CN1078236A - Pyridine a pair of horses going side by side (1,2,3)-1, the catalysis synthesizing technology of 4-benzene a pair of horses going side by side oxazine derivative - Google Patents
Pyridine a pair of horses going side by side (1,2,3)-1, the catalysis synthesizing technology of 4-benzene a pair of horses going side by side oxazine derivative Download PDFInfo
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- CN1078236A CN1078236A CN 93100133 CN93100133A CN1078236A CN 1078236 A CN1078236 A CN 1078236A CN 93100133 CN93100133 CN 93100133 CN 93100133 A CN93100133 A CN 93100133A CN 1078236 A CN1078236 A CN 1078236A
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- pair
- horses going
- benzene
- pyridine
- going side
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
9,10-two fluoro-2,3-dihydro-3-methyl-7-oxygen-7H-pyridine a pair of horses going side by side [1,2,3-dc]-1, the catalysis synthesizing technology of 4-benzene a pair of horses going side by side piperazine-6-carboxylic acid.The invention belongs to chemistry medicine and make relevant compound synthesis technology, wherein R represents low-carbon alkyl.
Based compound of the present invention (A) is under sodium alkoxide catalysis, and condensation, cyclisation, hydrolysis directly make compound (C), and product (B) need not to separate productive rate height (75～80%) in the middle of it.
Description
Indication compound of the present invention is to have a plurality of substituent pyridine a pair of horses going side by sides [1,2,3-de]-1,4-Ben Pian oxazine, and its substituting group and the position of substitution are respectively 2, the 3-dihydro; The 3-methyl; The 6-carboxyl; 7-oxygen-7H; 9, the 10-difluoro.The invention belongs to chemistry medicine and make relevant compound synthesis technology, that is:
R=CH wherein
3, C
2H
5, C
3H
7, (CH
3)
2CH, C
4H
9Deng.
With 7,8-two fluoro-2,3-dihydro-3-methyl-4H-1,4-benzene a pair of horses going side by side oxazine (being compd A) is a starting raw material, produces 9,10-two fluoro-2,3-dihydro-3-methyl-7-oxygen-7H-pyridine a pair of horses going side by side [1,2,3-de]-1,4-Ben Pian oxazine-6-carboxylic acid [9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-Carboxylicacid] method.
Prior art is as (spy opens clear 61-246172, and the spy opens clear 61-246188,1986) compound (A) is proposed in Glacial acetic acid, through the 6h condensation separate compound (I), cyclisation 1.5h again, go into frozen water, crystallization, the chloroform extracting, alkali cleaning, washing, drying, evaporate compound (II).Be dissolved in concentrated hydrochloric acid-acetic acid mixed solution back flow reaction 2h.Cooling, crystallization, suction filtration, washing, ethanol are washed, ether is washed, dry compound (C), the productive rate 58.4% of getting.
After and for example (spy opens clear 62-252790,1987) proposes compound (A) condensation 1h, be dissolved in Glacial acetic acid, ice-cold dropping Glacial acetic acid one vitriol oil mixed solution down, cyclisation 1.5h.With frozen water, neutralization, chloroform extracting, alkali cleaning, after the washing, dry, distillation, the crystallization that adds diethyl ether, filter compound (II).Be dissolved in the acetic acid, add concentrated hydrochloric acid, backflow 3h.Below operation is opened clear 61-246188 with the spy, productive rate 69.3%.
And for example (E.P.0368410,1990) propose compound (A) at N
2Middle condensation 2h, cyclisation 1h.Below operation is opened clear 62-252790 with the spy, productive rate 63.7%.
The subject matter that above-mentioned technology exists is that productive rate is low, operates cumbersomely, and the production cycle is long.
The present invention has designed compound (A) is directly produced compound (C) under sodium alkoxide catalysis technology, has saved the loaded down with trivial details step of separation intermediate compound (B).Carry out for making to react completely to depress at alkali.Catalyzer adopts sodium alkoxide (as sodium ethylate etc.), and its weight ratio is:
Compound (A): catalyzer=1000: 0.1～5.0.
Temperature of reaction is 120～150 ℃.
Reaction times is 4～8h
Productive rate is 75～80%
Compound (C) analytical results:
Ultimate analysis conforms to theoretical value.
Mass spectroscopy records molecular weight and equates with theoretical value.
[embodiment]
15.8g compound (A), 24g ethoxymethylidene diethyl malonate and 5mg sodium ethylate mixing, decompression be 135～140 ℃ of stirring 1.5h down.Add 158g Tripyrophosphoric acid ethyl ester, 1.5h is stirred in the equality of temperature decompression.Be chilled to room temperature, add 200ml concentrated hydrochloric acid-acetic acid (1: 4) mixed solution, backflow 3h.In the impouring frozen water, stir that folding is brilliant, suction filtration, use frozen water in turn, cold ethanol, ether cleaning, drying get white powder compound (C) 19.2g, productive rate 80.0%, M.P.＞300 ℃.
Ultimate analysis: C
13H
9F
2NO
4
Element: C H N
Theoretical value: 55.52 3.23 4.98
Measured value: 56.10 3.53 5.12
Claims (7)
1, produces 9 for one, 10-two fluoro-2,3-dihydro-3-methyl-7-oxygen-7H-pyridine a pair of horses going side by side [1,2,3-de]-1, the method for 4-benzene a pair of horses going side by side oxazine-6-carboxylic acid.Feature of the present invention is:
(a), starting raw material is 7,8-two fluoro-2,3-dihydro-3-methyl-4H-1,4-benzene a pair of horses going side by side oxazine (being compd A).
(b), catalyzer carries out condensation, cyclisation, hydrolysis under existing.
2, method according to claim 1 is characterized in that intermediate product 9,10-two fluoro-2, and 3-dihydro-3-methyl-7-oxygen-7H-pyridine a pair of horses going side by side [1,2,3-de]-1,4-benzene a pair of horses going side by side oxazine-6-carboxylicesters (being compd B) without separation, directly is hydrolyzed.
3, method according to claim 1 is characterized in that catalyst system therefor is a sodium alkoxide.
4, method according to claim 3 is characterized in that used sodium alkoxide can be sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide etc.
5, method according to claim 1, the weight ratio in it is characterized in that reacting is:
Compound (A): catalyzer=1000: 0.1～5.0.
6, method according to claim 1 is characterized in that temperature of reaction is 120～150 ℃.
7, method according to claim 1 is characterized in that the reaction times is 4～8h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93100133 CN1078236A (en) | 1993-01-08 | 1993-01-08 | Pyridine a pair of horses going side by side (1,2,3)-1, the catalysis synthesizing technology of 4-benzene a pair of horses going side by side oxazine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93100133 CN1078236A (en) | 1993-01-08 | 1993-01-08 | Pyridine a pair of horses going side by side (1,2,3)-1, the catalysis synthesizing technology of 4-benzene a pair of horses going side by side oxazine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1078236A true CN1078236A (en) | 1993-11-10 |
Family
ID=4982821
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 93100133 Pending CN1078236A (en) | 1993-01-08 | 1993-01-08 | Pyridine a pair of horses going side by side (1,2,3)-1, the catalysis synthesizing technology of 4-benzene a pair of horses going side by side oxazine derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1078236A (en) |
-
1993
- 1993-01-08 CN CN 93100133 patent/CN1078236A/en active Pending
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |