Synthesis and purification of substituted pyrazines

Abstract

The present disclosure provides a method for producing a substituted pyrazine. The present disclosure also provides a method for purifying a substituted pyrazine.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 385,098, filed November 28, 2022, the entire disclosure of which is incorporated herein by reference.

[0002] (Technical field) The field of the disclosure relates generally to the chemical synthesis and purification of substituted pyrazines.

[0003] More particularly, the present disclosure relates to novel chemical synthesis methods, including catalytic hydrogenation, for producing substituted pyrazines used in the production of high-value products such as imaging agents, and novel precipitation-based purification methods for purifying substituted pyrazines. [Background technology]

[0004] Methods for producing substituted pyrazines are known in the art. Problems with conventional methods include low yields and high impurities. For example, catalytic hydrogenation can cause over-reduction of the target compound. These low yields and impurities limit the use of catalytic hydrogenation to produce substituted pyrazines.

[0005] Therefore, there is a need for improved methods for the preparation and purification of substituted pyrazines that can provide increased yields. Summary of the Invention [Means for solving the problem]

[0006] In some embodiments of the present disclosure, there is provided a method for preparing a compound of formula II or a salt thereof, comprising: forming a mixture comprising a compound of formula I or a salt thereof, an organic solvent, a catalyst, and a hydrogenating agent; reacting the mixture.

[0007] [ka]

[0008] [ka]

[0009] In the above formula, PG, X 1 , X 2 , Y 1 , and Y 2 is as defined herein.

[0010] In some embodiments of the present disclosure, there is provided a method for purifying a compound of formula II or a salt thereof, comprising: precipitating a compound of formula II below or a salt thereof with a first solvent and a non-solvent; and optionally removing the first solvent from the compound of formula II or a salt thereof:

[0011] [ka]

[0012] In the above formula, PG, X 1 , X 2 , Y 1 , and Y 2 is as defined herein. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 is an exemplary flowchart of the method of the present disclosure. [Figure 2] FIG. 2 shows a first representative reaction according to the present disclosure. [Figure 3] FIG. 3 shows a second exemplary reaction according to the present disclosure. [Figure 4]4 shows high performance liquid chromatography (HPLC) chromatograms obtained after partial completion of a reaction according to the present disclosure, with the upper and lower chromatograms differing only in scale. [Figure 5] 5 shows high performance liquid chromatography (HPLC) chromatograms obtained after completion of a reaction according to the present disclosure, with the upper and lower chromatograms differing only in scale. [Figure 6] 6 shows high performance liquid chromatography (HPLC) chromatograms obtained at an absorption wavelength of 264 nm after completion of an aqueous reaction not in accordance with the present disclosure. The upper and lower chromatograms differ only in scale. [Figure 7] 7 shows high performance liquid chromatography (HPLC) chromatograms obtained at an absorbance wavelength of 215 nm after completion of an aqueous reaction not in accordance with the present disclosure. The upper and lower chromatograms differ only in scale. [Figure 8] FIG. 8 is an exemplary flowchart of the method of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0014] The present disclosure relates generally to improved methods for preparing compounds of formula II and / or salts thereof from compounds of formula I or salts thereof. Compounds of formula II and salts thereof are imaging compounds that can be used, for example, but not limited to, as fluorescent dyes for assessing renal function and imaging blood vessels, such as those of the eye.

[0015] It has been surprisingly discovered that catalytic hydrogenation of protected substituted pyrazines can be achieved using organic solvents. In certain embodiments, the use of ethyl acetate instead of water as a co-solvent with ethanol increased yields from 35-70% to over 90%.

[0016] 1 is an exemplary flowchart 110 of a method of the present disclosure. In this exemplary embodiment, flowchart 110 illustrates essential steps of an embodiment of a method of the present disclosure and is not intended to limit the embodiment of the method of the present disclosure. In step 112, a mixture is formed that includes a compound of Formula I or a salt thereof, an organic solvent, a catalyst, and a hydrogenation agent. In step 114, the mixture is reacted.

[0017] In one embodiment, the compound of formula II or a salt thereof is prepared according to the method shown in Figure 2. 1 , X 2 , Y 1 , and Y 2 is as defined herein. In Formula I, for ease of viewing, X 1 teeth 1 It is marked X.

[0018] This aspect involves forming a mixture comprising a compound of Formula I or a salt thereof, an organic solvent, a catalyst, and a hydrogenating agent, and then reacting the mixture.

[0019] In some embodiments, Y 1 and Y 2 are each independently selected from the group consisting of hydrogen, halogen, amine, nitroso, nitro, amide, ester, and carboxyl.

[0020] In some embodiments, X 1 and X 2are, independently of one another, one or more natural or unnatural α-amino acids, or polypeptide chains comprising one or more natural or unnatural α-amino acids linked to one another by peptide bonds. The polypeptide chains (AA) can be homopolypeptide chains or heteropolypeptide chains and can be of any suitable length. For example, in some embodiments, the polypeptide chains may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, In some embodiments, the α-amino acids of the polypeptide chain (AA) are selected from aspartic acid, asparagine, arginine, histidine, lysine, glutamic acid, glutamine, serine, and homoserine. In some embodiments, the α-amino acids of the polypeptide chain (AA) are selected from aspartic acid, glutamic acid, serine, and homoserine. In some embodiments, the polypeptide chain (AA) refers to a single amino acid (e.g., aspartic acid or serine). In some embodiments, the amino acid is D-serine.

[0021] In some embodiments, X 1 and X 2 are, independently of each other, N(R 1 )(R 2 )

[0022] In these embodiments, each R 1 are independent of each other, -(CH2) a (CH2CH2O) b (CH2) c NR 10 CONR 11 (CH2) d (CH2CH2O) e R 20 , -(CH2) a (CH2CH2O) b (CH2) c NR 12 CSNR 13 (CH2) d (CH2CH2O) e R 21 , -(CH2) a (CH2CH2O) b (CH2) c CONR 14 (CH2) d (CH2CH2O) e R 22 , -(CH2) a (CH2CH2O) b (CH2) c NR 15 SO2(CH2) d (CH2CH2O) e R 23 , -(CH2) a (CH2CH2O) b (CH2) c SO2NR 16 (CH2) d (CH2CH2O) e R 24 , -(CH2) a (CH2CH2O) b (CH2) c NR 17 CO(CH2) d (CH2CH2O) e R 25 , -(CH2) a (CH2CH2O) b(CH2) c NR 18 CO2(CH2) d (CH2CH2O) e R 26 、 -(CH2) a (CH2CH2O) b (CH2) c OC(O)NR 19 CO2(CH2) d (CH2CH2O) e R 27 、 -(CH2) c OR 68 、-CH2(CHOH) c R 69 、-CH2(CHOH) c CO2H,-(CHCO2H) c CO2H,-(CH2) c NR 70 R 71 、-CH[(CH2) f NH2] c CO2H、-CH[(CH2) f NH2] c CH2OH、-CH2(CHNH2) c CH2NR 72 R 73 、-(CH2CH2O) e R 74 ,-(CH2) t CO(CH2CH2O) e R 75 、 -(CH2) u (CH2CH2O) j (CH2) k NR 58 C(O)NR 59 (CH2) l (CH2CH2O) o R 76 、 -(CH2) u (CH2CH2O) j (CH2) k NR 60 C(S)NR 61 (CH2) l (CH2CH2O) o R 77 、 -(CH2) u (CH2CH2O) j (CH2) k C(O)NR 62 (CH2) l (CH2CH2O) o R 78 、 -(CH2) u (CH2CH2O) j (CH2) k S(O)2NR 63 (CH2) l (CH2CH2O) o R 79 、 -(CH2) u (CH2CH2O) j (CH2) k NR 64 S(O)2(CH2) l (CH2CH2O) o R 80 、 -(CH2) u (CH2CH2O) j (CH2) k NR 65 C(O)(CH2) l (CH2CH2O) o R 81 、 -(CH2) u (CH2CH2O) j (CH2) k NR 66 C(O)O(CH2) l (CH2CH2O) o R 82 、 -(CH2) u (CH2CH2O) j (CH2) k OC(O)NR 67 (CH2) l (CH2CH2O) o R 83 、 -(CH2) a SO3H-(CH2) a SO3 - -(CH2) a OSO3H-(CH2) a SO3- , -(CH2) a NHSO3H, -(CH2) a NHSO3 - , -(CH2) a PO3H2, -(CH2) a PO3H - , -(CH2) a PO3 2- , -(CH2) a OPO3H2, -(CH2) a OPO3H - , or -(CH2) a OPO 3 is.

[0023] R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 65 , R 66 , and R 67 are, independently of each other, —H or —CH 3 .

[0024] R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , and R 27 each of which, independently of the other, -H, -CH3, -(CH2) f NR 28 C(O)NR 29 (CH2) g (CH2CH2O) h R 38 , -(CH2) f NR 30 CSNR 31 (CH2) g (CH2CH2O) h R 39 , -(CH2) f C(O)NR 32 (CH2) g (CH2CH2O) h R 40 , -(CH2) f S(O)NR 33 (CH2) g (CH2CH2O) h R 41 , -(CH2) f NR 34 S(O)2(CH2) g (CH2CH2O) h R 42 , -(CH2) f NR 35 C(O)(CH2) g (CH2CH2O) h R 43 , -(CH2) f NR 36 C(O)O(CH2) g (CH2CH2O) h R 44 , -(CH2) f OC(O)NR 37 (CH2) g (CH2CH2O) h R 45 , -CO(AA) or -CONH(PS).

[0025] R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39, R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , and R 48 are, independently of each other, —H or —CH 3 .

[0026] R 68 , R 69 , R 70 , R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , R 79 , and R 80 each of which, independently of the other, -H, -CH3, -(CH2) p S(O)NR 84 (CH2) q (CH2CH2O) s R 81 , -(CH2) p NR 85 S(O)2(CH2) q (CH2CH2O) s R 83 , -(CH2) p NR 86 C(O)(CH2) q (CH2CH2O) s R 85 , -(CH2) p NR 86 C(O)O(CH2) q (CH2CH2O) s R 87 ,or, -(CH2) p OC(O)NR 88 (CH2) q (CH2CH2O) s R 89 is.

[0027] R 81 , R 82 , R 83 , R 84 , R 85 , R 86 , R 87 , R 88 , and R 89 are, independently of each other, —H or —CH 3 .

[0028] AA is as defined above.

[0029] Each (PS) is independently a sulfated or non-sulfated polysaccharide chain comprising one or more monosaccharide units linked together by glycosidic bonds. The polysaccharide chain (PS) can be of any suitable length. For example, in some embodiments, the polysaccharide chain can comprise 1-100 monosaccharide units, 1-90 monosaccharide units, 1-80 monosaccharide units, 1-70 monosaccharide units, 1-60 monosaccharide units, 1-50 monosaccharide units, 1-40 monosaccharide units, 1-30 monosaccharide units, 1-20 monosaccharide units, or 1-10 monosaccharide units. In some embodiments, the polysaccharide chain (PS) is a homopolysaccharide chain composed of either pentaose monosaccharide units or hexose monosaccharide units. In other embodiments, the polysaccharide chain (PS) is a heteropolysaccharide chain composed of one or both of pentaose monosaccharide units and hexose monosaccharide units. In some embodiments, the monosaccharide units of the polysaccharide chain (PS) are selected from glucose, fructose, mannose, xylose, or ribose. In some embodiments, the polysaccharide chain (PS) refers to a single monosaccharide unit (e.g., either glucose or fructose).

[0030] t and u are, independently of each other, 1, 2, 3, 4, or 5.

[0031] Each of a, d, g, l, and q, independently of one another, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0032] Each of c, f, k, and p is, independently of the others, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0033] b, j, e, h, o, and s each independently represent 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100.

[0034] PG is a protecting group. Generally, the protecting group can be any suitable protecting group known in the art. Suitable protecting groups include, but are not limited to, benzyl ("Bn"), t-butyl, pt-butylbenzyl, methyl, p-methoxybenzyl, p-sec-butyl, pi-propylbenzyl, pn-propylbenzyl, p-ethylbenzyl, or p-methylbenzyl.

[0035] In some embodiments, the protecting group protects a single amino acid. In some embodiments, the amino acid is aspartic acid, asparagine, arginine, histidine, lysine, glutamic acid, glutamine, serine, or homoserine. In some embodiments, the amino acid is aspartic acid or serine. In some embodiments, the amino acid is D-serine with a Bn protecting group.

[0036] Generally, reactants can be present in any suitable amount known in the art. In some embodiments, reactants are present in an amount of from about 0.001 g / mL to about 1 g / mL. In some embodiments, reactants are present in an amount of from about 0.0067 g / mL to about 0.04 g / mL.

[0037] Generally, the organic solvent can be any suitable organic solvent known in the art. In some embodiments, the organic solvent is selected from the group consisting of alcohol, methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, t-butanol, acetate, methyl acetate, ethyl acetate, acetic acid, n-propionic acid, n-butanoic acid, isobutyric acid, and any combination thereof.

[0038] In some embodiments, the mixture is substantially free of aqueous solvents. In some embodiments, the mixture is substantially free of water. In some embodiments, the mixture is free of water.

[0039] In some embodiments, the mixture further comprises an aqueous solvent, hi some embodiments, the mixture further comprises water.

[0040] In some embodiments, the solvent comprises an organic solvent and an aqueous solvent in a ratio of about 100:0 to about 50:50.In some embodiments, the solvent is 100% organic solvent.

[0041] Generally, the hydrogenation agent can be any suitable hydrogenation agent known in the art, hi some embodiments, the hydrogenation agent is selected from the group consisting of a hydrogen hydride source, hydrogen (H), formic acid, formate salts, isopropanol, dihydroanthracene, 1,4-cyclohexadiene, 1,3-cyclohexadiene, 1-methyl-1,4-cyclohexadiene, and any combination thereof.

[0042] Generally, the hydrogenation agent can be present in any suitable amount known in the art. In some embodiments, the hydrogenation agent is present in an amount from about 1 molar equivalent to an excess amount relative to hydrogen. In some embodiments, the hydrogenation agent is present in an amount from about 20 molar equivalents to about 30 molar equivalents relative to hydrogen.

[0043] Generally, the catalyst can be any suitable catalyst known in the art. In some embodiments, the catalyst is selected from hydrogenation catalysts, noble metal catalysts, palladium (Pd), platinum (Pt), gold (Au), rhodium (Rh), ruthenium (Ru), silver (Ag), osmium (Os), iridium (Ir), transition metal catalysts, nickel (Ni), Raney nickel, Urushibara nickel, iron (Fe), molybdenum (Mo), cobalt (Co), copper (Cu), chromium (Cr), catalysts supported on catalyst supports, catalysts supported on carbon, catalysts supported on alumina, catalysts supported on silica, Pd / C, Pt / C, Pd / C containing water in an amount ranging from about 1% to about 50%, Pd / C containing water in an amount of about 50%, and any combination thereof.

[0044] Generally, the catalyst can be present in any suitable amount known in the art. In some embodiments, the catalyst is present in an amount of about 1% to about 30% by weight. In some embodiments, the catalyst is present in an amount of about 5% to about 20% by weight.

[0045] Generally, the formation of the mixture can be carried out according to any suitable formation process known in the art. In some embodiments, the components of the mixture are added simultaneously to form the mixture. In some embodiments, the components of the mixture are added separately to form the mixture. In some embodiments, the components of the mixture are added separately in any suitable combination to form the mixture.

[0046] Generally, the reaction of the mixture is carried out under any suitable reaction temperature known in the art, hi some embodiments, the reaction of the mixture is carried out at a reaction temperature ranging from about -20°C to about 100°C.

[0047] Generally, the reaction of the mixture is carried out under any suitable reaction pressure known in the art. In some embodiments, the reaction of the mixture is carried out under atmospheric pressure. In some embodiments, the reaction of the mixture is carried out under elevated reaction pressure. In some embodiments, the reaction of the mixture is carried out under a reaction pressure ranging from about 6.89 kPaG to about 172.37 kPaG (about 1 PSIG to about 25 PSIG). In some embodiments, the reaction of the mixture is carried out under a reaction pressure greater than about 172.37 kPaG (about 25 PSIG). In some embodiments, the reaction of the mixture is carried out under a reaction pressure ranging from about 6.89 kPaG to about 344.75 kPaG (about 1 PSIG to about 50 PSIG).

[0048] Generally, the reaction of the mixture is carried out for any suitable reaction time known in the art, hi some embodiments, the reaction of the mixture is carried out for a reaction time ranging from about 1 hour to about 48 hours.

[0049] Generally, the reaction of the mixture is carried out in any suitable reactor known in the art, hi some embodiments, the reaction of the mixture is carried out in a reactor selected from a glass reactor, a glass-lined steel reactor, a stainless steel reactor, a glass-lined stainless steel reactor, a steel reactor with a disposable liner, a stainless steel reactor with a disposable liner, a steel reactor with a polymeric liner, a stainless steel reactor with a polymeric liner, a Hastelloy reactor, an atmospheric pressure reactor, a pressure reactor, and any combination thereof.

[0050] In general, the methods of the present disclosure can include any further suitable processing steps known in the art, hi some embodiments, the methods of the present disclosure further include a step selected from the group consisting of filtration, centrifugation, centrifugal filtration, separation, washing, drying, concentration, catalyst removal, purification, and any combination thereof.

[0051] In some embodiments, the method further comprises purifying the compound of formula II or a salt thereof with a first solvent and a non-solvent (anti-solvent), and optionally removing the first solvent from the compound of formula II or a salt thereof.

[0052] In some embodiments, the first solvent is selected from the group consisting of an organic solvent, dimethyl sulfoxide (DMSO), and combinations thereof. In some embodiments, the non-solvent is selected from the group consisting of acetate, ethyl acetate, isopropyl acetate, and any combination thereof.

[0053] The present disclosure also generally relates to a method for purifying a compound of Formula II or a salt thereof, in some embodiments, the method includes precipitating the compound of Formula II or a salt thereof with a first solvent and a non-solvent, and optionally removing the first solvent from the compound of Formula II or a salt thereof.

[0054] 8 is an exemplary flowchart 810 of a method of the present disclosure. In this exemplary embodiment, flowchart 810 illustrates essential steps of an embodiment of a method of the present disclosure and is not intended to limit the embodiment of the method of the present disclosure. In step 812, a compound of Formula II or a salt thereof is precipitated with a first solvent and a non-solvent. In step 814, optionally, the first solvent is removed from the compound of Formula II or a salt thereof.

[0055] In some embodiments, removing the first solvent from the compound of formula II or its salt comprises removing the first solvent from the compound of formula II or its salt using a solvent precipitation process, the solvent precipitation process comprising washing the compound of formula II or its salt with the first solvent and mixing the washed compound of formula II or its salt with a second solvent to precipitate the compound of formula II or its salt.

[0056] In some embodiments, the first solvent is selected from the group consisting of an organic solvent, dimethyl sulfoxide (DMSO), and combinations thereof. In some embodiments, the second solvent is selected from the group consisting of an aqueous solvent, water, and combinations thereof.

[0057] In some embodiments, the compound of Formula I or a salt thereof and the compound of Formula II or a salt thereof may each independently have a molecular weight of 20,000 or less. In such embodiments, the molecular weight is 15,000, 14,000, 13,000, 12,000, 11,000, 10,000, 9,000, 8,000, 7,000, 6,000, 5,000, 4,500, 4,000, 3,500, 3,000, 2,500, 2,000, 1,500, 1,000, 900, 800, 700, 600, 500, 400, or 300 or less. In other embodiments, the compound of Formula I or a salt thereof and the compound of Formula II or a salt thereof may each independently have a molecular weight greater than 20,000. In some embodiments, the molecular weight is preferably about 300 to about 1,000, or about 300 to about 750. In some embodiments, the compound of formula II or salt thereof has a molecular weight of about 300 to about 600, or about 300 to about 500.

[0058] In some embodiments, the reaction yield is at least 70%. In some embodiments, the reaction yield is at least 75%. In some embodiments, the reaction yield is at least 80%. In some embodiments, the reaction yield is at least 85%. In some embodiments, the reaction yield is at least 90%. In some embodiments, the reaction yield is at least 95%. In some embodiments, the reaction yield is at least 97%. In some embodiments, the reaction yield is at least 99%.

[0059] In some embodiments, the purity of the reaction product is at least 70%. In some embodiments, the purity of the reaction product is at least 75%. In some embodiments, the purity of the reaction product is at least 80%. In some embodiments, the purity of the reaction product is at least 85%. In some embodiments, the purity of the reaction product is at least 90%. In some embodiments, the purity of the reaction product is at least 95%. In some embodiments, the purity of the reaction product is at least 97%. In some embodiments, the purity of the reaction product is at least 99%.

[0060] In one embodiment, the compound of Formula II, (2R,2′R)-2,2′-((3,6-diaminopyrazine-2,5-dicarbonyl))bis(azanediyl)bis(3-hydroxypropanoic acid), is prepared according to the method depicted in FIG.

[0061] Embodiments of the present disclosure include the following embodiments 1 to 20.

[0062] Embodiment 1: A method for preparing a compound of formula II or a salt thereof, comprising: forming a mixture comprising a compound of formula I or a salt thereof, an organic solvent, a catalyst, and a hydrogenating agent; and reacting the mixture.

[0063] [ka]

[0064] [ka]

[0065] In the above formula, PG is a protecting group; Y 1 and Y 2are each independently selected from the group consisting of hydrogen, halogen, amine, nitroso, nitro, amide, ester, and carboxyl; X 1 and X 2 each of which, independently of the other, (i) one or more natural or unnatural α-amino acids, or a polypeptide chain comprising one or more natural or unnatural α-amino acids linked to each other by peptide bonds; and (ii) N(R 1 )(R 2 ), and In the above formula, Each R 1 are independent of each other, -(CH2) a (CH2CH2O) b (CH2) c NR 10 CONR 11 (CH2) d (CH2CH2O) e R 20 , -(CH2) a (CH2CH2O) b (CH2) c NR 12 CSNR 13 (CH2) d (CH2CH2O) e R 21 , -(CH2) a (CH2CH2O) b (CH2) c CONR 14 (CH2) d (CH2CH2O) e R 22 , -(CH2) a (CH2CH2O) b (CH2) c NR 15 SO2(CH2) d (CH2CH2O) e R 23 , -(CH2) a (CH2CH2O) b (CH2)c SO2NR 16 (CH2) d (CH2CH2O) e R 24 、 -(CH2) a (CH2CH2O) b (CH2) c NR 17 CO(CH2) d (CH2CH2O) e R 25 、 -(CH2) a (CH2CH2O) b (CH2) c NR 18 CO2(CH2) d (CH2CH2O) e R 26 、 -(CH2) a (CH2CH2O) b (CH2) c OC(O)NR 19 CO2(CH2) d (CH2CH2O) e R 27 、 -(CH2) c OR 68 、-CH2(CHOH) c R 69 、-CH2(CHOH) c CO2H,-(CHCO2H) c CO2H,-(CH2) c NR 70 R 71 、-CH[(CH2) f NH2] c CO2H、-CH[(CH2) f NH2] c CH2OH、-CH2(CHNH2) c CH2NR 72 R 73 、-(CH2CH2O) e R 74 ,-(CH2) t CO(CH2CH2O) e R 75 、 -(CH2) u (CH2CH2O)j (CH2) k NR 58 C(O)NR 59 (CH2) l (CH2CH2O) o R 76 、 -(CH2) u (CH2CH2O) j (CH2) k NR 60 C(S)NR 61 (CH2) l (CH2CH2O) o R 77 、 -(CH2) u (CH2CH2O) j (CH2) k C(O)NR 62 (CH2) l (CH2CH2O) o R 78 、 -(CH2) u (CH2CH2O) j (CH2) k S(O)2NR 63 (CH2) l (CH2CH2O) o R 79 、 -(CH2) u (CH2CH2O) j (CH2) k NR 64 S(O)2(CH2) l (CH2CH2O) o R 80 、 -(CH2) u (CH2CH2O) j (CH2) k NR 65 C(O)(CH2) l (CH2CH2O) o R 81 、 -(CH2) u (CH2CH2O) j (CH2) k NR 66 C(O)O(CH2) l (CH2CH2O) o R82 , -(CH2) u (CH2CH2O) j (CH2) k OC(O)NR 67 (CH2) l (CH2CH2O) o R 83 , -(CH2) a SO3H, -(CH2) a SO3 - , -(CH2) a OSO3H, -(CH2) a SO3 - , -(CH2) a NHSO3H, -(CH2) a NHSO3 - , -(CH2) a PO3H2, -(CH2) a PO3H - , -(CH2) a PO3 2- , -(CH2) a OPO3H2, -(CH2) a OPO3H - , or -(CH2) a OPO 3 and; R 2 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 65 , R 66 , and R 67 each independently of the other is -H or -CH; R 20 , R 21 , R 22 , R 23 , R24 , R 25 , R 26 , and R 27 each of which, independently of the other, -H, -CH3, -(CH2) f NR 28 C(O)NR 29 (CH2) g (CH2CH2O) h R 38 , -(CH2) f NR 30 CSNR 31 (CH2) g (CH2CH2O) h R 39 , -(CH2) f C(O)NR 32 (CH2) g (CH2CH2O) h R 40 , -(CH2) f S(O)NR 33 (CH2) g (CH2CH2O) h R 41 , -(CH2) f NR 34 S(O)2(CH2) g (CH2CH2O) h R 42 , -(CH2) f NR 35 C(O)(CH2) g (CH2CH2O) h R 43 , -(CH2) f NR 36 C(O)O(CH2) g (CH2CH2O) h R 44 , -(CH2) f OC(O)NR 37 (CH2) g (CH2CH2O) h R 45 , -CO(AA) or -CONH(PS); R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , and R 48 each independently of the other is -H or -CH; R 68 , R 69 , R 70 , R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , R 79 , and R 80 each of which, independently of the other, -H, -CH3, -(CH2) p S(O)NR 84 (CH2) q (CH2CH2O) s R 81 , -(CH2) p NR 85 S(O)2(CH2) q (CH2CH2O) s R 83 , -(CH2) p NR 86 C(O)(CH2) q (CH2CH2O) s R 85 , -(CH2) p NR 86C(O)O(CH2) q (CH2CH2O) s R 87 ,or, -(CH2) p OC(O)NR 88 (CH2) q (CH2CH2O) s R 89 and; R 81 , R 82 , R 83 , R 84 , R 85 , R 86 , R 87 , R 88 , and R 89 each independently of the other is -H or -CH; each (AA) is, independently of the other, one or more natural or unnatural α-amino acids or a polypeptide chain comprising one or more natural or unnatural α-amino acids linked to each other by peptide bonds; each (PS) is, independently of the other, a sulfated or non-sulfated polysaccharide chain comprising one or more monosaccharide units linked together by glycosidic bonds; t and u are, independently of each other, 1, 2, 3, 4, or 5; each of a, d, g, l, and q, independently of one another, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each of c, f, k, and p, independently of one another, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; b, j, e, h, o, and s each independently represent 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100.

[0066] Embodiment 2: 2. The method of embodiment 1, comprising: X 1 and X 2 each of which is D-serine, Y 1 and Y 2 each of which is an amine; PG is a benzyl protecting group; The compound of formula I above is dibenzyl 2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))(2R,2'R)-bis(3-hydroxypropanoate), represented by the following formula:

[0067] [ka]

[0068] Embodiment 3: 2. The method of embodiment 1, comprising: X 1 and X 2 each of which is D-serine, Y 1 and Y 2 each of which is an amine; The compound of formula II above is (2R,2'R)-2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3-hydroxypropanoic acid), which is represented by the following formula:

[0069] [ka]

[0070] Embodiment 4: 2. The method of embodiment 1, comprising: The method wherein the PG is selected from the group consisting of benzyl ("Bn"), t-butyl, pt-butylbenzyl, methyl, p-methoxybenzyl, p-sec-butyl, pi-propylbenzyl, pn-propylbenzyl, p-ethylbenzyl, and p-methylbenzyl.

[0071] Embodiment 5: 2. The method of embodiment 1, comprising: The method wherein the organic solvent is selected from the group consisting of alcohol, methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, t-butanol, acetate, methyl acetate, ethyl acetate, acetic acid, n-propionic acid, n-butanoic acid, isobutyric acid, and any combination thereof.

[0072] Embodiment 6: 2. The method of embodiment 1, comprising: wherein the hydrogenation agent is selected from the group consisting of a hydrogen hydride source, hydrogen (H), formic acid, formate salts, isopropanol, dihydroanthracene, 1,4-cyclohexadiene, 1,3-cyclohexadiene, 1-methyl-1,4-cyclohexadiene, and any combination thereof.

[0073] Embodiment 7: 2. The method of embodiment 1, comprising: The catalyst is selected from a hydrogenation catalyst, a noble metal catalyst, palladium (Pd), platinum (Pt), gold (Au), rhodium (Rh), ruthenium (Ru), silver (Ag), osmium (Os), iridium (Ir), a transition metal catalyst, nickel (Ni), Raney nickel, Urushibara nickel, iron (Fe), molybdenum (Mo), cobalt (Co), copper (Cu), chromium (Cr), a catalyst supported on a catalyst support, a catalyst supported on carbon, a catalyst supported on alumina, a catalyst supported on silica, Pd / C, Pt / C, Pd / C containing water in an amount ranging from about 1% to about 50%, Pd / C containing water in an amount of about 50%, and any combination thereof.

[0074] Embodiment 8: 2. The method of embodiment 1, comprising: The method wherein the step of reacting the mixture is carried out at a reaction temperature ranging from about -20°C to about 100°C.

[0075] Embodiment 9: 2. The method of embodiment 1, comprising: The method wherein the step of reacting the mixture is carried out at atmospheric pressure.

[0076] Embodiment 10: 2. The method of embodiment 1, comprising: The method wherein the step of reacting the mixture is carried out under high reaction pressure.

[0077] Embodiment 11: 2. The method of embodiment 1, comprising: The method wherein the step of reacting the mixture is carried out under a reaction pressure ranging from about 6.89 kPaG to about 344.75 kPaG (about 1 PSIG to about 50 PSIG).

[0078] Embodiment 12: 2. The method of embodiment 1, comprising: The method wherein the step of reacting the mixture is carried out for a reaction time ranging from about 1 hour to about 48 hours.

[0079] Embodiment 13: 2. The method of embodiment 1, comprising: The method, wherein the mixture is substantially free of aqueous solvent.

[0080] Embodiment 14: 2. The method of embodiment 1, comprising: The method, wherein the mixture further comprises an aqueous solvent.

[0081] Embodiment 15: 2. The method of embodiment 1, comprising: The method further comprising a step selected from the group consisting of filtration, centrifugation, centrifugal filtration, separation, washing, drying, concentration, catalyst removal, purification, and any combination thereof.

[0082] Embodiment 16: 2. The method of embodiment 1, comprising: purifying the compound of formula II or a salt thereof with a first solvent and a non-solvent; Optionally, the method further comprises the step of removing said first solvent from said compound of formula II or salt thereof.

[0083] Embodiment 17: 17. The method of embodiment 16, comprising: the first solvent is selected from the group consisting of an organic solvent, dimethyl sulfoxide (DMSO), and combinations thereof; The method wherein the non-solvent is selected from the group consisting of acetate, ethyl acetate, isopropyl acetate, and any combination thereof.

[0084] Embodiment 18: A method for purifying a compound of formula II or a salt thereof, comprising: precipitating a compound of formula II below or a salt thereof with a first solvent and a non-solvent; and optionally removing the first solvent from the compound of formula II or a salt thereof:

[0085] [ka]

[0086] In the above formula, Y 1 and Y 2 are each independently selected from the group consisting of hydrogen, halogen, amine, nitroso, nitro, amide, ester, and carboxyl; X 1 and X 2 each of which, independently of the other, (i) one or more natural or unnatural α-amino acids, or a polypeptide chain comprising one or more natural or unnatural α-amino acids linked to each other by peptide bonds; and (ii) N(R 1 )(R 2 ), and In the above formula, Each R 1 are independent of each other, -(CH2) a (CH2CH2O) b (CH2) c NR 10 CONR 11 (CH2) d (CH2CH2O) e R 20 , -(CH2) a (CH2CH2O) b (CH2) c NR 12 CSNR 13 (CH2) d (CH2CH2O) e R 21 , -(CH2) a (CH2CH2O) b (CH2) c CONR 14 (CH2) d (CH2CH2O) e R 22 , -(CH2) a (CH2CH2O) b (CH2)c NR 15 SO2(CH2) d (CH2CH2O) e R 23 、 -(CH2) a (CH2CH2O) b (CH2) c SO2NR 16 (CH2) d (CH2CH2O) e R 24 、 -(CH2) a (CH2CH2O) b (CH2) c NR 17 CO(CH2) d (CH2CH2O) e R 25 、 -(CH2) a (CH2CH2O) b (CH2) c NR 18 CO2(CH2) d (CH2CH2O) e R 26 、 -(CH2) a (CH2CH2O) b (CH2) c OC(O)NR 19 CO2(CH2) d (CH2CH2O) e R 27 、 -(CH2) c OR 68 、-CH2(CHOH) c R 69 、-CH2(CHOH) c CO2H,-(CHCO2H) c CO2H,-(CH2) c NR 70 R 71 、-CH[(CH2) f NH2] c CO2H、-CH[(CH2) f NH2] c CH2OH、-CH2(CHNH2) c CH2NR 72 R 73、-(CH2CH2O) e R 74 、-(CH2) t CO(CH2CH2O) e R 75 、 -(CH2) u (CH2CH2O) j (CH2) k NR 58 C(O)NR 59 (CH2) l (CH2CH2O) o R 76 、 -(CH2) u (CH2CH2O) j (CH2) k NR 60 C(S)NR 61 (CH2) l (CH2CH2O) o R 77 、 -(CH2) u (CH2CH2O) j (CH2) k C(O)NR 62 (CH2) l (CH2CH2O) o R 78 、 -(CH2) u (CH2CH2O) j (CH2) k S(O)2NR 63 (CH2) l (CH2CH2O) o R 79 、 -(CH2) u (CH2CH2O) j (CH2) k NR 64 S(O)2(CH2) l (CH2CH2O) o R 80 、 -(CH2) u (CH2CH2O) j (CH2) k NR 65 C(O)(CH2) l (CH2CH2O) o R81 、 -(CH2) u (CH2CH2O) j (CH2) k NR 66 C(O)O(CH2) l (CH2CH2O) o R 82 、 -(CH2) u (CH2CH2O) j (CH2) k OC(O)NR 67 (CH2) l (CH2CH2O) o R 83 、 -(CH2) a SO3H-(CH2) a SO3 - -(CH2) a OSO3H-(CH2) a SO3 - -(CH2) a NHSO3H-(CH2) a NHSO3 - -(CH2) a PO3H2,-(CH2) a PO3H - -(CH2) a PO3 2- -(CH2) a OPO3H2,-(CH2) a OPO3H - 、または、-(CH2) a OPO 3 であり; R 2 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 58 R 59 R 60 R 61 R 62 R 63 R 64 R65 , R 66 , and R 67 each independently of the other is -H or -CH; R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , and R 27 each of which, independently of the other, -H, -CH3, -(CH2) f NR 28 C(O)NR 29 (CH2) g (CH2CH2O) h R 38 , -(CH2) f NR 30 CSNR 31 (CH2) g (CH2CH2O) h R 39 , -(CH2) f C(O)NR 32 (CH2) g (CH2CH2O) h R 40 , -(CH2) f S(O)NR 33 (CH2) g (CH2CH2O) h R 41 , -(CH2) f NR 34 S(O)2(CH2) g (CH2CH2O) h R 42 , -(CH2) f NR 35 C(O)(CH2) g (CH2CH2O) h R 43 , -(CH2) f NR 36 C(O)O(CH2) g (CH2CH2O)h R 44 , -(CH2) f OC(O)NR 37 (CH2) g (CH2CH2O) h R 45 , -CO(AA) or -CONH(PS); R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , and R 48 each independently of the other is -H or -CH; R 68 , R 69 , R 70 , R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , R 79 , and R 80 each of which, independently of the other, -H, -CH3, -(CH2) p S(O)NR 84 (CH2) q (CH2CH2O) s R 81 , -(CH2) p NR 85 S(O)2(CH2) q (CH2CH2O) s R 83 , -(CH2) p NR 86 C(O)(CH2) q (CH2CH2O) s R 85 , -(CH2) p NR 86 C(O)O(CH2) q (CH2CH2O) s R 87 ,or, -(CH2) p OC(O)NR 88 (CH2) q (CH2CH2O) s R 89 and; R 81 , R 82 , R 83 , R 84 , R 85 , R 86 , R 87 , R 88 , and R 89 each independently of the other is -H or -CH; each (AA) is, independently of the other, one or more natural or unnatural α-amino acids or a polypeptide chain comprising one or more natural or unnatural α-amino acids linked to each other by peptide bonds; each (PS) is, independently of the other, a sulfated or non-sulfated polysaccharide chain comprising one or more monosaccharide units linked together by glycosidic bonds; t and u are, independently of each other, 1, 2, 3, 4, or 5; each of a, d, g, l, and q, independently of one another, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each of c, f, k, and p, independently of one another, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; b, j, e, h, o, and s each independently represent 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100.

[0087] Embodiment 19: 19. The method of embodiment 18, comprising: the step of removing the first solvent from the compound of formula II or salt thereof comprises removing the first solvent from the compound of formula II or salt thereof using a solvent precipitation process; The solvent precipitation process is washing the compound of formula II or a salt thereof with the first solvent; mixing the washed compound of formula II or a salt thereof with a second solvent to precipitate the compound of formula II or a salt thereof.

[0088] Embodiment 20: 20. The method of embodiment 19, comprising: The first solvent is selected from the group consisting of an organic solvent, dimethyl sulfoxide (DMSO), and combinations thereof. The method, wherein the second solvent is selected from the group consisting of an aqueous solvent, water, and combinations thereof.

[0089] Example

[0090] Without further elaboration, it is believed that one skilled in the art can utilize the present invention to its fullest extent based on the above description. Therefore, the following specific examples should be construed as merely illustrative, and not limiting to the remainder of the disclosure in any way. The starting materials in the following examples may not necessarily be prepared by the specific preparation method having the procedure described in other examples. Furthermore, numerical ranges described herein are understood to include all values ​​from the lower limit to the upper limit. For example, if a range is stated as 10 to 50, it is intended to include values ​​explicitly recited herein, such as 12 to 30, 20 to 40, or 30 to 0. These are merely specifically contemplated examples, and all combinations of numerical values, including the recited lower and upper limits, are considered to be expressly set forth in this application.

[0091] In the examples below, the following definitions are used:

[0092] MB-102: (2R,2´R)-2,2´-((3,6-diaminopyrazine-2,5-dicarbonyl))bis(azanediyl)bis(3-hydroxypropanoic acid)

[0093] MB-102int: Impurity of MB-102; Partially deprotected benzyl 2,2'-((3,-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))(2R,2'R)-bis(3-hydroxypropanoic acid)

[0094] MP-3269: Dibenzyl 2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))(2R,2'R)-bis(3-hydroxypropanoate)

[0095] Example 1: Catalytic hydrogenation

[0096] A pressure vessel was charged with 216 mL of ethyl acetate, 216 mL of ethanol, 9 g of MP-3269, and 1.8 g of 15 wt% Pd / C catalyst (Evonik). The vessel was pressurized with N2 to 15 PSIG (103.42 kPaG) while stirring (200 RPM), and then the pressure was released. This procedure was repeated three times. The vessel was then pressurized with H2 to 15 PSIG (103.42 kPaG) while stirring (200 RPM), and then the pressure was released. This procedure was repeated two times. The vessel was then again pressurized with H2 to 15 PSIG (103.42 kPaG) while stirring (200 RPM).

[0097] The catalytic hydrogenation reaction was carried out for 30 minutes in a pressure vessel with stirring, maintaining the pressure at 103.42-137.90 kPaG (15-20 PSIG) with H2. During the reaction, the pressure was continuously reduced over 3 hours, and the reaction temperature was increased from 16°C to 22°C. After 3 hours of reaction, the yield of MB-102 was 97%.

[0098] Figure 4 shows the HPLC chromatograms obtained after 3 hours of reaction. The upper and lower chromatograms differ only in scale. The chromatograms were obtained at an absorption wavelength of 264 nm. As shown, a single, intense peak for MB-102 was observed, indicating a highly pure product.

[0099] An additional 2 hours of reaction did not change the yield. Figure 5 shows the first set of HPLC chromatograms obtained after an additional 2 hours of reaction. The upper and lower chromatograms differ only in scale. The chromatograms were obtained at an absorption wavelength of 264 nm. As shown, a strong peak for MB-102 was still observed, indicating a highly pure product. Small amounts of unreacted reactant MP-3269 and impurity MB-102int were also observed. The unreacted reactant and impurities were observed only over a very narrow response scale.

[0100] The completed reaction product was filtered. Pd scavenger (SilaMetS) was added to the reaction mixture and stirred for at least 1 hour. The reaction was then filtered and allowed to stand overnight. After standing overnight, the reaction solution was concentrated to 75 mL and then stirred for 3 hours. The solid in the reaction mixture turned orange and then red. The solid was filtered and then washed twice with ethyl acetate. The solid was then dried in a vacuum oven at 55°C for 48 hours to obtain a red solid. The final yield of MB-102 was 5.59 g, a 92% yield.

[0101] Example 2: Catalytic hydrogenation

[0102] 125 g of MP-3269 and 25 g of 10% Pd / C Evonix Noblyst (50% wet) catalyst were placed in a pressure vessel. The pressure vessel was sealed and vacuumed to -5 PSIG (-34.47 kPaG). 3 L of ethyl acetate was added, followed by 3 L of ethanol. The pressure vessel was pressurized with N2 to 10 PSIG (68.95 kPaG), then released until 1 PSIG (6.89 kPaG) was reached, and the pressure vessel was placed under a nitrogen atmosphere. This procedure was repeated two more times.

[0103] Stirring was started. The pressure vessel was placed under a hydrogen atmosphere by pressurizing it with H2 to 68.95 kPaG (10 PSIG) and then releasing the pressure until it reached 6.89 kPaG (1 PSIG). This procedure was repeated once more. The pressure vessel was then pressurized with H2 to 137.90 kPaG (20 PSIG). The reaction was held under pressure and periodically replenished with H2 until the pressure stopped decreasing (approximately 10 hours for this 125 g scale). At this point, purity was assessed and found to be less than 1 wt% MP-3269 and MB-102int, respectively.

[0104] The H2 atmosphere was vented and the pressure vessel was switched to a nitrogen atmosphere. H2 pressure was used to push the slurry in the pressure vessel into a clean flask maintained under a N2 atmosphere. The slurry was filtered through Whatman No. 1 filter paper under a N2 atmosphere. 38.75 g of SiliaMetS thiourea Pd scavenger was added to the filtrate, and the slurry was stirred for a minimum of 1 hour and then filtered. The solution was concentrated and held for a minimum of 1 hour. The slurry was then filtered, and the solid was washed with ethyl acetate. The solid was dried in a vacuum oven (17 inches Hg, 55°C) to yield a red solid. The final yield of MB-102 was 76.7 g, a 91% yield. The purity was greater than 99% (99.2%).

[0105] Comparative Example 1: Comparative catalytic hydrogenation

[0106] The comparative reaction procedure followed that of Example 1, except that ethyl acetate was replaced with water. The yields were 35-70%.

[0107] Figure 6 shows the HPLC chromatograms obtained after the completion of the comparative aqueous reaction. The upper and lower chromatograms differ only in scale. The chromatograms were obtained at an absorption wavelength of 264 nm. As shown, in addition to the strong peak for MB-102, there was also a peak for MP-3269 visible on the same scale, indicating a relatively low purity product.

[0108] Figure 7 shows HPLC chromatograms obtained after the completion of the comparative aqueous reaction. The upper and lower chromatograms differ only in scale. The chromatograms were obtained at an absorption wavelength of 215 nm. As shown, at this wavelength, a strong peak for MB-102 was still observed, as was a peak for MP-3269 visible on the same scale. A peak was also observed at 11.171, corresponding to MB-102int. These chromatograms indicate a relatively low purity product.

[0109] This comparative example illustrates the shortcomings of aqueous reaction systems.

[0110] As demonstrated in this example, catalytic hydrogenation of protected substituted pyrazines in the presence of an organic solvent surprisingly achieved yields of over 90%, significantly higher than catalytic hydrogenation of protected substituted pyrazines in the presence of an aqueous solvent, an advantage gained from this discovery being particularly useful in the synthesis of substituted pyrazines.

[0111] Example 3: Purification

[0112] DMSO (3.56 kg) was placed in a round-bottom flask, followed by crude MB-102 (0.91 kg). DMSO (0.46 kg) was used to rinse the sides of the flask. The slurry was heated to 35-45°C until the solution was homogeneous. The homogeneous solution was held at 35-45°C for at least 30 minutes. IPAc (6.36 kg) was added at a rate that maintained the reaction solution temperature at 35-45°C. The slurry was held at 35-45°C for 1-2 hours and then slowly cooled to 15-25°C. The slurry was held at 15-25°C for a minimum of 8 hours. IPAc (3.19 kg) was added over at least 1 hour, maintaining the solution temperature at 15-25°C. The slurry was held at 15-25°C for at least 4 hours. The supernatant concentration was below 20 mg / mL, and the measured concentration was 13 mg / mL. The slurry was filtered and the solid was washed with IPAc (4.45 kg). The solid was dried under vacuum at 50 ± 5°C for a minimum of 18 hours, yielding 1.26 kg of a red solid. This sample was subjected to purity testing (AUC ≥ 98.0%), impurity testing (recorded ≥ 0.05%), and LoD testing (recorded 36.4%). DMSO (2.13 kg) was added to a clean container. MB-102 (1.26 kg) was added to this container. This container was washed with DMSO (0.40 kg). The slurry was heated to 35-45°C and held until homogeneous. The homogeneous solution was held at 35-45°C for at least 30 minutes. Water (11.49 kg) was added to a second clean container. The MB-102 / DMSO solution was added to this container over a period of at least 1 hour, maintaining the solution temperature between 15-25°C. The slurry was held at 15–25°C for at least 4 hours. The slurry was filtered and washed with water (2 × 3.62 kg). The solid was dried under vacuum at 50 ± 5°C for at least 4 hours to give 660 g (73% yield) of MB-102.

[0113] This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and practicing any methods incorporated therein. The patentable scope of the invention is defined by the claims, and may include alternative embodiments that occur to those skilled in the art. Such alternative embodiments are within the scope of the claims if they include elements that do not deviate from the literal language of the claims, or if they include equivalent elements that do not deviate substantially from the literal language of the claims.

[0114] As used herein, the terms "comprises," "comprising," "includes," "including," or "has," "having," "contains," "containing," "characterized by," and variations thereof, are intended to be non-exclusive inclusions unless expressly limited. For example, a composition, mixture, process, or method that includes listed components is not necessarily limited to only those components, but may include other components not expressly listed or that are inherent to such composition, mixture, process, or method.

[0115] The transitional phrase "consisting of" excludes any unspecified element, step, or ingredient. In a claim, such language excludes the inclusion of materials other than those recited, except for impurities ordinarily associated therewith. When the language "consisting of" appears in a passage in the body of a claim, it limits only the elements recited in that passage, rather than immediately following the preamble, and does not exclude other elements from the claim as a whole.

[0116] The transitional phrase "consisting essentially of" is used to define a composition or method that includes materials, steps, features, components, or elements in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristics of the claimed invention. The phrase "consisting essentially of" occupies a middle ground between "comprising" and "consisting of."

[0117] It should be readily understood that where an invention or part thereof is defined in open-ended terms such as "comprising," the description should (unless otherwise stated) be construed as describing the invention using the terms "consisting essentially of" or "consisting of."

[0118] Furthermore, unless expressly stated otherwise, the term "or" means an inclusive "or," not an exclusive "or." For example, condition A "or" B satisfies any one of the following: if A is true (or exists) and B is false (or does not exist), if A is false (or does not exist) and B is true (or exists), and if both A and B are true (or exist).

[0119] Additionally, the indefinite articles "a" and "an" preceding an element or component of the present invention are intended to be open-ended regarding the number of events (steps, occurrences) of the corresponding element or component. Thus, "a" and "an" should be interpreted to mean "one" or "at least one," and the singular form of an element or component also includes the plural, unless the number is clearly intended to be singular.

[0120] As used herein, the term "about" means plus or minus 10% of the value to which the term refers.

[0121] As used herein, the term "salt thereof" refers to a suitable salt of the compound covered by this term. Suitable salts include, but are not limited to, alkali metal salts, sodium salts, potassium salts, lithium salts, cesium salts, alkali metal salts, calcium salts, magnesium salts, halogen salts, chloride salts, bromide salts, iodide salts, sulfate salts, disulfate salts, nitrate salts, phosphate salts, dihydroxyphosphate salts, hydroxyphosphate salts, carbonate salts, bicarbonate salts, mesylate salts, and any combination thereof. It should be understood that a particular compound of the present disclosure can exist as a pure compound, the compound itself, a salt thereof, and any combination thereof.

[0122] As used herein, the term "halogen" refers to, but is not limited to, fluorine, chlorine, bromine, and iodine.

[0123] As used herein, the term "amine" refers to, but is not limited to, a functional group containing a nitrogen atom having a lone pair of electrons. Amines include primary amines, secondary amines, and tertiary amines.

[0124] As used herein, the term "nitroso" refers to, but is not limited to, a functional group that includes a nitroso group (-N=O).

[0125] As used herein, the term "nitro" refers to a functional group including, but not limited to, a nitro group (-N(=O)-O-).

[0126] As used herein, the term "amide" refers to a functional group including, but not limited to, an amide group (-C(=O)-N-).

[0127] As used herein, the term "ester" refers to a functional group that includes, but is not limited to, an ester group (C(=O)-O-).

[0128] As used herein, the term "carboxyl" refers to a functional group that includes, but is not limited to, a carboxyl group (-C(=O)-O).

Claims

1. 1. A method for preparing a compound of formula II or a salt thereof, comprising: forming a mixture comprising a compound of Formula I or a salt thereof, an organic solvent, a catalyst, and a hydrogenating agent; and reacting the mixture. 【Chemistry 1】 【Chemistry 2】 In the above formula, PG is a protecting group; Y １ and Y ２ are each independently selected from the group consisting of hydrogen, halogen, amine, nitroso, nitro, amide, ester, and carboxyl; X １ and X ２ each of which, independently of the other, (i) one or more natural or unnatural α-amino acids, or a polypeptide chain comprising one or more natural or unnatural α-amino acids linked to each other by peptide bonds; and (ii) N(R １ ) (R ２ ), and is selected from the group consisting of In the above formula, Each R １ are independent of each other, -(CH ２ ) ａ (CH) ２ CH ２ O) ｂ (CH) ２ ) ｃ NR １０ CONR １１ (CH) ２ ) ｄ (CH) ２ CH ２ O) ｅ R ２０ 、 -(CH ２ ) ａ (CH) ２ CH ２ O) ｂ (CH) ２ ) ｃ NR １２ CSNR １３ (CH) ２ ) ｄ (CH) ２ CH ２ O) ｅ R ２１ 、 -(CH ２ ) ａ (CH) ２ CH ２ O) ｂ (CH) ２ ) ｃ CONR １４ (CH) ２ ) ｄ (CH) ２ CH ２ O) ｅ R ２２ 、 -(CH ２ ) ａ (CH ２ CH ２ O) ｂ (CH ２ ) ｃ NR １５ SO ２ (CH ２ ) ｄ (CH ２ CH ２ O) ｅ R ２３ 、 -(CH ２ ) ａ (CH ２ CH ２ O) ｂ (CH ２ ) ｃ SO ２ NR １６ (CH ２ ) ｄ (CH ２ CH ２ O) ｅ R ２４ 、 -(CH ２ ) ａ (CH) ２ CH ２ O) ｂ (CH) ２ ) ｃ NR １７ CO(CH) ２ ) ｄ (CH) ２ CH ２ O) ｅ R ２５ 、 -(CH ２ ) ａ (CH) ２ CH ２ O) ｂ (CH) ２ ) ｃ NR １８ CO ２ (CH) ２ ) ｄ (CH) ２ CH ２ O) ｅ R ２６ 、 -(CH ２ ) ａ (CH) ２ CH ２ O) ｂ (CH) ２ ) ｃ OC(O)NR １９ CO ２ (CH) ２ ) ｄ (CH) ２ CH ２ O) ｅ R ２７ 、 -(CH ２ ) ｃ OR ６８ 、-CH ２ (CHOH) ｃ R ６９ 、-CH ２ (CHOH) ｃ CO ２ H, - (CHCO) ２ H) ｃ CO ２ H, -(CH) ２ ) ｃ NR ７０ R ７１ 、-CH[(CH ２ ) ｆ NH ２ ] ｃ CO ２ H, -CH[(CH] ２ ) ｆ NH ２ ] ｃ CH ２ OH,-CH ２ (CHNH) ２ ) ｃ CH ２ NR ７２ R ７３ 、-(CH ２ CH ２ O) ｅ R ７４ 、-(CH ２ ) ｔ CO(CH) ２ CH ２ O) ｅ R ７５ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ NR ５８ C(O)NR ５９ (CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ７６ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ NR ６０ C(S)NR ６１ (CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ７７ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ C(O)NR ６２ (CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ７８ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ S(O) ２ NR ６３ (CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ７９ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ NR ６４ S(O) ２ (CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ８０ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ NR ６５ C(O)(CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ８１ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ NR ６６ C(O)O(CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ８２ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ OC(O)NR ６７ (CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ８３ 、 -(32) ２ ) ) ａ 39 ３ 2、-(32 ２ ) ) ａ 39 ３ － 、-(3) ２ ) ) ａ 939 ３ 2、-(32 ２ ) ) ａ 39 ３ － 、-(3) ２ ) ) ａ 8839 ３ 2、-(32 ２ ) ) ａ 8839 ３ － 、-(3) ２ ) ) ａ PO ３ 8 ２ 、-(3) ２ ) ) ａ PO ３ 8 － 、-(3) ２ ) ) ａ PO ３ ２－ 、-(3) ２ ) ) ａ 90O ３ 8 ２ 、-(3) ２ ) ) ａ 90O ３ 8 － 、または、-(32 ２ ) ) ａ 90O ３ であり; R ２ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ５８ , R ５９ , R ６０ , R ６１ , R ６２ , R ６３ , R ６４ , R ６５ , R ６６ , and R ６７ are each independently —H or —CH ３ and R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , and R ２７ each of which, independently of the other, -H, -CH ３ 、 -(CH ２ ) ｆ NR ２８ C(O)NR ２９ (CH ２ ) ｇ (CH ２ CH ２ O) ｈ R ３８ 、 -(CH ２ ) ｆ NR ３０ CSNR ３１ (CH) ２ ) ｇ (CH) ２ CH ２ O) ｈ R ３９ 、 -(CH ２ ) ｆ C(O)NR ３２ (CH ２ ) ｇ (CH ２ CH ２ O) ｈ R ４０ 、 -(CH ２ ) ｆ S(O) ２ NR ３３ (CH ２ ) ｇ (CH ２ CH ２ O) ｈ R ４１ 、 -(CH ２ ) ｆ NR ３４ S(O) ２ (CH ２ ) ｇ (CH ２ CH ２ O) ｈ R ４２ 、 -(CH ２ ) ｆ NR ３５ C(O)(CH ２ ) ｇ (CH ２ CH ２ O) ｈ R ４３ 、 -(CH ２ ) ｆ NR ３６ C(O)O(CH ２ ) ｇ (CH ２ CH ２ O) ｈ R ４４ 、 -(CH ２ ) ｆ OC(O)NR ３７ (CH ２ ) ｇ (CH ２ CH ２ O) ｈ R ４５ 、 -CO(AA) or -CONH(PS); R ２８ , R ２９ , R ３０ , R ３１ , R ３２ , R ３３ , R ３４ , R ３５ , R ３６ , R ３７ , R ３８ , R ３９ , R ４０ , R ４１ , R ４２ , R ４３ , R ４４ , R ４５ , R ４６ , R ４７ , and R ４８ are each independently —H or —CH ３ and R ６８ , R ６９ , R ７０ , R ７１ , R ７２ , R ７３ , R ７４ , R ７５ , R ７６ , R ７７ , R ７８ , R ７９ , and R ８０ each of which, independently of the other, -H, -CH ３ 、 -(CH ２ ) ｐ S(O) ２ NR ８４ (CH ２ ) ｑ (CH ２ CH ２ O) ｓ R ８１ 、 -(CH ２ ) ｐ NR ８５ S(O) ２ (CH ２ ) ｑ (CH ２ CH ２ O) ｓ R ８３ 、 -(CH ２ ) ｐ NR ８６ C(O)(CH ２ ) ｑ (CH ２ CH ２ O) ｓ R ８５ 、 - (CH ２ ) ｐ NR ８６ C(O)O(CH ２ ) ｑ (CH ２ CH ２ O) ｓ R ８７ ,or, - (CH ２ ) ｐ OC(O)NR ８８ (CH ２ ) ｑ (CH ２ CH ２ O) ｓ R ８９ and R ８１ , R ８２ , R ８３ , R ８４ , R ８５ , R ８６ , R ８７ , R ８８ , and R ８９ are each independently —H or —CH ３ and each (AA) is, independently of the other, one or more natural or unnatural α-amino acids or a polypeptide chain comprising one or more natural or unnatural α-amino acids linked together by peptide bonds; each (PS) is, independently of the other, a sulfated or non-sulfated polysaccharide chain comprising one or more monosaccharide units linked together by glycosidic bonds; t and u are, independently of each other, 1, 2, 3, 4, or 5; each of a, d, g, l, and q, independently of one another, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; c, f, k, and p are each, independently of one another, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; b, j, e, h, o, and s each independently represent 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100.

2. 10. The method of claim 1, X １ and X ２ each of which is D-serine; Y １ and Y ２ each of which is an amine; PG is a benzyl protecting group; The compound of formula I above is dibenzyl 2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))(2R,2'R)-bis(3-hydroxypropanoate), represented by the following formula: 【Transformation 3】

3. 10. The method of claim 1, X １ and X ２ each of which is D-serine; Y １ and Y ２ each of which is an amine; The compound of formula II is (2R,2'R)-2,2'-((3,6-diaminopyrazine-2,5-dicarbonyl)bis(azanediyl))bis(3-hydroxypropanoic acid), which is represented by the following formula: 【Chemistry 4】

4. 10. The method of claim 1, wherein said PG is selected from the group consisting of benzyl ("Bn"), t-butyl, p-t-butylbenzyl, methyl, p-methoxybenzyl, p-sec-butyl, p-i-propylbenzyl, p-n-propylbenzyl, p-ethylbenzyl, and p-methylbenzyl.

5. 10. The method of claim 1, wherein the organic solvent is selected from the group consisting of alcohol, methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, t-butanol, acetate, methyl acetate, ethyl acetate, acetic acid, n-propionic acid, n-butanoic acid, isobutyric acid, and any combination thereof.

6. 10. The method of claim 1, The hydrogenation agent is a hydrogen hydride source, hydrogen (H ２ ), formic acid, formate salts, isopropanol, dihydroanthracene, 1,4-cyclohexadiene, 1,3-cyclohexadiene, 1-methyl-1,4-cyclohexadiene, and any combination thereof.

7. 10. The method of claim 1, 10. The method of claim 1, wherein the catalyst is selected from a hydrogenation catalyst, a noble metal catalyst, palladium (Pd), platinum (Pt), gold (Au), rhodium (Rh), ruthenium (Ru), silver (Ag), osmium (Os), iridium (Ir), a transition metal catalyst, nickel (Ni), Raney nickel, Urushibara nickel, iron (Fe), molybdenum (Mo), cobalt (Co), copper (Cu), chromium (Cr), a catalyst supported on a catalyst support, a catalyst supported on carbon, a catalyst supported on alumina, a catalyst supported on silica, Pd / C, Pt / C, Pd / C containing water in an amount ranging from about 1% to about 50%, Pd / C containing water in an amount of about 50%, and any combination thereof.

8. 10. The method of claim 1, The method wherein the step of reacting the mixture is carried out at a reaction temperature ranging from about -20°C to about 100°C.

9. 10. The method of claim 1, The method wherein the step of reacting the mixture is carried out at atmospheric pressure.

10. 10. The method of claim 1, The method wherein said step of reacting said mixture is carried out under high reaction pressure.

11. 10. The method of claim 1, The method wherein the step of reacting the mixture is carried out under a reaction pressure ranging from about 6.89 kPaG to about 344.75 kPaG (about 1 PSIG to about 50 PSIG).

12. 10. The method of claim 1, The method wherein said step of reacting said mixture is carried out for a reaction time ranging from about 1 hour to about 48 hours.

13. 10. The method of claim 1, The method, wherein the mixture is substantially free of aqueous solvent.

14. 10. The method of claim 1, The method, wherein the mixture further comprises an aqueous solvent.

15. 10. The method of claim 1, The method further comprising a step selected from the group consisting of filtration, centrifugation, centrifugal filtration, separation, washing, drying, concentration, catalyst removal, purification, and any combination thereof.

16. 10. The method of claim 1, purifying the compound of formula II or a salt thereof with a first solvent and a non-solvent; Optionally, removing said first solvent from the compound of formula II or salt thereof.

17. 17. The method of claim 16, the first solvent is selected from the group consisting of an organic solvent, dimethyl sulfoxide (DMSO), and combinations thereof; The method, wherein the non-solvent is selected from the group consisting of acetate, ethyl acetate, isopropyl acetate, and any combination thereof.

18. A method for purifying a compound of formula II or a salt thereof, comprising: precipitating a compound of formula II below or a salt thereof with a first solvent and a non-solvent; and optionally removing said first solvent from a compound of formula II or a salt thereof: 【Transformation 5】 In the above formula, Y １ and Y ２ are each independently selected from the group consisting of hydrogen, halogen, amine, nitroso, nitro, amide, ester, and carboxyl; X １ and X ２ each of which, independently of the other, (i) one or more natural or unnatural α-amino acids, or a polypeptide chain comprising one or more natural or unnatural α-amino acids linked to each other by peptide bonds; and (ii) N(R １ ) (R ２ ), and is selected from the group consisting of In the above formula, Each R １ are independent of each other, -(CH ２ ) ａ (CH) ２ CH ２ O) ｂ (CH) ２ ) ｃ NR １０ CONR １１ (CH) ２ ) ｄ (CH) ２ CH ２ O) ｅ R ２０ 、 -(CH ２ ) ａ (CH) ２ CH ２ O) ｂ (CH) ２ ) ｃ NR １２ CSNR １３ (CH) ２ ) ｄ (CH) ２ CH ２ O) ｅ R ２１ 、 -(CH ２ ) ａ (CH) ２ CH ２ O) ｂ (CH) ２ ) ｃ CONR １４ (CH) ２ ) ｄ (CH) ２ CH ２ O) ｅ R ２２ 、 -(CH ２ ) ａ (CH ２ CH ２ O) ｂ (CH ２ ) ｃ NR １５ SO ２ (CH ２ ) ｄ (CH ２ CH ２ O) ｅ R ２３ 、 -(CH ２ ) ａ (CH ２ CH ２ O) ｂ (CH ２ ) ｃ SO ２ NR １６ (CH ２ ) ｄ (CH ２ CH ２ O) ｅ R ２４ 、 -(CH ２ ) ａ (CH) ２ CH ２ O) ｂ (CH) ２ ) ｃ NR １７ CO(CH) ２ ) ｄ (CH) ２ CH ２ O) ｅ R ２５ 、 -(CH ２ ) ａ (CH) ２ CH ２ O) ｂ (CH) ２ ) ｃ NR １８ CO ２ (CH) ２ ) ｄ (CH) ２ CH ２ O) ｅ R ２６ 、 -(CH ２ ) ａ (CH) ２ CH ２ O) ｂ (CH) ２ ) ｃ OC(O)NR １９ CO ２ (CH) ２ ) ｄ (CH) ２ CH ２ O) ｅ R ２７ 、 -(CH ２ ) ｃ OR ６８ 、-CH ２ (CHOH) ｃ R ６９ 、-CH ２ (CHOH) ｃ CO ２ H, - (CHCO) ２ H) ｃ CO ２ H, -(CH) ２ ) ｃ NR ７０ R ７１ 、-CH[(CH ２ ) ｆ NH ２ ] ｃ CO ２ H, -CH[(CH] ２ ) ｆ NH ２ ] ｃ CH ２ OH,-CH ２ (CHNH) ２ ) ｃ CH ２ NR ７２ R ７３ 、-(CH ２ CH ２ O) ｅ R ７４ 、-(CH ２ ) ｔ CO(CH) ２ CH ２ O) ｅ R ７５ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ NR ５８ C(O)NR ５９ (CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ７６ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ NR ６０ C(S)NR ６１ (CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ７７ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ C(O)NR ６２ (CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ７８ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ S(O) ２ NR ６３ (CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ７９ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ NR ６４ S(O) ２ (CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ８０ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ NR ６５ C(O)(CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ８１ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ NR ６６ C(O)O(CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ８２ 、 -(CH ２ ) ｕ (CH ２ CH ２ O) ｊ (CH ２ ) ｋ OC(O)NR ６７ (CH ２ ) ｌ (CH ２ CH ２ O) ｏ R ８３ 、 -(32) ２ ) ) ａ 39 ３ 2、-(32 ２ ) ) ａ 39 ３ － 、-(3) ２ ) ) ａ 939 ３ 2、-(32 ２ ) ) ａ 39 ３ － 、-(3) ２ ) ) ａ 8839 ３ 2、-(32 ２ ) ) ａ 8839 ３ － 、-(3) ２ ) ) ａ PO ３ 8 ２ 、-(3) ２ ) ) ａ PO ３ 8 － 、-(3) ２ ) ) ａ PO ３ ２－ 、-(3) ２ ) ) ａ 90O ３ 8 ２ 、-(3) ２ ) ) ａ 90O ３ 8 － 、または、-(32 ２ ) ) ａ 90O ３ であり; R ２ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ５８ , R ５９ , R ６０ , R ６１ , R ６２ , R ６３ , R ６４ , R ６５ , R ６６ , and R ６７ are each independently —H or —CH ３ and R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , and R ２７ each of which, independently of the other, -H, -CH ３ 、 -(CH ２ ) ｆ NR ２８ C(O)NR ２９ (CH ２ ) ｇ (CH ２ CH ２ O) ｈ R ３８ 、 -(CH ２ ) ｆ NR ３０ CSNR ３１ (CH) ２ ) ｇ (CH) ２ CH ２ O) ｈ R ３９ 、 -(CH ２ ) ｆ C(O)NR ３２ (CH ２ ) ｇ (CH ２ CH ２ O) ｈ R ４０ 、 -(CH ２ ) ｆ S(O) ２ NR ３３ (CH ２ ) ｇ (CH ２ CH ２ O) ｈ R ４１ 、 -(CH ２ ) ｆ NR ３４ S(O) ２ (CH ２ ) ｇ (CH ２ CH ２ O) ｈ R ４２ 、 -(CH ２ ) ｆ NR ３５ C(O)(CH ２ ) ｇ (CH ２ CH ２ O) ｈ R ４３ 、 -(CH ２ ) ｆ NR ３６ C(O)O(CH ２ ) ｇ (CH ２ CH ２ O) ｈ R ４４ 、 -(CH ２ ) ｆ OC(O)NR ３７ (CH ２ ) ｇ (CH ２ CH ２ O) ｈ R ４５ 、 -CO(AA) or -CONH(PS); R ２８ , R ２９ , R ３０ , R ３１ , R ３２ , R ３３ , R ３４ , R ３５ , R ３６ , R ３７ , R ３８ , R ３９ , R ４０ , R ４１ , R ４２ , R ４３ , R ４４ , R ４５ , R ４６ , R ４７ , and R ４８ are each independently —H or —CH ３ and R ６８ , R ６９ , R ７０ , R ７１ , R ７２ , R ７３ , R ７４ , R ７５ , R ７６ , R ７７ , R ７８ , R ７９ , and R ８０ each of which, independently of the other, -H, -CH ３ 、 -(CH ２ ) ｐ S(O) ２ NR ８４ (CH ２ ) ｑ (CH ２ CH ２ O) ｓ R ８１ 、 -(CH ２ ) ｐ NR ８５ S(O) ２ (CH ２ ) ｑ (CH ２ CH ２ O) ｓ R ８３ 、 -(CH ２ ) ｐ NR ８６ C(O)(CH ２ ) ｑ (CH ２ CH ２ O) ｓ R ８５ 、 - (CH ２ ) ｐ NR ８６ C(O)O(CH ２ ) ｑ (CH ２ CH ２ O) ｓ R ８７ ,or, - (CH ２ ) ｐ OC(O)NR ８８ (CH ２ ) ｑ (CH ２ CH ２ O) ｓ R ８９ and R ８１ , R ８２ , R ８３ , R ８４ , R ８５ , R ８６ , R ８７ , R ８８ , and R ８９ are each independently —H or —CH ３ and each (AA) is, independently of the other, one or more natural or unnatural α-amino acids or a polypeptide chain comprising one or more natural or unnatural α-amino acids linked together by peptide bonds; each (PS) is, independently of the other, a sulfated or non-sulfated polysaccharide chain comprising one or more monosaccharide units linked together by glycosidic bonds; t and u are, independently of each other, 1, 2, 3, 4, or 5; each of a, d, g, l, and q, independently of one another, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each of c, f, k, and p, independently of one another, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; b, j, e, h, o, and s each independently represent 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100.

19. 20. The method of claim 18, the step of removing the first solvent from the compound of Formula II or salt thereof comprises removing the first solvent from the compound of Formula II or salt thereof using a solvent precipitation process; The solvent precipitation process comprises: washing the compound of formula II or salt thereof with the first solvent; mixing the washed compound of formula II or a salt thereof with a second solvent to precipitate the compound of formula II or a salt thereof.

20. 20. The method of claim 19, the first solvent is selected from the group consisting of an organic solvent, dimethyl sulfoxide (DMSO), and combinations thereof; The method, wherein the second solvent is selected from the group consisting of an aqueous solvent, water, and combinations thereof.

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