CN106928171A - Fmoc‑Arg（Pbf）The synthetic method of OH - Google Patents
Fmoc‑Arg（Pbf）The synthetic method of OH Download PDFInfo
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- CN106928171A CN106928171A CN201710305099.XA CN201710305099A CN106928171A CN 106928171 A CN106928171 A CN 106928171A CN 201710305099 A CN201710305099 A CN 201710305099A CN 106928171 A CN106928171 A CN 106928171A
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- 0 CC(C1C)C(OC(C)(C)C2)=C2C(C)=C1*(*C1(C*CCCCC(*C=C)C(O)=O)CC1)=O Chemical compound CC(C1C)C(OC(C)(C)C2)=C2C(C)=C1*(*C1(C*CCCCC(*C=C)C(O)=O)CC1)=O 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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Abstract
The present invention relates to the synthetic method of Fmoc Arg (Pbf) OH, belong to arginic protection technique field.The synthetic method of Fmoc Arg (Pbf) OH of the invention is first by arginic carboxyl esterification; Boc bases are introduced on amino again amido protecting gets up, Pbf groups are introduced on guanidine radicals, slough Boc groups; saponification, finally introduces Fmoc groups on amino.Fmoc Arg (Pbf) OH is synthesized using the method for the present invention, only needing to just can be Arg total overall reaction using 1.1 times of Pbf Cl, still there is arginine unreacted when the consumption of Pbf Cl is arginic 2 times compared to existing technology, Pbf Cl consumptions of the invention are substantially reduced, and it is remaining without Arg, Pbf Cl are expensive, therefore cost of the invention is greatly reduced, and is conducive to industrial application.
Description
Technical field
The present invention relates to the synthetic method of Fmoc-Arg (Pbf)-OH, belong to arginic protection technique field.
Background technology
Arginine is that one kind can spontaneous essential amino acid in vivo.In life science, in order to avoid
The generation of accessory substance, it is necessary to protected to arginic amino and guanidine radicals.
Fmoc-Arg (Pbf)-OH is exactly to protect amino using Fmoc (9-fluorenylmethyloxycarbonyl), with Pbf (2,2,4,6,7- five
Methyl benzofuran -5- sulfonyls) protection guanidine radicals.
Synthesis [J] chemical reagent of big vast abundant grade .Fmoc-Arg (Pbf)-OH of a large bell, 2006,28 (1), 57~58.Disclose
A kind of synthetic method of Fmoc-Arg (Pbf)-OH, the method carries out middle protection using Cbz (benzyloxycarbonyl group) to amino, in guanidine
Cbz is sloughed after introducing Pbf on base, then Fmoc is introduced on amino, protected in aqueous phase reactions, Pbf- using the Cbz of the above method
Cl consumptions are very high, easily decompose, and reaction is not thorough, and Pbf is expensive thus benefit is not obvious, non-industrial applications.
The Chinese patent application of Application No. 200810034390.9 discloses a kind of arginine double-protective preparation technique, its
After first protecting amino with Boc (tertbutyloxycarbonyl), then Pbf is introduced on guanidine radicals, then slough the Boc on amino, introduce Fmoc pairs
Arginine is protected.The above method avoids hydrogenolysis, and product purity >=99.0%, total recovery can reach 63.51%.But
It is big using the consumption of above method Pbf-Cl, also has a large amount of arginine remnants, the consumption of Pbf-Cl is arginic 2 times
When, still there is arginine unreacted.
Additionally, in the prior art, when introducing Pbf, its reaction temperature must be controlled in -15 DEG C~+15 DEG C relatively low of temperature,
If rising, high reaction temperature is high, reaction effect can be excessively poor, and Pbf consumptions can increase, while accessory substance can be very serious, produces big
The citrulling derivative and ornithine derivative of amount, purifying are difficult, without economic benefit.Prior art is preferably at 5-10 DEG C
Pbf is introduced, but Pbf consumptions are still very big, it is ineffective, therefore, since 2006, applicant just stopped using original work
Skill, starts to be devoted to the profitable new technology of research and development.
The content of the invention
The invention provides a kind of synthetic method of Fmoc-Arg (Pbf)-OH, the consumption of Pbf-Cl is reduced, low cost.
In order to solve the above technical problems, the synthetic method of Fmoc-Arg (Pbf)-OH of the invention comprises the following steps：
(1) it is esterified
(2) Boc groups are introduced
(3) Pbf is introduced
(4) Boc is taken off
(5) saponification
(6) Fmoc-Arg (Pbf)-OH synthesis
Wherein, the R is methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, benzyl, benzhydryl or triphen first
At least one in base.
Preferably, the R is methyl or ethyl.
Preferably, the preferred arginine monohydrochloride of the arginine or arginine alkali.
Preferably, the technique of step (1) esterification comprises the following steps：
A1. to thionyl chloride, reaction temperature -10~0 DEG C is added dropwise in absolute ethyl alcohol or absolute methanol；
B1. Arg.HCl is added, 0 DEG C~50 DEG C is warming up to and is reacted 24~72 hours；
C1. after reaction terminates, Arg.Oet.2HCl the or Arg.OMe.2HCl intermediates of grease are concentrated under reduced pressure to give.
Preferably, the absolute ethyl alcohol or absolute methanol are with the mol ratio of thionyl chloride：5~30:1.
Preferably, the technique of the introducing Pbf described in step (3) comprises the following steps：
A3. mol ratio Boc-ArgOR.HCl is taken：Pbf-Cl：Solvent：Potassium carbonate：Water=1:1~2:15~90：3~8:1
~20 material, mixes；
B3. after the completion of reacting, suction filtration removes solid insoluble, and vacuum distillation removes solvent, obtains Boc-Arg (Pbf)
OR；
Wherein, the solvent is tetrahydrofuran, dioxane, at least one in acetone.
Preferably, a3 steps temperature maintains 40~45 DEG C.
Preferably, Boc-ArgOR.HCl described in a3 steps：The mol ratio of Pbf-Cl is 1:1.1.
Preferably, the technique of step (5) described saponification comprises the following steps：
H-Arg (Pbf) OR that step (4) is obtained adds ethanol to dissolve, and regulation pH 10~12 carries out saponification, saponification time 3
~4 hours, purifying obtained final product H-Arg (Pbf) OH.
Preferably, step 5 controls pH 10~12 using sodium hydroxide solution.
Beneficial effect：
Fmoc-Arg (Pbf)-OH is synthesized using the method for the present invention, it is only necessary to use 1.1 times of Pbf-Cl of arg moles
Just can still there is arginine not anti-when the consumption of Pbf-Cl is arginic 2 times compared to existing technology arg total overall reactions
Should, Pbf-Cl consumptions of the invention are substantially reduced, and remaining without arg, and Pbf-Cl is expensive, therefore cost of the invention
Substantially reduce, additionally, the introducing temperature of Pbf is high, it is profitable, be conducive to industrial application.
Specific embodiment
The synthetic method of Fmoc-Arg (Pbf)-OH of the invention comprises the following steps：
(1) it is esterified
(2) Boc groups are introduced
(3) Pbf is introduced
(4) Boc is taken off
(5) saponification
(6) Fmoc-Arg (Pbf)-OH synthesis
Wherein, the R is methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, benzyl, benzhydryl or triphen first
At least one in base.
Preferably, the R is methyl or ethyl
Preferably, the preferred arginine monohydrochloride of the arginine or arginine alkali.
Preferably, the technique of step (1) described esterification comprises the following steps：
A1. to thionyl chloride, reaction temperature -10~0 DEG C is added dropwise in absolute ethyl alcohol or absolute methanol；
B1. Arg.HCl is added, is heated up naturally, 0 DEG C~50 DEG C are reacted 24~72 hours；
C1. after reaction terminates, Arg.Oet.2HCl the or Arg.OMe.2HCl intermediates of grease are concentrated under reduced pressure to give.
Preferably, the absolute ethyl alcohol or absolute methanol are with the mol ratio of thionyl chloride:5~30:1.
Preferably, the technique of the introducing Pbf described in step (3) comprises the following steps：
A3. mol ratio Boc-ArgOR.HCl is taken：Pbf-Cl：Solvent：Potassium carbonate：Water=1:1~2:15~90：3~8:1
~20 material, mixes；
B3. after the completion of reacting, suction filtration removes solid insoluble, and vacuum distillation removes solvent, obtains Boc-Arg (Pbf)
OR；
Wherein, the solvent is tetrahydrofuran, dioxane, at least one in acetone.
Preferably, a3 steps temperature maintains 40~45 DEG C.
Preferably, Boc-ArgOR.HCl described in a3 steps：The mol ratio of Pbf-Cl is 1:1.1.
Preferably, the technique of step (5) described saponification comprises the following steps：
H-Arg (Pbf) OR that step (4) is obtained adds ethanol to dissolve, and regulation pH 10~12 carries out saponification, saponification time 3
~4 hours, purifying obtained final product H-Arg (Pbf) OH.
Preferably, step 5 controls pH 10~12 using sodium hydroxide solution.
Specific embodiment of the invention is further described with reference to embodiment, is not therefore limited the present invention
System is among described scope of embodiments.
Embodiment 1
(1) it is esterified
A1. 100L absolute ethyl alcohols are added in pre-dry 300L reactors, logical brine ice is cooled to -5~-10 DEG C,
Thionyl chloride 13L is added dropwise.
B1. the Arg.HCl 21.5kg of D types are added, brine ice is closed, room temperature reaction is warmed naturally to 24 hours.
C1. 35 DEG C of reactions are warming up to, TLC points plate tracking response situation, reaction about 48h terminates.
D1. concentrate：After reaction terminates, the ArgOet2HCl intermediates of grease are concentrated under reduced pressure to give.
(2) Boc groups are introduced
A2. 150L water is added in 300L reactors, sodium acid carbonate 25.2kg is added, is stirred；
It is gradually added into ArgOet2HCl grease；Add tetrahydrofuran 30L；It is dividedly in some parts (Boc)2O, 26.2kg are stirred
Mix, room temperature reaction；
TLC methods point plate tracks response situation, when ArgOet2HCl has reacted i.e. start to process.
B2. it is acidified：PH 3-4 are adjusted after the completion of reaction, with petrol ether/ethyl acetate (50L:25L), extract；
C2. plus salt loading, PH 6-7 are adjusted back, product is carried with ethyl acetate, with saturated common salt water washing organic phase.
D2. dry：To the anhydrous sodium sulfate that 60kg is added in organic phase (in the ethyl acetate solution with product), 8 are dried
Hour.
E2. purification concentration：Leach out solid sodium sulfate, vacuum distillation ethyl acetate phase.The Boc- obtained after concentration
ArgOet.HCl grease.
(3) Pbf is introduced
A3. the Boc-ArgOet.HCl, Pbf-Cl 31.9kg, acetone for adding step 2 to obtain in 300L reactors
200L, potassium carbonate 41.7kg, stirring, plus a small amount of water, maintain 40-45 DEG C of temperature, are monitored with TLC and reacted, and treat Boc-
ArgOet.HCl reacts completely carries out suction filtration,
B3. suction filtration, removes solid insoluble, and vacuum distillation acetone obtains Boc-Arg (Pbf) Oet grease after concentration
It is stand-by.
(4) Boc is taken off
A4. in dry 300L reactors, 3N HCl/ ethyl acetate solution 120L are added, stirring is lower to add Boc-Arg
(Pbf) Oet grease, maintains 10-15 DEG C of temperature, is stirred at room temperature.
B4. take off after the completion of Boc, add water washing, product is washed till water phase, plus proper amount of sodium carbonate regulation water phase pH7.
(5) saponification
A5. step (4) gained water is added 95% ethanol 100L, stirring is added dropwise 10N NaOH aqueous solution regulation pH 11-
12 carry out saponification.
B5. after saponification terminates, the pH value of reaction solution is adjusted to 7 with 6NHCl, be cooled to -10-0 DEG C of freezing and crystallizing；From
The heart, solid ethyl acetate is stirred to be washed once, and centrifuge dripping collects solid；It is recrystallized to give H-Arg (Pbf) OH solids.
(6) Fmoc-Arg (Pbf)-OH synthesis
A6. H-Arg (Pbf)-OH, water 120L, THF is added in a kettle., uses Na2CO3Regulation PH=8.5.
B6. Fmoc-Osu (fluorenes methoxy carbonyl acyl succinimide) is gradually added into, 15-20 DEG C of temperature is controlled, PH=8-9 is with handle
Arg (Pbf) has been reacted, and Fmoc-Osu excess is avoided as far as possible.
TLC points plate tracks response situation, is calculated since Fmoc-Osu is added, 6 hours reaction time.
C6. purify：With petrol ether/ethyl acetate (2:1) extract；Water HCl is acidified to pH=3, stirs 2 hours.Acid
Change 0-10 DEG C of temperature；Plus ethyl acetate extracted products；PH is washed to saturated common salt reach 6；Anhydrous sodium sulfate drying, vacuum is taken out
Solid is filtered, filtrate concentration is concentrated under reduced pressure to give solid, and vacuum drying obtains product.
Product purity 99.6%, maximum single miscellaneous 0.09%, L-type isomers 0.15%.
Embodiment 2
(1) it is esterified
A1. 100L absolute methanols are added in pre-dry 300L reactors, logical brine ice is cooled to -5~-10 DEG C,
Thionyl chloride 13L is added dropwise.
B1. the Arg.HCl 21.5kg of L-type are added, brine ice is closed, room temperature reaction is warmed naturally to 24 hours.
C1. 35 DEG C of reactions are warming up to, TLC points plate tracking response situation, reaction terminates for about 48 hours.
D1. concentrate：After reaction terminates, the ArgOMe2HCl intermediates of grease are concentrated under reduced pressure to give.
(2) Boc groups are introduced
A2. 150L water is added in 300L reactors, sodium acid carbonate 25.2kg is added, is stirred；
It is gradually added into ArgOMe2HCl grease；Add tetrahydrofuran 30L；It is dividedly in some parts (Boc)2O, 26.16kg
Stirring, room temperature reaction；
TLC methods point plate tracks response situation, when ArgOMe2HCl has reacted i.e. start to process.
B2. it is acidified：PH 3-4 are adjusted after the completion of reaction, with petrol ether/ethyl acetate (50L:25L) extract,
C2. plus salt loading, pH 6-7 are adjusted back, product is carried with ethyl acetate, with saturated common salt water washing organic phase.
D2. dry：To the anhydrous sodium sulfate that 70kg is added in organic phase (in the ethyl acetate solution with product), 8 are dried
Hour.
E2. purification concentration：Leach out solid sodium sulfate, vacuum distillation ethyl acetate phase.The Boc- obtained after concentration
ArgOMe.HCl grease.
(3) Pbf is introduced
A3. the Boc-ArgOMe.HCl, Pbf-Cl 31.9kg, acetone for adding step 2 to obtain in 300L reactors
200L, potassium carbonate 41.7kg, stirring, plus a small amount of water；40-45 DEG C of temperature is maintained, is monitored with TLC and reacted, treat Boc-
ArgOet.HCl reacts completely carries out suction filtration,
B3. suction filtration, removes solid insoluble, and vacuum distillation acetone obtains Boc-Arg (Pbf) OMe grease after concentration
It is stand-by.
(4) Boc is taken off
A4. in dry 300L reactors, 3NHCl/ ethyl acetate solution 120L are added, stirring is lower to add Boc-Arg
(Pbf) OMe.HCl grease, maintains 10-15 DEG C of temperature.It is stirred at room temperature.
B4. take off after the completion of Boc, add water washing, product is washed till water phase, plus proper amount of sodium carbonate regulation water phase pH7.
(5) saponification
A5. upper gained water is added 95% ethanol 100L, stirring, dropwise addition 10N NaOH aqueous solution regulations pH11-12 is carried out
Saponification.
B5. after saponification terminates, the pH value of reaction solution is adjusted to 7 with 6NHCl, be cooled to -10-0 DEG C of freezing and crystallizing；From
The heart, solid ethyl acetate is stirred to be washed once, and centrifuge dripping collects solid.It is recrystallized to give H-Arg (Pbf) OH solids.
(6) Fmoc-Arg (Pbf)-OH synthesis
A6. H-Arg (Pbf)-OH, water 120L, THF is added in a kettle., and PH=8.5 is adjusted with Na2CO3.
B6. Fmoc-Osu (fluorenes methoxy carbonyl acyl succinimide) is gradually added into, 15-20 DEG C of temperature is controlled, PH=8-9 is with handle
Arg (Pbf) has been reacted, and Fmoc-Osu excess is avoided as far as possible.
TLC points plate tracks response situation, is calculated since Fmoc-Osu is added, 6 hours reaction time.
C6. purify：With petrol ether/ethyl acetate (2:1) extract；Water HCl is acidified to pH=3, stirs 2 hours.Acid
Change 0-10 DEG C of temperature；Plus ethyl acetate extracted products；PH is washed to saturated common salt reach 6；
Plus anhydrous sodium sulfate drying, 8 hours；Vacuum filtration removes solid sodium sulfate, and filtrate concentration is concentrated under reduced pressure to give solid
Body, vacuum drying obtains product.
Product purity 99.5%, maximum single miscellaneous 0.11%, D types isomers 0.17%
Comparative example
Design tri- groups of parallel comparative examples of A, B and C, comparative example A and B synthesize Boc- using method for optimizing of the prior art
Arg (Pbf), in the prior art, improves reaction temperature, and reaction effect can be excessively poor, and Pbf consumptions can increase, while accessory substance meeting
Very serious, preferred reaction temperature is 5-10 DEG C.Comparative example C synthesizes Boc-Arg (Pbf) using the method for the present invention.
Comparative example A：Boc-Arg.HCl.H is added in 300ml acetone2O 32.88g (water content 6.1%, 0.1mol),
Stirring, maintains 5-10 DEG C of temperature, maintains pH 10-12, is gradually added into Pbf-Cl, and 31.77g (0.11mol) samplings react 3-4 small
When sample, HPLC determines residue Boc-Arg.HCl.H2O measures M1。
Comparative example B：Boc-Arg.HCl.H is added in 300ml acetone2O 32.88g (water content 6.1%, 0.1mol),
Stirring, maintains 5-10 DEG C of temperature, maintains pH 10-12, adds Pbf-Cl, 57.76 (0.2mol) to react 3-4 hours and samples, HPLC
Determine residue Boc-Arg.HCl.H2O measures M2。
Comparative example C：Boc-Arg-Oet.HCl.33.9g (0.1mol) is added in 300ml acetone, stirring maintains pH
10-12, maintains 40-45 DEG C of temperature to add Pbf-Cl, 31.77g (0.11mol), reacts 3-4 hours, and TLC detections, ninhydrin shows
Color, Boc-Arg-Oet.HCl is without residue.
As a result：
Measure the M of A1Boc-Arg.HCl.H2O residues 24.4%, the M of B2Boc-Arg.HCl.H2O residues 4.6%.C's
Boc-Arg-Oet.HCl reacts completely.
Can be seen by comparative example, in the case of being lacked using technical scheme Pbf-Cl consumptions, arginine also can be complete
Full response, Pbf-Cl is expensive, therefore cost of the invention is greatly reduced, and is conducive to industrial application.
Claims (10)
- The synthetic method of 1.Fmoc-Arg (Pbf)-OH, it is characterised in that comprise the following steps：(1) it is esterified(2) Boc groups are introduced(3) Pbf is introduced(4) Boc is taken off(5) saponification(6) Fmoc-Arg (Pbf)-OH synthesisWherein, the R is in methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, benzyl, benzhydryl or trityl At least one.
- 2. the synthetic method of Fmoc-Arg (Pbf)-OH according to claim 1, it is characterised in that the R be methyl or Ethyl.
- 3. the synthetic method of Fmoc-Arg (Pbf)-OH according to claim 1 and 2, it is characterised in that the arginine It is arginine monohydrochloride or arginine alkali.
- 4. the synthetic method of Fmoc-Arg (Pbf)-OH according to Claims 2 or 3, it is characterised in that step (1) is esterified Technique comprise the following steps：A1. to thionyl chloride, reaction temperature -10~0 DEG C is added dropwise in absolute ethyl alcohol or absolute methanol；B1. Arg.HCl is added, 0 DEG C~50 DEG C is warming up to and is reacted 24~72 hours；C1. after reaction terminates, it is concentrated under reduced pressure, obtains Arg.Oet.2HCl the or Arg.OMe.2HCl intermediates of grease.
- 5. the synthetic method of Fmoc-Arg (Pbf)-OH according to claim 4, it is characterised in that the absolute ethyl alcohol or Absolute methanol is with the mol ratio of thionyl chloride：5~30:1.
- 6. the synthetic method of Fmoc-Arg (Pbf)-OH according to any one of claim 1-5, it is characterised in that step (3) technique of the introducing Pbf described in comprises the following steps：A3. mol ratio Boc-ArgOR.HCl is taken：Pbf-Cl：Solvent：Potassium carbonate：Water=1:1~2:15~90：3~8:1~20 Material, mix；B3. after the completion of reacting, suction filtration removes solid insoluble, and vacuum distillation removes solvent, obtains Boc-Arg (Pbf)-OR；Wherein, the solvent is tetrahydrofuran, dioxane, at least one in acetone.
- 7. the synthetic method of Fmoc-Arg (Pbf)-OH according to claim 6, it is characterised in that a3 steps temperature is maintained 40~45 DEG C.
- 8. the synthetic method of Fmoc-Arg (Pbf)-OH according to claim 6, it is characterised in that Boc- described in a3 steps ArgOR.HCl：The mol ratio of Pbf-Cl is 1:1.1.
- 9. the synthetic method of Fmoc-Arg (Pbf)-OH according to any one of claim 2-8, it is characterised in that step (5) technique of the saponification comprises the following steps：H-Arg (Pbf) OR that step (4) is obtained adds ethanol to dissolve, and regulation pH 10~12 carries out saponification, saponification time 3~4 Hour, purifying obtains final product H-Arg (Pbf) OH.
- 10. the synthetic method of Fmoc-Arg (Pbf)-OH according to any one of claim 2-9, it is characterised in that step 5 control pH 10~12 using sodium hydroxide solution.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109470799A (en) * | 2018-12-29 | 2019-03-15 | 成都市科隆化学品有限公司 | The purity and impurity position finding and detection method of Fmoc-Arg (Pbf)-OH |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101250172A (en) * | 2008-03-07 | 2008-08-27 | 上海瀚鸿化工科技有限公司 | Arginine double-protective preparation technique |
| WO2015154031A1 (en) * | 2014-04-03 | 2015-10-08 | Amgen Inc. | Method for preparing amg 416 |
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2017
- 2017-05-03 CN CN201710305099.XA patent/CN106928171B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101250172A (en) * | 2008-03-07 | 2008-08-27 | 上海瀚鸿化工科技有限公司 | Arginine double-protective preparation technique |
| WO2015154031A1 (en) * | 2014-04-03 | 2015-10-08 | Amgen Inc. | Method for preparing amg 416 |
Non-Patent Citations (2)
| Title |
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| PEREZ-LOPEZ, ANA M.等: "Synthesis of L-octaarginine through microencapsulated palladium-catalyzed allyl ester deprotection", 《SYNLETT》 * |
| 洪镛裕等: "Fmoc-Arg(Pbf)-OH 的合成", 《化学试剂》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109470799A (en) * | 2018-12-29 | 2019-03-15 | 成都市科隆化学品有限公司 | The purity and impurity position finding and detection method of Fmoc-Arg (Pbf)-OH |
| CN109470799B (en) * | 2018-12-29 | 2021-07-27 | 成都市科隆化学品有限公司 | Fmoc-Arg (Pbf) -OH purity and impurity localization detection method |
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