* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With hydrogenchloride In ethanol; water at 25 - 30℃; for 1 h;
The 50g tartaric acid moxifloxacin is added to250ml water and 250ml of ethanol and stirred, was added 16. 6ml of concentratedhydrochloric acid at 25~30 ° C, the reaction was stirred at this temperaturefor 1 hour, suction filtered, the filter cake was washed with 100ml of ethanol,50~55 ° C for 3 hours in vacuo give moxifloxacin hydrochloride 35. 10g (88.3percent). Yield: 86 61percent isomer content: 0?05percent
Stage #1: at 90 - 100℃; for 3 h; Stage #2: With triethylamine In acetonitrile at 20℃; for 0.5 h;
In a 2000 mL three-necked round-bottomed flask, 150.00 g of acetic anhydride was added, stirred, heated to 80 °C,boric acid 28. 00g, stirring evenly, slowly warming to 110 °C, stirring reaction 2 hours. Cooled to 60-70 ° C, ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylate 100 was added. And the reaction was continued at 90 to 100 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. 650 mL of acetonitrile and 592 mL of triethylamine were added to the reaction solution, and the mixture was stirred for 30 minutes. To the reaction solution was added 39.39 g of (S, S) -2,8-diazabicyclo [4.3.0] nonane (1.01eq), heating reflux reaction 3 hours, TLC detection reaction is completed, down to room temperature, stirring 30 minutes, ice bath temperature 5 ~ 10 °C 90mL concentrated hydrochloric acid, adjust PH = 1. 2, continue ice bath Stirring and crystallization for 8 hours, filtration, ice-ethanol 50mLX2 washing filter cake, filter cake 50 ~ 60 ° C / _0.095MPa vacuum drying 12 hours to obtain crude moxifloxacin hydrochloride 121. 48g light yellow powder, yield: 89 78percent, HPLC: 99.7percent.
Stage #1: With triethylamine In acetonitrile at 15℃; Stage #2: With hydrogenchloride In water
To the other reactor was added 60 g of (S, S) -2,8-diazabicyclo [4.3.0] nonane,40 (^ acetonitrile,4 (^ triethylamine,120 g of the above-prepared moxifloxacin hydrochloride intermediate was added with stirring,The reaction temperature was 15 ° C,The tracking reaction was monitored by TLC,To (S, S) -2,8-diazabicyclo [4.3.0] nonane;After the reaction is complete,The filtrate was added with 50 g of purified water, Keeping the temperature of the reaction solution at about 20 ° C,Concentrated hydrochloric acid,To a pH of 0.5, Stirring crystallization centrifugal filtration, And the resulting solid was dried at 70 ° C for about 7 hours,Moxifloxacin hydrochloride was crude 114g,The crude yield of moxifloxacin hydrochloride was 91.8percent and the purity of HPCL was 99.45percent.
Stage #1: With triethylamine In acetonitrile at 80 - 90℃; for 5 h; Large scale Stage #2: With hydrogenchloride In methanol at 0 - 20℃; for 3 h; Large scale
(1) The 100L reactor was sequentially charged with 24.49 kg of Im-1 and 60 L of acetonitrile.Further, 8.77 kg of SM2 and 11.71 kg of triethylamine were added, and the mixture was heated to reflux at 80 to 90 ° C with stirring.(2) Reflow reaction for 5 h, TLC monitoring (developing solvent: ethyl acetate).(3) After the reaction is completed, the temperature is lowered to room temperature, and the reaction liquid is transferred to a 500 L reaction vessel.60 L of methanol was added with stirring.(4) Add hydrochloric acid dropwise under stirring to adjust pH ≈0.5, about 18.44L concentrated hydrochloric acid, dark green solid precipitated.(5) After the completion of the dropwise addition, stirring at room temperature for 2 h; cooling to 0 to 5 ° C, stirring for 1 h;(6) Centrifugation, the filter cake is washed with 24 L of methanol cooled to 0-5 ° C.Drying at 50-55 ° C for 20 to 24 hours, to obtain crude product Im-2 19.35kg,Yellow powder solid, yield 76.3percent.
Reference：
[1] Patent: CN108276402, 2018, A, . Location in patent: Paragraph 0075; 0083; 0084; 0085; 0086; 0087; 0088; 0089
5
[ 151096-09-2 ]
[ 186826-86-8 ]
Yield
Reaction Conditions
Operation in experiment
77%
With hydrogenchloride In methanol at 0 - 5℃; for 1 h;
Moxifloxacin base 50.0 g was stirred in 200.0 ml methanol for 10-15 minutes at 25-3-0C. The pH was adjusted to 1.0 -2.0 using methanolic hydrochloric acid. The reaction mass was chilled to 0-50C and maintained for 1 hour. The solids were filtered and dried under vacuum at 85-900C to yield 52.5 g (105percent) of moxifloxacin hydrochloride; 70.0 g of moxifloxacin base was stirred with 350.0 ml of methanol at 25- 30°. The pH was adjusted to 1.0 - 2.0 using methanolic hydrochloric acid and contents were chilled to 0-5°C and stirred for 1 hour at the same temperature. The solid was filtered and dried under vacuum at 85-9O°C to yield 78.Og (77percent) of moxifloxacin hydrochloride
54.84%
With hydrogenchloride; edetate disodium In methanol; water at 0 - 38℃; for 2 h;
The compound obtained from the example 6(85g) was taken in methanol (250 ml) and purified water (150 ml) followed by the addition of hydrochloric acid (17.14 g) and EDTA disodium salt (57 mg) the contents was heated to 35-38°C and maintained for 1 hour ,cooled to 0-5°C for 1 hour. The product was filtered washed with methanol treated with activated carbon (5.0 g) to get the desired product. Dry wt: 53.0g, Yield: 54.84percent
44.3 g
With hydrogenchloride In ethanol; water at 20 - 60℃; for 6 h;
68.2 g of purified Moxifloxacin Tosylate of example 2 (1.0 mol. Equiv.) (HPLC purity equivalent to 99.30percent and impurity of formula (VII) equivalent to 0.27percent), 409.2 mL of saturated NaHCO3 solution, 136.4 mL of purified water, 409.2 mL of dichloromethane and 68.2 mL of isopropanol were introduced into a 4-neck flask provided with a mechanical stirrer, thermometer, cooler and thermostat. Heating is carried out at 30-35°C and stirring is carried out for one hour up to complete dissolution. Then the phases are separated and the aqueous phase is extracted using 136.4 mL of Dichloromethane. The organic phases are collected and dried. The obtained solid is recovered with 954.8 mL of Ethanol and 136.4 mL of purified water. Heating is carried out at reflux up to complete dissolution, then it is brought to 60°C and a solution of 12.3 mL of concentrated hydrochloric acid (32percent) (1.05 mol. equiv.) and 136.4 mL of Ethanol is dripped in 2 hours. It is brought to r.t in 4 hours, it is left at room temperature for at least 4 hours, then it is cooled at 0°C and it is left at 0°C for another 4 hours. The obtained crystal is filtered washing it with 68.2 mL of Ethanol. The obtained salt is dried at 50°C under vacuum for 24 hours. 44.3 g of Moxifloxacin hydrochloride with a molar yield equivalent to 85.1percent with HPLC purity equivalent to 99.79percent and a formula (VII) impurity content equivalent to 0.08percent are obtained. The obtained product does not contain, even at ppm level, any ester of the sulfonic acids as an impurity, which is an essential aspect it being widely known that such impurities are genotoxic.#10;
44.3 g
With hydrogenchloride In ethanol; water at 20 - 60℃; for 10 h;
68.2 g of purified moxifloxacin tosylate of example 2 (1.0 mol. Equiv.) (HPLC purity equivalent to 99.30percent and impurity of formula (VII) equivalent to 0.27percent), 409.2 mL of saturated NaHCO3 solution, 136.4 mL of purified water, 409.2 mL of dichloromethane and 68.2 mL of isopropanol were introduced into a 4-neck flask provided with a mechanical stirrer, thermometer, cooler and thermostat. Heating was carried out at 30-35°C and stirring was carried out for one hour up to complete dissolution. Then the phases were separated and the aqueous phase was extracted using 136.4 mL of Dichloromethane. The organic phases were collected and dried. The obtained solid was recovered with 954.8 mL of Ethanol and 136.4 mL of purified water. Heating was carried out at reflux up to complete dissolution, then it was brought to 60°C and a solution of 12.3 mL of concentrated hydrochloric acid (32percent) (1.05 mol. equiv.) and 136.4 mL of Ethanol was dripped in 2 hours. It was brought to r.t in 4 hours, it was left at room temperature for at least 4 hours, then it was cooled at 0°C and it was left at 0°C for another 4 hours. The obtained crystal was filtered washing it with 68.2 mL of Ethanol. The obtained salt was dried at 50° C. under vacuum for 24 hours. 44.3 g of moxifloxacin hydrochloride with a molar yield equivalent to 85.1percent with HPLC purity equivalent to 99.79percent and a formula (VII) impurity content equivalent to 0.08percent was obtained. The obtained product does not contain, even at ppm level, any ester of sulfonic acids as an impurity. This is important because it is well-known that such impurities are genotoxic.
With tetrabutyl-ammonium chloride In <i>N</i>-methyl-acetamide; hydrogenchloride; ethanol; water
Example 1 Synthesis of Moxifloxacin HCl (I-HCl)-Exemplifying the Invention In a 250 mL three-neck flask provided with a mechanical stirrer, thermometer and thermostat, 20.0 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acid (67.74 mmol), 7.37 g of magnesium methoxide (85.3 mmol, 1.26 mol. eq.), 4.33 g of magnesium hydroxide (74.2 mmol, 1.10 mol. eq.) and 120 mL of dimethylformamide (DMF) (6 vol.) were loaded under inert atmosphere. The mixture is heated at 30° C. for one hour and the methanol which is formed is removed by means of low pressure distillation. To the solution is then added 0.5 g of tetrabutylammonium chloride (TBAC) (2.5percent by weight on the substrate. 10.25 g of (4aS, 7aS)-Octahydro-1H-pyrrole[3,4-b]pyridine (81.29 mmol, 1.20 mole equiv.) is then added. The reaction mixture is heated at 45° C. and maintained at T=45-50° C. until the HPLC monitored reaction is completed, i.e. about 16 hours. The solvent is vacuum distilled and about 110 mL DMF are recovered. To the residual suspension 200 mL water and 25 mL HCl 12 N (300 mmol) is added, thereby bringing the solution pH to 3-4. The suspension is heated at 30° C. and stirred at that temperature for 30 minutes, then it is cooled at T<10° C. and, after the product has precipitated, it is stirred at this temperature for 30 minutes. The suspension is filtered and the solid is washed with water. The crude is dissolved in 150 mL hydrochloric acid 5.5 mol/L. The whole is stirred for at least 20 minutes until it is dissolved. The small amount of insolute material, being an impurity, is eliminated through filtration. The filtrate is concentrated to a small volume under low pressure. To the obtained solution is added 70 mL anhydrous ethanol. The mixture is stirred and cooled below 5° C. for at least one hour after solid precipitation. The suspension is filtrated and the solid is washed with mL ethyl acetate. The solid is vacuum dried for 3 hours at 25° C. then at Tmax.=70° C. for 4 hours. 26.4 g of Moxifloxacin hydrochloride is obtained (molar yield=89percent) with HPLC (A percent) purity>99.0percent.
Reference：
[1] Patent: US2011/230661, 2011, A1,
7
[ 139693-52-0 ]
[ 151213-40-0 ]
[ 186826-86-8 ]
Yield
Reaction Conditions
Operation in experiment
45 g
Stage #1: With triethylamine In ethanol at 70℃; for 4 h; Stage #2: With hydrogenchloride In water at 30℃; for 1 h; Heating
The main ring chelate compound 50g, anhydrous ethanol 200g, (3,3)-2,8-diazabicyclo[4,3,0]nonane 15.7g and triethylamine 12.0g were added to the reaction flask. Temperature 70 °C reaction 4. Oh; the end of the reaction, temperature control 30 ° C to the solution was added dropwise 12mol / L of hydrochloric acid, stirring while stirring, adjust the pH to 1, stirring for 1h, temperature control to 10 °C, Crystal growth 2h; After crystal growth, filtration, washing with 95 percent ethanol twice, each time 50g; Wet powder 60 °C vacuum drying to 2.8percent moisture, to obtain moxifloxacin hydrochloride dry powder 45.0g, a single impurity 0.1percent, The total impurity is 0.2percent; after refining with ethanol and water, the content is 99percent, which meets the quality standards of the European Pharmacopoeia EP-7.0 and the total impurity is less than 0.1percent
Stage #1: With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20 - 85℃; for 36 h; Inert atmosphere Stage #2: With hydrogenchloride In water at 15℃; for 1 h; Inert atmosphere
Under nitrogen protection, 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid 10.0 g (0·0339 mοl) and (S,S) -2,8-diazabicyclo[4,3,0] nonane 5 .13g(0.0406mol)were added to 70 mL acetonitrile, it was stirred at 20 ° C~30 ° C and 1,8-diazabicyclo[5·4·0]undec-7-ene 7.74 g (0.0508 mol) was added, it was stirred at 75 ° C~85 ° C for 36 h. Concentrated in vacuo (temperature 45 ° C ~ 65 ° C, pressure -0 · 08MPa ~ -0.1MPa) to remove most of the solvent, it was then dissolved in chloroform, the mass concentration is 2percent aqueous acetic acid solution (the mass concentration refers to the mass of acetic acid as a percentage of the total mass of the aqueous acetic acid solution), the mass concentration was 10percent saline (the mass concentration refers to the mass of sodium chloride as a percentage of the total mass of brine were sequentially added, respectively, then the mixture was stirred, allowed to stand, and the aqueous layer was separated. The organic layer was concentrated in vacuo (temperature 35 ° C ~ 55 ° C, pressure -0.08MPa ~ -0.1MPa) to remove most of the solvent, ethyl acetate was added, and the mixture was cooled to 10 ° C to 20 ° C and stirred for 2 hours to 3 hours. Centrifugation, rinsed three times with ethyl acetate, dried in vacuo (vacuum degree -0.01MPa~-0.1MPa, temperature 45~55°C) dried for 14 to 18 hours, to obtain 4.01g of moxifloxacin , yield 29.5percent.HPLC purity 93.54percent. Under nitrogen protection, add 4.0 g of moxifloxacin to 2.5 mL of water and 10 mL of methanol.Stir at 170 ° C for 1 hour, filter, and cool to 35 ° C.The pH was adjusted to 1.4 to 1.8 by the addition of 6N hydrochloric acid. Cool to 15 ° C and stir for 1 hour.It was filtered, washed with water, and stirred at 15 ° C for 1 hour in a solution of water 5 mL and concentrated hydrochloric acid.Filtered, washed with water, vacuum dried (vacuum degree - 0.01 MPa ~ -0.1 MPa, temperature 45 ~ 55 ° C) for 16 hours, to obtain 3.3 g of moxifloxacin hydrochloride,Yield 75.6percent (total yield 22.3percent, based on 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid ). The HPLC purity was 99.23percent, and the maximum single impurity was 0.47percent.
Reference：
[1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2014, vol. 121, p. 254 - 258
[2] Patent: CN109096276, 2018, A, . Location in patent: Paragraph 0090-0093
9
[ 1403836-23-6 ]
[ 186826-86-8 ]
Reference：
[1] Patent: CN105524060, 2016, A, . Location in patent: Paragraph 0020; 0024; 0025; 0026
10
[ 1028205-69-7 ]
[ 186826-86-8 ]
Yield
Reaction Conditions
Operation in experiment
6.4 g
Stage #1: With water; sodium hydroxide In ethylene glycol at 115℃; Inert atmosphere Stage #2: With hydrogenchloride In water at 15℃; for 1 h; Inert atmosphere
Under nitrogen protection, add 35g (0.875mol) of sodium hydroxide to 165mL of water and 150mL of ethylene glycol.And 7-((S,S)-2,8-diazabicyclo[4,3,0]decane-8-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro- 8-methoxy-4-oxo-3-quinolinecarboxylic acid dimethylamide 12.0 g (0.0263 mol),Stir for 15 hours while heating to 115 °C.Cool to 5 ° C and adjust the pH to 5-6 with concentrated hydrochloric acid. Stir at 0.5 ° C for 0.5 hours.Filtration, water washing, vacuum drying (vacuum degree -0.01MPa~-0.1MPa, temperature 45°C55 ° C) for 16 hours, 8.0 g of moxifloxacin was obtained, and the yield was 75.8percent. The HPLC purity was 93.25percent.Under nitrogen protection, 8.0 g of moxifloxacin was added to 5 mL of water and 20 mL of methanol, and the mixture was stirred at 70 ° C for 1 hour, filtered, cooled to 35 ° C, and adjusted to pH 1.4 to 1.8 by adding 6 N hydrochloric acid.Cool to 15 ° C and stir for 1 hour. It was filtered, washed with water, and stirred at 15 ° C for 1 hour in 10 mL of water and 0.2 mL of concentrated hydrochloric acid.Filtration, washing with water, vacuum drying (vacuum degree - 0.01 MPa ~ -0.1 MPa, temperature 45 ~ 55 ° C) for 16 hours, 6.4 g of moxifloxacin hydrochloride was obtained, the yield was 73.3percent.(Total yield 29.4percent based on 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid). The HPLC purity was 99.16percent and the maximum single impurity was 0.54percent.
Reference：
[1] Patent: CN109096276, 2018, A, . Location in patent: Paragraph 0084; 0085; 0088; 0089
11
[ 496919-99-4 ]
[ 151213-40-0 ]
[ 186826-86-8 ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: at 10 - 100℃; for 3 h; Stage #2: With hydrogenchloride In methanol; butan-1-ol at 25 - 30℃; for 2 h;
1 -cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-l, 4-dihydro-3-quinoline carboxylic acid- O3,O4 bis(propyloxy-O)borate (100.Og) was suspended in n-butanol (500.0 ml) to which (S,S)-2,8-diazabicyclo (4,3,0) nonane (29.0 g) diluted with 100.0 ml n-butanol was added slowly at 10-15°C. The contents were heated to 100°C and maintained for 3 hours. After the completion of reaction it was cooled to 25-3O0C. 200.0 ml methanol was added and pH was adjusted 1.0-2.0 using methanolic hydrochloric acid. The contents were stirred at 25-3O0C for 2 hours. After completion of reaction the reaction mass was distilled to residue. Purified water 500 ml was added and pH was adjusted to 7.5-9.0 using liquor ammonia. The reaction mass was then extracted with dichloromethane. The organic layer was dried using sodium <n="15"/>sulphate and concentrated to residue. The residue was stripped with 100 ml methanol. 300 ml methanol was charged and pH was adjusted to 1.0-2.0 using methanolic hydrochloric acid, the contents were further cooled to 0-50C and maintained for 1 hour. The solid was filtered and washed with chilled methanol (50.0 ml) and dried under vacuum at 85-9O0C to yield 75.0 g (75percent) of moxifloxacin hydrochloride.
In a 2000 mL three-necked round-bottomed flask, 150.00 g of acetic anhydride was added, stirred, heated to 80 C,boric acid 28. 00g, stirring evenly, slowly warming to 110 C, stirring reaction 2 hours. Cooled to 60-70 C, ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylate 100 was added. And the reaction was continued at 90 to 100 C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. 650 mL of acetonitrile and 592 mL of triethylamine were added to the reaction solution, and the mixture was stirred for 30 minutes. To the reaction solution was added 39.39 g of (S, S) -2,8-diazabicyclo [4.3.0] nonane (1.01eq), heating reflux reaction 3 hours, TLC detection reaction is completed, down to room temperature, stirring 30 minutes, ice bath temperature 5 ~ 10 C 90mL concentrated hydrochloric acid, adjust PH = 1. 2, continue ice bath Stirring and crystallization for 8 hours, filtration, ice-ethanol 50mLX2 washing filter cake, filter cake 50 ~ 60 C / _0.095MPa vacuum drying 12 hours to obtain crude moxifloxacin hydrochloride 121. 48g light yellow powder, yield: 89 78%, HPLC: 99.7%.
1-cyclopropyl-6-fluoro-7-((4aS,7aS)-1-(4-(hydroxymethyl)benzyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Moxifloxacin hydrochloride (6.1; 80 mg, 0.199 mmol, 1 eq) was added to a 1:1 mix of acetonitrile and distilled water ( mL total). After stirring for minutes, potassium carbonate (82.63 mg, o.8 mmol, 3 eq) was added and the mixture stirred for a further minutes. Once fully dissolved, (<strong>[71831-21-5](4-(bromomethyl)phenyl)methanol</strong> (36.06 mg, 0.18 mmol, 0.90 eq) was added slowly over the course of 1 hour and the mixturesubsequently stirred for 18 hours. Upon completion, the product was extracted with dichloromethane (2 x 20 mL) using a 1M solution of citric acid to neutralise the aqueous phase. Combined organic fractions were washed with distilled water (20 mL) and dried over MgSO4, filtered and concentrated in vacuo to give the pure product 6.6.
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