CN102408427B - Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane - Google Patents

Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane Download PDF

Info

Publication number
CN102408427B
CN102408427B CN 201110323201 CN201110323201A CN102408427B CN 102408427 B CN102408427 B CN 102408427B CN 201110323201 CN201110323201 CN 201110323201 CN 201110323201 A CN201110323201 A CN 201110323201A CN 102408427 B CN102408427 B CN 102408427B
Authority
CN
China
Prior art keywords
dioxy
nonane
diazabicyclo
benzyl
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN 201110323201
Other languages
Chinese (zh)
Other versions
CN102408427A (en
Inventor
戴鹏
张柏林
张柯华
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Apeloa Pharmaceutical Co ltd
Shanghai Puluochuangzhi Pharmaceutical Technology Co ltd
ZHEJIANG APELOA KANGYU PHARMACEUTICAL CO Ltd
Original Assignee
SHANGHAI APELOA PHARMACEUTICAL RESEARCH Co Ltd
APELOA KANGYU PHARMACEUTICAL Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SHANGHAI APELOA PHARMACEUTICAL RESEARCH Co Ltd, APELOA KANGYU PHARMACEUTICAL Co Ltd filed Critical SHANGHAI APELOA PHARMACEUTICAL RESEARCH Co Ltd
Priority to CN 201110323201 priority Critical patent/CN102408427B/en
Publication of CN102408427A publication Critical patent/CN102408427A/en
Application granted granted Critical
Publication of CN102408427B publication Critical patent/CN102408427B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention discloses a preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane. Crystallization of (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine diastereomeric salts is formed by Cis-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane and N-acetyl-L-leucine in a splitting solvent and dissociates in a alkaline liquid such as Na2CO3 or NaHCO3. The crystallization is extracted through an organic solvent and decompressed and concentrated through organic phases to obtain (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane. The preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane has low production cost and is simple and convenient to split; moreover, fussy purge process during subsequent reaction is avoided. Products of the preparation method not only have high optical purity, but also have higher content.

Description

The preparation method of Moxifloxacin midbody (1S, 6R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane
Technical field
The present invention relates to the medicine intermediate production technical field, particularly a kind of Moxifloxacin midbody (1 S, 6 R)-8-benzyl-7,9-dioxy-2, the preparation method of 8-diazabicyclo [4.3.0] nonane.
Background technology
Moxifloxacin is a 8-methoxy fluoroquinolone class extensive pedigree antibiotic, is used to treat the adult of acute sinusitis, acute episode of chronic bronchitis, community acquired pneumonia respiratory tract infection, and skin and soft tissue infection.Went on the market in the Germany and the U.S. in 1999, went on the market in China in 2002.The chemical name of Moxifloxacin is 1-cyclopropyl-6-fluoro-8-methoxyl group-7-[(4a S, 7a S)-octahydro-6 H-pyrrolo-[3,4-b] pyridine-6-yl]-4-oxygen-1,4-dihydro quinoline-3-carboxylic acid hydrochloride.
Figure 116055DEST_PATH_IMAGE001
A kind of Moxifloxacin midbody (1 is disclosed in the U.S. Pat 6566523 S, 6 R)-8-benzyl-7,9-dioxy-2, the preparation method of 8-diazabicyclo [4.3.0] nonane is specially: cis-8-benzyl-7; 9-dioxy-2,8-diazabicyclo [4.3.0] nonane and (-)-2,3:4; 6-two isopropylidenes-2-ketone-L-gulonic acid (gulonic acid) monohydrate salify in butanone filter, and first-time filtrate adds hydrochloric acid and becomes hydrochloride; Filter, secondary filtrating is washed with ammoniacal liquor and saturated sodium-chloride water solution, organic phase concentrated (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane, optical purity 99.6% ee.The resolving agent price that this method is used is more expensive, consumption big (molecular weight is big), and resolving agent is unstable under acidic condition, is unfavorable for improving its recovery and causes resolving agent proportion in raw materials consumption big, and the sepn process complicated operation is made troubles to scale prodn; The product optical purity is high, but content is low, increases subsequent reactions purifying difficulty.
Summary of the invention
The objective of the invention is to solve the problems referred to above that prior art exists, a kind of Moxifloxacin midbody (1 is provided S, 6 R)-8-benzyl-7,9-dioxy-2, the preparation method of 8-diazabicyclo [4.3.0] nonane; It is more expensive to avoid the use of price, and molecular weight is big, unstable resolving agent (-)-2 under the acidic conditions; 3:4,6-two isopropylidenes-2-ketone-L-gulonic acid monohydrate, fractured operation is easy; Avoided the loaded down with trivial details purge process of subsequent reactions, product not only optical purity is high, and content is higher.
The technical solution adopted for the present invention to solve the technical problems is: a kind of Moxifloxacin midbody (1 S, 6 R)-8-benzyl-7; 9-dioxy-2, the preparation method of 8-diazabicyclo [4.3.0] nonane, described preparation method is: with the cis shown in the structural formula as I-8-benzyl-7; 9-dioxy-2; 8-diazabicyclo [4.3.0] nonane is a raw material, splits in resolution solvent with the resolving agent N-acetyl-L-leucine shown in the structural formula as I II, forms (1 shown in the structural formula as I V S, 6 R)-8-benzyl-7,9-dioxy-2, the crystallization of 8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt is filtered and wash crystallization; This crystallization is free in alkaline aqueous solution, and with toluene or dichloromethane extraction, organic phase is through drying; Filter, concentrating under reduced pressure, obtain structural formula shown in V (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane, preparation flow is as follows:
Figure 2011103232011100002DEST_PATH_IMAGE002
Raw material cis of the present invention-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane are shown in the structural formula as I I (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane and (1 R, 6 S)-8-benzyl-7,9-dioxy-2, the mixture that 8-diazabicyclo [4.3.0] nonane=1:1 forms,
Figure 95512DEST_PATH_IMAGE003
。
The used resolving agent of the present invention is from the acid resolving agent of different sorts cheap and easy to get, to screen to obtain.
As preferably, described fractionation is specially: earlier raw material is dissolved in the resolution solvent, adds resolving agent, heat up up to the reaction solution clarification, be cooled to-10 ~ 50 ℃ of crystallizations then, agitation condition insulation 12 ~ 24 hours down.Tc preferably is cooled to 10 ~ 30 ℃ of crystallizations.When the present invention split, raw material (compound shown in the structural formula I) was dissolved in resolution solvent, adds resolving agent; Intensification is clarified (after adding resolving agent up to reaction solution; Be warming up to solvent boiling point, the constant clarification of reaction solution then keeps reflux state number minute); Slowly cool to-10 ~ 50 ℃ of crystallizations then, agitation condition is incubated 12 ~ 24 hours down.
As preferably, the mol ratio of described raw material and resolving agent is 1:0.4 ~ 2.More preferably, the mol ratio of described raw material and resolving agent is 1:0.5 ~ 1.
As preferably; Described resolution solvent is a single organic solvent; Single organic solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, ETHYLE ACETATE, isopropyl acetate, n-butyl acetate, THF, methyltetrahydrofuran, 1; 4-dioxane, ether, MTBE, acetone, butanone, 4-methyl-2 pentanone, acetonitrile, toluene, methylene dichloride, 1; A kind of in the 2-ethylene dichloride, the consumption of described single organic solvent is that every 1g raw material adds 1 ~ 30ml single organic solvent.More preferred, the consumption of described single organic solvent is that every 1g raw material adds 3 ~ 10ml single organic solvent.
As preferably; Described resolution solvent is a mixed solvent; Mixed solvent is mixed with water by single organic solvent and forms; Single organic solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, ETHYLE ACETATE, isopropyl acetate, n-butyl acetate, THF, methyltetrahydrofuran, 1; 4-dioxane, ether, MTBE, acetone, butanone, 4-methyl-2 pentanone, acetonitrile, toluene, methylene dichloride, 1, a kind of in the 2-ethylene dichloride, the consumption of described mixed solvent is: the single organic solvent add-on is that every 1g raw material is with 1 ~ 30ml single organic solvent; The water add-on is raw material and water mol ratio 1:0.5 ~ 10, the mixed solvent amount that is combined to form.
During fractionation, the blending means of mixed solvent is: raw material (compound shown in the structural formula I) is dissolved in single organic solvent earlier, adds water again, adds resolving agent at last.
More preferred, the consumption of described mixed solvent is: the single organic solvent add-on be every 1g raw material with 3 ~ 10ml single organic solvent, the water add-on is raw material and water mol ratio 1:0.5 ~ 3, the mixed solvent amount that is combined to form.
As preferably, (1 shown in the structural formula as I V S, 6 R)-8-benzyl-7,9-dioxy-2, the crystallization of 8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt is with acetonitrile or THF recrystallization.Recrystallization can further improve (1 shown in the structural formula as I V S, 6 R)-8-benzyl-7,9-dioxy-2, the optical purity of 8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt makes that the chemical purity of product and optical purity are higher.
The invention has the beneficial effects as follows:
1, resolving agent is amino acid derivative, and is cheap and easy to get, molecular weight little (molecular weight=173.21); Consumption is few, and it is higher to avoid the use of price, big (molecular weight=292.28) resolving agent (-)-2 of molecular weight; 3:4; Therefore 6-two isopropylidenes-2-ketone-L-gulonic acid (gulonic acid) monohydrate can reduce raw materials consumption, thereby reduce production costs.
2, fractured operation is easy, directly obtains required configuration after the fractionation and gets (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine diastereoisomeric salt behind the recrystallization, can obtain the higher product of chemical purity and optical purity, avoids the loaded down with trivial details purge process of subsequent reactions.
3, be fit to large-scale production.
Embodiment
Below by specific embodiment, technical scheme of the present invention is further specified.
The raw materials used cis of the present invention-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane are pressed the preparation of 2004 3 phase 129-131 of Chinese Journal of Pharmaceuticals page or leaf report method.
One, preparation (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt
Figure DEST_PATH_IMAGE004
Method 1
5.00g (20.47mmol) cis-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane is in the 50ml reaction flask; Add the 15g acetonitrile, stirring at room is treated its whole dissolvings, adds 1.80g (10.39mmol) N-acetyl-L-leucine; Be warming up between 60-70 ℃ and reacted 10 minutes, solid all dissolves, and gets settled solution; Slowly be cooled to 27 ℃, have crystallization to separate out, stirred overnight under this temperature.Second day, filtration, reaction flask is cleaned with filtrating, and crystallization gets (1 with 4ml * 2 ETHYLE ACETATE washing S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt, weight in wet base 3.33g, 40 ℃ of drying under reduced pressure, heavy 3.18g, theoretical yield 74.42%, optical purity 97.61% ee.
Method 2 ~ 13
Operation is with method 1, and solvent load is: the 1g raw material is used the 5ml solvent, sees table 1 for details.
Table 1 method 2 ~ 13
Method Raw material Resolving agent The solvent title Solvent load Optical purity (ee) Product Yield
2 2g 0.72g Acetonitrile 10ml 98.78% 1.27g 74.31%
3 2g 0.72g Ethanol 10ml 88.53% 0.92g 53.83%
4 2g 0.72g N-propyl alcohol 10ml 97.22% 1.03g 60.27%
5 2g 0.72g Propyl carbinol 10ml 95.76% 1.04g 60.86%
6 2g 0.72g Virahol 10ml 92.03% 1.25g 73.14%
7 2g 0.72g ETHYLE ACETATE 10ml 96.27% 1.43g 83.68%
8 2g 0.72g Acetone 10ml 97.89% 1.24g 72.56%
9 2g 0.72g Butanone 10ml 97.01% 1.14g 66.71%
10 5g 1.76g Acetonitrile 25ml 96.92% 3.29g 77.01%
11 5g 1.76g THF 25ml 97.77% 2.90g 67.88%
12 2.0 0.72g Methyltetrahydrofuran 10ml 94.25% 1.39g 81.34%
13 5g 1.76g Acetonitrile 25ml 96.79% 3.12g 73.03%
Annotate: raw material is cis-8-benzyl-7,9-dioxy-2, and 8-diazabicyclo [4.3.0] nonane, resolving agent are N-acetyl-L-leucine, product is (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt.
Method 14 ~ 27
Operation is with method 1, only increases solvent load to be: the 1g raw material is used the 10ml solvent, sees table 2 for details.
Table 2 method 14 ~ 27
Method Raw material Resolving agent The solvent title Solvent load Optical purity (ee) Product Yield
14 2.0g 0.72g Ethanol 20ml 97.68% 0.59g 34.52%
15 2.0g 0.72g N-propyl alcohol 20ml 96.01% 0.75g 43.89%
16 2.0g 0.72g Propyl carbinol 20ml 94.43% 0.88g 51.49%
17 2.0g 0.72g Virahol 20ml 93.82% 1.08g 63.20%
18 2.0g 0.72g THF 20ml 15.59% 0.76g 44.47%
19 2.0g 0.72g Dioxane 20ml 53.88% 0.67g 39.21%
20 2.0g 0.72g ETHYLE ACETATE 20ml 86.20% 1.17g 68.46%
21 2.0g 0.72g Acetonitrile 20ml 97.64% 1.04g 60.86%
22 2.0g 0.72g Acetone 20ml 95.23% 1.03g 60.27%
23 2.0g 0.72g Butanone 20ml 95.27% 1.15g 67.29%
24 2.0g 0.72g 4-methyl-2 pentanone 20ml 86.24% 1.44g 84.26%
25 2.0g 0.72g Toluene 20ml 93.64% 1.23g 71.97%
26 2.0g 0.72g Isopropyl acetate 20ml 87.65% 1.44g 84.26%
27 2.0g 0.72g N-butyl acetate 20ml 96.11% 1.47g 86.02%
Annotate: raw material is cis-8-benzyl-7,9-dioxy-2, and 8-diazabicyclo [4.3.0] nonane, resolving agent are N-acetyl-L-leucine, product is (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt.
Method 28 ~ 45
Operation is with method 1, and solvent load is: the 1g raw material is with 5ml solvent or 10ml solvent, and water consumption is: the 1g raw material is a 0.1g water, sees table 3 for details.
Table 3 method 28 ~ 45
Embodiment Raw material Resolving agent Water The solvent title Solvent load Optical purity (ee) Product Yield
28 2g 0.72g 0.2g Acetonitrile 10ml 100% 0.94g 55.00%
29 2g 0.72g 0.2g THF 10ml 99.39% 0.62g 36.28%
30 2g 0.72g 0.2 Methyltetrahydrofuran 10ml 98.99% 1.18g 69.05%
31 2g 0.72g 0.2g Ethanol 10ml 99.32% 0.58g 33.94%
32 2g 0.72g 0.2g N-propyl alcohol 10ml 97.91% 0.63g 36.86%
33 2g 0.72g 0.2g Propyl carbinol 10ml 98.85% 0.77g 45.06%
34 2g 0.72g 0.2g Virahol 10ml 98.03% 0.98g 57.34%
35 2g 0.72g 0.2g ETHYLE ACETATE 10ml 99.03% 1.22g 71.39%
36 2g 0.72g 0.2g Isopropyl acetate 20ml 96.85% 1.26g 73.73%
37 2g 0.72g 0.2g N-butyl acetate 20ml 97.04% 1.29g 75.48%
38 2g 0.72g 0.2g Acetone 10ml 97.46% 1.16g 67.88%
39 2g 0.72g 0.2g Toluene 10ml 82.41% 1.22g 71.39%
40 2g 0.72g 0.2g MTBE 10ml 65.03% 1.71g 100.06%
41 2g 0.72g 0.2g Dioxane 10ml 98.97% 0.73g 42.72%
42 2g 0.72g 0.2g Butanone 10ml 83.07% 1.31g 76.65%
43 2g 0.72g 0.2g Methylene dichloride 10ml 98.75% 0.95g 55.59%
44 2g 0.72g 0.2g Ethylene dichloride 10ml 98.37% 1.18g 69.05%
45 2g 0.72g 0.2g 4-methyl-2 pentanone 10ml 83.74% 1.34g 78.41%
Annotate: raw material is cis-8-benzyl-7,9-dioxy-2, and 8-diazabicyclo [4.3.0] nonane, resolving agent are N-acetyl-L-leucine, product is (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt.
Method 46
10.03g (41.06mmol) cis-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane is in the 250ml reaction flask; Add the 80ml n-butyl acetate, stirring at room is treated its whole dissolvings, adds 3.55g (20.49mmol) N-acetyl-L-leucine; Be warming up to 120 ℃, the reaction solution clarification slowly is cooled to 40 ℃; There is mass crystallization to separate out, continues 25 ℃ of coolings, stirred overnight.Second day, filtration, reaction flask is cleaned with filtrating, and crystallization is drained with the washing of 6g n-butyl acetate, gets (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt, weight in wet base 7.31g, 40 ℃ of drying under reduced pressure, heavy 7.28g, theoretical yield 84.94%, optical purity 92.63% ee.
Method 47
20.00g (81.87mmol) cis-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane is in the 250ml reaction flask; Add the 60ml acetonitrile, stirring at room is treated its whole dissolvings, adds 2g water and 7.10g (40.99mmol) N-acetyl-L-leucine; Be warming up between 70-80 ℃, treat that solid all dissolves, slowly be cooled to 40 ℃; There is mass crystallization to separate out, continues 30 ℃ of coolings, stirred overnight.Second day, reaction solution stirred 50min in 20-25 ℃, filters, and reaction flask is cleaned with filtrating, and crystallization is drained with the washing of 15ml acetonitrile, gets (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt, weight in wet base 12.61g, 60 ℃ of drying under reduced pressure, heavy 12.36g, mp 147.6-148.1 ℃, theoretical yield 72.32%, optical purity 99.02% ee.
Two, preparation (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane
Figure 875249DEST_PATH_IMAGE005
Embodiment 1
10.00g (40.94mmol) cis-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane is in the 250ml reaction flask; Add the 100ml isopropyl acetate, stirring at room is treated its whole dissolvings, adds 4.25g (24.54mmol) N-acetyl-L-leucine; Be warming up between 70-80 ℃ and reacted 40 minutes, slowly be cooled to 40 ℃, have crystallization to separate out; Continue 25 ℃ of coolings, stirred overnight.Second day, filtration, reaction flask is cleaned with filtrating, and crystallization gets (1 with 4g * 2 isopropyl acetates washing S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt, weight in wet base 7.80g, 40 ℃ of drying under reduced pressure, heavy 7.75g, theoretical yield 90.69%, optical purity 95.05% ee.
The above-mentioned 7.75g that obtains (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt, with 44g acetonitrile recrystallization, the heavy 6.31g of 40 ℃ of drying under reduced pressure of gained crystallization, total recovery 73.84%, optical purity 99.49% ee.
Embodiment 2
(1 of embodiment 1 preparation S, 6 R)-8-benzyl-7,9-dioxy-2 in the floating outstanding 15g methylene dichloride of 8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt 6.31g (15.11mmol), adds 16g water and 1.5g NaHCO 3, two all clarifications are mutually treated in 31 ℃ of stirrings, tell organic phase, water is with 5g * 2 dichloromethane extraction.Merge organic phase, the 5g anhydrous sodium sulfate drying filters, the 5g washed with dichloromethane, and the gained filtrate decompression reclaims methylene dichloride, gets product (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane 3.44g, [α] D 20=-24.4 (c=0.005, ethanol), optical purity 99.31%ee.
1HNMR?(CDCl 3,?MHz)?δppm:?7.23-7.34?(m,?5H),?4.62?(s,?2H),?3.79-3.81?(d,?1H),?2.79-2.85?(dd,?1H),?2.73-2.78?(m,1H),?2.61-2.67?(m,?1H),?2.16?(br?s,?1H),?1.89-1.97?(m,?1H),?1.59-1.68?(m,?1H),?1.45-1.51?(m,2H).
13CNMR?(CDCl 3,?MHz)?δppm:?177.92,?177.76,?135.83,?128.61,?128.41,?127.80,?55.37,?42.29,?42.07,?39.21,?22.99,?22.35.
Embodiment 3
Method 46 preparations (1 S, 6 R)-8-benzyl-7,9-dioxy-2 in the floating outstanding 15g toluene of 8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt 7.27g (17.41mmol), adds 16g water and 1.6 g NaHCO 3, two all clarifications are mutually treated in 30 ℃ of stirrings, tell organic phase, water is with 5g * 2 methylbenzene extraction.Merge organic phase, the 5g anhydrous sodium sulfate drying filters, and uses the 4.5g toluene wash, and the gained filtrate decompression reclaims toluene, gets product (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane 4.26g, optical purity: 92.63%ee.
Embodiment 4
The 3.18g (1 of method 1 preparation S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt dissociates according to embodiment 3 methods and obtains (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane 1.82g, optical purity 97.61% ee.
Embodiment 5
2g cis-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane is in the 25ml reaction flask; Add 10ml ETHYLE ACETATE, stir and treat its whole dissolvings, add 0.72g N-acetyl-L-leucine; Be warming up to backflow, slowly be cooled to room temperature, stirred overnight then.Second day, filter, get crystallization, with the amount of ethyl acetate washing, get (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt, drying, heavy 1.43g, optical purity 96.27% ee.
1.43g (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt dissociates according to embodiment 3 methods and obtains (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane 0.82g, optical purity 96.27% ee.
Embodiment 6
2g cis-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane adds the 20ml butanone in the 50ml reaction flask, stir and treat its whole dissolvings, adds 0.72g N-acetyl-L-leucine, and intensification 60-70 C slowly is cooled to room temperature, stirred overnight then.Second day, filter, get crystallization, with a small amount of butanone washing, get (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt, drying, heavy 1.15g, optical purity 95.27% ee.
1.15g (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt dissociates according to embodiment 3 methods and obtains (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane 0.64g, optical purity 95.27% ee.
Embodiment 7
2g cis-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane is in the 25ml reaction flask; Add the 10ml methyltetrahydrofuran, stir and treat its whole dissolvings, add 0.2g water and 0.72g N-acetyl-L-leucine; Be warming up to backflow, slowly be cooled to room temperature, stirred overnight then.Second day, filter, get crystallization, with a small amount of methyltetrahydrofuran washing, get (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt, drying, heavy 1.18g, optical purity 98.99% ee.
1.18g (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt dissociates according to embodiment 3 methods and obtains (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane 0.67g, optical purity 98.99% ee.
The mensuration reference Tetrahedron:Asymmetry of optical purity, 2011,22,379 – 380.
Prepare target compound (1 by U.S. Pat 6566523 report methods S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane and the inventive method preparing product carry out chirality HPLC and analyze, and both RTs are consistent, confirm the product configuration.
Above-described embodiment is a kind of preferable scheme of the present invention, is not that the present invention is done any pro forma restriction, under the prerequisite that does not exceed the technical scheme that claim puts down in writing, also has other variant and remodeling.

Claims (9)

1. Moxifloxacin midbody (1 S, 6 R)-8-benzyl-7; 9-dioxy-2, the preparation method of 8-diazabicyclo [4.3.0] nonane, it is characterized in that: described preparation method is: with the cis shown in the structural formula as I-8-benzyl-7; 9-dioxy-2; 8-diazabicyclo [4.3.0] nonane is a raw material, splits in resolution solvent with the resolving agent N-acetyl-L-leucine shown in the structural formula as I II, forms (1 shown in the structural formula as I V S, 6 R)-8-benzyl-7,9-dioxy-2, the crystallization of 8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt is filtered and wash crystallization; This crystallization is free in alkaline aqueous solution, and with toluene or dichloromethane extraction, organic phase is through drying; Filter, concentrating under reduced pressure, obtain structural formula shown in V (1 S, 6 R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane, preparation flow is as follows:
Figure DEST_PATH_IMAGE002
Described fractionation is specially: earlier raw material is dissolved in the resolution solvent, adds resolving agent, heat up up to the reaction solution clarification, be cooled to-10 ~ 50 ℃ of crystallizations then, insulation is 12 ~ 24 hours under the agitation condition.
2. preparation method according to claim 1 is characterized in that: be cooled to 10 ~ 30 ℃ of crystallizations.
3. preparation method according to claim 1 and 2 is characterized in that: the mol ratio of described raw material and resolving agent is 1:0.4 ~ 2.
4. preparation method according to claim 3 is characterized in that: the mol ratio of described raw material and resolving agent is 1:0.5 ~ 1.
5. preparation method according to claim 1 and 2; It is characterized in that: described resolution solvent is a single organic solvent; Single organic solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, ETHYLE ACETATE, isopropyl acetate, n-butyl acetate, THF, methyltetrahydrofuran, 1; 4-dioxane, ether, MTBE, acetone, butanone, 4-methyl-2 pentanone, acetonitrile, toluene, methylene dichloride, 1; A kind of in the 2-ethylene dichloride, the consumption of described single organic solvent is that every 1g raw material adds 1 ~ 30ml single organic solvent.
6. preparation method according to claim 5 is characterized in that: the consumption of described single organic solvent is that every 1g raw material adds 3 ~ 10ml single organic solvent.
7. preparation method according to claim 1 and 2; It is characterized in that: described resolution solvent is a mixed solvent; Mixed solvent is mixed with water by single organic solvent and forms; Single organic solvent is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, ETHYLE ACETATE, isopropyl acetate, n-butyl acetate, THF, methyltetrahydrofuran, 1; 4-dioxane, ether, MTBE, acetone, butanone, 4-methyl-2 pentanone, acetonitrile, toluene, methylene dichloride, 1, a kind of in the 2-ethylene dichloride, the consumption of described mixed solvent is: the single organic solvent add-on is that every 1g raw material is with 1 ~ 30ml single organic solvent; The water add-on is raw material and water mol ratio 1:0.5 ~ 10, the mixed solvent amount that is combined to form.
8. preparation method according to claim 7; It is characterized in that: the consumption of described mixed solvent is: the single organic solvent add-on is that every 1g raw material is with 3 ~ 10ml single organic solvent; The water add-on is raw material and water mol ratio 1:0.5 ~ 3, the mixed solvent amount that is combined to form.
9. preparation method according to claim 1 and 2 is characterized in that: (1 shown in the structural formula as I V S, 6 R)-8-benzyl-7,9-dioxy-2, the crystallization of 8-diazabicyclo [4.3.0] nonane N-acetyl-L-leucine salt is with acetonitrile or THF recrystallization.
CN 201110323201 2011-10-22 2011-10-22 Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane Active CN102408427B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 201110323201 CN102408427B (en) 2011-10-22 2011-10-22 Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 201110323201 CN102408427B (en) 2011-10-22 2011-10-22 Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane

Publications (2)

Publication Number Publication Date
CN102408427A CN102408427A (en) 2012-04-11
CN102408427B true CN102408427B (en) 2012-12-12

Family

ID=45910813

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 201110323201 Active CN102408427B (en) 2011-10-22 2011-10-22 Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane

Country Status (1)

Country Link
CN (1) CN102408427B (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103030638B (en) * 2012-11-29 2014-12-24 中国科学院成都生物研究所 Preparation method of (S, S)-8H-6H-pyrrolo [3, 4-b] pyridine
CN103865976B (en) * 2014-03-19 2016-01-20 杭州师范大学 A kind of biological chemistry splits the method for 8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane
CN104163821B (en) * 2014-03-27 2016-05-18 江苏永达药业有限公司 A kind of preparation method of diazabicyclo compounds
CN114085219B (en) * 2020-08-25 2023-08-01 武汉理工大学 Synthesis of (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane
CN112707901B (en) * 2020-12-07 2022-03-22 泰安汉威集团有限公司 Preparation method of compound A
CN112920184B (en) * 2021-02-06 2022-03-01 台州市生物医化产业研究院有限公司 Method for preparing moxifloxacin intermediate (S, S) -2, 8-diazabicyclo [4,3,0] nonane

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1074218A (en) * 1992-01-10 1993-07-14 拜尔公司 Quinolonecarboxylic acid and naphthalene piperidine ketone acid derivant
US6566523B1 (en) * 1999-06-16 2003-05-20 Bayer Aktiengesellschaft Method for the enantiomer separation of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane
CN101591336A (en) * 2009-06-25 2009-12-02 浙江燎原药业有限公司 8-benzyl-2, the method for reducing of 8-diazabicyclo [4,3,0] nonane and chiral isomer thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1074218A (en) * 1992-01-10 1993-07-14 拜尔公司 Quinolonecarboxylic acid and naphthalene piperidine ketone acid derivant
US6566523B1 (en) * 1999-06-16 2003-05-20 Bayer Aktiengesellschaft Method for the enantiomer separation of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane
CN101591336A (en) * 2009-06-25 2009-12-02 浙江燎原药业有限公司 8-benzyl-2, the method for reducing of 8-diazabicyclo [4,3,0] nonane and chiral isomer thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
徐丹丹等.莫西沙星中间体的合成.《精细与专用化学品》.2011,第19卷(第1期),43-44.
莫西沙星中间体的合成;徐丹丹等;《精细与专用化学品》;20110131;第19卷(第1期);43-44 *

Also Published As

Publication number Publication date
CN102408427A (en) 2012-04-11

Similar Documents

Publication Publication Date Title
CN102408427B (en) Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane
CN106866553B (en) Synthesis method of Favipiravir
EA018227B1 (en) A method for the preparation of dabigatran and its intermediates
CN105732765B (en) The novel synthesis of hepatitis drug Wei Patawei
CN109912624A (en) A kind of synthetic method of Ba Luoshawei ester key parent nucleus intermediate
WO2011055188A1 (en) An improved process for the preparation of iloperidone
CN106256824A (en) A kind of preparation method of high-purity De Lasha star meglumine salt
CN113214320A (en) Preparation method of Reidesciclovir compound
CN114957101A (en) Synthesis method of 3-aryl substituted dipiperidinone and nilapali
CN107406444A (en) A kind of Preparation Method And Their Intermediate compound of praziquantel
CN103450201B (en) Preparation method of chiral 8-(3-aminopiperidine-1-yl)-xanthine
CN106883227B (en) The method for preparing ergometrine by ergot fermentation waste
CN103562207B (en) For preparing the preparation method of 2-amino-9-((2-phenyl-1,3-dioxane-5-base epoxide) methyl)-1H-purine-6 (9H) the-one compound of valganciclovir
CN114478658A (en) Synthesis method of monatibavir
CN105017147A (en) Method for recycling and utilizing Bedaquiline stereochemical isomers
CN105384654B (en) A kind of crystallization purifications of hydroxyalkyl amide
CN110804022B (en) Preparation method of dexrazoxane
CN106117104A (en) A kind of preparation method of vildagliptin
CN102757414B (en) Preparation method of eseitalopram oxalate
CN105131050A (en) Preparation method of chlorinating agent and method therewith for preparing sucralose
CN104910183B (en) A kind of synthetic method of flucloxacillin sodium-hydrate
CN115536558B (en) Refining process of bumetanide crude product
CN103012264A (en) Method for resolving 3-substituted amino-hexahydro-1H-azacycloheptane
CN111100144B (en) Synthesis process of cefathiamidine
CN104163821A (en) Diazabicyclo compound preparation method

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
ASS Succession or assignment of patent right

Owner name: SHANGHAI YUYUAN BIO-PHARMACEUTICAL RESEARCH + DEVE

Free format text: FORMER OWNER: SHANGHAI APELOA PHARMACEUTICAL INSTITUTE CO., LTD.

Effective date: 20131205

C41 Transfer of patent application or patent right or utility model
TR01 Transfer of patent right

Effective date of registration: 20131205

Address after: 322118, 333 Jiangnan Road, Dongyang, Zhejiang, Jinhua, Hengdian

Patentee after: ZHEJIANG APELOA KANGYU PHARMACEUTICAL Co.,Ltd.

Patentee after: SHANGHAI YUYUAN BIOLOGICAL MEDICINE RESEARCH AND DEVELOPMENT Co.,Ltd.

Address before: 322118, 333 Jiangnan Road, Dongyang, Zhejiang, Jinhua, Hengdian

Patentee before: ZHEJIANG APELOA KANGYU PHARMACEUTICAL Co.,Ltd.

Patentee before: SHANGHAI APELOA PHARMACEUTICAL RES Co.,Ltd.

TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20221008

Address after: 322118 No.333 Jiangnan Road, Hengdian, Dongyang City, Jinhua City, Zhejiang Province

Patentee after: ZHEJIANG APELOA KANGYU PHARMACEUTICAL Co.,Ltd.

Patentee after: Shanghai Puluochuangzhi Pharmaceutical Technology Co.,Ltd.

Patentee after: APELOA PHARMACEUTICAL CO.,LTD.

Address before: 322118 No.333 Jiangnan Road, Hengdian, Dongyang City, Jinhua City, Zhejiang Province

Patentee before: ZHEJIANG APELOA KANGYU PHARMACEUTICAL Co.,Ltd.

Patentee before: SHANGHAI YUYUAN BIOLOGICAL MEDICINE RESEARCH AND DEVELOPMENT Co.,Ltd.