CN1241935C - Liquid phase sgnthesis method of thymus pentapeptide - Google Patents
Liquid phase sgnthesis method of thymus pentapeptide Download PDFInfo
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- CN1241935C CN1241935C CN 03134355 CN03134355A CN1241935C CN 1241935 C CN1241935 C CN 1241935C CN 03134355 CN03134355 CN 03134355 CN 03134355 A CN03134355 A CN 03134355A CN 1241935 C CN1241935 C CN 1241935C
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Abstract
The present invention relates to a synthetic method of thymopentin. Tyrosine benzyl ester is orderly connected with valine, aspartic acid, lysine and arginine. Finally, the thymopentin Arg-Lys-Asp-Val-Tyr-OH is obtained by deaminating a protecting radical on the product Z-Arg(NO2)-Lys(2-Cl-Z)-Asp-Val-Tyr (OBzl).
Description
Technical field
It is synthetic to the present invention relates to the synthetic method of thymopeptide-5, particularly liquid phase method, and applicable to the method for scale operation thymopeptide-5.
Background technology
Thymopeptide-5 is the biological active center of thymine-thymopoietin II, is to be made of thymopoietin II 32-36 amino acids residue, in vivo with external physiology and the pharmacologically active that all has whole thymopoietin II.And thymopeptide-5 now has been clinical medicine.
Present stage, the production technology of Zadaxin can be divided into two classes.Wherein a class is to adopt biotechnology production, disclosed as Chinese invention patent application 02117757.0, the buffered soln that adds pH2.0-4.0 with fresh thymus gland slurries, with inhibitory enzyme activity, with ultrasonic wave homogenizer or ultra-fine technology fresh thymic tissue is being handled below 10 ℃, smudge cells again through frozen centrifugation and ultrafiltration, is produced the Zadaxin production technology to the gained raw product with nanofiltration again; Or adopt clone technology and adopt the compound clone technology to produce, as Chinese invention patent 96105293.7 disclosed technology.Another kind of technology is to adopt synthetic method production Zadaxin, as U.S. Pat 005218089 disclosed liquid phase synthetic technology, the polypeptide process for solid phase synthesis that perhaps discloses in pertinent data.Technology is comparatively complicated on the one hand to make thymopeptide-5 with biotechnology in the prior art, and technology is also immature, and is subjected to the restriction of factors such as raw material, also may cause the pollution of goods on the other hand owing to the reason of raw material; The synthetic production technology of existing liquid phase need be used some comparatively expensive reagent, and technology controlling and process is also comparatively difficult; More employings is solid phase synthesis technique in the prior art, but the industrial scale of solid phase synthesis technique is less, the solvent amount of expending used in the synthesis process is bigger, in synthesis technique, need large-scale plant and instrument such as polypeptide automatic DNA synthesizer DNA, high performance liquid chromatograph, in addition, the deficiency that also has the on the low side and reaction product purifying excessive cycle of productive rate during solid phase synthesis.
Summary of the invention
The invention provides the technology that a kind of new liquid phase is synthesized thymopeptide-5, this technology can overcome the deficiency that prior art exists, can use the comparatively cheap reagent of price in synthesis technique, synthetic yield is higher, and does not need a large amount of expensive instruments in whole technology.Synthetic technology particularly of the present invention can be used as the technology that a kind of scale operation is adopted.
The present invention reacts tyrosine benzyl ester tosilate and N-tertbutyloxycarbonyl-L-Xie Ansuan earlier, then the N-tertbutyloxycarbonyl on the product is sloughed, and obtains Val-Tyr (OBzl).Make N-tertbutyloxycarbonyl-L-aspartic acid Acibenzolar reaction solution with N-tertbutyloxycarbonyl-L-aspartic acid again, adding Val-Tyr (OBzl) again in reaction solution reacts, after reaction is finished the N-tertbutyloxycarbonyl on the reaction product is sloughed, obtained Asp (OBzl)-Val-Tyr (OBzl).Again N-tertbutyloxycarbonyl-L-Methionin is made N-tertbutyloxycarbonyl-L-Methionin Acibenzolar reaction solution, in this reaction solution, added Asp (OBzl)-Val-Tyr (OBzl) and react.After reaction is finished the N-tertbutyloxycarbonyl on the reaction product is sloughed, obtained Lys (2-Cl-z)-Asp-Val-Tyr (OBzl).Again Z-nitro arginine and Lys (2-Cl-z)-Asp-Val-Tyr (OBzl) and 2-hydroxy benzo ribavirin are dissolved in methylene dichloride and the N-N dimethyl formamide mixed solution, adding dicyclohexylcarbodiimide under ice bath again reacts, gained reaction clear liquid after washing in methyl alcohol recrystallization, isolate xln Z-Arg (NO
2)-Lys (2-Cl-z)-Asp-Val-Tyr (OBzl).At last with Z-Arg (NO
2Protecting group on)-Lys (2-Cl-z)-Asp-Val-Tyr (OBzl) slough Arg-Lys-Asp-Val-Tyr-OH.
Be to adopt corresponding product to be dissolved in reaction in an amount of trifluoroacetic acid to slough N-tertbutyloxycarbonyl on it in the present invention,, and then product carried out concentrating under reduced pressure more successively with using anhydrous sodium sulfate drying behind the alkaline solution neutralized salt solution washing.
Tyrosine benzyl ester tosilate and N-tertbutyloxycarbonyl-L-Xie Ansuan and reaction are that tyrosine benzyl ester tosilate and N-tertbutyloxycarbonyl L-Xie Ansuan are dissolved in the methylene dichloride among the present invention, add dicyclohexylcarbodiimide again and react under ice bath.
N-tertbutyloxycarbonyl-L-aspartic acid Acibenzolar reaction solution is earlier N-tertbutyloxycarbonyl-L-aspartic acid to be dissolved in right amount (with solute degree of being dissolved as fully in the present invention, below identical) methylene dichloride and N-N dimethyl formamide mixed solution in, add under ice bath that the dicyclohexylcarbodiimide reaction obtains.
N-tertbutyloxycarbonyl among the present invention-L-Methionin Acibenzolar reaction solution is that N-tertbutyloxycarbonyl-L-Methionin is dissolved in an amount of methylene dichloride N-N dimethyl formamide mixed solution, and ice bath adds the reaction of dicyclohexylcarbodiimide and 2-hydroxy benzo ribavirin down and obtains.
Adopt method of the present invention to obtain Z-Arg (NO
2)-Lys (2-Cl-z)-Asp-Val-Tyr (OBzl) back is available sloughs protecting group on it with any following method:
With Z-Arg (NO
2)-Lys (2-Cl-z)-Asp-Val-Tyr (OBzl) is dissolved in the methyl alcohol, adds palladium carbon and carries out catalytic hydrogenation, adds ether again, use high-efficient liquid phase chromatogram purification, acquisition Arg-Lys-Asp-Val-Tyr-OH after separating out crystal;
Perhaps, with Z-Arg (NO
2In)-Lys (2-Cl-z)-sulfuration phenylmethylether-phenylmethylether of an amount of 1: 1: 1 of Asp-Val-Tyr (OBzl)-cresols mixed solution, feeding waits the anhydrous hydrogen fluoride reaction of capacity again, and then wash with ether, add an amount of acetic acid aqueous solution again, add ether again, get Arg-Lys-Asp-Val-Tyr-OH with high-efficient liquid phase chromatogram purification after separating out crystal.
The present invention compared with prior art has following advantage:
1, production cost is relatively low, is example with the solid phase synthesis thymopeptide-5, and its actual yield is 50% of a theoretical yield only, and productive rate of the present invention is greater than 80% of theoretical yield;
2, used reagent price is relatively low in whole production technique;
3, in whole production process main what adopt is glass equipment, need to rely on main equipment in the prior art and do not resemble, so its productive expense is lower;
4, production technique is comparatively simple, and reaction process is easy to control, and the repeatability of production technique is strong;
5, comprehensively the production cycle is shorter, further reduces production cost, enhances productivity;
6, synthetic scale can increase substantially, and realizes industrialized scale operation easily.
Embodiment
One embodiment of the present of invention below are provided
Earlier with L-tyrosine (L-Tyr-OH, 100 grams) with tosic acid (TOS, 100 grams) be dissolved in the benzene (600ml), add phenylcarbinol (300ml) again, back flow reaction 3～5 hours, cool off, add sherwood oil or ether (1000ml) again, stirring and crystallizing is dissolved in the ethanol (300ml) crystallisation by cooling again under refluxing, leach tyrosine benzyl ester tosilate Tyr (OBzl) TOS (244 gram) that solids gets purifying, again itself and N-tertbutyloxycarbonyl-L-Xie Ansuan are reacted, then the N-tertbutyloxycarbonyl on the product is sloughed, obtain Val-Tyr (OBzl).
N-tertbutyloxycarbonyl-L-Xie Ansuan (Boc-Val-OH, 117 grams) is dissolved in the methylene dichloride (700ml) with tyrosine benzyl ester Val-Tyr (OBzl), adds dicyclohexylcarbodiimide (112 gram) under ice bath, reaction is spent the night.Suction filtration obtains light yellow clear liquid, uses weakly acid soln more successively, as citric acid etc., after weak caustic solution and the salts solution washing, carry out drying treatment with anhydrous sodium sulphate again after, the concentrating under reduced pressure reaction solution obtains white solid.Put into petroleum ether-ethyl acetate system (900ml: 200ml) carry out recrystallization, obtain Boc-Val-Tyr (OBzl) (242 gram) after these white solid things are leached again.
Above-mentioned products therefrom Boc-Val-Tyr (OBzl) (206 gram) is dissolved in (210ml) in an amount of trifluoroacetic acid, reacted 3～5 hours, and then neutralize with alkaline solution, after the salts solution washing, carry out drying treatment with anhydrous sodium sulphate, carry out concentrating under reduced pressure again, obtain product Val-Tyr (OBzl) (155 gram).
With N-tertbutyloxycarbonyl-L-aspartic acid (Boc-Asp (OBzl)-OH, 135 grams) be dissolved in an amount of methylene dichloride and N-N dimethyl formamide mixed solution (700ml: 200ml), ice bath adds dicyclohexylcarbodiimide (80 gram) and 2-hydroxy benzo ribavirin (70 gram) down, reaction is spent the night, and makes N-tertbutyloxycarbonyl-L-aspartic acid Acibenzolar reaction solution.
Val-Tyr (OBzl) (155 gram) is added in N-tertbutyloxycarbonyl-L-aspartic acid Acibenzolar reaction solution, and reaction is spent the night.The suction filtration reaction solution gets clear liquid, uses weakly acid soln successively, after weak caustic solution and the salts solution washing, carries out drying treatment with anhydrous sodium sulphate again, and the concentrating under reduced pressure reaction solution obtains white solid.Put into petroleum ether-ethyl acetate system (550ml: 180ml) carry out recrystallization, obtain Boc-Asp (OBzl)-Val-Tyr (OBzl) (226 gram) after these white solid things are leached again.
To be dissolved in (95ml) in an amount of trifluoroacetic acid by last gained reaction product Boc-Asp (OBzl)-Val-Tyr (OBzl), reacted 3～5 hours, and then neutralize with alkaline solution, after the salts solution washing, carry out drying treatment with anhydrous sodium sulphate, carry out concentrating under reduced pressure again, obtain product A sp (OBzl)-Val-Tyr (OBzl) (103 gram).
With N-tertbutyloxycarbonyl-L-Methionin (Boc-Lys (2-Cl-Z)-OH, 75 grams) be dissolved in an amount of methylene dichloride and N-N dimethyl formamide mixed solution (700ml: 200ml), ice bath adds dicyclohexylcarbodiimide (37 gram) and 2-hydroxy benzo ribavirin (30 gram) down, reaction is spent the night, and makes N-tertbutyloxycarbonyl-L-Methionin Acibenzolar reaction solution.
Asp (OBzl)-Val-Tyr (OBzl) (103 gram) is added N-tertbutyloxycarbonyl-L-Methionin Acibenzolar reaction solution, reaction is spent the night, the suction filtration reaction solution gets clear liquid, use weakly acid soln successively, after weak caustic solution and the salts solution washing, carry out drying treatment with anhydrous sodium sulphate again, with the filtrate stand at low temperature, until separating out white solid, insert again after solid isolated and carry out recrystallization in the ethyl acetate system, obtain product B oc-Lys (2-Cl-Z)-Asp-Val-Tyr (OBzl) (161 gram).
Above products therefrom Boc-Lys (2-Cl-Z)-Asp-Val-Tyr (OBzl) (161 gram) is dissolved in (70ml) in an amount of trifluoroacetic acid, reacted about 3 hours, and then neutralize with alkaline solution, after the salts solution washing, carry out drying treatment with anhydrous sodium sulphate, carry out concentrating under reduced pressure again, obtain product Lys (2-Cl-z)-Asp-Val-Tyr (OBzl) (80 gram).
With Z-nitro arginine (Z-Arg (NO
2), 29 grams) be dissolved in methylene dichloride and N-N dimethyl formamide mixed solution (700ml: 200ml) with Lys (2-Cl-z)-Asp-Val-Tyr (OBzl) (60 gram) and 2-hydroxy benzo ribavirin (14 gram), under ice bath, add dicyclohexylcarbodiimide (18 gram) again, reaction is spent the night, the suction filtration reaction solution gets clear liquid, use weakly acid soln successively, after weak caustic solution and the salts solution washing, carry out drying treatment with anhydrous sodium sulphate again, put filtrate chamber is gentle and quiet, until separating out white solid, insert again after solid isolated and carry out recrystallization in the methanol system, obtain product Z-Arg (NO
2)-Lys (2-Cl-z)-Asp-Val-Tyr (OBzl) (75 gram).
Will be by last products therefrom Z-Arg (NO
2Each protecting group on)-Lys (2-Cl-z)-Asp-Val-Tyr (OBzl), that is: (NO
2), (2-Cl-z) and (OBzl) slough, just can obtain thymopeptide-5 Z-Arg-Lys-Asp-Val-Tyr-OH.Two kinds of methods of the most effectively sloughing protecting group are provided among the present invention:
First method
With Z-Arg (NO
2)-Lys (2-Cl-z)-Asp-Val-Tyr (OBzl) (120 gram) is dissolved in the amount of methanol, add palladium carbon, carry out catalytic hydrogenation, add ether again, leach after separating out white crystal, carry out obtaining behind the purifying purity greater than 99% thymopeptide-5 Arg-Lys-Asp-Val-Tyr-OH (65 gram) with high performance liquid chromatography again.
Second method:
With Z-Arg (NO
2)-Lys (2-Cl-z)-Asp-Val-Tyr (OBzl) (120 gram) is dissolved in an amount of sulfuration phenylmethylether-phenylmethylether-cresols, and (100ml: 100ml: 100ml) in the mixed solution, the anhydrous hydrogen fluoride (300ml) of capacity such as feedings grade reacted 30 minutes again.Drain hydrogen fluoride, divide with ether again wash (using the 200ml ether) for 3 times at every turn after, the acetic acid aqueous solution (concentration is 10%) that in system, adds 20ml again, add ether (600ml) again, leach after separating out crystal, get Arg-Lys-Asp-Val-Tyr-OH (67 gram) with high-efficient liquid phase chromatogram purification again.
It should be noted that also can be directly with commercial tyrosine benzyl ester tosic acid salt product in the production process of reality.
Claims (3)
1, a kind of thymopeptide-5 liquid phase synthesizing method is characterized in that:
(a) with tyrosine benzyl ester tosilate and N-tertbutyloxycarbonyl-L-Xie Ansuan reaction, then the N-tertbutyloxycarbonyl on the product is sloughed, is obtained Val-Tyr (OBzl),
(b) N-tertbutyloxycarbonyl-L-aspartic acid 135 grams are dissolved in an amount of methylene dichloride and the N-N dimethyl formamide mixed solution, methylene dichloride: N-N dimethyl formamide=700ml: 200ml, ice bath adds the dicyclohexylcarbodiimide and the 70 gram 2-hydroxy benzo ribavirins of 80 grams down, reaction is spent the night, make N-tertbutyloxycarbonyl-L-aspartic acid Acibenzolar reaction solution, in N-tertbutyloxycarbonyl-L-aspartic acid Acibenzolar reaction solution, add 155 grams again by a products therefrom Val-Tyr (OBzl), reaction is spent the night, after reaction is finished the N-tertbutyloxycarbonyl on the reaction product is sloughed, obtain Asp (OBzl)-Val-Tyr (OBzl)
(c) N-tertbutyloxycarbonyl-L-Methionin 75 grams are dissolved in an amount of methylene dichloride and the N-N dimethyl formamide mixed solution, methylene dichloride: N-N dimethyl formamide=700ml: 200ml, ice bath adds 37 gram dicyclohexylcarbodiimide and 30 gram 2-hydroxy benzo ribavirins down, reaction is spent the night, make N-tertbutyloxycarbonyl-L-Methionin Acibenzolar reaction solution, in N-tertbutyloxycarbonyl-L-Methionin Acibenzolar reaction solution, add again by b products therefrom Asp (OBzl)-Val-Tyr (OBzl) 103 grams, reaction is spent the night, after reaction is finished the N-tertbutyloxycarbonyl on the reaction product is sloughed, obtain Lys (2-Cl-z)-Asp-Val-Tyr (OBzl)
(d) be dissolved in methylene dichloride and the N-N dimethyl formamide mixed solution with Z-nitro arginase 12 9 grams and by c products therefrom Lys (2-Cl-z)-Asp-Val-Tyr (OBzl) 60 grams and 14 gram 2-hydroxy benzo ribavirins, methylene dichloride: N-N dimethyl formamide=700ml: 200ml, adding 18 gram dicyclohexylcarbodiimide under ice bath again reacts, reaction is spent the night, gained reaction clear liquid after washing in methyl alcohol recrystallization, isolate xln Z-Arg (NO
2)-Lys (2-Cl-z)-Asp-Val-Tyr (OBzl),
(e) with Z-Arg (NO
2)-Lys (2-Cl-z)-Asp-Val-Tyr (OBzl) 120 grams are dissolved in the methyl alcohol, add palladium carbon, carry out catalytic hydrogenation, add ether again, leach after separating out white crystal, carry out obtaining thymopeptide-5 Arg-Lys-Asp-Val-Tyr-OH behind the purifying with high performance liquid chromatography again
In above-mentioned reaction: the reaction of sloughing the N-tertbutyloxycarbonyl is to adopt corresponding product is dissolved in an amount of trifluoroacetic acid to react, and then successively with using anhydrous sodium sulfate drying behind the alkaline solution neutralized salt solution washing, and product is carried out concentrating under reduced pressure.
2, a kind of thymopeptide-5 liquid phase synthesizing method is characterized in that:
(a) with tyrosine benzyl ester tosilate and N-tertbutyloxycarbonyl-L-Xie Ansuan reaction, then the N-tertbutyloxycarbonyl on the product is sloughed, is obtained Val-Tyr (OBzl),
(b) N-tertbutyloxycarbonyl-L-aspartic acid 135 grams are dissolved in an amount of methylene dichloride and the N-N dimethyl formamide mixed solution, methylene dichloride: N-N dimethyl formamide=700ml: 200ml, ice bath adds the dicyclohexylcarbodiimide and the 70 gram 2-hydroxy benzo ribavirins of 80 grams down, reaction is spent the night, make N-tertbutyloxycarbonyl-L-aspartic acid Acibenzolar reaction solution, in N-tertbutyloxycarbonyl-L-aspartic acid Acibenzolar reaction solution, add 155 grams again by a products therefrom Val-Tyr (OBzl), reaction is spent the night, after reaction is finished the N-tertbutyloxycarbonyl on the reaction product is sloughed, obtain Asp (OBzl)-Val-Tyr (OBzl)
(c) N-tertbutyloxycarbonyl-L-Methionin 75 grams are dissolved in an amount of methylene dichloride and the N-N dimethyl formamide mixed solution, methylene dichloride: N-N dimethyl formamide=700ml: 200ml, ice bath adds 37 gram dicyclohexylcarbodiimide and 30 gram 2-hydroxy benzo ribavirins down, reaction is spent the night, make N-tertbutyloxycarbonyl-L-Methionin Acibenzolar reaction solution, in N-tertbutyloxycarbonyl-L-Methionin Acibenzolar reaction solution, add again by b products therefrom Asp (OBzl)-Val-Tyr (OBzl) 103 grams, reaction is spent the night, after reaction is finished the N-tertbutyloxycarbonyl on the reaction product is sloughed, obtain Lys (2-Cl-z)-Asp-Val-Tyr (OBzl)
(d) be dissolved in methylene dichloride and the N-N dimethyl formamide mixed solution with Z-nitro arginase 12 9 grams and by c products therefrom Lys (2-Cl-z)-Asp-Val-Tyr (OBzl) 60 grams and 14 gram 2-hydroxy benzo ribavirins, methylene dichloride: N-N dimethyl formamide=700ml: 200ml, adding 18 gram dicyclohexylcarbodiimide under ice bath again reacts, reaction is spent the night, gained reaction clear liquid after washing in methyl alcohol recrystallization, isolate xln Z-Arg (NO
2)-Lys (2-Cl-z)-Asp-Val-Tyr (OBzl),
(e) with Z-Arg (NO
2)-Lys (2-Cl-z)-Asp-Val-Tyr (OBzl) 120 grams are dissolved in 300 milliliters of sulfuration phenylmethylether-phenylmethylethers-cresols mixed solution of 1: 1: 1, the anhydrous hydrogen fluoride reaction of capacity such as feeding is 30 minutes again, wash with ether again after draining hydrogen fluoride, add an amount of acetic acid aqueous solution and ether again, get Arg-Lys-Asp-Val-Tyr-OH with high-efficient liquid phase chromatogram purification after separating out crystal.
In above-mentioned reaction: the reaction of sloughing the N-tertbutyloxycarbonyl is to adopt corresponding product is dissolved in the trifluoroacetic acid to react, and then successively with using anhydrous sodium sulfate drying behind the alkaline solution neutralized salt solution washing, and product is carried out concentrating under reduced pressure.
3, thymopeptide-5 liquid phase synthesizing method according to claim 1 and 2, the reaction that it is characterized in that tyrosine benzyl ester tosilate and N-tertbutyloxycarbonyl-L-Xie Ansuan is that tyrosine benzyl ester tosilate and N-tertbutyloxycarbonyl-L-Xie Ansuan are dissolved in the methylene dichloride, adds dicyclohexylcarbodiimide again and react under ice bath.
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| CN 03134355 CN1241935C (en) | 2003-06-10 | 2003-06-10 | Liquid phase sgnthesis method of thymus pentapeptide |
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| CN 03134355 CN1241935C (en) | 2003-06-10 | 2003-06-10 | Liquid phase sgnthesis method of thymus pentapeptide |
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| CN1241935C true CN1241935C (en) | 2006-02-15 |
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| CN1865279B (en) * | 2005-05-18 | 2010-07-14 | 周达明 | Solid phase polypeptide synthesis preparation method for thymopoietin pentapeptide |
| CN101195653B (en) * | 2006-12-08 | 2010-05-12 | 吉尔生化（上海）有限公司 | solid-liquid synthesizing method for leuprorelin |
| CN101270153B (en) * | 2008-05-09 | 2011-11-09 | 暨南大学 | Cyclo-pentapeptide and synthesizing method |
| CN107629111B (en) * | 2017-10-26 | 2021-06-04 | 陕西慧康生物科技有限责任公司 | Liquid phase synthesis method of acetyl tetrapeptide-2 |
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Assignee: HAINAN ZHONGHE PHARMACEUTICAL Co.,Ltd. Assignor: Lanzhou University Contract fulfillment period: 2008.11.9 to 2013.11.9 Contract record no.: 2008460000016 Denomination of invention: Liquid phase sgnthesis method of thymus pentapeptide Granted publication date: 20060215 License type: Exclusive license Record date: 20081110 |
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