CN102675307A - Method for preparing chiral compound 8-phenethyl-2,8-diazabicyclo[4.3.0]nonane - Google Patents
Method for preparing chiral compound 8-phenethyl-2,8-diazabicyclo[4.3.0]nonane Download PDFInfo
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- CN102675307A CN102675307A CN2011100643479A CN201110064347A CN102675307A CN 102675307 A CN102675307 A CN 102675307A CN 2011100643479 A CN2011100643479 A CN 2011100643479A CN 201110064347 A CN201110064347 A CN 201110064347A CN 102675307 A CN102675307 A CN 102675307A
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- nonane
- diazabicylo
- styroyl
- chipal compounds
- metal
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Abstract
The invention discloses a method for synthesizing an intermediate chiral compound 8-phenethyl-2,8-diazabicyclo[4.3.0]nonane of moxifloxacin side chain (S,S)-2,8-diazabicyclo[4.3.0]nonane. The method comprises the following steps of: taking a chiral compound 8-phenethyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]naonane as a raw material and adopting a metal boron hydride-metal halide MXn reduction system to react; and reducing carbonyl to obtain a target product. Due to the adoption of the metal boron hydride-metal halide MXn reduction system, lithium aluminum hydride which serves as a reducing agent and is high in price and is dangerous for producing and operating is avoided, production cost is lowered, production safety is enhanced, and an economic and safe synthesizing route is provided for the industrial production of the moxifloxacin side chain (S,S)-2,8-diazabicyclo[4.3.0]nonane.
Description
Technical field
The present invention relates to pharmaceutical chemistry and organic synthesis field, be specifically related to a kind of preparation method of quinolones anti-infectives key intermediate.
Background technology
Moxifloxacin (moxifloxacin); Chemistry 1-cyclopropyl by name-6-fluoro-8-methoxyl group-7-([S; S]-2,8-diazabicylo [4.3.0] nonanal-8-group]-4-oxo-1,4-dihydro-3-quinoline carboxylic acid; Be Bayer A.G exploitation the 4th generation fluoroquinolone antibiotics, its hydrochloride of clinical usefulness VI.Moxifloxacin all has very strong anti-microbial activity to common respiratory tract germ like streptococcus pneumoniae, bloodthirsty hemophilus influenza, catarrh Mo Lahan bacterium and part streptococcus aureus, and particularly to streptococcus pneumoniae, anti-microbial effect is powerful.At present Moxifloxacin is mainly used in the acute aggravation patient, chronic obstructive pulmonary disease, CAP, acute bacterial sinusitis of chronic bronchitis etc.; This medical instrument has the favorable tissue penetration power; In lung tissue, also can reach very high density, so result of treatment is good, short treating period.Moxifloxacin in September, 1999 first in Germany listing, go on the market in the U.S. December in the same year, went on the market in China in 2002.Moxifloxacin hydrochloride IV be by (S, S)-2,8-diazabicylo [4.3.0] nonane V and 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-4-oxos-1,4-dihydro-3-quinoline carboxylic acid VI two portions coupling, and handle and get through ethanol solution hydrochloride.
Chirality cis 8-styroyl-2,8-diazabicylo [4.3.0] nonane I I are synthetic Moxifloxacin side chains [S, S]-2; One of midbody of 8-diazabicylo [4.3.0] nonane V; Synthetic route has been described by Japan KANEKA company in the patent WO2010122774 of their application: chipal compounds 8-styroyl-pyrrolo-[3,4-b] pyridine-5, and 7-diketone III is through palladium carbon catalytic reduction; Obtain having necessarily optionally chipal compounds 8-styroyl-7; 9-dioxo-2,8-diazabicylo [4.3.0] nonane I, recrystallization obtains the compound I of high d.e. value; Reduction obtains chirality cis 8-styroyl-2,8-diazabicylo [4.3.0] nonane II through lithium aluminium hydride then.
Above route relates to and uses lithium aluminium hydride to come reducing carbonyl as reductive agent, because the lithium aluminium hydride price is more expensive, and exists higher danger on using, is unfavorable for amplifying and produces, thereby make its utilization in industriallization be restricted.Therefore seek a kind of lower operational danger that has, and can efficiently reduce, and be applicable to that industrial substitute is necessary.
Summary of the invention
The technical problem that the present invention will solve is to provide a kind of preparation chirality cis 8-styroyl-2; The method of 8-diazabicylo [4.3.0] nonane; To avoid using price more expensive in process of production; The chemical reagent lithium aluminium hydride of high risk is for the industrialization of Moxifloxacin side chain provides a competitive synthetic route that cost is low, safe.
For solving technique scheme, the present invention adopts following technical scheme: with the chipal compounds 8-styroyl-7 shown in the structural formula I, and 9-dioxo-2,8-diazabicylo [4.3.0] nonane is a raw material, adopts metal hydroboration thing and metal halide MX
nReduction system reduces, and obtains chirality cis 8-styroyl-2,8-diazabicylo [4.3.0] nonane II.
The present invention adopts metal hydroboration thing and metal halide MX
nReduction system is to raw material chipal compounds 8-styroyl-7,9-dioxo-2, and 8-diazabicylo [4.3.0] nonane reduces, metal hydroboration thing and metal halide MX
nIn the reduction system, metal hydroboration thing recommends to use Peng Qinghuana and POTASSIUM BOROHYDRIDE 97MIN, preferred POTASSIUM BOROHYDRIDE 97MIN.Metal halide MX
nCan be LiCl, LiBr, LiI, MgCl
2, MgBr
2, AlCl
3, CaCl
2, ZnCl
2, ZrCl
4, CoCl
2In any one, preferred AlCl
3In reaction process, metal hydroboration thing (Peng Qinghuana and POTASSIUM BOROHYDRIDE 97MIN) at first with metal halide MX
nReaction generates active higher metal hydroboration thing (MBH
n, M=Li, Mg, Al; Ca, Zn, Zr, Co); Highly active then metal hydroboration thing is raw material chipal compounds 8-styroyl-7,9-dioxo-2, and 8-diazabicylo [4.3.0] nonane is reduced into chirality cis 8-styroyl-2,8-diazabicylo [4.3.0] nonane.Metal hydroboration thing and metal halide MX
nReaction equation (is example with POTASSIUM BOROHYDRIDE 97MIN and aluminum chloride) as follows:
3KBH
4+AlCl
3→Al(BH
4)
3+3KCl
The present invention recommends raw material chipal compounds 8-styroyl-7,9-dioxo-2,8-diazabicylo [4.3.0] nonane, metal borohydride and metal halide MX when feeding intake
nMolar feed ratio be 1: 1～10: 1～10, preferred molar feed ratio is 1: 2～6: 2～6.
Reduction reaction according to the invention is carried out in inert organic solvents, and this solvent not to be to exert an influence to good to reduction reaction, such as using ethers or varsol, and perhaps their mixture arbitrarily.When using the mixed solvent of ethers and hydro carbons, their volume ratio is not done special requirement.
It is one of following that described ether solvent can be selected from: ether, isopropyl ether, THF, 2-methyltetrahydrofuran, MTBE, glycol dimethyl ether.Preferred solvent is THF, 2-methyltetrahydrofuran and glycol dimethyl ether.
It is one of following that described varsol can be selected from: sherwood oil, normal hexane, hexanaphthene, normal heptane, benzene,toluene,xylene.Preferred solvent is a toluene.
Reduction reaction according to the invention is in-10～150 ℃ TR, to carry out, and preferred range is 0～80 ℃.Reaction times carried out in the scope at 5～72 hours, and preferred time range is 10～36 hours.
Described reduction reaction process can be operated according to ordinary method; Generally can carry out: in reaction vessel, add raw material chipal compounds 8-styroyl-7 according to following steps; 9-dioxo-2; 8-diazabicylo [4.3.0] nonane and inert organic solvents, controlled temperature add metal borohydride and metal halide MX then successively at 0～10 ℃
n, after adding, the insulated and stirred certain hour is warming up to 50～60 ℃ then, insulation reaction 10～36 hours; Reaction finishes, cool to room temperature, and dripping hydrochloric acid solution then, controlled temperature dropwises at 0～20 ℃; Be warming up to 30～40 ℃, insulation reaction 1～2 hour is cooled to room temperature, filters, and filtrate decompression concentrates; To wherein adding toluene and aqueous sodium hydroxide solution stirring reaction, leave standstill then, the separatory layer that anhydrates, organic layer is through washing; Drying is filtered, and concentrating under reduced pressure obtains corresponding title product chirality cis 8-styroyl-2,8-diazabicylo [4.3.0] nonane.
Compared with prior art, advantage of the present invention is:
The present invention adopts metal hydroboration thing and metal halide MX
nReduction system is to chipal compounds 8-styroyl-7,9-dioxo-2, and 8-diazabicylo [4.3.0] nonane reduces, and has avoided expensive, and the reagent lithium aluminium hydride that production operation is dangerous has not only reduced production cost, and has improved the security of producing.(S, S)-2, the suitability for industrialized production of 8-diazabicylo [4.3.0] nonane provides more economical, a safer synthetic route for the Moxifloxacin side chain.
Embodiment
With specific embodiment technical scheme of the present invention is done further explanation below, but protection scope of the present invention is not limited thereto:
Embodiment 1
In 250mL four-hole reaction flask, add chipal compounds 8-styroyl-7,9-dioxo-2,8-diazabicylo [4.3.0] nonane 10g (0.039mol), THF 100mL are cooled to 0 ℃, add POTASSIUM BOROHYDRIDE 97MIN 6.31g (0.117mol); Aluminum chloride 5.20g (0.039mol) keeps stirring 2 hours under 0～10 ℃ of the temperature, is warming up to 55 ℃ then, insulation reaction 10 hours; Reaction finishes, and cool to room temperature drips 2N hydrochloric acid soln 50mL then, and controlled temperature is at 0～20 ℃; Dropwise, be warming up to 50～80 ℃, insulation reaction 2 hours is cooled to room temperature; Filter and remove the white solid inorganic salt, filtrate decompression concentrates, then to wherein adding 50mL toluene and 2N aqueous sodium hydroxide solution 50mL, stirring reaction 1 hour; Leave standstill, the separatory layer that anhydrates, organic layer with the 50mL purified water through washing once stir dry with SODIUM SULPHATE ANHYDROUS 99PCT; Filter, filtrate decompression is concentrated into dried, obtains corresponding title product colorless oil chipal compounds 8-styroyl-2,8-diazabicylo [4.3.0] nonane 8.25g (0.036mol); Yield 93%, HPLC purity 99%, 99.2%d.e. value, ultimate analysis: Calcd for C
15H
21N
2: C, 78.56%; H, 9.23%; N, 12.21%; Found:C, 78.54%; H, 9.26%; N, 12.20%.
Embodiment 2
In 250mL four-hole reaction flask, add chipal compounds 8-styroyl-7,9-dioxo-2,8-diazabicylo [4.3.0] nonane 10g (0.039mol), THF 100mL are cooled to 0 ℃, add Peng Qinghuana 4.43g (0.117mol); Aluminum chloride 5.20g (0.039mol) keeps stirring 2 hours under 0～10 ℃ of the temperature, is warming up to 55 ℃ then, insulation reaction 10 hours; Reaction finishes, and cool to room temperature drips 2N hydrochloric acid soln 50mL then, and controlled temperature is at 0～20 ℃; Dropwise, be warming up to 50～80 ℃, insulation reaction 2 hours is cooled to room temperature; Filter and remove the white solid inorganic salt, filtrate decompression concentrates, then to wherein adding 50mL toluene and 2N aqueous sodium hydroxide solution 50mL, stirring reaction 1 hour; Leave standstill, the separatory layer that anhydrates, organic layer with the 50mL purified water through washing once stir dry with SODIUM SULPHATE ANHYDROUS 99PCT; Filter, filtrate decompression is concentrated into dried, obtains corresponding title product colorless oil chipal compounds 8-styroyl-2,8-diazabicylo [4.3.0] nonane 7.87g (0.034mol); Yield 88%, HPLC purity 95%, 98.9%d.e. value, ultimate analysis: Calcd for C
15H
21N
2: C, 78.56%; H, 9.23%; N, 12.21%; Found:C, 78.58%; H, 9.25%; N, 12.17%.
Embodiment 3
Metal halide aluminum chloride among the embodiment 1 is replaced with zinc dichloride 7.97g (0.059mol); Other operations are all identical, also obtain colorless oil chipal compounds 8-styroyl-2,8-diazabicylo [4.3.0] nonane 6.80g (0.030mol); Yield 76%; HPLC purity 94%, 98.7%d.e. value, ultimate analysis: Calcd for C
15H
21N
2: C, 78.56%; H, 9.23%; N, 12.21%; Found:C, 78.52%; H, 9.21%; N, 12.27%.
Embodiment 4
Metal halide aluminum chloride among the embodiment 1 is replaced with lithium chloride 7.97g (0.059mol); Other operations are all identical, also obtain colorless oil chipal compounds 8-styroyl-2,8-diazabicylo [4.3.0] nonane 7.51g (0.033mol); Yield 84%; HPLC purity 95%, 97.9%d.e. value, ultimate analysis: Calcd for C
15H
21N
2: C, 78.56%; H, 9.23%; N, 12.21%; Found:C, 78.59%; H, 9.18%; N, 12.23%.
Embodiment 5
Solvents tetrahydrofurane among the embodiment 1 is replaced with the 2-methyltetrahydrofuran; Other operations are all identical, also obtain colorless oil chipal compounds 8-styroyl-2,8-diazabicylo [4.3.0] nonane 8.05g (0.035mol); Yield 90%; HPLC purity 94%, 98.2%d.e. value, ultimate analysis: Calcd for C
15H
21N
2: C, 78.56%; H, 9.23%; N, 12.21%; Found:C, 78.59%; H, 9.18%; N, 12.23%.
Embodiment 6
Solvents tetrahydrofurane among the embodiment 1 is replaced with glycol dimethyl ether; Other operations are all identical, also obtain colorless oil chipal compounds 8-styroyl-2,8-diazabicylo [4.3.0] nonane 7.16g (0.031mol); Yield 80%; HPLC purity 96%, 99.1%d.e. value, ultimate analysis: Calcd for C
15H
21N
2: C, 78.56%; H, 9.23%; N, 12.21%; Found:C, 78.60%; H, 9.24%; N, 12.16%.
Embodiment 7
Solvents tetrahydrofurane among the embodiment 1 is replaced with toluene; Other operations are all identical, also obtain colorless oil chipal compounds 8-styroyl-2,8-diazabicylo [4.3.0] nonane 7.51g (0.033mol); Yield 84%; HPLC purity 98%, 98.5%d.e. value, ultimate analysis: Calcd for C
15H
21N
2: C, 78.56%; H, 9.23%; N, 12.21%; Found:C, 78.50%; H, 9.20%; N, 12.30%.
Embodiment 8
Solvents tetrahydrofurane among the embodiment 1 is replaced with THF and toluene; Other operations are all identical, also obtain colorless oil chipal compounds 8-styroyl-2,8-diazabicylo [4.3.0] nonane 7.87g (0.034mol); Yield 88%; HPLC purity 95%, 96.1%d.e. value, ultimate analysis: Calcd for C
15H
21N
2: C, 78.56%; H, 9.23%; N, 12.21%; Found:C, 78.52%; H, 9.27%; N, 12.21%.
Embodiment 9
Solvents tetrahydrofurane among the embodiment 1 is replaced with 2-methyltetrahydrofuran and toluene; Other operations are all identical, also obtain colorless oil chipal compounds 8-styroyl-2,8-diazabicylo [4.3.0] nonane 7.16g (0.031mol); Yield 80%; HPLC purity 96%, 97.5%d.e. value, ultimate analysis: Calcd for C
15H
21N
2: C, 78.56%; H, 9.23%; N, 12.21%; Found:C, 78.55%; H, 9.26%; N, 12.19%.
Claims (9)
1. one kind prepares chipal compounds 8-styroyl-2; The method of 8-diazabicylo [4.3.0] nonane, with structural formula suc as formula the chipal compounds 8-styroyl-7 shown in the I, 9-dioxo-2; 8-diazabicylo [4.3.0] nonane is a raw material, adopts metal borohydride and metal halide MX
nReduction system reacts, and obtains structure suc as formula the chipal compounds 8-styroyl-2 shown in the II, 8-diazabicylo [4.3.0] nonane.
2. preparation chipal compounds 8-styroyl-2 as claimed in claim 1, the method for 8-diazabicylo [4.3.0] nonane is characterized in that said metal borohydride and metal halide MX
nThe metal borohydride that reduction system uses is lithium borohydride, Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN or hydroboration calcium.
3. preparation chipal compounds 8-styroyl-2 as claimed in claim 1, the method for 8-diazabicylo [4.3.0] nonane is characterized in that said metal borohydride and metal halide MX
nThe metal halide MX that reduction system uses
nBe selected from following inorganic salt or its any mixture: LiCl, LiBr, LiI, MgCl
2, MgBr
2, AlCl
3, CaCl
2, ZnCl
2, ZrCl
4, CoCl
2
4. preparation chipal compounds 8-styroyl-2 as claimed in claim 1; The method of 8-diazabicylo [4.3.0] nonane; It is characterized in that said chipal compounds 8-styroyl-7,9-dioxo-2,8-diazabicylo [4.3.0] nonane, metal borohydride and metal halide MX
nMolar feed ratio be 1: 1～10: 1～10, preferred molar feed ratio is 1: 2～6: 2～6.
5. preparation chipal compounds 8-styroyl-2 as claimed in claim 1, the method for 8-diazabicylo [4.3.0] nonane is characterized in that said metal borohydride and metal halide MX
nThe reduction reaction that reduction system carries out is carried out in inert organic solvents, and said inert organic solvents is ethers, varsol or its any mixture.
6. preparation chipal compounds 8-styroyl-2 as claimed in claim 5; The method of 8-diazabicylo [4.3.0] nonane is characterized in that described ether solvent is selected from down one of kind solvent: ether, isopropyl ether, THF, 2-methyltetrahydrofuran, MTBE, glycol dimethyl ether.
7. preparation chipal compounds 8-styroyl-2 as claimed in claim 5; The method of 8-diazabicylo [4.3.0] nonane is characterized in that described varsol is selected from down one of kind solvent: sherwood oil, normal hexane, hexanaphthene, normal heptane, benzene,toluene,xylene.
8. preparation chipal compounds 8-styroyl-2 as claimed in claim 1; The method of 8-diazabicylo [4.3.0] nonane; It is characterized in that the reduction reaction that said metal borohydride and metal halide MXn reduction system are carried out is in-10～150 ℃ TR, to carry out, preferred range is 0～80 ℃.
9. preparation chipal compounds 8-styroyl-2 as claimed in claim 1; The method of 8-diazabicylo [4.3.0] nonane; The time that it is characterized in that the reduction reaction that said metal borohydride and metal halide MXn reduction system are carried out carried out in the scope at 5～72 hours, and preferred time range is 10～36 hours.
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|---|---|---|---|
| CN2011100643479A CN102675307A (en) | 2011-03-17 | 2011-03-17 | Method for preparing chiral compound 8-phenethyl-2,8-diazabicyclo[4.3.0]nonane |
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|---|---|---|---|
| CN2011100643479A CN102675307A (en) | 2011-03-17 | 2011-03-17 | Method for preparing chiral compound 8-phenethyl-2,8-diazabicyclo[4.3.0]nonane |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104163820A (en) * | 2014-01-13 | 2014-11-26 | 江苏永达药业有限公司 | Preparation method of moxifloxacin intermediate compound |
Citations (4)
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|---|---|---|---|---|
| EP0550903A1 (en) * | 1992-01-10 | 1993-07-14 | Bayer Ag | Quinolone- and naphthyridone carboxylic acid derivatives as antibacterial agents |
| JP2001039979A (en) * | 1999-07-28 | 2001-02-13 | Koei Chem Co Ltd | PRODUCTION OF OCTAHYDROPYRROLO[3,4-b]PYRIDINE |
| 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 |
| WO2010122774A1 (en) * | 2009-04-20 | 2010-10-28 | 株式会社カネカ | Processes for producing (1s,6s)- or (1r,6r)-cis-2,8-diazabicyclo[4.3.0]nonane and intermediate thereof |
-
2011
- 2011-03-17 CN CN2011100643479A patent/CN102675307A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0550903A1 (en) * | 1992-01-10 | 1993-07-14 | Bayer Ag | Quinolone- and naphthyridone carboxylic acid derivatives as antibacterial agents |
| JP2001039979A (en) * | 1999-07-28 | 2001-02-13 | Koei Chem Co Ltd | PRODUCTION OF OCTAHYDROPYRROLO[3,4-b]PYRIDINE |
| WO2010122774A1 (en) * | 2009-04-20 | 2010-10-28 | 株式会社カネカ | Processes for producing (1s,6s)- or (1r,6r)-cis-2,8-diazabicyclo[4.3.0]nonane and intermediate thereof |
| 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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104163820A (en) * | 2014-01-13 | 2014-11-26 | 江苏永达药业有限公司 | Preparation method of moxifloxacin intermediate compound |
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Application publication date: 20120919 |