* 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.
Stage #1: With methyl iodide In methanol; water at 20℃; for 48 h; Stage #2: for 15 h; Reflux
According to a literature procedure,19D-methionine (1) (25.0 g,167.5 mmol, 1 equiv) was suspended in H2O/MeOH (466 mL/66 mL), and methyl iodide (25.2 mL, 405.4 mmol, 2.4 equiv) wasadded. The resulting suspension was stirred vigorously at roomtemperature for 48 h. Then the volume of the reaction mixturewas reduced to one-third by evaporation under vacuo and alongwith this, excess of methyl iodide was also removed. Water(155 mL) was added to the remaining reaction mixture followedby NaHCO3 (14.07 g, 167.5 mmol, 1 equiv). The resulting solutionwas refluxed for 15 h and cooled to room temperature. Solventwas removed under vacuo to yield thick syrup. This was dissolvedin water (45 mL) with heating. Addition of acetone (90 mL) followedby ethanol (1000 mL) resulted in the precipitation of a whitesolid, which was filtered and dried under vacuum to give 2 aswhite solid. Yield: 9.9 g (83 mmol, 50percent). Mp 202 C. 1H NMR(300 MHz, D2O): d = 1.92–1.78 (m, 1H, 3-CH), 2.09–2.92 (m, 1H,3-CH), 3.65–3.58 (m, 2H, 4-CH2), 3.68 (dd, 3JH,H = 4.8, 3JH,H = 7.5 Hz,1H, 2-CH). 13C NMR (75 MHz, D2O): d = 32.1 (s, 3-C), 53.3 (s, 2-C),58.5 (s, 4-C), 174.5 (s, 1-C). HRMS (ESI+, MeOH): m/z = 142.0468[M+Na]+ calcd for C4H9NO3Na+ 142.0475.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 19, p. 5168 - 5181
[2] Tetrahedron, 1988, vol. 44, # 2, p. 637 - 642
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[1] Journal of the American Chemical Society, 1980, vol. 102, # 15, p. 5115 - 5117
[2] Analytical Chemistry, 2001, vol. 73, # 22, p. 5499 - 5508
[3] Analytical Chemistry, 2003, vol. 75, # 6, p. 1508 - 1513
[4] Journal of Organic Chemistry, 2009, vol. 74, # 17, p. 6526 - 6533
[5] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 10, p. 3481 - 3484
[6] Patent: US2013/204014, 2013, A1, . Location in patent: Paragraph 0074; 0075
[7] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 7, p. 2186 - 2188
[8] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 7, p. 2186 - 2188
[9] Chinese Journal of Chemistry, 2017, vol. 35, # 7, p. 1037 - 1042
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[ 59-51-8 ]
[ 348-67-4 ]
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[1] Journal of Biological Chemistry, 1944, vol. 153, p. 398
[2] Journal of the American Chemical Society, 1958, vol. 80, p. 953,954, 957
[3] Helvetica Chimica Acta, 1948, vol. 31, p. 352
[4] Journal of the American Chemical Society, 1951, vol. 73, p. 4604
[5] Archiv der Pharmazie (Weinheim, Germany), 1957, vol. 290, p. 571,574
[6] Tetrahedron Letters, 2002, vol. 43, # 4, p. 707 - 710
[7] Journal of Biological Chemistry, 1948, vol. 173, p. 471,475, 476
[8] Journal of Biological Chemistry, 1948, vol. 173, p. 471,475, 476
[9] Journal of Biological Chemistry, 1948, vol. 173, p. 471,475, 476
4
[ 1509-92-8 ]
[ 348-67-4 ]
Yield
Reaction Conditions
Operation in experiment
1 μmol
at 4℃; for 0.0166667 h; Enzymatic reaction
N-d-AAase activity was measured using N-acetyl-d-methionine as a substrate. Concentration of reaction product was measured by applying a d-amino acid oxidase coupling with horse radish peroxidase. The detailed condition was as previously described [17]. Basically, N-d-AAase and N-acetyl-d-methionine were incubated at 4 ◦C. Then the mixture of d-amino acid oxidase and colorimetric solution containing peroxidase (10 U/ml), 4-aminoantipyrine (0.04 g/ml) and 0.8 l phenol was added. The OD at wavelength 520 nm was measured. One unit was defined as generation of 1 mol d-methionine in 1 min. Protein concentration was determined by the Bradford method and bovine serum albumin as the standard [32]. Kinetic parameters kcat and Km values were determined by fitting the initial rates as a function of substrate concentration to the Michaelis–Menten equation.
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 4058
[2] Journal of Biological Chemistry, 1952, vol. 194, p. 455,458
[3] Journal of the American Chemical Society, 1951, vol. 73, p. 4604
[4] Bulletin of the Agricultural Chemical Society of Japan, 1957, vol. 21, p. 235,237
[5] Bioscience, biotechnology, and biochemistry, 1992, vol. 56, # 9, p. 1392 - 1395
[6] Process Biochemistry, 2012, vol. 47, # 12, p. 1785 - 1790
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[ 348-67-4 ]
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[1] Recueil des Travaux Chimiques des Pays-Bas, 1991, vol. 110, # 5, p. 206 - 208
6
[ 44978-50-9 ]
[ 348-67-4 ]
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[1] Journal of the American Chemical Society, 1931, vol. 53, p. 3493
[2] Journal of Biological Chemistry, 1938, vol. 122, p. 426
7
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[ 348-67-4 ]
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[1] Journal of the American Chemical Society, 2006, vol. 128, # 33, p. 10923 - 10929
8
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[ 348-67-4 ]
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[1] Journal of Biological Chemistry, 1948, vol. 173, p. 471,475, 476
[2] Journal of the American Chemical Society, 1953, vol. 75, p. 5323,5326
9
[ 452-95-9 ]
[ 348-67-4 ]
[ 63-68-3 ]
Reference：
[1] European Journal of Organic Chemistry, 2008, # 20, p. 3506 - 3512
10
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[ 348-67-4 ]
Reference：
[1] Journal of the American Chemical Society, 1957, vol. 79, p. 639,642
11
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Reference：
[1] Journal of the American Chemical Society, 1931, vol. 53, p. 3493
12
[ 50-00-0 ]
[ 454-29-5 ]
[ 348-67-4 ]
Reference：
[1] Agricultural and Biological Chemistry, 1984, vol. 48, # 1, p. 143 - 148
13
[ 107-97-1 ]
[ 454-29-5 ]
[ 348-67-4 ]
Reference：
[1] Agricultural and Biological Chemistry, 1984, vol. 48, # 1, p. 143 - 148
14
[ 1118-68-9 ]
[ 454-29-5 ]
[ 348-67-4 ]
Reference：
[1] Agricultural and Biological Chemistry, 1984, vol. 48, # 1, p. 143 - 148
15
[ 56-45-1 ]
[ 454-29-5 ]
[ 348-67-4 ]
Reference：
[1] Agricultural and Biological Chemistry, 1984, vol. 48, # 1, p. 143 - 148
16
[ 454-29-5 ]
[ 107-43-7 ]
[ 348-67-4 ]
Reference：
[1] Agricultural and Biological Chemistry, 1984, vol. 48, # 1, p. 143 - 148
17
[ 454-29-5 ]
[ 141-53-7 ]
[ 348-67-4 ]
Reference：
[1] Agricultural and Biological Chemistry, 1984, vol. 48, # 1, p. 143 - 148
18
[ 454-29-5 ]
[ 56-40-6 ]
[ 348-67-4 ]
Reference：
[1] Agricultural and Biological Chemistry, 1984, vol. 48, # 1, p. 143 - 148
19
[ 4703-38-2 ]
[ 348-67-4 ]
Reference：
[1] Yakugaku Zasshi, 1958, vol. 78, p. 767[2] Chem.Abstr., 1958, p. 18237
[3] Journal of Biological Chemistry, 1948, vol. 173, p. 471,475, 476
[4] Journal of Biological Chemistry, 1948, vol. 173, p. 471,475, 476
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 47, p. 19310 - 19313
22
[ 21691-49-6 ]
[ 348-67-4 ]
Reference：
[1] Chemische Berichte, 1958, vol. 91, p. 2410,2413
[2] Yakugaku Zasshi, 1951, vol. 71, p. 718[3] Chem.Abstr., 1952, p. 1978
[4] Yakugaku Zasshi, 1951, vol. 71, p. 1277[5] Chem.Abstr., 1952, p. 5531
[6] Yakugaku Zasshi, 1953, vol. 73, p. 355[7] Chem.Abstr., 1954, p. 3259
[8] Yakugaku Zasshi, 1953, vol. 73, p. 355[9] Chem.Abstr., 1954, p. 3259
23
[ 4703-38-2 ]
[ 348-67-4 ]
Reference：
[1] Journal of Biological Chemistry, 1948, vol. 173, p. 471,475, 476
24
[ 13253-44-6 ]
[ 348-67-4 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 1-2, p. 91 - 95
[2] Agricultural and Biological Chemistry, 1987, vol. 51, # 3, p. 715 - 720
[3] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 1-2, p. 91 - 95
[4] Agricultural and Biological Chemistry, 1987, vol. 51, # 3, p. 715 - 720
25
[ 4434-61-1 ]
[ 348-67-4 ]
Reference：
[1] Journal of Biological Chemistry, 1948, vol. 173, p. 471,475, 476
26
[ 10332-17-9 ]
[ 348-67-4 ]
Reference：
[1] Chemische Berichte, 1958, vol. 91, p. 2410,2413
[2] Yakugaku Zasshi, 1951, vol. 71, p. 1277[3] Chem.Abstr., 1952, p. 5531
[4] Yakugaku Zasshi, 1951, vol. 71, p. 718[5] Chem.Abstr., 1952, p. 1978
27
[ 23479-37-0 ]
[ 348-67-4 ]
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[1] Agricultural and Biological Chemistry, 1987, vol. 51, # 3, p. 721 - 728
[2] Tetrahedron Asymmetry, 1995, vol. 6, # 6, p. 1257 - 1260
[3] Agricultural and Biological Chemistry, 1987, vol. 51, # 3, p. 721 - 728
28
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[ 348-67-4 ]
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[1] Yakugaku Zasshi, 1953, vol. 73, p. 355[2] Chem.Abstr., 1954, p. 3259
[3] Yakugaku Zasshi, 1953, vol. 73, p. 355[4] Chem.Abstr., 1954, p. 3259
29
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[ 348-67-4 ]
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[1] Helvetica Chimica Acta, 1949, vol. 32, p. 333,335
30
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[ 348-67-4 ]
Reference：
[1] Helvetica Chimica Acta, 1949, vol. 32, p. 333,335
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[1] Journal of Biological Chemistry, 1949, vol. 178, p. 503,508[2] Journal of Biological Chemistry, 1949, vol. 180, p. 201
[3] Journal of Biological Chemistry, 1949, vol. 179, p. 1173
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[1] Agricultural and Biological Chemistry, 1984, vol. 48, # 1, p. 143 - 148
[2] Agricultural and Biological Chemistry, 1984, vol. 48, # 1, p. 143 - 148
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[1] Journal of Organic Chemistry, 1989, vol. 54, # 19, p. 4529 - 4535
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[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 21, p. 3773 - 3781
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[ 63-68-3 ]
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[ 1509-92-8 ]
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[1] Journal of the American Chemical Society, 2012, vol. 134, # 47, p. 19310 - 19313
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[1] Patent: US5994344, 1999, A,
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38
[ 348-67-4 ]
[ 24424-99-5 ]
[ 5241-66-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium carbonate; citric acid In 1,4-dioxane; water
(a) Preparation of t-butoxycarbonyl-D-methionine D-Methionine (50.3 g, 0.34 mol) was dissolved in water (700 ml) containing sodium carbonate (71.5 g, 0.675 mol). To this solution was added a solution of di-tert-butyl dicarbonate (81.0 g, 0.37 mol) in dioxan (250 ml) and the mixture left stirring for 16 h at room temperature. Water (1.51) was added and the solution was washed twice with diethyl ether. The aqueous phase was acidified to pH 3 by addition of solid citric acid and the product extracted three times with ethyl acetate (500 ml). The combined organic phases were washed successively twice with water, once with saturated brine, then were dried over magnesium sulfate. Evaporation gave t-butoxycarbonyl-D-methionine as an oil (87.6 g, 100percent). [α]D +19.0° (c=1percent, MeOH).
Reference：
[1] Patent: US4863953, 1989, A,
[2] Journal of the Chemical Society - Series Chemical Communications, 1989, # 22, p. 1740 - 1742
[3] Journal of Organic Chemistry, 1999, vol. 64, # 14, p. 5166 - 5175
[4] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4815 - 4830
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[1] Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999), 1984, p. 2305 - 2308
In water at 37℃; for 0.166667h; D-aminocyclase from Alcaligenes denitrificans DA181, pH 7.8, bovine serum albumin; enzyme activity; effect of temperature, pH, metal ions and EDTA on activity; other D-aminocyclases; also with N-acetyl-D-phenylglycine;
1 μmol
With 4-amino-2,3-dimethyl-1-phenylpyrazolin-5-one; 5'-ATGTGACCCACCTGCGGCACGAGGACC-3'; catalase; horseradish peroxidase; phenol at 4℃; for 0.0166667h; Enzymatic reaction;
2.5. Enzyme activity assay and determination of kinetic parameters
N-d-AAase activity was measured using N-acetyl-d-methionine as a substrate. Concentration of reaction product was measured by applying a d-amino acid oxidase coupling with horse radish peroxidase. The detailed condition was as previously described [17]. Basically, N-d-AAase and N-acetyl-d-methionine were incubated at 4 ◦C. Then the mixture of d-amino acid oxidase and colorimetric solution containing peroxidase (10 U/ml), 4-aminoantipyrine (0.04 g/ml) and 0.8 l phenol was added. The OD at wavelength 520 nm was measured. One unit was defined as generation of 1 mol d-methionine in 1 min. Protein concentration was determined by the Bradford method and bovine serum albumin as the standard [32]. Kinetic parameters kcat and Km values were determined by fitting the initial rates as a function of substrate concentration to the Michaelis-Menten equation.
With sodium carbonate; citric acid; In 1,4-dioxane; water;
(a) Preparation of t-butoxycarbonyl-D-methionine D-Methionine (50.3 g, 0.34 mol) was dissolved in water (700 ml) containing sodium carbonate (71.5 g, 0.675 mol). To this solution was added a solution of di-tert-butyl dicarbonate (81.0 g, 0.37 mol) in dioxan (250 ml) and the mixture left stirring for 16 h at room temperature. Water (1.51) was added and the solution was washed twice with diethyl ether. The aqueous phase was acidified to pH 3 by addition of solid citric acid and the product extracted three times with ethyl acetate (500 ml). The combined organic phases were washed successively twice with water, once with saturated brine, then were dried over magnesium sulfate. Evaporation gave t-butoxycarbonyl-D-methionine as an oil (87.6 g, 100percent). [alpha]D +19.0° (c=1percent, MeOH).
According to a literature procedure,19D-methionine (1) (25.0 g,167.5 mmol, 1 equiv) was suspended in H2O/MeOH (466 mL/66 mL), and methyl iodide (25.2 mL, 405.4 mmol, 2.4 equiv) wasadded. The resulting suspension was stirred vigorously at roomtemperature for 48 h. Then the volume of the reaction mixturewas reduced to one-third by evaporation under vacuo and alongwith this, excess of methyl iodide was also removed. Water(155 mL) was added to the remaining reaction mixture followedby NaHCO3 (14.07 g, 167.5 mmol, 1 equiv). The resulting solutionwas refluxed for 15 h and cooled to room temperature. Solventwas removed under vacuo to yield thick syrup. This was dissolvedin water (45 mL) with heating. Addition of acetone (90 mL) followedby ethanol (1000 mL) resulted in the precipitation of a whitesolid, which was filtered and dried under vacuum to give 2 aswhite solid. Yield: 9.9 g (83 mmol, 50%). Mp 202 C. 1H NMR(300 MHz, D2O): d = 1.92-1.78 (m, 1H, 3-CH), 2.09-2.92 (m, 1H,3-CH), 3.65-3.58 (m, 2H, 4-CH2), 3.68 (dd, 3JH,H = 4.8, 3JH,H = 7.5 Hz,1H, 2-CH). 13C NMR (75 MHz, D2O): d = 32.1 (s, 3-C), 53.3 (s, 2-C),58.5 (s, 4-C), 174.5 (s, 1-C). HRMS (ESI+, MeOH): m/z = 142.0468[M+Na]+ calcd for C4H9NO3Na+ 142.0475.
With urea hydrogen peroxide adduct In ethanol at 20℃; for 0.25h;
2.1. General procedure for catalytic oxidation of organic sulfides to sulfones
Organic sulfide (1.0 mmol), UHP (5.0 mmol) and catalyst (0.05 mmol) were stirred in ethanol (5 mL) at room temperature and the progress of the reaction was monitored using thin layer chromatography (TLC). After completion of the reaction, precipitate formed was filtered off, washed with cold ethanol and dried to obtain the pure organic sulfone. In case of soluble organic sulfones, solvent was evaporated under reduced pressure; residue was triturated with dichloromethane (5 mL) and filtered to remove the insoluble urea and catalyst. The filtrate containing sulfone was dried and recrystallized from dichloromethane/hexane mixture.
99 % Spectr.
With Oxone In water-d2 for 0.166667h; Ambient temperature; pH 6.8 (phosphate buffer);
100 % Spectr.
With magnesium monoperoxyphthalate hexahydrate In water-d2 for 0.166667h; Ambient temperature; pH 6.5 (phosphate buffer);
With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 5h;
At room temperature (2R)-2-amino-4-(methylsulfanyl)butanoic acid (4.90 g, 32.84 minol) and sodium carbonate (16.91 g, 159.54 minol) were dissolved in water (100 mL), to which was added a solution of benzyl chloroformate (5.59 g, 32.74 minol) in dioxane (50 mL) dropwise over 10 min period. The resulting solution was then stirred for 5 h at room temperature. When the reaction was done, it was quenched by the addition of water (100 mL). The resultingminxture was extracted with ethyl acetate (300 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified in a C18 reverse phase column eluting with acetonitrile in water (0% to 50% gradient in 30 min) to yield (2R)-2- [ [(benzyloxy)carbonylj aminoj -4-(methylsulfanyl)butanoic acid as yellow oil (3.48 g, 36%).
Stage #1: D-methionine With sodium hydroxide In water monomer at 0℃; for 0.0833333h;
Stage #2: methyl chloroformate In 1,4-dioxane; water monomer at 25 - 30℃; for 24h;
5.1.2 Procedure for the synthesis of amino acids carbamate (caps) which are shown in Scheme 1
General procedure: In a round-bottomed flask, the required amino acid (24mmol) was dissolved in an aqueous solution of NaOH (75mL, 1M) and left to cool in an ice bath at 0°C for 5min. Then, the respective chloroformate (33mmol) in 1,4-dioxane (30mL) was added portionwise to the above solution and stirred overnight at 25-30°C. Then, the reaction mixture was extracted twice using diethyl ether and the aqueous layer was acidified using HCl until the pH=2. The respective carbamates were isolated from the aqueous layer by extraction with diethyl ether (twice). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum to give the product. The product was used without further purification.
51%
Stage #1: D-methionine With sodium hydroxide In water monomer at 0℃; for 0.0833333h;
Stage #2: methyl chloroformate In 1,4-dioxane; water monomer at 25 - 30℃; for 24h;
5.1.2 Procedure for the synthesis of amino acids carbamate (caps) which are shown in Scheme 1
General procedure: In a round-bottomed flask, the required amino acid (24mmol) was dissolved in an aqueous solution of NaOH (75mL, 1M) and left to cool in an ice bath at 0°C for 5min. Then, the respective chloroformate (33mmol) in 1,4-dioxane (30mL) was added portionwise to the above solution and stirred overnight at 25-30°C. Then, the reaction mixture was extracted twice using diethyl ether and the aqueous layer was acidified using HCl until the pH=2. The respective carbamates were isolated from the aqueous layer by extraction with diethyl ether (twice). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum to give the product. The product was used without further purification.
With sodium hydroxide at 0 - 20℃;
With sodium hydroxide In 1,4-dioxane; water monomer at 0 - 20℃;
4.1.1 General procedures for the preparation of capping groups CG 1-20
General procedure: A 500mL round bottom flask was equipped with a magnetic stir bar, charged with distilled H2O (100mL) and NaOH (100mmol, 4.0g) and cooled in an ice bath to 0°C. l-Phenylglycine/l-Methionine/d-Phenylglycine/d-Methionine (35mmol) was added, and stirred until the solution was homogeneous. The corresponding carbonyl chloride (45.5mmol) in 1,4-dioxane (40mL) was added dropwise using an addition funnel. The reaction mixture was left to stir overnight at room temperature. The solution was extraction of the solution with Et2O (3×50mL) was done, and the organic layers were discarded. The aqueous layer was cooled in an ice bath to 0°C, and concentrated HCl was added dropwise until the pH=2. The re-extraction of the aqueous solution was done with Et2O (3×100mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuum to give the product as clear viscous oil. No further purification was required.
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃;
4.1.1 General procedures for the preparation of capping groups CG 1-20
General procedure: A 500mL round bottom flask was equipped with a magnetic stir bar, charged with distilled H2O (100mL) and NaOH (100mmol, 4.0g) and cooled in an ice bath to 0°C. l-Phenylglycine/l-Methionine/d-Phenylglycine/d-Methionine (35mmol) was added, and stirred until the solution was homogeneous. The corresponding carbonyl chloride (45.5mmol) in 1,4-dioxane (40mL) was added dropwise using an addition funnel. The reaction mixture was left to stir overnight at room temperature. The solution was extraction of the solution with Et2O (3×50mL) was done, and the organic layers were discarded. The aqueous layer was cooled in an ice bath to 0°C, and concentrated HCl was added dropwise until the pH=2. The re-extraction of the aqueous solution was done with Et2O (3×100mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuum to give the product as clear viscous oil. No further purification was required.
With sodium tetrahydroborate; iodine In tetrahydrofuran at 66℃; for 18h;
With lithium aluminium tetrahydride In tetrahydrofuran
With sodium tetrahydroborate; iodine In tetrahydrofuran Heating;
With lithium aluminium tetrahydride In tetrahydrofuran Heating;
With sodium tetrahydroborate; iodine In tetrahydrofuran Inert atmosphere; Reflux;
With sodium tetrahydroborate; iodine In tetrahydrofuran at 0℃; for 6h; Reflux;
Stage #1: D-methionine With sodium tetrahydroborate; iodine In tetrahydrofuran Reflux; Inert atmosphere;
Stage #2: With potassium hydroxide In water Reflux; Inert atmosphere;
With lithium aluminium tetrahydride In tetrahydrofuran
With sodium hydroxide; potassium hydrogensulfate; In 1,4-dioxane; ethyl acetate;
2R-tert-Butoxycarbonylamino4-methylsulfanyl-butyric acid A suspension of (R)-methionine in 1,4-dioxane (1000 ml) and 1.25M NaOH (1330ml) was stirred and cooled to 6 C. before a solution of di-tert-butyldicarbonate (384 g) in 1,4-dioxane (300ml) was added to it in one portion. The cooling bath was removed and the reaction stirred for 3.5 hours. The 1,4-dioxane was removed from the mixture in vacuo before ethyl acetate (1000 ml) was added, followed by 1 M KHSO4 (1700 ml). After mixing, and separation of the phases, the aqueous phase was further extracted with ethyl acetate (600 ml). The combined organic phases were washed with water (600 ml), brine (100 ml), dried (Na2 SO4), filtered and the solvent removed in vacuo to give the title compound (449 g) as a pale yellow oil, containing some ethyl acetate. Mass spec MH+ (found)=250 MH+ (calc)=250
3 Specification for Synthesis of D-Met-OMe*HCl
Example 3 Specification for Synthesis of D-Met-OMe*HCl 50.0 g (0.335 mol) of D-methionine was suspended in 500 ml methanol and HCl gas was passed through at a moderate rate until saturated. The methionine dissolved and the solution heated up to 55° C. Then the reaction mixture was stirred overnight at room temperature. Next morning, the mixture was concentrated to dryness in the rotary evaporator at 40° C. and the residue obtained was recrystallized twice from diethyl ether. 47.1 g (86%) of D-methionine methyl ester hydrochloride was isolated as a white crystalline solid.
With caesium carbonate;copper(l) iodide; In dimethyl sulfoxide; at 90℃; for 23h;
A mixture of D-methionine A (2.50 g, 16.8 mmol), 1 ,3-dichloro-5-iodo-benzene B (4.6 g, 17 mmol), copper(I) iodide (0.80 g, 4.2 mmol) and Cs2C03 (6.6 g, 20 mmol) in DMSO (20 mL) was heated at 90 °C for 23 h. To the reaction mixture was added 5percent citric acid until pH = 4, and then the mixture was extracted with EtOAc (3 x 50 mL), This crude was purified via column chromatography (gradient MeOH/CH2Cl2) to afford the desired product (2.59 g, 54percent yield) as an oil. A mixture of the methionine C and Mel (15 mL, 240 mmol) was stirred at 25 °C for 18 h, followed by adding TBME to form a precipitate which was filtered to afford a brown solid D (3.1 g, 42percent). .H NMR (400MHz ,DMSO-d6) delta = 6.72 (d, J = 2.0 Hz, 1 H), 6.65 (d, J = 2.0 Hz, 2 H), 4.33 - 4.15 (m, 1 H), 3.43 - 3.35 (m, 2 H), 2.89 (s, 3 H), 2.85 (s, 3 H); m/z 308 (M-128).
54 (2R)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-(methylsulfanyl)butanoic acid
Preparation 54 (2R)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-(methylsulfanyl)butanoic acid A solution of (R)-2-amino-4-(methylthio)butanoic acid (50 g, 335 mmol), finely ground phthalic anhydride (49.6 g, 335 mmol) and triethlamine (4.67 ml, 33.5 mmol) in toluene (450 ml) was stirred and heated under vigorous reflux in a Dean-Stark apparatus for 2.5 h. Volatiles were evaporated and to the residue was added 600 ml water and 6 ml hydrochloric acid and the mixture stirred vigorously with a mechanical stirrer. After stirring for 30 minutes, the suspension was filtered and filtrate evaporated under vacuum to give the title compound (87.24 g=92% yield). LC-MS Rt. 1.8 min (>97%). LRMS m/z 280 [M+H].
With sodium hydroxide In water; N,N-dimethyl-formamide at 0 - 20℃; for 12h;
4.1.3. General procedure of synthesis of 12a-f
General procedure: p-Nitrophenyl 2-N1-5-fluorouracil-ylacetate 11 (1.4 g, 5 mmol) was dissolved in DMF (10 mL), then the solution of aqueous 5% NaOH (5 mL) of appropriate α-amino acid (6 mmol) was added and the mixture stirred for 2 h at 0 °C, then continuously stirred for 10 h at room temperature while the pH value of the reaction mixture was kept at 8-10. The solvent was removed under vacuum, the residue was crystallized from water, and compounds 12a-f were provided in needle crystal.
With pyridoxal 5'-phosphate; recombinant Lactobacillus salivarius UCC118 D-amino acid aminotransferase In aq. phosphate buffer at 30℃; for 0.0166667h; Enzymatic reaction;
General procedure: Amino donor specificity was determined using UPLC by measuring the rate of D-glutamate formation from α-ketoglutarate in the presence of various D-amino acids. The standard reaction mixture (1 ml) contained 100 mM potassium phosphate buffer (pH 7.5), 50 mM D-amino acid, 20 mM α-ketoglutarate, 0.05 mM pyridoxal-5′-phosphate (PLP) and the purified D-AAT. The enzyme reaction was run at 30 °C for 1 min and was stopped by adding 1 ml of 20% trichloroacetic acid. The reaction mixture was then incubated for 1 min on ice and 0.5 ml of 4 M NaOH was added to neutralize the mixture. UPLC analysis was performed using an ACQUITY UPLC TUV system consisting of a Waters Binary Solvent Manager, Sample Manager, FLR Detector and AccQ-Tag Ultra 2.1 × 100-mm column (Waters, Tokyo, Japan) with an eluent flow rate of 0.25 ml/min [14]. The column temperature was 30 °C, and the fluorescent wavelengths used for the FLR Detector were 350 and 450 nm. The eluent was linearly graduated using 85% 50 mM sodium acetate buffer (pH 5.9) and 15% acetonitrile.
at room temperature, the 5-methoxy isatin lever acid (5.79g, 30mmol) was dissolved in an aqueous solution of triethylamine (4.2 mL triethylamine, 30 mL of water), the prepared 1.0mol / L solution was added L - methionine (4.5g, 30mmol), the reaction was stirred for 5 hours at room temperature, concentrated under reduced pressure to remove moisture, drained oil pump, without intermediate separation and purification, as the raw material for the next reaction directly.the upper intermediate step was added in DMSO (1000mL) was heated at 135-150 After stirring for 5 hours, cooled to0 deg.] C, and ice water was added 1000mL under cooling, and extracted with ether (150mL × 6), and the combined organic phases were washed with saturated sodium chloride solutionWashing solution, dried over anhydrous sodium sulfate. Filtered and concentrated to give compound 1 (step total yield of about 85%). White solidBody, Mp180-183 (EtOAc)
With recombinant Trigonopsis variabilis D-amino acid oxidase; recombinant Bacillus cereus leucine dehydrogenase; recombinant Candida boidinii formate dehydrogenase In aq. buffer at 30℃; for 2h; Enzymatic reaction;
Stage #1: D-methionine With Cupric sulfate; pyridoxal 5'-phosphate; sodium hydroxide In lithium hydroxide monohydrate at 20℃;
Stage #2: With C39H34N2O4 In chloroform-d1
Stage #3: With hydrogenchloride In lithium hydroxide monohydrate at 20℃; for 2h;
7 Example 1: Repeat process of EECR and hydrolysis 5 times for phenylalanine
General procedure: Preparation of organic layer and aqueous layer:D-phenylalanine (0.66 g, 4.0 mmol), NaOH (0.164 g, 4.08 mmol), pyridoxal-5'-phosphate (PLP; pyridoxal-5'-phosphate) (0.011 g, 0.04 mmol), CuSO4·5H2O (0.01) g, 0.04 mmol) was dissolved in water (2 ml) to prepare an aqueous layer, (R)-Compound 1 (0.60 g, 1.0 mmol) and Aliquat-336 (0.43 g, 1.05 mmol) were dissolved in CDCl3 (1.0 mL) to prepare an organic layer.1A is a photograph of enantioselective liquid-liquid extraction using the following conventional binaphthol aldehyde derivative compound as an amino acid chiral extracting agent, and Cu2+/PLP for racemizing phenylalanine in an aqueous solution layer; This indicates that when enantioselective liquid-liquid extraction is attempted by adding a catalyst, Cu 2+ ions migrate to the organic layer and contaminate it. This makes it impossible to try liquid-liquid chiral extraction methods any more.[Conventional Binaphthol Derivative Compound].1b is a photograph of a liquid-liquid chiral extraction method using Compound 1, which is a t-butylketone derivative, as a chiral extracting agent, and a liquid-liquid chiral by adding Cu2+/PLP catalyst to racemize phenylalanine in the aqueous layer. The results of trying the extraction method are shown. Although the experiment of extracting and hydrolyzing phenylalanine and then extracting phenylalanine was repeated 5 times, it can be seen that Cu 2+ ions of the aqueous solution layer remain in the aqueous solution layer as they are. As a result of analyzing the chirality of the amino acids in the aqueous solution layer by HPLC, it can be seen that the racemization state is continuously maintained.2 shows the structural differences between the imine bond between the binaphthol derivative not containing t-butylketone-phenylalanine and compound 1-phenylalanine and when compound 1 is used as an extractant, the Cu2+ ions in the aqueous solution do not move to the organic layer. explained the reason. EECR process: After mixing the aqueous solution layer and the organic layer in a vial container, the organic layer was separated by stirring at room temperature for 6 hours. 1H NMR result of the organic layer,More than ~99% of phenylalanine obtained as imine showed very high chiral selectivity in the L-form.By reacting in a continuous process through a continuous reactor, all amino acids in the aqueous layer are optically converted to L-amino acids or all DL-amino acids to D-amino acids, or all D-amino acids or DL-amino acids to L-amino acids to obtain pure amino acids can be obtained.3A schematically illustrates the limitations of the conventional ELLE method. The ELLE method has a disadvantage in that up to 50% of the amino acids in the aqueous solution layer can be extracted into the organic layer.Figure 3b schematically illustrates the EECR process. The EECR can be extracted into the organic layer so that all of the amino acids in the aqueous solution layer have one chirality (maximum 100%).4 shows the crystal structure of Compound 1-phenylalanine obtained by recrystallizing an organic layer obtained through chiral selective extraction of phenylalanine. Hydrolysis process: The organic layer from which amino acids were extracted by the enantioselective extraction coupled with racemization (EECR) process was mixed with an aqueous hydrochloric acid solution (1.0N, 2 mL) and stirred at room temperature for 2 hours. All amino acids in the organic layer moved to the aqueous layer, and it was confirmed through 1H NMR that the organic layer returned to the state before the start of the EECR process. Repeat EECR and hydrolysis process 5 times: After the hydrolysis process, the recovered organic layer is neutralized by injecting an aqueous Na2CO3 solution, and 1 equivalent of amino acid is added to the aqueous solution layer used in the EECR process, then mixed together and stirred to perform the EECR process was performed, and a hydrolysis process was performed on the organic layer. In this way, the EECR/hydrolysis process was repeated 5 times. Recovery of optically pure phenylalanine: The EECR/hydrolysis process was repeated 5 times and the optical purity of each aqueous phenylalanine solution obtained in the hydrolysis process was measured by HPLC. As a result, the average L-type phenylalanine was 98.7%. NaOH 2.0 N aqueous solution was added to the aqueous solution to adjust the pH to 6.0, and 0.55 g of phenylalanine produced by precipitation was obtained as a solid (yield 343% based on compound 1). At this time, the imine formation rate of phenylalanine was maintained at 90% to 95% for 5 times.
With sulfuric acid In methanol at 30 - 40℃; for 10h;
2.1
Step (1): To a 2 L four-necked flask was added 153.10 g of D-methionine, 420 g of water, 200 mL of methanol and 158.21 g of diethyl sulfate, and the mixture was stirred at room temperature, and 45 g of concentrated sulfuric acid After the end of heating to 30 ~ 40 , 10h, the recovery of methanol under reduced pressure.After the reaction with anhydrous sodium carbonate solid to adjust the pH to 8 ~ 9, continue 40 reaction 10h.After the reaction is over,The solvent was distilled off under reduced pressure.
With Sodium hydrogenocarbonate In water monomer; acetone at 43℃; for 2h;
Marfey¢s or C3-Marfey¢s Analysis
General procedure: The dried hydrolysate was dissolved in 120 μL water and then NaHCO3 (1 M, 20 μL) and 1% FDAA in acetone (400 μL) were added to the solution of the hydrolysate. The mixture was stirred at 43°C for 2 h and the reaction was terminated by an addition of 20 μL of 1 N HCl. The reaction mixture was diluted with 500 μL acetone to give amino acid-FDAA derivatives for the HPLC analysis. Each standard amino acid (1 mg) of L-isoleucine, D-isoleucine, L-isoleucine, L-allo-isoleucine, D-allo-isoleucine, L-leucine, D-leucine, L-methionine, D-methionine, L-phenylalanine, D-phenylalanine, L-proline, D-proline, L-valine, and D-valine was also converted to its FDAA derivatives.
With Sodium hydrogenocarbonate In aq. phosphate buffer
To a 2L four-necked flask, 150 g (1.0 mol) of D-methionine, 141.8 g (1.5 mol) of chloroacetic acid, and 1 L of water were added, and the mixture was stirred uniformly, and slowly heated to 80 C for 8 hours. Recovering solvent water under reduced pressure and reduced pressure. A total of 268.4 g of a mixture of D-homoserine lactone hydrochloride, (methylthio)acetic acid and thiodiacetic acid was obtained, and the next step reaction was carried out without isolation;
Stage #1: D-methionine With triethylamine In methanol at 20℃; for 0.25h;
Stage #2: ethyl trifluoroacetate, In methanol at 20℃;
(S)-6-(Methylthio)-2-(2,2,2-trifluoroacetamido) hexanoic acid (L-2).
General procedure: To L-methionine L-1 (500 mg, 3.35 mmol)in dry MeOH (1.68 mL), Et3N (508 mg, 5.03 mmol) was added at rt. After the reaction mixture was stirred for15 min at rt, ethyl trifluoroacetate (619 mg, 4.36 mmol) was slowly added at same temperature. The reactionmixture was stirred overnight at rt. After H2O (100 mL) and 12 M HCl (4 mL) were added, the reaction mixturewas stirred 15 min at rt. The reaction mixture was partitioned between water and EtOAc. The organic layerwas washed with brine, dried over MgSO4, filtered and concentrated. The residue was precipitated bypetroleum ether to give a colorless solid (791 mg, 79 %).
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃;
4.1.1 General procedures for the preparation of capping groups CG 1-20
General procedure: A 500mL round bottom flask was equipped with a magnetic stir bar, charged with distilled H2O (100mL) and NaOH (100mmol, 4.0g) and cooled in an ice bath to 0°C. l-Phenylglycine/l-Methionine/d-Phenylglycine/d-Methionine (35mmol) was added, and stirred until the solution was homogeneous. The corresponding carbonyl chloride (45.5mmol) in 1,4-dioxane (40mL) was added dropwise using an addition funnel. The reaction mixture was left to stir overnight at room temperature. The solution was extraction of the solution with Et2O (3×50mL) was done, and the organic layers were discarded. The aqueous layer was cooled in an ice bath to 0°C, and concentrated HCl was added dropwise until the pH=2. The re-extraction of the aqueous solution was done with Et2O (3×100mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuum to give the product as clear viscous oil. No further purification was required.
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃;
4.1.1 General procedures for the preparation of capping groups CG 1-20
General procedure: A 500mL round bottom flask was equipped with a magnetic stir bar, charged with distilled H2O (100mL) and NaOH (100mmol, 4.0g) and cooled in an ice bath to 0°C. l-Phenylglycine/l-Methionine/d-Phenylglycine/d-Methionine (35mmol) was added, and stirred until the solution was homogeneous. The corresponding carbonyl chloride (45.5mmol) in 1,4-dioxane (40mL) was added dropwise using an addition funnel. The reaction mixture was left to stir overnight at room temperature. The solution was extraction of the solution with Et2O (3×50mL) was done, and the organic layers were discarded. The aqueous layer was cooled in an ice bath to 0°C, and concentrated HCl was added dropwise until the pH=2. The re-extraction of the aqueous solution was done with Et2O (3×100mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuum to give the product as clear viscous oil. No further purification was required.
6 Example 6
To the 2mL methanol solution containing D-methionine (D-Met, 164.1mg, 1.1mmol), dropwise add 1-(2,4-dinitrophenyl)-3-carbamoylpyridine chloride Salt (324.7mg, 1mmol) in 2mL methanol solution. After the addition is complete, add 1mmol of tributylamine, add in three times at 0h, 4h, and 9h, respectively. After stirring at room temperature for 24h, TLC detection, raw material 1-(2, The reaction of 4-dinitrophenyl)-3-carbamoylpyridine chloride and 1-(2,4-dinitrophenyl)-3-carbamoylpyridine chloride was complete.The insoluble matter in the reaction solution was removed by filtration. The filtrate was concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography to obtain a brown foamy solid D-Met-NAD (244 mg, 95.6%).
Stage #1: D-methionine; C39H34N2O4 With Cupric sulfate; pyridoxal 5'-phosphate; sodium hydroxide In chloroform-d1; lithium hydroxide monohydrate at 20℃;
Stage #2: With hydrogenchloride In lithium hydroxide monohydrate at 20℃; for 2h;
7 Example 1: Repeat process of EECR and hydrolysis 5 times for phenylalanine
General procedure: Preparation of organic layer and aqueous layer:D-phenylalanine (0.66 g, 4.0 mmol), NaOH (0.164 g, 4.08 mmol), pyridoxal-5'-phosphate (PLP; pyridoxal-5'-phosphate) (0.011 g, 0.04 mmol), CuSO4·5H2O (0.01) g, 0.04 mmol) was dissolved in water (2 ml) to prepare an aqueous layer, (R)-Compound 1 (0.60 g, 1.0 mmol) and Aliquat-336 (0.43 g, 1.05 mmol) were dissolved in CDCl3 (1.0 mL) to prepare an organic layer.1A is a photograph of enantioselective liquid-liquid extraction using the following conventional binaphthol aldehyde derivative compound as an amino acid chiral extracting agent, and Cu2+/PLP for racemizing phenylalanine in an aqueous solution layer; This indicates that when enantioselective liquid-liquid extraction is attempted by adding a catalyst, Cu 2+ ions migrate to the organic layer and contaminate it. This makes it impossible to try liquid-liquid chiral extraction methods any more.[Conventional Binaphthol Derivative Compound].1b is a photograph of a liquid-liquid chiral extraction method using Compound 1, which is a t-butylketone derivative, as a chiral extracting agent, and a liquid-liquid chiral by adding Cu2+/PLP catalyst to racemize phenylalanine in the aqueous layer. The results of trying the extraction method are shown. Although the experiment of extracting and hydrolyzing phenylalanine and then extracting phenylalanine was repeated 5 times, it can be seen that Cu 2+ ions of the aqueous solution layer remain in the aqueous solution layer as they are. As a result of analyzing the chirality of the amino acids in the aqueous solution layer by HPLC, it can be seen that the racemization state is continuously maintained.2 shows the structural differences between the imine bond between the binaphthol derivative not containing t-butylketone-phenylalanine and compound 1-phenylalanine and when compound 1 is used as an extractant, the Cu2+ ions in the aqueous solution do not move to the organic layer. explained the reason. EECR process: After mixing the aqueous solution layer and the organic layer in a vial container, the organic layer was separated by stirring at room temperature for 6 hours. 1H NMR result of the organic layer,More than ~99% of phenylalanine obtained as imine showed very high chiral selectivity in the L-form.By reacting in a continuous process through a continuous reactor, all amino acids in the aqueous layer are optically converted to L-amino acids or all DL-amino acids to D-amino acids, or all D-amino acids or DL-amino acids to L-amino acids to obtain pure amino acids can be obtained.3A schematically illustrates the limitations of the conventional ELLE method. The ELLE method has a disadvantage in that up to 50% of the amino acids in the aqueous solution layer can be extracted into the organic layer.Figure 3b schematically illustrates the EECR process. The EECR can be extracted into the organic layer so that all of the amino acids in the aqueous solution layer have one chirality (maximum 100%).4 shows the crystal structure of Compound 1-phenylalanine obtained by recrystallizing an organic layer obtained through chiral selective extraction of phenylalanine. Hydrolysis process: The organic layer from which amino acids were extracted by the enantioselective extraction coupled with racemization (EECR) process was mixed with an aqueous hydrochloric acid solution (1.0N, 2 mL) and stirred at room temperature for 2 hours. All amino acids in the organic layer moved to the aqueous layer, and it was confirmed through 1H NMR that the organic layer returned to the state before the start of the EECR process. Repeat EECR and hydrolysis process 5 times: After the hydrolysis process, the recovered organic layer is neutralized by injecting an aqueous Na2CO3 solution, and 1 equivalent of amino acid is added to the aqueous solution layer used in the EECR process, then mixed together and stirred to perform the EECR process was performed, and a hydrolysis process was performed on the organic layer. In this way, the EECR/hydrolysis process was repeated 5 times. Recovery of optically pure phenylalanine: The EECR/hydrolysis process was repeated 5 times and the optical purity of each aqueous phenylalanine solution obtained in the hydrolysis process was measured by HPLC. As a result, the average L-type phenylalanine was 98.7%. NaOH 2.0 N aqueous solution was added to the aqueous solution to adjust the pH to 6.0, and 0.55 g of phenylalanine produced by precipitation was obtained as a solid (yield 343% based on compound 1). At this time, the imine formation rate of phenylalanine was maintained at 90% to 95% for 5 times.
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