CN103275189A - Cracking liquid for peptide resin, and application thereof in synthesizing somatostatin by solid phase cracking - Google Patents
Cracking liquid for peptide resin, and application thereof in synthesizing somatostatin by solid phase cracking Download PDFInfo
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Abstract
The invention belongs to the technical field of medicine synthesis, and discloses a cracking liquid for a peptide resin. The cracking liquid comprises, by volume, 85%-90% of trifluoroacetic acid (TFA), 0%-10% of 1,2-ethanedithiol (EDT), 0%-10% of water and 0-10% of methyl-phenoxide (PhOMe), wherein at least two components of EDT, water and PhOMe are not 0 at the same time. Besides, the invention discloses a method for preparing somatostatin and an application of the cracking liquid in synthesizing the somatostatin, wherein the cracking liquid is used for a cracking reaction. Analytical comparison tests show that by adopting the improved cracking liquid to crack the solid-phase synthesis resin, crude peptide purity and conversion rate of peptide oxide are effectively increased; a yield of an oxidation reaction is increased by about 10%. Therefore, the cracking liquid has obvious economic benefits and can effectively reduce production cost.
Description
Technical field
The present invention relates to technical field of medicine synthesis, be specifically related to a kind of lysate for peptide resin and in the application of solid phase cracking synthetically grown chalone.
Background technology
Somatostatin, i.e. somatostatin, English name is Somatostatin, molecular formula is C
76H
104N
18O
19S
2, molecular weight is 1637.890.It is the human body internal memory a kind of endogenous regulate hormone, different physiological roles is had restraining effect widely, the amino acid structure skeleton symbol is:
Ala-Gly-Cys-Lys-Asn-Phe-Phe-T rp-Lys-Thr-Phe-Thr-Ser-Cys (disulfide linkage).
The Somatostatin chemical structure is the tetradecapeptide that intramolecularly has a pair of disulfide linkage, mainly is present in the central nervous system peripheral organs (as: stomach, intestines, film, skin etc.) of unifying in human body, and peak concentration sees with hypothalamus, but with digestive tube content maximum.
Internal secretion and external secretion, the inhibition stomach mucous membrane that the Somatostatin biological function can suppress body of gland growth hormone releasing, inhibition thyrotrophic hormone(TH) and adrenocortical hormone, inhibition film gland discharges gastrin, the inhibition intestinal mucosa discharges intestines and urgees film hormone and kidney release feritin; reducing portal venous pressure, loose biliary tract mouth expands about flesh, irritates mononuclear phagocyte system and alleviate endotoxemia; suppress the release of platelet activation factor; directly or indirectly regulate the cytokine chain and produce cytoprotection, and can strengthen the antiproliferative effect of cancer therapy drug.The clinical serious acute esophageal varices bleeding that often is applied to, serious acute stomach, the duodenum room of bursting is hemorrhage, acute honest and clean mashed property gastritis or hemorrhagic gastritis, and pancreas, courage and intestines assisting therapy repeatly, diabetes are because of with the acidosic assisting therapy of disease.Some other effect and purposes are just along with its fundamental research and clinical deeply constantly being found.Therefore having a extensive future of Somatostatin, market demand increases just year by year.
US Patent No. 4337194,3862925 and 3917578 and the L.Moroder etc. of Germany and Canadian Hans U.Immer etc. reported respectively at 1973 to 1981 and adopt the liquid phase polypeptide synthesis to prepare the method for Somatostatin.In reported method such as L.Moroder etc. and Hans U.Immer, adopt Z protection amino acid to carry out the depsipeptides reaction, need multistep carry out the H2/Pd reaction suddenly, difficulty is bigger in actually operating, and is difficult to preparation in enormous quantities.In US3862925, adopt hydrogen fluoride to go protecting group, test conditions and hydrofluoric storing etc. all are difficult to realize in the technology.US3917578 adopts after 14 peptide line peptides are synthetic, needs to form earlier the disulfide linkage ring, goes the method for protecting group then, makes the disulfide linkage ring form the steric hindrance yield and reduces.Therefore these reports all are difficult to be selected as the method for preparing Somatostatin in enormous quantities.
The synthetic route of US Patent No. 4337194 reports is suitable for industrialized mass; but this liquid phase method exists reactions steps many; route is tediously long, intermediate is difficult for purifies and separates; solvent steams except difficulty is big, source and the preparation difficulty of reagent and used amino acid side chain protecting group are bigger in the actually operating; cost advantage is reduced, be difficult to be suitable for many shortcomings such as production in enormous quantities.
Therefore, the optimal method for preparing Somatostatin is the solid-phase polypeptide synthesis method.The solid-phase polypeptide synthesis method has that cost is low, easy to operate, reaction time plurality of advantages such as weak point, environmental friendliness.The synthetic patent of existing solid-phase polypeptide mainly concentrates on uses Wang Resin or 2-chlorine resin to be starting raw material, carries out progressively solid phase coupling or fragment, uses lytic reagent to carry out cracking then, carries out oxidation, purifying etc. again.Yet, in the above-mentioned solid phase polypeptide synthesis method, all adopt classical lysate proportioning to prepare lysate, thereby finish synthesizing Somatostatin, as CN 1508152A, CN 1552728A and CN 1923851A etc., seldom relevant for improving lysate, and then effectively improve the report of oxidizing reaction yield.
Summary of the invention
The present invention is directed to the above-mentioned defective that exists in the prior art, a kind of lysate for peptide resin is provided and in the application of solid phase cracking synthetically grown chalone, by adopting this lysate, has effectively improved the yield of oxidizing reaction.
For this reason, one aspect of the present invention provides a kind of lysate for peptide resin, it is made up of following components in percentage by volume: trifluoroacetic acid (TFA) 85%～90%, 1,2-dithioglycol (EDT) 0%～10%, water 0%～10%, methyl-phenoxide (PhOMe) 0%～10%, wherein among component EDT, water and the PhOMe at least two be not 0 simultaneously.
In different preferred embodiments, lysate is three components or four set of dispense ratio, and the volume ratio of each component can be respectively TFA:EDT:H
2O=85:10:5, TFA:EDT:H
2O=85:5:10, TFA:EDT:H
2O=90:5:5, TFA:EDT:PhOMe=85:10:5, TFA:EDT:PhOMe=85:5:10, TFA:EDT:PhOMe=90:5:5, TFA:H
2O:PhOMe=85:10:5, TFA:H
2O:PhOMe=85:5:10, TFA:H
2O:PhOMe=90:5:5, TFA:EDT:H
2O:PhOMe=85:5:5:5, TFA:EDT:H
2O:PhOMe=90:4:3:3.
Another aspect of the present invention provides a kind of method for preparing Somatostatin, and it comprises the steps:
1) Fmoc-Cys (Try)-OH and vector resin reaction obtains Fmoc-Cys (Try)-resin,
2) Fmoc-Cys (Try)-resin adopts other amino acid of the mode coupling Fmoc blocking group of coupling one by one, obtains the Somatostatin peptide resin,
3) the Somatostatin peptide resin obtains the linear thick peptide of Somatostatin through scission reaction,
4) the linear thick peptide of Somatostatin obtains the thick peptide of Somatostatin after oxidation,
5) the purified and freeze-drying of the thick peptide of Somatostatin obtains Somatostatin;
Wherein, the scission reaction in the step 3) adopts any in the above-mentioned lysate.
At last, the present invention also provides the application of above-mentioned lysate in the preparation Somatostatin.
Comparison test by analysis, the present invention finds, adopt the improved lysate of the present invention that the solid phase synthesis resin is carried out cracking, the linear thick peptide of gained carries out oxidizing reaction and adopts the linear thick peptide of classical R reagent cracking gained to carry out oxidizing reaction to compare, effectively improved the transformation efficiency of thick peptide purity and oxidation peptide, the oxidizing reaction yield improves near 10%.Therefore, the present invention has tangible economic benefit, can effectively reduce production costs.
Embodiment
The present invention is described in further detail below by embodiment, is intended to non-limiting the present invention for explanation the present invention.Should be pointed out that to those skilled in the art, under the prerequisite that does not break away from the principle of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification fall within protection scope of the present invention too.
During the implication of abbreviation used in the present invention is listed in the table below.
| English abbreviation | The Chinese implication |
| Fmoc | 9-fluorenylmethyloxycarbonyl |
| Boc | Tertbutyloxycarbonyl |
| tBu | The tertiary butyl |
| Trt | Trityl |
| DMF | N, dinethylformamide |
| DCM | Methylene dichloride |
| DIC | N, the N-DIC |
| DIPEA | N, the N-diisopropylethylamine |
| HOBT | I-hydroxybenzotriazole |
| TFE | Trifluoroethanol |
| TFA | Trifluoroacetic acid |
| EDT | 1 |
Embodiment 1: peptide resin synthetic
Taking by weighing substitution degree is the 2-CTC resin 15.38g(10.0mmol of 0.65mmol/g), join in the solid state reaction post, with DMF washing 2 times, with DMF swelling resin after 30 minutes, get 11.714gFmoc-Cys (Try)-OH (20.0mmol) with the DMF dissolving, add 6.6mL DIEA(40mmol under the ice-water bath) after the activation, add in the above-mentioned reaction column that resin is housed, reacted 2 hours, and added 20mL anhydrous methanol sealing 1 hour, with DMF washing 6 times.Remove Fmoc protection 15 minutes+15 minutes with DBLK, then with DMF washing 6 times.
With 7.668g Fmoc-Ser (tBu)-OH (20mmol), 2.702g HOBt (20mmol), 3.08ml DIC (20mmol) is dissolved in DCM and DMF mixing solutions 60ml that volume ratio is 1:1, add in the solid state reaction post, room temperature reaction 2h(reaction end detects with ninhydrin method and is as the criterion, if the resin water white transparency, then react completely, the resin colour developing, the expression reaction not exclusively needs linked reaction 1h again).Repeat the step that the above-mentioned Fmoc of removing protected and added corresponding amino acid coupling; according to the peptide order, coupling Fmoc-Thr (tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr (tBu)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Trp (Boc)-OH, Fmoc-Phe-OH, Fmoc-Phe-OH, Fmoc-Asn (Trt)-OH, Fmoc-Lys (Boc)-OH, Fmoc-Cys (Trt)-OH, Fmoc-Gly-OH, Fmoc-Ala-OH successively.Reaction finishes the back shrinks with methyl alcohol, and resin vacuum-drying is spent the night, and obtains peptide resin 41.70g, resin synthesis yield 94.3%.
Embodiment 2: the cracking of peptide resin
With the peptide resin 41.70g that embodiment 1 obtains, join in the 1000ml flask configuration 400ml lysate TFA:EDT:H
2O=85:10:5, V/V joins lysate in the flask, room temperature reaction 2.5 hours, reaction finishes, and filters resin, collects filtrate.With a small amount of TFA washing resin, merging filtrate, filtrate joined in the 4000ml anhydrous diethyl ether precipitate, centrifugal, anhydrous diethyl ether washing, and vacuum-drying obtain the linear thick peptide 16.21g of Somatostatin, linear thick peptide yield 98.8%.MS=1639.9。
Embodiment 3: the cracking of peptide resin
With the peptide resin 41.70g that embodiment 1 obtains, join in the 1000ml flask configuration 400ml lysate TFA:EDT:H
2O=85:5:10, V/V joins lysate in the flask, room temperature reaction 2.5 hours, reaction finishes, and filters resin, collects filtrate.With a small amount of TFA washing resin, merging filtrate, filtrate joined in the 4000ml anhydrous diethyl ether precipitate, centrifugal, anhydrous diethyl ether washing, and vacuum-drying obtain the linear thick peptide 16.11g of Somatostatin, linear thick peptide yield 98.2%.MS=1639.9。
Embodiment 4: the cracking of peptide resin
With the peptide resin 41.70g that embodiment 1 obtains, join in the 1000ml flask configuration 400ml lysate TFA:EDT:H
2O=90:5:5, V/V joins lysate in the flask, room temperature reaction 2.5 hours, reaction finishes, and filters resin, collects filtrate.With a small amount of TFA washing resin, merging filtrate, filtrate joined in the 4000ml anhydrous diethyl ether precipitate, centrifugal, anhydrous diethyl ether washing, and vacuum-drying obtain the linear thick peptide 16.0g of Somatostatin, linear thick peptide yield 97.6%.MS=1639.9。
Embodiment 5: the cracking of peptide resin
With the peptide resin 41.70g that embodiment 1 obtains, join in the 1000ml flask, configuration 400ml lysate TFA:EDT: methyl-phenoxide=85:10:5, V/V joins lysate in the flask, room temperature reaction 2.5 hours, reaction finishes, and filters resin, collects filtrate.With a small amount of TFA washing resin, merging filtrate, filtrate joined in the 4000ml anhydrous diethyl ether precipitate, centrifugal, anhydrous diethyl ether washing, and vacuum-drying obtain the linear thick peptide 15.81g of Somatostatin, linear thick peptide yield 96.3%.MS=1639.9。
Embodiment 6: the cracking of peptide resin
With the peptide resin 41.70g that embodiment 1 obtains, join in the 1000ml flask, configuration 400ml lysate TFA:EDT: methyl-phenoxide=85:5:10, V/V joins lysate in the flask, room temperature reaction 2.5 hours, reaction finishes, and filters resin, collects filtrate.With a small amount of TFA washing resin, merging filtrate, filtrate joined in the 4000ml anhydrous diethyl ether precipitate, centrifugal, anhydrous diethyl ether washing, and vacuum-drying obtain the linear thick peptide 15.92g of Somatostatin, linear thick peptide yield 97.1%.MS=1639.9。
Embodiment 7: the cracking of peptide resin
With the peptide resin 41.70g that embodiment 1 obtains, join in the 1000ml flask, configuration 400ml lysate TFA:EDT: methyl-phenoxide=90:5:5, V/V joins lysate in the flask, room temperature reaction 2.5 hours, reaction finishes, and filters resin, collects filtrate.With a small amount of TFA washing resin, merging filtrate, filtrate joined in the 4000ml anhydrous diethyl ether precipitate, centrifugal, anhydrous diethyl ether washing, and vacuum-drying obtain the linear thick peptide 16.33g of Somatostatin, linear thick peptide yield 99.6%.MS=1639.9。
Embodiment 8: the cracking of peptide resin
With the peptide resin 41.70g that embodiment 1 obtains, join in the 1000ml flask configuration 400ml lysate TFA:H
2O: methyl-phenoxide=85:10:5, V/V joins lysate in the flask, room temperature reaction 2.5 hours, reaction finishes, and filters resin, collects filtrate.With a small amount of TFA washing resin, merging filtrate, filtrate joined in the 4000ml anhydrous diethyl ether precipitate, centrifugal, anhydrous diethyl ether washing, and vacuum-drying obtain the linear thick peptide 16.24g of Somatostatin, linear thick peptide yield 99.0%.MS=1639.9。
Embodiment 9: the cracking of peptide resin
With the peptide resin 41.70g that embodiment 1 obtains, join in the 1000ml flask configuration 400ml lysate TFA:H
2O: methyl-phenoxide=85:5:10, V/V joins lysate in the flask, room temperature reaction 2.5 hours, reaction finishes, and filters resin, collects filtrate.With a small amount of TFA washing resin, merging filtrate, filtrate joined in the 4000ml anhydrous diethyl ether precipitate, centrifugal, anhydrous diethyl ether washing, and vacuum-drying obtain the linear thick peptide 15.93g of Somatostatin, linear thick peptide yield 97.1%.MS=1639.9。
Embodiment 10: the cracking of peptide resin
With the peptide resin 41.70g that embodiment 1 obtains, join in the 1000ml flask configuration 400ml lysate TFA:H
2O: methyl-phenoxide=90:5:5, V/V joins lysate in the flask, room temperature reaction 2.5 hours, reaction finishes, and filters resin, collects filtrate.With a small amount of TFA washing resin, merging filtrate, filtrate joined in the 4000ml anhydrous diethyl ether precipitate, centrifugal, anhydrous diethyl ether washing, and vacuum-drying obtain the linear thick peptide 15.77g of Somatostatin, linear thick peptide yield 96.1%.MS=1639.9。
Embodiment 11: the cracking of peptide resin
With the peptide resin 41.70g that embodiment 1 obtains, join in the 1000ml flask configuration 400ml lysate TFA:EDT:H
2O: methyl-phenoxide=85:5:5:5, V/V joins lysate in the flask, room temperature reaction 2.5 hours, reaction finishes, and filters resin, collects filtrate.With a small amount of TFA washing resin, merging filtrate, filtrate joined in the 4000ml anhydrous diethyl ether precipitate, centrifugal, anhydrous diethyl ether washing, and vacuum-drying obtain the linear thick peptide 16.13g of Somatostatin, linear thick peptide yield 98.3%.MS=1639.9。
Embodiment 12: the cracking of peptide resin
With the peptide resin 41.70g that embodiment 1 obtains, join in the 1000ml flask configuration 400ml lysate TFA:EDT:H
2O: methyl-phenoxide=90:4:3:3, V/V joins lysate in the flask, room temperature reaction 2.5 hours, reaction finishes, and filters resin, collects filtrate.With a small amount of TFA washing resin, merging filtrate, filtrate joined in the 4000ml anhydrous diethyl ether precipitate, centrifugal, anhydrous diethyl ether washing, and vacuum-drying obtain the linear thick peptide 16.25g of Somatostatin, linear thick peptide yield 99.1%.MS=1639.9。
Embodiment 13: the cracking of peptide resin
With the peptide resin 41.70g that embodiment 1 obtains, join in the 1000ml flask configuration 400ml R reagent lysate TFA:EDT: thioanisole: methyl-phenoxide=90:2:5:3, V/V joins lysate in the flask, room temperature reaction 2.5 hours, reaction finishes, and filters resin, collects filtrate.With a small amount of TFA washing resin, merging filtrate, filtrate joined in the 4000ml anhydrous diethyl ether precipitate, centrifugal, anhydrous diethyl ether washing, and vacuum-drying obtain the linear thick peptide 16.32g of Somatostatin, linear thick peptide yield 99.5%.MS=1639.9。
Embodiment 14: linear thick peptide oxidation
The thick peptide of whole linearities of getting embodiment 2～12 gained respectively carries out liquid-phase oxidation, it is complete with dissolved in purified water linear thick peptide that it is operating as the ratio that is dissolved in 1ml in the thick peptide of 1g, and stirring at room is transferred pH value of solution to 6.5～7.0 with weak ammonia, logical oxygen carries out oxidizing reaction, and oxidation reaction in 2 days finishes.HPLC detects, thick peptide purity 70～75%, and its content is 0.45g/L～0.50g/L.
The thick peptide of whole linearities of getting embodiment 13 gained carries out liquid-phase oxidation, it is complete with dissolved in purified water linear thick peptide that it is operating as the ratio that is dissolved in 1ml in the thick peptide of 1g, and stirring at room is transferred pH value of solution to 6.5～7.0 with weak ammonia, logical oxygen carries out oxidizing reaction, and oxidation reaction in 2 days finishes.HPLC detects, thick peptide purity 65.2%, and its content is 0.38g/L.
Embodiment 15: purifying
Get the thick peptide of embodiment 14 gained and carry out the HPLC purifying, get qualified smart peptide.
Claims (14)
1. lysate that is used for peptide resin, it is made up of following components in percentage by volume: trifluoroacetic acid (TFA) 85%～90%, 1,2-dithioglycol (EDT) 0%～10%, water 0%～10%, methyl-phenoxide (PhOMe) 0%～10% is characterized in that, at least two is not 0 simultaneously among component EDT, water and the PhOMe.
2. lysate according to claim 1, wherein the volume ratio of each component is TFA:EDT:H
2O=85:10:5.
3. lysate according to claim 1, wherein the volume ratio of each component is TFA:EDT:H
2O=85:5:10.
4. lysate according to claim 1, wherein the volume ratio of each component is TFA:EDT:H
2O=90:5:5.
5. lysate according to claim 1, wherein the volume ratio of each component is TFA:EDT:PhOMe=85:10:5.
6. lysate according to claim 1, wherein the volume ratio of each component is TFA:EDT:PhOMe=85:5:10.
7. lysate according to claim 1, wherein the volume ratio of each component is TFA:EDT:PhOMe=90:5:5.
8. lysate according to claim 1, wherein the volume ratio of each component is TFA:H
2O:PhOMe=85:10:5.
9. lysate according to claim 1, wherein the volume ratio of each component is TFA:H
2O:PhOMe=85:5:10.
10. lysate according to claim 1, wherein the volume ratio of each component is TFA:H
2O:PhOMe=90:5:5.
11. lysate according to claim 1, wherein the volume ratio of each component is TFA:EDT:H
2O:PhOMe=85:5:5:5.
12. lysate according to claim 1, wherein the volume ratio of each component is TFA:EDT:H
2O:PhOMe=90:4:3:3.
13. a method for preparing Somatostatin comprises the steps:
1) Fmoc-Cys (Try)-OH and vector resin reaction obtains Fmoc-Cys (Try)-resin,
2) Fmoc-Cys (Try)-resin adopts other amino acid of the mode coupling Fmoc blocking group of coupling one by one, obtains the Somatostatin peptide resin,
3) the Somatostatin peptide resin obtains the linear thick peptide of Somatostatin through scission reaction,
4) the linear thick peptide of Somatostatin obtains the thick peptide of Somatostatin after oxidation,
5) the purified and freeze-drying of the thick peptide of Somatostatin obtains Somatostatin;
It is characterized in that the scission reaction in the step 3) adopts each described lysate of claim 1-12.
14. the application of each described lysate of claim 1-12 in the preparation Somatostatin.
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| CN103275189B (en) | 2014-08-06 |
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