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CAS No. : | 20989-17-7 | MDL No. : | MFCD00064404 |
Formula : | C8H11NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IJXJGQCXFSSHNL-MRVPVSSYSA-N |
M.W : | 137.18 | Pubchem ID : | 134797 |
Synonyms : |
(+)-Phenylglycinol
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 40.08 |
TPSA : | 46.25 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.04 cm/s |
Log Po/w (iLOGP) : | 1.3 |
Log Po/w (XLOGP3) : | 0.13 |
Log Po/w (WLOGP) : | 0.35 |
Log Po/w (MLOGP) : | 0.94 |
Log Po/w (SILICOS-IT) : | 0.98 |
Consensus Log Po/w : | 0.74 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.08 |
Solubility : | 11.3 mg/ml ; 0.0823 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.66 |
Solubility : | 30.2 mg/ml ; 0.22 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.89 |
Solubility : | 1.78 mg/ml ; 0.013 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.19 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: With N-ethyl-N,N-diisopropylamine In acetonitrile at 5 - 20℃; for 4.5 h; Stage #2: With hydrogenchloride In ethyl acetate at 15℃; for 0.333333 h; |
(5S)-5-Phenylmorpholin-2-one HCl salt A solution of phenyl bromoacetate (Aldrich, 862.17 g, 4.0 moles, 1.1 equivalents) in acetonitrile (reagent grade, 1500 ml) was cooled in an ice bath (internal temperature below 5° C.). To this was added a cold slurry (internal temperature below 5° C.) of S-(+)-2-phenyl glycinol (Aldrich, 500 g, 3.65 moles, 1 equivalent) and diisopropylethylamine (DIPEA) (Aldrich, 1587 ml, 9.11 moles, 2.5 equivalents) in acetonitrile (2900 ml) in portions while keeping the internal temperature below 10° C. The mixture was stirred at this temperature for 30 minutes before the ice bath was removed and the mixture was allowed to stir at room temperature for an additional 4 hours. The solvent was removed in vacuo while maintaining the bath temperature at 25° C. The mixture was coevaporated with ethyl acetate (2*500 ml) to produce a light yellow viscous oil. To the reaction mixture, ethyl acetate (4500 ml) was added and the flask was immersed in an ice bath with agitation. The mixture was allowed to cool below 8° C. The solid was filtered and washed with ethyl acetate (3*250 ml). The solution was cooled to below 5° C. Dry HCl gas was passed slowly into the solution while maintaining the internal temperature below 15° C. until the pH was below 2 (wet pH paper). The mixture was allowed to stir at this temperature and pH for an additional 20 minutes before the solid was suction filtered. The solid was washed with ethyl acetate (3×200 ml) and dried under high vacuum for about 20 hours. The yield was 412 g (53percent). 1H NMR was consistent with the (5S)-5-phenylmorpholin-2-one HCl salt. |
50% | Stage #1: With N-ethyl-N,N-diisopropylamine In acetonitrile at 10 - 20℃; Inert atmosphere Stage #2: With hydrogenchloride In ethyl acetate |
To a (S) + phenyl glycinol (100g) add N, N-diisopropylethylamine (314ml) and acetonitrile (2000ml) under nitrogen atmosphere at room temperature. It was cooled to 10- 15° C. Phenyl bromoacetate (172.4g) dissolved in acetonitrile (500ml) was added to the above solution at 15° C over a period of 30 min. The reaction mixture is allowed to room temperature and stirred for 16-20h. Progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature less than 25° C to get a residue. The residue was dissolved in ethyl acetate (1000ml) and stirred for 1 h at 15-20°C to obtain a white solid. The solid material obtained was filtered and washed with ethyl acetate (200ml). The filtrate was dried over anhydrous sodium sulphate (20g) and concentrated under reduced pressure at a water bath temperature less than 25° C to give crude compound (1000g) as brown syrup. The Crude brown syrup is converted to HCI salt by using HCI in ethyl acetate to afford 5-phenyl morpholine-2-one hydrochloride (44g) as a white solid. Yield: 50percent, Mass: m/z = 177.6; HPLC (percent Area Method): 90.5percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With N-ethyl-N,N-diisopropylamine; In acetonitrile;Inert atmosphere; | (5S)-5-Phenylmorpholin-2-One A solution of S-(+)-Phenyl glycinol (Aldrich, 10.17 g, 78.12 mmol) and Diisopropylethylamine (Aldrich, 34 mL, 195 mmol, 2.5 equivalents) was prepared in CH3CN (200 mL). This solution was added to phenyl-alpha-bromoacetate (18.48 g, 85.9 mnol, 1.1 equivalents) dissolved in CH3CN (50 mL) under nitrogen dropwise over 2 hours. The resulting solution was stirred under nitrogen for 16-20 hours. The solvent was removed by rotoevaporation keeping the bath temperature at below 25° C. To the oil was added ethyl acetate (120 mL) and the mixture was stirred for 15 minutes. The resulting white precipitate was filtered off and the solid washed with ethyl acetate (25 mL). The filtrate was rotoevaporated to an oil keeping the bath temperature below 25° C. After drying under vacuum for 0.5 hours, the oil was dissolved in CH2Cl2 (17 mL) and loaded onto a silica gel column (60 g packed with 10percent ethyl acetate/hexanes. The upper byproduct spots were eluted with 10percent ethyl acetate/hexanes and the product was eluted with 50percent ethyl acetate/hexanes-100percent ethyl acetate. The fractions containing the product were rotoevaporated to an oil keeping the bath temperature below 25° C. This oil was dissolved in ethyl acetate (12 mL) and hexanes (60 mL) was added slowly in an ice bath to precipitate the product. The resulting precipitate was filtered. The white to yellow solid was vacuum dried. The (5S)-5-phenylmorpholin-2-one obtained (7.4 g, 41.8 mmol, 53percent) was used directly in the next step. |
53% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at -5 - 20℃; for 20.5h;Inert atmosphere; | The raw material EGS-A0'18.48g was dissolved in 50 ml of acetonitrile at 25 to 30 °C and transferred into a 500 ml three-necked flask. The raw material EGS-A010.17g and DIPEA 34ml were dissolved in 200ml acetonitrile, and into the constant pressure titration funnel, nitrogen replacement 2 times, ice bath for 30min, the temperature dropped to -5 °C, drop EGS-A0 and DIPEA, dropping speed to control the internal temperature below 5 °C, dropping for about 2h, continue stirring for 30min, the nitrogen protection at room temperature for 20h, TLC (EA: EA = 1: 1; raw material Rf = 0.2 and 0.8; product Rf = 0.4) to the point where the starting material disappears, the reaction is terminated, the solvent in the reaction solution is vacuum dried at 20 °C. Add 10mlEA spin dry, repeat once, add 120mlEA, stirring, ice bath, cooling to below 8 , filter the solid, 10mlEA wash three times,The solvent was centrifuged at 20 ° C and dried on a PE: EA = 1: 1 column to give the title product (7.4 g, white solid) in 53percent yield. |
A flask was charged with (S)-2-amino-2-phenylethanol (100 g), acetonitrile (2000mL) and stirred for 10 minutes followed by addition of N-ethyl-diisopropyl amine (236 mL) and further stirring for 5-10 minutes. Then a mixture of <strong>[620-72-4]phenyl 2-bromoacetate</strong> (180 g) in acetonitrile (500 mL) was slowly added to the above reaction mixture at room temperature over a period of about 75 minutes. The mixture was maintained at room temperature for about 2.5 hours and then kept under cold conditions for further experimentation purpose. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; ethyl acetate; at 25 - 68℃;Heating / reflux; | Example 3 Preparation of the (S)-(+)-phenylglycinol salt of (S)-(+)-3-(carbamoylmethyl)-5- methylhexanoic acid.1O g (53.4 mmoles) of <strong>[181289-15-6]3-(carbamoylmethyl)-5-methylhexanoic acid</strong> racemate are added to a mixture of ethyl acetate (60 ml) and methanol (29 ml) at 25C. 6.6 g (48.1 mmoles) of (S)-(+)-phenylglycinol are added and the mixture heated to reflux temperature (68C) to obtain complete dissolution. The mixture is cooled slowly to 250C to obtain the crystallisation of the salt. The solid is filtered and washed with 30 ml of ethyl acetate. The wet product is dried at 40C for 6 hours giving 6.1 g of the (S)-(+)-phenylglycinol salt of (S)-(+)-<strong>[181289-15-6]3-(carbamoylmethyl)-5-methylhexanoic acid</strong> as a white solid. The filtration mother liquor (approx. 80 ml) is used to obtain the desired (R)-(-)-<strong>[181289-15-6]3-(carbamoylmethyl)-5-methylhexanoic acid</strong> enantiomer |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h; | (2S)-2-Amino-2-phenyl-ethanol (0.44g, 3. 2MMOL) was added to a solution of (2S)-2-tert- BUTOXYCARBONYLAMINO-SUCCINIC ACID-1-BENZYL ester (0.87g, 2. 7MMOL), 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.52g, 2. 7MMOL), 1- HYDROXYBENZOTRIAZOLE hydrate hydrate (0. 36G, 2. 6MMOL) and 4-METHYLMORPHOLINE (0.74mL, 6. 7MMOL) in dichloromethane (25mL) and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (20mL), washed with 2M hydrochloric acid (30mL), dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with DICHLOROMETHANE : methanol (95: 5) to yield the title product, 0.77g ; 'HNMR (DMSOD6, 400MHZ) : 1.26 (s, 9H), 2.60 (m, 2H), 3.48 (brs, 2H), 4.77 (m, 2H), 5.06 (s, 2H), 7.25 (m, 10H), 8.17-8. 38 (m, 2H); MS ES+ m/z 465 [MNa] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With triethylamine; In dimethyl sulfoxide; at 140℃; for 0.333333h;Microwave irradiation; | Example 10 (S)-2-(6-Methyl-5-nitro-pyridin-2-ylamino)-2-phenyl-ethanol 6-Chloro-3-nitro-2-picoline (22 mg, 0.13 mmol) was coupled with (2-amino-2-phenyl)- propanol (34 mg, 0.25 mmol) in triethylamine (0.030 mL, 0.25 mmol) in DMSO (1 mL). The reaction was heated to 140 °C for 1200 seconds in a microwave oven (Parameters : high absorbance, fixed holding time, pre-stirring 25 seconds). The mixture was diluted with 20 mL of EtOAc and then washed with NI-14CI (aq) three times. The organic phase was collected, dried with anhydrous MgSO4 and filtered. The dry organic phase was evaporated and purification on silica column with 5: 1 n-Heptane : EtOAc gave 22 mg (63percent) of (R)-2- (6-methyl-5-nitro-pyridin-2-ylamino) 2-phenyl-ethanol as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h; | Part A (S)4-(4-hydroxyphenoxy)benzoic Acid N-2-hydroxy-1-phenylethyl Amide A solution of 2-(1H-benxotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (706 mg, 2.2 mmol), 1-hydroxybenztriazole (54 mg, 0.4 mmol), diisopropylethylamine (1.29 g, 10.0 mmol), <strong>[500-76-5]4-(4-hydroxyphenoxy)benzoic acid</strong> (460 mg, 2.0 mmol) and (S) 2-hydroxy-1-phenylethylamine (302 mg, 2.2 mmol) in dimethylformamide (3.2 mL) was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, saturated sodium bicarbonate solution, and brine. The extract was dried with magnesium sulfate, filtered and concentrated to a white solid. Drying under high vacuum gave 756 mg of the title compound. LC-MS (m/z, APCI): 350 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With carbon disulfide; In potassium hydroxide; hexane; water; | a. 4-(S)-Phenyl-thiazolidine-2-thione To a solution of (S)-(+)-2-Phenylglycinol(1.40 g, 10 mmol) in 1N KOH/H2 O (10 ml) at room temperature, was added carbon disulfide (3 ml, 50 mmol). The resulting solution was heated by a pre-heated oil-bath (110 C.) to reflux for 20 h after which the reaction mixture was cooled to room temperature and extracted with CH2 Cl2 (3*30 ml), dried over Na2 SO4. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/CH2 Cl2 followed by CH2 Cl2 as the eluding system (Rf =0.09, CH2 Cl2:hexane=7:3) to obtain 4(S)-phenyl-thiazolidine-2-thione (170 mg, 9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In dichloromethane; | Example 4 Preparation of D-homophenylalanine. To a stirred solution of glyoxylic acid monohydrate (291 mg, 3.163 mmol) in dichloromethane (14 mL) was added (S)-(-)-2-phenylglycinol (434 mg, 3.163 mmol) in one portion. After 5 min (E)-2-phenylethenyl boronic acid (469 mg, 3.169 mmol) was added. and the reaction mixture was stirred vigorously at room temperature for 12 hours. The precipitate was isolated by filtration, washed with cold dichloromethane (15 mL) and acetone (10 mL) and dried under vacuum to give the expected adduct (733 mg, 78% yield, >99% de). 1H-NMR (360 MHz, d6-DMSO) delta 7.2-7.5 (m, 10H), 6.54 (d, J=15.2 Hz, 1H), 6.20 (dd, J=15.2 Hz, 7.3 Hz, 1H), 3.84 (m, 1H), 3.64 (d, J=7.3 Hz, 1H), 3.45 (d, J=7.1 Hz, 2H). 13-NMR (90 MHz, d6-DMSO) delta 172.83, 139.79, 136.23, 131.07, 128.62, 128.34, 127.68, 127.51, 126.95, 126.38, 126.25, 65.97, 63.02, 60.96. HRMS-CI(M++1) calcd 298.1365, obsd 298.1449. Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C, 72.27; H, 6.41 N, 4.69. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; for 24h; | 4-Pyridin-4-ylbenzoic acid (5.86 g, 29.4 mmol) was dissolved in 300 ml of THF. Subsequently, N-methylmorpholine (4.04 g, 29.5 mmol), (2S)-2-amino-2-phenylethanol (3.96 g, 29.3 mmol) and 1-hydroxybenzotriazol (3.96 g, 29.3 mmol) were added. Finally EDC (5.63 g, 29.4 mmol) was added over a period of 5 min and the heterogenic reaction mixture was stirred for 24 h, whereupon an oily precipitation occured. After evaporation of the solvent under reduced pressure the residue was dissolved in DCM (500 ml), washed twice with aqueous NaOH (50 ml of a 2 M solution) and subsequently with water. After drying the organic phase over sodium sulfate and evaporating the solvent under reduced pressure the raw title compound was obtained as an oily residue (8.4 g). Column chromatography (silica gel; eluent: EtOAc with an increasing amount of MeOH (0 up to 5percent)) yielded the pure title compound (5.2 g, yield: 56percent) as a white crystalline product.1H NMR (400 MHz, DMSO-d6): 8,83 (d, 1 H), 8,67 (d, 2H), 8,06 (d, 2H), 7,93 (d, 2H), 7,77 (d, 2H), 7,41 (d, 2H), 7,32 (dd, 2H), 7,23 (dd, 1 H), 5,14-5,07 (m, 1 H), 4,98 (t, 1 H), 3,79-3,63 (m, 2H). Formula: C20 Hi8 N2 O2 CaIc MW: 318,37 MS: m/z: 319.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; at 140℃; for 20h;Molecular sieve; | Synthesis 67; (S)-2-[(/?)-2-(4-Fluoro-phenyl)-piperidin-1-yl]-2-phenyl-ethanol hydrochloride <n="140"/>; 5-(4-Fluoro-phenyl)-5-oxo-pentanoic acid (1g, 5.10 mmol) and (S)-(+)-2-phenylglycinol (0.839 g, 6.12 mmol) in toluene (15 ml.) together with 4A molecular sieves was heated at 1400C under Dean-Stark conditions for 20 hours. The reaction mixture was filtered through Celite, evaporated and the residue dissolved in ethyl acetate then re- evaporated. The crude material was purified by column chromatography eluting with 20- 40% ethyl acetate in cyclohexane to afford (3S,8aS)-8a-(4-fluoro-phenyl)-3-phenyl- hexahydro-oxazolo[3,2-a]pyridin-5-one (1.08g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | Step (i): Synthesis of (S)-2-(2-chloro-6-phenyl-pyrimidin-4-ylamino)-2-phenyl-ethanol To <strong>[26032-72-4]2,4-dichloro-6-phenylpyrimidine</strong> (642 mg, 2.8 mmol), dissolved in 30 mL methanol, was added DIEA (0.41 mL, 3 mmol) and was stirred for 25 min at about 20-35 C. under a nitrogen atmosphere. To this mixture was added (S)-(+)-2-phenyl glycinol (411 mg, 3 mmol) and stirred for 22 h. An additional DIEA (0.41 mL, 3 mmol) was added, and the mixture was stirred for about 10-19 h. The mixture after concentrating by rotary evaporation and purification (Biotage Horizon HPFC system chromatography, SiO2, 35:65 EtOAc:hexane) gave the title compound as a white solid (367 mg, 39% yield).1H NMR (300 MHz, DMSO-d6): delta 8.43 (apt d, J=7.8 Hz, 1H), 7.92 (b s, 2H), 7.50-7.22 (m, 8H), 7.08 (s, 1H), 5.18 (b s, 1H), 5.03 (b s, 1H), 3.68 (b s, 2H).LC-MSD (ES+): m/z [326 (M+H)+, 100]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; for 4h;Inert atmosphere; Reflux; | Preparation of Example 72 - (3.pound.4fl)-iV-((y)-l-(6-methoxypyridin-2- yl)ethyl)-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxamide; (S)-I -(6-methoxypyridin-2-yl)ethanamine (51) was prepared by the following procedures.[0216] In a 250 mL of round bottom flask, equipped with Dean-Stark trap and a reflux condenser, 6-methoxypicolinaldehyde 45 (500 mg, 3.65 mmol), (S)-2 (+)- phenylglycinol 46 (500 mg, 3.65 mmol) and anhydrous THF (30 mL) were mixed and heated at reflux under argon for 4 h. (S,E)-2-((6-methoxypyridin-2-yl)methyleneamino)- 2-phenylethanol 47 was used directly in the next step without further purification.[0217] HDMS (470 mg, 2.92 mmol), (NH4)2SO4 (53 mg, 0.4 mmol) and anhydrous THF (15 mL) were added to compound 47 (934 mg, 3.65 mmol). The reaction mixture was heated at 800C for 2 h under argon. Then the solvent was removed in vacuo to afford crude (S,E)-N-((6-methoxypyridin-2-yl)methylene)-l-phenyl-2-(trimethylsilyloxy)ethanamine 48 (1.2 g).[0218] In a 100 mL of round bottom flask (flame-dried), at -78 "C, were added anhydrous THF (10 mL) and CH3MgBr (3.0 M in Et2O, 3.5 mL). At -50 0C, compound 48 (1.2 g, 3.65 mmL) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was stirred at -40 0C for 1 h, and at rt. for 1 h. The reaction was then quenched with a cold, sat. NH4Cl with stirring at 00C. EtOAc was added and layers were separated. The organic layer was concentrated to afford (S)-N-((S)-l-(6-methoxypyridin- 2-yl)ethyl)-l-phenyl-2-(trimethylsilyloxy)ethanamine 49 (1 g).[0219] A solution of compound 49 (1 g, 0.29 mmol) in THF was cooled to 0 °C, H2SO4 (2.5 M, 5 rnL) was added dropwise with stirring. The resulting mixture was stirred at rt. for 2 h. The mixture was basified with 2N NaOH at 0 °C and extracted with EtOAc (3 x 30 mL). Combined organic layers were dried over Na2SO4 and concentrated. The residue was purified with flash column (eluted with 30percent EtOAc/hexane) to give (S)- 2-((S)-l-(6-methoxypyridin-2-yl)ethylamino)-2-phenylethanol 50 (860 mg).[0220] Methylamine in water (40 percent in water, 10 mL) was added to a solution of compound 50 (860 m g, 3.16 mmol) in MeOH (15 mL). At 0 0C, H5IO6 (4.33 g,) in water (15 mL) was added dropwise. White precipitates were formed. The resulting mixture was stirred at rt overnight. EtOAc and water were added. Organic layer was separated, and aq. layer was extracted with EtOAc. Combined organic layers were concentrated. The crude product was purified by prep. HPLC to give (S)-I -(6- methoxypyridin-2-yl)ethanamine 51 (80 mg).[0221] Data for compound 51: 1H NMR (400 MHz, CD3OD) delta 7.62 (t, IH), 6.89 (d, IH), 6.64 (d, IH), 3.97 (m, IH), 3.90 (s, 3H), 1.42 (d, 3H). The above method can be used to prepare other chiral amines. For examples, the chiral amines used in Example 117, 118 and 120. Example 72[0223] Example 72 was prepared from (-)-5 (prepared from Procedure K) and (S)-l-(6-methoxypyridin-2-yl)ethanamine 51 using the similar procedures in Example 96. 1H NMR Data for Example 72 (see Table 5). Preparation of Example 91 - (3S,4R)-4-(3,4-dichlorophenyl)-N-((S)-l-(3- methoxyphenyl)ethyl)pyrrolidine-3-carboxamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With diisopropylamine; at 70℃;sealed tube; | Example IX. 2-chloro-6-[4-phenyl-2-(2-pyridyl)oxazolidin-3-yl]-4-(trifluoromethyl) pyridine-3-carbonitrile (Compound 18).; Step 1 : Synthesis of 2-chloro-6-[[l-(hydroxymethyl)-2-phenyl]amino]-4- (trifluoromethyl) pyridine-3-carbonitrile.; Neat 3-cyano-2,6-dichloro-4-trifluoromethylpyridine (0.641 g, 6 mmol) was added by pipette at a dropwise rate over 3 minutes to 2-amino-2-phenylethanol (1.5 g, 6 mmol). Di-isopropylamine (0.9 g, 7 mmol) was added after 10 minutes and the resultant mixture was heated in a sealed tube at 70 C for 30 minutes to selectively displace the chlorine at position 6 before quenching in ice-cold water and extracted with dichloromethane. Organic extracts were washed twice with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was washed with diethylether and the resultant solid was used in the next step without further purification. 2-Chloro-6-[[ 1 -(hydroxymethyl)-2-phenyl]amino]-4-(trifluoromethyl) pyridine-3-carbonitrile was isolated in 60 % yield.1HNMR (CDCl3, 400 MHz) delta / ppm7.42 - 7.33 (m, 5H), 6.51 (br, 2H), 4.06 - 4.03 (m, 1.4 H), 3.96 (br, 1.1 H), 1.89 (br, 0.96 H), 1.60 (m, 1.1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In methanol; at 115℃; for 12h;Sealed tube; | [60] In a sealed tube, a mixture of 1 [61] (2.74 g,10 mmol) and (R or S)-phenylglycinol (3.43 g, 25 mmol) in methanol (10 mL) was stirred at 115 C for 12 h. After cooling toroom temperature, the crude product was poured into ice water(100 mL), stirred for 15 min, filtered, washed with water(20 mL 3) and the residues was dried under vacuum. The whiteproduct was used for the next step without further purification (4.41 g, 91%). 1H NMR (400 MHz, CDCl3): d 8.60 (d, J 7.6 Hz, 2 H),8.45 (s, 2 H), 7.37-7.29 (m, 10 H), 5.26-5.22 (m, 2 H), 4.01 (d,J 4.4 Hz, 4 H), 2.21 (br, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With N-ethyl-N,N-diisopropylamine; 1,2-dichloro-benzene; In toluene; at 195℃; for 24h;Dean-Stark; | General procedure: A 250 mL round-bottomed flask containing a stirrer bar was chargedwith (R)-2-phenylglycinol [(R)-2; 10.00 g, 72.80 mmol, 1.05 equiv), odichlorobenzene(34.5 mL, 2.0 M), i-Pr2NEt (31.0 mL, 173.6 mmol, 2.5equiv), and <strong>[615-20-3]2-chlorobenzothiazole</strong> (1; 8.60 mL, 69.43 mmol, 1.0equiv). The resulting yellow suspension was stirred vigorously andheated to reflux at 195 C (DrySyn temperature), at which point thesuspended solid had dissolved to leave a yellow solution. After 24 h atreflux,24 the orange reaction mixture was allowed to cool to r.t. Oncecooled, the mixture was diluted with distilled H2O (100 mL) and toluene(75 mL) with vigorous stirring. A precipitate formed over the next15 min and stirring was maintained for a further 1 h. The reactionmixture was filtered through a 1.0 L sintered glass filter funnel (porosity3) under vacuum to leave the solid precipitate. The solid waswashed with toluene (2 × 100 mL) and dried on the sinter under vacuumfor 30 min until a free-flowing powder was obtained. The crudeproduct (typically 22-24 g) was transferred to a 500 mL round-bottomedflask containing a stirrer bar, followed by toluene (100 mL). A10 mL Dean-Stark trap filled with toluene and a reflux condenserwere fitted to the flask, and the suspension heated to reflux (180 CDrySyn temperature). Once at reflux, further 10 mL portions of toluenewere added down the condenser, waiting ~5 min between portions,until a clear solution was obtained (4-6 portions were typicallyneeded). The reflux was maintained until no further H2O was observedcondensing into the trap (typically 30 min were sufficient).The flask was removed from the heating block and allowed to coolslowly to r.t., over which time a precipitate formed. Once cooled, theflask was further cooled to -10 C in a NaCl/ice/water bath for 30 min.The solid precipitate was recovered by vacuum filtration on a 1.0 Lsintered glass filter funnel (porosity 3), and washed with further portionsof toluene (2 × 100 mL). The solid was dried on the sinter undervacuum for 30 min, then transferred to a 250 mL round-bottomedflask and dried in vacuo to constant weight. This gave title compound(R)-3 as fluffy white crystals; yield: 14.81 g (54.78 mmol, 79%). A secondrecrystallisation from toluene at reflux may be required if a powderis obtained from the first attempt. Typical mass loss on secondrecrystallisation was 99% ee.1H NMR (500 MHz, MeOH-d4): delta = 3.80 [1 H, dd, J = 11.4, 7.4 Hz,C(1)HAHB], 3.85 [1 H, dd, J 11.4, 5.0 Hz, C(1)HAHB], 5.00 [1 H, dd, J = 7.4,5.0 Hz, C(2)H], 7.03 (1 H, td, J = 7.5, 1.1 Hz, ArH), 7.22 (1 H, td, J = 7.5,1.2 Hz, ArH), 7.26 (1 H, t, J = 7.4 Hz, p-PhH), 7.34 (2 H, t, J = 7.4 Hz, m-PhH), 7.38 (1 H, d, J = 8.1 Hz, ArH), 7.44 (2 H, d, J = 7.4 Hz, o-PhH), 7.55(1 H, d, J = 7.8 Hz, ArH).13C{1H} NMR (126 MHz, MeOH-d4): delta = 62.2, 66.9, 119.0, 121.7, 122.7,126.8, 128.1, 128.6, 129.5, 131.3, 141.1, 153.0, 169.0.Anal. Calcd for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36. Found: C,66.57; H, 5.31; N, 10.33.1H and 13C NMR data were consistent with literature values.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; at 20℃; for 1h; | Example 11: Synthesis of 5-hydroxy-l-(2-hydroxy-l-(S)-phenyI-ethyI)-4- i-propyI-l,5- dihydro-pyrrol-2-one [Vile]; 5-Hydroxy-4-«-propyl-5H-furan-2-one (10.0 g) is dissolved in methanol (100 mL) and (S)- phenyl glycinol (9.71 g) is added to it at room temperature. The mixture is stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC, 1 : 1 ethyl acetate: hexane), the solvent is evaporated under reduced pressure in a rotary evaporator to afford 5- hydroxy- l -(2-hydroxy-l-phenyl-ethyl)-4-«-propyl-l ,5-dihydro-pyrrol-2-one as dark yellow oil(15.0 g).FTIR (neat): 3337, 2933, 1740, 1 167, 757 cm"1. NMR (CDCI3, 200 MHz): delta 0.90-0.98 (m, 3H), 1.47-1.71 (m, 2H), 2.29-2.40 (q, 2H), 3.50- 3.60 (t, 1 H), 3.72-3.74 (d, 1H), 4.31 (s, 1H), 5.77-5.80 (d, 1 H), 5.99 (s, 1 H), 7.30-7.36 (m, 5H). MS (EI): Ci5H,9N03: 261 ; [M+H]+: 262.30. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of N-Boc-cis-4-Fmoc-amino-L-proline (2.0 g, 4.42 mmol) in DMF cooled to 0 C. were sequentially added, DIPEA (3.86 mL, 22.10 mmol), HOBt (776 mg, 5.75 mmol) and HBTU (2.18 g, 5.75 mmol). After stirring for 10 minutes (S)-2-amino-2-phenylethanol (728 mg, 5.30 mmol) was added and the reaction mixture was stirred overnight at room temperature. Water and ethyl acetate were added, the organic layer was separated, washed with 10% citric acid, saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography provided intermediate 7-a as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | In toluene; for 72.0h;Reflux; | General procedure: A solution of <strong>[7500-53-0]o-phenylenediacetic acid</strong> (5, 300 mg, 1.54 mmol) and (R)-phenylglycinol (211 mg, 1.54 mmol) in toluene (40 mL) was heated to reflux for 3 days. Then the mixture was cooled, concentrated in vacuum, and the residue was dissolved in EtOAc (50 mL). The solution was washed with 1 M NaOH (3×15 mL), the aqueous layer was extracted thrice with EtOAc and the combined EtOAc layers were washed with 1 M HCl (3×15 mL). The organic layer was dried (Na2SO4), concentrated in vacuo, and the residue was purified by fc (d=2 cm, l=25 cm, V=25 mL, cyclohexane/EtOAc 80:20, Rf=0.33 (petroleum ether/EtOAc 1:1). The product was further purified by recrystallization (CH2Cl2/n-hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53%; 24% | With carbon tetrabromide; triethylamine; triphenylphosphine; In toluene; at 90℃; for 14.0h;Inert atmosphere; | General procedure: A 200 mL three-necked flask equipped with a condenser was charged with Ph3P (2.20 g, 8.4 mmol), Et3N (0.85 g, 8.4 mmol), CBr4 (16.8 g, 8.4 mmol), substrate 1 (3.3 mmol), and aromatic acid 2 (2.8 mmol) in toluene (15.0 mL) under a nitrogen atmosphere. The solution was stirred for approximately 20 min at room temperature, then the mixture was heated at 90 C with stirring for 6-14 h. The solvent was evaporated under reduced pressure, and the residue was diluted with petroleum ether (60-90 C) and filtered. The residual solid Ph3PO and Et3N·HBr was washed with petroleum ether three times. The filtrate was concentrated, and the residue was separated by column chromatography (ethyl acetate/petroleum ether, 1:8) to afford product 3 and 3?. If the mixture was processed after stirring for 0.5 h at 90 C, intermediate 6 was obtained by column chromatography (ethyl acetate/petroleum ether=1:8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With carbon tetrabromide; triethylamine; triphenylphosphine; In toluene; at 0 - 90℃;Inert atmosphere; | General procedure: A 200 mL three-necked flask equipped with a condenser was charged with Ph3P (2.20 g, 8.4 mmol), Et3N (1.42 g, 14.0 mmol), CBr4 (16.8 g, 8.4 mmol), substrate 1 (3.3 mmol), and fluorinated carboxylic acid 2 (2.8 mmol) in toluene (15.0 mL) under a nitrogen atmosphere. The solution was stirred for about 20 min under 0 C, then the mixture was heated at 90 C with stirring for 18-55 h. The solvent was evaporated under reduced pressure, and the residue was diluted with petroleum ether (60-90 C) and filtered. The residual solid Ph3PO and Et3N·HBr was washed with petroleum ether three times. The filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate/petroleum ether, 1:8) to afford product 4. If the mixture of Ph3P (2.20 g, 8.4 mmol), Et3N (1.42 g, 14.0 mmol), CCl4 (15 mL), substrate 1 (3.3 mmol), and trifluoroacetic acid 2k (2.8 mmol) in toluene (15.0 mL) was processed after stirring for 2 h at 90 C, intermediate 8k and 9k? were obtained by column chromatography (ethyl acetate/petroleum ether=1:8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In ethanol; for 3h;Reflux; | General procedure: A solution of 5 mmol of R(-)-phenylglycinol 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 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; | At room temperature, the compound 4-chloro-6-bromo-thieno [2,3-d] pyrimidine (1g, 4.0mmol) and L- glycine benzyl alcohol (1g, 7.2mmol) Was dissolved in N, N- dimethylformamide (20ml, 0.259mol) was added dropwise 1ml triethylamine (363mg, 7.19mmol), Stirred at room temperature until the reaction was complete as monitored by TLC starting material, was added 200ml of water, vacuum filtration, the cake was washed with water (100ml * 2) : The compound 2- (6-bromo - thieno [2,3-d] pyrimidin-4-yl-amine) -2-phenyl-1- ethanol (1.3 g of, as a pale yellow solid), yield: 93% |
86% | In butan-1-ol; at 145℃; for 24h; | General procedure: Compound 1 (1.00 g, 4.01 mmol) was mixed with the benzylamine (12.03 mmol) and 1-butanol (3.5 mL) and agitated at 145 C for 18-24 h. Then the mixture was cooled to rt, diluted with water (50 mL) and diethyl ether (150 mL) or EtOAc (150 mL). After phase separation, the water phase was extracted with more diethyl ether (2 × 50 mL) or EtOAc (2 × 50 mL). The combined organic phases were washed with saturated aq NaCl solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo, before the crude oil was dried under reduced pressure to constant weight to remove excess benzylamine. The compounds were purified by silica-gel column chromatography or crystallized as specified for each individual compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In butan-1-ol; at 145℃; | General procedure: Compound 1a-d or 54 (1 mmol) was mixed with the selected amine, 2-25, (3 mmol) and n-butanol (5 ml) and agitated at145 C for 14-24 h. Then the mixture was cooled to 22 C, dilutedwith water (15 ml) and ethyl acetate (40 ml). After phase separation,the water phase was back extracted with more ethyl acetate(2 10 ml). The combined organic phases were washed with brine(10 ml), dried over anhydrous Na2SO4, filtered and concentrated invacuo, before the crude mixture was purified as specified for eachindividual compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | (5S)-5-Phenylmorpholin-2-one HCl salt A solution of phenyl bromoacetate (Aldrich, 862.17 g, 4.0 moles, 1.1 equivalents) in acetonitrile (reagent grade, 1500 ml) was cooled in an ice bath (internal temperature below 5° C.). To this was added a cold slurry (internal temperature below 5° C.) of S-(+)-2-phenyl glycinol (Aldrich, 500 g, 3.65 moles, 1 equivalent) and diisopropylethylamine (DIPEA) (Aldrich, 1587 ml, 9.11 moles, 2.5 equivalents) in acetonitrile (2900 ml) in portions while keeping the internal temperature below 10° C. The mixture was stirred at this temperature for 30 minutes before the ice bath was removed and the mixture was allowed to stir at room temperature for an additional 4 hours. The solvent was removed in vacuo while maintaining the bath temperature at 25° C. The mixture was coevaporated with ethyl acetate (2*500 ml) to produce a light yellow viscous oil. To the reaction mixture, ethyl acetate (4500 ml) was added and the flask was immersed in an ice bath with agitation. The mixture was allowed to cool below 8° C. The solid was filtered and washed with ethyl acetate (3*250 ml). The solution was cooled to below 5° C. Dry HCl gas was passed slowly into the solution while maintaining the internal temperature below 15° C. until the pH was below 2 (wet pH paper). The mixture was allowed to stir at this temperature and pH for an additional 20 minutes before the solid was suction filtered. The solid was washed with ethyl acetate (3×200 ml) and dried under high vacuum for about 20 hours. The yield was 412 g (53percent). 1H NMR was consistent with the (5S)-5-phenylmorpholin-2-one HCl salt. | |
50% | To a (S) + phenyl glycinol (100g) add N, N-diisopropylethylamine (314ml) and acetonitrile (2000ml) under nitrogen atmosphere at room temperature. It was cooled to 10- 15° C. Phenyl bromoacetate (172.4g) dissolved in acetonitrile (500ml) was added to the above solution at 15° C over a period of 30 min. The reaction mixture is allowed to room temperature and stirred for 16-20h. Progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature less than 25° C to get a residue. The residue was dissolved in ethyl acetate (1000ml) and stirred for 1 h at 15-20°C to obtain a white solid. The solid material obtained was filtered and washed with ethyl acetate (200ml). The filtrate was dried over anhydrous sodium sulphate (20g) and concentrated under reduced pressure at a water bath temperature less than 25° C to give crude compound (1000g) as brown syrup. The Crude brown syrup is converted to HCI salt by using HCI in ethyl acetate to afford 5-phenyl morpholine-2-one hydrochloride (44g) as a white solid. Yield: 50percent, Mass: m/z = 177.6; HPLC (percent Area Method): 90.5percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In isopropyl alcohol; at 80℃; for 23h;Inert atmosphere; | General procedure: Compound 1 (1.00 g, 4.01 mmol) was mixed with the benzylamine (2-3 eq.) and i-PrOH (2-10 mL) and agitated at 80 C for 1-50 h, under nitrogen atmosphere. Then the mixture was cooled to rt, concentrated in vacuo, diluted with water (50 mL) and diethyl ether (100 mL) or EtOAc (100 mL). After phase separation, the water phase was extracted with more diethyl ether (2×50 mL) or EtOAc (2×50 mL). The combined organic phases were washed with saturated aq NaCl solution (25-50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude oil was purified by drying under reduced pressure to constant weight, by silica-gel column chromatography or crystallized as specified for each individual compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | In water; tert-butyl alcohol; at 70℃; for 16h;Inert atmosphere; | [0053] Example J. Synthesis of (2S)-2-[({4-amino-5H-pyrrolo[3,2-d]pyrimidin-7- yl}methyl)amino]-2-phenylethan-l-ol (J. l). (0088) (0089) [0054] (2S)-2-[({4-Amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl}methyl)amino]-2- phenylethan-l-ol (J. l). (25)-2-Amino-2-phenyl-ethanol (0.150 g, 1.09 mmol) 9- <strong>[2227-98-7]deazaadenine</strong> (0.147 g, 1.10 mmol), and aq. formaldehyde solution (37%, 0.098 mL, 1.31 mmol) were stirred and heated in tert-butanol (3 mL) at 70 C for 16 h. Silica gel was added to absorb all the solvent then the solvent was evaporated and the residue purified by chromatography on silica gel (CHC13-7M NH3/MeOH, 92:8 then 89: 11 then 85: 15) to afford J.l as a colourless foam (0.117 g, 38%). NMR (500 MHz, CD3OD): delta 8.14 (s, 1H), 7.38- 7.31 (m, 5H), 7.28-7.24 (m, 1H), 3.88-3.82 (m, 2H), 3.75 (d, J= 13.8 Hz, 1H), 3.65 (dd, J = 11.0, 4.9 Hz, 1H), 3.60 (dd, J = 11.0, 8.4 Hz, 1H). 13C NMR (125.7 MHz, CD3OD, centre line delta 49.0): delta 152.0 (C), 150.8 (CH), 146.6 (C), 141.5 (C), 129.6 (CH), 129.0 (CH), 128.8 (CH), 128.6 (CH), 115.5 (C), 114.7 (C), 67.7 (CH2), 65.4 (CH), 41.7 (CH2). ESI-HRMS calcd for Ci5H18N50+, (M+H)+, 284.1506, found 284.1501. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With triethylamine; In N,N-dimethyl-formamide; at 60℃; | At room temperature, the compound 6-bromo-4-chloro-thieno [3,2-d] pyrimidine (2g, 8.01mmol) and L- glycine benzyl alcohol (1.65g, 12.02mmol) Was dissolved in N, N- dimethylformamide (25ml, 0.32mol) was added dropwise 2.8ml of triethylamine (2.03 g of, 20.025mmol), Heated to 60 C until the starting material the reaction was complete as monitored by TLC, cooled to room temperature, 100ml of water was added Washed with dichloromethane (3 * 100ml) extraction, (100ml * 2) The organic phase was washed with saturated brine, the resulting organic Phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, to give: compound 2- (6-bromo - thieno [3,2-d] pyrimidin-4-ylamine) -2- 1- phenyl ethanol (1.7g, pale yellow solid), yield: 61%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A flask was charged with (S)-2-amino-2-phenylethanol (25 g) and acetonitrile (400 mL), diisopropylethyl amine (47.lg) at room temperature. The mixture was allowed to cool to about 16°C followed by slow addition of a solution of phenyibromoacetate (43.lg) in acetonitrile (125 mL) over a period of 30 minutes. The reaction mixture is stirred at the same temperature for about 2 hours at which point completion of the reaction was checked by HPLC. Then, 2,3-dihydrobenzo[b][1 ,4]dioxine-6-carbaldehyde (59.8 g) was added to the mixture and temperature was increased to reflux point. The reaction mixture was stirred at reflux temperature for about 4 hours. The solvent was completely distilled and the obtained mixture was maintained at 110°C for about 2 hours and then cooled to room temperature followed by addition of ethyl acetate (250 mL) and water (250 mL). The organic layer was separated and washed with 5percent aqueous sodium hydroxide solution (250 mL), then water (250 mL). The organic layer was subjected to complete distillation under vacuum at 55°C. To the obtained crude compound, toluene (37.5 mL) was added and mixture was cooled to 5°C under stirring. Then methanol (60 mL) was added at the same temperature, the solid obtained was filtered and washed with chilled methanol (25 mL), dried under vacuum to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A solution of 9a-d (2 mmol), EDCI (3 mmol) and HOBt (3 mmol) in dry DCM (20 mL) was stirred at 0C for 3.5 h. Then different substituted amines (2.2 mmol) and DIPEA (4 mmol) were added and the reaction was stirred at r.t. for another 1.5 h. The organic layer was washed with water and brine and dried over Na2SO4. Removal of the solvent gave a residue that was purified by column chromatography (silica gel, CH2Cl2-MeOH 100: 1 as an eluent) to furnish 10a-n as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A solution of 9a-d (2 mmol), EDCI (3 mmol) and HOBt (3 mmol) in dry DCM (20 mL) was stirred at 0C for 3.5 h. Then different substituted amines (2.2 mmol) and DIPEA (4 mmol) were added and the reaction was stirred at r.t. for another 1.5 h. The organic layer was washed with water and brine and dried over Na2SO4. Removal of the solvent gave a residue that was purified by column chromatography (silica gel, CH2Cl2-MeOH 100: 1 as an eluent) to furnish 10a-n as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | N-Cbz-2-methylalanine 26 (8.43 mmol, 2 g) wasdissolved in THF (70 mL) and the solution was cooled in an ice bath. NMethylmorpholine(9.27 mmol, 1.02 mL) was then added, followed byisobutylchloroformate (9.27 mmol, 1.22 mL). The resulting mixture wasallowed to stir at 0 C for 1 h. (S)-2-Phenylglycinol 17 (8.43 mmol, 1.16 g;dissolved in 14 mL of THF) was then added dropwise and the reaction mixture gradually warmed to roomtemperature. After stirring for 10 h, the white solid formed was filtered out and the filtrate was washedwith water. Combined organics were dried over anhydrous sodium sulfate, filtered, concentrated andpurified by flash chromatography to give the product as a white solid in 90% yield (Rf = 0.30 inHexanes/EtOAc 30:70 v/v). [alpha]D25 +2.2 (c 0.5, CHCl3); IR (KBr) 3306, 3032, 2941, 1538, 1519, 1258,1088 cm-1; 1H NMR (500 MHz, CDCl3) delta 7.36-7.26 (comp, 6H), 7.26- 7.16 (comp, 4H), 6.90 (br s, 1H),5.63 (s, 1H), 5.12-4.96 (comp, 3H), 3.87-3.80 (m, 1H), 3.64 (dd, J = 11.6, 6.7 Hz, 1H), 3.05 (br s, 1H),1.52 (s, 3H), 1.48 (s, 3H); 13C NMR (125 MHz, CDCl3) delta 174.3, 155.5, 138.9, 136.0, 128.6, 128.5, 128.2,128.1, 127.6, 126.6, 66.9, 65.7, 57.1, 55.5, 25.9, 25.0; HRMS (ESI) m/z calculated for C20H24N2NaO4 [M+ Na]+ 379.1628, found 379.1633. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 3h; | To a 200 mL round bottom flask equipped with a stir bar and charged with a solution of <strong>[51940-64-8]ethyl 2,4-dichloropyrimidine-5-carboxylate</strong> (6.00 g, 27.1 mmol) in acetonitrile (80 mL) was added Hiinig's base (9.46 mL, 54.3 mmol) followed by (5)-2-amino-2- phenylethanol (3.91 g, 28.5 mmol). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and purified using silica gel chromatography eluting with a gradient from 0 to 50% EtOAc in hexanes to afford ( (0402) [M+H]+. NMR (400 MHz, CDCh) delta 9.18 (br d, J=7.8 Hz, 1H), 8.72 (s, 1H), 7.45- 7.39 (m, 4H), 7.38-7.32 (m, 1H), 5.51 (dt, J=8.0, 4.9 Hz, 1H), 4.47-4.35 (m, 2H), 4.07- 3.96 (m, 2H), 2.06 (br d, J=7.5 Hz, 1H), 1.42 (t, J=7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 50℃; for 72h;Inert atmosphere; | A solution of <strong>[65973-52-6]methyl 4,6-dichloronicotinate</strong> (1.5 g, 7.3 mmol), ( |
Tags: 20989-17-7 synthesis path| 20989-17-7 SDS| 20989-17-7 COA| 20989-17-7 purity| 20989-17-7 application| 20989-17-7 NMR| 20989-17-7 COA| 20989-17-7 structure
A812348[ 88026-82-8 ]
(S)-2-Amino-2-phenylethan-1-ol hydrochloride
Reason: Free-salt
[ 1256974-17-0 ]
(S)-2-Amino-2-(p-tolyl)ethanol hydrochloride
Similarity: 0.97
[ 1810074-71-5 ]
(S)-2-(Methylamino)-2-phenylethanol hydrochloride
Similarity: 0.85
[ 1245623-77-1 ]
(R)-3-(1-Amino-2-hydroxyethyl)benzonitrile hydrochloride
Similarity: 0.81
[ 146812-68-2 ]
3-(1-Amino-2-hydroxyethyl)phenol hydrochloride
Similarity: 0.81
[ 1391355-45-5 ]
(R)-4-(1-Amino-2-hydroxyethyl)phenol hydrochloride
Similarity: 0.81
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P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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