A nemofloxacin intermediate and its preparation method and application

Abstract

This application provides a nemofloxacin intermediate and its preparation method and application, relating to the field of pharmaceutical chemistry. The nemofloxacin intermediate structure is shown in Formula I. The borate ester is prepared by adding lithium oxalate and lithium tetraborate to an organic solvent, heating the system to reflux, maintaining the reflux state for 2-6 hours, adding acetic anhydride, and refluxing the system for 2-4 hours. Compound II is then added, the system refluxes for 5-7 hours, and then cooled to room temperature. The system is separated, the organic phase is collected, and concentrated to produce Compound I. The nemofloxacin intermediate provided in this application has good stability, higher subsequent conversion rate, and shorter reaction time, thereby greatly reducing subsequent production costs.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a nemofloxacin intermediate 4,5-dicarbonyl-1,3,2-dioxaborolan-2-yl 1-cyclopropyl-7-fluoro-8-methoxy-4-carbonyl-1,4-dihydroquinoline-3-carboxylate, a preparation method and an application thereof. Background Art

[0002] Nemonoxacin malate (Structural Formula V) is indicated for the treatment of community-acquired pneumonia in adults (≥18 years) caused by nemonoxacin-sensitive Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Klebsiella pneumoniae, Pseudomonas aeruginosa, as well as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. Similar to moxifloxacin, nemonoxacin exhibits dual inhibition of bacterial DNA helicase and topoisomerase IV. It exhibits high antibacterial activity against common pathogens of community-acquired respiratory tract infections, including multidrug-resistant Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila, and holds great market potential.

[0003]

[0004] Currently, the main synthetic route of nemofloxacin is the compound synthetic route reported in patent CN101045724B as follows:

[0005]

[0006] This route has made process improvements in multiple steps based on the compound patent. In step 1, the borate activates the para-fluorine atom of the quinoline ring. However, due to certain stability issues in the subsequent nucleophilic substitution in step 2, the system temperature reaction must be maintained at 50°C for 3 days. In addition, the unstable removal of the borate ester leads to incomplete conversion of some parts of the system, resulting in a loss of yield. Summary of the Invention

[0007] The object of the present invention is to provide a nemonoxacin intermediate and its preparation method and application, so as to solve the problems raised in the above background technology. The nemonoxacin intermediate of the present invention has good stability, higher subsequent conversion rate and shorter reaction time, thereby greatly reducing subsequent production costs.

[0008] In order to solve the above problems, the present invention provides the following technical solutions:

[0009] In the first aspect, the present application provides a nemonoxacin intermediate, the structure of which is shown in the following formula:

[0010]

[0011] In a second aspect, the present application provides a method for preparing a nemofloxacin intermediate, comprising the following steps:

[0012]

[0013] Compound Ⅰ is prepared by reacting compound Ⅱ with boric acid ester in an organic solvent; wherein R1 in compound Ⅱ is hydrogen, methyl or ethyl.

[0014] In one embodiment of the present application, lithium oxalate and lithium tetraborate are added to an organic solvent, heated to reflux, and maintained at reflux for 2-6 hours. Acetic anhydride is added, and the system is refluxed for 2-4 hours to obtain a borate ester. Compound II is then added, the system is refluxed for 5-7 hours, and then cooled to room temperature. The system is separated, the organic phase is collected, and concentrated to obtain compound I.

[0015] In one embodiment of the present application, lithium oxalate and lithium tetraborate are added to an organic solvent, heated to reflux, and maintained at reflux for 3-5 hours, acetic anhydride is added, and the system is refluxed for 3 hours to obtain a borate ester; compound II is added, the system is refluxed for 6 hours, and then cooled to room temperature, water is added, the system is separated, the organic phase is collected, and concentrated to obtain compound I.

[0016] In one embodiment of the present application, lithium oxalate and lithium tetraborate are added to an organic solvent, heated to reflux, and maintained at reflux for 3 hours. Acetic anhydride is added, and the system is refluxed for 3 hours to obtain a borate ester. Compound II is added, the system is refluxed for 6 hours, and then cooled to room temperature. Water is added, the system is separated, the organic phase is collected, and concentrated to obtain compound I.

[0017] In one embodiment of the present application, the organic solvent is selected from one of toluene, acetic acid, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide.

[0018] In one embodiment of the present application, the organic solvent is selected from toluene.

[0019] In one embodiment of the present application, the molar ratio of lithium oxalate to lithium tetraborate is 4:1.

[0020] In one embodiment of the present application, the molar ratio of Compound II to lithium tetraborate is 3.4:1.

[0021] In one embodiment of the present application, the volume ratio of the organic solvent to acetic anhydride is 10:1.

[0022] In one embodiment of the present application, the usage ratio of acetic anhydride to lithium oxalate is 0.5 mL:1 g.

[0023] In one embodiment of the present application, the reflux temperature of the system is 100-110°C.

[0024] In a third aspect, the present application provides the use of a ninoxacin intermediate in the preparation of ninoxacin or an intermediate thereof.

[0025] In a fourth aspect, the present application provides a method for preparing Tylofloxacin, comprising the following steps:

[0026] Compound I, a tert-butyloxycarbonyl (Boc) monoprotected chiral amino fragment, and triethylamine are added to a second organic solvent, and the system is heated to reflux. After maintaining the reflux state for 1-3 hours, the organic solvent, borate, and Boc are removed, and the liquids are separated by extraction. The aqueous phase is crystallized by adjusting the pH value, filtered, and dried to obtain tylofloxacin.

[0027] In one embodiment of the present application, the second organic solvent is selected from one of toluene, acetic acid, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide.

[0028] In one embodiment of the present application, the second organic solvent is selected from acetonitrile.

[0029] In one embodiment of the present application, the molar ratio of compound I, tert-butyloxycarbonyl (Boc) monoprotected chiral amino fragment and triethylamine is 1:1:1-1.5.

[0030] Compared with the prior art, the present application provides a nemofloxacin intermediate 4,5-dicarbonyl-1,3,2-dioxaborolan-2-yl 1-cyclopropyl-7-fluoro-8-methoxy-4-carbonyl-1,4-dihydroquinoline-3-carboxylate and its preparation method and application. 4,5-dicarbonyl-1,3,2-dioxaborolan-2-yl 1-cyclopropyl-7-fluoro-8-methoxy-4-carbonyl-1,4-dihydroquinoline-3-carboxylate has good stability, a higher subsequent conversion rate, and a shorter reaction time, thereby greatly reducing subsequent production costs and providing a good foundation for further obtaining the raw material drug nemofloxacin. DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all of the embodiments.

[0032] As used herein, "ranges" are defined in terms of lower and upper limits. A given range is defined by selecting a lower limit and an upper limit, the selected lower and upper limits defining the boundaries of the particular range. Ranges defined in this manner may be inclusive or exclusive and may be combined arbitrarily, i.e., any lower limit may be combined with any upper limit to form a range.

[0033] Unless otherwise specified, the terms used in this application have the commonly known meanings commonly understood by those skilled in the art. Unless otherwise specified, the numerical values ​​of the various parameters mentioned in this application can be measured using various measurement methods commonly used in the art.

[0034] Example 1

[0035]

[0036] In a 200 mL three-necked reaction flask, toluene (50 mL), lithium oxalate (10 g, 0.1 mol) and lithium tetraborate (4.2 g, 0.025 mol) were added in sequence and the system was refluxed for 3 hours at a reflux temperature of 100-110°C. Subsequently, acetic anhydride (5 mL) was added and the system continued to react at 100-110°C for 3 hours. 1-Cyclopropyl-7-fluoro-8-methoxy-4-carbonyl-1,4-dihydroquinoline-3-carboxylate (25 g, 0.085 mol) was further added, and the system was refluxed for 6 hours. The starting material disappeared after TLC monitoring. The reaction system was then cooled to room temperature, and water (50 mL) was added. The system was separated, and the organic phase was collected and concentrated to give the product 4,5-dicarbonyl-1,3,2-dioxaborolan-2-yl 1-cyclopropyl-7-fluoro-8-methoxy-4-carbonyl-1,4-dihydroquinoline-3-carboxylate (structural formula I, 28.6 g yield: 90%) as an off-white solid.

[0037] 1 H-NMR (300MHz, d6-CD3Cl) δ9.23(s,1H),8.37-8.33(m,1H),7.55(t,1H),4.43-4.40(m,1H),4.14(s,3H),1.45-1.42(m,2H),1.33-1.30(m,2H).

[0038] LCMS (ESI) m / z, 376.2 (M+1) + .

[0039] Example 2

[0040]

[0041] A 2 L reaction flask was charged with acetonitrile (50 mL), 4,5-dicarbonyl-1,3,2-dioxaborolan-2-yl 1-cyclopropyl-7-fluoro-8-methoxy-4-carbonyl-1,4-dihydroquinoline-3-carboxylate (10 g, 0.026 mol), a Boc monoprotected chiral amino fragment (5.7 g, 0.026 mol), and triethylamine (3.3 g, 0.03 mol). After the system was heated to reflux for 2 hours, the starting material disappeared as monitored by TLC. The system was concentrated to remove acetonitrile, and the temperature was lowered. Aqueous NaOH solution (1.5M 50 mL) was added and stirred for 3 hours to remove borate. Acetic acid was then added to adjust the pH to 6-8. Dichloromethane (30 mL) was added to extract the aqueous phase 3-4 times. The organic phase was concentrated to remove dichloromethane. 6M HCl (30 mL) was added and stirred at room temperature for 2 hours to remove Boc. After the reaction was complete as monitored by TLC, 30 mL of water and 30 mL of dichloromethane were added, the liquid was extracted, and the organic phase was discarded. The pH of the aqueous phase was adjusted to 7.8-8 using NaOH. The system was kept warm at 0-10°C for crystallization for 10 hours, filtered, and dried to obtain the product structural formula III (8.5 g, off-white solid, yield: 88%).

Claims

1. A nemofloxacin intermediate, characterized in that: The structure is shown below; 。 2. A method for preparing the nemofloxacin intermediate according to claim 1, characterized in that: The following steps are involved: ； Lithium oxalate and lithium tetraborate are added to an organic solvent, heated to reflux, and maintained at reflux for 2-6 hours. Acetic anhydride is added, and the system is refluxed for 2-4 hours to obtain a borate ester. Compound II is then added, and the system is refluxed for 5-7 hours. The system is then cooled to room temperature, the system is separated, and the organic phase is collected and concentrated to obtain compound I; wherein R1 in compound II is hydrogen, methyl or ethyl.

3. The method for preparing a nemofloxacin intermediate according to claim 2, wherein: The organic solvent is selected from one of toluene, acetic acid, acetonitrile, tetrahydrofuran, N,N-dimethylformamide and dimethyl sulfoxide.

4. The method for preparing a nemofloxacin intermediate according to claim 2, wherein: The molar ratio of the lithium oxalate to the lithium tetraborate is 4:

1.

5. The method for preparing a nemofloxacin intermediate according to claim 2, wherein: The molar ratio of the compound II to lithium tetraborate is 3.4:

1.

6. The method for preparing a nemofloxacin intermediate according to claim 2, wherein: The volume ratio of the organic solvent to acetic anhydride is 10:

1.

7. The method for preparing a nemofloxacin intermediate according to claim 2, wherein: The usage ratio of the acetic anhydride and lithium oxalate is 0.5 mL:1 g.

8. The use of the nemofloxacin intermediate according to claim 1, characterized in that: Used for preparing nemofloxacin or its intermediates.

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