CN111620889A - Preparation method of levofloxacin intermediate - Google Patents
Preparation method of levofloxacin intermediate Download PDFInfo
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- CN111620889A CN111620889A CN201911374996.1A CN201911374996A CN111620889A CN 111620889 A CN111620889 A CN 111620889A CN 201911374996 A CN201911374996 A CN 201911374996A CN 111620889 A CN111620889 A CN 111620889A
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- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 title claims abstract description 23
- 229960003376 levofloxacin Drugs 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 10
- 239000007789 gas Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000003570 air Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 22
- 239000003960 organic solvent Substances 0.000 abstract description 9
- 230000007062 hydrolysis Effects 0.000 abstract description 7
- 238000005273 aeration Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000007363 ring formation reaction Methods 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 238000004321 preservation Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- NVKWWNNJFKZNJO-YFKPBYRVSA-N Ofloxacin impurity a Chemical compound N1([C@@H](C)CO2)C=C(C(O)=O)C(=O)C3=C1C2=C(F)C(F)=C3 NVKWWNNJFKZNJO-YFKPBYRVSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- VXGYRCVTBHVXMZ-UHFFFAOYSA-N quinoline-6-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CC=C21 VXGYRCVTBHVXMZ-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention relates to a preparation method of a levofloxacin intermediate, which comprises the following steps: adding the compound of the formula I into water, adding alkali under the condition of aeration to carry out alkali hydrolysis, and further reacting with acid to obtain the compound of the formula II. The method has simple post-treatment, low impurity content in the product and no need of adding organic solvent.
Description
Technical Field
The invention belongs to the field of chemical medicines, relates to a preparation method of a levofloxacin intermediate, and particularly relates to a preparation method of (S) -9, 10-difluoro-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido [1,2, 3-delta ] -1, 4-benzoxazine-6-carboxylic acid.
Background
Levofloxacin (Levofloxacin) is chemically (S) - (-) -9-fluoro-2, 3-dihydro-3-methyl-10- [ 4-methyl-1-piperazinyl ] -7-oxo-7-hydropyrido [1,2, 3-delta ] - [1,4] benzoxazine-6-carboxylic acid (formula III), and is a commercially available fluoroquinolone antibacterial drug developed by japan first pharmaceutical company, having the following structural formula:
(S) -9, 10-difluoro-2, 3-dihydro-3-methyl-7-oxo- (3S) -7H-pyrido [1,2, 3-delta ] -1, 4-benzoxazine-6-carboxylic acid (formula II) or a salt thereof is a key intermediate in the synthesis of levofloxacin having the following structural formula:
the compound of formula II can be prepared by hydrolysis of (S) -9, 10-difluoro-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido [1,2, 3-delta ] -1, 4-benzoxazine-6-carboxylic acid ethyl ester (formula I) which has the following structural formula:
at present, the compound of formula II is synthesized by a heating reflux reaction method which uses formula I as a raw material, acetic acid as a solvent and sulfuric acid as a catalyst in industry, but the method has the disadvantages of great environmental pollution, high solvent cost and serious equipment corrosion.
The preparation of compounds of formula II can also be carried out by hydrolysis with bases, for example, WO2009035684, Journal of medicinal chemistry, 1987,30(12), 2283-containing 2286, and Tetrahedron,2010, (66), 6565-containing 6568, et al, report on the preparation of compounds of similar structure. The common characteristic of the alkaline hydrolysis method is that after alkaline hydrolysis, the pH value is adjusted to acidity by acid, and the product is obtained by filtering and washing. However, the method of hydrolysis with alkali can produce alcohol by-product, and nucleophilic substitution reaction is easy to occur to produce impurity (S) -10-ethoxy-9-fluoro-3-methyl-7-oxo-2, 3-dihydro-7H- [1,4] benzoxazine [2,3,4-ij ] quinoline-6-carboxylic acid (formula IV), and the formula IV is difficult to remove by simple purification method, and the content is difficult to control below 0.1%, which can not meet the requirement of medicinal use.
Patent document CN102850376A discloses a method for preparing a compound of formula II by hydrolysis with a mixed solvent of an organic solvent selected from tetrahydrofuran, acetonitrile and water. However, in the case of a mixed solvent of tetrahydrofuran, acetonitrile and water, tetrahydrofuran and acetonitrile are highly toxic, and this reaction requires removal of the alcohol formed during the reaction, thereby reducing the production of impurity formula IV, but it is difficult to control impurity formula IV to 0.1% or less.
Patent document CN103755722A prepares a compound of formula II by hydrolysis in a mixed solvent of an organic solvent selected from N, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane, N-dimethylacetamide, or acetonitrile and water. Also, this reaction requires removal of the alcohol formed in the reaction.
Patent document CN105732660A discloses a method for preparing a compound of formula II by hydrolysis of one or more selected from C3-C6 straight-chain or branched-chain alkyl alcohols, acetone, and methyl ethyl ketone in a mixed solvent with water. However, when the reaction solvent is recovered, it is necessary to separate ethanol, and it is difficult to industrially produce the reaction solvent.
Disclosure of Invention
In order to overcome the defects of the prior art and reduce the impurity content in the compound product of the formula II, the inventor innovates the preparation process of the compound of the formula II, and replaces acid hydrolysis with alkaline hydrolysis, thereby solving the problems of large environmental pollution and easy corrosion of equipment; water is used as the alkaline hydrolysis reaction solvent instead of the organic solvent/water mixed solvent, so that the problem that the mixed solvent is difficult to recycle is solved.
The present inventors have found that, in the scale-up production of the compound of formula II using water as a solvent for the alkaline hydrolysis reaction, when the reaction raw material is scaled up to several hundred grams and several kilograms, the amount of ethoxy impurities (formula IV) in the product is large and cannot be controlled to 0.05% or less. Through repeated experiments and groping, the inventor develops a simple and efficient method, and finally obtains a high-quality key intermediate II of levofloxacin by introducing gas in the alkaline hydrolysis reaction and controlling the reaction temperature, wherein the content of an ethoxy impurity IV of levofloxacin carboxylic acid is less than 0.05%. Specifically, the present invention adopts the following technical solutions.
A process for the preparation of a levofloxacin intermediate which is the compound (S) -9, 10-difluoro-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido [1,2, 3-delta ] -1, 4-benzoxazine-6-carboxylic acid of formula II comprising the steps of:
1) adding ethyl (S) -9, 10-difluoro-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido [1,2, 3-delta ] -1, 4-benzoxazine-6-carboxylate of the compound of formula I into water, and adding a base under gas passing conditions to perform a basic hydrolysis reaction to generate (S) -9, 10-difluoro-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido [1,2, 3-delta ] -1, 4-benzoxazine-6-carboxylate, such as sodium salt or potassium salt, wherein the temperature of the basic hydrolysis reaction is above 95 ℃;
2) reacting (S) -9, 10-difluoro-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido [1,2, 3-delta ] -1, 4-benzoxazine-6-carboxylic acid salt with an acid to give the compound of formula II.
The alkali in the step 1) may be selected from sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate or a mixture of two or more thereof, and is preferably sodium hydroxide or potassium hydroxide.
In the step 1), the introduced gas is non-reactive gas, i.e. does not participate in the alkaline hydrolysis reaction, according to the common knowledge in the art. The gas may be air, nitrogen, helium or argon, preferably nitrogen.
In the preparation method, the ethanol generated in the reaction system is removed by introducing gas and matching with the reaction temperature, so that the content of the compound of the formula IV in the product is reduced.
The temperature of the alkaline hydrolysis reaction in the step 1) is preferably over 98.5 ℃ so as to quickly carry the ethanol out of the reaction system.
In some preferred embodiments of the invention, in step 1), the mass of the compound of formula I is above 1kg, more preferably above 6 kg.
The acid in the step 2) may be hydrochloric acid, sulfuric acid or acetic acid, preferably hydrochloric acid.
Preferably, the content of the compound of formula IV in the levofloxacin intermediate II obtained by the invention is not higher than 0.05 wt%.
The method has simpler process, does not need to add an organic solvent, is easy to carry out post-treatment, can reduce the production cost of the levofloxacin intermediate II, and effectively reduces the content of the impurity IV. The process of the present invention is particularly suitable for the industrial scale production of over kilogram (kg).
Detailed Description
The compound shown in the formula IV is an impurity which seriously affects the quality of a levofloxacin intermediate II and levofloxacin bulk drug, and the reduction of the content of the impurity is a problem to be solved urgently in the field. In order to reduce the amount of the generated impurities and ensure that the quality of the levofloxacin is qualified, the preparation method of the invention replaces the organic solvent which is necessary in the prior art, particularly the organic solvent used for dissolving the compound of the formula I, and directly carries out hydrolysis reaction in water.
Herein, the term "compound of formula x" is sometimes expressed as "compound of formula x" or "compound x", which means the same meaning, as can be understood by those skilled in the art.
For convenience of description, the compounds of formula I are sometimes referred to herein in terms of chemical structural features as "levofloxacin cyclization esters" and the compounds of formula IV as "ethoxy impurities".
It is well known in the chemical and biological engineering fields that, for reasons of many unpredictable factors and of reasonable interpretation, there are often so great differences between laboratory techniques and process conditions on both pilot and industrial scale that large amounts of laboratory work are difficult to scale up and translate into industrial production practices. Scaling from laboratory to industrial scale overcomes many technical hurdles. This is the case for the preparation of compound II of high chemical purity and high optical purity.
The inventors have surprisingly found, after several attempts, that even when compounds I and II are reacted in a strong base such as sodium hydroxide solution at high temperatures, e.g. above 95 ℃, their optical activity is retained, which surprising finding is an important basis for the present invention.
In the hydrolysis reaction of the compound I, the feeding rate of the alkali should be controlled to avoid the generation of by-products as much as possible, and for example, the alkali solution may be added dropwise.
In a preferred embodiment, the hydrolysis reaction temperature of compound I should not be too low, e.g. above 95 ℃, preferably above 96 ℃, above 97 ℃, above 98 ℃, above 98.5 ℃, above 99 ℃, above 99.5 ℃ or 100 ℃. If the reaction temperature is lower than 95 ℃, the ethoxy impurity IV in the product may be higher, and exceed the limit of 0.05%. Because no organic solvent is needed, the preparation process of the invention has simple post-treatment and effectively reduces the impurity content in the product.
The process for preparing the compound II is suitable for gram-grade laboratory scale and kilogram-grade or above industrial production.
The invention is further illustrated by the following examples. It is to be understood that these examples are for illustrative purposes only and are not limiting upon the present invention. Various changes or modifications thereof, which may occur to those skilled in the art based on the teachings of the present invention, are within the scope of the present invention.
The addition amount, content and concentration of various substances are referred to herein, wherein the percentage refers to the mass percentage unless otherwise specified.
In the examples herein, if no specific description is made about the reaction temperature or the operation temperature, the temperature is usually referred to as room temperature (15 to 30 ℃).
In the examples of the present invention, all of the alkali solutions used were aqueous solutions.
Examples
Reagent: the organic solvents and the like used in the examples of the present invention are all industrial grade and used directly. The reagents were purchased from Shanghai element chemical Co., Ltd.
Example 1
Firstly, 6.00kg of levofloxacin cyclization ester (a compound shown in a formula I) and 30.20kg of water are put into a 100L reaction kettle; then stirring and heating to 100 ℃, and introducing nitrogen into the reaction liquid for carrying to remove ethanol; next, a sodium hydroxide solution (32.90kg, 2.42 wt%) was added dropwise over a period of 4 hours, and the mixture was further incubated for 1 hour after the addition. And (4) after the heat preservation is finished, adding acid to adjust the pH value to 4, filtering, rinsing with water, and drying to obtain the product (the compound shown in the formula II). 5.12kg of product (compound of formula II) was harvested, 0.04% of ethoxy impurity (compound of formula IV).
MS(EI)m/z:M+1＝282.3
Comparative example 1
Firstly, 6.00kg of levofloxacin cyclization ester and 30.20kg of water are put into a 100L reaction kettle; then stirring and heating to 90 ℃, introducing nitrogen into the reaction liquid for carrying and removing the ethanol; next, a sodium hydroxide solution (32.90kg, 2.42 wt%) was added dropwise over a period of 4 hours, and the mixture was further incubated for 1 hour after the addition. And (5) after heat preservation, adding acid to adjust the pH value to 4, filtering, rinsing with water, and drying to obtain the target product. 5.13kg of the product was harvested, 0.23% ethoxy impurity.
The ethoxy impurity IV level was increased relative to example 1 due to the poor gas entrainment effect induced by the decrease in temperature.
Comparative example 2
Firstly, 6.00kg of levofloxacin cyclization ester and 30.20kg of water are put into a 100L reaction kettle; then stirring and heating to 100 ℃; next, a sodium hydroxide solution (32.90kg, 2.42 wt%) was added dropwise over a period of 4 hours, and the mixture was further incubated for 1 hour after the addition. And (5) after heat preservation, adding acid to adjust the pH value to 4, filtering, rinsing with water, and drying to obtain the target product. The product was harvested at 5.13kg, with 0.13% ethoxy impurity.
The ethoxy impurity IV content was elevated relative to example 1 due to the absence of gassing.
Example 4
Firstly, 6.00kg of levofloxacin cyclization ester (a compound shown in a formula I) and 30.20kg of water are put into a 100L reaction kettle; then stirring and heating to 98.5 ℃, and introducing argon into the reaction liquid for carrying to remove ethanol; next, a sodium hydroxide solution (32.90kg, 2.42 wt%) was added dropwise over a period of 4 hours, and the mixture was further incubated for 1 hour after the addition. And (4) after the heat preservation is finished, adding acid to adjust the pH value to 4, filtering, rinsing with water, and drying to obtain the product (the compound shown in the formula II). 5.12kg of product (compound of formula II) was harvested, 0.04% of ethoxy impurity (compound of formula IV).
Example 5
Firstly, 6.00kg of levofloxacin cyclization ester (a compound shown in a formula I) and 30.20kg of water are put into a 100L reaction kettle; then stirring and heating to 98.5 ℃, and introducing nitrogen into the reaction liquid for carrying to remove ethanol; next, a sodium carbonate solution (33.92kg, 6.25 wt%) was added dropwise over a period of 4 hours, and the mixture was allowed to stand for 1 hour after the addition. And (4) after the heat preservation is finished, adding acid to adjust the pH value to 4, filtering, rinsing with water, and drying to obtain the product (the compound shown in the formula II). 5.12kg of the product (compound of formula II) was harvested, 0.03% of ethoxy impurity (compound of formula IV).
Example 6
Firstly, 6.00kg of levofloxacin cyclization ester (a compound shown in a formula I) and 30.20kg of water are put into a 100L reaction kettle; then stirring and heating to 100 ℃, and introducing argon into the reaction liquid for carrying to remove ethanol; next, a sodium carbonate solution (33.92kg, 6.25 wt%) was added dropwise over a period of 4 hours, and the mixture was allowed to stand for 1 hour after the addition. And (4) after the heat preservation is finished, adding acid to adjust the pH value to 4, filtering, rinsing with water, and drying to obtain the product (the compound shown in the formula II). 5.12kg of the product (compound of formula II) was harvested, 0.03% of ethoxy impurity (compound of formula IV).
Claims (10)
1. A process for preparing a levofloxacin intermediate, which is a compound of formula II, comprising the steps of:
1) adding ethyl (S) -9, 10-difluoro-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido [1,2, 3-delta ] -1, 4-benzoxazine-6-carboxylate of the compound shown in the formula I into water, and adding alkali under the condition of introducing gas to perform alkali hydrolysis reaction to generate (S) -9, 10-difluoro-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido [1,2, 3-delta ] -1, 4-benzoxazine-6-carboxylate, wherein the temperature of the alkali hydrolysis reaction is more than 95 ℃;
2) reacting (S) -9, 10-difluoro-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido [1,2, 3-delta ] -1, 4-benzoxazine-6-carboxylic acid salt with an acid to give the compound (S) -9, 10-difluoro-3-methyl-7-oxo-2, 3-dihydro-7H-pyrido [1,2, 3-delta ] -1, 4-benzoxazine-6-carboxylic acid of formula II.
2. The method of claim 1, wherein the base in step 1) is selected from the group consisting of sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, and mixtures of two or more thereof.
3. The method of claim 1, wherein the base in step 1) is sodium hydroxide or potassium hydroxide.
4. The method of claim 1, wherein the gas in step 1) is air, nitrogen, helium, or argon.
5. The method of claim 1, wherein the gas in step 1) is nitrogen or argon.
6. The method of claim 1, wherein the temperature of the alkaline hydrolysis reaction in step 1) is 98.5 ℃ or higher.
7. The method of claim 1, wherein the acid in step 2) is hydrochloric acid, sulfuric acid, or acetic acid.
8. The process of claim 1, wherein the levofloxacin intermediate is obtained in an amount not greater than 0.05% by weight of the compound of formula IV:
9. the method according to any one of claims 1 to 8, wherein in step 1) the mass of the compound of formula I is above 1 kg.
10. The method according to any one of claims 1 to 8, wherein in step 1) the mass of the compound of formula I is above 6 kg.
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| CN201911374996.1A CN111620889A (en) | 2019-12-27 | 2019-12-27 | Preparation method of levofloxacin intermediate |
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| CN201911374996.1A CN111620889A (en) | 2019-12-27 | 2019-12-27 | Preparation method of levofloxacin intermediate |
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| CN114478572A (en) * | 2022-01-26 | 2022-05-13 | 上虞京新药业有限公司 | Preparation method of levofloxacin carboxylic acid |
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| CN114478572A (en) * | 2022-01-26 | 2022-05-13 | 上虞京新药业有限公司 | Preparation method of levofloxacin carboxylic acid |
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