CN104003908A - Preparing method of hydroxyl-protected serine - Google Patents
Preparing method of hydroxyl-protected serine Download PDFInfo
- Publication number
- CN104003908A CN104003908A CN201410020773.6A CN201410020773A CN104003908A CN 104003908 A CN104003908 A CN 104003908A CN 201410020773 A CN201410020773 A CN 201410020773A CN 104003908 A CN104003908 A CN 104003908A
- Authority
- CN
- China
- Prior art keywords
- serine
- preparation
- solvent
- reaction
- weight part
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a preparing method of hydroxyl-protected serine. According to the method, a protecting group introducing agent and serine take a reaction in solvents to obtain the protected serine; the protecting group introducing agent is bromoacetophenone; and the serine is N-Fmoc-L-serine. The preparing method has the advantages that the bromoacetophenone is adopted to be used as the protecting group introducing agent, and the main characteristics of easy preparation, high stability, goodcrystal forms and high activity are achieved; the yield is high, the product purity is high, and through NMR (Nuclear Magnetic Resonance) detection, almost no dipeptide side reaction occurs; the reaction is carried out at normal temperature and normal pressure, and the protection by protection atmosphere is not needed, so the operation is simple, and the control and the amplified production are easy; reaction solvents are directly removed after the reaction completion, pure products can be obtained through crystallization for many times, and chromatographic separation is not needed, so the production cost is greatly reduced, and the production efficiency is improved; and the recovery and reutilization of filter liquid after crude product filtering can reach 4 to 6 times, and the total conversion rate of reaction raw materials is greatly improved.
Description
Technical field
The invention belongs to Peptides Synthesis, particularly a kind of simple to operate, preparation method of Serine of being easy to the protection hydroxyl of controlling.
Background technology
The protein that glycoprotein is sugary, is formed so that glycosidic link is covalently bound by the certain amino-acid residue in oligonucleotide chain and peptide chain.Its main biological function is the bio-identification of cell or molecule, and during as ovum fertilization, sperm need be identified corresponding glycoprotein on ovum cytolemma.Film participates in cell recognition in conjunction with glycoprotein, and can be used as specific cells or cell surface marker or the surface antigen in specified phase.Participate in identification, adhesion and the migration of cell, and the propagation of regulating cell and differentiation.In sugar chain structure, can store enough identifying informations, thereby play a decisive role in molecular recognition and cell recognition.The physiological function that glycoprotein participates in comprises that adjusting, cell migration, the cell of blood coagulation, immunity, secretion, endocytosis, substance transportation, information transmission, nerve conduction, growth and differentiation are gone back to the nest, trauma repair and regeneration etc.Glycoprotein and a lot of diseases as the generation of infection, tumour, cardiovascular diseases, hepatopathy, ephrosis, diabetes and some heredopathia etc., develop relevant.Also interventional therapy day by day of glycoprotein.For example, can be used as the directed carrier of targeted therapy medicine for the antibody of specific cells surface specific sugar structure.Utilize the anti-infective and anti metastasis of carbohydrate (monose, oligosaccharides or glycopeptide) also to show up prominently.
The glycopeptide connecting key of glycoprotein, is called for short cardohydrata-peptide linkage.Mainly contain following four kinds:
N-glucosides of bonding: amino being connected of W-of the amide group of oligonucleotide chain (beta-hydroxy of GlcNAC) and Asn, a-amino, Lys or the Arg of N-end;
S-glycosides of bonding: the cardohydrata-peptide linkage taking halfcystine as tie point;
Ester glucosides of bonding: taking the free carboxy of aspartic acid, L-glutamic acid as tie point;
O-glycosides of bonding: oligonucleotide chain (Alpha-hydroxy of GalNAC) is connected with the hydroxyl of oxylysine, oxyproline with Ser, Thr.
At present; in the solid phase synthesis of polypeptide; amino, hydroxyl and carboxyl often need protection; conventional amino and the blocking group of hydroxyl are respectively: 9-fluorenylmethyloxycarbonyl (9-fluorenylmethoxycarbonyl; be called for short Fmoc; lower same) and the tertiary butyl (tert-butyl, is called for short t-Bu, lower same).Because amino hydroxyl unstable and t-Bu protection under alkali condition of Fmoc protection is unstable under sour condition.
Existing more protected amino acid is main mainly with protection amino with carboxyl, protects the less of hydroxyl, and in the time that synthetic Serine connects glycoprotein, hydroxyl mainly needs protection.And amino acid whose preparation method's yield of existing protection hydroxyl is low, in reactant, degradation production impurity is restricted mother liquor access times more.
China Patent Publication No. CN1793110A, in open day on June 28th, 2006, name is called a kind of with (Boc)
2o prepares the amino acid whose method of Boc protection, and this application case discloses a kind of use (Boc)
2o prepares the amino acid whose method of Boc protection, taking acetone and water as solvent, and triethylamine (Et
3n) under existing, amino acid reacts the amino acid that makes Boc protection with tert-Butyl dicarbonate.Its weak point is, although the method has well been protected amino, does not but protect hydroxyl, and when preparation mother liquor cannot repeatedly utilize.
Summary of the invention
The object of the invention is to amino acid whose preparation method's yield in order to solve existing protection hydroxyl low; in reactant, degradation production impurity makes the defect that mother liquor access times are restricted more; and provide a kind of yield high, simple to operate, be easy to control, the preparation method of the Serine of the reused protection hydroxyl of mother liquor.
To achieve these goals, the present invention is by the following technical solutions:
Protect a preparation method for the Serine of hydroxyl, the method makes protecting group introducing agent and Serine in solvent, react to obtain the Serine of described protection, and it is bromoacetophenone that described protecting group is introduced agent, and Serine is N-Fmoc-L-Serine.In the technical program, the carboxyl on N-Fmoc-L-Serine reacts with bromoacetophenone, obtains N-fluorenylmethyloxycarbonyl Serine-a-phenacyl ester, thus protection hydroxyl; The molecular formula of N-fluorenylmethyloxycarbonyl Serine-a-phenacyl ester is C
26h
23nO
6english referred to as Fmoc-Ser-OPAC, this product is that synthetic Serine connects a key intermediate in glycoprotein, and the N-fluorenylmethyloxycarbonyl Serine-a-phenacyl ester product yield being made by preparation method of the present invention is high, simple to operate, technological process is easy to control.
Reaction formula is:
+
→
As preferably, solvent is dimethyl formamide or dimethyl sulfoxide (DMSO).
As preferably, to react and carry out at 25-37 DEG C, the reaction times is 4-20 hour.
As preferably, preparation method comprises the following steps:
A) dissolve: the bromoacetophenone of the N-Fmoc-L Serine of 1 weight part and 1-2.33 weight part is dissolved in the dimethyl formamide or dimethyl sulfoxide (DMSO) of 6.67-20 weight part, obtain mixing solutions, to the catalyzer fluorochemical that adds 0.1-1 weight part in mixing solutions;
B) reaction: react 4-20 hour at 25-37 DEG C, drain solvent after having reacted, obtain crude product and primary solvent;
C) concentrated, crystallization: add methylene dichloride, ethylene dichloride or the trichloromethane of 6.67-13.33 weight part to dissolve in the crude product obtaining to step b), concentrated, crystallization, filtration obtains crude product, then in crude product, add ethyl acetate or trichloromethane to dissolve, add the silica gel of 0.167-0.667 weight part to stir 0.5-5 hour, condensing crystal after filtering, the Serine that obtains sterling protection hydroxyl, obtains secondary solvent filtrate gathering;
D) solvent recycling: the secondary solvent that the primary solvent that step b) is obtained and step c) obtain stirs, to adding the dimethyl formamide of 6.67-20 weight part or dimethyl sulfoxide (DMSO), the N-Fmoc-L-Serine of 1 weight part, the bromoacetophenone of 0.33-0.667 weight part in above-mentioned mixed solvent, repeating step b) and step c).
In the technical program, building-up reactions is that bromoacetophenone is greatly excessive, can make N-Fmoc-L-Serine fully react taking N-Fmoc-L-Serine and bromoacetophenone as raw material; Directly go out after completion of the reaction reaction solvent, repeatedly crystallization can obtain sterling, does not need through chromatographic separation, significantly reduce production cost, improved production efficiency, the filtrate recycling after crude product filters can reach 4-6 time, has increased substantially the total transformation efficiency of reaction raw materials.
As preferably, in step c) the add-on of ethyl acetate or trichloromethane be crude product quality 2-4 doubly.
As preferably, in step c), be concentrated into for the first time and occur that muddiness is with regard to crystallization, crystallization 10-12 hour at 0-4 DEG C.
As preferably, the pH of reaction is 9.1-9.7, and regulating the reagent of pH is sodium bicarbonate, triethylamine or sodium hydroxide.
As preferably, the number of times of solvent recycling is at 4-6 time.
As preferably, catalyzer is Sodium Fluoride or Potassium monofluoride.
Beneficial effect of the present invention:
(1) the present invention adopts bromoacetophenone to introduce agent as protecting group, and main characteristic is easy preparation, and stability is high, has good crystal formation and active high;
(2) preparation method's yield of the present invention is high, and product purity is high, is detected and is not almost had the side reaction of dipeptides to occur by NMR;
(3) the present invention's reaction is carried out at normal temperatures and pressures; protect without protective atmosphere; simple to operate, be easy to control and amplify and produce, directly go out after completion of the reaction reaction solvent; repeatedly crystallization can obtain sterling; do not need through chromatographic separation, significantly reduced production cost, improved production efficiency; filtrate recycling after crude product filters can reach 4-6 time, has increased substantially the total transformation efficiency of reaction raw materials.
Brief description of the drawings
Fig. 1 is the NMR detection figure of the product that makes of embodiment 1.
Embodiment
Below, by specific embodiment, the present invention will be further explained:
In the present invention, if not refer in particular to, the raw material adopting all can be buied from market or this area is conventional, and the method in following embodiment, if no special instructions, is the ordinary method of this area.
N-Fmoc-L-Serine is purchased from Shanghai Yan Sheng Industrial Co., Ltd.; Bromoacetophenone is purchased from Shanghai Nuo Tai Chemical Co., Ltd..
Embodiment 1
A preparation method who protects the Serine of hydroxyl, preparation method comprises the following steps:
A) dissolve: the N-Fmoc-L Serine of 30kg and 30kg bromoacetophenone are dissolved in the dimethyl formamide of 200kg, obtain mixing solutions, to the catalyzer Sodium Fluoride that adds 3kg in mixing solutions;
B) reaction: react at 25 DEG C 4 hours, drain solvent after having reacted, obtain crude product and primary solvent;
C) concentrated, crystallization: add 200kg methylene dichloride to dissolve in the crude product obtaining to step b), be concentrated into and occur muddiness crystallization 10 hours at 0 DEG C at once, filtration obtains crude product, then to the acetic acid ethyl dissolution that adds twice crude product weight in crude product, add the silica gel of 5kg to stir 0.5 hour, filter rear condensing crystal, obtain sterling N-fluorenylmethyloxycarbonyl Serine-a-phenacyl ester of 40kg, obtain secondary solvent filtrate gathering;
D) solvent recycling: the secondary solvent that the primary solvent that step b) is obtained and step c) obtain stirs, in above-mentioned mixed solvent, add the dimethyl formamide of 200kg, the N-Fmoc-L-Serine of 30kg, the bromoacetophenone of 10kg, repeating step b) and step c).Wherein, the pH of reaction is 9.1, and regulating the reagent of pH is sodium bicarbonate; The number of times of solvent recycling is at 4 times.
Embodiment 2
A preparation method who protects the Serine of hydroxyl, preparation method comprises the following steps:
A) dissolve: the N-Fmoc-L Serine of 30kg and 50kg bromoacetophenone are dissolved in the dimethyl formamide of 400kg, obtain mixing solutions, to the catalyzer Sodium Fluoride that adds 15kg in mixing solutions;
B) reaction: react at 30 DEG C 15 hours, drain solvent after having reacted, obtain crude product and primary solvent;
C) concentrated, crystallization: add 300kg ethylene dichloride to dissolve in the crude product obtaining to step b), be concentrated into and occur muddiness crystallization 11 hours at 2 DEG C at once, filtration obtains crude product, then to the acetic acid ethyl dissolution that adds three times of crude product weight in crude product, add the silica gel of 10kg to stir 3 hours, filter rear condensing crystal, obtain sterling N-fluorenylmethyloxycarbonyl Serine-a-phenacyl ester of 42kg, obtain secondary solvent filtrate gathering;
D) solvent recycling: the secondary solvent that the primary solvent that step b) is obtained and step c) obtain stirs, in above-mentioned mixed solvent, add the dimethyl formamide of 400kg, the N-Fmoc-L-Serine of 30kg, the bromoacetophenone of 30kg, repeating step b) and step c).Wherein, the pH of reaction is 9.3, and regulating the reagent of pH is sodium carbonate; The number of times of solvent recycling is at 5 times.
Embodiment 3
A preparation method who protects the Serine of hydroxyl, preparation method comprises the following steps:
A) dissolve: the N-Fmoc-L Serine of 30kg and 70kg bromoacetophenone are dissolved in the dimethyl sulfoxide (DMSO) of 600kg, obtain mixing solutions, to the catalyzer Potassium monofluoride that adds 30kg in mixing solutions;
B) reaction: react at 37 DEG C 20 hours, drain solvent after having reacted, obtain crude product and primary solvent;
C) concentrated, crystallization: add 400kg trichloromethane to dissolve in the crude product obtaining to step b), be concentrated into and occur muddiness crystallization 12 hours at 4 DEG C at once, filtration obtains crude product, then in crude product, add the trichloromethane of four times of crude product weight to dissolve, add the silica gel of 10kg to stir 5 hours, filter rear condensing crystal, obtain sterling N-fluorenylmethyloxycarbonyl Serine-a-phenacyl ester of 43kg, obtain secondary solvent filtrate gathering;
D) solvent recycling: the secondary solvent that the primary solvent that step b) is obtained and step c) obtain stirs, in above-mentioned mixed solvent, add the dimethyl sulfoxide (DMSO) of 600kg, the N-Fmoc-L-Serine of 30kg, the bromoacetophenone of 50kg, repeating step b) and step c).Wherein, the pH of reaction is 9.7, and regulating the reagent of pH is sodium hydroxide; The number of times of solvent recycling is at 6 times.
Table 1 is the quality of N-fluorenylmethyloxycarbonyl Serine-a-phenacyl ester of preparing of embodiment 1-3
| ? | Embodiment 1 | Embodiment 2 | Embodiment 3 |
| Solvent recycling number of times | 4 | 5 | 6 |
| First batch of newly-designed products quality/kg | 40 | 42 | 43 |
| Repeat for the first time to obtain quality product/kg | 39 | 40 | 41 |
| Repeat for the second time to obtain quality product/kg | 37 | 38 | 39 |
| Repeat for the third time to obtain quality product/kg | 35 | 37 | 38 |
| Repeat to obtain quality product/kg the 4th time | 34 | 36 | 37 |
| Repeat to obtain quality product/kg the 5th time | ? | 35 | 35 |
| Repeat to obtain quality product/kg the 6th time | ? | ? | 34 |
N-fluorenylmethyloxycarbonyl Serine-a-phenacyl ester that embodiment 1 is made carries out magnetic resonance detection, the results are shown in Figure 1, as seen from Figure 1, the N-fluorenylmethyloxycarbonyl Serine-a-phenacyl ester purity being made by the present invention is high, the present invention's reaction is carried out at normal temperatures and pressures, protect without protective atmosphere, simple to operate, be easy to control and amplify and produce, directly go out after completion of the reaction reaction solvent, repeatedly crystallization can obtain sterling, do not need through chromatographic separation, significantly reduce production cost, improve production efficiency, filtrate recycling after crude product filters can reach 4-6 time, increase substantially the total transformation efficiency of reaction raw materials.
Above-described embodiment is a kind of preferred version of the present invention, not the present invention is done to any pro forma restriction, also has other variant and remodeling under the prerequisite that does not exceed the technical scheme that claim records.
Claims (9)
1. protect the preparation method of the Serine of hydroxyl for one kind; the method makes protecting group introducing agent and Serine in solvent, react to obtain the Serine of described protection; it is characterized in that, it is bromoacetophenone that described protecting group is introduced agent, and Serine is N-Fmoc-L-Serine.
2. the preparation method of a kind of Serine of protecting hydroxyl according to claim 1, is characterized in that, solvent is dimethyl formamide or dimethyl sulfoxide (DMSO).
3. the preparation method of a kind of Serine of protecting hydroxyl according to claim 1, is characterized in that, reaction is carried out at 25-37 DEG C, and the reaction times is 4-20 hour.
4. the preparation method of a kind of Serine of protecting hydroxyl according to claim 1, is characterized in that, preparation method comprises the following steps:
A) dissolve: the bromoacetophenone of the N-Fmoc-L Serine of 1 weight part and 1-2.33 weight part is dissolved in the dimethyl formamide or dimethyl sulfoxide (DMSO) of 6.67-20 weight part, obtain mixing solutions, to the catalyzer fluorochemical that adds 0.1-1 weight part in mixing solutions;
B) reaction: react 4-20 hour at 25-37 DEG C, drain solvent after having reacted, obtain crude product and primary solvent;
C) concentrated, crystallization: add methylene dichloride, ethylene dichloride or the trichloromethane of 6.67-13.33 weight part to dissolve in the crude product obtaining to step b), concentrated, crystallization, filtration obtains crude product, then in crude product, add ethyl acetate or trichloromethane to dissolve, add the silica gel of 0.167-0.667 weight part to stir 0.5-5 hour, condensing crystal after filtering, the Serine that obtains sterling protection hydroxyl, obtains secondary solvent filtrate gathering;
D) solvent recycling: the secondary solvent that the primary solvent that step b) is obtained and step c) obtain stirs, to adding the dimethyl formamide of 6.67-20 weight part or dimethyl sulfoxide (DMSO), the N-Fmoc-L-Serine of 1 weight part, the bromoacetophenone of 0.33-0.667 weight part in above-mentioned mixed solvent, repeating step b) and step c).
5. the preparation method of a kind of Serine of protecting hydroxyl according to claim 4, is characterized in that, in step c) the add-on of ethyl acetate or trichloromethane be crude product quality 2-4 doubly.
6. the preparation method of a kind of Serine of protecting hydroxyl according to claim 4, is characterized in that, is concentrated into for the first time and occurs that muddiness is with regard to crystallization, crystallization 10-12 hour at 0-4 DEG C in step c).
7. according to the preparation method of a kind of Serine of protecting hydroxyl described in claim 1 or 2 or 3 or 4 or 5 or 6, it is characterized in that, the pH of reaction is 9.1-9.7, and regulating the reagent of pH is sodium bicarbonate, triethylamine or sodium hydroxide.
8. according to the preparation method of a kind of Serine of protecting hydroxyl described in claim 1 or 2 or 3 or 4 or 5 or 6, it is characterized in that, the number of times of solvent recycling is at 4-6 time.
9. according to the preparation method of a kind of Serine of protecting hydroxyl described in claim 1 or 2 or 3 or 4 or 5 or 6, it is characterized in that, catalyzer is Sodium Fluoride or Potassium monofluoride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410020773.6A CN104003908B (en) | 2014-01-17 | 2014-01-17 | A kind of preparation method of the serine protecting hydroxyl |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410020773.6A CN104003908B (en) | 2014-01-17 | 2014-01-17 | A kind of preparation method of the serine protecting hydroxyl |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104003908A true CN104003908A (en) | 2014-08-27 |
| CN104003908B CN104003908B (en) | 2016-08-17 |
Family
ID=51364843
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410020773.6A Expired - Fee Related CN104003908B (en) | 2014-01-17 | 2014-01-17 | A kind of preparation method of the serine protecting hydroxyl |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104003908B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112094205A (en) * | 2019-06-18 | 2020-12-18 | 成都郑源生化科技有限公司 | Method for preparing Fmoc-Ser (tBu) -OH |
| CN115340472A (en) * | 2022-09-19 | 2022-11-15 | 合肥工业大学 | Glutamic acid derivative and synthetic method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004084812A2 (en) * | 2003-03-21 | 2004-10-07 | Joullie Madeleine M | Tamandarin analogs and fragments thereof and methods of making and using |
| CN101177449A (en) * | 2006-11-10 | 2008-05-14 | 中国医学科学院药物研究所 | Furca polypeptide, drug composition and use thereof |
-
2014
- 2014-01-17 CN CN201410020773.6A patent/CN104003908B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004084812A2 (en) * | 2003-03-21 | 2004-10-07 | Joullie Madeleine M | Tamandarin analogs and fragments thereof and methods of making and using |
| CN101177449A (en) * | 2006-11-10 | 2008-05-14 | 中国医学科学院药物研究所 | Furca polypeptide, drug composition and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| ADRIO, JAVIER等: "Total synthesis and biological evaluation of Tamandarin B analogues", 《JOURNAL OF ORGANIC CHEMISTRY》, vol. 72, no. 14, 8 June 2007 (2007-06-08), pages 5129 - 5138, XP002527477, DOI: 10.1021/JO070412R * |
| WAKAMIYA, TATEAKI等: "Preparations of Nα-Fmoc-O-[(benzyloxy)hydroxyphosphinyl] β-hydroxy α-amino acid derivatives", 《BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN》, vol. 69, no. 2, 31 December 1996 (1996-12-31), pages 465 - 468 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112094205A (en) * | 2019-06-18 | 2020-12-18 | 成都郑源生化科技有限公司 | Method for preparing Fmoc-Ser (tBu) -OH |
| CN112094205B (en) * | 2019-06-18 | 2022-06-21 | 成都郑源生化科技有限公司 | Method for preparing Fmoc-Ser (tBu) -OH |
| CN115340472A (en) * | 2022-09-19 | 2022-11-15 | 合肥工业大学 | Glutamic acid derivative and synthetic method and application thereof |
| CN115340472B (en) * | 2022-09-19 | 2024-05-07 | 合肥工业大学 | Glutamic acid derivative and synthesis method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104003908B (en) | 2016-08-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107129444B (en) | (S) -2- t-butoxycarbonyl aminos -3- (4- carbamyl -2,6- 3,5-dimethylphenyls) propionic acid preparation method | |
| CN105524143B (en) | A method of synthesis Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2 | |
| CN106632335A (en) | Preparation method of valaciclovir hydrochloride | |
| CN105504012A (en) | Preparation method of polypeptide | |
| CN104003908A (en) | Preparing method of hydroxyl-protected serine | |
| JP4942295B2 (en) | Method for producing L-alanine-L-glutamine | |
| CN112645912B (en) | Preparation method of high-purity M2 crystal form meclofenol sodium | |
| CN107936090B (en) | Method for synthesizing ARK-Cu at low cost | |
| Iwakura et al. | Stepwise synthesis of oligopeptides with N‐carboxy α‐amino acid anhydrides | |
| CN109180752A (en) | A method of recycling kanamycin A from amikacin Synthesis liquid | |
| CN103351426B (en) | A kind of polypeptide synthesis method of octreotide acetate | |
| CN101508724B (en) | Method of preparing tetradecapeptide somatostatin | |
| CN102690325B (en) | Synthesis of polypeptide PyroGlu-Pro-Arg-pNA.HCl | |
| CN104817631A (en) | Method for synthesizing sinapultide | |
| Inouye et al. | A synthesis of thyrotropin-releasing factor | |
| CN108948157A (en) | A method of preparing Te Lawan star | |
| US3862113A (en) | Process for the selective elimination of aralkyloxycarbonyl and trityl n-protecting groups with 2,2,2-trifluoroethanol | |
| WO2021103458A1 (en) | Solid-phase synthesis method for degarelix | |
| CN110330560B (en) | Synthetic method of lanreotide acetate | |
| CN101033248B (en) | Process of preparing calf thymus alphal | |
| CN102628072A (en) | Preparation method of insulin | |
| CN103570639A (en) | Synthetic method of linezolid | |
| US3655636A (en) | Process for the synthesis of peptides using 4-pyridylmethyl and related groups for the protection of c-terminal carboxyl groups | |
| CN103059027A (en) | Method for preparing tebipenem pivoxil | |
| CN107266373A (en) | A kind of bulk drug Da Shabuwei preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160817 Termination date: 20180117 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |