CN113880731A - Fmoc-D-Cit optical purity purification method and obtained product - Google Patents
Fmoc-D-Cit optical purity purification method and obtained product Download PDFInfo
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- CN113880731A CN113880731A CN202111259681.XA CN202111259681A CN113880731A CN 113880731 A CN113880731 A CN 113880731A CN 202111259681 A CN202111259681 A CN 202111259681A CN 113880731 A CN113880731 A CN 113880731A
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- NBMSMZSRTIOFOK-GOSISDBHSA-N (2r)-5-(carbamoylamino)-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@H](CCCNC(=O)N)C(O)=O)C3=CC=CC=C3C2=C1 NBMSMZSRTIOFOK-GOSISDBHSA-N 0.000 title claims abstract description 61
- 230000003287 optical effect Effects 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000000746 purification Methods 0.000 title claims abstract description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 88
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000000047 product Substances 0.000 claims abstract description 45
- 239000000706 filtrate Substances 0.000 claims abstract description 21
- 239000007864 aqueous solution Substances 0.000 claims abstract description 18
- 238000001914 filtration Methods 0.000 claims abstract description 17
- 239000012043 crude product Substances 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000243 solution Substances 0.000 claims abstract description 15
- 238000010438 heat treatment Methods 0.000 claims abstract description 10
- 239000012264 purified product Substances 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 239000011259 mixed solution Substances 0.000 claims abstract description 3
- 238000005303 weighing Methods 0.000 claims abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 5
- 230000007547 defect Effects 0.000 abstract description 4
- 238000003756 stirring Methods 0.000 description 20
- 230000000052 comparative effect Effects 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000001514 detection method Methods 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000006329 citrullination Effects 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/189—Purification, separation, stabilisation, use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
- C07C275/16—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for purifying Fmoc-D-Cit optical purity and an obtained product, comprising the following steps: s1, mixing the components in a mass ratio of 3: 1, preparing a mixed solution of acetone and water to obtain an acetone aqueous solution; s2, weighing a certain amount of Fmoc-D-Cit crude product, adding the Fmoc-D-Cit crude product into the acetone aqueous solution of S1, heating to dissolve the Fmoc-D-Cit crude product, and filtering to obtain filtrate; s3, concentrating the filtrate, adding a certain amount of ethyl acetate into the filtrate, crystallizing, and filtering to obtain a purified product. The Fmoc-D-Cit crude product is dissolved in acetone aqueous solution, the solubility difference between Fmoc-D-Cit and an isomer Fmoc-L-Cit in the acetone aqueous solution is obtained, then the Fmoc-D-Cit is crystallized and separated out by using ethyl acetate, and other impurities and the Fmoc-L-Cit isomer are remained in a solution system, so that the Fmoc-D-Cit product with high optical purity is obtained, and the defects of the existing purification method are overcome.
Description
Technical Field
The invention relates to the technical field of polypeptide synthesis, in particular to a method for purifying Fmoc-D-Cit optical purity and an obtained product.
Background
The protected amino acid is a basic raw material for synthesizing the directional peptide, and the stereo configuration of the peptide drug can be directly influenced by the optical purity of the protected amino acid. Therefore, improving the optical purity of the protected amino acid is of great significance to peptide synthesis. During the production of protected amino acids, some amino acids are prone to racemization. For example, citrulline has a serious racemization during the citrullination process, about 3-5% of isomers, and the existence of the isomers can have a significant negative effect on the optical purity of protected amino acids, so how to eliminate the effect of the isomers is an important research topic for those skilled in the art.
At present, for the purification of Fmoc-D-Cit (containing Fmoc-L-Cit isomers) in optical purity, the following are generally used: and (3) putting the Fmoc-D-Cit crude product into ethyl acetate, heating, stirring, cooling, filtering and collecting a solid, and losing part of the product to achieve the purification purpose. However, the method has the disadvantages of unobvious optical purity purification effect, incapability of meeting the requirement of high quality, large product loss (loss amount is 30-40%), large solvent consumption, treatment of 1kg of Fmoc-D-Cit crude product by using 30-40kg of ethyl acetate, and high purification cost.
Disclosure of Invention
The invention aims to: in order to solve the problems, the invention provides a method for purifying Fmoc-D-Cit optical purity and an obtained product, wherein the method comprises the steps of dissolving a Fmoc-D-Cit crude product in an acetone aqueous solution, carrying out solubility difference on Fmoc-D-Cit and an isomer Fmoc-L-Cit in the acetone aqueous solution, crystallizing and separating the Fmoc-D-Cit by using ethyl acetate, and leaving other impurities and the Fmoc-L-Cit isomer in a solution system, so that the Fmoc-D-Cit product with high optical purity is obtained, and the defects of the existing purification method are overcome.
The technical scheme adopted by the invention is as follows: a method for purifying Fmoc-D-Cit optical purity, comprising the following steps:
s1, mixing the components in a mass ratio of 2-3: 1, preparing a mixed solution of acetone and water to obtain an acetone aqueous solution;
s2, weighing a certain amount of Fmoc-D-Cit crude product, adding the Fmoc-D-Cit crude product into the acetone aqueous solution of S1, heating to dissolve the Fmoc-D-Cit crude product, and filtering to obtain filtrate;
s3, concentrating the filtrate, adding a certain amount of ethyl acetate into the filtrate, crystallizing, and filtering to obtain a purified product.
In the purification method, the inventor finds that after acetone and water are prepared into an acetone aqueous solution according to a certain proportion, the Fmoc-D-Cit and the isomer thereof have obvious solubility difference in the solution, the Fmoc-D-Cit and the isomer Fmoc-L-Cit show solubility difference in the acetone aqueous solution, then the Fmoc-D-Cit is crystallized and separated out by using ethyl acetate, and other impurities and a small amount of Fmoc-L-Cit isomer are left in the solution system, so that the isomer and other impurities can be effectively removed, and the defects of the existing purification method are overcome.
Further, in the above, the mixing ratio of acetone and water is very important, and too high or too low may have a significant influence on the overall purification effect. When the ratio of acetone to water is too low, the solubility of the product in the solvent system is low, and the product loss is large; when the ratio of acetone to water is too high, the product has high solubility in the solvent system and poor isomer removal effect. According to experimental summary, when the mass ratio of acetone to water is 2-3: 1 is most suitable, and preferably 3: 1.
in the invention, the mass ratio of the Fmoc-D-Cit crude product to the acetone aqueous solution is 1: 3-4. Correspondingly, when the ratio of the acetone water to the product is too low, the product is less dissolved in the solvent system, and the undissolved product is mixed with Fmoc-L-Cit, so that the product is not easy to separate and has large product loss; when the ratio of acetone to water is too high, the dissolving amount of Fmoc-L-Cit in the solvent system is increased, the post-treatment difficulty is increased, and preferably, the mass ratio of the Fmoc-D-Cit crude product to the acetone aqueous solution is 1: 4.
further, the crude Fmoc-D-Cit product contains 3-5 w% of Fmoc-L-Cit isomer.
Further, in S2, the temperature of the acetone aqueous solution after the temperature rise was controlled to 40 to 50 ℃. The temperature should not be too high, otherwise the acetone will vaporize and affect the purification process.
In the present invention, the amount of ethyl acetate added (for the purpose of product dispersion crystallization) is 25% by mass of the aqueous acetone solution.
The invention also comprises an Fmoc-D-Cit product with high optical purity, which is obtained by purifying the Fmoc-D-Cit product by the purification method.
In the Fmoc-D-Cit product, the content of Fmoc-L-Cit isomer is not higher than 0.2 w%, which meets the requirement of high optical purity of protected amino acid products in China.
In summary, due to the adoption of the technical scheme, the invention has the beneficial effects that: the Fmoc-D-Cit crude product is dissolved in acetone aqueous solution, the solubility difference between Fmoc-D-Cit and an isomer Fmoc-L-Cit in the acetone aqueous solution is utilized, ethyl acetate is utilized to crystallize and separate out Fmoc-D-Cit, other impurities and a small amount of Fmoc-L-Cit isomer are left in a solution system, and therefore the Fmoc-D-Cit product with high optical purity is obtained, the Fmoc-L-Cit content of the obtained purified product is below 0.2 w%, the product loss is below 10%, the purification effect is obvious, the purification method is simple to operate, the defects of the existing purification technology can be effectively overcome, and the method plays a positive role in preparing high-quality protected amino acid products in China.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
A method for purifying Fmoc-D-Cit optical purity, comprising the following steps:
s1: putting 3000g of industrial-grade acetone raw material into a flask, adding 1000ml of pure water, adding 1000g of Fmoc-D-Cit (containing Fmoc-L-Cit3.0w percent), heating to 45 ℃, and stirring for 1.5 h;
s2: stopping stirring after stirring is finished, and filtering while the solution is hot to obtain insoluble solids and filtrate;
s3: after the acetone in the filtrate is concentrated, 1000g of ethyl acetate is added, stirred and crystallized for 2 hours, and the product 940g is obtained after filtration and drying.
Example 2
A method for purifying Fmoc-D-Cit optical purity, comprising the following steps:
s1: putting 3000g of industrial-grade acetone raw material into a flask, adding 1000ml of pure water, adding 1000g of Fmoc-D-Cit (containing Fmoc-L-Cit 3.8w%), heating to 45 ℃, and stirring for 1.5 h;
s2: stopping stirring after stirring is finished, and filtering while the solution is hot to obtain insoluble solids and filtrate;
s3: after the acetone in the filtrate is concentrated, 1000g of ethyl acetate is added, stirred and crystallized for 2 hours, and the product 922g is obtained after filtration and drying;
example 3
A method for purifying Fmoc-D-Cit optical purity, comprising the following steps:
s1: putting 3000g of industrial-grade acetone raw material into a flask, adding 1000ml of pure water, adding 1000g of Fmoc-D-Cit (containing Fmoc-L-Cit 4.3w%), heating to 45 ℃, and stirring for 1.5 h;
s2: stopping stirring after stirring is finished, and filtering while the solution is hot to obtain insoluble solids and filtrate;
s3: after the acetone in the filtrate is concentrated, 1000g of ethyl acetate is added, stirred and crystallized for 2 hours, and the product 910g is obtained after filtration and drying.
Comparative example 1
S1: putting 500g of industrial-grade acetone raw material into a flask, adding 2500ml of pure water, adding 1000g of product Fmoc-D-Cit (containing Fmoc-L-Cit3.0w percent), heating to 45 ℃, and stirring for 1.5 h;
s2: stopping stirring after stirring is finished, and filtering while the solution is hot to obtain insoluble solids and filtrate;
s3: after the acetone in the filtrate is concentrated, 1000g of ethyl acetate is added, stirred and crystallized for 2 hours, filtered to obtain the product, and dried to obtain 220g of the product.
Comparative example 2
S1: putting 1500g of industrial-grade acetone raw material into a flask, adding 500ml of pure water, adding 1000g of product Fmoc-D-Cit (containing Fmoc-L-Cit3.0w percent), heating to 45 ℃, and stirring for 1.5 h;
s2: stopping stirring after stirring is finished, and filtering while the solution is hot to obtain insoluble solids and filtrate;
s3: after the acetone in the filtrate is concentrated, 1000g of ethyl acetate is added, stirred and crystallized for 2 hours, filtered to obtain the product 800 g.
Comparative example 3
S1: putting 3000g of industrial-grade ethyl acetate raw material into a flask, adding 1000g of product Fmoc-D-Cit (containing Fmoc-L-Cit3.0w percent), heating to 45 ℃, and stirring for 1.5 h;
s2: stopping stirring after stirring is finished, and filtering while the solution is hot to obtain insoluble solids and filtrate;
s3: and after concentrating the ethyl acetate in the filtrate, stirring, crystallizing, filtering, and drying to obtain 28g of a product.
Experimental detection and analysis
The Fmoc-L-Cit content detection adopts liquid chromatography for detection, and the detection conditions are as follows:
detection conditions are as follows: mobile phase A: trifluoroacetic acid: water 1: 1000
B: trifluoroacetic acid: acetonitrile 1: 1000
Preparation of sample solution 1 part: dissolve 10mg of sample in 10ml of mobile phase solvent. Preparation of control sample solution 1 part: dissolve 10mg of sample in 10ml of mobile phase solvent. And after the chromatographic system is stabilized, taking a blank (sample solvent) and a reference substance, respectively, adding one needle, adding the sample into two needles, and calculating the optical purity according to an area normalization method.
The examples 1 to 3 and the comparative examples 1 to 3 were tested at the same time, and the test results are shown in table 1:
TABLE 1 results of measuring isomer contents in examples 1 to 3 and comparative examples 1 to 3
As shown in Table 1, the purified product obtained in example 1 of the present invention had an Fmoc-L-Cit content of 0.2 w% or less, a product loss of 10% or less, and a significant purification effect. In comparative example 1, when the amount of acetone was too small, although the purification result satisfied the requirement, the product loss was 78%, which made it difficult to satisfy the production requirements. Correspondingly, in comparative example 2, when the amount of acetone water is too much, the loss of the product is about 20%, and the loss is large; in comparative example 3, neither the purification effect nor the product loss of comparative example 3 satisfied the production requirements of enterprises, and it was difficult to implement industrially.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (9)
1. A method for purifying Fmoc-D-Cit optical purity, which is characterized by comprising the following steps:
s1, mixing the components in a mass ratio of 2-3: 1, preparing a mixed solution of acetone and water to obtain an acetone aqueous solution;
s2, weighing a certain amount of Fmoc-D-Cit crude product, adding the Fmoc-D-Cit crude product into the acetone aqueous solution of S1, heating to dissolve the Fmoc-D-Cit crude product, and filtering to obtain filtrate;
s3, concentrating the filtrate, adding a certain amount of ethyl acetate into the filtrate, crystallizing, and filtering to obtain a purified product.
2. The method for purifying Fmoc-D-Cit optical purity of claim 1, wherein the mass ratio of acetone to water is 3: 1.
3. the method for purifying Fmoc-D-Cit optical purity of claim 2, wherein the mass ratio of crude Fmoc-D-Cit product to aqueous acetone is 1: 3-4.
4. the method for purifying Fmoc-D-Cit optical purity of claim 3, wherein the mass ratio of crude Fmoc-D-Cit product to aqueous acetone is 1: 4.
5. the method for purifying Fmoc-D-Cit optical purity of claim 1, wherein said crude Fmoc-D-Cit product comprises 3-5 w% of Fmoc-L-Cit isomer.
6. The method for purifying Fmoc-D-Cit optical purity of claim 1, wherein the temperature of the acetone aqueous solution is controlled to 40-50 ℃ after the temperature is raised in S2.
7. The method for purifying Fmoc-D-Cit optical purity of claim 1, wherein said ethyl acetate is added in an amount of 25% by mass of the aqueous acetone solution.
8. Fmoc-D-Cit product having high optical purity, characterized in that it is purified by the purification method according to any of claims 1 to 7.
9. The Fmoc-D-Cit product with high optical purity of claim 8, wherein the Fmoc-L-Cit isomer is contained in the Fmoc-D-Cit product in an amount of not more than 0.2 w%.
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| CN202111259681.XA CN113880731A (en) | 2021-10-28 | 2021-10-28 | Fmoc-D-Cit optical purity purification method and obtained product |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103373940A (en) * | 2012-04-26 | 2013-10-30 | 长春百克生物科技股份公司 | Novel process for synthesizing N-FMOC-amino acid crude product of non-active side chain |
| CN105873614A (en) * | 2013-12-16 | 2016-08-17 | 基因泰克公司 | Peptidomimetic compounds and antibody-drug conjugates thereof |
| CN107427591A (en) * | 2014-07-16 | 2017-12-01 | 南京明德新药研发股份有限公司 | Connector and its application for ADC |
| CN108912015A (en) * | 2018-06-19 | 2018-11-30 | 南京肽业生物科技有限公司 | A kind of Fmoc amino acid refining methd |
-
2021
- 2021-10-28 CN CN202111259681.XA patent/CN113880731A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103373940A (en) * | 2012-04-26 | 2013-10-30 | 长春百克生物科技股份公司 | Novel process for synthesizing N-FMOC-amino acid crude product of non-active side chain |
| CN105873614A (en) * | 2013-12-16 | 2016-08-17 | 基因泰克公司 | Peptidomimetic compounds and antibody-drug conjugates thereof |
| CN107427591A (en) * | 2014-07-16 | 2017-12-01 | 南京明德新药研发股份有限公司 | Connector and its application for ADC |
| CN108912015A (en) * | 2018-06-19 | 2018-11-30 | 南京肽业生物科技有限公司 | A kind of Fmoc amino acid refining methd |
Non-Patent Citations (3)
| Title |
|---|
| EARL E. RUTENBER ET AL.: "The Discovery, Characterization and Crystallographgically Determined Binding Mode of an FMOC-Containing Inhibitor of HIV-1 Protease", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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| 赵临襄: "《化学制药工艺学》", 31 August 2015, 中国医药科技出版社 * |
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