CN105237535A - Method for preparing moxifloxacin hydrochloride - Google Patents
Method for preparing moxifloxacin hydrochloride Download PDFInfo
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- CN105237535A CN105237535A CN201510786503.0A CN201510786503A CN105237535A CN 105237535 A CN105237535 A CN 105237535A CN 201510786503 A CN201510786503 A CN 201510786503A CN 105237535 A CN105237535 A CN 105237535A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a method for preparing moxifloxacin hydrochloride. The method comprises the following steps: in the existence of protective gas, enabling boric acid and propionic anhydride to have contact reaction for 1h at 95 to 105 DEG C, and cooling to 75 to 80 DEG C; adding a stable accelerant, adding 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxyl-4-oxo-3-quinolinecarboxylate, continuously stirring to react for 1.5h to 3h at 75 to 80 DEG C, monitoring and tracking until the reaction is completed, cooling to the room temperature, adding acetonitrile and organic amine, enabling the acetonitrile and organic amine to react with (S,S)-2,8-diazabicyclo[4.3.0] nonane for 1h to 2h at 65 to 75 DEG C, cooling to the room temperature, filtering insoluble articles, adding methanol, dropwise adding concentrated hydrochloric acid at the room temperature, adjusting the pH value to 1 to 3, stirring for 2h, then cooling to -10 to -5 DEG C, precipitating, suction filtering, washing by cold ethanol, and vacuum drying to obtain moxifloxacin hydrochloride, wherein the stable accelerator is selected from one or more of glycine, serine and threonine. The method is high in yield, high in product purity, simple and feasible in process and suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, particularly, relate to a kind of method preparing Moxifloxacin hydrochloride.
Background technology
Moxifloxacin hydrochloride (moxifloxacinhydrochloride), chemistry is by name: 1-cyclopropyl-7-(S, S-2,8-diazabicyclo [4.3.0] nonane-8-base) the fluoro-8-methoxyl group of-6--4-oxo-1,4-dihydro-3-quinoline carboxylic acid hydrochloride is wide spectrum and the 8-methoxy fluoroquinolone class antibacterials with anti-microbial activity.It can treat the infection that various bacteria causes effectively, demonstrates and has good activity to gram positive organism and atypical pathogens, and concrete structure formula is as follows:
The method of research staff to synthesis Moxifloxacin of this area conducts extensive research, but these methods all still exist many problems, affect the large-scale production of Moxifloxacin.
EP0550903 discloses and adopts 1-cyclopropyl-6,7-difluoro-8-methoxyl-4-oxo-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid and (S, S)-2,8-diazacyclo [4.3.0] nonane, under triethylamine does acid binding agent condition, directly carries out the substitution reaction of 7-position, prepares Moxifloxacin hydrochloride.The method is simple, but the 6-position having vast scale in the product of the method replaces by product, and purification difficult, have impact on the yield of product, greatly have impact on the popularization of the method.
CN104031043A discloses a kind of synthetic method of Moxifloxacin hydrochloride, and the method employs Lewis acid (ZnCl in chelatropic reaction
2) as catalyzer, this catalyzer is in dissolving or with substrate-function process, the a large amount of heat release of meeting, condition is difficult to control, and affects the stability of inner complex, thus affects follow-up substitution reaction, and the temperature drift of this reaction, capital makes productive rate not high, and the method step is complicated, is not suitable for scale operation.
CN102731496A discloses a kind of method preparing Moxifloxacin hydrochloride, with 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester is raw material, through boron chelatropic reaction and (S, S)-2, 8 diazabicyclos [4.3.0] nonane nucleophilic substitution reaction then acidifying prepares Moxifloxacin hydrochloride, the method adopts " one kettle way " simple, reduce labour intensity, but because it does not adopt catalyzer, reaction times is longer, substitution reaction process adopts the organic or inorganic alkali that tradition is stronger, have impact on Stability of Chelate, reduce reaction yield, and major part is 6-replacement by product in impurity, be further purified difficulty, even the security of Moxifloxacin is had an impact.
Therefore, the huge application demand of the anti-microbial activity good in view of Moxifloxacin hydrochloride and market, this area is needed badly a kind of simple, stable, is applicable to commercial scale production and the high method preparing Moxifloxacin hydrochloride of yield.
Summary of the invention
The object of the invention is to overcome and existingly prepare the defect that in the method for Moxifloxacin hydrochloride, product yield is low, product purity is not high, complicated operation is not suitable for suitability for industrialized production, provide a kind of simple, stable, be applicable to commercial scale production and the high method preparing Moxifloxacin hydrochloride of yield.
The present inventor surprisingly finds under study for action, by boric acid and propionic anhydride after 95 ~ 105 DEG C of contact reactss at glycine, in Serine and Threonine one or more as under the existence of stable promotor with 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester carries out reaction can form stable boric acid ester inner complex, can without separation directly organic bases deposit in case with (S, S)-2, 8-diazabicyclo [4.3.0] nonane carries out nucleophilic substitution reaction, this process inner complex can stable existence, can not be come off the position that affects nucleophilic substitution and occur the by product that 6-position replaces.Further research finds, in nucleophilic substitution reaction process, if the alkalescence of organic bases is too strong, also can have an impact to the stability of boric acid ester inner complex, increase the ratio of by product, cause yield to decline.
To achieve these goals, the invention provides a kind of method preparing Moxifloxacin hydrochloride, the method comprises the following steps:
Under shielding gas exists, by boric acid and propionic anhydride 95 ~ 105 DEG C of contact reactss 1 hour, be cooled to 75 ~ 80 DEG C, add stable promotor and then add 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester, stirring reaction is continued 1.5 ~ 3 hours at 75 ~ 80 DEG C, it is complete that monitoring tracks to reaction, be cooled to room temperature, add acetonitrile and organic amine, again with (S, S)-2, 8-diazabicyclo [4.3.0] nonane reacts 1 ~ 2 hour at 65 ~ 75 DEG C, be down to room temperature, filtering insolubles, add methyl alcohol, concentrated hydrochloric acid is dripped under room temperature, adjust ph to 1 ~ 3, stir and be cooled to-10 ~-5 DEG C of crystallizatioies after 2 hours, suction filtration, cold washing with alcohol, vacuum-drying, obtain Moxifloxacin hydrochloride, wherein, described stable promotor is selected from glycine, one or more in Serine and Threonine.
In the present invention, abandon use Lewis acid, avoid Lewis acid and to dissolve or in mechanism, a large amount of heat release affects problem to product stability.
In the building-up process of Moxifloxacin hydrochloride, parent nucleus phenyl ring 6-position and 7-position and (S in nucleophilic reaction, S)-2, there is competitive relation during 8-diazabicyclo [4.3.0] nonane reacts, we adopt the mode forming boric acid ester inner complex, from the adjustment of electronic effect, make 7-position cloud density lower, thus accelerate the nucleophilic substitution of 7-position, accordingly, reduce the possibility that nucleophilic substitution occurs in 6-position.The improvement of these methods makes nucleophilic reaction when temperature is all lower than prior art in conjunction with other schemes of the present invention, and reaction is faster, and yield is higher.
In the contact reacts of boric acid of the present invention and propionic anhydride, the mol ratio of boric acid and propionic anhydride can be 1:3 ~ 3.5, and catalytic temperature can be 95 ~ 100 DEG C.
Under preferable case, the mol ratio of the fluoro-Isosorbide-5-Nitrae of described 1-cyclopropyl-6,7-bis--dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester and boric acid is 1:1.4 ~ 1.6; The weight ratio of promotion stablizer used and quinoline carboxylic acid ethyl ester is 0.1 ~ 0.2:1.
Under preferable case, the mol ratio of described organic amine and the fluoro-Isosorbide-5-Nitrae of 1-cyclopropyl-6,7-bis--dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester is 2.5 ~ 3.5:1.
In the present invention, in reaction, the amount of solvent for use can conventionally as required be selected, and the consumption of such as acetonitrile is (S, S)-2,10 times of volumes (mL) of 8-diazabicyclo [4.3.0] nonane weight, the consumption of methyl alcohol can be two times of acetonitrile content.
In the present invention, the alkalescence of organic amine is not be the bigger the better, although alkalescence can accelerate nucleophilic reaction greatly, alkaline conference destroys boric acid ester Stability of Chelate, by product is increased, productive rate reduces, and contriver studies discovery, uses diisopropyl ethyl amine or N-methylmorpholine, particularly during N-methylmorpholine, can stablize promotor generation with a little in reaction to act synergistically, the yield of nucleophilic reaction can be higher, and speed of response is also fast.
In the present invention, stablize the amino in promotor and the nitrogen element in carboxyl and oxygen element and can form polynary cyclic transition state with the inner complex of boric acid ester or boric acid ester by weak interaction, thus stable carry out correlated response, especially, after forming transition state with the inner complex of boric acid ester, be also more conducive to 7-position nucleophilic substitution from electronic effect.In order to improve the yield of reaction further, under preferable case, described stable promotor is glycine.
In prior art, all excessive with the chiral substrates that cost is higher in nucleophilic reaction, waste raises the cost on the one hand, on the other hand, the direction that the increase of chiral substrates can make reaction increase to the by product that two replacement or 6-position replace is moved, therefore, under preferable case, described (S, S)-2,8-diazabicyclo [4.3.0] nonane consumption and 1-cyclopropyl-6, the mol ratio of the fluoro-Isosorbide-5-Nitrae of 7-bis--dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester is 1:1.05 ~ 1.1.
In the present invention, described shielding gas can be nitrogen, helium or argon gas.The room temperature of indication of the present invention refers to 25 DEG C ± 5 DEG C.The present invention uses cold ethanol to carry out washing the purity that ensure that product, and be unlikely to product loss too much, cold ethanol can be the ethanol of 0-10 DEG C simultaneously.
In the present invention, can adopt the method for this area routine to reaction carry out monitoring follow the tracks of, such as TLC, LCMS, GCMS etc., react complete fingers TLC monitor inexcessive also raw material disappeared or in LCMS, GCMS not excess raw material remain be less than 2%.
Particularly, synthetic route of the present invention is as follows:
In the present invention, Moxifloxacin hydrochloride, in crystal formation Crystallization Process, needs strict temperature control, and the too fast then easy crystallization instantaneously of temperature too high crystal condensation, makes to be mingled with impurity in product, be difficult to removing; And temperature is too low, crystallization time is long or crystal is too small, can cause production cycle long or product loss.The present inventor stirs two hours through putting into practice in a large number to find to adjust after pH, is then cooled to-10 ~-5 DEG C, particularly-8 ~-5 DEG C time, the product yield that crystallization obtains is better, and purity is higher.
Compared with prior art, the present invention has simple, stable, yield advantages of higher, really achieves " one kettle way " prepared by Moxifloxacin hydrochloride.
Other features and advantages of the present invention are described in detail in embodiment part subsequently.。
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.But these embodiments are only limitted to the present invention instead of the further restriction to protection scope of the present invention are described.
Embodiment 1
A preparation method for Moxifloxacin hydrochloride, comprises the following steps:
Under nitrogen protection, boric acid 6.2g (100mmol) and propionic anhydride 39g (300mmol) is joined in there-necked flask and is heated to 95 DEG C of contact reactss 1 hour, be cooled to 75 DEG C, add glycine (3.5g) and then add 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester 23.3g (72mmol), stirring reaction is continued 1.5 hours at 75 DEG C, TLC monitoring reaction is complete, be cooled to room temperature, add acetonitrile (86ml) and N-methylmorpholine 21.2g (210mmol), again with (S, S)-2, 8-diazabicyclo [4.3.0] nonane 8.6g (68mmol) reacts 1.5 hours at 68 DEG C, be down to room temperature, filtering insolubles, add methyl alcohol (170ml), concentrated hydrochloric acid is dripped under room temperature, adjust ph to 1.5, stir and be cooled to-8 DEG C of crystallizatioies after 2 hours, suction filtration, cold washing with alcohol (50ml × 3 time), vacuum-drying, obtain Moxifloxacin hydrochloride white solid 27.2g, yield: 91.4%, purity 99.76% (HPLC area normalization method).
Embodiment 2
A preparation method for Moxifloxacin hydrochloride, comprises the following steps:
Under nitrogen protection, boric acid 6.2g (100mmol) and propionic anhydride 45.5g (350mmol) is joined in there-necked flask and is heated to 100 DEG C of contact reactss 1 hour, be cooled to 75 DEG C, add glycine (4.3g) and then add 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester 21.7g (67mmol), stirring reaction is continued 2 hours at 75 DEG C, TLC monitoring reaction is complete, be cooled to room temperature, add acetonitrile 80ml (2 times of nonane weight) and N-methylmorpholine 23.8g (235mmol), again with (S, S)-2, 8-diazabicyclo [4.3.0] nonane 8.1g (64mmol) reacts 1 hour at 65 DEG C, be down to room temperature, filtering insolubles, add methyl alcohol (160ml), concentrated hydrochloric acid is dripped under room temperature, adjust ph to 1, stir and be cooled to-5 DEG C of crystallizatioies after 2 hours, suction filtration, cold washing with alcohol (50ml × 3 time), vacuum-drying, obtain Moxifloxacin hydrochloride white solid 25.4g, yield: 90.6%, purity 99.65% (HPLC area normalization method).
Embodiment 3
A preparation method for Moxifloxacin hydrochloride, comprises the following steps:
Under argon shield, boric acid 6.2g (100mmol) and propionic anhydride 39g (300mmol) is joined in there-necked flask and is heated to 98 DEG C of contact reactss 1 hour, be cooled to 80 DEG C, add glycine (2g) and then add 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester 20.4g (63mmol), stirring reaction is continued 1.5 hours at 80 DEG C, TLC monitoring reaction is complete, be cooled to room temperature, add acetonitrile (75ml) and N-methylmorpholine 16.2g (160mmol), again with (S, S)-2, 8-diazabicyclo [4.3.0] nonane 7.3g (58mmol) reacts 2 hours at 75 DEG C, be down to room temperature, filtering insolubles, add methyl alcohol (150ml), concentrated hydrochloric acid is dripped under room temperature, adjust ph to 3, stir and be cooled to-10 DEG C of crystallizatioies after 2 hours, suction filtration, cold washing with alcohol (50ml × 3 time), vacuum-drying, obtain Moxifloxacin hydrochloride white solid 23.6g, yield: 92.9%, purity 99.45% (HPLC area normalization method).
Embodiment 4
A preparation method for Moxifloxacin hydrochloride, comprises the following steps:
Under nitrogen protection, boric acid 6.2g (100mmol) and 39g propionic anhydride (300mmol) are joined in there-necked flask and is heated to 95 DEG C of contact reactss 1 hour, be cooled to 80 DEG C, add Serine (3.5g) and then add 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester 23.3g (72mmol), stirring reaction is continued 3 hours at 80 DEG C, TLC monitoring reaction is complete, be cooled to room temperature, add acetonitrile (82ml) and diisopropyl ethyl amine 27.1g (210mmol), again with (S, S)-2, 8-diazabicyclo [4.3.0] nonane 8.2g (65mmol) reacts 1 hour at 70 DEG C, be down to room temperature, filtering insolubles, add methyl alcohol (164ml), concentrated hydrochloric acid is dripped under room temperature, adjust ph to 1, stir and be cooled to-8 DEG C of crystallizatioies after 2 hours, suction filtration, cold washing with alcohol (50ml × 3 time), vacuum-drying, obtain Moxifloxacin hydrochloride white solid 24.4g, yield: 85.8%, purity 99.49% (HPLC area normalization method).
Embodiment 5
A preparation method for Moxifloxacin hydrochloride, comprises the following steps:
Under nitrogen protection, boric acid 6.2g (100mmol) and propionic anhydride 45.5g (350mmol) is joined in there-necked flask and is heated to 105 DEG C of contact reactss 1 hour, be cooled to 75 DEG C, add Threonine (2.3g) and then add 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester 23.3g (72mmol), stirring reaction is continued 2.5 hours at 75 DEG C, TLC monitoring reaction is complete, be cooled to room temperature, add acetonitrile (90ml) and diisopropyl ethyl amine 23.3g (180mmol), again with (S, S)-2, 8-diazabicyclo [4.3.0] nonane 8.8g (70mmol) reacts 2 hours at 65 DEG C, be down to room temperature, filtering insolubles, add methyl alcohol (180ml), concentrated hydrochloric acid is dripped under room temperature, adjust ph to 2, stir and be cooled to-10 DEG C of crystallizatioies after 2 hours, suction filtration, cold washing with alcohol (50ml × 3 time), vacuum-drying, obtain Moxifloxacin hydrochloride white solid 24.8g, yield: 81.0%, purity 98.19% (HPLC area normalization method).
Comparative example 1
Prepare Moxifloxacin hydrochloride according to the method for CN102731496A, comprise the following steps:
In 250ml tri-mouthfuls of round-bottomed flasks, add diacetyl oxide 15g, stir, be warming up to 80 DEG C, slowly add boric acid 2.8g, stir, be slowly warming up to 110 DEG C, stirring reaction 2 hours.Be cooled to 60 ~ 70 DEG C, add the fluoro-Isosorbide-5-Nitrae of 1-cyclopropyl-6,7-bis--dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester 10g, temperature control continues reaction 2 hours at 80 ~ 90 DEG C.TLC detection reaction is complete, be down to room temperature, acetonitrile 65ml is added in reaction solution, Trimethylamine 99 37ml, stir 30 minutes, add (S, S)-2, 8-diazabicyclo [4.3.0] nonane 3.9g, heating reflux reaction 3 hours, TLC detection reaction is complete, be down to room temperature, add methyl alcohol 40ml, stir 30 minutes, temperature control 5 ~ 10 DEG C concentrated hydrochloric acid 9.1ml at a low price under ice bath, regulate pH=1.0, continue ice bath stirring and crystallizing 8 hours, filter, ice ethanol 50ml washes twice, filter cake 50 ~ 60 DEG C/-0.095MPa vacuum-drying 12 hours, obtain Moxifloxacin hydrochloride 11g pale yellow powder, yield 81.7%, HPLC:99.11% (HPLC area normalization method).
Comparative example 2
As the preparation method of the Moxifloxacin hydrochloride in embodiment 1, difference is, does not add glycine, finally obtains Moxifloxacin hydrochloride white solid 19.1g, yield: 64.2%, purity 97.48% (HPLC area normalization method).
In embodiment 1-5 gained Moxifloxacin hydrochloride product in single assorted be all less than 0.03%, and 6-replaces by product and is all less than 0.01%, and in comparative example 1-2, singly mix in the product of gained Moxifloxacin hydrochloride at 0.05-0.5%, wherein 6-position replace by product all close to or more than 0.05%.
Claims (7)
1. prepare a method for Moxifloxacin hydrochloride, it is characterized in that, the method comprises the following steps:
Under shielding gas exists, by boric acid and propionic anhydride 95 ~ 105 DEG C of contact reactss 1 hour, be cooled to 75 ~ 80 DEG C, add stable promotor and then add 1-cyclopropyl-6, 7-bis-fluoro-1, 4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester, stirring reaction is continued 1.5 ~ 3 hours at 75 ~ 80 DEG C, it is complete that monitoring tracks to reaction, be cooled to room temperature, add acetonitrile and organic amine, again with (S, S)-2, 8-diazabicyclo [4.3.0] nonane reacts 1 ~ 2 hour at 65 ~ 75 DEG C, be down to room temperature, filtering insolubles, add methyl alcohol, concentrated hydrochloric acid is dripped under room temperature, adjust ph to 1 ~ 3, stir and be cooled to-10 ~-5 DEG C of crystallizatioies after 2 hours, suction filtration, cold washing with alcohol, vacuum-drying, obtain Moxifloxacin hydrochloride, wherein, described stable promotor is selected from glycine, one or more in Serine and Threonine.
2. method according to claim 1, is characterized in that, in the contact reacts of boric acid and propionic anhydride, the mol ratio of boric acid and propionic anhydride is 1:3 ~ 3.5, and catalytic temperature is 95 ~ 100 DEG C.
3. method according to claim 1, is characterized in that, the mol ratio of the fluoro-Isosorbide-5-Nitrae of described 1-cyclopropyl-6,7-bis--dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester and boric acid is 1:1.4 ~ 1.6; The weight ratio of promotion stablizer used and quinoline carboxylic acid ethyl ester is 0.1 ~ 0.2:1.
4. method according to claim 1, is characterized in that, the mol ratio of described organic amine and the fluoro-Isosorbide-5-Nitrae of 1-cyclopropyl-6,7-bis--dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester is 2.5 ~ 3.5:1; Described (S, S)-2,8-diazabicyclo [4.3.0] nonane consumption and the mol ratio of the fluoro-Isosorbide-5-Nitrae of 1-cyclopropyl-6,7-bis--dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid ethyl ester be 1:1.05 ~ 1.1.
5. the method according to claim 1 or 4, is characterized in that, described organic amine is diisopropyl ethyl amine or N-methylmorpholine.
6. the method according to claim 1 or 3, is characterized in that, described stable promotor is glycine.
7. method according to claim 1, is characterized in that, described shielding gas is nitrogen, helium or argon gas.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112645947A (en) * | 2020-12-17 | 2021-04-13 | 张维 | Preparation method of single norfloxacin raw material medicine |
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| CN112645947A (en) * | 2020-12-17 | 2021-04-13 | 张维 | Preparation method of single norfloxacin raw material medicine |
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