CN1715295A - Liquid phase synthetic method for endomorphine -1 and endomorphine -2 - Google Patents
Liquid phase synthetic method for endomorphine -1 and endomorphine -2 Download PDFInfo
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- CN1715295A CN1715295A CN 200410026315 CN200410026315A CN1715295A CN 1715295 A CN1715295 A CN 1715295A CN 200410026315 CN200410026315 CN 200410026315 CN 200410026315 A CN200410026315 A CN 200410026315A CN 1715295 A CN1715295 A CN 1715295A
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Abstract
The liquid phase synthesis process of endomorphine-1 and endomorphine-2 based on the different characteristics of various amino acids and peptide chains includes minimum or no protection on amino acid, [2+2] polypeptide segment condensation process, DCC-HOSu condensation for creating segment peptide bond, DCC/HOBt condensation for segment coupling of complete synthesis; crystal separation to purifying intermediate product; and common silicon gel column chromatography for purifying final product so as to obtain high purity product. The process of the present invention has less steps, high yield, simple purification and production and low production cost, provides the lab production and industrial production of endomorphine with reliable technological support, and can promote the development and application research of endomorphine and relevant peptides.
Description
Technical field
The present invention relates to the preparation of peptide, the liquid-phase synthesis process of especially a kind of interior morphine peptide-1 and interior morphine peptide-2.
Background material
(endomorphins EMs) is divided into interior morphine peptide-1 (endomorphin-1, EM-1, Tyr-Pro-Trp-Phe-NH to interior morphine peptide
2, endomorphin-1) and interior morphine peptide-2 (endomorphin-2, EM-2, Tyr-Pro-Phe-Phe-NH
2Endomorphin-2), be mu opioid receptor (mu-opioid receptor, endogenous agonist MOR), MOR is had high avidity and selectivity, and have the particularly potent analgesic activity of physiology, pharmacological effect widely.
The amino acid of interior morphine peptide is formed and structure is shown below:
EM-1：Tyr-Pro-Trp-Phe-NH
2 EM-2：Tyr-Pro-Phe-Phe-NH
2
Studies show that interior morphine peptide not only has vital role at aspects such as cardiovascular systems, respiratory regulation and cell injury protections, has potent analgesic activity simultaneously.Intracerebroventricular (icv.), the interior morphine peptide of intrathecal injection (it.) all can produce analgesic activity [Zadina JE etc., Nature, 1997, the 386:499-502 with the morphine equivalence; Tseng LF etc., J Pharmacol Exp Ther, 2000,292:576-583], but do not produce some side effect [Carrigan K A etc., Psychopharmacology, 2000, the 151:299-305 that morphine has; Czapla M A etc., Am.J.Respir.Crit.Care Med, 2000,162:994-999].The unusual pain of more particularly interior morphine Toplink dose-dependently ground antagonism, particularly in the adjusting of neuropathic pain, interior morphine peptide has stronger restraining effect than morphine, therefore, interior morphine peptide may be used for the treatment of current more thorny neuropathic pain [Przewlocka B etc., Eur J Pharmacol, 1999,367 (2-3): 189-96].Simultaneously, EMs also has analgesic activity to the rat that morphine relies on, and this point has important enlightenment to development, the raising analgesic effect of clinical improvement opioid drug.
Existingly discover in a large number, although EMs only is made up of four amino-acid residues, but contained abundant life-information, pass through high-affinity, highly selective and μ receptors bind and mediate many physiological functions, its unique effect in pain sensation impression and pain sensation regulate process particularly, enriched the understanding that people regulate the pain sensation, man develops potent for chemiluminescent polypeptide man and pharmacy, the new type analgesic of low toxicity provides new approaches, and its conformation is simple relatively, research for the opium field, the exploitation of the chemical simulation of opioid peptides and new and effective anodyne provides pattern more easily, thereby has evoked the extensive studies upsurge.Simultaneously, along with going deep into of research, the commerce of EMs and stand-in thereof and clinical application will become inevitable.Therefore, how simple, efficient, cheap and can obtain EMs on a large scale, to be used for research needs and large-scale production, very important.
In the existing document, forefathers to adopt the method for extracting or adopts morphine peptide in the acquisition of solid-phase synthesis synthetic method from biomaterial, but limited amount is not suitable for large-scale production, and the cost height.The invention provides a kind of brand-new interior morphine peptide-1 and the liquid phase synthetic route of interior morphine peptide-2, under the strategy that adopts minimum protection, we adopt carbobenzoxy-(Cbz) (Z-) protection to amino acid whose N-end, because the amino acid and the easy crystallization of peptide of Z-protection, therefore, greatly facilitate the purifying of intermediate product; Adopt [2+2] fragment condensation simultaneously; segmental synthetic employing DCC-HOSu (dicyclohexylcarbodiimide/N-hydroxy-succinamide) method is carried out; the combination condensation mode that the fragment coupling then adopts DCC-HOBt (dicyclohexylcarbodiimide/1-hydroxyl benzotriazole) method to carry out is carried out the complete synthesis of EMs; removing of Z-protecting group adopts catalytic hydrogenation to carry out; and adopt common silica gel column chromatography method directly to obtain highly purified end product; thereby synthesis step and purification process have been simplified; made things convenient for synthetic; improve productive rate greatly, saved production cost.
Summary of the invention
The object of the present invention is to provide one through the interior morphine peptide-1 optimization and in the liquid-phase synthesis process of morphine peptide-2, have simple to operate, the simple and effective feature of low cost, high purity, high yield, and can be applicable to large-scale production.
Purpose of the present invention can be achieved through the following technical solutions:
Technical solution of the present invention is: the different characteristics at each amino acid or peptide chain adopts minimum to protect or do not protect, and adopts different condensation modes according to its feature, and in conjunction with the DCC-HOBt condensation method, the DCC-HOSu active ester method carries out complete synthesis; Intermediate product needn't purifying or is only adopted low temperature crystallization method to get final product purifying, end product ordinary silicon plastic column chromatography.
The present invention adopts [2+2] fragment condensation, is the I fragment with carbobenzoxy-(Cbz) tyrosyl proline(Pro) (Z-Tyr-Pro), with carbobenzoxy-(Cbz) tryptophyl hydrocinnamamide (Z-Trp-Phe-NH
2) or carbobenzoxy-(Cbz) phenylalanyl hydrocinnamamide (Z-Phe-Phe-NH
2) as the II fragment, under the strategy that adopts minimum protection, amino acid whose N-end being adopted the Z-protection, the C-end then adopts simple Na
+Salt protection or the strategy of not protecting; Removing of protecting group adopts palladium carbon (Pd/C) catalytic hydrogenation or acidolysis to carry out respectively, and segmental synthetic employing DCC-HOSu method is carried out, and the fragment coupling then adopts the DCC-HOBt method to carry out.
Carbobenzoxy-(Cbz) tyrosyl proline(Pro) (Z-Tyr-Pro) is segmental synthetic: Z-Tyr-OH and L-Pro-OH adopt DCC-HOSu method, tetrahydrofuran (THF) (THF) or THF, NaHCO
3/ H
2The O mixing solutions is as reaction solvent; After connecing the reactive polypeptide termination, handle with hcl acidifying; Adopt the crystallization of low temperature sherwood oil after the conventional aftertreatment, get solid Z-Tyr-Pro-OH;
Carbobenzoxy-(Cbz) tryptophyl hydrocinnamamide (Z-Trp-Phe-NH
2) and carbobenzoxy-(Cbz) phenylalanyl hydrocinnamamide (Z-Phe-Phe-NH
2) segmental synthetic: carbobenzoxy-(Cbz) tryptophane (Z-Trp-OH) and hydrocinnamamide hydrochloride (Phe-NH
2.HCl) adopt the condensation of DCC-HOSu method, use NaHCO
3Aqueous solution neutralized salt hydrochlorate, (1: 2, v/v) crystallization got Z-Trp-Phe-NH with THF/EA
2Solid; Z-Phe-OH and Phe-NH
2.HCl adopt the condensation of DCC-HOSu method, NaHCO
3Aqueous solution neutralized salt hydrochlorate gets Z-Phe-Phe-NH with ethyl acetate (EA) crystallization
2Crystal;
Carbobenzoxy-(Cbz) tyrosyl prolyl tryptophyl hydrocinnamamide (Z-Tyr-Pro-Trp-Phe-NH
2) and carbobenzoxy-(Cbz) endomorphin-2 (Z-Tyr-Pro-Phe-Phe-NH
2) synthetic: adopt palladium carbon catalytic hydrogenation deprotection, Z-Tyr-Pro-OH and H
2N-Trp-Phe-NH
2Adopt the condensation of DCC-HOBt method, (1: 2, V/V) crystallization obtained Z-Tyr-Pro-Trp-Phe-NH to EA/PE
2Solid; Z-Tyr-Pro-OH and H
2N-Phe-Phe-NH
2Adopt the condensation of DCC-HOBt method, the EA crystallization obtains Z-Tyr-Pro-Phe-Phe-NH
2Solid;
Adopt palladium carbon catalytic hydrogenation to slough protection tetrapeptide Z-Tyr-Pro-Trp-Phe-NH
2The Z-protecting group, again through silica gel column chromatography (EA: MeOH: dense NH
3.H
2O=50: 10: 1, v/v) purifying, morphine peptide-1 in getting (endomorphin-1,, H
2N-Tyr-Pro-Trp-Phe-NH
2, tyrosyl prolyl tryptophyl hydrocinnamamide), purity 〉=98%; Slough protection tetrapeptide Z-Tyr-Pro-Phe-Phe-NH
2The Z-protecting group, again through silica gel column chromatography (EA: MeOH: dense NH
3.H
2O=60: 12: 1, v/v) purifying, morphine peptide-2 (endomorphin-2, H in getting
2N-Tyr-Pro-Phe-Phe-NH
2, endomorphin-2), purity 〉=95%.
The beneficial effect of advantage of the present invention and generation is:
1, the present invention adopts one to optimize synthetic route; different qualities at each amino acid and peptide chain; adopt the synthesis strategy of fragment condensation; adopt minimum to protect or do not protect and different method of condensing to amino acid; segmental synthetic employing DCC-HOSu method is carried out; the combination condensation mode that the fragment coupling then adopts the DCC-HOBt method to carry out is carried out; protection and deprotection to group are all simple efficient; it is simple to have synthetic route; step is few; the notable feature that cost is low is specially adapted to large-scale production or industrial production.
2, another notable feature of the present invention is that purification process is simple, and intermediate product needn't purifying, or only adopts low temperature crystallization method to get final product purifying; End product needn't only can obtain high-purity product with the ordinary silicon plastic column chromatography through the HPLC of costliness purifying, thereby has simplified synthesis step and purification process, made things convenient for synthetic, improved productive rate widely, saved production cost, the morphine peptide is promoted to produce in making becomes possibility.
3, good interior morphine peptide synthetic route and the method for a cover that go out of research trial of the present invention, reach simplified control, purifying is simply efficient, convenient for production reliable, the purpose of low production cost, for the commercial scale production and the laboratory limited production of interior morphine peptide all provides the reliable technique support, and in can greatly promoting the morphine peptide further investigation and as the exploitation and the clinical application research of polypeptide drugs; Simultaneously, the synthetic and large-scale production that also can be other polypeptide and polypeptide drugs provides thinking.
Embodiment
Mode with embodiment is described further technical scheme of the present invention again below:
Embodiment 1: the liquid phase of interior morphine peptide-1 is synthetic
(1) Z-Tyr-Pro-OH's is synthetic: the Z-Tyr and the HOSu of equimolar amount are dissolved among the anhydrous THF, under ℃ cooling and fully stirring, slowly are added dropwise to the precooling THF solution that has dissolved equivalent DCC, room temperature reaction spends the night again.Suction filtration gets Z-Tyr-OSu solution.Stir, then with the L-Pro NaHCO of 1.5 times of amounts
3After the solution dissolving, be added dropwise in the Z-Tyr-OSu solution the about 2d of room temperature reaction.After reaction finishes, slowly drip 6mol/L HCl, to solution PH be 2.Concentrating under reduced pressure removes THF then, uses ethyl acetate extraction, and pickling again is washed till neutrality with NaCl solution then, adds anhydrous sodium sulfate drying.Filter anhydrous sodium sulphate, concentrating under reduced pressure removes ethyl acetate again, gets syrup.Grind filtration, washing through ice-cold sherwood oil, obtain faint yellow solid Z-Tyr-Pro-OH, yield 68.2%, R
f=0.25 (PE: EA=1: 3 (adding a small amount of ice HAc), V/V).Mass spectrum (ESI-MS) [M+H]
+: 413; With calculated value: 413 is consistent.
(2) Z-Trp-Phe-NH
2Synthetic: Z-Trp and the HOSu of equimolar amount are dissolved among the anhydrous THF, in ℃ cooling and fully under the stirring, slowly are added dropwise to the precooling THF solution that has dissolved equivalent DCC, room temperature reaction spends the night again.Suction filtration, elimination DCU, filtrate suction filtration get Z-Trp-OSu solution to round-bottomed flask.Stir, then with the Phe-NH of 1.2 times of amounts
2.HCl use excessive N aHCO slightly
3After the solution dissolving neutralization, be added dropwise in the Z-Trp-OSu solution the about 2d of room temperature reaction.After TLC detected the disappearance of raw material point, concentrating under reduced pressure removed THF, residual solution acetic acid ethyl dissolution, extraction.Ethyl acetate layer merges, and carries out pickling, saturated NaHCO successively
3Washing is washed till neutrality with NaCl solution at last again.Add anhydrous sodium sulfate drying, spend the night.Filter anhydrous sodium sulphate, concentrating under reduced pressure removes ethyl acetate, gets solids.With THF/EA (1: 2, v/v) recrystallization, drying, white solid Z-Trp-Phe-NH
2, yield 86.1%, R
f=0.24 (PE: EA=1: 3, V/V).Mass spectrum (ESI-MS) [M+H]
+: 485; With calculated value: 485 is consistent.
(3) tryptophyl hydrocinnamamide (H
2N-Trp-Phe-NH
2) synthetic: with Z-Trp-Phe-NH
2Be dissolved in the anhydrous methanol, add 10% Pd/C of 0.15 times of amount, stir, feed hydrogen hydrogenation 3h, the elimination catalyzer, filtrate decompression is concentrated into dried (bathe temperature and be no more than 40 ℃), H
2N-Trp-Phe-NH
2,, directly carry out next step reaction as amino group.
(4) Z-Tyr-Pro-Trp-Phe-NH
2: the Z-Tyr-Pro-OH and the HOBt of equimolar amount are dissolved in the anhydrous DCM/DMF mixed solvent, cryosel is bathed under the cooling and stirring, slowly is added dropwise to the precooling DCM solution that has dissolved equimolar amount DCC, again behind the room temperature reaction 12h, elimination DCU gets Z-Tyr-Pro-OBt solution.Cryosel is bathed, and stirs the H that is dissolved in the anhydrous DCM of precooling of step gained in the adding
2N-Trp-Phe-NH
2Solution, cryosel are bathed reaction 1h, return to room temperature reaction then.Behind about 30h, concentrating under reduced pressure removes DCM, residue with acetic acid ethyl dissolution after, carry out pickling, saturated NaHCO successively
3Washing is washed till neutrality with NaCl solution at last again, and anhydrous sodium sulfate drying gets crude product.With EA/PE (1: 2, V/V) recrystallization, drying, Z-Tyr-Pro-Trp-Phe-NH
2Solid, yield 91.6%, R
f=0.24 (PE: EA: HAc=3: 30: 1, V/V).Mass spectrum (ESI-MS) [M+H]
+: 745; With calculated value: 745 is consistent.
(5) interior morphine peptide-1 (H
2N-Tyr-Pro-Trp-Phe-NH
2) acquisition: with Z-Tyr-Pro-Trp-P he-NH
2Be dissolved in the anhydrous methanol, add the Pd/C of 0.15 times of amount 10%, stir, feed hydrogen hydrogenation, behind the 5h, the elimination catalyzer, filtrate decompression is concentrated into dried (bathe temperature and be no more than 40 ℃), gets thick peptide.Adopt ordinary silicon plastic column chromatography (EA: MeOH: dense NH
3.H
2O=50: 10: 1, v/v) purifying, drying gets pure peptide H
2N-Tyr-Pro-Trp-Phe-NH
2(interior morphine peptide-1, endomorphin-1), yield 73.1%, purity 〉=98%; R
f=0.39 (EA: MeOH: dense NH
3.H
2O=50: 10: 1, v/v), R
f=0.45 (CH
3CN: MeOH: H
2O=4: 1: 1, v/v); RP-HPLC analyzes (system: 35% acetonitrile/water (containing 0.1%TFA)): t
R=7.1min; Mass spectrum (ESI-MS) [M+H]
+: 611; With calculated value: 611 is consistent.
Embodiment 2: the liquid phase of interior morphine peptide-2 is synthetic
(1) Z-Phe-Phe-NH
2: operation steps is with interior morphine peptide-1 (2); The Z-Phe of equimolar amount and HOSu, DCC reaction are spent the night, and get Z-Phe-OSu solution; Then with use NaHCO
3The Phe-NH of solution dissolving neutral equimolar amount
2.HCl the about 2d of reaction after aftertreatment and the drying, obtains white solid at last.Use the EA recrystallization, drying gets the needle-like white crystal, yield 90.5%, R
f=0.65 (PE: EA=1: 3, V/V).Mass spectrum (ESI-MS) [M+H]
+446; With calculated value: 446 is consistent.
(2) phenylalanyl hydrocinnamamide (H
2N-Phe-Phe-NH
2) synthetic: operation steps is with interior morphine peptide-1 synthesis step (3).With Z-Phe-Phe-NH
2Be dissolved in the anhydrous methanol, add the Pd/C of 0.15 times of amount 10%, reaction times 3h gets H
2N-Phe-Phe-NH
2,, directly carry out next step reaction as amino group.
(3) Z-Tyr-Pro-Phe-Phe-NH
2: operation steps is with interior morphine peptide-1 synthesis step (4).The Z-Tyr-Pro-OH of equimolar amount, HOBt, DCC, reaction 12h gets Z-Tyr-Pro-OBt solution.To go up step gained amino group H
2N-Phe-Phe-NH
2Add, react about 30h, the last crude product that gets in aftertreatment and dry back.Use the EA recrystallization, drying gets Z-Tyr-Pro-Phe-Phe-NH
2White solid, yield 81.4%; R
f=0.27 (PE: EA: HAc=3: 30: 1, V/V).Mass spectrum (ESI-MS) [M+H]
+: 706; With calculated value: 706 is consistent.
(4) interior morphine peptide-2 (H
2N-Tyr-Pro-Phe-Phe-NH
2) acquisition: operation steps is with interior morphine peptide-1 synthesis step (5).With Z-Tyr-Pro-Phe-Phe-NH
2Be dissolved in the anhydrous methanol, add 10%Pd/C0.15 and doubly measure, reaction times 5h, drain at last thick peptide.Adopt ordinary silicon plastic column chromatography (EA: MeOH: dense NH
3.H
2O=60: 12: 1, v/v) purifying, drying, pure peptide (interior morphine peptide-2, endomorphin-2), yield 84.0%, purity 〉=95%; R
f=0.30 (EA: MeOH: dense NH
3.H
2O=60: 12: 1, V/V), R
f=0.43 (CH
3CN: MeOH: H
2O=4: 1: 1, v/v); RP-HPLC analyzes (system: 35% acetonitrile/water (containing 0.1%TFA)): t
R=6.5min; Mass spectrum (ESI-MS) [M+H]
+: 572; With calculated value: 572 is consistent.
Claims (4)
1, the liquid phase synthesizing method of a kind of interior morphine peptide-1 and interior morphine peptide-2, it is characterized in that: at the different characteristics of each amino acid or peptide chain, adopt minimum to protect or do not protect and different condensation modes to amino acid, and be peptide bond generation method with DCC-HOSu method (dicyclohexylcarbodiimide/N-hydroxy-succinamide method) or DCC-HOBt method (dicyclohexylcarbodiimide/1-hydroxyl benzotriazole method), adopt [2+2] polypeptide fragment condensation method to carry out complete synthesis; Removing of protecting group adopts catalytic hydrogenation or acidolysis to remove respectively; According to the characteristic of different intermediate products, middle product is taked needn't purifying or only adopt low temperature crystallization method method purifying, and morphine peptide-1 or interior morphine peptide-2 adopt common silica gel column chromatography purifying in the end product.
2, the liquid phase synthesizing method of a kind of interior morphine peptide-1 according to claim 1 and interior morphine peptide-2, it is characterized in that: with carbobenzoxy-(Cbz) tyrosyl proline(Pro) (Z-Tyr-Pro) is the I fragment, with carbobenzoxy-(Cbz) tryptophyl hydrocinnamamide (Z-Trp-Phe-NH
2) or carbobenzoxy-(Cbz) phenylalanyl hydrocinnamamide (Z-Phe-Phe-NH
2) as the II fragment, the synthetic employing DCC-HOSu method of fragment I, II is carried out, and uses NaHCO
3Aqueous solution neutralized salt hydrochlorate, the coupling of fragment I, II then adopt the DCC-HOBt method to carry out; To adopting Z-(carbobenzoxy-(Cbz)-) protection as the amino acid N of carboxyl group-end, the C-end as the proline(Pro) (Pro) of amino group is then adopted Na
+The salt protection is to the hydrocinnamamide hydrochloride (Phe-NH as amino group
2.HCl) use excessive N aHCO slightly
3Solution or dissolution of sodium hydroxide neutralization; The Z-protecting group remove employing palladium/carbon (Pd/C) or palladium hydroxide/carbon (Pd (OH)
2/ C) catalytic hydrogenation, Na
+Salt protection remove the employing hcl acidifying.
3, the liquid phase synthesizing method of a kind of interior morphine peptide-1 according to claim 1 and interior morphine peptide-2 is characterized in that: intermediate product Z-Tyr-Pro-OH obtains intermediate product Z-Trp-Phe-NH through the sherwood oil grinding crystallization of ice-cold (＜0 ℃)
2Obtain intermediate product Z-Phe-Phe-NH with tetrahydrofuran (THF)/ethyl acetate crystallization
2Obtain Z-protection tetrapeptide Z-Tyr-Pro-Trp-Phe-NH with the ethyl acetate crystallization
2Obtain Z-protection tetrapeptide Z-Tyr-Pro-Phe-Phe-NH with the ethyl acetate/petroleum ether crystallization
2Obtain with the ethyl acetate crystallization.
4, according to the liquid phase synthesizing method of each described a kind of interior morphine peptide-1 of claim 1 to 3 and interior morphine peptide-2, it is characterized in that: morphine peptide-1 and interior morphine peptide-2 are respectively by Z-protection tetrapeptide (Z-Tyr-Pro-Trp-Phe-NH in the final product
2And Z-Tyr-Pro-Phe-Phe-NH
2) through Pd/C or Pd (OH)
2Catalytic hydrogenation is taken off Z-protection and is obtained, and adopts the system that constitutes with ethyl acetate, methyl alcohol, the strong aqua silica gel column chromatography purifying as moving phase.
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|---|---|---|---|
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101134774B (en) * | 2006-08-31 | 2010-09-08 | 兰州大学 | Combined chemical modified endomorphin-1 and method for preparing same |
| CN104109189A (en) * | 2013-04-18 | 2014-10-22 | 中国人民解放军军事医学科学院毒物药物研究所 | Liquid-phase synthetic method of Thr-Pro-Pro-Thr tetrapiptide |
| CN107722108A (en) * | 2017-11-20 | 2018-02-23 | 陕西慧康生物科技有限责任公司 | A kind of liquid-phase synthesis process of acetyl group tetrapeptide 9 |
| CN107857799A (en) * | 2017-11-20 | 2018-03-30 | 陕西慧康生物科技有限责任公司 | A kind of liquid-phase synthesis process of tetrapeptide 21 |
| EP3474878A4 (en) * | 2016-06-27 | 2020-01-15 | Ruey J. Yu | Endomorphin-2, tetrapeptide derivatives thereof, and uses thereof |
| CN113896761A (en) * | 2021-09-15 | 2022-01-07 | 湖北泓肽生物科技有限公司 | Synthetic method of L-tyrosyl-L-proline |
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2004
- 2004-07-03 CN CNB200410026315XA patent/CN100363380C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101134774B (en) * | 2006-08-31 | 2010-09-08 | 兰州大学 | Combined chemical modified endomorphin-1 and method for preparing same |
| CN104109189A (en) * | 2013-04-18 | 2014-10-22 | 中国人民解放军军事医学科学院毒物药物研究所 | Liquid-phase synthetic method of Thr-Pro-Pro-Thr tetrapiptide |
| CN104109189B (en) * | 2013-04-18 | 2019-05-10 | 中国人民解放军军事医学科学院毒物药物研究所 | The liquid-phase synthesis process of Thr-Pro-Pro-Thr tetrapeptide |
| EP3474878A4 (en) * | 2016-06-27 | 2020-01-15 | Ruey J. Yu | Endomorphin-2, tetrapeptide derivatives thereof, and uses thereof |
| CN107722108A (en) * | 2017-11-20 | 2018-02-23 | 陕西慧康生物科技有限责任公司 | A kind of liquid-phase synthesis process of acetyl group tetrapeptide 9 |
| CN107857799A (en) * | 2017-11-20 | 2018-03-30 | 陕西慧康生物科技有限责任公司 | A kind of liquid-phase synthesis process of tetrapeptide 21 |
| CN107722108B (en) * | 2017-11-20 | 2021-05-04 | 陕西慧康生物科技有限责任公司 | Liquid phase synthesis method of acetyl tetrapeptide-9 |
| CN107857799B (en) * | 2017-11-20 | 2021-06-04 | 陕西慧康生物科技有限责任公司 | Liquid phase synthesis method of tetrapeptide-21 |
| CN113896761A (en) * | 2021-09-15 | 2022-01-07 | 湖北泓肽生物科技有限公司 | Synthetic method of L-tyrosyl-L-proline |
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| Publication number | Publication date |
|---|---|
| CN100363380C (en) | 2008-01-23 |
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