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Chemical Structure| 51-35-4
Chemical Structure| 51-35-4
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Product Details of [ 51-35-4 ]

CAS No. :51-35-4 MDL No. :MFCD00064320
Formula : C5H9NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 131.13 Pubchem ID :-
Synonyms :
(2S,4R)-4-Hydroxypyrrolidine-2-carboxylic acid;trans-4-hydroxy L-Proline;Oxaceprol;Hydroxyproline;NSC 46704;4(R)-Hydroxy-2(S)-pyrrolidinecarboxylic acid;(S)-(-)-trans-4-Hydroxyproline

Calculated chemistry of [ 51-35-4 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.8
Num. rotatable bonds : 1
Num. H-bond acceptors : 4.0
Num. H-bond donors : 3.0
Molar Refractivity : 33.69
TPSA : 69.56 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) : -9.35 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.62
Log Po/w (XLOGP3) : -3.17
Log Po/w (WLOGP) : -1.59
Log Po/w (MLOGP) : -3.44
Log Po/w (SILICOS-IT) : -0.67
Consensus Log Po/w : -1.65

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 1.41
Solubility : 3370.0 mg/ml ; 25.7 mol/l
Class : Highly soluble
Log S (Ali) : 2.28
Solubility : 24800.0 mg/ml ; 189.0 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : 0.66
Solubility : 597.0 mg/ml ; 4.55 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.23

Safety of [ 51-35-4 ]

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

Application In Synthesis of [ 51-35-4 ]

* 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 [ 51-35-4 ]
  • Downstream synthetic route of [ 51-35-4 ]

[ 51-35-4 ] Synthesis Path-Upstream   1~55

  • 1
  • [ 51-35-4 ]
  • [ 13500-53-3 ]
Reference: [1] Journal of Organic Chemistry, 2006, vol. 71, # 13, p. 5004 - 5007
[2] Tetrahedron Letters, 1994, vol. 35, # 3, p. 451 - 454
[3] Journal of Organic Chemistry, 1991, vol. 56, # 8, p. 2787 - 2800
[4] Canadian Journal of Biochemistry and Physiology, 1959, vol. 37, p. 583,584
[5] Journal of Molecular Catalysis A: Chemical, 2012, vol. 363-364, p. 404 - 410,7
[6] Journal of Organic Chemistry, 2017, vol. 82, # 23, p. 12366 - 12376
[7] Chemical and Pharmaceutical Bulletin, 2018, vol. 66, # 5, p. 575 - 580
[8] Patent: US2013/65935, 2013, A1,
  • 2
  • [ 618-28-0 ]
  • [ 3398-22-9 ]
  • [ 51-35-4 ]
Reference: [1] Chemistry of Materials, 2011, vol. 23, # 5, p. 1280 - 1287
  • 3
  • [ 51-35-4 ]
  • [ 2584-71-6 ]
YieldReaction ConditionsOperation in experiment
57%
Stage #2: With hydrogenchloride In water
Synthetic access to the two additional stereoisomers of the pro4 monomer class has been established. Using a controlled epimerization procedure[34], 30 grams of trans-4-hydroxy-(L)-proline 5 were converted to the diastereomer cis-4-hydroxy-(D)-proline 14 with 57percent isolated yield. By carrying this material through the synthesis described in Scheme 1, synthesis of the other two enantiomers of the pro4 building block class 3:pro4(2R4R) and 4:pro4(2R4S) can be accomplished. (Scheme 3)
44.5%
Stage #1: at 50 - 120℃; for 5.5 h;
Stage #2: at 120℃; for 3 h;
A mixture of AcOH (628.70 g, 10.47 mol) and Ac2O (203.45 g, 1.99 mol) was heated to 50 C, then (2S, 4R)-4-hydroxypyrrolidine-2-carboxylic acid (47.00 g, 358.42 mmol) was added in one portion. The mixture was heated to 120 C and stirred for 5.5 h. After cooling to r.t., the solvent was removed. The residue was dissolved in HCl (650 mL), and then the mixture was heated to 120 C and stirred for 3 h. Then activated charcoal (2.5 g) was added, the hot mixture was filtered immediately through a Celite layer and the cake was washed with hot water. The colorless solution was neutralized with triethylamine and evaporated to dryness. The crude product was refluxed in ethanol (2500 mL) and water was added carefully to the boiling mixture until the solid disappeared (but the solution remained still a little turbid). The solution was thenyleft to stand overnight at -20 C to give white crystals, which were filtered off and washed with cold ethanol afford the title compound (22.00 g, 44.5percent) as a white solid.
570 mmol
Stage #1: With acetic anhydride In acetic acid for 24 h; Reflux
Stage #2: for 24 h; Reflux
 Trans-4-hydroxyproline (100g, 763 mmol) was dissolved in acetic acid (1.0 L) and acetic anhydride (500mL), and refluxed for 24 h. The reaction was then distilled to remove approximately 1 L of solvent, and the remaining solvent removed in vacuo. The compound was redissolved in 2 M HCl (1.0 L) and refluxed for another 24 h, at which time the solvent was removed in vacuo utilizing toluene as an azeotrope. The product was subsequently dissolved in EtOH (1.0 L) and TEA (106 mL), and heated to ~70 °C, after which H2O wasadded until a dark, clear solution was obtained. This solution was left to cool to room temperature, and then placed in a -20 °C freezer overnight. Theresulting crystals were collected via vacuum filtration and washed with cold EtOH to yield 570 mmol of cis-4-hydroxyproline.Recrystallization can be repeated as necessary if there is NMR evidence of trans-4-hydroxyproline.
Reference: [1] Tetrahedron Asymmetry, 2003, vol. 14, # 20, p. 3141 - 3152
[2] Tetrahedron Asymmetry, 2002, vol. 13, # 2, p. 197 - 201
[3] Tetrahedron, 2009, vol. 65, # 4, p. 862 - 876
[4] Patent: US2004/77879, 2004, A1, . Location in patent: Page 13
[5] Patent: WO2018/13867, 2018, A1, . Location in patent: Paragraph 339
[6] Organic Letters, 2000, vol. 2, # 56, p. 4161 - 4164
[7] Journal of Biological Chemistry, 1952, vol. 195, p. 383,384
[8] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 11, p. 1650 - 1654
[9] Journal of Organic Chemistry, 2007, vol. 72, # 1, p. 288 - 291
[10] Tetrahedron Asymmetry, 2002, vol. 13, # 2, p. 197 - 201
[11] Tetrahedron Letters, 2010, vol. 51, # 41, p. 5375 - 5377
[12] Tetrahedron Letters, 2016, vol. 57, # 44, p. 4882 - 4884
  • 4
  • [ 232262-93-0 ]
  • [ 2584-71-6 ]
  • [ 51-35-4 ]
Reference: [1] Advanced Synthesis and Catalysis, 2001, vol. 343, # 6-7, p. 587 - 590
  • 5
  • [ 46122-47-8 ]
  • [ 2584-71-6 ]
  • [ 51-35-4 ]
Reference: [1] Nucleosides and Nucleotides, 1999, vol. 18, # 3, p. 493 - 508
  • 6
  • [ 108-24-7 ]
  • [ 64-19-7 ]
  • [ 51-35-4 ]
  • [ 2584-71-6 ]
Reference: [1] Journal of Biological Chemistry, 1952, vol. 195, p. 383,384
  • 7
  • [ 501-53-1 ]
  • [ 51-35-4 ]
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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
[5] Chemical and Pharmaceutical Bulletin, 2018, vol. 66, # 5, p. 575 - 580
[6] Organic Process Research and Development, 2018, vol. 22, # 9, p. 1241 - 1256
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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,
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  • [ 13504-85-3 ]
Reference: [1] Patent: US5942537, 1999, A,
  • 10
  • [ 51-35-4 ]
  • [ 13504-86-4 ]
Reference: [1] Bioscience, Biotechnology, and Biochemistry, 1995, vol. 59, # 6, p. 1161 - 1162
[2] Tetrahedron Letters, 1994, vol. 35, # 3, p. 451 - 454
[3] Journal of Fluorine Chemistry, 1991, vol. 54, # 1-3, p. 195
[4] Journal of Medicinal Chemistry, 1991, vol. 34, # 2, p. 717 - 725
[5] Journal of the American Chemical Society, 1957, vol. 79, p. 185,190
[6] Patent: JP5703654, 2015, B2,
  • 11
  • [ 636-98-6 ]
  • [ 51-35-4 ]
  • [ 4533-42-0 ]
YieldReaction ConditionsOperation in experiment
78% With copper(l) iodide; caesium carbonate In dimethyl sulfoxide at 110℃; for 24 h; General procedure: to a stirred solution of iodo benzene (1.0 mmol) and trans-4-hydroxy-L-proline (2.0 equiv) in dry DMSO (3.0 mL) at rt was added CuI (20 mol percent) followed by Cs2CO3 (2.5 equiv) and heated at 110 °C for 24 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was allowed to cool, and a 1:1 mixture of ethyl acetate/water (20 mL) was added. The combined organic extracts were dried with anhydrous Na2SO4. The solvent and volatiles were completely removed under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 9:1) to afford the corresponding coupling product.
70% With copper(II) ferrite; caesium carbonate In dimethyl sulfoxide at 100℃; for 20 h; Inert atmosphere General procedure: To astirred solution of: Aryl iodide (1.0 mmol), trans-4-Hydroxy-L-proline (1.5 mmol), nano CuFe2O4 (0.01 mmol), base (2 equiv), solvent (3.0 mL), 20h, 100 oC. The progress of the reaction was monitored by TLC. After the reaction was complete CuFe2O4 nano were placed on the bottom of the flask by a neodymium magnet, and the supernatant solution was removed. The crude residue was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were extracted with water, saturated brine solution, and dried over anhydrous Na2SO4.The organic layers were evaporated under reduced pressure and the resulting crude product was purified by column chromatography to give the corresponding N-substituted pyrrole in excellent yields. The identity and purity of the product were confirmed by 1H,13C NMR, and mass spectra.
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  • [ 37813-30-2 ]
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  • [ 51-35-4 ]
  • [ 37813-30-2 ]
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[2] Tetrahedron Asymmetry, 2002, vol. 13, # 2, p. 167 - 172
[3] Chemistry Letters, 2001, # 7, p. 634 - 635
[4] Journal of Organic Chemistry, 1981, vol. 46, # 14, p. 2954 - 2960
[5] Journal of Organic Chemistry, 1980, vol. 45, # 23, p. 4728 - 4739
[6] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 5, p. 1132 - 1139
[7] Patent: TW2017/8221, 2017, A,
[8] Journal of Medicinal Chemistry, 2018, vol. 61, # 9, p. 4030 - 4051
  • 14
  • [ 67-56-1 ]
  • [ 51-35-4 ]
  • [ 40216-83-9 ]
YieldReaction ConditionsOperation in experiment
100% at 0 - 20℃; for 2.5 h; To a stirred solution of (2S, 4i?)-4-hydroxypyrrolidine-2-carboxylic acid (13.1 g, 0.1 mol) in methanol (400 mL) cooled to 0°C was added acetyl chloride (14.3 mL, 0.2 mol) over a period of 30 min. The reaction mixture was warmed to room temperature and stirred for 2 h. The volatiles were removed under reduced pressure and the residue was triturated with ether several times to get methyl (25',4/?)-4-hydroxypyrrolidine-2- carboxylate hydrochloride salt as a white powder (14.5 g) in 100percent yield, m/z (M+l) 145; 1H NMR (DMSOd6) 300 MHz δ 5.7-5.5 (s (br), IH), 4.55-4.35 (m, 2H), 3.76 (s, 3H), 3.35 (d, J= 12 Hz IH), 3.10 (d, J= 12 Hz IH), 2.25-2.0 (m, 2H).
100% With hydrogenchloride; thionyl chloride In water at 20℃; for 18 h; Reflux A solution of trans-4-hydroxy-ι-proline (10.0 g, 76.3 mmol) in MeOH (80 mL) was cooled to 0 °C andthionyl chloride (11.1 mL, 152 mmol) was added dropwise. The mixture was allowed to stir at roomtemperature for 1 h before being heated under reflux for a further 17 h. The resulting solution wasconcentrated and the residue azeotroped with MeOH (3 × 200 mL) to give the desired compound14·HCl (13.6 g, 100percent) as a colourless solid; mp 169–171 °C;−21.6 (c 1.0, EtOH); νmax/cm-1 3317,2952, 2707, 1740, 1439, 1240, 1074, 1025, 956, 901, 625; δH (500 MHz; MeOD) 4.63–4.59 (2 H, m),3.86 (3 H, s), 3.46 (1 H, dd, J 3.2, 10.0 Hz), 3.34–3.30 (1 H, m), 2.45–2.41 (1 H, m), 2.21 (1 H, ddd, J2.4, 8.0, 11.2 Hz); δC (125 MHz; CDCl3) 170.6, 70.6, 59.4, 55.0, 54.0, 38.6; m/z (+ESI) 146 ([M - Cl],100).
100% at 0 - 64℃; for 8 h; At room temperature,Trans-4-hydroxy-L-proline 2A (20.0 g, 152.6 mmol) was dissolved in anhydrous methanol (200 mL)Cooling to 0 ,Dichloro sulfoxide (20.6g, 172.4mmol),The temperature was raised to 64 ° C and the reaction was refluxed for 8 hours.The reaction solution was lowered to -20 ° C, and a white solid was precipitated. Methyl tertiary butyl ether (50 mL) was added and the reaction was continued for 30 minutes.The filter cake was washed with methyl tertiary butyl ether (50 mL x 2) and dried to give white solid 4A (28 g, yield 100percent).
99% at 0℃; for 8 h; Heating / reflux Acetyl chloride (4.14 g, 52.8 mmol) is dropped into a three neck round bottom flask containing anhydrous methanol (33 ml) in ice bath and under N2 flux. [(2S,4R)-(-)-4-Hydroxypyrrolidine-2-carboxylic acid (1) (5.0 g, 37.7 mmol) is added and the so obtained reaction mixture is firstly brought to room temperature (r.t.) then refluxed for 8 hours. Afterwards, the reaction is brought to room temperature and diethyl ether is added till complete precipitation of the reaction product, which, after Buchner filtration, is (2S,4R)-4-hydroxy-2-(methoxy- carbonyl)pyrrolidine chloride (2). Yield 99percent; white solid m.p. 149-152 0C.1H NMR (DMSO, 500 MHz): δ 2.07 (ddd, IH, J = 4.5, 11.0, 13.0 Hz), 2.18 (m, IH), 3.05 (d, IH, J =12.0 Hz), 3.35 (m, IH), 3.74 (s, 3H, OMe), 4.40 (t, IH, J = 4,5 Hz), 4.44 (dd, IH, J = 6.5, 11.0 Hz), 4.68 (bs, OH), 9.32 (IH, NH), 10.44 (IH, NH).13C NMR (DMSO, 50 MHz): δ 37.0, 53.0, 57.4, 57.8, 68.4, 169.0.Elemental analysis. Calculated for C6Hi2ClNO3: C, 39.68; H, 6.66; Cl, 19.52; N, 7.71. Found: C, 39.66; H, 6.64; Cl, 19.50; N, 7.71. Theoretical mass for C6Hi2ClNO3: 181.05. Found: 181.00.
98%
Stage #1: for 0.166667 h; Inert atmosphere
Stage #2: at 0℃; Inert atmosphere
4-Hydroxy proline (10.0 g, 76.33 m mol)dissolved in dry methanol (150 ml) and stirred for 10 minutes under nitrogen atmosphere.The reaction mixture cooled to 0°C by ice bath and thionyl chloride (152.6 mmol, 11.07 ml)added dropwise under nitrogen atmosphere .The ice bath removed and the reaction mixturerefluxed for six hours. The solvents were removed under reduced pressure to obtain a whitesolid which was dissolved in methanol and again evapourated to dryness to yield 13.54 g ofthe title compound in 98percent yield.
96% With thionyl chloride In neat (no solvent) at 0 - 25℃; for 16 h; To a stirred solution of (25,4R)-4-hydroxypyrrolidine-2-carboxylic acid (75.0 g, 572 mmol) in MeOH (800 mL), SOCI2 (75 mL) was added at 0 °C and the reaction mixture was stirred at room temperature for 16 h. After consumption of the starting material (by TLC), the reaction mixture was concentrated under reduced pressure. The residue was triturated with Et20 (500 mL x 2), filtered, dried to afford compound 1 (100.0 g, 96percent) as a white solid as a HCI salt of compound 1. LCMS (ESI): m/z 146.0 [M++l].
95% at -78℃; for 4.16667 h; Heating / reflux Step 1 : (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (2). Thionyl chloride (11.6 ml, 160 mmol) was added to a stirred solution of (2S,4R)-4- hydroxypyrrolidine-2-carboxylic acid (10.0 g, 76.26 mmol) (1) in methanol (150 ml) at - 780C for 10 min. The mixture was then stirred in an ice bath for 30 minutes followed by stirring at RT for 30 min. Finally the mixture was refluxed for three hours and concentrated in vacuo to give (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (2) (17.90 g, 95percent) as a white solid. Used without further purification. MS m/z 146.2 (M+H)+; retention time = 0.19 min, method [I].
94% at 0 - 45℃; for 4 h; SOCl2 (5.2 mL,71.3 mmol) was dissolved in 35.0 mL of anhydrous MeOHat 0 oC.Then trans-4-OH-proline (5.0 g, 38.1 mmol) was added and the reactionmixture was kept refluxing at 45 oC for 4 h, then the solvent was evaporated undervacuum. The residue was dissolved with methanol and recrystallized with diethylether to afford 15 as a white solid (6.5 g, 94percent yield). mp:167.3-167.5 oC; 1H NMR (600 MHz, D2O) δ 4.57–4.65 (m, 2H), 3.76 (s, 3H), 3.44 (dd, J = 12.5, 3.7 Hz, 1H), 3.32 (d, J = 12.6 Hz, 1H), 2.40 (dd, J = 13.5, 7.5 Hz, 1H), 2.21 (ddd, J = 14.3, 10.6, 4.0 Hz, 1H). 13C NMR (150 MHz, D2O) δ 170.24, 69.42, 58.16, 53.84, 53.46,36.68; IR (KBr, cm-1): ν 3328.59, 2960.67, 2869.04, 2705.78, 2602.05, 2421.58,1742.53, 1592.75, 1444.85, 1335.67, 1288.54, 1248.41, 1184.02, 1074.38, 1036.12, 958.20,902.21, 863.95, 710.91, 639.52; HRMS (ESI): m/z calculated forC6H12NO2 (M+H)+: 146.0817, found:146.0813.
92% at 10 - 45℃; for 5 h; Absolute methanol (8.0 equiv) was poured into a four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser and a drop funnel. L-hydroxyproline (1 equiv) was placed into the flask with stirring. To the suspension obtained was added dropwise at 10-15 0C distilled thionyl chloride (1.1 equiv). Then the mixture was stirred at 45 0C until TLC indicated completion (5 h) of the reaction. The suspension was cooled to 5-10 0C and then filtered and washed with dry diethyl ether. The mother liquor was evaporated in vacuo and the residue was recrystallized from dry methanol to give the title compound in 92-97percent yield.
90% for 2 h; Reflux 26.2 g (200 mmol) trans-4-hydroxy-L-proline (1) in methanol(300 ml) was treated with dry hydrogen chloride until homogeneous.The solution was heated to the reflux temperature for 2 h and concentrated in vacuo. Upon cooling, the product was crystallizedfrom the solvent, collected by filtration, washed with acetoneand ether, and dried to yield trans-4-hydroxy-L-proline methylesterhydrochloride (2) as white crystal (32.7 g, 90percent), mp 159–162 C.
88%
Stage #1: for 0.5 h; Cooling with ice
Stage #2: for 4 h; Reflux
Acetyl chloride (14 mL, 198 mmol) was slowly added into the anhydrous methanol (100 mL) in an ice bath.
After stirred for 30 min, compound 2 (7.87 g, 60.0 mmol) was added to the solution.
Then the reaction was refluxed for 4 h in an oil bath.
After the methanol was removed under reduced pressure, about 10 mL acetone was added into the residue and filtered to give 8.67 g of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride as a white powder. Yield: 88percent, mp: 160-164 °C. Di-tert-butyl dicarbonate (11.42 g, 52.3 mmol) in 50 mL dichloromethane was slowly added to the solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (8.64 g, 47.6 mmol), triethylamine (13.5 mL, 96.0 mmol) in 150 mL dichloromethane.
After stirred overnight at room temperature, the reaction mixture was concentrated under reduced pressure and dissolved with EtOAc.
The EtOAc layer was washed two times by 1 M citric acid, saturated sodium bicarbonate and brine, respectively.
Finally, the organic layer was dried over anhydrous MgSO4 and concentrated to obtain compound 3 as a white powder. Yield: 88percent, mp: 93-94 °C. 1H NMR (CDCl3, 300 MHz), δ 1.41 (s, 9H), 2.06-2.09 (m, 1H), 2.27-2.34 (m, 1H), 3.43-3.64 (m, 2H), 3.73 (s, 3H), 4.37-4.48 (m, 2H), ESI-MS m/z: 246.3 (M+H)+.
87% at 0 - 20℃; Trans-4-hydroxy-L-proline (15.0 g, 114.3 mmol) in dry methanol (250 mL) at 0 - 4 °C, was added dropwise thionyl chloride (17 ml .. 231 mmol). The resulting mixture was sl irrcd for at RT overnight, concentrated, crystallized with EtOH/hexane to provide the title compound (18.0 g, 87percent yield), ESI MS m//+ 168.2 (M + Na).
87% at 0 - 20℃; To a solution of trans-4-hydroxy-L-proline (15.0 g, 114.3 mmol) in dry methanol (250 mL) was added thionyl chloride (17 mL, 231 mmol) dropwise at 0 to 4 °C. The resulting mixture was stirred for at r.t. overnight, concentrated, crystallized with EtOH/hexane to provide the title compound (18.0 g, 87percent yield). ESI MS m/z 168.2 ([M+Na]+).
20.5 g at 0 - 20℃; Step-1:
Synthesis of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate
To a suspension of (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (15 g, 114.5 mmol) in MeOH (150 mL) was added SOCl2 (17 mL, 229 mmol) dropwise at 0° C.
The resultant mixture was allowed to stir at RT overnight.
The reaction mixture was concentrated under vacuum, azeotroped with toluene and dried to afford (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate as the HCl salt (20.5 g).

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  • 15
  • [ 51-35-4 ]
  • [ 75-36-5 ]
  • [ 40216-83-9 ]
YieldReaction ConditionsOperation in experiment
88% With thionyl chloride In methanol Step C-1.
Preparation of an ester compound
To a suspension of trans-4-hydroxy-L-proline (200 g: 1.525 mole) in methanol (800 ml), acetylchloride (163 ml: 2.288 mole) is added dropwise under ice cooling in a nitrogen atmosphere.
The mixture is warmed to room temperature, mixed with thionyl chloride (55.7 ml: 0.763 mole), and stirred for 4 hours at 40° C. to give (2S,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine hydrochloride (244.27 g). Yield: 88percent.
Colorless crystals. NMR δ(D2 O) ppm: 1.8 to 2.0(m, 1H), 2.0 to 2.2(m, 1H), 2.9 to 3.1(m, 1H), 3.17(dd, J=12.6 Hz, J=3.6 Hz, 1H), 3.49(s, 3H), 4.2 to 4.4(m, 2H). IR ν (KBr) cm-1: 3380, 3330, 2695, 2960, 1742.
Reference: [1] Patent: US5317016, 1994, A,
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Reference: [1] Archiv der Pharmazie, 2003, vol. 336, # 11, p. 495 - 503
  • 17
  • [ 77-76-9 ]
  • [ 51-35-4 ]
  • [ 40216-83-9 ]
Reference: [1] Acta Chemica Scandinavica, 1990, vol. 44, # 3, p. 243 - 251
  • 18
  • [ 51-35-4 ]
  • [ 114086-15-6 ]
Reference: [1] Synthesis, 1990, vol. 1, # 10, p. 925 - 930
[2] Journal of Organic Chemistry, 1990, vol. 55, # l, p. 1684 - 1687
[3] Journal of Organic Chemistry, 1990, vol. 55, # l, p. 1684 - 1687
  • 19
  • [ 51-35-4 ]
  • [ 104706-47-0 ]
YieldReaction ConditionsOperation in experiment
76%
Stage #1: at 45 - 154℃; for 5 h;
Stage #2: With hydrogenchloride In ethyl acetate; butanone; cyclohexanol at 0 - 25℃; for 2 - 3 h;
EXAMPLE 1 : PREPARATION OF 3-(R)-(-)-HYDROXYPYRROLIDINE HYDROCHLORIDE (FORMULA VII); Cyclohexanol (80 liters) were taken into a reactor and heated to about 155 0C. Water was removed azeotropically till the MC of the solvent is not more than 0.2percentW/W. The solvent was then cooled to about 45 0C, and (2S, 4R)-(-)-4- hydroxy-2-pyrrolidinecarboxylic acid (15 kg) was added to it and stirred for about 10 minutes. Methyl isobutyl ketone (4.275 liters) was added to the reaction mass and the reaction mass was heated to about 154 °C. The reaction mass was maintain at the same temperature for about 5 hours. Reaction completion was checked using thin layer chromatography. After the reaction is completed, the reaction mass was cooled to about 0 °C under nitrogen atmosphere, and pH of the reaction mass was adjusted to 1.0- 2.0 using EA-HCI (41 liters) at the same{00010077.1} <n="35"/>temperature. After pH adjustment is complete, the temperature was raised to about 25°C and maintained for about 2-3 hours. The isolated solid was filtered and washed with ethyl acetate (30 liters) in two equal lots under nitrogen atmosphere, and finally washed with isopropyl alcohol (15 liters). The wet solid was dried under suction for about 1 to 2 hours, followed by drying at about 55 0C under reduced pressure for about 5 hours to yield 10.7 kg of the title compound. (percent yield: 76percent). Purity By HPLC: 98.5percent
51% at 154℃; for 48 h; Step 1; Preparation of 3-(R)-hydroxypyrrolidine hydrochloride (VIII): To a stirred suspension of commercially available (25, 4i?)-4-hydroxy-2- pyrrolidinecarboxylic acid (L-hydroxyproline) (VII) (100 g, 0.762 mol) in anhydrous cyclohexanol (500 ml), was added 2-cyclohexen-l-one (5 ml). The resulting mixture was heated under reflux at about 154°C for about 48 hour. The obtained clear solution was allowed to cool to room temperature and then was cooled further to 10°C. To this, about 15 percent solution of hydrochloric acid in ethanol (234 ml) was added and then stirred for 30 minutes. The separated solid was filtered under suction and washed with ethyl acetate (2 x 100 ml). The solid was dried under reduced pressure to obtain 47.5 g of 3-(R)- hydroxypyrrolidine hydrochloride (VIII) in 51 percent yield. The solid was used without further purification in the next step. Analysis: Mass: 87.8 (M+l) as free base; for Molecular weight of 123.57 and Molecular Formula of C4Hi0ClNO; and 1H NMR (400MHz, DMSO): 5 9.58 - 9.32 (brd, 2H), 5.36 (brs, 1H), 4.36 - 3.39 (brs, 1H), 3.17 (brs, 2H), 3.11-2.96 (dd, 2H), 1.90 - 1.81 (m, 2H).
35%
Stage #1: at 155 - 160℃; for 11 h;
Stage #2: With hydrogenchloride In cyclohexene-1-one, 2-; ethanol; cyclohexanol at 0 - 5℃;
The compound trans-4-hydroxy-L-proline (10.0 g, 76.3 mM) was taken in a mixture of anhydrous cyclohexanol (50.0 ml) and 2-cyclohexen-l-one (0.5 ml). The reaction mixture was heated at 155-160°C for about 11 hours. To the reaction mixture, ethanolic hydrochloric acid (70.0 ml) was added with constant stirring, and kept at 0-5°C overnight. The separated solid was filtered under nitrogen atmosphere, washed with ethyl acetate (10.0 ml) and dried under vacuum to get the title compound. Yield = 35percent (3.3 g, 26.7 MM). 1H NMR (DMSO-d6): δ 9.57 (brs, 1H), 9.33 (brs, 1H), 5.00-5.75 (brs, 1H), 4.38 (s, 1H), 3.01-3.47 (M, 4H), 1.84-1.92 (M, 2H)
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  • 20
  • [ 24424-99-5 ]
  • [ 51-35-4 ]
  • [ 61478-26-0 ]
YieldReaction ConditionsOperation in experiment
78%
Stage #1: With sodium carbonate In tetrahydrofuran; water at 20℃; for 2 h;
Stage #2: With 4-methyl-morpholine; isobutyl chloroformate In 1,2-dimethoxyethane at -20℃; for 0.5 h;
Stage #3: With sodium tetrahydroborate In water at -20℃; for 0.5 h;
Di-tert-butyl carbonate (15.8 g, 72.4 mmol) was dissolved in THF (40 mL), and commercially available (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (10.0 g, 76.0 mmol) and a 10percent sodium carbonate aqueous solution (80 mL) were added. The mixture was stirred at room temperature for 24 hours. The organic solvent was removed under reduced pressure, and washed with ethyl acetate. After adjusting the pH to 3 by adding 1 mol/L hydrochloric acid to the aqueous layer, the mixture was extracted once with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. [0306] The obtained residue was dissolved in 2,2-dimethoxyethane (70 mL), and cooled to -20°C. Then, isobutyl chloroformate (9.51 mL, 72.4 mmol) and N-methylmorpholine (7.96 mL, 72.4 mmol) were added, and the mixture was stirred at -20°C for 30 minutes. After removing the precipitate by filtration, the filtrate was cooled to 20°C, and a sodium borohydride (2.74 g, 72.4 mmol) aqueous solution (60 mL) was added. The mixture was stirred at -20°C for 30 minutes. The reaction mixture was concentrated under reduced pressure, and then, after adding a 1 mol/L sodium hydroxide aqueous solution, extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give (2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (12.3 g, 78percent). ESI-MS: m/z 118 [M - Boc + H]+. 1H-NMR (CDCl3, 80°C) δ (ppm): 1.43 (s, 9H), 1.66 (br m, 1H), 2.01 (m, 1H), 3.33-3.73 (m. 5H), 4.14 (m, 1H), 4.35 (br m, 1H), 5.25 (br d, J = 6.5 Hz, 1H)
Reference: [1] Patent: EP2708540, 2014, A1, . Location in patent: Paragraph 0305-0306
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Reference: [1] Chemistry - A European Journal, 2006, vol. 12, # 15, p. 4121 - 4143
[2] Tetrahedron Letters, 2005, vol. 46, # 30, p. 4985 - 4987
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 22, p. 5699 - 5702
[4] Synthesis, 2004, # 3, p. 334 - 340
[5] Journal of Organic Chemistry, 2001, vol. 66, # 10, p. 3593 - 3596
[6] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 12, p. 3771 - 3773
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[8] Journal of Organic Chemistry, 2012, vol. 77, # 12, p. 5286 - 5296
[9] Patent: WO2011/50146, 2011, A1,
[10] Patent: WO2013/102242, 2013, A1,
[11] Patent: US2013/287731, 2013, A1,
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[13] Patent: WO2015/28850, 2015, A1,
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[2] Patent: EP2730572, 2015, B1,
[3] Patent: EP2730572, 2015, B1,
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YieldReaction ConditionsOperation in experiment
90%
Stage #1: for 6 h; Reflux
Stage #2: With hydrogenchloride In water for 3 h; Reflux
A mixture of (2S,4R)-4-hydroxypyrrolidine-2-carboxylicacid(50 mmol, 6550 mg) and Ac2O (250 mmol, 23.5 mL) in AcOH (100 mL) wasstirred at reflux for 6 h. The resulting mixture was concentrated to give thecrude intermediate. The solution of this crude intermediate in 2 N HCl (50 mL)was stirred at reflux for 3 h. Then activated charcoal (1 g) was added, the hotmixture was ltered immediately through a Celite layer. The filtrate was concentrated in vacuo to give the crude intermediate.The crude intermediate was dissolved in acetone and filtered. The residue was washed twice with ether anddried in vacuo to give 17 as a white solid (7.54 g, 90percent). 1H NMR (400 MHz, D2O) δ 4.57-4.37(m, 2H), 3.42-3.21 (m, 2H), 2.46-2.31 (m, 1H), 2.31-2.20 (m, 1H). 13C NMR (100 MHz, D2O) δ 172.3, 68.9, 58.4, 53.3, 36.8.
75%
Stage #1: at 50 - 90℃; for 5.5 h;
Stage #2: for 3 h; Heating / reflux
PREPARATION 25
(2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid, hydrochloride
To a mixture of acetic anhydride (408 g) and acetic acid (1.2 L) at 50° C. add trans-4-hydroxy-L-proline (0.36 mol, 94 g) in a single portion.
Heat the reaction mixture for 5.5 h at 90° C. and then concentrate it.
Dissolve the residue in 2 N hydrochloric acid and reflux for 3 h.
Cool the reaction mixture to room temperature, filter through diatomaceous earth, and concentrate under vacuum until white needles form.
Filter the crystals, wash with ether, and dry under vacuum to obtain the title compound (90.0 g, 75percent).
[α]D20+10.0 (c=1.0 in methanol).
1H NMR (400 MHz, D2O), δ 2.34-2.39 (m, 1H), 2.45-2.53 (m, 1H), 3.38 (dd, 1H), 3.45 (d, 1H), 4.50 (dd, 1H), 4.58 (br s, 1H).
65%
Stage #1: With acetic anhydride In acetic acid at 20 - 90℃;
Stage #2: With hydrogenchloride In water for 3 h; Reflux
Following a procedure essentially as described in Tetrahedron: Asymmetry, 14, (2003) 3141-3152, to a mixture of acetic anhydride (1.437 kg, 5.65 eq) and acetic acid (4.225 L) at 500C add ?raws-4-hydroxy-L-proline (331 g, 2.49 mol) in portions over 30 min. Heat the reaction mixture for 5.5 h at 90 0C then allow to cool to room temperature. Stir the reaction at room temperature overnight and then concentrate. Dissolve the residue in 2 N hydrochloric acid (4.57 L) and reflux for 3 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, and concentrate under vacuum at 70 0C to approximately 700 mL. Allow the material to cool to room temperature and let sit overnight. Dilute the resulting slurry with ether (IL), filter the crystals, wash with ether, and dry under vacuum to obtain the title compound (340 g). Dissolve the solid in hot ethanol (2.5 L), cool, stir slowly at 35 0C, and add ether (2.5 L) slowly in portions over one hour. Stir for 2 h, filter the resulting white solid, and dry overnight in a vacuum oven to obtain the title compound (270.6 g, 65percent). [α]D20 + 12.0 (c = 1.0 in methanol). 1H NMR (400 MHz, D2O), δ 2.34-2.39 (m, IH), 2.45-2.53 (m, IH), 3.38 (dd, IH), 3.45 (d, IH), 4.50 (dd, IH), 4.58 (br s, IH).
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[3] Journal of the American Chemical Society, 2013, vol. 135, # 11, p. 4333 - 4363
[4] Patent: US2009/163472, 2009, A1, . Location in patent: Page/Page column 21
[5] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 5, p. 1132 - 1139
[6] Journal of Organic Chemistry, 2010, vol. 75, # 5, p. 1620 - 1629
[7] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 4099 - 4101
[8] Patent: WO2010/104721, 2010, A1, . Location in patent: Page/Page column 21
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[10] Journal of Organic Chemistry, 1994, vol. 59, # 13, p. 3616 - 3625
[11] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 4, p. 539 - 546
[12] Patent: WO2014/32, 2014, A1,
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[2] Patent: WO2014/32, 2014, A1,
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[2] Patent: US9994614, 2018, B2,
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[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 10, p. 2434 - 2437
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[3] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 16, p. 1845 - 1847
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  • 33
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  • [ 84348-37-8 ]
YieldReaction ConditionsOperation in experiment
91%
Stage #1: With sodium hydrogencarbonate In 1,4-dioxane; water at 0 - 20℃;
Stage #2: With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane at 0 - 20℃; for 1 h;
To synthesize intermediate compound 16b, saturated NaHCO3 solution (200 mL) is added to a solution of trans-4-hydroxy-L-proline (5 g, 38.0 mmol) in dioxane and water (1 : 1 , 100 mL). The solution is cooled to 0°C and (Boc)2O (9.2g, 9.7 mL, 41 .8 mmol) was added drop wise. The reaction is stirred at room temperature overnight. The pH is maintained at 3 by addition of 2M HCI and the reaction mixture is extracted with EtOAc. The organic layers are combined, dried over MgSO4 and filtered. The solvent is removed under reduced pressure to give crude product (8.0 g, 91 percent) as a colorless oil. This crude oil (1 .5 g, 6.5 mmol) is dissolved in CH2CI2 (32 mL), and trichloroisocyanuric acid (1 .5 g, 6.5 mmol) is added in one portion. The mixture is then cooled to 0 °C and TEMPO (51 mg, 0.325 mmol) is added to the reaction. The mixture is stirred at 0 °C for 0.5 h, then warmed to room temperature, stirred for another 0.5 h. No more starting material is visible on TLC. Water (5 mL) is then added to the mixture. After stirring for 10 min, the organics are removed in vacuo, diluted with ethyl acetate (20 mL), filtered through Celite. The filtrate is acidified with HCI solution (1 M, 40 mL), washed with water (10 mL) four times, brine (10 mL), dried over MgSO4 and filtered. The solvent is removed under reduced pressure to give compound 16b (1 .35 g, 91 percent) as a white solid, which is directly used in next step without purification.
75% With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; triethylamine In tetrahydrofuran; water at 0 - 25℃; Large scale 1 kg of L-hydroxyproline was dissolved in 50 kg of water to obtain a reaction liquid;The temperature of the reaction solution was lowered to -5 ° C, and 1.9 kg of trichloroisocyanuric acid was taken.Adding to the reaction solution, controlling the reaction temperature to be less than 0 ° C, taking 238 g of tetramethylpiperidine oxynitride (TEMPO),Slowly added to the reaction solution;After the addition, keep the temperature of the reaction solution below 0 ° C, carry out the reaction, and control the temperature of the reaction solution after the TLC monitoring reaction is completed.Less than 0 ° C, the pH of the reaction solution was adjusted to 8-9 with triethylamine;2 kg of di-tert-butyl dicarbonate was dissolved in 2 L of tetrahydrofuran to obtain a solution of the amino-protecting agent in THF, and dissolved therein.The liquid is slowly added to the reaction solution, and the pH is maintained at 8-9 during the feeding;After the addition is completed, the temperature of the reaction solution is slowly raised to 25 ° C, and the reaction is carried out for 4-5 hours;After TLC monitors the reaction, the temperature of the reaction solution is lowered to -5 ° C, and 5 kg of 10percent aqueous sodium thiosulfate solution is taken.Slowly added to the reaction solution;After the addition, 10 kg of ethyl acetate was added, and the pH of the system was adjusted to 3-4 with a 6 M hydrochloric acid solution to separate the organic phase;The aqueous phase was extracted twice with 5 kg of ethyl acetate. After the aqueous phase extraction by TLC, the organic phase was saturated with 10 kg.The solution was washed once with anhydrous sodium sulfate and concentrated under reduced pressure to remove solvent.This gave 1.3 kg of a white solid.Yield: 75percent;
Reference: [1] Patent: WO2017/53990, 2017, A1, . Location in patent: Paragraph 00149
[2] Patent: CN104788353, 2018, B, . Location in patent: Paragraph 0062; 0065; 0066; 0067; 0068; 0069; 0070; 0071
[3] Patent: CN107954990, 2018, A,
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[2] Patent: WO2015/19238, 2015, A1,
[3] Patent: WO2016/79699, 2016, A1,
[4] Patent: CN105801462, 2016, A,
[5] Patent: CN106543062, 2017, A,
[6] Journal of the American Chemical Society, 2017, vol. 139, # 17, p. 6152 - 6159
[7] Patent: CN108218755, 2018, A,
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[2] Patent: CN106543062, 2017, A,
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  • [ 147266-92-0 ]
YieldReaction ConditionsOperation in experiment
90% With sodium hydroxide In 1,4-dioxane at 0 - 20℃; Preparation 1: Methyl (25,45)-l-Boc-4-aminopyrrolidin-2-carboxyIate [285] Step A: (4/?)-l-Boc-4-hydroxy-L-proline [286] (4/?)-hydroxy-L-proline (5.08 g, 38.77 mmol) was dissolved in IN NaOH (40 ml) and 1,4-dioxane (40 ml), and to the resulting solution, di-t-butyl dicarbonate (9.3g, 42.6 mmol) was added dropwise at 00C. The reaction mixture was stirred at room tem.not. perature for 8 hours, concentrated in vacuo, acidified with IN HCl, and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (8.84g, 99 percent).[287] MS[M+H] = 232 (M+l) [288] [289]
Reference: [1] Patent: WO2010/56022, 2010, A2, . Location in patent: Page/Page column 21
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Reference: [1] Tetrahedron Letters, 2013, vol. 54, # 39, p. 5345 - 5347
[2] Journal of Enzyme Inhibition and Medicinal Chemistry, 2017, vol. 32, # 1, p. 1129 - 1135
  • 38
  • [ 28920-43-6 ]
  • [ 51-35-4 ]
  • [ 88050-17-3 ]
YieldReaction ConditionsOperation in experiment
150 g With sodium hydrogencarbonate In tetrahydrofuran; water at 25 - 30℃; Example 2
Synthesis of (2S, 4R)-1-[(9H-fluoren-9-ylmethoxy) carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid
To a solution of (2S,4R)-4-hydroxy-L-proline (100 g) in tetrahydrofuran (200 ml) was added sodium bicarbonate (80 g), water (400 ml) and 9-fluorenylmethyloxycarbonyl (Fmoc) chloride (226 g) solution (in 200 ml THF) at 25-30° C.
The reaction mixture was stirred at about 25-30° C. for about 10-12 h.
After completion of reaction, water was added.
Then the aq.
reaction mass was washed with diisopropyl ether (DIPE) and acidified with 1N hydrochloric acid.
The reaction mixture was stirred for about 2-3 hours.
The solid was collected by filtration to give the 150 g of title compound as white solid.
1H NMR (300 MHz, DMSO-d6): δ 1.89-2.24 (m, 2H), 3.34-3.43 (m, 2H), 3:43-3.54 (m, 0.5H), 4.12-4.21 (m, 3H), 4.25 (s, 2H), 4.28-4.42 (m, 0.5H), 5.16 (brs, 1H), 7.29-7.34 (m, 2H), 7.38-7.65 (m, 21-1), 7.63-7.65 (m, 2H), 7.87-7.89 (m, 2H)
Melting point:-188-190° C.
Mass-(M+H):-354.33
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[2] Angewandte Chemie - International Edition, 2009, vol. 48, # 10, p. 1784 - 1787
[3] Patent: US9518048, 2016, B2, . Location in patent: Page/Page column 24
  • 39
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  • [ 88050-17-3 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydrogencarbonate In 1,4-dioxane; water; toluene Example 89
N-Fmoc-4R-Hydroxy-L-Proline
trans-4-Hydroxy-L-proline (5.00 g, 38.2 mmol) and NaHCO3 (8.00 g, 95.2 mmol) were suspended in 150 ml H2O/Dioxane (1:1).
Fluorenylmethyl chloroformate (11.4 g, 44.0 mmol) in 25 ml toluene was added dropwise.
The temperature of the reaction was not allowed to rise above 25° C. during the addition.
The mixture was stirred vigorously overnight, and then quenched with 50 ml saturated NaHCO3 solution and 50 ml water.
The solution was then extracted with 100 ml diethyl ether.
The aqueous layer was acidified to pH 1 with concentrated HCl, and extracted twice with ethyl acetate, and the organic extracts washed with brine.
The solution was dried with MgSO4, filtered and the solvent removed in vacuo.
The pure product crystallized from the concentrated solution. Yield: 13.4 g (100percent).
1H NMR: (CDCl3, 200 MHz) δ7.75-7.15 (8H, m, ArH), 4.55-4.05 (5H, m, ArCHCH2, H2, H4), 3.65-3.45 (2H, m, 2 H5), 2.35-2.10 (2H, m, 2 H3).
100% With sodium hydrogencarbonate In 1,4-dioxane; water; toluene EXAMPLE 1
N-Fmoc-trans-4-Hydroxy-L-Proline
trans-4-Hydroxy-L-proline (5.00 g, 38.2 mmol) and NaHCO3 (8.00 g, 95.2 mmol) were suspended in 150 ml H2 O/Dioxane (1:1).
Fluorenylmethyl chloroformate (11.4 g, 44.0 mmol) in 25 ml toluene was added dropwise.
The temperature of the reaction was not allowed to rise above 25° C. during the addition.
The mixture was stirred vigorously overnight, and then quenched with 50 ml saturated NaHCO3 solution and 50 ml water.
The solution was then extracted with 100 ml diethyl ether.
The aqueous layer was acidified to pH 1 with concentrated HCl, and extracted twice with ethyl acetate, and the organic extracts washed with brine.
The solution was dried with MgSO4, filtered and the solvent removed in vacuo.
The pure product crystallized from the concentrated solution. Yield: 13.4 g (100percent).
1 H NMR: (CDCl3, 200 MHz) δ 7.75-7.15 (8H, m, ArH), 4.55-4.05 (5H, m, ArCHCH2, H2, H4), 3.65-3.45 (2H, m, 2 H5), 2.35-2.10 (2H, m, 2 H3).
100% With sodium hydrogencarbonate In 1,4-dioxane; water; toluene EXAMPLE 1
N-Fmoc-trans-4-Hydroxy-L-Proline
trans-4-Hydroxy-L-proline (5.00 g, 38.2 mmol) and NaHCO3 (8.00 g, 95.2 mmol) were suspended in 150 ml H2O/Dioxane (1:1).
Fluorenylmethyl chloroformate (11.4 g, 44.0 mmol) in 25 ml toluene was added dropwise.
The temperature of the reaction was not allowed to rise above 25° C. during the addition.
The mixture was stirred vigorously overnight, and then quenched with 50 ml saturated NaHCO3 solution and 50 ml water.
The solution was then extracted with 100 ml diethyl ether.
The aqueous layer was acidified to pH 1 with concentrated HCl, and extracted twice with ethyl acetate, and the organic extracts washed with brine.
The solution was dried with MgSO4, filtered and the solvent removed in vacuo.
The pure product crystallized from the concentrated solution. Yield: 13.4 g (100percent).
1H NMR: (CDCl3, 200 MHz) δ 7.75-7.15 (8H, m, ArH), 4.55-4.05 (5H, m, ArCHCH2, H2, H4), 3.65-3.45 (2H, m, 2 H5), 2.35-2.10 (2H, m, 2 H3).
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