- Method for preparing moxifloxacin intermediate (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane
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The invention provides a method for preparing a moxifloxacin intermediate (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane, and relates to the technical field of organic synthesis. According to the present invention, the 2-chloromethyl methyl nicotinate is subjected to asymmetric hydrogenation catalysis so as to obtain the intermediate with high chiral purity, chiral resolution is not required, and the moxifloxacin intermediate (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane can be obtained through ammonolysis, reduction and cyclization. According to the method provided by the invention, chiral resolution is not needed, the process is simple, the process steps are short, the cost is low, and the product is high in chiral purity and high in total yield.
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- (S, S)-2, 8-diazabicyclo[4.3.0]nonane intermediate, and preparation method and application thereof
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The invention discloses a (S, S)-2, 8-diazabicyclo[4.3.0]nonane intermediate, and a preparation method and application thereof. New compounds, namely compounds II-V, are taken as key intermediates, a new route for synthesizing (S, S)-2, 8-diazabicyclo[4.3.0]nonane is developed, and in the route, dialkoxy acetate taken as an initial raw material in the route sequentially undergoes Claisen condensation, substitution reaction, intramolecular dehydration cyclization, catalytic hydrogenation reduction, chiral resolution, dissociation, hydrolysis, intramolecular dehydration cyclization and catalytic hydrogenation to obtain the(S, S)-2, 8-diazabicyclo[4.3.0]nonane. The preparation method is simple, the total reaction yield is high, the product quality is good, the process route is green and environment-friendly, and the method has a good industrial application prospect.
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Paragraph 0107-0112
(2021/06/13)
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- Method for preparing moxifloxacin intermediate (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane
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The invention provides a method for preparing a moxifloxacin intermediate (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane, and relates to the technical field of organic synthesis. According to the method, the azaphthalide is used as a raw material, and due to the ring structure of the azaphthalide, the other two non-corresponding chiral isomers which are not needed in chiral reduction are almost not generated; the chiral purity of the intermediate obtained through reduction is very high, resolution is not needed, and (S, S)-2, 8-diazabicyclo [4, 3, 0] nonane can be obtained directly through ammonolysis, reduction, chlorination and cyclization subsequently. According to the method provided by the invention, chiral resolution is not needed, the process is simple, the process steps are short, the cost is low, and the product is high in chiral purity and high in total yield. Furthermore, in the subsequent product salifying and refining step, carboxylic acid with a chiral structure does not need to be used for salifying, and common achiral carboxylic acid can be used for refining, so the product purity is further improved.
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- Preparation method of intermediate
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The invention relates to a preparation method of an intermediate, and belongs to the field of medicinal chemistry. The preparation method comprises at least one reaction step of an addition elimination reaction, a cyclization reaction, a reduction reaction, a decarboxylation reaction and a hydrogenation reaction. According to the method disclosed by the invention, the target intermediate with a single configuration can be simply and conveniently obtained, chiral resolution is effectively avoided, the yield is improved, the cost is reduced, and industrial production is facilitated.
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Paragraph 0101-0103
(2021/03/31)
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- Preparation method of moxifloxacin intermediate
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The invention discloses a preparation method of a moxifloxacin intermediate. The invention provides a preparation method of a compound as shown in a formula III, which comprises the following step: ina solvent, in the presence of alkali, carrying out cyclization reaction as shown in the specification on a compound as shown in a formula II to obtain the compound as shown in the formula III. The method is simple to operate, high in chiral selectivity, simple in process, high in yield and high in purity.
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- Asymmetric synthesis method for (S,S)-2,8-diazabicyclo[4,3,0]nonane
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The invention relates to an asymmetric synthesis method for (S,S)-2,8-diazabicyclo[4,3,0]nonane. N-benzyl-butene imidodicarbonic diamide is taken as a raw material, in presence of a chiral squaramidecatalyst (III), the N-benzyl-butene imidodicarbonic diamide and N-para-toluene sulfonyl-N'-propylene imidogen hydrazine (II) are subjected to an asymmetric [2+4] addition reaction, and 8-benzyl-2-para-toluene sulfonamide-7,9-dioxo-(1S,6R)-2,8-diazabicyclo[4,3,0]-3-alkene nonane is obtained; through the steps of recrystallization, reduction, acid-catalyzed hydrolysis and reduction, the (S,S)-2,8-diazabicyclo[4,3,0]nonane is obtained. The synthesis method is simple, the yield of the asymmetric catalysis product is high, the enantioselectivity of the product through recrystallization can reach 90% or above, and the asymmetric synthesis method is mild in condition, simple to implement, low in production cost and capable of being used for industrialized production.
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Paragraph 0056; 0057; 0083-0095; 0096; 0097; 0107-0109; 0110
(2019/10/23)
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- New moxifloxacin impurity and preparation method and use thereof
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The invention provides a new moxifloxacin impurity and provides a preparation method and use as an impurity control of the new impurity. A commercially available bulk simple chemical is used as a starting material to construct a chiral dual ring, and further an impurity compound is synthesized; the reaction process has no need of chiral resolution; in addition, the operation is simple, the reaction condition is mild, and the application prospect is good. The moxifloxacin prepared by the invention has high impurity purity, and effectively ensures the purity of the impurity control and the accuracy of analysis work.
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Paragraph 0019-0023
(2019/10/01)
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- Method for synthesizing moxifloxacin and derivatives thereof
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The invention provides a method for synthesizing moxifloxacin and derivatives thereof. Aminopyrrolidone derivatives are constructed to further obtain (S,S)-2,8-diazo-bicyclo[4.3.0]nonane so as to synthesize the moxifloxacin and the derivatives thereof. The method has the beneficial effects that raw materials are wide in source and low in price; chiral resolution is not needed in a preparation process; the yield and purity are relatively high; the process cost is further reduced; obvious economic value is achieved.
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Paragraph 0033; 0044-0045
(2019/10/01)
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- Synthetic method for moxifloxacin chiral side chain intermediate
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The invention provides a synthetic method for a moxifloxacin chiral side chain intermediate. The method provided by the invention uses an easily-available and inexpensive L-asparagine as a starting material to obtain the moxifloxacin chiral side chain intermediate through an eight-step reaction; and the whole route has novel design and avoids a chiral separation process adopted by most routes, andthe method has higher practicability, a high yield, a quick reaction speed and few by-products, and is very suitable for industrial application.
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Paragraph 0050-0053
(2019/10/01)
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- Method for synthesizing (S,S)-2,8-diazabicyclo[4.3.0]nonane
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The invention discloses a method for synthesizing (S,S)-2,8-diazabicyclo[4.3.0]nonane. The method comprises the following steps of: (a) adopting a compound which is shown in a formula V and comprisesa chiral auxiliary group and an amino protecting group as a raw material, and performing an intramolecular cyclization reaction to obtain a compound shown in a formula VI; (b) removing the chiral auxiliary group and amino protecting group from the compound shown in the formula V so as to obtain a compound shown in a formula VII, wherein when X is a hydrogen atom, the compound shown in the formulaVII is (S,S)-2,8-diazabicyclo[4.3.0]nonane; and (c) when X is an oxygen atom, performing a reduction reaction on the compound shown in the formula VII by using amide so as to obtain (S,S)-2 ,8-diazabicyclo[4.3.0]nonane.
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Paragraph 0175-0177; 0185
(2018/03/25)
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- Method for preparing moxifloxacin side chain and intermediate thereof
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The invention relates to a method for synthesizing a moxifloxacin side chain ((S,S)-2,8-diazabicyclo[4,3,0]nonane (I)) from a moxifloxacin side chain dihydrochloride (V). The method has the advantagesof low process cost, short process flow and simple operation, and presents great market application value and potential for large-scale promotion and application. The invention also discloses a method for synthesizing the moxifloxacin side chain dihydrochloride from (4S,7S)-6-benzyl-1-((R)-1-phenethyl)-octahydro-1H-pyrrolo[3,4-b]pyridine (II) and a method for synthesizing (4S,7S)-6-benzyl-1-((R)-1-phenethyl)-octahydro-1H-pyrrolo[3,4-b]pyridine (II). Process flow of the invention is as described in the specification.
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- Efficient synthesis of (S,S)-2,8-diazabicyclo[4.3.0]nonane
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An efficient synthetic route for moxifloxacin chiral intermediate via five steps was established. First, dehydration, N-acylation, and cyclization were combined in one pot to meet the industrial requirement. Then relatively low hydrogen pressure was employed in the catalytic hydrogenation reaction with high yield. Isopropanol/water system was used in resolution, which guaranteed high yield and perfect optical purity. The racemic process conducted by manganese dioxide and Pd/C successfully converted the undesired enantiomer into the racemate and hence the total yield increased remarkably. Furthermore, mild hydrogen transfer catalytic hydrogenation method was utilized in debenzylation process instead of high-pressure hydrogenation. Total yield of 39.0% was achieved, which was much higher than that of 29.0% in literature.
- Chen, Shipeng,Liu, Dongqi,Si, Leilei,Chen, Ligong,Yan, Xilong
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p. 238 - 244
(2017/01/22)
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- A 3 - amino-pyrrolidine compound and its synthesis and use
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The invention relates to 3-aminopyrrolidine compounds, and a synthetic method and uses thereof. 3-pyrrolidone compounds (compounds IIIa or IIIb) are adopted as substrates and subjected to transaminase reactions under the actions of transaminase and an amino donator to obtain the (S)-3-aminopyrrolidine compounds (compounds II). Then intramolecular cyclization and removal of amino protective groups are performed to obtain (S,S)-2,8-diazabicyclo[4,3,0] nonane (a compound I). According to the 3-aminopyrrolidine compounds, the synthetic method and the uses, a synthetic technology that is low in cost, short in process steps and environmental friendly is provided for a moxifloxacin intermediate, and the synthetic technology will have great market application value and is suitable for large-scale industrial production.
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- Synthesis method for moxifloxacin side chain
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The invention discloses a synthesis method for a moxifloxacin side chain.With 2,3-dipicolinic acid being a raw material, cyclization, catalytic hydrogenation, resolution and racemization are performed, and then chemical reduction and debenzylation are performed to obtain moxifloxacin side chain.Resolution, racemization and chemical reduction are performed in sequence, sodium borohydride is used for replacing high-risk lithium aluminum hydride to synthesize the moxifloxacin side chain, and the synthesis method has the advantages that industrial waste materials are reduced, the production cost is lowered, and productivity is increased.
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- Preparation method of (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane
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The invention discloses a preparation method of (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane and belongs to the field of the preparation method of a moxifloxacin intermediate. The preparation method comprises eight processes. A resolving process is carried out in initial of the preparation method, in the third process, an ester is resolved to form a chiral intermediate and then through a simple chemical reaction, the (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane is prepared. The invention provides the preparation method utilizing an effective and economic synthesis route to prepare the high-chiral purity (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane. The preparation method is free of an expensive resolving agent and greatly reduces a process cost. In the whole technology, the intermediate is not purified and the crude product can be directly used. The preparation method has simple processes and a high overall yield and can produce the product with chiral purity of 99%.
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- A (4aS, 7aS) - octahydro - 1H - pyrrolo [3, 4 - b] pyridine purification method
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The invention relates to a purification method for (4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine. The method comprises: enabling a crude product (4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine (I) with the ee value of 90-98% to form a (4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine dihydro halate (II), and further performing crystallization purification to obtain (4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine dihydro halate (II) with the ee value larger than 99.0%, and performing dissociation to prepare (4aS,7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine (I) with relatively high chiral purity. The method is simple to operate, convenient and practical, the product has the ee value larger than 99.0%, the total yield is relatively high and even up to 94.0%, and the method is suitable for industrial large-scale production.
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Paragraph 0034; 0036; 0037; 0038; 0039; 0041-0062
(2017/06/10)
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- (S, S) - 2,8-diazabicyclo [4, 3, 0] nonane synthetic method
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The invention discloses a preparation method of a compound 1 (S,S)-2,8-diazabicyclo[4.3.0]nonane. With existing methods, chiral separations are carried out in the last process, and chiral control are not realized in pre-stage main ring synthesis process, such that a final total yield is substantially low, and synthesizing cost of (S,S)-2,8-diazabicyclo[4.3.0]nonane is severely influenced. According to the method provided by the invention, in an organic solvent, under the existence of organic amine and under a temperature of 0-30 DEG C, benzenesulfonamide is subjected to a reaction with acrolein, such that a compound 5 is prepared; under the existence of organic amine and a chiral catalyst, the compound 5 is subjected to a D-A addition reaction with a compound 4, such that a compound 6 is prepared; the compound 6 is processed through catalytic hydrogenation and carbonyl reduction; and protective group removing and chiral separation purification are carried out under an acidic condition. With the method provided by the invention, a problem of low total yield of finished product caused by chiral separation of prior arts is completely solved, and product yield is improved.
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Paragraph 0035-0040
(2017/03/08)
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- Chiral synthesis of (S, S) - 2,8-diazabicyclononane method
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The invention provides a method for chiral synthesis of (S,S)-2-8-diazabicyclo[4.3.0]nonane. A target product with a desired structure is prepared by using pyridine 2,3-diformate as a raw material and carrying out a four-step reaction comprising hydrogenation, resolution, aminolysis and reduction. According to the method, a synthetic route is simple and short, the step of resolution is carried out at an early stage, and reaction raw materials and reagents are saved; thus, production cost is reduced, and production efficiency is improved.
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- ASYMMETRIC SYNTHESIS METHOD, RELATED RAW MATERIAL AND PREPARATION METHOD OF (S,S)-2,8-DIAZABICYCLO[4,3,0]NONANE
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The present invention relates to an asymmetric synthesis method of a chiral intermediate (S,S)-2,8-diazabicyclo[4,3,0]nonane (I) of moxifloxacin, wherein an imide or enamine compound is obtained by dehydration reaction of the pyrrolidine-3-ketone as shown in formula (II) and chiral amine(R)-1-phenylethylamine, followed by the reduction of the imide or enamine compound to obtain a compound of formula (III) or (IV) having the chiral structure of formula (I), and then a compound of formula (I) is obtained by intramolecular cyclization, and removal of the chiral auxiliary group and amino-protecting group. The present invention also relates to pyrrolidine-3-ketone as shown in formula (II) and a preparation method therefor, and in the formula (I), (II), (III), (IV), R is an amino-protecting group, especially C1-4 alkoxycarbonyl, benzyloxycarbonyl or benzyl which can be removed by hydrolysis or hydrogenation. Z=H2 or O; when Z=H2, Y is chlorine, bromine, iodine, methanesulfonate, tosylate, hydroxyl or hydroxyl with protection; and when Z=O, Y is OR1, and R1 is C1-4 alkyl.
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- IR, FT-ICR-MS studies on (1′S, 6′S)-1-cyclopropyl-7-(2,8- diazabicyclo[4.3.0] non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3- carboxylic acid hydrochloride salt
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The infrared spectra of (1′S, 6′S)-1-cyclopropyl-7-(2,8- diazabicyclo[4.3.0] non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3- carboxylic acid hydrochloride salt (CLF-HCl) were studied and compared with free base. Their fragmentation pathways were investigated using tandem mass spectrometric (MS/MS) techniques on Fourier-transform ion cyclotron resonance spectrum, and many characteristic fragment ions were found.
- Lin, Zhiwei
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p. 254 - 258
(2013/12/04)
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- ASYMMETRIC SYNTHESIS METHOD, RELATED RAW MATERIAL AND PREPARATION METHOD OF (S,S)-2,8-DIAZABICYCLO[4,3,0]NONANE
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The present invention relates to an asymmetric synthesis method of a chiral intermediate (S,S)-2,8-diazabicyclo[4,3,0]nonane (I) of moxifloxacin, wherein an imide or enamine compound is obtained by dehydration reaction of the pyrrolidine-3-ketone as shown in formula (II) and chiral amine(R)-1-phenylethylamine, followed by the reduction of the imide or enamine compound to obtain a compound of formula (III) or (IV) having the chiral structure of formula (I), and then a compound of formula (I) is obtained by intramolecular cyclization, and removal of the chiral auxiliary group and amino-protecting group. The present invention also relates to pyrrolidine-3-ketone as shown in formula (II) and a preparation method therefor, and in the formula (I), (II), (III), (IV), R is an amino-protecting group, especially C1-4 alkoxycarbonyl, benzyloxycarbonyl or benzyl which can be removed by hydrolysis or hydrogenation. Z═H2 or O; when Z═H2, Y is chlorine, bromine, iodine, methanesulfonate, tosylate, hydroxyl or hydroxyl with protection; and when Z═O, Y is OR1, and R1 is C1-4 alkyl.
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Page/Page column
(2014/03/25)
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- A novel synthesis of (4aS,7aS)-Octahydro-1H-pyrrolo[3,4-b]pyridine:An intermediate of Moxifloxacin Hydrochloride
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A novel synthesis of (4aS, 7aS)-octahydro-1H-pyrrolo[3,4-b]pyridine (1) is demonstrated alongwith recovery and reuse of chiral auxiliary naproxen. Further to this alternative stereoselective reduction procedures on 6-benzyl-5H- pyrrolo[3,4-b]pyridine-5,7(6H)-dione 3 enabling the desired chirality in the nonane 1 is demonstrated.
- Reddy, G. Prashanth,Bandichhor, Rakeshwar
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p. 8701 - 8707
(2013/11/06)
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- First way of enantioselective synthesis of moxifloxacin intermediate
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A new method of enantioselective synthesis of (S,S)-2,8-diazobicyclo [4.3.0] nonane was found by using (R)-2-amino-2- phenyl-ethanol as chiral induction reagent. The entire synthetic process included 8 steps which were easy to operate with high yield. The purification method was only simple recrystallization or even used directly in the next step without further purification. The total yield was 29%.
- Li, Guang Xun,Wu, Lei,Fu, Qing Quan,Tang, Zhuo,Zhang, Xiao Mei
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p. 307 - 311
(2013/07/26)
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- PROCESSES FOR PRODUCING (1S,6S)- OR (1R,6R)-CIS-2,8-DIAZABICYCLO[4.3.0]NONANE AND INTERMEDIATE THEREOF
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The present invention relates to a process for producing (1S,6S)- or (1R,6R)-cis-2,8-diazabicyclo[4.3,0]nonane with high optical purity by forming a salt from a (1S,6R)- or (1R,6S)-cis-7,9-dioxo-8-substituted-2,8-diazabicyclo[4.3.0]nonane derivative and an acid, precipitating the salt with high excess diastereomer ratio as a solid, reducing the solid, and removing the substituent on the nitrogen atom at 8-position. According to the present invention, it is possible to easily and effectively produce (lS,6S)- or (1R,6R)-cis-2,8-diazabicyclo[4.3.0]nonane or the salt thereof with high optical purity without troublesome procedure from inexpensive and versatile starting material. The target compound is important as a raw material for a medicine.
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Page/Page column 18
(2012/03/26)
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- SYNTHESIS OF (4aS,7aS)-OCTAHYDRO-1H-PYRROLO[3,4-b]PYRIDINE
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The present invention relates to the stereoselective synthesis of (4aS,7aS)-octahydro-1H-pyrrolo [3, 4-b]pyridine, as well as the conversion thereof, to give Moxifloxacin. Particularly, the present invention relates to a method for the synthesis of (4aS,7aS)-octahydro-1H-pyrrolo[3, 4-b]pyridine of formula (I) comprising : (a) the optical resolution by enzymatic hydrolysis of the intermediate dialkyl-1-alkylcarbonylpiperidine-2,3-dicarboxylate racemate of formula (II) to give, following isolation, the intermediate dialkyl-(2S,3R)-1-alkylcarbonyl-piperidine-2,3-dicarboxylate of formula (III) in which AIk is a straight or branched C1-C5 alkyl group; (b) the conversion of the intermediate (III) to (4aR,7aS)-1-alkylcarbonylhexahydrofuro[3, 4-b]pyridine-5,7-dione of formula (IV) in which AIk has the meanings set forth above; (c) the conversion of the intermediate (IV) to (4aS,7as)-octahydro-1H-pyrrolo[3, 4-b]pyridine of formula (I) with an optical purity above 99%.
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Page/Page column 36-37
(2010/09/18)
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- IMPROVED PROCESS FOR THE PREPARATION OF (S.S)-2.8-DIAZABICYCLO[4.3.0]NONANE
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The present invention is directed to an improved industrially viable, cost effective process for manufacturing (S,S)-2,8-Diazabicyclo[4.3.0]nonane in a substantially pure form and consequent conversion to Moxifloxacin hydrochloride monohydrate.
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Page/Page column 6; 11
(2009/11/29)
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- A NOVEL AND ECONOMICAL PROCESS FOR PREPARING (S,S)-2, 8-DIAZABICYCLO[4.3.0]NONANE AND ITS ENANTIOMER
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The present invention relates to a novel and economical process for preparing (S, S)-2, 8-diazabicyclo[4.3.0]nonane, a valuable intermediate used for constructing quinolone and naphthyridine derivatives having antibacterial effectiveness,e.g. moxifloxacin and its enantiomer.
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Page/Page column 14
(2008/12/07)
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- PHENYLAMINOPYRIMIDINES AND THEIR USE AS RHO-KINASE INHIBITORS
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The invention relates to the phenylaminopyrimidines of formula (I), wherein A, D, R1, R2, R3 and R4 are defined as in the description. The invention also relates to methods for producing said phenylaminopyrimidines and to their use for producing drugs for the treatment and/or the prophylaxis of diseases, especially cardiovascular diseases.
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Page column 56,57
(2010/02/06)
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- Quinolonecarboxylic acids
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The invention relates to novel derivatives of quinolonecarboxylic acid and naphthyridonecarboxylic acid which are linked to a β-lactam antibiotic, to their salts, to processes for their preparation and to antibacterial agents containing these derivatives.
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- 8-vinyl- and 9-ethinyl-quinolone-carboxylic acids
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The invention relates to new 8-vinyl- and 8-ethinylquinolonecarboxylic acids, process for their preparation, and antibacterial agents and feed additives containing them.
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