CN103102341A - Preparation method of balofloxacin dihydrate - Google Patents
Preparation method of balofloxacin dihydrate Download PDFInfo
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- CN103102341A CN103102341A CN2012105449107A CN201210544910A CN103102341A CN 103102341 A CN103102341 A CN 103102341A CN 2012105449107 A CN2012105449107 A CN 2012105449107A CN 201210544910 A CN201210544910 A CN 201210544910A CN 103102341 A CN103102341 A CN 103102341A
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- VHAHDRVRXVSPOY-UHFFFAOYSA-O CCC(OB(OC(CC)=O)OC(C(C(c1cc(F)c2N(CCC3)CC3NC)=[OH+])=CN(C3CC3)c1c2OC)=O)=O Chemical compound CCC(OB(OC(CC)=O)OC(C(C(c1cc(F)c2N(CCC3)CC3NC)=[OH+])=CN(C3CC3)c1c2OC)=O)=O VHAHDRVRXVSPOY-UHFFFAOYSA-O 0.000 description 1
- MGQLHRYJBWGORO-UHFFFAOYSA-N CNC(CCC1)CN1c(c(F)cc1c2N(C3CC3)C=C(C(O)=O)C1=O)c2OC Chemical compound CNC(CCC1)CN1c(c(F)cc1c2N(C3CC3)C=C(C(O)=O)C1=O)c2OC MGQLHRYJBWGORO-UHFFFAOYSA-N 0.000 description 1
- LJAXTAOSOVPBQH-UHFFFAOYSA-N CNC1CNCCC1 Chemical compound CNC1CNCCC1 LJAXTAOSOVPBQH-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to the field of compound synthesis and particularly relates to a preparation method of balofloxacin dihydrate. The method comprises the following steps of: reacting 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxyl-4-oxoquinoline-3-carboxylate radical-O<3>, O<4>-dipropionate boron as an intermediate with side chain 3-methylamino piperidine to generate 1-cyclopropyl-6-fluorine-1, 4-dihydro-8-methoxyl-7-(3-methylamino piperidine-1-radical)-4-oxoquinoline-3-carboxylate radical-O<3>, O<4>-dipropionate boron, and then hydrolyzing boric acid chelate, thus preparing the balofloxacin dihydrate. Compared with the traditional method, the preparation method has the advantages that the intermediate is more reliable and the yield is higher, and therefore the preparation method has a more industrial production prospect.
Description
Technical field
The present invention relates to the synthetic field of fluoroquinolone antibacterial agent, specifically relate to a kind of preparation method of Q-35 dihydrate.
Background technology
Q-35, chemical name: 1-cyclopropyl-7-(3-methylamino--piperidino)-8-methoxyl group-6-fluoro-Isosorbide-5-Nitrae-dihydro-4-oxo-3-quinoline carboxylic acid, be the compound shown in formula 4,
It is fluoroquinolone antibacterial agent.Be mainly used in treatment by responsive microbial non-complex urinary tract infections such as staphylococcus, suis, faecalis, the root fungus that rubs, intestinal bacteria, Pu Luofeideng bacterium, lemon bacterium, bacillus canalis capsulatus, enterobacteria, Serratia, Bacillus proteus, pseudomonas, peptostreptococcuses, as urocystitis, urethritis etc.
Traditional Q-35 synthesis technique is as follows:
The synthetic method of the Q-35 dihydrate of reporting in patent EP0342675 is:
The method is direct with quinolone acid and the pendant amine reaction, and still, mainly there are the problems such as severe reaction conditions, yield is low, purification of products is difficult in the method.
Publication number is that the synthetic method in the Chinese invention patent of CN101195614A and CN101627999A is:
Before comparing, quinolone acid directly reacts with pendant amine; the reaction conditions milder of this route; more easy to control, yield higher (70～78%) and end product purifying are easier, but ethanoyl boric acid inner complex less stable in reaction process of formula 7 quinolone acids.
Summary of the invention
The object of the invention is to, a kind of cheap raw material that uses is provided, under relatively mild condition, adopt simple technique, can synthesize efficiently the method for Q-35 dihydrate.
The objective of the invention is to be implemented by the following technical programs:
A kind of preparation method of Q-35 dihydrate comprises the steps:
(1) take formula 2 compounds and 3-methylamino piperidine or 3-methylamino piperidine pharmaceutically acceptable salt as raw material, react in solvent under alkaline condition, temperature of reaction is 20～50 ℃, the reaction times is 6～18h, obtains formula 3 compounds; 3-methylamino piperidine or 3-methylamino piperidine be the consumption of acceptable salt pharmaceutically, with respect to formula 2 compound 1mol, is generally 1～1.5mol,
(2) formula 3 compounds obtain the Q-35 crude product through hydrolysis reaction under alkaline condition, and the temperature of hydrolysis reaction is 40～90 ℃, and the time of hydrolysis reaction is 1～5h, the Q-35 crude product is again through neutralization, filtration, recrystallization, obtain formula 1 compound, i.e. Q-35 dihydrate product
In the present invention, the chemistry of formula 2 compounds is by name: 1-cyclopropyl-6,7-two fluoro-Isosorbide-5-Nitrae-dihydros-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid root-O
3, O
4-dipropyl acid group closes boron; The chemistry of formula 3 compounds is by name: 1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(3-methylamino piperidin-1-yl)-4-Oxoquinoline-3-carboxylic acid root-O
3, O
4-dipropyl acid group closes boron.
In order to prepare the Q-35 dihydrate from formula 2 compounds, at first should allow 7 fluorine atoms in formula 2 compounds, the secondary amine on the piperidine ring that is optionally provided by the 3-methylamino piperidine replaces, and then is hydrolyzed under the alkali effect.Because two nitrogen nucleophilicities of 3-methylamino piperidine are different, therefore select suitable reaction conditions, can obtain the substitution product of secondary amine on the piperidine ring of high yield.Due to the orientation effect on the quinoline ring, the fluorine atom on 7 of formula 2 compounds is easier to be replaced by the nitrogen-atoms of nucleophilicity, therefore under suitable reaction conditions, can optionally obtain 7 single substitution products.Experiment shows, the propionyl inner complex that formula 2 compounds adopt is compared with the ethanoyl inner complex that tradition is used, and preparation method's yield is higher, and the stability of formula 2 compounds is better.
The reaction of formula 2 compounds → formula 3 compounds, the alkali of the using 3-methylamino piperidine that at first dissociates, secondly also with reaction in the HF effect that produces, what alkali played is the effect of acid binding agent.
In above-mentioned preparation method, after step (1) reaction finished, reclaiming the solid that obtains after solvent was formula 3 compound crude products, and formula 3 compound crude products just can be directly used in next step reaction without separation and purification, compare with traditional method, operate easier.
As preferably, preparation method according to a kind of Q-35 dihydrate of the present invention, wherein, solvent in described step (1) is acetonitrile, tetrahydrofuran (THF), 4-methyl-2 pentanone, 2-butanone, DMF, N-Methyl pyrrolidone, methyl-sulphoxide, acetone, toluene or ethanol etc.Because this reaction is nucleophilic substitution reaction, select the benefit of non-protonic solvent to be, in non-protonic solvent, as the nucleophilic performance of the nitrogen-atoms on piperidine ring on the free 3-methylamino piperidine of nucleophilic reagent, than strong in protic solvent, be conducive to the carrying out that reacts.Solvent is recyclable.
As preferably, according to the preparation method of a kind of Q-35 dihydrate of the present invention, wherein, the consumption of the solvent in described step (1) with respect to formula 2 compound 1g, is generally 3～10 mL.
Reaction solvent for use and two step total recoverys are as follows:
Table 1 prepares the Q-35 dihydrate in different solvents
| Solvent | The two-step reaction total recovery | End product purity |
| Acetonitrile | 72～78% | 99.3～99.6% |
| DMF | 75～83% | 99.3～99.7% |
| NMP | 74～81% | 99.2～99.3% |
| THF | 61～65% | 98.4～99.0% |
| DMSO | 11% | 86.7% |
| Acetone | 15% | 79.5% |
| Toluene | 22% | 94.4% |
| Ethanol | 29% | 95.1% |
| 2-butanone | 68～75% | 99.3～99.5% |
| 4-methyl-2 pentanone | 71～78% | 99.1～99.5% |
| DME | 68～71% | 98.5～98.9% |
As preferably, according to the preparation method of a kind of Q-35 dihydrate of the present invention, wherein, the alkali that the alkaline condition in described step (1) adopts is triethylamine, DIPEA, salt of wormwood or sodium carbonate etc.
As preferably, preparation method according to a kind of Q-35 dihydrate of the present invention, wherein, the consumption of the alkali of the alkaline condition in described step (1), with respect to 3-methylamino piperidine or its acceptable salt (example hydrochloric acid salt, acetate etc.) 1mol pharmaceutically, be generally 3～5 mol.
As preferably, according to the preparation method of a kind of Q-35 dihydrate of the present invention, wherein, described step is as solvent with water in (2), be hydrolyzed under alkaline condition the reaction, wherein alkali is sodium hydroxide, potassium hydroxide, sodium carbonate or salt of wormwood etc.
As preferably, according to the preparation method of a kind of Q-35 dihydrate of the present invention, wherein, the consumption of the alkali of described step (2) neutral and alkali condition with respect to formula 3 compound 1mol, is generally 6～10 mol.
Raw material formula 2 compounds of the present invention are with reference to WO3014108 and the preparation of EP464823 report method.Boric acid and the mixed acid anhydrides of propionic anhydride reaction preparation, then with 1-cyclopropyl-6,7-difluoro-8-methoxyl-4-oxygen-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester reaction obtains 1-cyclopropyl-6,7-two fluoro-Isosorbide-5-Nitrae-dihydros-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid root-O
3, O
4-dipropyl acid group closes boron.
The present invention compared with prior art has the following advantages:
Under starting raw material formula 2 compounds of the present invention exist with 3-methylamino piperidine dihydrochloride and excess of triethylamine in containing water-acetonitrile, facile hydrolysis not, therefore can reduce (the raw water hydrolysis products 1-cyclopropyl-6 of impurity in product, 7-difluoro-8-methoxyl-4-oxygen-1,4-dihydroquinoline-3-carboxylic acid) content, improve the quality of products.
Two-step reaction of the present invention adopts " one pot of stir-fry " method, and is easy and simple to handle, is fit to scale operation.
Raw materials of the present invention is cheap and easy to get, and reaction solvent is recovery directly, and the two-step reaction total recovery is high, can reduce preparation Q-35 dihydrate material cost.
Embodiment
Below in conjunction with embodiment, be described more specifically content of the present invention.Should be appreciated that enforcement of the present invention is not limited to the following examples, any pro forma accommodation and/or change that the present invention is made all will fall into protection domain of the present invention.
In the present invention, if not refer in particular to, all equipment and raw material etc. all can be buied from market or the industry is commonly used.Method in following embodiment if no special instructions, is the ordinary method of this area.
Embodiment 1:
The synthetic line of the present embodiment is substantially:
Formula 2 compounds (15g, 33.26mmol) are dissolved in the 60mL acetonitrile, and room temperature adds triethylamine (18mL, 129.14mmol) and 3-methylamino piperidine dihydrochloride (6.5g, 34.74mmol) next time, keeps 30～35 ℃ of temperature.After reaction 12h, acetonitrile is reclaimed in underpressure distillation, gets yellow compound crude product 28.9g.This yellow compound crude product is directly used in next step reaction.The yellow compound analytic sample is through column chromatography purification, detects to be formula 3 compounds.ESI-MS?m/z：546[M+H]
+1。H-NMR(CDCl
3)δ：1.02(6H,?t),?1.3-1.26(2H,?t),?1.34-1.43(2H,?m),?1.75-1.85(1H,?m),?1.90-2.04(2H,?m),?2.35-2.41(4H,?m),?2.43-2.53(1H,?m),?2.73(3H,?s),?3.26-3.32(2H,?m),?3.53-3.59(2H,?t),?3.77(3H,?s),?3.97-3.99(1H,?d)?4.21-4.26(1H,?m),?7.97(1H,?d),?9.14(1H,?s)。
The 100mL aqueous solution that adds 9g sodium hydroxide in the formula 3 compound crude products of the 28.9g that obtains slowly is warming up to 65～70 ℃ and react 2.5h at this temperature, and reaction solution is cooled to room temperature, filter, filtrate is transferred pH to 7.5, stirring at room 1h with 4M hydrochloric acid, be cooled to 4 ℃, hold over night is filtered.Add 100mL7% acetic acid in the gained solid, stirring at room 2h filters, filtrate is transferred pH to 7.5 with 10% aqueous sodium hydroxide solution, stirring at room 2h is cooled to 4 ℃, hold over night, filter, solid washing (15mL * 2), 60 ℃ of vacuum-drying 24h obtain white solid 11.0g, total recovery 77.8% (in formula 2 compounds), HPLC (peak area %): 99.35%.
After testing, the white solid that obtains is target product formula 1 compound.ESI-MS?m/z：390[M+H]
+。
1H-NMR(DMSO-d
6)δ：0.99-1.15(4H,?m),?1.16-1.27(1H,?m),?1.59-1.68(1H,?m),?1.76-1.79(1H,?m),?1.97-2.01(1H,?m),?2.30(3H,?s),?2.53-2.58(1H,?m),?2.78-2.80(1H,?m),?3.07-3.13(1H,?t),?3.43-3.47(1H,?m),?3.57-3.59(1H,?m),?3.74(3H,?s),?4.14-4.19(1H,?m),?7.73(1H,?d),?8.69(1H,?s)。
Embodiment 2-6:
The reaction conditions identical with embodiment 1 prepares 5 batches of Q-35 two hydrates.
Table 2 formula 2 compounds are by intermediate formula 3 compound preparation formula 1 compound the results lists
Annotate: formula 5 compound amount 6.7g, triethylamine consumption 18mL, acetonitrile consumption 60mL.
In the following examples 7-10: two-step reaction is all followed the tracks of with HPLC, the differential responses condition, in formula 3 compounds and formula 2 compound retention time and embodiment 2-6 is all consistent, therefore, need not again obtaining formula 3 compounds under different condition and formula 2 compounds carry out structure verification with regard to this area, and the HPLC result shows that also reaction product is target product.
Embodiment 7:
With formula 2 compound (15g, 33.26mmol) be dissolved in 60mL DMF, room temperature adds triethylamine (18mL next time, 129.14mmol) and 3-methylamino piperidine dihydrochloride (6.5g, 34.74mmol), keep 30～35 ℃ of temperature, reaction 12h, DMF is reclaimed in underpressure distillation, gets yellow compound crude product 35.5g, is directly used in next step reaction.
The 100mL aqueous solution that adds 9g sodium hydroxide in formula 3 compound crude products slowly is warming up to 65～70 ℃ and react 2.5h, and reaction solution is cooled to room temperature, filters, and filtrate is transferred pH to 7.5 with 4M hydrochloric acid, and stirring at room 1h is cooled to 4 ℃, and hold over night is filtered.Add 100mL7% acetic acid in the gained solid, stirring at room 2h, filter, filtrate is transferred pH to 7.5, stirring at room 2h with 10% aqueous sodium hydroxide solution, be cooled to 4 ℃, hold over night is filtered, solid washing (15mL * 2), 60 ℃ of vacuum-drying 24h get white solid 11.5g, yield 81.3% (in formula 2 compounds).HPLC (peak area %): 99.51%.
Embodiment 8
With formula 2 compound (15g, 33.26mmol) be dissolved in the 60mL N-Methyl pyrrolidone, room temperature adds triethylamine (18mL next time, 129.14mmol) and 3-methylamino piperidine dihydrochloride (6.5g, 34.74mmol), keep 30～35 ℃ of temperature, reaction 12h, N-Methyl pyrrolidone is reclaimed in underpressure distillation, gets yellow compound crude product 33.7g, is directly used in next step reaction.
The 100mL aqueous solution that adds 9g sodium hydroxide in formula 3 compound crude products slowly is warming up to 65～70 ℃ of reaction 2.5h, and afterreaction liquid is cooled to room temperature, filters, and filtrate is transferred pH to 7.5 with 4M hydrochloric acid, and stirring at room 1h is cooled to 4 ℃, and hold over night is filtered.The acetic acid that adds 100mL 7% in the gained solid, stirring at room 2h, filter, filtrate is transferred pH to 7.5, stirring at room 2h with 10% aqueous sodium hydroxide solution, be cooled to 4 ℃, hold over night is filtered, solid washing (15mL * 2), 60 ℃ of vacuum-drying 24h get white solid 11.3g, yield 79.9% (in formula 2 compounds).HPLC (peak area %): 99.38%.
Embodiment 9
With formula 2 compound (15g, 33.26mmol) be dissolved in the 60mL 2-butanone, room temperature adds triethylamine (18mL next time, 129.14mmol) and 3-methylamino piperidine dihydrochloride (6.5g, 34.74mmol), keep 30～35 ℃ of temperature, reaction 12h, 2-butanone is reclaimed in underpressure distillation, gets yellow compound crude product 28.7g, is directly used in next step reaction.
The 100mL aqueous solution that adds 9g sodium hydroxide in formula 3 compound crude products slowly is warming up to 65～70 ℃ of reaction 2.5h, and afterreaction liquid is cooled to room temperature, filters, and filtrate is transferred pH to 7.5 with 4M hydrochloric acid, and stirring at room 1h is cooled to 4 ℃, and hold over night is filtered.The acetic acid that adds 100mL 7% in the gained solid, stirring at room 2h, filter, filtrate is transferred pH to 7.5, stirring at room 2h with 10% aqueous sodium hydroxide solution, be cooled to 4 ℃, hold over night is filtered, solid washing (15mL * 2), 60 ℃ of vacuum-drying 24h get white solid 10.2g, yield 72.1% (in formula 2 compounds).HPLC (peak area %): 99.32%.
Embodiment 10
With formula 2 compound (15g, 33.26mmol) be dissolved in the 60mL 4-methyl-2 pentanone, room temperature adds triethylamine (18mL next time, 129.14mmol) and 3-methylamino piperidine dihydrochloride (6.5g, 34.74mmol), keep 30～35 ℃ of temperature, reaction 12h, 4-methyl-2 pentanone is reclaimed in underpressure distillation, gets yellow compound crude product 29.1g, is directly used in next step reaction.
The 100mL aqueous solution that adds 9g sodium hydroxide in formula 3 compound crude products slowly is warming up to 65～70 ℃ of reaction 2.5h, and afterreaction liquid is cooled to room temperature, filters, and filtrate is transferred pH to 7.5 with 4M hydrochloric acid, and stirring at room 1h is cooled to 4 ℃, and hold over night is filtered.The acetic acid that adds 100mL 7% in the gained solid, stirring at room 2h, filter, filtrate is transferred pH to 7.5, stirring at room 2h with 10% aqueous sodium hydroxide solution, be cooled to 4 ℃, hold over night is filtered, solid washing (15mL * 2), 60 ℃ of vacuum-drying 24h get white solid 11.0g, yield 77.8% (in formula 2 compounds).HPLC (peak area %): 99.44%.
Above preferred embodiment just is used for description and interpretation content of the present invention, does not consist of the restriction to content of the present invention.Although the contriver has done in more detail the present invention and has enumerated, but, the content that those skilled in the art discloses according to summary of the invention part and embodiment, can make various modifications or/and to replenish or adopt similar mode to substitute be obvious to described specific embodiment, and can realize technique effect of the present invention, therefore, give unnecessary details no longer one by one herein.The term that occurs in the present invention is used for elaboration and the understanding to technical solution of the present invention, is not construed as limiting the invention.
Claims (7)
1. the preparation method of a Q-35 dihydrate, is characterized in that comprising the steps:
(1) take formula 2 compounds and 3-methylamino piperidine or 3-methylamino piperidine pharmaceutically acceptable salt as raw material, react in solvent under alkaline condition, temperature of reaction is 20～50 ℃, the reaction times is 6～18h, obtains formula 3 compounds; 3-methylamino piperidine or 3-methylamino piperidine be the consumption of acceptable salt pharmaceutically, with respect to formula 2 compound 1mol, is generally 1～1.5mol,
(2) formula 3 compounds obtain the Q-35 crude product through hydrolysis reaction under alkaline condition, and the temperature of hydrolysis reaction is 40～90 ℃, and the time of hydrolysis reaction is 1～5h, the Q-35 crude product is again through neutralization, filtration, recrystallization, obtain formula 1 compound, i.e. Q-35 dihydrate product
2. the preparation method of a kind of Q-35 dihydrate according to claim 1, it is characterized in that, solvent in described step (1) is acetonitrile, tetrahydrofuran (THF), 4-methyl-2 pentanone, 2-butanone, N, dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, methyl-sulphoxide, acetone, toluene or ethanol.
3. the preparation method of a kind of Q-35 dihydrate according to claim 1 and 2, is characterized in that, the consumption of the solvent in described step (1) with respect to formula 2 compound 1g, is generally 3～10 mL.
4. the preparation method of a kind of Q-35 dihydrate according to claim 1, is characterized in that, the alkali that the alkaline condition in described step (1) adopts is triethylamine, DIPEA, salt of wormwood or sodium carbonate.
5. the preparation method of according to claim 1 or 4 described a kind of Q-35 dihydrates, it is characterized in that, the consumption of the alkali of the alkaline condition in described step (1) with respect to 3-methylamino piperidine or its acceptable salt 1mol pharmaceutically, is generally 3～5 mol.
6. the preparation method of a kind of Q-35 dihydrate according to claim 1, it is characterized in that, in described step (2) be with water as solvent, be hydrolyzed under alkaline condition the reaction, wherein alkali is sodium hydroxide, potassium hydroxide, sodium carbonate or salt of wormwood.
7. the preparation method of according to claim 1 or 6 described a kind of Q-35 dihydrates, is characterized in that, the consumption of the alkali of described step (2) neutral and alkali condition with respect to formula 3 compound 1mol, is generally 6～10 mol.
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| CN115819402A (en) * | 2022-12-13 | 2023-03-21 | 无锡福祈制药有限公司 | Preparation method of balofloxacin |
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| CN115819402A (en) * | 2022-12-13 | 2023-03-21 | 无锡福祈制药有限公司 | Preparation method of balofloxacin |
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