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[ CAS No. 13504-85-3 ] {[proInfo.proName]}

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Chemical Structure| 13504-85-3
Chemical Structure| 13504-85-3
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Product Details of [ 13504-85-3 ]

CAS No. :13504-85-3 MDL No. :MFCD00037329
Formula : C13H15NO5 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 265.26 Pubchem ID :-
Synonyms :
N-Cbz-hydroxy-L-proline

Calculated chemistry of [ 13504-85-3 ]

Physicochemical Properties

Num. heavy atoms : 19
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.38
Num. rotatable bonds : 5
Num. H-bond acceptors : 5.0
Num. H-bond donors : 2.0
Molar Refractivity : 69.55
TPSA : 87.07 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) : -7.38 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.65
Log Po/w (XLOGP3) : 0.76
Log Po/w (WLOGP) : 0.31
Log Po/w (MLOGP) : 0.5
Log Po/w (SILICOS-IT) : 0.14
Consensus Log Po/w : 0.67

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -1.87
Solubility : 3.6 mg/ml ; 0.0136 mol/l
Class : Very soluble
Log S (Ali) : -2.17
Solubility : 1.8 mg/ml ; 0.00679 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.28
Solubility : 14.0 mg/ml ; 0.0528 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.1

Safety of [ 13504-85-3 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P330-P363-P501 UN#:
Hazard Statements:H302-H312-H332 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 13504-85-3 ]

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

  • Upstream synthesis route of [ 13504-85-3 ]
  • Downstream synthetic route of [ 13504-85-3 ]

[ 13504-85-3 ] Synthesis Path-Upstream   1~20

  • 1
  • [ 100-39-0 ]
  • [ 13504-85-3 ]
  • [ 13500-53-3 ]
YieldReaction ConditionsOperation in experiment
50% With triethylamine In tetrahydrofuran at 0 - 20℃; for 18 h; Triethylamine was added to the solution of compound 2 (15 mmol, 3.98 g) and benzyl bromide (16.5 mmol, 2.82 g) in THF (25 mL) at 0 °C. After the mixture was stirred for 18 h at room temperature, the solvent was evaporated in vacuo. The residue was dissolved in 50 mL of CH2Cl2, washed with HCl (1 N), H2O, Na2CO3 (5percent), and H2O, and then dried over Na2SO4. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (hexane/AcOEt, 2:1) to afford (2S,4R)-1,2-dibenzyloxycarbonyl-4-hydroxypyrrolidine (compound 3) as pale yellow oil (2.66 g, yield 50percent).
250 g With caesium carbonate In N,N-dimethyl-formamide at 22℃; for 5 h; Cooling with ice To a 3 L round bottom flask were added (25,4R)-1-(benzyloxycarbonyl)-4- hydroxypyrrolidine-2-carboxylic acid (190.0 g, 716 mmol, 1.0 eq.), DMF (2.0 L) and C52CO3 (117 g, 358 mmol, 0.5 eq.). The resulting mixture was cooled in an ice-water bath and benzyl bromide (172 g, 1000 mmol, 1.4 eq.) was slowly added. After the addition, the resulting suspension was stirred at 22 °C for 5 h. The reaction mixture wasdiluted with water (5 L) and EtOAc (5 L). The aqueous layer was removed and the organic layer washed with brine (2 x 3L), dried over Mg504, filtered and concentrated under reduced pressure to provide 250 g of the title comround as an oil, which was used in the next step without purification. LCMS: MS = 377.9 (M+23).
Reference: [1] Advanced Synthesis and Catalysis, 2008, vol. 350, # 17, p. 2747 - 2760
[2] Journal of Organic Chemistry, 2001, vol. 66, # 3, p. 1038 - 1042
[3] Angewandte Chemie - International Edition, 2007, vol. 46, # 47, p. 9073 - 9077
[4] Synlett, 1999, # 9, p. 1465 - 1467
[5] Tetrahedron, 2008, vol. 64, # 10, p. 2480 - 2488
[6] Angewandte Chemie - International Edition, 2008, vol. 47, # 44, p. 8429 - 8432
[7] Advanced Synthesis and Catalysis, 2010, vol. 352, # 1, p. 108 - 112
[8] Tetrahedron Letters, 1994, vol. 35, # 3, p. 451 - 454
[9] Chemical and Pharmaceutical Bulletin, 2018, vol. 66, # 5, p. 575 - 580
[10] Journal of Organic Chemistry, 2017, vol. 82, # 23, p. 12366 - 12376
[11] Tetrahedron, 1998, vol. 54, # 5-6, p. 981 - 996
[12] Journal of Organic Chemistry, 2006, vol. 71, # 13, p. 5004 - 5007
[13] Synlett, 2010, # 13, p. 1943 - 1946
[14] Journal of Molecular Catalysis A: Chemical, 2012, vol. 363-364, p. 404 - 410,7
[15] Journal of Organic Chemistry, 1991, vol. 56, # 8, p. 2787 - 2800
[16] Carbohydrate Research, 1996, vol. 286, p. 123 - 138
[17] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 1096 - 1101
[18] Synlett, 2011, # 4, p. 503 - 507
[19] Macromolecules, 2010, vol. 43, # 15, p. 6374 - 6380
[20] Patent: US2013/65935, 2013, A1, . Location in patent: Paragraph 0097; 0098
[21] Patent: WO2018/20358, 2018, A1, . Location in patent: Page/Page column 85
  • 2
  • [ 541-41-3 ]
  • [ 100-51-6 ]
  • [ 13504-85-3 ]
  • [ 13500-53-3 ]
Reference: [1] Advanced Synthesis and Catalysis, 2005, vol. 347, # 10, p. 1395 - 1403
  • 3
  • [ 100-51-6 ]
  • [ 13504-85-3 ]
  • [ 13500-53-3 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 24, p. 9353 - 9356
  • 4
  • [ 100-44-7 ]
  • [ 13504-85-3 ]
  • [ 13500-53-3 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 7, p. 1755 - 1760
[2] Canadian Journal of Biochemistry and Physiology, 1959, vol. 37, p. 583,584
  • 5
  • [ 501-53-1 ]
  • [ 51-35-4 ]
  • [ 13504-85-3 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; General procedure: To a solution of 1 or 7 (78.7 g, 600 mmol) and NaHCO3 (126 g, 1.5 mol) in H2O (900 mL), benzyl chloroformate (89.6 mL, 630 mmol) in dioxane (90 mL) was added, and the reaction stirred overnight. Upon completion (monitored by TLC), the reaction was cooled to 0 °C in an ice bath, and acidified with 12 M HCl to pH2 (approximately 75 mL). The aqueous phase was then extracted (3 x 500 mL EtOAc), and the organic phase washed with brine (3 x200 mL), dried with Na2SO4, and concentrated to yield a colorless, viscous oil. Yield was quantitative, and product was utilized in thenext step without purification. 
97% With water; sodium hydrogencarbonate; sodium carbonate In acetone at 15 - 20℃; General procedure: The (S)-amino acid (10.0 g) was dissolved in H2O (300 ml) and Na2CO3 (2.0 equiv) and NaHCO3 (1.0 equiv) were added at rt, with stirring, to give a clear solution. Acetone (4.0 vol, with respect to the amino acid) was added and the slightly turbid solution was cooled in an ice water bath to 15-20 °C. Cbz-Cl (1.25 equiv) was added slowly, with stirring, and the reaction mixture allowed to warm to rt. After stirring for an additional 3 h at rt the mixture was extracted with Et2O (50 ml). To the aqueous phase was slowly added aqueous HCl to give a pH of 2. The resulting oil was extracted into EtOAc (150 ml) and this was washed with H2O (100 ml) and then concentrated in vacuo to give the N-Cbz amino acid as a white solid, see Table 1.
91% With sodium hydroxide In water at 0 - 20℃; for 5 h; Typical procedure for the preparation of (2S,4R)-1-benzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid (10): A solution of 2 (6.56 g, 0.05 mol) in H2O (50 mL) was added NaOH (4 g, 0.1 mol) at 0 °C. Benzyl chloroformate (8.5 g, 0.05 mol) was then added dropwise at 0 °C and stirred for 5 h at room temperature.
The reaction mixture was extracted with ether (20 mL), and the aqueous layer was neutralized with 2 mol/L HCl to pH 2, and extracted with ethyl acetate (30 mL * 3).
The organic layer was combined, washed with brine, dried over Na2SO4, and concentrated under vacuum to give the target compound (12.1 g, yield: 91percent).
The 1H NMR spectra were in accordance with the literature data
[7]
. 1H NMR (400 MHz, CDCl3): δ 7.27-7.32 (m, 5 H), 6.17 (brs, 1 H), 5.09-5.12 (m, 2 H), 4.45-4.51 (m, 2 H), 3.60 (brs, 2 H), 2.14-2.30 (m, 2 H).
87% With sodium hydroxide In water at 0 - 20℃; Trans-4-OH-proline (5.0 g, 38.1mmol) wasadded at 0 oCto a solution of NaOH (3.1 g, 76.3mmol) in water (30 mL). The reaction was allowed to stir at 0 oC for 20 min,then PhCH2OCOCl (5.2 mL, 38.1 mmol) was added into the reaction mixture dropwiseat 0 oC.After addition, the resultant mixture was kept stirring at room temperature overnightbefore quenching with 1N HCl to a pH of 2. White precipitate was formed and extractedwith EtOAc (3 x 200 mL). The combined organic layers were dried over MgSO4.After removal of solvent under reduced pressure, the product 8 was obtained as a colorlessviscous liquid (8.8 g, 87percent).[α]D25= -48.4 (c = 0.22, CHCl3);1H NMR (600 MHz, CDCl3) δ7.50–7.12 (m,5H), 6.69 (br, 2H), 5.35–4.90(m, 2H), 4.62–4.35(m, 2H), 3.62–3.51(m,2H), 2.53–2.18 (m,1H), 2.22–2.00 (m,1H); 13CNMR (150 MHz, CDCl3) δ 176.76/175.62,155.97/155.00, 136.10/136.04, 128.55/128.44, 128.20/128.00, 127.88/127.63,69.89/69.24, 67.73/67.55, 57.98/57.61, 54.97/54.50, 38.91/37.97; IR (KBr, cm-1): ν 3404.98, 2951.21, 2632.96, 1716.36, 1682.99,1430.79, 1369.00, 1357.01, 1210.83, 1183.17, 1128.29, 1083.56, 963.21, 920.32, 762.15,699.90, 605.99, 455.96; HRMS (ESI): m/z calculated for C13H14NO5(M-H)-: 264.0872, found: 264.0875. 
86.6%
Stage #1: With sodium hydroxide In water at 20℃;
Stage #2: for 1.5 h;
A stirrer, a dropping funnel, a Dimroth condenser, a thermometer, 4-neck flask 2000 ml with apH meter fitted, L- hydroxyproline 132.0 g (1.0 mol), 48percent aqueous sodium hydroxide solution 86g (1.03 mol ), was charged with water 655g, and the mixture was stirred at room temperature.While maintaining the pH at 11.5 to 12.0, was added dropwise benzyloxycarbonyl chloride 179 g(1.05 mol) and 48percent aqueous sodium hydroxide solution 84g alternately. Toluene 300g Afterstirring After completion of the dropwise addition, 1.5 hours added to remove the toluene layerwas separated. CPME600g was added to the aqueous layer, it was added 95percent sulfuric acid 63.8gstirring. Stirring was stopped, after removing the aqueous layer was separated and subjected tovacuum concentration at 40 kPa. The aqueous layer of the distillate was separated and removed,subjected to vacuum concentrated again to return the upper layer to the flask, trans - to give aCPME solution 888g, including benzyloxycarbonyl-4-hydroxy-proline (trans - benzyloxycarbonyl-4 - 26percent by weight as hydroxyproline, 229.6g (0.87 mol, 86.6percent yield) containing). The yield ofthis step was 86.6percent.
85% With sodium hydrogencarbonate In water; acetone at 20℃; for 2.5 h; Cooling with ice In ice bath, benzyl chloroformate (24 mmol, 4.09 g) was added dropwise to a mixture of l-4-hydroxyproline (20 mmol, 2.62 g) and NaHCO3 (60 mmol, 5.04 g) in acetone (20 mL) and distilled water (40 mL) under continuous stirring. The resulting mixture was kept stirring in ice environment for 30 min and followed by reacting at room temperature for 2 h. Then the pH value of the reaction system was adjusted to 3–4 with 1 mol/L HCl. Acetone was removed by vacuum distillation and the aqueous phase was extracted by CH2Cl2 (4 × 30 mL). The organic layer was dried on anhydrous Na2SO4, filtered and evaporated. (2S,4R)-1-benzyloxycarbonyl-4-hydroxyproline (compound 2) was obtained as colorless oil (4.51 g, yield 85percent).
78%
Stage #1: With sodium hydrogencarbonate In diethyl ether; water at 20℃; for 20.1667 h;
Stage #2: With hydrogenchloride In water
(2S, 4R)-N-(Benzyloxycarbonyl)-2-carboxy-4-hydroxy-pyrrolidine (4).; A solution of benzyl chloroformate (50 mL, 0.35 mol) in EtaO (160 mL) was added dropwise, during 10 min, to a rapidly stirred mixture of trans-4-hydroxy-L-proline (39.8 g, 0.308 mol), NaHCO3 (63.7 g, 0.758 mol) and H20 (660 mL). The reaction mixture was stirred at room temperature for 20 h. The layers were separated, and the aqueous layer was washed with Et2O (4 x 200 mL), cooled, and then acidified to pH 1-2 with concentrated hydrochloric acid. The resulting emulsion was extracted with EtOAc (5 x 200 mL). Combined EtOAc extracts were washed in succession with H20 (3 x 500 mL) and brine (3 x 500 mL), dried over MgSO4, and then concentrated in vacuo to give intermediate (4) as a colorless foam (62.7 g, 78percent). Additional reactions were carried out to give a total of 284 g of product suitable for further transformation
71%
Stage #1: With sodium hydrogencarbonate In water at 0 - 20℃; for 2.5 h;
Stage #2: With hydrogenchloride In water at 0℃;
Sodium hydrogencarbonate (16 O g, 191 mmol) was added to a stirred solution of frans-4-hydroxy-L-prolιne (105a) (10 0 g, 76 mmol) in water (8 7 mL) at 00C Benzyl chloroformate (12 mL, 84 mmol) was added and the mixture was stirred for 1 h at 00C, followed by 1 5h at rt The mixture cooled to 0°C was acidified to pH 2 with concentrated HCI, and extracted with EtOAc three times The organic layer were washed with brine, dried with MgSO4 and filtered The solution was evaporated and the crude residue was purified by flash column chromatography on silica gel, using gradient from 0-20percent MeOH / CH2CI2 to EPO <DP n="102"/>afford the title Compound 106a (14.4 g, 71 percent yield): LRMS (ESI): (calc.) 265.3; (found) 288.1 (M+Na) +.

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[3] Patent: EP1193270, 2002, A2, . Location in patent: Page 14, 35-36, 105
[4] Tetrahedron Letters, 2016, vol. 57, # 44, p. 4882 - 4884
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[10] Tetrahedron Asymmetry, 2003, vol. 14, # 1, p. 139 - 143
[11] Tetrahedron Letters, 2011, vol. 52, # 13, p. 1493 - 1494
[12] Tetrahedron Asymmetry, 2006, vol. 17, # 17, p. 2479 - 2486
[13] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2008, vol. 63, # 11, p. 1300 - 1304
[14] Synlett, 2010, # 13, p. 1943 - 1946
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  • 6
  • [ 51-35-4 ]
  • [ 501-53-1 ]
  • [ 13504-85-3 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydrogencarbonate In water; toluene (2S,4R)-N-(Benzoxycarbonyl)-2-carboxy-4-hydroxypyrrolidine (45)
A solution of benzyl chloroformate (12.5 mL, 87.7 mL) in toluene (40 mL) was added to a solution of trans-4-hydroxy-L-proline 11 (10 g, 76.3 mmol) and NaHCO3 (16 g, 190 mmol) in H2O (165 mL) over a period of 15 minutes.
After stirring at room temperature for 12 hours the two phases were allowed to separate.
The aqueous phase was washed with diethyl ether (4*50 mL), cooled in an ice bath, and then acidified to pH 2 with conc. HCl.
The resultant product was extracted with ethyl acetate (5*50 mL) and the combined organic extracts were dried (MgSO4) and the excess solvent evaporated in vacuo to afford a colourless viscous oil (20.30 g, 100percent).
[α]27D=-565° (c 0.1, MeOH).
1H NMR (CDCl3): δ 2.07-2.31 (m, 3H, H1), 3.52-3.59 (m, 2H, H3), 4.43-4.53 (m, 2H, H2, H11a), 5.8 and 5.11 (s, 2H, minor and major rotamers of H6, 1:2), 6.0 (bs, 2H, OH), 7.26-7.29 and 7.32-7.34 (m, 5H, minor and major rotamers of H arom, 1:2). IR (thin film): ν=3414 (OH), 2940 (OH), 1682 (C=O), 1495, 1429, 1359 (CO2-), 1314, 1269, 1205, 1180, 1174, 1127, 1082, 1051, 993, 914, 866, 826, 769, 741, 697 cm-1. MS (EI): m/e (relative intensity): 266 (M+., 1), 265 (6), 220 (5), 176 (15), 130 (34), 108 (2).
91 (100), 86 (4), 68 (11). HRMS calcd. for C13H11NO=265.0950 found 265.0976
Reference: [1] Patent: US2003/120069, 2003, A1,
  • 7
  • [ 85201-91-8 ]
  • [ 13504-85-3 ]
Reference: [1] Tetrahedron Letters, 1992, vol. 33, # 37, p. 5441 - 5444
[2] Journal of Organic Chemistry, 2006, vol. 71, # 24, p. 9045 - 9050
  • 8
  • [ 501-53-1 ]
  • [ 2584-71-6 ]
  • [ 13504-85-3 ]
YieldReaction ConditionsOperation in experiment
190 g With sodium hydrogencarbonate; sodium carbonate In acetone at 22℃; for 15 h; Cooling with ice To a 3 L flask were added (25,4R)-4-hydroxypyrrolidine-2-carboxylic acid (87.0 g,663.46 mmol, 1.0 eq.), water (1500 ml), Na2CO3 (141.0 g, 1330 mmol, 2.0 eq.) andNaHCO3 (55.7 g, 663 mmol, 1.0 eq.). Acetone (250 ml) was added to the solution which was then cooled in an ice-water bath. To the mixture was slowly added Cbz-Cl (141.0 g, 829 mmol, 1.25 eq.). After addition, the reaction mixture was warmed gradually to 22 °C and was stirred for 15 h. The reaction mixture was washed with MTBE (600 ml x 2). To the aqueous phase was slowly added aqueous 1 N HCI until pH—2 was achieved. The resulting mixture was extracted with EtOAc (1 L x 3) and the combined organic layer was dried over MgSO4, filtered and concentrated underreduced pressure to provide 190 g of the title compound as an oil, which was taken to the next step without further purification. LCMS: MS = 287.8 (M+H).
Reference: [1] Patent: WO2018/20358, 2018, A1, . Location in patent: Page/Page column 84; 85
  • 9
  • [ 51-35-4 ]
  • [ 501-53-1 ]
  • [ 13504-85-3 ]
Reference: [1] Patent: US5942537, 1999, A,
  • 10
  • [ 117811-78-6 ]
  • [ 100-51-6 ]
  • [ 13504-85-3 ]
  • [ 13504-86-4 ]
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[2] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9-10
[3] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
[4] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
[5] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
  • 11
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  • [ 13504-85-3 ]
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  • 12
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  • [ 13504-85-3 ]
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  • 13
  • [ 13504-85-3 ]
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[2] Bioscience, Biotechnology, and Biochemistry, 1995, vol. 59, # 6, p. 1161 - 1162
[3] Tetrahedron Letters, 1994, vol. 35, # 3, p. 451 - 454
[4] Journal of Fluorine Chemistry, 1991, vol. 54, # 1-3, p. 195
[5] Journal of Medicinal Chemistry, 1991, vol. 34, # 2, p. 717 - 725
[6] Journal of the American Chemical Society, 1957, vol. 79, p. 185,190
  • 14
  • [ 117811-78-6 ]
  • [ 100-51-6 ]
  • [ 13504-85-3 ]
  • [ 13504-86-4 ]
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[2] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9-10
[3] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
[4] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
[5] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
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Reference: [1] Patent: CN108440507, 2018, A,
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YieldReaction ConditionsOperation in experiment
86% With dimethylsulfide borane complex In tetrahydrofuran at 0℃; for 13 h; Heating / reflux Benzyl (4R)-hydroxy-(2S)-hydroxymethylpyrrolidine-1-carboxylate
N-benzyloxycarbonyl-(4R)-hydroxy-L-proline (150 g, 0.565 mol) was dissolved in THF (1.5 L), and borane - dimethyl sulfide complex (59.0 ml, 0.622 mol) was added dropwise to the solution with stirring at 0°C.
After completing the addition, the reaction mixture was heated under reflux with stirring.
After stirring for another 3 hours, the reaction mixture was again cooled to 0°C. Borane - dimethyl sulfide complex (16.1 ml, 0.170 mol) was added, and the reaction mixture was stirred for another 10 hours.
After cooling the reaction mixture, water (500 ml) was gradually added at 0°C to decompose excessive borane - dimethyl sulfide complex.
The reaction mixture was then extracted with ethyl acetate and chloroform-methanol (10:1, v/v), and the extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to give the title compound (122.06 g, 86percent) as a pale yellow oily product. (This compound was used in the subsequent reaction without further purification.)
1H-NMR (CDCl3) δ: 1.52-1.81 (m, 3H), 2.06 (m, 1H), 3.40-3.85 and 4.04-4.61 (series of m, total6H), 5.15 (s, 2H, ArCH2), 7.20-7.44 (m, 5H, Ar).
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