CN104402891A - Synthetic method of drug intermediate 3-methyl-3,7-diazabicyclo(3.3.0)octane - Google Patents
Synthetic method of drug intermediate 3-methyl-3,7-diazabicyclo(3.3.0)octane Download PDFInfo
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- CN104402891A CN104402891A CN201410664648.9A CN201410664648A CN104402891A CN 104402891 A CN104402891 A CN 104402891A CN 201410664648 A CN201410664648 A CN 201410664648A CN 104402891 A CN104402891 A CN 104402891A
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- methyl
- diazabicyclo
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- octane
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- SLEWLTIVHNDEEP-UHFFFAOYSA-N CN(CC1C(N2Cc3ccccc3)=O)CC1C2=O Chemical compound CN(CC1C(N2Cc3ccccc3)=O)CC1C2=O SLEWLTIVHNDEEP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a synthetic method of a drug intermediate 3-methyl-3,7-diazabicyclo(3.3.0)octane. The method comprises steps as follows: (1) cyclization reaction: heating N-methyl glycine and dimethyl maleate in methylbenzene in a backflow manner to prepare a compound a; (2) reacting the compound a with benzylamine to prepare a compound b; (3) reducing the compound b with lithium aluminum hydride under the protection of argon to produce a compound c; (4) performing hydrogenation deprotection on the compound c to prepare the drug intermediate 3-methyl-3,7-diazabicyclo(3.3.0)octane. According to the synthetic method, the utilization cost is low, the dimethyl maleate and the N-methyl glycine which are easy to obtain are used as raw materials, and the 3-methyl-3,7-diazabicyclo(3.3.0)octane is obtained through four steps of reactions. The method is low in cost, simple in reaction, easy to control, simple to treat and high in yield, the raw materials are easy to obtain, and large-scale production is facilitated.
Description
Technical field
The present invention relates to a kind of synthetic method of pharmaceutical intermediate 3-methyl-3,7-diazabicyclo [3.3.0] octane.
Background technology
In recent years, 3-methyl-3,7-diazabicyclo [3.3.0] octane becomes the important intermediate of numerous new drug, and synthetic method synthetic route of the prior art is longer, and yield is lower, the loaded down with trivial details difficulty of aftertreatment, and raw materials cost is high, and the three wastes are many, pollutes large.Therefore scientific research personnel is still constantly seeking more easy synthetic method.
Summary of the invention
The invention provides a kind of synthetic method of pharmaceutical intermediate 3-methyl-3,7-diazabicyclo [3.3.0] octane, to solve defect of the prior art.
In order to achieve the above object, technical scheme of the present invention is: a kind of synthetic method of pharmaceutical intermediate 3-methyl-3,7-diazabicyclo [3.3.0] octane, and the method comprises the following step:
Step (1): cyclization: sarcosine, dimethyl maleate reflux in toluene is prepared compound a;
Step (2): compound a and benzylamine react prepares compound b;
Step (3): under argon shield, compound b is hydrogenated the reduction of aluminium lithium and generates compound c;
Step (4): obtain 3-methyl-3,7-diazabicyclo [3.3.0] octane pharmaceutical intermediate through hydrogenation deprotection;
As preferably, step (1) reaction times is 2 ~ 4h.
As preferably, step (2) reaction solvent is dehydrated alcohol.
As preferably, step (3) reaction solvent is anhydrous tetrahydro furan.
As preferably, the catalyzer used in step (4) is palladium catalyst.
The synthetic method of pharmaceutical intermediate 3-methyl-3,7-diazabicyclo [3.3.0] octane provided by the invention, utilizes cost low, the dimethyl maleate of easy acquisition and sarcosine are raw material, through four-step reaction, obtain 3-methyl-3,7-diazabicyclo [3.3.0] octane.Present method raw material is easy to get, and cost is low, and simply, be easy to control, process is simple, and yield is high in reaction, and is easy to amplify production.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.
A kind of structural formula is the synthetic method of I pharmaceutical intermediate 3-methyl-3,7-diazabicyclo [3.3.0] octane, and the method comprises the following step:
Step (1): cyclization: sarcosine, dimethyl maleate reflux in toluene is prepared compound a;
Specific as follows: by 5.2g (0.05mol, 1.5eq) sarcosine, 4.2g (0.034mol, 1eq) dimethyl maleate and 3g (0.1mol, 3eq) be added in the toluene of 60ml, reflux, stir 2h, TLC detects, react completely, be spin-dried for, in residual night, add 50mL ethyl acetate, with saturated common salt water washing (3*50mL), dried over mgso, is spin-dried for obtain compound a (8.8g, 80%).
Step (2): compound a and benzylamine react prepares compound b;
Specific as follows: 4.02g (20mmol, 1eq) compound a and 2.15g (20mmol, 1eq) benzylamine to be joined in 40mL dehydrated alcohol, heated overnight at reflux, TLC endpoint detection, be spin-dried for obtain 4g compound b, yield 81%
Step (3): under argon shield, compound b is hydrogenated the reduction of aluminium lithium and generates compound c;
Specific as follows: under argon shield, 6.6g Li-Al hydrogen (0.18mol is added in 250mL is tri-bottles, 3eq) with the anhydrous THF of 180mL, under ice-water bath, 14g compound b (0.058mo1) is dissolved in the anhydrous THF of 70mL, be added drop-wise in reaction flask, after dropwising, naturally room temperature is risen to, stir 40min, then reflux 5h, be cooled to 0 degree, drip 6.6g water successively, 13.3g15% aqueous sodium hydroxide solution and 6.6g water, filter, filter cake washed with diethylether 3 times, each use 200mL ether, filtrate is by extracted with diethyl ether 3 times, each use 200mL ether, by dried over mgso, filtration is spin-dried for, underpressure distillation obtains compound c (7g, 58%)
Step (4): obtain 3-methyl-3,7-diazabicyclo [3.3.0] octane pharmaceutical intermediate through hydrogenation deprotection.
Specific as follows: in the single port bottle of 100mL, 8g compound c to be dissolved in 80mL methyl alcohol, 0.8gPd/C (10%w/w) joins in reaction solution, by hydrogen exchange three times, stirred overnight at room temperature, TLC detection reaction is complete, filter, concentrated, 3-methyl-3,7-diazabicyclo [3.3.0] octane (4.2g must be obtained, 93%), purity GC > 98.0%.
The synthetic method of pharmaceutical intermediate 3-methyl-3,7-diazabicyclo [3.3.0] octane provided by the invention, utilizes cost low, the dimethyl maleate of easy acquisition and sarcosine are raw material, through four-step reaction, obtain 3-methyl-3,7-diazabicyclo [3.3.0] octane.Present method raw material is easy to get, and cost is low, and simply, be easy to control, process is simple, and yield is high in reaction, and is easy to amplify production.The present invention is the synthetic method that green chemical industry provides a practicable medicine intermediate.
Those skilled in the art can carry out various change and modification to invention and not depart from the spirit and scope of the present invention.Like this, if these amendments of the present invention and modification belong within the scope of the claims in the present invention and equivalent technologies thereof, then the present invention is also intended to comprise these change and modification.
Claims (5)
1. the synthetic method of pharmaceutical intermediate 3-methyl-3,7-diazabicyclo [3.3.0] octane, it is characterized in that, the method comprises the following step:
Step (1): cyclization: sarcosine, dimethyl maleate reflux in toluene is prepared compound a;
Step (2): compound a and benzylamine react prepares compound b;
Step (3): under argon shield, compound b is hydrogenated the reduction of aluminium lithium and generates compound c;
Step (4): obtain 3-methyl-3,7-diazabicyclo [3.3.0] octane pharmaceutical intermediate through hydrogenation deprotection;
2. the synthetic method of pharmaceutical intermediate 3-methyl-3,7-diazabicyclo [3.3.0] octane according to claim 1, it is characterized in that, step (1) reaction times is 2 ~ 4h.
3. the synthetic method of pharmaceutical intermediate 3-methyl-3,7-diazabicyclo [3.3.0] octane according to claim 1, it is characterized in that, step (2) reaction solvent is dehydrated alcohol.
4. the synthetic method of pharmaceutical intermediate 3-methyl-3,7-diazabicyclo [3.3.0] octane according to claim 1 is characterized in that, step (3) reaction solvent is anhydrous tetrahydro furan.
5. the synthetic method of pharmaceutical intermediate 3-methyl-3,7-diazabicyclo [3.3.0] octane according to claim 1 is characterized in that, the catalyzer used in step (4) is palladium catalyst.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410664648.9A CN104402891A (en) | 2014-11-19 | 2014-11-19 | Synthetic method of drug intermediate 3-methyl-3,7-diazabicyclo(3.3.0)octane |
| PCT/CN2014/092277 WO2016078108A1 (en) | 2014-11-19 | 2014-11-26 | Method for synthesizing 3-methyl-3,7-diazabicyclo[3.3.0]octane pharmaceutical intermediate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410664648.9A CN104402891A (en) | 2014-11-19 | 2014-11-19 | Synthetic method of drug intermediate 3-methyl-3,7-diazabicyclo(3.3.0)octane |
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| CN104402891A true CN104402891A (en) | 2015-03-11 |
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| CN201410664648.9A Pending CN104402891A (en) | 2014-11-19 | 2014-11-19 | Synthetic method of drug intermediate 3-methyl-3,7-diazabicyclo(3.3.0)octane |
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| WO (1) | WO2016078108A1 (en) |
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| CN111363005B (en) * | 2018-12-26 | 2021-08-17 | 联宁（苏州）生物制药有限公司 | Synthetic method for antibody-coupled drug intermediate CLB-SN38 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5179090A (en) * | 1989-09-11 | 1993-01-12 | Klaus Rudolf | Condensed diazepinones and medicaments containing these compounds |
| CN101619064A (en) * | 2008-07-01 | 2010-01-06 | 韶远化学科技（上海）有限公司 | Synthesis and process method for novel polynitrogen heterocycle pharmaceutical intermediates |
| CN102101861A (en) * | 2008-07-01 | 2011-06-22 | 韶远化学科技（上海）有限公司 | Synthesis and process method of nitrogen-containing bis-heterocyclic medicine intermediate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102180874B (en) * | 2008-07-01 | 2012-09-05 | 韶远化学科技（上海）有限公司 | Synthetic process method for azabicyclo medicinal intermediates |
| CN102977105A (en) * | 2012-11-30 | 2013-03-20 | 盛世泰科生物医药技术(苏州)有限公司 | Synthesis method of 3(methyl),7-diazabicyclooctane |
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- 2014-11-19 CN CN201410664648.9A patent/CN104402891A/en active Pending
- 2014-11-26 WO PCT/CN2014/092277 patent/WO2016078108A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5179090A (en) * | 1989-09-11 | 1993-01-12 | Klaus Rudolf | Condensed diazepinones and medicaments containing these compounds |
| CN101619064A (en) * | 2008-07-01 | 2010-01-06 | 韶远化学科技（上海）有限公司 | Synthesis and process method for novel polynitrogen heterocycle pharmaceutical intermediates |
| CN102101861A (en) * | 2008-07-01 | 2011-06-22 | 韶远化学科技（上海）有限公司 | Synthesis and process method of nitrogen-containing bis-heterocyclic medicine intermediate |
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| WO2016078108A1 (en) | 2016-05-26 |
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Application publication date: 20150311 |