CN118307460A - Synthesis method of 9-fluorenylmethyl-N-succinimidyl carbonate - Google Patents
Synthesis method of 9-fluorenylmethyl-N-succinimidyl carbonate Download PDFInfo
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- CN118307460A CN118307460A CN202410399859.8A CN202410399859A CN118307460A CN 118307460 A CN118307460 A CN 118307460A CN 202410399859 A CN202410399859 A CN 202410399859A CN 118307460 A CN118307460 A CN 118307460A
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- fluorenylmethyl
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- succinimidyl carbonate
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- WMSUFWLPZLCIHP-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 9h-fluoren-9-ylmethyl carbonate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)ON1C(=O)CCC1=O WMSUFWLPZLCIHP-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000001308 synthesis method Methods 0.000 title claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 30
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000007787 solid Substances 0.000 claims abstract description 25
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 claims abstract description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 16
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims abstract description 15
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- XXSCONYSQQLHTH-UHFFFAOYSA-N 9h-fluoren-9-ylmethanol Chemical compound C1=CC=C2C(CO)C3=CC=CC=C3C2=C1 XXSCONYSQQLHTH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000001035 drying Methods 0.000 claims abstract description 13
- 238000001914 filtration Methods 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
- 239000000843 powder Substances 0.000 claims abstract description 6
- 239000013078 crystal Substances 0.000 claims abstract description 5
- 239000003208 petroleum Substances 0.000 claims abstract description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000047 product Substances 0.000 claims description 18
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 239000002274 desiccant Substances 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 4
- 150000007530 organic bases Chemical class 0.000 abstract description 6
- 230000035484 reaction time Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- -1 fluorenylmethoxycarbonyl succinimide Chemical compound 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- HAHFLCWVYBLDQV-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl 2,5-dioxopyrrolidine-3-carboxylate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)C1CC(=O)NC1=O HAHFLCWVYBLDQV-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 230000006750 UV protection Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000005201 scrubbing Methods 0.000 description 1
- KLBOFRLEHJAXIU-UHFFFAOYSA-N tributylazanium;chloride Chemical compound Cl.CCCCN(CCCC)CCCC KLBOFRLEHJAXIU-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a method for synthesizing 9-fluorenylmethyl-N-succinimidyl carbonate, which comprises the following steps: (1) preparation of Fmoc-Cl: tetrahydrofuran, 9-fluorenylmethanol and pyridine are introduced into a reaction kettle to react to obtain Fmoc-Cl; (2) Preparation of 9-fluorenylmethyl-N-succinimidyl carbonate: fmoc-Cl is dissolved in tetrahydrofuran, solid HOSU is added at one time, and morpholine, indole and tetrahydrofuran are introduced into an elevated tank for reaction; (3) post-treatment: after the reaction is finished, filtering, adding petroleum ether to separate out white crystal powder of 9-fluorenylmethyl-N-succinimidyl carbonate, and drying to obtain the 9-fluorenylmethyl-N-succinimidyl carbonate. The invention adopts morpholine and indole as organic base, which is helpful to improve the yield and purity of Fmoc-Osu, and in addition, the reaction time can be obviously shortened.
Description
Technical Field
The invention relates to the technical field of fine chemical engineering, in particular to a method for synthesizing 9-fluorenylmethyl-N-succinimidyl carbonate.
Background
9-Fluorenylmethyl-N-succinimidyl carbonate (Fmoc-Osu) is widely used as an amino acid protecting agent, and can selectively protect an amino acid containing a hydroxyl group. The chemical structure and CAS number of Fmoc-Osu are as follows:
(9-fluorenylmethyl-N-succinimidyl carbonate, fmoc-OSU)
CAS No.82911-69-1
Chemical Formula：C19H15NO5
Molecular Weight：337.33
Fmoc-Osu synthesis is reported both at home and abroad. For example, chinese patent CN104030962B discloses a process for producing fluorenylmethoxycarbonyl succinimide and co-producing N, N' -disuccinimidyl carbonate, comprising the steps of: (1) Preparing Fmoc-Cl, adding THF, 9-fluorenylmethanol and an organic amine catalyst into a reaction kettle, cooling to 0-10 ℃, adding solid phosgene, and continuing to react until the reaction is complete, (2) preparing Fmoc-Osu and DSC: adding Hosu, cooling to-5 to +5 ℃, dropwise adding tetrahydrofuran solution of tributylamine, heating to room temperature after the addition until the reaction is completed, (3) filtering to obtain DSC crude product, and (4) carrying out post-treatment on mother liquor to obtain Fmoc-Osu. According to the invention, a proper amount of 9-fluorenyl methanol is added into Hosu, solid phosgene and tributylamine system, so that two products of Fmoc-Osu and DSC can be quantitatively generated, wherein DSC is precipitated as a crystalline solid, and Fmoc-Osu and tributylamine hydrochloride are still dissolved in tetrahydrofuran solvent; therefore, both products can be subjected to conventional operations such as filtration, purification and the like to obtain refined products with purity of more than 99 percent. However, the reaction requires a large excess of Hosu, and recovery of excess Hosu is difficult. This results in high Hosu raw material consumption.
For another example, chinese patent CN101817776B discloses a method for synthesizing 9-fluorenylmethoxycarbonyl succinimide ester, which comprises the steps of: a) Adding an organic solvent, reactants Fmoc-Cl, N-hydroxysuccinimide and a catalyst into a reaction container for reaction; b) Filtering the reaction product in the reaction vessel to obtain a solid and a residual liquid, and drying the solid to obtain a 9-fluorenylmethoxycarbonyl succinimide ester product; in the step a), the organic solvent is an aprotic solvent. The method has the advantages of simple process, safety, convenience, mild conditions and high yield, and the synthesized Fmoc-ONSu product can reach more than 98% in purity without refining. However, the crude Fmoc-Osu product generated by the reaction contains triethylamine hydrochloride impurity, so that removal is difficult, and the product quality of Fmoc-Osu is affected.
For another example, chinese patent application CN1693303a discloses a new process for synthesizing 9-fluorenylmethoxycarbonyl succinimide (abbreviated as Fmoc-ONSu), which comprises the following steps: adding aqueous solution of succinimide into ethyl acetate solution of fluorenylmethoxycarbonyl chloroformate, adding inorganic base in batches, stirring for reaction, filtering, washing and drying to obtain the product. The Fmoc-ONSu synthesis method provided by the application of the invention has the advantages of simple process, mild condition, use of nontoxic and harmless ethyl acetate solvent, complete recycling and easy industrial production; the synthesized product is easy to separate, has high yield and high purity, and can be directly applied to the preparation of the protected amino acid required in polypeptide synthesis without refining. However, in this reaction, unreacted Fmoc-cl was dissolved in ethyl acetate and was readily hydrolyzed with water to give 9-fluorenylmethanol impurity. When the solvent is used for the next reaction according to the method disclosed in the patent, impurities which are not easy to separate appear in the Fmoc-Osu product, and the product quality of the Fmoc-Osu is also influenced.
Therefore, how to provide a method for synthesizing 9-fluorenylmethyl-N-succinimidyl carbonate with low cost and high yield and purity is still a technical problem to be solved urgently by those skilled in the art.
Disclosure of Invention
Based on the background technology, the invention aims to provide a dry powder coating with good water resistance, alkali resistance, scrubbing resistance, ultraviolet resistance and temperature resistance. In order to achieve the aim of the invention, the following technical scheme is adopted:
the invention relates to a method for synthesizing 9-fluorenylmethyl-N-succinimidyl carbonate, which comprises the following steps:
(1) Preparation of Fmoc-Cl: tetrahydrofuran, 9-fluorenyl methanol and pyridine are introduced into a reaction kettle, and the mixture is cooled to 0-2 ℃ under stirring. Adding solid light in batches, adding solid phosgene after 8-12hr, and reacting at 5-6deg.C for 2-3hr; cooling the reaction liquid to below 10 ℃, quenching, washing with water, saturated saline washing, drying with a drying agent, and filtering to obtain Fmoc-Cl;
(2) Preparation of 9-fluorenylmethyl-N-succinimidyl carbonate: fmoc-Cl is dissolved in tetrahydrofuran, solid HOSU is added at one time, and the mixture is fully dissolved under stirring, so that the feed liquid in the kettle is kept at-2 ℃ to 0 ℃; introducing morpholine, indole and tetrahydrofuran into a high-level tank, mixing uniformly, slowly adding into a reaction kettle for reaction within 8-10hr, keeping the temperature in the kettle not higher than 5 ℃, and continuing to react for 3-4hr at room temperature after dripping is finished;
(3) Post-treatment: filtering to obtain filtrate, vacuum-controlling the temperature to 0-5 deg.C, removing tetrahydrofuran solvent, adding petroleum ether to separate out 9-fluorenylmethyl-N-succinimidyl carbonate white crystal powder, transferring the material in the kettle into a centrifugal machine, drying to obtain 9-fluorenylmethyl-N-succinimidyl carbonate wet product, placing in a vacuum drying oven, drying to constant weight at 40-50 deg.C for 10-12 hr to obtain 9-fluorenylmethyl-N-succinimidyl carbonate.
In a preferred embodiment of the invention, the molar ratio of 9-fluorenylmethanol to solid HOSU is 3 to 4:5-6; preferably 1 to 1.5:2.
In a preferred embodiment of the invention, the molar ratio of morpholine to indole is from 6 to 8:2-3; preferably 2:1.
In a preferred embodiment of the present invention, the purity of the 9-fluorenylmethyl-N-succinimidyl carbonate is 99.5% or more.
In a preferred embodiment of the present invention, the yield of the 9-fluorenylmethyl-N-succinimidyl carbonate is 93.5% or more in terms of 9-fluorenylmethanol; preferably 95.2% or more.
Advantageous effects
The invention adopts morpholine and indole as organic base, which is helpful to improve the yield and purity of Fmoc-Osu, and in addition, the reaction time can be obviously shortened.
Detailed Description
In order to further understand the present invention, a technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless otherwise specified, all reagents involved in the examples of the present invention are commercially available products and are commercially available.
Example 1:
(1) Preparation of Fmoc-Cl: into 2000L glass lining reactor, 900Kg tetrahydrofuran, 75Kg 9-fluorenylmethanol (0.38 Kmol) and 1.5Kg pyridine are introduced and cooled to 0-2 deg.c under stirring. 80Kg of solid phosgene (0.27 Kmol) is added in batches, 8Kg of solid phosgene is added each time, 10 times of solid phosgene is added each time, 1hr is used, 10hr is added after the solid phosgene is added, and the reaction is carried out at the temperature of 5-6 ℃ for 2.5hr; the reaction solution is cooled to below 10 ℃, quenched, washed with water, saturated brine, dried with a drying agent and filtered to obtain Fmoc-Cl.
(2) Fmoc-Osu preparation: fmoc-Cl was dissolved in tetrahydrofuran, and HOSU Kg (0.6 Kmol) of solid was added at one time, and the mixture was sufficiently dissolved with stirring to keep the temperature of the feed liquid in the reactor at-2℃to 0 ℃. Introducing morpholine 52.3Kg (0.6 Kmol), indole 35.1Kg (0.3 Kmol) and tetrahydrofuran 450Kg into a high-level tank, mixing, slowly adding into the reaction kettle for reaction within 8-10hr, keeping the temperature in the kettle not higher than 5 ℃, and continuing to react at room temperature for 3.5hr after the dripping is completed.
(3) Post-treatment: after the reaction is finished, adding acid water to quench the reaction, filtering to obtain filtrate, removing tetrahydrofuran solvent under reduced pressure and vacuum at the temperature of 0-5 ℃, adding 200L petroleum ether, precipitating a large amount of Fmoc-Osu white crystal powder, transferring the material in the kettle into a centrifugal machine for drying to obtain 160Kg of Fmoc-Osu wet product, placing the Fmoc-Osu wet product in a vacuum drying oven at the temperature of 40-50 ℃ to constant weight, drying for 10-12 hr to obtain 122Kg (0.362 Kmol) of Fmoc-Osu, and carrying out HPLC analysis to obtain the content of 99.5%.
Example 2:
(1) Preparation of Fmoc-Cl: into 2000L glass lining reactor, 900Kg tetrahydrofuran, 75Kg 9-fluorenylmethanol (0.38 Kmol) and 1.5Kg pyridine are introduced and cooled to 0-2 deg.c under stirring. 80Kg of solid phosgene (0.27 Kmol) is added in batches, 8Kg of solid phosgene is added each time, 10 times of solid phosgene is added each time, 1hr is used, 10hr is added after the solid phosgene is added, and the reaction is carried out at the temperature of 5-6 ℃ for 2.5hr; the reaction solution is cooled to below 10 ℃, quenched, washed with water, saturated brine, dried with a drying agent and filtered to obtain Fmoc-Cl.
(2) Fmoc-Osu preparation: fmoc-Cl was dissolved in tetrahydrofuran, and HOSU Kg (0.6 Kmol) of solid was added at one time, and the mixture was sufficiently dissolved with stirring to keep the temperature of the feed liquid in the reactor at-2℃to 0 ℃. 70Kg (0.8 Kmol) of morpholine, 23.54Kg (0.2 Kmol) of indole and 450Kg of tetrahydrofuran are introduced into a high-level tank, and after being uniformly mixed, the mixture is slowly added into a reaction kettle for reaction within 8-10 hours, the temperature in the kettle is kept not to exceed 5 ℃, and the reaction is continued for 3.5 hours at room temperature after the dripping is finished.
(3) Post-treatment: after the reaction is finished, adding acid water to quench the reaction, filtering to obtain filtrate, removing tetrahydrofuran solvent under reduced pressure and vacuum at the temperature of 0-5 ℃, adding 200L petroleum ether, precipitating a large amount of Fmoc-Osu white crystal powder, transferring the material in the kettle into a centrifugal machine for drying to obtain 158Kg of Fmoc-Osu wet product, placing the Fmoc-Osu wet product in a vacuum drying oven at the temperature of 40-50 ℃ to constant weight, drying for 10-12 hr to obtain 120Kg (0.356 Kmol) of Fmoc-Osu, and carrying out HPLC analysis to obtain the content of 99.5%.
Comparative example 1:
the same procedure as in example 1 was repeated, except that triethanolamine (1.1 Kmol) was used as an organic base instead of the combination of morpholine and indole, and the reaction was continued at room temperature for 7.5hr after the completion of the dropwise addition in step (2), to give Fmoc-Osu 87Kg (0.258 Kmol) and an HPLC analysis content of 99.1%.
Comparative example 2:
The same procedure as in example 1 was followed except that morpholine and indole were replaced with the same molar weight (1.1 Kmol) of morpholine in combination as the organic base to give Fmoc-Osu 65Kg (0.193 Kmol) with an HPLC analysis of 98.1%.
Comparative example 3:
The same procedure as in example 1 was followed except that an equivalent molar weight (1.1 Kmol) of indole was used as the organic base in place of the combination of morpholine and indole, to give Fmoc-Osu 106Kg (0.315 Kmol) with an HPLC analysis of 98.7%.
The experimental results show that the combination of morpholine and indole as organic base is helpful to improve the yield and purity of Fmoc-Osu.
The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations to the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.
Claims (8)
1. A method for synthesizing 9-fluorenylmethyl-N-succinimidyl carbonate, which comprises the following steps:
(1) Preparation of Fmoc-Cl: tetrahydrofuran, 9-fluorenyl methanol and pyridine are introduced into a reaction kettle, and the mixture is cooled to 0-2 ℃ under stirring. Adding solid light in batches, adding solid phosgene after 8-12hr, and reacting at 5-6deg.C for 2-3hr; cooling the reaction liquid to below 10 ℃, quenching, washing with water, saturated saline washing, drying with a drying agent, and filtering to obtain Fmoc-Cl;
(2) Preparation of 9-fluorenylmethyl-N-succinimidyl carbonate: fmoc-Cl is dissolved in tetrahydrofuran, solid HOSU is added at one time, and the mixture is fully dissolved under stirring, so that the feed liquid in the kettle is kept at-2 ℃ to 0 ℃; introducing morpholine, indole and tetrahydrofuran into a high-level tank, mixing uniformly, slowly adding into a reaction kettle for reaction within 8-10hr, keeping the temperature in the kettle not higher than 5 ℃, and continuing to react for 3-4hr at room temperature after dripping is finished;
(3) Post-treatment: filtering to obtain filtrate, vacuum-controlling the temperature to 0-5 deg.C, removing tetrahydrofuran solvent, adding petroleum ether to separate out 9-fluorenylmethyl-N-succinimidyl carbonate white crystal powder, transferring the material in the kettle into a centrifugal machine, drying to obtain 9-fluorenylmethyl-N-succinimidyl carbonate wet product, placing in a vacuum drying oven, drying to constant weight at 40-50 deg.C for 10-12 hr to obtain 9-fluorenylmethyl-N-succinimidyl carbonate.
2. The synthetic method of claim 1, wherein the molar ratio of 9-fluorenylmethanol to solid HOSU is 3-4:5-6.
3. The synthetic method of claim 1, wherein the molar ratio of 9-fluorenylmethanol to solid HOSU is 1 to 1.5:2.
4. The synthetic method of claim 1, wherein the molar ratio of morpholine to indole is 6-8:2-3.
5. The synthetic method of claim 1, wherein the molar ratio of morpholine to indole is 2:1.
6. The synthesis method according to claim 1, wherein the purity of the 9-fluorenylmethyl-N-succinimidyl carbonate is 99.5% or higher.
7. The synthesis method according to claim 4, wherein the yield of the 9-fluorenylmethyl-N-succinimidyl carbonate is 93.5% or more in terms of 9-fluorenylmethanol.
8. The synthesis method according to claim 4, wherein the yield of the 9-fluorenylmethyl-N-succinimidyl carbonate is 95.2% or more based on 9-fluorenylmethanol.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991008190A1 (en) * | 1989-12-05 | 1991-06-13 | Research Corporation Technologies, Inc. | Amino acid protecting groups |
| CN101245001A (en) * | 2007-02-16 | 2008-08-20 | 宝山钢铁股份有限公司 | Process for synthesizing carbonochloridic acid 9-fluorene methyl ester |
| CN104030962A (en) * | 2014-06-19 | 2014-09-10 | 常州吉恩化工有限公司 | Method for producing fluorenylmethoxycarbonylacyl succinimide and coproducing N,N'-disuccinimidocarbonate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991008190A1 (en) * | 1989-12-05 | 1991-06-13 | Research Corporation Technologies, Inc. | Amino acid protecting groups |
| CN101245001A (en) * | 2007-02-16 | 2008-08-20 | 宝山钢铁股份有限公司 | Process for synthesizing carbonochloridic acid 9-fluorene methyl ester |
| CN104030962A (en) * | 2014-06-19 | 2014-09-10 | 常州吉恩化工有限公司 | Method for producing fluorenylmethoxycarbonylacyl succinimide and coproducing N,N'-disuccinimidocarbonate |
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