• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    FORMATION OF BIS-3,6- [4-AMINOalkyl] -2,5-DICETOPIPERAZINE N-PROTECTED The disclosed embodiments detail improved methods for the synthesis of diketopiperazines from amino acids. In particular, improved methods for cyclocondensation and purification of N-protected 3,6- [aminoalkyl] -2,5-diketopiperazine from N-protected amino acids. The disclosed embodiments describe methods for the synthesis of 3,6-bis- [N-protected aminoalkyl] -2,5-diketopiperazine, comprising heating an amino acid mixture of a catalyst in an organic solvent. The catalyst being selected from the group consisting of: sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 1-propylphosphonic acid cyclic anhydride, tributyl phosphate, phenyl phosphonic acid, phosphorus pentoxide, among others. The solvent being selected from the group consisting of: dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, ethylglyme, proglimate, ethildiglyme, m-cresol, pcresol, o-cresol, xylenes, ethylene glycol, phenol, among others.
    公开号:BR112013020514B1
    申请号:R112013020514-8
    申请日:2012-02-07
    公开日:2020-12-08
    发明作者:John J. Freeman；Adrienne Stamper；Melissa Heitmann
    申请人:Mannkind Corporation；
    IPC主号:
    专利说明:

    Field of invention
    [001] The present invention relates to compositions for the delivery of active agents, and particularly biologically active agents. Described embodiments are within the scope of chemical synthesis and more particularly are related to improved synthetic methods for the preparation and purification of 3,6-di-substituted-2,5-diketopiperazines. Fundamentals of the Invention
    [002] Drug delivery is a persistent problem in administering active agents to patients. Conventional means for administering active agents are often severely limited by biological, chemical and physical barriers. Typically, these barriers are imposed by the environment through which delivery takes place, the target's environment for supply, or by the target itself.
    [003] Biologically active agents are particularly vulnerable to these barriers. For example, when delivering pharmacological and therapeutic agents to humans, barriers are imposed by the body. Examples of physical barriers are the skin and various membranes in the body that must be crossed before reaching a target. Chemical barriers include, but are not limited to, pH variations, lipid bilayers, and degradation enzymes.
    [004] These barriers are of particular importance in the design of oral delivery systems. Oral delivery of many of the biologically active agents would be the route of choice for administration to animals if not for biological, physical and chemical barriers, such as pH variation in the gastrointestinal (GI) tract, powerful digestive enzymes, and gastrointestinal membranes impermeable to the agents gastrointestinal. Within the numerous agents that are not typically susceptible to oral administration are biologically active peptides, such as calcitonin and insulin; polysaccharides, and in particular mucopolysaccharides including, but not limited to heparin; heparinoids, antibiotics, and other organic substances. These agents are quickly neutralized or destroyed in the gastrointestinal tract by means of acid hydrolysis, enzymes or the like.
    [005] However, the use of broad-spectrum drug delivery systems is often prevented because: (1) the systems require toxic amounts of adjuvants or inhibitors, (2) suitable active low molecular weight agents are not available, (3) the systems exhibit poor stability and inadequate shelf life, (4) the systems are difficult to manufacture, (5) the systems fail to protect the active agent, (6) the systems adversely alter the active agent, or (7 ) the systems fail to allow or promote the absorption of the active agent.
    [006] There is still a need in the art for simple, low-cost delivery systems that are easily prepared and that can offer a wide range of active agents. One class of delivery system that has shown promise as excipients is diketopiperazines (DKP). In particular, 3,6-bis-substituted-2,5-diketopiperazines have been shown to be effective for delivering biologically active agents through the lung mucosa.
    [007] The conventional synthesis of diketopiperazines proceeds through a cyclocondensation of two molecules of amino acids or a dipeptide. An exemplary process for the synthesis of diketopiperazines involves heating an amino acid (Cbz-L-lysine, for example) in m-cresol, for between 17 and 22 hours at 160-170 ° C and the recrystallization of diketopiperazine from acid acetic with a yield of about 48%.
    [008] U.S. Patent No. 7,709,639 to Stevenson et. al. details methods for the synthesis of bis-Cbz-N-protected diketopiperazines, the disclosure of which is hereby incorporated by reference in its entirety as if it had been fully mentioned here.
    [009] Others have generated dipeptide diketopiperazines isolated by heating in a suitable solvent, while water is removed by distillation. Although these provide the desired diketopiperazines, the methods provide sub-optimal yields and may require prolonged purification. Thus, there is a need for an improved method for the synthesis of disubstituted 2,5-diketopiperazines that provide N-protected diketopiperazine in good yield while preserving protective groups and requiring minimal purification. Summary of the Invention
    [0010] These and other unmet needs of the prior art are met by the compounds and methods, as described in more detail below. The use of N-substituted 3,6-aminoalkyl-2,5-diketopiperazines as pharmaceutical excipients has shown considerable promise. As indicated above, these compounds are often synthesized through cyclocondensation of amino acids. If the amino acid has a free nitrogen atom in its side chain (such as, for example, lysine or ornithine), it is often necessary to have this nitrogen blocked before the cyclization reaction. Due to the potential for different synthesis processes after cyclization, compatibility with a variety of protecting groups is desired. Thus, a method of synthesis, which can accommodate a number of different N-protecting groups and produce a good yield of N-protected diketopiperazine is desired.
    [0011] Some useful protecting groups include trifluoroactyl, acetyl and other amide-forming protecting groups; carbamate protecting groups including benzyloxycarbonyl (Cbz) and t-butoxycarbonyl (BOC).
    [0012] In one embodiment, 3,6- (N-trifluoroacetyl) -aminobutyl-2,5-diketopiperazine is formed by heating ε-trifluoroacetyl-L-lysine in a water-miscible solvent such as N-methyl-2-pyrrolidone (NMP) in the presence of a catalyst chosen from the group comprising phosphoric acid, sulfuric acid and phosphorus pentoxide at a temperature of about 150-175 ° C. Diketopiperazine is isolated by rapid cooling with water and filtration of the resulting solid.
    Formula I
    [0013] The disclosed modalities describe methods for the synthesis of 3,6-bis- [N-protected aminoalkyl] -2,5-diketopiperazine which comprises heating a mixture of an amino acid of general formula I, in the presence of a catalyst in an organic solvent, where the catalyst is selected from the group comprising sulfuric acid, phosphoric acid, p-toluenesulfonic acid, cyclic 1-propylphosphonic acid, tributyl phosphate, phenyl phosphonic acid and phosphorus pentoxide, among others, and wherein the solvent is selected from the group comprising: dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, ethylglyme, proglimate, ethildiglyme, m-cresol, p-cresol, o-cresol, xylene, ethylene glycol and phenol, among others.
    [0014] The described modalities also describe methods in which n is between 1 to 7, where n is equal to 3, where n is equal to 2, where the GP is an amide-forming Protective Group, in which the protecting group is trifluoroacetyl, where the GP is a carbamate-forming protecting group, where the protecting group is Cbz, where the solvent is substantially miscible with water, where the solvent is N-methyl-2-pyrrolidone, where the amino acid is ε-trifluoroacetyl-L-lysine, where the amino acid group is ε-Cbz-L-lysine, where the amino acid is y-trifluoroacetyl-ornithine, where the amino acid is y-Cbz-ornithine, where the catalyst is phosphorus pentoxide, in which the concentration of phosphorus pentoxide is 10% to about 50% of that of the amino acid and, in embodiments further comprising the step of cooling the mixture with water.
    [0015] The disclosed modalities describe methods for the synthesis of 3,6-bis- [N-protected aminobutyl] -2,5-diketopiperazine comprising: heating a mixture of an N-protected lysine in the presence of a catalyst in an organic solvent , at a temperature between 110 ° and 175 ° C, for between 0.25 and 5 hours, in which the catalyst is selected from the group comprising sulfuric acid, phosphoric acid and phosphorus pentoxide, the catalyst concentration of from about 5% to about 50% of that of lysine, and the solvent is selected from the group comprising: dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, glyme acetate, proglimate, etildiglyme, m-cresol, p -cresol, o-cresol, xylenes, ethylene glycol and phenol.
    [0016] The disclosed modalities describe methods for the synthesis of 3,6-bis-4- (N-trifluoroacetyl) -aminobutyl-2,5-diketopiperazine comprising: heating a mixture of ε-trifluoroacetyl-L-lysine, in the presence phosphorus pentoxide in N-methyl-2-pyrrolidone, at a temperature of between 150 ° 1 and 75 ° C, for between 0.25 and 5 hours, the concentration of phosphorus pentoxide is about 10% to about 40% of that of lysine; and quenching the mixture with a second solvent, or alternatively, where the concentration of phosphorus pentoxide to lysine is between 20% and 35% and the mixture is cooled with water.
    [0017] Any combination of the elements described above in all its possible variations is covered by the revealed modalities unless otherwise indicated here or otherwise clearly contradicted by the context. Brief Description of Drawings
    [0018] A better understanding of the representative modalities of the invention will be appreciated when taken in conjunction with the attached drawings, in which the identical parts are identified with the same numerical references, and where:
    [0019] Figure 1 is a schematic showing the cyclocondensation of an N-protected amino acid in a diketopiperazine.
    [0020] Figure 2 is a schematic showing the cyclocondensation of ε trifluoroacetyl-lysine.
    [0021] Figure 3 is a schematic showing the cyclocondensation of y-Cbz-ornithine. Detailed Description of the Invention
    [0022] As used herein, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ter-butyl, pentyl, hexyl, heptyla or octyl and all binding isomers should be considered as one alkyl group. These can be mono- or polysubstituted with (alkoxy (C1-C8), haloalkyl (C1-C8), OH, halogen, NH2, NO2, SH, S-alkyl (C1-C8). Alkenyl (C2-C8), with with the exception of methyl, is understood to mean a (C1-C8) alkyl group, as illustrated above having at least one double bond.
    [0023] A side chain group of an a-amino acid is understood to mean the substitutable group on the a-C atom of glycine as the basic amino acid. Natural amino acids are given, for example, in Bayer-Walter, Lehrbuch der organischen Chemie, S. Hirzel Verlag, Stuttgart, 22 edition, 822ff page. Preferred synthetic amino acids and protected amino acids are available from Sigma-Aldrich Company. The side chain groups can be derived from those referred to therein.
    [0024] The chemical structures indicated concern all possible stereoisomers that can be obtained by varying the configuration of individual chiral centers, axes or surfaces, in other words, all possible diastereomers as well as all optical isomers (Enantiomers) that fall into that group.
    [0025] Returning to the drawings for a better understanding, Figure 1 shows a general scheme for the synthesis of a disubstituted diketopiperazine. This scheme shows an N-protected amino acid that undergoes a cyclocondensation with a second amino acid molecule. In this modality, GP represents a protective group for nitrogen and n can be from 0 to 7. It is evident from the scheme that is necessary when forming a diketopiperazine with an amine in a side chain that the nitrogen (s) it must be blocked before the cyclization reaction or the yields will be influenced by unwanted parallel condensations. Depending on the chemistry that will be performed after the ring is formed, a variety of protecting groups is desired, and so a method that accommodates many groups is preferred. Some useful protecting groups include trifluoracetyl, acetyl and other amide-forming protecting groups; carbamate protecting groups including benzyloxycarbonyl (Cbz) and t-butoxycarbonyl (BOC).
    [0026] Known methods of amino acid cyclocondensation to form DKP employed solvents such as n-butanol (water miscibility of about 7-8%), while solvents such as NMP are more miscible with water allowing for inactivation / washing simple with water to remove the reaction solvent and, if the catalyst has significantly solubility in water, the catalyst, all at once. In one embodiment, the catalyst for the amino acid cyclocondensation is soluble in water allowing for inactivation with water and subsequent removal by filtration.
    [0027] Figure 2 illustrates an embodiment in which the GP is trifluoroacetyl and n is equal to 3. Thus, the starting amino acid is ε-trifluoroacetyl lysine and the product is 3,6-bis-4- (N-trifluoroacetyl ) -aminobutyl-2,5-diketopiperazine. An example of a method for the synthesis of 3,6-bis-4- (N-trifluoroacetyl) -aminobutyl-2,5-diketopiperazine is shown below: Examples Examples 1 and 2

    [0028] In a 1L 3-neck round bottom flask equipped with a nitrogen purge, a distillation equipment, a mechanical stirrer and a thermocouple with a temperature indicator were added: NMP (256 mL), TFA-Lys ( 125 g, 0.52 mol) and P2O5 (22 g, 0.15 mol). The reaction mixture was heated to 160 ° C, and held there for 1.5 hours. The mixture was then cooled to 100 ° C, and poured into deionized water (DI). The mixture was then cooled to below 25 ° C and the solids were isolated by filtration, washed with DI water and vacuum dried at 50 ° C, to produce 3,6-bis-4- (N-trifluoroacetyl) -aminobutyl-2,5-diketopiperazine (65.28g, 56.4%). 1H-NMR (DMSO-d6): 1.3 (m, 4H), 1.5 (m, 4H), 1.7 (m, 4H), 3.2 (q, 4H), 3.8 (m , 2H), 8.1 (s, 2H), 9.4 (s, 2H). Elemental analysis: Calculated: C: 42.86, H: 4.95, N 12.50, F: 25.42. Found: C: 42.95, H: 4.91, N: 12.53; F: 24.99.
    [0029] To a glass-lined reactor with a capacity of 100 gallons was added N-methyl-2-pyrrilidone (200 L) and stirring was initiated. To the solvent, TFA-lysine (100 kg, 413 mol) was added at room temperature. To the resulting suspension, phosphorus pentoxide (15.2 kg, 107 mol) was added. The mixture was then heated to 160 ° C for 1 h. After 1 h at 160 ° C, the mixture was cooled to 100 ° C, and water (500 L) was added. The resulting mixture was cooled to 25 ° C, and held there for 90 minutes. The resulting solids were washed twice with water (265 L each) and isolated by filtration to give 3,6-bis-4- (N-trifluoroacetyl) -aminobutyl-2,5-diketopiperazine in 50% yield.
    [0030] A variety of catalysts have been analyzed for the formation of bis-substituted diketopiperazines. The results of the catalyst search are shown in Table 1. A general outline and example for such a search is presented below:

    [0031] Cbz-lysine (10.0 g), diethylene glycol dimethyl ether (diglyme, 50 ml), and a catalyst were loaded into a 250 ml round bottom flask. The mixture was heated to 160-165 ° C for 2.5 hours. The reaction mixture was poured into water and cooled to room temperature overnight. The precipitated solid was isolated by filtration, washed with water, and dried in vacuo at 50 ° C.

    [0032] Sulfuric acid and phosphorus pentoxide (at two concentrations) were further investigated for the synthesis of 3,6-bis-4- (N-trifluoroacetyl) -aminobutyl-2,5-diketopiperazine in diglyme. The results are shown in Table 2.

    [0033] TFA-lysine (10.0 g), diethylene glycol dimethyl ether (50 ml), and a catalyst were loaded into a 250 ml round bottom flask. The mixture was heated to 160-165 ° C for 2.5 hours. The reaction mixture was poured into water and cooled to room temperature. The precipitated solid was isolated by filtration, washed with water and dried in vacuo at 50 ° C.

    [0034] Sulfuric acid and phosphorus pentoxide (at two concentrations) were further investigated for the synthesis of 3,6-bis-4- (N-trifluoroacetyl) -aminobutyl-2,5-diketopiperazine in dimethylacetamide (DMAC). The results are shown in Table 3.

    [0035] TFA-lysine (25.0 g), dimethylacetamide (125 ml), and a catalyst were loaded into a 250 ml round bottom flask. The mixture was heated to 160165 ° C for 2.5 hours. The reaction mixture was cooled to 100 ° C, poured into water and then cooled to room temperature. The precipitated solid was isolated by filtration, washed with water and dried in vacuo at 50 ° C. The results are shown in Table 3.

    [0036] The use of phosphorus pentoxide was examined for the synthesis of 3,6-bis- 4- (N-trifluoroacetyl) -aminobutyl-2,5-diketopiperazine in N-methyl-2-pyrrolidone (NMP) at different times and temperatures. The results are shown in Table 4. Example 6

    [0037] TFA-lysine (50 g), N-methyl pyrrolidone (125 ml), and P2O5 (8.8 g, 0.3 eq.) Were loaded into a round bottom flask. The mixture was heated to a reaction temperature for a reaction time. The reaction mixture was cooled and poured into water and then cooled to room temperature. The precipitated solid was isolated by filtration, washed with water and dried in vacuo at 50 ° C. Table 4. Reaction Times and Temperatures for the Synthesis of TFA-Lysine Diketopiperazine


    [0038] TFA-lysine (10.0 g), m-cresol (22 ml), and P2O5 were loaded into a 250 ml round bottom flask. The mixture was heated at 160-165 ° C for 1 hour. The reaction mixture was cooled to 65 ° C, poured into an aqueous solution of 5% NaOH and methanol, and then cooled to room temperature. The precipitated solid was isolated by filtration, washed with water and dried in vacuo at 50 ° C. The product yield was 12%.

    [0039] TFA-lysine (50.0 g) and ethylene glycol (150 ml) were loaded into a 500 ml round bottom flask. The mixture was heated to 160-170 ° C for 2 hours. The reaction mixture was poured into water and cooled to room temperature. The precipitated solid was isolated by filtration, washed with water and dried in vacuo at 50 ° C. The product yield was 2%.

    [0040] Cbz-lysine (100.0 g) and ethylene glycol (300 ml) were loaded into a 1000 ml round bottom flask. The mixture was heated to 160-170 ° C for 6 hours. The reaction mixture was poured into a mixture of water and methanol and cooled to room temperature. The precipitated solid was isolated by filtration, washed with water and dried in vacuo at 50 ° C. The product yield was 64%.
    [0041] Figure 3 shows a general cyclocondensation scheme of y-Cbz-ornithine.

    [0042] CBZ-ornithine (100 g), N-methyl-pyrrolidone (194 ml), and P2O5 (8 g) were loaded into a 1000 ml round bottom flask. The mixture was heated to 160165 ° C for 2 hours. The reaction mixture was poured into water and cooled to room temperature. The precipitated solid was isolated by filtration, washed with methanol and water and dried in vacuo at 50 ° C. The product yield was 51%.
    [0043] Unless otherwise indicated, all numbers expressing amounts of ingredients, properties, such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all cases by the term "about". Therefore, unless otherwise indicated, the numerical parameters presented in the following description and in the appended claims are approximations that may vary depending on the desired properties sought to be obtained by the disclosed modalities. At a minimum, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be considered in the light of the number of significant digits reported by applying the usual rounding techniques. Despite the numerical intervals and parameters that establish the broad scope of the disclosed modalities being approximations, the numerical values presented in the specific examples are reported as the most accurate possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective test measurements.
    [0044] The terms "one" and "o" and similar references used in the context of the description of the revealed modalities (especially in the context of the claims presented below) are to be interpreted to cover both the singular and the plural, unless otherwise form indicated here or clearly denied by the context.
    [0045] The mention of the ranges of values here is merely intended to serve as an abbreviated method of individually referring to each value separately that falls within the range. Unless otherwise indicated here, each individual value is incorporated into the specification as if it were individually mentioned here. All of the methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all examples, or example language (for example, "such as") that is provided here are only to better illustrate the revealed modalities and do not impose any limitations on the scope of the revealed modalities, unless otherwise established way. No language in the specification should be interpreted as indicative of any unclaimed element essential to the practice of the revealed modalities or any of its variants.
    [0046] The groups of alternative elements or embodiments described here are not to be interpreted as limitations. Each member of the group can be referred and claimed individually or in any combination with the other members of the group or other elements found here. It is envisaged that one or more members of a group may be included or excluded, a group, for reasons of convenience and / or patentability. When such an insertion or deletion occurs, the specification is here considered to contain the group as modified thus meeting the described description of any and all Markush groups used in the attached claims.
    [0047] Preferred embodiments of the present invention are described herein, including the best way known to the inventors for carrying out the invention. Naturally, the variations of the revealed modalities will become evident by those usually versed in the technique when reading the presented description. The inventors expect that the one usually skilled in the art will employ such variations as appropriate, and the inventors intend that the invention be practiced in a manner other than that presented herein. Accordingly, this disclosure includes all modifications and equivalents relating to the subject mentioned in the attached claims, as permitted by applicable law. In addition, any combination of the elements described above in all possible variations of the same is covered by the disclosed modalities, unless otherwise indicated herein or clearly contradicted by the context.
    [0048] In addition, references are made to patents and printed publications in the course of this specification. Each of the references cited above and printed publications are individually incorporated herein by reference in their entirety.
    [0049] Having shown and described one embodiment of the invention, those usually skilled in the art will realize that many variations and modifications can be made to influence the described invention and still remain in the context of the invention as claimed. In addition, many of the elements mentioned above can be changed or replaced by different elements that will give the same result and fall within the spirit of the claimed invention. It is therefore intended to limit the invention only as indicated by the scope of the claims.
    权利要求:
    Claims (7)
    [0001]
    1. Method for the synthesis of 3,6-bis-4- (N-trifluoroacetyl) aminobutyl-2,5-diketopiperazine, CHARACTERIZED by the fact that it comprises: heating a mixture of ε-trifluoroacetyl-L-lysine, in the presence of phosphorus pentoxide in N-methyl-2-pyrrolidone, at a temperature between 150 ° C and 175 ° C for between 0.25 and 5 hours, the concentration of phosphorus pentoxide is 20% to 35% of that of lysine; and cool the mixture with water.
    [0002]
    2. Method according to claim 1, CHARACTERIZED by the fact that the mixture is heated to a temperature between 160 ° C and 170 ° C.
    [0003]
    3. Method, according to claim 1, CHARACTERIZED by the fact that the mixture is heated for between 1 and 2 hours.
    [0004]
    4. Method, according to claim 1, CHARACTERIZED by the fact that the mixture is cooled before cooling.
    [0005]
    5. Method, according to claim 1, CHARACTERIZED by the fact that the mixture is heated to a temperature between 160 ° C and 165 ° C.
    [0006]
    6. Method, according to claim 1, CHARACTERIZED by the fact that the mixture is heated for about 1.5 hours.
    [0007]
    7. Method, according to claim 1, CHARACTERIZED by the fact that the concentration of phosphorus pentoxide is about 20% to 30% of that of lysine.
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    法律状态:
    2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-10-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2019-11-19| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-04-14| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-09-08| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-12-08| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 07/02/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201161441525P| true| 2011-02-10|2011-02-10|
    US61/441,525|2011-02-10|
    PCT/US2012/024160|WO2012109256A2|2011-02-10|2012-02-07|Formation of n-protected bis-3,6- -2,5,diketopiperazine|
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