CN101851213A - Synthetic methods of 3,6-bis(4-bisfumaroyl aminobutyl)-2,5-diketopiperazine and salt substitute thereof - Google Patents
Synthetic methods of 3,6-bis(4-bisfumaroyl aminobutyl)-2,5-diketopiperazine and salt substitute thereof Download PDFInfo
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Abstract
The invention relates to two synthetic methods of 3,6-bis(4-bisfumaroyl aminobutyl)-2,5-diketopiperazine and a salt substitute thereof. The first synthetic method comprises the following steps of: obtaining a final product through the steps of cyclodehydration, hydrogenation, coupling, saponification, recrystallization and the like by using epsilon-benzoyloxycarbonyl-L-lysine and p-nitryl monoethyl fumarate as starting materials. The second synthetic method comprises the following steps of: obtaining the final product through the steps of cyclodehydration, coupling, saponification, recrystallization and the like by using N-6-trifluoroacetyl-L-lysine and the p-nitryl monoethyl fumarate (or p-nitryl monoethyl fumarate acyl chloride) as the starting materials. Meanwhile, the salt substitute of the 3,6-bis(4-bisfumaroyl aminobutyl)-2,5-diketopiperazine can also be generated by directly carrying out substitution reaction on the 3,6-bis(4-bisfumaroyl aminobutyl)-2,5-diketopiperazine as a reaction product and corresponding salt.
Description
Technical field
The present invention relates to the synthetic method of diketopiperazines organic compound and salt substituent thereof, especially relate to 3, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, the synthetic method of 5-diketopiperazine and salt substituent thereof.
Background technology
Effectively the medicine transmission is a technical barrier for a long time, and a lot of in actual applications multiple medicines thing effective ingredients had been taken off with regard to dividing before sending to the intravital appointed part of patient, can't reach the administering effect of expection.Effective ways that solve this difficult problem are to be chosen under certain pH value and the temperature to keep stable, can dissolve rapidly, be absorbed by the body under another specific pH value and temperature environment simultaneously and to send to the chemical substance that suits of appointed part fast, adopt special process to make to have suitable character the pharmaceutical carrier particle of (as granular size, shape, structural strength, solubleness etc. and hypotoxicity), the active drug composition is loaded on this pharmaceutical carrier particle, uses administering modes such as oral, injection or suction to realize that effective medicine transmits.3, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, 5-diketopiperazine and salt substituent thereof a kind of suitable chemical substance that comes to this.
The synthetic of diketopiperazines organic compound had very long history.Katchalski is to form with amino acid ester derivative dimer such as dipeptides ester dehydration condensation in the synthetic method of the diketopiperazines organic compound that nineteen forty-six proposes, and Kopple is to be formed by amino acid derivative heat dehydration in high boiling organic solvent in the synthetic method of the diketopiperazines organic compound that nineteen sixty-eight proposes.
But up to the present, also not about 3, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, the report of 5-diketopiperazine and salt substituent synthetic method thereof.Therefore inquire into the synthetic method of effective this material of a kind of success and salt substituent thereof, have very significant meaning for the effective transmission that realizes medicine.
Summary of the invention
3, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, the general molecular formula of 5-diketopiperazine and salt substituent thereof is:
When X is hydrogen, be 3 wherein, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, 5-diketopiperazine; When X is metal ion such as lithium, sodium, potassium etc. or ammonium radical ion, then be corresponding 3, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, 5-diketopiperazine salt substituent.
When X is hydrogen; 3, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, the molecular formula of 5-diketopiperazine is C20H28N4O8; molecular weight is 452.5; normal temperature is white powder down, fusing point: 280 ℃, and pKa value: 3.8-4.0; substantially water insoluble; be dissolved in weakly alkaline or basic solution, the pH value is that the solubleness under 8.0 is every ml soln 0.15 gram, and water-intake rate is 5% under room temperature, 50%RH.Molecular structure is:
Use special process; can be with 3; two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-; 5-diketopiperazine or its salt substituent are made the have suitable character pharmaceutical carrier particle of (as granular size, shape, structural strength, solubleness and hypotoxicity etc.); the active drug composition is loaded on this pharmaceutical carrier particle formed drug microparticles can be stablized under low pH value; under the physiological pH value, decompose, be suitable for administering modes such as oral, injection or suction and realize that effective medicine transmits.
This patent has been invented two kinds of different synthesis paths; be a parent material with ε-carbobenzoxy-(Cbz)-L-Methionin or N-6-trifluoroacetyl group-L-Methionin respectively; with be another parent material to nitro monomethyl ester (or monomethyl ester acyl chlorides); obtain final product 3 through steps such as dehydration condensation, hydrogenation, coupling, saponification, recrystallizations; two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, 5-diketopiperazine and salt substituent thereof.
Method one, be the synthetic method of parent material with ε-carbobenzoxy-(Cbz)-L-Methionin with to the nitro monomethyl ester:
As shown in Figure 1,3, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, a synthetic route of 5-diketopiperazine and salt substituent thereof be with ε-carbobenzoxy-(Cbz)-L-Methionin as starting raw material A, under the effect of catalyzer (as Vanadium Pentoxide in FLAKES), generate intermediate 3, two [4-(N-tertbutyloxycarbonyl) the ammonia butyl]-2 of 6-through dehydration condensation, the 5-diketopiperazine, generate intermediate 3 through hydrogenation again, two (the ammonia butyl)-2 of 6-, 5-diketopiperazine; The intermediate 3 that generates; two (the ammonia butyl)-2 of 6-; the 5-diketopiperazine generates intermediate (E) 3 to the nitro monomethyl ester through linked reaction with starting raw material B again; two [4-(N-ethoxycarbonyl-2-propenyl acyl) the ammonia butyl]-2 of 6-; the 5-diketopiperazine; generate thick 3 through saponification reaction; two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-; 5-diketopiperazine or its salt substituent; can obtain final product 3 through recrystallization again; two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, 5-diketopiperazine or its salt substituent.
Method two, be the synthetic method of parent material with N-6-trifluoroacetyl group-L-Methionin with to nitro monomethyl ester (or monomethyl ester acyl chlorides):
As shown in Figure 2,3, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, another synthetic route of 5-diketopiperazine and salt substituent thereof is as starting raw material H with N-6-trifluoroacetyl group-L-Methionin, under the effect of catalyzer (as Vanadium Pentoxide in FLAKES), generate intermediate 3 through dehydration condensation, two (trifluoroacetyl groups-1-ammonia butyl)-2 of 6-, the 5-diketopiperazine; The intermediate 3 that generates; two (trifluoroacetyl groups-1-ammonia butyl)-2 of 6-; the 5-diketopiperazine generates intermediate (E) 3 with starting raw material B (can be to nitro monomethyl ester or monomethyl ester acyl chlorides) through linked reaction again; two [4-(N-ethoxycarbonyl-2-propenyl acyl) the ammonia butyl]-2 of 6-; the 5-diketopiperazine; generate thick 3 through saponification reaction; two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-; 5-diketopiperazine or its salt substituent; can obtain final product 3 through recrystallization again; two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, 5-diketopiperazine or its salt substituent.
In addition; as shown in Figure 3; also can be with the product 3 of above-mentioned reaction, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, the 5-diketopiperazine directly carries out substitution reaction with corresponding salt; generate 3; two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, 5-diketopiperazine salt substituent crude product can obtain final product 3 through recrystallization again; two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, 5-diketopiperazine salt substituent.The recrystallization here is not necessary step, can omit in actual applications yet.
Description of drawings:
Fig. 1 is 3, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, the synthetic route one of 5-diketopiperazine and salt substituent thereof.
Fig. 2 is 3, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, the synthetic route two of 5-diketopiperazine and salt substituent thereof.
Fig. 3 is 3, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, the substitution reaction of 5-diketopiperazine salt.
Embodiment
Embodiment 1: an example of method 1;
Step 1, dehydration condensation reaction: in Erlenmeyer flask, add 30 gram ε-carbobenzoxy-(Cbz)-L-Methionins and 50 gram meta-cresols, and 5 the gram Vanadium Pentoxide in FLAKES, be heated to 200 ℃, in reaction process, moisture content is distilled away, then reactant is cooled off in the mixing solutions of water and sodium hydroxide (10: 1) and generate precipitation.Throw out is separated and, promptly obtained intermediate 3 after the filtration, two [4-(N-tertbutyloxycarbonyl) the ammonia butyl]-2 of 6-, crude product 20.6 grams of 5-diketopiperazine with behind 30 milliliters of alcohol flushings.The crude product that obtains is heated (100 ℃) in 100 milliliters of glacial acetic acid solutions, add 30 milliliters of pure water coolings afterwards again, after with 50 milliliters of glacial acetic acid solutions crystallisate being washed then, promptly obtain intermediate 3, two [4-(N-tertbutyloxycarbonyl) the ammonia butyl]-2 of 6-, smart product 11.2 grams of 5-diketopiperazine.Step 2, hydrogenation: with the intermediate 3 that obtains, two [4-(N-tertbutyloxycarbonyl) the ammonia butyl]-2 of 6-, smart product 11.2 grams of 5-diketopiperazine are dissolved in and add catalyzer (palladium+activated carbon) in 50 milliliters of glacial acetic acid solutions again, carry out hydrogenation in being full of the reactor of hydrogen.With the mixed solution cooled and filtered that obtains, to remove the catalyzer composition.Then the solution that leaches is distilled to remove the Glacial acetic acid composition, promptly obtain 3, two (the ammonia butyl)-2 of 6-, the aqueous solution of 5-diketopiperazine.Analytical results shows that the solid composition in the solution is about 6.3 grams.
Step 3, linked reaction: 2 gram yellow soda ash are dissolved in 50 ml waters, add obtain 3, two (the ammonia butyl)-2 of 6-, the aqueous solution of 5-diketopiperazine.10 grams are dissolved in 30 milliliters of acetone to the nitro monomethyl ester form solution.Above-mentioned two solution are slowly mixed, and reflux also stirs to carry out linked reaction.Add 100 ml waters after the reactant cooling, then the solid matter that obtains is separated, promptly obtain (E) 3, two [4-(N-ethoxycarbonyl-2-propenyl acyl) the ammonia butyl]-2 of 6-, solid crude product 5.8 grams of 5-diketopiperazine.The solid crude product that obtains is added 20 milliliters of Glacial acetic acid, add the cooling of 20 ml waters again.After with 10 milliliters of glacial acetic acid solutions crystallisate being washed afterwards, promptly obtain link coupled (E) 3, two [4-(N-ethoxycarbonyl-2-propenyl acyl) the ammonia butyl]-2 of 6-, smart product 3.8 grams of 5-diketopiperazine.
Step 4, saponification reaction: will go up (E) 3 that the step obtains, two [4-(N-ethoxycarbonyl-2-propenyl acyl) the ammonia butyl]-2 of 6-, the mixing solutions that the 5-diketopiperazine adds 20 ml methanol and sodium hydroxide is heated to 70 ℃, filters then.Add the Glacial acetic acid cool to room temperature afterwards.Solid matter is separated the back obtain 3 with after the 20 ml waters flushings, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, the crude product 2.5 of 5-diketopiperazine restrains.
Step 5; recrystallization: will go up the step obtain 3; two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, 5-diketopiperazine crude product add 10 milliliters of trifluoroacetic acid post-heating to 90 ℃, will filtering solution cooling back after will mixture filtering add further cooling again behind 10 milliliters of Glacial acetic acid.Solid matter is separated the back with 10 ml methanol flushings, use then behind 10 milliliters of purified rinse waters, promptly obtain 3 the solid matter drying, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, the smart product 1.8 of 5-diketopiperazine or its salt substituent restrains.
Embodiment 2: an example of method 2;
Step 1; dehydration condensation reaction: in Erlenmeyer flask, add 30 gram N-6-trifluoroacetyl group-L-Methionins, 30 grams two (2-methoxy ethyl ether) and 5 gram Vanadium Pentoxide in FLAKESs; mix to stir post-heating to 180 ℃; in reaction process, use the distillation means that moisture content is removed, then with reactant cool to room temperature and generation precipitation in the mixing solutions of water and sodium hydroxide (10: 1).Throw out is separated and, promptly obtained intermediate 3, two (trifluoroacetyl groups-1-ammonia butyl)-2 of 6-, crude product 18.5 grams of 5-diketopiperazine with behind 30 milliliters of alcohol flushings.The crude product that obtains is heated to 130 ℃ in 100 milliliters of glacial acetic acid solutions; add 20 milliliters of pure water coolings afterwards again; after with 60 milliliters of glacial acetic acid solutions crystallisate being washed then; use 60 milliliters of purified rinse waters again; promptly obtain intermediate 3; two (trifluoroacetyl groups-1-ammonia butyl)-2 of 6-, smart product 12.8 grams of 5-diketopiperazine.
Step 2, linked reaction: what will obtain obtains intermediate, and 4 gram yellow soda ash are dissolved in 100 ml waters, add obtain 3, two (trifluoroacetyl groups-1-ammonia butyl)-2 of 6-, the aqueous solution of 5-diketopiperazine.20 grams are dissolved in 50 milliliters of acetone to the nitro monomethyl ester form solution.Above-mentioned two solution are slowly mixed, and heating is also stirred to carry out linked reaction.After reactant added 100 ml waters coolings, then the solid matter that obtains is separated, with 50 milliliters of acetone rinsings after, promptly obtained (E) 3, two [4-(N-ethoxycarbonyl-2-propenyl acyl) the ammonia butyl]-2 of 6-, the solid crude product 7.3 of 5-diketopiperazine restrains.The solid crude product that obtains is added 20 milliliters of Glacial acetic acid and 15 ml waters, cool to room temperature then.After with 20 milliliters of glacial acetic acid solutions crystallisate being washed afterwards, promptly obtain link coupled (E) 3, two [4-(N-ethoxycarbonyl-2-propenyl acyl) the ammonia butyl]-2 of 6-, smart product 5.2 grams of 5-diketopiperazine.
Step 3, saponification reaction: will go up (E) 3 that obtain of step, two [4-(N-ethoxycarbonyl-2-propenyl acyl) the ammonia butyl]-2 of 6-, 5-diketopiperazine add the mixing solutions post-heating to 70 ℃ of 40 ml methanol and sodium hydroxide, filtration then.Add Glacial acetic acid afterwards, solid matter is separated the back with the flushing of 40 ml waters, obtain 3, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, crude product 3.7 grams of 5-diketopiperazine.
Step 4, recrystallization: will go up that the step obtains 3, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, 5-diketopiperazine crude product add 10 milliliters of trifluoroacetic acid post-heating to 90 ℃, after will mixture filtering filtering solution cooling back are added 20 milliliters of Glacial acetic acid.Solid matter is separated the back with 20 ml methanol flushings, use then behind 20 milliliters of purified rinse waters, promptly obtain 3 the solid matter drying, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, the smart product 2.2 of 5-diketopiperazine or its salt substituent restrains.
Claims (4)
1. organic compound 3, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, and the synthetic method of 5-diketopiperazine and salt substituent thereof is characterized in that: with ε-carbobenzoxy-(Cbz)-L-Methionin and to the nitro monomethyl ester is parent material, may further comprise the steps:
A, with ε-carbobenzoxy-(Cbz)-L-Methionin as starting raw material, under the effect of catalyzer, generate intermediate 3, two [4-(N-tertbutyloxycarbonyl) the ammonia butyl]-2 of 6-, 5-diketopiperazine through dehydration condensation;
B, intermediate 3, two [4-(N-tertbutyloxycarbonyl) the ammonia butyl]-2 of 6-, the 5-diketopiperazine generates intermediate 3 through hydrogenation again, two (the ammonia butyl)-2 of 6-, 5-diketopiperazine;
The intermediate 3 of C, generation, two (the ammonia butyl)-2 of 6-, the 5-diketopiperazine generates intermediate (E) 3 to the nitro monomethyl ester through linked reaction with starting raw material again, two [4-(N-ethoxycarbonyl-2-propenyl acyl) the ammonia butyl]-2 of 6-, 5-diketopiperazine;
D, intermediate (E) 3, two [4-(N-ethoxycarbonyl-2-propenyl acyl) the ammonia butyl]-2 of 6-, the 5-diketopiperazine generates thick 3 through saponification reaction, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, 5-diketopiperazine or its salt substituent;
E, described crude product obtain final product 3 through recrystallization again, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, 5-diketopiperazine or its salt substituent.
2. organic compound 3 as claimed in claim 1; two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-; the synthetic method of 5-diketopiperazine and salt substituent thereof; it is characterized in that: starting raw material ε-carbobenzoxy-(Cbz)-L-Methionin replaces with N-6-trifluoroacetyl group-L-Methionin, may further comprise the steps:
A, with N-6-trifluoroacetyl group-L-Methionin as starting raw material, under the effect of catalyzer, generate intermediate 3, two (trifluoroacetyl groups-1-ammonia butyl)-2 of 6-, 5-diketopiperazine through dehydration condensation;
The intermediate 3 of B, generation, two (trifluoroacetyl groups-1-ammonia butyl)-2 of 6-, the 5-diketopiperazine generates intermediate (E) 3 to the nitro monomethyl ester through linked reaction with starting raw material again, two [4-(N-ethoxycarbonyl-2-propenyl acyl) the ammonia butyl]-2 of 6-, 5-diketopiperazine;
C, intermediate (E) 3, two [4-(N-ethoxycarbonyl-2-propenyl acyl) the ammonia butyl]-2 of 6-, the 5-diketopiperazine generates thick 3 through saponification reaction, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, 5-diketopiperazine or its salt substituent;
D, described crude product can obtain final product 3 through recrystallization again, two (the two fumaroyl base ammonia butyl of 4-)-2 of 6-, 5-diketopiperazine or its salt substituent.
3. synthetic method as claimed in claim 1 or 2 is characterized in that: it is Vanadium Pentoxide in FLAKES that the dehydration condensation in the steps A reacts employed catalyzer.
4. synthetic method as claimed in claim 2 is characterized in that: parent material wherein replaces with the monomethyl ester acyl chlorides to the nitro monomethyl ester.
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