* 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.
In water;Liquid chromatography;Purification / work up;
Example 1; This example demonstrates purification of theanine from a concentrated aqueous tea extract.Preparation of the Aqueous Tea Extract:Broken mixed fannings (BMF) of black tea were extracted with water. The resulting extract was centrifuged, nanofiltered and dried to yield a tea extract comprising 6 wt % theanine, 16 wt % mono- and di-saccharides, 15 wt % ash, 6 wt % polyphenols, 6 wt % amino acids other than theanine, and 4 wt % caffeine.The tea extract was then re-dissolved in water and filtered through a 5 mum filter to yield the aqueous tea extract having a total solids content of 20 wt % and pH of 4.85.Preparation of the Column:The resin used was Diaion UBK550 in the K+ form. This resin is a sulfonated polystyrenic polymer in the form of beads with a narrow size distribution and an average diameter of 220 mum.The column was half-filled with degassed deionised water. Resin was then added and hot water recycled through the column for 30 minutes to adjust the resin level.The column was then packed. This was achieved by performing two elutions without any sampling or data recording, using a flow rate of 4 Vc per hour. This resulted in compaction due to the swelling and the shrinking of the resin, following injection of product then water. After these two elutions, the resin level was adjusted to the top of the column by adjusting a piston in the column.The packed column had a height of 113 cm and a diameter of 1.5 cm. Thus the column volume (Vc) was 200 ml. The column was fitted with a water jacket and maintained at a temperature of 60 C.Separation of the Extract:The tea extract was injected into the column in an amount of 9 ml (0.05 Vc). The mobile phase (degassed deionised water) was then pumped through the column at a rate of 5 ml per minute (1.5 Vc per hour). The output from the column was fed to a fraction collector with a fresh fraction being collected every minute (equivalent to every 0.025 Vc of product eluted). Each fraction was analysed for total solids (Brix scale using a Bellingham & Stanley RFM 3000 refractometer) and theanine content (using High Performance Liquid Chromatography). The results are shown in table 1. As is apparent from the data in table 1, most of the impurities are eluted in the first 60% of the column volume whilst theanine is only beginning to be eluted at this point. Thus fractions collected after this point (fractions 14 onwards) are enriched in theanine compared with the aqueous tea extract which was injected into the column (theanine content of 6 wt % on dry matter).
L-Theanine (5 g) (Sun<strong>[3081-61-6]theanine</strong>) was slurried in dry MeOH (50 ml). Then 5.145 g of Cl2SO were added drop-wise over 5 minutes (part way through the addition all of the solids dissolve to give a clear colourless solution) and the resulting solution was held for 12 hours at 20 C. to allow the reaction shown in scheme (II) to occur:
Examples; EXAMPLE 1; This example demonstrates the manufacture of a compound of the invention (N-ethyl-3- [5- (2-ethylcarbamoyl-ethyl) -3, 6-dioxo- piperazin-2-yl] -propionamide; see formula (4)).; L-Theanine (5 g) (Sun<strong>[3081-61-6]theanine</strong>) was slurried in dry MeOH (50 ml). Then 5.145 g of CI2SO were added drop-wise over 5 minutes (part way through the addition all of the solids dissolve to give a clear colourless solution) and the resulting solution was held for 12 hours at 200C to allow the reaction shown in scheme (II) to occur:; MeOH, SO2 and HCl were then removed under vacuum to leave a thick clear oil to which dry MeOH (50 ml) was added. The pH was then raised by adding MeONa while testing pH by intermittently spotting onto wet indicator paper. After adding 3.17 g of MeONa, the pH had increased to >11, which resulted in the reaction shown in scheme (III) :; The resulting solution was held for 12 hours at 200C to allow the reaction shown in scheme (IV) to occur:The resulting suspension was then filtered to remove NaCl and the filtrate subjected to vacuum to remove MeOH. The product was a white solid.The product was analysed with LC-MS (Liquid-Chromatography coupled Mass Spectroscopy) under the following conditions:Column: Phenomonex Gemini 5mu C18 IIOA 150mm x 2.00mmSolvents: A: 0.1% Formic Acid / WaterB: 0.1% Formic Acid / AcetonitrileFlow rate: 0.2 ml / minuteColumn Temperature: 300C Stop Time: 25 minutes; Mass Spectrometer Detection:Selected Ion Recording at m/z 175.6 for Theanine. Selected Ion Recording at m/z 313.5 for Theanine dimer .The results showed that the product was free from <strong>[3081-61-6]theanine</strong> (retention time of <strong>[3081-61-6]theanine</strong> = 3.7 min) and had a characteristic new peak with a retention time of around 7.4 min.The high resolution proton NMR spectrum of the product in MeOD-d4 is shown in Figure 1.
With boric acid;glutaminase; In water; at 30℃; for 22h;pH 11;
0.3 M glutamine and 1.5 M methylamine hydrochloride were reacted in the presence of 0.3 U glutaminase (commercially available) at 30 C. for 22 hours in a buffer solution of 0.05 M boric acid (pH 11), whereby 225 nm theanine was obtained. Reaction liquid was applied to Dowex 50×8 columnar chromatgraphy and Dowex 1×2 columnar chromatography (both made by Muromachi Chemical Co., Ltd.) thereby to be processed by ethanol, whereby an object substance is isolated from the reaction liquid. The isolated substance was applied to an amino acid analyzer (made by Hitachi Co.) and paper chromatography. Since the isolated substance behaved in the same way as a standard substance, it was recognized as L-theanine. When the isolated substance was processed by hydrolysis using hydrochloric acid or glutaminase, glutamine acid and ethylamine were produced in a ratio of 1:1. Thus, since the isolated substance was hydrolyzed by glutaminase, it was shown that ethylamine was gamma-ethylamine of glutamine acid. Furthermore, it was confirmed on the basis of glutamate dehydrogenase that glutamine acid produced by hydrolysis was L-glutamine acid. As a result, 8.5 g theanine was obtained.
glutaminase; In water; at 30℃; for 22h;pH 11;Aqueous boric buffer;
Example 1; Production of Theanine by an Enzymatic Method; 0.3 M glutamine and 1.5 M ethylamine hydrochloride in 0.05 M boric acid buffer (pH11) were reacted in the presence of 0.3 U glutaminase (commercial product) at 30 C. for 22 hours, and 225 nmol of L-theanine was obtained. Subsequently, the reaction solution was applied to Dowex 50×8 and Dowex 1×2 column chromatography (MUROMACHI CHEMICALS INC.), followed by ethanol treatment, to isolate the objective substance from the reaction solution. The isolated substance was analyzed by an amino acid analyzer (Hitachi, Ltd.) and paper chromatography, and was confirmed to be L-theanine due to the same pattern of movement as that of the standard substance. Hydrolysis treatment with hydrochloric acid or glutaminase produced glutamic acid and ethylamine at a ratio of 1:1. Thus, the isolated substance was hydrolyzed by glutaminase, demonstrating the binding of ethylamine at the gamma position of glutamic acid. L-glutamic acid generated by hydrolysis was confirmed by glutamate dehydrogenase. Thus, 8.5 g of L-theanine was obtained.
glutaminase; In water; at 30℃; for 22h;pH 11;Aqueous boric buffer;
Example 6; Production of a Mixture of Theanyl-Glutamine and Glutaminyl-Theanine; 0.4 M L-<strong>[3081-61-6]theanine</strong> and 0.4 M L-glutamine in 0.05 M boric acid buffer (ph11) were reacted in the presence of 0.3 U glutaminase (commercial product) at 30 C. for 22 hours to obtain 120 nmol of a mixture of theanyl-glutamine and glutaminyl-<strong>[3081-61-6]theanine</strong>. Subsequently, the reaction solution was applied to Dowex 50×8 and Dowex 1×2 column chromatography (MUROMACHI CHEMICALS INC.) to isolate the objective substance from the reaction solution. Structural analysis was conducted on the theanyl-glutamine and glutaminyl-<strong>[3081-61-6]theanine</strong> by mass spectrum analysis and NMR for confirmation.
glutaminase; In water; at 30℃; for 22h;pH 11;Aqueous boric buffer;
Example 4; Production of Theanyl-Theanine; 0.32 M L-<strong>[3081-61-6]theanine</strong> in 0.05 M boric acid buffer (pH11) was reacted in the presence of 0.3 U glutaminase (commercial product) at 30 C. for 22 hours, and 150 nmol of theanyl-<strong>[3081-61-6]theanine</strong> was obtained. Subsequently, the reaction solution was applied to Dowex 50×8 and Dowex 1×2 column chromatography (MUROMACHI CHEMICALS INC.) to isolate the objective substance from the reaction solution.
With glutaminase; water; boric acid; at 30℃; for 22h;pH 11;Enzymatic reaction;
0.3 M glutamine and 1.5 M methylamine hydrochloride were reacted in the presence of 0.3 U glutaminase (commercially available) at 30°C for 22 hours in a buffer solution of 0.05 M boric acid (pH 11), whereby 225 nm theanine was obtained. Reaction liquid was applied to Dowex 50.x.8 columnar chromatography and Dowex 1.x.2 columnar chromatography (both made by Muromachi Chemical Co., Ltd.) thereby to be processed by ethanol, whereby an object substance is isolated from the reaction liquid. As a result, 8.5 g theanine was obtained. The isolated substance was applied to an amino acid analyzer (made by Hitachi Co.) and paper chromatography. Since the isolated substance behaved in the same way as a standard substance, it was recognized as L-theanine. When the isolated substance was processed by hydrolysis using hydrochloric acid or glutaminase, glutamine acid and ethylamine were produced in a ratio of 1:1. Thus, since the isolated substance was hydrolyzed by glutaminase, it was shown that ethylamine was gamma-ethylamine of glutamine acid. Furthermore, it was confirmed on the basis of glutamate dehydrogenase that glutamine acid produced by hydrolysis was L-glutamine acid.
With glutaminase; at 30℃; for 22h;pH 11;borate buffer; Enzymatic reaction;
By reacting 0.3M glutamine and 1.5M ethylamine hydrochloride in 0.05M borate buffer (pH 11) at 30°C for 22 hours under the presence of 0.3U glutaminase (commercially available product), 225nmol of theanine were obtained. The reaction solution was then subject to chromatography using Dowex 50 x 8 and Dowex 1 x 2 columns (both made by Muromachi Technos Co. , Ltd.) and to ethanol treatment to isolate the target substance from the reaction solution. 8.5g of theanine were thus obtained. The isolated substance was then subject to an amino acid analyzer (made by Hitachi, Ltd.) and paper chromatography and, by exhibition of the same behavior as a standard substance, was confirmed to be L-theanine. Upon hydrolytic treatment with hydrochloric acid or glutaminase, monosodium glutamate and ethylamine were produced at a ratio of 1:1. That the isolated substance is hydrolyzed by glutaminase indicates that ethylamine is bonded to the gamma position of monosodium glutamate. That the monosodium glutamate resulting from hydrolysis is the L-isomer was confirmed by means of monosodium glutamate dehydrogenase.
Example 1: Preparation of N (5) -ethyl-L-glutamine (theanine)5.8 g of N-phthaloyl-L-glutamic acid 5-methyl ester(formula 1: R = Me, Xi = X2 = X3 = X4 = H) was added to 12.9 g of 70% ethylamine solution at 0C and stirred for one hour. Then, the reaction temperature was raised up to20C. After stirring the resulting solution at 20C for 22 hours, the ethylamine existing excessively was removed under reduced pressure. After adding 38.6 g of acetone to the resulting solution, the pH of the solution was regulated as 5 to 6 using acetic acid. Then, the resulting solution was stirred for one hour. Produced solids were filtrated and washed with ethanol . The filtrated white solids were dried to obtain a target compound (3.1 g, 89%).NMR (D2O) delta(ppm) : 3.77(t, IH), 3.20(q, 2H), 2.40(m, 2H), 2.13 (dd, 2H), l.ll(t, 3H) [alpha]20 +8.0 (c=5, H2O)
[0041] 8.7 g (50 mmol) of <strong>[3081-61-6]theanine</strong> and 19.3 g (53.6 mmol) of maltose were added in 130 ml of methanol and refluxedat 65 C for 18 hours. After the completion of the reaction, the mixture was kept at the room temperature for 3 hoursand subjected to filtration to obtain a mixture of maltulosyl <strong>[3081-61-6]theanine</strong> represented by the following formula 3 or 4 (12.9 g,52% yield) as a white powder.[0042] 1H NMR(D2O, delta): 5.24(1H), 4.20(1H), 4.07(1H), 3.99(2H), 3.79(7H), 3.57(1H), 3.43(1H), 3.33(1H), 3.20(2H)2.46(2H), 2.17(2H), 1.11(3H) (Peaks are shown for major compounds only.)[0043] LC-Mass: 499 [M+H][
Step 1: preparation of <strong>[3081-61-6]theanine</strong> methyl ester IIa (0063) Theanine was dissolved in methanol in an proportion of 87g/L (namely, 87g of <strong>[3081-61-6]theanine</strong> was dissolved in one liter of methanol), then sulfonyl chloride was slowly added into the system in an volume ratio of 55 ml, the mixture was stirred at room temperature for 1 h, and the resulting mixture was concentrated under reduced pressure to afford <strong>[3081-61-6]theanine</strong> methyl ester IIa.
Step 1: preparation of <strong>[3081-61-6]theanine</strong> ethyl ester IIb (0066) Theanine was dissolved in ethanol in an proportion of 87g/L (namely, 87g of <strong>[3081-61-6]theanine</strong> was dissolved in one liter of methanol), then sulfonyl chloride was slowly added into the system in a volume ratio of 55 ml, the mixture was stirred at room temperature for 1 h, and then the resulting mixture was concentrated under reduced pressure to obtain <strong>[3081-61-6]theanine</strong> ethyl ester IIb.
Example 1 (0059) A cocrystal product of the present invention was prepared by weighing 352 mg of acetylsalicylic acid and 340 mg of L-<strong>[3081-61-6]theanine</strong>, and transferring the solids to an agate mortar. The solids were wetted with 500 muL of methanol, and hand-ground with a pestle until a dried crystalline mass was obtained. This product was characterized using differential scanning calorimetry ("DSC;" see FIG. 2), x-ray powder diffraction ("XRPD;"see FIG. 3), Fourier-transform infrared spectroscopy with attenuated total reflectance sampling ("FTIR-ATR;"see FIG. 4), and Raman spectroscopy with diffuse reflectance sampling ("RAM-DR;" see FIG. 5). In addition, 117 mg of the cocrystal product was found to dissolve in 13 mL of water, making the aqueous solubility approximately 9 mg/mL.
0.327 g of amoxicillin trihydrate (0.780 mmol) and 0.136 g of L-<strong>[3081-61-6]theanine</strong> (0.781 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 1 a, while the FTIR spectrum is shown in Figure 1 b. The DSC melting endotherm of the product was characterized by a peak maximum at 208C.
0.31 1 g of ampicillin trihydrate (0.771 mmol) and 0.141 g of L-<strong>[3081-61-6]theanine</strong> (0.809 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 2a, while the FTIR spectrum is shown in Figure 2b. The DSC melting endotherm of the product was characterized by a peak maximum at 212C.
0.315 g of aripiprazole (0.703 mmol) and 0.129 g of L-<strong>[3081-61-6]theanine</strong> (0.741 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 3a, while the FTIR spectrum is shown in Figure 3b. The DSC melting endotherm of the product was characterized by a peak maximum at 148C.
0.165 g of bromocriptine (0.252 mmol) and 0.046 g of L-<strong>[3081-61-6]theanine</strong> (0.264 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 4a, while the FTIR spectrum is shown in Figure 4b. The DSC melting endotherm of the product was characterized by a peak maximum at 197C.
0.218 g of cabergoline (0.483 mmol) and 0.088 g of L-<strong>[3081-61-6]theanine</strong> (0.505 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 5a, while the FTIR spectrum is shown in Figure 5b. The DSC melting endotherm of the product was characterized by a peak maximum at 52C.
0.314 of cefadroxil monohydrate (0.849 mmol) and 0.151 g of L-<strong>[3081-61-6]theanine</strong> (0.867 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 6a, while the FTIR spectrum is shown in Figure 6b. The DSC melting endotherm of the product was characterized by a peak maximum at 213C.
0.335 of cefdinir monohydrate (0.810 mmol) and 0.140 g of L-<strong>[3081-61-6]theanine</strong> (0.804 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 7a, while the FTIR spectrum is shown in Figure 7b. The DSC melting endotherm of the product was characterized by a peak maximum at 157C.
0.208 g of cabergoline (0.662 mmol) and 0.1 15 g of L-<strong>[3081-61-6]theanine</strong> (0.660 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 8a, while the FTIR spectrum is shown in Figure 8b. The DSC melting endotherm of the product was characterized by a peak maximum at 209C.
0.256 g of daptomycin (0.158 mmol) and 0.030 g of L-<strong>[3081-61-6]theanine</strong> (0.172 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 9a, while the FTIR spectrum is shown in Figure 9b. The DSC melting endotherm of the product was characterized by a peak maximum at 213C.
0.373 g of diflunisal (1 .491 mmol) and 0.269 g of L-<strong>[3081-61-6]theanine</strong> (1 .544 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 10a, while the FTIR spectrum is shown in Figure 10b. The DSC melting endotherm of the product was characterized by a peak maximum at 172C.
0.077 g of doxorubicin (0.142 mmol) and 0.027 g of L-<strong>[3081-61-6]theanine</strong> (0.155 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 1 1 a, while the FTIR spectrum is shown in Figure 1 1 b. The DSC melting endotherm of the product was characterized by a peak maximum at 209C.
0.315 g of efavirenz (0.998 mmol) and 0.177 g of L-<strong>[3081-61-6]theanine</strong> (1 .016 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 12a, while the FTIR spectrum is shown in Figure 12b. The DSC melting endotherm of the product was characterized by a peak maximum at 136C.
0.227 g of entacapone (0.744 mmol) and 0.132 g of L-<strong>[3081-61-6]theanine</strong> (0.758 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 13a, while the FTIR spectrum is shown in Figure 13b. The DSC melting endotherm of the product was characterized by a peak maximum at 160C.
0.316 g of epinephrine (1 .725 mmol) and 0.305 g of L-<strong>[3081-61-6]theanine</strong> (1 .751 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 14a, while the FTIR spectrum is shown in Figure 14b. The DSC melting endotherm of the product was characterized by a peak maximum at 205C.
0.417 g of erythromycin (0.568 mmol) and 0.101 g of L-<strong>[3081-61-6]theanine</strong> (0.580 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 15a, while the FTIR spectrum is shown in Figure 15b. The DSC melting endotherm of the product was characterized by a peak maximum at 219C.
0.326 g of febuxostat (1 .030 mmol) and 0.180 g of L-<strong>[3081-61-6]theanine</strong> (1 .033 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 16a, while the FTIR spectrum is shown in Figure 16b. The DSC melting endotherm of the product was characterized by a peak maximum at 182C.
0.330 g of fexofenadine (0.658 mmol) and 0.1 19 g of L-<strong>[3081-61-6]theanine</strong> (0.683 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 17a, while the FTIR spectrum is shown in Figure 17b. The DSC melting endotherm of the product was characterized by a peak maximum at 206C.
0.355 g of fluconazole (1 .159 mmol) and 0.204 g of L-<strong>[3081-61-6]theanine</strong> (1 .171 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 18a, while the FTIR spectrum is shown in Figure 18b. The DSC melting endotherm of the product was characterized by a peak maximum at 102C.
0.181 g of furosemide (0.547 mmol) and 0.094 g of L-<strong>[3081-61-6]theanine</strong> (0.540 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 19a, while the FTIR spectrum is shown in Figure 19b. The DSC melting endotherm of the product was characterized by a peak maximum at 193C.
L-theanine hydrochlorothiazide cocrystal[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; isopropyl alcohol;
0.408 g of hydrochlorothiazide (1 .370 mmol) and 0.239 g of L-<strong>[3081-61-6]theanine</strong> (1 .372 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 20a, while the FTIR spectrum is shown in Figure 20b. The DSC melting endotherm of the product was characterized by a peak maximum at 204C.
0.246 g of R-ibuprofen (1 .193 mmol) and 0.213 g of L-<strong>[3081-61-6]theanine</strong> (1 .223 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70percent isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 21 a, while the FTIR spectrum is shown in Figure 21 b. The DSC melting endotherm of the product was characterized by a peak maximum at 51 °C.
0.309 g of irinotecan (0.527 mmol) and 0.094 g of L-<strong>[3081-61-6]theanine</strong> (0.540 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70percent isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 22a, while the FTIR spectrum is shown in Figure 22b. The DSC melting endotherm of the product was characterized by a peak maximum at 218°C.
0.215 g of levodopa (1 .090 mmol) and 0.191 g of L-<strong>[3081-61-6]theanine</strong> (1 .096 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 23a, while the FTIR spectrum is shown in Figure 23b. The DSC melting endotherm of the product was characterized by a peak maximum at 21 1 C.
0.142 g of memantine (0.792 mmol) and 0.140 g of L-<strong>[3081-61-6]theanine</strong> (0.804 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 24a, while the FTIR spectrum is shown in Figure 24b. The DSC melting endotherm of the product was characterized by a peak maximum at 207C.
0.335 g of metronidazole (1 .957 mmol) and 0.348 g of L-<strong>[3081-61-6]theanine</strong> (1 .998 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 25a, while the FTIR spectrum is shown in Figure 25b. The DSC melting endotherm of the product was characterized by a peak maximum at 160C.
0.271 g of nilotinib (0.512 mmol) and 0.090 g of L-<strong>[3081-61-6]theanine</strong> (0.517 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 26a, while the FTIR spectrum is shown in Figure 26b. The DSC melting endotherm of the product was characterized by a peak maximum at 21 1 C.
0.206 g of prednisone (0.575 mmol) and 0.103 g of L-<strong>[3081-61-6]theanine</strong> (0.591 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 27a, while the FTIR spectrum is shown in Figure 27b. The DSC melting endotherm of the product was characterized by a peak maximum at 201 C.
0.368 g of sulfamethoxazole (1 .453 mmol) and 0.259 g of L-<strong>[3081-61-6]theanine</strong> (1 .487 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 28a, while the FTIR spectrum is shown in Figure 28b. The DSC melting endotherm of the product was characterized by a peak maximum at 169C.
0.425 g of sumitriptan (0.963 mmol) and 0.168 g of L-<strong>[3081-61-6]theanine</strong> (0.964 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 29a, while the FTIR spectrum is shown in Figure 29b. The DSC melting endotherm of the product was characterized by a peak maximum at 173C.
0.348 g of valganciclovir (0.982 mmol) and 0.174 g of L-<strong>[3081-61-6]theanine</strong> (0.999 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 30a, while the FTIR spectrum is shown in Figure 30b. The DSC melting endotherm of the product was characterized by a peak maximum at 212C.
0.397 g of zafirlukast (0.690 mmol) and 0.122 g of L-<strong>[3081-61-6]theanine</strong> (0.700 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 31 a, while the FTIR spectrum is shown in Figure 31 b. The DSC melting endotherm of the product was characterized by a peak maximum at 21 1 C.
0.343 g of zidovudine (1 .283 mmol) and 0.226 g of L-<strong>[3081-61-6]theanine</strong> (1 .297 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 32a, while the FTIR spectrum is shown in Figure 32b. The DSC melting endotherm of the product was characterized by a peak maximum at 122C.
0.398 g of gluconate zinc (0.873 mmol) and 0.157 g of L-<strong>[3081-61-6]theanine</strong> (0.901 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 33a, while the FTIR spectrum is shown in Figure 33b. The DSC melting endotherm of the product was characterized by a peak maximum at 164C.
0.384 g of Acyclovir (1 .705 mmol) and 0.298 g of L-<strong>[3081-61-6]theanine</strong> (1 .71 1 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in Figure 34a, while the FTIR spectrum is shown in Figure 34b. The DSC melting endotherm of the product was characterized by a peak maximum at 1 19C.
With hydrogenchloride; potassium hydroxide; In water;pH 6 - 7;
L-5-Methyltetrahydrofolic acid (3.3 g) was added to a 30% aqueous potassium hydroxide solution (18 ml)L-<strong>[3081-61-6]theanine</strong> (1.5 g) was added, the pH was adjusted to 6-7 with 20% aqueous hydrochloric acid, and the mixture was stirred. The mixture was added to acetonitrile(230 ml), a pale yellow solid precipitated, which was isolated, to give L-5-methyltetrahydrofolic acid L-<strong>[3081-61-6]theanine</strong> salt (3.2 g), HPLC purity99.3%.
An aqueous solution of <strong>[3081-61-6]theanine</strong> was added to 50 mM sodium borate buffer solution (50 muL)(1 mM, 50 muL), ethanol solution of fluorinated thiol (100 mM, 50 muL)And ethanol solution of ortho-phthalaldehyde (OPA) (100 mM, 25 muL)And the mixture was reacted at room temperature for 1 minute.
With C9H12N2O8(2-)*2Na(1+); In water; at 60℃; for 9h;
(3) Add the crude L-glutamic acid-5-methyl ester copper chelate obtained in step (2) to a 500mL reaction vessel, add 180g of water, and add an ethylamine aqueous solution (mass fraction 70) dropwise at 45 C %) 24.0g, 30.3g of EDTA disodium salt was added after 6 hours of reaction, then the reaction solution was heated to 60 C for 3 hours to stop the reaction, and the water in the reaction solution was concentrated to dryness to obtain crude L-theanine;Recrystallize the crude L-theanine with ethanol to obtain L-theanine; the specific recrystallization method includes: adding 160g of ethanol to the crude L-theanine, heating to reflux and stirring for 1 to 2 hours, and filtering while hot. After cooling and crystallizing, filtering and drying, 19.4 g of L-theanine was obtained.
1; 2; 3; 4 Synthesis of Magnesium di-L-theanate Using Magnesium Ethoxide
L-Theanine (87.1 g, 500 mmol) and magnesium ethoxide (28.6 g, 250 mmol) were slurried in 500 mL of absolute ethanol. The slurry was stirred and warmed as water (total 150 mL) was added in portions until a clear, yellow solution was obtained. The solution was cooled but no solid was obtained. The solution was concentrated to a solid by evaporation under vacuum. The solid was slurried with methanol to break up the bulk into fine particles. The slurry was filtered to isolate the product, a white solid. The product was slurried in 250 mL of hot ethanol and water was added until a solution was obtained. The yellow solution was treated with charcoal and filtered. The filtrate was concentrated to dryness and then further dried at 50° C. under vacuum to obtain a brittle solid. The solid was crushed into fine particles. About 92.6 g (100% of theoretical yield) of off-white magnesium di-L-theanate (Lot BLS-DN-13) was thus obtained. The 1H-NMR spectrum of magnesium di-L-theanate (FIG. 4) confirms that the salt was successfully prepared. A sample was submitted for magnesium analysis. The result confirmed that 5.80% by weight magnesium was present vs. a theoretical value of 5.97% by weight. This result indicates a purity of 97%. The product exhibited an optical rotation of 4°.
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