(S)-2-amino-3,3-dimethylbutanoic acid by Asch

Query Query O

1. Query

H 2N

Results

Date

76 reactions in Reaxys

2016-06-10 04h:35m:58s (EST)

76 reactions in Reaxys

2016-06-10 04h:36m:44s (EST)

OH H

Search as: As drawn 2. Query

(1. Query) AND itemno in (1,2)

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NH 2 OH Cl

HCl

OH O

Rx-ID: 11023603 View in Reaxys 1/76 Yield

Conditions & References

98 %

With hydrogen, palladium on activated charcoal in methanol, Time= 8h, T= 20 °C , p= 760.051Torr Pan, Subhas Chandra; Zhou, Jian; List, Benjamin; Angewandte Chemie - International Edition; vol. 46; nb. 4; (2007); p. 612 - 614 View in Reaxys

O HO

H 2N

OH H

O O

Rx-ID: 10399513 View in Reaxys 2/76 Yield 97 %

Conditions & References With hydrogenchloride in 1,4-dioxane Agosta, Eleonora; Caligiuri, Antonio; D'Arrigo, Paola; Servi, Stefano; Tessaro, Davide; Canevotti, Renato; Tetrahedron Asymmetry; vol. 17; nb. 13; (2006); p. 1995 - 1999 View in Reaxys

75 %

9 : Production of (S)-tert-leucine Example 9 Production of (S)-tert-leucine Methanesulfonic acid (576 mg, 6 mmol) was added to a solution of (S)-N-(tert-butoxycarbonyl)-tert-leucine (1155 mg, 5 mmol) and methylene chloride (5 mL), and the mixture was stirred at 25° C. for 3 hours. When triethylamine (708 mg, 7 mmol) was added thereto, a solid was precipitated. The solid was sufficiently precipitated, and then the solution was stirred at 25° C. for 30 minutes and further stirred at 25° C. for 30 minutes. Thereafter, the solid was separated by filtration under reduced pressure. The solid was washed with methylene chloride (5 mL), and then was subjected to vacuum drying. Thereby, the titled compound was produced as a white solid (514 mg, yield of 75percent). Titled Compound: 1H-NMR (D O): δ (ppm) 0.87 (s, 9H), 3.40 (s, 1H) 2 Stage 1: With methanesulfonic acid in dichloromethane, Time= 3h, T= 25 °C Stage 2: With triethylamine in dichloromethane, Time= 1h, T= 25 °C Patent; Kaneka Corporation; Ohnuki, Masatoshi; Nishiyama, Akira; US2014/343289; (2014); (A1) English View in Reaxys Reference Example Crystal A of N-tert-butoxycarbonyl-L-tert-leucine (100 g, 432 mmol) was dissolved in toluene (400 g). To the solution, 35percent hydrochloric acid (54 g, 519 mmol) was added at room temperature. After the mixture was stirred in a hot-water bath at 60°C for 3 hours, the water layer was obtained by separating the organic layer. A solution consisting of methanol (80 g) and triethylamine (52.6 g, 520 mmol) was kept in a hot-water bath at 60°C, and the water layer was slowly added thereto to obtain a slurry. Then, the mixture was cooled using a ice bath for 1 hour. The crystal of L-tert-leucine was obtained by separation and drying (52 g, yield: 92percent). With hydrogenchloride in water, toluene, Time= 3h, T= 60 °C Patent; Kaneka Corporation; EP2423187; (2012); (A1) English View in Reaxys

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NHHO 2

H 2N

Rx-ID: 23242021 View in Reaxys 3/76 Yield

Conditions & References

90.6 %

1 :N-Carbamoyl-L-tert-leucine (15.0 g, 0.086 mol) and pure water (250 ml) were charged in a 500 ml four-necked vessel equipped with a gas outlet, a stirrer, a temperature indicator and an introduction tube reaching the lower part of the reaction vessel, and this slurry was heated to 40°C and stirred for a while. Thereto was added 35 wtpercent hydrochloric acid (34.7 g) with stirring, and aqueous sodium nitrite solution (31.3 g) containing sodium nitrite (6.26 g) was added from the introduction tube over 45 min using a constant rate pump. After the completion of the addition, the mixture was reacted at the same temperature for 11 hr with stirring. By this reaction, 328 g of the reaction mixture was obtained. The reaction mixture was analyzed under HPLC analysis condition 1. As a result, the content of L-tert-leucine was 3.12 wtpercent and the yield was 90.6percent. With hydrogenchloride, sodium nitrite in water, Time= 11.75h, T= 40 °C Patent; Ajinomoto Co., Inc.; EP1498410; (2005); (A1) English View in Reaxys

O O HN

O H 2N

OH H

Rx-ID: 4794516 View in Reaxys 4/76 Yield

Conditions & References

95 %

With hydrogen, trifluoroacetic acid, palladium dihydroxide in methanol, water, Time= 24h, p= 3750.3Torr Harwood, Laurence M.; Tyler, Simon N. G.; Anslow, A. Susan; MacGilp, Iain D.; Drew, Michael G. B.; Tetrahedron Asymmetry; vol. 8; nb. 24; (1997); p. 4007 - 4010 View in Reaxys

H 2N

OH H

Rx-ID: 21588968 View in Reaxys 5/76 Yield 80 %

Conditions & References 2 : 2.8 Reductive amination of TMP to l-tert-leucine in liter-scale Bioconversion of TMP to l-tert-leucine was carried out by recombinant whole-cells harboring pET28a-E-G. In a reactor (2L), 1L of water was added to a mixture of 178.2g glucose (0.9mol), 78.1g TMP (0.6mol), 26.8g NH4Cl (0.5mol) and 10.0g of the whole cells of E. coli BL21/pET28a-E-G. The reaction pH was adjusted to 8.5 with NaOH solution. During the reaction process, the pH was automatically adjusted to 8.5 by titrating 50percent (v/v) NH3·H2O. When the reaction was terminated, the reaction mixture was heated to 60°C, followed by centrifugation to remove the biocatalysts. The remained solution was adjusted to pH 5.9 and concentrated via rotary evaporator. Then the solution temperature was decreased slowly to 25°C and continued to decrease to 4°C, the l-tert-leucine crystals were obtained. With ammonium hydroxide, D-glucose, ammonium chloride, sodium hydroxide in water, Time= 5.5h, pH= 8.3, Enzymatic reaction, Time, Reagent/catalyst, stereoselective reaction Li, Jing; Pan, Jiang; Zhang, Jie; Xu, Jian-He; Journal of Molecular Catalysis B: Enzymatic; vol. 105; (2014); p. 11 - 17 View in Reaxys

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73 %

With L- ornithine, L- glutamic acid, Bacillus subtilis ornithine aminotransferase, Escherichia coli branched-chain amino acid aminotransferase, sodium hydroxide in aq. phosphate buffer, Time= 16h, T= 37 °C , pH= 8.5, Enzymatic reaction, Reagent/catalyst, Concentration, Time Li, Tao; Kootstra, Anna B.; Fotheringham, Ian G.; Organic Process Research and Development; vol. 6; nb. 4; (2002); p. 533 - 538 View in Reaxys Reaction Steps: 2 1: 87 percent / acetic acid 2: hydrogenation in acetic acid Viret, Joelle; Patzelt, Heiko; Collet, Andre; Tetrahedron Letters; vol. 27; nb. 48; (1986); p. 5865 - 5868 View in Reaxys With L- glutamic acid, recombinant Escherichia coli K12 aminotransferase, Time= 24h, T= 37 °C , pH= 7.5, aq. phosphate buffer, Enzymatic reaction, optical yield given as percent ee, enantioselective reaction Seo, Young-Man; Kim, Aran; Bea, Han-Seop; Lee, Sang-Hyeup; Yun, Hyungdon; Biocatalysis and Biotransformation; vol. 30; nb. 2; (2012); p. 171 - 176 View in Reaxys With L-2-aminobutyric acid, branched-chain transaminase from Escherichiacoli, S-selective ω-transaminase from Ochrobactrum anthropi, (3-hydroxy-5-hydroxymethyl)-2-methylisonicotinic acid 5-phosphate, isopropylamine in aq. phosphate buffer, Time= 18h, pH= 7 Park, Eul-Soo; Dong, Joo-Young; Shin, Jong-Shik; ChemCatChem; vol. 5; nb. 12; (2013); p. 3538 - 3542 View in Reaxys With Glutamic acid, (R) -2-hydroxyglutarate dehydrogenase from Acidaminococcusfermentans, branched chain amino acid aminotransferase, NADH in aq. buffer, pH= 8, Enzymatic reaction, Kinetics Yu, Xuejing; Wang, Xingguo; Engel, Paul C.; FEBS Journal; vol. 281; nb. 1; (2014); p. 391 - 400 View in Reaxys With NADH, ammonium formate in aq. phosphate buffer, Time= 0.5h, T= 37 °C , pH= 8, Enzymatic reaction, Catalytic behavior, Concentration, Reagent/catalyst Gao, Xin; Yang, Shuai; Zhao, Chengcheng; Ren, Yuhong; Wei, Dongzhi; Angewandte Chemie - International Edition; vol. 53; nb. 51; (2014); p. 14027 - 14030; Angew. Chem.; vol. 126; nb. 51; (2014); p. 14251 - 14254,4 View in Reaxys 1 : Reference Example 1 Synthesis of L-tert-Leucine by Reductive Amination Reference Example 1 Synthesis of L-tert-Leucine by Reductive Amination (0083) To 81.2 mg of trimethylpyruvic acid with a purity of 98.5percent were added the cell concentrate of the transformant having leucine dehydrogenase activity and formate dehydrogenase activity in the same amount as used in Comparative Example 1, and ammonium formate in an amount of 1.4 molar equivalents with respect to trimethylpyruvic acid. In addition, 5M ammonia solution was added to adjust the pH of the fluid to 8.0, and deionized water was added to prepare 2 ml of a reaction fluid. (0084) To the reaction fluid was added NAD in an amount of 0.0009 molar equivalents with respect to the substrate, and the reaction was allowed to proceed for 22 hours at 30° C. while being stirred. (0085) Analysis was performed by following the same procedure as in Comparative Example 1, and the results reveal that trimethylpyruvic acid had disappeared and L-tert-leucine was produced at a conversion ratio of 96.4 mol percent with an optical purity of 99percent e.e. or more. With ammonium hydroxide, NAD, ammonium formate in water, Time= 22h, T= 30 °C , pH= 8, Reagent/catalyst, Temperature Patent; Kaneka Corporation; Kanamaru, Hiroyuki; Ueda, Makoto; Nanba, Hirokazu; (8 pag.); US9273332; (2016); (B2) English View in Reaxys

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H 2N

Rx-ID: 2292266 View in Reaxys 6/76 Yield

Conditions & References With hydrogen, palladium on activated charcoal in ethyl acetate, Time= 13h, p= 760Torr , Yield given Corey, E. J.; Link, John O.; Journal of the American Chemical Society; vol. 114; nb. 5; (1992); p. 1906 - 1908 View in Reaxys

H 2N

NH 2 OH Cl

O NH 2

Rx-ID: 28091536 View in Reaxys 7/76 Yield

Conditions & References

85 %

13 :Synthesis of (S)-2-amino-3,3-d9-dimethylbutanoic acid hydrochloride (XXV, R2/3 = C(CD3)3).; A mixture of compound XXIIc (R2 = R3 = C(CD3)3) (31.0 g, 222.6 mmol) in 6M aqueous HCI solution (1.5 L) was heated at reflux for 24 hrs. The mixture was concentrated in vacuo to give the crude product. The solid was redissolved in water (500 mL) and washed with EtOAc (2x200mL) to remove impurities from previous steps. The aqueous layer was then concentrated in vacuo, chased with toluene, and dried under vacuum at 50°C to afford the HCl salt of the desired compound (S)-2-amino-3,3-dimethylbutanoic acid-d9 hydrochloride (XXV, R2 = R3 = C(CD3)3) (33.6 g, 85percent yield) as a white solid, With hydrochlorid acid, water, Time= 24h, Heating / reflux Patent; Concert Pharmaceuticals Inc.; EP2003120; (2008); (A1) English View in Reaxys

O OH NH 2

OH H

-1 HO O

H 2N

Rx-ID: 34105373 View in Reaxys 8/76 Yield

Conditions & References 1 :(DL)-tert-Leucine (15 g, 0.1145 mol) was dissolved in water (180 mL). To the solution was added dibenzoyl-d-tartaric acid monohydrate (21.5 g, 0.057 mol) and stirred for 24 hours at 28°C (+/-3). The reaction mixture was filtered to collect L-tert-leucine dibenzoyl-d-tartrate salt. The filtrate was reserved for isolating D-tert-leucine later. The tartrate salt was added to water (150 mL) followed by concentrated sulphuric acid (3 mL) and stirred for 4 hours. Liberated dibenzoyl-d-tartaric acid was collected and dried (19.8 g, 92percent yield). The filtrate was washed with diisopropyl ether (50 mL) to remove any traces of dibenzoyl-d-tartaric acid, cooled to 5°C and treated with a saturated solution of barium hydroxide till the pH was neutral. It was filtered to remove the precipitated barium sulphate. The filtrate was concentrated under reduced pressure to remove all the solvent. The residue obtained was stirred with acetone (15 mL x 2), filtered and dried to obtain colorless solid L-tert-leucine (6 g, 80percent yield, 99percent chemical purity, 99.9percent chiral purity). The filtrate obtained after removing L-tert-leucine dibenzoyl-d-tartrate salt was concentrated under reduced pressure. The residue obtained was stirred with acetone (15 mL x 2), filtered and dried to obtain colorless solid of D-tert-leucine (6.37 g, 85percent yield, 98.5percent chemical purity, 98percent chiral purity). Stage 1: With sulfuric acid in water, Time= 4h

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Stage 2: With Ba(OH)2 in water, T= 5 °C Patent; Divi's Laboratories Limited; EP2502896; (2012); (A1) English View in Reaxys

H 2N

OH H

NH 2

Rx-ID: 3032465 View in Reaxys 9/76 Yield

Conditions & References

86 %

With hydrogenchloride, Time= 24h, T= 100 °C Boesten, Wilhelmus H. J.; Seerden, Jean-Paul G.; De Lange, Ben; Dielemans, Hubertus J. A.; Elsenberg, Henk L. M.; Kaptein, Bernard; Moody, Harold M.; Kellogg, Richard M.; Broxterman, Quirinus B.; Organic Letters; vol. 3; nb. 8; (2001); p. 1121 - 1124 View in Reaxys

76 %

With hydrogenchloride, T= 100 °C Speelman, Johanna C.; Talma, Auke G.; Kellogg, Richard M.; Meetsma, A.; Boer, J. L. de; et al.; Journal of Organic Chemistry; vol. 54; nb. 5; (1989); p. 1055 - 1062 View in Reaxys

HO O

O O

H 2N

N H

Rx-ID: 4078527 View in Reaxys 10/76 Yield

Conditions & References

74 %

With hydrogenchloride, Amberlite IRA-67, 1.) propan-2-ol, 70 deg C, 15 h; 2.) water, 15 h Turner, Nicholas J.; Winterman, James R.; McCague, Raymond; Parratt, Julian S.; Taylor, Stephen J. C.; Tetrahedron Letters; vol. 36; nb. 7; (1995); p. 1113 - 1116 View in Reaxys L-tert-leucine L-tert-leucine N-benzoyl-L-tert-leucine (31.5 g, 133 mmol) was suspended in water (250 ml) and potassium hydroxide (56 g, 1 mol) was added. The mixture was then heated to reflux for 114 h at which point 91percent conversion had been achieved. The solution was concentrated to 100 ml and acetone (500 ml) was added. The mixture was filtered and the solid obtained was added to hot methanol (250 ml). The undissolved solid was filtered off and the solvent evaporated to yield a white solid. This was added to water (50 ml) and the undissolved solid filtered off. Evaporation of the water gave a white solid identified by 1H nmr as tert-leucine, e.e. =99.4percent L-tert-leucine. With potassium hydroxide in methanol, water, acetone Patent; Chirotech Technology, Inc.; US6180374; (2001); (B2) English View in Reaxys

O H 2N

F F

OH H

Rx-ID: 9423349 View in Reaxys 11/76

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Yield

Conditions & References

68 %

Stage 1: With ruthenium trichloride, sodium periodate in tetrachloromethane, water, acetonitrile, Time= 24h, T= 20 °C , Sharpless oxidation Stage 2: With sodium hydroxide in methanol, Time= 16h, T= 20 °C Boezio, Alessandro A.; Solberghe, Geoffrey; Lauzon, Caroline; Charette, Andre B.; Journal of Organic Chemistry; vol. 68; nb. 8; (2003); p. 3241 - 3245 View in Reaxys

NH 2 OH Cl

H 2N

Rx-ID: 34004031 View in Reaxys 12/76 Yield

Conditions & References 2 :It was suspended in toluene (50 mL) and epichlorohydrin (5.8 g) was added. The reaction mixture was stirred till the pH was neutral. It was filtered, the solid obtained was stirred with acetone (15 ml*2) and again filtered to obtain L-tert-leucine (5.6 g, 75percent yield, 98.5percent chemical purity, 99.9percent chiral purity). With epichlorohydrin in toluene Patent; DIVI'S LABORATORIES LIMITED; US2012/245379; (2012); (A1) English View in Reaxys 2 :A mixture of L-tert-leucine.dibenzoyl-d-tartrate salt (27 g) as obtained in Example-1, water (150 mL) and concentrated hydrochloric acid (50 mL) was stirred for 12 hours. The liberated dibenzoyl-d-tartaric acid was filtered and dried (20 g). The filtrate was concentrated under reduced pressure to remove all the solvent. The residue obtained was stirred with acetone (15 ml x 2), filtered and dried to obtain colorless solid L-tert-leucine hydrochloride salt. It was suspended in toluene (50 mL) and epichlorohydrin (5.8 g) was added. The reaction mixture was stirred until the pH was neutral. It was filtered, the solid obtained was stirred with acetone (15 ml x 2) and again filtered to obtain Ltert-leucine (5.6 g, 75 percent yield, 98.5 percent chemical purity, 99.9percent chiral purity). With epichlorohydrin in toluene Patent; Divi's Laboratories Limited; EP2502896; (2012); (A1) English View in Reaxys

H N

NH 2 OH Cl

Rx-ID: 11655721 View in Reaxys 13/76 Yield

Conditions & References Reaction Steps: 3 1: 96 percent / sulfuric acid / H2O / 16 h / 45 °C 2: 98 percent / aq. HCl / 6 h / 100 °C 3: 98 percent / hydrogen / palladium on carbon / methanol / 8 h / 20 °C / 760.05 Torr With hydrogenchloride, sulfuric acid, hydrogen, palladium on activated charcoal in methanol, water Pan, Subhas Chandra; Zhou, Jian; List, Benjamin; Angewandte Chemie - International Edition; vol. 46; nb. 4; (2007); p. 612 - 614 View in Reaxys

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NH 2 OH Cl

OH O

Rx-ID: 11669092 View in Reaxys 14/76 Yield

Conditions & References Reaction Steps: 2 1: 98 percent / aq. HCl / 6 h / 100 °C 2: 98 percent / hydrogen / palladium on carbon / methanol / 8 h / 20 °C / 760.05 Torr With hydrogenchloride, hydrogen, palladium on activated charcoal in methanol Pan, Subhas Chandra; Zhou, Jian; List, Benjamin; Angewandte Chemie - International Edition; vol. 46; nb. 4; (2007); p. 612 - 614 View in Reaxys

E N

NH 2 OH Cl

Rx-ID: 11685163 View in Reaxys 15/76 Yield

Conditions & References Reaction Steps: 4 1: chiral 1,2-diaminocyclohexane based reagent / toluene / -40 °C 2: 96 percent / sulfuric acid / H2O / 16 h / 45 °C 3: 98 percent / aq. HCl / 6 h / 100 °C 4: 98 percent / hydrogen / palladium on carbon / methanol / 8 h / 20 °C / 760.05 Torr With hydrogenchloride, sulfuric acid, hydrogen, palladium on activated charcoal in methanol, water, toluene Pan, Subhas Chandra; Zhou, Jian; List, Benjamin; Angewandte Chemie - International Edition; vol. 46; nb. 4; (2007); p. 612 - 614 View in Reaxys

Cl Cl

H 2N

OH H

Rx-ID: 20986426 View in Reaxys 16/76 Yield

Conditions & References Reaction Steps: 3 1: 96 percent / (S)-α,α-diphenylprolinol - n-butylboronic acid, catecholborane / toluene / 56 h / -20 °C 2: 80 percent / NaN3, NaOH, H2O / 1,2-dimethoxy-ethane / 24 h / 23 °C 3: H2 / 10percent Pd/C / ethyl acetate / 13 h / 760 Torr With sodium hydroxide, sodium azide, (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol, n-butyl boronic acid, water, hydrogen, benzo[1,3,2]dioxaborole, palladium on activated charcoal in ethylene glycol dimethyl ether, ethyl acetate, toluene Corey, E. J.; Link, John O.; Journal of the American Chemical Society; vol. 114; nb. 5; (1992); p. 1906 - 1908 View in Reaxys

Cl Cl

O H 2N

OH H

Rx-ID: 21010442 View in Reaxys 17/76

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Yield

Conditions & References Reaction Steps: 2 1: 80 percent / NaN3, NaOH, H2O / 1,2-dimethoxy-ethane / 24 h / 23 °C 2: H2 / 10percent Pd/C / ethyl acetate / 13 h / 760 Torr With sodium hydroxide, sodium azide, water, hydrogen, palladium on activated charcoal in ethylene glycol dimethyl ether, ethyl acetate Corey, E. J.; Link, John O.; Journal of the American Chemical Society; vol. 114; nb. 5; (1992); p. 1906 - 1908 View in Reaxys

NH 2

H 2N

Rx-ID: 23935209 View in Reaxys 18/76 Yield

Conditions & References

92%

1 : EXAMPLE 1 EXAMPLE 1 An aqueous solution containing L-tert-leucine and D-tert-leucine amide, 200 g, obtained in Reference Example 1 was vacuum concentrated to 72 g. Thereafter, 300 g of isopropyl alcohol was added to the solution. The solution was further vacuum concentrated to obtain a final concentrate of 140 g. The water content of the concentrate was 6.5percent by mass. After this concentrate was stirred at 50° C. for 1 hour, the solution was cooled and stirred at 15° C. for an additional 4 hours. Precipitated crystals were collected by suction filtration and 18.4 g (dry mass) of L-tert-leucine was obtained (yield 92percent). The amount of D-tert-leucine amide contained in crystalline L-tert-leucine was 0.01percent by mass or lower. Patent; Katoh, Osamu; Uragaki, Toshitaka; Nakamura, Tetsuji; US2003/171597; (2003); (A1) English View in Reaxys

O OH

NH 2

OH Cl

Rx-ID: 33959935 View in Reaxys 19/76 Yield

Conditions & References 2 :Example 2 A mixture of L-tert-leucine.dibenzoyl-d-tartrate salt (27 g) as obtained in example-1, water (150 mL) and concentrated hydrochloric acid (50 mL) was stirred for 12 hours. The liberated dibenzoyl-d-tartaric acid was filtered and dried (20 g). The filtrate was concentrated under reduced pressure to remove all the solvent. The residue obtained was stirred with acetone (15 ml*2), filtered and dried to obtain colorless solid of L-tert-leucine hydrochloride salt. With hydrogenchloride in water, Time= 12h Patent; DIVI'S LABORATORIES LIMITED; US2012/245379; (2012); (A1) English View in Reaxys

O OH

NH 2

O O

H 2N

OH H

Rx-ID: 34004032 View in Reaxys 20/76

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Yield

Conditions & References 1 :Example 1 (DL)-tert-Leucine (15 g, 0.1145 mol) was dissolved in water (180 mL). To the solution was added dibenzoyl-d-tartaric acid monohydrate (21.5 g, 0.057 mol) and stirred for 24 hours at 28° C. (±3). The reaction mixture was filtered to collect L-tert-leucine dibenzoyl-d-tartrate salt. The filtrate was reserved for isolating D-tert-leucine later. Stage 1: With sulfuric acid in water, Time= 4h Stage 2: With Ba(OH)2 in water Patent; DIVI'S LABORATORIES LIMITED; US2012/245379; (2012); (A1) English View in Reaxys

NH 2

NH 2 OH Cl

-1 OHHO O

Rx-ID: 34105374 View in Reaxys 21/76 Yield

Conditions & References 2 :A mixture of L-tert-leucine.dibenzoyl-d-tartrate salt (27 g) as obtained in Example-1, water (150 mL) and concentrated hydrochloric acid (50 mL) was stirred for 12 hours. The liberated dibenzoyl-d-tartaric acid was filtered and dried (20 g). The filtrate was concentrated under reduced pressure to remove all the solvent. The residue obtained was stirred with acetone (15 ml x 2), filtered and dried to obtain colorless solid L-tert-leucine hydrochloride salt. It was suspended in toluene (50 mL) and epichlorohydrin (5.8 g) was added. The reaction mixture was stirred until the pH was neutral. It was filtered, the solid obtained was stirred with acetone (15 ml x 2) and again filtered to obtain Ltert-leucine (5.6 g, 75 percent yield, 98.5 percent chemical purity, 99.9percent chiral purity). With hydrogenchloride in water, Time= 12h Patent; Divi's Laboratories Limited; EP2502896; (2012); (A1) English View in Reaxys

H N

H 2N

OH H

Rx-ID: 41386618 View in Reaxys 22/76 Yield

Conditions & References 2.4. Enantioselective hydrolysis of N-PhAc-amino acid racemic mixtures General procedure: The reactions were carried out in a pH-stat at 30°C under continuous stirring. A water solution (25 mL) containing 0.025 MN-PhAc-amino acid racemic mixture was incubated at pH 7.5 for 30 min. 50 U of PGAEc or PGAA were added to the reaction mixture and the pH was maintained at 7.5 by titration (2 M NH4OH). With penicillin G acylase from Achromobacter sp. CCM 4824, water, T= 30 °C , pH= 7, Enzymatic reaction, Reagent/ catalyst, enantioselective reaction Grulich, Michal; Brezovsk, Jan; tpnek, Vclav; Palyzov, Andrea; Kyslkov, Eva; Kyslk, Pavel; Journal of Molecular Catalysis B: Enzymatic; vol. 122; (2015); p. 240 - 247 View in Reaxys

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OH O NH 2

H 2N

Rx-ID: 23242020 View in Reaxys 23/76 Yield

Conditions & References

100 %, 96.5 - 97.0 %

3 :The obtained salt (5.84 g, containing 0.018 mol of L-tert-leucine) was dissolved in pure water (160 ml) at 30°C, passed through a column packed with an ion exchange resin (DIAION SK1B, product name, MITSUBISHI CHEMICAL CORPORATION, H+ type, 30 ml) at a space velocity (SV) 2, and washed with pure water (60 ml) to recover 3,4-dimethylbenzenesulfonic acid in a transfluent solution and a washing solution. An analysis under HPLC analysis condition 1 revealed the rate of recovery of 3,4-dimethylbenzenesulfonic acid was quantitative. Elution with 5 wtpercent aqueous ammonia (90 ml) and washing with pure water (90 ml) gave L-tert-leucine in the eluate and washing solution. The eluate and washing solution were combined to recover L-tert-leucine. An eluted fraction (179 g) was obtained, which was analyzed under HPLC analysis condition 1 to find that an L-tert-leucine content was 1.33 wtpercent and the rate of recovery of L-tert-leucine was quantitative. Subsequently, the eluted fraction was concentrated under reduced pressure to 6.99 g at 50°C, and isopropyl alcohol (70 ml) was added. The mixture was heated to 70°C, stirred for 10 min, cooled to 10°C and crystals were allowed to precipitate for 3 hr. The precipitated crystals were collected by filtration, and vacuum dried at 60°C for 4 hr to give L-tert-leucine (2.32 g). The crystals were analyzed under HPLC analysis condition 1 to find that the L-tert-leucine content was 99.3 wtpercent and the rate of recovery relative to the salt was 96.5percent. In addition, the analysis under HPLC analysis condition 2 revealed an optical purity of 100percent ee.; Separately, the obtained salt (9.52 g, containing 0.030 mol of L-tert-leucine) was dissolved in pure water (200 ml) at 45°C, passed through a column packed with an ion exchange resin (DIAION WA30, product name, MITSUBISHI CHEMICAL CORPORATION, OH- type, 30 ml) at a space velocity (SV) 2, and washed with pure water (60 ml). The transfluent solution and a washing solution are combined and L-tert-leucine was recovered. As a result, a transfluent fraction (274 g) was obtained, an L-tert-leucine content was 1.42 wtpercent and the rate of recovery of L-tert-leucine was quantitative. Subsequently, a transfluent fraction was concentrated under reduced pressure to 11.9 g at 50°C and isopropyl alcohol (90 ml) was added. The mixture was heated to 70°C, stirred for 10 min, cooled to 10°C and crystals were allowed to precipitate for 17 hr. The precipitated crystals were collected by filtration, and vacuum dried at 60°C for 4 hr to give L-tert-leucine (3.79 g). The crystals were analyzed under HPLC analysis condition 1 to find that the L-tert-leucine content was 99.9 wtpercent and the rate of recovery relative to the salt was 97.0percent. In addition, the analysis under HPLC analysis condition 2 revealed an optical purity of 100percent ee. Elution with 5 wtpercent aqueous ammonia (90 ml) and washing with pure water (90 ml) gave 3,4dimethylbenzenesulfonic acid in the eluate and washing solution. An analysis under HPLC analysis condition 1 revealed that the rate of recovery of 3,4-dimethylbenzenesulfonic acid was quantitative. in water, T= 30 - 45 °C , Product distribution / selectivity Patent; Ajinomoto Co., Inc.; EP1498410; (2005); (A1) English View in Reaxys

NH 2 O

H 2N

OH H

H 2N

Rx-ID: 23912572 View in Reaxys 24/76 Yield 98%

Conditions & References 2 : EXAMPLE 2 EXAMPLE 2 An aqueous solution containing L-tert-leucine and D-tert-leucine amide, 400 g, obtained in Reference Example 1 was vacuum concentrated to 140 g. Thereafter, 300 g of n-butanol was added to the solution. The solution was further vacuum concentrated to obtain a final concentrate of 265 g. The water content of the concentrate was 0.9percent by mass. n-butanol, 10 g, was added to the concentrate, and the resultant solution was stirred at 60° C. for 1 hour. Thereafter, the solution was cooled and stirred at 20° C. for an additional 3 hours. Precipitated crystals were collected by centrifugal filtration and 39.2 g (dry mass) of L-tert-leucine was obtained (yield 98percent). The amount of D-tert-leucine amide contained in crystalline L-tert-leucine was 0.05percent by mass.

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Patent; Katoh, Osamu; Uragaki, Toshitaka; Nakamura, Tetsuji; US2003/171597; (2003); (A1) English View in Reaxys H (v4)

N (v4)

N – Ni 2+O–

(v4)(v3)

N H

(v2)

NH 2 OH Cl

Rx-ID: 41152718 View in Reaxys 25/76 Yield

Conditions & References

84 %

With hydrochlorid acid in methanol, water, Time= 2h, T= 70 °C Nian, Yong; Wang, Jiang; Zhou, Shengbin; Wang, Shuni; Moriwaki, Hiroki; Kawashima, Aki; Soloshonok, Vadim A.; Liu, Hong; Angewandte Chemie - International Edition; vol. 54; nb. 44; (2015); p. 12918 - 12922; Angew. Chem.; vol. 127; nb. 44; (2015); p. 13110 - 13114,5 View in Reaxys

H 2N

OH H

O HO

Rx-ID: 31638268 View in Reaxys 26/76 Yield

Conditions & References

45%

5 : Synthesis of L-tert-leucine from N-succinyl-DL-tert-leucine using the L-succinylaminoacylase of the present invention The sample was collected after finishing the reaction and subjected to an HPLC measurement under the condition same as the Example 4 to confirm the peaks of succinyl-form compound and free-form compound whereby the synthesis of L-tert-leucine from N-succinyl-DL-tert-leucine was confirmed. As a result, the yield was 45percent or more and the value near 50percent which is the theoretically highest yield was achieved. Patent; TOYO BOSEKI KABUSHIKI KAISHA; SEKISUI MEDICAL CO., LTD.; US2011/244530; (2011); (A1) English View in Reaxys 5 : Synthesis of L-tert-leucine from N-succinyl-DL-tert-leucine using the L-succinylaminoacylase of the present invention Example 5 Synthesis of L-tert-leucine from N-succinyl-DL-tert-leucine using the L-succinylaminoacylase of the present invention An L-succinylaminoacylase solution (1 mL; 2.3 mg/mL) was added to a 1 wt percent solution of N-succinyl-DL-tertleucine (pH 7 to 8; 10 mL; containing 1 mM of CoCl2) and made to react at 57° C. for 90 hours with stirring to give Ltert-leucine. With CoCl2 Patent; TOYO BOSEKI KABUSHIKI KAISHA; SEKISUI MEDICAL CO., LTD.; US2011/244530; (2011); (A1) English View in Reaxys

HO O HO

H 2N

OH H

Rx-ID: 3214861 View in Reaxys 27/76 Yield 76 %

Conditions & References With formic acid, palladium in methanol, water, Ambient temperature

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Inaba, Takashi; Kozono, Ichiro; Fujita, Makoto; Ogura, Katsuyuki; Bulletin of the Chemical Society of Japan; vol. 65; nb. 9; (1992); p. 2359 - 2365 View in Reaxys

O H 2N

NH 2 H

O H 2N

OH H

Rx-ID: 3584470 View in Reaxys 28/76 Yield

Conditions & References

35 %

With sodium hydroxide, manganese (II) chloride, leucine aminopeptidase in water, Time= 40h, T= 37 °C Fauchere; Petermann; Helvetica Chimica Acta; vol. 63; nb. 4; (1980); p. 824 - 831 View in Reaxys

H2N-Val-Phe-PAL-TM support

H 2N

OH H

Rx-ID: 15510597 View in Reaxys 29/76 Yield

Conditions & References Reaction Steps: 4 1: 92.4 percent / acetic acid / H2O / 30 - 70 °C 2: 94 percent / conc. H2SO4 / CH2Cl2 / 20 - 40 °C 3: 90 percent / H2 / Pd/C / ethanol / 20 h / 1500.15 Torr 4: 86 percent / aq. HCl / 24 h / 100 °C With hydrogenchloride, sulfuric acid, hydrogen, acetic acid, palladium on activated charcoal in ethanol, dichloromethane, water Boesten, Wilhelmus H. J.; Seerden, Jean-Paul G.; De Lange, Ben; Dielemans, Hubertus J. A.; Elsenberg, Henk L. M.; Kaptein, Bernard; Moody, Harold M.; Kellogg, Richard M.; Broxterman, Quirinus B.; Organic Letters; vol. 3; nb. 8; (2001); p. 1121 - 1124 View in Reaxys

H N

O N

H 2N

OH H

NH 2

Rx-ID: 15523916 View in Reaxys 30/76 Yield

Conditions & References Reaction Steps: 3 1: 94 percent / conc. H2SO4 / CH2Cl2 / 20 - 40 °C 2: 90 percent / H2 / Pd/C / ethanol / 20 h / 1500.15 Torr 3: 86 percent / aq. HCl / 24 h / 100 °C With hydrogenchloride, sulfuric acid, hydrogen, palladium on activated charcoal in ethanol, dichloromethane Boesten, Wilhelmus H. J.; Seerden, Jean-Paul G.; De Lange, Ben; Dielemans, Hubertus J. A.; Elsenberg, Henk L. M.; Kaptein, Bernard; Moody, Harold M.; Kellogg, Richard M.; Broxterman, Quirinus B.; Organic Letters; vol. 3; nb. 8; (2001); p. 1121 - 1124 View in Reaxys

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H N

NH 2 O

H 2N

OH H

NH 2

Rx-ID: 15525622 View in Reaxys 31/76 Yield

Conditions & References Reaction Steps: 2 1: 90 percent / H2 / Pd/C / ethanol / 20 h / 1500.15 Torr 2: 86 percent / aq. HCl / 24 h / 100 °C With hydrogenchloride, hydrogen, palladium on activated charcoal in ethanol Boesten, Wilhelmus H. J.; Seerden, Jean-Paul G.; De Lange, Ben; Dielemans, Hubertus J. A.; Elsenberg, Henk L. M.; Kaptein, Bernard; Moody, Harold M.; Kellogg, Richard M.; Broxterman, Quirinus B.; Organic Letters; vol. 3; nb. 8; (2001); p. 1121 - 1124 View in Reaxys

H 2N

O H 2N

N H

OH H

Rx-ID: 19162521 View in Reaxys 32/76 Yield

Conditions & References Reaction Steps: 2 1: 80 percent / hydrogen / 10percent Pd/C / acetic acid; methanol / 760 Torr / Ambient temperature 2: 35 percent / MnCl2*4H2O, 1N NaOH, leucine aminopeptidase / H2O / 40 h / 37 °C With sodium hydroxide, hydrogen, manganese (II) chloride, leucine aminopeptidase, palladium on activated charcoal in methanol, water, acetic acid Fauchere; Petermann; Helvetica Chimica Acta; vol. 63; nb. 4; (1980); p. 824 - 831 View in Reaxys Reaction Steps: 2 1: 96 percent / H2 / 10percent Pd/C / aq. ethanol / 2280 Torr 2: 76 percent / conc. HCl / 100 °C With hydrogenchloride, hydrogen, palladium on activated charcoal in ethanol Speelman, Johanna C.; Talma, Auke G.; Kellogg, Richard M.; Meetsma, A.; Boer, J. L. de; et al.; Journal of Organic Chemistry; vol. 54; nb. 5; (1989); p. 1055 - 1062 View in Reaxys

O O

H 2N

OH H

Rx-ID: 19162631 View in Reaxys 33/76 Yield

Conditions & References Reaction Steps: 5 1: diethyl ether / -10 °C 2: 75 percent / ethanol 3: 81 percent / H2SO4 4: 80 percent / hydrogen / 10percent Pd/C / acetic acid; methanol / 760 Torr / Ambient temperature 5: 35 percent / MnCl2*4H2O, 1N NaOH, leucine aminopeptidase / H2O / 40 h / 37 °C With sodium hydroxide, sulfuric acid, hydrogen, manganese (II) chloride, leucine aminopeptidase, palladium on activated charcoal in methanol, diethyl ether, ethanol, water, acetic acid Fauchere; Petermann; Helvetica Chimica Acta; vol. 63; nb. 4; (1980); p. 824 - 831 View in Reaxys

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Reaction Steps: 4 1: 82 percent / methanol / 20 h / Ambient temperature 2: 77 percent / conc. sulfuric acid / 48 h / Ambient temperature 3: 96 percent / H2 / 10percent Pd/C / aq. ethanol / 2280 Torr 4: 76 percent / conc. HCl / 100 °C With hydrogenchloride, sulfuric acid, hydrogen, palladium on activated charcoal in methanol, ethanol Speelman, Johanna C.; Talma, Auke G.; Kellogg, Richard M.; Meetsma, A.; Boer, J. L. de; et al.; Journal of Organic Chemistry; vol. 54; nb. 5; (1989); p. 1055 - 1062 View in Reaxys

O N H

H 2N

OH H

NH 2

Rx-ID: 3076694 View in Reaxys 34/76 Yield

Conditions & References

70 %

With hydrogenchloride, Time= 24h, T= 80 °C Kunz; Pfrengle; Ruck; Sager; Synthesis; nb. 11; (1991); p. 1039 - 1042 View in Reaxys

NH 2

CH3 COOH

H 2N

Rx-ID: 24661159 View in Reaxys 35/76 Yield

Conditions & References

750 mg (41%)

12 : EXAMPLE 12 EXAMPLE 12 A solution of (S)-N-methyl-tert-leucinamide in 100 ml of a 6N solution of HCl/CH3 COOH (1:1) was heated under reflux for 14 days. Then, the mixture was evaporated, the residue was chromatographic over AMBERLITE. Evaporation and drying gave 750 mg (41percent) of (S)-tert-leucine, [α]=+6.2 (c=1.62, 5N HCl), 97percent e.e. With hydrogenchloride Patent; Hoffmann-La Roche Inc.; US5710322; (1998); (A1) English View in Reaxys

NH 2

O H 2N

OH H

N H

Rx-ID: 24663219 View in Reaxys 36/76 Yield

Conditions & References 13 : EXAMPLE 13 EXAMPLE 13 A solution of 1.0 g of (S)-N-tert-butyl-tert-leucinamide in 10 ml of 6N HCl was heated at 80° C. for 2 days. The solution was evaporated to dryness. The residue was dissolved in water and chromatographed over AMBERLITE. There were obtained 550 mg (78percent) of (S)-tert-leucine, 100percent e.e. in hydrogenchloride, water Patent; Hoffmann-La Roche Inc.; US5710322; (1998); (A1) English View in Reaxys

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OH O

H 2N

Rx-ID: 31638267 View in Reaxys 37/76 Yield

Conditions & References 4 : Synthesis of L-tert-leucine from N-succinyl-L-tert-leucine using the L-succinylaminoacylase of the present invention Example 4 Synthesis of L-tert-leucine from N-succinyl-L-tert-leucine using the L-succinylaminoacylase of the present invention An L-succinylaminoacylase solution (1 mL; 2.3 mg/mL) was added to a 1 wt percent solution of N-succinyl-L-tertleucine (pH 7 to 8; 10 mL; containing 1 mM of CoCl2) and made to react at 57° C. for 90 hours with stirring to give Ltert-leucine. With CoCl2 Patent; TOYO BOSEKI KABUSHIKI KAISHA; SEKISUI MEDICAL CO., LTD.; US2011/244530; (2011); (A1) English View in Reaxys

NH 2 OH Cl

O N

Rx-ID: 17771856 View in Reaxys 38/76 Yield

Conditions & References Reaction Steps: 3 1: 84 percent / selenium dioxide / dioxane / 2 h / Heating 2: 82 percent / hydrogen / 10percent Pd-C / ethyl acetate / 3 h / 760 Torr / Ambient temperature 3: 1.) HCl gas, 2.) H2, 3.) conc. HCl / 2.) Pd-C With hydrogenchloride, selenium(IV) oxide, hydrogen, palladium on activated charcoal in 1,4-dioxane, ethyl acetate Shafer; Molinski; Journal of Organic Chemistry; vol. 61; nb. 6; (1996); p. 2044 - 2050 View in Reaxys

O O N

NH 2 OH Cl

Rx-ID: 17773322 View in Reaxys 39/76 Yield

Conditions & References Reaction Steps: 2 1: 82 percent / hydrogen / 10percent Pd-C / ethyl acetate / 3 h / 760 Torr / Ambient temperature 2: 1.) HCl gas, 2.) H2, 3.) conc. HCl / 2.) Pd-C With hydrogenchloride, hydrogen, palladium on activated charcoal in ethyl acetate Shafer; Molinski; Journal of Organic Chemistry; vol. 61; nb. 6; (1996); p. 2044 - 2050 View in Reaxys

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O H 2N

N H

OH H

Rx-ID: 20482638 View in Reaxys 40/76 Yield

Conditions & References Reaction Steps: 3 1: 77 percent / conc. sulfuric acid / 48 h / Ambient temperature 2: 96 percent / H2 / 10percent Pd/C / aq. ethanol / 2280 Torr 3: 76 percent / conc. HCl / 100 °C With hydrogenchloride, sulfuric acid, hydrogen, palladium on activated charcoal in ethanol Speelman, Johanna C.; Talma, Auke G.; Kellogg, Richard M.; Meetsma, A.; Boer, J. L. de; et al.; Journal of Organic Chemistry; vol. 54; nb. 5; (1989); p. 1055 - 1062 View in Reaxys

H 2N

OH H

NH 2

Rx-ID: 22176798 View in Reaxys 41/76 Yield

Conditions & References Reaction Steps: 3 2: brucine / durch Zerlegung mit Hilfe 3: aqueous HBr With hydrogen bromide, (-)-Brucine Abderhalden; Faust; Haase; Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie; vol. 228; (1934); p. 193 View in Reaxys Reaction Steps: 2 1: water / 24 h / 28 °C 2: sulfuric acid / water / 4 h With sulfuric acid in water Patent; DIVI'S LABORATORIES LIMITED; US2012/245379; (2012); (A1) English View in Reaxys Reaction Steps: 3 1: water / 24 h / 28 °C 2: hydrogenchloride / water / 12 h 3: epichlorohydrin / toluene With hydrogenchloride, epichlorohydrin in water, toluene Patent; DIVI'S LABORATORIES LIMITED; US2012/245379; (2012); (A1) English View in Reaxys Reaction Steps: 2 1.1: water / 24 h / 28 °C / Resolution of racemate 2.1: sulfuric acid / water / 4 h 2.2: 5 °C With sulfuric acid in water Patent; Divi's Laboratories Limited; EP2502896; (2012); (A1) English View in Reaxys Reaction Steps: 3 1: water / 24 h / 28 °C / Resolution of racemate 2: hydrogenchloride / water / 12 h 3: epichlorohydrin / toluene

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With hydrogenchloride, epichlorohydrin in water, toluene Patent; Divi's Laboratories Limited; EP2502896; (2012); (A1) English View in Reaxys Reaction Steps: 2 1: ω-transaminase 2: (S)-(+)-2-aminobutyric acid; branched-chain transaminase from Escherichiacoli; S-selective ω-transaminase from Ochrobactrum anthropi; (3-hydroxy-5-hydroxymethyl)-2-methylisonicotinic acid 5-phosphate; isopropylamine / aq. phosphate buffer / 18 h / pH 7 With (S)-(+)-2-aminobutyric acid, ω-transaminase, branched-chain transaminase from Escherichiacoli, S-selective ω-transaminase from Ochrobactrum anthropi, (3-hydroxy-5-hydroxymethyl)-2-methylisonicotinic acid 5-phosphate, isopropylamine in aq. phosphate buffer Park, Eul-Soo; Dong, Joo-Young; Shin, Jong-Shik; ChemCatChem; vol. 5; nb. 12; (2013); p. 3538 - 3542 View in Reaxys

O H 2N

NH 2

O HO

Rx-ID: 4960837 View in Reaxys 42/76 Yield

Conditions & References With ammonia, lithium in tetrahydrofuran, tert-butyl alcohol, Time= 0.5h, T= -78 °C , Yield given. Title compound not separated from byproducts Sabelle, Stephane; Lucet, Denis; Le Gall, Thierry; Mioskowski, Charles; Tetrahedron Letters; vol. 39; nb. 15; (1998); p. 2111 - 2114 View in Reaxys

H 2N

OH H

Rx-ID: 19179028 View in Reaxys 43/76 Yield

Conditions & References Reaction Steps: 4 1: 75 percent / ethanol 2: 81 percent / H2SO4 3: 80 percent / hydrogen / 10percent Pd/C / acetic acid; methanol / 760 Torr / Ambient temperature 4: 35 percent / MnCl2*4H2O, 1N NaOH, leucine aminopeptidase / H2O / 40 h / 37 °C With sodium hydroxide, sulfuric acid, hydrogen, manganese (II) chloride, leucine aminopeptidase, palladium on activated charcoal in methanol, ethanol, water, acetic acid Fauchere; Petermann; Helvetica Chimica Acta; vol. 63; nb. 4; (1980); p. 824 - 831 View in Reaxys

N H

H 2N

OH H

Rx-ID: 19179483 View in Reaxys 44/76 Yield

Conditions & References Reaction Steps: 3 1: 81 percent / H2SO4

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2: 80 percent / hydrogen / 10percent Pd/C / acetic acid; methanol / 760 Torr / Ambient temperature 3: 35 percent / MnCl2*4H2O, 1N NaOH, leucine aminopeptidase / H2O / 40 h / 37 °C With sodium hydroxide, sulfuric acid, hydrogen, manganese (II) chloride, leucine aminopeptidase, palladium on activated charcoal in methanol, water, acetic acid Fauchere; Petermann; Helvetica Chimica Acta; vol. 63; nb. 4; (1980); p. 824 - 831 View in Reaxys

OH O O

NH 2

H 2N

OH H

Rx-ID: 23242019 View in Reaxys 45/76 Yield

Conditions & References 4; 11 :The obtained salt (3.81 g, containing 0.012 mol of L-tert-leucine) was dissolved in pure water (80 ml) at 45°C, and treated in the same manner as in Example 3 using an ion exchange resin (DIAION WA30, product name, MITSUBISHI CHEMICAL CORPORATION, OH- type, 30 ml) to recover L-tert-leucine. As a result, a transfluent fraction (151 g) was obtained, an L-tert-leucine content was 1.00 wtpercent and the rate of recovery of L-tert-leucine relative to the salt was 95.8percent. Subsequently, a transfluent fraction was concentrated under reduced pressure to 9.33 g at 50°C and isopropyl alcohol (72 ml) was added. The mixture was heated to 70°C, stirred for 30 min, cooled to 10°C and crystals were allowed to precipitate for 4 hr. The precipitated crystals were collected by filtration, and vacuum dried at 60°C for 4 hr to give L-tert-leucine (1.33 g). The crystals were analyzed under HPLC analysis condition 1 to find that the L-tert-leucine content was 99.4 wtpercent and the rate of recovery was 87.9percent. In addition, the analysis under HPLC analysis condition 2 revealed an optical purity of 100percent ee.; The obtained salt (4.28 g, containing 0.013 mol of L-tert-leucine) was dissolved in pure water (100 ml) at 70°C, and treated in the same manner as in Example 3 using an ion exchange resin (DIAION WA30, product name, MITSUBISHI CHEMICAL CORPORATION, OH- type, 30 ml) to recover L-tert-leucine. As a result, a transfluent fraction (159 g) was obtained, the Ltert-leucine content was 1.09 wtpercent, and the rate of recovery of L-tert-leucine relative to the salt was 97.5percent. Subsequently, a transfluent fraction was concentrated under reduced pressure to 7.58 g at 50°C and isopropyl alcohol (45 ml) was added. The mixture was heated to 70°C, stirred for 30 min, cooled to 10°C and the crystals were allowed to precipitate for 3 hr. The precipitated crystals were collected by filtration, vacuum dried at 60°C for 4 hr to give L-tert-leucine (1.54 g). The crystals were analyzed under HPLC analysis condition 1 to find that the L-tert-leucine content was 99.3 wtpercent and the rate of recovery was 88.6percent. In addition, an analysis under HPLC analysis condition 2 revealed an optical purity of 100percent ee. Furthermore, by an analysis by an amino acid analyzer, L-alanine, L-aspartic acid and L-glutamic acid were not detected. in water, T= 45 - 70 °C , Product distribution / selectivity Patent; Ajinomoto Co., Inc.; EP1498410; (2005); (A1) English View in Reaxys

O HO HN

O H 2N

OH H

O H

NH OH O

Rx-ID: 3192504 View in Reaxys 46/76 Yield

Conditions & References With potassium hydroxide, potassium phosphate buffer, porcine kidney acylase I, T= 40 °C , relative initial rate of hydrolysis, also with Aspergillus acylase I as a catalyst; with or without CoCl2 Chenault, H. Keith; Dahmer, Juergen; Whitesides, George M.; Journal of the American Chemical Society; vol. 111; nb. 16; (1989); p. 6354 - 6364 View in Reaxys

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O O

NH 2 OH Cl

Rx-ID: 4501533 View in Reaxys 47/76 Yield

Conditions & References With hydrogenchloride, hydrogen, palladium on activated charcoal, Yield given. Multistep reaction Shafer; Molinski; Journal of Organic Chemistry; vol. 61; nb. 6; (1996); p. 2044 - 2050 View in Reaxys

O –C

K+

H 2N

OH H

Rx-ID: 29388974 View in Reaxys 48/76 Yield

Conditions & References Stage 1: With acetic acid in water, toluene, Time= 0.416667h, T= 0 °C , Inert atmosphere Stage 2: With 1-amino diphenylmethane in toluene, Inert atmosphere, Strecker amino acid synthesis, enantioselective reaction, Further stages Zuend, Stephan J.; Coughlin, Matthew P.; Lalonde, Mathieu P.; Jacobsen, Eric N.; Nature; vol. 461; nb. 7266; (2009); p. 968 - 970 View in Reaxys

O N H

H 2N

Rx-ID: 1337977 View in Reaxys 49/76 Yield

Conditions & References With hydrogenchloride in ethanol Tanabe,T. et al.; Bulletin of the Chemical Society of Japan; vol. 41; (1968); p. 2178 - 2179 View in Reaxys

O O HN

O O

H 2N

OH H

Rx-ID: 12073419 View in Reaxys 50/76 Yield

Conditions & References Reaction Steps: 2 1: subtilisin / H2O; various solvent(s) / 18 h / 35 °C / pH 7.5 2: 97 percent / HCl / dioxane With hydrogenchloride, subtilisin in 1,4-dioxane, water Agosta, Eleonora; Caligiuri, Antonio; D'Arrigo, Paola; Servi, Stefano; Tessaro, Davide; Canevotti, Renato; Tetrahedron Asymmetry; vol. 17; nb. 13; (2006); p. 1995 - 1999 View in Reaxys Reaction Steps: 2 1: 93 percent / Bacillus licheniformis / H2O; various solvent(s) / 23 h / 35 °C / pH 7.8 2: 97 percent / HCl / dioxane

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With Bacillus licheniformis, hydrogenchloride in 1,4-dioxane, water Agosta, Eleonora; Caligiuri, Antonio; D'Arrigo, Paola; Servi, Stefano; Tessaro, Davide; Canevotti, Renato; Tetrahedron Asymmetry; vol. 17; nb. 13; (2006); p. 1995 - 1999 View in Reaxys Reaction Steps: 2 1: subtilisin / H2O; various solvent(s) / 15 h / 35 °C / pH 7.5 2: 97 percent / HCl / dioxane With hydrogenchloride, subtilisin in 1,4-dioxane, water Agosta, Eleonora; Caligiuri, Antonio; D'Arrigo, Paola; Servi, Stefano; Tessaro, Davide; Canevotti, Renato; Tetrahedron Asymmetry; vol. 17; nb. 13; (2006); p. 1995 - 1999 View in Reaxys

O H 2N

OH H

N O

Rx-ID: 16903440 View in Reaxys 51/76 Yield

Conditions & References Reaction Steps: 2 1: 89 percent / NaNO2, AcOH / dimethylsulfoxide / 28 h / 40 °C 2: Li, NH3 / tetrahydrofuran; 2-methyl-propan-2-ol / 0.5 h / -78 °C With ammonia, lithium, acetic acid, sodium nitrite in tetrahydrofuran, dimethyl sulfoxide, tert-butyl alcohol Sabelle, Stephane; Lucet, Denis; Le Gall, Thierry; Mioskowski, Charles; Tetrahedron Letters; vol. 39; nb. 15; (1998); p. 2111 - 2114 View in Reaxys

H 2N

O O

O NH

Rx-ID: 18121901 View in Reaxys 52/76 Yield

Conditions & References Reaction Steps: 2 1: 59 percent / 0.1 M potassium phosphate buffer, Alcalase-Bacillus licheniformis / propan-2-ol / 48 h / pH=8 2: 74 percent / 1.) 6 M hydrochloric acid; 2.) Amberlite IRA-67 / 1.) propan-2-ol, 70 deg C, 15 h; 2.) water, 15 h With hydrogenchloride, potassium phosphate buffer, Alcalase-Bacillus licheniformis, Amberlite IRA-67 in isopropyl alcohol Turner, Nicholas J.; Winterman, James R.; McCague, Raymond; Parratt, Julian S.; Taylor, Stephen J. C.; Tetrahedron Letters; vol. 36; nb. 7; (1995); p. 1113 - 1116 View in Reaxys

N HO

N H

O H 2N

OH H

Rx-ID: 19752481 View in Reaxys 53/76

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Yield

Conditions & References Reaction Steps: 2 1: 81 percent / aq. HCl / 2 h / 50 °C 2: 76 percent / formic acid, Pd black / methanol; H2O / Ambient temperature With hydrogenchloride, formic acid, palladium in methanol, water Inaba, Takashi; Kozono, Ichiro; Fujita, Makoto; Ogura, Katsuyuki; Bulletin of the Chemical Society of Japan; vol. 65; nb. 9; (1992); p. 2359 - 2365 View in Reaxys

O O

H 2N

Rx-ID: 21552568 View in Reaxys 54/76 Yield

Conditions & References Reaction Steps: 3 1: aq. KMnO4, aq. NaOH / 0 °C 2: 87 percent / acetic acid 3: hydrogenation With sodium hydroxide, potassium permanganate in acetic acid Viret, Joelle; Patzelt, Heiko; Collet, Andre; Tetrahedron Letters; vol. 27; nb. 48; (1986); p. 5865 - 5868 View in Reaxys

H 2N

Rx-ID: 21593879 View in Reaxys 55/76 Yield

Conditions & References Reaction Steps: 3 1: 85 percent / ZnCl2 / tetrahydrofuran; diethyl ether / 72 h / -25 °C 2: 1.) HCl / 1.) MeOH, 2.) H2O 3: 1.) 6N HCl, 2.) Amberlite IR-120 / 1.) 80 deg C With hydrogenchloride, Amberlite IR-120, zinc(II) chloride in tetrahydrofuran, diethyl ether Kunz, Horst; Pfrengle, Waldemar; Sager, Wilfried; Tetrahedron Letters; vol. 30; nb. 31; (1989); p. 4109 - 4110 View in Reaxys

HO O

O HN

O H 2N

OH H

Rx-ID: 22601530 View in Reaxys 56/76 Yield

Conditions & References Reaction Steps: 2 1: acetic acid 2: aq. HCl / aq. ethanol With hydrogenchloride in ethanol, acetic acid Tanabe,T. et al.; Bulletin of the Chemical Society of Japan; vol. 41; (1968); p. 2178 - 2179 View in Reaxys

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O–

H 2N

Rx-ID: 29952689 View in Reaxys 57/76 Yield

Conditions & References

100 %

With Glutamate, Time= 0.5h, T= 37 °C , pH= 8, aq. phosphate buffer, Enzymatic reaction, Kinetics, Reagent/catalyst, optical yield given as percent ee Hong, Eun Young; Cha, Minho; Yun, Hyungdon; Kim, Byung-Gee; Journal of Molecular Catalysis B: Enzymatic; vol. 66; nb. 1-2; (2010); p. 228 - 233 View in Reaxys

NH 2 OH Cl

HO NH 2

Rx-ID: 34004030 View in Reaxys 58/76 Yield

Conditions & References Reaction Steps: 2 1: water / 24 h / 28 °C 2: hydrogenchloride / water / 12 h With hydrogenchloride in water Patent; DIVI'S LABORATORIES LIMITED; US2012/245379; (2012); (A1) English View in Reaxys Reaction Steps: 2 1: water / 24 h / 28 °C / Resolution of racemate 2: hydrogenchloride / water / 12 h With hydrogenchloride in water Patent; Divi's Laboratories Limited; EP2502896; (2012); (A1) English View in Reaxys

HO H

O H 2N

OH H

Rx-ID: 366614 View in Reaxys 59/76 Yield

Conditions & References With methanol, palladium, acetic acid, Hydrogenation Izumiya et al.; Journal of Biological Chemistry; vol. 205; (1953); p. 221,229 View in Reaxys (hydrogenolysis) Miyazawa,T. et al.; Bulletin of the Chemical Society of Japan; vol. 52; (1979); p. 1539 - 1540 View in Reaxys

NH 2 O

H 2N

OH H

H 2N

Rx-ID: 200868 View in Reaxys 60/76 Yield

Conditions & References mit Hilfe eines Enzym-Praeparats aus Schweine-Nieren

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Izumiya et al.; Journal of Biological Chemistry; vol. 205; (1953); p. 221,229 View in Reaxys Reaction Steps: 3 1: chlorocarbonic acid benzyl ester 2: amidase-substance from pig's kidney 3: palladium; methanol; acetic acid / Hydrogenation With methanol, amidase-substance from pig's kidney, palladium, acetic acid, benzyl chloroformate Izumiya et al.; Journal of Biological Chemistry; vol. 205; (1953); p. 221,229 View in Reaxys

O H 2N

OH H

Rx-ID: 29388992 View in Reaxys 61/76 Yield

Conditions & References With hydrogenchloride, sulfuric acid, water, T= 120 °C , Inert atmosphere Zuend, Stephan J.; Coughlin, Matthew P.; Lalonde, Mathieu P.; Jacobsen, Eric N.; Nature; vol. 461; nb. 7266; (2009); p. 968 - 970 View in Reaxys

O NH 2

H 2N

OH H

Rx-ID: 22096662 View in Reaxys 62/76 Yield

Conditions & References Reaction Steps: 2 1: amidase-substance from pig's kidney 2: palladium; methanol; acetic acid / Hydrogenation With methanol, amidase-substance from pig's kidney, palladium, acetic acid Izumiya et al.; Journal of Biological Chemistry; vol. 205; (1953); p. 221,229 View in Reaxys

S H 2N

NH 2

OH O

Rx-ID: 4375841 View in Reaxys 63/76 Yield

Conditions & References With hydrogenchloride, Yield given. Yields of byproduct given. Title compound not separated from byproducts Davis, Franklin A.; Portonovo, Padma S.; Reddy, Rajarathnam E.; Chiu, Yu-Hung; Journal of Organic Chemistry; vol. 61; nb. 2; (1996); p. 440 - 441 View in Reaxys

O–

H 2N

O O

OH H

H 2N

Rx-ID: 41314271 View in Reaxys 64/76

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Yield

Conditions & References

94 %

With pyridoxal 5'-phosphate, (S)-selective ω-transaminase from Paracoccus denitrificans, branched-chain aminoacid transaminase, 2-aminobutanoic acid in aq. phosphate buffer, hexane, Time= 61h, pH= 7, Enzymatic reaction, Kinetics, Solvent, Reagent/catalyst, enantioselective reaction Park, Eul-Soo; Shin, Jong-Shik; Journal of Molecular Catalysis B: Enzymatic; vol. 121; (2015); p. 9 - 14; Art.No: 3203 View in Reaxys

H 2N

H+

N H

OH H

NH 2

Rx-ID: 2539224 View in Reaxys 65/76 Yield

Conditions & References With hydrogenchloride, Amberlite IR-120, 1.) 80 deg C, Yield given. Multistep reaction Kunz, Horst; Pfrengle, Waldemar; Sager, Wilfried; Tetrahedron Letters; vol. 30; nb. 31; (1989); p. 4109 - 4110 View in Reaxys

H 2N

N HO

Rx-ID: 22180566 View in Reaxys 66/76 Yield

Conditions & References Reaction Steps: 4 1: amalgamated aluminium; aqueous ethanol 3: brucine / durch Zerlegung mit Hilfe 4: aqueous HBr With ethanol, aluminium amalgam, hydrogen bromide, (-)-Brucine Abderhalden; Faust; Haase; Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie; vol. 228; (1934); p. 193 View in Reaxys Reaction Steps: 2 1: (i) Et2O, (ii) Al-Hg, H2O, (iii) (racemate resolution using dibenzoyl-(R)-tartaric acid) 2: aq. HCl With hydrogenchloride Pracejus,H.; Winter,S.; Chemische Berichte; vol. 97; (1964); p. 3173 - 3182 View in Reaxys

O N H

OH H

O H 2N

OH H

Rx-ID: 202865 View in Reaxys 67/76 Yield

Conditions & References With hydrogen bromide Abderhalden; Faust; Haase; Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie; vol. 228; (1934); p. 193 View in Reaxys

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NH 2

H 2N

Rx-ID: 1110870 View in Reaxys 68/76 Yield

Conditions & References With hydrogenchloride Pracejus,H.; Winter,S.; Chemische Berichte; vol. 97; (1964); p. 3173 - 3182 View in Reaxys

O O

H N

H 2N

F F

H H

Rx-ID: 1366601 View in Reaxys 69/76 Yield

Conditions & References With hydrogenchloride Steglich,W. et al.; Chemische Berichte; vol. 104; (1971); p. 687 - 690 View in Reaxys

O O

O–

NH 2

H 2N

OH H

O– O

O–

O– O O

Rx-ID: 8686519 View in Reaxys 70/76 Yield

Conditions & References With pyridoxal 5-triphosphate, branched-chain-amino-acid transaminase from E. coli in phosphate buffer, T= 298.15 °C , pH= 7.15 - 7.24, Enzymatic reaction, transfer of amino group; catabolism, Product distribution, Thermodynamic data, Equilibrium constant Tewari, Yadu B.; Goldberg, Robert N.; Rozzell, J. David; Journal of Chemical Thermodynamics; vol. 32; nb. 10; (2000); p. 1381 - 1398 View in Reaxys

HO O

H 2N

OH H

Rx-ID: 22177084 View in Reaxys 71/76 Yield

Conditions & References Reaction Steps: 2 1: brucine / durch Zerlegung mit Hilfe 2: aqueous HBr With hydrogen bromide, (-)-Brucine Abderhalden; Faust; Haase; Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie; vol. 228; (1934); p. 193 View in Reaxys

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O (v1)

Pol

H 2N

NH 2 O

Rx-ID: 32659283 View in Reaxys 72/76 Yield

Conditions & References With trifluoroacetic acid, solid phase reaction Tuchman-Shukron, Lital; Miller, Scott J.; Portnoy, Moshe; Chemistry - A European Journal; vol. 18; nb. 8; (2012); p. 2290 - 2296 View in Reaxys

NH 2 O

H 2N

OH H

Rx-ID: 1022586 View in Reaxys 73/76 Yield

Conditions & References (i) liq. NH3, (ii) (racemate resolution using D-tartaric acid), (iii) aq. HCl, Multistep reaction Tanabe,T. et al.; Bulletin of the Chemical Society of Japan; vol. 41; (1968); p. 2178 - 2179 View in Reaxys

H N

H 2N

Rx-ID: 1975627 View in Reaxys 74/76 Yield

Conditions & References hydrogenation, Yield given Viret, Joelle; Patzelt, Heiko; Collet, Andre; Tetrahedron Letters; vol. 27; nb. 48; (1986); p. 5865 - 5868 View in Reaxys

HO H

H 2N

OH H

Rx-ID: 22621057 View in Reaxys 75/76 Yield

Conditions & References Reaction Steps: 2 2: (hydrogenolysis) Miyazawa,T. et al.; Bulletin of the Chemical Society of Japan; vol. 52; (1979); p. 1539 - 1540 View in Reaxys

O H 2N

OH H

Rx-ID: 24367969 View in Reaxys 76/76 Yield

Conditions & References N(im)-A-His: histidine which is substituted by A in the 1-position or 3-position of the imidazole ring Hph: homophenylalanine (2-amino-4-phenylbutyric acid) Ile: isoleucine

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Leu: leucine tert.-Leu: tert.-leucine Lys: lysine Met: methionine Patent; Merck Patent Gesellschaft mit beschrankter Haftung; US5215967; (1993); (A1) English View in Reaxys ...ctive aliphatic carboxylic acids (XIX) can be obtained by oxidation of corresponding alcohols or reductive deamination of amino acid and some of others can be derived from the following optically active amino acids or optically active oxyacids which occur in nature or are obtained by resolution. ... threonine, allothreonine, homoserine, alloisoleucine, tert-leucine, 2-aminobutyric acid, norvaline, norleucine, ... Patent; Sumitomo Chemical Company, Limited; US5124070; (1992); (A1) English View in Reaxys

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