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CAS No. : | 1155-62-0 | MDL No. : | MFCD00002801 |
Formula : | C13H15NO6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PVFCXMDXBIEMQG-JTQLQIEISA-N |
M.W : | 281.26 | Pubchem ID : | 70866 |
Synonyms : |
N-Carbobenzoxy-L-glutamic acid
|
Chemical Name : | Z-Glu-OH |
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.31 |
Num. rotatable bonds : | 9 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 68.27 |
TPSA : | 112.93 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.36 cm/s |
Log Po/w (iLOGP) : | 0.99 |
Log Po/w (XLOGP3) : | 0.92 |
Log Po/w (WLOGP) : | 1.08 |
Log Po/w (MLOGP) : | 0.82 |
Log Po/w (SILICOS-IT) : | 0.55 |
Consensus Log Po/w : | 0.87 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.79 |
Solubility : | 4.55 mg/ml ; 0.0162 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.88 |
Solubility : | 0.373 mg/ml ; 0.00133 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.15 |
Solubility : | 2.01 mg/ml ; 0.00714 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.84 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With acetic anhydride at 55℃; for 0.5h; | |
90% | With acetic anhydride at 55℃; for 0.166667h; | 2.2. Benzyl (S)-(2,6-dioxotetrahydro-2H-pyran-3-yl)carbamate (1, NCarbobenzoxyglutamicanhydride) Z-Glu-OH (2.5 g, 8.89 mmol) was suspended in acetic anhydride(20 mL) and the temperature was slowly raised to 55 °C (oil bathtemperature), whereupon a clear solution was formed. From the time ofcomplete dissolution, stirring was continued for additional 10 min. Thesolution was concentrated under high vacuum (rotary evaporatorequipped with hybrid vacuum pump) to obtain a nearly colourless oil.Ether (30 mL) was added to the crude product and ethyl acetate(5-10 mL) was added until a homogeneous solution was obtained uponheating. The solution was transferred to an Erlenmeyer flask and cyclohexane(15-20 mL) was added until the solution became turbid. Themixture was kept at -20 °C over night, whereupon an oil separated.Crystallisation was initiated by scratching with a glass rod. More cyclohexane(10 mL) was added and the mixture was kept again at-20 °C over night. The crystalline material was collected by vacuumfiltration and dried in vacuo to obtain 1 (2.1 g, 0.80 mmol, 90%) as awhite powder; Mp 82-86 °C (lit 86-88 °C [18]); 1H NMR (400 MHz,CDCl3), δ (ppm): 1.94 (qd, 2J = 13.1 Hz, 3J = 5.6 Hz, 1H, Cβ-HH),2.45-2.59 (m, 1H, Cβ-HH), 2.90 (ddd, 2J = 18.9 Hz, 3J = 13.0 Hz,3J = 6.2 Hz, 1H, Cγ-HH), 3.06 (ddd, 2J = 18.7 Hz, 3J = 5.6 Hz, 3J = 2.2 Hz, 1H, Cγ-HH), 4.38-4.52 (m, 1H, Cα-H), 5.15 (s, 2H, CH2O),5.57 (br s, 1H, NH), 7.30-7.42 (m, 5H, Ph-H); 13C NMR (100 MHz,CDCl3), δ (ppm): 23.72 (Cβ), 29.83 (Cγ), 51.48 (Cα), 67.77 (CH2O),128.39, 128.64, 128.80, 135.80, (Carom), 155.81, OCONH), 164.53,166.65 (2 × C]O anhydride). NMR data are in agreement to thosereported in Ref. [17]. Elemental analysis C13H13NO5, calcd. C: 59.31%,H: 4.98%, N: 5.32%, found: C: 58.33%, H: 5.15%, N: 5.16%. |
75% | With dicyclohexyl-carbodiimide In tetrahydrofuran for 14h; Ambient temperature; |
60% | With dicyclohexyl-carbodiimide In ethyl acetate 1.) 1 h, 0 deg C, 2.) 24 h, r.t.; | |
With acetic anhydride | ||
With dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; | ||
With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 144h; | ||
With dicyclohexyl-carbodiimide In ethyl acetate at 10℃; | ||
With acetic anhydride at 0 - 20℃; | (S)-Benzyl 2-(N-benzyloxycarbonyl)amino-5-hydroxypentanoate (7) To a solution of L-glutamic acid (5.0 g, 34.0 mmol) in saturated NaHCO3 aq. (113 mL)was added CbzCl (7.3 mL, 51.0 mmol) at 0oC and then the mixture was stirred for 2 h at room temperature. The reaction mixture was added to Et2O and 1M HCl and extracted with AcOEt. The organic layer was washed with H2O and brine, dried over MgSO4, and evaporated under reduced pressure to give crude Cbz-Glu-OH as a white solid. To the residue was added Ac2O (30 mL) at 0oC and then the mixture was stirred for over night at room temperature. The reaction mixture was evaporated under reduced pressure to give crude N-benzyloxycarbonyl glutamic anhydride as an oil. To the residue in toluene(153 mL) was added BnOH (4.8 mL, 46.2 mmol) at room temperature and then the mixture was heated to reflux. After the stirring for 8 h, saturated NaHCO3 aq. was added to the reaction mixture and the resulting solution was washed with Et2O. The aqueous phase is acidified to pH 1 with 1M HCl and extracted with AcOEt. The organic phase was washed with H2O, brine, dried over MgSO4 and evaporated under reduced pressure to give crude product (8.91 g) as red oil. To the crude product (2.40 g, 6.5 mmol)in THF (65 mL) were added EtOCOCl (1.9 mL, 19.5 mmol) and Et3N (2.7 mL, 19.5mmol) at -15oC. After the stirring for 2 h, NaBH4 (733 mg, 19.5 mmol) and H2O (223mL) were added to the solution at same temperature. The reaction mixture was stirred for 2 h and then neutralized with 1M KHSO4. The organic solvents were evaporated and the product was extracted with AcOEt. The organic phase was washed with H2O and brine, dried over MgSO4, and the solvent was evaporated. The residue was purified by column chromatography (Hexane:AcOEt = 2:1~1:1) to afford 7 (rotamer ratio = 3:1)(1.76 g, 4.9 mmol, 53%, 4 steps) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With ammonium hydroxide In water for 5h; Ambient temperature; | |
(i) ClCO2iBu, Et3N, THF, (ii) NH3; Multistep reaction; | ||
(i) Ac2O, (ii) aq. NH3; Multistep reaction; |
With ammonia; triethylamine; isobutyl chloroformate 1.) THF, -20 deg C, 1 h, 2.) -20 deg C (30 min), -> room temperature (1 h); Yield given. Multistep reaction; | ||
Multi-step reaction with 3 steps 1: acetic acid anhydride 2: 120 - 130 °C 3: aqueous NH3 | ||
Stage #1: N-benzyloxycarbonyl-L-glutamic acid With 1,3,5-Trioxan; ammonium hydroxide; methanesulfonic acid In water; acetonitrile at 20℃; Stage #2: With phosphoric acid In water; acetonitrile | 2A.1 Step 1: Synthesis of Compound 7 Compound 3, 1 ,3,5-trioxane, methane sul fonic acid (MsOH) and acetonitrile (CH3CN) were charged to a reactor and warmed. The batch was then transferred to ammonium hydroxide (NH4OH, aq.) in water and agitated to form the ammonium salt of compound 7, which was filtered and isolated. The ammonium salt of compound 7 was charged back to a reactor, followed by the addition of acetonitrile, water, phosphoric acid (H3PO4), and compound 7 seeds. The resulting compound 7 slurry was filtered, washed with acetonitrile/water, and dried to afford final compound 7. | |
Multi-step reaction with 2 steps 1: 1,3,5-Trioxan / acetonitrile / 65 - 75 °C 2: ammonium hydroxide / methanol / 120 h / 20 - 25 °C | ||
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / toluene / 3 h / 110 °C / Dean-Stark 2: ammonium hydroxide / methanol / 120 h / 20 - 25 °C | ||
Multi-step reaction with 3 steps 1: 1,3,5-Trioxan / acetonitrile / 65 - 75 °C 2: ammonium hydroxide / water; acetonitrile / 25 - 30 °C 3: phosphoric acid / water; acetonitrile / 0.5 h / 25 °C | ||
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / toluene / 3 h / 110 °C / Dean-Stark 2: ammonium hydroxide / water; acetonitrile / 25 - 30 °C 3: phosphoric acid / water; acetonitrile / 0.5 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In methanol for 3h; | |
98% | With sodium hydroxide In water at 0 - 20℃; for 6.5h; | |
96% | In water at 0℃; for 2h; | 1.3 (3) Preparation of N-CBZ-L-glutamic acid: L-glutamic acid 1.47g (0.01mol),Add 10ml of water to adjust the pH to alkaline to all glutamic acid,Cool down to below 0 °C,Cbz-Cl 1.70g (0.01mol) was added dropwise,After the addition, the reaction was carried out for 2 h.After the completion of the reaction, pH 11 was maintained, ethyl acetate was extracted twice, the aqueous phase was adjusted to pH 3-4, ethyl acetate was extracted twice, dried over anhydrous sodium sulfate and evaporated under reduced pressure.Obtained 2.61 g of a white solid, yield 96%; |
90% | ||
84% | With sodium hydroxide In water at 0 - 25℃; for 17h; | 1.1; 2 Step 1. Synthesis of Compound 3 To L-glutamic acid (2, 10 g, 68.0 mmol) was charged water 60 ml. To the resulting suspension, benzyl chloroformate (CbzCl, 9.16 ml, 63.9 mmol) was slowly charged. 2N NaOH (60 mL) was simultaneously charged to maintain a pH of 10-12. The addition rates were adjusted to maintain a batch temperature of 0-5 °C. After addition of the CbzCl the mixture was stirred at 5 °C for 1 hr then 20 to 25 °C for an additional 16 hr. The mixture was then washed with EtOAc. The product containing aqueous layer was acidified to pH=2-3 by adding cone. HC1, and was then extracted into EtOAc. The organic layer was dried over Na2S04 and concentrated under reduced pressure. The resulted solid was dried in oven at 35-40 °C overnight to give 16 g of compound 3 (84%). LC-MS: Calc. m/e (M+l), 282.1 ; found: 282.2. 'H NMR (DMSO-de,): δ (ppm) = 1.68-1.83 (m, 1H), 1.91-2.03 (m, 1H), 2.27-2.35 (m, 2H), 3.99-4.22 (m, 1H), 5.03 (s, 2H), 7.29-7.40 (m, 5H), 7.59 (d, J= 8.13 Hz, 1H), 12.40 (broad s, 2H). |
80% | With sodium hydroxide In water; acetone at 0 - 20℃; for 7h; | |
77% | Stage #1: L-glutamic acid; benzyl chloroformate With sodium hydroxide In water at 20℃; for 12h; Cooling with ice; Stage #2: With hydrogenchloride In water | N-(2-benzoyloxycarboxy)-l-glutamic acid (g-Z) Benzoyloxycarboxy acid chloride (10.5 mL, 65.0 mmol) and aqu. NaOH solution (2 N, 33 mL) were alternately added dropwise to the solution of l-glutamic acid (7.5 g, 55.0 mmol) in aqu. NaOH solution (0.1 N, 130 mL) at room temperature. The reaction solution was stirred for 12 hours in ice bath, and then the solution was washed with diethyl ether (30 mL, 3 times). 1N HCl added dropwise to the aqueous layer until pH 2, and the solution was extracted with ethyl acetate (60 mL 3 times). The separated organic layers were dried with anhydride sodium sulfate, and concentrated under reduced pressure. The residue was added dropwise to n-hexane. The resulting precipitate was filtered, dried in vacuo, and the target compound (g-Z) was obtained as white powder. (11.47 g, 77%): mp 121-122 °C, FT-IR (KBr) 3304, 3033, 2953, 1704, 1689, 1550 cm-1. |
75% | With water; sodium hydrogencarbonate; sodium carbonate In acetone at 15 - 20℃; | 3 General procedure: The (S)-amino acid (10.0 g) was dissolved in H2O (300 ml) and Na2CO3 (2.0 equiv) and NaHCO3 (1.0 equiv) were added at rt, with stirring, to give a clear solution. Acetone (4.0 vol, with respect to the amino acid) was added and the slightly turbid solution was cooled in an ice water bath to 15-20 °C. Cbz-Cl (1.25 equiv) was added slowly, with stirring, and the reaction mixture allowed to warm to rt. After stirring for an additional 3 h at rt the mixture was extracted with Et2O (50 ml). To the aqueous phase was slowly added aqueous HCl to give a pH of 2. The resulting oil was extracted into EtOAc (150 ml) and this was washed with H2O (100 ml) and then concentrated in vacuo to give the N-Cbz amino acid as a white solid, see Table 1. |
51% | With sodium hydrogencarbonate for 1.5h; | |
46% | With sodium hydroxide In 1,2-dimethoxyethane; ethanol; water | |
With sodium hydroxide for 2h; 0 to 23 deg C; | ||
With sodium hydroxide; sodium hydrogencarbonate In water | ||
With sodium hydroxide In water at 0 - 20℃; for 16.1667h; | ||
With sodium hydroxide In water at 0 - 20℃; | ||
With sodium hydroxide | ||
With sodium hydrogencarbonate In water at 0 - 20℃; for 2h; | (S)-Benzyl 2-(N-benzyloxycarbonyl)amino-5-hydroxypentanoate (7) To a solution of L-glutamic acid (5.0 g, 34.0 mmol) in saturated NaHCO3 aq. (113 mL)was added CbzCl (7.3 mL, 51.0 mmol) at 0oC and then the mixture was stirred for 2 h at room temperature. The reaction mixture was added to Et2O and 1M HCl and extracted with AcOEt. The organic layer was washed with H2O and brine, dried over MgSO4, and evaporated under reduced pressure to give crude Cbz-Glu-OH as a white solid. To the residue was added Ac2O (30 mL) at 0oC and then the mixture was stirred for over night at room temperature. The reaction mixture was evaporated under reduced pressure to give crude N-benzyloxycarbonyl glutamic anhydride as an oil. To the residue in toluene(153 mL) was added BnOH (4.8 mL, 46.2 mmol) at room temperature and then the mixture was heated to reflux. After the stirring for 8 h, saturated NaHCO3 aq. was added to the reaction mixture and the resulting solution was washed with Et2O. The aqueous phase is acidified to pH 1 with 1M HCl and extracted with AcOEt. The organic phase was washed with H2O, brine, dried over MgSO4 and evaporated under reduced pressure to give crude product (8.91 g) as red oil. To the crude product (2.40 g, 6.5 mmol)in THF (65 mL) were added EtOCOCl (1.9 mL, 19.5 mmol) and Et3N (2.7 mL, 19.5mmol) at -15oC. After the stirring for 2 h, NaBH4 (733 mg, 19.5 mmol) and H2O (223mL) were added to the solution at same temperature. The reaction mixture was stirred for 2 h and then neutralized with 1M KHSO4. The organic solvents were evaporated and the product was extracted with AcOEt. The organic phase was washed with H2O and brine, dried over MgSO4, and the solvent was evaporated. The residue was purified by column chromatography (Hexane:AcOEt = 2:1~1:1) to afford 7 (rotamer ratio = 3:1)(1.76 g, 4.9 mmol, 53%, 4 steps) as a white solid. | |
167 g | With sodium hydroxide In water for 6h; | 1.1.1; 2.2.1; 3.3.1; 4.4.1; 5.5.1; 6.6.1; 7.7.1 Example 3 3.1. Add 1000ml of water to a 3000ml three-necked flask, then add 100g (0.68mol) L-glu-oh, mechanically stir, cool down, adjust the pH of the system to 8-9 with 2N sodium hydroxide aqueous solution, and then add 174g (1.02 mol) z-cl, after all the drops, control the pH value to 8-9, naturally heat up the reaction for about 6 hours, TLC tracks the reaction process, after the reaction is completed, the impurities are extracted, acidified, extracted, concentrated and crystallized, filtered, and the crystals are treated with ethyl acetate. Washed with n-hexane and dried to obtain 171g (0.608mol) of white crystals, which is N-benzyloxycarbonyl-L-glutamic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With methanesulfonic acid In dichloromethane for 30h; Ambient temperature; | |
With sulfuric acid In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With toluene-4-sulfonic acid In toluene for 1.67h; Heating; | |
100% | With toluene-4-sulfonic acid In toluene for 1.66667h; Heating; | |
98% |
98% | With toluene-4-sulfonic acid In benzene | |
98% | With toluene-4-sulfonic acid In toluene for 2h; Reflux; | |
96% | With toluene-4-sulfonic acid In benzene for 3h; Reflux; regioselective reaction; | |
94% | With toluene-4-sulfonic acid In benzene Heating; | |
94% | With toluene-4-sulfonic acid In benzene for 1h; Heating; | |
90% | With o-toluenesulfonic acid In toluene for 3h; Heating; | |
86% | In toluene Heating; | |
85% | In toluene | |
76% | With toluene-4-sulfonic acid In toluene for 3h; Reflux; Dean-Stark; | (S)-3-(3-((Benzyloxy)carbonyl)-5-oxo-oxazolidin-4-yl)propanoic acid (6) A suspension of Z-L-Glu-OH (5, 1.0 g, 3.6 mmol, 1 equiv), paraformaldehyde (162 mg,5.4 mmol, 1.5 equiv) and p-TsOH (10 mg, 1% w/w) in toluene (50 mL) was refluxedusing a Dean-Stark apparatus for 3 h, and then allowed to cool to rt. The reactionmixture was then filtered through a silica plug equilibrated with toluene; the product waseluted with ethyl acetate, conc. in vacuo and residual solvent co-evaporated withdichloromethane to afford 6 as a colorless oil (0.80 g, 2.7 mmol, 76%). |
61% | With toluene-4-sulfonic acid In benzene for 7h; Heating; | |
89.9 g | With toluene-4-sulfonic acid In benzene | |
With toluene-4-sulfonic acid In benzene for 0.5h; Heating; Yield given; | ||
With toluene-4-sulfonic acid for 1h; Heating; Yield given; | ||
With toluene-4-sulfonic acid In benzene Heating; | ||
With toluene-4-sulfonic acid | ||
With toluene-4-sulfonic acid In toluene for 7h; Heating; | ||
In toluene Heating; | ||
With toluene-4-sulfonic acid In toluene for 3h; Inert atmosphere; Reflux; | ||
With toluene-4-sulfonic acid In toluene at 110℃; for 3h; Dean-Stark; | 1.2; 2 Step 2: Synthesis of Compound 4 To Compound 3 (10 g, 35.6 mmol) in toluene (150 ml) was added paraformaldehyde (2.67 g, 89 mmol) and toluensulfonic acid (0.62 g, 3.56 mmol). The mixture was refluxed with removal of water using a Dean-Stark apparatus for approximately 3 hrs. The mixture was concentrated under reduced pressure and the resulting oil was used in next step without further purification. | |
With toluene-4-sulfonic acid In toluene at 120℃; for 16h; | 1-1 Compound aa150-a (Toluene (500 mL) of (2S) -2- (phenylmethoxycarbonylamino) pentandioic acid) (50 g, 177.8 mmol), paraformaldehyde (11.87 g) and p-toluenesulfonic acid (1.84 g, 10.69 mmol) ) MixedThe mixture was stirred at 120 ° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, the reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give compound aa150-b as a crude product (52 g, 96%). The next reaction without purifying this crude productUsed accordingly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With diethyl cyanophosphonate; triethylamine In tetrahydrofuran at 0 - 20℃; for 13h; | |
51% | With diethyl cyanophosphonate; triethylamine In tetrahydrofuran at 0 - 20℃; for 6.5h; | |
With diethyl cyanophosphonate; triethylamine |
With diethyl cyanophosphonate; triethylamine In tetrahydrofuran | ||
With diethyl dicarbonate | ||
With diethyl cyanophosphonate; triethylamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With diethyl cyanophosphonate; triethylamine In tetrahydrofuran for 0.5h; Cooling with ice; | |
With diethyl cyanophosphonate; triethylamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine In water Ambient temperature; | |
62% | With triethylamine In water for 7h; pH=9.0; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine In dichloromethane at 0℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium hydroxide; 15-crown-5 In N,N-dimethyl-formamide at 40℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.75h; | |
With diisopropyl-carbodiimide In dichloromethane at 20℃; for 18h; | 12.a 7V-hydroxysuccinimide (1.35 g; 11.7 mmol) and diisopropylcarbodiimide (1.48 g; 11.7 mmol) were added to a suspension of 1 (1.11 g; 3.90 mmol) (commercially available) in CH2Cl2 (12 mL). After stirring at room temperature for 18 h, the suspension was filtered and evaporated under vacuum. Crude 2 (3.94 g) was dissolved in DMF (70 mL) and the amine 3 (Takahashi, M et al. Tetrahedron Lett. 2000, 41, 8485-8488) (6.86 g; 7.80 mmol) was added. The clear solution was stirred at 650C for 48 h. Another portion of 3 (1.50 g; 1.71 mmol) was added and the mixture was stirred at 65°C for further 24 h. The solvent was removed and the crude was taken up with CH2Cl2 (200 mL) and washed with sat. aq. NaHCO3 (2 x 50 mL) and sat. aq. NH4Cl. (50 mL). The organic layer was dried over Na2SO4 and evaporated. The crude was purified by column chromatography on silica gel to afford compound 4 (3.44 g; 1.72 mmol). Yield 44 %. MS: 2005.7 (M+H); 2027.7 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With diethyl cyanophosphonate; triethylamine In tetrahydrofuran at 20℃; for 24h; | |
91% | With diethyl cyanophosphonate; triethylamine In tetrahydrofuran at 0 - 20℃; for 12h; | N2,N3-dibutyl-N-(2-benzoyloxycarboxy-l-glutamide (C4-g-Z) Diethylphosphonatecyan (8.64 mL, 58.30 mmol) were added dropwise to the solution of g-Z (6.16 g, 21.89 mmol), 1-butylamine (4.85 mL, 48.16 mmol) and triethylamine (9.36 mL, 67.42 mmol) in dried THF (200 mL) in ice both. The reaction solution was stirring for 2 hours at 0 C and then 10 hours at room temperature. The solution was concentrated in vacuo. The residue was dissolved in chloroform (100 mL). The mixture was washed with aqu. NaOH solution (0.2N, 50 mL) at three times, HCl (0.1 N, 50 mL) at three times, and water (50 mL). Organic layer was dried with anhydride sodium sulfate, concentrated in vacuo. The residue was added dropwise to n-hexane. The precipitate was filtrated, dried in vacuo, and the target compound (C4-g-Z) was obtained as white powder (7.81 g, 91%): mp 179-181 C. FT-IR (KBr) 3298, 3091, 2931, 1690, 1650, 1537 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: N-benzyloxycarbonyl-L-glutamic acid With dmap; TEA; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 1h; Stage #2: tryptamine With dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triethylamine In methanol at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 20℃; for 24h; | |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 20℃; for 24h; | |
77% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 20℃; for 24h; | |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydrogen sulfate; silica gel In dichloromethane at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dichloromethane at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dichloromethane at 20℃; for 12h; | |
90% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dichloromethane at 20℃; | |
90% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere; | 4 Tetra-tert-butyl-10-amino-2,20-bis(2-(tert-butoxy)-2-oxoethyl)-9,13-dioxo- 2,8,14,20-tetraazahenicosane-l,3,19,21-tetracarboxylate (32) EXAMPLE 4 Synthesis of 3-(3-oxo-3-((l,3,19,21-tetracarboxy-2,20-bis(carboxymethyl)-9,13- dioxo-2,8514,20-tetraazahenicosan-10-yI)amino)propyl)-2-((l-(3-oxo-3-((l,3 FontWeight="Bold" FontSize="10" 19,21- tetracarboxy-2,20-bis(carboxymethyl)-9,13-dioxo-2,8,14,20-tetraazahenicosan-10- yl)amino)propyl)quinoIin-4(lH)-ylidene)methyl)benzo thiazol-3-ium iodide (Figure 18, protein sensor 33). Tetra-tert-butyl-10-amino-2,20-bis(2-(tert-butoxy)-2-oxoethyl)-9,13-dioxo- 2,8,14,20-tetraazahenicosane-l,3,19,21-tetracarboxylate (32) [00121] 23 (0.25 g, 0.58 mmol) was dissolved in dry dichloromethane (40 ml) then cooled in an ice bath to 0°C. Then Z-L-Glutamic acid(0.0576 g, 0.205 mmol), HBTU (0.225 g, 0.594 mmol) and DIPEA (124.8 μ, 0.716 mmol) were added. The resulted slurry solution was purged with N2 and stirred overnight at room temperature. The volatiles were then removed under reduced pressure and the crude was partitioned between dichloromethane (25 ml) and water (3x7.5 ml). The organic phase was dried over anhydrous sodium sulphate and the volatiles were removed under reduced pressure to obtain an oily mass which was further purified by combiflash with DCM:MeOH. Yield: 0.99 g (0.9 mmol), 90 %. 1HNMR (300 MHz, CDC13); δ=1.43 (s, 36H), 1.45 (s, 18H), 1.45-1.67 (m, 12H), 2.30-2.36 (m,2H), 3.2-3.3 (m,2H), 3.36-3.5 (m, 6H), 3.46 (m, 8H), 3.56 (m, 1H), 6.34 (d,lH), 6.55 (s,lH), 7.07 (s,lH), 7.34 (s, 5H) .ES-MS (m/z): calcd: 1105.68, found: 1106.76 (MH+), 1129.76 (M+Na), 564.94 ((M+Na)/2). Benzyl group was deprotected by dissolving the intermediate (0.572 g, 1.01 mmol) in methanol (28.6 ml); the resulting solution was purged with argon followed by addition of 10% Pd/C (11 mg). The reaction mixture was stirred overnight under a H2 atmosphere at room temperature. Pd/C was removed by filtration over celite and the reaction mixture was evaporated under reduced pressure, yielding compound 3. Yield: 0.420 g (96%). 1HNMR (300 MHz, CDC13); 6=1.43 (s, 36H), 1.45 (s, 18H), 1.47-1.65 (m, 12H), 2.37- 2.44 (m, 2H), 3.2-3.3 (m,2H), 3.36-3.5 (m, 6H), 3.46 (m, 8H), 3.56 (m, 1H). ES-MS (m/z): calcd: 971.64, found: 972.66 (MH+), 994.59 (M+Na), 497.87 ((M+Na+H)/2), 508.83 ((M+2Na)/2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: N-benzyloxycarbonyl-L-glutamic acid With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; Stage #2: L-glutamic acid diethyl ester In dichloromethane at 0 - 20℃; Further stages.; | |
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: N-benzyloxycarbonyl-L-glutamic acid With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; Stage #2: Tetraethyl-α,γ-bis-(L-Glutamyl-L-glutamat) In dichloromethane at 0 - 20℃; Further stages.; | |
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: N-benzyloxycarbonyl-L-glutamic acid With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; Stage #2: di-tert-butyl L-glutamate With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 3.75h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: N-benzyloxycarbonyl-L-glutamic acid With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.333333h; Stage #2: H-Phe-OEt With triethylamine In dichloromethane at 0 - 20℃; for 6.75h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With silver carbonate; dimethyl methane phosphonate In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 1,2,3-Benzotriazole With thionyl chloride In tetrahydrofuran at 40 - 50℃; for 0.333333h; Stage #2: N-benzyloxycarbonyl-L-glutamic acid In tetrahydrofuran at 20℃; for 2h; | |
92% | Stage #1: 1,2,3-Benzotriazole With thionyl chloride In tetrahydrofuran at 20℃; for 0.333333h; Stage #2: N-benzyloxycarbonyl-L-glutamic acid In tetrahydrofuran at 20℃; for 2h; | |
With thionyl chloride In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With diethyl cyanophosphonate; triethylamine In tetrahydrofuran at 0 - 20℃; | |
With diethyl cyanophosphonate; triethylamine In tetrahydrofuran at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: HBTU; DIPEA / CH2Cl2 / 0 °C 2: ammonium formate; H2 / Pd/C / methanol | ||
Multi-step reaction with 2 steps 1.1: HBTU; N-hydroxybenzotriazole; DIPEA / CH2Cl2 / 0 °C 1.2: 92 percent / CH2Cl2 / 0 - 20 °C 2.1: 88 percent / ammonium formate; H2 / Pd/C / methanol / 6 h / sonication | ||
Multi-step reaction with 3 steps 1: 84 percent / 1,3-dicyclohexylcarbodiimide, 4-dimethylaminopyridine / CH2Cl2 / 0.75 h / 0 °C 2: 87 percent / Et3N / 1,2-dimethoxy-ethane / 1 h / 0 °C 3: 94 percent / iodotrimethylsilane / acetonitrile / 0.08 h / 0 °C |
Multi-step reaction with 2 steps 1: (i) DCC, N-hydroxysuccinimide, (ii) /BRN= 3597595/, Et3N 2: H2, aq. HCl / Pd-C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: CSA / toluene / Heating 2: SOCl2 / 0.25 h / Heating | ||
Multi-step reaction with 2 steps 1: 90 percent / toluenesulfonic acid / toluene / 3 h / Heating 2: thionyl chloride / CH2Cl2 / 0.5 h / Heating | ||
Multi-step reaction with 2 steps 1: 61 percent / p-TsOH / benzene / 7 h / Heating 2: 94 percent / oxalyl chloride, DMF / CH2Cl2 / 1 h / Ambient temperature |
Multi-step reaction with 2 steps 1: 61 percent / p-TsOH / benzene / 7 h / Heating 2: 94 percent / (COCl)2, DMF / CH2Cl2 / 1 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: 94 percent / p-TsOH*H2O / benzene / 1 h / Heating 2: SOCl2 / CHCl3 / 3 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: 85 percent / pTsOH / toluene 2: 78 percent / SOCl2 / 0.33 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: p-toluenesulfonic acid monohydrate / toluene / 7 h / Heating 2: 9.46 g / 4-(dimethylamino)pyridine; dicyclohexylcarbodiimide / CH2Cl2 / 4 - 20 °C 3: triethylsilane / palladium on carbon / CH2Cl2 / 0.5 h / 20 °C | ||
Multi-step reaction with 3 steps 1: 98 percent / TsOH / benzene 2: Me2S*BH3 / tetrahydrofuran 3: PCC; NaHCO3; Celite / CH2Cl2 | ||
Multi-step reaction with 3 steps 1: 86 percent / toluene / Heating 2: BH3*SMe2 / tetrahydrofuran / 0 - 25 °C 3: PCC / CH2Cl2 / 25 °C |
Multi-step reaction with 3 steps 1: p-TsOH / benzene / 0.5 h / Heating 2: 87 percent / DCC, DMAP / acetonitrile / 0.33 h / 0 °C 3: triethylsilane / 10 percent Pd/C / acetone / 0.67 h / 23 °C | ||
Multi-step reaction with 3 steps 1: 85 percent / pTsOH / toluene 2: 78 percent / SOCl2 / 0.33 h 3: Li(OtBu)3AlH, H2O / 1.) THF, -78 deg C, 1 h, r. t., 1 h | ||
Multi-step reaction with 2 steps 1.1: toluene-4-sulfonic acid / toluene / 16 h / 120 °C 2.1: thionyl chloride / 1 h / 85 °C 2.2: 5.5 h / -78 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: DCC; pyridine / tetrahydrofuran / 48 h / 20 °C 2: 65 percent / H2 / Pd/C / tetrahydrofuran; methanol / 72 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: H2SO4 / CH2Cl2 2: H2 / Pd-C / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | In ethanol for 12h; | 3 EXAMPLE 3 2.0 g of silica was taken in 50ML of round-bottomed flask containing 20 ML of ethanol. To this 0.12gm of Cbz-protected D, L-Glutamic acid was added and stirring CONTINUED. AFTER 12 H 63 % OF (L) -GLUTAMIC ACID DERIVATIVE WAS IN EQUILIBRIUM WITH THE imprinted silica and analyzed by chiral HPLC |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃; | 4.1 PREPARATIVE EXAMPLE 4(1) PREPARATION OF Z-BENZYLOXYCARBONYLAMINO-PENTADIOIC ACID To a solution of L-glutamic acid (20 g, 136 mmol) in water/THF(1/1, 400 ml), sodium bicarbonate (45.7 g, 544 mmol) was added and cooled to0 °C in an ice bath. To the reaction mixture, CbzOSu (37.3 g, 150 mmol) wasadded and stirred overnight at room temperature. After the reaction wascompleted, the resulting reaction mixture was extracted with EA. Theaqueous layer was separated, acidified to pH 2 with cone. HCI at 0 °C, andagain extracted with EA (4 times). The organic layers were concentrated togive a crude product, which was purified by column chromatography to obtainthe title compound (16 g) as colorless oil.Rf:0.2inMC/MeOH(9/1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With molecular sieve; toluene-4-sulfonic acid In toluene Heating / reflux; | 4.2 2) PREPARATION OF 4-(2-CARBOXY-ETHYL)-5-OXO-OXAZOLIDINE-3-CARBOXYLICACID BENZYL ESTER In a Dean-Stark apparatus, N-Cbz-L-glutamic acid (4 g, 14.22mmol) obtained in the above step (1), paraformaldehyde (5 g), a catalyticamount of pTsOH, molecular sieves (5 g), and toluene (100 ml) were placedand refluxed until the starting material disappeared. The resultant reactionmixture was cooled to room temperature, filtered and concentrated to give acrude product, which was purified by column chromatography to obtain the titlecompound (2 g) as colorless oil.Rf: 0.45 in only EA |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With p-toluenesulfonic acid monohydrate; paraformaldehyde In ethyl acetate; toluene | 1.1 Production of STR42 (1) To 1 liter of toluene were added 300 g of DL-N-benzyloxycarbonylglutamic acid, 48 g of paraformaldehyde and 12 g of p-toluenesulfonic acid monohydrate, and azeotropic dehydration was then carried out for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the oily substance thus obtained was dissolved in 500 ml of ethyl acetate, after which the resulting solution was washed with water and then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain oily DL-3-benzyloxycarbonyl-4-(2-carboxyethyl)oxazolidin-5-one. | |
With p-toluenesulfonic acid monohydrate; paraformaldehyde In ethyl acetate; toluene | 8.1 Production of STR49 (1) To 300 ml of toluene were added 100 g of DL-N-benzyloxycarbonylglutamic acid, 20 g of powdery paraformaldehyde and 4 g of p-toluenesulfonic acid monohydrate, and the resulting mixture was subjected to azeotropic dehydration for 3 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and the oily product thus obtained was dissolved in 200 ml of ethyl acetate, after which the resulting solution was washed with water. The organic layer thus formed was then separated and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain oily DL-3-benzyloxycarbonyl-4-(2-carboxyethyl)oxazolidin-5-one. | |
In toluene | P.4.2 (2) (2) PREPARATION OF 4-(2-CARBOXY-ETHYL)-5-OXO-OXAZOLIDINE-3-CARBOXYLIC ACID BENZYL ESTER In a Dean-Stark apparatus, N-Cbz-L-glutamic acid (4 g, 14.22 mmol) obtained in the above step (1), paraformaldehyde (5 g), a catalytic amount of pTsOH, molecular sieves (5 g), and toluene (100 ml) were placed and refluxed until the starting material disappeared. The resultant reaction mixture was cooled to room temperature, filtered and concentrated to give a crude product, which was purified by column chromatography to obtain the title compound (2 g) as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | (i) 2-(Benzyloxycarbonylamino)-5-(4-chloro-2-(methoxycarbonyl)phenylamino)-5-oxopentanoic AcidA mixture of 2.0 g (7.1 mmol) of DL-Cbz-Glu-OH and 1.47 g (7.1 mmol) of DCC was stirred in ethyl acetate at room temperature overnight. After filtering the reaction mixture and concentrating the filtrate, 1.3 g (7.1 mmol) of <strong>[5202-89-1]methyl 2-amino-5-chlorobenzoate</strong> and 10 ml of DMSO were added, and the mixture was heated at 100 C. for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and then dried over anhydrous sodium sulfate. After the organic solvent was distilled off under reduced pressure, the reaction mixture was separated and purified by silica gel column chromatography to give 850 mg of 2-(benzyloxycarbonylamino)-5-(4-chloro-2-(methoxycarbonyl)phenylamino)-5-oxopentanoic acid (yield 27%).1H-NMR (CD3OD) delta: 1.85-2.70 (4H, m), 3.92 (3H, s), 4.15-4.35 (1H, m), 5.05 (2H, s), 7.20-7.40 (5H, m), 7.51 (1H, dd, J=9.0, 2.4 Hz), 7.94 (1H, d, J=2.4 Hz), 8.48 (1H, d, 9.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With CLEA-Alcalase In tert-butyl methyl ether at 50℃; for 16h; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With CLEA-Alcalase In tert-butyl methyl ether at 50℃; for 16h; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.6% | With diethyl cyanophosphonate; triethylamine In tetrahydrofuran at 20℃; Cooling with ice; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.5% | With diethyl cyanophosphonate; triethylamine In tetrahydrofuran at 20℃; Cooling with ice; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: N-benzyloxycarbonyl-L-glutamic acid With sodium hydroxide In water for 0.5h; Stage #2: Pt(trans-(+/-)-1,2-diaminocyclohexane)SO4 In water at 20℃; for 4h; | 4 Example 4Preparation of (N-carbobenzyloxy-L-glutamato-O,O)(trans-(+-)-1,2-diamino cyclohexane-N,N)platinum(II), [Pt(dach)(CbzGlu)] N-carbobenzyloxy-L-glutamic acid (0.28 g) and 1M aqueous sodium hydroxide (2 ml) were add to 10 ml of distilled water, and the resulting solution was stirred for 30 minutes. An aqueous solution of (trans-(+/-)-1,2-diaminocyclohexane-N,N)platinum(II) sulfate (Pt(dach)SO4.H2O, 0.42 g) in 20 ml of water was added to the above solution. The resulting solution was stirred for 4 hours at room temperature. The precipitate obtained was filtered and washed with water, ethanol and ethyl ether, and then vacuum-dried, to obtain the desired product in 80% yield. [0048] Composition: C19H27N3O6Pt.2H2O [0049] Elemental Analysis: C 36.80, H 4.91, N 6.62; theoretical value: C 36.54, H 5.00, N 6.73 [0050] IR absorption spectrum (KBr, cm-1): 3227w, 3119w, 1705m, 1623s, 1338s, 1344s, 1252m |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: N-benzyloxycarbonyl-L-glutamic acid With sodium hydroxide In water for 0.5h; Stage #2: ((-)-trans-1,2-cyclohexanediamine)platinum(II) sulfate In water at 20℃; for 4h; | 4 N-carbobenzyloxy-L-glutamic acid (0.28 g) and 1M aqueous sodium hydroxide (2 mi) were add to 10 ml of distilled water, and the resulting solution was stirred for 30 minutes. An aqueous solution of (trans-(+-)-1,2-diaminocyclohexane-N,N)platinum(II) sulfate (Pt(dach)SO4.H2O, 0.42 g) in 20 ml of water was added to the above solution. The resulting solution was stirred for 4 hours at room temperature. The precipitate obtained was filtered and washed with water, ethanol and ethyl ether, and then vacuum-dried, to obtain the desired product in 80% yield : Composition: C19H27N3O6Pt.2H2O Elemental Analysis : C 36.80, H 4.91, N 6.62 ; theoretical value : C 36.54, H 5.00, N 6.73 IR absorption spectrum (KBr, cm-1) : 3227w, 3119w, 1705m, 1623s, 1338s, 1344s, 1252m |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With samarium(III) chloride at 80℃; for 48h; sealed tube; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With diethyl cyanophosphonate; triethylamine In tetrahydrofuran at 0 - 20℃; for 12h; | N2,N3-dioctyl-N-(2-benzoyloxycarboxy-l-glutamide (C8-g-Z) Diethylphosphonatecyan (5.20 mL, 35.1 mmol) were added dropwise to the solution of g-Z (4.13 g, 15.3 mmol) and 1-octylamine (5.30 mL, 32.0 mmol) and triethylamine (5.80 mL, 41.8 mmol) in dried THF (150 mL) in ice both. The reaction solution was stirred for 2 hours at 0 C and then 12 hours at room temperature. The solution was concentrated in vacuo. The residue was dissolved in chloroform (100 mL). The mixture was washed with aqu. NaOH solution (0.2 N, 50 mL) at three times, HCl (0.1 N, 50 mL) at three times, and water (50 mL). Organic layer was dried with anhydride sodium sulfate, concentrated in vacuo. The residue was recrystallized from acetonitrile to yield white powder (5.88 g, 76%): mp 146-147 C. FT-IR (KBr) 3288, 3095, 2921, 2852, 1689, 1649, 1541, cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: (S)-2-((phenylmethoxycarbonyl)amino)-4-cyanobutanoic acid With dihydrogen peroxide; sodium hydroxide In water at 20℃; for 0.5h; Stage #2: With hydrogenchloride In water at 0℃; | N-Phenylmethoxycarbonyl-L-glutamic acid (7). Aq. H2O2 (35%, 1.5 mL) was added to 6 (110 mg, 0.42 mmol) in aq. NaOH (0.5 M, 15 mL), followed by aq. NaOH (2 M, 1.0 mL) and the mixture was stirred for 30 min. The mixture was cooled to 0°C and the pH was adjusted to 2.0 with aq. HCl (1.0 M). Extraction (CH2Cl2, thrice), drying and evaporation gave 7 (120 mg, quant.) as a colourless viscous oil: IR (liquid film) max 3290, 1697 cm-1; 1H NMR (CD3OD) 1.96 (1 H, m, -H), 2.19 (1 H, m, -H), 2.32 (1 H, m, -H), 2.40 (1 H, m, -H), 4.18 (1 H, m, -H), 4.88 (2 H, s, PhCH2), 5.09 (1 H, br, OH), 7.32 (5 H, s, Ph-H5); MS (ES+) m/z 282.1023 (M + H) (C13H16NO6 requires 282.0972). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: N-benzyloxycarbonyl-L-glutamic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 1,3-di-O-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-2-deoxy-2-amino-glycerol With 4-methyl-morpholine In tetrahydrofuran at 0 - 20℃; for 38h; | 4.1.20. N-{2-[1,3-di-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)propanyl]-2-carbobenzyloxyamino-pentane-1,5-diamide (26) N-Carbobenzyloxy-L-glutamic acid (0.03 g, 0.11 mmol) was dissolvedin anhydrous THF (1 mL) that was cooled to 0 C, then HOBt(0.05 g, 0.37 mmol) and DCC (0.08 g, 0.39 mmol) were added. Themixture was stirred for 0.5 h at 0 C. A solution (pH 8-9) of compound23 (0.17 g, 0.22 mmol) in dry THF (2 mL) in the presenceof NMM was added dropwise and the mixture was stirred at 0 Cfor 2 h, followed by stirring at room temperature for 36 h. The mixturewas concentrated and the residue was then diluted with CH2-Cl2 (10 mL). The solution was filtered and the filtrate was washedwith aqueous sodium bicarbonate, aqueous citric acid and water,dried (Na2SO4), and evaporated under diminished pressure. Thecrude product was purified by flash chromatography with 1:1petroleum ether (60-90 C)-acetone as eluent to afford 26(0.16 g) as a colorless syrup in 85% yield; a25D 21:3 (c 0.75 inCHCl3); 1H NMR (400 MHz, CDCl3): d = 7.37-7.32 (m, 5H; Ph),6.29 (d, 1H; NH), 6.11 (d, 1H; NH), 5.24-5.07 (m, 6H, PhCH2O, H-3), 5.05-4.94 (m, 4H; H-2), 4.51 (d, J1,2 = 7.8 Hz, 4H; H-1), 4.58,4.31-4.21 (m, 8H; H-6a,b), 4.17-3.59 (m, 19H; H-4,5, CH2O,COCHNH, CHNHCO), 2.10-2.00 (m, 52H; CH3CO, COCH2, CH2-CHNH); 13C NMR (CDCl3, 100 MHz): d = 170.7, 170.6, 170.1,169.4, 169.3, 169.2 (CO), 136.4, 128.5, 128.2, 128.0, 127.9 (Ph),101.2, 100.9 (C-1), 76.7 (C-4), 72.7 (C-3), 72.5 (C-5), 71.9, 71.3 (C-2), 68.3, 68.2 (CH2O), 66.8 (PhCH2O), 61.8, 61.7 (C-6), 53.8 48.8(CHNHCO), 31.7, 29.3 (CH2CO, CH2CHNH), 20.7, 20.6, 20.5 (CH3);HRESI-TOF MS: m/z calcd for C75H101N3O44: 1748.58362 [M+1]+;found: 1748.58307. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: N-benzyloxycarbonyl-L-glutamic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 2-amino-1,3-di-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)propane With 4-methyl-morpholine In tetrahydrofuran at 0 - 20℃; for 38h; | 4.1.21. N-{2-[1,3-di-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)propanyl]-2-carbobenzyloxyamino-pentane-1,5-diamide (27) Compound 27 was prepared by the same procedure as describedfor the preparation of 26 using compound 24 as the linkingunit and the crude product was purified by chromatography with1:1 petroleum ether (60-90 C)-acetone as eluent to afford 27 asa colorless syrup in 80% yield; aD 16:2 (c 0.74 in CHCl3); 1HNMR (400 MHz, CDCl3): d = 7.36-7.34 (m, 5H; Ph), 6,30 (d, 1H;NH), 6.00 (d, 1H; NH), 5.38 (d, 4H; H-4), 5.18-5.11 (m, 6H; PhCH2O,H-2), 5.05-5.00 (m, 4H; H-3), 4.47 (d, J1,20 = 7.8 Hz, 4H; H-10), 4.50,4.20-4.10 (m, 8H; H-6a,b), 3.97-3.59 (m, 15H; H-5, CH2O,COCHNH2, CHNHCO), 2.16-1.98 (m, 52H; CH3CO, COCH2, CH2-CHNH); 13C NMR (100 MHz, CDCl3): d = 170.4, 170.3, 170.2,170.1, 170.0, 169.7, 169.6 (CO), 136.3, 128.5, 128.1, 127.9 (Ph),101.7, 101.6, 101.4 (C-1), 70.8, 70.7 (C-5), 70.6 (C-3), 69.1, 68.9(C-2, CH2O), 67.0, 66.9 (C-4, PhCH2O), 61.1 (C-6), 48.9, 48.5(CHNHCO), 31.7, 29.2 (CH2CO, CH2CHNH), 20.8, 20.7, 20.6, 20.5(CH3); HRESI-TOF MS: m/z calcd for C75H101N3O44: 1748.58362[M+1]+; found: 1748.58289. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: N-benzyloxycarbonyl-L-glutamic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 2-amino-1,3-di-[2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl-(1→4)-2,3,6-tri-O-acetyl-β-D-glucopyranosyloxy]propane With 4-methyl-morpholine In tetrahydrofuran at 0 - 20℃; for 38h; | 4.1.22. N-{2-[1,3-di-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl-(1→4)-2,3,6-tri-O-acetyl-β-D-glucopyranosyloxy)]propanyl}-2-carbobenzyloxyamino-pentane-1,5-diamide (28) Compound 28 was prepared by the same procedure asdescribed for the preparation of 26 using compound 25 as the linking unit and the crude product was purified by chromatographywith 1:1 petroleum ether (60-90 C)-acetone as eluent to afford28 as a colorless syrup in 88% yield; aD 6:6 (c 1.22 inCHCl3); 1H NMR (400 MHz, CDCl3): d = 7.35-7.34 (m, 5H; Ph),6,30 (d, 1H; NH), 6.00 (d, 1H; NH), 5.19-5.13 (m, 6H; PhCH2O,H-30), 5.07 (t, 4H; H-20), 4.92 (t, 4H; H-3), 4.85 (t, 4H; H-2),4.42 (d, J1,2 = 8.0 Hz, 8H; H-1, H-10), 4.53, 4.38-4.35 (m, 16H; H-6a,b, H-6a0,b0), 4.13-3.51 (m, 27H; H-4,5, H-40,50, CH2O, COCHNH2,CHNHCO), 2.18-1.98 (m, 88H; CH3CO, COCH2, CH2CHNH); 13CNMR (100 MHz, CDCl3): d = 170.4, 170.2, 169.7, 169.3, 169.0(CO), 128.5, 128.1, 127.9 (Ph), 100.7 (C-1, C-10), 76.4 (C-4, C-40),72.9, 72.8 (C-3, C-30), 72.3 (C-5, C-50), 71.9, 71.6 (C-2, C-20),67.7, 66.8 (CH2O, PhCH2O), 61.5 (C-6, C-60), 53.8 (CHNHCO),31.7, 29.2 (CH2CO, CH2CHNH), 20.8, 20.6, 20.5 (CH3); HRESI-TOFMS: m/z calcd for C123H165N3O76: 2901.92504 [M+1]+; found:2901.92480. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: N-benzyloxycarbonyl-L-glutamic acid With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 2-amino-1-[2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl-(1→4)-2,3,6-tri-O-acetyl-β-D-glucopyranosyloxy]-3-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyloxy)propane In tetrahydrofuran at 0 - 20℃; for 38h; | 4.1.33. N-{2-[1-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl-(1→4)-2,3,6-tri-O-acetyl-β-D-glucopyranosyloxy)-3-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyloxy)]propanyl}-2-carbobenzyloxyamino-pentane-1,5-diamide (39) Compound 39 was prepared by the same procedure as describedfor the preparation of 9 using N-carbobenzyloxy-L-glutamicacid as the linker and the crude product was purified by chromatographywith 1:1 petroleum ether (60-90 C)-acetone as eluentto afford 39 as a colorless syrup in 85% yield; a25D 16:0 (c1.00 in CHCl3); 1H NMR (400 MHz, CDCl3): d = 7.32 (m, 5H; Ph),6,10 (d, 1H; NH), 6.00 (d, 1H; NH), 5.32 (d, 2H; H-40), 5.29-5.05(m, 8H; H-3, H-20 , H-300 , PhCH2O), 4.93 (dd, 2H; H-30), 4.85-4.80(m, 4H; H-2, H-100), 4.47 (d, J1,2 = J10,20 = 7.8 Hz, 4H; H-1, H-10),4.48, 4.28-4.03 (m, 14H; H-200 , H-6a,b, H-6a0,b0 , H-6a00,b00), 3.87-3.52 (m, 20H; H-4,5, H-50 , H-400,500, CH2O, CHNH), 2.30-1.69 (m,70H; CH2, CH3); 13C NMR (100 MHz, CDCl3): d = 170.7, 170.6,170.4, 170.3, 170.1 170.0, 169.7, 169.6, 169.5, 169.4, 169.0 (CO),136.4, 128.5, 128.1, 127.9, 127.8 (Ph), 101.1 (C-10), 100.6 (C-1),97.4 (C-100), 76.4 (C-4), 76.2 (C-400), 72.8 (C-3), 72.6 (C-5), 71.5 (C-2), 71.0 (C-300), 70.7 (C-50), 70.1 (C-30), 69.5, 69.1 (C-200), 69.0,68.6, 68.2, 67.8 (CH2O, PhCH2O), 66.8, 66.6 (C-20), (C-500), 65.7,65.6 (C-40), 62.4, 62.2 (C-60), 61.9, 61.8 (C-600), 60.7 (C-6), 53.8,48.3 (CHNHCO), 31.7, 29.2 (CH2CO, CH2CHNH2), 20.8, 20.7, 20.6,20.5 (CH3); HRESI-TOF MS: m/z calcd for C99H133N3O60:2325.75601 [M+1]+; found: 2325.75546. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Methyl 2-(3-(((benzyloxy)carbonyl)amino)-2, 6-dioxopiperidin-l-yl)-S-cyclohexyl- propanoate 1 To a solution of (L) N-Cbz-glutamic acid (5.62 g; 20 mmol) in dry DMF (100 mL) was added HATU (8.36 g; 22 mmol) and DMAP (0.56 g) followed by the dropwise addition of TEA (6 mL; 44 mmol). The reaction mixture was stirred at room temperature for 1 h (solution A). In the meantime, to a solution of (L) cyclohexylalanine-OMe(HCl) (5.32 g; 24 mmol) in dry DMF (30 mL) was added DIEA (9.28 g; 72 mmol) and the reaction mixture was stirred for 15 min (solution B). Solution B was mixed with solution A and stirred overnight at room temperature. The solvent was removed on the rotary evaporator and the residue was taken up in ethyl acetate (300 mL). The organic layer was washed sequentially with saturated sodium bicarbonate (2 x 100 mL), 5% HCl (2 x 100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, yielding a crude product which was purified by flash chromatography (silica gel; hexane/ethyl acetate 75 :25) to give 1 as a white solid (2.15 g ; 32% yield). NMR (CDC13): delta 8.0 (s, 1H), 7.32 (m, 5H), 5.04 (m, 2H), 4.62 (m, 1H), 4.0 (m 1H), 3.73 (s, 3H), 2.3 (m, 2H), 2.0 (m, 2H), 1.65 (m, 6H), 1.46 (m, 1H), 1.18 (m, 4H), 0.89 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 24h; | 18.A benzyl [(2S)-1,5-dioxo-1,5-bis({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)pentan-2-yl]carbamate Step A: To a solution of N-[(benzyloxy)carbonyl]-L-glutamic acid (1.1 g, 3.91 mmol) and 2-aminoethyl α-L-fucopyranoside (2.026 g, 9.78 mmol) in DMF (10 mL) was added EDC (3.00 g, 15.64 mmol) and DMAP (0.048 g, 0.391 mmol). After stirring at rt for 24 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (80 g), eluting with 100% EtOAc for 5 column volume and then isocratic EtOAc:AcCN:MeOH 6:1:1 to give the title compound. 1H NMR (CD3OD) δ 7.38-7.29 (m, 5H), 5.13-5.05 (m, 2H), 4.76 (s, 2H), 4.09 (dd, J=5.3, 8.6, 1H), 3.95-3.91 (m, 2H), 3.74-3.65 (m, 6H), 3.53-3.25 (m, 8H), 2.30 (t, J=7.5, 2H), 2.06-2.04 (m, 1H), 1.92-1.89 (m, 1H), 1.19 (d, J=6.5, 6H). | |
With dmap; 1,2-dichloro-ethane In N,N-dimethyl-formamide at 20℃; for 24h; | 18.A Step A: benzyl [(2S)-1,5-dioxo-1,5-bis({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)pentan-2- yl]carbamate To a solution of N-[(benzyloxy)carbonyl]-L-glutamic acid (1.1 g, 3.91 mmol) and 2- aminoethyl α-L-fucopyranoside (2.026 g, 9.78 mmol) in DMF (10 mL) was added EDC (3.00 g, 15.64 mmol) and DMAP (0.048 g, 0.391 mmol). After stirring at rt for 24 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (80 g), eluting with 100% EtOAc for 5 column volume and then isocratic EtOAc:AcCN:MeOH 6:1:1 to give the title compound. 1H NMR (CD3OD) δ 7.38-7.29 (m, 5H), 5.13-5.05 (m, 2H), 4.76 (s, 2H), 4.09 (dd, J = 5.3, 8.6, 1H), 3.95-3.91 (m, 2H), 3.74-3.65 (m, 6H), 3.53-3.25 (m, 8H), 2.30 (t, J = 7.5, 2H), 2.06-2.04 (m, 1H), 1.92-1.89 (m, 1H), 1.19 (d, J = 6.5, 6H). | |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; | 3.4 Step 4. benzyl (S)-[ 1 ,5-dioxo-l ,5-bis({2-[(a-L-fucopyranosyl)oxy] ethyl}amino)pentan-2- yl]carbamate To a solution of Z-Glu-OH (l.lg, 3.91mmol) and 2-aminoethyl a-L-fucopyranoside (2.03g, 9.78mmol) in DMF (20mL) was added EDC (3.00g, 15.64mmol) and HOBt (60mg, 0.391mmol). The mixture was stirred at rt. After overnight, the reaction mixture was diluted with H2O (20mL) and purified using HPLC (C4, 50x250mm, gradient 5-30% AcCN with 0.1% TFA in H2O with 0.1% TFA over 20min, flow rate 85mL/min). The desired fractions were combined and freeze-dried to give the title compound. UPLC-MS Method A: m/z = 660.29 (z = 1); tR = 2.78min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: N-benzyloxycarbonyl-L-glutamic acid; L-glutamic dimethyl ester hydrochloride With 1-hydroxy-pyrrolidine-2,5-dione; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h; Stage #2: With sulfuric acid In dichloromethane; water Stage #3: With water; sodium hydrogencarbonate In dichloromethane | 4.3.2. Synthesis of S5b. To a well-stirred and ice-cooled solution of Z-Glutamic acid S4b (1.7 g, 5.75 mmol), N-hydroxysuccinimide (1.45 g, 12.65 mmol), and DCC (2.61 g, 12.65 mmol) in dry CH2Cl2 (100 mL) was added a solution of Glu.diOMe.HCl (2.68 g, 12.65 mmol), NEt3 (1.7 mL, 13.31 mmol). After stirring for 24 h at room temperature, the reaction mixture was filtered. The residue was washed with CH2Cl2 (4×20 mL) and the combined filtrates were washed sequentially with 2 N H2SO4, water, and 5% aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, evaporated in vacuo and the crude product was chromatographed on a column of silica gel using EtOAc/hexane as eluents to afford the dendron S5b. Yield: 75%. Mp: 116-118 °C; [α]D25 -40.4 (c 0.5, MeOH); 1H NMR (CDCl3, 300 MHz) δ 1.80-2.10 (br s, 3H), 2.10-2.35 (m, 3H), 2.35-2.51 (br m, 6H), 3.68 (s, 3H), 3.69 (s, 3H), 3.77 (s, 3H), 3.79 (s, 3H), 4.06 (br, 1H), 4.60-4.85 (br m, 2H), 5.08 (s, 2H), 5.33 (d, 1H, J=5.4 Hz), 7.34 (s, 5H), 7.67 (d, 1H, J=7.8 Hz), 8.03 (d, 1H, J=7.8 Hz); IR (KBr): 3301, 3059, 2953, 1737, 1693, 1652, 1536, 1440, 1387, 1334, 1276, 1250, 1215, 1176, 1055, 1000 cm-1; HRMS calcd for C27H37N3O12Na m/z 618.2264, found m/z 618.2273. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.2% | Stage #1: N-benzyloxycarbonyl-L-glutamic acid; 3-aminopropyl-2-O-[2,3,4-tri-O-benzoyl-α-D-mannosyl]-3,4,6-tri-O-benzyl-α-D-mannoside hydrochloride With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile for 16h; Stage #2: With N-ethyl-N,N-diisopropylamine In acetonitrile for 21h; | 4.A To a solution of 23 (3.77 g, 2.95 mmol) in dry acetonitrile (50 mL) was added N-benzyloxycarbonyl glutamic acid (0.3661 g, 1.3 mmol), N-hydroxybenzotriazole (HOBt) (0.4g, 2.95 mmol), DBU (4.6 mL, 4 mmol), and 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide (EDC) (0.75 g, 8.85 mmol). After 16 h Hünig’s base (0.25 mL) was added followedby more EDC (0.75 g, 8.85 mmol). After 21 h the solution was concentrated to a syrup and purified by silica gel flashcolumn chromatography using 10% 2-propanol in DCM against DCM 0 - 50 % affording N-benzyloxycarbonylamino 1,5-di-[3-amidopropyl 2-O-[2,3,4-tri-O-benzoyl-6-O-dibenzylphosphoryl-α-D-mannosyl]-3,4,6-tri-O-benzyl-α-D-mannosyl]glutamate 24 as a white foam (0.97 g, 11.2 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 18h; | 37; 16.4 Step 4. Preparation of compound 89 A solution of 88 (2g, 3.38mmol) and Z-glutamic acid (427mg, 1.52mmol) in CH2CI2 (50mL) was treated with HBTU (1.41g, 3.7mmol) and Hiinig's base (1.77mL, l O. lmmol). After stirring (18h) the mixture was concentrated and subjected to chromatography to yield 89 (871 mg, 48%) as a colorless foam. Rf 0.5 (10% CH30H-CH2C12). |
48% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 18h; | 16a.4 Step 4. Preparation of compound 89a A solution of 88a (2g, 3.38mmol) and Z- L-glutamic acid (427 mg, 1.52mmol) in CH2CI2 (50mL) was treated with HBTU (1.41g, 3.7mmol) and Hunig's base (1.77mL, 10. Immol). After stirring (18h) the mixture was concentrated and subjected to chromatography to yield 89a (871 mg, 48%) as a colorless foam. Rf 0.5 (10% CH3OH- |
48% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 18h; | 16a.4 Step 4. Preparation of compound 89a A solution of 88a (2g, 3.38mmol) and Z- L-glutamic acid (427 mg, 1.52mmol) inCH2CI2 (50mL) was treated with HBTU (1.41g, 3.7mmol) and Hunig's base (1.77mL,10. Immol). After stirring (18h) the mixture was concentrated and subjected to chromatography to yield 89a (871 mg, 48%) as a colorless foam. Rf 0.5 (10% CH3OH-CH2CI2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 1.5h; | 37; 16.6 Step 6. Preparation of compound 91 A solution of 90 (850mg, 0.72mmol) and Z-glutamic acid (91mg, 0.32mmoi) in CH2C12 (lOmL) was treated with HBTU (300mg, 0.79mmol) and Hiinig's base (502μΙ , 2.9mmol). After stirring (1.5h) the mixture diluted with CH2C12 and washed with NaHC03 (Sat. Aq.), dried (MgS04), filtered and concentrated. The crude material was subjected to chromatography to yield 91 (590mg, 76%) as a colorless foam. Rf 0.5 (10% CH30H-CH2C12). |
76% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 1.5h; | 16a.6 Step 6. Preparation of compound 91a A solution of 90a (850 mg, 0.72mmol) and Z-glutamic acid (91 mg, 0.32mmol) in CH2CI2 (lOmL) was treated with HBTU (300 mg, 0.79mmol) and Hunig' s base (502μΙ-, 2.9mmol). After stirring (1.5h) the mixture diluted with CH2CI2 and washed with NaHC03 (Sat. Aq.), dried (MgSO t), filtered and concentrated. The crude material was subjected to chromatography to yield 91a (590 mg, 76%) as a colorless foam. Rf 0.5 (10% CH3OH-CH2CI2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.2% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 14h; | (3S,7S,14S,23S,27S)-hexa-tert-butyl 14-(benzyloxycarbonylamino)-5,13,17,25-tetraoxo-4,6,12,18,24,26-hexaazanonacosane-1,3,7,23,27,29-hexacarboxylate (5) Z-Glu-OH (0.380 g, 1.35 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.777 g, 4.05 mmol), and hydroxybenzotriazole (0.548 g, 4.06 mmol) were dissolved in DMF (10 mL). Subsequently, a solution of compound 2 (1.98 g, 4.05 mmol) in DMF (5 mL) was added to the stirred mixture at 0 oC, which was followed by addition of triethylamine (0.942 mL, 6.76 mmol). After being stirred for 14 h at room temperature, the resulting mixture was diluted with ethyl acetate (40 mL) and washed with H2O (40 mL). The aqueous phase was extracted with ethyl acetate (40 mL). The combined organic phase was dried over with Na2SO4, filtered, and evaporated. The residue was purified by flash column chromatography (dichloromethane/methanol = 40/1) on silica gel to yield compound 5 (1.32 g, 80.2%) as a white solid, mp 136-139 oC. 1H NMR (600 MHz, CDCl3) δ 7.39-7.28 (m, 7H), 6.95 (br s, 1H), 6.52 (d, J = 6.6 Hz, 1H), 5.82 (br s, 3H), 5.11 (s, 2H), 4.38-4.30 (m, 4H), 4.17-4.15 (m, 1H), 3.51-3.50 (m, 1H), 3.40-3.37 (m, 1H), 3.13-3.10 (m, 1H), 2.98-2.97 (m, 1H), 2.42-2.26 (m, 6H), 2.13-2.01 (m, 4H), 1.83-1.71 (m, 4H), 1.54-1.48 (m, 6H), 1.44-1.41 (m, 54H), 1.36-1.27 (m, 4H). 13C NMR (150 MHz, CDCl3) δ 173.6, 173.3 (2C), 172.8, 172.6, 172.5, 172.4, 172.2, 157.8, 157.7, 156.8, 136.3, 128.6 (2C), 128.4, 128.3 (2C), 82.1, 82.0, 81.5, 81.4, 80.6, 80.5, 67.3, 54.8, 53.2, 53.14, 53.05, 53.01, 39.1, 38.9, 32.9, 32.1, 31.9, 31.8 (2C), 29.3, 28.6, 28.4 (2C), 28.2 (7C), 28.1 (9C), 28.1 (3C), 22.0, 21.8. HRMS (ESI) m/z (M + H)+ calcd for C61H102N7O18 = 1220.7281, found 1220.7288. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With urea In dimethyl sulfoxide at 150℃; for 2h; | 3.4 N-CBZ-L-glutamic acid 2.81 g (0.01 mol),Urea 1.2g (0.2mol) was added to DMSO to dissolve and reflux at 150 ° C. After 2 h, the temperature was lowered.HCl gas, a white solid 1.518 g, a yield of 92%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 1.5h; | 16a.6 Step 6. Preparation of compound 91a A solution of 90a (850 mg, 0.72mmol) and Z-glutamic acid (91 mg, 0.32mmol) in CH2CI2 (lOmL) was treated with HBTU (300 mg, 0.79mmol) and Hunig's base (502uL, 2.9mmol). After stirring (1.5h) the mixture diluted with CH2CI2 and washed with NaHC03 (Sat. Aq.), dried (MgS04), filtered and concentrated. The crude material was subjected to chromatography to yield 91a (590 mg, 76%) as a colorless foam. Rf 0.5 (10% CH3OH- CH2CI2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 48h; | 23.D Step D. benzyl [(S)-1,5-dioxo-1,5-bis({2-[(α-D-mannopyranosyl)oxy]ethyl}amino)pentan-2- yl]carbamate To a solution of Z-glutamic acid (600 mg, 2.13 mmol) and 2-aminoethyl α-D- mannopyranoside (1.19 g, 5.33 mmol) in DMF (12 mL) at rt was added EDC (1.64 g, 8.53 mmol) and DMAP (261 mg, 2.13 mmol). After stirring for 48 hr, the reaction mixture was evaporated, and the residue was added slowly to AcCN (180 mL). The resulting suspension was centrifuged 2 x (3500 rpm 8 min). The supernatent was decanted off, and the residual white pellets was dissolved in MeOH, combined and evaporated. The residue was purified by silica gel column chromatography (CombiFlash Teldyne ISCO: 80g RediSep column) eluent: gradient EtOAc/:MeOH/AcCN (v/v/v = 6/2/2) to EtOAc/MeOH/AcCN/H2O (v/v/v/v = 6/2/2/2) over 12 CV then to EtOAc/:MeOH/AcCN/H2O (v/v/v/v = 6/2/2/2) over 5 CV to give the title compound. UPLC-MS Method A: m/z = 691.5 (z = 1); tR = 0.40 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,3,5-Trioxan In acetonitrile at 65 - 75℃; | 2B.1 Step 1: Synthesis of Compound 7 Compound 3 (250 g, 1.00 x wt), 1,3,5-trioxane (96.0 g, 0.384 x wt), and MeCN (2L, 8 x vol) were charged to reactor 1. 2x vol to 20x volume MeCN can be used. Alternative formaldehyde sources to 1 ,3,5-trioxane, such as paraformaldehyde, can be used.Methanesulfonic acid (7.5 ml, 0.030 x vol) was charged to reactor 1. Alternative charges from 0.01 to 0.1 x vol can be used. Alternative acids, such as benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, sulfuric acid, or trichloroacetic acid, can be used. The reaction mixture was agitated and heated to 70 °C for 12 hours. 60 to 80 °C can be used. 6 hours to 36 hours can be used. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; | 10.I Step I. benzyl (S)-(J25-bis[(a-D-mannopyranosyl)oxy]-3,23-bis{2-[(a-D- mannopyranosyl)oxy ]ethyl}-4, H,15, 22-tetraoxo-3, 10,16, 23-tetraazapentacosan-12-yl)carbamate To a mixture of 6-amino-/V,/V-bis{2-[(a-D-mannopyranosyl)oxy]ethyl}hexanamide (0602) (2.3 g, 4.27 mmol) and Z-Glu-OH (500 mg, 1.78 mmol) in DMF (15 mL) was added EDC (1.02 g, 5.33 mmol) and HOBt (681 mg, 2.5 mmol). After stirring at rt overnight, the reaction mixture was added dropwise to stirred AcCN (200 mL). The resulting white precipitate collected by filtration and purified by flash chromatography on C18 silica gel (270 g), eluting with 5-60% AcCN/H20, to give the title compound. UPLC-MS Method A: tR = 3.30 min; m/z = 1330.75 (z = 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 18h; | 16a.4 Step 4. Preparation of compound 89a A solution of 88a (2g, 3.38mmol) and Z-L-glutamic acid (427mg, 1.52mmol) in CH2Cl2 (50mL) was treated with HBTU (1.41g, 3.7mmol) and Hünig’s base (1.77mL, 10.1mmol). After stirring (18h) the mixture was concentrated and subjected to chromatography to yield 89a (871mg, 48%) as a colorless foam. Rf 0.5 (10% CH3OH- CH2Cl2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 1.5h; | 16a.6 Step 6. Preparation of compound 91a A solution of 90a (850mg, 0.72mmol) and Z-glutamic acid (91mg, 0.32mmol) in CH2Cl2 (10mL) was treated with HBTU (300mg, 0.79mmol) and Hünig’s base (502mL, 2.9mmol). After stirring (1.5h) the mixture diluted with CH2Cl2 and washed with NaHCO3 (Sat. Aq.), dried (MgSO4), filtered and concentrated. The crude material was subjected to chromatography to yield 91a (590mg, 76%) as a colorless foam. Rf 0.5 (10% CH3OH- CH2Cl2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.6% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 14h; | (S)-Benzyl 1,5-bis(2-(2-nitro-1H-imidazol-1-yl)ethylamino)-1,5-dioxopentan-2-ylcarbamate (7) (S)-2-(Benzyloxycarbonylamino)pentanedioic acid 6 (0.69 g, 2.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.4 g, 7.4 mmol), and hydroxybenzotriazole(1.0 g, 7.4 mmol) were dissolved in DMF (10 mL). Subsequently,a solution of compound 2 (2.0 g, 7.4 mmol) and triethylamine(1.0 mL, 7.2 mmol) in DMF (5 mL) was added to the stirred mixture at0 C, which was followed by addition of triethylamine (1.7 mL, 12mmol). After being stirred for 14 h at room temperature, the resultingmixture was diluted with ethyl acetate (40 mL) and washed with H2O(40 mL). The aqueous phase was extracted with ethyl acetate (40 mL ×2). The combined organic phase was dried over with Na2SO4, filtered,and evaporated. The residue was purified by column chromatography(dichloromethane/methanol = 12/1) on silica gel to yield compound 7(1.01 g, 73.6%) as a yellowish solid. mp 79-82 C. 1H NMR (600 MHz,DMSO-d6) δ 8.01 (t, J = 6.0 Hz, 1H), 7.91 (t, J = 5.4 Hz, 1H), 7.49 (s,1H), 7.42-7.41 (m, 2H), 7.39-7.30 (m, 5H), 7.13 (s, 1H), 7.09 (s, 1H),5.05-4.99 (m, 2H), 4.45-4.39 (m, 4H), 3.80 (td, J = 8.4, 5.4 Hz, 1H), 3.52-3.43 (m, 4H), 2.05-1.96 (m, 2H), 1.78-1.72 (m, 1H), 1.61-1.55(m, 1H). 13C NMR (150 MHz, DMSO-d6) δ 172.0, 171.9, 155.9, 144.7,144.6, 136.9, 128.6, 128.42, 128.37 (2C), 127.9, 127.8 (2C), 127.7,127.5, 65.6, 54.5, 49.2 (2C), 38.22, 38.16, 31.6, 27.4. HRMS (ESI) m/z(M + H)+ calcd for C23H28N9O8 = 558.2061, found 558.2065. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide for 3h; | 23 Example 23. Synthesis of Compound 16 To a solution of compound 15 (40 g, 31.82 mmol) in DMF (400 mL), compound 15A (4.0 g, 14.32 mmol) and HBTU (14.5 g, 38.18 mmol) were added. The reaction mixture was cooled to 10 °C to 15 °C TEA (10.6 mL, 76.36 mmol) was added while maintaining internal temperature at 10 °C to 15 °C. The reaction mixture allowed to warm to 20 °C to 25 °C and stir for not less than 3 hours until completion of reaction as confirmed by UPLC. He reaction mixture was quenched by addition of water (400 mL) and Ethyl acetate (400 mL). The aqueous layer was separated and extracted with DCM (3 x 400 mL). The DCM layers were pooled, washed with water (5 x 200 mL), dried over Na2SO4, filtered and evaporated to complete dryness. Compound 16 (31.7 g, 87% yield) was obtained as light-yellow foam solid. m/z 2563.9 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In dichloromethane at 25℃; for 6h; | 21 Example 21. Synthesis of Compound 16D To a solution of compound 16-5 (32.5g, 92.7 mmol) in methylene chloride (455 mL), compound 15A (11.7 g, 41.7 mmol) and HBTU (52.7 g, 139 mmol) were added. To this mixture TEA (28.1 g, 278 mmol) was added while maintaining internal temperature at 15 °C to 25 °C. Reaction mixture allowed to stir at the same temperature for not less than 6 hours until completion of reaction as confirmed by UPLC. Reaction mixture was sequentially washed with water (320 mL), aqs. NaHCO3 (320 mL), brine (320 mL), dried over Na2SO4 and evaporated to dryness. The crude residue was purified by column chromatography (30% to 100% EA/Hexanes) to give compound 16D (45.2 g, 51% Yield) as a white solid. m/z 946.5 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.39 (d, J = 15.5 Hz, 5H), 8.22 (t, J = 5.7 Hz, 1H), 8.05 (s, 2H), 7.35 - 7.24 (m, 5H), 5.06 (t, J = 9.3 Hz, 2H), 4.05 (q, J = 7.1 Hz, 1H), 3.98 - 3.87 (m, 4H), 2.28 (hept, J = 7.9, 7.1 Hz, 2H), 1.96 (dt, J = 18.0, 6.7 Hz, 1H), 1.82 (dd, J = 14.5, 7.2 Hz, 1H), 1.53 (d, J = 3.5 Hz, 36H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: N-benzyloxycarbonyl-L-glutamic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 5℃; for 0.166667h; Stage #2: glycine ethyl ester hydrochloride In N,N-dimethyl-formamide at 25 - 30℃; for 16h; | 8 Example 8. Synthesis of Compound 15C A solution of DMF (1000 mL) and DIPEA (275.3 g, 2.13 mmol) was cooled to 0 to 5 °C. Sequentially charged compound 15-A (100 g, 0.35 mol), EDC.HCl (217.1 g, 1.13 mol) and HOBt monohydrate (173.9 g, 1.13 mol) while maintaining temperature 0 to 5 °C. Agitated for 10 min and then compound 15-B (163.4 g, 1.17 mol) was charged. The reaction mixture was allowed to warm to 25 °C to 30 °C and stirred for not less than 16 hours until completion of reaction as confirmed by UPLC. The reaction mixture was diluted by slow addition of Ethanol (1000 mL) followed by water (4500 mL) and allowed to stir for not less than 4 h at 25 °C to 30 °C. A precipitate formed which was filtered, washed with water (1000 mL) and solids dried in vacuum at <50 °C. Compound 15C (134.0 g, 83% Yield) was obtained as a white solid. m/z 452.21 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
133.6 g | Stage #1: N-benzyloxycarbonyl-L-glutamic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at -5℃; for 48h; Stage #2: N-cyclohexyl-cyclohexanamine In dichloromethane at 5℃; | 1.1.2-1.1.3; 2.2.2-2.2.3; 3.3.2-3.3.3; 4.4.2-4.4.3; 5.5.2-5.5.3; 6.6.2-6.6.3; 7.7.2-7.7.3 5.2. Dissolve 166g (0.59mol) of N-benzyloxycarbonyl-L-glutamic acid in 1660ml of DCM, then cool to -5°C, then add 152g DCC and 72g DMAP, mix and stir for 48h, and cool to -5°C. Then the white solid was removed by filtration, the mother liquor was washed with a little water and saturated brine to obtain a DCM solution of crude N-benzyloxycarbonyl-L-glutamic acid, which was kept for use.5.3. Cool the DCM solution of the crude N-benzyloxycarbonyl-L-glutamic acid obtained in step 4.2 to about 5°C, then add about 175g of DCHA to a pH of about 8, then filter, and wash the filter cake with DCM once , Dried to get 133.6g, which is N-benzyloxycarbonyl-L-glutamic acid dicyclohexylamine salt. |
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