[ CAS No. 139986-03-1 ] {[proInfo.proName]}

Name: 139986-03-1|(R)-tert-Butyl 3-(tosyloxy)pyrrolidine-1-carboxylate|95%
Brand: Ambeed
SKU: A145459
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Quality Control of [ 139986-03-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 139986-03-1 ]

SDS Specification

Alternatived Products of [ 139986-03-1 ]

Product Details of [ 139986-03-1 ]

CAS No. :	139986-03-1	MDL No. :	MFCD16621198
Formula :	C₁₆H₂₃NO₅S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MWACHFODPQVXHF-CYBMUJFWSA-N
M.W :	341.42	Pubchem ID :	23560883
Synonyms :

Calculated chemistry of [ 139986-03-1 ]

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 :	81.29 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.5 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.3
Log Po/w (XLOGP3) :	2.65
Log Po/w (WLOGP) :	3.41
Log Po/w (MLOGP) :	2.26
Log Po/w (SILICOS-IT) :	1.44
Consensus Log Po/w :	2.61

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.42
Solubility :	0.129 mg/ml ; 0.000377 mol/l
Class :	Soluble
Log S (Ali) :	-4.01
Solubility :	0.0335 mg/ml ; 0.0000981 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-3.53
Solubility :	0.101 mg/ml ; 0.000294 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.71

Safety of [ 139986-03-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

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.

Upstream synthesis route of [ 139986-03-1 ]
Downstream synthetic route of [ 139986-03-1 ]

[ 139986-03-1 ] Synthesis Path-Upstream 1~4

1
[ 83220-73-9 ]
[ 98-59-9 ]
[ 139986-03-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine In dichloromethane at 20℃; for 8 h;	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
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 percent 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 percent). 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 (5percent 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"/>NaHCψ3 (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 percent). 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 percent 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 percent). 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 R_f 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 5percent MeOH in DCM) to afford the title compound as a beige oil (52g, 75percent). 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 R_f 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 5percent MeOH in DCM) to afford the title compound as a beige oil (52g, 75percent).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 R_f 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 5percent MeOH in DCM) to afford the title compound as a beige oil (52 g, 75percent).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 R_f 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 5percent MeOH in DCM) to afford 52 g (75percent 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 R_f 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 5percent MeOH in DCM) to afford 52 g (75percent 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 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 R_f 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 5percent MeOH in DCM) to afford 52 g (75percent 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 R_f 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 5percent MeOH in DCM) to afford 52 g (75percent 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%	at 20℃; for 16 h;	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, 74percent) 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 10 h; 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] ⁺.

Reference： [1] Patent: WO2008/133734, 2008, A2, . Location in patent: Page/Page column 40
[2] Patent: WO2009/52065, 2009, A1, . Location in patent: Page/Page column 31
[3] Patent: WO2009/52068, 2009, A1, . Location in patent: Page/Page column 15; 25-26
[4] Patent: WO2009/52062, 2009, A1, . Location in patent: Page/Page column 15; 26-27
[5] Patent: WO2010/65803, 2010, A1, . Location in patent: Page/Page column 28-29
[6] Patent: WO2011/143148, 2011, A1, . Location in patent: Page/Page column 33
[7] Patent: WO2011/143163, 2011, A1, . Location in patent: Page/Page column 27
[8] Patent: WO2011/143161, 2011, A1, . Location in patent: Page/Page column 21-22
[9] Patent: WO2011/143162, 2011, A1, . Location in patent: Page/Page column 21-22
[10] Patent: WO2011/143155, 2011, A1, . Location in patent: Page/Page column 20-21
[11] Patent: WO2011/143145, 2011, A1, . Location in patent: Page/Page column 23-24
[12] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 14, p. 4044 - 4047
[13] Patent: EP2202223, 2010, A1, . Location in patent: Page/Page column 46
[14] Patent: US6335445, 2002, B1, . Location in patent: Page column 102
[15] Patent: WO2016/34134, 2016, A1, . Location in patent: Paragraph 00468
[16] Chemische Berichte, 1997, vol. 130, # 3, p. 385 - 397

2
[ 98-59-9 ]
[ 101469-92-5 ]
[ 139986-03-1 ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine In dichloromethane at 20℃; Cooling with ice	Intermediate (xiii)(R)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250ml 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 R_f 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 5percent MeOH in DCM) to afford the title compound as a beige oil(52g, 75percent).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).
25%	With dmap; triethylamine In dichloromethane at 20℃; for 10 h;	The compound (R) -3- hydroxy-pyrrolidine-1-carboxylate (1.0g, 5.3mmol), methyl chloride (1.5g, 8.0mmol),three Ethylamine (1.1g, 11mmol) and 4-dimethylaminopyridine (65mg, 0.53mmol) was dissolved indichloromethane (10mL), the reaction at room temperature after 10h Stop the reaction, water (20 mL),dichloromethane (10mL × 3) was extracted, the combined organic phase was dried over anhydrous Na 2 SO 4,the solvent was removed Concentrate was separated by column chromatography (eluent: Petroleumether /EtOAc (v / v) = 5/1), to give 460mg of colorless liquid: (R) -3- pairs Methylphenylsulfonyloxy pyrrolidine-1-carboxylate, yield: 25percent.

Reference： [1] Patent: WO2010/65798, 2010, A1, . Location in patent: Page/Page column 33-34
[2] Patent: CN105399698, 2016, A, . Location in patent: Paragraph 1334-1336

3
[ 24424-99-5 ]
[ 139986-03-1 ]

Reference： [1] Chemische Berichte, 1997, vol. 130, # 3, p. 385 - 397
[2] Patent: WO2008/133734, 2008, A2,

4
[ 139986-03-1 ]
[ 147081-44-5 ]

Reference： [1] Patent: WO2016/34134, 2016, A1,
[2] Patent: CN105399698, 2016, A,

[ 139986-03-1 ] Synthesis Path-Downstream 1~2

1
[ 109431-87-0 ]
[ 98-59-9 ]
[ 139986-03-1 ]

Yield	Reaction Conditions	Operation 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] +.

Reference： [1]Patent: WO2008/133734,2008,A2 .Location in patent: Page/Page column 40
[2]Patent: TW2019/38538,2019,A .Location in patent: Page/Page column 28-29
[3]Patent: WO2009/52065,2009,A1 .Location in patent: Page/Page column 31
[4]Patent: WO2009/52068,2009,A1 .Location in patent: Page/Page column 15; 25-26
[5]Patent: WO2009/52062,2009,A1 .Location in patent: Page/Page column 15; 26-27
[6]Patent: WO2010/65803,2010,A1 .Location in patent: Page/Page column 28-29
[7]Patent: WO2011/143148,2011,A1 .Location in patent: Page/Page column 33
[8]Patent: WO2011/143163,2011,A1 .Location in patent: Page/Page column 27
[9]Patent: WO2011/143161,2011,A1 .Location in patent: Page/Page column 21-22
[10]Patent: WO2011/143162,2011,A1 .Location in patent: Page/Page column 21-22
[11]Patent: WO2011/143155,2011,A1 .Location in patent: Page/Page column 20-21
[12]Patent: WO2011/143145,2011,A1 .Location in patent: Page/Page column 23-24
[13]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4044 - 4047
[14]Patent: EP2202223,2010,A1 .Location in patent: Page/Page column 46
[15]Patent: US6335445,2002,B1 .Location in patent: Page column 102
[16]Patent: WO2016/34134,2016,A1 .Location in patent: Paragraph 00468
[17]Chemische Berichte,1997,vol. 130,p. 385 - 397

2
[ 61893-00-3 ]
[ 139986-03-1 ]
C₁₆H₂₄N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With caesium carbonate In dimethyl sulfoxide at 60℃; for 4h; Inert atmosphere;	PREPARATION OF INTERMEDIATE 141 To a solution of 5,6-dimethylpyridin-3-ol (CAS: 61893-00-3; 100 mg, 0.81 mmol) in DMSO (2.56 mL) under N2 atmosphere were added CS2CO3 (337 mg, 1.03 mmol) and (R)-tert- butyl 3-(tosyloxy)pyrrolidine-l-carboxylate (CAS: 139986-03-1; 252 mg, 0.74 mmol). The reaction mixture was stirred at 60 °C for 4 h. Water was added and the mixture was extracted with EtOAc. The organic layer was dried (Na2S04), filtered and concentrated in vacuo. The crude mixture was purified by flash column chromatography (silica, EtOAc in heptane, gradient from 0/100 to 80/20). The desired fractions were collected and the solvents were evaporated in vacuo to afford intermediate 141 (146 mg, 68%) as a light yellow solid.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2019/243527, 2019, A1 Location in patent: Page/Page column 80

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P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 139986-03-1 ] {[proInfo.proName]}

Quality Control of [ 139986-03-1 ]

Related Doc. of [ 139986-03-1 ]

Product Details of [ 139986-03-1 ]

Calculated chemistry of [ 139986-03-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 139986-03-1 ]

Application In Synthesis of [ 139986-03-1 ]

[ 139986-03-1 ] Synthesis Path-Upstream 1~4

[ 139986-03-1 ] Synthesis Path-Downstream 1~2

Related Functional Groups of [ 139986-03-1 ]

Aryls

Amides

Sulfonates

Related Parent Nucleus of [ 139986-03-1 ]

Aliphatic Heterocycles

Pyrrolidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 139986-03-1 ]

Related Parent Nucleus of
[ 139986-03-1 ]