CN1083063A - 6-fluoro-1, the improvement method for making of 8-7-naphthyridine derivatives - Google Patents
6-fluoro-1, the improvement method for making of 8-7-naphthyridine derivatives Download PDFInfo
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- CN1083063A CN1083063A CN 92106679 CN92106679A CN1083063A CN 1083063 A CN1083063 A CN 1083063A CN 92106679 CN92106679 CN 92106679 CN 92106679 A CN92106679 A CN 92106679A CN 1083063 A CN1083063 A CN 1083063A
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Abstract
By 2, the 6-replacement-the 5-fluoronicotinic alkyl acetate is a starting raw material, through becoming with the triethyl orthoformate cyclization and phosphorus oxychloride/DMF catalytic chlorination-cyclization, makes 6-fluoro-1, the improvement method for making of 8-7-naphthyridine derivatives.The present invention need not 2, and 6-two these intermediates of chloro-5-fluorocyanopyridine have solved fundamentally that toxicity is big, problems such as labour protection and environmental pollution, can directly synthesize chloro naphthyridines ester or methoxy naphthyridines ester, and total recovery can reach 70% ±.The processing condition gentleness is suitable for industrialization, helps enlarging producing.
Description
The present invention relates to a kind of pyridone acids antibacterials intermediate preparation field, improvement method for making of particularly a kind of 6-fluoro-1,8-7-naphthyridine derivatives of belonging to.
This compound has following structure:
In the formula, R-OCH
3Or Cl,
The present invention be pyridone acids antimicrobial drug (Pyridonecarboxylic acids as Antibacterial agents) for example, the important intermediate of fluorine pyridine acid (Enoxacin), A-6096 (Tosufloxacin) etc.
Their has a broad antifungal spectrum, antimicrbial power is strong, and oral absorption is good, and is to systems such as whole body, especially uropoiesis, digestion, breathing and skin infections etc., evident in efficacy.
When prior art prepares 6-fluoro-1,8-naphthyridines ring, following three kinds of methods are arranged usually:
(1) Dieckmann cyclization method, (day disclosure special permission communique 57-72981,1982);
(2) internal nucleophilic substitution method, (day disclosure special permission communique 60-172981,1985, day disclosure special permission communique 61-72753,1986, Guo Huiyuan etc.; " medicine industry " 19(10) 433～5,1988 is CA 111 39315
s, 1989);
(3) Gould-Jacobs method (J.P.Sanchez et al; J.Heterocyclic Chem 24 215～7 1987)
By the synthetic naphthyridines ring of above-mentioned (1), (2) two methods, all must be via 2,6-two chloro-5-fluorocyanopyridines, its toxicity is very big, and labour protection and problem of environmental pollution are serious.
In addition, (1) method needs raw material in short supply-tetrachlorobenzoquinone oxydehydrogenation and used piperazine also to need first acetylize, and hydrolysis deacetylate has again increased reactions steps and cost meaninglessly at last.
(2) disposal of three wastes of method existing problems, productive rate is also low.
(3) synthetic route of method is longer.
Therefore, the above-mentioned three therapeutic methods of traditional Chinese medicine all can't be put to industrializing implementation.
Purpose of the present invention is exactly to avoid the deficiency of prior art, by the variation route that begins by the 5-fluoronicotinic alkyl acetate, and synthetic 1,8-naphthyridines ring, synthetic fluorine pyridine acid at last etc.
The objective of the invention is to implement by following technical solution:
(1) by 2,6-replaces-the 5-fluoronicotinic alkyl acetate is a starting raw material.
(2) through with the triethyl orthoformate cyclization or with phosphorus oxychloride/DMF catalytic chlorination-cyclization, make 6-fluoro-1,8-7-naphthyridine derivatives.
Above-mentioned 6-fluoro-1, the improvement method for making of 8-7-naphthyridine derivatives, the material molecular ratio when it is characterized in that described the reaction is:
2,6-replaces-5-fluorine Yan ethyl sodio acetoacetic ester: triethyl orthoformate=1 :≤10.
Above-mentioned 6-fluoro-1, the improvement method for making of 8-7-naphthyridine derivatives, the material molecular ratio when it is characterized in that described the reaction is:
2,6-replaces-5-fluorine Yan ethyl sodio acetoacetic ester: phosphorus oxychloride=1: 3～6.
Above-mentioned 6-fluoro-1, the improvement method for making of 8-7-naphthyridine derivatives is characterized in that described and the temperature range triethyl orthoformate ring-closure reaction is 100～140 ℃.
Above-mentioned 6-fluoro-1, the improvement method for making of 8-7-naphthyridine derivatives is characterized in that described and the time triethyl orthoformate ring-closure reaction is 1～4h.
Above-mentioned 6-fluoro-1, the improvement method for making of 8-7-naphthyridine derivatives is characterized in that described and temperature range phosphorus oxychloride/DMF catalytic chlorination-ring-closure reaction is 25～60 ℃.
Above-mentioned 6-fluoro-1, the improvement method for making of 8-7-naphthyridine derivatives is characterized in that described and time phosphorus oxychloride/DMF catalytic chlorination-ring-closure reaction is 5～12h.
The present invention compared with the prior art, the present invention has following advantage:
1. need not 2,6-two these intermediates of chloro-5-fluorocyanopyridine, solved fundamentally that toxicity is big, problems such as labour protection and environmental pollution.
2. can directly synthesize chloro naphthyridines ester or methoxy naphthyridines ester, total recovery can reach 70% ±.
3. the processing condition gentleness is suitable for industrialization, helps enlarging producing.
The present invention is further elaborated below in conjunction with embodiment and accompanying drawing:
Fig. 1 is a technological process synoptic diagram provided by the invention.
Fig. 2 is a Dieckmann cyclization method, the technological process synoptic diagram of (day disclosure special permission communique 57-72981,1982);
Fig. 3 is the internal nucleophilic substitution method, and (day disclosure special permission communique 60-172981,1985, day disclosure special permission communique 61-72753,1986, Guo Huiyuan etc.: " medicine industry " 19(10) 433～5,1988 is CA 111 39315
s, 1989) the technological process synoptic diagram;
Fig. 4 is the technological process synoptic diagram of Gould-Jacobs method (J.P.Sanchez et al:J.Heterocyclic Chem 24 215～7 1987);
[embodiment one]
0.1 mole of charging capacity 2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester, the mol ratio of other material is:
2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester: triethyl orthoformate=1: 10.
2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester 28.4g with dosage, triethyl orthoformate 165ml is heated to 140 ℃, reaction 1h, the reclaim under reduced pressure triethyl orthoformate, the gained crystallization is dissolved, separates, is extracted with water 200ml with ethyl acetate 300ml, water layer continues and uses ethyl acetate extraction, and united extraction liquid washs with saturated nacl aqueous solution, dried over sodium sulfate.The reclaim under reduced pressure ethyl acetate, the gained crystallization promptly gets 7-methoxyl group-1-ethyl-6-fluoro-1,4-dihydro-4-oxygen-1,8-naphthyridines-3-carboxylic acid, ethyl ester 20.7g, 178～179 ℃ of mp, productive rate 70.4% with chloroform-hexanaphthene recrystallize.
Mass spectroscopy: C
14H
15N
2O
4F=294
M/e: theoretical value 294; Measured value 294.
[embodiment two]
0.1 mole of charging capacity 2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester, the mol ratio of other material is:
2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester: triethyl orthoformate=1: 10.
2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester 28.4g with dosage, triethyl orthoformate 165ml is heated to 140 ℃, reaction 4h, the reclaim under reduced pressure triethyl orthoformate, the gained crystallization is dissolved, separates, is extracted with water 200ml with ethyl acetate 300ml, water layer continues and uses ethyl acetate extraction, and united extraction liquid washs with saturated nacl aqueous solution, dried over sodium sulfate.The reclaim under reduced pressure ethyl acetate, the gained crystallization promptly gets 7-methoxyl group-1-ethyl-6-fluoro-1,4-dihydro-4-oxygen-1,8-naphthyridines-3-carboxylic acid, ethyl ester 20g, 178～179 ℃ of mp, productive rate 68.02% with chloroform-hexanaphthene recrystallize.
[embodiment three]
0.1 mole of charging capacity 2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester, the mol ratio of other material is:
2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester: phosphorus oxychloride=1: 3.
2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester 28.4g with dosage is dissolved among the DMF 200ml, drips POCl
346g, in 25～30 ℃, reaction 12h, the gained reaction solution drips in 800ml water in 15～20 ℃, stirs and separates out yellow crystal, places 4h, filter, be washed to neutrality, be drying to obtain 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxygen-1,8-naphthyridines-3-carboxylic acid, ethyl ester 21g, mp186～187 ℃, productive rate 70.35%.
[embodiment four]
0.1 mole of charging capacity 2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester, the mol ratio of other material is:
2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester: phosphorus oxychloride=1: 3.
2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester 28.4g with dosage is dissolved among the DMF 200ml, drips POCl
346g, in 60 ℃, reaction 5h, the gained reaction solution drips in 800ml water in 15～20 ℃, stirs and separates out yellow crystal, places 4h, filter, be washed to neutrality, be drying to obtain 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxygen-1,8-naphthyridines-3-carboxylic acid, ethyl ester 21.3g, mp186～188 ℃, productive rate 70.35%.
[embodiment five]
0.1 mole of charging capacity 2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester, the mol ratio of other material is:
2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester: phosphorus oxychloride=1: 6.
2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester 28.4g with dosage is dissolved among the DMF 200ml, drips POCl
392g, in 25～30 ℃, reaction 12h, the gained reaction solution drips in 800ml water in 15～20 ℃, stirs and separates out yellow crystal, places 4h, filter, be washed to neutrality, be drying to obtain 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxygen-1,8-naphthyridines-3-carboxylic acid, ethyl ester 20.5g, mp186.5～187.5 ℃, productive rate 68.67%.
[embodiment six]
0.1 mole of charging capacity 2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester, the mol ratio of other material is:
2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester: phosphorus oxychloride=1: 6.
2-ethylamino--6-methoxyl group-5-fluorine Yan ethyl acetoacetic acid ethyl ester 28.4g with dosage is dissolved among the DMF 200ml, drips POCl
392g, in 60 ℃, reaction 5h, the gained reaction solution drips in 800ml water in 15～20 ℃, stirs and separates out yellow crystal, places 4h, filter, be washed to neutrality, be drying to obtain 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxygen-1,8-naphthyridines-3-carboxylic acid, ethyl ester 21.5g, mp186.5～188 ℃, productive rate 72.02%.
Claims (7)
1, a kind of pyridone acids antibacterials intermediate preparation field that belongs to is by 2,6-replaces-5-fluorine Yan acyl acetic acid ethyl ester, through triethyl orthoformate/aceticanhydride and ethamine condensation, again through K
2CO
3/ DMF cyclization becomes 1, the 6-fluoro-1 of 8-naphthyridines ring, the method for making of 8-7-naphthyridine derivatives, and this compound has following structure:
In the formula, R-OCH
3Or Cl,
Feature of the present invention is:
(1) by 2,6-replaces-the 5-fluoronicotinic alkyl acetate is a starting raw material,
(2) through with the triethyl orthoformate cyclization or with phosphorus oxychloride/DMF catalytic chlorination-cyclization, make 6-fluoro-1,8-7-naphthyridine derivatives.
2, according to the improvement method for making of the described 6-fluoro-1 of claim 1,8-7-naphthyridine derivatives, the material molecular ratio when it is characterized in that described the reaction is:
2,6-replaces-5-fluorine Yan ethyl sodio acetoacetic ester: triethyl orthoformate=1 :≤10
3, according to the improvement method for making of the described 6-fluoro-1 of claim 1,8-7-naphthyridine derivatives, the material molecular ratio when it is characterized in that described the reaction is:
2,6-replaces-5-fluorine Yan ethyl sodio acetoacetic ester: phosphorus oxychloride=1:3～6.
4,, it is characterized in that described and the temperature range triethyl orthoformate ring-closure reaction are 100～140 ℃ according to the improvement method for making of the described 6-fluoro-1 of claim 1,8-7-naphthyridine derivatives.
5,, it is characterized in that described and the time triethyl orthoformate ring-closure reaction are 1～4h according to the improvement method for making of the described 6-fluoro-1 of claim 1,8-7-naphthyridine derivatives.
6,, it is characterized in that described and temperature range phosphorus oxychloride/DMF catalytic chlorination-ring-closure reaction are 25～60 ℃ according to the improvement method for making of the described 6-fluoro-1 of claim 1,8-7-naphthyridine derivatives.
7,, it is characterized in that described and time phosphorus oxychloride/DMF catalytic chlorination-ring-closure reaction are 5～12h according to the improvement method for making of the described 6-fluoro-1 of claim 1,8-7-naphthyridine derivatives.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92106679 CN1083063A (en) | 1992-08-21 | 1992-08-21 | 6-fluoro-1, the improvement method for making of 8-7-naphthyridine derivatives |
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|---|---|---|---|
| CN 92106679 CN1083063A (en) | 1992-08-21 | 1992-08-21 | 6-fluoro-1, the improvement method for making of 8-7-naphthyridine derivatives |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100364992C (en) * | 2006-03-16 | 2008-01-30 | 云南师范大学 | A class of pyrrolo-naphthyridine derivatives |
| CN101792443A (en) * | 2010-03-09 | 2010-08-04 | 北京欧凯纳斯科技有限公司 | Fluoro-carbostyril derivative as well as preparation method and application thereof |
| CN110981869A (en) * | 2019-12-10 | 2020-04-10 | 天津科技大学 | Synthesis method of 1, 8-bis-azachromone and application of 1, 8-bis-azachromone in antidiabetic drugs |
-
1992
- 1992-08-21 CN CN 92106679 patent/CN1083063A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100364992C (en) * | 2006-03-16 | 2008-01-30 | 云南师范大学 | A class of pyrrolo-naphthyridine derivatives |
| CN101792443A (en) * | 2010-03-09 | 2010-08-04 | 北京欧凯纳斯科技有限公司 | Fluoro-carbostyril derivative as well as preparation method and application thereof |
| CN110981869A (en) * | 2019-12-10 | 2020-04-10 | 天津科技大学 | Synthesis method of 1, 8-bis-azachromone and application of 1, 8-bis-azachromone in antidiabetic drugs |
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