CN110818607A - Method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate by one-pot two-phase method - Google Patents
Method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate by one-pot two-phase method Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 39
- 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 23
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 21
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 40
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims abstract description 22
- 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
- 238000003756 stirring Methods 0.000 claims abstract description 16
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229940014800 succinic anhydride Drugs 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 claims abstract description 9
- 239000007788 liquid Substances 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 239000012044 organic layer Substances 0.000 claims abstract description 6
- 230000018044 dehydration Effects 0.000 claims abstract description 5
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 5
- 239000008213 purified water Substances 0.000 claims abstract description 5
- 238000007171 acid catalysis Methods 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- PAKCPTPGEKUCBR-UHFFFAOYSA-N C(O)(O)=O.C1=CC=CC=2C3=CC=CC=C3C(C12)CC1C(=O)NC(C1)=O Chemical compound C(O)(O)=O.C1=CC=CC=2C3=CC=CC=C3C(C12)CC1C(=O)NC(C1)=O PAKCPTPGEKUCBR-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000012295 chemical reaction liquid Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 16
- 238000010992 reflux Methods 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- -1 chloro-9-fluorenylmethyl chloroformate Chemical compound 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000004321 preservation Methods 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
- 239000001384 succinic acid Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000011282 treatment Methods 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)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate by a one-pot two-phase method, which comprises the following steps: adding purified water and hydroxylamine sulfate into a reaction container, dropwise adding liquid alkali under stirring, after dropwise adding, adding succinic anhydride in batches, and carrying out high-temperature vacuum dehydration under acid catalysis until no water is extracted to prepare an N-hydroxysuccinimide solution; adding a chloroformic acid-9-fluorenylmethyl ester solution into the N-hydroxysuccinimide solution, and controlling the temperature to be 0-60 ℃; after the addition is finished, the dropwise addition of an alkaline water solution is started; and separating an organic layer after the dropwise addition is finished, concentrating to be dry, and recrystallizing to obtain a finished product of the 9-fluorenylmethylsuccinimidyl carbonate. The method innovatively adopts a one-pot two-phase method, and the reaction liquid containing the N-hydroxysuccinimide is directly used for synthesizing the 9-fluorenylmethylsuccinimidyl carbonate in a two-phase reaction mode, so that the process steps are effectively reduced, and the method is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate by a one-pot two-phase method.
Background
9-fluorenylmethylsuccinimidyl carbonate is a high-efficiency amino acid protective agent and is widely applied to the synthesis of polypeptides.
At present, the synthesis method of the raw material N-hydroxysuccinimide of 9-fluorenylmethyl succinimide carbonate is mature, and the commonly adopted method is that succinic anhydride reacts with hydroxylamine, and the finished product of the N-hydroxysuccinimide is obtained through a series of post-treatments, such as Henan chemical 1995(5) 18; application chemistry 2003.20(6) 611; jiangxi chemical 2002(11)37, etc.; another method is to react succinic acid with hydroxylamine and process to obtain N-hydroxysuccinimide product, such as the patent applied by Tanakesair chemical science and technology Co., Ltd: CN108558728A, the method can obtain the N-hydroxysuccinimide finished product with better quality, but has the problems of complicated steps, low yield and high process cost.
On the basis of N-hydroxysuccinimide, two general methods for further synthesizing 9-fluorenylmethylsuccinimidyl carbonate exist at present, one is an organic system, such as patent CN101817776A applied by Shanghai Baogang chemical industry Co., Ltd; the other is the reaction of 9-fluorenylmethyl chloroformate with N-hydroxysuccinimide in an aqueous alkaline solution to obtain the product, as described in the patent of Shunhong chemical Co., Ltd: CN1693303A, the above two methods, have higher quality requirements for the raw material N-hydroxysuccinimide.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the method solves the problems of complicated steps, low yield and high process cost in the prior art for synthesizing 9-fluorenylmethylsuccinimidyl carbonate, and provides a method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate by a one-pot two-phase method.
The technical scheme for solving the technical problems is as follows:
a method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate by a one-pot two-phase method comprises the following steps:
(1) adding purified water and hydroxylamine sulfate into a reaction container, dropwise adding liquid alkali under stirring, after dropwise adding, adding succinic anhydride in batches, and carrying out high-temperature vacuum dehydration under acid catalysis until no water is extracted to prepare an N-hydroxysuccinimide solution;
(2) adding a chloroformic acid-9-fluorenylmethyl ester solution into the N-hydroxysuccinimide solution obtained in the step (1), and controlling the temperature to be 0-60 ℃; after the addition is finished, the dropwise addition of an alkaline water solution is started; separating out an organic layer after the dropwise addition is finished, concentrating to be dry, and recrystallizing to obtain a finished product of 9-fluorenylmethylsuccinimidyl carbonate; the specific reaction formula is as follows:
preferably, the heating temperature for high-temperature vacuum dehydration in the step (1) is 100-160 ℃; the vacuum degree is 1000Pa to 2000 Pa.
Preferably, the molar ratio of hydroxylamine sulfate, succinic anhydride, sodium hydroxide and acid in the step (1) is 1: 1-4: 2-6: 0.01 to 0.1; further, the molar ratio of hydroxylamine sulfate, succinic anhydride, sodium hydroxide and acid in the step (1) is 1: 1-3: 2-6: 0.05 to 0.1; further, in the step (1), the molar ratio of hydroxylamine sulfate, succinic anhydride, sodium hydroxide and acid is 1: 2-2.4: 2.6-4: 0.06-0.08.
Preferably, the catalyst acid in step (1) is selected from sulfuric acid or phosphoric acid.
Preferably, before the chloroformic acid-9-fluorenylmethyl ester solution is added in the step (2), a water-carrying agent is added into the N-hydroxysuccinimide solution obtained in the step (1) and heated and refluxed until no water is separated out.
Preferably, the water-carrying agent in step (2) is selected from organic solvents capable of azeotroping with water, such as toluene or xylene; the dosage of the water-carrying agent is 0.5-1 time of the total mass of the water added in the step (1); and (2) calculating the total mass of the water added in the step (1) by the sum of the mass of the added purified water and the mass of the water in the liquid caustic soda.
Preferably, the mole ratio of chloroformate-9-fluorenylmethyl ester, N-hydroxysuccinimide to base in step (2) is 1: 1-3: 0.5 to 2; further, in the step (2), the mole ratio of the chloroformate-9-fluorenylmethyl ester to the N-hydroxysuccinimide to the base is 1: 1.5-2: 0.5 to 2; further, in the step (2), the mole ratio of the chloroformate-9-fluorenylmethyl ester to the N-hydroxysuccinimide to the base is 1: 1.5-1.7: 0.5 to 1.2; the amount of the N-hydroxysuccinimide is calculated according to the feeding amount of the succinic anhydride in the step (1).
Preferably, the solution of chloroformate-9-fluorenylmethyl ester in step (2) is a solution of chloroformate-9-fluorenylmethyl ester in tetrahydrofuran, ethyl acetate or toluene; the mass concentration of the chloroformic acid-9-fluorenylmethyl ester solution is 30-60%.
Preferably, the base in the step (2) is selected from sodium carbonate, potassium carbonate, sodium hydroxide or triethylamine; the mass concentration of the alkaline water solution is 10-30%; further, the mass concentration of the alkaline water solution is 10-25%.
Preferably, the solvent used in the recrystallization step in step (2) is dichloromethane, cyclohexane or ethyl acetate.
The Chinese naming of the compounds of the present invention conflicts with the structural formula, whichever is more.
The method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate innovatively adopts a one-pot two-phase method, and the reaction liquid containing N-hydroxysuccinimide is directly used for synthesizing 9-fluorenylmethylsuccinimidyl carbonate in a two-phase reaction mode, so that the process steps are effectively reduced, and the method is suitable for large-scale industrial production.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1:
adding 100g of water into a 1000ml four-neck flask, adding 125g of hydroxylamine sulfate (molecular weight 164.1, 0.76mol) while stirring, adding 200g of liquid alkali with the mass fraction of 40% (molecular weight 40.0, 2mol), adding 152.3g of succinic anhydride (molecular weight 100.1, 1.52mol) while stirring, dissolving completely, adding 5g of 85% phosphoric acid (molecular weight 98, 0.043mol), dehydrating in vacuum, controlling the temperature in the flask to be not higher than 160 ℃ until no water is removed, cooling to below 100 ℃, adding 250g of toluene, heating to reflux while stirring, refluxing, separating water until no water is removed, cooling to 25-30 ℃, adding an ethyl acetate solution (molecular weight 258.7, 0.89mol) containing 230g of chloro-9-fluorenylmethyl chloroformate, and adding an aqueous alkali solution into the reaction flask: 500g (liquid caustic soda with the concentration of 40% 118g, water 382g), the solid in the bottle disappears at this time, the rapid stirring is carried out, the dripping is finished, the heat preservation is carried out for 2 hours, the standing is carried out, the water layer is separated, the organic layer is concentrated to be dry, 600g of ethyl acetate is added, the temperature is raised to the reflux, the temperature is reduced to the room temperature for crystallization, the suction filtration is carried out, and the filter cake is dried: 220g, yield: 51.6%, purity 99.8% by HPLC: melting point: 148 ℃ and 150 ℃.
Example 2:
adding 100g of water into a 1000ml four-neck flask, adding 105g of hydroxylamine hydrochloride (molecular weight 164.1, 0.64mol) while stirring, adding 250g of liquid alkali (molecular weight 40.0, 2.5mol) with the mass fraction of 40%, adding 152.3g of succinic anhydride (molecular weight 100.1, 1.52mol) while stirring, fully dissolving, adding 5g of sulfuric acid (molecular weight 98, 0.05mol) with the mass fraction of 98%, vacuum dehydrating, controlling the temperature in the flask to be not higher than 160 ℃, removing water, cooling to below 100 ℃, adding 200g of toluene, heating to reflux while stirring, separating water by reflux, cooling to 25-30 ℃, adding a toluene solution (molecular weight 258.7, 0.89mol) containing 230g of chloroformate-9-fluorenylmethyl ester, adding 500g of sodium carbonate aqueous solution (47 g, 453g) into the reaction flask, removing the solid in the flask, rapidly stirring, and adding dropwise, preserving heat for 2 hours, standing, removing a water layer, concentrating an organic layer to be dry, adding 600g of dichloromethane, heating to reflux, cooling to room temperature for crystallization, performing suction filtration, and drying a filter cake: 240g, yield: 56.3%, purity by HPLC 99.9%, melting point: 148-150 ℃.
Example 3:
adding 100g of water into a 1000ml four-neck flask, adding 125g of hydroxylamine sulfate (molecular weight 164.1, 0.76mol) while stirring, dropwise adding 200g of liquid alkali (molecular weight 40.0, 2mol) with the mass fraction of 40%, adding 145g of succinic anhydride (molecular weight 100.1, 1.45mol) while stirring, stirring for complete dissolution, adding 5g of phosphoric acid (molecular weight 98, 0.043mol) with the mass fraction of 85%, dehydrating under vacuum, controlling the temperature in the flask to be not higher than 160 ℃ until no water is removed, cooling to be below 100 ℃,adding 250g of toluene, heating to reflux under stirring, refluxing, carrying out water diversion until no water is separated, cooling to 25-30 ℃, adding a toluene solution (with the molecular weight of 258.7 and 0.89mol) containing 230g of chloroformate-9-fluorenylmethyl ester, dropwise adding 500g of a sodium carbonate aqueous solution (47 g of sodium carbonate and 453g of water) into a reaction bottle, allowing solids in the bottle to disappear, rapidly stirring, carrying out dropwise addition, keeping the temperature for 2 hours, standing, removing a water layer, concentrating an organic layer to be dry, adding 600g of cyclohexane, heating to reflux, cooling to room temperature for crystallization, carrying out suction filtration, and drying a filter cake: 230g, yield: 53.9%, purity by HPLC 99.9%, melting point: 148-150 ℃.1H NMR(600MHz,d6-DMSO):δ2.75(s,4H,CH2),4.42(d,J＝6.0Hz,1H,8-CH),4.82(t,J＝6.0Hz,2H,1-CH2),7.36(dt,J＝1.0,7.5Hz,2H,2-CH and 7-CH),7.45(t,J＝7.4Hz,2H,3-CH and 6-CH),7.69(dd,J＝0.6,7.5Hz,2H,1-CH and8-CH),7.92(d,J＝7.5Hz,2H,4-CH and 5-CH)。
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (10)
1. A method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate by a one-pot two-phase method is characterized by comprising the following steps:
(1) adding purified water and hydroxylamine sulfate into a reaction container, dropwise adding liquid alkali under stirring, after dropwise adding, adding succinic anhydride in batches, and carrying out high-temperature vacuum dehydration under acid catalysis until no water is extracted to prepare an N-hydroxysuccinimide solution;
(2) adding a chloroformic acid-9-fluorenylmethyl ester solution into the N-hydroxysuccinimide solution obtained in the step (1), and controlling the temperature to be 0-60 ℃; after the addition is finished, the dropwise addition of an alkaline water solution is started; separating out an organic layer after the dropwise addition is finished, concentrating to be dry, and recrystallizing to obtain a finished product of 9-fluorenylmethylsuccinimidyl carbonate; the specific reaction formula is as follows:
2. the method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate according to claim 1, wherein the heating temperature for the high-temperature vacuum dehydration in the step (1) is 100 to 160 ℃; the vacuum degree is 1000Pa to 2000 Pa.
3. The method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate according to claim 1, wherein the molar ratio of hydroxylamine sulfate, succinic anhydride, sodium hydroxide and acid in step (1) is 1: 1-4: 2-6: 0.01 to 0.1.
4. The method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate according to claim 1, wherein the catalyst acid in step (1) is selected from sulfuric acid or phosphoric acid.
5. The method for synthesizing 9-fluorenylmethylsuccinimide carbonate according to any of claims 1 to 4, wherein before the chloroformic acid-9-fluorenylmethyl ester solution is added in the step (2), a water-carrying agent is added in the N-hydroxysuccinimide solution obtained in the step (1) and heated and refluxed until no water is separated out.
6. The method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate according to claim 5, wherein the water-carrying agent is selected from organic solvents that can be azeotroped with water, such as toluene or xylene; the dosage of the water-carrying agent is 0.5-1 time of the total mass of the water added in the step (1); and (2) calculating the total mass of the water added in the step (1) by the sum of the mass of the added purified water and the mass of the water in the liquid caustic soda.
7. The method for synthesizing 9-fluorenylmethylsuccinimide carbonate according to any of claims 1 to 4, wherein the molar ratio of chloroformate-9-fluorenylmethyl ester, N-hydroxysuccinimide and base in step (2) is 1: 1-3: 0.5 to 2.
8. The method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate according to any one of claims 1 to 4, wherein the solution of 9-fluorenylmethyl chloroformate in step (2) is a solution of 9-fluorenylmethyl chloroformate in tetrahydrofuran, ethyl acetate or toluene; the mass concentration of the chloroformic acid-9-fluorenylmethyl ester solution is 30-60%.
9. The method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate according to any one of claims 1 to 4, wherein the base in step (2) is selected from sodium carbonate, potassium carbonate, sodium hydroxide or triethylamine; the mass concentration of the alkaline water solution is 10-30%.
10. The method for synthesizing 9-fluorenylmethylsuccinimidyl carbonate according to any one of claims 1 to 4, wherein the solvent used in the recrystallization step in step (2) is dichloromethane, cyclohexane or ethyl acetate.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5426190A (en) * | 1994-06-16 | 1995-06-20 | Ppg Industries, Inc. | Preparation of N-(organocarbonyloxy)-succinimide derivatives of N-hydroxysuccinimide |
| ES2156505A1 (en) * | 1998-10-14 | 2001-06-16 | Univ Alicante | Production of amine group protection reagents consists of reacting a chloroformate derivative with e.g. N-hydroxysuccinimide |
| CN103145601A (en) * | 2013-03-22 | 2013-06-12 | 上海其新生物科技有限公司 | Preparation method of N-hydroxysuccinimide |
| CN108558728A (en) * | 2018-03-21 | 2018-09-21 | 泰安科赛尔化学科技有限公司 | A kind of N- hydroxysuccinimides preparation method |
-
2019
- 2019-11-20 CN CN201911138798.5A patent/CN110818607A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5426190A (en) * | 1994-06-16 | 1995-06-20 | Ppg Industries, Inc. | Preparation of N-(organocarbonyloxy)-succinimide derivatives of N-hydroxysuccinimide |
| ES2156505A1 (en) * | 1998-10-14 | 2001-06-16 | Univ Alicante | Production of amine group protection reagents consists of reacting a chloroformate derivative with e.g. N-hydroxysuccinimide |
| CN103145601A (en) * | 2013-03-22 | 2013-06-12 | 上海其新生物科技有限公司 | Preparation method of N-hydroxysuccinimide |
| CN108558728A (en) * | 2018-03-21 | 2018-09-21 | 泰安科赛尔化学科技有限公司 | A kind of N- hydroxysuccinimides preparation method |
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