CN102603736A - Preparation method of (S,S)-2, 8-diazabicyclo[4,3,0] nonane - Google Patents
Preparation method of (S,S)-2, 8-diazabicyclo[4,3,0] nonane Download PDFInfo
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Abstract
The invention relates to a preparation method of (S,S)-2, 8-diazabicyclo[4,3,0] nonane. The preparation method comprises the following steps: taking 2,3-dimethylpyridine as a raw material, performing halogenation on 2,3-dimethylphyridine through N-chloro succinimide to be in cyclization with benzylamine, performing hydrogenation on pyridine ring and removing benzyl groups, and finally performing chiral resolution to obtain the (S,S)-2, 8-diazabicyclo[4,3,0] nonane. According to the invention, the preparation method has advantages of short process flow, low cost and high yield, reaches total yield of 23% and ee value of above 99% and is safe and reliable, thereby being applicable in industrial production.
Description
Technical field
The present invention relates to Moxifloxacin (moxifloxacin) intermediate preparation field, especially relate to a kind of (S, S)-2, the preparation method of 8-diazabicyclo [4,3,0] nonane.
Background technology
Moxifloxacin (moxifloxacin); Chemistry 1-cyclopropyl by name-6-fluoro-1; 4-dihydro-8-methoxyl group-7-[(4aS, 7aS)-octahydro-6H-pyrrolo-[3,4-b] pyridine-6-yl]-4-oxo-3-quinoline carboxylic acid; Be by the research and development of German Bayer company the 4th generation fluoroquinolone antibacterial agent, clinical its hydrochloride of using.These article go on the market in Germany in September, 1999 first, and go on the market in the U.S. December in the same year, is used to treat acute sinus gland inflammation, the acute attack of chronic bronchitis, community acquired pneumonia, and uncomplicated skin infections and skin soft-tissue infection.Its chemical formula is (I).(S, S)-2,8-diazabicyclo [4,3,0] nonane is the Moxifloxacin side chain, is the key intermediate of synthetic Moxifloxacin.Moxifloxacin is introduced side chain at 7 carbon atoms of quinolone parent nucleus, and it is active and make it not produce tangible phototoxicity, increased its solubleness to have strengthened this medicine resisting gram-positive aerophil, has reduced the danger that forms crystalluria.Its chemical formula (II).
About (S, S)-2,8-diazabicyclo [4,3,0] nonane be the method for Moxifloxacin side chain common have following several kinds:
Patent US5480879, US5607942, EP-A-0350733, JP2001039979 roughly adopt following route:
This type route is with 2, and the 3-dinicotinic acid is a starting raw material, generates acid anhydrides through dehydration earlier; Benzylamine is to the acid anhydrides open loop, and cyclization generates imide compound under the effect of diacetyl oxide again, passes through the hydrogenated pyridine ring then; The reduction imide, chiral separation, last hydrogenation debenzylation obtains target compound II.This route steps is more, and raw materials used reagent is more, and cost is than higher, and yield is lower.
Patent US5480879 has adopted with top route roughly the same, and difference is to split earlier, restores imide:
Sharp US200702633 has adopted another kind of method:
This route is starting raw material with the 2,3 dimethyl pyridine, through two halos of two methyl; With alkylsulphonic acid ammonia the dihalo methyl is carried out the nucleophilic cyclization then, generate twin nuclei, in the hydrogenation of process pyridine ring; Desulfonation, chiral separation obtains target compound II at last.This route steps is more, and cost is higher, and yield is higher.
Summary of the invention
The present invention is for solving the problems of the technologies described above, and is to provide a kind of preparing method's technical process short, and cost is low, and yield is high, and the ee value reaches more than 99%, and is safe and reliable, is suitable for suitability for industrialized production.
Synthetic route of the present invention is following:
The technical problem that the present invention solved adopts following technical scheme to realize:
A kind of (S, S)-2, the preparation method of 8-diazabicyclo [4,3,0] nonane comprises:
(1) under nitrogen protection, 2,3 dimethyl pyridine is dissolved in the solvent; Obtain the solution that concentration is 0.8-1mol/L, under agitation condition, add N-chlorosuccinimide, ultra violet lamp 20-30h; Cooling (0-5 ℃) reaction solution is removed succimide and unreacted N-chlorosuccinimide, adds the N-chlorosuccinimide of equivalent again; React 20-30h again, cooling (temperature 0-5 ℃) reaction solution after-filtration feeds excessive anhydrous HCl again; Filter, the recrystallization in Virahol of the filter cake after the filtration obtains 2, the hydrochloride bullion of 3-dichloromethyl pyridine;
(2) under the normal temperature, with above-mentioned make 2,3-dichloromethyl pyridine hydrochloride bullion adds in the solvent, volumetric molar concentration is 2 of 0.4-0.8mol/L, the acetonitrile solution of 3-dichloromethyl pyridine hydrochloride bullion; Add benzylamine again, then add alkali and potassiumiodide, be stirred to reaction 4-6h, filter afterwards, with the filter cake washing after filtering, merging filtrate and washing lotion concentrate, and get red 6-benzyl-pyrrolo-[3,4-b] pyridine;
(3) the 6-benzyl-pyrrolo-in the step (2) [3,4-b] pyridine is dissolved in the solvent, obtains the solution that concentration is 0.2-0.5mol/L; In solution, add palladium-carbon catalyst, reaction 4-8h filters under temperature 90-100 ℃, hydrogen pressure 9-10MPa, evaporate to dryness filtrating, 2,8-diazabicyclo [4,3,0] nonane;
(4) with make in the step (3) 2,8-diazabicyclo [4,3,0] nonane uses chemical resolving agent to carry out chiral separation, promptly get (S, S)-2,8-diazabicyclo [4,3,0] nonane.
Solvent in the above-mentioned steps (1) is tetracol phenixin, trifluoroacetic acid, chloroform or acetic acid.
2,3 dimethyl pyridine in the above-mentioned steps (1) is 0.38-0.6 with the mol ratio of the N-chlorosuccinimide that adds first.Preferred mol ratio is 0.48 or 0.39.
Solvent in the above-mentioned steps (2) is toluene, acetonitrile or ethylene glycol monomethyl ether.
In the above-mentioned steps (2) 2, the mol ratio of 3-dichloromethyl pyridine hydrochloride and benzylamine is 0.5-1; 2, the mol ratio of 3-dichloromethyl pyridine hydrochloride, alkali, potassiumiodide is 1: 2-3: 0.4-0.6.Above-mentioned alkali is soda ash light or salt of wormwood.
Filter cake in the above-mentioned steps (2) is used washed with dichloromethane.
Solvent in the above-mentioned steps (3) is THF, ethylene glycol monomethyl ether, toluene or methyl alcohol.
Palladium-carbon catalyst in the above-mentioned steps (3) uses Palladous chloride, palladous oxide or palladium hydroxide to be equal to alternative; The preferred 5% palladium carbon of palladium carbon wherein.Palladium-carbon catalyst and substrate mol ratio are 1: 5-15.
Chemical resolving agent in the said step (4) is D-(-)-tartrate or D-(-)-to methoxy dibenzoyl tartrate, 2, and the mol ratio of 8-diazabicyclo [4,3,0] nonane and resolving agent is 0.8-1.5.
Chiral separation in the above-mentioned steps (4), concrete steps comprise, D-(-)-tartrate is dissolved in N in 80 ℃-100 ℃; In the dinethylformamide (DMF), be added drop-wise in 0.5-1 hour (S, S)-2; In the DMF solution of 8-diazabicyclo [4,3,0] nonane; Equality of temperature stirs 1-2.5h, stirs 12-24h after being cooled to room temperature naturally; Filter, filtering filter cake is washed with DMF and ethanol successively; Filter cake is dissolved in the 50ml-80 water, stirs the NaOH solution 17ml-25ml that adds 10-15mol/L down, stirring at room 1-1.5h, hexanaphthene extraction 200mlx3; Extraction liquid is used anhydrous sodium sulfate drying, filter, the filtrating evaporate to dryness get the yellow mucus shape (S, S)-2; 8-diazabicyclo [4,3,0] nonane.
Above-mentioned racemize-2,8-diazabicyclo [4,3,0] nonane and resolving agent D-(-)-tartaric mol ratio are 0.8-1.5.
Above-mentioned resolution solvent N, dinethylformamide (DMF) and resolving agent D-(-)-tartaric weight ratio are at 1: 100, preferably at 40-60.
Raw material and reagent that the present invention uses are all buied through commercially available.
The beneficial effect that the present invention has is:
(1) preparation method of the present invention is simple, and cost is low, and yield is high, and total recovery 23% and ee value reach more than 99%, and be safe and reliable, is suitable for suitability for industrialized production;
(2) the present invention compares with original technology, has shortened technical process, and a step is accomplished the reduction and the debenzylation of pyridine ring, has attempted multiple catalyzer, has obtained good yield, has improved economic benefit.
Description of drawings
Fig. 1 is a synthetic route of the present invention.
Embodiment
For technique means, creation characteristic that the present invention is realized, reach purpose and effect and be easy to understand and understand, below in conjunction with concrete diagram, further set forth the present invention.
Embodiment 1
A kind of (S, S)-2, the preparation method of 8-diazabicyclo [4,3,0] nonane comprises:
The preparation of (1) 2,3-dichloromethyl pyridine hydrochloride
Under the nitrogen protection, (9.4g, 0.088mol) (24g 0.180mol) is dissolved in CCl with the N-chlorosuccinimide with 2,3 dimethyl pyridine under stirring
4(900ml), 200w ultra violet lamp 24h, cooling (0-5 ℃) reaction solution is removed succimide and unreacted N-chlorosuccinimide, and (24g 0.180mol), reacts 24h again to add equivalent N-chlorosuccinimide again; Cooling (0-5 ℃) reaction solution after-filtration feeds excessive anhydrous HCl again, filters, and the recrystallization in Virahol of the filter cake after the filtration obtains 2, and the hydrochloride bullion of 3-dichloromethyl pyridine (14.3g, 0.0724mol), yield is 82%;
(2) preparation of 6-benzyl-pyrrolo-[3,4-b] pyridine
Under the normal temperature, with make in the step (1) 2,3-dichloromethyl pyridine hydrochloride (17g; 0.097mol) be dissolved in the acetonitrile (200ml), in solution, add (12.5g, 0.116mol) benzylamine; Then add Anhydrous potassium carbonate (26.7g; 0.194mol) and potassiumiodide (8g 0.048mol), is stirred to reaction finish (5h); Filter reaction mixture, filter cake is used washed with dichloromethane, merging filtrate and washing lotion concentrate, red 6-benzyl-pyrrolo-[3,4-b] pyridine (15.9g, 0.076mol), productive rate is 78%;
The preparation of (3) 2,8-diazabicyclos [4,3,0] nonane
(6g 0.028mol) is dissolved in the methyl alcohol (100ml), adds 5% palladium carbon (0.6g) with the 6-benzyl-pyrrolo-that makes in the step (2) [3,4-b] pyridine; Drop in the autoclave, reaction 5h filters the evaporate to dryness reaction solution under 90 ℃ of temperature, hydrogen pressure 9MPa; Get 2,8-diazabicyclo [4,3; 0] nonane (3.5g, 0.025mol), yield is 89%;
(4) (S, S)-2, the preparation of 8-diazabicyclo [4,3,0] nonane
With D-(-)-tartrate (6.4g 0.061mol) is dissolved among the DMF in 80 ℃, be added drop-wise in 0.5 hour (S, S)-2,8-diazabicyclo [4,3,0] nonane (6.4g, in DMF solution 0.050mol), equality of temperature stirs 1h, is cooled to stirred overnight after the room temperature naturally; Filter, filter cake is washed with DMF and ethanol successively; Filter cake is dissolved in the 60ml water, stirs the NaOH solution 17ml that adds 15mol/L down, stirring at room 1h, hexanaphthene extraction 200mlx3; Extraction liquid is used anhydrous sodium sulfate drying, filter, the filtrating evaporate to dryness get the yellow mucus shape (S, S)-2; 8-diazabicyclo [4,3,0] nonane (2.5g; 0.020mol), yield is 40%, ee＞99%.
Embodiment 2
A kind of (S, S)-2, the preparation method of 8-diazabicyclo [4,3,0] nonane comprises:
The preparation of (1) 2,3-dichloromethyl pyridine hydrochloride
Under the nitrogen protection, (9.4g 0.088mol) is dissolved in CCl with N-chlorosuccinimide (0.225mol) with 2,3 dimethyl pyridine under stirring
4(1000ml), 200w ultra violet lamp 28h, cooling (0-5 ℃) reaction solution is removed succimide and unreacted N-chlorosuccinimide, adds equivalent N-chlorosuccinimide (0.225mol) again, reacts 28h again; Cooling (0-5 ℃) reaction solution after-filtration feeds excessive anhydrous HCl again, filters, and the recrystallization in Virahol of the filter cake after the filtration obtains 2, and the hydrochloride bullion of 3-dichloromethyl pyridine (14.1g, 0.0716mol), yield is 81%;
(2) preparation of 6-benzyl-pyrrolo-[3,4-b] pyridine
Under the normal temperature, with make in the step (1) 2,3-dichloromethyl pyridine hydrochloride (17g; 0.097mol) be dissolved in the acetonitrile (200ml), in solution, add (12.5g, 0.116mol) benzylamine; Then add soda ash light (25.8g; 0.243mol) and potassiumiodide (6.5g 0.039mol), is stirred to reaction finish (6h); Filter reaction mixture, filter cake is used washed with dichloromethane, merging filtrate and washing lotion concentrate, red 6-benzyl-pyrrolo-[3,4-b] pyridine (15.3g, 0.073mol), productive rate is 75%;
The preparation of (3) 2,8-diazabicyclos [4,3,0] nonane
(6g 0.028mol) is dissolved in the THF (100ml), adds 5% palladium carbon (0.4g) with the 6-benzyl-pyrrolo-that makes in the step (2) [3,4-b] pyridine; Drop in the autoclave, reaction 7h filters the evaporate to dryness reaction solution under 100 ℃ of temperature, hydrogen pressure 10MPa; Get 2,8-diazabicyclo [4,3; 0] nonane (3.3g, 0.024mol), yield is 86%;
(4) (S, S)-2, the preparation of 8-diazabicyclo [4,3,0] nonane
With D-(-)-to methoxy dibenzoyl tartrate (18.8g 0.045mol) is dissolved among the DMF in 80 ℃, be added drop-wise in 0.5 hour (S, S)-2; 8-diazabicyclo [4,3,0] nonane (6.4g; 0.050mol) DMF solution in, equality of temperature stirs 1h, is cooled to stirred overnight after the room temperature naturally; Filter, filter cake is washed with DMF and ethanol successively; Filter cake is dissolved in the 60ml water, stirs the NaOH solution 20ml that adds 10mol/L down, stirring at room 1h, hexanaphthene extraction 200mlx3; Extraction liquid is used anhydrous sodium sulfate drying, filter, the filtrating evaporate to dryness get the yellow mucus shape (S, S)-2; 8-diazabicyclo [4,3,0] nonane (2.4g; 0.019mol), yield is 38%, ee＞99%.
Embodiment 3
Step (2), (3), (4) are identical with (2), (3), (4) step of embodiment 1, and different with embodiment 1 step (1) is that 2,3 dimethyl pyridine is 0.6 with the mol ratio of the N-chlorosuccinimide that adds first; Final product yellow mucus shape (S, S)-2,8-diazabicyclo [4,3,0] nonane, total recovery is 23%, ee＞99%.
More than show and described ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; The present invention is not restricted to the described embodiments; That describes in the foregoing description and the specification sheets just explains principle of the present invention; Under the prerequisite that does not break away from spirit and scope of the invention, the present invention also has various changes and modifications, and these variations and improvement all fall in the scope of the invention that requires protection.The present invention requires protection domain to be defined by appending claims and equivalent thereof.
Claims (10)
1. one kind (S, S)-2, the preparation method of 8-diazabicyclo [4,3,0] nonane comprises:
(1) under nitrogen protection, 2,3 dimethyl pyridine is dissolved in the solvent; Obtain the solution that concentration is 0.8-1mol/L, under agitation condition, add N-chlorosuccinimide, ultra violet lamp 20-30h; Cooling reaction liquid is removed succimide and unreacted N-chlorosuccinimide, adds the N-chlorosuccinimide of equivalent again; React 20-30h again, cooling reaction liquid after-filtration feeds excessive anhydrous HCl again; Filter, the recrystallization in Virahol of the filter cake after the filtration obtains 2, the hydrochloride bullion of 3-dichloromethyl pyridine;
(2) under the normal temperature, with above-mentioned make 2,3-dichloromethyl pyridine hydrochloride bullion adds in the solvent, obtaining volumetric molar concentration is 2 of 0.4-0.8mol/L, the acetonitrile solution of 3-dichloromethyl pyridine hydrochloride bullion; Add benzylamine again, then add alkali and potassiumiodide, be stirred to reaction 4-6h, filter afterwards, with the filter cake washing after filtering, merging filtrate and washing lotion concentrate, and get red 6-benzyl-pyrrolo-[3,4-b] pyridine;
(3) the 6-benzyl-pyrrolo-that makes in the step (2) [3,4-b] pyridine is dissolved in the solvent, obtains the solution that concentration is 0.2-0.5mol/L; In solution, add palladium-carbon catalyst, reaction 4-8h filters under temperature 90-100 ℃, hydrogen pressure 9-10MPa, evaporate to dryness filtrating, 2,8-diazabicyclo [4,3,0] nonane;
(4) with make in the step (3) 2,8-diazabicyclo [4,3,0] nonane uses chemical resolving agent to carry out chiral separation, promptly get (S, S)-2,8-diazabicyclo [4,3,0] nonane.
2. according to claim 1 a kind of (S, S)-2, the preparation method of 8-diazabicyclo [4,3,0] nonane, it is characterized in that: the solvent in the said step (1) is tetracol phenixin, trifluoroacetic acid, chloroform or acetic acid.
It is 3. according to claim 1 that a kind of (S, S)-2, the preparation method of 8-diazabicyclo [4,3,0] nonane is characterized in that: the mol ratio 0.38-0.6 of the 2,3 dimethyl pyridine in the said step (1) and the N-chlorosuccinimide that adds first.
4. according to claim 1 a kind of (S, S)-2, the preparation method of 8-diazabicyclo [4,3,0] nonane, it is characterized in that: the solvent in the said step (2) is toluene, acetonitrile or ethylene glycol monomethyl ether.
5. according to claim 1 a kind of (S, S)-2, the preparation method of 8-diazabicyclo [4,3,0] nonane is characterized in that: 2 in the said step (2), the mol ratio of 3-dichloromethyl pyridine hydrochloride and benzylamine is 0.5-1; 2, the mol ratio of 3-dichloromethyl pyridine hydrochloride, alkali, potassiumiodide is 1: 2-3: 0.4-0.6; Described filter cake is used washed with dichloromethane.
According to claim 1 or 5 described a kind of (S, S)-2, the preparation method of 8-diazabicyclo [4,3,0] nonane, it is characterized in that: the alkali in the said step (2) is soda ash light or salt of wormwood.
7. according to claim 1 a kind of (S, S)-2, the preparation method of 8-diazabicyclo [4,3,0] nonane, it is characterized in that: the solvent in the said step (3) is THF, ethylene glycol monomethyl ether, toluene or methyl alcohol.
8. according to claim 1 a kind of (S, S)-2, the preparation method of 8-diazabicyclo [4,3,0] nonane is characterized in that: palladium-carbon catalyst in the said step (3) uses Palladous chloride, palladous oxide or palladium hydroxide to be equal to alternative; Wherein catalyzer and substrate mol ratio are 1: 5-15.
9. according to claim 1 a kind of (S, S)-2,8-diazabicyclo [4; 3,0] preparation method of nonane is characterized in that: the chemical resolving agent in the said step (4) is D-(-)-tartrate or D-(-)-to methoxy dibenzoyl tartrate; 2; The mol ratio of 8-diazabicyclo [4,3,0] nonane and resolving agent is 0.8-1.5.
10. according to claim 1 a kind of (S, S)-2, the preparation method of 8-diazabicyclo [4,3,0] nonane; It is characterized in that: the chiral separation in the said step (4), concrete steps comprise, D-(-)-tartrate is dissolved in N in 80 ℃-100 ℃, in the dinethylformamide; 0.5-1 be added drop-wise in hour (S, S)-2,8-diazabicyclo [4,3; 0] N of nonane, in the dinethylformamide solution, equality of temperature stirs 1-2.5h, stirs 12-24h after being cooled to room temperature naturally; Filter, filtering filter cake is used N successively, and dinethylformamide and ethanol are washed; Filter cake is soluble in water, stir the NaOH solution that adds 10-15mol/L down, stirring at room 1-1.5h, the hexanaphthene extraction, extraction liquid is dry, filter, the filtrating evaporate to dryness get the yellow mucus shape (S, S)-2,8-diazabicyclo [4,3,0] nonane.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418606A (en) * | 2015-11-24 | 2016-03-23 | 浙江省诸暨合力化学对外贸易有限公司 | Preparation method for 8-benzyl-2,8-diazabicyclo[4.3.0]-nonane |
| WO2022166440A1 (en) * | 2021-02-06 | 2022-08-11 | 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 |
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| US3709894A (en) * | 1971-02-11 | 1973-01-09 | Research Corp | Thieno(3,4-b)pyridine and thieno(3,4-c)pyridine |
| 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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| US3709894A (en) * | 1971-02-11 | 1973-01-09 | Research Corp | Thieno(3,4-b)pyridine and thieno(3,4-c)pyridine |
| 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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| 常瑜等: "(S，S)-8-苄基-2，8-二氮杂双环[4. 3. 0]壬烷拆分工艺的优化", 《太原理工大学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418606A (en) * | 2015-11-24 | 2016-03-23 | 浙江省诸暨合力化学对外贸易有限公司 | Preparation method for 8-benzyl-2,8-diazabicyclo[4.3.0]-nonane |
| WO2022166440A1 (en) * | 2021-02-06 | 2022-08-11 | 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 |
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Application publication date: 20120725 |