* 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.
Stage #1: With sodium hydroxide In water at 20℃; for 24 h; Stage #2: With hydrogenchloride In water
To a solution of 2[36] and [37] (5 g, 12.7 mmol) in NaOH 2N (80 mL) was added Boc2O (4.5 g, 20 mmol) and the reaction mixture was stirred at room temperature for 24 h. The aqueous solution was then acidified with HCl concentrated until pH 2 and extracted with CH2Cl2 (2 .x. 100 mL); the combined organic phases were washed with brine, dried and concentrated under reduce pressure to give without any further purification compound 3 (5.3 g, 90percent) as white foam.1H NMR (DMSO): δ (ppm) 1.37 (s, 9H, 3 .x. CH3); 2.29-2.58 (m, 2H, CH2); 3.76-3.79 (m, 1H, CH); 6.84 (d, J = 7.8 Hz, 1H, NH); 7.14-7.38 (m, 15H, trityl-H).MALDI-TOF MS: m/z 464.8 Da [M + H], C27H29NO4S, Mol. Wt.: 463.59.
86.21%
With sodium hydroxide In 1,4-dioxane; water at 20℃; for 8 h; Cooling with ice
The compound S-trityl-L-cysteine (5 g, 13.76 mmol)Was dissolved in dioxane (40 ml)Water (20 ml),1M sodium hydroxide solution (14 ml)Stir under ice bath,Boc-anhydride (3.5 ml, 15.14 mmol) was added,The reaction naturally rose to room temperature,Stirring for 8 hours,TLC detection reaction is completed,The reaction mixture was concentrated to 20-25 ml,Ethyl acetate was added,A solution of sodium bisulfate was added dropwise under stirring in an ice bath,After adjusting the pH to 2-3,Extracted with ethyl acetate,The organic layer was washed with saturated brine,Then dried over sodium sulfate,concentrate,Column chromatography (methanol: dichloromethane 1percent -5percent),The product was a white solid (5.5 g, yield: 86.21percent).
60%
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 40℃; Stage #2: With hydrogenchloride In water
To the solution of Trt-Cys-OH (22.68 g, 62.5 mmol) in dioxane (60 mL) and water (125 mL) was added di-tert-butyldicarbonate (41 g, 187 mmol) at 45 0C, and the solution was adjusted with NaOH(4M) until pH = 9.5, and then stirred at the same temperature overnight. Once the reaction was done, water and dioxane was removed under reduced pressure. The residue was dissolved into water (150 mL) , extracted with ethyl acetate (2 x 100 mL) . The aqueous layer was adjusted to pH = 2 with dilute HCl while in an ice bath, and then the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried over magnesium sulfate. Removal of the solvent under vacuum yielded a yellow oil. The residue was then dissolved into ethyl ether and carefully added a 1 : 1 mixture of ethyl ether and hexane while stirring to <n="32"/>precipitate out the white solid in 60percent yield. Ic: 1H NMR (300 MHz, CDC13): δl.46 (s, 9H), 2.69 (br, 2H), 4.21 (s, IH), 4.97 (s, IH), 7.20-7.44 (m, 15H), 10.2 (br, IH); 13C NMR (75.5 MHz, CDC13): δ 28.1, 33.5, 52.4, 144.1, 155.4, 175.1
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 383 - 392
[2] Chemical Communications, 2013, vol. 49, # 92, p. 10808 - 10810
[3] Patent: CN106432014, 2017, A, . Location in patent: Paragraph 0096; 0100; 0101; 0102; 0142; 0146; 0147; 0148
[4] Patent: WO2009/137251, 2009, A2, . Location in patent: Page/Page column 30; 31
[5] Chemistry of Natural Compounds, 1979, vol. 15, p. 471 - 476[6] Khimiya Prirodnykh Soedinenii, 1979, vol. 15, p. 543 - 548
[7] Organic Letters, 2005, vol. 7, # 13, p. 2615 - 2618
[8] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 20, p. 7353 - 7361
[9] Patent: CN107434776, 2017, A, . Location in patent: Paragraph 0075; 0077
2
[ 1070-19-5 ]
[ 2799-07-7 ]
[ 21947-98-8 ]
Reference：
[1] Chemische Berichte, 1969, vol. 102, p. 1048 - 1052
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1977, vol. 15, p. 80 - 81
3
[ 76-84-6 ]
[ 52-89-1 ]
[ 2799-07-7 ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: for 2 h; Stage #2: With sodium acetate; sodium hydroxide In diethyl ether; water at 0℃;
Triphenylmethanol (3.3 g, 12.7 mmol) was added to a solution of Cysteine chlorydrate (2 g, 12.7 mmol) in TFA (25 mL) and the mixture was stirred for 2 h. After cooling to 0 °C, NaOH 4N and diethyl ether (40 mL) were added until pH 4-5 and then 10percent sodium acetate aqueous solution was added until pH 5-6. The precipitated obtained was filtered, washed with fresh Et2O and finally dried to obtain the desired product (5 g, 98percent yield).1H NMR (DMSO): δ (ppm) 2.35-2.61 (m, 2H, CH2); 2.85-2.98 (m, 1H, CH); 7.2-7.45 (m, 15H, trityl-H).MALDI-TOF MS: m/z364.7 Da [M + H]+, C22H21NO2S, Mol. Wt.: 363.47.
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 383 - 392
[2] Chemical Communications, 2013, vol. 49, # 92, p. 10808 - 10810
[3] Journal of the Chemical Society [Section] C: Organic, 1970, p. 2687
[4] Journal of Medicinal Chemistry, 1970, vol. 13, p. 414 - 418
[5] Canadian Journal of Chemistry, 1981, vol. 59, # 2, p. 406 - 421
4
[ 52-89-1 ]
[ 76-83-5 ]
[ 2799-07-7 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 20℃; for 48 h;
L-Cysteine hydrochloride (100 g, 0.634 mol) and trityl chloride (270 g, 0.969 mol) were stirred in DMF (400 mL) for 2 days at room temperature. A 10percent sodium acetate solution (3.5 L) was then added dropwise and the white precipitate which formed was filtered and washed with distilled water. Afterward, the residue was stirred in acetone at 50° C. for 30 min after which it was cooled to 0° C. and filtered. The precipitate was washed with a little acetone and diethyl ether and dried in vacuo. S-Trityl-L-cysteine 1b (205 g, 89percent) was obtained as a white powder. 1b: m.p. 192° C. (decomp). 1H NMR (DMSO-d6) δ 2.45 (dd, 1H, J=9 Hz, 12 Hz), 2.58 (dd, 1H, J=4.4 Hz, 12 Hz), 2.91 (m, 1H), 7.22-7.36 (m, 15H); 13C NMR (75.5 MHz, DMSO-d6): δ 33.8, 53.7, 66.4, 127.1, 127.8, 128.1, 128.4, 129.5, 144.5, 168.4. This material was directly used in the next step without further purification.
89%
With sodium acetate In N,N-dimethyl-formamide at 20℃; for 48 h;
L-Cysteine hydro-chloride (100 g, 0.634 mol) and trityl chloride (270 g, 0.969 mol) were stirred in DMF (400 mL) for 2 days at room temperature. A 10percent sodium acetate solution (3.5 L) was then added dropwise and the white precipitate which formed was filtered and washed with distilled water. Afterward, the residue was stirred in acetone at 50 0C for 30 min after which it was cooled to 00C and filtered. The precipitate was washed with a little acetone and diethyl ether and dried in vacuo. S-Trityl-L-cysteine Ic (205 g, 89percent) was obtained as a white powder. Ic: m.p. 192 °C (decomp) ; 1H NMR (300 MHz, DMSCW5) δ 2.45 (dd, IH, J= 9 Hz, 12 Hz), 2.58 (dd, IH, J= 4.4 Hz, 12 Hz), 2.91 (m, IH), 7.22-7.36 (m, 15H); 13C NMR (75.5 MHz, DMSO- d6): δ 33.8, 53.7, 66.4, 127.1, 127.8, 128.1, 128.4, 129.5, 144.5, 168.4. This material was directly used in the next step without further purification.
78%
at 20℃; for 48 h;
Preparation 75: Synthesis of (R)-3-amino-4-tritylsulfanyl-butyric acid methyl ester hydrochloride; (Step 1); L-cysteine hydrochloride (5Og, 284.7mmol) was dissolved in N,N- dimethylformamide (200ml). Trityl chloride (119g, 427.0mmol) was added thereto, and the mixture was stirred for 48 h at room temperature. After completion of the reaction, 10percent sodium acetate (1.5L) was added. The mixture was filtered to give a solid, which was then added to acetone (1.5L), and stirred for 30 min at 50 °C . The insoluble solid was filtered, and dried to give a trityl compound (80g, Yield 78percent).
77%
at 20℃; for 48 h;
Synthetic Example 1; (R)-3-Mercapto-2-(5-methyl-4-phenyl-thiazoI-2-yIamino)-propionic acid; Step 1 : S-Trityl-L-cysteine falso known as (R)-2-amino-3- (tritylsulfanyl)propanoic acid); L-Cysteine hydrochloride (5.0 g, 31.7 mmol) and trityl chloride (13.5 g, 48.4 mmol) were stirred in DMF (20 ml) for 48 h at room temperature. A 10percent NaOAc solution (175 mL) was then added, and the precipitate was filtered and washed with water. Afterward, the residue was suspended in acetone and stirred at 50 °C for 30 min, then cooled and filtered. The residue was washed with acetone (cold) and diethyl ether. After drying 8.86 g (77percent) S-trityl-L-cysteine was obtained.
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 4, p. 619 - 626
[2] Organic Letters, 2005, vol. 7, # 13, p. 2615 - 2618
[3] Patent: US7829709, 2010, B1, . Location in patent: Page/Page column 19-20
[4] Patent: WO2009/100431, 2009, A1, . Location in patent: Page/Page column 28
[5] Patent: WO2009/82152, 2009, A2, . Location in patent: Page/Page column 214
[6] Patent: WO2009/151744, 2009, A1, . Location in patent: Page/Page column 93
[7] Chemical Communications, 2009, # 4, p. 407 - 409
[8] Acta Chemica Scandinavica (1947-1973), 1959, vol. 13, p. 383
[9] Journal of the American Chemical Society, 1962, vol. 84, p. 3887 - 3897
5
[ 76-84-6 ]
[ 52-90-4 ]
[ 2799-07-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 20℃; for 5 h;
To a solution of l-cysteine (1.0 g, 5.69 mmol) in acetic acid (15 mL) was added triphenyl methanol (1.64 g, 6.30 mmol), followed by adding trifluoroboron ethylether (720 μL, 5.69 mmol) dropwise and the reaction was stirred at room temperature. After 5 h, the reaction mixture was neutralized with saturated sodium acetate. The resulting precipitate was washed with ethylether and collected to give the desired compound 3 (1.87 g, 90percent) as a white solid. 1H NMR (300 MHz, acetone-d6): δ = 7.46-7.23 (m, 15H), 3.64 (dd, J = 8.10 Hz, 4.20 Hz, 1H), 2.67-2.52 (m, 2H). 13C NMR (75 MHz, DMSO-d6): δ = 169.89, 144.42, 129.25, 128.11, 126.78, 65.95, 53.64, 34.39. MALDI-TOF-MS: Calcd for C22H20NO2S 362.1. Found 362.1 [M-H]-.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 11, p. 3465 - 3469
6
[ 76-83-5 ]
[ 2799-07-7 ]
Yield
Reaction Conditions
Operation in experiment
76.15%
at 60 - 65℃; for 8 h;
The compound L-cysteine hydrochloride (10 g, 63.45 mmol)Was dissolved in N, N-dimethylformamide (120 ml)Triphenylchloromethane (19.46 g, 69.795 mmol) was added,Heated to 60-65 ° C,Reaction for 8 hours,TLC detection reaction is completed,Cooled to room temperature,A 10percent sodium acetate solution (300 ml) was added,Precipitation of white solid,filter,The residue was washed with pure water (300 ml)Then washed with acetone (200 ml)dry,The product was a white solid (17.56 g, yield: 76.15percent).
Reference：
[1] Patent: CN106432014, 2017, A, . Location in patent: Paragraph 0096; 0097; 0098; 0099; 0142; 0143; 0144; 0145
7
[ 103213-32-7 ]
[ 2799-07-7 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 26, p. 8116 - 8128
[2] Amino Acids, 2014, vol. 46, # 2, p. 367 - 374
[3] Journal of the American Chemical Society, 2016, vol. 138, # 15, p. 5069 - 5075
Triphenylmethanol (3.3 g, 12.7 mmol) was added to a solution of Cysteine chlorydrate (2 g, 12.7 mmol) in TFA (25 mL) and the mixture was stirred for 2 h. After cooling to 0 °C, NaOH 4N and diethyl ether (40 mL) were added until pH 4-5 and then 10percent sodium acetate aqueous solution was added until pH 5-6. The precipitated obtained was filtered, washed with fresh Et2O and finally dried to obtain the desired product (5 g, 98percent yield).1H NMR (DMSO): delta (ppm) 2.35-2.61 (m, 2H, CH2); 2.85-2.98 (m, 1H, CH); 7.2-7.45 (m, 15H, trityl-H).MALDI-TOF MS: m/z364.7 Da [M + H]+, C22H21NO2S, Mol. Wt.: 363.47.
To a solution of 2[36] and [37] (5 g, 12.7 mmol) in NaOH 2N (80 mL) was added Boc2O (4.5 g, 20 mmol) and the reaction mixture was stirred at room temperature for 24 h. The aqueous solution was then acidified with HCl concentrated until pH 2 and extracted with CH2Cl2 (2 .x. 100 mL); the combined organic phases were washed with brine, dried and concentrated under reduce pressure to give without any further purification compound 3 (5.3 g, 90percent) as white foam.1H NMR (DMSO): delta (ppm) 1.37 (s, 9H, 3 .x. CH3); 2.29-2.58 (m, 2H, CH2); 3.76-3.79 (m, 1H, CH); 6.84 (d, J = 7.8 Hz, 1H, NH); 7.14-7.38 (m, 15H, trityl-H).MALDI-TOF MS: m/z 464.8 Da [M + H], C27H29NO4S, Mol. Wt.: 463.59.
86.21%
With sodium hydroxide; In 1,4-dioxane; water; at 20℃; for 8h;Cooling with ice;
The compound <strong>[2799-07-7]S-trityl-L-cysteine</strong> (5 g, 13.76 mmol)Was dissolved in dioxane (40 ml)Water (20 ml),1M sodium hydroxide solution (14 ml)Stir under ice bath,Boc-anhydride (3.5 ml, 15.14 mmol) was added,The reaction naturally rose to room temperature,Stirring for 8 hours,TLC detection reaction is completed,The reaction mixture was concentrated to 20-25 ml,Ethyl acetate was added,A solution of sodium bisulfate was added dropwise under stirring in an ice bath,After adjusting the pH to 2-3,Extracted with ethyl acetate,The organic layer was washed with saturated brine,Then dried over sodium sulfate,concentrate,Column chromatography (methanol: dichloromethane 1percent -5percent),The product was a white solid (5.5 g, yield: 86.21percent).
60%
To the solution of Trt-Cys-OH (22.68 g, 62.5 mmol) in dioxane (60 mL) and water (125 mL) was added di-tert-butyldicarbonate (41 g, 187 mmol) at 45 0C, and the solution was adjusted with NaOH(4M) until pH = 9.5, and then stirred at the same temperature overnight. Once the reaction was done, water and dioxane was removed under reduced pressure. The residue was dissolved into water (150 mL) , extracted with ethyl acetate (2 x 100 mL) . The aqueous layer was adjusted to pH = 2 with dilute HCl while in an ice bath, and then the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried over magnesium sulfate. Removal of the solvent under vacuum yielded a yellow oil. The residue was then dissolved into ethyl ether and carefully added a 1 : 1 mixture of ethyl ether and hexane while stirring to <n="32"/>precipitate out the white solid in 60percent yield. Ic: 1H NMR (300 MHz, CDC13): deltal.46 (s, 9H), 2.69 (br, 2H), 4.21 (s, IH), 4.97 (s, IH), 7.20-7.44 (m, 15H), 10.2 (br, IH); 13C NMR (75.5 MHz, CDC13): delta 28.1, 33.5, 52.4, 144.1, 155.4, 175.1
With sodium hydroxide; at 20℃; for 24h;
(1) 1.1 g of <strong>[2799-07-7]S-trityl-L-cysteine</strong> (II), 1.0 g of di-tert-butyl dicarbonate (Boc2O) and 19 mL of 2N aqueous sodium hydroxide were mixed and allowed to react at room temperature for 24 hours. Drop to room temperature, slowly dropping 1mol / L HCl to adjust pH = 2,The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with distilled water to a pH of 7. The organic layer was dried over anhydrous sodium sulfate and removed with water. The filtrate was collected by filtration and the filtrate was evaporated to remove the extractant to give a white foamy solid amino-S-Trityl-Cys (III).
methyl 6-[2-(1'-allyloxycarbonylamino-2'-tritylsulfanyl-ethyl)-thiazol-4-yl]-5-(4-methoxycarbonyl-thiazol-2-yl)-3-trifluoromethanesulfonyloxy-pyridine-2-carboxylate[ No CAS ]
methyl 6-[2-(1'-allyloxycarbonylamino-2'-tritylsulfanyl-ethyl)-thiazol-4-yl]-5-(4-methoxycarbonyl-thiazol-2-yl)-3-trifluoromethanesulfonyloxy-pyridine-2-carboxylate[ No CAS ]
(R)-2-{7-[(S)-1-carboxy-2-(1-trityl-1H-imidazol-4-yl)-ethyl]-1,3,6,8-tetraoxo-3,6,7,8-tetrahydro-1H-benzo[lmn][3,8]phenanthrolin-2-yl}-3-tritylsulfanyl-propionic acid[ No CAS ]
To 2.68g (7.37 mmol) of <strong>[2799-07-7]S-trityl-L-cysteine</strong> and 40 mL of methanol was added 7 mL (96 mmol) of thionyl chloride dropwise. After heating at reflux for 6h the solution was cooled to room temperature and then concentrated in vacuo. The resulting residue was taken up in 20 mL of methanol, treated with activated carbon, filtered and concentrated in vacuo yielding the methyl ester as an off-white foam. This material was dissolved in 6 mL of methanol in a sealable tube and cooled to -78°. After 30 mL of liquid ammonia was added, the tube was sealed and the reaction was stirred at room temperature for 14h After recooling to -78° the reaction tube was unsealed and the solution was carefully reduced to dryness. The residue was chromatographed on silica gel eluting with methylene chloride/methanol (10:1) furnishing 1.52g (57percent) of the primary amide as a white solid. Electrospray Mass Spec: 363.2 (M+H)+
With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 19h;
Example 18 N-(1-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2 (R)-(2, 2, 2-TRIFLUORO-1 (S)-4- fluorophenylethylamino) propionamide STEP 1 To a slurry of <strong>[2799-07-7]S-trityl-L-cysteine</strong> (4.86 g, 13.37 mmol) in dichloromethane (97 mL, 20 mL/g AA) at room temperature was added diisopropylethylamine (9.32 mL, 53.48 mmol) followed by a solution of trifluoromethanesulfonic acid 2,2, 2-trifluoro-l (RS)-phenylethyl ester (5.32 g, 16. 04 mmol) (major enantiomer (USD), 90 ee) in dichloromethane (15 mL) via syringe all at once. After 19 h, the reaction mixture was concentrated on the rotovap to give an oil. Diethyl ether was added and the solution was washed with IN HCl and brine. The organic layer was dried over MGS04, filtered, and concentrated. Flash chromatography of the residue with 2 hexanes/1 ethyl acetate/. 25percent acetic acid as the eluent provided 2 (R)- [2, 2, 2-TRIFLUORO-L (RS)-(4- FLUOROPHENYL) ETHYLAMINO]-3-TRITYLSULFANYL-PROPIONIC acid (6 g) (major diastereomer (R,S), 90 de) as an OIL/FOAM.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 19h;
Reference DSynthesis of 2(i?)-[2,2,2-trifluoro-l(>S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionic To a slurry of <strong>[2799-07-7]S-trityl-L-cysteine</strong> (4.86 g, 13.37 mmol) in dichloromethane (97 mL, 20 EPO <DP n="75"/>mL/g AA) at room temperature was added diisopropylethylamine (9.32 mL, 53.48 mmol) followed by a solution of trifluoromethanesulfonic acid 2,2,2-trifluoro-l(i?)S)-phenylethyl ester (5.32 g, 16.04 mmol) (major enantiomer (S), 90 ee) in dichloromethane (15 mL) via syringe all at once. After 19 h, the reaction mixture was concentrated on the rotovap to give an oil. Diethyl ether was added and the solution was washed with IN HCl and brine. The organic layer was dried over MgSO4, filtered, and concentrated. Flash chromatography of the residue with 2 hexanes/1 ethyl acetate/.25percent acetic acid as the eluent provided 2(i?)-[2,2,2-trifiuoro-l(S)-(4- fluorophenyl)ethylamino]-3-tritylsulfanyl-propionic acid (6 g) (major diastereomer (RJS), 90 de) as an oil/foam.
(R)-[2,2-difluoro-1(S)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethylamino]-3-tritylsulfanylpropionic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 19h;
Step 4; A mixture of trifluoromethanesulfonic acid 2,2~difluoro-l(i?)-(4-fmorophenyl)-2-(4- EPO <DP n="70"/>methylsulfanylphenoxy)ethyl ester (1.70 g, 3.8 mmol), 2(izeta)-ammo-3-tritylsulfanyrpropionic acid (1.38 g, 38 mmol) and diisiopropylethylamine (2.65 ml, 15.2 mol) in DCM (35 ml) was stirred for 19 h at room temperature. The solvent was evaporated under vacuum and the residue dissolved in ethyl ether (20 ml). The solution was washed with IN HCl solution and brine. After dring over sodium sulfate, the solvent was evaporated and the crude was purified by flash chromatography, using a mixture of EA/H (1/3) as eluentto give 2(i?)-[2,2-difluoro-l(5)-(4-fluorophenyl)-2-(4- methylsulfanylphenoxy)ethylamino]-3-tritylsulfanylpropionic acid (0.693 g, 27 percent) as a foam.
O-α-benzyl-N-α-(benzyloxycarbonyl)-L-γ-glutamyl-S-triphenylmethyl-L-cysteine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran; water;
O-a-benzyl-N-a-(benzyloxycarbonyl)-L-?-glutamyl-S-triphenylmethyl-L-cysteinyl-2-phenyl-(2R)-glycine may be prepared by standard methods of peptide synthesis. A convenient synthesis, using the readily available starting materials N-a-(benzyloxycarbonyl)-L-?-glutamic acid a-benzyl ester, S-triphenylmethyl-L-cysteine, and D-phenylglycine, is as follows. N-a-(benzyloxycarbonyl)-L-?-glutamic acid a-benzyl ester is activated as the N-hydroxysuccinimide ester by reaction with N-hydroxysuccinimide and dicyclohexylcarbodiimide in anhydrous 1,4-dioxane. The N-a-(benzyloxycarbonyl)-L-?-glutamic acid a-benzyl ester ?-N-hydroxysuccinimide ester is dissolved in anhydrous tetrahydrofuran, and added to a solution of S-triphenylmethyl-L-cysteine and triethylamine in water to give O-a-benzyl-N-a-(benzyloxycarbonyl)-L-?-glutamyl-S-triphenylmethyl-L-cysteine. This is activated as the N-hydroxysuccinimide ester and coupled with D-phenylglycine in the same way as for the ?-glutamine-cysteine coupling to give the desired O-a-benzyl-N-a-(benzyloxycarbonyl)-L-?-glutamyl-S-triphenylmethyl-L-cysteinyl-2-phenyl (2R)-glycine.
2(i?)-Amino-3-tritylsulfanylpropionic acid (78 g, 214.6mmol) was dissolved in CH2Cl2 and DIPEA (112 mL, 643.8mmol) was added and the reaction mixture was stirred for 10 min at room temperature. Trifluoromethanesulfonic acid 2,2,2-trifluoro-l(i-)-(4-fluorophenyl)ethyl ester (70 g, 214.6mmol) in CH2Cl2 was added and the reaction mixture was stirred overnight at room temperature. Solvent was removed under the reduced pressure and the residue was dissolved in Et2O and washed with IN HCl, brine and dried over MgSO4. Solvent was removed give 2(i-)-[2,2,2-trifluoro-l(iS)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionic acid (90 g) as a yellow solid.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 20h;
To a suspension of L-trityl-cysteine (15.45 g, 42 mmol) and diisopropyl ethyl amine (29.3 mL, 168 mmol) in dichloromethane (350 mL), a solution of trifluoromethanesulfonic acid (R)-2,2,3;3,3-pentafluoro-1-(4-fluorophenyl)-propyl ester (16.0 g, 42 mmol) in dichloromethane (20 mL) was added at room temperature. The reaction mixture was stirred for 20 h and then concentrated. The residue was dissolved in ethyl acetate (300 mL). The organic phase was washed with cold IN HCl (100 mL), brine and dried over magnesium EPO <DP n="82"/>sulfate. After solvent evaporation, the crude was purified by flash chromatography, using a mixture 1:2 of EA/hexanes to give2(R)-[2.2,3,3,3-pentafluoro-1-(S)-(4- fluorophenyl)propylamino]-3-tritylsulfanyl-propionic acid as an oil (6.93 g).
trifluoromethanesulfonic acid 2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethyl ester[ No CAS ]
[ 2799-07-7 ]
[ 880762-37-8 ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 19h;
Example 7; N-(l-cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(i?)-(2,2,2-trifluoro-l(5)-4- fluorophenylethylamino)propionamide Step 1To a slurry of <strong>[2799-07-7]S-trityl-L-cysteine</strong> (4.86 g, 13.37 mmol) in dichloromethane (97 mL, 20 mL/g AA) at room temperature was added diisopropylethylamine (9.32 mL, 53.48 mmol) followed by a solution of trifluoromethanesulfonic acid 2,2,2-trifluoro-l(i?5)-phenylethyl ester (5.32 g, 16.04 mmol) (major enantiomer (S), 90 ee) in dichloromethane (15 mL) via syringe all at once. After 19 h, the reaction mixture was concentrated on the rotovap to give an oil. Diethyl ether was added and the solution was washed with IN HCl and brine. The organic layer was dried over MgSO4, filtered, and concentrated. Flash chromatography of the residue with 2 hexanes/1 ethyl acetate/.25percent acetic acid as the eluent provided 2(i?)-[2,2,2-trifluoro- l(LambdaS)-(4-fluorophenyl)ethylamino]-3-tritylsulfanyl-propionic acid (6 g) (major diastereomer (R,8), 90 de) as an oil/foam.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 19h;
Reference D; [0194] Synthesis of 2(i?)-[2,2,2-trifluoro-l (S)-(4-fluorophenyl)ethylamino]-3- tritylsulfanylpropionic acid; [0195] To a slurry of <strong>[2799-07-7]S-trityl-L-cysteine</strong> (4.86 g, 13.37 mmol) in dichloromethane (97 mL, 20 niL/g AA) at room temperature was added diisopropylethylamine (9.32 mL, 53.48 mmol) followed by a solution of trifluoromethanesulfonic acid 2,2,2-trifluoro- 1 (i?5)-phenylethyl ester (5.32 g, 16.04 mmol) (major enantiomer (S), 90 ee) in dichloromethane (15 mL) via syringe all at once. After 19 h, the reaction mixture was concentrated on the rotovap to give an oil. Diethyl ether was added and the solution was washed with IN HCl and brine. The organic layer was dried over MgSO4, filtered, and concentrated. Flash chromatography of the residue with 2 hexanes/1 ethyl acetate/.25percent acetic acid as the eluent provided 2(i?)-[2,2,2- trifluoro-l(i?S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanyl-propionic acid (6 g) (major diastereomer (R,S), 90 de) as an oil/foam.
A. N-boc-S-trityl-cysteine, dicyclohexylammonium salt (XX) To a solution of S-trityl cysteine (see Hiskey and Adams, J. Org. Chem., 30:1340, (1965)) (36.3 g, 0.10 mol) in dioxane (200 ml) and 1M aqueous NaOH (100 ml, 0.10 mol) was added di-t-butyl carbonate (25.36 g, 0.12 mol). The resulting opaque solution became warm and effervesced and the pH fell from 12 to 8 over one hour. After stirring for 90 min, 50percent aqueous citric acid (40 ml) was added and the resulting mixture (pH 4) was extracted with ether. The ether was washed with water, then saturated brine, dried (MgSO4), filtered and evaporated to give N-BOC-S-(triphenylmethyl)-cysteine as an oil. Half of this material was dissolved in ether (200 ml) and treated with dicyclohexylamine (10 ml, 50 mmol) to give compound (XX) as a white precipitate which was filtered off, washed with ether and dried (25.1 g, 78percent), mp 205°-207°.
magnesium bromide; In acetonitrile; at 40 - 50℃;Product distribution / selectivity;
Example 16: H-Cys(Tr)-OH (S-trityl cysteine) by selective S- tritylation of cysteine.Method A.; 0.20 g of cysteine (1.7 mmol) are dissolved in a solution of 0.46 g of triphenylmethyl chloride (1.7 mmol) and 0.31 g of MgBr2 (1.7 mmol) in 4 mL of MeCN, kept under stirring at 40 - 50°. The clear, yellow solution loses its colour when its temperature is lowered at room temperature. An equal volume of water containing 0.32 g (1.7 mmol) of citric acid is added to the final mixture and TEA is added until the pH is about 5. The evaporation under vacuum of MeCN gives rise to a suspension. The solid, isolated by filtration and washings with water, is thoroughly washed with Ac and the organic washings are added to a second portion of the water solution of citric acid, and treated as previously described, obtaining a second portion of the solid insoluble in Ac. The amount of solid, chromatographically pure H-Cys (Tr) -OH recovered in the two successive EPO <DP n="33"/>treatments is 0.28 g (th. 0.60 g, 46.67percent; mp 182 - 84 dec; an. C 72.63 (72.70), H 6.11 (5.87), N 3.85 (3.85), S 8.55 (8.82) .
zinc(II) chloride; In acetonitrile; at 20℃; for 0.166667h;Product distribution / selectivity;
Method B.; 0.10 g of cysteine (0.8 mmol) , on dissolving under stirring in 4 piiL of hot MeCN containing 0.11 g of ZnC12 (0.8 mmol) and 0.23 g of TrCl (0.8 mmol), gives rise to complete dissolution and loss of colour in about 5 min. After further 5 min at room temperature, the liquid becomes turbid. The reaction mixture is poured into 100 mL of water and kept under vigorous stirring after the pH is adjusted to 5, the suspension was filtered off, the solid washed with water. The dried solid is dissolved in 4 mL of Ac and mixed with an equal volume of water containing citric acid in a molar ratio 8:1. The mixture, alkalinised to pH 6 with TEA becomes clear. Ac is distilled under vacuum and 4 mL of water are added to the remaining suspension. Filtration leads to the isolation of a solid only partially soluble in Ac. After washing with this solvent, 0.23 g of chromatographically pure H-Cys (Tr) -OH are obtained. The treatment of the organic filtrate, reunited with washings, with citric acid, according to the procedure described above, produces further product (0.18 g) with analogous features (th. 0.60 g, 68.33percent; mp 183 - 84° dec; an.: C 72.65 (72.70), H 6.05 (5.82), N 3.83 (3.85), S 8.72 (8.82) .
To a suspension ofS-trityl-L-csyteine Ic (4.4 g, 12 mmol) in chloroform (92 mL) containing triethylamine (2.7 g, 26.4 mmol) cooled in ice, was added a solution of phenylacetyl chloride (1.8 g, 12 mmol) in chlorform (20 mL). The mixture was stirred at 0-5 0C for 15 min. and at room temperature for 24 hrs. Water was added (100 mL) and pH was adjusted to 1.5 with 5 N aqueous HCl. The aqueous phase was removed and the organic phase was washed with saturated sodium chloride (100 mL), dried (Na2SO4) and concentrated to give a white crystalline solid (4.9 g) in 85percent yield. Phenyl acetyl- <strong>[2799-07-7]S-trityl-L-cysteine</strong>: m.p. 60-62 0C ; [alpha]D= +21.8 ° (c 2, CH3OH); 1H NMR (300 MHz, CDCl3): delta 2.60-2.71 (m, 2 H), 3.5 (s, 1 H), 4.15-4.23 (m, 1 H), 5.92 (d, J= 6.48 Hz, 1 H), 7.21-7.33 (m, 20 H); ); 13C NMR (75.5 MHz, CDCl3): delta 32.9, 43.1, 51.4, 67.8, 126.8, 127.2, 127.4, 127.8, 127.9, 128.4, 128.9, 129.1, 129.4, 144.1, 171.5, 172.5.
3-mercaptotrityl-2-(2-mercaptotritylacetylamino)propionic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
b) 3-mercaptotrityl-2-(2-mercaptotritylacetylamino)propionic Acid 2.5 g of N,N'-dicyclohexylcarbodiimide were added to a solution of 5 g (0.015 mol) of S-tritylthioglycolic acid obtained above in 80 cm3 of N,N-dimethylformamide, and cooled to a temperature ranging from 0° C. to 5° C. with an ice bath. The stirring was maintained for 1 h and then a suspension of 5.2 g (0.016 mol) of S-tritylcysteamine in 80 cm3 of N,N'dimethylformamide was added. The stirring was maintained for 16 h, allowing the mixture to return to ambient temperature. The reaction mixture was poured into 1 litre of water acidified with HCl. The precipitate formed was filter-dried through sintered glass and thoroughly washed with water until a neutral pH was obtained. After drying under vacuum at 45° C., 9.7 g of 3-mercaptotrityl-2-(2-mercaptotritylacetylamino)propionic acid were obtained in the form of a white solid having a melting point of 208° C. The 1H NMR spectrum at 400 MHz (CD3CN) and the 13C NMR spectrum at 100 MHz (CD3CN) were in accordance with the expected structure.
To a solution of (S)-I, l-difluoro-l-(4-(methylthio)rhohenoxy)pent-3-yn-2-ol (1.58 g) in ether at 0°C was added sodium hydride (292 mg of 60percent). The mixture was stirred for 1 hour, then trifluoromethanesulfonyl chloride (1.53 g) added. The mixture was stirred for 1 hour, to form the triflate derivative of (S)-I, l-difluoro-l-(4-(methylthio)phenoxy)pent-3-yn-2-ol. This solution was cooled to -78°C, and a mixture of diisopropylethylamine and the trityl derivative of 2-amino-3-mercaptopropanoic acid (1.85 g) in dichloromethane was added dropwise. The reaction mixture was warmed to 00C, and ethyl acetate added, washed with water, brine, dried over sodium sulfate, and the solvent removed, to provide the trityl derivative of (R)-2-((S)-l , 1 -difluoro- 1 -(4-(methylthio)phenoxy)pent-3-yn-2-ylamino)-3- mercaptopropanoic acid.
2-(2,2-difluoro-2-(4-fluorophenoxy)ethylamino)-3-(tritylthio)propanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dichloromethane; at -78 - 20℃;
To the product of Example 3 (2,2-difluoro-2-(4-fiuorophenoxy)ethyl trifluoromethanesulfonate in dichloromethane) at -780C was added <strong>[2799-07-7]S-trityl-L-cysteine</strong> (2.23 g), and the mixture stirred for 1 hour. The temperature was raised to O0C, and the mixture stirred for 48 hours. The solvent was removed under reduced pressure, the residue diluted with ethyl acetate, washed with dilute hydrochloric acid (IN), brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue chromatogrqphed on silica gel, eluting with ethyl acetate/hexane 1/2 containing a few drops of acetic acid, to provide 2-(2,2-difluoro-2-(4-fluorophenoxy)ethylamino)-3-(tritylthio)propanoic acid (2.08 g).
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