrile is 521 mg (4.52 MMOL) of (S)- (+)-2- (methoxymethyl) pyrrolidinone followed by 314 mg (2.28 MMOL) of potassium carbonate. The reaction is heated at 55 °C for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 450 mg (82 % yield) of 2- CHLORO-5- (2-METHOXYMETHYL-PYRROLIDIN-1-YLMETHYL)-PYRIDINE. DIAGNOSTIC H NMR (400 MHz, CDCI3) 3.35 (s, 2h), 7.28 (d, 1 H< J = 7.9 Hz), 7.40-7. 50 (m, 1 H), 8.31 (d, 1 H, J = 2.1 Hz); MS 241.3 (M+H).
  • 4
  • [ 67828-44-8 ]
  • [ 84025-81-0 ]
  • [ 1023885-02-0 ]
YieldReaction ConditionsOperation in experiment
74% Stage #1: 5-chloro-2,4-dihydroxy-benzoic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: (2R)-methoxymethylpyrrolidine In N,N-dimethyl-formamide at 20℃; for 12h; Stage #3: With hydrogenchloride In methanol; dichloromethane; water at 20℃; for 12h; 2 DIEA (0.8 mL, 4.3 mmol) was added to a solution of compound C in General Procedure G10 (120 mg, 0.43 mmol) and HATU (182 mg, 0.48 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 20 minutes (after a few minutes, solution turned from light yellow clear to light brown yellow clear). (R)-2-Methoxymethyl-pyrrolidine (MN-1634, 100 mg, 0.87 mmol in 15 mL of DMF) was added to the above reaction mixture via a syringe. The mixture was stirred at room temperature for 12hours. Saturated NaHCO3 (20 mL) was added to the mixture to stir. EtOAc (2X50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to obtain a brown yellow oil. Hydrogen chloride (1 mL, 4 mmol) was then added to a solution of the above compound (in 5 mL of DCM and 5 mL of methanol). The reaction was stirred at room temperature for 12hours. The solvent was then evaporated to obtain a brown solid residue. The mixture was then neutralized with saturated NaHCO3 (10 mL). EtOAc (2x50 mL) was added to extract the aqueous solution. The combined organic layer was dried, filtered, and concentrated to obtain a brown yellow oil. The residue was purified by silica gel chromatography (gradient elution 50→60% EtOAc in hexanes) to give the desired product as a white solid (92 mg, 74% yield over 2 steps).1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (sc, J=8.10, 6.00, 1.20, 0.67, -12.30 Hz, 1 H) 1.68 (sc, J=12.60, 8.10, 7.75, 1.11, 0.70 Hz, 1 H) 2.06 (sc, J=8.10, 6.00, 1.20, 1.00, -12.30 Hz, 1 H) 2.06 (sc, J=12.60, 8.10, 7.75, 2.00, 1.11, 0.70 Hz, 1 H) 2.88 (sc, J=- 0.97 Hz, 3 H) 3.68 (sc, J=9.60, 8.60, 1.50, 1.20, 0.70, -0.97 Hz, 1 H) 3.70 (sc, J=10.00, 6.00, 1.50, 1.17, 1.11 Hz, 1 H) 3.79 (sc, J=9.60, 3.60, 1.50, 1.20, 0.70, -0.97 Hz, 1 H) 3.80 (sc, J=10.00, 6.00, 2.00, 1.50, 1.17, 1.11 Hz, 1 H) 4.59 (sc, J=8.60, 7.75, 3.60, 1.17, 1.00, 0.67 Hz, 1 H) 6.42 (sc, J=LOO Hz, 1 H) 7.30 (sc, J=LOO Hz, 1 H). Anal. Calcd for C13H16CINO4«0.25H2O: C, 53.80; H, 5.73; N, 4.83. Found: C,53.86; H, 5.72; N, 4.66.
  • 5
  • [ 20965-27-9 ]
  • [ 84025-81-0 ]
  • [ 1229442-72-1 ]
YieldReaction ConditionsOperation in experiment
68% With potassium carbonate In 4-methyl-2-pentanone at 70℃; 85 1.90 ml of (2R)-2-(methoxymethyl)pyrrolidine (1.1 ml, 8.9 mmol) were dissolved in 25 ml of methylisobutylketone and 1.2 g of potassium carbonate (8.68 mmol) were added. To this mixture was added 0.85 ml g of 7-bromoheptanenitrile (15.78 mmol). The reaction was kept overnight at 70 °C. The solvent was evaporated under vacuum and the residue taken up in ethyl acetate. The organics were washed with water and brine, dried over magnesium sulphate, filtered and evaporated. 0.99 g (68%) of the title compound were obtained as an oil. HPLC/MS (10 min) retention time 0.7 min. LRMS: m/z 225 (M+1)
  • 6
  • [ 1240186-30-4 ]
  • [ 84025-81-0 ]
  • [ 1242180-87-5 ]
YieldReaction ConditionsOperation in experiment
94% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 140℃; for 20h; INTERMEDIATE 98(S)- 1 - { 8 -Chlor o-2- r('i?V2-(metlioxymethyls)p yrrolidin- 1 -yl] quinolin-3 - yl) ethanamine A solution of Intermediate 11 (150 mg, 0.44 mmol), (i?)-2-(methoxymethyl)- pyrrolidine (0.082 mL, 0.66 mmol) and DIPEA (0.39 mL, 2.2 mmol) in NMP (2 mL) was heated at 14O0C for 20 h. After cooling, the mixture was dissolved in a 1 :1 mixture of EtOAc and Et2O (200 mL) and washed with saturated brine (3 x 30 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 5-10% EtOAc in isohexane) gave an off-white solid (174 mg, 94%). LCMS (ES+) 420, 422 (M+H)+. To the off-white solid (174 mg, 0.415 mmol) dissolved in DCM (5 mL) was added TFA (2 mL). The reaction mixture was stirred at r.t. for 2 h. The solvent was removed in vacuo and the residue azeotroped with toluene. Ion exchange chromatography (SCX cartridge eluting with 0.35M NH3 in MeOH) gave the title compound (95 mg, 72%) as a yellow solid. δH (CDCl3) 7.98 (IH, s), 7.65 (IH, dd, J 7.51, 1.31 Hz), 7.57 (IH, d, J8.02 Hz), 7.17 (IH, t, J7.76 Hz), 5.00-4.92 (IH, m), 4.48 (IH, q, J6.43 Hz), 3.86-3.77 (IH, m), 3.69 (IH, dd, J9.61, 3.29 Hz), 3.60 (IH, dd, J 9.61, 5.88 Hz), 3.38-3.27 (IH, m), 3.34 (3H, s), 2.25-2.16 (IH, m), 2.08-1.84 (5H, m), 1.60 (3H, d, J 6.40 Hz).
  • 7
  • [ 84025-81-0 ]
  • [ 161796-10-7 ]
  • [ 910447-77-7 ]
YieldReaction ConditionsOperation in experiment
73% Stage #1: 3-bromo-5-(methoxycarbonyl)benzoic acid With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane for 0.5h; Stage #2: (2R)-methoxymethylpyrrolidine In dichloromethane at 20℃; for 6h; H.1 Step H (1): (No.)-methyl 3-bromo-5-(2-(methoxymethyl)pyrrolidine-l- carbonyl)benzoate.; To a solution of 3-bromo-5-(methoxycarbonyl)benzoic acid (1.8 g, 6.95 mmol) in dichloromethane (100 mL) and was added Hunig's base (2.7 g, 20.85 mmol) to make a clear solution and HATU (3.17 g, 8.34 mmol) was then added. After stirring for 30 min, the reaction mixture was added (R)-2- (methoxymethyl)pyrrolidine (800 mg, 6.95 mmol) and the reaction mixture was stirred at rt for 6 h. Dichloromethane (100 mL) was added and the mixture was washed with IN NaOH, H2O and concentrated under vacuum. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% EtOAc/Hexane step gradient) to give 1.8 g of the title compound (73% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 1.77 - 2.08 (4H, m), 3.14 - 3.47 (5H, m), 3.63 (2H, brd s), 3.82 (3H, s), 4.41 (IH, brd s), 7.83 (IH, s), 8.07 (IH, s), 8.20 (IH, m).
  • 8
  • [ 910447-76-6 ]
  • [ 84025-81-0 ]
  • [ 910447-94-8 ]
YieldReaction ConditionsOperation in experiment
95% Stage #1: 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acid With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane for 0.333333h; Stage #2: (2R)-methoxymethylpyrrolidine In dichloromethane at 20℃; 8.A Step 8 (A): (2i?,4i?)-tert-butyl 2-((15,21S)-l-(tert-butyldimethylsilyloxy)- 3-(3,5-difluorophenyl)-2-(3-((i?)-2-(methoxymethyl)pyrrolidine-l-carbonyl)-5- methylbenzamido)propyl)-4-propoxypyrrolidine-l-carboxylate.; To a solution of 3-(((15',21S)-l-((2i?,4i2)-l-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-l-(/ert- butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5- methylbenzoic acid (Preparation G, 28 mg, 0.038 mmol) in dichloromethane (1 niL) was added Hunig's base (14mg, 0.114 mmol) to make a clear solution and HATU (19 mg, 0.05 mmol) was then added. After stirring for 20 min, the reaction mixture was added (i?)-2-(methoxymethyl)pyrrolidine (65 mg, 0.057 mmol) and the reaction mixture was stirred at rt overnight. Ethyl acetate (100 HiL) was added and the mixture was washed with Brine, H2O, dried and concentrated to give 30 mg of the title compound (95% yield): 1H NMR (CDCl3; 500 MHz) δ ppm 0.01 (3H, s), 0.06 (3H, s), 0.85 (9H, s), 0.88 (3H, t, J- 5 Hz), 1.48 - 1.54 (HH, m), 1.73 (IH, m), 1.92 - 2.09 (5H, m), 2.18 (IH, m), 2.38 (3H, s), 2.62 (IH, m), 2.96 (IH, m), 3.05 (IH, m), 3.26 - 3.39 (5H, m), 3.47 (IH, m), 3.58 (IH, m), 3.68 (IH, m), 3.76 (IH, dd, J= 5, 15 Hz), 3.97 (IH, m), 4.04 -4.07 EPO (IH, m), 4.11 - 4.14 (IH, m), 4.41 (IH, brd s), 4.56 (IH, m), 6.59 (IH, m), 6.76 (IH, s), 6.77 (IH, s), 7.43 (IH, s), 7.72 (IH, s), 7.74 (IH, s), 7.98 (IH, brd s). MS (ESI) (M+H)+ 788.61.
  • 9
  • [ 910447-84-6 ]
  • [ 84025-81-0 ]
  • [ 910447-85-7 ]
YieldReaction ConditionsOperation in experiment
79% Stage #1: 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)benzoic acid With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane; N,N-dimethyl-formamide for 0.333333h; Stage #2: (2R)-methoxymethylpyrrolidine In dichloromethane; N,N-dimethyl-formamide at 20℃; 1.D Step 1 (D): (2i?54i?)-tert-butyl 2-((1552(S)-l-(te7't-butyldimethylsilyloxy)- 3-(355-difluorophenyl)-2-(3-((i?)-2-(methoxymethyl)pyrrolidine-l- carbonyl)benzamido)propyl)-4-propoxypyrrolidine-l -carboxylate.; To a solution of 3-(((15r521S)-l-((2i?54i?)-l-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-l- (tert-butyldimethylsilyloxy)-3-(355-difluorophenyl)propan-2- yl)carbamoyl)benzoic acid (Step 1 (C)5 50 mg5 0.074 mmol) in dichloromethane (2 mL) and DMF (5 mL) was added Hunig's base (28 mg, 0.222 mmol) to make a clear solution and HATU (36 mg5 0.0962 mmol) was then added. After stirring for 20 min, the reaction mixture was added (i?)-2-(methoxymethyl)pyrrolidine (17 EPO mg, 0.148 mmol) and the reaction mixture was stirred at rt overnight. Ethyl acetate (100 mL) was added and the mixture was washed with Brine, H2O, dried and concentrated to give 45 mg of the title compound (79% yield): 1H NMR (CDCl3, 500 MHz) δ 0.02 (3H, s), 0.05 (3H, s), 0.83 (9H, s), 0.86 - 0.89 (3H, m), 1.48 - 1.51 (HH5 m), 1.72 (IH, m), 1.91 - 2.07 (4H, m), 2.18 (IH, d, J= 15 Hz), 2.64 (IH, dd, J= 10, 15 Hz), 2.90 - 2.94 (IH, m), 3.02 (IH, brd s), 3.28 - 3.38 (6H, m), 3.48 (IH, m), 3.55 (IH5 m), 3.67 (IH, m), 3.74 (IH, m), 3.98 (IH, m), 4.04 - 4.12 (2H, m), 4.42 (IH, m), 4.59 (IH, m), 6.57 - 6.60 (IH, m), 6.76 (2H, d, J= 5 Hz), 7.41 - 7.44 (IH, m), 7.60 - 7.62 (IH, m), 7.88 (IH, d, J= 5 Hz), 7.96 (IH, s), 8.08 (IH, brd s). MS (ESI) (M+H)+ 774.40.
  • 10
  • [ 1295602-22-0 ]
  • [ 84025-81-0 ]
  • [ 1295601-32-9 ]
YieldReaction ConditionsOperation in experiment
77% With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 3h; 11 Example 11 To a solution of Compound A (0.25 g, 0.60 mmol) in acetonitrile (6 mL) at room temperature were added diisopropylethylamine (0.42 mL, 2.4 mmol) and (R)-2-(methoxymethyl)pyrrolidine (0.105 g, 0.91 mmol) and the reaction mixture was heated to 80° C. On heating, the reaction mixture became clear and after 15 min commencement of precipitation of solid was observed. Heating was continued for 3 hr and then the reaction mixture was cooled. The solid obtained was collected by filtration, washed with acetonitrile and dried under vacuum. LC/MS: (M+H)+: 490. An NMR spectrum is provided in FIG. 11.Yield: 0.23 g (77%).
  • 11
  • [ 1295602-29-7 ]
  • [ 84025-81-0 ]
  • [ 1295601-69-2 ]
YieldReaction ConditionsOperation in experiment
76% With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 3h; 33 Example 33 To a solution of Compound B (0.25 g, 0.67 mmol) in acetonitrile (5 mL) at room temperature were added diisopropylethylamine (0.5 mL, 2.9 mmol) and (R)-2-(methoxymethyl)pyrrolidine (0.116 g, 1.0 mmol) and the reaction mixture was heated to 80° C. On heating, the reaction mixture became clear and after 15 min commencement of precipitation of solid was observed. Heating was continued for 3 hr and then the reaction mixture was cooled. The solid obtained was collected by filtration, washed with acetonitrile and dried under vacuum. LC/MS: (M+H)+: 450. An NMR spectrum is provided in FIG. 33.Yield: 0.23 g (76%).
  • 12
  • [ 1312684-94-8 ]
  • [ 84025-81-0 ]
  • [ 1312685-10-1 ]
YieldReaction ConditionsOperation in experiment
96% With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In tetrahydrofuran at 65℃; 14.1 A stirred mixture of 5-chloro-7-[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (0.150 g, 0.376 mmol), (2R)-2-(methoxymethyl)pyrrolidine (0.0521 g, 0.452 mmol, Fluka), palladium acetate (2 mg, 0.008 mmol), 2,2'-bis(diphenylphosphino)-l,l'- binaphthyl (7 mg, 0.01 mmol), and cesium carbonate (0.343 g, 1.05 mmol) in tetrahydrofuran (4 mL) was heated at 65 °C overnight. The mixture was cooled, diluted with dichloromethane, and filtered. The filtrate was washed with brine, dried over sodium sulfate, and evaporated to dryness. The resultant residue was purified on silica gel, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product (132 mg, 96%). LCMS calculated forCi8H23ClN303(M+H)+: m/z = 364.1; found: 364.1.
  • 13
  • [ 1384850-39-8 ]
  • [ 84025-81-0 ]
  • [ 1396752-63-8 ]
YieldReaction ConditionsOperation in experiment
81% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 75℃; for 4h; 67.1 Step 1. Methyl 3-[(2/?)-2-(methoxymethyl)pyrrolidin-l-yl]-2-oxo-l ,2-dihydroquinoxaline-6- carboxylateTo a solution of methyl 3-chloro-2-oxo-l, 2-dihydroquinoxaline-6-carboxylate (600 mg, 2.51 mmol) in DMSO (8 rriL) was added DIEA (650 mg, 5.03 mmol), and (2R)-2- (methoxymethyl)pyrrolidine (318 mg, 2.76 mmol). The solution was stirred for 4 h at 75°C. Then the reaction was quenched by the addition of water (50 rriL) to give the precipitate, which was collected by filtration to afford methyl 3-[(2/?)-2-(methoxymethyl)pyrrolidin-l- yl]-2-oxo-l ,2-dihydroquinoxaline-6-carboxylate as a gray solid (650 mg, 81 %). LC/MS (ES, m/z):[M+H]+ 317.0'H-NMR (300 MHz, CDCI3) δ 11.09 (s, 1H), 8.18 (s, 1H), 7.79 - 7.82 (m, 1H), 7.11 (d, / = 8.4 Hz, 1H), 4.11 - 4.20 (m, 1H), 3.91 - 4.01 (m, 4H), 3.67 - 3.72 (m, 1H), 3.41 - 3.46 (m, 4H), 2.65 (s, 4H), 1.96 - 2.12 (m, 4H)
  • 14
  • [ 1628606-32-5 ]
  • [ 84025-81-0 ]
  • [ 1628606-56-3 ]
YieldReaction ConditionsOperation in experiment
83% Stage #1: 4-methoxy-5-(6-methyl-5-((2-( 1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(methylthio)pyrimidine With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 2h; Stage #2: (2R)-methoxymethylpyrrolidine In dichloromethane at 20℃; 23 Example 23 Example 23: Example C2 (0.10 g, 0.24 mmol) was dissolved in DCM (5 mL) and then mCPBA (60 mg, 0.24 mmol) was added portion wise. The mixture was stirred at RT mfor 2 hours. (R)-2-(methoxymethyl)pyrrolidine (0.28 g, 2.38 mmol) was added and then the mixture was stirred at RT overnight. The mixture was quenched with NaHC03 solution and the solution was extracted with DCM (2x). The organic was dried over Na2S04, filtered and concentrated to obtain the crude. The material was purified via silica gel chromatography (MeOH/DCM) to obtain (R)-4-methoxy-2-(2-(methoxymethyl)pyrrolidin-l-yl)-5-(6-methyl- 5 -((2-(l -methyl- lH-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidine (96 mg, 83% yield). MS (ESI) m/z: 488.3 (M+H+).
 

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[ 84025-81-0 ]

Chemical Structure| 63126-47-6

A742383 [63126-47-6]

(S)-2-(Methoxymethyl)pyrrolidine

Reason: Optical isomers