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Structure of 139986-03-1

Chemical Structure| 139986-03-1

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Product Details of [ 139986-03-1 ]

CAS No. :139986-03-1
Formula : C16H23NO5S
M.W : 341.42
SMILES Code : O=C(N1C[C@H](OS(=O)(C2=CC=C(C)C=C2)=O)CC1)OC(C)(C)C
MDL No. :MFCD16621198
InChI Key :MWACHFODPQVXHF-CYBMUJFWSA-N
Pubchem ID :23560883

Safety of [ 139986-03-1 ]

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

Computational Chemistry of [ 139986-03-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 23
Num. arom. heavy atoms 6
Fraction Csp3 0.56
Num. rotatable bonds 6
Num. H-bond acceptors 5.0
Num. H-bond donors 0.0
Molar Refractivity 90.45
TPSA ?

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

81.29 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.3
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

2.65
Log Po/w (WLOGP)?

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

3.41
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.

2.26
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

1.44
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.61

Water Solubility

Log S (ESOL):?

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

-3.42
Solubility 0.129 mg/ml ; 0.000377 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-4.01
Solubility 0.0335 mg/ml ; 0.0000981 mol/l
Class?

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

Moderately soluble
Log S (SILICOS-IT)?

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

-3.53
Solubility 0.101 mg/ml ; 0.000294 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

Yes
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

Yes
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.

-6.5 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

0.0
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

1.0 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<0.0
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)

3.71

Application In Synthesis of [ 139986-03-1 ]

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

  • Downstream synthetic route of [ 139986-03-1 ]

[ 139986-03-1 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 109431-87-0 ]
  • [ 98-59-9 ]
  • [ 139986-03-1 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine;dmap; In dichloromethane; at 20℃; for 8h; The above alcohol (7.3 g, 39 mmol), p-TsCl (8.2 g, 43 mmol), Et3N (9.8 g, 97 mmol), DMAP (240 mg) in CH2Cl2 (100 mL) were allowed to stirr for 8 hours at room temperature. Then the reaction mixture was washed with brine (100 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated. Purification of the resulting crude by flash silica gel chromatography provided the ester in quantitative yield
94% With dmap; triethylamine; In dichloromethane; at 20℃; for 12h; Compound (R) -3-hydroxypyrrolidine-1-carboxylic acid third butyl ester 1a (3.5g, 18.7mmol), triethylamine (5.25mL, 37.9mmol), 4-dimethylaminopyridine (0.35g, 2.87mmol) were dissolved in dichloromethane (50mL), and p-toluenesulfonyl chloride (5.4 g, 28.1 mmol), and the reaction mixture was stirred at room temperature for 12 hours.Dilute with water (50 mL) and extract with ethyl acetate (100 mL x 3).The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) to obtain the target product (R)- 3- (Toluenesulfonyloxo) pyrrolidine-1-carboxylic acid third butyl ester 1b (6.0 g, yellow oil), yield: 94%.
82.8% With dmap; triethylamine; In dichloromethane; at 0 - 20℃; Intermediate (ix); 3-(3R)-(Toluene-4-sulfonyloxy)-pyrrolidine-l-carboxylic acid tert-butyl ester; A round-bottomed flask was charged with p-toluenesulfonyl chloride (16.01 g, 83.98 mmol, 1.5 equiv.) and 150 ml of anhydrous DCM. The solution was cooled to an ice-water bath and evacuated and purged with nitrogen. To this solution was added a solution of (3R)- (-)-N-BOC-3-hydroxypyrrolidine (purchased from Aldrich) (10.47 g, 55.99 mmol) in 50 mL of DCM, followed by DMAP (0.66 g) and triethylamine (16.2 mL). The solution was stirred under nitrogen overnight from O0C to rt. TLC (5 % MeOH in DCM) showed the completion of the reaction. The reaction was quenched by addition of polymer-supported amine (8 g), stirred 30 min. 100 mL of DCM was added. The organic layer was washed with H3PO4 (IM, 2 x 5OmL), followed by NaHCO3 (50 mL), brine (50 mL), dried (K2CO3), filtered through a silica gel pad, and concentrated to obtain the title compound as a liquid, 15.82 g (82.8 %). MS: 363 (M+Na+); TLC (DCM) Rf= 0.3. 1H NMR (CDCl3, 300MHz): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, IH), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H).
82.8% With dmap; triethylamine; In dichloromethane; at 0 - 20℃; Intermediate (v); 3-(3R)-(Toluene-4-sulfonyloxy)-pyrrolidine-l-carboxylic acid tert-butyl ester; A round-bottomed flask was charged with p-toluenesulfonyl chloride (16.01 g, 83.98 mmol, 1.5 equiv.) and 150 ml of anhydrous DCM. The solution was cooled to an ice-water bath and evacuated and purged with nitrogen. To this solution was added a solution of (3R)-(- )-N-BOC-3-hydroxypyrrolidine (purchased from Aldrich, 10.47 g, 55.99 mmol) in 50 mL of DCM, followed by DMAP (0.66 g) and triethylamine (16.2 mL). The solution was stirred under nitrogen overnight at a temperature from about 0 C to rt. TLC (5% MeOH in DCM for SM and DCM for product) showed the completion of the reaction. The reaction was quenched by addition of polymer-supported amine (8 g), stirred for 30 min. and 100 mL of DCM was added. The organic layer was washed with H3PO4 (IM, 2 x 5OmL), followed by <n="27"/>NaHCθ3 (50 mL), brine (50 mL), dried (K2CO3), filtered through a silica gel pad, and concentrated to obtain the title compound as a liquid, 15.82 g (82.8 %). MS: 363 (M+Na+); TLC (DCM) Rf= 0.3.1H NMR (CDCl3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, IH), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H).
82.8% With dmap; triethylamine; In dichloromethane; at 0 - 20℃; Intermediate (ix); 3-(3R)-(Toluene-4-sulfonyloxy)-pyrrolidine-l-carboxylic acid tert-butyl ester; A round-bottomed flask was charged with p-toluenesulfonyl chloride (16.01 g, 83.98 mmol, 1.5 equiv.) and 150 ml of anhydrous DCM. The solution was cooled to an ice-water bath and evacuated and purged with nitrogen. To this solution was added a solution of (3R)- (-)-N-BOC-3-hydroxypyrrolidine (purchased from Aldrich) (10.47 g, 55.99 mmol) in 50 mL of DCM, followed by DMAP (0.66 g) and triethylamine (16.2 mL). The solution was stirred under nitrogen overnight from O0C to rt. TLC (5 % MeOH in DCM) showed the completion of the reaction. The reaction was quenched by addition of polymer-supported amine (8 g), stirred 30 min. 100 mL of DCM was added. The organic layer was washed with H3PO4 (IM, 2 x 5OmL), followed by NaHCO3 (50 mL), brine (50 mL), dried (K2CO3), filtered through a silica gel pad, and concentrated to obtain the title compound as a liquid, 15.82 g (82.8 %). MS: 363 (M+Na+); TLC (DCM) Rf= 0.3. 1H NMR (CDCl3, 300MHz): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, IH), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H).
75% With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; Intermediate (iii) (R)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester To a 2L round-bottom flask equipped with a mechanical stirring rod and a250ml addition funnel was added p-tosyl chloride (58g, 305mmol, 1.5eq) and 600ml of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65ml) and DMAP (2.65g) were added. A solution of (R)-3-(-)-N-Boc-hydroxy pyrrolidine (38g, 203 mmol, 1.0eq) in 200 ml of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 (TLC developed in DCM). The reaction was cooled by ice-water bath. Polymer-supported trisamine (32g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 mL of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 mL), and brine (200 mL). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 75Og silica gel cartridge (DCM to 5% MeOH in DCM) to afford the title compound as a beige oil (52g, 75%). MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1H NMR (CDCI3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H).
75% With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice-water bath; Intermediate (ix)(R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 ml addition funnel was added p-tosyl chloride (58 g, 305mmol, 1 .5 eq) and 600 ml of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65 g) were added. A solution of (R)-3-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 ml of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 (TLC developed in DCM). The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 mL of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 mL), and brine (200 mL). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford the title compound as a beige oil (52g, 75%).MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1H NMR (CDCIs, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H).
75% With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; Intermediate (v)(R)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester To a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 ml addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 ml of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65 g) were added. A solution of (R)-3-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 eq) in 200 ml of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 (TLC developed in DCM). The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 mL of DCM. The organic layer was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 mL), and brine (200 mL). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford the title compound as a beige oil (52 g, 75%).MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCI3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H).
75% With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; Intermediate (i) (R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 mL addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 mL of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65g) were added. A solution of (3R)-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 mL of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 in DCM. The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 ml of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 ml), and brine (200 ml). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford 52 g (75% yield) of the title compound as a beige oil.MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCIs, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H).
75% With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; Intermediate (i)(R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 mL addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 mL of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65g) were added. A solution of (3R)-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 mL of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 in DCM. The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 ml of DCM. The organic solution was washed with 200 mL of H3PO (1 M) solution twice, followed by saturated NaHCO3 solution (200 ml), and brine (200 ml). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford 52 g (75% yield) of the title compound as a beige oil.MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCIs, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H).
75% With triethylamine;dmap; In dichloromethane; at 20℃;cooling with ice-water; Intermediate (i)(R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 mL addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 mL of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65g) were added. A solution of (3R)-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 mL of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 in DCM. The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 ml of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 ml), and brine (200 ml). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford 52 g (75% yield) of the title compound as a beige oil.MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCI3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H).
75% With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; Intermediate (i)(R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 mL addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 mL of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65g) were added. A solution of (3R)-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 mL of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 in DCM. The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 ml of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 ml), and brine (200 ml). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford 52 g (75% yield) of the title compound as a beige oil.MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCI3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H).
74% With pyridine; at 20℃; for 16h; To a stirred solution of R-(-)-N-Boc-3-pyrrolidinol (5.03 g, 26.9 mmol) in pyridine (30.0 mL) was added p-TsCl (5.63 g, 30.0 mmol) at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate (200.0 mL) and 1.0 N hydrochloric acid (200.0 mL) and separated. The organic layer was washed with water (2 * 100 mL), saturated sodium chloride (100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 80:20 to 50:50 heptane/ethyl acetate) to provide tert-butyl 3-(tosyloxy)pyrrolidine-1-carboxylate (6.79 g, 74%) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 5.05 (br s, 1H), 3.48-3.38 (m, 4H), 2.46 (s, 3H), 2.17-1.91 (m, 1H), 1.91-1.71 (m, 1H), 1.46 (s, 9H).
25% With dmap; triethylamine; In dichloromethane; at 20℃; for 10h;Inert atmosphere; A mixture of (R) -tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0 g, 5.3 mmol) , p-methyl benzene sulfonic chloride (1.5 g, 8.0 mmol) , triethylamine (1.1 g, 11 mmol) and N, N-dimethylaminopyridine (65 mg, 0.53 mmol) in DCM (10 mL) was stirred at rt for 10 h and diluted with water (20 mL) . The resulting mixture was extracted with DCM (10 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 5/1 to give (R) -tert-butyl 3- (tosyloxy) pyrrolidine-1-carboxylate as colorless liquid (460 mg, 25) .1H NMR (400 MHz, CDCl3) : δ ppm 7.79 (d, J 8.0 Hz, 2H) , 7.35 (d, J 7.7 Hz, 2H) , 5.04 (s, 1H) , 3.38-3.50 (m, 4H) , 2.45 (s, 3H) , 1.97-2.15 (m, 2H) , 1.43 (m, 9H) and MS-ESI: m/z 286.20 [M-55] +.

 

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