CN103739551A - Method for purifying antitumor drug histamine dihydrochloride - Google Patents
Method for purifying antitumor drug histamine dihydrochloride Download PDFInfo
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- CN103739551A CN103739551A CN201310436201.1A CN201310436201A CN103739551A CN 103739551 A CN103739551 A CN 103739551A CN 201310436201 A CN201310436201 A CN 201310436201A CN 103739551 A CN103739551 A CN 103739551A
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- water
- acetonitrile
- peremin
- purification process
- ethanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
Abstract
The invention provides a method for purifying antitumor drug histamine dihydrochloride. The chemical synthetic method of histamine dihydrochloride mainly comprises the following steps at present: decarboxylation of L-histidine at high temperature and salt forming reaction for synthesis. The histamine dihydrochloride is difficult to be separated and purified, because the histamine dihydrochloride has the disadvantages of easy oxidation, easy light decomposition, and high hygroscopicity. According to the method for purifying antitumor drug histamine dihydrochloride provided by the invention, anti-oxidant is added, and then recrystallization is carried out, and after vacuum drying, the histamine dihydrochloride of high purity is obtained. The separating and purifying condition is mild, and the operation is convenient and easy to be controlled, and the method is suitable for industrial expanding production.
Description
Technical field
The present invention relates to organic compound purifying process and improve, say more specifically a kind of separation purification method of antitumor drug Peremin.
Background technology
Histamine is a kind of material with extremely strong physiologically active, also be a kind of important pharmaceutical intermediate and medicament additive. find again that in recent years histamine can be used to prepare number of chemical medicine, treatment various diseases, as can be used for, prepare antitumor drug, treatment carcinoma of the pancreas, epidermal carcinoma, bladder cancer, colorectal carcinoma, malignant melanoma, prostate cancer etc. also can be used for antineoplastic combination medication. therefore need synthesis of high purity Peremin. but itself be liquid, keep in dark place, so oxidizable. be prepared into histamine dihydrochloric acid, relatively stable, more easily processing, purifying and accumulating.
Peremin, its structural formula is as follows:
The synthetic of Peremin is mainly that raw material makes by L-Histidine, its bibliographical information is more, but detailed purifying process is little, comprises the people such as Hashimoto [1] (Hashimoto, M., etal., Chemistry Letters, 893-896 (1986)) utilize 2-tetrahydrobenzene-1-ketone as catalyzer, hexalin is as solvent, reflux state makes Histidine decarboxylic reaction, adds toluene and passes into HCl gas afterwards in decarboxylation solution, obtains Peremin product.
The people [2] such as W-L leaf C An Techake utilize methyl phenyl ketone as catalyzer decarboxylation, and salify synthesizes Peremin.
Finally by recrystallization separation and purification. but the tired lock of post-treating method, whole process needs strict nitrogen protection.
Summary of the invention
The object of the invention is to provide a kind of Peremin purifying process, and the method is simple to operate, and it is convenient to process, and can obtain highly purified Peremin purified product.
Purifying process of the present invention is as follows:
Peremin purification process is as follows:
Under lucifuge condition, add ethanol, acetonitrile the solvent mixture, stir, add antioxidant, add again Peremin crude product, stir, be heated to reflux state, slowly drip purified water, after solution clear, stir and naturally cool to 15-25 ℃, stirring and crystallizing 3 ~ 5 hours, filters, a small amount of washing with alcohol, vacuum drying obtains sterling.
Advantage of the present invention: easy to operate simple, the aftertreatments such as the synthetic and purifying of raw material do not need rare gas element whole process protection, easily obtain highly purified Peremin.
Accompanying drawing explanation
Fig. 1 is patent route map; Fig. 2 is Peremin crude product liquid phase analysis spectrogram; Fig. 3 is example 1 liquid phase analysis spectrogram; Fig. 4 is example 2 liquid phase analysis spectrograms; Fig. 5 is example 3 liquid phase analysis spectrograms.
embodiment:
embodiment 1: Peremin crude product refining
Under lucifuge condition, add the each 1.5L of dehydrated alcohol and acetonitrile, under whipped state, add antioxidant BHA 3g, then add Peremin crude product 300g, stir, be heated to reflux state, slowly drip purified water 100mL, dissolve after clarification, add 15g gac under reflux state, to stir 0.5 hour, filtered while hot is removed gac, obtains colorless cleared solution and be naturally cooled to 15 ~ 25 under whipped state
oc, stirring and crystallizing 3 ~ 5 hours, filters, dehydrated alcohol 200mL washing, 40 ℃ of vacuum-dryings obtain white powder Peremin fine work 156g, yield 52%.HPLC:?99.85%.
embodiment 2: Peremin crude product refining
Under lucifuge condition, add ethanol 1.5L, acetonitrile 1.5L solvent, under whipped state, add antioxidant vitamin C 3g, then add Peremin crude product 300g, stir, be heated to reflux state, slowly drip purified water 100mL, dissolve after clarification, add 15g gac under reflux state, to stir 0.5 hour, filtered while hot is removed gac, obtains colorless cleared solution and be naturally cooled to 15 ~ 25 under whipped state
oc, stirring and crystallizing 3 ~ 5 hours, filters, dehydrated alcohol 200mL washing, 40 ℃ of vacuum-dryings obtain white powder Peremin fine work 162g, yield 54%.HPLC:?99.86%.
embodiment 3: Peremin crude product refining
Under lucifuge condition, add ethanol 1.5L, acetonitrile 1.5L solvent, under whipped state, add antioxidant Sodium Nitrite 3g, then add Peremin crude product 300g, stir, be heated to reflux state, slowly drip purified water 100mL, dissolve after clarification, add 15g gac under reflux state, to stir 0.5 hour, filtered while hot is removed gac, obtains colorless cleared solution and be naturally cooled to 15 ~ 25 under whipped state
oc, stirring and crystallizing 3 ~ 5 hours, filters, dehydrated alcohol 200mL washing, 40 ℃ of vacuum-dryings obtain white powder Peremin fine work 154g, yield 51.3%.HPLC:?99.86%。
Claims (6)
1. a purification process for Peremin, the method comprises following process:
A. Peremin crude product is joined in the solvent of recrystallization, stirs.
B. in this solution, add a certain amount of antioxidant, start reflux.
C. slowly cooling after clarification to be dissolved, stirring and crystallizing, by the solid suction filtration of separating out, filter cake obtains highly purified Peremin highly finished product through decompression drying.
2. according to the purification process in claims a, it is characterized in that, recrystallization solvent can be selected methyl alcohol, ethanol, 2-propyl alcohol, acetonitrile, water, methanol/water, ethanol/water, acetone/water, acetonitrile/water, acetone/methanol, ketone/ethanol, methyl alcohol/acetonitrile/water, ethanol/acetonitrile/water, preferred alcohol/acetonitrile/water.
3. according to the purification process in claims a, it is characterized in that the solvent mixture volume ratio: ethanol/acetonitrile/water=10:10:1.
4. according to the purification process in claims b, it is characterized in that the optional organic compound of anti-oxidant reagent:
Butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), Tenox PG (PG), the tertiary butyl pair
Dihydroxy-benzene (TBHQ), vitamins C, inorganic salts compound: S-WAT, Sodium Nitrite etc. preferably support one's family
Element C.
5. according to the purification process in claims b, it is characterized in that recrystallization heating for dissolving temperature control 80 ~ 85
oc.
6. according to the purification process in claims c, it is characterized in that stirring and crystallizing temperature 15 ~ 25
oc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310436201.1A CN103739551B (en) | 2013-09-24 | 2013-09-24 | A kind of purification process of Peremin |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310436201.1A CN103739551B (en) | 2013-09-24 | 2013-09-24 | A kind of purification process of Peremin |
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| CN103739551A true CN103739551A (en) | 2014-04-23 |
| CN103739551B CN103739551B (en) | 2016-03-23 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1008594A (en) * | 1963-07-03 | 1965-10-27 | Nat Res Dev | Process for the production of amines |
| CN1331681A (en) * | 1998-12-23 | 2002-01-16 | 马克西姆药品公司 | Synthesis of histamine dihydrochloride |
| CN102477014A (en) * | 2010-11-27 | 2012-05-30 | 山东新时代药业有限公司 | Preparation method of histamine dihydrochloride |
-
2013
- 2013-09-24 CN CN201310436201.1A patent/CN103739551B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1008594A (en) * | 1963-07-03 | 1965-10-27 | Nat Res Dev | Process for the production of amines |
| CN1331681A (en) * | 1998-12-23 | 2002-01-16 | 马克西姆药品公司 | Synthesis of histamine dihydrochloride |
| CN102477014A (en) * | 2010-11-27 | 2012-05-30 | 山东新时代药业有限公司 | Preparation method of histamine dihydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| MITSUNORI HASHIMOTO，等: "A NOVEL DECARBOXYLATION OF α-AMINO ACIDS. A FACILE METHOD OF DECARBOXYLATION BY THE USE OF 2-CYCLOHEXEN-1-ONE AS A CATALYST", 《CHEMISTRY LETTERS》, 31 December 1986 (1986-12-31), pages 893 - 896, XP000891448, DOI: 10.1246/cl.1986.893 * |
| 秦翠群，等: "一类天然的功能性添加剂-抗氧化剂的开发和应用前景研究", 《中国食品添加剂》, no. 3, 30 June 2002 (2002-06-30), pages 59 - 63 * |
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| CN103739551B (en) | 2016-03-23 |
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Effective date of registration: 20161214 Address after: Wenshan Road Economic Zone 234000 Anhui city of Hefei province and the bustling Avenue intersection Patentee after: HEFEI YIFAN BIOLOGICAL PHARMACEUTICAL CO.,LTD. Address before: 130616 Jilin province Changchun Shuangyang Economic Development Zone on the road No. 1 Patentee before: SINOPHARM A-THINK PHARMACEUTICAL Co.,Ltd. Patentee before: Changchun University of Technology |
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Effective date of registration: 20170630 Address after: 230000 intersection of Jinxiu Avenue and Qinglong Road, Hefei economic and Technological Development Zone, Anhui Patentee after: HEFEI E-FAN BIOMEDICINE CO.,LTD. Address before: Wenshan Road Economic Zone 234000 Anhui city of Hefei province and the bustling Avenue intersection Patentee before: HEFEI YIFAN BIOLOGICAL PHARMACEUTICAL CO.,LTD. |
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Granted publication date: 20160323 |