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Chemical Structure| 56-40-6
Chemical Structure| 56-40-6
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Product Details of [ 56-40-6 ]

CAS No. :56-40-6 MDL No. :MFCD00008131
Formula : C2H5NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :DHMQDGOQFOQNFH-UHFFFAOYSA-N
M.W :75.07 Pubchem ID :750
Synonyms :
Glycine, Gly

Calculated chemistry of [ 56-40-6 ]

Physicochemical Properties

Num. heavy atoms : 5
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.5
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 16.21
TPSA : 63.32 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) : -9.04 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.37
Log Po/w (XLOGP3) : -3.21
Log Po/w (WLOGP) : -0.97
Log Po/w (MLOGP) : -3.58
Log Po/w (SILICOS-IT) : -1.04
Consensus Log Po/w : -1.69

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 3.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 1.78
Solubility : 4550.0 mg/ml ; 60.7 mol/l
Class : Highly soluble
Log S (Ali) : 2.45
Solubility : 21200.0 mg/ml ; 282.0 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : 0.83
Solubility : 510.0 mg/ml ; 6.79 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 56-40-6 ]

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 [ 56-40-6 ]

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

  • Upstream synthesis route of [ 56-40-6 ]
  • Downstream synthetic route of [ 56-40-6 ]

[ 56-40-6 ] Synthesis Path-Upstream   1~151

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Reference: [1] Chemistry Letters, 1980, p. 73 - 76
  • 2
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Reference: [1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1983, vol. 37, # 10, p. 879 - 890
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Reference: [1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1983, vol. 37, # 10, p. 879 - 890
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Reference: [1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1983, vol. 37, # 10, p. 879 - 890
  • 5
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Reference: [1] Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 18, p. 4697 - 4708
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Reference: [1] Chemistry Letters, 1980, p. 73 - 76
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Reference: [1] Chemistry Letters, 1980, p. 73 - 76
  • 8
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  • [ 302-72-7 ]
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YieldReaction ConditionsOperation in experiment
0.18 mg With ferric sulfate nonahydrate In water at 80℃; for 24 h; General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference: [1] Biochemistry, 2016, vol. 55, # 19, p. 2806 - 2811
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YieldReaction ConditionsOperation in experiment
0.12 mg With magnesium sulfate In water at 80℃; for 24 h; General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference: [1] Biochemistry, 2016, vol. 55, # 19, p. 2806 - 2811
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  • [ 57-13-6 ]
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YieldReaction ConditionsOperation in experiment
1.6 mg With copper(II) choride dihydrate In water at 80℃; for 24 h; General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference: [1] Biochemistry, 2016, vol. 55, # 19, p. 2806 - 2811
  • 11
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Reference: [1] Journal of the American Chemical Society, 1981, vol. 103, # 5, p. 1241 - 1243
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Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
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Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
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Reference: [1] Chemistry Letters, 1980, p. 73 - 76
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Reference: [1] Patent: US6369235, 2002, B1, . Location in patent: Example 1
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YieldReaction ConditionsOperation in experiment
97.3% at 85 - 95℃; for 9 h; General procedure: o-Phenylenediamine (0.54 g, 5 mmol) and required amino acid or anthranilic acid (7 mmol) was added sequentially to 10 ml of toluene in a quickfit flask. The reacting mixture was heated under reflux at carefully controlled temperature of 85 – 95 oC for 9 h under the influence of a magnetic stirrer to obtain coloured solution which was allowed to cool overnight. The crystals formed was filtered and air-dried to afford (1H-benzo[d]imidazol-2-yl)methanamine, 10a in 97.3percent yield. Due to high efficiency observed in Method B for the synthesis of 10a,it was therefore adopted as the viable method for the synthesis of the rest of the compounds 10b-i. Synthesis of (1H-benzo[d] imidazol- 2- yl) methanamine, 10aTreatment ofo-phenylenediamine (0.54 g, 5 mmol) with L-glycine (0.53 g, 7 mmol) afforded(1H-benzo[d]imidazol-2-yl)methanamine, 10a.1HNMR (400 MHz, DMSO-d6) δ: 7.95 (s, 1H, NH), 7.82-7.80 (d, J= 8.03 Hz, 2H, Ar-H), 7.17-7.13 (m, 2H, Ar-H), 6.44-6.42 (t, J= 5.78 Hz, 2H, NH2-CH2), 3.55-3.53 (t, J= 5.78 Hz, 2H, CH2-NH2). 13C-NMR (100 MHz, DMSO-d6) δ: 142.6, 139.3, 138.9, 125.3, 125.3, 119.2, 119.2, 41.7 ppm. lmax in nm (log εmax): 236 (1.7782), 290 (1.324), 407 (0.8541). IR (KBr): 3384, 3363 (N-H of NH2, two bands), 3245 (N-H), 3021 (C-H aromatic), 2930 (C-H aliphatic), 1605 (C=C), 1580 (C=N), 741 (Ar-H) cm-1. MS: in m/z (rel. percent): 295.04 (2M + 1, 10.5percent), 148.01 (MH, 24.5percent), 147.03 (M+, 20percent), 132.04 (M – NH, 100percent), 118.07 (M – CH2=NH, 35.3percent), 76.11 (68.3percent).
87% With hydrogenchloride In water for 2 h; Reflux A solution of 1,2-phenylenediamine (13 g, 0.12 mol) and glycine (18 g, 0.24 mol) in 4 N hydrochloric acid (40 mL) was heated to reflux with stirring for 2 h. The progress of the reaction was monitored by TLC. On completion of the reaction, the reaction mixture was cooled to room temperature and the pH was adjusted to 7.2 using 1 N sodium hydroxide solution to obtain buff colored product 1. The product was recrystallized using rectified sprit as solvent.Yield: 87 percent, mp 261−263 °C, Rf: 0.72, IR (KBr) 3371 (NH2), 3053 (=C−H), 1591 (C=N) cm−1; 1H NMR (400 MHz, DMSO-d6) δ 12.1 (s, 1H, NH), 7.2−6.9 (m, 4H), 5.2 (s,2H, NH2), 2.3 (d, J = 12.7 Hz, 2H, CH2).
61% With hydrogenchloride In water for 5 h; Reflux General procedure: General procedure for the synthesis of (1H-benzimidazole-2-yl)alkylamines was adapted from the Phillips procedure.18 L-Amino acid was added to a stirred solution of 4-nitro-o-phenylendiamine and aqueous HCl (5.5 M). The mixture was heated under reflux for 5 h. The blue reaction mixture was cooled to room temperature. The mixture was allowed to stand for overnight where upon the desired (1H-benzimidazole-2-yl)alkylamine was crystallized in its HCl salt form. The free base was obtained by neutralization of the reaction mixture with 1M K2CO3 solution followed by extraction with ethyl acetate. The extract was evaporated to dryness and recrystallized from an ethanol.
Reference: [1] Oriental Journal of Chemistry, 2016, vol. 32, # 1, p. 109 - 120
[2] Molecules, 2015, vol. 20, # 8, p. 15206 - 15223
[3] Journal of the Korean Chemical Society, 2014, vol. 58, # 5, p. 450 - 455
[4] Asian Journal of Chemistry, 2014, vol. 26, # 3, p. 926 - 932
[5] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 550 - 558
[6] Die Pharmazie, 1980, vol. 35, # 2, p. 73 - 75
[7] Journal of the Indian Chemical Society, 1988, vol. 65, # 12, p. 853 - 854
[8] Bulletin de la Societe Chimique de France, 1991, p. 255 - 259
[9] Organic Letters, 2009, vol. 11, # 4, p. 907 - 910
[10] European Journal of Medicinal Chemistry, 2003, vol. 38, # 5, p. 473 - 480
[11] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 8, p. 1800 - 1807
[12] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 13, p. 3437 - 3446
[13] Bangladesh Journal of Pharmacology, 2016, vol. 11, # 1, p. 67 - 74
[14] Tetrahedron, 2016, vol. 72, # 27-28, p. 3980 - 3985
  • 17
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Reference: [1] Arkivoc, 2018, vol. 2018, # 3, p. 338 - 352
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YieldReaction ConditionsOperation in experiment
82.5%
Stage #1: With sodium hydroxide In water at 100℃; for 0.0833333 h; Microwave irradiation
Stage #2: at 40 - 100℃; for 0.0833333 h; Microwave irradiation
General procedure: Mixture of amine or amino acid (1 mol), sodium hydroxide (22 percent) and carbon disulfide (1 mol) in 3 ml water was reacted in a microwave reactor (CEM Discover, Benchmate,USA) for 5 min at 100 °C at 80 W. After automatedcooling to 40 °C, sodium chloroacetate (1 mol) was addedand the mixture was reacted again at 100 °C for 5 min.After cooling (40 °C), conc. HCl (3 ml) was added and thereaction was completed at 110 C for 20–30 min. Thecrude product was extracted with ethyl acetate and purified(Nitsche and Klein, 2012).2-(4-Oxo-2-thioxothiazolidin-3-yl)acetic acid (2a) Yield;82.5 percent; mp 245–247 °C; UV λmax 266, 215 nm; IR(KBr)νmax 3439, 1663, 1512, 1321, 896 cm-1; 1H NMR(DMSO-d6, 400 MHz): δ = 4.56 (2H, s, N–CH2), 4.41(2H, s, H-5); 13C NMR (DMSO-d6, 100 MHz): δ= 202.80(C = S, C-2), 173.72 (C = O, COOH), 167.29 (C = O,C-4), 44.77 (CH2, N–CH2), 35.94 (CH2, C-5); Anal.calcd.for C5H5NO3S2: C, 31.40; H, 2.64; N, 7.32. Found: C,31.55; H, 2.53; N, 7.22.
55%
Stage #1: With sodium hydroxide In water at 20℃; for 16 h;
Stage #2: at 20℃; for 3 h;
Stage #3: With hydrogenchloride In water for 16 h; Reflux
General Procedure for the Synthesis of Λ/-substituted Rhodanines (7a-f) To a solution of the requisite natural amino acid (typically 5 g, 30 mmol) in water (100 mL) was added NaOH (2.4 g, 2 eq) and CS2 (1.81 ml_, 30 mmol). The reaction mixture was stirred for 16h at room temperature after which a solution of sodium chloroacetate (2.82 g, 30 mmol) was added. The reaction mixture was stirred for a further 3h at room temperature, then acidified with aqueous HCI (6N, 30 mL). The resulting solution was refluxed for 16h, then cooled to ambient temperature. The crude product was extracted from the aqueous layer with ethyl acetate (3 x 50 ml_), and the combined organic layer was dried with MgSO4, filtered, and the solvent removed in vacuo.2-(4-oxo-2-thioxothiazolidin-3-yl)acetic acid (7a).The title compound was recrystallized from ethanol as a yellow solid in 55percent yield. Mp 148 0C (lit. 148 0C). 1H NMR (CDCI3): δ 4.16 (s, 2H, NCH2), 4.79 (s, 2H, SCH2).
Reference: [1] Archiv der Pharmazie, 2012, vol. 345, # 1, p. 73 - 80
[2] Medicinal Chemistry Research, 2016, vol. 25, # 5, p. 994 - 1004
[3] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 4, p. 359 - 364
[4] Patent: WO2010/24783, 2010, A1, . Location in patent: Page/Page column 79; 80
[5] Archives of Pharmacal Research, 2014, vol. 37, # 7, p. 852 - 861
[6] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 15, p. 3052 - 3056
[7] Research on Chemical Intermediates, 2016, vol. 42, # 8, p. 6607 - 6626
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YieldReaction ConditionsOperation in experiment
< 5 %Spectr. at 160℃; for 0.25 h; Microwave irradiation General procedure: A suspension of amine (5 mmol) and bis(carboxymethyl)trithiocarbonate (5.5 mmol) in water was reacted in a microwave reactor (Monowave 300, Anton Paar) at the different described time and temperature conditions. After automated cooling to 40°C the crude product was extracted with ethyl acetate and purified by flash chromatography (cyclohexane/ethyl acetate) using a Biotage Isolera One system.#10;#10;
Reference: [1] Tetrahedron Letters, 2012, vol. 53, # 39, p. 5197 - 5201
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Reference: [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8389 - 8403
  • 21
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  • [ 1080-44-0 ]
YieldReaction ConditionsOperation in experiment
99.34% With sodium carbonate In water for 5 h; General procedure: Sodium carbonate (Na2CO3, 1.590g, 15mmol) was added to a solution of amino acids (2a-h, 12.5mmol) in water (15mL) with continuous stirring until all the solutes had dissolved. The solution was cooled to−5°C and the appropriate benzenesulphonyl chloride (1a-c, 15mmol) was added in four portions over a period of 1h. The slurry was further stirred at room temperature for about 4h. The progress of the reaction was monitored using TLC (MeOH/DCM, 1:9). Upon completion, the mixture was acidified using 20percent aqueous hydrochloric acid to pH 2. The crystals was filtered via suction and washed with pH 2.2 buffer. The pure products (3a-x) were dried over self-indicating fused silica gel in a desiccator. 2.2.1 2-(4-methylphenylsulphonamido) acetic acid (3a) The amino acid was glycine, yield (2.8410g, 99.34percent), mp, 88.4–88.6°C, FTIR (KBr, cm−1): 3448 (OH of COOH), 3277 (NH), 2957 (C-H aliphatic), 1730 (C=O), 1598, 1440 (C=C), 1354, 1321 (2S=O), 1185 (SO2-NH), 1111, 1094 (C-N, C-O). 1H NMR (DMSO-d6)δ: 7.90–7.88 (t, J=6.3Hz, 1H, NH), 7.65–7.63 (d, J=8.6Hz, 2H, ArH), 7.34–7.33 (d, J=8.05Hz, 2H, ArH), 3.52–3.51 (d, J=5.7Hz, CH2), 2.34 (s, 3H, CH3). 13C NMR (DMSO-d6)δ: 170.7 (C=O), 143.1, 138.4, 130.0, 127.1 (aromatic carbons), 44.3 (CH2), 21.5 (CH3). HRMS-ESI (m/z): 228.0412 (M-H)-, calculated, 228.0408.
99.34% With sodium carbonate In water for 4 h; General procedure: Sodium carbonate (Na2CO3, 1.590 g, 15 mmol) was added to a solution of amino acids (6a-h,12.5 mmol) in water (15 mL) with continuous stirring until all the solutes dissolved. The solutionwas cooled to -5°C and an appropriate benzenesulphonyl chloride (5a-c, 15 mmol) wasadded in four portions over a period of 1 h. The slurry was further stirred at room temperaturefor 4 h. The progress of the reaction was monitored by using TLC (MeOH/DCM, 1:9). Uponcompletion, the mixture was acidified using 20percent aqueous hydrochloric acid to pH 2. The crystalswas filtered via suction and washed with pH 2.2 buffer. The pure products (7a-x) weredried over self-indicating fused silica gel in a desiccator. 2-(4-methylphenylsulphonamido) acetic acid (7a). The amino acid was glycine, yield(2.8410 g, 99.34percent), appearance white needles, mp, 88.4-88.6°C, FTIR (KBr, cm-1): 3448 (OHof COOH), 3277 (NH), 2957 (C-H aliphatic), 1730 (C = O), 1598, 1440 (C = C), 1354, 1321(2S = O), 1185 (SO2-NH), 1111, 1094 (C-N, C-O). 1H NMR (500 MHz, DMSO-d6) δ: 7.89 (t,J = 6.3 Hz, 1H, NH), 7.64 (d, J = 8.6 Hz, 2H, ArH), 7.33 (d, J = 8.05 Hz, 2H, ArH), 3.51 (d,J = 5.7 Hz, CH2), 2.34 (s, 3H, CH3). 13C NMR (500 MHz, DMSO-d6) δ: 170.8 (C = O), 143.1, 138.4, 130.0, 127.1 (aromatic carbons), 44.3 (CH2), 21.5 (CH3). HRMS-ESI (m/z): 228.0410(M-H)-, calculated, 228.0408.
86% With sodium hydrogencarbonate In water; acetone at 25℃; for 0.25 h; General procedure: Sulfonyl chloride (0.20 mmol) was dissolved in acetone (2 mL) and the resulting solution was injected in the reagent loop A. An aqueous NaHCO3 0.4 M (1 mL) was added to a solution of the amine (0.22 mmol) dissolved in PEG-400 (1 mL). The H2O/PEG400 solution (2 mL, 1:1,v/v) was then injected in the reagent loop B. A degassed solution of acetone and water were connected with pump A and B, respectively, and the flow rate was fixed at 0.5 mL min−1 (0.25 mL min−1 + 0.25 mL min−1). After switching the sample loops, the mixtures exited were joined in a T-piece, entered in a 10 mL PTFE coil reactor warmed at 25 °C, fitted with the back pressure regulator (100 psi), directed in UV detector and the output was recovered in a fraction collector. The reaction mixture was drooped in a tube containing Et2O/HCl 3 N (5 mL, 4:1, v/v). The two phases were separated, and the organic one was washed with H2O (2 × 1 mL), dried over Na2SO4, and concentrated under reduced pressure to give the desired pure compound.
81% at 20 - 25℃; General procedure: Syntheses of G1 and P1:
To a stirred solution of glycine (0.75 g, 10.0 mmol) or l-phenylalanine (1.65 g, 10.0 mmol) in 20 mL of 1 M NaOH solution at 25 °C, p-toluenesulfonyl chloride (1.91 g, 10.0 mmol) was added.
After overnight stirring at room temperature, the solid residue was filtered off and the aqueous reaction portion was acidified with 1 M HCl.
The obtained solid was filtered and purified by column chromatography on silica with hexane and EtOAc (1:2) to obtain compounds G1 and P1 as white solids. (Yields, 81percent and 76percent, respectively.)
Compound G1: Yield 81percent as white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.66 (broad singlet, 1H, -COOH), 7.93 (t, J = 6.1 Hz, 1H, -NH-), 7.67 (d, J = 8.4 Hz, 2H, ArH), 7.37 (d, J = 8.3 Hz, 2H, ArH), 3.54 (d, J = 6.1 Hz, 2H, -CH2-), 2.37 (s, 3H, -CH3) ppm. 13C NMR (100 MHz, CDCl3): δ 171.1, 143.8, 136.3, 129.9, 127.3, 40.3, 21.6 ppm. Anal. Calcd [C9H11NO4S]: C, 47.15; H, 4.84; N, 6.11; S, 13.99. Found: C, 48.36; H, 5.11; N, 5.93; S, 14.27.
72%
Stage #1: With sodium carbonate In water at 70 - 85℃; for 0.75 h;
Stage #2: With hydrogenchloride In water at 20℃;
General procedure: The nitrogen tosylation was done using a reported procedure. In a round bottom flask, 2.4 equiv. of Na2CO3 was dissolved in 70 °C water (C = 0.66 mol/L). Then 1.0 equiv. of the desired anthranilic acid was added followed by 1.4 equiv. of tosyl chloride. The suspension was stirred at 70 °C for 40 min then at 85 °C for 5 min. The reaction mixture was then directly filtrated and the solid washed with 85 °C water. The filtrate was cooled to room temperature and then acidified to pH = 1 using an aqueous 6M HCl solution. The precipitated solid was collected by suction and dried over vacuum. The resulting tosyl anthranilic acids were used without further purification.
21%
Stage #1: With sodium hydroxide In diethyl ether; water at 20℃; for 3.16667 h;
Stage #2: With hydrogenchloride In water
Glycine (1 g, 13.32 mmol) was dissolved in IN NaOH (aq.) and a solution of tosyl chloride (2.62 g, 13.72 mmol) in diethyl ether (15 ml) was added portion wise with stirring over 10 min. The resulting mixture was allowed to stir at room temperature for 3 h. The ethereal layer was separated and the aqueous layer treated with 2N HCl solution until acidified to pH 5. After cooling the resulting solution to 0 0C, the product began to precipitate from the solution. The solid was collected by filtration and the mother liquor placed in a fridge overnight causing more of the desired product to precipitate. The solid was again collected by filtration and the combined collected solid was dried under high vacuum affording 9 as a white powder (613 mg, 21percent). δH (400 MHz, MeOD) 2.41 (3H, s, CH3), 3.66 (2H, S5 CH2), 7.35 (2H, d, J=8 Hz5 ArH)5 7.73 (2H5 d, J=8 Hz, ArH); δc (100.6 MHz, MeOD) 20.3, 43.6, 127.0, 129.5, 137.6, 143.6, 171.0; MS (ES+) 246.8 (100percent, [M+H20]+); MS (ES') 227.9 (100percent, [M-H]-); HRMS [M-H]' requires 228.03360, found 228.03364.

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YieldReaction ConditionsOperation in experiment
1.6 mg With copper(II) choride dihydrate In water at 80℃; for 24 h; General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
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YieldReaction ConditionsOperation in experiment
81%
Stage #1: With sodium hydroxide In acetone at 20℃; for 6 h; Cooling with ice
Stage #2: With hydrogenchloride In water
l-Glycin (100 mg, 1.33 mmol) was dissolved in 2 M sodium hydroxide solution (2 mL), then acetone (2 mL) was added and the mixture was cooled under ice-bath. Phenyl acetyl chloride (161 μL, 1.21 mmol) was added dropwise at the same temperature, followed by warming to room temperature. After 6 h, the solvent was evaporated off, and the residue was adjust to pH = 2-3 using 1 M HCl and extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to give 2 (190 mg, 81percent) as a white solid. 1H NMR (300 MHz, acetone-d6): δ = 7.41-7.20 (m, 5H), 3.95 (d, J = 5.74 Hz, 1H), 3.59 (s, 2H). 13C NMR (75 MHz, DMSO-d6): δ = 717.53, 170.81, 136.32, 129.25, 128.36, 126.55, 42.15, 40.95. MALDI-TOF-MS: Calcd for C10H12NO3 194.1. Found 194.1 [M+H]+.
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  • [ 87619-96-3 ]
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  • 51
  • [ 122-01-0 ]
  • [ 56-40-6 ]
  • [ 13450-77-6 ]
YieldReaction ConditionsOperation in experiment
11.2 g With sodium hydroxide In water at 15 - 26℃; for 1.5 h; To a stirred and cooled (15 °C) solution of glycine (5.0 g, 66.602 mmol) in 10percent aqueous sodium hydroxide solution (50 mL) was added benzoyl chloride (11.8 mL, 92.57 mmol) in portions. The reaction mixture was stirred at RT for 1.5 h. The reaction mixture was poured in to crushed ice and acidified with conc. HC1 till pH 3-4.The obtained precipitate was collected by filtration and dried to yield 11.2 g of thetitle product as a solid. ‘H NMR (300 MHz, DMSO-d6) ö 4.08 (s, 2H), 7.49 (d, J = 8.7Hz, 2H), 7.85 (d, J = 8.1 Hz, 2H), 8.00 (d, J = 8.4 Hz, 1H).
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[2] Naunyn-Schmiedebergs Archiv fuer Experimentelle Pathologie und Pharmakologie, 1931, vol. 161, p. 719,724
[3] Journal of the American Chemical Society, 1980, vol. 102, # 22, p. 6828 - 6837
[4] Chemical & Pharmaceutical Bulletin, 1984, vol. 32, # 8, p. 3100 - 3104
[5] Journal of Medicinal Chemistry, 1989, vol. 32, # 5, p. 1033 - 1038
[6] Journal of Medicinal Chemistry, 1997, vol. 40, # 12, p. 1771 - 1772
[7] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 1, p. 37 - 41
[8] Journal of Chemical Research, 2006, # 11, p. 738 - 739
[9] Heterocycles, 2011, vol. 83, # 1, p. 153 - 161
[10] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 15, p. 4642 - 4647
[11] Oriental Journal of Chemistry, 2010, vol. 26, # 4, p. 1533 - 1536
[12] Biopharmaceutics and Drug Disposition, 2011, vol. 32, # 6, p. 343 - 354
[13] European Journal of Medicinal Chemistry, 2015, vol. 96, p. 425 - 435
[14] Patent: WO2015/159233, 2015, A1, . Location in patent: Page/Page column 70; 71
[15] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 13, p. 3043 - 3051
[16] Archiv der Pharmazie, 2018, vol. 351, # 2,
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  • [ 56-40-6 ]
  • [ 21732-17-2 ]
Reference: [1] Journal of Organic Chemistry, 1997, vol. 62, # 26, p. 9099 - 9106
  • 53
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[2] European Journal of Medicinal Chemistry, 2009, vol. 44, # 12, p. 5094 - 5098
[3] Organic and Biomolecular Chemistry, 2009, vol. 7, # 16, p. 3308 - 3318
[4] Organic Letters, 2010, vol. 12, # 9, p. 1920 - 1923
[5] Bioconjugate Chemistry, 2012, vol. 23, # 12, p. 2417 - 2433
[6] Patent: EP1188746, 2002, A1, . Location in patent: Page 8
[7] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 1124 - 1127
[8] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 2, p. 162 - 167
[9] Oriental Journal of Chemistry, 2018, vol. 34, # 1, p. 286 - 294
[10] Journal of Peptide Science, 2018, vol. 24, # 4-5,
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  • [ 6066-82-6 ]
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  • [ 3392-07-2 ]
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  • 55
  • [ 6066-82-6 ]
  • [ 19506-72-0 ]
  • [ 56-40-6 ]
  • [ 2899-60-7 ]
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  • 56
  • [ 58-86-6 ]
  • [ 56-40-6 ]
  • [ 3658-77-3 ]
  • [ 27538-10-9 ]
Reference: [1] Journal of Agricultural and Food Chemistry, 2003, vol. 51, # 9, p. 2708 - 2713
  • 57
  • [ 50-00-0 ]
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Reference: [1] Chemistry and Physics of Lipids, 1997, vol. 86, # 2, p. 171 - 181
[2] Tetrahedron Letters, 2007, vol. 48, # 43, p. 7680 - 7682
[3] Synthesis, 2011, # 3, p. 490 - 496
[4] Tetrahedron Letters, 1991, vol. 32, # 31, p. 3847 - 3848
[5] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 10, p. 3021 - 3025
[6] Yakugaku Zasshi, 1946, vol. 66, p. 4[7] Chem.Abstr., 1951, p. 7956
[8] Journal of the Chemical Society, 1950, p. 1342,1345
[9] Journal of the American Chemical Society, 1951, vol. 73, p. 864
[10] Journal of the American Chemical Society, 1933, vol. 55, p. 4576
[11] Journal of pharmaceutical sciences, 1969, vol. 58, # 10, p. 1228 - 1232
[12] Bulletin of the Chemical Society of Japan, 1968, vol. 41, # 7, p. 1679 - 1681
[13] Analytical Chemistry, 2007, vol. 79, # 22, p. 8631 - 8638
[14] Patent: US2013/78728, 2013, A1, . Location in patent: Sheet 4
[15] Journal of Mass Spectrometry, 2015, vol. 50, # 5, p. 771 - 781
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  • [ 50-00-0 ]
  • [ 56-40-6 ]
  • [ 107-97-1 ]
  • [ 1118-68-9 ]
Reference: [1] Biochemische Zeitschrift, 1913, vol. 51, p. 123
  • 59
  • [ 50-00-0 ]
  • [ 64-18-6 ]
  • [ 56-40-6 ]
  • [ 1118-68-9 ]
  • [ 124-38-9 ]
  • [ 75-50-3 ]
Reference: [1] Journal of the American Chemical Society, 1933, vol. 55, p. 4576
  • 60
  • [ 50-00-0 ]
  • [ 64-19-7 ]
  • [ 56-40-6 ]
  • [ 1118-68-9 ]
  • [ 124-38-9 ]
  • [ 75-50-3 ]
Reference: [1] Journal of the American Chemical Society, 1933, vol. 55, p. 4576
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  • [ 617-65-2 ]
  • [ 1068-84-4 ]
  • [ 56-40-6 ]
  • [ 617-45-8 ]
Reference: [1] Tetrahedron Letters, 1983, vol. 24, # 44, p. 4839 - 4842
  • 62
  • [ 302-72-7 ]
  • [ 1068-84-4 ]
  • [ 302-84-1 ]
  • [ 5735-66-0 ]
  • [ 64-19-7 ]
  • [ 127-17-3 ]
  • [ 56-40-6 ]
Reference: [1] Tetrahedron Letters, 1983, vol. 24, # 44, p. 4839 - 4842
  • 63
  • [ 59-51-8 ]
  • [ 1068-84-4 ]
  • [ 13100-82-8 ]
  • [ 88547-35-7 ]
  • [ 3226-62-8 ]
  • [ 56-40-6 ]
  • [ 617-45-8 ]
Reference: [1] Tetrahedron Letters, 1983, vol. 24, # 44, p. 4839 - 4842
  • 64
  • [ 106-95-6 ]
  • [ 56-40-6 ]
  • [ 54594-06-8 ]
  • [ 16338-48-0 ]
Reference: [1] Angewandte Chemie - International Edition, 2001, vol. 40, # 10, p. 1948 - 1951
  • 65
  • [ 556-56-9 ]
  • [ 56-40-6 ]
  • [ 54594-06-8 ]
  • [ 16338-48-0 ]
Reference: [1] Angewandte Chemie - International Edition, 2001, vol. 40, # 10, p. 1948 - 1951
  • 66
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Reference: [1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1988, vol. 37, # 12, p. 2541 - 2544[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1988, # 12, p. 2818 - 2821
[3] Tetrahedron Asymmetry, 1998, vol. 9, # 12, p. 2121 - 2131
[4] Tetrahedron Asymmetry, 2010, vol. 21, # 24, p. 2956 - 2965
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  • [ 348-67-4 ]
Reference: [1] Agricultural and Biological Chemistry, 1984, vol. 48, # 1, p. 143 - 148
  • 68
  • [ 120-57-0 ]
  • [ 96293-17-3 ]
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  • [ 2280-27-5 ]
  • [ 88375-62-6 ]
Reference: [1] Journal of the American Chemical Society, 1985, vol. 107, # 14, p. 4252 - 4259
  • 69
  • [ 96293-17-3 ]
  • [ 67-64-1 ]
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  • [ 2280-27-5 ]
  • [ 88375-62-6 ]
Reference: [1] Journal of the American Chemical Society, 1985, vol. 107, # 14, p. 4252 - 4259
  • 70
  • [ 638-45-9 ]
  • [ 56-40-6 ]
  • [ 106819-03-8 ]
  • [ 116783-26-7 ]
Reference: [1] Angewandte Chemie - International Edition, 2001, vol. 40, # 10, p. 1948 - 1951
  • 71
  • [ 77287-34-4 ]
  • [ 302-72-7 ]
  • [ 302-84-1 ]
  • [ 3130-87-8 ]
  • [ 56-40-6 ]
Reference: [1] Chemistry Letters, 1997, # 5, p. 393 - 394
[2] Chemistry Letters, 1997, # 5, p. 393 - 394
[3] Chemistry Letters, 1997, # 5, p. 393 - 394
  • 72
  • [ 64-18-6 ]
  • [ 56-40-6 ]
  • [ 2491-15-8 ]
YieldReaction ConditionsOperation in experiment
74%
Stage #1: at 45℃; for 1 h;
Stage #2: at 20℃; for 24 h;
General procedure: Formic acid (140mL, 3.71mol) and acetic anhydride (47mL, 0.50mol) were stirred at 45°C for 1h. After the addition of the appropriate amino acid (0.05mol), the mixture was left stirring at room temperature for 24h, and evaporated until dryness.
67% at 20℃; for 24 h; Glycine (5.20 g, 69.23 mmol) was dissolved in formic acid (25 mL), was added acetic anhydride (3.0 eq, 21.3 mL), was stirred for 24 hours at room temperature the reaction. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, recrystallized by adding methanol and ethyl acetate, the corresponding formamide (1a) was obtained (4.81 g, 46.66 mmol, 67percent).Compound 1a (0.95 g, 9.18 mmol) and, DMF (20 mL) inAt, benzyl bromide (1.5 eq, 1.64 mL) and potassium carbonate (3.2 eq, 3.99 g) and, at room temperatureIt was stirred for 48 hours. After completion of the reaction, water is added to inactivate the reaction mixture, with ethyl acetateExtracted. The organic layer was washed with saturated brine, dried with magnesium sulfate, filtered, concentrated under reduced pressureIt was carried out. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1 → 1: 9) To give the corresponding benzyl ester (1b) (400 mg, was obtained 2.02 mmol, 22percent).Compound 1b (514.8 mg, 2.66 mmol) was added in DCM (10 mL), the mixture obtained (PhO) 2POCl (1.5 eq, 582 μL) and pyridine (5.0 eq, 1.88 mL) was added, and 2.5 hours with stirring to line the reactionWas Tsu. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer, hydrochloric acid, carbonSodium acid hydrogen, water, and successively washed with saturated brine, and dried over magnesium sulfate,After filtration, it was concentrated under reduced pressure.
Reference: [1] Organic and Biomolecular Chemistry, 2015, vol. 14, # 1, p. 93 - 96
[2] Synthetic Communications, 1983, vol. 13, # 9, p. 745 - 752
[3] Organic Letters, 2018, vol. 20, # 18, p. 5877 - 5880
[4] Chemical Communications, 2012, vol. 48, # 31, p. 3775 - 3777
[5] Tetrahedron, 2013, vol. 69, # 43, p. 9161 - 9165
[6] Patent: JP2015/42622, 2015, A, . Location in patent: Paragraph 0124
[7] Chemische Berichte, 1905, vol. 38, p. 3999
[8] Chemische Berichte, 1905, vol. 38, p. 3999
[9] Journal of Organic Chemistry, 1961, vol. 26, p. 4698 - 4701
[10] Journal of the American Chemical Society, 1984, vol. 106, # 11, p. 3344 - 3353
[11] Journal of the American Chemical Society, 1999, vol. 121, # 7, p. 1434 - 1443
[12] Patent: CN106831628, 2017, A, . Location in patent: Paragraph 0011; 0030; 0034; 0036; 0041; 0046
  • 73
  • [ 77287-34-4 ]
  • [ 2491-15-8 ]
  • [ 113-00-8 ]
  • [ 127-17-3 ]
  • [ 56-40-6 ]
YieldReaction ConditionsOperation in experiment
0.0034 mg With iron(II) chloride tetrahydrate In water at 80℃; for 24 h; General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
0.0052 mg With zinc(II) chloride In water at 80℃; for 24 h; General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference: [1] Biochemistry, 2016, vol. 55, # 19, p. 2806 - 2811
[2] Biochemistry, 2016, vol. 55, # 19, p. 2806 - 2811
  • 74
  • [ 77287-34-4 ]
  • [ 156-81-0 ]
  • [ 849585-22-4 ]
  • [ 617-48-1 ]
  • [ 2491-15-8 ]
  • [ 110-15-6 ]
  • [ 108-53-2 ]
  • [ 71-30-7 ]
  • [ 113-00-8 ]
  • [ 127-17-3 ]
  • [ 66-22-8 ]
  • [ 66224-66-6 ]
  • [ 56-40-6 ]
  • [ 302-72-7 ]
  • [ 18514-52-8 ]
YieldReaction ConditionsOperation in experiment
0.18 mg With ferric sulfate nonahydrate In water at 80℃; for 24 h; General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference: [1] Biochemistry, 2016, vol. 55, # 19, p. 2806 - 2811
  • 75
  • [ 77287-34-4 ]
  • [ 156-81-0 ]
  • [ 849585-22-4 ]
  • [ 617-48-1 ]
  • [ 2491-15-8 ]
  • [ 110-15-6 ]
  • [ 108-53-2 ]
  • [ 71-30-7 ]
  • [ 113-00-8 ]
  • [ 127-17-3 ]
  • [ 66-22-8 ]
  • [ 66224-66-6 ]
  • [ 56-40-6 ]
  • [ 302-72-7 ]
YieldReaction ConditionsOperation in experiment
0.12 mg With magnesium sulfate In water at 80℃; for 24 h; General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference: [1] Biochemistry, 2016, vol. 55, # 19, p. 2806 - 2811
  • 76
  • [ 56-40-6 ]
  • [ 2258-42-6 ]
  • [ 2491-15-8 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1934, vol. &lt;5&gt; 1, p. 1665
[2] Bulletin of the Chemical Society of Japan, 1965, vol. 38, p. 244 - 246
[3] The Journal of organic chemistry, 1976, vol. 41, # 7, p. 1112 - 1117
  • 77
  • [ 77287-34-4 ]
  • [ 51953-18-5 ]
  • [ 1455-77-2 ]
  • [ 120-89-8 ]
  • [ 849585-22-4 ]
  • [ 73-40-5 ]
  • [ 328-42-7 ]
  • [ 2491-15-8 ]
  • [ 110-15-6 ]
  • [ 71-30-7 ]
  • [ 120-73-0 ]
  • [ 144-62-7 ]
  • [ 113-00-8 ]
  • [ 127-17-3 ]
  • [ 66-22-8 ]
  • [ 56-06-4 ]
  • [ 66224-66-6 ]
  • [ 57-13-6 ]
  • [ 56-40-6 ]
  • [ 302-72-7 ]
  • [ 18588-61-9 ]
Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
  • 78
  • [ 77287-34-4 ]
  • [ 51953-18-5 ]
  • [ 120-89-8 ]
  • [ 849585-22-4 ]
  • [ 73-40-5 ]
  • [ 328-42-7 ]
  • [ 2491-15-8 ]
  • [ 110-15-6 ]
  • [ 71-30-7 ]
  • [ 144-62-7 ]
  • [ 113-00-8 ]
  • [ 127-17-3 ]
  • [ 66-22-8 ]
  • [ 66224-66-6 ]
  • [ 56-40-6 ]
  • [ 18588-61-9 ]
  • [ 18514-52-8 ]
Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
  • 79
  • [ 77287-34-4 ]
  • [ 51953-18-5 ]
  • [ 1455-77-2 ]
  • [ 120-89-8 ]
  • [ 73-40-5 ]
  • [ 328-42-7 ]
  • [ 2491-15-8 ]
  • [ 110-15-6 ]
  • [ 71-30-7 ]
  • [ 120-73-0 ]
  • [ 144-62-7 ]
  • [ 113-00-8 ]
  • [ 127-17-3 ]
  • [ 66-22-8 ]
  • [ 66224-66-6 ]
  • [ 57-13-6 ]
  • [ 56-40-6 ]
  • [ 302-72-7 ]
Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
  • 80
  • [ 77287-34-4 ]
  • [ 56-40-6 ]
  • [ 2491-15-8 ]
Reference: [1] Chemische Berichte, 1947, vol. 80, p. 38
  • 81
  • [ 64-18-6 ]
  • [ 77287-34-4 ]
  • [ 56-40-6 ]
  • [ 2491-15-8 ]
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  • 82
  • [ 74-96-4 ]
  • [ 56-40-6 ]
  • [ 2566-29-2 ]
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  • 83
  • [ 75-03-6 ]
  • [ 56-40-6 ]
  • [ 2566-29-2 ]
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  • 84
  • [ 56-40-6 ]
  • [ 920-46-7 ]
  • [ 23578-45-2 ]
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  • [ 23578-45-2 ]
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  • [ 79-41-4 ]
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  • [ 23578-45-2 ]
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  • 87
  • [ 56-40-6 ]
  • [ 108-12-3 ]
  • [ 16284-60-9 ]
Reference: [1] Biochemische Zeitschrift, 1910, vol. 23, p. 500
  • 88
  • [ 503-74-2 ]
  • [ 56-40-6 ]
  • [ 16284-60-9 ]
Reference: [1] Biomedical Mass Spectrometry, 1979, vol. 6, # 10, p. 439 - 443
  • 89
  • [ 56-40-6 ]
  • [ 6244-91-3 ]
  • [ 16284-60-9 ]
  • [ 85-61-0 ]
Reference: [1] Drug Metabolism and Disposition, 2012, vol. 40, # 2, p. 346 - 352
  • 90
  • [ 383-63-1 ]
  • [ 56-40-6 ]
  • [ 383-70-0 ]
YieldReaction ConditionsOperation in experiment
85% With triethylamine In methanol at 20℃; for 24 h; General procedure: The TFA-α-amino acid was prepared with reported procedure [1,2] with slightly modification.Triethylamine (33 mmol, 1.5 equiv.) was added to a solution of α-amino acid (22 mmol) inMeOH (22 mL). After 5 min, ethyl trifluoroacetate (29 mmol, 1.3 equiv.) was added and thereaction was allowed to stir for 24 h. The solvent was removed by rotary evaporation and theresidue that remained was dissolved in H2O (35 mL) and acidified with concentrated HCl (4 mL).After stirring for 15 min, the mixture was extracted with ethyl acetate and the organic layerswere combined and washed with brine, dried by MgSO4, filtered, and concentrated by rotaryevaporation. Further subjection into high vacuum for overnight, if needed to solidify the product(L-/D-1a–L-/D-2a, 3a, L-/D-4a–L-/D-8a).
Reference: [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 30, p. 8298 - 8309
[2] Organic Letters, 2018, vol. 20, # 18, p. 5877 - 5880
[3] Molecules, 2017, vol. 22, # 10,
[4] European Journal of Organic Chemistry, 2012, # 29, p. 5774 - 5788,15
[5] European Journal of Organic Chemistry, 2012, # 29, p. 5774 - 5788
[6] Angewandte Chemie - International Edition, 2009, vol. 48, # 11, p. 1995 - 1997
[7] European Journal of Organic Chemistry, 2009, # 28, p. 4882 - 4892
[8] Patent: WO2015/63020, 2015, A1, . Location in patent: Page/Page column 38
[9] Chemical Communications, 2018, vol. 54, # 43, p. 5410 - 5413
  • 91
  • [ 56-40-6 ]
  • [ 407-25-0 ]
  • [ 383-70-0 ]
YieldReaction ConditionsOperation in experiment
81% at 0 - 70℃; for 2 h; Large scale To a 30 L reactor equipped with a mechanical stirrer, a thermometer,a reflux condenser, an addition funnel, and nitrogeninlet-outlet was charged TFA (2 L), glycine 16 (2.0 kg, 26.6 mol)with stirring while keeping the inner temperature below 0 Cresulting in a suspension. Then to the suspension was added dropwiseTFAA (6.6 kg, 31.4 mol) with stirring while keeping the innertemperature below 70 C. After addition, the reaction mixture waskept at 70 C and stirred for another 2 h until all solid was dissolved.Completion was demonstrated by disappearance of thestarting material by HPLC after 2 h. The mixture was concentratedto dryness under vacuum at 50 C to obtain the crude 17 as a lightyellow solid. The crude material was purified by re-crystallizationfrom EtOAc (6 L) and heptane (12 L) to afford pure 17 (3.7 kg, 81percent)as a white solid: mp 120–121 C. 1H NMR (400 MHz, D2O) d 4.01 (s,2 H). 13C NMR (101 MHz, D2O) d 40.86, 117.08, 159.37, 171.66;HRMS (ESI) [C4H4F3NO3H]) calcd 170.0065, found 170.0044.
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1985, p. 1355 - 1362
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 13, p. 2452 - 2458
[3] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 4, p. 957 - 969
[4] European Journal of Organic Chemistry, 2014, vol. 2014, # 13, p. 2664 - 2667
[5] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 4, p. 1764 - 1774
[6] Chemische Berichte, 1954, vol. 87, p. 248,256
[7] Angewandte Chemie, 1952, vol. 64, p. 136
[8] Journal of Biological Chemistry, 1954, vol. 210, p. 227,230
[9] Journal of the American Chemical Society, 1972, vol. 94, # 1, p. 265 - 268
  • 92
  • [ 431-47-0 ]
  • [ 56-40-6 ]
  • [ 383-70-0 ]
YieldReaction ConditionsOperation in experiment
87% With triethylamine In methanol for 18 h; Methyl trifluoroacetate (804 μL, 7.99 mmoles) and triethylamine (928 μL, 6.66 mmoles) were added to a suspension of glycine (500 mg, 6.66 mmoles) in methanol (2.5 mL). After the mixture was stirred vigorously for 18 h, 1 N HCl was added dropwise until the a pH of 2 was obtained. The reaction was added to ethyl acetate (30 mL) was washed with 1 N HCl (2 x 10 mL), dried over MgSO4, and concentrated in vacuo to yield the amide as a white solid (991 mg, 5.79 mmoles, 87percent). LRMS: (CI+) calcd for C4H4NO3F3 (M + NH4): 189; found: 189. 1H NMR: spectrum is consistent with the predicted structure.
Reference: [1] Russian Journal of General Chemistry, 1994, vol. 64, # 5.2, p. 791 - 792[2] Zhurnal Obshchei Khimii, 1994, vol. 64, # 5, p. 878
[3] Patent: EP1235851, 2006, B1, . Location in patent: Page/Page column 46
[4] Synthesis, 1976, p. 399 - 401
  • 93
  • [ 56-40-6 ]
  • [ 383-70-0 ]
Reference: [1] Patent: US6191150, 2001, B1,
[2] Patent: US2014/100217, 2014, A1, . Location in patent: Page/Page column
  • 94
  • [ 848860-95-7 ]
  • [ 56-40-6 ]
  • [ 383-70-0 ]
Reference: [1] Synlett, 2005, # 2, p. 255 - 258
  • 95
  • [ 383-64-2 ]
  • [ 56-40-6 ]
  • [ 383-70-0 ]
Reference: [1] Journal of the American Chemical Society, 1955, vol. 77, p. 2779,2782
  • 96
  • [ 500-73-2 ]
  • [ 56-40-6 ]
  • [ 383-70-0 ]
Reference: [1] Chemische Berichte, 1959, vol. 92, p. 2095,2098
  • 97
  • [ 354-32-5 ]
  • [ 56-40-6 ]
  • [ 383-70-0 ]
Reference: [1] Journal of Pharmaceutical Sciences, 1979, vol. 68, # 4, p. 496 - 499
  • 98
  • [ 64-17-5 ]
  • [ 144-62-7 ]
  • [ 56-40-6 ]
  • [ 29655-79-6 ]
Reference: [1] Bulletin of the Chemical Society of Japan, 1972, vol. 45, p. 1917 - 1918
  • 99
  • [ 144122-68-9 ]
  • [ 56-40-6 ]
  • [ 1953-02-2 ]
YieldReaction ConditionsOperation in experiment
190 g at 0℃; for 5 h; 90 g of glycine was added into a multi-necked reaction bottle, and 400 mL of water was added to dissolve the solution, and 64 g of anhydrous sodium carbonate was gradually added. After cooling to 0 ° C, 150 g of 2-mercaptopropionyl chloride was slowly added dropwise,After the addition, a certain amount of sodium carbonate solution was added to keep the reaction solution weakly alkaline. The reaction was continued for 5 hours, acidified to pH 2 with dilute hydrochloric acid, extracted with ethyl acetate and evaporated under reduced pressure to give 190 g of tiopronin
Reference: [1] Patent: CN106146365, 2016, A, . Location in patent: Paragraph 0038; 0039
  • 100
  • [ 78-84-2 ]
  • [ 56-40-6 ]
  • [ 5817-22-1 ]
  • [ 10148-70-6 ]
Reference: [1] Journal of the American Chemical Society, 1997, vol. 119, # 49, p. 11734 - 11742
[2] Tetrahedron, 2007, vol. 63, # 34, p. 8088 - 8093
  • 101
  • [ 78-84-2 ]
  • [ 56-40-6 ]
  • [ 5817-22-1 ]
  • [ 10148-70-6 ]
  • [ 87421-23-6 ]
  • [ 87421-24-7 ]
Reference: [1] Angewandte Chemie, 1994, vol. 106, # 1, p. 106 - 108
  • 102
  • [ 3154-51-6 ]
  • [ 56-40-6 ]
  • [ 459-73-4 ]
  • [ 2999-46-4 ]
Reference: [1] Patent: US2003/236429, 2003, A1, . Location in patent: Page 11
  • 103
  • [ 169268-03-5 ]
  • [ 2381-21-7 ]
  • [ 24463-15-8 ]
  • [ 61577-80-8 ]
  • [ 56-40-6 ]
Reference: [1] Photochemistry and Photobiology, 1995, vol. 61, # 5, p. 431 - 434
  • 104
  • [ 2251-65-2 ]
  • [ 56-40-6 ]
  • [ 17794-48-8 ]
YieldReaction ConditionsOperation in experiment
95%
Stage #1: With sodium hydroxide In acetonitrile at 4 - 6℃; for 2.5 h;
Stage #2: With hydrogenchloride In water; acetonitrile at 0 - 6℃; for 1.5 h;
A 12-L 4-neck round bottom flask equipped with a thermocouple controller, mechanical stirrer, heating mantle, condenser and a nitrogen in/outlet adapter was charged with gycine (1, Alfa Aesar) (318 g; 4.19 mol), acetonitrile (1.2 L), and a solution of sodium hydroxide (5.31 L; 10.62 mo) and the mixture was cooled to 4° C. with stirring.
A solution of 3-(trifluoromethyl)benzoyl chloride (2, Alfa Aesar) (885.0 g; 4.12 mol) (640 mL) in acetonitrile (0.75 L) (total 1.39 L) was added dropwise over 2 h while the internal temperature was maintained between 4-6° C., and the slightly orange-pinkish solution was stirred at 4° C. for an additional 30 min.
The reaction was acidified to pH=3 with conc. 37percent HCl solution (400 mL added over 30 min) at 0-6° C., and stirred for 1 h at 0° C. (until a slightly yellowish suspension resulted).
The solid was collected by filtration, washed with cold (0° C.) deionized ("D.I") H2O (300 mL*2), dried under air-suction for 2 h, and then placed in a drying oven at 60° C. under house vacuum (120 mmHg) for 20 h to afford pure 3 as an off-white solid.
The filtrate was extracted with EtOAc (1 L*2), and the combined organic phases washed with brine (300 mL), and concentrated at 66° C. under house vacuum and then high vacuum (20 mmHg) to give crude product as an off-white waxy solid, which was triturated and sonicated with toluene (1 L) and stirred at 10° C. for 1 h.
The resulting solid was collected by filtration, washed with hexanes (50 mL*2), dried in an vacuum oven at 50° C. under house vacuum to afford additional pure title compound, 3, as an off-white solid.
The structure of 3 was confirmed with its 1H-NMR.
91% With hydrogenchloride; sodium hydroxide In acetonitrile at 0 - 3℃; for 1 h; Manufacturing example 1: (3-trifluoromethylbenzoylamino)-acetic acid [Show Image] Glycine 0.763 g (10.16 mmol) were suspended in acetonitrile 20 ml and 2 M NaOH aqueous solution 12.7 ml (25.40 mmol, 2.5 eq.) were also added. After chilling at 0-3°C, 2.12 g (10.16 mmol, 1.0 eq.) of 3- (trifluoromethyl) -benzoyl chloride were diluted with 4 ml acetonitrile and added dropwise slowly to reaction mixture. After one hour agitation at the same temperature, pH was controlled to 2 to 3 with 3N hydrochloric acid aqueous solution. After keeping upright at room temperature, upper organic solution was separated, and lower aqueous solution was extracted with ethylacetate three times. Those organic solutions obtained as described above were brought all together, dried with anhydrous magnesium sulfate and concentrated, removing the solvent under decompression. Residues were solidified with toluene, filtered, washed with normal hexane and 2.28 g (91percent) target compound as white solid were yielded. 1H NMR(400MHz,DMSO-d6) 3.94(2H,d), 7.74(1H,t), 7.93(1H,d), 8.16(1H,d), 8.20(1H,s), 9.12(1H,t)
91% With hydrogenchloride; sodium hydroxide In water; acetonitrile at 0 - 3℃; for 1 h; Manufacturing Example 1
(3-trifluoromethylbenzoylamino)-acetic acid
Glycine 0.763 g (10.16 mmol) was suspended into acetonitrile 20 ml and 2M NaOH aqueous solution 12.7 ml (25.40 mmol, 2.5 eq.) was also added.
After chilling at 0-3° C., 2.12 g (10.16 mmol, 1.0 eq.) of 3-(trifluoromethyl)-benzoyl chloride was diluted with 4 ml acetonitrile and was added dropwise slowly to reaction mixture.
After one hour agitation at same temperature, pH was controlled to 2 to 3 with 3N hydrochloric acid aqueous solution.
After keeping upright at room temperature, upper organic solution was separated, and lower aqueous solution was extracted with ethylacetate three times.
Those organic solution obtained as above was brought all together, dried with anhydrous magnesium sulfate and concentrated removing its solvent under decompression.
Residues was solidified with tolene, filtered, washed with normal hexane and 2.28 g (91percent) target compound as white solid was yielded.
1H NMR (400 MHz, DMSO-d6) 3.94 (2H, d), 7.74 (1H, t), 7.93 (1H, d), 8.16 (1H, d), 8.20 (1H, s), 9.12 (1H, t)
90%
Stage #1: With sodium hydroxide In water; acetonitrile at 0℃; for 1 h;
Stage #2: With hydrogenchloride In water; acetonitrile
(3-Trifluoromethyl-benzoylamino)acetic acid. To a rapid stirring solution of glycine (15.014 g, 0.20 mol) in MeCN (400 mL) and 2 M NaOH (250 mL) at 0° C. was slowly added a solution of 3-(trifluoromethyl)-benzoyl chloride (41.714 g, 0.20 mol) in 75 mL of MeCN over 30 min. The cloudy yellow solution was stirred at 0° C. for 30 min. The reaction mixture was acidified with 3 M HCl to pH=3, followed by removal of MeCN on rotary evaporator. The resulting mixture was then extracted with EtOAc (400 mL.x.3). The combined organic layers were dried, filtered and concentrated to give a light yellow solid (48.53 g), which was triturated with toluene (500 mL). After filtration, the solid product was washed with cold toluene until the filtrate was colorless. After dried under high vacuum over the weekend, a white powder product: 44.60 g (90percent) was afforded. MS (M+H+)=248.1. 1H NMR (DMSO-d6) δ 12.70 (br s, 1 H), 9.17 (m, 1H), 8.20 (dd, 2H), 7.94 (dd, 1H), 7.78 (m, 1H), 3.97 (d, 2H).
90%
Stage #1: With sodium hydroxide In water; acetonitrile at 0℃; for 1 h;
Stage #2: With hydrogenchloride In water; acetonitrile
Step A(3-Trifluoromethyl-benzoylamino)acetic acid. To a rapid stirring solution of glycine (15.014 g, 0.20 mol) in MeCN (400 mL) and 2 M NaOH (250 mL) at 0 °C was slowly added a solution of 3-(trifluoromethyl)-benzoyl chloride (41.714 g, 0.20 mol) in 75 mL of MeCN over 30 min. The cloudy yellow solution was stirred at 0 °C for 30 min. The reaction mixture was acidified with 3 M HCI to pH = 3, followed by removal of MeCN on rotary evaporator. The resulting mixture was then extracted with EtOAc (400 mL x 3). The combined organic layers were dried, filtered and concentrated to give a light yellow solid (48.53 g), which was triturated with toluene (500 mL). After filtration, the solid product was washed with cold toluene until the filtrate was colorless. After dried under high vacuum over the weekend, a white powder product: 44.60 g (90percent) was afforded. MS (M+H+) = 248.1. 1H NMR (DMSO-d6) δ 12.70 (br s, 1 H), 9.17 (m, 1 H), 8.20 (dd, 2H), 7.94 (dd, 1 H), 7.78 (m, 1 H), 3.97 (d, 2H).

Reference: [1] Patent: US2010/144695, 2010, A1, . Location in patent: Page/Page column 61-62
[2] Patent: EP2452939, 2012, A2, . Location in patent: Page/Page column 17
[3] Patent: US2012/190689, 2012, A1, . Location in patent: Page/Page column 11-12
[4] Patent: US2005/192302, 2005, A1, . Location in patent: Page/Page column 21
[5] Patent: WO2012/114223, 2012, A1, . Location in patent: Page/Page column 36
[6] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 1, p. 37 - 41
[7] Patent: US4904680, 1990, A,
[8] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 7, p. 2099 - 2102
[9] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7473 - 7478
  • 105
  • [ 3392-09-4 ]
  • [ 56-40-6 ]
  • [ 32991-17-6 ]
YieldReaction ConditionsOperation in experiment
75.7% With sodium hydrogencarbonate In 1,4-dioxane; water REFERENCE EXAMPLE 155
Preparation of Boc-Leu-Gly--OH
2.63 g of H-Gly--OH and 3.50 g of sodium hydrogencarbonate were suspended in 50 ml of water.
Thereto was added 50 ml of a dioxane solution containing 10.0 g of Boc-Leu-OSu, and the mixture was stirred for 30 minutes with ice-cooling and then for 15 hours at room temperature.
The reaction mixture was concentrated under reduced pressure.
The residue was extracted with 70 ml of ethyl acetate.
The ethyl acetate layer was washed with 1N hydrochloric acid and a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was recrystallized from ethyl acetate-n-hexane to obtain 6.65 g (yield: 75.7percent) of the above objective compound having a melting point of 115°-123° C.
Reference: [1] Journal of the Chemical Society. Perkin Transactions 2, 1996, vol. 1996, # 12, p. 2701 - 2706
[2] Patent: US5162305, 1992, A,
[3] Russian Journal of Bioorganic Chemistry, 2012, vol. 38, # 4, p. 354 - 359,6
  • 106
  • [ 3655-05-8 ]
  • [ 56-40-6 ]
  • [ 31972-52-8 ]
Reference: [1] Organic Process Research and Development, 2015, vol. 19, # 9, p. 1257 - 1262
  • 107
  • [ 56-40-6 ]
  • [ 18185-77-8 ]
  • [ 31972-52-8 ]
Reference: [1] Science China Chemistry, 2013, vol. 56, # 2, p. 159 - 168
  • 108
  • [ 66866-43-1 ]
  • [ 56-40-6 ]
  • [ 31972-52-8 ]
Reference: [1] Chemical Biology and Drug Design, 2016, vol. 88, # 6, p. 884 - 888
  • 109
  • [ 541-47-9 ]
  • [ 56-40-6 ]
  • [ 33008-07-0 ]
Reference: [1] Biomedical Mass Spectrometry, 1979, vol. 6, # 10, p. 439 - 443
  • 110
  • [ 56-40-6 ]
  • [ 6712-03-4 ]
  • [ 33008-07-0 ]
  • [ 85-61-0 ]
Reference: [1] Drug Metabolism and Disposition, 2012, vol. 40, # 2, p. 346 - 352
  • 111
  • [ 100-39-0 ]
  • [ 56-40-6 ]
  • [ 17360-47-3 ]
Reference: [1] Helvetica Chimica Acta, 2001, vol. 84, # 4, p. 786 - 796
  • 112
  • [ 100-52-7 ]
  • [ 56-40-6 ]
  • [ 17360-47-3 ]
  • [ 17136-36-6 ]
Reference: [1] Polish Journal of Chemistry, 2002, vol. 76, # 6, p. 823 - 830
  • 113
  • [ 100-44-7 ]
  • [ 56-40-6 ]
  • [ 17360-47-3 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1954, p. 1015
[2] Journal of Heterocyclic Chemistry, 1972, vol. 9, p. 203 - 206
  • 114
  • [ 100-52-7 ]
  • [ 56-40-6 ]
  • [ 17360-47-3 ]
Reference: [1] Journal of the American Chemical Society, 1971, vol. 93, p. 5542 - 5551
  • 115
  • [ 56-40-6 ]
  • [ 113484-74-5 ]
  • [ 35665-38-4 ]
YieldReaction ConditionsOperation in experiment
90% With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water for 20 h; For Fmoc-GlyGly-OH 1a, Glycine (75 mg, 1 mmol) and NaHCO3 (100 mg, 1.2 mmol) were dissolved in H2O (10 ml) and dimethoxyethane (DME) (5 ml). Fmoc-Gly-NHS solution in DME (5 ml, 1 mmol) was added. THF (2.5 ml) was added, the mixture was sonicated to make it homogeneous and stirred for 20 h. All volatiles were removed on a rotovap, the residue was treated with EtOAc and 5percent KHCO3 solution in H2O. Product was extracted four times with EtOAc, washed with brine at pH=3, dried (Na2SO4), concentrated and dried in vacuo. Yield 321 mg (90percent). MS: 775.0 [2M +2Na]+; 377.4 [M+Na]+; 355.1 [M+1]+.
Reference: [1] Patent: WO2015/21092, 2015, A1, . Location in patent: Page/Page column 37
[2] Journal of the American Chemical Society, 2003, vol. 125, # 45, p. 13680 - 13681
  • 116
  • [ 35661-61-1 ]
  • [ 56-40-6 ]
  • [ 35665-38-4 ]
Reference: [1] Journal of Organic Chemistry, 1972, vol. 37, # 22, p. 3404 - 3409
  • 117
  • [ 2483-49-0 ]
  • [ 56-40-6 ]
  • [ 28782-78-7 ]
Reference: [1] Synlett, 2011, # 10, p. 1427 - 1430
  • 118
  • [ 83904-90-9 ]
  • [ 56-40-6 ]
  • [ 28782-78-7 ]
Reference: [1] Synlett, 2011, # 10, p. 1427 - 1430
  • 119
  • [ 56-40-6 ]
  • [ 7306-46-9 ]
  • [ 32161-30-1 ]
  • [ 33605-56-0 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 305 - 312
[2] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1986, vol. 35, # 10, p. 2142 - 2144[3] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1986, # 10, p. 2340 - 2342
  • 120
  • [ 56-40-6 ]
  • [ 352-11-4 ]
  • [ 1132-68-9 ]
Reference: [1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 7.2, p. 1479 - 1485[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 7, p. 1630 - 1636
  • 121
  • [ 63-91-2 ]
  • [ 56-84-8 ]
  • [ 7423-92-9 ]
  • [ 587-33-7 ]
  • [ 60-18-4 ]
  • [ 56-40-6 ]
Reference: [1] Chemistry Letters, 1984, p. 1629 - 1632
  • 122
  • [ 123-11-5 ]
  • [ 56-40-6 ]
  • [ 20839-78-5 ]
YieldReaction ConditionsOperation in experiment
33%
Stage #1: for 2 h;
Stage #2: at 10 - 20℃;
Caution Hydrogen is evolved as a by-product. All flames in thevicinity must be extinguished during the experiment.Glycine (15.0 g, 0.2 mol) was dissolved in aqueous NaOHsolution (8.0 g, 0.2 mol in 200 mL), after which p-methoxybenzaldehyde(27.5 g, 0.2 mol) and ethanol (75 mL) were added[Note 1]. From this point to the end of the experiment, the reaction mixture was stirred using a hot-plate magnetic stirrer.The clear yellow solution, which formed after a few minutes,was heated to 60°C and then stirred without heating for an additional 2 h. After cooling to 10°C in an ice bath, the solution was maintained at that temperature and treated with NaBH4(2.50 g, 0.06 mol), which was added in small portions over a 30-min period. The stirring was continued for the next 30 min without cooling, after which a second portion of p-methoxybenzaldehyde(13.6 g, 0.1 mol) was added. After cooling to108C, the mixture was treated portionwise with NaBH4(1.25 g, 0.03 mol) within 15 min, and stirring was continued for 30 min. The reaction mixture was again cooled to 10°C and subsequently treated with a third portion of p-methoxybenzaldehyde(13.6 g, 0.1 mol) and NaBH4 (1.50 g, 0.04 mol) in the earlier described manner. Then, the reaction mixture was left to stand overnight in a refrigerator (~5°C). Then, the volume of thesolution was reduced to 200mL in a fume hood to remove ethanol and, after cooling, extracted with chloroform (first with100 mL, then twice with 50 mL). The (upper) aqueous layer wasacidified to pH E 6.5 with diluted hydrochloric acid (60 mL;1 : 1, v/v) and left to stand for 2 h. The white powder [Note 2] thathad separated was filtered off, and the volume of the filtrate wasreduced to 100 mL, after which the product started to crystallize.After cooling in an ice bath, the product was filtered off bysuction and quickly washed with ice water (40 mL). Yield:13.2 g (33 percent).
Reference: [1] Australian Journal of Chemistry, 2016, vol. 69, # 11, p. 1285 - 1291
  • 123
  • [ 345-35-7 ]
  • [ 56-40-6 ]
  • [ 19883-78-4 ]
Reference: [1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 7.2, p. 1479 - 1485[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 7, p. 1630 - 1636
  • 124
  • [ 2835-06-5 ]
  • [ 31932-87-3 ]
  • [ 25178-38-5 ]
  • [ 6324-01-2 ]
  • [ 56-40-6 ]
Reference: [1] Tetrahedron Letters, 1984, vol. 25, # 8, p. 885 - 888
[2] Chemistry Letters, 1984, p. 1629 - 1632
  • 125
  • [ 40248-73-5 ]
  • [ 56-40-6 ]
  • [ 475-31-0 ]
Reference: [1] Journal of the American Chemical Society, 1937, vol. 59, p. 2532
[2] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1906, vol. 47, p. 499,504
  • 126
  • [ 623-00-7 ]
  • [ 56-40-6 ]
  • [ 42288-26-6 ]
Reference: [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 19, p. 4153 - 4161
  • 127
  • [ 56-40-6 ]
  • [ 456-41-7 ]
  • [ 19883-77-3 ]
  • [ 110117-84-5 ]
Reference: [1] Angewandte Chemie - International Edition, 2001, vol. 40, # 10, p. 1948 - 1951
  • 128
  • [ 56-40-6 ]
  • [ 74-88-4 ]
  • [ 107-43-7 ]
Reference: [1] Journal of Mass Spectrometry, 2012, vol. 47, # 1, p. 79 - 88
  • 129
  • [ 186581-53-3 ]
  • [ 56-40-6 ]
  • [ 107-43-7 ]
Reference: [1] Chemische Berichte, 1950, vol. 83, p. 420,425,430
[2] Chemische Berichte, 1922, vol. 55, p. 1069
  • 130
  • [ 56-40-6 ]
  • [ 107-43-7 ]
Reference: [1] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1942, vol. 277, p. 97,105
[2] M.Florkin,H.S.Mason, Comaparative Biochemistry,Bd.1 &lt;New York 1960&gt;S.190/1,
  • 131
  • [ 186581-53-3 ]
  • [ 60-29-7 ]
  • [ 7732-18-5 ]
  • [ 56-40-6 ]
  • [ 107-43-7 ]
Reference: [1] Chemische Berichte, 1937, vol. 70, p. 1333,1339
[2] Chemische Berichte, 1950, vol. 83, p. 420,425,430
[3] Chemische Berichte, 1922, vol. 55, p. 1069
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YieldReaction ConditionsOperation in experiment
100%
Stage #1: for 1 h; Cooling with ice
Stage #2: at 20 - 66℃; for 6.5 h;
(2)
Preparation of glycine methyl ester hydrochloride
Under ice bath, 100 ml round-bottom flask was added with 60 ml of methanol, and then slowly added with 4 ml of SOCl2 through constant pressure dropping funnel (with a drying tube on the top), and NaOH solution was used to absorb exhaust.
After stirring for 1 h, 8 mmol of glycine was added and stirred at room temperature for 30 min, and then refluxed at 66° C. for 6 h.
The reaction was tracked by TLC until the raw materials disappeared, with a solution of 2percent ninhydrin in ethanol as chromogenic reagent.
The solvent was evaporated out to obtain glycine methyl ester hydrochloride. Yield: 100percent.
99% at -5 - 20℃; for 3 h; Inert atmosphere Under N2 dryCH3OH (100 mL) was cooled down to -5 °C and SOCl2 (21 mL,0.3mol) was added dropwise. Glycine (7.5 g, 0.1mol) was added to this solutionand stirring was continued at rt for 3 h. The solvent and gaseous reactionproducts were removed under reduced pressure to obtain the pure product ascolorless crystals, mp 180 °C (ref. 175-178 oC)9, yield12.4 g (99 percent). C3H8ClNO2 (125.5 g / mol).FT-IR (neat): v (cm-1) =2879 (s, vC-H aliphatic), 1744 (s, vC=O ester), 1582/1496(m, vN-H). 1H NMR(400MHz, CD3OD): δ (ppm) = 3.84 (s, 3H, CO2CH3),3.89 (s, 2H, CH2). The signal for NH3+-protonsis not seen in the 1H NMR-spectrum. 13C NMR (101MHz, CD3OD):δ (ppm) = 40.2 (1C, CH2), 53.5 (1C, CO2CH3), 168.8 (1C, C=O).
98% at -5 - 20℃; General procedure: A suspension of L-amino acid (50mmol) in methanol (50mL) was stirred under ice cold conditions. Thionyl chloride (5mL) was slowly dropped to the solution at−5°C. Then, the mixture was allowed to slowly warm to room temperature while being stirred. The reaction was monitored by TLC (N-butanol: water: acetic acid=4:1:1). When the reaction was completed, the solvent was evaporated under reduced pressure to afford the crude product, which was recrystallized from methanol/ether to give a white solid.
96% at 0 - 20℃; To a solution of SOCl2(2.33mL; 3.2 10-2 mol) in MeOH at 0°C, the glycine (2g, 2.6610-2mol) was added. The mixture was stirred at rt overnight. Reaction mixture was evaporated under vacuum. The residue was dissolved in MeOH and evaporated again under vacuum. This procedure was repeated three times. The residue was recrystallized in a mixture of MeOH and Et2O to provide a fluffy powder (2.27g, 96percent). IR (ATR): 3109,3012, 2882, 2687, 2635, 1743, 1584, 1557 cm-1. 1H NMR(300 MHz, DMSO D6) δ ppm 8.64(s, 3H), 3.76 (s, 2H), 3.72 (s, 3H). 13C NMR (75MHz, DMSO D6) δ 167.9,52.4, 39.3.
90% at 20℃; for 24 h; Sealed tube Amino acid is placed into a 50 ml one-port flask and added with 2.0 eq. TMSC1 dropwise before adding 5 mL of dry methanol as the solvent. The reaction mixture is sealed and allowed to react at room temperature with stirring for 24 h. Upon completion of the reaction, the solvent is evaporated and methanol (3X10 mL) is further added to co-evaporate the residual hydrochloride. Ethyl ether is then added to the oily product obtained after the evaporation and a white solid is precipitated and further recrystallized with methanol-ethyl ether.
90% at 20℃; for 24 h; Sealed tube Example 4 [0068] Synthesis of amino acid methyl ester hydrochloride is described as follows. Amino acid is placed into a 50 ml one-port flask and added with 2.0 eq. TMSCl dropwise before adding 5 mL of dry methanol as the solvent. The reaction mixture is sealed and allowed to react at room temperature with stirring for 24 h. Upon completion of the reaction, the solvent is evaporated and methanol (3×10 mL) is further added to co-evaporate the residual hydrochloride. Ethyl ether is then added to the oily product obtained after the evaporation and a white solid is precipitated and further recrystallized with methanol-ethyl ether. Experimental data for the products are shown in the table below.
90% for 2 h; Reflux General procedure: 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.
90.68%
Stage #1: at -5 - 5℃; for 1 h;
Stage #2: at 70℃; for 5 h;
Control the temperature of -5 ~ 5 ° C, acetyl chloride 23.56g drop by drop to no waterMethanol 60ml, the drip after the incubation reaction lh, divided into two batches of glycine 7.51g, add the system temperature to 70 ° C reaction 5h, minusPressure to remove the excess solvent,The residue was further added with acetone 30 ml for 5 h,filter,The filter cake was dried in vacuo to give 11.39 g of glycine methyl ester hydrochloride in a yield of 90.68percent and a melting point of 174-176 ° C.
81% at 0 - 20℃; for 16 h; To a stirred solution of 2-aminoacetic acid 8-1 (2 g, 26.64 mmol) in MeOH (20 mL) was added thionyl chloride (5.8 mL, 79.92 mmol) at 0 °C, and stirred at RT for 16 hr. The solvents were evaporated under reduced pressure and the crude residue was purified by washings with pentane/ether to afford 9-10A (2.7 g, 21.6 mmol, 81percent yield) as a brown solid.
4.93 g at 65 - 70℃; for 1.25 h; In the first step, glycine methyl ester hydrochloride is prepared by weighing 3 g of glycine, adding 150mL of anhydrous methanol, heating in an oil bath at 65 ° C to 70 ° C, continuously feeding dry Hcl gas,completely dissolving glycine in about 60 min, and continuing to pass Hcl gas. After 15 min, the reactionwas stopped, concentrated under reduced pressure, and the residue was stirred with acetone to givewhite crystals 4.93g

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YieldReaction ConditionsOperation in experiment
88.4% at 10℃; for 2 h; Autoclave; Reflux; Large scale To 2000L is put in the reactor 270 kg P-toluenesulfonic acid monohydrate, toluene 550 kg, turning on the agitation, heating to reflux, with the water to drop the generated water, until there is no water generating, glycine is added in to the reaction solution 100 kg, benzalcohol 850 kg, to continue heating to reflux, water constantly by the generated water is separated, water until no, continue to reflux 2 hours, cooling to 10 °C, stirring 1 hour, filtering, with 100 kg of acetone washing the filter cake, drying to be 395 kg glycine benzyl ester P-toluenesulfonate, yield 88.4percent, purity 99.62percent.
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YieldReaction ConditionsOperation in experiment
86% at 0℃; Reflux Glycine (lg, 13.3 mmol) was dissolved in isopropanol (10 mL) at 0°C. SOCl2 (1.93 mL, 26.6 mmol) was added dropwise. The mixture was stirred at reflux overnight. After cooling, the solvent was evaporated under reduced pressure and hexane was added at 0°C. The suspension was filtered to afford the product (1.76 g, 86percent) as a white solid. NMR (300 MHz, MeOD) δ 5.13 (hept, J = 6.3 Hz, 1H, (CH3)2CHO), 3.81 (s, 2H, CH2), 1.32 (s, 3H, (CH3 2CHO . 1.30 (s, 3H, iCH3}2CHO). 13C NMR (75 MHz, MeOD) δ 168.0 (C), 71.7 ((CH3)2CHO), 41.2 (CH2), 21.9 ((CH3 2CHO . HRMS [M+H]+ C5H12NO2: Calcd. 1 18.0858 found 1 18.0863.
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  • 149
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  • [ 56-40-6 ]
  • [ 52558-24-4 ]
YieldReaction ConditionsOperation in experiment
81.5%
Stage #1: With 4-methyl-morpholine In 1,4-dioxane; water at 0 - 20℃;
Stage #2: for 0.333333 h;
N-Boc-3-amino-2 (^-hydroxy-propionic acid OHTo a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: H2O (100 mL, 1 :1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by BoC2O (11.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to 0°C and sat aq. NaHCO3 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHSO4. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to give the desired N-Boc-3-amino-2(5)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): 1H NMR (400 MHz, CDC13) δ 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (100 MHz, CDC13) δ 174.72, 158.17, 82, 71.85, 44.28, 28.45.
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  • [ 20150-34-9 ]
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  • 151
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  • [ 475473-26-8 ]
YieldReaction ConditionsOperation in experiment
90.1% With sodium methylate In methanol at 20℃; for 24 h; Inert atmosphere [Ru(CO)3Cl2]2 (147.8 mg,0.29 mmol) and glycine (43.5 mg, 0.58 mmol) were placed under nitrogen in a round-bottomed flask. Methanol (15 ml) and sodium methoxide (32 mg, 0.59 mmol) were added and the reaction was allowed to continue under stirring for 24 h at room temperature. The solvent was then removed under pressure and the yellow residue redissolved in tetrahydrofuran (THF); this was filtered and excess light petroleum added. The yellow solution was evaporated down to give a pale yellow solid (153.9 mg, 90.1percent yield). It was stored in closed vials at -20 °C and used freshly on the day of the experiments. IR (KBr, cm-1): 3223.3 (m, NH2), 3137.7 (m, NH2), 2143.5 (s, CO), 2065.0 (s, CO), 1989.0 (s, CO), 1569.8 (s, COO-). 1H NMR (DMSO-d6, TMS, ppm): δ 5.398 (br, 1H, NH), 4.723 (br, 1H, NH), 3.479 (m, 1H, CH), 3.249 (m, 1H, CH). 13C NMR (DMSO-d6, TMS, ppm): δ 200.9 (Ru-CO), 198.5 (Ru-CO), 196.9 (Ru-CO), 181.1, 180.7, 41.3. ESI-MS: calcd for C5H4NO5ClRuNa [M + Na]+ 317.8719, found 317.8611. Elemental Anal. Calcd for C5H4NO5ClRu: C, 20.38; H, 1.37; N, 4.75percent. Found: C, 20.94; H, 1.68; N, 4.27percent.
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[ 107-97-1 ]

N-Methylglycine

Similarity: 0.79

Chemical Structure| 302-72-7

[ 302-72-7 ]

DL-Alanine

Similarity: 0.71

Chemical Structure| 5680-79-5

[ 5680-79-5 ]

H-Gly-OMe.HCl

Similarity: 0.71

Chemical Structure| 1118-68-9

[ 1118-68-9 ]

2-(Dimethylamino)acetic acid

Similarity: 0.71