CN104016981B - A kind of Moxifloxacin hydrochloride analog and preparation method thereof - Google Patents
A kind of Moxifloxacin hydrochloride analog and preparation method thereof Download PDFInfo
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Abstract
The invention provides a kind of new fluoro-8-methoxyl group of Moxifloxacin hydrochloride analog 1-cyclopropyl-6--4-oxo-7-(4-oxo six hydrogen-1H-pyrrolo-[3,4-c] pyridine-6 (2H) base)-1,4-dihydroquinoline-3-carboxylic acid (I) and preparation method thereof, and the application of this compound in the quality controling research of Moxifloxacin hydrochloride.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to a kind of new Moxifloxacin hydrochloride analog and preparation method thereof.
Background technology
Moxifloxacin hydrochloride (moxifloxacinhydrochloride, 1-cyclopropyl-7-(S, S-2,8-diazonium-two ring [4.3.0] nonane-8-base) the fluoro-8-methoxyl group-1 of-6-, 4-dihydro-4-oxo-3-quinoline carboxylic acid hydrochloride) be the forth generation Comprecin that Bayer A.G researches and develops, go on the market in Germany first in September, 1999, for the clinical a kind of extensive pedigree antibiotic generally used, it has the features such as wide spectrum, efficient, low resistance, low toxicity, and structural formula is as follows:
The quality standard of this medicine is existing in British Pharmacopoeia, European Pharmacopoeia and American Pharmacopeia to be recorded, and wherein explicitly points out and may amount to 5 kinds of impurity containing A, B, C, D, E, and the single assorted content of restriction can not more than 0.1%, and five kinds of impurity structures are as follows respectively:
But when carrying out the experiment of Moxifloxacin hydrochloride finished product stability, found the impurity that a structure is brand-new, and along with experiment process, this foreign matter content obviously increases, for one of impurity that content in finished dosage form is larger, it has vital impact to the safety and effectiveness of the medicine that finally dispatches from the factory.Therefore, determine chemical structure and the preparation method of this impurity, to setting up detection method, analysing impurity content, and determine rational limit of impurities thus carry out the quality control of Moxifloxacin hydrochloride and clinical drug safety to detect and all serve vital effect.
Summary of the invention
The invention provides the fluoro-8-methoxyl group of a kind of Moxifloxacin hydrochloride analog 1-cyclopropyl-6--4-oxo-7-(4-oxo six hydrogen-1H-pyrrolo-[3,4-c] pyridine-6 (2H) base)-1,4-dihydroquinoline-3-carboxylic acid (I) and its preparation method and application, structural formula is as follows:
Synthetic route of the present invention is as follows:
Specifically comprise the steps:
A () 2-cyclopentenone, N-methoxyl methyl-N-trimethyl silicane methyl-benzyl amine in organic solvent, add acid catalysis, reaction generates 2-benzyl six hydrogen cyclopentano [C] pyrroles-4-(1H)-one (II);
Wherein, organic solvent is selected from methylene dichloride, acetonitrile, acetone, DMF, dimethyl sulfoxide (DMSO) and N,N-dimethylacetamide.
Wherein, acid is selected from trifluoroacetic acid, trifluoroacetic anhydride, Glacial acetic acid, phenylformic acid, formic acid, acetic acid, oxalic acid.
B () 2-benzyl six hydrogen cyclopentano [C] pyrroles-4-(1H)-one (II) and oxammonium hydrochloride are obtained by reacting 2-benzyl six hydrogen cyclopentano [C] pyrroles-4-(1H)-one oxime (III) under the effect of alkali;
Wherein, alkali is selected from salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, sodium hydroxide, potassium hydroxide.
(c) 2-benzyl six hydrogen cyclopentano [C] pyrroles-4-(1H)-one oxime (III) under the effect of acid binding agent with acyl chloride reaction, products therefrom and glacial acetic acid and diacetyl oxide are reset and are obtained 2-benzyl six hydrogen-1H-pyrrolo-[3,4-c] pyridine-4 (2H)-one (IV);
Wherein, acid binding agent is selected from sodium hydroxide, potassium hydroxide, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, triethylamine.
Wherein, acyl chlorides is selected from a kind of in methylsulfonyl chloride, benzene sulfonyl chloride, Tosyl chloride or both mixtures.
There is debenzylation reaction and obtain six hydrogen-1H-pyrrolo-[3,4-c] pyridine-4 (2H)-one (V) in (d) 2-benzyl six hydrogen-1H-pyrrolo-[3,4-c] pyridine-4 (2H)-one (IV).
E the fluoro-Isosorbide-5-Nitrae of () 1-cyclopropyl-6,7-bis--dihydro-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid ethyl ester obtains the fluoro-Isosorbide-5-Nitrae of 1-cyclopropyl-6,7-bis--dihydro-8-methoxy-4-oxo 3-carboxylate radical-O under Lewis acid catalysis with acid reaction
3, O
4-diethyl acid group closes boron (VI).
Wherein, Lewis acid is selected from a kind of in iron trichloride, tin tetrachloride, aluminum chloride, tindichloride, boron trichloride, boron trifluoride, zinc dichloride or both mixtures.
The fluoro-Isosorbide-5-Nitrae of (f) 1-cyclopropyl-6,7-bis--dihydro-8-methoxy-4-oxo-3-carboxylate radical-O
3, O
4-diethyl acid group closes boron (VI) and six hydrogen-1H-pyrrolo-es [3,4-c] pyridine-4 (2H)-one (V) is in polar aprotic solvent, add base catalysis, reaction generates 1-cyclopropyl-7-(4-oxo six hydrogen-1H-pyrrolo-[3,4-c] pyridine-4 (2H)-one-6-base) the fluoro-8-methoxy-Isosorbide-5-Nitrae of-6--dihydro-4-Oxoquinoline-3-carboxylic acid root-O
3, O
4-diethyl acid group closes boron (VII).
Wherein, polar aprotic solvent is selected from acetonitrile, dimethyl formamide, 1, a kind of in 3 dimethyl-2-imidazolinones, dimethyl sulfoxide (DMSO), HMPA or both mixtures.
Wherein, alkali is selected from triethylamine, pyridine, Di-n-Butyl Amine, n-Butyl Amine 99, diethylamine, Diisopropylamine.
(g) 1-cyclopropyl-7-(4-oxo six hydrogen-1H-pyrrolo-[3,4-c] pyridine-4 (2H)-one-6-base) the fluoro-8-methoxy-Isosorbide-5-Nitrae of-6--dihydro-4-Oxoquinoline-3-carboxylic acid root-O
3, O
4-diethyl acid group closes boron (VII) and obtains the fluoro-8-methoxyl group of Moxifloxacin hydrochloride analog 1-cyclopropyl-6--4-oxo-7-(4-oxo six hydrogen-1H-pyrrolo-[3 in alkaline condition hydrolysis, 4-c] pyridine-6 (2H) base)-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid (I).
Wherein, alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus.
Standard reference material can be provided for the quality control of Moxifloxacin hydrochloride and clinical drug safety detect by the present invention, ensure clinical drug safety reliability.And this preparation method is simple to operate, reaction conditions is gentle, can with the highly purified Moxifloxacin hydrochloride analog of the acquisition of higher yields.
Figure of description
Accompanying drawing 1: the HPLC collection of illustrative plates of compound (I) embodiment 7;
Accompanying drawing 2: compound (I) embodiment 7
1hNMR schemes;
Accompanying drawing 3: compound (I) embodiment 7
13cNMR schemes;
Accompanying drawing 4: the ESI figure of compound (I) embodiment 7.
Specific embodiment
Content for a better understanding of the present invention, is described further below in conjunction with specific embodiment, but concrete embodiment is not the restriction done content of the present invention.
Embodiment 1: the preparation of compound ii
In 1L three-necked bottle, add 57.0g2-cyclopentenone, 165.0gN-methoxyl methyl-N-trimethyl silicane methyl-benzyl amine, 750mlDCM, stir cooling.Slow dropping 180mlTFA, in controlling, temperature is at-5 ~ 0 DEG C, after dropwising, heats up, and TLC monitoring reaction to terminal.Poured into by reaction solution in pre-configured 2M sodium hydroxide (3750ml) solution, add DCM (300ml*2) extraction, merge organic layer, anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure obtains brown oil (II).
Embodiment 2: the preparation of compound III
149.61g2-benzyl six hydrogen cyclopentano [C] pyrroles-4-(1H)-one (II), 72.47g oxammonium hydrochloride, 144.07g salt of wormwood, 1500ml methyl alcohol and 52.5ml water is added in 3L three-necked bottle, temperature rising reflux, stir, TLC monitoring reaction to terminal.After being cooled to room temperature, suction filtration, filtrate reduced in volume oozes to absence of liquid.In concentrated gained oily matter, add 800ml water, with DCM (800ml*2) extraction, merge organic phase, anhydrous magnesium sulfate drying.Suction filtration, concentrating under reduced pressure obtains brown oil 153.0g, and decolouring, obtains white solid, i.e. compound III.
Embodiment 3: the preparation of compounds Ⅳ
17.42g2-benzyl six hydrogen cyclopentano [C] pyrroles-4-(1H)-one oxime (III), 8.71g sodium hydroxide, 430ml acetone and 160ml water is added in 1L three-necked bottle, add 20.20g Tosyl chloride in whipping process in batches, finish, stirring reaction, TLC monitoring reaction to terminal.Reaction solution DCM (250ml*2) extraction, merge organic layer, anhydrous magnesium sulfate drying, suction filtration, is evaporated to dripless, obtains 59.81g brown oil.
In above-mentioned gained oily matter, add 42ml glacial acetic acid and 42ml diacetyl oxide, stir, TLC monitoring reaction to terminal.Add 210ml water, with ethyl acetate (50ml*2) washing, the aqueous phase sodium hydroxide solution of 15% regulates pH to 12 ~ 14, washs with sherwood oil (50ml*3), aqueous phase uses ethyl acetate (150ml*2) to extract again, merge organic layer, anhydrous magnesium sulfate drying, suction filtration, dry white solid, i.e. 2-benzyl six hydrogen-1H-pyrrolo-[3,4-c] pyridine-4 (2H)-one (IV), yield 32.4%.
Embodiment 4: the preparation of compound V
In 250ml single port bottle, add 5.15g2-benzyl six hydrogen-1H-pyrrolo-[3,4-c] pyridine-4 (2H)-one (IV), 1.03g10%Pd/C, 5.15g ammonium formiate and 60ml methyl alcohol, stirring reaction, TLC monitoring reaction to terminal.Suction filtration, filtrate reduced in volume, to dripless, obtains colorless oil, i.e. compound V, yield 100%.
Implement 5: the preparation of compound VI
In 500ml three-necked bottle, add boric acid, zinc chloride and aceticanhydride, stir.Slow heat temperature raising, reacts 1.5 hours, adds 38.76ml acetic acid, reaction, then adds the fluoro-Isosorbide-5-Nitrae of 1-cyclopropyl-6,7-bis--dihydro-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid ethyl ester and 15.96ml acetic acid, reacts about 5 hours.It is complete that TLC tracks to reaction, removes solvent under reduced pressure, then add ethyl acetate evaporated under reduced pressure.Stir, wash, filter, obtain 24.31g faint yellow solid compound VI, yield: 95.9%.
Implement 6: the preparation of compound VII
The fluoro-Isosorbide-5-Nitrae of 1-cyclopropyl-6,7-bis--dihydro-8-methoxy-4-Oxoquinoline-3-carboxylic acid root-O is added in 250ml three-necked bottle
3, O
4-diethyl acid group closes boron (VI), six hydrogen-1H-pyrrolo-es [3,4-c] pyridine-4 (2H)-one (V), triethylamine and second eyeball, stirring at room temperature is reacted, and reaction solution is a large amount of solid of molten clear rear precipitation first, and TLC monitoring is complete to raw material reaction.Filter, a small amount of acetonitrile wash of filter cake, dry 7.52g greenish yellow solid compound VII, yield 76.9%.
Embodiment 7: the preparation of chemical compounds I
7.52g1-cyclopropyl-7-(4-oxo six hydrogen-1H-pyrrolo-[3,4-c] pyridine-4 (2H)-one-6-base) the fluoro-8-methoxy-Isosorbide-5-Nitrae of-6--dihydro-4-Oxoquinoline-3-carboxylic acid root-O is added in 250ml three-necked bottle
3, O
4-diethyl acid group closes boron and 60ml5% sodium hydroxide solution, and heated and stirred becomes clarification to reaction solution, and TLC monitoring is complete to raw material reaction.With 2N salt acid for adjusting pH to 4.0 ~ 5.0, continue to stir, filter, filter cake is transferred in 100ml reaction flask and pulls an oar 2 hours by 50ml methyl alcohol reflux, suction filtration, dry, obtain 5.53g faint yellow solid, i.e. chemical compounds I (yield 96.2%), HPLC purity detecting value is 94.83% (referring to accompanying drawing 1);
1hNMR (300MHz, d
6-DMSO) δ: 8.65 (s, 1H), 7.62 (s, 1H), 4.15 (m, 1H), 3.87 ~ 3.73,3.46 ~ 3.42 (m, 4H), 3.58 (s, 3H), 3.25 (m, 2H), 2.96 (q, 1H), 2.72 (m, 1H), 1.94 ~ 1.88,1.71 ~ 1.61 (m, 2H), 1.15 ~ 1.02 (m, 4H) (referring to accompanying drawing 2);
13cNMR (300MHz, d
6-DMSO) δ: 175.8,170.6,165.5,155.5,152.0,149.9,142.5,136.5,134.3,134.0,106.1,61.2,55.3,52.8,42.6,40.4,39.2,35.2,24.2,8.83,8.58 (referring to accompanying drawing 3); ESIm/z416.2 [M+H]
+, 438.2 [M+Na]
+(referring to accompanying drawing 4).
Claims (8)
1. a Moxifloxacin hydrochloride analog, is characterized in that, chemical structure is as shown in I:
2. the preparation method of Moxifloxacin hydrochloride analog as claimed in claim 1, it is characterized in that, reaction process is as follows:
Specifically comprise following reactions steps:
A () 2-cyclopentenone, N-methoxyl methyl-N-trimethyl silicane methyl-benzyl amine in organic solvent, add acid catalysis, reaction generates 2-benzyl six hydrogen cyclopentano [C] pyrroles-4-(1H)-one (II);
Wherein, organic solvent is selected from the one in methylene dichloride, acetonitrile, acetone, DMF, dimethyl sulfoxide (DMSO) and N,N-dimethylacetamide;
Wherein, acid is selected from the one in trifluoroacetic acid, trifluoroacetic anhydride, phenylformic acid, formic acid, acetic acid, oxalic acid;
B () 2-benzyl six hydrogen cyclopentano [C] pyrroles-4-(1H)-one (II) and oxammonium hydrochloride are obtained by reacting 2-benzyl six hydrogen cyclopentano [C] pyrroles-4-(1H)-one oxime (III) under the effect of alkali;
Wherein, alkali is selected from the one in salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, sodium hydroxide, potassium hydroxide;
(c) 2-benzyl six hydrogen cyclopentano [C] pyrroles-4-(1H)-one oxime (III) under the effect of acid binding agent with acyl chloride reaction, products therefrom and glacial acetic acid and diacetyl oxide are reset and are obtained 2-benzyl six hydrogen-1H-pyrrolo-[3,4-c] pyridine-4 (2H)-one (IV);
Wherein, acid binding agent is selected from the one in sodium hydroxide, potassium hydroxide, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, triethylamine;
Wherein, acyl chlorides is selected from a kind of in methylsulfonyl chloride, benzene sulfonyl chloride, Tosyl chloride or both mixtures;
There is debenzylation reaction and obtain six hydrogen-1H-pyrrolo-[3,4-c] pyridine-4 (2H)-one (V) in (d) 2-benzyl six hydrogen-1H-pyrrolo-[3,4-c] pyridine-4 (2H)-one (IV);
E the fluoro-Isosorbide-5-Nitrae of () 1-cyclopropyl-6,7-bis--dihydro-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid ethyl ester obtains the fluoro-Isosorbide-5-Nitrae of 1-cyclopropyl-6,7-bis--dihydro-8-methoxy-4-oxo 3-carboxylate radical-O under Lewis acid catalysis with acid reaction
3, O
4-diethyl acid group closes boron (VI);
Wherein, Lewis acid is selected from a kind of in iron trichloride, tin tetrachloride, aluminum chloride, tindichloride, boron trichloride, boron trifluoride, zinc dichloride or both mixtures;
The fluoro-Isosorbide-5-Nitrae of (f) 1-cyclopropyl-6,7-bis--dihydro-8-methoxy-4-oxo-3-carboxylate radical-O
3, O
4-diethyl acid group closes boron (VI) and six hydrogen-1H-pyrrolo-es [3,4-c] pyridine-4 (2H)-one (V) is in polar aprotic solvent, add base catalysis, reaction generates 1-cyclopropyl-7-(4-oxo six hydrogen-1H-pyrrolo-[3,4-c] pyridine-4 (2H)-one-6-base) the fluoro-8-methoxy-Isosorbide-5-Nitrae of-6--dihydro-4-Oxoquinoline-3-carboxylic acid root-O
3, O
4-diethyl acid group closes boron (VII);
Wherein, polar aprotic solvent is selected from acetonitrile, dimethyl formamide, 1, a kind of in 3 dimethyl-2-imidazolinones, dimethyl sulfoxide (DMSO), HMPA or both mixtures;
Wherein, alkali is selected from the one in triethylamine, pyridine, Di-n-Butyl Amine, n-Butyl Amine 99, diethylamine, Diisopropylamine;
(g) 1-cyclopropyl-7-(4-oxo six hydrogen-1H-pyrrolo-[3,4-c] pyridine-4 (2H)-one-6-base) the fluoro-8-methoxy-Isosorbide-5-Nitrae of-6--dihydro-4-Oxoquinoline-3-carboxylic acid root-O
3, O
4-diethyl acid group closes boron (VII) and obtains the fluoro-8-methoxyl group of Moxifloxacin hydrochloride analog 1-cyclopropyl-6--4-oxo-7-(4-oxo six hydrogen-1H-pyrrolo-[3 in alkaline condition hydrolysis, 4-c] pyridine-6 (2H) base)-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid (I);
Wherein, alkali is selected from the one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus.
3. preparation method according to claim 2, is characterized in that, the organic solvent described in step (a) is methylene dichloride; Described acid is trifluoroacetic acid.
4. preparation method according to claim 2, is characterized in that, the alkali described in step (b) is salt of wormwood.
5. preparation method according to claim 2, is characterized in that, the acid binding agent described in step (c) is Tosyl chloride.
6. preparation method according to claim 2, is characterized in that, the Lewis acid described in step (e) is zinc dichloride.
7. preparation method according to claim 2, is characterized in that, the polar aprotic solvent described in step (f) is acetonitrile; Alkali is triethylamine.
8. preparation method according to claim 2, is characterized in that, the alkali described in step (g) is sodium hydroxide.
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