CN114163354B - Preparation method of N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine - Google Patents
Preparation method of N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine Download PDFInfo
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Abstract
The invention discloses a preparation method of N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine, which takes asparagine as a raw material to prepare the N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine through condensation reaction and carbonylation reaction, and has the advantages of easily available raw materials, simple route, convenient operation, low cost and the like; meanwhile, the post-treatment method is simple and feasible, can ensure that the product has higher yield and purity, and is suitable for the industrial production of N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine.
Background
Desotamide B is a hexacyclic peptide (glycine-tryptophan-leucine-D-leucine-valine-asparagine) extracted from metabolic products of actinomycetes Streptomyces scopuliridis SCSIO ZJ in deep sea, has a wider antibacterial range, has a good inhibitory effect on methicillin-resistant staphylococcus epidermidis (MRSE), has low toxicity to cells of mammals, and has high value as an antibacterial drug development. Among them, asparagine (Asn) plays a key role in the antibacterial activity of Desotamide B.
N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine is not reported in the literature as an important intermediate for the synthesis of Desotamide B.
Patent CN10129970a discloses a method for synthesizing N-fluorenylmethoxycarbonyl-N-trityl-D-glutamine, wherein D-glutamic acid is used as a raw material, and is reacted with benzyloxycarbonyl chloride to obtain N-benzyloxycarbonyl-D-glutamic acid, and then selectively protecting α -carboxyl groups, and then converting the α -carboxyl groups into N-benzyloxycarbonyl-D-glutamine benzyl ester, and then performing trityl alcohol methylation, debenzyloxycarbonyl and benzyl group removal, and Fmoc group protection to obtain N-fluorenylmethoxycarbonyl-N-trityl-D-glutamine. The method has the advantages of complicated route, poor selectivity and comprehensive yield of about 20%, is not suitable for industrial preparation of key intermediates, and has no reference significance for development of the preparation method of the N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a preparation method of N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine.
The technical scheme for solving the technical problems is as follows:
the invention provides a preparation method of N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine, which is characterized by comprising the following steps:
(1) Taking asparagine as a raw material, and carrying out condensation reaction with triphenylmethanol under the participation of a dehydrating agent and a catalyst to obtain N- (trityl) -L-asparagine;
(2) Ethyl acetate/water is used as a reaction solvent, and N- (trityl) -L-asparagine reacts with a 9-fluorenylmethoxy carbonylation reagent to obtain N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine;
further, the molar ratio of the triphenylmethanol to the asparagine in the step (1) is 1.0-2.0:1, preferably 1.3-1.5:1; the triphenylmethanol is added in portions;
further, the dehydrating agent in the step (1) is acetic anhydride or propionic anhydride; the molar ratio of the dehydrating agent to the asparagine is 1.5-3.0:1, preferably 1.6-2.0:1;
further, the catalyst in the step (1) is concentrated sulfuric acid or methanesulfonic acid; the molar ratio of the catalyst to the asparagine is 1.0-1.5:1, preferably 1.1-1.3:1;
further, the reaction solvent in the step (1) is acetic acid or propionic acid; the mass ratio of the reaction solvent to the asparagine is 10-30:1, preferably 13-22:1;
further, the reaction temperature in the step (1) is 30-40 ℃, preferably 33-37 ℃; the reaction time is 4 to 7 hours, preferably 5 to 6 hours; after the reaction is finished, dropwise adding liquid caustic soda to adjust the pH to 6-7, cooling and carrying out centrifugal filtration to obtain a reaction product;
wherein, before the liquid alkali is added dropwise, the reaction liquid is added into water, and the temperature is controlled within 30 ℃ in the dropping process; the temperature is reduced to 10-20 ℃;
further, the step (1) further comprises the steps of dissolving the reaction product with ethyl acetate and/or water for a plurality of times, cooling and carrying out centrifugal filtration;
wherein, after adding ethyl acetate, the mixture needs to be heated and refluxed to 80 ℃; the temperature is reduced to 10-20 ℃;
further, the 9-fluorenylmethoxycarbonyl reagent in step (2) is preferably 9-fluorenylmethyl-N-succinimidyl carbonate; the molar ratio of the 9-fluorenylmethoxy carbonylation reagent to the N- (trityl) -L-asparagine is 1.0-1.5:1, preferably 1.0-1.05:1;
further, 9-fluorenylmethyl-N-succinimidyl carbonate in the step (2) is added in batches until the raw materials are completely reacted, and the pH=8 of the reaction system is controlled in the adding process;
further, the step (2) further comprises the following post-treatment steps:
s1: after the reaction is finished, adding water into the washed ester layer, cooling, stirring, adjusting the pH to 2-4, and separating out solids;
s2: stirring, washing and filtering the solid obtained in the step S1 for a plurality of times by using water until the pH value of the water phase is neutral, and collecting the solid;
s3: pulping and carrying out throwing filtration on the solid obtained in the step S2 by using ethyl acetate/petroleum ether until the product is qualified; the volume ratio of the ethyl acetate to the petroleum ether is 2:1.
The Chinese naming of the compound in the invention conflicts with the structural formula, and the structural formula is taken as the reference; except for obvious structural errors.
The invention has the beneficial effects that: the N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine is prepared by taking asparagine as a raw material through condensation reaction and carbonylation reaction, and has the advantages of easily available raw material, simple route, convenient operation, low cost and the like; meanwhile, the post-treatment method is simple and feasible, can ensure that the product has higher yield and purity, and is suitable for the industrial production of N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine.
Drawings
Fig. 1: hydrogen profile of N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine in example 1
Detailed Description
The invention is illustrated but not limited by the following examples. Simple alternatives and modifications of the invention will be apparent to those skilled in the art and are within the scope of the invention as defined by the appended claims.
Example 1:
28kg of glacial acetic acid and acetic anhydride (2.8 kg,27.45 mol) are added into a dry and clean reaction kettle, 1.76kg of concentrated sulfuric acid (within 30 ℃ C. And after about 1 hour of dripping) is added dropwise under stirring, and triphenylmethanol (5.5 kg,21.13 mol) is added in batches for 0.5 hour until the system is dissolved, and asparagine (1.4 kg,10.61 mol) is added. Heating to 35 ℃ by introducing hot water, reacting for 1.5h, dissolving the system, adding asparagine (0.6 kg,4.55 mol), continuing to react for 1.5h, dissolving the system, continuing to keep the temperature for 2h, sampling and controlling the temperature until the reaction is finished. Under the stirring condition, the reaction liquid is pressed into 24kg of water, the temperature is reduced to 10-20 ℃, the alkali is added dropwise (about 50kg, the specific dosage is based on the pH value), the pH value is regulated to be 6-7 (the temperature is controlled within 30 ℃ in the dropping process, the pH value is regulated, and the pH value is not obviously changed in 0.5h after stirring); cooling to 10-20 deg.c, throwing and filtering to collect solid. Adding the solid into 15kg of ethyl acetate, heating to reflux (about 80 ℃) and stirring for 2 hours, introducing water and cooling to normal temperature, then adding 15kg of water, stirring for 0.5 hour, cooling to 10-20 ℃, carrying out centrifugal filtration, and collecting the solid; repeated three times. And (3) sampling and analyzing, if the solid is not qualified, adding 15kg of ethyl acetate into the solid, heating to reflux (about 80 ℃) and stirring for 2 hours, introducing water and cooling to 10-20 ℃, carrying out throwing filtration, and collecting the solid to obtain about white solid with the purity of 5.37kg and the yield of 94.7 percent.
Adding 10kg of ethyl acetate and 5kg of water into a reaction kettle, adding 5.37kg of the intermediate under stirring, adding 2-3 kg of 10% sodium carbonate solution, and adjusting pH to about 8; cooling to 5-10 ℃, adding 9-fluorenylmethyl-N-succinimidyl carbonate (4.44 kg,13.16 mol) in batches, and controlling the pH to be about 8 after 3-4 h. Heating to room temperature, preserving heat for 4-5 h, sampling and analyzing, and supplementing 9-fluorenylmethyl-N-succinimidyl carbonate according to analysis results (0.49 kg and 1.45mol are added by two supplements) until the raw materials are basically reacted completely. Standing, and separating out a reaction liquid layer; adding 3 kg/time of saturated saline into the ester layer, stirring for 10min, standing, and separating; adding 20kg of water into the washed ester layer, cooling to 10 ℃, stirring, and adjusting pH to about 3 with 5mol/L hydrochloric acid to precipitate a solid; collecting solids; stirring and washing the solid with 10kg of water for 20min, carrying out the filtering, and repeating for 2-3 times until the pH value of the water phase is neutral; pulping the solid for 1h by using 10kg of ethyl acetate/petroleum ether (2:1), carrying out centrifugal filtration, and repeating for 1-2 times until the product is qualified. The target product of 7.93kg is obtained by blast drying at 60 ℃, the purity is 99.5%, and the yield is 92.7%.
Example 2:
28kg of glacial acetic acid and acetic anhydride (3.1 kg,30.39 mol) were added to the dry and clean reaction vessel, 1.76kg of concentrated sulfuric acid (within 30 ℃ C., after about 1 hour of dropping) was added dropwise under stirring, and after completion of addition of triphenylmethanol (5.9 kg,22.67 mol) for 0.5 hour, asparagine (1.4 kg,10.61 mol) was added until the system was dissolved. Heating to 35 ℃ by introducing hot water, reacting for 1.5h, dissolving the system, adding asparagine (0.6 kg,4.55 mol), continuing to react for 1.5h, dissolving the system, continuing to keep the temperature for 2h, sampling and controlling the temperature until the reaction is finished. Under the stirring condition, the reaction liquid is pressed into 24kg of water, the temperature is reduced to 10-20 ℃, the alkali is added dropwise (about 50kg, the specific dosage is based on the pH value), the pH value is regulated to be 6-7 (the temperature is controlled within 30 ℃ in the dropping process, the pH value is regulated, and the pH value is not obviously changed in 0.5h after stirring); cooling to 10-20 deg.c, throwing and filtering to collect solid. Adding the solid into 15kg of ethyl acetate, heating to reflux (about 80 ℃) and stirring for 2 hours, introducing water and cooling to normal temperature, then adding 15kg of water, stirring for 0.5 hour, cooling to 10-20 ℃, carrying out centrifugal filtration, and collecting the solid; repeated three times. And (3) sampling and analyzing, if the solid is not qualified, adding 15kg of ethyl acetate into the solid, heating to reflux (about 80 ℃) and stirring for 2 hours, introducing water and cooling to 10-20 ℃, carrying out throwing filtration, and collecting the solid to obtain about 5.35kg of off-white solid with the purity of 99.1% and the yield of 94.4%.
Adding 10kg of ethyl acetate and 5kg of water into a reaction kettle, adding 5.35kg of the intermediate under stirring, adding 2-3 kg of 10% sodium carbonate solution, and adjusting pH to about 8; cooling to 5-10 ℃, adding 9-fluorenylmethyl-N-succinimidyl carbonate (4.44 kg,13.16 mol) in batches, and controlling the pH to be about 8 after 3-4 h. Heating to room temperature, preserving heat for 4-5 h, sampling and analyzing, and supplementing 9-fluorenylmethyl-N-succinimidyl carbonate according to analysis results (0.56 kg and 1.66mol are added by two supplements) until the raw materials are basically reacted completely. Standing, and separating out a reaction liquid layer; adding 3 kg/time of saturated saline into the ester layer, stirring for 10min, standing, and separating; adding 20kg of water into the washed ester layer, cooling to 10 ℃, stirring, and adjusting pH to about 3 with 5mol/L hydrochloric acid to precipitate a solid; collecting solids; stirring and washing the solid with 10kg of water for 20min, carrying out the filtering, and repeating for 2-3 times until the pH value of the water phase is neutral; pulping the solid for 1h by using 10kg of ethyl acetate/petroleum ether (2:1), carrying out centrifugal filtration, and repeating for 1-2 times until the product is qualified. The target product of 7.88kg is obtained after blast drying at 60 ℃, the purity is 99.2%, and the yield is 92.4%.
Example 3:
28kg of glacial acetic acid and acetic anhydride (1.86 kg,18.19 mol) are added into a dry and clean reaction kettle, 1.76kg of concentrated sulfuric acid (within 30 ℃ C. And after about 1 hour of dripping) is added dropwise under stirring, triphenylmethanol (5.5 kg,21.13 mol) is added in batches for 0.5 hour until the system is dissolved, and asparagine (1.4 kg,10.61 mol) is added. Heating to 35 ℃ by introducing hot water, reacting for 1.5h, dissolving the system, adding asparagine (0.6 kg,4.55 mol), continuing to react for 1.5h, dissolving the system, continuing to keep the temperature for 2h, sampling and controlling the temperature until the reaction is finished. Under the stirring condition, the reaction liquid is pressed into 24kg of water, the temperature is reduced to 10-20 ℃, the alkali is added dropwise (about 50kg, the specific dosage is based on the pH value), the pH value is regulated to be 6-7 (the temperature is controlled within 30 ℃ in the dropping process, the pH value is regulated, and the pH value is not obviously changed in 0.5h after stirring); cooling to 10-20 deg.c, throwing and filtering to collect solid. Adding the solid into 15kg of ethyl acetate, heating to reflux (about 80 ℃) and stirring for 2 hours, introducing water and cooling to normal temperature, then adding 15kg of water, stirring for 0.5 hour, cooling to 10-20 ℃, carrying out centrifugal filtration, and collecting the solid; repeated three times. And (3) sampling and analyzing, if the solid is not qualified, adding 15kg of ethyl acetate into the solid, heating to reflux (about 80 ℃) and stirring for 2 hours, introducing water and cooling to 10-20 ℃, carrying out throwing filtration, and collecting the solid to obtain about white solid with the purity of 4.82kg and the yield of 85 percent.
Adding 10kg of ethyl acetate and 5kg of water into a reaction kettle, adding 4.82kg of the intermediate under stirring, adding 2-3 kg of 10% sodium carbonate solution, and adjusting pH to about 8; cooling to 5-10 deg.c, adding 9-fluorenyl methyl-N-succinimidyl carbonate (4.56 kg,13.52 mol) once for 3-4 hr without regulating the pH value. Heating to room temperature, and preserving heat for 4-5 h. Standing, and separating out a reaction liquid layer; adding 3 kg/time of saturated saline into the ester layer, stirring for 10min, standing, and separating; adding 20kg of water into the washed ester layer, cooling to 10 ℃, stirring, and adjusting pH to about 3 with 5mol/L hydrochloric acid to precipitate a solid; collecting solids; stirring and washing the solid with 10kg of water for 20min, carrying out the filtering, and repeating for 2-3 times until the pH value of the water phase is neutral; pulping the solid for 1h by using 10kg of ethyl acetate/petroleum ether (2:1), carrying out centrifugal filtration, and repeating for 1-2 times until the product is qualified. The target product of 6.51kg is obtained by blast drying at 60 ℃, the purity is 98.8%, and the yield is 84.8%.
Example 4:
28kg of glacial acetic acid and acetic anhydride (2.8 kg,27.45 mol) are added into a dry and clean reaction kettle, 1.76kg of concentrated sulfuric acid (within 30 ℃ C. And after about 1 hour of dripping) is added dropwise under stirring, and triphenylmethanol (5.5 kg,21.13 mol) is added in batches for 0.5 hour until the system is dissolved, and asparagine (1.4 kg,10.61 mol) is added. Heating to 35 ℃ by introducing hot water, reacting for 1.5h, dissolving the system, adding asparagine (0.6 kg,4.55 mol), continuing to react for 1.5h, dissolving the system, continuing to keep the temperature for 2h, sampling and controlling the temperature until the reaction is finished. Under the stirring condition, the reaction liquid is pressed into 24kg of water, the temperature is reduced to 10-20 ℃, the alkali is added dropwise (about 50kg, the specific dosage is based on the pH value), the pH value is regulated to be 6-7 (the temperature is controlled within 30 ℃ in the dropping process, the pH value is regulated, and the pH value is not obviously changed in 0.5h after stirring); cooling to 10-20 deg.c, throwing and filtering to collect solid. The solid was added to 15kg of ethyl acetate, extracted with 15kg of water again, repeated three times, the ethyl acetate layer was collected, concentrated under reduced pressure, and the solid was collected to give about 4.67kg of an off-white solid with a purity of 97.9% and a yield of 82.4%.
Adding 10kg of ethyl acetate and 5kg of water into a reaction kettle, adding 4.67kg of the intermediate under stirring, adding 2-3 kg of 10% sodium carbonate solution, and adjusting pH to about 8; cooling to 5-10 ℃, adding 9-fluorenylmethyl-N-succinimidyl carbonate (4.02 kg,11.92 mol) in batches, and controlling the pH to be about 8 after 3-4 hours. Heating to room temperature, preserving heat for 4-5 h, sampling and analyzing, and supplementing 9-fluorenylmethyl-N-succinimidyl carbonate according to analysis results (0.19 kg and 0.56mol are added by two supplements) until the raw materials are basically reacted completely. Standing, and separating out a reaction liquid layer; adding 3 kg/time of saturated saline into the ester layer, stirring for 10min, standing, and separating; adding 20kg of water into the washed ester layer, cooling to 10 ℃, stirring, and adjusting pH to about 3 with 5mol/L hydrochloric acid to precipitate a solid; collecting solids; stirring and washing the solid with 10kg of water for 20min, carrying out the filtering, and repeating for 2-3 times until the pH value of the water phase is neutral; pulping the solid for 1h by using 10kg of ethyl acetate/petroleum ether (2:1), carrying out centrifugal filtration, and repeating for 1-2 times until the product is qualified. The target product of 6.91kg is obtained after blast drying at 60 ℃, the purity is 99.2%, and the yield is 92.9%.
Example 5:
28kg of glacial acetic acid and acetic anhydride (2.8 kg,27.45 mol) are added into a dry and clean reaction kettle, 1.76kg of concentrated sulfuric acid (within 30 ℃ C. And after about 1 hour of dripping) is added dropwise under stirring, and triphenylmethanol (5.5 kg,21.13 mol) is added in batches for 0.5 hour until the system is dissolved, and asparagine (1.4 kg,10.61 mol) is added. Heating to 35 ℃ by introducing hot water, reacting for 1.5h, dissolving the system, adding asparagine (0.6 kg,4.55 mol), continuing to react for 1.5h, dissolving the system, continuing to keep the temperature for 2h, sampling and controlling the temperature until the reaction is finished. Under the stirring condition, the reaction liquid is pressed into 24kg of water, the temperature is reduced to 10-20 ℃, the alkali is added dropwise (about 50kg, the specific dosage is based on the pH value), the pH value is regulated to be 6-7 (the temperature is controlled within 30 ℃ in the dropping process, the pH value is regulated, and the pH value is not obviously changed in 0.5h after stirring); cooling to 10-20 deg.c, throwing and filtering to collect solid. Adding the solid into 15kg of ethyl acetate, heating to reflux (about 80 ℃) and stirring for 2 hours, introducing water and cooling to normal temperature, then adding 15kg of water, stirring for 0.5 hour, cooling to 10-20 ℃, carrying out centrifugal filtration, and collecting the solid; repeated three times. And (3) sampling and analyzing, if the solid is not qualified, adding 15kg of ethyl acetate into the solid, heating to reflux (about 80 ℃) and stirring for 2 hours, introducing water and cooling to 10-20 ℃, carrying out throwing filtration, and collecting the solid to obtain about 5.38kg of off-white solid with the purity of 99.1% and the yield of 94.9%.
Adding 10kg of ethyl acetate and 5kg of water into a reaction kettle, adding 5.38kg of the intermediate under stirring, adding 2-3 kg of 10% sodium carbonate solution, and adjusting pH to about 8; cooling to 5-10 ℃, adding 9-fluorenylmethyl-N-succinimidyl carbonate (4.44 kg,13.16 mol) in batches, and controlling the pH to be about 8 after 3-4 h. Heating to room temperature, preserving heat for 4-5 h, sampling and analyzing, and supplementing 9-fluorenylmethyl-N-succinimidyl carbonate according to analysis results (0.50 kg and 1.45mol are added by two supplements) until the raw materials are basically reacted completely. Standing, and separating out a reaction liquid layer; adding 3 kg/time of saturated saline into the ester layer, stirring for 10min, standing, and separating; adding 20kg of water into the washed ester layer, cooling to 10 ℃, stirring, and adjusting pH to about 3 with 5mol/L hydrochloric acid to precipitate a solid; collecting solids; stirring and washing the solid with 10kg of water for 20min, carrying out the filtering, and repeating for 2-3 times until the pH value of the water phase is neutral; pulping the solid for 1h by using 10kg of ethyl acetate/petroleum ether (1:1), carrying out centrifugal filtration, and repeating for 1-2 times until the product is qualified. And 7.32kg of target product is obtained by blast drying at 60 ℃, the purity is 98.8%, and the yield is 85.5%.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and improvements could be made by those skilled in the art without departing from the inventive concept, which falls within the scope of the present invention.
Claims (6)
1. The preparation method of the N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine is characterized by comprising the following steps of:
(1) Taking asparagine as a raw material, and carrying out condensation reaction with triphenylmethanol under the participation of a dehydrating agent and a catalyst to obtain N- (trityl) -L-asparagine; in the step (1), the molar ratio of the triphenylmethanol to the asparagine is 1.3-1.5:1, and the triphenylmethanol is added in batches; the reaction solvent in the step (1) is acetic acid or propionic acid; the mass ratio of the reaction solvent to the asparagine is 13-22:1; the reaction temperature of the step (1) is 30-40 ℃; the reaction time is 4-7 h; after the reaction is finished, dropwise adding liquid caustic soda to adjust the pH to 6-7, cooling and carrying out centrifugal filtration to obtain a reaction product; the dehydrating agent in the step (1) is acetic anhydride; the catalyst in the step (1) is concentrated sulfuric acid;
(2) Ethyl acetate/water is used as a reaction solvent, and N- (trityl) -L-asparagine reacts with a 9-fluorenylmethoxy carbonylation reagent to obtain N-fluorenylmethoxycarbonyl-N-trityl-L-asparagine; the step (2) further comprises the following post-treatment steps:
s1: after the reaction is finished, adding water into the washed ester layer, cooling, stirring, adjusting the pH to 2-4, and separating out solids;
s2: stirring, washing and filtering the solid obtained in the step S1 for a plurality of times by using water until the pH value of the water phase is neutral, and collecting the solid;
s3: pulping and carrying out throwing filtration on the solid obtained in the step S2 by using ethyl acetate/petroleum ether until the product is qualified;
the 9-fluorenylmethoxy carbonylation reagent in the step (2) is 9-fluorenylmethyl-N-succinimidyl carbonate; in the step (2), the 9-fluorenylmethyl-N-succinimidyl carbonate is added in batches until the raw materials are completely reacted, and the pH=8 of the reaction system is controlled in the adding process.
2. The method of claim 1, wherein the molar ratio of dehydrating agent to asparagine is 1.5-3.0:1.
3. The method of claim 1, wherein the molar ratio of catalyst to asparagine is 1.0-1.5:1.
4. The method according to claim 1, wherein the step (1) further comprises the steps of dissolving the reaction product with ethyl acetate and/or water a plurality of times, cooling, and filtering.
5. The process according to claim 1, wherein the molar ratio of the 9-fluorenylmethoxycarbonyl reagent to the N- (trityl) -L-asparagine is from 1.0 to 1.5:1.
6. The method according to claim 1, wherein the volume ratio of ethyl acetate/petroleum ether is 2:1.
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| DE59002361D1 (en) * | 1989-04-17 | 1993-09-23 | Calbiochem Novabiochem Ag | PROTECTED AMINO ACIDS AND METHOD FOR THEIR PRODUCTION. |
| US5536815A (en) * | 1994-03-31 | 1996-07-16 | Research Corporation Technologies, Inc. | Cyclopropyl based O- and N- and S-protecting groups |
| US5952497A (en) * | 1996-07-10 | 1999-09-14 | University Of Georgia Research Foundation | N.sup.α -Bpoc amino acid pentafluorophenyl (Pfp) esters and 3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl (ODhbt) esters |
| AU2002950136A0 (en) * | 2002-07-11 | 2002-09-12 | La Trobe University | N-methyl amino acids |
| CN105566486B (en) * | 2015-12-31 | 2019-03-01 | 南京工业大学 | α -helical polypeptide with antitumor activity and preparation method thereof |
| US20190084900A1 (en) * | 2016-05-02 | 2019-03-21 | Retrotope, Inc. | Isotopically modified composition and therapeutic uses thereof |
| CN108912015A (en) * | 2018-06-19 | 2018-11-30 | 南京肽业生物科技有限公司 | A kind of Fmoc amino acid refining methd |
| CN110627686A (en) * | 2019-09-11 | 2019-12-31 | 上海吉奉生物科技有限公司 | Synthesis method of fluorenylmethyloxycarbonyl-O-trityl-L-threonine |
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