CN115594640A - Refining method of dibenzoyl thiamine disulfide - Google Patents
Refining method of dibenzoyl thiamine disulfide Download PDFInfo
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- CN115594640A CN115594640A CN202211292021.6A CN202211292021A CN115594640A CN 115594640 A CN115594640 A CN 115594640A CN 202211292021 A CN202211292021 A CN 202211292021A CN 115594640 A CN115594640 A CN 115594640A
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- CN
- China
- Prior art keywords
- thiamine disulfide
- solvent
- dibenzoyl
- dibenzoyl thiamine
- refining method
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229960001385 thiamine disulfide Drugs 0.000 title claims abstract description 63
- AZJUFRDUYTYIHV-NKFKGCMQSA-N Dibenzoyl Thiamine Chemical compound C=1C=CC=CC=1C(=O)OCC\C(SC(=O)C=1C=CC=CC=1)=C(/C)N(C=O)CC1=CN=C(C)N=C1N AZJUFRDUYTYIHV-NKFKGCMQSA-N 0.000 title claims abstract description 50
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000007670 refining Methods 0.000 title claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 18
- 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
- 238000001816 cooling Methods 0.000 claims abstract description 15
- GFEGEDUIIYDMOX-BMJUYKDLSA-N n-[(4-amino-2-methylpyrimidin-5-yl)methyl]-n-[(z)-3-[[(z)-2-[(4-amino-2-methylpyrimidin-5-yl)methyl-formylamino]-5-hydroxypent-2-en-3-yl]disulfanyl]-5-hydroxypent-2-en-2-yl]formamide Chemical compound C=1N=C(C)N=C(N)C=1CN(C=O)C(\C)=C(CCO)/SSC(/CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N GFEGEDUIIYDMOX-BMJUYKDLSA-N 0.000 claims abstract description 15
- 239000012535 impurity Substances 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 238000000967 suction filtration Methods 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 5
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 238000001291 vacuum drying Methods 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 7
- 239000000203 mixture Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 238000002386 leaching Methods 0.000 description 4
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 3
- 229960003495 thiamine Drugs 0.000 description 3
- 235000019157 thiamine Nutrition 0.000 description 3
- 239000011721 thiamine Substances 0.000 description 3
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 3
- 229960000344 thiamine hydrochloride Drugs 0.000 description 3
- 235000019190 thiamine hydrochloride Nutrition 0.000 description 3
- 239000011747 thiamine hydrochloride Substances 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 2
- 206010047601 Vitamin B1 deficiency Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000002894 beriberi Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- -1 thiamine inorganic acid salt Chemical class 0.000 description 1
- 150000003544 thiamines Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention discloses a refining method of dibenzoyl thiamine disulfide, which comprises the following steps: taking a crude product of dibenzoyl thiamine disulfide, adding an organic solvent, heating to dissolve completely, cooling and crystallizing, performing suction filtration, washing and drying to obtain high-purity dibenzoyl thiamine disulfide, wherein the solvent comprises a first solvent and a second solvent, and the first solvent is at least one of tetrahydrofuran, acetone, acetonitrile, toluene, ethyl acetate and N, N-dimethylformamide; the second solvent is at least one of water and ethanol; the mass ratio of the first solvent to the second solvent is 1. The method can effectively remove the monobenzoyl thiamine disulfide impurities with similar structures in the dibenzoyl thiamine disulfide crude product, and ensures that the purity of the product reaches more than 99.5 percent and the quality of the product has obvious competitiveness.
Description
Technical Field
The invention belongs to the field of purification of dibenzoyl thiamine disulfide, and particularly relates to a refining method of dibenzoyl thiamine disulfide.
Background
Dibenzoyl thiamine disulfide is a derivative of thiamine disulfide, and has a chemical formula of C 38 H 42 N 8 O 6 S 2 Is a white solid, is used for vitamin B1 deficiency, and has the following structural formula:
the conventional thiamine salts have many drawbacks which are difficult to overcome, such as unpleasant odor, poor stability and solubility in water, low oral bioavailability, etc., and in addition, for some people, oral administration of such people is not effective because they contain thiamine-decomposing enzymes in their intestines. Dibenzoyl thiamine disulfide, as a derivative of thiamine disulfide, completely overcomes various defects of the traditional thiamine inorganic acid salt, such as considerable stability under alkaline conditions, and unstable thiamine hydrochloride under alkaline conditions; compared with thiamine hydrochloride, the thiamine hydrochloride preparation can antagonize the hydrolysis of thiamine enzyme, and has short peak reaching time, long acting time and great kidney excretion. In conclusion, its oral absorption is far better than the various salts of traditional thiamine.
In the synthesis process of dibenzoyl thiamine disulfide, impurities with similar structures are inevitably generated, wherein the impurities are thiamine disulfide, monobenzoyl thiamine disulfide and the like, and various salts are also included, and the impurities are difficult to remove by adopting a single solvent. With the aggravation of commercial competition, the high-quality and high-purity medical products are direct expression of product competitiveness, and the preparation and improvement of the high-purity dibenzoyl thiamine disulfide have very important significance in view of medication safety and product competitiveness improvement.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a refining method of dibenzoyl thiamine disulfide. The method can effectively remove impurities in the product, and the purity of the product can reach above 99.5%.
The purpose of the invention is realized by the following technical scheme:
a refining method of dibenzoyl thiamine disulfide comprises the following steps: adding an organic solvent into a crude product of dibenzoyl thiamine disulfide, heating to reflux, dissolving completely, cooling and crystallizing, performing suction filtration, washing and drying to obtain high-purity dibenzoyl thiamine disulfide, wherein the organic solvent comprises a first solvent and a second solvent, and the first solvent is at least one of tetrahydrofuran, acetone, acetonitrile, toluene, ethyl acetate and N, N-dimethylformamide; the second solvent is at least one of water and ethanol; the mass ratio of the first solvent to the second solvent is 1.
Preferably, the mass ratio of the first solvent to the second solvent is 1.
Preferably, the impurities of the dibenzoyl thiamine disulfide crude product comprise at least one of thiamine disulfide and monobenzoyl thiamine disulfide.
Preferably, the content of the thiamine disulfide is 0.1-0.5 wt%, and the content of the monobenzoyl thiamine disulfide is 5-18 wt%.
Preferably, the mass ratio of the dibenzoyl thiamine disulfide crude product to the organic solvent is 1:2-10.
Preferably, the mass ratio of the dibenzoyl thiamine disulfide crude product to the organic solvent is 1:2-6.
Preferably, the temperature of the temperature rise is 25 to 90 ℃.
Preferably, the temperature for cooling crystallization is 0-20 ℃, and more preferably, the temperature for cooling crystallization is 5 ℃.
Preferably, the washing mode is as follows: washing is carried out by adopting a mixed solution of tetrahydrofuran and water with equal volume ratio.
Preferably, the drying is vacuum drying.
Compared with the prior art, the invention has the beneficial effects that:
(1) The inventor finds that the dibenzoyl thiamine disulfide and impurities have good solubility in an organic solvent, but the dibenzoyl thiamine disulfide has poor solubility in water or ethanol, and the impurities have certain solubility in the water or ethanol, so that the refining effect is ensured by recrystallization through adjusting the proportion of the mixed solvent.
(2) The invention creatively uses the mixed solvent as a recrystallization solvent to heat and dissolve the crude dibenzoyl thiamine disulfide, and then cools and crystallizes, thereby effectively removing impurities contained in the dibenzoyl thiamine disulfide and leading the purity of the dibenzoyl thiamine disulfide to reach more than 99.5 percent.
(3) The refining method has low cost and is suitable for industrial application.
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.
The crude dibenzoyl thiamine disulfide solid described in the examples and comparative examples was obtained from the Chinese medicinal industry, inc. and contained the following impurities: 0.1 to 0.5 weight percent of thiamine disulfide and 5 to 18 weight percent of monobenzoyl thiamine disulfide.
Example 1
A refining method of dibenzoyl thiamine disulfide comprises the following steps:
taking 100.0g of dibenzoyl thiamine disulfide solid crude product, adding 500.0g of tetrahydrofuran and 100.0g of purified water, heating to reflux, dissolving completely, naturally cooling, cooling in a cold trap at 5 ℃ for crystallization, performing suction filtration, leaching a filter cake for 1 time by using cooled tetrahydrofuran/water with equal proportion, performing vacuum drying, collecting 70.0g of material, obtaining 70% yield and 99.8% purity.
Example 2
A refining method of dibenzoyl thiamine disulfide comprises the following steps:
100.0g of dibenzoyl thiamine disulfide solid crude product is taken, 100.0g of acetone and 200.0g of purified water are added, the mixture is heated until reflux, the mixture is completely dissolved, the temperature is naturally reduced, the mixture is cooled in a cold trap at 5 ℃ for crystallization, the filtration is carried out, a filter cake is leached for 1 time by using cooled acetone/water with equal proportion, the vacuum drying is carried out, 60.0g of material is collected, the yield is 60 percent, and the purity is 99.7 percent.
Example 3
A refining method of dibenzoyl thiamine disulfide comprises the following steps:
taking 100.0g of dibenzoyl thiamine disulfide solid crude product, adding 50.0g of N, N-dimethylformamide and 150.0g of purified water, heating to reflux, dissolving completely, naturally cooling, cooling in a cold trap at 5 ℃ for crystallization, performing suction filtration, leaching a filter cake for 1 time by using cooled N, N-dimethylformamide/water in equal proportion, performing vacuum drying, collecting 50.0g of the product, obtaining the yield of 50%, and obtaining the purity of 99.9%.
Comparative example 1
100.0g of dibenzoyl thiamine disulfide solid crude product is taken, 3500.0g of tetrahydrofuran is added, the mixture is heated until the mixture flows back, the mixture is completely dissolved, the mixture is naturally cooled, the mixture is cooled in a cold trap at 5 ℃ for crystallization, the mixture is filtered, a filter cake is leached for 1 time by using cooled tetrahydrofuran, the vacuum drying is carried out, 50.0g of material is collected, the yield is 50 percent, and the purity is 88 percent.
Comparative example 2
Taking 100.0g of dibenzoyl thiamine disulfide solid crude product, adding 3500.0g of acetone, heating to reflux, dissolving completely, naturally cooling, cooling in a cold trap at 5 ℃ for crystallization, performing suction filtration, leaching a filter cake with cooled acetone for 1 time, performing vacuum drying, collecting 55.0g of material, obtaining 55% yield and 86% purity.
Comparative example 3
100.0g of dibenzoyl thiamine disulfide solid crude product is taken, 1000.0g of N, N-dimethylformamide is added, the mixture is heated to 50 ℃, completely dissolved, naturally cooled, cooled in a cold trap at 0 ℃ for crystallization, filtered, leached by suction, and a filter cake is leached by the cooled N, N-dimethylformamide for 1 time, and is dried in vacuum, 45.0g of material is collected, the yield is 45%, and the purity is 85%.
Comparative example 4
Taking 100.0g of dibenzoyl thiamine disulfide solid crude product, adding 1000.0g of purified water, heating to 50 ℃, not dissolving, naturally cooling, cooling in a cold trap at 5 ℃ for crystallization, performing suction filtration, leaching a filter cake with cooled purified water for 1 time, performing vacuum drying, collecting 71.0g of material, obtaining a yield of 71%, and obtaining a purity of 94%.
The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. A refining method of dibenzoyl thiamine disulfide is characterized by comprising the following steps: taking a crude product of dibenzoyl thiamine disulfide, adding an organic solvent, heating to reflux, cooling for crystallization, and carrying out suction filtration, washing and drying to obtain high-purity dibenzoyl thiamine disulfide; the organic solvent comprises a first solvent and a second solvent, wherein the first solvent is at least one of tetrahydrofuran, acetone, acetonitrile, toluene, ethyl acetate and N, N-dimethylformamide; the second solvent is at least one of water and ethanol; the mass ratio of the first solvent to the second solvent is 1.
2. The refining method of dibenzoyl thiamine disulfide according to claim 1, wherein the mass ratio of the first solvent to the second solvent is 1.
3. The refining method of dibenzoyl thiamine disulfide according to claim 1 or 2, wherein the mass ratio of the dibenzoyl thiamine disulfide crude product to the organic solvent is 1:2-10.
4. The refining method of dibenzoyl thiamine disulfide according to claim 3, wherein the mass ratio of dibenzoyl thiamine disulfide crude product to organic solvent is 1:2-6.
5. The refining method of dibenzoyl thiamine disulfide, according to claim 1 or 2, wherein the impurities of the crude dibenzoyl thiamine disulfide comprise at least one of thiamine disulfide and monobenzoyl thiamine disulfide.
6. The refining method of dibenzoyl thiamine disulfide, according to claim 5, wherein the content of thiamine disulfide is 0.1-0.5 wt%, and the content of monobenzoyl thiamine disulfide is 5-18 wt%.
7. The refining method of dibenzoyl thiamine disulfide according to claim 6, wherein the temperature of the temperature rise is 25-90 ℃.
8. The refining method of dibenzoyl thiamine disulfide according to claim 1 or 2, wherein the temperature for cooling and crystallization is 0-20 ℃.
9. The refining method of dibenzoyl thiamine disulfide according to claim 8, wherein said washing mode is: washing by adopting a mixed solution of tetrahydrofuran and water in an equal volume ratio;
the temperature for cooling and crystallizing is 5 ℃.
10. The refining method of dibenzoyl thiamine disulfide according to claim 1 or 2, wherein the drying is vacuum drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211292021.6A CN115594640A (en) | 2022-10-20 | 2022-10-20 | Refining method of dibenzoyl thiamine disulfide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211292021.6A CN115594640A (en) | 2022-10-20 | 2022-10-20 | Refining method of dibenzoyl thiamine disulfide |
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| Publication Number | Publication Date |
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| CN115594640A true CN115594640A (en) | 2023-01-13 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211292021.6A Pending CN115594640A (en) | 2022-10-20 | 2022-10-20 | Refining method of dibenzoyl thiamine disulfide |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1954519A1 (en) * | 1969-10-29 | 1971-06-16 | Hitachi Kagaku Co Ltd | Vitamin b, active o-arylthiaminedisulphides - selective preparation |
| JPS4913797B1 (en) * | 1969-04-18 | 1974-04-03 | ||
| JPH02282372A (en) * | 1989-04-21 | 1990-11-19 | Daiso Co Ltd | Production of o-acylthiamine disulfides |
-
2022
- 2022-10-20 CN CN202211292021.6A patent/CN115594640A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4913797B1 (en) * | 1969-04-18 | 1974-04-03 | ||
| DE1954519A1 (en) * | 1969-10-29 | 1971-06-16 | Hitachi Kagaku Co Ltd | Vitamin b, active o-arylthiaminedisulphides - selective preparation |
| JPH02282372A (en) * | 1989-04-21 | 1990-11-19 | Daiso Co Ltd | Production of o-acylthiamine disulfides |
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