* 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.
Reference：
[1] Journal of Biological Chemistry, 1939, vol. 127, p. 727,730
[2] Journal of Biological Chemistry, 1939, vol. 127, p. 727,730
13
[ 3775-73-3 ]
[ 61477-40-5 ]
Yield
Reaction Conditions
Operation in experiment
84.3%
With sodium tetrahydroborate; trifluoroacetic acid In tetrahydrofuran at 20℃; Inert atmosphere; Cooling with ice
Under a nitrogen atmosphere, 120 g of sodium borohydride and 124 g of (R)-3-aminobutyric acid were placed in a reaction flask, 1.5 L of tetrahydrofuran was added, and the mixture was cooled with ice water. 506 g of trifluoroacetic acid was slowly added dropwise to the reaction flask, and the tail gas was absorbed by a sodium hydroxide solution. After the completion of the dropwise addition, the temperature was raised to 20 ° C until the starting material disappeared. The reaction was quenched by the addition of sodium hydroxide solution, and the layers were allowed to stand, and the organic phase was distilled to recover tetrahydrofuran. The aqueous phase was extracted with chloroform, and the combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. Yield: 84.3percent, purity: 99.5percent, ee: 99.6percent.
54%
With sodium tetrahydroborate; zinc(II) chloride In tetrahydrofuran at 20 - 60℃; for 3.5 h; Autoclave
To a 50 L autoclave, 13 L of anhydrous tetrahydrofuran and 1067 g of anhydrous zinc chloride (with little exotherm) were added, Carefully add 590 grams of sodium borohydride (note the heat and gas). Stirred at room temperature for 30 minutes and then warmed to 50 to 60 ° C for 3 hours. After cooling to room temperature, 1280 g of a white solid obtained above was added in portions and the temperature was controlled at 10 to 40 ° C. After the addition was complete, the temperature was slowly raised to reflux for 24 hours. The system was turned into a gray suspension system, cooled to 10-15 ° C, and 640 ml of methanol and 200 g of 40percent aqueous sodium hydroxide solution were slowly added dropwise and the temperature was controlled at 10 to 40 ° C. After adding, stir at room temperature for 3 to 5 hours. Filtered, washed with THF and filtered to give a colorless liquid; Distillation distillation (10 to 65 ° C) Get a transparent viscous liquid R-3-aminobutanol 495 g, yield 54percent. Purity 99.2percent, 99.3percent.
Reference：
[1] Patent: CN108689866, 2018, A, . Location in patent: Paragraph 0016-0020
[2] Patent: CN104370755, 2017, B, . Location in patent: Paragraph 0119; 0121
14
[ 3775-73-3 ]
[ 501-53-1 ]
[ 67843-72-5 ]
Reference：
[1] Journal of the American Chemical Society, 2007, vol. 129, # 41, p. 12563 - 12570
15
[ 67-56-1 ]
[ 3775-73-3 ]
[ 139243-54-2 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 20℃;
(1) (R)-3-aminobutyric acid (70 g, 0.68 mol) was dissolved in methanol (1.0L), the ice-water bath was cooled to T <20 ° C, the dropwise addition of thionyl chloride (97g, 0.82mol), the end of the reaction, the natural reaction overnight, 40-50 ° C the reaction solution was concentrated to dry oil 99g, yield 95percent.
Reference：
[1] Journal of Organic Chemistry, 1992, vol. 57, # 8, p. 2396 - 2398
17
[ 3775-73-3 ]
[ 24424-99-5 ]
[ 159991-23-8 ]
Yield
Reaction Conditions
Operation in experiment
90%
With triethylamine In 1,4-dioxane; water at 0 - 20℃; for 16 h;
Intermediate 72: (4S,7R,10aS)-4-Amino-7-methylhexahydro-2H-pyrido[2, l- b] [ 1 ,3 ]thiazepin-5(7H)-one.A: (R)-3-(tert-Butoxycarbonylamino)butanoic acid [00344] To a stirred suspension of (R)-3-aminobutanoic acid (2.415 g, 23.42 mmol) in dioxane (15 mL) and water (15.00 mL) was added TEA (4.90 mL, 35.1 mmol) dropwise. To the resulting light brown solution cooled at 0 °C was added portionwise di-tert-butyl carbonate (4.69 g, 26.9 mmol). The mixture was then stirred at rt for 16 hr. The reaction mixture was partitioned between water (80 mL) and EtOAc (80 mL). The separated aqueous layer was washed with EtOAc and acidified with 1 M aqueous KHSO4 to pH = 3 and extracted with EtOAc (2x). The combined EtOAc extracts were washed with saturated aqueous NaCl (2x), dried over Na2S04, filtered and concentrated to give (R)-3- (tert-butoxycarbonylamino)butanoic acid (4.301 g, 21.16 mmol, 90percent yield) as a pale yellow solid. XH NMR (400 MHz, CDC13) δ ppm 4.92 (s, 1H), 4.14 - 3.96 (m, 2H), 2.56 (d, J = 5.2 Hz, 2H), 1.45 (s, 9H), 1.25 (d, J = 6.9 Hz, 3H).
Reference：
[1] Patent: WO2012/125622, 2012, A1, . Location in patent: Page/Page column 135-136
[2] Chinese Chemical Letters, 2015, vol. 26, # 1, p. 103 - 107
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 5, p. 1421 - 1425
[4] Angewandte Chemie - International Edition, 2018, vol. 57, # 31, p. 9707 - 9710[5] Angew. Chem., 2018, vol. 130, # 31, p. 9855 - 9858,4
18
[ 3775-73-3 ]
[ 34619-03-9 ]
[ 159991-23-8 ]
Yield
Reaction Conditions
Operation in experiment
93.5%
With sodium carbonate In water at 25℃; Green chemistry
Sequentially put 103g of R-3-aminobutyric acid,105g sodium carbonate,218g di-tert-butyl carbonate,Add to the reaction flask containing 500 mL of water,React at 25 °C for 2-6 hours,After the reaction is completed, adjust the pH to 3-4 with 2N hydrochloric acid.The product was extracted twice with 500 mL of ethyl acetate.Spin dry,That is, N-Boc-(R)-3-aminobutyric acid (I),The white solid was 190 g, the yield was 93.5percent, and the content was 98percent (HPLC method).
Reference：
[1] Patent: CN108424370, 2018, A, . Location in patent: Paragraph 0087; 0088
With sodium methylate; In 2-methoxy-ethanol; for 3.0h;Reflux;
Example 142(i?)-3-[(l-Benzyl-5-hydroxy-2-oxo-3-phenyl-l,2-dihydro-[l,7]naphthyridine-6-carbonyl)- amino] -butyric acid[0464] A mixture of l-benzyl-5-hydroxy-2-oxo-3-phenyl-l,2-dihydro-[l,7]naphthyridine-6- carboxylic acid methyl ester (35 mg, 0.090 mmol), (R)-3-amino-butyric acid (94 mg, 0.90 mmol) and NaOMe (39 mg, 0.73 mmol) in 2-methoxyethanol (10 mL) was refluxed for 3 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHC03 and washed with ether. The aqueous layer was acidified to pH about 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 28 mg of the title compound as a yellow solid. MS: (+) m/z 458.30 (M+
With triethylamine; In 1,4-dioxane; water; at 0 - 20℃; for 16h;
Intermediate 72: (4S,7R,10aS)-4-Amino-7-methylhexahydro-2H-pyrido[2, l- b] [ 1 ,3 ]thiazepin-5(7H)-one.A: (R)-3-(tert-Butoxycarbonylamino)butanoic acid [00344] To a stirred suspension of <strong>[3775-73-3](R)-3-aminobutanoic acid</strong> (2.415 g, 23.42 mmol) in dioxane (15 mL) and water (15.00 mL) was added TEA (4.90 mL, 35.1 mmol) dropwise. To the resulting light brown solution cooled at 0 C was added portionwise di-tert-butyl carbonate (4.69 g, 26.9 mmol). The mixture was then stirred at rt for 16 hr. The reaction mixture was partitioned between water (80 mL) and EtOAc (80 mL). The separated aqueous layer was washed with EtOAc and acidified with 1 M aqueous KHSO4 to pH = 3 and extracted with EtOAc (2x). The combined EtOAc extracts were washed with saturated aqueous NaCl (2x), dried over Na2S04, filtered and concentrated to give (R)-3- (tert-butoxycarbonylamino)butanoic acid (4.301 g, 21.16 mmol, 90% yield) as a pale yellow solid. XH NMR (400 MHz, CDC13) delta ppm 4.92 (s, 1H), 4.14 - 3.96 (m, 2H), 2.56 (d, J = 5.2 Hz, 2H), 1.45 (s, 9H), 1.25 (d, J = 6.9 Hz, 3H).
With sodium methylate; In N,N-dimethyl-formamide; at 140℃; for 4.0h;Microwave irradiation; Sealed tube;
l-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (75 mg, 0.234 mmol) and 3-(R)-amino-butyric acid (103 mg, 1.0 mmol) were placed in a CEM 10 mL Microwave vessel and dissolved in anhydrous N,N-dimethylformamide (2 mL.) Sodium methoxide (54 mg, 1.0 mmol) was added to solution and the vessel was sealed. The reaction was heated to 140 C in a CEM microwave apparatus for four hours. Upon completion, the reaction mixture was diluted with water and treated with IN hydrochloric acid. The precipitate was dissolved in dichloromethane and dried over anhydrous sodium sulfate. The crude product was purified by MPLC (methylene chloride- ethyl acetate) to provide the title compound as a light-yellow solid in 75% yield. MS ESI(-) m/e: 390.091 (M-l).
At 0C, 4 M HCI-dioxane (37.8 mL, 151 mmol) was added dropwise to a mixture of (R)-homo-3-alanine (35; 13.0 g, 126 mmol) in CH2CI2 (170 mL). PCI5 (31.5 g, 151 mmol) was added to the suspension. The mixture was stirred at 0C to rt for 15 h. A clear solution resulted. The volatiles were evaporated. The residue was dissolved in CH2CI2 (150 mL). Allyl alcohol (10.3 mL, 151 mmol) was added slowly and the mixture was stirred for 2 h at rt. The volatiles were evaporated to afford crude 36 HCI (25.6 g).
With acetic anhydride; In water; at 0 - 20℃; for 4.16667h;
To a solution of <strong>[3775-73-3](R)-3-aminobutanoic acid</strong> (10.8 g, 105 mmol) in 1 15 mL of 80% formic acid was added dropwise 70 mL of acetic anhydride at 0 C, stirred for 10 min, then stirred for 4 h at r.t. The reaction mixture was quenched with water (70 mL), concentrated. The residue was recrystallized from water to afford the title compound (13.6 g).
With hydrogenchloride; phosphorus pentachloride; In 1,4-dioxane; dichloromethane; at 0 - 20℃; for 15.0h;
At 0 C., 4 M HC1-dioxane (37.8 mE, 151 mmol) was added dropwise to a mixture of (R)-homo-13-alanine (35; 13.0 g, 126 mmol) in CH2C12 (170 mE). PC15 (31.5 g, 151 mmol) was added to the suspension. The mixture was stirred at 0 C. to it for 15 h. A clear solution resulted. The volatiles were evaporated. The residue was dissolved in CH2C12 (150 mE). Allyl alcohol (10.3 mE, 151 mmol) was added slowly and the mixture was stirred for 2 h at it. The volatiles were evaporated to afford crude 36.HC1 (25.6 g).
With sodium hydroxide; In methanol; water; at 20℃; for 72h;
Synthesis of Compound 219 (fi)-Aminobutyric acid SM01 (750 mg, 7.27 mmol) and 2-methyl-2-thiopseudourea sulfate (MTS, 1 .21 g, 4.36 mmol) were suspended in methanol (4 m L). After addition of 3N sodium hydroxide in water (2.62 mL, 1 .09 eq.), the clear solution was stirred for 3 days at room temperature. Subsequently, the white precipitate was filtered off and washed with water/methanol (15 mL, 1 /2). The white powder was air dried for 1 hour and then put under high vacuum for 2 days to yield the (3R)-3-carbamimidamidobutanoic acid (21 9) as a white solid (879 mg, 83%) ; 1 H-NMR (300 MHz, D20) : 5 3.81 (m , 1 H), 2.31 (m, 2H), 1 .15 (d, 3H) ; ES(pos)MS m/z 146.1 (M+H+).
Put 240g methanol, 50g (R) -3-aminobutyric acid in the clean reaction bottle, cool with ice water, the temperature drops to 0 10 , and slowly add 66.4g sulfoxide chloride dropwise. After the dropwise addition, the temperature was raised to reflux reaction until the raw materials disappeared.The reaction solution is directly concentrated under reduced pressure to obtain the product.Yield: 98.5%, purity: 99.7%, ee: 99.9%.
With sodium hydroxide; In methanol; water; at 20℃; for 72.0h;
Synthesis of Compound 219 (/=?)-Aminobutyric acid SM01 (750 mg, 7.27 mmol) and 2-methyl-2-thiopseudourea sulfate (MTS, 1 .21 g, 4.36 mmol) were suspended in methanol (4 mL). After addition of 3N sodium hydroxide in water (2.62 mL, 1 .09 eq.), the clear solution was stirred for 3 days at room temperature. Subsequently, the white precipitate was filtered off and washed with water/methanol (15 mL, 1 /2). The white powder was air dried for 1 hour and then put under high vacuum for 2 days to yield the (3fi)-3-carbamimidamidobutanoic acid (219) as a white solid (879 mg, 83%); 1 H-NMR (300 MHz, D20): 5 3.81 (m, 1 H), 2.31 (m, 2H), 1 .15 (d, 3H); ES(pos)MS m/z 146.1 (M+H+).
(3R)-3-[(pyridin-2-yl)amino]butanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃;Sealed tube; Inert atmosphere;
Synthesis of Compound 223 2-chloro-pyridine (25 mmol), palladium (II) acetate (2.5 mmol), racemic 2,2'-bis(diphenylphosphino)- 1 ,1 '-binaphthyl (2.5 mmol) and cesium carbonate (65 mmol) are dissolved in toluene (75 mL) in a previously degassed sealed vessel. The mixture is flushed with nitrogen gas. Methyl-^-S-aminobutyrate SM01 (20 mmol) is added to the solution under nitrogen and the sealed mixture is heated overnight at 100 C. The reaction is cooled to room temperature, diluted with diethyl ether and washed with pH 7 buffer and water. The organic layer is concentrated and purified by silica gel column chromatography (10:90 methanol- dichloromethane) to afford (3/:?)-3-[(pyridin-2-yl)amino]butanoic acid (223).
With sodium tetrahydroborate; trifluoroacetic acid; In tetrahydrofuran; at 20℃;Inert atmosphere; Cooling with ice;
Under a nitrogen atmosphere, 120 g of sodium borohydride and 124 g of (R)-3-aminobutyric acid were placed in a reaction flask, 1.5 L of tetrahydrofuran was added, and the mixture was cooled with ice water. 506 g of trifluoroacetic acid was slowly added dropwise to the reaction flask, and the tail gas was absorbed by a sodium hydroxide solution. After the completion of the dropwise addition, the temperature was raised to 20 C until the starting material disappeared. The reaction was quenched by the addition of sodium hydroxide solution, and the layers were allowed to stand, and the organic phase was distilled to recover tetrahydrofuran. The aqueous phase was extracted with chloroform, and the combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. Yield: 84.3%, purity: 99.5%, ee: 99.6%.
54%
With sodium tetrahydroborate; zinc(II) chloride; In tetrahydrofuran; at 20 - 60℃; for 3.5h;Autoclave;
To a 50 L autoclave, 13 L of anhydrous tetrahydrofuran and 1067 g of anhydrous zinc chloride (with little exotherm) were added, Carefully add 590 grams of sodium borohydride (note the heat and gas). Stirred at room temperature for 30 minutes and then warmed to 50 to 60 C for 3 hours. After cooling to room temperature, 1280 g of a white solid obtained above was added in portions and the temperature was controlled at 10 to 40 C. After the addition was complete, the temperature was slowly raised to reflux for 24 hours. The system was turned into a gray suspension system, cooled to 10-15 C, and 640 ml of methanol and 200 g of 40% aqueous sodium hydroxide solution were slowly added dropwise and the temperature was controlled at 10 to 40 C. After adding, stir at room temperature for 3 to 5 hours. Filtered, washed with THF and filtered to give a colorless liquid; Distillation distillation (10 to 65 C) Get a transparent viscous liquid R-3-aminobutanol 495 g, yield 54%. Purity 99.2%, 99.3%.
With hydrogenchloride; In water; at 95 - 100℃; for 12.0h;Industrial scale; Green chemistry;
A 20 L four-necked reaction flask equipped with a mechanical stirrer, reflux condenser, thermometer was charged with Example 4 The resulting (R) -3-acetamidobutyric acid ethyl ester was 1750 g and 3650 g of water, 5500 grams of concentrated hydrochloric acid (concentrated hydrochloric acid in the hydrogen chloride content of 36%), Heated to 95 ~ 100 C for 12 hours. Steamed under reduced pressure, to the reaction solution near dry, cooled to 30 ~ 40 C by adding 3.4L acetone beating; precipitation of solid, filtration, acetone leaching, drying about 1200 grams of white solid. The white solid and 1.5 liters of anhydrous tetrahydrofuran were added to a 10-liter round bottom flask and stirred. After cooling, 660 g of a 50% aqueous solution of sodium hydroxide was added dropwise and the temperature was controlled at 10 to 50 C. After completion of the dropwise addition, the milky white syrup was passed off, cooled to room temperature, filtered, the solid was washed with a small amount of THF, The resulting solid blast was dried (60 C) to give about 1280 g of a white solid.
(1) (R)-3-aminobutyric acid (70 g, 0.68 mol) was dissolved in methanol (1.0L), the ice-water bath was cooled to T <20 C, the dropwise addition of thionyl chloride (97g, 0.82mol), the end of the reaction, the natural reaction overnight, 40-50 C the reaction solution was concentrated to dry oil 99g, yield 95%.
With sodium carbonate; In water; at 25℃;Green chemistry;
Sequentially put 103g of R-3-aminobutyric acid,105g sodium carbonate,218g di-tert-butyl carbonate,Add to the reaction flask containing 500 mL of water,React at 25 C for 2-6 hours,After the reaction is completed, adjust the pH to 3-4 with 2N hydrochloric acid.The product was extracted twice with 500 mL of ethyl acetate.Spin dry,That is, N-Boc-(R)-3-aminobutyric acid (I),The white solid was 190 g, the yield was 93.5%, and the content was 98% (HPLC method).
(R)-3-benzamidobutanoic acid ethyl ester[ No CAS ]
[ 3775-73-3 ]
Yield
Reaction Conditions
Operation in experiment
95%
With hydrogenchloride; In water; for 3.0h;Reflux;
In a 1000ml clean reaction bottle,Add 150 g of (R)-3-benzamide-butanoic acid ethyl ester material at room temperature.Concentrated hydrochloric acid 300g,Industrial water 300g,Heated back to reflux for 3 h,The TLC detected that the starting material was completely reacted (the developing solvent was n-hexane: ethyl acetate = 2:1).The reaction was completed, cooled to room temperature, filtered to remove impurities, and the filtrate was extracted with dichloromethane.(The developing solvent was n-hexane: ethyl acetate = 2:1). The water layer is distilled under reduced pressure to obtain an oil.The oil is dissolved in methanol, and the water is removed by anhydrous sodium sulfate, and the temperature is lowered to 15 C.Add sodium hydroxide to neutral,Filter and concentrate the filtrate to an oil
With thionyl chloride; In ethanol; at 0 - 30℃;Inert atmosphere;
Under nitrogen protection,2000 ml of absolute ethanol and 200.0 g (1.94 mol) of R-3-aminobutyric acid (material II) were charged into a 3 L reactor.Stir well; cool down and control temperature to 0-10 C,509.2 g (4.28 mol, 2.2 N) of thionyl chloride was added dropwise.After the dropwise addition, the temperature is raised to 20 to 30 C, and the reaction is kept overnight.The TLC detected until the material II material point disappeared (developing agent: ethyl acetate: methanol = 2:1).After the reaction was completed, distillation under reduced pressure gave a pale yellow concentrate (322.5 g).Yield: 99.2%.
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