(3R)-3-Amino-1-butanol

Colorless Liquid

1.2 Release of (R)-3-amino-1-butanol From the (S)-mandelic Salt Thereof; The (S)-mandelic salt of (R)-3-amino-1-butanol obtained in Example 1.1 (372 g, 1.54 mol) was suspended in triethanolamine (1 I) at 80° C., and the slurry was admixed with sodium methoxide (277.6 g, 1.54 mol; 30percent in methanol), which gave a clear solution. This was heated to 100° C. and vacuum was applied. In a stepwise manner, a pressure of 750, 500, 250, 100, 50 and finally 20 mbar was applied. Through an attached Claisen distillation head (no return stream, no column), a clear distillate distilled over at a top temperature of 50 to 60° C., which was predominantly methanol. The pressure was then lowered further to 5 mbar, and (R)-3-amino-1-butanol distilled over at a top temperature of 76° C. The product was distilled once again in a water jet pump vacuum, in the course of which (R)-3-amino-1-butanol distilled over at 93° C. and 26 mbar. This gave 125 g (91percent of theory) of (R)-3-amino-1-butanol as a colorless liquid with an optical purity of 99.6percent ee.The optical purity of (R)-3-amino-1-butanol was determined by means of GC. To this end, (R)-3-amino-1-butanol (200 mg) and triethylamine (300 mg) were dissolved in diethyl ether (15 ml) and admixed with trifluoroacetic anhydride (0.6 ml). After stirring for 30 minutes, saturated ammonium chloride solution (5 ml) was added and the mixture was stirred for a further 15 minutes. Subsequently, the mixture was left to stand until two phases had formed, and a sample of the upper clear phase was analyzed by GC.Column: Hydrodex-TBDAc, 25 m.x.0.25 mm, Macherey NagelInlet temperature: 250° C.Detector temperature: 250° C.Injection volume : 0.5 μlMode: SplitSplit ratio: 100:1Carrier gas: HeFlow: 0.8 ml/min (constant flow)Program:Initial temperature: 135° C.Initial time: 10 minRate: 5° C./minFinal temperature: 170° C.Final time: 35 minRetention times:R enantiomer: 17.68 min (N-trifluoroacylated) 21.23 min (N, O-bis-trifluoroacylated)S enantiomer: 18.24 min (N-trifluoroacylated) 20.11 min (N, O-bis-trifluoroacylated)The obtained product R-3-aminobutanol-S-mandelate was added into methanol (300 mL), and then a methanol solution (200 mL) dissolved with sodium methoxide (50 g) was slowly added and reacted at room temperature for 2 h, The reaction solution was concentrated, and further ethyl acetate (500 mL) was added. The reaction solution was filtered and the ethyl acetate was distilled off under reduced pressure to obtain the target product R-3-aminobutanol (35 g, 0.393 mol).The compound of formula II (65 g) was dissolved in 510 mL of methylene chloride and cooled to 0 to 10 ° C. 47 g of trifluoroacetic acid was slowly added dropwise to the system. The temperature was kept until the conversion of the raw material was completed. Sodium hydroxide solid , The system pH adjusted to 9 ~ 10, too Filtration, concentration and distillation gave 29.3 g of (R) -3-aminobutanol, yield 95.8percentTake 50g N-Boc-(R)-3-aminobutanol, dissolved in 350mL of concentrated hydrochloric acid / methanol system, the reaction for 6 hours at 25 °C, the GC detects completion of the reaction starting material, 54g of potassium carbonate was added, stirred for 1 hour, filtered The filtrate was concentrated and distilled under reduced pressure to give a product, m.p., 21 g, yield: 90percent, purity 99percent, ee.To a solution of (R)-tert-butyl(4-hydroxybutan-2-yl) carbamate (1.3 g, 6.87 mmol) in methanol (30 mL) was added HC1 (30 mL, 4M in MeOH), stirred at 25°C overnight, concentrated to afford the title compound (0.5 g).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.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.Procedures and post-treatment in the same manner as in Example 11, by a 60g 3 (R) - amino butyric acid methyl ester hydrochloride, 42g 300mL methanol and potassium borohydride, a reduction reaction, to give 3 (R) - amino-1- (IV), colorless viscous liquid, 26.4 g, yield 76percent, ee value 99.4percent, content 99.2percent (GC method) Example 9Hydrogenation of Methyl (R)-3-aminobutanoate A ruthenium complex 1 (0.333 mmol) was charged into a 100-mL autoclave equipped with a stirrer, and air inside the autoclave was replaced with nitrogen. Tetrahydrofuran (40 mL) and methyl (R)-3-aminobutanoate (100 mmol, 99percent ee or more) were charged thereinto. Then, the mixture was subjected to hydrogenation at a hydrogen pressure of 3.5 MPa to 5 MPa at 80° C. for 14 hours. The reaction liquid was concentrated, and the obtained residue was distilled. Thus, (R)-3-aminobutanol (7.39 g; boiling point of 84 to 86° C./14 Torr) was obtained. The obtained alcohol had an optical purity of 99percent ee or more.A mixture of 0.9 gm enzyme ECS-ATA-134 and 7.5 ml PLP solution was added to asol uti on of phosphate buffer (15 ml, of example 2), secondary butyl amine (20 ml) andmagnesium chloride (5 ml) followed Li addition of a substrate solution (0.6 gm 4-Hydroxy butanone in S ml Dimethyl sulfoxide). The reaction mixture was stirred at 1Sfor 24 hours. The reaction mixture was extracted with ethyl acetate and the solvent wasremav’ed by distillation to obtain (R)-3-aminobutan-1 -ol. Y ield: 0.45 gm, 100percent R-isomer.The purity was measured directly by gas chromatography. Measurement: The 3-aminobutanol was first reacted with benzyloxycarbonyl chloride in aqueous sodium hydroxide to form N-Cbc-3-aminobutanol and then detected by liquid phase. Column AD-H; Flowable n-hexane: isopropanol (9: 1); flow rate, 1 ml / min. Detection wavelength, 210 nm. Retention time, S-isomer, 11.1 min, R-isomer for 12.2 minutes.49.03 g of the compound III in the third step is dissolved in 500.0 mL of acetonitrile, and 17.2 g of SM2 (R-aminobutanol) and 3.87 g of formic acid are added under stirring to prepare a mixed solution. The reaction was carried out at 62 C for 13 to 14 hours. The reaction liquid was removed under reduced pressure, and 100.0 mL of acetonitrile was added to the residue, and then distilled under reduced pressure to give 60.0 g of an oily compound.Specifically, the method for synthesizing compound IV is as follows: 49.03 g of compound III in step 3 is dissolved in 500.0 mL of acetonitrile, and 17.2 g of SM2 (R-aminobutanol) and 3.87 g of formic acid are added under stirring to make a mixed solution. The reaction was performed at 62 C for 13 to 14 hours. The reaction solution was removed under reduced pressure, 100.0 mL of acetonitrile was added to the residue, and distillation under reduced pressure was performed to obtain 60.0 g of an oily substance, which was Compound IV.To a stirred solution of 1 .6 g (18 mmol) (/^-S-aminobutan-l -ol in 30 mL of xylene was added 2.8 g (19 mmol) of 1 , 3-dihydro-2-benzofuran-1 , 3-dione at rt. The mixture was stirred at 140 C overnight and cooled to rt. It was diluted with 100 mL of ethyl acetate, washed with 50 mL of saturated NaHC03solution and 50 mL of 10 % citric acid solution. The organic phase was dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure to afford crude compound 9, which was used in the next step directly without further purification. LC-MS: m/e = 220 [M+H]+.Compound 4 (3.38 g, 107.24 mmol) was dissolved in 33 ml of acetonitrile.Add glacial acetic acid (3 ml) and methanesulfonic acid (0.21 ml, 3.24 mmol) in a 150 ml round bottom flask at room temperature.The reaction was heated to 60 C for 19 h; Compound 5 was obtained.(R)-3-Amino-1-butanol (1.44 ml, 1.34 g, dissolved in 2.25 ml of CH3CN) was slowly added dropwise to the above reaction solution.The reaction was continued to stir at 60 C for 18 h to give a white suspension.The reaction solution was concentrated to dryness under reduced pressure to give a concentrate.Add 25 ml of CH2Cl2 and 1N HCl (25 ml).The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 (25 ml x 2).The organic layers were combined and concentrated to dryness under reduced pressure to give crude 6 2.2g.The crude product was recrystallized from 15 ml of MeOH/petroleum ether = 6/1 solvent.After filtration and drying, a pale yellow solid product of compound 6 was obtained, 1.72 g.(Rf=0.42, TLC developing agent: CH2Cl2/MeOH=20/1+0.5% HOAc), The yield was 52% and the HPLC purity was 95.3%.A solution of l-(2, 2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-l, 4- dihydropyridine-3 -carboxylic acid (V) in acetic acid / Dimethyl carbonate ( 5.0Kg, 15.8 moles) and methane sulfonic acid (533.0 g, 5.6 moles) were introduced in micro channel reactor. After residence time of 9 mins at l30C gives 5-methoxy- 6-(methoxycarbonyl)-4-oxo- 1 -(2-oxoethyl)- 1 , 4-dihydropyridine-3 -carboxylic acid (IVa). The reaction mixture was further introduced in a Tube Flow reactor and cyclised with solution of R-3 amino butanol ( 1.97 kg, 22.2 moles) in Dimethyl carbonate at l00C at a residence time of 5.15 mins followed by quenching with Aq HC1 solution. The organic layer containing (4S, l2aR)-7-methoxy-4-methyl- 6, 8-dioxo-3, 4, 6, 8, l2, l2a-hexahydro-2H-pyrido[r, 2':4, 5]pyrazino[2, l- b][l, 3]oxazine-9-carboxylic acid (III) was separated and introduced in a Tube Flow Reactor with a solution of N-Methyl Morpholine (2.25 Kg, 22.22 moles) and a solution of 2, 4-diflurobenzylamine(3.l8 kg, 22.2 moles) in MDC solvent and reacted in presence of Ethyl chloroformate (1.73 Kg, 20.63 moles) at 0C. After a residence time of l. l5mins yields (4S, l2aR)-N-(2, 4-Difluorobenzyl)-7-methoxy- 4-methyl-6, 8-dioxo-3, 4, 6, 8, l2, l2a-hexahydro-2H-pyrido[r, 2':4, 5]pyrazino[2, l- b][l, 3]oxazine-9-carboxamide (Ila) which was isolated in IPA after acid base workup. (0250) HPLC purity: 99.0% (0251) Yield: 80.0%.

Molecular Weight:89.14
XLogP3:-0.6
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:89.084063974
Monoisotopic Mass:89.084063974
Topological Polar Surface Area:46.2
Heavy Atom Count:6
Complexity:30.7
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes