CN115286536A - Crystallization and purification method of product after amino group in amino acid is grafted with protecting group - Google Patents
Crystallization and purification method of product after amino group in amino acid is grafted with protecting group Download PDFInfo
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- CN115286536A CN115286536A CN202210793069.9A CN202210793069A CN115286536A CN 115286536 A CN115286536 A CN 115286536A CN 202210793069 A CN202210793069 A CN 202210793069A CN 115286536 A CN115286536 A CN 115286536A
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- 238000002425 crystallisation Methods 0.000 title claims abstract description 37
- 230000008025 crystallization Effects 0.000 title claims abstract description 37
- 125000006239 protecting group Chemical group 0.000 title claims abstract description 34
- 150000001413 amino acids Chemical class 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title claims abstract description 20
- 125000003277 amino group Chemical group 0.000 title claims abstract description 19
- 238000000746 purification Methods 0.000 title claims abstract description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000000047 product Substances 0.000 claims abstract description 34
- 239000002904 solvent Substances 0.000 claims abstract description 24
- 239000002608 ionic liquid Substances 0.000 claims abstract description 14
- 239000012043 crude product Substances 0.000 claims abstract description 11
- 239000013078 crystal Substances 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 10
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 239000005457 ice water Substances 0.000 claims abstract description 9
- 238000002386 leaching Methods 0.000 claims abstract description 9
- 239000012046 mixed solvent Substances 0.000 claims abstract description 9
- 238000001291 vacuum drying Methods 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 8
- 239000012065 filter cake Substances 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- -1 preferably-H Chemical group 0.000 claims description 7
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 2
- 238000001514 detection method Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- XYVMOLOUBJBNBF-UHFFFAOYSA-N 3h-1,3-oxazol-2-one Chemical class OC1=NC=CO1 XYVMOLOUBJBNBF-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000007068 beta-elimination reaction Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to the technical field of biological medicine, in particular to a crystallization and purification method of a product after amino in amino acid is grafted with a protecting group, which comprises the following steps: (1) Adding a dichloromethane solvent into a crude product of which an amino group in an amino acid is grafted with a protective group as a raw material, and stirring for dissolving; (2) Adding ionic liquid and n-heptane solvent into the mixed solvent obtained in the step (1), cooling to 0-10 ℃ in an ice water bath, stirring, and crystallizing; (3) And after the crystals are completely separated out, filtering the mixed solvent, leaching a filter cake by using n-heptane, draining the solvent, and drying in a vacuum drying oven to obtain a product with qualified purity. The crystallization and purification method of the product after the amino group in the amino acid is grafted with the protective group can reduce the crystallization times, greatly reduce the product and solvent loss caused in the multiple purification processes, reduce the time consumption and have good economic benefit.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a crystallization and purification method of a product obtained by grafting a protecting group to an amino group in amino acid.
Background
Functional group protection is a common operation in organic synthesis, and protecting groups are often used for protecting groups which are active and easy to react. Because of the reactivity of amino groups in amino acids, protection by protecting groups is often required, and many amino protecting groups have been used, but they can be classified into three main groups, namely, alkoxycarbonyl, acyl and alkyl.
The alkoxycarbonyl group is most used because the N-alkoxycarbonyl protected amino acid is not easily racemized during peptide grafting. Racemization occurs in base-catalyzed coupling reactions of N-protected carboxy-activated amino acids, as well as in intermediate oxazolones that are readily formed from N-acyl protected amino acids.
To minimize the degree of racemization, it is effective to use a nonpolar solvent, the weakest base, a low reaction temperature, and an alkoxycarbonyl-type protected amino acid. Of these, the Boc group which is easily deprotected by acidic hydrolysis, cbz group which is deprotected by catalytic hydrogenolysis, fmoc group which is deprotected by β -elimination with a base are commonly used.
However, in the purification process of the product after amino protection, some amino acid impurities which are not introduced with the protecting group often appear, and the amino acid impurities have electric charges and cannot be removed by a conventional crystallization purification method, so that after multiple crystallization, the purity of the product is not obviously increased or even not improved, the loss of the product and a solvent in the multiple crystallization process is caused, the waste of time is caused, and the economic cost is further increased.
In order to solve the problems, the method is improved, and a method for crystallizing and purifying a product after a protection group is grafted to an amino group in an amino acid is provided.
Disclosure of Invention
In order to solve the technical problems, the invention provides the following technical scheme:
the invention provides a crystallization purification method of a product after amino in amino acid is grafted with a protecting group, which comprises the following steps:
(1) Adding a dichloromethane solvent into a crude product of amino acid with amino grafted with a protecting group as a raw material, and stirring for dissolving;
(2) Adding ionic liquid and an n-heptane solvent into the mixed solvent obtained in the step (1), cooling to 0-10 ℃ in an ice water bath, stirring, and crystallizing;
(3) And after the crystals are completely separated out, filtering the mixed solvent, leaching a filter cake by using n-heptane, draining the solvent, and drying in a vacuum drying oven to obtain a product with qualified purity.
As a preferable technical scheme of the invention, the structural formula of the ionic liquid is shown in the specification
Wherein R3, R4, R5, R6 are independently selected from-H or C1-C10 alkyl, preferably-H, -CH3 or-C2H 5, and R7 is selected from BF4-, cl-, br-, I-, NO3-, PF6-.
As a preferred technical scheme of the invention, the amino group of the amino acid is connected with a protecting group and then has a structural formula
Wherein R1 is a functional protecting group including but not limited to Boc group, cbz group, fmoc group, and R2 is selected from-H or C1-C10 alkyl, preferably-H, -CH3 or-C2H 5.
As a preferred technical scheme of the invention, the ratio of the dichloromethane solvent to the crude product of the amino group of the amino acid after being grafted with the protecting group is 1.5 (ml): 1 (g).
As a preferred technical scheme of the invention, the ratio of the ionic liquid to the crude product of amino-grafted protecting group in the amino acid is (0.01-0.1) (ml): 1 (g).
As a preferable technical scheme of the invention, the volume ratio of the n-heptane solvent to the dichloromethane solvent is 1: (5-6).
The beneficial effects of the invention are: this kind of crystallization purification method of product after amino inserts protective group in amino acid, through adding proper amount ionic liquid, can increase the solubility of impurity in the mixed solvent, in the mixed solvent crystallization process, make impurity stay in the mixed solvent system to the greatest extent, let it can not follow along with the crystallization of product and follow and separate out, thereby reduce the crystallization number of times, the condition that the product purity of having avoided crystallizing out is not up to standard, and reduce product and solvent loss that causes in the purification process many times by a wide margin, reduce time consumption, and has good economic benefits.
Detailed Description
The following description of the preferred embodiments of the present invention is provided for the purpose of illustration and description, and is in no way intended to limit the invention.
The ionic liquid structures used in the examples are shown in table 1 below:
TABLE 1 Structure of Ionic liquids
Example 1
200g of NH-Boc-D-serine crude product grafted with Boc protective group is taken, 300ml of dichloromethane is added and stirred to be dissolved, 10ml of ionic liquid I is added, 1800ml of n-heptane is added, and ice water is used for cooling crystallization. And after the crystals are completely separated out, filtering, leaching for three times by using n-heptane, draining the solvent, and drying in a vacuum drying oven. The HPLC detection shows that the product purity is 99.2 percent, and the single crystallization yield is 75 percent.
Example 2
150g of crude NH-Fmoc-D-serine grafted with Fmoc protecting groups is taken, 230ml of dichloromethane is added and stirred for dissolution, 15ml of ionic liquid I is added, 1300ml of n-heptane is added, and ice water is used for cooling and crystallization. And after the crystals are completely separated out, filtering, leaching for three times by using n-heptane, draining the solvent, and drying in a vacuum drying oven. The HPLC detection shows that the product purity is 99.7 percent and the single crystallization yield is 80 percent.
Example 3
Taking 200g of NH-Boc-D-serine crude product grafted with the Boc protective group, adding 300ml of dichloromethane, stirring and dissolving, adding 20ml of ionic liquid II, adding 1800ml of n-heptane, and cooling and crystallizing by using ice water. And after the crystals are completely separated out, filtering, leaching for three times by using n-heptane, draining the solvent, and drying in a vacuum drying oven. The HPLC detection shows that the product purity is 99.6%, and the single crystallization yield is 82%.
Example 4
Taking 250g of NH-Cbz-D-serine crude product grafted with Cbz protecting groups, adding 380ml of dichloromethane, stirring and dissolving, adding 25ml of ionic liquid III, adding 2100ml of n-heptane, and cooling and crystallizing by using ice water. And after the crystals are completely separated out, filtering, leaching for three times by using n-heptane, draining the solvent, and drying in a vacuum drying oven. The product purity is 99.4% and the single crystallization yield is 78% by HPLC detection.
Comparative example 1
200g of NH-Boc-D-serine crude product grafted with the Boc protective group is taken, 300ml of dichloromethane is added and stirred for dissolution, 1800ml of n-heptane is added, and ice water is used for cooling crystallization. And after the crystals are completely separated out, filtering, leaching for three times by using n-heptane, draining the solvent, and drying in a vacuum drying oven. The product purity is 95.6 percent and the single crystallization yield is 64 percent through HPLC detection.
The crystal after drying is repeated the last crystallization process again, the purity of the product obtained by the second crystallization is 96.7%, and the single crystallization yield is 56%. The purity of the product obtained by the third crystallization is 98 percent, and the single crystallization yield is 65 percent. The purity of the product obtained by the fourth crystallization is 98.2 percent, and the yield of the single crystallization is 60 percent.
Comparative example 2
150g of crude NH-Fmoc-D-serine grafted with Fmoc protecting groups is taken, 230ml of dichloromethane is added and stirred for dissolution, 1300ml of n-heptane is added, and ice water is used for cooling crystallization. And after the crystals are completely separated out, filtering, leaching with n-heptane for three times, draining the solvent, and drying in a vacuum drying oven. The product purity is 97% and the single crystallization yield is 58% by HPLC detection.
The crystallization process is repeated again for the dried crystal, the purity of the product obtained by the second crystallization is 97.3 percent, and the single crystallization yield is 62 percent. The purity of the product obtained by the third crystallization is 97.3 percent, and the single crystallization yield is 57 percent.
In the description of the present invention, it should be noted that the terms "vertical", "upper", "lower", "horizontal", and the like indicate orientations or positional relationships based on the illustrated orientations or positional relationships, which are only used for convenience in describing the present invention and simplifying the description, but do not indicate or imply that the referred device or element must have a specific orientation, be constructed in a specific orientation, and be operated, and thus, should not be construed as limiting the present invention.
In the description of the present invention, it should also be noted that, unless otherwise explicitly stated or limited, the terms "disposed," "mounted," "connected," and "connected" are to be construed broadly and may be, for example, fixedly connected, detachably connected, or integrally connected; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The specific meanings of the above terms in the present invention can be understood according to specific situations by those of ordinary skill in the art.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. A crystallization purification method of a product after a protecting group is grafted to an amino group in amino acid comprises the following steps:
(1) Adding a dichloromethane solvent into a crude product of which an amino group in an amino acid is grafted with a protective group as a raw material, and stirring for dissolving;
(2) Adding ionic liquid and n-heptane solvent into the mixed solvent obtained in the step (1), cooling to 0-10 ℃ in an ice water bath, stirring, and crystallizing;
(3) And after the crystals are completely separated out, filtering the mixed solvent, leaching a filter cake by using n-heptane, draining the solvent, and drying in a vacuum drying oven to obtain a product with qualified purity.
2. The method for purifying and crystallizing a product obtained by attaching a protecting group to an amino group in an amino acid according to claim 1,it is characterized in that the structural formula of the ionic liquid is shown as
Wherein R3, R4, R5 and R6 are respectively selected from-H or C1-C10 alkyl, preferably-H, -CH3 or-C2H 5, and R7 is selected from BF4-, cl-, br-, I-, NO 3-and PF6-.
3. The method for crystallizing and purifying the product after the amino group in the amino acid is grafted with the protecting group according to claim 1, wherein the amino group in the amino acid has a structural formula
Wherein R1 is a functional protecting group including but not limited to Boc group, cbz group, fmoc group, and R2 is selected from-H or C1-C10 alkyl, preferably-H, -CH3 or-C2H 5.
4. The method for purifying and crystallizing the product after the amino group in the amino acid is grafted with the protecting group according to claim 1, wherein the ratio of the dichloromethane solvent to the crude product after the amino group in the amino acid is grafted with the protecting group is 1.5 (ml): 1 (g).
5. The method for purifying and crystallizing a product after a protective group is attached to an amino group in an amino acid according to claim 1, wherein the ratio of the ionic liquid to the crude product after the protective group is attached to the amino group in the amino acid is (0.01-0.1) (ml): 1 (g).
6. The method for purifying and crystallizing a product after a protecting group is grafted to an amino group in an amino acid according to claim 1, wherein the volume ratio of the n-heptane solvent to the dichloromethane solvent is 1: (5-6).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210793069.9A CN115286536B (en) | 2022-07-05 | 2022-07-05 | Crystallization and purification method for product after amino group in amino acid is accessed with protecting group |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210793069.9A CN115286536B (en) | 2022-07-05 | 2022-07-05 | Crystallization and purification method for product after amino group in amino acid is accessed with protecting group |
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| Publication Number | Publication Date |
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| CN115286536A true CN115286536A (en) | 2022-11-04 |
| CN115286536B CN115286536B (en) | 2023-10-27 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1793110A (en) * | 2005-12-20 | 2006-06-28 | 武汉大学 | Process for preparing Boc protected amino acid by (Boc) O |
| JP2007238495A (en) * | 2006-03-08 | 2007-09-20 | Mitsubishi Rayon Co Ltd | Production method for crystal of n-alkoxycarbonylamino acid |
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| CN114436930A (en) * | 2022-02-15 | 2022-05-06 | 重庆市碚圣医药科技股份有限公司 | Synthesis method of Boc-L-hydroxyproline |
| CN114436929A (en) * | 2021-12-31 | 2022-05-06 | 都创(重庆)医药科技有限公司 | Synthesis method of N-protected 3, 4-dehydro-L-proline ester |
-
2022
- 2022-07-05 CN CN202210793069.9A patent/CN115286536B/en active Active
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| CN1793110A (en) * | 2005-12-20 | 2006-06-28 | 武汉大学 | Process for preparing Boc protected amino acid by (Boc) O |
| JP2007238495A (en) * | 2006-03-08 | 2007-09-20 | Mitsubishi Rayon Co Ltd | Production method for crystal of n-alkoxycarbonylamino acid |
| 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 |
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| CN115286536B (en) | 2023-10-27 |
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