CN109485702A - The preparation method of icatibant acetate - Google Patents
The preparation method of icatibant acetate Download PDFInfo
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- CN109485702A CN109485702A CN201811653237.4A CN201811653237A CN109485702A CN 109485702 A CN109485702 A CN 109485702A CN 201811653237 A CN201811653237 A CN 201811653237A CN 109485702 A CN109485702 A CN 109485702A
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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Abstract
The present invention provides a kind of preparation method of icatibant acetate, particularly provide it is a kind of purity is high, impurity content is low, combined coefficient is high and the preparation method of the icatibant acetate of high income, products obtained therefrom quality stablize.Method reaction condition of the invention is mild, and, simple process low to equipment damage is environmentally protective and at low cost, it can be ensured that continuously produces the product of high quality, application value with higher is suitble to industrialization production.
Description
Technical field
The present invention relates to medical synthesis fields, and in particular to a kind of preparation method of icatibant acetate.
Background technique
Icatibant acetate (Firazyr) is bradykinin b 2 receptor antagonist, has structural formula as follows:
Icatibant acetate is developed by Sanofi, and in November, 2001 Jerini company obtains icatibant acetate
Development rights.In September, 2008 lists, in October, 2011 is in the U.S. in March, 2009 for the first time in Germany and Britain's listing in European Union
City.Hereditary angioedema (hereditary angioedema, HAE) of the FDA approval for 18 years old and the above adult is acute
Breaking-out treatment, hereditary angioedema are due to caused by a kind of protein level for being known as C1 inhibitor is low or dysfunction, no
The ictal oedema and swelling of predictable hand, foot, face, larynx and abdomen cause to disfeature, disable or dead.Icatibant is logical
The embolism crossed the influence for inhibiting bradykinin related with the embolism local swelling of HAE, inflammation, pain symptom and treat acute HAE
Local swelling.
However, product purity is low, impurity content is high, combined coefficient is low, yield for the preparation method of existing icatibant acetate
It is low, it is unable to ensure the stable product of continuous production mass, is not suitable for industrialization production, application value is low.
The method that patent application 201210028377.9 reports direct synthesis in solid state Icatibant, using 2- chlorine triphenyl
Chlorine resin is initial vector, but technological reaction condition requirement is high, complicated for operation, at high cost, has part in the synthesis process
Peptide chain falls off from resin, causes ultimate yield low, is not suitable for industrialization production.
Patent application 201410347572.1 is using Wang (king) resin or to hydroxymethyl phenoxy methyl polystyrene resin
As carrier, Fmoc-Arg (Pbf)-OH carries out esterification and obtains under coupling reagent and activating reagent effect with resin carrier
Peptide resin, but impurity content is high in product made from this method, efficiency and yield are low.
In addition, there is also synthesize acetic acid by solid phase carrier of Boc-Arg (Tos)-Merrifield- resin in the prior art
The method of Icatibant needs largely to use the strong corrosives solvent such as anhydrous hydrogen fluoride in this method synthesis process, to equipment requirement
It is high with damage, while being unfavorable for environmental protection and labour protection.
Summary of the invention
In view of the above-mentioned problems, the purpose of the present invention is to provide a kind of purity is high, impurity content is low, combined coefficient is high, anti-
Answer mild condition, simple process, the preparation method of icatibant acetate environmental-friendly, at low cost and high income.
Above-mentioned purpose of the present invention is achieved by the following technical solution:
Fmoc-Arg (Pbf)-Wang resin successively with Fmoc-Oic-OH, Fmoc-D-Tic-OH, Fmoc-Ser (tBu)-
OH、Fmoc-Thi-OH、Fmoc-Gly-OH、Fmoc-Hyp(tBu)-OH、Fmoc-Pro-OH、Fmoc-Arg(Pbf)-OH、
Fmoc-D-Arg (Pbf)-OH reaction, then cracking obtains intermediate 1, and intermediate 1 obtains acetic acid by purifying, turning salt, be lyophilized
Icatibant.
Preferably, using sedimentation solvent in preparation process, the sedimentation solvent is in isopropyl ether, methyl tertiary butyl ether(MTBE)
It is one or two kinds of.
Preferably, the lysate that cleavage step uses is selected from tri isopropyl silane, 1,2 one dithioglycols, phenol, two sulphur Soviet Union
Sugar alcohol, trifluoroacetic acid, thioanisole, methyl phenyl ethers anisole, the combination in water.
Preferably, lysate includes trifluoroacetic acid, dithiothreitol (DTT), tri isopropyl silane, thioanisole and water.
The usage ratio of preferred lysate is trifluoroacetic acid: dithiothreitol (DTT): water: thioanisole: tri isopropyl silane
=(80-95): (1-5): (1-5): (1-5): (1-5).
Preferably, cracking temperature is 27-33 DEG C.
Preferably, pyrolysis time is 2-6 hours.
Preferably, purification procedures are that purifying is respectively once to be purified using phosphate system twice；Using trifluoro second
Acid system carries out secondarily purified.
Inventors have found that the purity of product and yield advantage are obvious when sedimentation solvent is selected from isopropyl ether, methyl tertiary butyl ether(MTBE).
Lysate is selected from tri isopropyl silane, 1,2 one dithioglycols, phenol, dithiothreitol (DTT), trifluoroacetic acid, C10H8OS3
When ether, methyl phenyl ethers anisole, combination in water, especially comprising in said combination when five kinds or more of composition, the purity and yield of product
Can effectively it be promoted.
Inventor also found that, when controlling in a certain range cracking temperature and time respectively, impurity content obviously drops
Low, combined coefficient and product yield are promoted obviously.
In addition, using phosphate system (mobile phase A: 0.01M phosphate sodium dihydrogen buffer solution, Mobile phase B: acetonitrile 0.1-
0.25% gradient slope) once purified, using trifluoroacetic acid system (mobile phase A: 0.05% trifluoroacetic acid aqueous solution, stream
Dynamic phase B:0.05% trifluoroacetic acid acetonitrile solution 0.25-0.5% gradient slope) carry out secondarily purified, impurity can be obviously improved
Separating effect.
The present invention through the above technical solutions, realize purity is high, impurity content is low, combined coefficient is high and the vinegar of high income
The preparation of sour Icatibant, products obtained therefrom quality are stablized, and reaction condition is mild, simple process low to equipment damage, green ring
It protects, is environmental-friendly and at low cost, it can be ensured that continuously producing the product of high quality, application value with higher is suitble to produce
Industry metaplasia produces.
Specific embodiment
Following specific embodiment of the invention is only that the present invention is further explained and described, and is not necessarily to be construed as to this hair
Bright any restrictions.
Embodiment 1
Fmoc-Arg (Pbf)-Wang resin is added in synthesising container, successively with Fmoc-Oic-OH, Fmoc-D-
Tic-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thi-OH、Fmoc-Gly-OH、Fmoc-Hyp(tBu)-OH、Fmoc-Pro-OH、
Fmoc-Arg (Pbf)-OH, Fmoc-D-Arg (Pbf)-OH carry out coupling reaction, and products therefrom is cracked to obtain intermediate 1,
Lysate is trifluoroacetic acid: dithiothreitol (DTT): water: thioanisole: tri isopropyl silane=80:5:5:5:5, cracking temperature 28
DEG C, reaction 3 hours, lysate addition methyl tertiary butyl ether(MTBE) stirring after reaction, removal supernatant, solid are centrifuged, are beaten, is true
Sky is dry, obtains off-white powder, and product is once purified by phosphate system, in phosphate system, mobile phase A: 0.01M phosphoric acid
Sodium dihydrogen buffer, Mobile phase B: acetonitrile, gradient slope 0.25%, product done by trifluoroacetic acid system it is secondarily purified, three
In fluoroacetic acid system, mobile phase A: 0.05% trifluoroacetic acid aqueous solution, Mobile phase B: 0.05% trifluoroacetic acid acetonitrile solution, gradient
Slope is 0.25%, and product, which carries out preparing column, turns salt, is further lyophilized, obtains icatibant acetate sterling, total recovery is
75.12%, purity 99.78%.
Embodiment 2
Fmoc-Arg (Pbf)-Wang resin is added in synthesising container, successively with Fmoc-Oic-OH, Fmoc-D-
Tic-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thi-OH、Fmoc-Gly-OH、Fmoc-Hyp(tBu)-OH、Fmoc-Pro-OH、
Fmoc-Arg (Pbf)-OH, Fmoc-D-Arg (Pbf)-OH carry out coupling reaction, and products therefrom is cracked to obtain intermediate 1,
Lysate is trifluoroacetic acid: dithiothreitol (DTT): water: thioanisole: tri isopropyl silane=90:2.5:2.5:2.5:2.5, cracking
Temperature is 32 DEG C, is reacted 3.5 hours, lysate addition isopropyl ether stirring after reaction, removal supernatant, is beaten at solid centrifugation
Slurry, vacuum drying obtain off-white powder, and product is once purified by phosphate system, in phosphate system, mobile phase A:
0.01M phosphate sodium dihydrogen buffer solution, Mobile phase B: acetonitrile, gradient slope 0.1%, product are done secondary by trifluoroacetic acid system
It purifies, in trifluoroacetic acid system, mobile phase A: 0.05% trifluoroacetic acid aqueous solution, Mobile phase B: 0.05% trifluoroacetic acid acetonitrile is molten
Liquid, gradient slope 0.5%, product, which carries out preparing column, turns salt, is further lyophilized, obtains icatibant acetate sterling, total recovery
It is 81.72%, purity 99.95%.
Embodiment 3
Fmoc-Arg (Pbf)-Wang resin is added in synthesising container, successively with Fmoc-Oic-OH, Fmoc-D-
Tic-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thi-OH、Fmoc-Gly-OH、Fmoc-Hyp(tBu)-OH、Fmoc-Pro-OH、
Fmoc-Arg (Pbf)-OH, Fmoc-D-Arg (Pbf)-OH carry out coupling reaction, and products therefrom is cracked to obtain intermediate 1,
Lysate is trifluoroacetic acid: dithiothreitol (DTT): water: thioanisole: tri isopropyl silane=85:4:4:3.5:3.5, cracking temperature
It is 30 DEG C, reacts 4 hours, lysate addition methyl tertiary butyl ether(MTBE) stirring after reaction, removal supernatant, is beaten at solid centrifugation
Slurry, vacuum drying obtain off-white powder, and product is once purified by phosphate system, in phosphate system, mobile phase A:
0.01M phosphate sodium dihydrogen buffer solution, Mobile phase B: acetonitrile, gradient slope 0.2%, product are done secondary by trifluoroacetic acid system
It purifies, in trifluoroacetic acid system, mobile phase A: 0.05% trifluoroacetic acid aqueous solution, Mobile phase B: 0.05% trifluoroacetic acid acetonitrile is molten
Liquid, gradient slope 0.4%, product, which carries out preparing column, turns salt, is further lyophilized, obtains icatibant acetate sterling, total recovery
It is 74.39%, purity 99.69%.
Embodiment 4
Fmoc-Arg (Pbf)-Wang resin is added in synthesising container, successively with Fmoc-Oic-OH, Fmoc-D-
Tic-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thi-OH、Fmoc-Gly-OH、Fmoc-Hyp(tBu)-OH、Fmoc-Pro-OH、
Fmoc-Arg (Pbf)-OH, Fmoc-D-Arg (Pbf)-OH carry out coupling reaction, and products therefrom is cracked to obtain intermediate 1,
Lysate is trifluoroacetic acid: dithiothreitol (DTT): water: thioanisole: tri isopropyl silane=95:1:1:1.5:1.5, cracking temperature
It is 31 DEG C, reacts 2 hours, lysate addition isopropyl ether stirring after reaction, removal supernatant, solid centrifugation, mashing, vacuum
It is dry, off-white powder is obtained, product is once purified by phosphate system, in phosphate system, mobile phase A: 0.01M di(2-ethylhexyl)phosphate
Hydrogen sodium buffer, Mobile phase B: acetonitrile, gradient slope 0.15%, product do secondarily purified, trifluoro by trifluoroacetic acid system
In acetic acid, mobile phase A: 0.05% trifluoroacetic acid aqueous solution, Mobile phase B: 0.05% trifluoroacetic acid acetonitrile solution, gradient are oblique
Rate is 0.3%, and product, which carries out preparing column, turns salt, is further lyophilized, and obtains icatibant acetate sterling, total recovery 77.47%,
Purity is 99.85%.
Comparative example 1
Fmoc-Arg (Pbf)-Wang resin is added in synthesising container, successively with Fmoc-Oic-OH, Fmoc-D-
Tic-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thi-OH、Fmoc-Gly-OH、Fmoc-Hyp(tBu)-OH、Fmoc-Pro-OH、
Fmoc-Arg (Pbf)-OH, Fmoc-D-Arg (Pbf)-OH carry out coupling reaction, and products therefrom is cracked to obtain intermediate 1,
Lysate is trifluoroacetic acid: dithiothreitol (DTT): water: thioanisole: tri isopropyl silane=75:5:7.5:7.5:5, cracking temperature
It is 35 DEG C, reacts 1 hour, lysate addition ether stirring after reaction, removal supernatant, solid centrifugation, mashing, vacuum is dry
It is dry, off-white powder is obtained, product is once purified by phosphate system, in phosphate system, mobile phase A: 0.01M biphosphate
Sodium buffer, Mobile phase B: acetonitrile, gradient slope 0.5%, product do secondarily purified, trifluoroacetic acid by trifluoroacetic acid system
In system, mobile phase A: 0.05% trifluoroacetic acid aqueous solution, Mobile phase B: 0.05% trifluoroacetic acid acetonitrile solution, gradient slope are
0.2%, product, which carries out preparing column, turns salt, is further lyophilized, obtains icatibant acetate sterling, total recovery 57.4%, purity
It is 98.4%.
Comparative example 2
Fmoc-Arg (Pbf)-Wang resin is added in synthesising container, successively with Fmoc-Oic-OH, Fmoc-D-
Tic-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thi-OH、Fmoc-Gly-OH、Fmoc-Hyp(tBu)-OH、Fmoc-Pro-OH、
Fmoc-Arg (Pbf)-OH, Fmoc-D-Arg (Pbf)-OH carry out coupling reaction, and products therefrom is cracked to obtain intermediate 1,
Lysate is trifluoroacetic acid: dithiothreitol (DTT): water: thioanisole: tri isopropyl silane=75:5:7.5:7.5:5, cracking temperature
It is 35 DEG C, reacts 1 hour, lysate adds isopropyl ether after reaction, and removal supernatant, solid centrifugation, mashing, vacuum are dry
It is dry, off-white powder is obtained, product is once purified by phosphate system, in phosphate system, mobile phase A: 0.01M biphosphate
Sodium buffer, Mobile phase B: acetonitrile, gradient slope 0.1%, product do secondarily purified, trifluoroacetic acid by trifluoroacetic acid system
In system, mobile phase A: 0.05% trifluoroacetic acid aqueous solution, Mobile phase B: 0.05% trifluoroacetic acid acetonitrile solution, gradient slope are
0.5%, product, which carries out preparing column, turns salt, is further lyophilized, obtains icatibant acetate sterling, total recovery 59.2%, purity
It is 98.9%.
Comparative example 3
Fmoc-Arg (Pbf)-Wang resin is added in synthesising container, successively with Fmoc-Oic-OH, Fmoc-D-
Tic-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thi-OH、Fmoc-Gly-OH、Fmoc-Hyp(tBu)-OH、Fmoc-Pro-OH、
Fmoc-Arg (Pbf)-OH, Fmoc-D-Arg (Pbf)-OH carry out coupling reaction, and products therefrom is cracked to obtain intermediate 1,
Lysate is trifluoroacetic acid: dithiothreitol (DTT): water: thioanisole: tri isopropyl silane=75:5:7.5:7.5:5, cracking temperature
It is 30 DEG C, reacts 3 hours, lysate adds isopropyl ether after reaction, and removal supernatant, solid centrifugation, mashing, vacuum are dry
It is dry, off-white powder is obtained, product is once purified by phosphate system, in phosphate system, mobile phase A: 0.01M biphosphate
Sodium buffer, Mobile phase B: acetonitrile, gradient slope 0.1%, product do secondarily purified, trifluoroacetic acid by trifluoroacetic acid system
In system, mobile phase A: 0.05% trifluoroacetic acid aqueous solution, Mobile phase B: 0.05% trifluoroacetic acid acetonitrile solution, gradient slope are
0.5%, product, which carries out preparing column, turns salt, is further lyophilized, obtains icatibant acetate sterling, total recovery 61.7%, purity
It is 99.4%.
Comparative example 4
Fmoc-Arg (Pbf)-Wang resin is added in synthesising container, successively with Fmoc-Oic-OH, Fmoc-D-
Tic-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thi-OH、Fmoc-Gly-OH、Fmoc-Hyp(tBu)-OH、Fmoc-Pro-OH、
Fmoc-Arg (Pbf)-OH, Fmoc-D-Arg (Pbf)-OH carry out coupling reaction, and products therefrom is cracked to obtain intermediate 1,
Lysate is trifluoroacetic acid: water: tri isopropyl silane=85:5:5, and cracking temperature is 30 DEG C, is reacted 3.5 hours, reaction terminates
Lysate adds isopropyl ether afterwards, and removal supernatant, solid centrifugation, mashing, vacuum drying obtain off-white powder, product passes through phosphorus
Silicate system once purifies, in phosphate system, mobile phase A: 0.01M phosphate sodium dihydrogen buffer solution, Mobile phase B: acetonitrile, gradient
Slope is 0.1%, product done by trifluoroacetic acid system it is secondarily purified, in trifluoroacetic acid system, mobile phase A: 0.05% trifluoro
Acetic acid aqueous solution, Mobile phase B: 0.05% trifluoroacetic acid acetonitrile solution, gradient slope 0.5%, product, which carries out preparing column, turns salt,
Further freeze-drying, obtains icatibant acetate sterling, total recovery 36.7%, purity 98.9%.
The above test results show that using synthetic method icatibant acetate product obtained of the invention purity and
Yield advantage is obvious；Method combined coefficient provided by the invention is high, easy to operate, small to environmental hazard.
Claims (10)
1. a kind of preparation method of icatibant acetate, which is characterized in that Fmoc-Arg (Pbf)-Wang resin successively with Fmoc-
Oic-OH、Fmoc-D-Tic-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thi-OH、Fmoc-Gly-OH、Fmoc-Hyp(tBu)-
OH, Fmoc-Pro-OH, Fmoc-Arg (Pbf)-OH, Fmoc-D-Arg (Pbf)-OH reaction, then cracking obtains intermediate 1, in
Mesosome 1 obtains icatibant acetate by purifying, turning salt, be lyophilized.
2. the method according to claim 1, wherein using sedimentation solvent, the sedimentation solvent in preparation process
Selected from one or both of isopropyl ether, methyl tertiary butyl ether(MTBE).
3. according to the method described in claim 1, the lysate that uses of the cleavage step is selected from tri isopropyl silane, 1,2 one
Dithioglycol, phenol, dithiothreitol (DTT), trifluoroacetic acid, thioanisole, methyl phenyl ethers anisole, the combination in water.
4. according to the method described in claim 1, the lysate include trifluoroacetic acid, dithiothreitol (DTT), tri isopropyl silane,
Thioanisole and water.
5. according to the method described in claim 1, the usage ratio of the lysate is trifluoroacetic acid: dithiothreitol (DTT): water: fennel
Fragrant thioether: tri isopropyl silane=(80-95): (1-5): (1-5): (1-5): (1-5).
6. according to the method described in claim 1, the temperature of the cleavage step is 27-33 DEG C.
7. according to the method described in claim 1, the time of the cleavage step is 2-6 hours.
8. according to the method described in claim 1, purifying is respectively adopted phosphate system and is once purified；Using trifluoroacetic acid
System carries out secondarily purified.
9. according to the method described in claim 1, phosphate system includes mobile phase A: 0.01M phosphate sodium dihydrogen buffer solution；Stream
Dynamic phase B: acetonitrile, gradient slope 0.1-0.25%.
10. according to the method described in claim 1, trifluoroacetic acid system include mobile phase A: 0.05% trifluoroacetic acid aqueous solution,
Mobile phase B: 0.05% trifluoroacetic acid acetonitrile solution, gradient slope 0.25-0.5%.
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| CN110343147A (en) * | 2019-08-22 | 2019-10-18 | 凯莱英医药集团（天津）股份有限公司 | The synthetic method of Icatibant |
| CN110776558A (en) * | 2019-07-01 | 2020-02-11 | 江苏豪森药业集团有限公司 | Solid-phase synthesis method of icatibant acetate |
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