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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Homovanillic Acid is a dopamine metabolite occurring in human biofluids, also barks of Ilex rotunda Thunb.
Synonyms: Vanilacetic acid; HVA; Homovanillic acid, HVA, NSC 16682, Vanilacetic Acid
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Synthesis of Homo-and Copolyesters Using an AB-Type Aromatic Monomer Based on Homovanillic Acid
Nguyen, Tam T ; Olsson, Emma ; V. Mankar, Smita ; Warlin, Niklas ; Valsange, Nitin G ; Engqvist, Jonas , et al.
Abstract: There is currently intensive research ongoing with the aim to utilize various lignin-derived molecules to produce aromatic monomers and polymers. In the present work, homovanillic acid (HVA), derived from lignin, was used to prepare sustainable polyesters for the first time. An AB-type monomer with an alcohol group and a carboxylate ester group was conveniently synthesized by using HVA and ethylene carbonate. The monomer was employed in bulk polycondensation to yield the corresponding homopolyester. The polymerization temperature, catalyst, and time were optimized, and it was found that the addition of a small quantity of a dicarboxylate monomer facilitated a stoichiometric balance throughout the homopolycondensation of the AB-type monomer, and thus significantly enhanced the molecular weight of the polyester (Mn = 36 kg mol−1, [η] ∼ 1.1 dL g−1). Copolymerization of the HVA-based monomer with another lignin-based AB monomer, methyl 4-(2-hydroxyethoxy) benzoate, produced a series of copolyesters with high yields and moderate molecular weights (Mn = 9.5−11 kg mol−1, [η] ∼ 0.5 dL g−1). The resulting copolyesters showed a reasonably high thermal stability (Td,5% > 318 °C) and tunable thermal properties, e.g., Tg = 44−72 °C and Tm = 154−200 °C, depending on the monomeric composition. Consequently, the findings of this work demonstrated the great potential of HVA in the development of new biobased aromatic (co)polyesters with modulated crystallinity.
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CAS No. : | 306-08-1 |
Formula : | C9H10O4 |
M.W : | 182.17 |
SMILES Code : | O=C(O)CC1=CC=C(O)C(OC)=C1 |
Synonyms : |
Vanilacetic acid; HVA; Homovanillic acid, HVA, NSC 16682, Vanilacetic Acid
|
MDL No. : | MFCD00004350 |
InChI Key : | QRMZSPFSDQBLIX-UHFFFAOYSA-N |
Pubchem ID : | 1738 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
With water;HUSY (Si/Al=15); at 250℃; under 5250.53 Torr; for 2h;Inert atmosphere;Product distribution / selectivity; | In an autoclave (batch reactor) lignin (0.5 g), HUSY (Si/Al=15) (0.5 g) and mixture of water and organic solvent (30 g) were charged. After flushing the reactor with nitrogen gas for 3 times, nitrogen (7 bar) was charged. Reactor was heated up to 230° C. under the stirring (100 rpm). After attaining the desired temperature of 230° C. stirring was increased up to 500 rpm. Reaction was stopped after 30 minutes. Analysis of reaction mixture was done by GC, GC-MS. The lignin used in these examples were organosolv or dealkaline.Yield: >25percentMass balance: >90percent.The effect of reaction temperature and reaction time on depolymerization reaction is demonstrated by the results presented in Table 8 using SiO2-Al2O3 as catalyst*. TABLE 8 Exp. Time Lignin Product yield, Mass balance, No. (min.) conversion percentpercentNo. percent 1. 30 85 26 80 2. 60 85 41 86 3. 90 92 50 84 4. 120 95 70 85 Lignin, 0.5 g; HUSY (Si/Al = 15), 0.5 g; N2 Pressure, 7 bar (at)RT; Temperature, 250° C.No.Monomer and dimer products soluble in water/organic solvents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | General procedure: General Procedure A for Rink Amide Resin Activation. Rink amide resin (Advanced ChemTech) was mixed with DCM (1 mL per 100 mg resin) and then shaken for 30 minutes. After activation, resin was washed three times with DMF (1 mL per 100 mg resin). [0079] General Procedure B for the Removal of the Fmoc Group from the Rink Amide Resin. Rink amide resin was mixed with 20% piperidine in DMF (1 mL per 100 mg resin) and shaken for 30 minutes, and then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times) sequentially. The removal of the Fmoc group was confirmed by the ninhydrin test.General Procedure C for the Removal the Alloc Group from the Rink Amide Resin. The resin (200 mg) was washed with DCM (2 mL, 5 times) and shaken under 2 overnight with a solution of tetrakis(triphenylphosphine)palladium(0) (10 mg), AcOH (0.5 mL), and NMM (0.2 mL) in DCM (10 mL). The resin was then washed with DMF (2 mL, 3 times), isopropanol (2 mL, 3 times), and DCM (2 mL, 3 times). The removal of the Alloc group was confirmed by the ninhydrin test.General Procedure E for the Coupling of Carboxylic Acids to the Rink Amide Resin. Carboxylic acids (5 equiv, 0.5 M in DMF) were first mixed with HBTU (5 equiv, 0.5 M in DMF), HOBt (5 equiv, 0.5 M in DMF), and NMM (15 equiv, 1.5 M inDMF). The mixed solution was then added to the resin and shaken for 2 hours. The resin was then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times). The completion of the coupling reaction was confirmed by the ninhydrin test. [0083] General Procedure F for Peptide Cleavage from the Rink Amide Resin. The resin was washed with DCM (1 mL per 100 mg resin, 5 times) and subsequently shaken with a solution of 95% TFA, 2.5% TIS, and 2.5% H20 (1 mL per 100 mg resin) for 2 hours. The resin was removed by filtration, and the TFA was evaporated under vacuum. The crude peptide was obtained after trituration with diethyl ether (5 mL per 100 mg resin, 2 times) Compound 8 was synthesized using standard Fmoc chemistry on the Rink amide resin (Figure 18). The resin (200 mg, 0.7 mmol/g loading) was first activated by DCM (General procedure A). The Fmoc group on the resin was removed by piperidine in DMF (General procedure B). The resin was then coupled with Fmoc-Dpr(Boc)-OH. The Fmoc group on the resin was removed by piperidine in DMF (General procedure B). The resin was then coupled with <strong>[147290-11-7]<strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>-OH</strong>. The Fmoc group was removed (General procedure B) and Fmoc-Phe-OH was attached to resin (General procedure E). The Fmoc group was again removed (general procedure B) and the amine group on the F2Pmp residue was coupled with BMBA (general procedure E). The resin was treated with Pd(0) for the deprotection of Alloc group (general procedure C). 3- Iodobenzoic acid (mlBA) was attached to resin (general procedure E). The resin was treated with TFA (general procedure F) to give the crude peptide intermediate, which was treated with a mixture of HVA (0.5 M in DMF, 100 muGamma), HBTU (0.5 M in DMF, 100 muGamma), HOBt (0.5 M in DMF, 100 muGamma) and NMM (1.5 M in DMF, 100 muGamma) to give the crude product 8. The crude product was purified by HPLC to afford 8 (15.8 mg, 12% yield). The assignment of proton NMR utilized additional information from COSY. 1H NMR (500 MHz, DMSO-d6): S= 8.70 (d, J= 8.1 Hz, 1 H, BMBA-NH), 8.60-8.55 (m, 1 H, mlBA- NH), 8.35 (d, J= 6.9 Hz, 1 H, Phe-NH), 8.19 (s, 1 H, mlBA-ArH), 8.04-7.95 (m, 2 H, Orn-NH, BMBA-ArH), 7.91-7.83 (m, 3 H, mlBA-ArH, HVA-NH), 7.67 (d, J= 7.5 Hz, 1 H, BMBA-ArH), 7.40-7.15 (m, 9 H, BMBA-ArH, Phe-ArH, -CONH2 , mlBA-ArH), 6.77 (s, 1 H, HVA-ArH), 6.63 (d, J= 7.6 Hz, 1 H, HVA-ArH), 6.58 (d, J= 7.6 Hz, 1 H, HVA- ArH), 4.78-4.72 (m, 1 H, Phe-CaH), 4.30-4.22 (m, 2 H, Dpr-CaH, Orn-CaH), 3.70 (s, 3 H, HVA-OCH3), 3.40-3.35 (m, 1 H, Dpr-CpHH'), 3.35-3.18 (m, HVA-CH2-CO, Dpr-CpHH', Omicronpiiota-OmicrondeltaEta2, Phe-CpHH'), 3.04-2.96 (m, 1 H, Phe-CpHH'), 2.35 (s, 3 H, BMBA-Ar-CH3), I.81-1.74 (m, 1 H, Orn-CpHH'), 1.68-1.52 (m, 3 H, Orn-CpHH', Orn-CYH2). 13C MR (125 MHz, DMSO-d6 ): S= 171.79, 171.39, 171.25, 171.17, 164.70, 164.52, 147.13, 144.94, 140.65, 139.46, 138.30, 136.49, 135.51, 133.34, 130.75, 130.32, 129.00, 127.92, 126.62, 126.54, 126.10, 123.78, 121.26, 1 15.05, 1 13.13, 94.53, 55.37, 54.77, 53.01, 52.80, 41.74, 40.57, 36.68, 28.99, 25.46, 22.26. MS (ESI): calculated for [M], 954, found [M+H]+ 955. HPLC purity analysis: > 95% (UV, lambda = 254 nm). Figure 18 depicts the synthesis of Compound 8: (a) 30% piperidine/DMF; (b) Fmoc-Dpr(Boc)-OH/HBTU/HOBt/NMM; (c) <strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>- OH/HBTU/HOBt/NMM; (d) Fmoc-Phe-OH/HBTU/HOBt/NMM; (e) 3-bromo-4- methylbenzoic acid/HBTU/HOBt/NMM; (f) Pd(0)/NMM/AcOH; (g) 3 -iodobenzoic acid/HBTU/HOBt/NMM; (h) 95% TFA/H2O/TIS; (i) homovanillic acid/HBTU/HOBt/NMM. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | General procedure: General Procedure A for Rink Amide Resin Activation. Rink amide resin (Advanced ChemTech) was mixed with DCM (1 mL per 100 mg resin) and then shaken for 30 minutes. After activation, resin was washed three times with DMF (1 mL per 100 mg resin). [0079] General Procedure B for the Removal of the Fmoc Group from the Rink Amide Resin. Rink amide resin was mixed with 20% piperidine in DMF (1 mL per 100 mg resin) and shaken for 30 minutes, and then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times) sequentially. The removal of the Fmoc group was confirmed by the ninhydrin test.General Procedure C for the Removal the Alloc Group from the Rink Amide Resin. The resin (200 mg) was washed with DCM (2 mL, 5 times) and shaken under 2 overnight with a solution of tetrakis(triphenylphosphine)palladium(0) (10 mg), AcOH (0.5 mL), and NMM (0.2 mL) in DCM (10 mL). The resin was then washed with DMF (2 mL, 3 times), isopropanol (2 mL, 3 times), and DCM (2 mL, 3 times). The removal of the Alloc group was confirmed by the ninhydrin test.General Procedure E for the Coupling of Carboxylic Acids to the Rink Amide Resin. Carboxylic acids (5 equiv, 0.5 M in DMF) were first mixed with HBTU (5 equiv, 0.5 M in DMF), HOBt (5 equiv, 0.5 M in DMF), and NMM (15 equiv, 1.5 M inDMF). The mixed solution was then added to the resin and shaken for 2 hours. The resin was then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times). The completion of the coupling reaction was confirmed by the ninhydrin test. [0083] General Procedure F for Peptide Cleavage from the Rink Amide Resin. The resin was washed with DCM (1 mL per 100 mg resin, 5 times) and subsequently shaken with a solution of 95% TFA, 2.5% TIS, and 2.5% H20 (1 mL per 100 mg resin) for 2 hours. The resin was removed by filtration, and the TFA was evaporated under vacuum. The crude peptide was obtained after trituration with diethyl ether (5 mL per 100 mg resin, 2 times). Compound 7 was synthesized using standard Fmoc chemistry on the Rink amide resin (Figure 17). The resin (200 mg, 0.7 mmol/g loading) was first activated by DCM (General procedure A). The Fmoc group on the resin was removed by piperidine in DMF (General procedure B). The resin was then coupled with Fmoc-Dpr(Boc)-OH. The Fmoc group on the resin was removed by piperidine in DMF (General procedure B). The resin was then coupled with <strong>[147290-11-7]<strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>-OH</strong>. The Fmoc group was removed (General procedure B) and Fmoc-F2Pmp-OH was attached to resin (General procedure E). The Fmoc group was again removed (general procedure B) and the amine group on the F2Pmp residue was coupled with BMBA (general procedure E). The resin was treated with Pd(0) for the deprotection of Alloc group (general procedure C). 3-Iodobenzoic acid (mlBA) was attached to resin (general procedure E). The resin was treated with TFA (general procedure F) to give the crude peptide intermediate, which was treated with a mixture of HVA (0.5 M in DMF, 100 LL), HBTU (0.5 M in DMF, 100 LL), HOBt (0.5 M in DMF, 100 LL) and NMM (1.5 M in DMF, 100 mu,) to give the crude product 7. The crude product was purified by HPLC to afford compound 7 (21.5 mg, 14% yield). The assignment of proton NMR utilized additional information from COSY. 1H NMR (500 MHz, CD3OD): delta= 8.16 (s, 1 H, mlBA-ArH), 7.92 (s, 1 H, BMBA-ArH), 7.86 (d, J= 7.9 Hz, 1 H, mlBA-ArH), 7.78 (d, J= 7.9 Hz, 1 H, mlBA-ArH) 7.64 (d, J= 8.2 Hz, 1 H, BMBA-ArH), 7.58-7.52 (m, 3 H, BMBA-ArH, F2Pmp-ArH), 7.39 (d, J= 7.9 Hz, 2 H, F2Pmp-ArH) 7.27 (d, J= 8.2 Hz, 1 H, BMBA-ArH), 7.21-7.16 (m, 1 H, mlBA-ArH), 6.81- 6.78 (m, 1 H, HVA-ArH), 6.71-6.63 (m, 2 H, HVA-ArH), 4.83-4.80 (m, 1 H, F2Pmp- CH), 4.48-4.42 (m, 1 H, Dpr- CH), 4.30-4.24 (m, 1 H, Orn- CH), 3.77 (s, 3 H, HVA- OCH3), 3.63-3.58 (m, 1 H, Dpr- CpHH'), 3.51-3.45 (m, 1 H, Dpr- CpHH'), 3.41 - 3.33 (m, 5 H, Orn-C5H2, F2Pmp-CpHH', HVA-CH2-CO-), 3.16-3.09 (m, 1 H, F2Pmp-CpHH'), 2.39 (s, 3 H, BMBA-Ar-CH3). 1.92-1.85 (m, 1 H, Orn-CpHH'), 1.75-1.62 (m, 3 H, Orn-CpHH', Orn-CYH2). 13C MR (125 MHz, CD30D): delta= 175.72, 174.20, 174.15, 168.85, 168.48, 148.97, 146.60, 143.20, 141.53, 141.41, 137.67, 137.41, 134.42, 132.45, 131.95, 131.35, 130.25, 127.83, 127.63, 127.60 127.53, 125.65, 122.83, 1 16.30, 1 13.84, 101.39, 94.73, 56.73, 56.43, 55.33, 43.37, 42.17, 4Figure 17 depicts the synthesis of Compound 7: (a) 30% piperidine/DMF; (b) Fmoc-Dpr(Boc)-OH/HBTU/HOBt/NMM; (c) <strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>- OH/HBTU/HOBt/NMM; (d) Fmoc-F2Pmp-OH/HBTU/HOBt/NMM; (e) 3-bromo-4- methylbenzoic acid/HBTU/HOBt/NMM; (f) Pd(0)/NMM/AcOH; (g) 3 -iodobenzoic acid/HBTU/HOBt/NMM; (h) 95% TFA/H2O/TIS; (i) homovanillic acid/HBTU/HOBt/NMM.0.39, 37.76, 29.54, 26.96, 23.03. MS (ESI): calculated for [M], 1084, found [M+H]+ 1085. HPLC purity analysis: > 95% (UV, lambda = 254 nm). |