CN1824658A - Improvement preparation method of using 2-aminothiazole-4-acetyl chloride hydrochloride as intermediate of preparation cephalosporin - Google Patents
Improvement preparation method of using 2-aminothiazole-4-acetyl chloride hydrochloride as intermediate of preparation cephalosporin Download PDFInfo
- Publication number
- CN1824658A CN1824658A CNA2006100683155A CN200610068315A CN1824658A CN 1824658 A CN1824658 A CN 1824658A CN A2006100683155 A CNA2006100683155 A CN A2006100683155A CN 200610068315 A CN200610068315 A CN 200610068315A CN 1824658 A CN1824658 A CN 1824658A
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- CN
- China
- Prior art keywords
- thiazolamine
- chemical formula
- acetyl chloride
- chloride hydrochloride
- guanidine
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an improved production of 2-aminothiazole-4-yl acetylchloride hydrochloride compound as the intermediate compound to produce cephalosporin, wherein said invention makes 2-aminothiazole-4-yl acetylchloride hydrochloride compound reacted in organic solvent to obtain the 2-aminothiazole-4-yl acetylchloride hydrochloride compound with high purity and high yield.
Description
Technical field
The present invention relates under economical and environment amenable condition, to produce the improvement manufacture method of the thiazolamine-4-base acetyl chloride hydrochloride that uses with intermediate as the cephalosporins manufacturing with high purity and high yield.
Background technology
With following chemical formula 4 represent (6R, 7R)-7-[2-(thiazolamine-4-yl) acetamido]-3-[(2-dimethyl aminoethyl-1H-tetrazolium-5-yl) thiomethyl]-
-3-m-4-carboxylic acid dihydrochloride
Be at first at United States Patent (USP) the 4th, 755, disclosed compound in No. 598, it is a cephalosporins of Gram-negative bacteria and gram-positive microorganism being represented good anti-microbial effect, and announces in Korean Patent that oneself discloses its manufacture method in 80-1672 number, 83-1415 number etc.
[chemical formula 4]
In the compound process of making above-mentioned chemical formula 4, use thiazolamine-4-base acetyl chloride hydrochloride of representing with following Chemical formula 1 as intermediate, by improving the manufacturing process of this intermediate, can simplify the manufacturing process of above-mentioned purpose compound.
[Chemical formula 1]
Korea S lands patent gazette No. 159833 and lands the manufacture method that patent gazette has been put down in writing the compound of above-mentioned Chemical formula 1 for No. 432425.Specifically, Korea S to land the feature of the method in No. the 159833rd, the patent gazette be thiazolamine acetate to be cooled to after-40 ℃, with phosphorus pentachloride (PCl
5) react, but this method exist produce yield low, because of using the shortcomings such as the very difficult industrialization of reaction virose phosphorus pentachloride difficult treatment, low temperature (40 ℃) under.In addition, in Korea S lands No. the 432425th, patent gazette, thiazolamine-4-guanidine-acetic acid hydrochloride and phosphorus oxychloride are reacted, but also intractable of the phosphorus oxychloride of using this moment, and might be residual and cause purity drop as impurity after the reaction.
As mentioned above; it is generally acknowledged; in the process of making cephalosporins; effective means was the acyl chlorides that utilizes compound as Chemical formula 1 and so on when the 7-amino of 7-aminocephalosporanic acid (7-ACA) was carried out acidylate; but there are the following problems to be used for making the method in the past of compound of above-mentioned Chemical formula 1; promptly; need to use strong toxicity, difficult treatment and cause the phosphorus pentachloride of phosphorus system of environmental pollution or phosphorus oxychloride etc., and in reactant, can generate impurity thus and make the purity and the stability decreases of final purpose compound.
Be directed to this, the present application artificially solves the conventional art problem and concentrates on studies, found that thiazolamine-4-guanidine-acetic acid and oxalyl chloride are reacted in organic solvent, just can produce thiazolamine-4-base acetyl chloride hydrochloride, and then finish the present invention with high purity and high yield.
Summary of the invention
Given this, the object of the present invention is to provide a kind of can under to the friendly more condition of environment, the minimized while of the generation of impurity can being produced as the improvement manufacture method of cynnematin manufacturing with the useful thiazolamine of intermediate-4-base acetyl chloride hydrochloride with high purity and high yield.
For achieving the above object, the invention provides the manufacture method of the thiazolamine that the following Chemical formula 1 of a kind of usefulness represents-4-base acetyl chloride hydrochloride, wherein, oxalyl chloride shown in thiazolamine shown in the following Chemical formula 2-4-guanidine-acetic acid and the following chemical formula 3 is reacted in organic solvent, wherein
[Chemical formula 1]
[Chemical formula 2]
[chemical formula 3]
Improved method of the present invention is preferably represented with following reaction formula 1.
[reaction formula 1]
At first, thiazolamine-4-guanidine-acetic acid (Chemical formula 2) is suspended and be cooled to-5 ℃～3 ℃, more preferably be cooled to after 0～3 ℃, stirred 15～30 minutes, more preferably stirred 20～30 minutes.At this moment, can use methylene dichloride, dimethyl formamide, chloroform, ethylene dichloride or their mixed solvent, but methylene dichloride most preferably as organic solvent.Then, in the thiazolamine of having prepared in the above-4-guanidine-acetic acid solution, keeping 0～5 ℃ more preferably keeps 0～3 ℃ on one side, on one side will be at methylene dichloride, dimethyl formamide with 20～30 minutes, dissolve oxalyl chloride (chemical formula 3) in chloroform, ethylene dichloride or their organic solvents such as mixed solvent and the solution of making slowly adds, afterwards, under same temperature, stirred 2～3 hours.At this moment, the mixing mol ratio of thiazolamine-4-guanidine-acetic acid and oxalyl chloride is preferably 1: 1 to 1: 1.5 scope.Slowly add maintaining 0～5 ℃ more preferably after the acetonitrile below 5 ℃ in this mixed solution, the limit is kept 0～5 ℃ of limit and was stirred 0.5～1 hour, makes white solid.With this white solid filtration under diminished pressure, utilize the acetonitrile washing, obtain purpose compound thiazolamine-4-base acetyl chloride hydrochloride.
Adopt manufacture method of the present invention, can be under the reaction conditions of comparing milder with method in the past make thiazolamine-4-base acetyl chloride hydrochloride simply as the core intermediate of cynnematin with high purity and high yield.In addition, easy and cheap to the processing of the oxalyl chloride that uses as initial substance, and the carbonic acid gas that produces as the main by product of reaction is very safe to environment, therefore helps industrialization of the present invention.
Embodiment
Below, will describe embodiments of the invention in detail.But following embodiment only is an example of the present invention, and content of the present invention also be can't help following embodiment and limited.
＜embodiment 1〉manufacturing of thiazolamine-4-base acetyl chloride hydrochloride
Thiazolamine-4-guanidine-acetic acid 10g is suspended among the methylene dichloride 40ml (4vol.), adds N, behind the dinethylformamide 3.85g, on one side it is cooled to 0～3 ℃, stirred 30 minutes on one side.Then, after in oxalyl chloride 9.78g, adding methylene dichloride 10ml and it being suspended, in thiazolamine-4-guanidine-acetic acid solution that this suspension is prepared above 30 minutes slowly add under keeping 0～5 ℃ condition.
After above-mentioned mixing solutions stirred 3 hours, slowly add the acetonitrile 925ml (18.5vol.) that maintains below 5 ℃ under same temperature, and this is stirred down at 0～5 ℃ once more reacted in 1 hour, obtain white solid.With the solid filtration under diminished pressure that obtains like this, utilize acetonitrile 12.2ml washing, obtain purpose compound thiazolamine-4-base acetyl chloride hydrochloride 44.66g (yield: 80%).
1HNMR(D
2O，300MHZ)δ6.97(s，1H)，3.62(s，2H)
According to the present invention, by thiazolamine-4-guanidine-acetic acid and oxalyl chloride are used as initial substance, can more economical and to environment under the more friendly condition with the minimized while of the generation of impurity, with high purity and produce thiazolamine-4-base acetyl chloride hydrochloride with high yield as the intermediate of cynnematin manufacturing usefulness.
Claims (4)
1. the manufacture method of a thiazolamine of representing with following Chemical formula 1-4-base acetyl chloride hydrochloride is characterized in that:
Comprise the step that the oxalyl chloride shown in the thiazolamine shown in the following Chemical formula 2-4-guanidine-acetic acid and the following chemical formula 3 is reacted in organic solvent,
Chemical formula 1
Chemical formula 2
Chemical formula 3
2. the manufacture method of thiazolamine as claimed in claim 1-4-base acetyl chloride hydrochloride is characterized in that, comprising:
1) thiazolamine-4-guanidine-acetic acid is suspended and be cooled to after-5 ℃～3 ℃, stir 20～30 minutes step;
2) keeping in 0～5 ℃, in the thiazolamine-4-guanidine-acetic acid solution of above-mentioned step 1), by being suspended in the oxalyl chloride solution of making in the organic solvent, under same temperature, stirring 2～3 hours step afterwards with interpolation in 20～30 minutes;
3) slowly add after the acetonitrile that maintains 0～5 ℃ in above-mentioned mixed solution, the limit is kept 0～5 ℃ of limit and was stirred 0.5～1 hour, generates the step of the compound of representing with Chemical formula 1.
3. the manufacture method of thiazolamine as claimed in claim 2-4-base acetyl chloride hydrochloride is characterized in that:
Above-mentioned steps 1) and step 2) in organic solvent be selected from methylene dichloride, dimethyl formamide, chloroform, ethylene dichloride and their mixed solvent.
4. the manufacture method of thiazolamine as claimed in claim 2-4-base acetyl chloride hydrochloride is characterized in that:
In step 2) in, the mixing mol ratio of thiazolamine-4-guanidine-acetic acid solution and oxalyl chloride solution is 1: 1 to 1: 1.5 a scope.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020060020210A KR100760429B1 (en) | 2006-03-03 | 2006-03-03 | Improved method for the preparation of 2-aminothiazole-4-yl acetylchloride hydrochloride |
| KR20060020210 | 2006-03-03 | ||
| KR2006-0020210 | 2006-03-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1824658A true CN1824658A (en) | 2006-08-30 |
| CN1824658B CN1824658B (en) | 2011-10-05 |
Family
ID=36935519
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006100683155A Expired - Fee Related CN1824658B (en) | 2006-03-03 | 2006-03-29 | Improvement preparation method of using 2-aminothiazole-4-acetyl chloride hydrochloride as intermediate of preparation cephalosporin |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR100760429B1 (en) |
| CN (1) | CN1824658B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL103110A (en) * | 1991-09-10 | 1997-04-15 | Bristol Myers Squibb Co | Anhydrous process for preparing cefepime dihydrochloride hydrate |
| GB9216759D0 (en) * | 1992-08-07 | 1992-09-23 | Finpael Spa | Process for the production of 7-amino thiazolyl cephalosporins |
-
2006
- 2006-03-03 KR KR1020060020210A patent/KR100760429B1/en active IP Right Grant
- 2006-03-29 CN CN2006100683155A patent/CN1824658B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1824658B (en) | 2011-10-05 |
| KR20060039410A (en) | 2006-05-08 |
| KR100760429B1 (en) | 2007-10-04 |
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Granted publication date: 20111005 Termination date: 20200329 |
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