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Structure of 2749-11-3 * Storage: {[proInfo.prStorage]}
* 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] Green Chemistry, 2012, vol. 14, # 8, p. 2137 - 2140
4
[ 50-00-0 ]
[ 2749-11-3 ]
[ 2812-31-9 ]
Reference:
[1] Journal of Medicinal Chemistry, 1975, vol. 18, p. 292 - 300
5
[ 2749-11-3 ]
[ 100-52-7 ]
[ 6940-80-3 ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: With magnesium sulfate In dichloromethane at 25℃; for 19 h; Stage #2: With sodium tetrahydroborate In methanol at 0 - 25℃; for 18 h;
Step 1: (S)-Alininol (17.5 g, 233 mmol), PhCHO (26 g), and MgSO4 (70 g) were taken up in DCM and stirred at 25 0C for 19 h. The solution was filtered and concentrated which furnished a yellow solid. The residue was taken up in MeOH and cooled to O 0C. Sodium borohydride (11 g, 288 mmol) was added in portions to the solution at 0 0C (gas evolution). After the addition, the solution was stirred at 25 0C for 18 h. The solution was concentrated, and the residue was quenched carefully with 3 M HCI (aq.) (gas evolution/exotherm). The aqueous acidic layer was extracted with Et2O (4 X 200 ml_). The aqueous layer was cooled to 0 0C and made basic via addition of NaOH pellets (pH = 11 -12). The aqueous layer was extracted with DCM. The combined DCM layers were dried (MgSO4). Filtration and concentration gave 23.2 g (60percent) of the amino-alcohol as a white solid.
Stage #1: With sodium hydride In toluene Stage #2: at 20℃; Reflux Stage #3: With potassium fluoride In N,N-dimethyl-formamideReflux
step 1, 2.6 g of sodium hydride, 50 ml of toluene and 8.8 g of ethyl acetate were sequentially placed in the reaction flask.Stir until it is gray and turbid.Then, 8.8 g of ethyl formate was slowly added dropwise, and stirring was continued while the bubbles were released.After the reaction was completed, it was filtered under reduced pressure, and the cake was dried in vacuo.Obtaining white formyl ethyl acetate sodium salt; Step 2. Add to the flask containing 50 ml of tolueneSodium formylacetate sodium salt 5.5gAnd ZIF-67ZnCoZIF catalyst 1.5g,Slowly add 7.7 g of 2,3,4,5-tetrafluorobenzoyl chloride at room temperature.After the reaction is completed, slowly add S-(+)-2-aminopropanol dropwise3.2g, heated to reflux,After the reaction is completed, a water layer is added, the water layer is extracted with toluene, the organic layers are combined, and toluene is distilled off to obtain a preliminary product; Step 3.The obtained initial product was slowly added dropwise to 30 ml of a DMF solution containing 5.8 g of KF, stirred, heated to reflux, and azeotropically dehydrated.After completion of the reaction, the solvent was evaporated, and washed with water to give a brown-yellow viscous solid.Drying to get the intermediate(S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7-hydropyrido[1,2,3-de][1,4 ] Benzoxazine-6-carboxylic acid ethyl ester.
Reference:
[1] Patent: CN108440562, 2018, A, . Location in patent: Paragraph 0008; 0010-0015; 0016-0018; 0029
8
[ 2749-11-3 ]
[ 124-38-9 ]
[ 4042-35-7 ]
Yield
Reaction Conditions
Operation in experiment
36%
With caesium carbonate In dimethylsulfoxide-d6 at 25 - 150℃; for 24 h; Autoclave
General procedure: To a DMSO-d6 (1 mL) solution of cesium carbonate (33 mg, 0.1 mmol) in a Teflon tube was added (S)-1b (78 μL, 1 mmol). The Teflon tube containing the reaction mixture was fitted into a 30 mL autoclave. The autoclave was frozen with liquid nitrogen (–196 °C) prior to connecting to a vacuum line for air removal. After the mixture was evaporated under vacuum at –196 °C and warmed up to room temperature, CO2 was filled into the autoclave (3 atm). The autoclave was stirred at 150 °C for 24 h. Upon completion, the reaction mixture was subjected to 1H NMR for crude product yield determination, which calculated based on the ratio between product and internal standard (N,N-dimethylformamide). After that, DMSO-d6 was removed through distillation under vacuum conditions; the syrupy product was then purified by column chromatography on silica gel (hexane/ethyl acetate 3:1) to give the product (S)-4-methyloxazolidin-2-one (S)-2b as colorless oil with an isolated yield of 36percent (36.4 mg, 0.36 mmol).
Reference:
[1] Journal of the American Chemical Society, 1989, vol. 111, # 6, p. 2211 - 2217
[2] Journal of Molecular Catalysis A: Chemical, 2011, vol. 338, # 1-2, p. 33 - 43
With sodium carbonate In 1,4-dioxane; water at 0 - 20℃;
To a mixture of (S)-2-aminopropan-l-ol (2 g, 26.6 mmol) and Na2C03 (5.6 g, 53.2 mmol) in 1,4-dioxane and water (25 mL / 25 mL) at 0 °C was added FmocCl (10.2 g, 39.9 mmol) and the resulting mixture was then warmed to room temperature gradually. After the amine was consumed completely as indicated by TLC, water (25 mL) was added. The mixture was extracted with DCM (3 x 50 mL). The organic phase was washed with brine (50 mL), and dried over anhydrous Na2S04. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (7.1 g, 90percent).
With sodium hydrogencarbonate; sodium carbonate In water; acetone
General procedure: Suitable N-protected amino alcohols (e.g. Fmoc and boc) can be obtained by reacting an amino alcohol with a desired protecting group precursor that protects the amine group with the desired protecting group Pgi . For example, N-Fmoc protected amino alcohols were prepared (in an Erlenmeyer flask) by suspending/dissolving Fmoc-O-Su in acetone (in a ratio of about 2.5-6 mL acetone per mmol of Fmoc-O-Su) with stirring. To this briskly stirring solution was added dropwise a solution of the amino alcohol (in a ratio of about 1 to 1 .2 eq. per mmol of Fmoc-O-Su) dissolved in acetone (in a ratio of about 0.4- 1 .2 mL acetone per mmol of the amino alcohol) and occasionally some water if the amino alcohol is not completely soluble in the acetone alone. When addition was complete, a solution containing NaHC03 and Na2C03 (in a ratio of about 1 to 1 .1 mmol NaHC03 and 0.5 to 0.55 mmol Na2C03 per mmol of Fmoc-O-Su) dissolved in deionized water (in a ratio of about 1 mL deionized water per 1 mL of acetone originally added to the Fmoc-O-Su) was added dropwise to the stirring reaction. After stirring and analysis by TLC (indicating complete reaction), a solution containing enough HCI (dissolved in about 0.3 mL water per 1 mL of acetone originally added to the Fmoc-O-Su) to completely neutralize the NaHC03 and Na2C03 was added dropwise over 30 minutes to one hour. The pH of the solution was then adjusted to approximately 4-5 (pH paper) by addition of 1 N HCI. The flask was then heated on a hot plate stirrer until the solid dissolved. The solution was then allowed to cool overnight and the product crystallized. The crystalline product was then collected by vacuum filtration. The product was then optionally recrystallized (usually by a mixture of acetonitrile and water) to the desired level of purity.
Stage #1: With sodium hydride In toluene at 0 - 20℃; for 0.5 h; Stage #2: for 20 h; Heating / reflux Stage #3: With ammonium chloride In toluene at 20℃; for 0.333333 h;
Step A: A solution of (S)-(+)-2-amino-1-propanol (5.0 g, 67.0 mmol) in toluene (60 mL) was added dropwise at 0° C. to a stirred suspension of NaH (60percent in mineral oil, 6.2 g, 145 mmol) in toluene (150 mL). The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 min. A solution of ethyl chloroacetate (8.0 mL, 73.8 mmol) in toluene (60 mL) was then added dropwise at room temperature and the resulting reaction mixture heated at reflux for 20 h. The reaction was cooled to room temperature and solid NH4Cl (5 g, 96.7 mmol) added to the reaction. The reaction mixture was stirred for 20 min, filtered and the filtrate concentrated under reduced pressure. Purification by column chromatography (silica gel, 94.5:5:0.5 CH2Cl2/CH3OH/NH4OH) afforded (S)-5-methylmorpholine-3-one (6.5 g, 84percent) as an off-white semi-solid. 1H NMR and MS consistent.
Reference:
[1] Patent: US2008/255114, 2008, A1, . Location in patent: Page/Page column 17
[2] Journal of Organic Chemistry, 1996, vol. 61, # 15, p. 4990 - 4998
16
[ 2749-11-3 ]
[ 79-04-9 ]
[ 119844-66-5 ]
Yield
Reaction Conditions
Operation in experiment
9 g
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1 h; Inert atmosphere
In the reaction flask,L-aminopropanol (7.5 g, 0.1 mol) was added to DMF (30 mL)After completely dissolving,Sodium hydride (50 wtpercent) (5 g, 0.10 mol) was added thereto at 0 & lt; 0 & gt; C under nitrogen,Then rose to room temperature,After stirring for 1 h, chloroacetyl chloride (11 g, 0.1 mol) was added,Reaction overnightTLC monitoring raw material reaction is complete,Saturated sodium chloride solution (500 mL) was added to the reaction solution,And extracted twice with ethyl acetate (400 mL)Combine organic phase,To the organic phase slowly dropping dilute hydrochloric acid solution,Gradually solid precipitation,When the pH of the reaction solution was 11,The precipitation of solids to achieve the most,The filter solution was filtered and the cake was dried to give (S) -3 methyl morpholinone hydrochloride,(S) -3-methylmorpholinone hydrochloride was added to methanol (50 mL)And then slowly dropping dilute hydrochloric acid solution,Solid gradually dissolved,After being completely dissolved, the solvent methanol was distilled off, the reaction solution was extracted with ethyl acetate,The organic phases were combined and concentrated to give 9 g of pale yellow liquid (S) -3 methylmorpholinone.
Reference:
[1] Patent: CN106749081, 2017, A, . Location in patent: Paragraph 0013; 0014; 0015
17
[ 2749-11-3 ]
[ 542-58-5 ]
[ 119844-66-5 ]
Yield
Reaction Conditions
Operation in experiment
17%
Stage #1: With sodium hydride In tetrahydrofuran for 0.583333 h; Stage #2: for 3.5 h; Heating / reflux
[Example 105] (+)(3S)-4-[1-(6-Methoxypyridazin-3-yl)-5-(2-pyridyl)-1H-pyrazole-3-carbonyl]-3-methylmorpholine [Show Image] 1) (5S)-5-Methyl-3-morpholinone Sodium hydride (55percent, 0.409 g) was added to a solution of (2S)-2-amino-1-propanol (0.665 mL) in tetrahydrofuran (100 mL), and the resultant mixture was stirred for 35 minutes. Chloroethyl acetate (0.900 mL) was added to the reaction solution, and the mixture was stirred for 30 minutes, and then heated to reflux for 3 hours. After air cooling, the reaction solution was filtered, and a residue obtained by evaporating the solvent of the filtrate under reduced pressure was purified by silica gel column chromatography (ethyl acetate-n-hexane), to obtain a crude product of (5S)-5-methyl-3-morpholinone (0.170 g, 17percent) as an amorphous material.
With sulfuric acid; In water; at 50 - 110℃; for 2.5h;
Example 1 (2S)-l-(Methylthio)propan-2-amine 75 g (1 mol) of (2S)-2-aminopropanol (L-Alaninol) and 1 mol Of H2SO4 as 80 % (w/w) aqueous solution were mixed together under cooling to keep the temperature below 50C. The formed solution was dried in the vacuum oven at 1 1O0C for 2.5 h to give 155 g of a white solid, of (2S) - 2- ammoniopropylsulfate, corresponding to a yield of 100 %. M. p. 260-2630C.1H NMR (d6-DMSO): delta 1.2 (d, 3H), 3.4 (m, IH), 3.6-3.8 (d.m. ABXsystem, 2 H), 7.8 (broad .s., NH3) ppm.
95%
With chlorosulfonic acid; In acetonitrile; at 25 - 40℃;
Example 2: (2S)-l-(Methylthio)propan-2-amine 75 g (1 mol) of (2S)-2-aminopropanol (L-Alaninol) and 1 mol of HSO3CI were mixed together in 300 ml acetonitrile under cooling to keep the temperature below 25C. The formed precipitate was filtered off and dried in the vacuum oven at 40C to give 147 g of (2S)-2-ammoniopropylsulfate as a white solid, corresponding to a yield of 95 %. M.p. 260-2630C.1H NMR (d6-DMSO): delta 1.2 (d, 3H), 3.4 (m, IH), 3.6-3.8 (d.m. ABXsystem, 2 H), 7.8 (broad .s., NH3) ppm.
With chlorosulfonic acid; In 1,2-dimethoxyethane; at 0℃; for 2h;
General procedure: Different 2-aminopropan-1-ols (1, 4, and 7) (20 mmol) were added to anhydrous 1,2-dimethoxyethane (20 mL) below 0C, and then chloronic sulfonic acid (34.960 g, 30 mmol) was dropwise added to the above mixture. After stirring for 2 h, the reaction was filtered and washed with anhydrous ethanol to afford the white solid 2-ammoniopropyl sulfates (2, 5, and 8). And then different 2-ammoniopropyl sulfates was dropwise added to the mixture of sodium methyl mercaptan (20% aq, 14 g, 40 mmol) and sodium hydroxide (1.6 g, 40 mmol). The reaction was stirred at 90C for 3 h, and then extracted with dichloromethane (30 ml). The organic layer was dried with anhydrous sodium sulfate and evaporated to obtain 1-(methylthio)propan-2-amines 3, 6, and 9 as light yellow oil.
With triethylamine; In methanol; at 0 - 20℃; for 12h;
To a solution of (S)-(+)-2-amino-l-propanol (2.00 g) and triethylamine (4.27 mL) in MeOH (20 mL) at 0 C, di-tert-butyl dicarbonate (6.42 g) was added. After stirring at room temperature for 12 h, the solvent was evaporated. The residue was diluted with CH2CI2, washed with water and the organic phase was evaporated to dryness to give (S)-2-(tert- butoxycarbonyl)amino-l-propanol (4.6 g, 100%) which was used without further purification in the next step. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): 5 6.40 (IH, d), 4. 51 (IH, m), 3.64 (IH, m), 3.10 (IH, m), 3.34 (IH, m), 1.46 (9H, s), 1.02 (3H, d).
99%
In dichloromethane; at 20℃; for 4h;
Commercially available (5)-2-aminopropan-l-ol (2.Og) was dissolved in CH2Cl2 (20 5 ml) and Boc2O (6.4g) was added. After stirring for 4h at room temperature the solvent was removed to afford the title compound (4.7 g, 99 %).1H-NMR delta (CDCl3): 1.10 (s, 3H), 1.50 (s, 9H), 2.40 (s, IH), 3.45-3.70 (m, 2H)5 3.75-3.80 (m, IH), 4.80 (s, IH).
97%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 6h;Inert atmosphere;
General procedure: (Boc)2O (2.10 g, 12 mmol) was added to a solution of amino alcohol (10 mmol) and diisopropylethylamine (DIPEA) (1.44 g, 12 mmol) in THF(40 mL) under N2 protection at 0 C. The mixture was stirred for 6 h at room temperature, then the solvent was removed under reduced pressure and the resulting residue was dissolved in 100 mL ethyl acetate. This solution was washed twice with 100 mL of water, once with 100 mL of saturated aqueous sodium chloride, dried over Na2SO4 and concentrated under reduced pressure to give product L-3 or L-4 as yellow oil. L-3: 1.70 g, yield 97%; = -8.4 (c 0.05, CHCl3); 1H NMR(CDCl3): delta 4.71 (s, 1H), 3.69-3.60 (m, 1H), 3.57-3.42 (m, 2H), 2.21 (s, 1H), 1.36 (s, 9H), 1.12 (d, J = 6.4 Hz, 3H).
87%
With copper; In neat (no solvent); at 20℃; for 0.166667h;
General procedure: To a mixture of amine (1.0 mmol) and (Boc)2O (1.2 mmol), copper nano particles (0.1 mmol) was added with vigorous stirring at room temperature or 70 oC for the appropriate time (Scheme 2 and Table 2) until disappearance of the precursor amine was observed in the TLC. After completion, the reaction mixture was diluted with dry ether (5 mL) and catalyst was separated by filtration and the residue was washed with ether. The combined filtrate was evaporated to dryness and dried under vacuum. The N-Boc product is essentially pure on TLC but for getting analytical data the sample was passed through silica-gel (100-200 mesh) column using 10-30% ethyl acetate in hexane as eluent. The physical data (m.p., FTIR, NMR) of the known compounds were found to be identical with those reported in the literature.
75%
In dichloromethane; at 0 - 25℃;
To a solution of L-alaninol (1.0 equiv.) in dichloromethane (10 times) was added di-tert-butyl dicarbonate (1.1 equiv.) slowly at about 0C to 5C. The reaction mixture was allowed to stir for about 3 hours at ambient temperature. After completion, the reaction mixture was diluted with dichloromethane and washed with water, brine, dried over anhydrous sodium sulphate and evaporated in vaccuo to get the desired product as a white solid. Yield: 75%
In dichloromethane; at 20℃; for 2h;
Example 21 N-[(1S)-2-(3-fluorophenoxy)-1-methylethyl]-N'-(isoquinolin-5-yl)urea TFA salt Step 1: t-butyl (1S)-2-hydroxy-1-methylethylcarbamate; To L-alaninol (5 g) were added di-t-butyl dicarbonate (17 g), triethylamine (9 ml) and dichloromethane (100 ml), and the mixture was stirred at room temperature for 2 hrs. The mixture was diluted with dichloromethane and, after washing with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane) to give the title compound (5.9 g).
With triethylamine; In tetrahydrofuran; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
(1-1) Production of t-butyl (S)-(2-hydroxy-1-methylethyl)carbamate 13.8 g of triethylamine was added to 100 ml of a tetrahydrofuran solution containing 10.0 g (133 mmol) of L-alaninol. Thereafter, 30.0 g (137 mmol) of di-t-butyl dicarbonate was added dropwise to the obtained mixture while cooling in ice water. The temperature of the reaction solution was returned to room temperature, and it was then stirred for 12 hours. Thereafter, the reaction solution was poured into ice water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, so as to obtain 24.0 g of t-butyl (S)-(2-hydroxy-1-methylethyl)carbamate. Yield: Quantitative Physical properties: [1H-NMR, CDCl3, delta (ppm)] 4.62(br, 1H), 3.77(br, 1H), 3.64(br, 1H), 3.49(br, 1H), 2.54(br, 1H), 1.44(s, 9H), 1.14(d, 3H).
In tetrahydrofuran; at 0 - 25℃; for 1.5h;
10.50 g (140 mmol) of (S)-(+)-2-amino-1-propanol was dissolved in 110 ml of THF and cooled at 0 C. A solution of 30.2 (139 mmol) of di-tert.-butyldicarbonate in 45 ml of THF was added in drops to this stirred solution. The reaction mixture was stirred for 90 minutes at 25 C. and concentrated by evaporation in a rotary evaporator. The residue was taken up in 300 ml of diethyl ether and then washed with 90 ml of 0.01 M HCl solution. The organic phase was dried by means of sodium sulfate and concentrated by evaporation in a rotary evaporator and at the oil pump. The crude product (20.4 g) was used without further purification for the following reaction.
With triethylamine; In dichloromethane; at 20℃; for 2h;
Di-t-butyldicarbonate (17 g), triethylamine (9 mL) and dichloromethane (100 mL) were added to L-alaninol (5 g) and stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and washed with water, and the organic layer was dried over anhydrous magnesium sulfate. After removing the solvent, the obtained crude material was purified with silica gel column chromatography (ethyl acetate-hexane) to obtain 5.9 g of the title compound.
With triethylamine; In tetrahydrofuran; at 20℃; for 3h;
Example 14Synthesis of: (65',9/?,13/?)-9-amino-13-(dodecanoyloxy)-6-methyl-8,16-dioxo-4,15-dioxa-l l-thia-7- azaheptacosylphosphonic acidStep 1: (S)-tert-butyl l-hydroxypropan-2-ylcarbamate[000465] To a solution of (5')-2-aminopropan-l-ol (1 eq) in THF (0.3 M) at room temperature was added di-½ri-butyl carbonate (1 eq) and triethylamine (1 eq). The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated en vaccuo; and the residue was diluted in ethyl acetate. The organic solution was washed with water (2x), 1 : 1 saturated aqueous NH4CI, water and brine, dried over anhydrous MgS04, and concentrated en vaccuo. The material was carried onto the next step without further purification.
With triethylamine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;
Step 1. tert-Butyl[(1S)-2-hydroxy-1-methylethyl]carbamate (57) To a mixture of (S)-(+)-2 amino-1-propanol 56 (3.76 g, 50 mmol) and triethylamine (6.97 mL, 50 mmol) in THF (70 mL) at 0 C. under nitrogen was added dropwise di-tert-butyl dicarbonate (10.91 g, 50 mmol) in THF (30 mL). The mixture was stirred at room temperature for 2 h. Solvent was evaporated off. Residue was dissolved in ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and evaporated to provide 57 (crude, 8.29 g, 95%) as a white solid which was used in the next step without purification. 1H NMR (400 MHz, CDCl3): delta 1.15 (3H, d, J=6.8 Hz), 1.46 (9H, s), 3.42-3.61 (3H, m), 3.75 (1H, br s), 4.94 (1H, br s). MS (ES+): m/z [M+H]+ calcd for C8H17NO3: 176.23. Found: 175.96.
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;
To a mixture of (S)-(+)-2 amino-1-propanol 56 (3.76 g, 50 mmol) and triethylamine (6.97 mL, 50 mmol) in THF (70 mL) at 0 C under nitrogen was added dropwise di-te/f-butyl dicarbonate (10.91 g, 50 mmol) in THF (30 mL). The mixture was stirred at room temperature for 2 h. Solvent was evaporated off. Residue was dissolved in ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and evaporated to provide 57 (crude, 8.29 g, 95 %) as a white solid which was used in the next step without purification. 1H NMR (400 MHz, CDCl3): delta 1.15 (3H, d, J = 6.8 Hz), 1.46 (9H, s), 3.42-3.61 (3H, m), 3.75 (1 H, br s), 4.94 (1 H, br s). MS (ES+): m/z [M+H]+ calcd for C8H17N03: 176.23. Found: 175.96.
18.5 g
With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃; for 3h;
A mixture of (2S)-2-aminopropan-l-ol (compound I-18a, 10 g, 133 mmol) in dioxane (100 mL) and saturated aqueous NaHC03 solution (100 mL) was added Boc20 (29.1 g, 133 mmol) at 20 C. The mixture was stirred at 20 C for 3 hours, then extracted with EtOAc (100 mL) for 3 times. The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated to give compound I-18b (18.5g) as a yellow oil
In dichloromethane; at 0℃; for 16.5h;
To (S)-2-aminopropan-1-ol (2.1 g, 28.0 mmol) in DCM (60 ml) was added BOC2O (9.74 ml, 41.9 mmol) at 0 C. The mixture was stirred at 0 C for 30 mm, then allowed to warm up toroom temperature and stirred for 16h. The mixture was concentrated to give tert-butyl (S)-(1- hydroxypropan-2-yl)carbamate as colorless oil. ?H NMR (400 MHz, Chloroform-d) oe 4.64 (s, 1H), 3.77 (s, 1H), 3.64 (dd,J= 11.0, 3.8Hz, 1H), 3.51 (dd,J= 11.0, 6.2Hz, 1H), 1.45 (s, 9H), 1.27 (s, 1H), 1.15 (d,J= 6.8 Hz, 3H).
With triethylamine; In dichloromethane;
General procedure: L-amino alcohol (1 equiv), (Boc)2O (1.2 equiv) and trimethylamine(2 equiv) were added to dichloromethane. The mixture wasstirred under ice bath conditions. The reactionwas followed by TLCand diluted with dichloromethane. The organic phase was washedwith citric acid (1 N) and saturated NaHCO3 then dried over Na2SO4and filtered. The filtrate was concentrated and purified by a silicacolumn to afford compounds 10a-g.
Step 1: (S)-Alininol (17.5 g, 233 mmol), PhCHO (26 g), and MgSO4 (70 g) were taken up in DCM and stirred at 25 0C for 19 h. The solution was filtered and concentrated which furnished a yellow solid. The residue was taken up in MeOH and cooled to O 0C. Sodium borohydride (11 g, 288 mmol) was added in portions to the solution at 0 0C (gas evolution). After the addition, the solution was stirred at 25 0C for 18 h. The solution was concentrated, and the residue was quenched carefully with 3 M HCI (aq.) (gas evolution/exotherm). The aqueous acidic layer was extracted with Et2O (4 X 200 ml_). The aqueous layer was cooled to 0 0C and made basic via addition of NaOH pellets (pH = 11 -12). The aqueous layer was extracted with DCM. The combined DCM layers were dried (MgSO4). Filtration and concentration gave 23.2 g (60percent) of the amino-alcohol as a white solid.
Preparation 11; Sodium triacetoxyborohydride (36.7 g) was added portion wisely to a mixture of (2S)-2-amino-1-propanol (10.0 g) and benzaldehyde (13.53 ml) in a mixture of dichloromethane (140 ml) and acetic acid (8.38 ml) at 0° C. and the whole was stirred at room temperature overnight. The mixture was washed successively with 2N sodium hydroxide and brine, and dried over sodium sulfate. The solution was evaporated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (30:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2S)-2-benzylamino-1-propanol (15.96 g). IR (KBr): 2843, 1496, 1454, 1377, 1340, 1065 cm-1 NMR (CDCl3, delta): 1.10 (3H, d, J=6.4 Hz), 2.77-2.93 (1H, m), 3.28 (1H, dd, J=10.6 and 6.9 Hz), 3.61 (1H, dd, J=10.6 and 4.0 Hz), 3.75, 3.87 (2H, ABq, J=13 Hz), 7.21-7.34 (5H, m) MASS (API-ES): 166 (M+H)+
With hydrogen;5% Pd(II)/C(eggshell); In ethanol; at 20℃; for 8h;
[Preparation 6]: Synthesis of Compound 6(1) Optically-Active Compound of 2-benzylaminopropan-1-olTo a solution of (S)-(+)-2-aminopropan-1-ol (50.0 g) and benzaldehyde (74 ml) in ethanol (500 ml) was added 5percent palladium carbon (5.0 g), and the mixture was hydrogenated at room temperature under ordinary pressure for 8 hours. The reaction mixture was filtered through Celite, and concentrated under reduced pressure to give the titled compound (111.2 g).1H-NMR (DMSO-D6) delta: 7.34-7.27 (4H, m), 7.23-7.18 (1H, m), 4.53-4.47 (1H, m), 3.76 (1H, d, J=13.5 Hz), 3.66 (1H, d, J=13.5 Hz), 3.29-3.24 (2H, m), 2.65-2.55 (1H, m), 1.99 (1H, br s), 0.93 (3H, d, J=6.4 Hz).
(1) [(1S)-2-(t-Butyldiphenylsilyloxy)-1-methyl-ethyl]carbamic acid benzyl ester [1545] To a solution of L-alaninol (2.00 g, 26.6 mmol) in methylene chloride (60 ml) were added chloroformic acid benzyl ester (4.57 ml, 32.0 mmol) and triethylamine (4.48 ml, 32.0 mmol) in an ice bath. The mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1?1:2) as the eluant to afford [(1S)-2-hydroxy-1-methylethyl]carbamic acid benzyl ester (4.61 g, yield 83%) as white crystals. [1546] Subsequently, to a solution of [(1S)-1-(hydroxymethyl)ethyl]carbamic acid benzyl ester (4.61 g, 22.0 mmol) in dimethylformamide (140 ml) were added t-butyldiphenylsilyl chloride (6.87 ml, 26.4 mmol) and imidazole (1.80 g, 26.4 mmol) in an ice bath. The resulting mixture was stirred at room temperature for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (8:1?6:1) as the eluant to afford [(1S)-2-(t-butyldiphenylsilyloxy)-1-methylethyl]carbamic acid benzyl ester (10.7 g, yield 100%) as a colorless oil. [1547] 1H-NMR (400 MHz, CDCl3): delta (ppm) 7.67-7.60 (4H, m), 7.42-7.29 (11H, m), 5.10 (2H, s), 4.96-4.85 (1H, br s), 3.91-3.80 (1H, m), 3.67 (1H, dd, J=10.3, 2.6 Hz), 3.56 (1H, dd, J=10.3, 3.7 Hz), 1.55 (3H, d, J=11.7 Hz), 1.09 (9H, s).
81%
In neat (no solvent); at 50℃; for 0.0666667h;Microwave irradiation; Green chemistry;
General procedure: Benzylcholoroformate Cbz-Cl (1 mmol) was added to amine (1 mmol) and the mixture was subjected to the microwave irradiation (100W) for the appropriate time (tables 2, 3, 4 and 5). After completion of the reaction (monitored by TLC) dichloromethane: methanol (98/2), the reaction mixture was treating with n-hexane (15-20 mL) and was allowed to stand at room temperature overnight. The solid products were collected by filtration, washed with n-hexane and dried to give the N-Cbz derivatives in good to excellent yields. During the reaction, the formation of hydrogen chloride (gas) was observed, confirming the protection of all amines structures proposal.
72.3%
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃; for 16h;
(i) Production of (S)-benzyl(1-hydroxypropan-2-yl)carbamate To a solution of (S)-(+)-2-amino-1-propanol (200 g, 2.66 mol) in purified water (400 mL) was added sodium bicarbonate (246 g, 2.93 mol). To this mixture was added benzyl chloroformate (500 g, 2.93 mol) in tetrahydrofuran (800 mL) at an internal temperature of 20 C. or below. Subsequently, the resulting reaction mixture was stirred at room temperature for 16 hours. After confirming the disappearance of the starting materials by TLC, the reaction mixture was then extracted with ethyl acetate. The organic layer was washed with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over anhydrous sodium sulfate. The resulting solution was filtered and concentrated under reduced pressure. The residue was crystallized from petroleum ether to give the target product as a white solid (403 g, yield 72.3%). 1H-NMR (CDCl3) delta: 1.17 (3H, d, J=6.8 Hz), 2.31 (1H, brs), 3.48-3.57 (1H, m), 3.62-3.71 (1H, m), 3.78-3.90 (1H, m), 4.90 (1H, s), 5.10 (2H, s), 7.29-7.39 (5H, m).
With hydrogen In methanol Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With hydrogen In methanol for 14h;
25.A
A mixture of (S)-2-aminopropan-1-ol (8.5 g, 110 mmol), hydroxyacetone (10.9 g, 147 mmol), and PtO2 (0.10 g, 0.44 mmol) was combined with methanol (200 mL) in a 1 L Parr bottle. The reaction vessel was placed on a Parr shaker for 14 h under an atmosphere of 30 psi of hydrogen. The catalyst was removed by filtration through a pad of diatomaceous earth, rinsing with excess methanol. The filtrate was concentrated in vacuo to provide a mixture of diastereomeric aminodiols as a viscous yellow liquid [7:5 (S,S):(S,R) based on crude 1H NMR]. The crude diol mixture (5.0 g, 37.5 mmol) was stirred in a 150 mL thick-walled sealable reaction vessel as 40 mL concentrated H2SO4 was added slowly (significant exotherm observed). The vessel was sealed and heated at 140° C. for 7 h. The dark brown mixture was poured into 100 mL crushed ice, and the flask was rinsed into the reaction mixture with 50 mL of H2O. The resulting mixture was cooled in an ice bath and made basic by the slow addition of 10 N NaOH. The aqueous mixture was extracted with diethyl ether (3×300 mL). Salts began to precipitate from the aqueous layer. The aqueous layer was filtered through a sintered glass funnel, and the precipitated salts were washed with H2O (100 mL). The aqueous filtrate was further extracted with diethyl ether (6×200 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give a mixture of cis- and trans-dimethylmorpholines as an orange liquid (1.8 g, 41%). To a mixture of the unpurified dimethylmorpholine isomers (1.8 g, 16 mmol), NaOH (1.2 g, 30 mmol), and H2O (7 mL) was added di-tert-butyl-dicarbonate (3.2 g, 15 mmol) in one portion at room temperature. The mixture was stirred overnight, then was poured into H2O (30 mL) and extracted with diethyl ether (3×30 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give the mixture of Boc-protected morpholines as an orange liquid. The diastereomers were separated by flash chromatography (EtOAc/petroleum ether) to provide (S,S)-3,5-dimethylmorpholine-4-carboxylic acid tert-butyl ester (2.0 g, 59%). TLC (10% EtOAc/petroleum ether): Rf=0.41. 1H NMR (500 MHz, CDCl3): 3.85-3.78 (m, 4H), 3.49-3.43 (m, 2H), 1.47 (s, 9H), 1.29 (d, J=6.4 Hz, 6H). In addition, (S,R)-meso-3,5-dimethylmorpholine-4-carboxylic acid tert-butyl ester (0.90 g, 27%) was obtained. TLC (10% EtOAc/petroleum ether): Rf=0.33. 1H NMR (500 MHz, CDCl3): 3.93 (dq, J=7.0, 3.9 Hz, 2H), 3.70 (d, J=11.5 Hz, 2H), 3.55 (dd, J=11.5, 3.9 Hz, 2H), 1.47 (s, 9H), 1.30 (d, J=7.0 Hz, 6H).
With potassium carbonate; In tetrahydrofuran; at 0 - 5℃; for 1h;
Step-2: Synthesis of (S)-2-chloro-N-(l-hydroxypropan-2-yl)acetamide (115 ):- 2-(S)-amino-propan- l -ol (84 gm) was dissolved in THF ( 1500 ml) in 5.0 Ltr RBF at 0C in and added K2CO3 (441 gm, 3.0eq) (solution in 1000ml H2O) at same temperature. Chloroacetyl chloride ( 137.9 gm) was added drop wise at 0-5C and stirred for 1 .0 Hr at same temperature. Added 2N-NaOH solution ( 100 to 120 ml) to maintain pH 13- 14 and stirred at room temperature for 10 minute. Added Ethyl acetate ( 1000 ml) and separate layer, aqueous layer again extracted with ethyl acetate two times ( 1000 ml X 2). Combined the organic layer and dried over anhydrous sodium sulfate and finally concentrated to yield product ( 145 gm, 85%). Analytical data: 'HNMR (300 MHz, CDC13), delta 6.73 (br, lH), 4.1 (m, 1 H), 4.05(s, 2H), 3.70 (m, 1 H), 3.57 (m, 1 H), 2.57 (br, 1 H), 1.22 (d, J= 6.0Hz, 3H), ESIMS: 152 (M+ + 1 )
83%
With sodium hydroxide; In dichloromethane; water; at 0℃; for 1h;
To a stirred solution of (S)-2-aminopropan-l-ol (10 g, 0.13 mol) in water at 0C was added simultaneously a solution of chloroacetyl chloride (18 g, 0.16 mol) in dichloromethane (50 mL) and 1.6M aqueous sodium hydroxide (100 mL) dropwise over 1 h. The dichloromethane was removed under reduced pressure then the aqueous layer was extracted with ethyl acetate. The separated organic layer was dried (Na2S04) and concentrated to afford (S)-2-chloro-N-(l- hydroxypropan-2-yl)acetamide (16.2 g, 83%) as a colourless oil which was used in the next step without further purification
With potassium carbonate; In tetrahydrofuran; water; at -10℃; for 1h;
General procedure: An aqueous solution of K2CO3 (3 equiv) in H2O (50 mL) was added to asolution of amino alcohol 1 (1 equiv) in THF (50 mL) at -10 C. Chloroacylchloride 2 (1.1 equiv) was added from a syringe at -10 C syringewith vigorous stirring, and the mixture was then stirred at -10 C for1 h. The mixture was poured into H2O (50 mL) and extracted withCH2Cl2 (2 × 100 mL). The organic layer was finally dried (Na2SO4), filtered,and concentrated.
With sodium hydrogencarbonate; sodium carbonate; In water; acetone;
General procedure: Suitable N-protected amino alcohols (e.g. Fmoc and boc) can be obtained by reacting an amino alcohol with a desired protecting group precursor that protects the amine group with the desired protecting group Pgi . For example, N-Fmoc protected amino alcohols were prepared (in an Erlenmeyer flask) by suspending/dissolving Fmoc-O-Su in acetone (in a ratio of about 2.5-6 mL acetone per mmol of Fmoc-O-Su) with stirring. To this briskly stirring solution was added dropwise a solution of the amino alcohol (in a ratio of about 1 to 1 .2 eq. per mmol of Fmoc-O-Su) dissolved in acetone (in a ratio of about 0.4- 1 .2 mL acetone per mmol of the amino alcohol) and occasionally some water if the amino alcohol is not completely soluble in the acetone alone. When addition was complete, a solution containing NaHC03 and Na2C03 (in a ratio of about 1 to 1 .1 mmol NaHC03 and 0.5 to 0.55 mmol Na2C03 per mmol of Fmoc-O-Su) dissolved in deionized water (in a ratio of about 1 mL deionized water per 1 mL of acetone originally added to the Fmoc-O-Su) was added dropwise to the stirring reaction. After stirring and analysis by TLC (indicating complete reaction), a solution containing enough HCI (dissolved in about 0.3 mL water per 1 mL of acetone originally added to the Fmoc-O-Su) to completely neutralize the NaHC03 and Na2C03 was added dropwise over 30 minutes to one hour. The pH of the solution was then adjusted to approximately 4-5 (pH paper) by addition of 1 N HCI. The flask was then heated on a hot plate stirrer until the solid dissolved. The solution was then allowed to cool overnight and the product crystallized. The crystalline product was then collected by vacuum filtration. The product was then optionally recrystallized (usually by a mixture of acetonitrile and water) to the desired level of purity.
Step A: A solution of (S)-(+)-2-amino-1-propanol (5.0 g, 67.0 mmol) in toluene (60 mL) was added dropwise at 0 C. to a stirred suspension of NaH (60% in mineral oil, 6.2 g, 145 mmol) in toluene (150 mL). The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 min. A solution of ethyl chloroacetate (8.0 mL, 73.8 mmol) in toluene (60 mL) was then added dropwise at room temperature and the resulting reaction mixture heated at reflux for 20 h. The reaction was cooled to room temperature and solid NH4Cl (5 g, 96.7 mmol) added to the reaction. The reaction mixture was stirred for 20 min, filtered and the filtrate concentrated under reduced pressure. Purification by column chromatography (silica gel, 94.5:5:0.5 CH2Cl2/CH3OH/NH4OH) afforded (S)-5-methylmorpholine-3-one (6.5 g, 84%) as an off-white semi-solid. 1H NMR and MS consistent.
[002301 (,S)-l-(ter/-butyldiphenylsilyloxy)propan-2-amine (67) - To a stirred solution of (S)-2- aminopropan-l-ol (3.0 g, 39.9 mmol) and DCM (20 mL) at RT under nitrogen was added TEA (11.1 mL, 79.9 mmol) and DMAP (0.488 g, 3.99 mmol) and the resulting solution stirred for 10 min. tert-Butyldiphenylsilyl chloride (12.1 g, 43.9 mmol) was added, and the reaction was stirred for 18 h, then poured into water, and extracted with DCM. The combined organic fractions were dried (MgS04), filtered, and concentrated to afford a crude product that was purified by Si02 chromatography eluting with 10% MeOH/DCM to afford 9.5 g (75.9%) of 67.
39%
With 1H-imidazole; In DMF (N,N-dimethyl-formamide); at 20℃; for 2h;
A solution of 10.0 g (133 mmol) of S-(+)-2-amino-1-propanol and 13.6 g (200 mmol) of imidazole in 100 mL of DMF was treated with 38.1 mL (146 mmol) of t-butyldiphenylsilyl chloride. The reaction mixture was stirred at room temperature until tic analysis indicated complete consumption of starting material (2 h), diluted with 250 mL of H2O, and extracted with EtOAc (3×200 mL). The combined organic layers were washed with H2O (3×300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give an oil. Purification by flash chromatography (2% then 5% MeOH in CH2Cl2) afforded 16.4 g (52.4 mmol; 39%) of the title ether as an oil. FDMS 314 (M+1); Anal. calcd for Cl9H27NOSi: C, 72.79; H, 8.68; N, 4.47. Found: C, 73.04; H, 8.78; N, 4.45.
With 1H-imidazole; In dichloromethane; at 25 - 40℃; for 1.5h;Inert atmosphere;
General procedure: To a solution of alcohol ba (13.3 mmol) in DCM (20 mL) was added imidazole (2 eq) and TBDPSCl (1.05 eq) at 25 C. under N2. The mixture was stirred at 40 C. for 1.5 h. LC-MS showed one main peak with desired MS. The reaction mixture was diluted with DCM (50 mL), and washed with H2O (15 mL*3). The combined organic layers were combined and washed with brine (15 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give g which was used directly in the next step without purification.
With dmap; potassium carbonate; In dichloromethane; at 40℃; for 0.5h;Microwave irradiation;
General procedure: A solution of 2a (0.103 g, 1 mmol) in anhydrous dichloromethane (20 mL) was cooled to 0 C. K2CO3 (0.552 g, 4 mmol), DMAP (24.0 mg, 0.2 mmol) and tosyl chloride (0.416 g, 2.2 mmol) were added to the reaction mixture. The mixture was stirred under microwave irradiation (400 W) at 40 C. After 30 min, the reaction mixture was washed with saturated brine. Organic phase was dried over anhydrous Na2SO4 and concentrated in vacuum. The crude product was purified by silica gel column to give 3a (0.209 g, 0.877 mmol, 87.7%) as a white solid.
88%
With pyridine; In dichloromethane; at 0 - 20℃; for 16h;
A 50 mL pear-shaped flask was charged with a mixture of tosyl chloride (4.19 g, 22 mmol), pyridine (3.5 mL) and dichloromethane (6.5 mL). The mixture was cooled to 0 C., and S-(-)-2-amino-1-propanol (1) (0.751 g, 10.0 mmol) was added dropwise. The mixture was allowed to warm to rt. and stirred for 16 h. The reaction mixture was then poured into a separatory funnel containing 50 mL of cold 1N HCl and 25 mL CH2Cl2. After extraction, the organic layer was separated and washed with saturated aqueous CuSO4 (1×25 mL) and saturated aqueous NaCl (1×25 mL). Each aqueous layer was back-extracted with CH2Cl2 (2×25 mL). The organic fractions were combined, dried (MgSO4), and concentrated in vacuo to give 3.9 g of a greenish oil which was taken up in 50 mL dry acetone and stirred over 5.0 g of K2CO3 for 14 h. This mixture was then filtered through Celite and concentrated in vacuo to give 3.4 g of a yellow oil. The yellow oil was purified by flash chromatography (50 mm×6 column, eluted with 18% v/v EtOAc/hexane) to give 1.99 g of a white solid which was further purified by recrystallization from refluxing petroleum ether to give 1.86 g (8.8 mmol, 88% yield) of the title compound (2) as colorless needles (m.p. 57-58C) [alpha]D25=+32.0 (MeOH, c=2.8), 1H NMR (500 MHz, C6D6): delta 7.86-7.89 (m, 2H), 6.72-6.76 (m, 2H), 2.61 (ddq, J=6.9, 4.4, 5.6 Hz, 1H, CHCH3), 1.84 (s, 3H, ArCH3), 2.34 (d, J=6.9 Hz, 1H, CHaHbCHNTs) 1.37(d, J=4.5 Hz, 1H, CHaHbCHNTs), 0.76 (d, J=5.6 Hz, 3H, CH3).
N-[(1S)-2-hydroxy-1-methylethyl]-2-nitrobenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.4%
With sodium hydrogencarbonate; In tetrahydrofuran; water; at -8 - 20℃; for 39h;Large scale;
(i) Production of (S)-N-(1-hydroxypropan-2-yl)-2-nitrobenzenesulfonamide [0073] To a solution of (S)-(+)-2-amino-1-propanol (2.6 kg, 35 mol) in purified water (10.5 L) was added sodium bicarbonate (4.4 kg, 52 mol). To the resulting mixture was added a solution of 2-nitrobenzenesulfonyl chloride (7.3 kg, 33 mol) in tetrahydrofuran (10.2 L) at an internal temperature of -8 C. to -6 C. Subsequently, the resulting reaction mixture was stirred at room temperature for 39 hours. After confirming the disappearance of 2-nitrobenzenesulfonyl chloride by TLC, the mixture was filtered. The filtrate was then extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The residue thus obtained was crystallized from petroleum ether/ethyl acetate to give the target product as a white solid (7.5 kg, yield 82.4%). [0074] 1H-NMR (CDCl3) delta: 1.14 (3H, d, J=6.8 Hz), 1.85 (1H, br s), 3.47-3.66 (3H, m), 5.48 (1H, d, J=6.8 Hz), 7.72-7.79 (2H, m), 7.86-7.92 (1H, m), 8.15-8.20 (1H, m). [0075] melting point: 82-83 C.
2.33 g
With triethylamine; In dichloromethane; at 0℃; for 2h;Inert atmosphere;
TFA (2 mL) and 10-20% Pd(OH)2/activated carbon (0.05 g) were added to a solution of (S)-5 (2.5 g, 13.1 mmol) in MeOH (15 mL), and the mixture was stirred under H2 at 60 psi for 8 h. When the reaction was complete (TLC), the catalyst was filtered off on a plug of Celite, and the solvent was evaporated under reduced pressure to halve the volume of the liquid, which was then basified with 2.5 M methanolic NaOH. Evaporation ofthe remaining solvent under reduced pressure followed by the filtration of the residue through a short bed of basic alumina with elution by MeOH gave the corresponding amino alcohol asa pale-brown oil (yield: 0.94 g, crude), which was used in the next reaction without further purification. A solution of 2-O2NC6H4SO2Cl (3.2 g, 14.37 mmol) in CH2Cl2 (8mL) and Et3N (2.6 mL, 17.97 mmol) were added slowly to a solution of the amino alcohol (0.9 g, 11.98 mmol) in anhyd CH2Cl2 (5mL) at 0 C under N2, and the solution was stirred for 2 h. When the reaction was complete (TLC), H2O (10 mL) was added and the mixture was extracted with CH2Cl2 (2 × 15 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification of the crude residue by column chromatography [silica gel, PE-EtOAc (60:40)] gave a pale-yellow oil; yield: 2.33 g (75%); [alpha]D22 +80.2 (c 2.1, CHCl3). IR (CHCl3): 3546, 3367, 3022, 2883, 2401, 1594, 1542, 1412, 1362,1216, 1170, 1125, 1059, 971, 854, 668 cm-1. 1H NMR (200 MHz, CDCl3): delta H= 1.13 (d, J= 6.5 Hz, 3 H), 2.16 (brs, 1 H), 3.45-3.70 (m, 3 H), 5.61 (d, J= 6.6 Hz, 1 H), 7.73-7.80 (m,2 H), 7.86-7.91 (m, 1 H), 8.13-8.22 (m, 1 H). 13C NMR (50 MHz, CDCl3): delta C= 147.8 (C), 134.4 (C), 133.7 (CH),133.0 (CH), 130.9 (CH), 125.5 (CH), 66.2 (CH2), 52.5 (CH), 17.8(CH3). MS: m/z = 283 [M + Na]+.
2.33 g
With triethylamine; In dichloromethane; at 0℃; for 2h;Inert atmosphere;
Example 4: Synthesis of (S)-N-(l-hydroxypropan-2-yl)-2-nitrobenzenesulfonamide [(S)- compound 5] To a solution of ^-compound 4 (2.5 g, 13.1 mmol) in methanol (15 mL), trifluoroacetic acid (2 mL) and palladium hydroxide on activated carbon (0.05 g, 10-20 wt %) were added and the reaction mixture was stirred under hydrogen (60 psi) for 8 hours. After completion of the reaction (indicated by TLC), the catalyst was filtered over a plug of celite and the solvent was evaporated under reduced pressure to half of its volume which was basified with 2.5 M methanolic NaOH. Evaporation of the remaining solvent under reduced pressure was done followed by filtration of the residue through a short bed of basic alumina (eluent; MeOH) to obtain the amino alcohol as a pale brown oil (0.94 g, crude) which was subjected to the next reaction without further purification. To a solution of amino alcohol (0.9 g, 1 1.98 mmol) in dry dichloromethane (5 mL), 2- nitrobenzenesulfonylchloride (3.2 g, 14.37 mmol) in dichloromethane (8 mL) and triethylamine (2.6 mL, 17.97 mmol) at 0 C were slowly added under nitrogen atmosphere. The solution was stirred for 2 hours. After completion of the reaction (indicated by TLC), water (10 mL) was added to the reaction mixture, then extracted with dichloromethane (2 x 15 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. Purification of the crude residue was done by column chromatography (silica gel, petroleum ether/EtOAc, 60:40) to yield (S)- compound 5 as a pale yellow oil (2.33 g, 75% ); [a]22D = +80.2 (c 2.1, CHClj); IR (CHC13): vmax 3546, 3367, 3022, 2883, 2401, 1594, 1542, 1412, 1362, 1216, 1170, 1 125, 1059, 971, 854, 668 cm"1; ]H NMR (200 MHz, CDC13): deltaEta 1.13 (d, J = 6.5 Hz, 3H), 2.16 (bs, 1H), 3.45-3.70 (m, 3H), 5.61 (d, J = 6.6 Hz, 1H), 7.73-7.80 (m, 2H), 7.86-7.91 (m, 1H), 8.13-8.22 (m, 1H); 13C NMR (50 MHz, CDC13): 5C 147.8 (C), 134.4 (C), 133.7 (CH), 133.0 (CH), 130.9 (CH), 125.5 (CH), 66.2 (CH2), 52.5 (CH), 17.8 (CH3); MS: m/z 283 [M+Na]+.
Examples 13 and 14; N-(4-((2S. 5S-4-ethyl-5-methylmorpholin-2-yl)phenyl)-4-isopropylbenzenesulfonamide andN-(4-((2R. 5S-4-ethyl-5-methylmorpholin-2-yl)phertv?-4- isopropylbenzenesulfonamide; (S)-2-(ethylamino)propan-1 -ol; To 4g of (S)-2-aminopropan-1-ol (50mmoles) dissolved in 100ml of CH2CI2 was added acetaldehyde (2.58g, 58.6mmoles), followed by pre-dried powdered 4A molecular sieves (8g) and the resulted slurry was stirred at room temperature for 18hrs. It was then filtered through a pad of celite, the pad washed with CH2CI2, and solvent evaporated to give clear oil. This oil was dissolved in 25ml of ethanol and hydrogenated over PtO2 (0.5g) at a pressure of 30 psi H2 for 18hrs. The reaction was filtered through a pad of celite and the solvent was removed by evaporation to obtain 3.32g (60% yield) of the title compound as colorless oil.LRMS m/z Calcd for C5H13NO, 103.17, found 103.9 (M+H), (APCI).1 H NMR (CDCI3) delta 3.53 (dd, J = 4.1 , 10.4 Hz, 1 H), 3.24 (dd, J = 7.5, 10.8 Hz, 1 H), 2.78-2.66 (m, 2H), 2.58-2.48 (m, 2H), 1.08 (t, J = 7.1 Hz, 3H), 1.01 (d, J = 6.2Hz, 3H).13C NMR (CDCI3) delta 65.7, 54.5, 41.5, 17.2, 15.7.
(S)-2-(6-methyl-5-nitro-pyridin-2-ylamino)-propan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With triethylamine; In dimethyl sulfoxide; at 140℃; for 0.305556h;Microwave irradiation;Product distribution / selectivity;
Procedure for Library synthesis (Examples 29-86). The following is the general procedure for library synthesis for the examples of 29-88. The compounds are shown in table 2. Smith-vials for the microwave oven were charged with 0.1 mmol either of the starting materials; 5-fluoro-2-nitro toluene, 5-fluoro-2-nitrobenzotrifluoride, 6-fluoro-2-methyl-3- nitro-pyridine. To each vial was added 0.5 ml DMSO, 20 uL triethylamine (1.4 equivalents), and 1.4 equivalents of the diverse amino alcohols. The vials were run 1100s in 140C in a microwave oven. After synthesis the products were analysed by LC-MS. The DMSO solutions were transferred to test tubes, and evaporated onto silica gel under reduced pressure. The silica gel from the tubes was placed on SPE SI columns, and a frit was placed on top. The products were purified with a gradient solution of heptane/EtOAc. The fractions were pooled and solvent was evaporated. Compounds which were more than 90% pure were tested in an in vitro assay which is described below. Purity was determined by analytic HPLC.
With triethylamine; In dimethyl sulfoxide; at 140℃; for 0.305556h;Microwave irradiation;
Procedure for Library synthesis (Examples 29-86). The following is the general procedure for library synthesis for the examples of 29-88. The compounds are shown in table 2. Smith-vials for the microwave oven were charged with 0.1 mmol either of the starting materials; 5-fluoro-2-nitro toluene, 5-fluoro-2-nitrobenzotrifluoride, 6-fluoro-2-methyl-3- nitro-pyridine. To each vial was added 0.5 ml DMSO, 20 uL triethylamine (1.4 equivalents), and 1.4 equivalents of the diverse amino alcohols. The vials were run 1100s in 140C in a microwave oven. After synthesis the products were analysed by LC-MS. The DMSO solutions were transferred to test tubes, and evaporated onto silica gel under reduced pressure. The silica gel from the tubes was placed on SPE SI columns, and a frit was placed on top. The products were purified with a gradient solution of heptane/EtOAc. The fractions were pooled and solvent was evaporated. Compounds which were more than 90% pure were tested in an in vitro assay which is described below. Purity was determined by analytic HPLC.
With triethylamine; In N,N-dimethyl-formamide; at 20℃;
Example 60; (11^-3-BrOmO-I l-methyl-10,1 l-dihydro-8H-[l,4]oxazino[4',3':l,2]imidazo[4,5- c] quinolin-6-amine; Part A; A 2-L, three-necked, Morton flask, equipped with overhead stirrer, was charged with <strong>[723280-98-6]7-bromo-4-chloro-3-nitroquinoline</strong> (28.75 g, 100 mmol), anhydrous DMF (200 mL) and triethylamine (28 mL, 200 mmol). The reaction mixture was stirred at ambient temperature and a solution of L-alaninol (7.51 g, 0.1 mol) in 100 mL of DMF was slowly added. After stirring overnight, the reaction mixture was treated with saturated aqueous K2CO3 solution (100 ml) and H2O (800 mL). The mixture was stirred vigorously for 2 hours to produce a yellow precipitate. The yellow solid was collected by vacuum filtration and dried with suction to give 30.9 g of (2S)-2-[7-bromo-3-nitroquinolin-4- yl)amino]propan-l-ol as bright-yellow crystals.
With triethylamine; In N-methyl-acetamide; dichloromethane;
(1) [(1S)-2-(t-Butyldiphenylsilyloxy)-1-methyl-ethyl]carbamic acid benzyl ester To a solution of L-alaninol (2.00 g, 26.6 mmol) in methylene chloride (60 ml) were added chloroformic acid benzyl ester (4.57 ml, 32.0 mmol) and triethylamine (4.48 ml, 32.0 mmol) in an ice bath. The mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (2: 1 ? 1: 2) as the eluant to afford [(IS)-2-hydroxy-1-methylethyl]carbamic acid benzyl ester (4.61 g, yield 83%) as white crystals. Subsequently, to a solution of [(1S)-1-(hydroxymethyl)ethyl]carbamic acid benzyl ester (4.61 g, 22.0 mmol) in dimethylformamide (140 ml) were added t-butyldiphenylsilyl chloride (6.87 ml, 26.4 mmol) and imidazole (1.80 g, 26.4 mmol) in an ice bath. The resulting mixture was stirred at room temperature for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (8: 1 ? 6: 1) as the eluant to afford [(1S)-2-(t-butyldiphenylsilyloxy)-1-methylethyl]carbamic acid benzyl ester (10.7 g, yield 100%) as a colorless oil. 1H-NMR (400 MHz, CDCl3): delta (ppm) 7.67 - 7.60 (4H, m), 7.42 - 7.29 (11H, m), 5.10 (2H, s), 4.96 - 4.85 (1H, br s), 3.91 - 3.80 (1H, m), 3.67 (1H, dd, J=10.3, 2.6Hz), 3.56 (1H, dd, J=10.3, 3.7Hz), 1.55 (3H, d, J=11.7Hz), 1.09 (9H, s).
With triethylamine; In 1,4-dioxane; water; at 20℃;
To a stirred solution of the commercially available 2-(S)-amino propanol (17.4 g) in water (200 ml) was added a solution of triethylamine (32 ml) in dioxane (200 ml). To the solution was added commercially available l-[2-(Trimetylsilyl)ethoxy- carbonyloxy]pyrrolidin-2,5-dione (60 g). The mixture was stirred at rt overnight, then diluted with water (200 ml), acidified with 1 N HCl, and extracted with Et2O (2 x 500 ml). The combined organic phase was washed with brine, dried over MgSO4 and evaporated to afford the title compound (44.2 g; 87 %).1H-NMR delta (CDCl3): 0.02 (s, 9H), 0.90-1.05 (m, 2H), 1.20 (d, 3H), 2.80 (br s, IH), 3.40-3.80 (m, 3H), 4.10-4.20 (m, 2H), 4.85 (s, IH).
With palladium 10% on activated carbon; hydrogen; In methanol; under 2844.39 Torr;
Stepl: To a solution of compound [128] (5.0g, 66.67 mmol, 1 eq.) in methanol ( 100ml) was added Pd/C (0. l Og, 10%). Hydroxyacetone (5.48mL, 80.0mmol. 1 .2 eq.) was added and mixture was hydrogenated overnight in parr shaker under 55 psi. The palladium was removed by passing the mixture through celite bed and combined filtrate was concentrated under vaccum to obtai n compound [129] (8.35 g, 93%) as yellow oil. ESIMS: 134 (M+ + l e)
[ETHYL-3- (2,] 3,4, 5-tetrafluorophenyl) -3-oxo-propanoate (10 g. 38 mmol) is dissolved in a mixture of triethyl orthoformate (10 [ML,] 60 mmol) and acetic anhydride (10 [ML,] 106 mmol) and the solution is heated at reflux for 3 hours. After concentration under vacuum, the residue is dissolved in CH2C12 and cooled at [0] C. 2S-aminopropanol (4.26 g, [55MMOL)] is added dropwise and the solution is allowed to warm to room temperature. The product is purified by flash chromatography on silica gel using 25% EtOAc in hexanes.
[Example 105] (+)(3S)-4-[1-(6-Methoxypyridazin-3-yl)-5-(2-pyridyl)-1H-pyrazole-3-carbonyl]-3-methylmorpholine [Show Image] 1) (5S)-5-Methyl-3-morpholinone Sodium hydride (55%, 0.409 g) was added to a solution of (2S)-2-amino-1-propanol (0.665 mL) in tetrahydrofuran (100 mL), and the resultant mixture was stirred for 35 minutes. Chloroethyl acetate (0.900 mL) was added to the reaction solution, and the mixture was stirred for 30 minutes, and then heated to reflux for 3 hours. After air cooling, the reaction solution was filtered, and a residue obtained by evaporating the solvent of the filtrate under reduced pressure was purified by silica gel column chromatography (ethyl acetate-n-hexane), to obtain a crude product of (5S)-5-methyl-3-morpholinone (0.170 g, 17%) as an amorphous material.
With sodium carbonate; In 1,4-dioxane; water; at 0 - 20℃;
To a mixture of (S)-2-aminopropan-l-ol (2 g, 26.6 mmol) and Na2C03 (5.6 g, 53.2 mmol) in 1,4-dioxane and water (25 mL / 25 mL) at 0 C was added FmocCl (10.2 g, 39.9 mmol) and the resulting mixture was then warmed to room temperature gradually. After the amine was consumed completely as indicated by TLC, water (25 mL) was added. The mixture was extracted with DCM (3 x 50 mL). The organic phase was washed with brine (50 mL), and dried over anhydrous Na2S04. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (7.1 g, 90%).
B. (3S,llaR)-3-Methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,ll,lla-hexahydro[l,3]oxazolo[3,2- a] p rido [1 ,2-d] pyrazine-8-carboxylic acid l-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-l,4-dihydro- 3-pyridinecarboxylic acid (22.54 g) was dissolved in 220 mL of CH3CN. HOAc (20 mL) and CH3S03H (1.4 mL) were added at room temperature and the mixture was heated to 58-65 C for 19.5 h. Alaninol (7.51 lg) in CH3CN (15 mL) was added slowly and the resultant mixture was stirred at 64 C for 18.5 h. The mixture was concentrated, and the residue was redissolved in CH2C12 (170 mL). HC1 (1 N, 170 mL) was added and the layers were separated. The aqueous layer was extracted with CH2C12 (170 mL*2) and the organic layers were combined and concentrated. MeOH (50 mL) was added and the resultant mixture was again concentrated. MeOH (80 mL) was added and the resultant mixture was heated at reflux for 4 h, gradually cooled to 20 C and held at 20 C for 15 h. The product was collected by filtration and dried under vacuum.
A solution of <strong>[5617-74-3]3-oxabicyclo[3.1.0]hexane-2,4-dione</strong> (1.0 g, 8.9 mmol), (S)-2- aminopropan- l -ol (1.5 g, 20 mmol), and toluene (20 mL) was refluxed under N2 for 1.75h, allowed to cool to rt, and concentrated. Acetic anhydride (10 mL) was added to the residue, and the reaction was heated at 80 C for 18.5 h, allowed to cool to rt, and concentrated. The residue was purified by silica gel chromatography (9:1?0:1; hexanes:ethyl acetate) to give 0.97 g of (2S)-2-(2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)propyl acetate. 'H NMR (DMSO-de): delta 4.25- 4.16 (m, 1H), 4.14-4.05 (m, 2H), 2.56 (dd, 2H), 1.96 (s, 3H), 1.52 (m, 1H), 1.34 (m, 1H), 1.21 (d, 3H).
Stage #1: 2,2-dimethylsuccinic acid With acetic anhydride at 85℃; for 0.5h;
Stage #2: (S)-Alaninol In toluene for 1h; Reflux; Inert atmosphere;
Stage #3: acetic anhydride at 80℃; Inert atmosphere;
21.1
A suspension of 2,2-dimethylsuccinic acid (10.5 g, 71.7 mmol) in acetic anhydride (50 mL) was heated at 85 °C for 30 minutes and then concentrated under reduced pressure. The residue was dissolved in toluene (150 mL) and (S)-2-aminopropan-l-ol (6.0 g, 80 mmol) was added. The mixture was heated at reflux for 1 h under nitrogen atmosphere and cooled to room temperature. The solvent was removed under reduced pressure, and the residue was heated in acetic anhydride (50 mL) at 80 °C under nitrogen overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified on a silica gel column (eluting with PE/EA = 3/1) to afford (S)-2-(3,3-dimethyl-2,5- dioxopyrrolidin-l-yl)propyl acetate (10.1 g, 62.3%). ^-NMR (CDC13) δ 4.41 (m, 2H), 4.25 (m, 1H), 2.50 (s, 2H), 1.97 (s, 3H), .137 (d, 3H), 1.29 (s, 3H), 1.28 (s, 3H).
Stage #1: (S)-Alaninol; 4-(3-fluoro-benzyloxy)-benzaldehyde In methanol at 20℃;
Stage #2: With sodium cyanoborohydride In methanol at 20℃; for 3h;
Stage #3: With water In ethyl acetate
31.B
Intermediate B: (S)-2-(4-(3-Fluorobenzyloxy)benzylamino)propan-1 -ol To a solution of compound A (3.36 g, 15 mmol) in methanol (30 mL) was added (S)-2- aminopropan-1 -ol (1 .29 mL, 16.5 mmol) and the resulting mixture was stirred at room temperature overnight. To the mixture was added NaCNBH3 (3.78 g, 60 mmol) and stirring was continued at room temperature for 3 h. The solvent was removed under reduced pressure and the residue was dissolved with EtOAc (300 mL) and washed with water (3 x 200 mL) then dried over Na2S04. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (CH2CI2/MeOH, 25/1 , v/v) to give (S)-2-(4-(3- fluorobenzyloxy)benzylamino)propan-1 -ol (3.13 g, 72%) as an oil.LC-MS (Agilent): Rt 3.04 min; m/z calculated for Ci7H2oFN02 [M+H]+ 290.15, found 290.1 .
72%
Stage #1: (S)-Alaninol; 4-(3-fluoro-benzyloxy)-benzaldehyde In methanol at 20℃;
Stage #2: With sodium cyanoborohydride In methanol at 20℃; for 3h;
31 Intermediate B: (S)-2-(4-(3-Fluorobenzyloxy)benzylamino)propan-1-ol
To a solution of compound A (3.36 g, 15 mmol) in methanol (30 mL) was added (S)-2-aminopropan-1-ol (1.29 mL, 16.5 mmol) and the resulting mixture was stirred at room temperature overnight. To the mixture was added NaCNBH3 (3.78 g, 60 mmol) and stirring was continued at room temperature for 3 h. The solvent was removed under reduced pressure and the residue was dissolved with EtOAc (300 mL) and washed with water (3*200 mL) then dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (CH2Cl2/MeOH, 25/1, v/v) to give (S)-2-(4-(3-fluorobenzyloxy)benzylamino)propan-1-ol (3.13 g, 72%) as an oil. LC-MS (Agilent): Rt 3.04 min; m/z calculated for C17H20FNO2 [M+H]+ 290.15. found 290.1.
μ-Oxido-bis({S(+)-2-[(1-oxidopropyl)iminomethyl]-3,5-dimethoxyphenolato-κ3N,O,O'}oxidovanadium(V))[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
General procedure: A solution of 5 mmol of S(+)-2-amino-1-propanol in 10 ml absolute ethanol was added with stirring to 5 mmol of an aromatic o-hydroxyaldehyde (salicylaldehyde, 3-methoxysalicylaldehyde, 5-methoxysalicylaldehyde, 4,6-dimethoxysalicylaldehyde, 5-methylsalicylaldehyde, 5-bromosalicylaldehyde, 5-nitrosalicylaldehyde, 2,4-dihydroxybenzaldehyde, 3-tert-butylsalicylaldehyde, 2-hydroxy-1-naphthaldehyde) in 20 ml absolute EtOH and heated under reflux for 1 h. Then a vanadium(V) oxytriethoxide (5 mmol) in 10 ml of absolute EtOH was added and stirred at room temperature for 2 h. After cooling in a fridge a solid was separated and filtered off, washed several times and recrystallized from absolute EtOH.
With caesium carbonate; In dimethylsulfoxide-d6; at 25 - 150℃; under 2280.15 Torr; for 24h;Autoclave;
General procedure: To a DMSO-d6 (1 mL) solution of cesium carbonate (33 mg, 0.1 mmol) in a Teflon tube was added (S)-1b (78 muL, 1 mmol). The Teflon tube containing the reaction mixture was fitted into a 30 mL autoclave. The autoclave was frozen with liquid nitrogen (-196 C) prior to connecting to a vacuum line for air removal. After the mixture was evaporated under vacuum at -196 C and warmed up to room temperature, CO2 was filled into the autoclave (3 atm). The autoclave was stirred at 150 C for 24 h. Upon completion, the reaction mixture was subjected to 1H NMR for crude product yield determination, which calculated based on the ratio between product and internal standard (N,N-dimethylformamide). After that, DMSO-d6 was removed through distillation under vacuum conditions; the syrupy product was then purified by column chromatography on silica gel (hexane/ethyl acetate 3:1) to give the product (S)-4-methyloxazolidin-2-one (S)-2b as colorless oil with an isolated yield of 36% (36.4 mg, 0.36 mmol).
A solution of iodine (4.92 g, 19.39 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise to a suspension of N-methyl-L-alanine (2.00 g, 10.39 mmol) and sodium borohydride (1.83 g, 48.49 mmol) in tetrahydrofuran (50 mL), pre-cooled in an ice-bath. Once the addition was complete the reaction mixture was heated to reflux. After 18 hours the reaction was allowed to cool to ambient temperature and then methanol (5 mL) was slowly added. The mixture was stirred at ambient temperature for 30 minutes and then concentrated under reduced pressure. The residue was dissolved in 20% KOH (w/w) (30 mL) and then stirred at ambient temperature for 4 hours. The aqueous reaction mixture was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide a clear oil (2.07 g, 100% yield).
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 100 - 120℃; for 70h;
General procedure: Step 2 A solution of C-2 (1.01 g, 4.47 mmol, 1.00 equiv.) in DMA (3.0 mL) was treated dropwise with (S)-2-aminopropan-1-ol (403 mg, 5.37 mmol, 1.20 equiv.) and DIPEA (1.17 mL, 6.70 mmol, 1.50 equiv.), and the mixture was heated to 100 C. for 22 h. LCMS analysis revealed a mixture of desired product (MH+281/283) and starting material (MH+ 226/228) in the ratio 1.5:1 (254 nm). The mixture was heated to 120 C. for 48 h and then cooled to RT. LCMS indicated a mixture of desired product and starting material in the ratio 9:1 (254 nm) contaminated by some O-arylated byproduct. The dark brown mixture was concentrated in vacuo to afford 1.56 g of a yellow-brown oily solid. The crude product was treated with EtOAc and washed twice with water then brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting green-yellow solid (1.08 g) by NMR was a 1:1.5 mixture of desired product to starting material. The crude was purified by automated SiO2 flash chromatography eluting with an EtOAc/heptane gradient (0 to 100% EtOAc) to afford 388 mg (31%) of (S)-2-(6-bromoisoquinolin-3-ylamino)propan-1-ol (C-3, R2=(S)-1-hydroxypropan-2-ylamino). 1H NMR (400 MHz, DMSO-d6) delta 8.84 (s, 1H), 7.79 (s, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.21 (dd, J=8.7, 1.7 Hz, 1H), 6.57 (s, 1H), 6.26 (d, J=8.1 Hz, 1H), 4.73 (t, J=5.6 Hz, 1H), 3.83 (septet, J=6 Hz, 1H), 3.51 (dt, J=10.4, 5.1 Hz, 1H), 3.45-3.3 (1H, obscured), 1.16 (d, J=6.5 Hz, 3H). LCMS: MH+281.2/283.2.
(S)-N-(1-hydroxypropan-2-yl)-2-(1H-imidazol-1-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
In toluene at 180℃; for 0.166667h; Microwave irradiation;
(S)-N-(1-Hydroxypropan-2-yl)-2-(1H-imidazol-1-yl)acetamide 1q
General procedure: In a capped 10mLMW-vessel, the ethyl azolyl-acetate derivatives 3a-c (1.0equiv), the corresponding 1,2-amino alcohol (1.0equiv) and toluene (3mL) were mixed. The tube was positioned in the irradiation cavity and the mixture was heated with stirring under microwave irradiation at 180°C and held for approximately 10min. The vessel was cooled to room temperature, and the residue was dissolved in methanol and then concentrated under vacuum. The crude product was purified either by flash chromatography on silica gel using EtOAc/Hex/MeOH (5:4:1) as eluent or by crystallization under ethyl acetate. The purity of the final products was determined by 1H NMR spectroscopy. (S)-N-(1-Hydroxypropan-2-yl)-2-(1H-imidazol-1-yl)acetamide 1q (0032) (417mg, 84%) as a white solid, mp 172-173°C. [α]D=-8.0 (c 1.0, MeOH). 1H NMR (400MHz, CD3OD): δ=1.14 (d, J=6.8Hz, 3H, CH3CH), 3.47 (dd, J=11.2, 5.2Hz, 1H, CH2OH), 3.51 (dd, J=11.2, 5.2Hz, 1H, CH2OH), 3.95 (m, 1H, CHCH3), 4.72 (s, 2H, CH2C=O), 6.97 (bs, 1H, CH=CH-N), 7.10 (bs, 1H, CH=CH-N), 7.65 (bs, 1H, N=CH-N). 13C NMR (100MHz, CD3OD): δ=17.1 (CH3), 30.0 (CH2C=O), 50.4 (CHCH3) 66.0 (CH2OH), 121.9, 129.0, 139.6, 169.0 (C=O). HRMS (FAB+): calculated for C8H14N3O2 [M+H]+, m/z 184.1086; found for [M+H]+, m/z 184.1092.
(S)-2-(4-nitropyridin-3-ylamino)propan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;
A mixture of <strong>[13505-01-6]3-fluoro-4-nitropyridine</strong> (0.400 mL, 4.05 mmol), (S)-2-aminopropan-1- ol (0.347 mL, 4.46 mmol) and potassium carbonate (0.616 g, 4.46 mmol) in DMF (5.0 mL) was stirred at 60 C for 2 h. Water was added and the mixture stirred at room temperature to afford a precipitate. The mixture was filtered to afford an orange solid. The filtrate was extracted with dichloromethane. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtrate, and concentrated to afford an orange solid. The solids were combined and purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 0- 10% methanol-dichloromethane) to afford (S)-2-(4-nitropyridin-3-ylamino)propan-1-ol (0.668 g, 84%) as an orange solid. MS (ESI, pos. ion) m/z 198.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100.0℃; for 3.0h;Inert atmosphere;
General procedure: A solution of A3 (1 eq.) in toluene (50 mL) was degassed by bubbling with argon gas for 15 min and then Pd2dba3 (0.03 eq.), BINAP (0.06 eq.) and Cs2C03 (3 eq.) were added to the solution followed by the addition aminoalcohol (2 eq.). The mixture was heated at 100 C under argon atmosphere for 3 h. Reaction mixture was cooled to room temperature, diluted with EtOAC and washed with water and brine. The organic layer was dried over Na2S04 and concentrated to get crude product. The crude compounds were purified by silica gel (100 - 200 mesh) column chromatography by using 0 - 5% MeOH in DCM. Yields: 25 - 45%.
(S)-2-((4-(hydroxymethyl)-2-nitrophenyl)amino)propan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68.1%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 120℃; for 1h;Microwave irradiation;
Intermediate 238: (S)-2-((4-(hydroxymethyl)-2-nitrophenyl)amino)propan-1-ol 4-fluoro-3-(nitrophenyl)methanol (2 g, 11.69 mmol) was dissolved in tetrahydrofuran (5 mL) and DIPEA (6.12 mL, 35.1 mmol) and (S)-2-aminopropan-1-ol (2.73 mL, 35.1 mmol) added. This mixture was heated to 120 C in a microwave reactor for 1 hour. The orange mixture was then partitioned between ethyl acetate (80mL) and saturated sodium bicarbonate (80mL). Phases were then separated and the aqueous phase was then extracted twice with ethyl acetate (80mL). Organics were then combined, dried using a hydrophobic frit then solvents removed in vacuo. To the oil was added cyclohexane and the mixture left to stand for 16hrs. Mixture was then stirred for 2.5hrs then the solvent was decanted. The mixture was then dissolved in dichloromethane/methanol then solvents removed in vacuo. This yielded the title compound (1.8 g, 7.96 mmol, 68.1 % yield) as a red/orange oil. LCMS (System B): tRET = 0.63 min; MH+ 328.
(S)-tert-butyl 2-(((S)-1-((S)-1-hydroxypropan-2-yl)amino-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrrolidin-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
General procedure: At 0oC and with stirring, to the solution of L-N-Boc-proline (2) (0.92 mmol) in dry THF, HOBt (1.0 mmol) was added, and stirred for 10 min, then DCC (in the case of tyrosine methyl ester, DIC) (1.0 mmol) was added. The mixture was stirred at 0oC for 1 h, and the amine or aminoalcohol (1.02 mmol) was added (in the case of amino acid ester hydrochloride, to the suspension of amino acid ester hydrochloride in dry THF, triethylamine (0.5 mL) was added and stirred at room temperature for 1 h, and this solution was added to the first mixture). The reaction mixture was stirred at room temperature for 24 h, and the reaction was monitored by TLC. The formed precipitate was removed by filtration, and the filtrate was evaporated under vacuum. The residue was dissolved in 50 mL of ethyl acetate, the formed solution was washed successively with saturated aqueous solution of NaHCO3 (30 ml x 3), 5 % aqueous solution of KHSO4 (30 ml x 3) and saturated aqueous solution of NaCl (30 ml x 3), and dried with anhydrous Na2SO4. After filtration, the filtrate was evaporated under vacuum to give the crude products which were purified by column chromatograpy on silica gel.
(1S)-Ν-(1-methyl-1-hydroxymethylmethyl)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-vinylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96.7%
Stage #1: 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-one With toluene-4-sulfonic acid In methanol at 5 - 15℃; Inert atmosphere; Molecular sieve;
Stage #2: (S)-Alaninol In methanol at 10℃; Inert atmosphere; Molecular sieve;
5
Under a nitrogen atmosphere, 300 g of methanol was added successively to a dry 1000 ml glass flask,A mixture of 137 g (0.5 mol) of 1-(3-ethoxy-4-methoxy)phenyl-2-methanesulfonylethaone (II) 6.0 g p-toluenesulfonic acid (0.037 mol) and 4 Å molecular sieves were added to maintain the internal temperature between 5 °C and 15 °C. A solution of 52.5 g of L-α-aminopropanol (0.7 moles) and 60 g of methanol was then added dropwise and the addition was complete for about 2 hours. After 10 °C incubation reaction for 2 to 3 hours. The resulting mixed solution, sample detection, HPLC showed a conversion rate of 97.1% for the starting material. The yield of (1S)-Ν-(1-methyl-1-hydroxymethylmethyl)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-vinylamine was 96.7%.
In the reaction flask,L-aminopropanol (7.5 g, 0.1 mol) was added to DMF (30 mL)After completely dissolving,Sodium hydride (50 wt%) (5 g, 0.10 mol) was added thereto at 0 & lt; 0 & gt; C under nitrogen,Then rose to room temperature,After stirring for 1 h, chloroacetyl chloride (11 g, 0.1 mol) was added,Reaction overnightTLC monitoring raw material reaction is complete,Saturated sodium chloride solution (500 mL) was added to the reaction solution,And extracted twice with ethyl acetate (400 mL)Combine organic phase,To the organic phase slowly dropping dilute hydrochloric acid solution,Gradually solid precipitation,When the pH of the reaction solution was 11,The precipitation of solids to achieve the most,The filter solution was filtered and the cake was dried to give (S) -3 methyl morpholinone hydrochloride,(S) -3-methylmorpholinone hydrochloride was added to methanol (50 mL)And then slowly dropping dilute hydrochloric acid solution,Solid gradually dissolved,After being completely dissolved, the solvent methanol was distilled off, the reaction solution was extracted with ethyl acetate,The organic phases were combined and concentrated to give 9 g of pale yellow liquid (S) -3 methylmorpholinone.
With triethylamine; In dichloromethane; at 0 - 20℃; for 18h;
To a mixture of (2S)-2-aminopropan-1-ol (compound 9a, 5 g, 66.57 mmol) and TEA (20.21 g, 199.71 mmol) in DCM (50 mL) at 0 oC was added a solution of triphosgene (7.90 g, 26.63 mmol) in DCM (20 mL) dropwise. The mixture was then stirred at room temperature for 18 hours and then concentrated and purified by silica gel column chromatography (DCM: (0360) MeOH=20:1) to give compound 9b (1.5 g, crude) as a colorless oil. 1H NMR: (400MHz, CDCl3) ppm 4.52 - 4.47 (m, 1H), 4.04 - 3.98 (m, 1H), 3.96 - 3.92 (m, 1H), 1.29 (d, J=6.0 Hz, 3H).
(S)-1-((1-hydroxypropan-2-yl)amino)-4-propoxy-9H-thioxanthen-9-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.97%
With copper(l) iodide; potassium carbonate; In methanol; at 100℃; for 48h;
General procedure: 1-Chloro-4-propoxy-9H-thioxanthen-9-one (Tx, 450 mg, 1.48 mmol) and a suitable chiral aminoalcohol (9-16, 1.72 mmol) were dissolved in methanol (30 mL) and CuI (0.15 mmol) and K2CO3(1.92 mmol) were added. The reaction mixture was heated at 100 C in a muffle furnace for 48 h.After the completion of the reaction, the crude material was filtrated, washed with dichloromethane,and the organic solvents were evaporated under reduced pressure. Then, the obtained solid wasdissolved in 50 mL of dichloromethane and extracted with HCl 1M(3 50 mL). The aqueous layer wasbasified with NaOH 20% and extracted with dichloromethane (3 100 mL). The organic layers weregathered, washed with water (3 50 mL), dried over anhydrous sodium sulphate and the solvent wasevaporated under reduced pressure. Then, a solid phase extraction using a cation exchange cartridgeDiscovery DSC-SCX was applied to further purify the extracted material. First, an activation ofthe cartridge with dichloromethane (50 mL) was performed followed by loading the cartridge withthe sample (previously incorporated in silica). Then, elution was carried out with the followingsolvents: dichloromethane, a mixture of dichloromethane/methanol 5:5 (v/v), methanol 100% andNH3 2% in methanol. The fractions containing the chiral ATxs were gathered and the solvent wasevaporated under reduced pressure. A flash column chromatography with n-hexane/ethyl acetate ingradient and crystallization from chloroform and petroleum ether (4:1) were also performed to obtainpure compounds.(S)-1-((1-Hydroxypropan-2-yl)amino)-4-propoxy-9H-thioxanthen-9-one (ATx 1 (+)). Yield: 1.97%. m.p.:116-118 C (dec.); [alpha]25D +112 (c = 3.4 103 g/mL in dichloromethane). IR (KBr) numax: 3419, 3270,2962, 2925, 2873, 2359, 2341, 1618, 1568, 1507, 1435, 1293, 1269, 1252, 1225, 746 cm1. 1H-NMR(300.13 MHz, CDCl3): delta: 8.50 (1H, d, J = 8.0 Hz, H-8), : 7.56 (2H, m, H-5 and H-6), : 7.43 (1H, m, H-7),: 7.13 (1H, d, J = 9.0 Hz, H-3), : 6.85 (1H, d, J = 9.0 Hz, H-2), : 4.03 (2H, t, J = 6.5 Hz, H-a), : 3.81 (3H,m, H-10 and CH2OH), : 1.90 (2H, m, H-b), : 1.32 (3H, d, J = 6.2 Hz, H-20), : 1.12 (3H, t, J = 7.4 Hz,H-c). 13C-NMR (75.47 MHz, CDCl3): delta: 183.55 (C-9), 146.50 (C-4), 144.02 (C-1), 136.85 (C-6), 131.92(C-8a), 129.85 (C-4a), 129.24 (C-9a), 126.08 (C-8), 125.98 (C-7), 125.20 (C-5), 119.12 (C-3), 114.10 (C-10a),109.80 (C-2), 72.48 (C-a), 65.96 (C-CH2OH), 51.91 (C-10), 22.66 (C-b), 16.86 (C-20), 10.71 (C-c). e.e. > 99%(HPLC; column: Lux Amylose-1 (250 4.6 mm i.d., 5 m), Mobile phase: n-hexane:ethanol (70:30v/v), 0.5 mL/min, max 254 nm).
(S)-4-(benzyloxy)-N-(1-hydroxypropan-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.33 g
In dichloromethane; at 20℃;
To a 250-mL round-bottom flask, was added (2S)-2-aminopropan-l-ol (2.1 g, 28 mmol, 4 equiv) and CH2CI2 (50 mL). This was followed by the dropwise addition of a solution of 4-(benzyloxy)benzene-l-sulfonyl chloride (1NT-L3 with R1=H, 2 g, 7.07 mmol, 1 equiv) in CH2CI2 (50 mL). The resulting solution was stirred for 40 min at room temperature. The resulting mixture was concentrated under vacuum The residue was applied onto a silica gel column with ethyl acetate (100%) providing 2.33 g of (iS)-4- ^enzyloxy)-N-(l-hy(koxypropan-2-yl)benzenesulfonamide (INT-B1) as a white solid.
step 1, 2.6 g of sodium hydride, 50 ml of toluene and 8.8 g of ethyl acetate were sequentially placed in the reaction flask.Stir until it is gray and turbid.Then, 8.8 g of ethyl formate was slowly added dropwise, and stirring was continued while the bubbles were released.After the reaction was completed, it was filtered under reduced pressure, and the cake was dried in vacuo.Obtaining white formyl ethyl acetate sodium salt; Step 2. Add to the flask containing 50 ml of tolueneSodium formylacetate sodium salt 5.5gAnd ZIF-67ZnCoZIF catalyst 1.5g,Slowly add 7.7 g of 2,3,4,5-tetrafluorobenzoyl chloride at room temperature.After the reaction is completed, slowly add S-(+)-2-aminopropanol dropwise3.2g, heated to reflux,After the reaction is completed, a water layer is added, the water layer is extracted with toluene, the organic layers are combined, and toluene is distilled off to obtain a preliminary product; Step 3.The obtained initial product was slowly added dropwise to 30 ml of a DMF solution containing 5.8 g of KF, stirred, heated to reflux, and azeotropically dehydrated.After completion of the reaction, the solvent was evaporated, and washed with water to give a brown-yellow viscous solid.Drying to get the intermediate(S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7-hydropyrido[1,2,3-de][1,4 ] Benzoxazine-6-carboxylic acid ethyl ester.
6-chloro-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
With dmap; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;
A solution of 7.5 g (43 mmol) of 3-chloro-6-oxo-1 H-pyridazine-5-carboxylic acid, 4.28 g (55 mmol) of (2S)-2-amino-1 -propanol, 32.7 g (86 mmol) of HATU, 22.5 ml. of ethyldiisopropylamine and 262 mg of 4-dimethylaminopyridine in 150 ml. of DMF was stirred over night at rt. The reaction mixture was quenched with water and extracted five times with dichloromethane. The combined organic phases were evaporated whereby a precipitate was formed. The precipitate was filtered off and dried to afford 2.21 g (22%) of the title compound. 1H NMR (400 MHz, DMSO-de) d ppm = 1.13 (d, 3 H), 3.38 - 3.47 (m, 2 H), 3.80 - 4.04 (m, 1 H), 4.92 (t, 1 H), 7.99 (s, 1 H), 9.32 - 9.55 (m, 1 H), 13.83 - 14.08 (m, 1 H).
5-methoxy-6-(methoxycarbonyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-3-carboxylic acid[ No CAS ]
[ 1335210-24-6 ]
Yield
Reaction Conditions
Operation in experiment
at 100℃;Flow reactor;
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 (25. Og, 0.079 moles) and methane sulfonic acid (3.79 g, 0.039 moles) were introduced in micro channel reactor. After residence time of 9 mins at l30C, the reaction mixture containing 5-methoxy-6-(methoxycarbonyl)-4-oxo-l-(2- oxoethyl)-l,4-dihydropyridine-3 -carboxylic acid (IVa) was further introduced into a second Tube Flow reactor and cyclised with solution of (S)-2-amino-propan-l- ol in (8.35g,0. l 1 moles) in Dimethyl carbonate at l00C at a residence time of 6 mins followed by quenching with Aq HC1 solution. The organic layer containing (3 S, 1 laR)-6-methoxy-3-methyl-5,7-dioxo-2,3,5,7,l 1,1 la-hexahydrooxazolo-[3,2- a] pyrido[ 1 ,2-ri/pyrazine -8-carboxylic acid (III b) was separated and introduced into a third Tube Flow Reactor with a solution of N-Methyl Morpholine (12. Og, 0.119 moles) and a solution of 2,4-diflurobenzylamine (l5.8g,0. l2moles) in MDC solvent and reacted in presence of Ethyl chloroformate (l2.06g,0. l l moles) at 0C . After a residence time of 2 mins yields (3S, l laR)-N-(2,4-Difluorobenzyl)- 6-methoxy-3-methyl-5,7-dioxo-2,3,5,7, l 1,1 la-hexahydrooxazolo-[3,2- a]pyrido[l,2- (0306) HPLC purity : 98.0% (0307) Yield : 85.0%.
Synthesis of chiral ligands.
General procedure: Thiophene-2-carbaldehydes1a and 1b, synthesized by the Vilsmeier-Haack method [66], were treated with both enantiomers of 2-aminopropanol (2) and norephedrine (3) to obtain chiral ligands 4-7 by the procedures in [55, 56]. (See Supplementary data for the 1H and 13C NMR of compounds 4-7). New compounds are described below. (R)-2-[(5-Methylthiophene-2-yl)methylamino]-propanol [(R)-4] was prepared from (R)-2-aminopropanol (5 mmol) and 5-methylthiophene-2-carbaldehyde (5 mmol). Yield 75 %,
Stage #1: (S)-Alaninol; 3-(2-pyridinyl)benzaldehyde In dichloromethane at 20℃; for 19h; Molecular sieve;
Stage #2: With N-Bromosuccinimide In dichloromethane at 20℃; for 3h; Molecular sieve;
(2S)-2-[4-chloro-6-(morpholin-4-yl)pyrimidin-2-yl]amino}propan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 70℃; for 12h;
To a stirred solution of <strong>[52127-83-0]4-(2,6-dichloropyrimidin-4-yl)morpholine</strong> (1.0 g, 4.28 mmol) in DMSO (15 mL) were added (S)-2-aminopropan-1-ol (420 mg, 5.56 mmol) and DIEA (830 mg, 6.42 mmol) at rt. The reaction mixture was stirred at 70 C for 12h. The resulting mixture was cooled to rt, diluted with water (30 mL) and extracted with EA (15 mL x 3). The combined organic layers was washed with brine (15 mL x 4), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by FCC (PE:EA = 1:1) to afford (S)-2-((4-chloro-6-morpholinopyrimidin-2-yl)amino)propan-1- ol (580 mg, 50%) as a white solid. MS Calcd.: 272, MS Found: 273 ([M+H]+).