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[ CAS No. 2133-40-6 ] {[proInfo.proName]}

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Chemical Structure| 2133-40-6
Chemical Structure| 2133-40-6
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Product Details of [ 2133-40-6 ]

CAS No. :2133-40-6 MDL No. :MFCD00012708
Formula : C6H12ClNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :HQEIPVHJHZTMDP-JEDNCBNOSA-N
M.W : 165.62 Pubchem ID :2733200
Synonyms :
Methyl prolinate hydrochloride

Calculated chemistry of [ 2133-40-6 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.83
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 43.81
TPSA : 38.33 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.66 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 0.91
Log Po/w (WLOGP) : 0.33
Log Po/w (MLOGP) : 0.35
Log Po/w (SILICOS-IT) : 0.63
Consensus Log Po/w : 0.45

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.31
Solubility : 8.15 mg/ml ; 0.0492 mol/l
Class : Very soluble
Log S (Ali) : -1.3
Solubility : 8.29 mg/ml ; 0.0501 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.85
Solubility : 23.5 mg/ml ; 0.142 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.85

Safety of [ 2133-40-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 2133-40-6 ]

* 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 [ 2133-40-6 ]
  • Downstream synthetic route of [ 2133-40-6 ]

[ 2133-40-6 ] Synthesis Path-Upstream   1~21

  • 1
  • [ 2133-40-6 ]
  • [ 22348-32-9 ]
Reference: [1] Journal of Fluorine Chemistry, 2007, vol. 128, # 1, p. 34 - 39
  • 2
  • [ 2133-40-6 ]
  • [ 1193-62-0 ]
YieldReaction ConditionsOperation in experiment
89% With β-cyclodextrin; 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In water at 20℃; for 4 h; General procedure: To an aqueous solution of βcyclodextrin (1.0 mmol of β-CD in 5mL of water), IBX (2.0 mmol), N-benzylpyrrolidine (1.0 mmol) was added while stirring, and stirring was continued for the stipulated reaction time as shown in the table at room temperature. After completion of reaction as indicated by TLC, the reaction mixture was extracted with ethylacetate (3 X 5mL), the combined organic layers were washed with saturated brine solution, dried and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate (9:1) as an eluent.
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 34, p. 4481 - 4484
  • 3
  • [ 67-56-1 ]
  • [ 1447695-69-3 ]
  • [ 39994-75-7 ]
  • [ 6306-52-1 ]
  • [ 60667-85-8 ]
  • [ 18598-74-8 ]
  • [ 18598-63-5 ]
  • [ 2133-40-6 ]
Reference: [1] Journal of Natural Products, 2013, vol. 76, # 7, p. 1388 - 1391
  • 4
  • [ 67-56-1 ]
  • [ 1447695-69-3 ]
  • [ 39994-75-7 ]
  • [ 6306-52-1 ]
  • [ 60667-85-8 ]
  • [ 18598-74-8 ]
  • [ 18598-63-5 ]
  • [ 2133-40-6 ]
Reference: [1] Journal of Natural Products, 2013, vol. 76, # 7, p. 1388 - 1391
  • 5
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  • [ 147-85-3 ]
  • [ 2133-40-6 ]
YieldReaction ConditionsOperation in experiment
100% for 2 h; Inert atmosphere; Reflux Methyl (S)-pyrrolidine-2-carboxylate was prepared29 from (S)-proline (10.2 g, 88.6 mmol) and SOCl2 (11.6 g, 7.10 mL, 97.5 mmol) in refluxing MeOH (60 mL) for 2 h. Subsequent removal of the excess solvent and SOCl2 yielded the proline ester (15.9 g, quant.) as a grey oil.30 The title compound 1 was prepared according to the literature15 from 2-fluoro-1-nitro benzene (6.92 g, 5.18 mL, 49.0 mmol) and methyl (S)-pyrrolidine-2-carboxylate (7.55 g, 45.6 mmol) as bright yellow crystals (12.0 g, quant.) and was used without further purification.
100% at 0 - 80℃; for 1.5 h; To a solution of L-proline (10 g, 86.9 mmol) in MeOH (100 mL) was added SOCl2 (12.6 mL, 174 mmol) at 0 °C. The mixture was stirred at 80 °C for 1.5 hours and concentrated in vacuo to afford the title compound 26-1 as a white solid (14.3 g, 100percent). The compound was characterized by the following spectroscopic data: MS-ESI: m/z 130.2 [M+H]+; and1H NMR (400 MHz, CD3OD): δ 4.45 (m, 1H), 3.85 (s, 1H), 3.40 (m, 2H), 2.42 (m, 1H), 2.12 (m, 1H), 2.07 (m, 1H).
100% at 0 - 80℃; for 1.5 h; To a solution of L-proline (10 g, 86.9 mmol) in MeOH (100 mL) was added SOCl2 (12.6 mL, 174 mmol) at 0°C. The mixture was stirred at 80 °C for 1.5 hours and concentrated in vacuo to afford the title compound 26-1 as a whitesolid (14.3 g, 100percent). The compound was characterized by the following spectroscopic data:MS-ESI: m/z 130.2 [M+H]+; and1H NMR (400 MHz, CD3OD): δ 4.45 (m, 1H), 3.85 (s, 1H), 3.40 (m, 2H), 2.42 (m, 1H), 2.12 (m, 1H), 2.07 (m, 1H).
100% at 25℃; for 12 h; To the solution L-proline (15.0 g, 130.3 mmol, 1.0 equiv) in MeOH (200 mL) at 0 °C,was added thionyl chloride (12.3 mL, 156.4 mmol, 1.2 equiv) over a period of 10 minutes. Thereaction mixture was slowly warm to room temperature and stirred it for 12 h. The resultedmixture was concentrated under reduced pressure by using KOH trapper attached rotaryevaporator and then the flask was connected with vacuum pump over a period of 1 h to affordcompound (14b) as colorless oil.
99.6%
Stage #1: With pyridine; hydrogenchloride In 1,2-dichloro-ethane at 20℃; for 0.5 h;
Stage #2: With hydrogenchloride In 1,2-dichloro-ethane at 84℃; for 3 h; Reflux
, 11.5 g (0.1 mol) of proline,20 ml of dichloroethane and step 2)The resulting mother liquor (i.e., step 2) was sprinkled with 20 ml of filtrate) into a 250 ml three-necked flask,A hydrogen chloride gas was introduced at a rate of 1.25 ml / s,Reaction at room temperature for 0.5 h,Consumption of HCl 0.1mol., then 4.16 g (0.13 mol) of methanol was put into a three-necked flask,Continue to pass hydrogen chloride gas (0.05ml / s) under reflux conditions,The aqueous dichloroethane was distilled off,And anhydrous dichloroethane was added dropwise to the reaction system at the same rate (using step 2)The dichloroethane obtained after the water treatment) was maintained so that the amount of dichloroethane in the reaction remained substantially unchanged. After 3 hours of reaction,Consumption of HCl 0.024 mol, co-distillation of azeotrope (water-containing dichloroethane) about 140ml.The resulting reaction solution was cooled to room temperature, and then the remaining dichloroethane (solvent) and methanol were removed by vacuum distillation (10 mmHg pressure, 40C). The reaction mixture was recrystallized at -10C to precipitate a solid,Washed with 20 ml of 0 ° C ice dichloroethane and filtered to obtain a filtrate and a filter cake, respectively,The filter cake was dried at 40 ° C for 5 hours to give a yield of 99.6percent of 16.5 g (0.0996 mol) of proline methyl ester hydrochloride.The distilled azeotrope (aqueous dichloroethane) was subjected to water removal to give anhydrous dichloroethane,The anhydrous dichloroethane can be used in the presence of anhydrous dichloroethane in the following cyclic application (thereby enabling recycling).The filtrate was steamed (40 ° C) to 20 ml as the next circulating mother liquor (i.e., as a starting materialIn the middle).The total amount of HCl in step 3) was 0.124 mol.
99% at 0℃; for 2.5 h; Reflux SOCl2 (76 mL, 1.04 mol) was added dropwise to a solution of (S)-proline (28.64 g, 0.25 mol)in MeOH (500 mL) at 0 °C. When the addition was complete, the mixture was refluxed for2.5 h. After cooling to room temperature, the solvent was evaporated under reduced pressure.The resultant (S)-1’ was obtained in 99percent yield (42 g, 0.25 mol) as a pale-yellow oil and wasused in the alkylation step without further purification.
98% Cooling with ice Optically active L-proline amino acid was purchased from LOBA Chemie and was commercial grade and used without further purification for thesynthesis of methyl L-prolinate hydrochloride. About1.0 g (6.0379 mmol) of L-proline was treated with methanol in the presence of 0.7183 g (6.0379 mmol)of SOCl2 to form this ester. It was synthetically an effective and well-known acid-catalyzed method for this esterification process.[11] Since the addition ofSOCl2 was an exothermic reaction, the entire reactionsystem was maintained under ice bath for about24 hr in a fume hood chamber. The completion ofthe reaction and purity of the product were checkedduring reasonable intervals using precoated Merckgraded thin layer chromatographic (TLC) plates inthe mixture of the hexane and ethyl acetate solventsystem. Finally, the formed ester was separated usinga Roto Vacuum Evaporator branded from BucheLabortechnike AG with appropriate temperatureand pressure. The percentage of yield was >98percent.The scheme of the reaction is shown in Fig.
96% Inert atmosphere To a solution of proline (5.00 g, 43.5 mmol) in MeOH (250 mL) at 0 °C was added thionyl chloride (10.3 mL, 86.9 mmol) (dropwise). The reaction was warmed to 50 °C and stirred for 20 h. Cooled the reaction to room temperature and concentrated under vacuum to afford methyl ester 6 as a clear yellow oil (6.88 g, 96percent); 1H-NMR (400 MHz, CDCl3) δ 10.57 (br s, 1H), 9.05 (br s, 1H), 4.51 (s, 1H), 3.85 (s, 3H), 3.62-3.52 (m, 2H), 2.47-2.41 (m, 1H), 2.24-2.07 (m, 3H).
143.9 g at 0℃; for 12 h; Reflux To a stirring solution of L-proline (SMI) (100 g, 0.87 mol) in methanol (800 mL) was slowly added thionyl chloride (76.9 mL, 1.04 mol) at 0°C. The reaction mixture was slowly warmed to RT and heated to reflux for 12 h. After consumption of the starting material (by TLC), the reaction was concentrated under reduced pressure to afford A (143.9 g, HCl salt). H-NMR: (400 MHz, CDC13): δ 3.89 (s, 3H), 3.68-3.62 (m, 2H), 3.59-3.47 (m, 2H), 2.49-2.37 (m, 1H), 2.27-2.05 (m, 3H). LCMS (m/z): 166 [M++l]
143.9 g at 0℃; Reflux To a stirred solution of L-proline 1 (100 g, 0.87 mol) in methanol (800 mL) was added thionyl chloride (76.9 mL, 1.04 mol) slowly drop wise at 0°C. The reaction mixture was heated to reflux for 12 h. After consumption of the starting material (by TLC), the reaction was concentrated under reduced pressure. The residue was washed with w-hexane to afford 2 (143.9 g, HC1 salt). 1H-NMR: (400 MHz, CDC13): δ 3.89 (s, 3H), 3.68-3.62 (m, 2H), 3.59-3.47 (m, 2H), 2.49-2.37 (m, 1H), 2.27-2.05 (m, 3H). LCMS (m/z): 166 [M++l]

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YieldReaction ConditionsOperation in experiment
88%
Stage #1: at 70℃; for 7.5 h; Inert atmosphere; Cooling with ice
Stage #2: With hydrogenchloride In dichloromethane; ethyl acetate at 20℃; for 0.0833333 h; Inert atmosphere
To a solution of (S) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (1.50 g, 6.97 mmol) in methanol (20 mL) was added sulfoxide chloride (0.51 mL, 6.97 mmol) dropwise in an ice-bath. The mixture was stirred in the ice-bath for 30 min, and then stirred at 70 for 7 h. The reaction mixture was concentrated, and DCM (8 mL) and a HCl in EtOAc solution (4 M, 6 mL) were added. The resulting mixture was stirred at rt for 5 min, and then concentrated to give the title compound as white thick oil (800 mg, 88) .1H NMR (400 MHz, CD3OD) : δ ppm 4.47 (t, J 7.8 Hz, 1H) , 3.88 (s, 3H) , 3.37-3.45 (m, 2H) , 2.41-2.50 (m, 1H) , 2.07-2.21 (m, 3H) .
88%
Stage #1: at 70℃; for 7.5 h; Cooling with ice
Stage #2: With hydrogenchloride In dichloromethane; ethyl acetate at 20℃; for 0.0833333 h;
To Boc-L- proline (1.50g, 6.97mmol) in methanol (20 mL) was added dropwise thionyl chloride (0.51 mL underice-cooling, 6.97mmol), The reaction under ice 30min, 70 ° C 7H reaction, the solvent is removed,dichloromethane (8mL) and HCl in ethyl acetate Solution (4M, 6mL), stirred at rt for 5min, the solvent wasremoved to give 800mg of white viscous material, yield: 88percent.
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YieldReaction ConditionsOperation in experiment
91% With triethylamine In dichloromethane at 20℃; for 17 h; Inert atmosphere; Cooling Et3N (77 mL, 55.9 g, 0.55 mol) was added dropwise to a cold solution of (S)-1’ (41.2g, 0.25mol) in dry CH2Cl2 under inert atmosphere. Then, benzyl bromide (33.2 mL, 47.74 g, 0.28mol) was added to the thick reaction mixture, allowing it to reach room temperature aftercomplete addition. This solution was stirred during 17 h and latter, it was extracted withCH2Cl2 (3 x 400 mL). The combined organic layers were dried over Na2SO4. After filtrationand evaporation of the solvents, the crude residue was purified by distillation under reducedpressure (120 °C, 0.5-1 mmHg), giving 49.6 g (0.23 mol) of the product, (S)-1’’, as a clearoil in 91 percent yield.
21% With triethylamine In dichloromethane at 0 - 20℃; for 24 h; To a stirring solution of compound II (18 g, 108 mmol) in DCM (200 mL) was added TEA (45.35 mL, 326 mmol) followed by benzyl bromide (15.5 mL, 130 mmol) at 0 °C and stirred at RT for 24 h. After completion of the reaction (by TLC) was diluted with water (75 mL) and EtOAc (500 mL). The organic layer was washed with water (2 x 100 mL), brine solution (2 x 50 mL). The organic layer was dried over anhydrous a2S04 and concentrated under vacuum. Obtained crude material was purified by column chromatography eluting with 10percent EtOAc/Hexane to afford J J (5 g, 21percent) as oily liquid. 1H-NMR: (400 MHz, DMSO-i/6): δ 7.32-7.22 (m, 5H), 3.86-3.80 (m, 1H), 3.58 (s, 3H), 3.48- 3.24 (m, 2H), 2.85-2.80 (m, 1H), 2.38-2.32 (m, 1H), 2.10-1.98 (m, 1H), 1.85-1.69 (m, 3H) LCMS (ESI): m/z 220.28 [M++l]
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  • [ 2133-40-6 ]
  • [ 100-44-7 ]
  • [ 113304-84-0 ]
Reference: [1] Organic Preparations and Procedures International, 2011, vol. 43, # 5, p. 477 - 483
[2] European Journal of Organic Chemistry, 2002, # 19, p. 3304 - 3314
[3] European Journal of Organic Chemistry, 2004, # 1, p. 129 - 137
  • 18
  • [ 24424-99-5 ]
  • [ 2133-40-6 ]
  • [ 145681-01-2 ]
YieldReaction ConditionsOperation in experiment
95% With triethylamine In dichloromethane at 0 - 20℃; for 16 h; To a stirring solution of 1 (35 g, 0.22 mol) in CH2C12 (175 niL) were added Et3N (90 rnL, 0.65 mol) followed by Boc-anhydride (56.9 mL, 0.26 mol) at 0°C. The reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (100 mL) and extracted with CH2CI2 (2x 100 mL). The organic layer was washed with water, brine, dried over Na2S04 and concentrated. Obtained crude material was purified by silica gel column chromatography eluting with 30percent EtOAc/Hexane to afford 2 (41 g, 95percent). 1H-NMR: (400 MHz, CDC13) (Rotamers): δ 4.25-4.21 (m, 1H), 3.75 (s, 3H), 3.57-3.26 (m, 2H), 2.29-2.10 (m, 1H), 1.99-1.75 (m, 3H), 1.45 (s, 9H). LCMS (ESI): 130 [(M++l)-Boc]
95% With triethylamine In dichloromethane at 0 - 20℃; for 16 h; To a stirred solution of 1 (35 g, 0.22 mol) in CH2C12 (175 mL) were added Et3N (90 mL, 0.65 mol) followed by Boc-anhydride (56.9 mL, 0.26 mol) at 0 °C. The reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (100 mL) and extracted with CH2CI2 (2x 100 mL). The organic layer was washed with water, brine, dried over Na2S04 and concentrated. The crude material was purified by silica gel column chromatography eluting with 30percent EtOAc/Hexane to afford 2 (41 g, 95percent). H-NMR: (400 MHz, CDC13) (Rotamers): δ 4.25-4.21 (m, 1H), 3.75 (s, 3H), 3.57-3.26 (m, 2H), 2.29-2.10 (m, 1H), 1.99-1.75 (m, 3H), 1.45 (s, 9H). LCMS (m/z): 130 [(M++l)-Boc]
95% With triethylamine In dichloromethane at 0 - 20℃; for 16 h; To a stirring solution of compound 4S-AJ (35 g, 0.22 mol) in CH2Cl2 (175 mL) were added Et3N (90 mL, 0.65 mol) followed by Boc-anhydride (56.9 mL, 0.26 mol) at 0 °C. The reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction was diluted with water (100 mL) and extracted with CH2Cl2 (2x 100 mL). The organic layer was washed with water (1 x 100 mL), brine (1 x 100 mL) and the separated organic layer was dried over Na2SO4 and concentrated. Obtained crude material was purified by silica gel column chromatography eluting with 30percent EtOAc/Hexane to afford compound 4S- AK (41 g, 95percent). 1H-NMR: (400 MHz, CDCl3): δ 4.25-4.21 (m, 1H), 3.75 (s, 3H), 3.57-3.26 (m, 2H), 2.29-2.10 (m, 1H), 1.99-1.75 (m, 3H), 1.45 (s, 9H). LCMS (ESI): 130 [(M++1)-Boc]
Reference: [1] Patent: WO2014/120784, 2014, A1, . Location in patent: Paragraph 00111
[2] Patent: WO2014/120783, 2014, A1, . Location in patent: Paragraph 00110
[3] Patent: WO2014/120786, 2014, A1, . Location in patent: Paragraph 0134
[4] Patent: US2008/76758, 2008, A1, . Location in patent: Page/Page column 91; 93
[5] Journal of Organic Chemistry, 2008, vol. 73, # 7, p. 2533 - 2541
[6] Patent: WO2007/122410, 2007, A1, . Location in patent: Page/Page column 103
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  • [ 24424-99-5 ]
  • [ 2133-40-6 ]
  • [ 73323-65-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6672 - 6684
  • 20
  • [ 2133-40-6 ]
  • [ 27957-91-1 ]
YieldReaction ConditionsOperation in experiment
80% With formaldehyd; sodium acetate trihydrate In hydrogenchloride 36 b. N-Methyl Proline Methyl Ester
To a methanolic (250 mL) solution of L-proline methyl ester HCl (10.42 g, 62.92 mmol, from step a above), sodium acetate trihydrate (8.6 g, 63.2 mmoL) and 37 wt percent aqueous formaldehyde (20 mL) was added 10percent Pd/C (1.05 g), and the reaction mixture was placed under 4 atmosphere H2 pressure.
Upon completion of the reaction the catalyst was removed by filtration, the methanolic solution concentrated, and the residue was dissolved in 10percent aq. HCl (~60 mL) and washed with ether (3*100 mL).
The aqueous layer was basified with K2 CO3 (solid) to pH ~12 and extracted with CH2 Cl2 (3*75 mL) The combined CH2 Cl2 layers were dried (MgSO4) and concentrated to afford the crude product as a clear oil (7.19 g, 80percent).-- MS (DCl/NH3) m/e (M+H)+, 1 H-NMR (CDCl3) δ: 1.78-2/03
(m, 3H); 2.13-2.21 (m, 1H); 2.29-2.38 (m, 1H); 2.42 (s, 3H); 2.97-3.02 (dd, 1H): 3.13-3.19 (m, 1H); 3.75 (s, 3H).
Reference: [1] Patent: US5409946, 1995, A,
  • 21
  • [ 50-00-0 ]
  • [ 2133-40-6 ]
  • [ 27957-91-1 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 19, p. 5138 - 5141
[2] Synthesis, 1995, # 7, p. 772 - 774
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