* 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.
L-tyrosine methyl ester hydrochloride (1.16 g, 5 mmol) and concentrated aqueous ammonia (40 mL) were added to a 50 ml reaction vessel and stirred for 4 h at room temperature. Rotary evaporation of ammonia, spin dry, with anhydrous ethanol (20mL × 2) with water, column chromatography (silica gel, 200-300 mesh; exhibition Preparative, ethyl acetate: methanol: aqueous ammonia = 300: 10: 15) gave L-tyrosinamide in 86percent yield.
Reference：
[1] Patent: CN107501114, 2017, A, . Location in patent: Paragraph 0059; 0060; 0061
[2] Fermentforschung, 1933, vol. 13, p. 262,274 Anm. 1
2
[ 3417-91-2 ]
[ 501-53-1 ]
[ 13512-31-7 ]
Yield
Reaction Conditions
Operation in experiment
390 g
With sodium carbonate In water; ethyl acetate
To the above-obtained solid Tyr-OMe · HCl (tyrosine hydrochloride), 300 g of AcOEt (ethyl acetate) was added, 100 g of Na2CO3 (sodium carbonate) was added with stirring, 50 g of water was added,And 230 g of Z-Cl (benzyl chloroformate) was slowly added dropwise.Control system pH = 8, by TLC (thin layer chromatography) to the reaction system without Tyr-OMe · HCl (tyrosine hydrochloride), after adding citric acid, acidified to pH = 3, static layer , The ester layer was washed with salt water as neutral.The ester layer was added with 20 ~ 50g anhydrous Na2SO4 (anhydrous sodium sulfate), stirred and dried for 4 hours. Na2SO4 (sodium sulfate) was removed by filtration. The filtrate was concentrated and then added to a crystallization kettle. The hot water was concentrated to dryness.Add PET (petroleum ether) 200g, stirring crystallization is completed.The white crystals of the white crystals Z-L-Tyr-OMe (N-benzyloxycarbonyl-L-tyrosine methyl ester) were filtered and dried to dryness to dryness of 390 g and water at 4percent.
Reference：
[1] Journal of the American Chemical Society, 2004, vol. 126, # 32, p. 10162 - 10173
[2] Croatica Chemica Acta, 2003, vol. 76, # 1, p. 23 - 36
[3] Journal of Organic Chemistry, 1986, vol. 51, # 14, p. 2728 - 2735
[4] Journal of the American Chemical Society, 2004, vol. 126, # 40, p. 12897 - 12906
[5] Patent: CN103833593, 2016, B, . Location in patent: Paragraph 0045; 0047
[6] Journal of Medicinal Chemistry, 2018, vol. 61, # 17, p. 7929 - 7941
3
[ 13139-17-8 ]
[ 3417-91-2 ]
[ 13512-31-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 16, p. 4041 - 4053
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 24, p. 5449 - 5460
With CuZn0.3Mg0.1AlO(x); hydrogen In ethanol at 80℃; for 10 h; Autoclave
General procedure: The activity of catalyst for hydrogenation of R-phenylglycinemethyl ester was tested in a 0.5 L stainless steelautoclave under stirring at a speed of 500rpm. After 1g catalyst (20–40 mesh) was put in the reactor, the reactorwas swept with H2 five times to flush out air. Thenthe catalyst was reduced at 1MPa H2and 250 °C for 4h. After the autoclave was cooled in H2atmosphere to roomtemperature, 1.5g R-phenylglycine methyl esters (R-p-m)diluted in 150 mL ethanol was added (R-p-m/Cat = 1.5,wt.). The typical reaction conditions were at 5 MPa of H2 and 80 °C for 10 h. After the reaction was ended, theautoclave was cooled in H2atmosphere to room temperature.Then solid catalyst was separated by centrifugation.The product was purified by column chromatography on silica gel with ethyl acetate/methanol (3/2, v/v) as the eluent.Thus we obtained the light yellow powder product byrotary evaporation. Reactants and products were analyzedby High Performance Liquid Chromatograph (HPLC, Agilent1260 Infinity) equipped with an ultraviolet detector anda column (Eclipse XDB-C18, 150 × 4.6mm, 5mm particlesize), then the conversion of R-phenylglycine methyl ester(X), yield (Y) and chemoselectivity to R-phenylglycinol (S)were calculated [18, 19], in which the yield is the LC yield.And the ee value of products was determined by HPLCequipped with an ultraviolet detector (wavelength 258nm)and a chiral column (CHIRALPAK AY-H, 250 × 4.6mm,5m particle size) [19].
General procedure: The methyl-esterification reaction of L-phenylalanine.To a suspension of L-phenylalanine (1 g, 6.05 mmol, 1.0 equiv) inmethanol (25 mL) cooled to 0 C was added thionyl chloride(475 mL, 6.66 mmol, 1.5 equiv) slowly. After 10 min, the reactionmixture was heated to 75 C to reflux for 2 h. After completion(monitored by TLC), the solvent was removed in vacuo, and at thistime, a white solid was formed methyl L-phenylalaninate hydrochloride(1.23 g, quantitative yield).
99.7%
at 0℃; for 5 h; Reflux
The L- tyrosine (110g, 0.607mol) was added to 500mL of methanol, cooled to 0 deg.] C, was added dropwise thionyl chloride (108.3g, 0.91mol). After the dropwise addition to naturally warm to room temperature and then the reaction was heated at reflux for 5h, TLC monitored the reaction was complete. It cooled to room temperature, filtered, the filter cake washed with 420mL of ethyl acetate with drying of 140.2 g of a white solid, a yield of 99.7percent.
99%
Stage #1: for 0.5 h; Cooling with ice Stage #2: for 4 h; Reflux
In an ice bath, acetyl chloride (21.32 mL, 300 mmol) was added into 200 mL anhydrous methanol slowly. After stirred for 30 min, L-tyrosine (18.1 g, 100 mmol) was added into the solution. Then the solution was reuxed for 4 h in an oil bath and the solvent was removed under reduced pressure. The residue was added some acetone and filtered to give 22.78 g of L-tyrosine methyl ester hydrochloride as a white powder, yield: 99percent. Di-tert-butyl dicarbonate (11.34 g, 52 mmol) in 50 mL 1,4-dioxane was slowly added into the solution of L-tyrosine methyl ester hydrochloride (9.26 g,40 mmol), K2CO3 (8.28 g, 60 mmol) in 160 mL mixture solvent (1,4-dioxane–H2O = 1:1). After stirred overnight at room temperature, the reaction mixture was concentrated under reduced pressure and EtOAc was added. The EtOAc layer was washed by 1 N citric acid, saturated NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and concentrated to give compound 2 as a white powder. It could be directly used in the further steps without purication.
96%
at 0℃; for 12 h; Reflux
Step A. Synthesis of L-p-tyrosine-methyl ester hydrochloride (2) and various isomers of (2) (D-p-tyr, DL-σ-tyr, L-m-fyr))[0094] A solution of tyrosine 1 (D-p-, DL-o-, L-m- or L-p-, 1.67 mmol) in anhydrous methanol was stirred at 00C. Thionyl chloride (5.00 mmol) was then added dropely. The mixture was heated to reflux for 12 h. Then, the solvent was evaporated and recristalized in diethyl ether. The desired compound was filtered, washed with cold ether and dried in a dessicator for a 1 day. The crude hydrochloric acid salt, obtained in a 100percent yield, was pure enough to be used as such in the next step.L-p-tyrosine methyl ester hydrochloride (2)IR (KBr, vmax, cm"1) : 3354 (N-H), 3078 (O-H), 1742 (C=O ester), 1224 (CO-O-C).1H-NMR (DMSCM6, .pound.ppm) : 9.46 (IH, br s, OH), 8.60 (3H, br s, NH3), 7.01 (2H, d, J = 8.6 Hz, 3-CH tyr), 6.73 (2H, d, J = 8.60 Hz, 2-CH tyr), 4.16 (IH, m, CHNH3),3.67 (3H, s, OCH3), 3.03 (2H, m, CH2CH).13C-NMR (DMSO-^6, .pound. ppm) : 170.1 (COOCH3), 157.4 (1-C tyr), 131.0 (2C, 3-C tyr), 125.0 (4-C tyr), 116.1 (2C, 2-C tyr), 54.1 (CHNH3), 53.2 (OCH3), 35.7(CH2CH).ESI+ HRMS: [M + H]+ calculated for C10H14NO3 = 196.0968; found = 196.0968.
91.6%
at 0 - 20℃; for 24 h;
Thionyl chloride (10 mL, 139 mmol) was added drop-wise to a stirred solution of L-tyrosine (10.0 g, 55.25 mmol) in dry MeOH (100 mL) at 0 C and the reaction mixture was stirred at ambient temperature for 24 h. Volatiles were removed under diminished pressure to afford L-tyrosine methyl ester hydrochloride (IUPAC name: methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate hydrochloride) as a white solid (11.73 g, 91.6 percent yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.49 (brs, 1H), 8.66 (brs, 3H), 7.0 (d,J = 8.4 Hz, 2H), 6.76–6.68 (m, 2H), 4.19–4.06 (m, 1H), 3.65 (s, 3H), 3.11 (dd, J = 14.1 Hz, J = 5.7 Hz, 1H), 3.02–2.95 (dd, J = 14.1 Hz, J = 7.1, 1H). 13C NMR (100 MHz, DMSO-d6), δ: 35.08, 52.51, 53.47, 115.43, 124.34, 130.36, 156.70, 169.44.
90%
Stage #1: at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 0 - 20℃; for 36 h; Inert atmosphere
SOCl2 (906 mL, 12.5 mmol) was added to anhydrous MeOH (18mL) in an ice-water bath. After 30 min, L-tyrosine (0.906 g, 5.00mmol) was added, and the mixture was stirred at room temperaturefor 36 h. After removal of the solvent, the residue was purifiedby silica gel chromatography (CHCl3:MeOH = 14:1?12:1?5:1?0:1) to afford L-tyrosine methyl ester hydrochloride (b, 0.876g, 90percent) as a white powder
84%
for 24 h; Reflux
(2S)-3-(4-hydroxyphenyl)-1-methoxy-1-oxopropan-2-aminium chlorideThionyl chloride (6.62 mmol, 0.48 mL) was added dropwise to a solution of L- tyrosine (0.600 g, 3.31 mmol) in methanol (22 mL). The reaction was heated to reflux with vigorous stirring for 24 h. After cooling, the reaction mixture was concentrated under reduced pressure and the residual methanol removed by azeotropic distillation with dichloromethane (10 mL) under reduced pressure to give the title compound as a white solid (0.646 g, 84percent).*H NMR (500 MHz, D20) δ = 7.08 (2H, d, J=7.7, 6, 7-H), 6.83 (2H, d, J=7.7, 8, 9-H), 4.31 (1 H, t, =5.9, 2-H), 3.76 (3H, s, 1 1-H), 3.24 - 3.02 (2H, m, 4-H).13C NMR (126 MHz, D20) δ = 170.1 (2-C), 155.2 (10-C), 130.8 (6, 7-CH), 125.4 (5- C), 116.0 (8, 9-CH), 54.2 (2-CH), 53.5 (11-CH3), 34.8 (4-CH2).IR (diamond, vMAX, cm 1) 3335 (NH st), 2877 (N+-H st), 1983 (Ar comb), 1741 (C=0 st), 1225 (CO-0 st as), 1199 (C-0 st as).Acc. Mass (FAB): CwriuN03 Found: 196.0962 m/z Calculated: 196.0966 fz.
84%
for 24 h; Reflux
Thionyl chloride (6.62 mmol, 0.48 mL) was added dropwise to a solution of L-tyrosine (0.600 g, 3.31 mmol) in methanol (22 mL). The reaction was heated to reflux with vigorous stirring for 24 h. After cooling, the reaction mixture was concentrated under reduced pressure and the residual methanol removed by azeotropic distillation with dichloromethane (10 mL) under reduced pressure to give the title compound as a white solid (0.646 g, 84percent). [0422] 1H NMR (500 MHz, D2O) δ=7.08 (2H, d, J=7.7, 6, 7-H), 6.83 (2H, d, J=7.7, 8, 9-H), 4.31 (1H, t, J=5.9, 2-H), 3.76 (3H, s, 11-H), 3.24-3.02 (2H, m, 4-H). [0423] 13C NMR (126 MHz, D2O) δ=170.1 (2-C), 155.2 (10-C), 130.8 (6,7-CH), 125.4 (5-C), 116.0 (8,9-CH), 54.2 (2-CH), 53.5 (11-CH3), 34.8 (4-CH2). [0424] IR (diamond, vmax, cm−1) 3335 (NH st), 2877 (N+-H st), 1983 (Ar comb), 1741 (C═O st), 1225 (CO—O st as), 1199 (C—O st as). [0425] Acc. Mass (FAB): C10H14NO3Found: 196.0962 m/z Calculated: 196.0968 m/z.
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13
[ 67-56-1 ]
[ 3417-91-2 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 0℃; Reflux
General procedure: Compounds 6–8 were synthesized using the following general procedure reported by Maiti and Banerjee [50]: a solution of amino acid (18.2mmol) in MeOH (20mL) was stirred at 0°C. Thionyl chloride (1.6mL, 22mmol) was added dropwise over 10min. The reaction mixture was then allowed to warm to room temperature before being heated under reflux for 3h. The solvent and volatiles were evaporated under reduced pressure and the product was triturated with ethyl acetate to give the methyl ester hydrochloride salt as a colorless solid (100percent). 7.29 (S)-Methyl 2-amino-3-(4-hydroxyphenyl)propanoate hydrochloride (8) White solid, 4.21 g (100percent). 1H NMR (300 MHz, DMSO-d6): δ 9.47 (1H, bs, OH), 8.63 (3H, bs, NH3), 7.00 (2H, d, J = 8.5 Hz, Ar-H), 6.71 (2H, d, J = 8.5 Hz, Ar-H), 4.13 (1H, t, J = 5.8 Hz, CHNH3), 3.65 (3H, s, OCH3), 3.07 (1H, dd, J = 15.0, 5.6 Hz, CHAHBCHN), 2.97 (1H, dd, J = 15.0, 7.2 Hz, CHAHBCHN). 13C NMR (75 MHz, DMSO-d6): δ 169.4 (CO2), 156.7 (Ar-C), 130.3 (Ar-C), 124.3 (Ar-C), 115.4 (Ar-C), 53.4 (CHN), 52.5 (CH3O), 35.0 (CH2CHN). The NMR spectra are in agreement with the literature
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 114, p. 318 - 327
14
[ 13512-31-7 ]
[ 3417-91-2 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 17, p. 6599 - 6601
15
[ 67-56-1 ]
[ 3978-80-1 ]
[ 3417-91-2 ]
Reference：
[1] Journal of Organic Chemistry, 1999, vol. 64, # 25, p. 9294 - 9296
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[1] Chemistry - A European Journal, 2017, vol. 23, # 53, p. 13033 - 13036
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[3] Journal of the American Chemical Society, 2009, vol. 131, # 32, p. 11286 - 11287
28
[ 3417-91-2 ]
[ 82911-79-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 21, p. 4270 - 4275
29
[ 28920-43-6 ]
[ 3417-91-2 ]
[ 82911-79-3 ]
Reference：
[1] Journal of the American Chemical Society, 1995, vol. 117, # 4, p. 1225 - 1239
30
[ 3417-91-2 ]
[ 83345-46-4 ]
Reference：
[1] Journal of Chemical Research, 2006, # 11, p. 696 - 697
With thionyl chloride; at 0℃; for 1h;Inert atmosphere; Reflux;
D, L-tyrosine (10.0 g, 55.1 mmol) was added to methanol (88 mL) under argon and the solution was cooled to 0 (after which thionyl chloride (3.97 mL, 60.6 mmol) was added dropwise. The reaction solution was concentrated under reduced pressure, and then recrystallized from a mixed solvent of methanol (5 mL) and diethylether (80 mL) to obtain 10 (10.8 g) of Compound 10.
With thionyl chloride; at 20℃;
Tyrosine (10.86 g 60.0 mmol) was added to a 250 mL three-necked flask, 120 mL of frozen methanol was added, and SOCl2 (10.0 g 85 mmol) was added dropwise dropwise.Stirred overnight at room temperature,Spin drySolvent to give the title compound as a white solid tyrosine methyl ester hydrochloride.The crude tyrosine hydrochloride (5 g 21.6 mmol) was dissolved in 75 mLTHF was added a white suspension, to which was added triethylamine (2.18 g, 21.6 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was filtered,The filter cake was washed 1-2 times with THF and the filtrate was spin dried to give 4.03 g of a yellow oil.
3,5-Bis-benzyloxy-4-(2-benzyloxy-6-benzyloxycarbonyl-benzoyl)-benzoic acid 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-methanesulfonylamino-propyl ester[ No CAS ]
Reference example 20 N-(2-Benzoylphenyl)tyrosine methyl ester A mixture of <strong>[3417-91-2]tyrosine methyl ester hydrochloride</strong> (4.8 g), 2-benzoylcyclohexanone (5.0 g), palladium on carbon (1.0 g, 10%), triethylamine (2.9 ml) and anisole (70 ml) was heated at reflux for 20 hours. The reaction mixture was filtered and the filtrate was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane: ethyl acetate=3:1 as the eluant to afford the title compound (1.83 g, Rf=0.39: thin layer chromatography on a silica gel plate using hexane: ethyl acetate=3:1 as the eluant).
28.4 g (122.6 mmol) of tyrosine methyl hydrochloride and 54.2 g (782.8 mmol) of potassium carbonate are placed in a 1L three-necked flask equipped with a mechanical stirrer. The solids are dissolved in a mixture of 160 mL water and 160 mL acetone. A clear solution is obtained, which is cooled to 5C on a water/ice bath. 27.5 mL (195.4 mmol) of benzyl chloroformate is added, in 30 minutes, via a pressure-equalizing dropping funnel. At the end of addition, the resulting yellowish suspension is stirred over night at room temperature. At the end of this time, 100 mL of ethyl acetate is added, the mixture is transferred to a decanting funnel and the organic phase is separated, which is dried and evaporated to dryness. 44.3 g (92.2% yield) of an oil is obtained, which is used in the next reaction of substitution. A 1L three-necked flask equipped with a magnetic stirrer is loaded with the 44.3 g (134.6 mmol) of oil obtained in the preceding stage, 37.3 g (162.5 mmol) of 2-(5-ethylpyridin-2-yl)ethyl methanesulphonate, obtained by evaporation of the solution in toluene resulting from the first stage of example 1.B, and 22.3 g (161.3 mmol) of potassium carbonate. The mixture is suspended in 500 mL of isopropyl acetate, and is heated under reflux for 96 hours. After 20 hours, 0.87 g (2.7 mmol) of tetrabutylammonium bromide is added. After leaving to cool to room temperature, the suspension obtained is transferred to a decanting funnel and is washed with 2 × 200 mL of 10% NaOH. The organic phase is dried and evaporated. 39.5 g of an oil is obtained, which is used without purification in the next reaction of deprotection. The oil obtained in the preceding stage is placed in a 2L single-necked flask equipped with a magnetic stirrer, and is dissolved in 100 mL of methanol. 100 mL of 10% NaOH is added, and the mixture is heated under reflux for 3 hours. Then 100 mL of concentrated hydrochloric acid (37%) is added and it is heated under reflux for 18 hours. At the end of this time, it is left to cool to room temperature and the methanol is evaporated in the rotary evaporator. The aqueous phase is washed with 100 mL of toluene. It is neutralized to pH 5 by adding 50% NaOH solution, observing the precipitation of a white solid, which is filtered in a Buchner funnel. 2.43 g (22.4% overall yield in the stages of substitution and deprotection) of compound (IV) is obtained. The overall yield from the methyl ester of L-tyrosine to compound (IV) using the benzyloxycarbonylamino protecting group is only 20.7%.
With triethylamine; In tetrahydrofuran; chloroform;
EXAMPLE 57 To a solution of 10 g of N-(4-methoxybenzoyl)-phenylananine and 100 ml of tetrahydrofuran was added 3.4 g of N-methoylmorpholine. To the mixture, 4.6 g of isobutyl chlorocarbonate was added while stirring at -15 C. The mixture was stirred for 30 minutes and then 100 ml of a mixture of 7.8 g of <strong>[3417-91-2]methyl tyrosinate hydrochloride</strong>, 3.4 g of triethylamine and 100 ml of chloroform were added. The resulting mixture was stirred at -10 C. for 2 hours and at room temperature for 3 hours. The precipitates were removed by filtration and the filtrate was concentrated and extracted with ethyl acetate. The extract was washed with 2% hydrochloric acid, 4% sodium bicarbonate and water, then dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 9.9 g of methyl N-(4-methoxybenzoyl)-phenylalanyltyrosinate with mp. 195-197 C. in a yield of 62%. Analysis, calculated for C27 H28 O6 N2: C, 68.05; H, 5.92; N, 5.88; found C, 68.34; H, 5.77; N, 5.91.
t-butoxycarbonylvalyltyrosine methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 4-methyl-morpholine; In diethyl ether; dichloromethane;
EXAMPLE 1 21.7 g of t-butoxycarbonylvaline is dissolved in 200 ml of methylene chloride. 22.2 ml of N-methylmorpholine is added to the solution. The solution is cooled to -70 C. 13.1 ml of isobutylchloroformate is then added. The reaction mixture is again cooled to -70 C. 23.2 g of <strong>[3417-91-2]tyrosine methyl ester hydrochloride</strong> is added to the reaction mixture. The reaction mixture is allowed to warm to room temperature, and then is stirred for 16 hours. The reaction mixture is extracted three times with 0.5 M potassium bisulfate and once with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The residue is dissolved in 200 ml of ethyl ether. The ether solution is added to cold rapidly stirring Skellysolve B. The white precipitate is filtered and dried to afford the product t-butoxycarbonylvalyltyrosine methyl ester.
3-(4-hydroxyphenyl)-2-palmitamidopropanoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; at 0℃;
(R)-3-(4-hydroxyphenyl)-2-palmitamidopropanoic acid To a solution of L-Tyrosine methyl ester hydrochloride (1 g, 4.3 mmol) in CH2Cl2 was added triethylamine (1.49 mL, 8.6 mmol) at room temperature. Palmitoyl chloride (1.53 g, 5.6 mmol) was then added to the reaction mixture at 0 C. After the reaction was completed, as judged by TLC, the reaction mixture was quenched and extracted with 1 N HCl (3*5 mL) then saturated sodium bicarbonate (1*5 mL). The combined organic layers were dried with Na2SO4 and evaporated under vacuum to a white solid (1.86 g, 4.3 mmol). The product was carried on without further purification. 1H NMR (300 MHz, CDCl3, 23 C., 6): 6.94 (d, 1H, J=8.5), 6.73 (d, 1H, J=8.5), 5.92 (d, 1, H, J=8.0), 4.90 (d, 1H, J=5.8), 4.85 (d, 1H, J=5.8), 3.73 (s, 3H), 3.04 (ddd, 1H, J=5.8, 14.0, 27.7), 2.26-2.12 (m, 1H), 1.58 (m, 2H), 1.25 (m, 24H), 0.90 (t, 3H, J=6.67).
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;
General procedure: First, 50 mg (0.13 mmol) of xyloketal B acid [16] and 22 mg (0.20 mmol) of p-fluoroaniline were dissolved in 10 mL of DMF in a 50 mL-round-bottom flask. Then, 80 mg (0.20 mmol) of BOP and 0.40 mL (2.0 mmol) of DIEA were added and stirred at room temperature overnight. The reaction was quenched with 10 mL saturated solution of ammonium chloride in ice water. The aqueous layer was extracted with ethyl acetate, 3 × 25 mL. The combined organic extracts were washed with saturated ammonium chloride and brine, dried over anhydrous MgSO4 and concentrated in vacuo. Purification by flash chromatography (petroleum ether: ethyl acetate = 5:1~2:1) gave the title compound.
Tyrosine (10.86 g 60.0 mmol) was added to a 250 mL three-necked flask, 120 mL of frozen methanol was added, and SOCl2 (10.0 g 85 mmol) was added dropwise dropwise.Stirred overnight at room temperature,Spin drySolvent to give the title compound as a white solid <strong>[3417-91-2]tyrosine methyl ester hydrochloride</strong>.The crude tyrosine hydrochloride (5 g 21.6 mmol) was dissolved in 75 mLTHF was added a white suspension, to which was added triethylamine (2.18 g, 21.6 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was filtered,The filter cake was washed 1-2 times with THF and the filtrate was spin dried to give 4.03 g of a yellow oil.
methyl 3-methyl-2-(9-oxo-9,10-dihydroacridine-4-carboxamido)butanoate[ No CAS ]
[ 3417-91-2 ]
methyl 3-(4-hydroxyphenyl)-2-(9-oxo-9,10-dihydroacridine-4-carboxamido)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With chloroformic acid ethyl ester; triethylamine; at 0℃; for 0.333333h;
For the preparation of compound 3, acridone (2 g) was treated with L-<strong>[3417-91-2]tyrosine methyl ester hydrochloride</strong> (2.5 g) in the presence of 3ml triethyl amine and 2 ml ethyl chloroformate at 0 oC for 20 min.After completion of reaction (TLC monitoring), the reaction mixture wasextracted with chloroform. The organic phase was dried over anhydrous Na2SO4and the residue was column chromatographed using ethyl acetate and hexane aseluents to isolate pure compound. (78%), mp 160 oC, [alpha]D+40o (c 1.00, MeOH). 1H NMR (500 MHz,DMSO-d6): delta 3.02-3.15 (2H, m, CH2), 3.68 (3H, s,OCH3), 4.72-4.76 (1H, m, CH), 6.67 (2H, d, J 8.4 Hz, ArH),7.13 (2H, d, J 8.3 Hz,ArH) 7.29-7.39 (2H, m, ArH), 7.71-7.74(2H, m, ArH), 8.21-8.32 (2H, m, ArH),8.45-8.47 (1H, m, ArH), 9.25-9.32 (2H, b, 1×OH+1×NH), 12.09 (1H, b, NH). 13C NMR (125 MHz.DMSO-d6 ): delta 176.96,172.49, 168.31, 156.49, 140.71, 134.46, 133.89, 131.09, 130.72, 127.87, 126.29,122.52, 120.92, 120.39, 118.95, 118.16, 115.59, 52.10, 52.60, 35.97. IR (KBr, thin lm) numax (cm-1): 3648(NH), 3628 (NH), 3287 (OH), 1747 (CO), 1616 (CO), 1578 (CO). HRMS-ESI (m/z): [M+H]+ calculated for C24H20N2O5,417.1444; found 417.148 .Following the same procedure, compound 3 was also prepared by using D- and DL- tyrosine methyl esterhydrochloride.
With sodium carbonate; In tetrahydrofuran; water; at 0℃; for 2h;
Compound 10 (10.8 g) was suspended in THF (184 mL), cooled to 0 C and Na2CO3 (5.9 g, 1.0eq) dissolved in water (92 mL) was added. Then, (Boc)2O (24 g, 2.0 eq.) was dropped, and the mixture was stirred at room temperature for 2 hours. After extraction with ethyl acetate, the mixture was washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a crude product of N-Boc-D, L-tyrosine-methyl ester. Then, this product was dissolved in acetonitrile (184 mL), DMAP (6.7 g, 1.0 eq.) Was added, and then (Boc) 2O (36.2 g, 3.0 eq.And the mixture was stirred for 12 hours. The mixture was concentrated under reduced pressure, extracted with ethyl acetate, and washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Compound 11 (22.9 g) was purified by silica gel column chromatography using a developing solvent of ethyl acetate: hexane = 1: 3.
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