CN103183673A - Synthesizing method of (S,S)-2,8-diazabicyclo[4.3.0]nonane - Google Patents
Synthesizing method of (S,S)-2,8-diazabicyclo[4.3.0]nonane Download PDFInfo
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- CN103183673A CN103183673A CN2011104551669A CN201110455166A CN103183673A CN 103183673 A CN103183673 A CN 103183673A CN 2011104551669 A CN2011104551669 A CN 2011104551669A CN 201110455166 A CN201110455166 A CN 201110455166A CN 103183673 A CN103183673 A CN 103183673A
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
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.
Description
Technical field
The present invention relates to the preparation of Azabicyclic compound and derivative thereof, specifically a kind of (S, S)-2, the synthetic method of 8-diazabicyclo [4,3,0] nonane.
Background technology
(S, S)-2,8-diazabicyclo [4,3,0] nonane is colourless to light yellow viscous liquid, is the important intermediate of synthesising bacteria anti-reflecting medicine Moxifloxacin hydrochloride.Moxifloxacin hydrochloride be the 4th generation the fluoroquinolone antibacterial agent thing, it has broad-spectrum antibacterial action, as human and animal's antibacterials, can treat the infection that various bacteria causes effectively.(S, S)-2, the structural formula of 8-diazabicyclo [4,3,0] nonane (to call compound 1 in the following text) is as follows:
Patent documentation WO125425 discloses with 2,3-dinicotinic acid and has dewatered in aceticanhydride, with carrying out cyclization with aceticanhydride again after the benzylamine ammonia solution; With lithium aluminum hydride carbonyl is reduced again behind the palladium carbon catalyst catalytic hydrogenating reduction; Use at last D-(-)-tartrate do chiral selectors split obtain having optically active (S, S)-2,8-diazabicyclo [4,3,0] nonane.
It is starting raw material that patent documentation US5570597 discloses with 2,3-dinicotinic acid, carries out esterification under hydrogenchloride catalysis, obtains 2,3-dihydroxymethyl pyridine through lithium aluminium hydride reduction; Again with sulfur oxychloride react 2,3-dichloromethyl pyridine; In the DMF of NaH solution, react with benzsulfamide again; Through Hydrogen bromide, phenol, propionic acid deprotection base; Hydrogenation under catalyst action at last, chiral separation obtain compound, and (S, S)-octahydro-pyrrolo-[3,4-b] pyridine, yield is 32.1%.
Patent documentation CN101514201 and patent documentation CN101657448 have done improvement to patent documentation US5570597 respectively.Patent documentation CN101514201 has substituted the reductive agent lithium aluminum hydride that uses among the patent US550597 with sodium borohydride and calcium chloride, reductase 12, and 3-dinicotinic acid methyl esters obtains 2,3-dihydroxymethyl pyridine; 2,3-dichloromethyl pyridine under salt of wormwood and potassiumiodide effect with the benzylamine cyclization, (4,7-is suitable)-octahydro-pyrrolo-[3,4-b] pyridine that hydrogenating reduction is not split, yield is 42%.Patent documentation CN101657448 then is that the compound sodium ethylate that extensively is to use replaces NaH; replace DMF to make solvent with ethanol, make 2,3-dichloromethyl pyridine and the sulphonamide condensation that suitably replaces form 6-and be substituted alkylsulfonyl-6; 7-dihydro-5H-pyrrolo-[3,4-b] pyridine.
It is starting raw material along butyl alkene imines that patent documentation CN1097759 discloses with N-dimethylamino propenyl imines and N-phenmethyl, through the alkene cycloaddition reaction, sloughs a dimethylamine molecule again; Make catalyzer with ruthenium charcoal and palladium charcoal successively, at twice hydrogenating reduction; With lithium aluminum hydride to carbonyl reduction; Use D-(-)-tartrate to make the resolution reagent chiral separation at last and obtain having optically active compound 1, yield about 30%.
It is raw material that patent documentation US5770597 discloses with 3-alanine ethyl ester etc.: with two kinds of material dissolutions stirring and refluxing in pyridine, concentrate and replace with methyl sulfuryl chloride, potassium cyanide successively after purifying; Through cyclization, at ZnHgCl
2Reducing carbonyl under the catalysis, chiral separation, debenzylation obtain target compound more at last, yield about 18%.
In the above-mentioned method, all adopt and carry out chiral separation at last, synthesize in early stage and all fail to control chirality in the main ring process, cause last total recovery obviously on the low side, had a strong impact on (S, S)-2, the synthetic cost of 8-diazabicyclo [4,3,0] nonane.
Summary of the invention
Technical problem to be solved by this invention is to overcome the defective that above-mentioned prior art exists, provide a kind of environmental friendliness, economy, highly selective and suitable suitability for industrialized production (S, S)-2,8-diazabicyclo [4,3,0] nonane synthetic method.
For this reason, the present invention adopts following technical scheme: (S, S)-2, the synthetic method of 8-diazabicyclo [4,3,0] nonane, its step is as follows:
A) propenal (compound 2) and compound 3 are used the organic amine catalyst in organic solvent, carry out the condensation reaction of amine aldehyde and obtain compound 5 under 0-30 ℃ of condition;
The organic amine that uses is alkylamine or arylamines, as triethylamine, methyl diethylamide, tribenzyl amine etc.The organic solvent that uses in the reaction is halogenated alkane, ether, ketone etc., as methylene dichloride, ether, acetone etc., the R in the compound 3
1=methyl, ethyl, propyl group, sec.-propyl, phenyl, benzyl etc.
B) compound 5 and compound 4 with toluene, THF or the former two's mixture as solvent, with organic amine and chiral catalyst catalysis, carry out the D-A addition at ambient temperature and obtain chipal compounds 6 under protection of inert gas;
Chiral catalyst is cyanates such as KCN, NaCN, and the chirality N-heterocyclic carbine, the preferred following compound 8,9 of chirality N-heterocyclic carbine,
The chiral catalyst consumption is the 5%-20% of reaction substrate, preferred 8%-12%, the R in the compound 4
2=hydrogen, methyl, allyl group, benzyl etc., R
1With R
2Can be the same or different.
C) chipal compounds 6 obtains compound 7 through shortening, carbonyl reduction;
The used reductive agent of carbonyl reduction is metal borohydride/boron trifluoride system, and wherein metal borohydride can be sodium borohydride, POTASSIUM BOROHYDRIDE or hydroboration calcium etc.; Boron trifluoride can add with the form of gas, also can be that the form of complex compound adds; The solvent that carbonyl reduction uses can be ether, isopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, normal hexane, hexanaphthene, sherwood oil, benzene,toluene,xylene etc., is preferably tetrahydrofuran (THF), toluene;
The catalyzer that shortening uses is selected from palladium/carbon, Raney's nickel etc., and the catalyzer usage quantity is the 2%-20% of substrate, preferred 5%-10%, and wherein the solvent that uses of shortening is hydrogenation inert solvents such as acetic acid, preferred acetic acid.
D) compound 7 deprotection base under acidic conditions, then by after the conventional separating treatment, again chiral separation purify target product 1, namely (S, S)-2,8-diazabicyclo [4,3,0] nonane.
Reaction scheme of the present invention is as follows:
Said conventional separating treatment can be various separation means commonly used such as crystallization, filtration, extraction among the present invention.
Compared with prior art, the present invention has the following advantages: raw material is cheap and easy to get, prepare the chiral intermediate of highly selective by specific N-heterocyclic carbine catalyst D-A addition, thereby fundamentally solve the prior art the finished product because chiral separation causes the low problem of total recovery, and then improve the yield of product.Under suitable catalyzer condition, the D-A addition (S, S) the configuration selectivity reaches more than 95%.
Embodiment
Embodiment 1
Take by weighing the 31.4g benzsulfamide and be dissolved in the 300ml tetrahydrofuran (THF), be cooled to 0 ℃, add the 10g triethylamine, mix all with after begin to drip the 11.2g propenal, 0.5h dropwises, feed in raw material finish after, temperature of reaction is risen to 30 ℃, insulation reaction 9h.Use anhydrous sodium sulfate drying, solids removed by filtration.
Embodiment 2
Feed nitrogen in the filtrate that obtains to embodiment 1, add 7g N-heterocyclic carbine compound 9,2gN successively, N-diisopropylethylamine, 17.5g maleimide, stirring reaction 24h under the room temperature.Concentrating under reduced pressure dry solid 47.7g, two the step total recoverys be 81.7%, (S, S) the isomer selectivity is 93%.
Embodiment 3
The solid, the 300ml acetic acid that under the nitrogen protection 2 oven dry of 2.4g 5% palladium/carbon, 47.7g embodiment are obtained add in the hydrogenation reactor, feed hydrogen to pressure and reach 9MPa, 80 ℃ of following hydrogenation 10h, be cooled to room temperature after, use nitrogen replacement hydrogen.Solids removed by filtration catalyzer, filtrate are transferred pH=11-12 with 20% aqueous sodium hydroxide solution after reclaiming acetic acid, with 150ml * 3 chloroform extractions.Chloroform is reclaimed in underpressure distillation, and vacuum-drying obtains the 45.6g solid, and yield is 95.0%.
Embodiment 4
In four-hole boiling flask, add solid, the 150ml tetrahydrofuran (THF) that 45.6g embodiment 3 obtains, stirring and dissolving, be cooled to 0 ℃, add sodium borohydride 14.8g, keep stirring 1h below 0 ℃, slowly drip boron trifluoride ether solution 51.8g then and maintain the temperature at below 5 ℃, drip Bi Houji continuation of insurance temperature reaction 3h, be warmed up to 45 ℃ of insulation 6h then, cool to room temperature, add 100ml 2mol/L HCl solution, stir 1h.Filter, add 200ml toluene and 100ml 2mol/L aqueous sodium hydroxide solution in the filtrate, behind the stirring 30min, leave standstill branch vibration layer, the toluene layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates and reclaims toluene, gets solid 38.4g, and yield is 93.1%.
Embodiment 5
The solid that 38.4g embodiment 4 is obtained is dissolved in the Hydrogen bromide of 150ml 48%, adds 72ml propionic acid and 14.4g phenol, reflux 8h again in solution.Be cooled to room temperature and be concentrated into dried after reaction finishes.Resistates is dissolved in the 150ml water, successively with the extraction of 150ml methyl tertiary butyl ether and 150ml ethyl acetate extraction.Isolate the aqueous solution, transfer pH=11-12 by 30% sodium hydroxide, the aqueous solution adds sodium-chlor to saturated, with 100ml * 4 chloroform extraction waters.Methylene dichloride gets the 16.8g oily liquids after merging back reclaim under reduced pressure methylene dichloride mutually, and yield is 92.3%.
Embodiment 6
Under 80 ℃ 20g D-(-)-tartrate is dissolved in 120ml N, in the N dimethyl formamide, the solid of embodiment 5 gained is dissolved in 50ml N, the N dimethyl formamide, the dissolving back that finishes adds in the above-mentioned tartrate that configures/DMF solution, stirs evenly, cool to 0 ℃ of crystallization 8h after, solid is separated out in filtration, and filter cake is drained after with the drip washing of 20ml ethylene glycol monomethyl ether.The gained filter cake changes in the four-hole boiling flask, adds 40ml deionized water and 100ml methylene dichloride, is cooled to below 10 ℃, drip 30% aqueous sodium hydroxide solution and transfer pH=9, standing demix behind the stirring 0.5h, the organic layer anhydrous sodium sulfate drying filters, concentrating under reduced pressure obtains compound 1 (S, S)-2,8-diazabicyclo [4,3,0] nonane 15.3g, yield are 911%.
Overall yield of reaction is 60.7%.
Embodiment 7
With embodiment 1,2, change maleimide into 35.8g N-benzyl maleimide, add 6g N-heterocyclic carbine compound 9,2g N, N-diisopropylethylamine.Reaction obtains the 65.4g solid chemical compound, and yield is 83.0%, and (S, S) the isomer selectivity is 95%.
Embodiment 8
With embodiment 1,2, change maleimide into 20.0g N-methyl maleimide, add 5g N-heterocyclic carbine compound 8,2gN, N-diisopropylethylamine.Reaction obtains the 46.5g solid chemical compound, and yield is 76.0%, and (S, S) the isomer selectivity is 87%.
Claims (10)
1. (S, S)-2, the synthetic method of 8-diazabicyclo [4,3,0] nonane, its step is as follows:
A) propenal and compound 3 are used the organic amine catalyst in organic solvent, carry out the condensation reaction of amine aldehyde and obtain compound 5 under 0-30 ℃ of condition;
B) compound 5 and compound 4 with toluene, THF or the former two's mixture as solvent, with organic amine and chiral catalyst catalysis, carry out the D-A addition at ambient temperature and obtain chipal compounds 6 under protection of inert gas;
C) chipal compounds 6 obtains compound 7 through shortening, carbonyl reduction;
D) compound 7 deprotection base under acidic conditions, then by after the conventional separating treatment, again chiral separation purify target product 1, namely (S, S)-2,8-diazabicyclo [4,3,0] nonane.
2. synthetic method according to claim 1 is characterized in that, in each above-mentioned structural formula, and R
1=methyl, ethyl, propyl group, sec.-propyl, phenyl or benzyl; R
2=hydrogen, methyl, allyl group or benzyl.
3. synthetic method according to claim 1 and 2 is characterized in that, the used chiral catalyst of step b) is cyanate or chirality N-heterocyclic carbine.
4. synthetic method according to claim 3 is characterized in that, described cyanate is KCN or NaCN, and described chirality N-heterocyclic carbine is following compound 8 or compound 9,
5. synthetic method according to claim 4 is characterized in that in the step b), and the chiral catalyst consumption is the 5%-20% of substrate.
6. synthetic method according to claim 5 is characterized in that in the step b), and the chiral catalyst consumption is the 8%-12% of substrate.
7. synthetic method according to claim 4, it is characterized in that in the step c), the used reductive agent of carbonyl reduction is metal borohydride/boron trifluoride system, wherein metal borohydride is sodium borohydride, POTASSIUM BOROHYDRIDE or hydroboration calcium, and boron trifluoride adds with the form of gas or adds with the form of complex compound; The solvent that carbonyl reduction uses is any in ether, isopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, normal hexane, hexanaphthene, sherwood oil, the benzene,toluene,xylene.
8. synthetic method according to claim 4 is characterized in that in the step c), and the catalyzer that shortening uses is selected from palladium/carbon or Raney's nickel, and the catalyzer usage quantity is the 2%-20% of substrate, and the solvent that shortening uses is acetic acid.
9. synthetic method according to claim 4 is characterized in that in the step d), and the employed acid of deprotection base is any or the mixing acid more than two kinds in hydrochloric acid, Hydrogen bromide, acetic acid, the propionic acid, and splitting agents useful for same is tartrate or camphor.
10. synthetic method according to claim 9 is characterized in that in the step d), and the employed acid of deprotection base is the mixing acid of Hydrogen bromide and propionic acid, and splitting agents useful for same is D-(-)-tartrate.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262225A (en) * | 2014-08-24 | 2015-01-07 | 浙江新东港药业股份有限公司 | 3-aminopyrrolidine compounds, and synthetic method and uses thereof |
| WO2018220355A1 (en) * | 2017-05-31 | 2018-12-06 | Mission Therapeutics Limited | Sulfonamide-substituted cyanopyrrolidines with activity as dub inhibitors |
| CN112920184A (en) * | 2021-02-06 | 2021-06-08 | 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 |
| CN112939849A (en) * | 2019-12-11 | 2021-06-11 | 浙江新和成股份有限公司 | (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate and preparation method and application thereof |
| CN112939847A (en) * | 2021-02-06 | 2021-06-11 | 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 (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101514201A (en) * | 2009-03-30 | 2009-08-26 | 浙江海翔药业股份有限公司 | Preparation method for (4,7-cis)-octahydro-pyrrolo[3,4-b]pyridine and moxifolxacin |
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- 2011-12-30 CN CN201110455166.9A patent/CN103183673B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101514201A (en) * | 2009-03-30 | 2009-08-26 | 浙江海翔药业股份有限公司 | Preparation method for (4,7-cis)-octahydro-pyrrolo[3,4-b]pyridine and moxifolxacin |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262225A (en) * | 2014-08-24 | 2015-01-07 | 浙江新东港药业股份有限公司 | 3-aminopyrrolidine compounds, and synthetic method and uses thereof |
| CN104262225B (en) * | 2014-08-24 | 2017-02-01 | 浙江新东港药业股份有限公司 | 3-aminopyrrolidine compounds, and synthetic method and uses thereof |
| WO2018220355A1 (en) * | 2017-05-31 | 2018-12-06 | Mission Therapeutics Limited | Sulfonamide-substituted cyanopyrrolidines with activity as dub inhibitors |
| US11414402B2 (en) | 2017-05-31 | 2022-08-16 | Mission Therapeutics Limited | Sulfonamide-substituted cyanopyrrolidines with activity as DUB inhibitors |
| CN112939849A (en) * | 2019-12-11 | 2021-06-11 | 浙江新和成股份有限公司 | (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate and preparation method and application thereof |
| CN112939849B (en) * | 2019-12-11 | 2022-05-03 | 浙江新和成股份有限公司 | (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate and preparation method and application thereof |
| CN112920184A (en) * | 2021-02-06 | 2021-06-08 | 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 |
| CN112939847A (en) * | 2021-02-06 | 2021-06-11 | 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 |
| CN112939847B (en) * | 2021-02-06 | 2022-05-13 | 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 |
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