CN1199975C - Preparation method of prolisaxin - Google Patents
Preparation method of prolisaxin Download PDFInfo
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- CN1199975C CN1199975C CN 03149866 CN03149866A CN1199975C CN 1199975 C CN1199975 C CN 1199975C CN 03149866 CN03149866 CN 03149866 CN 03149866 A CN03149866 A CN 03149866A CN 1199975 C CN1199975 C CN 1199975C
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Abstract
The present invention relates to a new method for preparing prulifloxacin. The method has the characteristics of simplicity and more suitable for industrial production.
Description
Invention field
The present invention relates to the new preparation process of Sword.This method has industrial characteristics simple and preferably.
Background technology
Sword is a known compound, and its chemical name is 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolane-4-yl) methyl isophthalic acid-piperazinyl]-4-oxo-4H-[1,3] thiophene fourth pyridine [3,2-a] quinoline-3-carboxylic acid ethyl ester also.Chinese patent application numbers 88107689.9 discloses Sword and preparation thereof.But in commercial scale production, still need to seek the new method for preparing Sword.
Summary of the invention
The inventor now finds a kind of new method that industrially scalable prepares Sword that is suitable for after deliberation, and it comprises formula I compound and the reaction of formula II compound shown in following.
Therefore, the present invention relates to prepare the method for Sword, it comprises the compound with formula I
With formula II compound in the presence of alkaline matter
React.
According to the present invention, used formula I or formula H compound is commercially available or by document currently known methods such as J.Med.Chem., 1992,35 4727-4738 in the inventive method; J.HeterocyclicChem., 1992,28 1117-1123; J.Heterocyclic Chem., 1997,34 1773-1779; US 4843070 and US 4554358 preparations.
Further, the used formula I compound of the present invention can be synthetic with following reaction scheme
Formula II compound can be by following reaction scheme preparation
According to the present invention, used alkaline matter can be mineral alkali or organic bases in the inventive method; Mineral alkali has oxyhydroxide or carbonate or supercarbonate, organic bases such as the diethylamine or the triethylamine etc. of basic metal or alkaline-earth metal for example.
Embodiment
The following examples are used to further specify the present invention, but it does not mean that any limitation of the invention.
The preparation of preparation example 1 formula 2 compounds
Drop into difluoroaniline (380 gram) in the reaction flask, triethylamine (936 gram), frozen water is cooled to below 10 ℃, begin to drip dithiocarbonic anhydride (252 gram), drip and finish temperature control 5-10 ℃, stirring is spent the night, and adds ether (1000 milliliters) and separates out faint yellow solid, filter 700 gram formulas, 2 compounds.
TLC: sherwood oil: ethyl acetate=3: 1
Preparation example 2 formulas 3 compound
Toward formula 2 compounds (700 gram), add methylene dichloride (2000 milliliters), after stirring, frozen water is chilled to 5 ℃, temperature control 5-10 ℃, drips Vinyl chloroformate (200 gram), finished in about 2 hours, solution becomes white by faint yellow suspension, continues to stir 20 minutes, reaction solution impouring frozen water (3000ml), solid is molten entirely, stirs layering, water layer extracts once with methylene dichloride (500 milliliters), organic layer merges, and washes once, washes drying with 3.6% hydrochloric acid (500ml).Remove solvent under reduced pressure, underpressure distillation is collected 68-70 ℃/4mmHg cut and is got title product 300 grams.
TLC: sherwood oil: ethyl acetate=5: 1
Preparation example 3 formulas 6 compound
Potassium hydroxide (146.2 gram), dioxane (3000 milliliters), stirring is cooled to below 10 ℃, drip diethyl malonate (132.3 gram), dripped off, and separated out solid in about 40 minutes, be warming up to 50 ℃, reacted 2 hours, be cooled to below 10 ℃, dropping formula 3 compounds (123 gram) dripped off in about 0.5 hour, and 50 ℃ were reacted 15 hours, be cooled to 10 ℃, dripping bromine ethane (290 gram) dripped off in about 0.5 hour, continue to stir 5 hours, be warming up to 100 ℃, reacted 30 minutes, cold slightly, to filter, filtrate decompression concentrates, impouring ice salt solution (1000ml) adds ethyl acetate (900ml), stirs separatory, water layer extracts with ethyl acetate (270ml * 2), merges organic layer, with saturated aqueous common salt (500ml * 2) washing, drying is filtered, and reclaims solvent, resistates adds dimethylbenzene (447ml), refluxes 48 hours, and is cold slightly, add sherwood oil (410ml), cool overnight is filtered, and sherwood oil is washed, drying gets formula 6 compounds (50 gram).
TLC: sherwood oil: ethyl acetate=5: 1
Preparation example 4 formulas 7 compound
Formula 6 compounds (100 gram), triethylamine (500 milliliters), methylene dichloride (5000 milliliters) mix, and are chilled to below 5 ℃, add aceticanhydride (40 milliliters), stir impouring frozen water (5000ml) 2 hours.Placed 2 hours, separatory, water layer extracts with methylene dichloride (5000 milliliters), the organic layer washing, drying is filtered, and removes methylene dichloride under reduced pressure, gets 95 gram formulas, 7 compounds.
TLC: sherwood oil: ethyl acetate=5: 1
Preparation example 5 formulas 9 compound
Formula 7 compounds (130 gram) mix with normal hexane (1100 milliliters), are warming up to backflow, drip normal hexane (470 milliliters) solution of SULPHURYL CHLORIDE (170 milliliters), finished in about 2 hours, refluxed 3 hours, be evaporated to dried, get pistac oily matter, resistates adds tetrahydrofuran (THF) (1200 milliliters), sodium acetate, anhydrous (111 gram), refluxed 4 hours, be chilled to room temperature, impouring frozen water (5000 milliliters) filters, be washed to neutrality, dry formula 9 compounds (100 gram) that get.
TLC: sherwood oil: ethyl acetate=5: 1
Preparation example 6 formulas 10 compound
Formula 9 compounds (200 gram), the trimethyl carbinol (3500 milliliters), the aqueous solution (1000 milliliters) of potassium hydroxide (300 gram) mixes, back flow reaction 3 hours is filtered 5000 milliliters of adding frozen water, transfers pH=7 with concentrated hydrochloric acid, filter washing, dry faint yellow solid formula 10 compounds (150 gram) that get
TLC: chloroform: methyl alcohol=1: 1 (2 ammoniacal liquor)
Preparation example 7 formulas 11 compound
3-hydroxyl-2 butanone (330 gram), N, accelerine (660 milliliters), methylene dichloride (600 milliliters) mixes, and frozen water is chilled to-10 ℃, temperature control-10--5 ℃, drip the methylene dichloride (1500 milliliters) of triphosgene (380 gram), finish temperature control and reacted 24 hours below 0 ℃, remove solvent under reduced pressure, resistates is warming up to 160 ℃ of reactions 5 hours, cooling, impouring frozen water (3000 milliliters) extracts with ether (1000 milliliters * 4), organic layer water (100 milliliters * 2) washing, anhydrous magnesium sulfate drying reclaims ether, gets white plates crystal formula 10 ' (85 gram).
Formula 10 ' (34.2 gram), N-bromosuccinimide (63.4 gram), Diisopropyl azodicarboxylate (2 gram), tetracol phenixin (1500 milliliters), mix, refluxed 5 hours, cooling, filter the elimination insolubles, the organic layer washing, drying is filtered, remove solvent under reduced pressure, the resistates underpressure distillation is collected 118-120 ℃/5mmHg cut and is got weak yellow liquid formula 11 compounds (45 gram)
The preparation of preparation example 8 Swords
Formula 11 compounds (205 gram), DMF (2000 milliliters), the frozen water cooling is down, drip the DMF (500 milliliters) of Piperazine anhydrous (86 gram), finish, continue to stir 5 minutes, add 10 (265 grams), saleratus (160 gram) was warming up to room temperature reaction 6 hours, filter, reaction solution impouring frozen water (10 liters) filters, washing, drying gets Sword crude product (240 gram).
Crude product (240 gram) is suspended from methylene dichloride (3000 milliliters), refluxes 1 hour, filter, add silica gel (800 gram), be evaporated to driedly, cross post, use earlier ethyl acetate, use chloroform/methanol=100: 1 again, collect finished product and get Sword (120 gram), gained Sword (120 gram) is with acetonitrile (2400 milliliters) recrystallization, get faint yellow elaboration 95 grams, 220 ℃ of fusing points
TLC: chloroform: methyl alcohol=5: 1
Embodiment 1
6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolane-4-yl) methyl isophthalic acid-piperazinyl]-4-oxo-4H-[1,3] thiophene fourth pyridine [3,2-a] quinoline-3-carboxylic acid ethyl esters (Sword) also
With 2.05g 4-brooethyl-5-methyl isophthalic acid, 3-dioxolane-2-ketone, 0.5g saleratus is suspended in 20ml N, in the dinethylformamide, under the frozen water cooling, dropping is dissolved in 10ml N by the 0.86g Piperazine anhydrous, the liquid of dinethylformamide finishes, and continues to stir 20 minutes, add 2.65g 6-fluoro-1-methyl-4-oxo-7-fluoro-4H-[1,3] thiophene fourth pyridine [3,2-a] quinoline-3-carboxylic acid ethyl ester also, saleratus 2.0g, be warming up to 40 ℃, stirred 6 hours, and filtered, decompression is steaming solvent below 50 ℃, use the chloroform extraction residue, wash extracting solution and dry with water, boil off solvent, gained solid acetonitrile (1g solid 1.5ml acetonitrile) recrystallization, get the 1.5g product, fusing point 241-243 ℃ (decomposition).
Ultimate analysis value: (%) C
23H
24FN
3O
6S
Calculated value: (%) C:56.43 H:4.94 N:8.58
Measured value: (%) C:55.95 H:4.92 N:8.61
Nucleus magnetic resonance: (CF
3CO
2D) ppm
1.2.35(3H，CH
3)
(2.3.45-4.35 8H, piperazine ring proton)
(3.7.10 1H, 8 protons)
Infrared spectra: (KBr)
V (cm
-1): 2950 carboxyls
1820,1730 carbonyls
Claims (2)
1. method for preparing Sword,
It is characterized in that this method makes the compound of Formula Il show that with following the compound that I represents reacts in the presence of alkaloids.
X is a halogen.
2. the process of claim 1 wherein that X is a fluorine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03149866 CN1199975C (en) | 2003-07-30 | 2003-07-30 | Preparation method of prolisaxin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03149866 CN1199975C (en) | 2003-07-30 | 2003-07-30 | Preparation method of prolisaxin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1478781A CN1478781A (en) | 2004-03-03 |
| CN1199975C true CN1199975C (en) | 2005-05-04 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 03149866 Expired - Fee Related CN1199975C (en) | 2003-07-30 | 2003-07-30 | Preparation method of prolisaxin |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100360539C (en) * | 2005-09-23 | 2008-01-09 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Preparation of plurichari |
| CN103483307A (en) * | 2013-09-27 | 2014-01-01 | 六安科瑞达新型材料有限公司 | Preparation method of 4,5-dimethyl-1,3-dioxole-2-ketone |
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Assignee: Beijing Wanpenglangge Pharmaceutical Technology Co., Ltd. Assignor: Gao Yang Contract record no.: 2011110000025 Denomination of invention: Preparation method of prolisaxin Granted publication date: 20050504 License type: Exclusive License Open date: 20040303 Record date: 20110420 |
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Granted publication date: 20050504 Termination date: 20150730 |
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