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Chemical Structure| 136725-50-3 Chemical Structure| 136725-50-3

Structure of 136725-50-3

Chemical Structure| 136725-50-3

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Product Details of [ 136725-50-3 ]

CAS No. :136725-50-3
Formula : C5H12ClNO
M.W : 137.61
SMILES Code : COC1CNCC1.[H]Cl
MDL No. :MFCD09261403
InChI Key :SQMYKVUSWPIFEQ-UHFFFAOYSA-N
Pubchem ID :22017630

Safety of [ 136725-50-3 ]

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

Computational Chemistry of [ 136725-50-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 8
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 38.8
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

0.65
Log Po/w (WLOGP)?

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

0.42
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

0.85
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.43

Water Solubility

Log S (ESOL):?

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

-1.04
Solubility 12.6 mg/ml ; 0.0919 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.

-0.67
Solubility 29.3 mg/ml ; 0.213 mol/l
Class?

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

Very soluble
Log S (SILICOS-IT)?

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

-0.86
Solubility 19.0 mg/ml ; 0.138 mol/l
Class?

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

Soluble

Pharmacokinetics

GI absorption?

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

High
BBB permeant?

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

No
P-gp substrate?

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

No
CYP1A2 inhibitor?

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

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.68 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)

1.55

Application In Synthesis of [ 136725-50-3 ]

* 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 [ 136725-50-3 ]

[ 136725-50-3 ] Synthesis Path-Downstream   1~18

  • 1
  • [ 136725-50-3 ]
  • [ 955919-48-9 ]
  • [ 955919-07-0 ]
YieldReaction ConditionsOperation in experiment
41% With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butylphosphonium tetrafluoroborate; In toluene; at 150℃; for 0.0833333h;Microwave irradiation; Example 68 5) 3-ethyl-6-{1-[4-(3-methoxypyrrolidin-1-yl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine 6-[1-(4-bromophenyl)-1H-pyrazol-5-yl]-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine (25 mg, 0.055 mmol, prepared as described above in Example 67), <strong>[136725-50-3]3-methoxypyrrolidine hydrochloride</strong> (6.8 mg, 0.050 mmol), toluene (0.8 mL), tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.003 mmol), tri-tert-butylphosphonium tetrafluoroborate (1.6 mg, 0.0055 mmol) and sodium tert-butoxide (10.6 mg, 0.110 mmol) were added to a 10 mL microwave tube, and the resulting mixture was subject to microwave irradiation at 150 C. for 5 minutes. The product was purified on a SFC Minigram instrument using 15% methanol modifier on a pyridine column (10×250 mm) at 120 bar pressure and a flow rate of 9.9 mL/min to afford 9.7 mg (41%) of 3-ethyl-6-{1-[4-(3-methoxypyrrolidin-1-yl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine as a yellow solid. 1H NMR (CDCl3) delta 1.4 (t, 3H); 1.7 (d, 2H); 2.1-2.4 (m, 4H); 2.9 (q, 2H); 3.3-3.6 (m, 6H); 3.4 (s, 3H); 3.9-4.1 (m, 3H); 4.6 (m, 1H); 6.5 (d, 2H); 6.8 (s, 1H); 7.2 (m, 3H); 7.7 (s, 1H); 7.9 (d, 1H), LC/MS (EI) tR 473.2 (Method E), m/z 5.04 (M++1).
  • 2
  • [ 677305-86-1 ]
  • [ 136725-50-3 ]
  • [ 932704-05-7 ]
YieldReaction ConditionsOperation in experiment
84% With caesium carbonate;palladium diacetate; XPhos; In tetrahydrofuran; for 67h;Heating / reflux;Product distribution / selectivity; Procedure L Procedure L provides a method for the coupling between brominated aminoquinuclidinecarboxamides and cyclic amines to form aniline derivatives. A mixture of <strong>[136725-50-3]3-methoxypyrrolidine hydrochloride</strong> (6.27 mmol), N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1,2-benzisothiazole-3-carboxamide (4.42 mmol), 2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl (0.845 mmol), palladium acetate (0.363 mmol), and cesium carbonate (9.97 mmol) was evacuated and back-filled with an atmosphere of argon. Tetrahydrofuran (60 mL) was added and the reaction was heated at reflux for 67 h. The reaction mixture was allowed to cool to rt and was filtered through Celite (MeOH) and concentrated. The residue was partitioned between 9/1 dichloromethane/methanol (100 mL) and sat sodium bicarbonate (40 mL) and the layers were separated. The aq layer was extracted with 9/1 dichloromethane/methanol (3×50 mL) and the combined organic layers were washed with brine and dried (sodium sulfate). The residue was purified by chromatography (70/30/1 ethyl acetate/methanol/ammonium hydroxide) to give the free base (84%) as a yellow foam. The mono-hydrochloride salt was prepared from methanolic hydrogen chloride [acetyl chloride (0.95 eq) in methanol (5 mL)] and was recrystallized from methanol/ethyl acetate. The following compound was prepared using this procedure: 49) N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-6-(3-methoxypyrrolidin-1-yl)-1,2-benzisothiazole-3-carboxamide hydrochloride. 1H NMR (CD3OD) delta 8.48 (d, J=9.1, 1H), 7.02 (d, J=1.9, 1H), 6.91 (dd, J=9.2, 2.1, 1H), 4.52-4.48 (m, 1H), 4.20-4.17 (m, 1H), 3.87-3.78 (m, 1H), 3.58 (dd, J=11.0, 4.7, 1H), 3.50-3.42 (m, 3H), 3.38 (s, 3H), 3.36-3.34 (m, 3H), 2.40-2.37 (m, 1H), 2.26-2.08 (m, 3H), 1.95-1.87 (m, 1H); LC/MS (EI) tR 3.47, m/z 387 (M++1).
  • 3
  • [ 146257-03-6 ]
  • [ 136725-50-3 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; water; In tetrahydrofuran; for 1h; Procedure 32 Procedure 32 provides a method for the preparation of 3-alkoxypyrrolidines from N-Boc-3-hydroxypyrrolidine. 1-Boc-3-hydroxypyrrolidine (16.1 mmol) was added in portions to a suspension of sodium hydride (22.0 mmol) in tetrahydrofuran (40 mL) at 0 C. The reaction mixture was diluted with tetrahydrofuran (60 mL) and allowed to warm to rt. Methyl iodide (21.0 mmol) was added to the cloudy suspension after 1 h and the reaction mixture was maintained at rt for 6 h. The reaction mixture was concentrated and redissolved in ethyl acetate (100 mL). The extract was washed with saturated ammonium chloride (20 mL), water (20 mL), and brine (20 mL) and was dried (sodium sulfate). The residue was purified by chromatography (1/4 ethyl acetate/hexane) to give the ether. The N-Boc product was dissolved in tetrahydrofuran (30 mL) and 6 N hydrochloric acid (20 mL) was added. The resultant mixture was stirred for 1 h and was concentrated to give an oil. Toluene (10 mL) and ethanol (10 mL) were added and the mixture was concentrated to give 1.79 g of brownish, very hygroscopic solid. The solid was suspended in ethyl acetate and stirred vigorously for 12 h. The solids were quickly collected by filtration and dried under high vacuum to give the product (81%) as a colorless solid.
With hydrogenchloride; water; In tetrahydrofuran; for 1h; Example 18 Example 18 provides a method for the preparation of 3-alkoxypyrrolidines from N-Boc-3-hydroxypyrrolidine. 1-Boc-3-hydroxypyrrolidine (16.1 mmol) was added in portions to a suspension of sodium hydride (22.0 mmol) in tetrahydrofuran (40 mL) at 0 C. The reaction mixture was diluted with tetrahydrofuran (60 mL) and allowed to warm to rt. Methyl iodide (21.0 mmol) was added to the cloudy suspension after 1 h and the reaction mixture was maintained at rt for 6 h. The reaction mixture was concentrated and re-dissolved in ethyl acetate (100 mL). The extract was washed with saturated ammonium chloride (20 mL), water (20 mL), and brine (20 mL) and was dried (sodium sulfate). The residue was purified by chromatography (1/4 ethyl acetate/hexane) to give the ether. The iV-Boc product was dissolved in tetrahydrofuran (30 mL) and 6 N hydrochloric acid (20 mL) was added. The resultant mixture was stirred for 1 h and was concentrated to give an oil. Toluene (10 mL) and ethanol (10 mL) were added and the mixture was concentrated to give 1.79 g of brownish, very hygroscopic solid. The solid was suspended in ethyl acetate and stirred vigorously for 12 h. The solids were quickly collected by' filtration and dried under high vacuum to give the product (81%) as a colorless solid. An alternative procedure used for the removal of the N-Boc groups entails exposure to trifluoroacetic acid for 4 h. followed by concentration of the reaction mixture. This procedure may be useful for the production of the amine as a free base.The following amine was prepared using this procedure:3-Methoxypyrrolidine hydrochloride.
  • 4
  • [ 136725-50-3 ]
  • [ 62848-20-8 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate; In water; The free base was obtained by neutralization of the salt residue with saturated sodium carbonate (5 mL), extraction with 9/1 dichloromethane/methanol (3 x 20 mL), drying (potassium carbonate), and concentration, followed by capturing the amine on a SCX column and eulting with 2M ammonia in methanol:3-Methoxypyrrolidine.
  • 5
  • [ 136725-50-3 ]
  • [ 1227934-69-1 ]
  • [ 1227934-71-5 ]
  • [ 1227934-96-4 ]
YieldReaction ConditionsOperation in experiment
2-(3-methoxypyrrolidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic Acid (A-29) Intermediate A-29 was prepared by the general procedure for intermediate A-4, by using A-2 and 3-methoxypyrrolidine hydrochloride as starting materials with N,N-diisopropylethylamine. MS (M+1): 281.
  • 6
  • [ 136725-50-3 ]
  • [ 122-85-0 ]
  • C14H20N2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h; A mixture of 4-acetamidobenzaldehyde (200mg), piperidine (0.121 mL), NaBH(OAc)3 (636mg) and DIPEA (0.617ml) in DCM (4ml) was stirred at RT for 4h. DCM and sat. NaHCO3 were added. The phases were separated, the org. layer was dried (Na2SO4), filtered off and evaporated to dryness to afford 267 mg of white solid. LC-MS (B): tR = 0.45 min; [M+H]+: 233.24.
  • 7
  • [ 136725-50-3 ]
  • methyl 2-[bis(tert-butoxycarbonyl)amino]-6-formylfuro[3,2-b]pyridine-3-carboxylate [ No CAS ]
  • methyl 2-[bis(tert-butoxycarbonyl)amino]-6-[(3-methoxypyrrolidin-1-yl)methyl]furo[3,2-b]pyridine-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium triacetoxyborohydride resin; In dichloromethane; at 20 - 30℃; for 16h; Step 1. Methyl 2-[bis(tert-butoxycarbonyl)amino]-6-[(3-methoxypyrrolidin-1-yl)methyl]furo[3,2-b]pyridine-3-carboxylate To a mixture of methyl 2-[bis(tert-butoxycarbonyl)amino]-6-formylfuro[3,2-b]pyridine-3-carboxylate (150 mg, 0.36 mmol) (prepared in Example 100, step 2) and 3-methoxypyrrolidine HCl (56 mg, 0.4 mmol) in DCM (1.9 mL) was added resin of sodium triacetoxyborohydride (290 mg, 0.66 mmol). The resulting mixture was stirred at room temperature for 16 h. The mixture was filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. LCMS calc. for C25H36N3O8 (M+H)+: m/z=506.2. Found: 506.2.
  • 8
  • [ 136725-50-3 ]
  • [4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl](6-fluoropyridin-3-yl)methanone [ No CAS ]
  • [4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl][6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 0.75h;Microwave irradiation; 70 mg (0.20 mmol) of the compound from Example 1OA and 54 mg of <strong>[136725-50-3]3-methoxypyrrolidine hydrochloride</strong> (0.40 mmol) were dissolved in 0.8 ml of N-methyl2-pyrrolidone and 0.2 ml of N,N-diisopropylethylamine (0.98 mmol), and the mixture was stirred in the microwave at 180 C. for 45 mm. The mixture was then diluted with methanol and purified by preparative HPLC [Method 9]. This gave 63 mg (73% of theory) of the title compound. LC-MS [Method 1]: R=0.44 mm; MS (ESIpos):m1z439 (M+H) ?H-NMR (400 MHz, DMSO-d5): oe [ppm]=0.98-1. 12 (m, 1H), 1.31-1.60 (m, 1H), 1.75-1.90 (m, 1H), 1.96-2.17 (m, 1H), 2.61-2.82 (m, 6H), 2.84-3.03 (m, 2H), 3.27 (s, 2H), 3.34-3.43 (m, 1H), 3.51 (d, 3H), 3.67 (s, 2H), 3.93-4.32 (m, 3H), 6.46 (d, 1H), 6.91 (d, 2H), 7.02-7.11 (m, 1H), 7.47-7.61 (m, 1H), 8.17 (d, 1H).
  • 9
  • [ 136725-50-3 ]
  • (6-fluoropyridin-3-yl) [4-(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl]methanone [ No CAS ]
  • [4-(6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl][6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 0.75h;Microwave irradiation; 80 mg (0.20 mmol) of the compound from Example 1 la and 68 mg of <strong>[136725-50-3]3-methoxypyrrolidine hydrochloride</strong> (0.49 mmol) were dissolved in 0.8 ml of N-methyl2-pyrrolidone and 0.2 ml of N,N-diisopropylethylamine (1.18 mmol, 6.0 eq.), and the mixture was stirred in the microwave at 180 C. for 45 mm. The mixture was then diluted with methanol and purified by preparative HPLC [Method 9]. This gave 67 mg (75% of theory) of the title compound. LC-MS [Method 1]: R=0.45 mm; MS (ESIpos):m1z451 (M+H)?H-NMR (400 MHz, DMSO-d5): oe [ppm]=1.35-1. 61 (m, 2H), 1.74-1.90 (m, 2H), 1.96-2.12 (m, 2H), 2.61-2.70 (m, 1H), 2.74 (s, 4H), 2.83-3.02 (m, 2H), 3.27 (s, 3H), 3.33-3.44 (m, 1H), 3.51 (d, 3H), 3.63 (s, 2H), 3.69 (s, 3H),3.93-4.34 (m, 3H), 6.35-6.53 (m, 1H), 6.64 (s, 2H), 6.88-7.00 (m, 1H), 7.49-7.62 (m, 1H), 8.01-8.27 (m, 1H).
  • 10
  • [ 136725-50-3 ]
  • (6-fluoropyridin-3-yl)[(3R)-3-methyl-1,4'-bipiperidin-1'-yl]methanone [ No CAS ]
  • [6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl][(3R)-3-methyl-1,4'-bipiperidin-1'-yl]methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
54% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 0.5h;Microwave irradiation; Example 13 [6-(3-Methoxypyrrolidin-1-yl)pyridin-3-yl][(3R)-3-methyl-1,4?-bipiperidin-1?-yl]methanone (0431) (0432) In a microwave, a mixture of 100 mg (0.38 mmol) of the compound from Example 9A, 90 mg (0.66 mmol) of <strong>[136725-50-3]3-methoxypyrrolidine hydrochloride</strong> and 0.29 ml (1.64 mmol) of N,N-diisopropylethylamine in 1.0 ml of N-methyl-2-pyrrolidone was heated at 180 C. for 30 min After cooling to room temperature, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative HPLC [Method 13], giving 70.0 mg (54% of theory) of the title compound. (0433) LC-MS [Method 8]: Rt=2.34 min; MS (ESIpos): m/z=387 (M+H)+ (0434) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=0.73-0.90 (m, 4H), 1.29-1.86 (m, 9H), 1.97-2.13 (m, 3H), 2.70-3.02 (m, 4H), 3.26 (s, 3H), 3.36-3.42 (m, 1H), 3.46-3.57 (m, 3H), 3.72-4.46 (m, 2H), 6.45 (d, 1H), 7.54 (dd, 1H), 8.15 (d, 1H).
  • 11
  • [ 136725-50-3 ]
  • 3-methoxypyrrolidine-1-sulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With SULFAMIDE; triethylamine; In 1,4-dioxane; for 16h;Reflux; A solution of <strong>[136725-50-3]3-methoxypyrrolidine hydrochloride</strong> ([136725-50-3], 136 mg, 0.98 mmol) in dioxane (2 mL) was treated with triethylamine (0.2 mL, 1.4 mmol) and sulfamide (7803-58-9, 130 mg, 1.3 mmol), and the mixture was refluxed for 16 hours. The mixture was then cooled to RT, and the residue was purified by column chromatography eluted with DCM/MeOH (9/1) to give the titled compound.
  • 12
  • [ 136725-50-3 ]
  • [ 32315-10-9 ]
  • tert-butyl methyl(2-(((2-oxo-2-((2’-oxo-1,1',2’,3-tetrahydrospiro[indene-2,3’-pyrrolo[2,3-b]pyridin]-5-yl)amino)ethyl)amino)methyl)benzyl)carbamate [ No CAS ]
  • tert-butyl N-[[2-[[(3-methoxypyrrolidine-1-carbonyl)-[2-oxo-2-[(2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,2’-indane]-5’-yl)amino]ethyl]amino]methyl]phenyl]methyl]-N-methyl-carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
35% To a solution of Intermediate V (80 mg, 0.15 mmol) in tetrahydrofuran (2 mL) was added triethylamine (44 mg, 0.44 mmol) and triphosgene (43 mg, 0.14 mmol) at 00C. The reaction mixture was stirred at 26C for 1 h. 3-Methoxypyrrolidine (22 mg, 0.16 mmol, HCI salt) was added into the mixture and the reaction mixture was stirred at 26C for 1 h. The reactionmixture was quenched by water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (3 x 20 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by prep-HPLC (column: Phenomenex Synergi 018 150x25mm, 10pm; mobile phase: [water (0.1%TFA)- acetonitrile]; B%: 42%-72%, ii mm). After lyophilisation, 32.lb (35 mg, 0.052 mmol, 35%yield) was obtained as colourless oil. LC-MS: rt 0.810 mm, (669 [M+H]).
  • 13
  • [ 136725-50-3 ]
  • 2-[5-bromo-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
  • 5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[3-methoxypyrrolidin-1-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
59% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 150℃; for 8h;Microwave irradiation; A solution of 2- { [5-bromo- 1 -(2-chlorophenyl)- 1 H-i ,2,4-triazol-3 -yl]methyl} -5-(4-chlorophenyl)-4- [(2S)-3 ,3,3 -trifluoro-2-hydroxypropyl] -2,4-dihydro-3H- 1 ,2,4-triazol-3 -one (Example 5A, 150mg, 259 jimol) in acetonitrile (1.5 ml) was treated with N,N-diisopropylethylamine (95 jil, 540 jimol) and <strong>[136725-50-3]3-methoxypyrrolidine hydrochloride</strong> (1:1) (357 mg, 2.59 mmol). The resulting mixturewas heated for 8 h at i50C under microwave irradiation and diluted with water. The resulting solution was purified by preparative HPLC (Method 5) affording 91.0 mg (59% of th.) of the title compound as a mixture of diastereomers.LC-MS (Method 2): R = 1.06 mm; MS (ESIpos): mlz = 598.3 [M-H]1H-NMR (400 MHz, DMSO-d6) [ppm]: 7.87-7.35 (m, 8H), 6.88 (d, 1H), 4.97-4.75 (m, 2H), 4.29(br ddd, 1H), 4.07-3.76 (m, 3H), 3.24-2.94 (m, 7H), 1.98-1.72 (m, 2H).
  • 14
  • [ 136725-50-3 ]
  • 6-(4,6-difluoro-2-pyridyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]
  • 6-[6-fluoro-4-(3-methoxypyrrolidin-1-yl)-2-pyridyl]-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]
  • 6-[4-fluoro-6-(3-methoxypyrrolidin-1-yl)-2-pyridyl]-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
34 mg; 5.4 mg With potassium carbonate; In N,N-dimethyl acetamide; at 110℃; for 12h; To a solution of 6-(4,6-difluoro-2-pyridyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H- pyrido[4,3-d]pyrimidine (one product of step 7 in Example 1 , 80 mg, 0.23 mmol) and <strong>[136725-50-3]3-methoxypyrrolidine hydrochloride</strong> (96 mg, 0.70 mmol) in DMA (1 mL) was added K2CO3(97 mg, 0.70 mmol). The mixture was heated at 110 C with stirring for 12 hrs and then cooled to rt. The mixture was concentrated in vacuo and the residue was partitioned between DCM (10 mL) and H20 (5 mL). The organic layer was concentrated in vacuo and the residue was purified by prep-HPLC to give 6-[6-fluoro-4-(3-methoxypyrrolidin-1-yl)-2-pyridyl]-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine (34.0 mg) as a white solid and 6-[4-fluoro-6-(3- methoxypyrrolidin-1-yl)-2-pyridyl]-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine (5.4 mg) as a white solid.Example 20: 6-[6-fluoro-4-(3-methoxypyrrolidin-1-yl)-2-pyridyl]-5-methyl-2-pyrimidin- 2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, 1H NMR(400 MHz, CDC13) delta ppm: 9.05 (d, 2H), 8.83 (s, 1H), 7.44 (t, 1H), 5.81 - 5.65 (m, 1H), 5.55 (s, 1H), 5.49 (s, 1H), 4.48 - 4.34 (m, 1H), 4.12 (d, 1H), 3.57 - 3.37 (m, 9H), 3.35 - 3.17 (m, 2H), 2.27 - 2.04 (m, 2H), 1.57 (d, 3H). MS obsd. (ESI+) [(M+H)+]: 422.Example 21 : 6-[4-fluoro-6-(3-methoxypyrrolidin-1-yl)-2-pyridyl]-5-methyl-2-pyrimidin- 2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, 1H NMR(400 MHz, CDC13) delta ppm: 8.96 (d, 2H), 8.72 (s, 1H), 7.35 (t, 1H), 5.73 - 5.59 (m, 2H), 5.40 (d, 1H), 4.37 (dd, 1H), 4.07 - 3.94 (m, 1H), 3.57 - 3.35 (m, 5H), 3.34 - 3.28 (m, 3H), 3.24 - 3.09 (m, 2H), 2.16 - 1.91 (m, 2H), 1.49 (d, 3H) . MS obsd. (ESI+) [(M+H)+]: 422.
  • 15
  • [ 136725-50-3 ]
  • 6-(2,6-difluoro-4-pyridyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]
  • 6-[2-fluoro-6-(3-methoxypyrrolidin-1-yl)-4-pyridyl]-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
30 mg With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 110℃; for 15h; A mixture of 6-(2,6-difluoro-4-pyridyl)-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine (one product of step 7 in Example 1 , 170 mg, 0.5 mmol), K2CO3(207 mg, 1.5 mmol) and <strong>[136725-50-3]3-methoxypyrrolidine hydrochloride</strong> (137 mg, 1.0 mmol) in NMP (5 mL) was heated at 110C with stirring for 15 hrs. The resulting mixture was poured into water (20 mL) and extracted with DCM (50 mL) twice. The combined organic layer was washed with brine, dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by prep-HPLC to give 6-[2-fluoro-6-(3-methoxypyrrolidin-1-yl)-4-pyridyl]-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine (30 mg) as a white powder. 1H NMR (400 MHz, Methanol-^) delta ppm: 9.05 (d, 2H), 8.90 (s, 1H), 7.62-7.70 (m, 1H), 5.89-5.97 (m, 1H), 5.67-5.75 (m, 1H), 5.33-5.43 (m, 1H), 4.12 (m, 2H), 3.42-3.64 (m, 5H), 3.39 (d, 3H), 3.14-3.28 (m, 2H), 2.04-2.21 (m, 2H), 1.61 (dd, 3H). MS obsd. (ESI+) [(M+H)+]: 422.
  • 16
  • [ 136725-50-3 ]
  • 6-(4,6-difluoro-2-pyridyl)-5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]
  • 6-[6-fluoro-4-(3-methoxypyrrolidin-1-yl)-2-pyridyl]-5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]
  • 6-[4-fluoro-6-(3-methoxypyrrolidin-1-yl)-2-pyridyl]-5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
23 mg; 10 mg With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 110℃; for 15h; A mixture of 6-(4,6-difluoro-2-pyridyl)-5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine (the product of step 4 in Example 59, 170 mg, 0.5 mmol), K2CO3(207 mg, 1.5 mmol) and <strong>[136725-50-3]3-methoxypyrrolidine hydrochloride</strong> (137 mg, 1.0 mmol) in NMP (5 mL) was heated at 1 10 C with stirring for 15 hrs. The resulting mixture was poured into water (20 mL) and extracted with DCM (50 mL) twice. The organic layers were combined and washed with brine, then dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by prep-HPLC to give 6-[6-Fluoro-4-(3-methoxypyrrolidin-1-yl)-2-pyridyl]-5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine (23 mg) as yellow powder 6-[4-fluoro-6-(3-methoxypyrrolidin-1-yl)-2-pyridyl]-5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine (10 mg) as yellow powder.Example 836-[6-Fluoro-4-(3-methoxypyrrolidin-1-yl)-2-pyridyl]-5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine 1H NMR (400 MHz, CDC13) delta ppm: 8.81-8.91 (m, 1H), 8.67-8.75 (m, 1H), 8.43-8.54 (m, 1H), 7.80-7.96 (m, 1H), 7.38-7.47 (m, 1H), 5.61-5.73 (m, 1H), 5.51-5.57 (m, 1H), 5.43-5.50 (m, 1H), 4.35-4.46 (m, 1H), 4.08-4.16 (m, 1H), 3.41-3.53 (m, 5H), 3.39 (d, 3H), 3.10-3.30 (m, 2H), 2.17-2.26 (m, 1H), 2.02-2.14 (m, 1H), 1.47-1.59 (m, 3H). MS obsd. (ESI+) [(M+H)+] : 421.Example 84: 6-[4-fluoro-6-(3-methoxypyrrolidin-1-yl)-2- pyridyl]-5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine, 1H NMR (400 MHz, CDC13) delta ppm: 8.71-8.82 (m, 1H), 8.62 (s, 1H), 8.37-8.46 (m, 1H), 7.73-7.84 (m, 1H), 7.28-7.36 (m, 1H), 5.62-5.70 (m, 1H), 5.53- 5.61 (m, 1H), 5.36-5.44 (m, 1H), 4.31 -4.41 (m, 1H), 3.97-4.05 (m, 1H), 3.51 (d, 2H), 3.40-3.47 (m, 2H), 3.33-3.39 (m, 1H), 3.31 (d, 3H), 3.00-3.18 (m, 2H), 1.96-2.12 (m, 2H), 1.47 (d, 3H). MS obsd. (ESI+) [(M+H)+] : 421.
  • 17
  • [ 136725-50-3 ]
  • [ 540-51-2 ]
  • 2-(3-methoxypyrrolidin-1-yl)ethanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
94.8% With potassium carbonate; In acetonitrile; at 80℃; for 3h; To a solution of 3-methoxypyrrolidine (450 mg, 3.27 mmol, HCl) and 2-bromoethanol (408 mg, 3.27 mmol) in CH 3CN (10 mL) was added K 2CO 3 (1.36 g, 9.81 mmol). The mixture was stirred at 80° C. for 3 hours. The solid was filtered and the filtrate was evaporated to give 2-(3-methoxypyrrolidin-1-yl)ethanol (450 mg, 3.10 mmol, 94.8% yield) as a colorless oil.
  • 18
  • [ 136725-50-3 ]
  • [ 627-18-9 ]
  • 3-(3-methoxypyrrolidin-1-yl)propan-1-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
93.3% With potassium carbonate; In acetonitrile; at 20℃; for 5h; To a solution of 3-methoxypyrrolidine (500 mg, 3.63 mmol, HCl) and 3-bromopropan-1-ol (505 mg, 3.63 mmol) in CH 3CN (10 mL) was added K 2CO 3 (1.51 g, 10.9 mmol). The mixture was stirred at 20° C. for 5 hours. The solid was filtered and the filtrate was evaporated to give 3-(3-methoxypyrrolidin-1-yl)propan-1-ol (540 mg, 3.39 mmol, 93.3% yield).
 

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