* 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.
With lithium hydroxide monohydrate In tetrahydrofuran; methanol; water at 0℃; for 1 h;
To a solution of compound 10 (498 mg, 1.61 mmol) in THF/MeOH/H2O (3:1:1, 5 mL)was added LiOHH2O (142 mg, 3.22 mmol)at 0 C. After stirring at 0 C for 1 h, the organic solvents wereevaporated. Then the residue was treated with 15percent aqueous citricacid to adjust the pH to 3, and the whole was extracted with ethylacetate (35 mL). The combined organic layers were washed withbrine (5 mL), dried with anhydrous Na2SO4, and concentrated invacuo. The crude product was subjected to silica gel column chromatography(ethyl acetate/petroleumether: 2:1) to give compound21 (466 mg, 98percent) as a colorless oil. 1H NMR (300 MHz, CD3OD):d 7.13 (2H, d, J8.4 Hz), 6.82 (2H, d, J8.4 Hz), 4.31e4.29 (1H, m),3.73 (3H, s), 3.08 (1H, dd, J13.8, 4.5 Hz), 2.85 (1H, dd, J13.5,8.7 Hz), 1.38 (9H, s). 13C NMR (75 MHz, CD3OD): d 175.42, 159.95,157.67, 131.27, 131.27, 130.37, 114.81, 114.81, 80.50, 56.37, 55.64,37.86, 28.67, 28.67, 28.67.
95%
With sodium hydroxide In methanol; water at 20℃;
Intermediate 11 (8.5 g, 27.5 mmol) was dissolved in 200 mLMethanol and water (v / v 1: 1),Sodium hydroxide (4.4 g, 110 mmol) was added portionwise at room temperature,Stir overnight at room temperature. Add 10percent aqueous hydrochloric acid to adjust the pH value to about 5, 500mL methylene chloride extraction, the organic layer was washed once with 100mL saturated brine,Dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give the desired product,Yield 95percent. The next reaction can be carried out without further purification.
95%
With sodium hydroxide In methanol; water at 20℃;
Intermediate 11 (8.5 g, 27.5 mmol) was dissolved in a mixed solution of 200 mL of methanol and water (v / v 1: 1), room temperatureSodium hydroxide (4.4 g, 110 mmol) was added in portions and stirred overnight at room temperature. Add 10percent aqueous hydrochloric acid to adjust the pH value to about 5, and extract with 500 mL of dichloromethane. The organic layer is washed once with 100 mL of saturated saline, dried over anhydrous sodium sulfate, filtered and the solvent is evaporated under reduced pressure to obtain the target product in 95percent yield. The next reaction can be carried out without further purification.
Reference:
[1] Tetrahedron, 2014, vol. 70, # 37, p. 6630 - 6640
[2] Patent: CN107353239, 2017, A, . Location in patent: Paragraph 0173; 0174
[3] Patent: CN107468690, 2017, A, . Location in patent: Paragraph 0173; 0174
[4] Synthesis, 1984, vol. NO. 7, p. 572 - 574
[5] Journal of Organic Chemistry, 1981, vol. 46, # 9, p. 1944 - 1946
[6] ChemMedChem, 2015, vol. 10, # 3, p. 498 - 510
2
[ 3978-80-1 ]
[ 77-78-1 ]
[ 53267-93-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 20 - 30℃; Inert atmosphere
A mixture of Boc-L-Tyr-OH (5.0 g, 17.8 mmol) in NaOH solution (4M, 10 mL) was treated with second portion of NaOHsolution (4 M, 2 mL) and then dimethyl sulfate (0.9 mL).The reaction temperature was controlled at 20-30 oC by acooling bath. The addition was repeated four times. The reaction was stirred for 2 h atroom temperature after completion of the addition of dimethyl sulfate. The solutionwas acidified with 1 M aq. HCl solution, and then extracted by EtOAc (2×100 mL).The combined organic extracts were washed with brine, dried over Na2SO4, filteredCO2BnNHBocMeOS9and evaporated, giving Boc-Tyr(OMe)-OH as a colorless oil (5.0 g, 95percent yield).
64%
Stage #1: With sodium hydroxide In acetone at 20 - 35℃; for 2 h; Stage #2: at 0 - 50℃;
N - tert-butoxycarbonyl - L - tyrosine added to acetone, completely dissolve, keep the reaction system 20 - 35 °C, batch by adding 6 equivalent of sodium hydroxide, after adding stirring 2 hours, maintaining the reaction system 0 - 20 °C, dropwise 3 equivalent of dimethyl sulfate, after adding the room temperature (20 - 30 °C) reaction overnight, water is added to a reaction system, in 40 - 50 °C between evaporating the acetone, acetone after removing, adding ethyl acetate and ice, citric acid solid is acidified to pH=2 - 3, layered, abandoned to the aqueous phase, the oil phase of the saturated salt water for washing three times, sodium sulfate drying 2 hours, filtering to remove sodium sulfate, evaporate most of the ethyl acetate, adding petroleum ether and stirring crystallization, to obtain N - tert butoxycarbonyl - O - methyl - L - tyrosine, yield 64percent. N - tert butoxycarbonyl - O - methyl - L - tyrosine soluble in acetone, maintaining the 10 - 25 °C, slow access after drying of hydrochloric acid gas, reaction 5 hours, insufflating hydrochloric acid gas, cooling to 0 - 10 °C, triethylamine for adjusting pH=7, separate out a large amount of white solid, filtered, and dried to obtain the O - methyl - L - tyrosine, purity 99.5percent, yield 66percent.
Reference:
[1] Tetrahedron Letters, 2014, vol. 55, # 44, p. 6109 - 6112
[2] Patent: CN108003048, 2018, A, . Location in patent: Paragraph 0016
[3] Tetrahedron, 1993, vol. 49, # 17, p. 3521 - 3532
3
[ 1070-19-5 ]
[ 6230-11-1 ]
[ 53267-93-9 ]
Reference:
[1] Journal of Medicinal Chemistry, 1980, vol. 23, # 6, p. 696 - 698
4
[ 24424-99-5 ]
[ 6230-11-1 ]
[ 53267-93-9 ]
Reference:
[1] Journal of the American Chemical Society, 1995, vol. 117, # 28, p. 7364 - 7378
[2] Patent: EP438233, 1991, A2,
[3] Journal of the American Chemical Society, 2011, vol. 133, # 34, p. 13698 - 13705
5
[ 24424-99-5 ]
[ 53267-93-9 ]
Reference:
[1] Patent: US5442044, 1995, A,
6
[ 1070-19-5 ]
[ 67423-44-3 ]
[ 53267-93-9 ]
Reference:
[1] Journal of Medicinal Chemistry, 1981, vol. 24, # 12, p. 1511 - 1514
7
[ 3978-80-1 ]
[ 74-88-4 ]
[ 53267-93-9 ]
Reference:
[1] Journal of Organic Chemistry, 1983, vol. 48, # 22, p. 4127 - 4129
[2] Journal of Organic Chemistry, 1983, vol. 48, # 22, p. 4127 - 4129
[3] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1694 - 1702
8
[ 24424-99-5 ]
[ 53267-93-9 ]
Reference:
[1] Journal of Organic Chemistry, 1981, vol. 46, # 9, p. 1944 - 1946
[2] Patent: CN107353239, 2017, A,
[3] Patent: CN107468690, 2017, A,
9
[ 4326-36-7 ]
[ 53267-93-9 ]
Reference:
[1] Journal of Organic Chemistry, 1981, vol. 46, # 9, p. 1944 - 1946
[2] ChemMedChem, 2015, vol. 10, # 3, p. 498 - 510
[3] Tetrahedron, 2014, vol. 70, # 37, p. 6630 - 6640
10
[ 3417-91-2 ]
[ 53267-93-9 ]
Reference:
[1] Journal of Organic Chemistry, 1981, vol. 46, # 9, p. 1944 - 1946
[2] Tetrahedron, 2014, vol. 70, # 37, p. 6630 - 6640
11
[ 60-18-4 ]
[ 53267-93-9 ]
Reference:
[1] Tetrahedron, 2014, vol. 70, # 37, p. 6630 - 6640
[2] Patent: CN107353239, 2017, A,
[3] Patent: CN107468690, 2017, A,
With lithium hydroxide monohydrate; In tetrahydrofuran; methanol; water; at 0℃; for 1h;
To a solution of compound 10 (498 mg, 1.61 mmol) in THF/MeOH/H2O (3:1:1, 5 mL)was added LiOHH2O (142 mg, 3.22 mmol)at 0 C. After stirring at 0 C for 1 h, the organic solvents wereevaporated. Then the residue was treated with 15% aqueous citricacid to adjust the pH to 3, and the whole was extracted with ethylacetate (35 mL). The combined organic layers were washed withbrine (5 mL), dried with anhydrous Na2SO4, and concentrated invacuo. The crude product was subjected to silica gel column chromatography(ethyl acetate/petroleumether: 2:1) to give compound21 (466 mg, 98%) as a colorless oil. 1H NMR (300 MHz, CD3OD):d 7.13 (2H, d, J8.4 Hz), 6.82 (2H, d, J8.4 Hz), 4.31e4.29 (1H, m),3.73 (3H, s), 3.08 (1H, dd, J13.8, 4.5 Hz), 2.85 (1H, dd, J13.5,8.7 Hz), 1.38 (9H, s). 13C NMR (75 MHz, CD3OD): d 175.42, 159.95,157.67, 131.27, 131.27, 130.37, 114.81, 114.81, 80.50, 56.37, 55.64,37.86, 28.67, 28.67, 28.67.
95%
With sodium hydroxide; In methanol; water; at 20℃;
Intermediate 11 (8.5 g, 27.5 mmol) was dissolved in 200 mLMethanol and water (v / v 1: 1),Sodium hydroxide (4.4 g, 110 mmol) was added portionwise at room temperature,Stir overnight at room temperature. Add 10% aqueous hydrochloric acid to adjust the pH value to about 5, 500mL methylene chloride extraction, the organic layer was washed once with 100mL saturated brine,Dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give the desired product,Yield 95%. The next reaction can be carried out without further purification.
95%
With sodium hydroxide; In methanol; water; at 20℃;
Intermediate 11 (8.5 g, 27.5 mmol) was dissolved in a mixed solution of 200 mL of methanol and water (v / v 1: 1), room temperatureSodium hydroxide (4.4 g, 110 mmol) was added in portions and stirred overnight at room temperature. Add 10% aqueous hydrochloric acid to adjust the pH value to about 5, and extract with 500 mL of dichloromethane. The organic layer is washed once with 100 mL of saturated saline, dried over anhydrous sodium sulfate, filtered and the solvent is evaporated under reduced pressure to obtain the target product in 95% yield. The next reaction can be carried out without further purification.
With lithium hydroxide monohydrate; water; In tetrahydrofuran; at 0℃; for 1h;
To a solution of compound 21 (1.2 g, 3.9 mmol, 1 eq) in THF/H2O (4:1, 50 mL) was added LiOHH2O (226 mg, 5.4 mmol, 1.38 eq) at 0 C. After stirring at 0 C for 1 h, the organic solvents were evaporated. Then the residue was treated with 15% aqueous citric acid to pH = 3, and the whole resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4, and filtered. The crude material was dissolved in ethyl acetate (50 mL) and then HCI (40 mL of a 4.0M solution in dioxane) was added to the solution. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness to afford compound 23 as white solid (0.9 g, 98%).1H NMR (500 MHz, D2O) d 7.15 (d, J = 7.4 Hz, 2H), 6.89 (d, J = 7.3 Hz, 2H), 4.16 (t, J = 6.0 Hz, 1H), 3.72 (d, J = 1.0 Hz, 3H), 3.18 (dd, J = 14.6, 5.1 Hz, 1H), 3.06 (dd, J = 14.6, 7.6 Hz, 1H).
With sodium hydroxide; at 20 - 30℃;Inert atmosphere;
A mixture of Boc-L-Tyr-OH (5.0 g, 17.8 mmol) in NaOH solution (4M, 10 mL) was treated with second portion of NaOHsolution (4 M, 2 mL) and then dimethyl sulfate (0.9 mL).The reaction temperature was controlled at 20-30 oC by acooling bath. The addition was repeated four times. The reaction was stirred for 2 h atroom temperature after completion of the addition of dimethyl sulfate. The solutionwas acidified with 1 M aq. HCl solution, and then extracted by EtOAc (2×100 mL).The combined organic extracts were washed with brine, dried over Na2SO4, filteredCO2BnNHBocMeOS9and evaporated, giving Boc-Tyr(OMe)-OH as a colorless oil (5.0 g, 95% yield).
64%
N - tert-butoxycarbonyl - L - tyrosine added to acetone, completely dissolve, keep the reaction system 20 - 35 C, batch by adding 6 equivalent of sodium hydroxide, after adding stirring 2 hours, maintaining the reaction system 0 - 20 C, dropwise 3 equivalent of dimethyl sulfate, after adding the room temperature (20 - 30 C) reaction overnight, water is added to a reaction system, in 40 - 50 C between evaporating the acetone, acetone after removing, adding ethyl acetate and ice, citric acid solid is acidified to pH=2 - 3, layered, abandoned to the aqueous phase, the oil phase of the saturated salt water for washing three times, sodium sulfate drying 2 hours, filtering to remove sodium sulfate, evaporate most of the ethyl acetate, adding petroleum ether and stirring crystallization, to obtain N - tert butoxycarbonyl - O - methyl - L - tyrosine, yield 64%. N - tert butoxycarbonyl - O - methyl - L - tyrosine soluble in acetone, maintaining the 10 - 25 C, slow access after drying of hydrochloric acid gas, reaction 5 hours, insufflating hydrochloric acid gas, cooling to 0 - 10 C, triethylamine for adjusting pH=7, separate out a large amount of white solid, filtered, and dried to obtain the O - methyl - L - tyrosine, purity 99.5%, yield 66%.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
L - tyrosine (2.8 g, 10 mmol) was dissolved in 50 mL DMF, then K2CO3(4.15 g, 30 mmol) and iodomethane (1.37 mL, 22 mmol) were added in a row. Stirred at room temperature till the reactant was run out, detected by TLC. Then, 150 mL water was added into the solution and extracted with EtOAc. After dried by MgSO4 and concentrated, the obtained oil was dissolved in 30 mL methanol and NaOH (1.3 mmol/mL) was added. After stirred for 5 h, the solution was neutralized by 1M HCl solution and extracted with EtOAc. 0.5M citric acid and brine were used to wash the organic phase, and concentrated to colorless oil. Finally, purification by column chromatography (PE/EA=10: 3) to generate compound 6a, colorless oil. Yield: 13%. 1H NMR (400 MHz,Chloroform-d) delta 7.12 (d, J=8.2 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 4.68- 4.49 (m, 1H), 3.81 (s, 3H), 3.11 (ddd, J=34.8, 13.6, 5.3 Hz, 2H),1.45 (s, 9H).
(+/-)-1-<(3'β,5'β)-5'-(tert-butyldimethylsiloxymethyl)piperidin-3'-yl>-2,4(1H,3H)pyrimidinedione[ No CAS ]
1-<(3'RS,5'SR)-1'-(2S-<tert-butoxycarbamoyl>-3-(4-methoxyphenyl)propanoyl)-5'-(tert-butyldimethylsilyloxymethyl)piperidin-3'-yl>-2,4(1H,3H)pyrimidinedione[ No CAS ]
(+/-)-6-(dimethylamino)-9-<(3'β,5'β)-5'-(tert-butyldimethylsilyloxymethyl)piperidin-3'-yl>purine[ No CAS ]
6-(dimethylamino)-9-<(3'RS,5'SR)-1'-(2S-<tert-butoxycarbamoyl>-3-<4-methoxyphenyl>propanoyl)-5'-(tert-butyldimethylsilyloxymethyl)piperidin-3'-yl>purine[ No CAS ]
Preparation of 35A solution of Boc-Tyr 34 (0.5 g, 101 mmol) in THF (337 mL) at 0 C was treated with 1M BH3.THF complex (4.3 mL) for 30min. The ice bath was removed and the solution was stirred at room temperature for 3 h. The reaction was cooled to 0 C and quenched slowly with the dropwise addition of brine. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried (MgS04), filtered and concentrated to provide 35 (82 %).
82%
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 3.5h;
[0575] Preparation of 35 [0576] A solution of Boc-Tyr 34 (0.5 g, 101 mmol) in THF (337 mL) at 0 C. was treated with 1M BH3. THF complex (4.3 mL) for 30min. The ice bath was removed and the solution was stirred at room temperature for 3 h. The reaction was cooled to 0 C. and quenched slowly with the dropwise addition of brine. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated to provide 35 (82%).
78%
1M BH3 in THF (47 mL, 47 mmol) was added to a THF (35 ml_) solution of Lambda/-[(1 , 1-dimethylethyl)oxy]carbonyl}-O-methyl-L-tyrosine (2.7 g, 9.4 mmol) at 0 C and stirred 2 hours then placed in freezer overnight. The reaction mixture was quenched by slow addition of a solution of AcOH (15 mL) in MeOH (30 mL) at 0 0C over 1 hour. The mixture was allowed to warm to room temperature and saturated NaHCO3 (100 mL) added. The layers were separated and organic layer evaporated to yield a clear oil (1.92 g, 78%) carried forward without further purification: LCMS (ES) m/z 266 (M+H)+.
73%
General procedure: (S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (2.65 g, 10 mmol) was dissolved in THF (20 ml) under a nitrogen atmosphere and cooled to 0 . Thriethylamine (1.42 ml, 1.1 eq) were then added to form a white precipitate. After 0.25 h, the solution was filtered. The filtrate was added to a solution of sodium borohydride (0.62 g, 1.5 eq) in water (8 ml) dropwise at 0 . After 0.5 h, the reaction mixture was warmed to room temperature and allowed to stir for a further 2 h. the reaction mixture was then acidified PH to 2 using 2 M hydrochloric acid and extracted with ethyl acetate. The organic layer was then washed with a saturated solution of NaHCO3, dried over MgSO4 and concentrated in vacuo to get compound 16a (1.88 g, 75%).
Synthesis of [(S)-2-hydroxy-l-(4-methoxy-benzyl)-ethyl]-carbamic acid tert-butyl ester [AA-54] A 1M solution of BH3 in THF (1.7 ml, 1.7 mmol) was added dropwise to a stirred solution of (S)-2-tert-butoxycarbonylamino-3-(4-methoxy-phenyl)-propionic acid (200 mg, 0.678 mmol) in dry THF (2.5 ml) at 0C. The mixture was stirred for 2 hours at 0C then hydro lysed by slow addition of excess of 10% acetic acid/MeOH (5 ml) and stirred at room temperature for a further 2 hours. The solvent was removed under reduced pressure the residue was dissolved in ethylacetate (5 ml) and washed with saturated sodium bicarbonate (2x5 ml) and brine (2x5 ml). The combined organic phases were dried with magnesium sulfate, filtered and evaporated under reduced pressure to provide the title compound as a white solid which was used without further purification in the next step. LCMS method: 1, RT: 2.82 min, MI: 441 [M+l].
With hydrogenchloride; sodium hydroxide; In tetrahydrofuran; water;
A. N-t-Butoxycarbonyl-O-methyl-L-tyrosine A solution of O-methyl-L-tyrosine (10.0 g, 0.0512 mol) and sodium hydroxide (2.05 g, 1.0 equivalent) in water (100 mL) and tetrahydrofuran (100 mL) was brought to pH 12.7 with added 6N NaOH and treated with di-t-butyldicarbonate (18 mL, 1.5 equivalents). The pH of the stirred solution gradually fell to 10.8. Most of the tetrahydrofuran was removed at reduced pressure and the aqueous residue was extracted twice with ether and mixed with an equal volume of ethyl acetate. The resulting mixture was stirred while aqueous 6N HCl was added to bring the pH to 1.5. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgSO4, and concentrated giving 13.1 g (87percent) of the title substance as a colorless foam, TLC Rf 0.22 (silica, 10percent ethanol-dichlorome- thane), HPLC (60/40): 2.88 minutes (96percent). 1H NMR (CDCl3, 300 mHz, partial, ppm) delta: 1.41 (s, 9H), 3.09 (m, 2H), 3.78 (s, 3H), 4.55 (m, 1H), 4.90 (d, 1H), 6.83 (d, 2H, J = 8.6 Hz), 7.09 (d, 2H, J = 8.6 Hz).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; for 25h;Inert atmosphere;
General procedure: Compounds 25e29 were synthesized following the above describedprocedure of preparing compound 20 using L-alaninemethyl ester hydrochloride salt 17 (140 mg, 1.0 mmol) and compound20, 21, 22, 23 or 24 (1.0 mmol). A solution of L-alanine methyl ester hydrochloride salt 17(140 mg, 1.0 mmol) and Boc-D-Ala-OH 18 (190 mg, 1.0 mmol) inanhydrous dichloromethane (10 mL) was treated with EDCI(222 mg, 1.1 mmol), HOBt (154 mg, 1.1 mmol), and Et3N (352 mL,2.5 mmol) at 0 C under nitrogen. After stirring at 0 C for 1 h, themixture was allowed to warm to room temperature and stirred for24 h. This solutionwas treated with 15% aqueous citric acid (10 mL)and extracted with dichloromethane (310 mL). The combinedorganic fractions were washed with saturated aqueous NaHCO3(10 mL), water (10 mL), and brine (10 mL), dried over anhydrousNa2SO4, and concentrated in vacuo. The residue was purified bycolumn chromatography over silica gel (petroleum ether/ethyl acetate: 2:1) to yield the desired product 19 (258 mg, 94%) asa white solid. 1H NMR (300 MHz, CDCl3): d 6.98 (1H, br s), 5.28 (1H,d, J5.7 Hz), 4.54e4.50 (1H, m), 4.20 (1H, br s), 3.69 (3H, s),1.40e1.30 (15H, m). 13C NMR (75 MHz, CDCl3): d 173.36, 172.49,155.62, 80.07, 52.45, 49.90, 47.96, 28.32, 28.32, 28.32, 18.35, 18.19.
tert-butyl (S)-[1-amino-3-(4-methoxyphenyl)-1-oxopropan-2-yl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26.5 g
With benzotriazol-1-ol; ammonium hydroxide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1.16667h;Cooling with ice;
To a solution of (S)-2- [(tert-butoxycarbonyl)aminoj -3-(4-methoxyphenyl)propanoic acid (29 g) in dichloromethane (485 mL) were added 1-hydroxybenzotriazole (16.5 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (20.4 g) to produce a reaction solution. To the reaction solution under ice-cooling was added 25% aqueous ammonia (29.4 mL) over 10 minutes, and the mixture was stirred at room temperature for 1 hour.To the reaction solution was added water, and the mixture was extracted with dichloromethane. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and then a brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was then washed with hexane to obtain the title compound as a white solid (26.5 g).1HNMR (400 MHz, DMSO-d6) oe 1.42 (9H, s), 2.98 (1H, dd, J = 13.9, 7.3 Hz), 3.06(1H, dd, J = 13.9, 6.1 Hz), 3.79 (3H, s), 4.30 (1H, m), 5.02 (1H, m), 5.25 (1H, s), 5.68 (1H, s), 6.85 (2H, d, J = 8.5 Hz), 7.15 (2H, d, J = 8.5 Hz).
diethyl 2-{4-[(2S)-2-amino-3-oxo-3-(pentylamino)propyl]phenoxy}malonate hydrochloride[ No CAS ]
2-(4-{(S)-2-[(S)-2-tert-Butoxycarbonylamino-3-(4-methoxy-phenyl)-propionylamino]-2-pentylcarbamoyl-ethyl}-phenoxy)-malonic acid diethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a mixture of the N-protected amino acid (0.34 mmol) in CH2Cl2 (1 mL) at 0 C. is added EDC (0.34 mmol). After stirring for a few minutes, the compound (B-4) (150 mg) and triethylamine (48 mL) are added, and the mixture is warmed to room temperature and stirred overnight. The mixture is partitioned between EtOAc and 1 M HCl. The organic phase is washed with sat. NaHCO3, sat. NaCl, and dried (MgSO4). The solvent is removed under reduced pressure to provide BB-1 which used directly in the next step.
(2S,3S)-3-Methyl-2-[methyl-((S)-2-methylamino-propionyl)-amino]-pentanoic acid methyl ester; compound with trifluoro-acetic acid[ No CAS ]
(2S,3S)-2-[((S)-2-[(S)-2-tert-Butoxycarbonylamino-3-(4-methoxy-phenyl)-propionyl]-methyl-amino}-propionyl)-methyl-amino]-3-methyl-pentanoic acid methyl ester[ No CAS ]
With dmap; triethylamine; In dichloromethane; at -5℃; for 3h;
A suspension of Boc-Tyr(Me)-OH (10 g) in anhydrous dichlormethane (450 mL) was cooled to -5 C. in an ice/acetone bath. To this suspension was added triethylamine (9.4 mL, 67.8 mmol) and DMAP (600 mg). A solution of benzylchloroformate (5.7 mL, 40.6 mmol) in dichloromethane (50 mL) was then added dropwise. The resulting solution was allowed to stir at -5 C. for three hours, and then allowed to warm to room temperature. A solution of saturated aqueous sodium bicarbonate (200 mL) was then added. The organic layer was separated and the aqueous layer was washed with dichloromethane (200 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using 80% hexanes/20% ethyl acetate to provide 11.43 g of a white solid. (88% yield) which was characterized by LC/MS (LCRS (MH) m/z: 386.42).
{1-(1S)-(4-methoxybenzyl)-2-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-2-oxoethyl}carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 4-methyl-morpholine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In DMF (N,N-dimethyl-formamide); at 20℃; for 36h;
Eine Loesung von 5,0 [G] BOC-Tyr (Me) -OH (5) und 2,6 g HOBt in 10 ml DMF wird mit 3,3 [G] DAPECI und 1,7 g NMM versetzt. Man ruehrt 4 Stunden bei Raumtemperatur, traegt 3,9 [G] (1) ein und ruehrt 16 Stunden nach. Man versetzt mit einem weiteren Aequivalent DAPECI und ruehrt 16 Stunden bei Raumtemperatur nach. Man arbeitet wie ueblich auf und erhaelt 7,0 [G] [I-A-14.]
With piperidine; 1-methyl-pyrrolidin-2-one; dmap; 4-phenoxy benzaldehyde; sodium cyanoborohydride; acetic acid; N-ethyl-N,N-diisopropylamine; methylamine; trifluoroacetic acid; diisopropyl-carbodiimide; In tetrahydrofuran; methanol; DMF (N,N-dimethyl-formamide); 1,2-Dichloropropane; dichloromethane; for 48h;
Step A: The product resin from general procedure C, step A, is used. To 0.18 g of this resin are added sequentially a solution of 0.468 mmol Boc-Lys(Fmoc)-OH in 1.6 ml of 1,2-dichloropropane/tetrahydrofuran (1:1), 0.045 ml (0.288 mmol) of diisopropylcarbodiimide, and a solution of 0.036 mmol of 4-dimethylamino pyridine in 0.2 ml of 1,2-dichloropropane. The mixture is shaken for 15 hours. The liquids are filtered off and the resin is washed with dimethylformamide (2 x 2 ml), tetrahydrofuran (2 x 2 ml), and dichloromethane (2 x 2 ml). Step B: The resin obtained by step A is shaken with a mixture of 2.5 ml trifluoroacetic acid/dichloromethane 1:1 for one hour. The liquids are filtered off and the resin is washed with tetrahydrofuran (2 x 2 ml), tetrahydrofuran/ethyidiisopropylamine 3:1 (3 x 2 ml), methanol (2 ml) and tetrahydrofuran (2 ml). Step C: To the resin obtained by step B, a solution of 0.36 mmol of 4-phenoxybenzaldehyde in 1.7 ml of 1-methyl-2-pyrrolidone and 0.1 ml of acetic acid are added. The mixture is shaken for three hours. The liquids are filtered off. The resin is shaken with a solution of 0.9 mmol of sodium cyanoborohydride in 1.7 ml of dichloromethane/methanol 1:1 for one hour. The liquids are filtered off. The resin is washed with methanol (2 x 2 ml), dichloromethane/ methanol 1:1 (2 ml), dichloromethane/ethyidiisopropylamine 19:1 (2 x 2 ml), and tetrahydrofuran (2 x 2.5 ml). Step D: To the resin obtained by step C, a solution of 0.468 mmol of Boc-Tyr (Me)-OH in 1.6 mi of 1,2-dichloropropane/tetrahydrofuran 1:1 is added, followed by a solution of 0.288 mmol of diisopropylcarbodiimide in 0.2 mi of 1,2-dichloropropane. The mixture is shaken for 30 minutes. 0.043 mi (0.252 mmol) of ethyldiisopropylamine is added, and shaking is continued for 14 hours. The liquids are filtered off and the resin is washed with tetrahydrofuran (2x2.5 ml). The same amounts of Boc-Tyr (Me) -OH and diisopropylcarbodiimide as described above are added and the mixture is shaken for 45 minutes. 0.043 mi (0.252 mmol) of ethyidiisopropylamine is added, and shaking is continued for 7 hours. The liquids are filtered off and the resin is washed with dimethylformamide (2 x 2 ml) and tetrahydrofuran (2 x 3 ml). Step E: The resin obtained by step D is shaken with a mixture of 1.5 ML of dimethylformamide and 0.5 ml of piperidine for 30 min. The liquids are filtered off and the resin is washed with dimethylformamide (2x2 mi) and tetrahydrofuran (2 x 3 ml). Step F: To the resin obtained by step E, a suspension of 0.36 mmol of imidazole-2-carbaldehyde in 1.8 ml of 1-methyl-2-pyrrolidone / tetrahydrofuran 17:1 is added, followed by 0.1 ml of acetic acid. The mixture is shaken for 2.5 hours. The liquids are filtered off and the resin is washed with dichloromethane (4x2 ml). A solution of 0.90 mmol of sodium cyanoborohydride in 1.7 ml of dichloromethane/methanol 1:1 and 0.05 ml of acetic acid are added and the mixture is shaken for one hour. The liquids are filtered off and the resin is washed with methanol (2 x 2 ml), dichloromethane/methanol 1:1 (2 ml), tetrahydrofuran (2x3 ml), dichloromethane/ethyldiisopropyiamine 8: 1 (2 x 1.8 ml), and dichloromethane (5x2 ml). Step G: The resin obtained by step F is shaken with 2.5 ml of dichloromethane/ trifluoroacetic acid 1:1 for 30 minutes. The liquids are filtered off and the resin is washed with dichloromethane (2x2 ml), tetrahydrofuran (2x2.5 ml), and methanol (2x2.5 ml). Step H: To the resin obtained by step G, 2.0 ML of dichloromethane and 1.0 ml of 40 % methylamine in methanol are added. The mixture is shaken for 3.5 hours. The mixture is filtered and the filtrate is collected. The resin is washed with 3.5 ml of dichloromethane/ methanol 6:1 and the washing filtrate is collected. Both filtrates are mixed and evaporated to give a residue. Step I: The residue obtained by step H is dissolved in a mixture of 4.8 ml of water, 3.2 ml of acetonitrile and 0.8 ml of 1 M aqueous hydrochloric acid and purified by HPLC. Addition of dilute aqueous hydrochloric acid and freeze-drying afforded 12.2 mg of the product. HPLC-MS (Method B): m/z = 568 (M+1); Rt = 4.67 min
Step A: The intermediate from example 39, Step A is used. Step B: 5.0 mmol, 1.5 g Boc-p-methoxy-Phe-OH is dissolved in 15 ml THF, 0.5 equi., 390 ul DIC is added and the resulting mixture is stirred for 30 min. Then 2.5 mmol of the crude product of step A is added in 15 ml THF. After 3.5 h 430 ul DIPEA is added and the mixture is stirred overnight. The solvent is removed in vacuo and the residue is taken up in 40 ml ethyl acetate. The org. phase is washed twice with 25 ml 1 M HCI and twice with 25 ml sat. NaHCO3 and dried over sodium sulfate. The solvent is removed in vacuo and the residual oil is purified on silica with ethyl acetate/heptane (2:3). Step C: The purified product from step B is dissolved in 30 ml DCM and 30 ml TFA is added. The solvents are removed in vacuo after 30 min. The residual oil is taken up in 30 ml DCM and 2.0 ml DIPEA is added. The solvent is removed in vacuo after 2.3 h and the product is purified on a C18 reverse phase column (Sep-Pak, Waters, 10 g) with 0.1 % TFA in water and acetonitril. HPLC-MS (Method C): m/z = 488 (M+1); Rt = 2.92 min
With potassium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;
To a solution of the above Boc-Tyr(OMe)-OH (20.0 g, 67.7mmol) in anhydrousDMF (300 mL) was added benzyl bromide (16.0 mL, 135.4mmol) and potassiumbicarbonate (20.0 g, 203.2mmol) at rt. The reaction was stirred for 2 h at roomtemperature, and then diluted with ethyl acetate (500 mL). The mixture was washedwith water (2×200mL), saturated NaHCO3 (200 mL), and brine (200 mL), dried overNa2SO4, filtered and concentrated under reduced pressure. The residue was purifiedby flash chromatography (ethyl acetate/petroleum ether, 8:1 to 6:1) to yield 16 (20.0 g,77%).
With potassium carbonate; In N-methyl-acetamide;
B. N-t-Butoxycarbonyl-O-methyl-L-tyrosine Benzyl Ester A mixture of N-t-butoxycarbonyl-O-methyl-L-tyrosine (13.1 g, 0. 0444 mol), potassium carbonate (6.14 g, 0.0444 mol, 1.0 equivalent) and benzyl bromide (5.3 mL, 0.0446 mol, 1.0 equivalent) in anhydrous dimethylformamide was stirred in an ice bath which was allowed to achieve room temperature overnight. The reaction mixture was filtered through filter aid (Supercel (trademark)) and the filter cake washed well with ethyl acetate. The combined filtrates were washed with aqueous 1M lithium chloride (3*50 mL), 1N NaOH (2*50 mL), water, and brine, dried over MgSO4, and concentrated in vacuo to a light brown oil which was chromatographed on 600 g silica packed in 10% ethyl acetate-hexanes and eluted with the same solvent (1.5 L) followed by 3 L of 15% ethyl acetate-hexanes. The pure fractions were pooled and evaporated giving 15.3 g (89%) of the title substance as a colorless crystalline solid, mp 67-69 C., TLC Rf 0.45 (silica, 1:3 ethyl acetate:hexanes), HPLC (60/40) 10.98 minutes (99%). 1 H NMR (300 mHz, CDCl3, 250 mHz, ppm) delta: 1.40 (s, 9H), 3.01 (m, 2H), 3.76 (s, 3H), 4.58 (m, 1H), 4.95 (d, 1H, J=7.9 Hz), 5.09 (d, 1H, J=11.2 Hz), 5.15 (d, 1H, J=11.2 Hz), 6.74 (d, 2H, J=8.5 Hz), 6.93 (d, 2H, J=8.4 Hz), 7.25-7.35 (m, 5H). FAB-MS m/e (relative intensity): 386 (11, MH+), 330 (50), 286 (100), 268 (50), 194 (23), 150 (45), 121 (99). Analysis: Calculated for C22 H27NOs: C, 68.55; H, 7.06; N, 3.63. Found: C, 68.46; H, 7.10; N, 3.60.
With potassium carbonate; In N-methyl-acetamide;
B. N-t-Butoxycarbonyl-O-methyl-L-tyrosine Benzyl Ester A mixture of N-t-butoxycarbonyl-O-methyl-L- tyrosine (13.1 g, 0.0444 mol), potassium carbonate (6.14 g, 0.0444 mol, 1.0 eauivalent) and benzyl bromide (5.3 mL, 0.0446 mol, 1.0 equivalent) in anhydrous dimethylformamide was stirred in an ice bath which was allowed to achieve room temperature overnight. The reaction mixture was filtered through filter aid (Supercel (trademark)) and the filter cake washed well with ethyl acetate. The combined filtrates were washed with aqueous 1M lithium chloride (3 x 50 mL), 1N NaOH (2 x 50 mL), water, and brine, dried over MgSO4, and concentrated in vacuo to a light brown oil which was chromatographed on 600 g silica packed in 10% ethyl acetate-hexanes and eluted with the same solvent (1.5 L) followed by 3 L of 15% ethyl acetate-hexanes. The pure fractions were pooled and evaporated giving 15.3 g (89%) of the title substance as a colorless crystalline solid, mp 67-69C, TLC Rf 0.45 (silica, 1:3 ethyl acetate:hexanes), HPLC (60/40) 10.98 minutes (99%). 1H NMR (300 mHz, CDCl3, 250 mHz, ppm) delta: 1.40 (s, 9H), 3.01 (m, 2H), 3.76 (s, 3H), 4.58 (m, 1H), 4.95 (d, 1H, J = 7.9 Hz), 5.09 (d, 1H, J = 11.2 Hz), 5.15 (d, 1H, J = 11.2 Hz), 6.74 (d, 2H, J = 8.5 Hz), 6.93 (d, 2H, J = 8.4 Hz), 7.25-7.35 (m, 5H). FAB-MS m/e (relative intensity): 386 (11, MH+), 330 (50), 286 (100), 268 (50), 194 (23), 150 (45), 121 (99). Analysis: Calculated for C22H27NO5: C, 68.55; H, 7.06; N, 3.63. Found: C, 68.46; H, 7.10; N, 3.60.
With hydrogenchloride; sodium hydroxide; In tetrahydrofuran; water;
A. N-t-Butoxycarbonyl-O-methyl-L-tyrosine A solution of 0-methyl-L-tyrosine (10.0 g, 0.0512 mol) and sodium hydroxide (2.05 g, 1.0 equivalent) in water (100 mL) and tetrahydrofuran (100 mL) was brought to pH 12.7 with added 6N NaOH and treated with di-t-butyldicarbonate (18 mL, 1.5 equivalents). The pH of the stirred solution gradually fell to 10.8. Most of the tetrahydrofuran was removed at reduced pressure and the aqueous residue was extracted twice with ether and mixed with an equal volume of ethyl acetate. The resulting mixture was stirred while aqueous 6N HCl was added to bring the pH to 1.5. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over MgSO4, and concentrated giving 13.1 g (87%) of the title substance as a colorless foam, TLC Rf 0.22 (silica, 10% ethanol-dichlorome- thane), HPLC (60/40): 2.88 minutes (96%). 1 H NMR (CDCl3, 300 mHz, partial, ppm) delta: 1.41 (s, 9H), 3.09 (m, 2H), 3.78 (s, 3H), 4.55 (m, 1H), 4.90 (d, 1H), 6.83 (d, 2H, J=8.6 Hz), 7.09 (d, 2H, J=8.6 Hz).
XXV.a a
a Methyl N-(tert.butyloxycarbonyl-O-methyl-L-tyrosyl)-4-piperidinyloxy-acetate Prepared from N-tert.butyloxycarbonyl-O-methyl-L-tyrosine, methyl 4-piperidinyloxy-acetate hydrochloride, isobutylchloroformate and triethylamine analogously to Example XXIVa.
1-2-1 Methyl (S)-2-amino-3-(4-methoxyphenyl)propionateTo 10 g (33.8 mmol) of (S)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid are added 75 ml of methanol and then 10 ml of sulfuric acid dropwise over 30 minutes. After 30 hours, the reaction medium is basified to pH 8-9 by adding aqueous 10N sodium hydroxide solution followed by saturated sodium hydrogen carbonate solution. The organic products are extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then filtered, and the solvents are evaporated off. 6.36 g of methyl (S)-2-amino-3-(4-methoxyphenyl)propionate in the form of a brown oil are obtained in a yield of 90%.
90%
2-1 Methyl (S)-2-amino-3-(4-methoxyphenyl)propionate; To 10 g (33.8 mmol) of (S)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid are added 75 mL of methanol and then 10 mL of sulfuric acid dropwise over 30 minutes. After 30 hours, the reaction medium is basified to pH 8-9 by adding aqueous 10N sodium hydroxide solution followed by saturated sodium hydrogen carbonate solution. The organic products are extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then filtered, and the solvents are evaporated off. 6.36 g of methyl (S)-2-amino-3-(4-methoxyphenyl)propionate in the form of a brown oil are obtained in a yield of 90%.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In acetonitrile; for 18h;
Compound 21 b:(S)-1 -{(S)-2-[(S)-2-iert-Butoxycarbonylamino-3-(4-methoxy- phenyl)-propionylamino]-3-[3-(er butyl-dimethyl-silanyloxy)-phenyl]-propionyl}- hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester; Trimethylsilyltrifluoromethanesulfonate (341 muIota_, 1 .89 mmol) was added dropwise to a solution of the (S)-1 -{(S)-2-ie -butoxycarbonylamino-3-[3-(ie -butyl-dimethyl- silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro- ethyl ester (670 mg, 1 .05 mmol) in dichloromethane (15 mL) at 0 C under N2 and the reaction was stirred for 85 minutes. To this was added A/JV-diisopropylethylamine (730 muIota_, 4.19 mmol) and the reaction was warmed to room temperature. The volatiles were evaporated to afford a colourless foam which was dissolved in acetonitrile (15 mL). To this solution was added 0-benzotriazole-/VJ/J/'J/-tetramethyl-uronium-hexafluoro- phosphate (477 mg, 1 .26 mmol), (S)-2-ieri-butoxycarbonylamino-3-(4-methoxy- phenyl)-propionic acid (340 mg, 1 .15 mmol) and A/JV-diisopropylethylamine (730 mu, 4.19 mmol) and the reaction was stirred for 18 h. The volatiles were evaporated and the residue partitioned between pH = 7 buffer and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the volatiles evaporated. The residue was purified by silica chromatography using a gradient of /so-hexanes/ethyl acetate 3:1 to 1 :1 to afford the title compound (570mg, 67%) as a colourless foam. H NMR (300 MHz, CDCI3) 0.18 (s, 6H), 1 .00 (s, 9H), 1 .43 (s, 9H), 1 .45-1 .60 (m, 2H) 1 .73-1 .83 (m, 1 H), 1 .85-1 .95 (m, 1 H), 2.30 {br s, 1 H), 2.65-3.00 (m, 5H), 3.50 (d, J = 1 1 .2 Hz, 1 H), 3.80 (s, 3H), 4.24-4.37 (m, 2H), 4.65 (d, J = 1 1 .8 Hz, 1 H), 4.95 (d, J = 1 1 .8 Hz, 1 H),4.96-5.04 (m, 1 H), 5.62-5.75 (m, 1 H), 6.45 (d, J = 8.3 Hz, 1 H), 6.64-6.75 (m, 2H), 6.78- 6.86 (m, 3H), 7.07-7.16 (m, 3H). LCMS (m/z) 817.3 [M+H], Tr = 5.89 min.
tert-butyl N-[(2S)-1-[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]-3-(4-methoxyphenyl)-1-oxopropan-2-yl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: A solution of compound 3 (10.0 g, 50.96 mmol) in CH3CN (50 mL) was added 4-methylbenzenesulfonic acid hydrate (14.54 g, 76.43 mmol) and stirred at room temperature for 24 h. After the reaction completed, the solution was removed in vacuo. The residual white solid was dissolved in EtOAc (100 mL) and put into fridge overnight, the product 4 (10.3 g, 75%) was precipitated as a white needle crystal. 1H NMR (300 MHz, CD3OD) delta 7.77 (d, J = 7.8 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 4.76-4.75 (m, 1H), 3.51-3.50 (m, 2H), 2.38 (s, 3H), 2.34-2.31 (m, 1H), 2.17-2.09 (m, 2H), 1.90-1.87 (m, 1H). MS (ESI) m/z 97 [M+H]+
General procedure: (S)-2-((tert-Butoxycarbonyl)amino)-3-phenylpropanoic acid (compound 5a, 203.6 mg, 0.768 mmol) in DMF (5 mL) was added HOBt (283.2 mg, 2.10 mmol) and EDCI (257.8 mg, 1.396 mmol). After stirring for 30 min compound 4 (187.2 mg, 0.698 mmol) and additional TEA (0.30 mL, 2.10 mmol) were added. This solution was allowed to stir at room temperature for 20 h and then the saturated NaHCO3 was added. The mixture was extracted with EtOAc and washed with saturated NaCl, dried over Na2SO4 and concentrated. The residue was purified with flash chromatography on silica gel, eluted with a mixture of PE/EA (4/1, v/v) to afford 6a (130 mg, 54%) as a white solid.
Boc-Phe(4-OMe)-His(N<SUP>im</SUP>Trt)-OMe[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; dichloromethane; at 0 - 20℃;
General procedure: The amino acid or peptide ester hydrochloride (1 mmol) was dissolved in CH2Cl2 (5 mL) and neutralized at 0 C with THF (1 mmol). Boc-aminoacid or Boc-peptide (1 mmol) and HOBt (1.5 mmol) were added followed by a solution of DCC (1.1 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at 0 C for 2-4 h and left at RT overnight. Dicyclohexylurea (DCU) was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in CHCl3, washed successively with 5% HCl, 5% NaHCO3, saturated NaCl solution, dried with anh. MgSO4 and conc. in vacuo. The peptide was purified by silica gel CC to yield the pure product.
Boc-Phe(4-OMe)-His(N<SUP>im</SUP>Bz)l-AHBA-OEt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; dichloromethane; at 0 - 20℃;
General procedure: The amino acid or peptide ester hydrochloride (1 mmol) was dissolved in CH2Cl2 (5 mL) and neutralized at 0 C with THF (1 mmol). Boc-aminoacid or Boc-peptide (1 mmol) and HOBt (1.5 mmol) were added followed by a solution of DCC (1.1 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at 0 C for 2-4 h and left at RT overnight. Dicyclohexylurea (DCU) was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in CHCl3, washed successively with 5% HCl, 5% NaHCO3, saturated NaCl solution, dried with anh. MgSO4 and conc. in vacuo. The peptide was purified by silica gel CC to yield the pure product.
Boc-Phe(4-OMe)-His-(N<SUP>im</SUP>Bzl)-ACHPA-OEt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; dichloromethane; at 0 - 20℃;
General procedure: The amino acid or peptide ester hydrochloride (1 mmol) was dissolved in CH2Cl2 (5 mL) and neutralized at 0 C with THF (1 mmol). Boc-aminoacid or Boc-peptide (1 mmol) and HOBt (1.5 mmol) were added followed by a solution of DCC (1.1 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at 0 C for 2-4 h and left at RT overnight. Dicyclohexylurea (DCU) was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in CHCl3, washed successively with 5% HCl, 5% NaHCO3, saturated NaCl solution, dried with anh. MgSO4 and conc. in vacuo. The peptide was purified by silica gel CC to yield the pure product.
Boc-Phe(4-OMe)-His(N<SUP>im</SUP>Bzl)-AHNAOEt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; dichloromethane; at 0 - 20℃;
General procedure: The amino acid or peptide ester hydrochloride (1 mmol) was dissolved in CH2Cl2 (5 mL) and neutralized at 0 C with THF (1 mmol). Boc-aminoacid or Boc-peptide (1 mmol) and HOBt (1.5 mmol) were added followed by a solution of DCC (1.1 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at 0 C for 2-4 h and left at RT overnight. Dicyclohexylurea (DCU) was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in CHCl3, washed successively with 5% HCl, 5% NaHCO3, saturated NaCl solution, dried with anh. MgSO4 and conc. in vacuo. The peptide was purified by silica gel CC to yield the pure product.
With 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 0 - 23℃; for 3h;
General procedure: A 250 mL round bottom flask was charged with N-Boc amino acid (10.0 mmol, 1.00 equiv),glycine methyl ester hydrochloride (1.256 g, 10.0 mmol, 1.00 equiv), DMF (50mL), and DIPEA (3.50 mL, 20.5 mmol, 2.05 equiv.) and the temperature was cooledto 0 C.HATU (3.802 g, 10.0 mmol, 1 equiv) was added and the reaction stirred for 3hours while warming to room temperature. EtOAc (150 mL) was added and theorganic layer was washed with 75 mL each of 0.5 N hydrochloric acid, saturatedaqueous sodium bicarbonate, water, and brine, dried with MgSO4,filtered and concentrated. The crude material was dissolved in CH2Cl2(33 mL) and TFA (17 mL) and stirred for 2 h at room temperature. The mixturewas then concentrated and azeotroped with toluene (2 × 40 mL). To this crudematerial was added 2N NH3 in methanol (40 mL). The reaction timeand workup procedure for the cyclization are specified for each compound. Enantiomericexcesses were determined by making the racemate and finding conditions thatseparated the enantiomers by SFC. In general a Chiralpak ADH column(4.6 x 150 mm) was used, eluting with 15-25% ethanol or methanol insupercritical CO2 (total flow was 4 mL/min).
tert-butyl ((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With 4-methyl-morpholine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 0.5h;
To a flask charged with Boc-Z-4-MeO-phenylalanine (3.1 g, 10.3 mmol), (S)-2- amino-l-((R)-2-methyloxiran-2-yl)-3-phenylpropan-l-one (TFA salt, 3.0 g, 9.4mmol) and HATU (3.2 g, 10.3 mmol) was added dichloromethane (DCM, 20 mL). The mixture was cooled to 0C and basified with N,N-Diisopropylethylamine (DIPEA) to pH=8. The reaction mixture was stirred at room temperature for 30 min and then quenched with water (30 mL). The resulting mixture was extracted with methyl tertiary butyl ether (MTBE; 30 mL><3). The organics were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 5: 1 to 4: 1) to afford Boc-(S)-2-amino-3-(4-methoxyphenyl)-N-((S)-l-((R)-2-methyloxiran-2- yl)-l-oxo-3-phenylpropan-2-yl)propanamide as a white solid (4.5 g, 88% yield).
(S)-2-amino-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)propan-1-one[ No CAS ]
[ 53267-93-9 ]
tert-butyl ((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With 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 0℃; for 0.25h;
To (S)-2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propanoic acid (2.00 g, 6.78 mmol) and (S)-2-amino-3-(cyclopent-l-en-l-yl)-l-((R)-2-methyloxiran-2-yl)propan- 1-one (1.98 g, 6.78 mmol) in DMF (10 mL) at 0 oC was added HATU (3.00 g, 8.36 mmol) followed by DIEA (5.90 mL, 33.9 mmol) and the mixture was stirred for 15 min then quenched with NaHC03 (sat., aq.), extracted with EtOAc (2x), washed with brine, dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (1 : 1 hexanes/EtOAc) provided tert-butyl ((S)-l-(((S)-3-(cyclopent-l-en-l-yl)-l-((R)-2- methyloxiran-2-yl)-l-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-l-oxopropan-2- yl)carbamate (2.62 g, 82%) as a colorless oil. MS(EI) for C26H36N206, found 473.3 (MH)+.
A solution of 8 (100 mg, 0.255 mmol) in CH2Cl2 (1.25 mL) at 0 C was treated with CF3CO2H (1.20 mL), and the mixture was stirred at 0 C for 1 h. The solvent was removed in vacuum, and the residue (123 mg) was dried by azeotropic removal of H2O with toluene. To a cooled (0 C) solution of the crude amine-TFA salt (123 mg, 0.255 mmol) and <strong>[53267-93-9]N-Boc-O-methyl-L-tyrosine</strong> ( 123 mg, 0.331 mmol) in THF (2.5 mL) and CH2Cl2 (0.5 mL) were added 1-hydroxybenzotriazole (HOBT,34.5 mg, 0.255 mmol), Et3N (62.0 mg, 0.0850 mL, 0.611 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 63.4 mg, 0.331 mmol). The mixture was stirred at 0 C for 0.5 h and then was allowed to warm to room temperature and was stirred for 18 h. The solvent was removed in vacuum. Then reaction mixture was diluted with EtOAc and washed with water, 5% HCl, saturated aqueous NaHCO3 solution, H2O, and brine. The organic layer was dried with Na2SO4 and the solvent was removed in vacuum, and the residue was purified by column chromatography to give 130 mg (0.228 mmol, 89%) of benzyl (2S)-2-[3-[(2S)-2-tert-Butoxycarbonylamino-3-(4-methoxyphenyl)propionylamino]-propionyloxy]-4-methylpentanoate as colourless oil. 1H NMR (400 MHz, CDCl3) delta 7.36 (m, 5H), 7.11 (d, J = 7.5 Hz, 2H), 6.81(d, J = 6.3 Hz, 2H), 5.12 (m, 4H), 3.75 (m, 3H), 3.51(m, 2H), 2.98 (m, 2H), 2.51(m, 2H), 1.66(m,3H), 1.38 (m, 9H), 0.91 (m, 6H); 13C NMR (100 MHz, CDCl3) delta 171.5, 171.3, 170.7, 158.2, 155.1,134.9, 130.1, 128.6, 128.0, 113.6, 79.5, 70.9, 67.0, 55.6, 54.9, 39.2, 37.7, 34.8, 33.9, 28.1, 24.4,23.1, 21.3.
(S)-tert-butyl (1-(1H-benzo[d]imidazol-2-yl)-2-(4-methoxyphenyl)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethylmorpholine;; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In acetonitrile; at 20℃;Inert atmosphere;
(S)-f erf-Butyl (1 -(1 H-benzo[ ]imidazol-2-yl)-2-(4-methoxyphenyl)ethyl)carbamate: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (S)-2-((te/f-butoxycarbonyl)amino)-3-(4- methoxyphenyl)propanoic acid (4470 mg, 15.1 mmol) in AcCN (125 mL) was treated at rt with 4-ethylmorpholine (3.95 mL, 30.3 mmol), TBTU (4.860 g, 15.1 mmol) and o- phenylenediamine (1.670 g, 15.1 mmol). The reaction mixture was stirred at rt until completion. The reaction mixture was diluted with EA and water. The org. phase was dried over MgS04, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in glacial acetic acid (125 mL) and the reaction mixture was stirred at 60 C for 60 min. The mixture was cooled to rt and the solvent was removed under reduced pressure. The residue was partitioned between EA (100 mL) and sat. aq. NaHCO3 (100 mL). The org. layer was washed with sat. aq. NaHC03 (twice 100 mL), dried over MgS04, filtered, and the solvent was removed under reduced pressure. Purification of the residue by MPLC (1 :0? 2: 1 hept-EA) gave the title compound as beige solid. LC- MS-conditions 06: tR = 0.69 min; [M+H]+ = 368.06.
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; acetonitrile; at 20℃;
General procedure: To a solution of appropriate amino protected carboxylic acidderivative (1 eq.) dissolved in a mixture of CH2Cl2 and CH3CN (1:1, 3.7 mL/mmol of carboxylic acid), EDC (1.3 eq.), HOBt (1.3 eq.), NMM (6.5 eq.) and HN(Me)OMe*HCl (2.1 eq.) were added. The mixture was stirred at room temperature over 24-72 h and then evaporated.The resulting crude product was dissolved in CH2Cl2, washed three times with saturated NaHCO3 solution, three times with 1 M HCl and once with brine. Organic layer was dried over MgSO4,filtered and concentrated in vacuo. Purification via flash chromatography was performed. 4.2.9 tert-Butyl N-[(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxo-ethyl]carbamate (13a) According to general method 1, 13a was obtained as a yellow solid (0.225 g, 48%). Analyses similar to literature description [55] .
3-((1-(3,4-dichlorophenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)-propan-1-amine hydrochloride[ No CAS ]
(S)-tert-butyl (1-((3-((1-(3,4-dichlorophenyl)-4-(2-(methylthio)ethyl)-3-(pyridin-3-yl)-1H-pyrazol-5-yl)oxy)propyl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
General procedure: To a solution of mixture of compounds 40 (0.15 g, 0.32 mmol) and 13 (0.068 g, 0.33 mmol) in CH2Cl2 (10 mL) was sequentially added hydroxybenzotriazole (0.050 g, 0.33 mmol), N-(3-dimethylaminopropyl)- N?-ethylcarbodiimide hydrochloride (0.084 g, 0.44 mmol) and Et3N (0.15 mL, 1.1 mmol), and the mixture was stirred overnight at room temperature. The reaction was diluted with ethyl acetate (20 mL) and washed with saturated aqueous NaHCO3 (10 mL), H2O (10 mL), and brine (10 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure. Column chromatography purifications of light yellow oily material, eluting with EtOAchexane (8:2), gave the product as a light green solid (yield 69 %).
ethyl (S)-5-(1-((tert-butoxycarbonyl)amino)-2-(4-methoxyphenyl)ethyl)oxazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
291 mg
To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propionic acid (1.0 g) in N,N-dimethylformamide (15 mL) were added potassium carbonate (955 mg) and ethyl 2-isocyanoacetate (510 IL), and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added diphenylphosphoryl azide (894 1iL), and the mixture was stirred at room temperature for 22 hours. A cold water was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate (x3). The organic layer was washed with water and then a brine, and the organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate : hexane = 1: 1) to obtain the title compound as a colorless oil (291 mg).1HNMR (400 MHz, DMSO-d6) oe 1.25 (3H, m), 1.30 (9H, br s), 2.85 (1H, m), 2.97(1H, dd, J = 13.3, 8.5 Hz), 3.68 (3H, s), 4.21 (2H, m), 5.40 (1H, m), 6.80 (2H, d, J =8.5 Hz), 7.05 (2H, d, J = 8.5 Hz), 7.60 (1H, d, J = 8.5 Hz), 8.42 (1H, s).
tert-butyl (S)-[1-hydrazinyl-(4-methoxyphenyl)-1-oxopropan-2-yl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrazine hydrate; In methanol; at 20℃; for 24h;
To a solution of methyl(S)-2- [(tert-butoxycarbonyl)aminoj -3-(4-methoxyphenyl)propionate (1.00 g, 3.23 mmol) in methanol (16.0 mL) was added hydrazine monohydrate (784 1iL, 16.2 mmol), and the mixture was stuffed at room temperature for a day. Then, to the reaction mixture under ice-cooling was added ethyl acetate (50 mL) and water (25 mL), the mixture of organic layer was separated, and the combined aqueous layer was extracted with ethyl acetate (50 mL). The organic layer was washed with a brine (20 mL) , dried over anhydrous sodium sulfate, and then filtrated. The filtrate was concentrated under reduced pressure to obtain the title compound a white solid (1.00 g, quant.).1HNMR (400 MHz, DMSO-d6) oe 1.29 (9H, s), 2.66 (1H, m), 2.78 (1H, m), 3.70(3H, s), 4.02 (1H, m), 4.34-4.74 (2H, br s), 6.81 (2H, d, J = 8.5 Hz), 6.86 (1H, d, J = 8.5 Hz), 7.14 (2H, d, J = 8.5 Hz), 9.15 (1H, br s).
The L-Boc-O-Methyl-Tyrosine-OH is preactivated by adding 1.0 eq TBTU and 3.3 eq DIPEA to a solution of 1.0eq Boc-AA2-OH in 5ml DMF. After 4 minutes, 4.5 mmol (1.0eq) H-D-Pro-NH-2Ad *HCl is added. The mixture is allowed to react for one hour at room temperature. The reaction mixture is transferred into a separation funnel with ethyl acetate and water. The combined organic phases are washed with 5% NaHCO3, 1 M KHSO4, and brine. The organic phase is dried over Na2SO4 and all volatile compounds are removed at 2mbar/ 40C water bath. The crude Boc-protected material is dissolved in 20ml/4M HCl in dioxane for 45 minutes. The pH of the solution is adjusted to 8 by NaHCO3, and the free base is extracted with ethyl acetate. The organic phase is dried over Na2SO4 and all volatile compounds are removed at 2mbar/ 40C water bath. The intermediate is used without further purification in procedure 3 and 6.
Boc-Tyr(Me)-OH (29.2 grams, 98.9 mM) was dissolved in DMF (360 mL), and the solution was cooled to 0-5 C. Next, TBTU (31.8 grams, 98.9 mM), HOBt (16.7 grams, 109.1 mM) were added to the above solution, followed by NMM (16.7 mL, 151.8 mM). The reactants were stirred for 15 minutes. In a separate flask, H-Ile-Gln(Trt)-Asn(Trt)-OMe (72.0 grams, 82.6 mM) was dissolved in DMF (360 mL) at 25-30 C, and the solution was cooled to 0-5 C. This was added to the first reaction mixture at 0-5 C over a period of 45 minutes. The reactants were stirred for 3 hours at 25-30 C. The progress of reaction was monitored by HPLC. After the completion of reaction, 2.5% aqueous NaHCC solution (2160 mL) was added at 10-15 C to quench the reaction. The suspension was stirred for 1 hour at 25-30 C. The resultant solid was filtered and washed with purified water. Next, EtOAc, (720 mL) was added to the solid and the suspension was stirred for 1 hour at 25-30 C. The solid was filtered and washed with heptane. Finally the product was dried under reduced pressure at 40 C to furnish the title compound (75.5 grams, 65.7 mM; Yield: 79.6%; Purity RP -HPLC: 97.84%; [M+H]+ 1 150 amu)
With hydrogenchloride; In acetone; at 10 - 25℃; for 5h;
N - tert-butoxycarbonyl - L - tyrosine added to acetone, completely dissolve, keep the reaction system 20 - 35 °C, batch by adding 6 equivalent of sodium hydroxide, after adding stirring 2 hours, maintaining the reaction system 0 - 20 °C, dropwise 3 equivalent of dimethyl sulfate, after adding the room temperature (20 - 30 °C) reaction overnight, water is added to a reaction system, in 40 - 50 °C between evaporating the acetone, acetone after removing, adding ethyl acetate and ice, citric acid solid is acidified to pH=2 - 3, layered, abandoned to the aqueous phase, the oil phase of the saturated salt water for washing three times, sodium sulfate drying 2 hours, filtering to remove sodium sulfate, evaporate most of the ethyl acetate, adding petroleum ether and stirring crystallization, to obtain N - tert butoxycarbonyl - O - methyl - L - tyrosine, yield 64percent. N - tert butoxycarbonyl - O - methyl - L - tyrosine soluble in acetone, maintaining the 10 - 25 °C, slow access after drying of hydrochloric acid gas, reaction 5 hours, insufflating hydrochloric acid gas, cooling to 0 - 10 °C, triethylamine for adjusting pH=7, separate out a large amount of white solid, filtered, and dried to obtain the O - methyl - L - tyrosine, purity 99.5percent, yield 66percent.
methyl (S)-2-methylpyrrolidine-2-carboxylate monohydrochloride[ No CAS ]
C22H32N2O6[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃;
To a stirred solution of methyl (S)-2-methylpyrrolidine-2-carboxylate hydrochloride (7.00 g, 39 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propanoic acid (0711) (12.08 g, 40.9 mmol) in DMF (100 ml) at 0 C was added DIPEA (17.01 ml, 97.0 mmol) followed by HATU (19.26 g, 50.7 mmol). The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with a 10% aqueous LiCI solution and extracted with EtOAc. The organic extract was washed with 10% aqueous LiCI and dried over MgS04. The solvent was removed under reduced pressure and the residue purified by column chromatography over silica gel (eluting with (0712) Hexanes/EtOAc 80:20 to 40:60) to provide 104.