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Chemical Structure| 608141-42-0
Chemical Structure| 608141-42-0
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Product Details of [ 608141-42-0 ]

CAS No. :608141-42-0 MDL No. :MFCD22677268
Formula : C12H19NO4S Boiling Point : -
Linear Structure Formula :- InChI Key :BXUJVINGXQGNFD-SNVBAGLBSA-N
M.W : 273.35 Pubchem ID :11282264
Synonyms :

Calculated chemistry of [ 608141-42-0 ]

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.5
Num. rotatable bonds : 6
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 70.48
TPSA : 87.0 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) : -7.61 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.23
Log Po/w (XLOGP3) : 0.5
Log Po/w (WLOGP) : 1.89
Log Po/w (MLOGP) : 0.75
Log Po/w (SILICOS-IT) : 1.28
Consensus Log Po/w : 1.33

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.7
Solubility : 5.45 mg/ml ; 0.0199 mol/l
Class : Very soluble
Log S (Ali) : -1.9
Solubility : 3.46 mg/ml ; 0.0127 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.46
Solubility : 0.0939 mg/ml ; 0.000344 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.83

Safety of [ 608141-42-0 ]

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 [ 608141-42-0 ]

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

  • Upstream synthesis route of [ 608141-42-0 ]
  • Downstream synthetic route of [ 608141-42-0 ]

[ 608141-42-0 ] Synthesis Path-Upstream   1~24

  • 1
  • [ 608141-42-0 ]
  • [ 1188-21-2 ]
  • [ 608141-43-1 ]
YieldReaction ConditionsOperation in experiment
98.3% for 1 h; Reflux Under a nitrogen atmosphere, a dry 1000 ml glass flask equipped with a mechanical stirrer, a thermometer and a condenser was added (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine (110 g), N-acetylleucine 69.3 g (0.4 mol) and 500g of methanol, Heated to reflux for 1 hour with stirring and then cooled to ambient temperature in a stirred state and stirred at room temperature for 3 hours, filtered and the filter cake was washed with methanol, then the cake was dried under vacuum to constant weight. To give 176.3 g of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine N-acetyl-1-leucine (Optical purity 99.6percent) yield 98.3percent. Chiral HPLC (ethanol: 20 mM KH2PO4 = 1:99, pH = 7.0, Agilent's ES-OVM chiral column, 150 mm x 4.6 mm, flow rate 0.5 ml/min, detection wavelength 240 nm): 18.1 min (S-isomer, 99.6percent), 25.0 min (R-isomer, 0.4percent).
1670 g for 1 h; Reflux To a stirred solution l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (2500gm) in methanol (20.01it) was added N-acetyl-L-Leucine (950.0gm) slowly at 25°C and then the reaction mixture was heated to reflux temperature and maintained for 1.Ohr. The reaction mass was cooled to 25-30°C and stirred for 4.0 hr at 25-30°C. The product was filtered and washed with methanol and dried under vacuum at 60°C for 4.0 hr to obtain 2000.0gm of crude product. The crude product was subjected to methanol purification to obtain 1670gm of N-acetyl L-leucine salt of (5)-2-(3-ethoxy-4- methoxyphenyl)-l-(methylsulphonyl) eth-2-ylamine. chiral purity >99.5percent.
Reference: [1] Patent: CN104447445, 2016, B, . Location in patent: Paragraph 0083; 0084
[2] Patent: CN105218428, 2016, A, . Location in patent: Paragraph 0012; 0019; 0020
[3] Patent: WO2017/33116, 2017, A1, . Location in patent: Paragraph 00115
  • 2
  • [ 1450657-43-8 ]
  • [ 608141-42-0 ]
YieldReaction ConditionsOperation in experiment
89.2% With 10% palladium on activated carbon; Degussa type; hydrogen In methanol at 25℃; for 24 h; In a 50 mL hydrogenation tube, the obtained 1.35 g of a white solid was dissolved in 20 mL of methanol, and 270 mgOf 10percent Pd / C, charged with 0.1 MPa of hydrogen, stirred at 25 ° C for 24 h. Filtration, steaming to remove the solvent, the crude over-alkaline trioxide(S) -2- [1- (3-ethoxy-4-methoxyphenyl)] - 1-methanesulfonyl-2-ethylamine as a white solid,The reaction yield was 89.2percent and the enantiomeric excess was 94.9percent.
Reference: [1] Patent: CN104761474, 2016, B, . Location in patent: Paragraph 0040; 0045
[2] Patent: WO2016/202806, 2016, A1, . Location in patent: Page/Page column 19
[3] Patent: WO2017/46319, 2017, A1, . Location in patent: Page/Page column 20-21
  • 3
  • [ 608141-43-1 ]
  • [ 608141-42-0 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydroxide In dichloromethane; water at 15 - 25℃; for 0.25 h; Example 3
Preparation of (1S)-1-(3-Ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine
After a mixture of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine N-acetyl-L-Leucine salt (1.10 kg, 2.46 moles), deionized water (4.40 L), and dichloromethane (DCM, 5.50 L) was charged into a reaction vessel, a solution of sodium hydroxide (196.0 g, 4.90 moles) in 1.00 L of deionized water was charged into the reaction vessel over about 5 minutes at 15-25° C.
The resulting mixture was stirred for at least 10 minutes at 15-25° C. and then the aqueous and organic phases were allowed to separate.
The pH of the upper aqueous phase was maintained or adjusted at pH 13-14.
The phases were separated and the upper aqueous phase was extracted with DCM (2*4.4 L).
The pH of the aqueous phase was maintained at 13-14 throughout the extractions.
The DCM extracts were combined and washed with deionized water (3.3 L) until the pH of the aqueous phase reached 11 or less.
DCM was removed under vacuum below 35° C.
The water content of the residual solid should be <0.1percent w/w as measured by Karl Fisher titration.
The residual solid was dried azeotropically with more DCM.
The solid was dried to a constant weight in vacuo at 30-35° C. to give (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine as a white powder (639.0-672.0 g, 95-100percent yield).
100% With sodium hydroxide In dichloromethane; water at 15 - 25℃; for 0.25 h; [011 8j After a mixture of (1 S)- 1 -(3 -ethoxy-4-methoxyphenyl)-2-methanesulfonyl- ethylamine N-acetyl-L-Leucine salt (1.10 kg, 2.46 moles), deionized water (4.40 L), and dichloromethane (DCM, 5.50 L) was charged into a reaction vessel, a solution of sodium hydroxide (196.0 g, 4.90 moles) in 1.00 L of deionized water was charged into the reaction vessel over about 5 minutes at 15-25°C. The resulting mixture was stirred for at least 10 minutes at 15-25°C and then the aqueous and organic phases were allowed to separate. The pH of the upper aqueous phase was maintained or adjusted at pH 13-14. The phases were separated and the upper aqueous phase was extracted with DCM (2x4.4 L). The pH of the aqueous phase was maintained at 13-14 throughout the extractions. The DCM extracts were combined and washed with deionized water (3.3 L) until the pH of the aqueous phase reached 11 or less. DCM was removed under vacuum below 35°C. The water content of the residual solid should be <0.1percent w/w as measured by Karl Fisher titration. The residual solid was dried azeotropically with more DCM. The solid was dried to a constant weight in vacuo at 30-35°C to give (1S)-1-(3-ethoxy-4- methoxyphenyl)-2-methanesulfonyl-ethylamine as a white powder (639.0-672.0 g, 95-100percent yield).
100% With sodium hydroxide In dichloromethane; water at 15 - 25℃; for 0.25 h; 6.5.3.
Preparation of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine
After a mixture of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine N-acetyl-L-Leucine salt (1.10 kg, 2.46 moles), deionizer water (4.40 L), and dichloromethane (DCM, 5.50 L) was charged into a reaction vessel, a solution of sodium hydroxide (196.0 g, 4.90 moles) in 1.00 L of deionizer water was charged into the reaction vessel over about 5 minutes at 15-25° C.
The resulting mixture was stirred for at least 10 minutes at 15-25° C. and then the aqueous and organic phases were allowed to separate.
The pH of the upper aqueous phase was maintained or adjusted at pH 13-14.
The phases were separated and the upper aqueous phase was extracted with DCM (2*4.4 L).
The pH of the aqueous phase was maintained at 13-14 throughout the extractions.
The DCM extracts were combined and washed with deionizer water (3.3 L) until the pH of the aqueous phase reached 11 or less.
DCM was removed under vacuum below 35° C.
The water content of the residual solid should be <0.1percent w/was measured by Karl Fisher titration.
The residual solid was dried azeotropically with more DCM.
The solid was dried to a constant weight in vacuo at 30-35° C. to give (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine as a white powder (639.0-672.0 g, 95-100percent yield).
99.3% With sodium hydroxide In dichloromethane at 0 - 5℃; for 2 h; Example 7: Preaparation of (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine (II)
Into a 200 ml glass flask was added sequentially 500g of dichloromethane, 44.5g (0.1mol) (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine N-acetyl-L-leucine salt (IV) (prepared as described in Example 5), and 11g of 40percent sodium hydroxide. The reaction was stirred at 0-5°C for 2 hours. The solution was extracted with dichloromethane. 3g of dichloromethane phase was dried over anhydrous sodium sulfate and filtered. After distilling off the dichloromethane, 27.1g (S)-1-(4-methoxy-3-ethoxyphenyl)-2-methanesulfonylethylamine (II) was obtained. Optical purity 99.9percent, Yield 99.3percent.
95% With sodium hydroxide In dichloromethane; water 6.5.3.
Preparation of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine
After a mixture of (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine N-acetyl-L-Leucine salt (1.10 kg, 2.46 moles), deionized water (4.40 L), and dichloromethane (DCM, 5.50 L) was charged into a reaction vessel, a solution of sodium hydroxide (196.0 g, 4.90 moles) in 1.00 L of deionized water was charged into the reaction vessel over about 5 minutes at 15-25° C.
The resulting mixture was stirred for at least 10 minutes at 15-25° C. and then the aqueous and organic phases were allowed to separate.
The pH of the upper aqueous phase was maintained or adjusted at pH 13-14.
The phases were separated and the upper aqueous phase was extracted with DCM (2*4.4 L).
The pH of the aqueous phase was maintained at 13-14 throughout the extractions.
The DCM extracts were combined and washed with deionized water (3.3 L) until the pH of the aqueous phase reached 11 or less.
DCM was removed under vacuum below 35° C.
The water content of the residual solid should be <0.1percent w/was measured by Karl Fisher titration.
The residual solid was dried azeotropically with more DCM.
The solid was dried to a constant weight in vacuo at 30-35° C. to give (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine as a white powder (639.0-672.0 g, 95-100percent yield).

Reference: [1] Patent: US2011/87033, 2011, A1, . Location in patent: Page/Page column 11
[2] Patent: WO2015/175773, 2015, A1, . Location in patent: Paragraph 0118
[3] Patent: US9272035, 2016, B2, . Location in patent: Page/Page column 29
[4] Patent: CN105348172, 2016, A, . Location in patent: Paragraph 0066; 0067
[5] Patent: US2012/276087, 2012, A1,
[6] Patent: WO2015/175956, 2015, A1, . Location in patent: Paragraph 0193
  • 4
  • [ 1450657-31-4 ]
  • [ 608141-42-0 ]
YieldReaction ConditionsOperation in experiment
70% With bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate; (R)-(-)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; hydrogen In 2,2,2-trifluoroethanol at 50℃; for 18 h; Inert atmosphere Example 2
(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (H-CH2-CH3-Compound D)
A solution of bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (36 mg, 0.074 mmol) and (S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (40 mg, 0.074 mmol) in 25 mL of 2,2,2-trifluoroethanol was prepared under nitrogen.
To this solution was then charged 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine (2.0 g, 7.4 mmol).
The resulting mixture was heated to 50° C. and hydrogenated under 90 psig hydrogen pressure.
After 18 h, the mixture was cooled to ambient temperature and removed from the hydrogenator.
The mixture was evaporated and the residue was purified by chromatography on a C18 reverse phase column using a water-acetonitrile gradient.
The appropriate fractions were pooled and evaporated to ˜150 mL.
To this solution was added brine (20 mL), and the resulting solution was extracted with EtOAc (3*50 mL).
The combined organic layers were dried (MgSO4) and evaporated to provide the product as a white crystalline solid (1.4 g, 70percent yield); achiral HPLC (Hypersil BDS C8, 5.0 μm, 250*4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1percent aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1percent aqueous TFA/MeOH over the next 15 min): 9.11 (99.6percent); chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250*4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-i-PrOH-diethylamine): 7.32 (97.5percent), 8.26 (2.47percent); 1H NMR (DMSO-d6) δ 1.32 (t, J=7.0 Hz, 3H), 2.08 (s, 2H), 2.96 (s, 3H), 3.23 (dd, J=3.6, 14.4 Hz, 1H), 3.41 (dd, J=9.4, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J=7.0 Hz, 2H), 4.26 (dd, J=3.7, 9.3 Hz, 1H), 6.89 (s, 2H), 7.02 (s, 1H); 13C NMR (DMSO-d6) δ 14.77, 41.98, 50.89, 55.54, 62.03, 63.68, 111.48, 111.77, 118.36, 137.30, 147.93, 148.09.
95.7 % ee With bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate; (S)-1-[(RP)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; hydrogen In 2,2,2-trifluoroethanol at 50℃; for 18 h; Inert atmosphere General procedure: For each reaction, a mixture of bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (9 mg, 0.018 mmol), 2,2,2-trifluoroethanol (3 mL), and the appropriate ligand (0.037 mmol) or a preformed complex of the ligand and metal (0.018 mmol) was prepared under nitrogen. Then, 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine (100 mg, 0.37 mmol) was added. The resultant mixture was heated to 50° C. and hydrogenated under 250 psig hydrogen pressure. After 18 h, the mixture was removed from the hydrogenator and monitored by achiral HPLC (Hypersil BDS C8, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1percent aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1percent aqueous TFA/MeOH over the next 15 min). Reactions containing >10 Area percent of the product enamine were also assayed for chiral purity by chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-1-PrOH-diethylamine or 50:40:10:0.1 heptane-EtOH-i-PrOH-diethylamine). The results are listed in Table 1 below.
Reference: [1] Patent: US2014/81032, 2014, A1, . Location in patent: Paragraph 0318; 0319
[2] Patent: US2013/217919, 2013, A1, . Location in patent: Paragraph 0280
[3] Patent: WO2016/199031, 2016, A1,
  • 5
  • [ 1450657-28-9 ]
  • [ 608141-42-0 ]
YieldReaction ConditionsOperation in experiment
15%
Stage #1: With ammonium acetate In 2,2,2-trifluoroethanolReflux
Stage #2: With bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate; (S)-1-[(RP)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; hydrogen In 2,2,2-trifluoroethanol at 50℃; for 18 h;
A mixture of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (2 g, 7.34 mmol) and ammonium acetate (1.868 g, 24.24 mmol) in TFE (20 mL) was heated to reflux. The batch was slowly distilled, while a solution of NH4OAc (5 g) in TFE (100 mL) was charged at a rate sufficient to maintain a constant volume. When the addition was complete, the mixture was distilled until the total volume was 20 mL. Then, the mixture was cooled to 20° C., and transferred to a hydrogenation reaction vessel. To the mixture was charged bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (0.034 g, 0.073 mmol) and (S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (0.040 g, 0.073 mmol). The mixture was warmed to 50° C. and hydrogenated under 90 psig hydrogen gas for 18 h. Then, 50 mL water and 5 mL concentrated HCl were added, and the mixture was stirred at 20° C. for 1 h. Then, the mixture was extracted with EtOAc (2×50 mL), and the aqueous phase was made basic with aqueous 10N NaOH until pH10. The mixture was then extracted with EtOAc (2×50 mL), and the combined organic extracts were dried (MgSO4) and evaporated under vacuum to provide the product as a white solid (0.30 g, 15percent yield); achiral HPLC (Hypersil BDS C8, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1percent aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1percent aqueous TFA/MeOH over the next 15 min): 8.85 (98.8percent); chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-1-PrOH-diethylamine): 7.23 (3.98percent), 8.17 (96.02percent); 1H NMR (DMSO-d6) δ 1.32 (t, J=7.0 Hz, 3H), 2.08 (s, 2H), 2.96 (s, 3H), 3.23 (dd, J=3.6, 14.4 Hz, 1H), 3.41 (dd, J=9.4, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J=7.0 Hz, 2H), 4.26 (dd, J=3.7, 9.3 Hz, 1H), 6.89 (s, 2H), 7.02 (s, 1H); Anal. (C12H19NO4S)C, H, N. Calcd C, 52.73; H, 7.01; N, 5.12. Found C, 52.55; H, 7.26; N, 5.25.
Reference: [1] Patent: US2013/217919, 2013, A1, . Location in patent: Paragraph 0294-0295
[2] Patent: US2013/217918, 2013, A1,
[3] Patent: CN104447445, 2016, B,
[4] Patent: CN104447445, 2016, B,
[5] Patent: CN104447445, 2016, B,
[6] Patent: CN104744323, 2016, B,
[7] Patent: WO2017/46319, 2017, A1,
[8] Patent: CN104761474, 2016, B,
  • 6
  • [ 1450759-47-3 ]
  • [ 608141-42-0 ]
YieldReaction ConditionsOperation in experiment
94% With Johnson & Matthey type 440; hydrogen In methanol at 20℃; Large scale Finally, the N-benzylated aminosulfone derivative Compound D (100 g, 0.211 mol) was hydrogenated with 5percent Pd/C (5.0 g), in methanol solvent (1000 ml) and at room temperature, to afford the pure S-aminosulfone Compound B (49-54 g) with 86-94percent yield and >99percent chiral and chemical purity.
Reference: [1] Patent: US2013/217918, 2013, A1, . Location in patent: Paragraph 0150
  • 7
  • [ 1450657-40-5 ]
  • [ 608141-42-0 ]
YieldReaction ConditionsOperation in experiment
68%
Stage #1: at 85℃; for 16 h;
Stage #2: With potassium carbonate In dichloromethane; water
To the product from Step 1 (0.30 g, 0.81 mmol) was added 6N HCl (15 mL), and the resulting mixture was heated to 85° C. for 16 h, and then cooled to 20° C. The mixture was filtered, and the filtrate was evaporated. The residue was partitioned between 10percent K2CO3 (8 mL) and CH2Cl2 (8 mL). The lower organic phase was removed and washed with CH2Cl2 (2×8 mL). To the organic phase was added CH2Cl2 (25 mL), and the resulting organic phase was washed with 10percent K2CO3 (2×25 mL) and water (25 mL), dried (MgSO4), and evaporated under vacuum. to provide the product as a white solid (150 mg, 68percent yield); achiral HPLC (Hypersil BDS C8, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1percent aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1percent aqueous TFA/MeOH over the next 15 min): 8.68 (99.5percent); chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-i-PrOH-diethylamine): 7.17 (1.9percent), 8.06 (98.1percent); 1H NMR (DMSO-d6) δ 1.32 (t, J=7.0 Hz, 3H), 2.08 (s, 2H), 2.96 (s, 3H), 3.23 (dd, J=3.6, 14.4 Hz, 1H), 3.41 (dd, J=9.4, 14.4 Hz, 1H), 3.73 (s, 3H), 4.02 (q, J=7.0 Hz, 2H), 4.26 (dd, J=3.7, 9.3 Hz, 1H), 6.89 (s, 2H), 7.02 (s, 1H); Anal. (C12H19NO4S)C, H, N. Calcd C, 52.73; H, 7.01; N, 5.12. Found C, 53.03; H, 6.78; N, 4.98.
Reference: [1] Patent: US2013/217919, 2013, A1, . Location in patent: Paragraph 0289-0290
  • 8
  • [ 1450657-31-4 ]
  • [ 608141-42-0 ]
  • [ 608142-27-4 ]
YieldReaction ConditionsOperation in experiment
94.4 % ee With bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate; (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-[bis[4-(trifluoromethyl)phenyl]phosphino]ferrocene; hydrogen In 2,2,2-trifluoroethanol at 50℃; for 18 h; Inert atmosphere General procedure: For each reaction, a mixture of bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (9 mg, 0.018 mmol), 2,2,2-trifluoroethanol (3 mL), and the appropriate ligand (0.037 mmol) or a preformed complex of the ligand and metal (0.018 mmol) was prepared under nitrogen. Then, 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine (100 mg, 0.37 mmol) was added. The resultant mixture was heated to 50° C. and hydrogenated under 250 psig hydrogen pressure. After 18 h, the mixture was removed from the hydrogenator and monitored by achiral HPLC (Hypersil BDS C8, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1percent aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1percent aqueous TFA/MeOH over the next 15 min). Reactions containing >10 Area percent of the product enamine were also assayed for chiral purity by chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-1-PrOH-diethylamine or 50:40:10:0.1 heptane-EtOH-i-PrOH-diethylamine). The results are listed in Table 1 below.
85.99 % ee With Ru(OAc)2((R)-dm-segphos); hydrogen In 2,2,2-trifluoroethanol at 50℃; for 18 h; Inert atmosphere General procedure: For each reaction, a mixture of bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (9 mg, 0.018 mmol), 2,2,2-trifluoroethanol (3 mL), and the appropriate ligand (0.037 mmol) or a preformed complex of the ligand and metal (0.018 mmol) was prepared under nitrogen. Then, 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethenamine (100 mg, 0.37 mmol) was added. The resultant mixture was heated to 50° C. and hydrogenated under 250 psig hydrogen pressure. After 18 h, the mixture was removed from the hydrogenator and monitored by achiral HPLC (Hypersil BDS C8, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1percent aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1percent aqueous TFA/MeOH over the next 15 min). Reactions containing >10 Area percent of the product enamine were also assayed for chiral purity by chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 70:30:0.1 heptane-1-PrOH-diethylamine or 50:40:10:0.1 heptane-EtOH-i-PrOH-diethylamine). The results are listed in Table 1 below.
25.72 % ee
Stage #1: With sodium tetrahydroborate; (S)-valinol In tetrahydrofuran at -10 - 0℃; for 1 h;
Stage #2: With boron trifluoride diethyl etherate In tetrahydrofuran at -10 - 30℃;
To a 2 L round bottom flask equipped with a mechanical stirrer, thermometer, and condenser, charge 500 mL of THF followed by (£/Z)- l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethenamine (50 grams, 0.184 mole) at 25-30 °C. The mixture was cooled at -10 °C to 0 °C. Charge sodium borohydride (8.36 grams, 0.221 mole) and L-valinol (4.7 grams, 0.046 mole) to reaction mass and stir for 1 hour at -10 °C to 0 °C. To the cooled the reaction mass add mixture of Borontrifluoride diethyl etherate (28.56 mL, 0.221 moles) in THF (30 mL) in 1 hour at - 10 to 0 °C. The mixture was allowed to warm at 25-30 °C in 2-3 hours and stirred overnight at 25-30 °C. Water (250 mL) was charged to reaction mass at 0-10 °C. After warming to 25-30 °C, the THF was distilled out from reaction mixture under vacuum. Charge ethyl acetate (200 mL) to reaction mass and add concentrated Hydrochloric acid (50 mL) till pH 2-3. Separate the organic and aqueous layer. To the aqueous layer charge 30 percent sodium hydroxide (225 mL) till pH 10-1 1. Extract the compound by using dichloromethane (2 *250 mL). Club the organic layers and wash with 10 percent aqueous sodium chloride solution. Distilled off dichloromethane for organic layer. To the crude solid charge THF (25 mL) and stir for 30 minutes. Filter the isolated solid on Buchner funnel. The wet solid dried in hot air oven at 40-45 °C for 4 hours to provide l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine as off white solid (41.7 grams, 83 percent yield). NMR (DMSO-d6) δ 1.35 (t, 3H), 2.09 (bs, 2H), 2.96 (s, 3H), 3.2 (m, 1H), 3.4 (m, 1H), 3.73 (s, 3H), 4.05 (q, 2H), 4.28 (m,l H), 6.89 (s, 2H), 7.02 (s, lH)~ppm;FTIR (KBr): 907, 1025, 1 142, 1256, 1312, 1517, 1590, 2983, 3362 cm-';MS (ESI) m/z= 274.23 (M+l );Chiral HPLC: 37.14percent (R-Isomer): 62.86percent (S-isomer).
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