CN101857596A - Synthetic method of mono-N-tert-butoxycarbonyl-2,6-diazaspiro[3,3]heptane oxalate - Google Patents
Synthetic method of mono-N-tert-butoxycarbonyl-2,6-diazaspiro[3,3]heptane oxalate Download PDFInfo
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- CN101857596A CN101857596A CN200910057042A CN200910057042A CN101857596A CN 101857596 A CN101857596 A CN 101857596A CN 200910057042 A CN200910057042 A CN 200910057042A CN 200910057042 A CN200910057042 A CN 200910057042A CN 101857596 A CN101857596 A CN 101857596A
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Abstract
The invention relates to a synthetic method of mono-N-tert-butoxycarbonyl-2,6-diazaspiro[3,3]heptane oxalate, which mainly solves the technical problems of excessive reaction steps and different purification of reaction products of a traditional synthetic method. The synthetic method of the mono-N-tert-butoxycarbonyl-2,6-diazaspiro[3, 3]heptane oxalate is characterized by comprising the following steps of: by using 2,6-diphenyl methyl-2,6-diazaspiro[3,3] heptane as a raw material, carrying out hydrogenation and mono-Boc protection reaction in the presence of di-tert-butyl dicarbonate to obtain mono-N-tert-butoxycarbonyl-2,6-diazaspiro[3,3]heptane, and then carrying out salt formation with oxalic acid to obtain the mono-N-tert-butoxycarbonyl-2,6-diazaspiro[3,3]heptane oxalate which can be used as template small molecules for synthesizing diverse compound libraries.
Description
Technical field:
The present invention relates to a kind of mono-N-tert-butoxycarbonyl base-2, the synthetic method of 6-diazaspiro [3,3] heptane oxalate.
Background technology:
2,6-diazaspiro [3,3] heptane has the charming ring system of structure.Can be used as the template small molecules and synthesize diversified compound library, might in medicine industry, provide new pharmacophoric group by the lead compound for future.For mono-N-tert-butoxycarbonyl base-2, the preparation of 6-diazaspiro [3,3] heptane, bibliographical information is less.Erick M.Carreira has reported that in June, 2008 with 3-bromine tetramethylolmethane be raw material, by 2 of eight steps prepared in reaction mono-N-tert-butoxycarbonyl base protection, the oxalate of 6-diazaspiro [3,3] heptane.The synthetic route of report is long, and wherein three steps were used column chromatography purification, and whole process has been used carbon tetrabromide, and triphenyl phosphorus etc. are to the disagreeableness reagent of environment.Ether has been used as reaction and processing solvent in many places.Wherein the single step reaction time is three days, overlong time, and wherein single step reaction has been used supersound process.These factors make this route be not suitable for amplifying and produce.(Organic?letters，2008，Vol.10，No，163525-3526)。Explore a simple synthetic route of easily amplifying again is the striving direction of current researcher always.
The document synthetic route:
Summary of the invention:
The object of the invention is to provide a kind of effective preparation mono-N-tert-butoxycarbonyl base-2, and the synthetic method of 6-diazaspiro [3,3] heptane oxalate mainly solves the technical problem that existing synthetic method reactions steps is too much, reaction product is difficult for purifying.It is few that the present invention has the reaction conditions step, reaction temperature and, short characteristics of reaction times, be suitable for large-scale production;
Technical scheme of the present invention: the present invention is with 2,6-ditan-2,6-diazaspiro [3,3] heptane is a precursor, (this precursor preparation is seen J.Org.Chem.2006,71,7885) prepare mono-N-tert-butoxycarbonyl base-2 by hydrogenation, 6-diazaspiro [3,3] heptane, the present invention can adopt 5% palladium carbon as catalyzer, obtain mono-N-tert-butoxycarbonyl base-2 by the oxalic acid salify, 6-diazaspiro [3,3] heptane oxalate, purity is more than 95%.
Be specially: 2 of mono-N-tert-butoxycarbonyl base protection; 6-diazaspiro [3; 3] synthetic method of heptane may further comprise the steps: with 2, and 6-ditan-2; 6-diazaspiro [3; 3] heptane is a raw material, protects the reaction for the treatment of different things alike by hydrogenation and Boc in the presence of tert-Butyl dicarbonate, and question response finishes the back and obtains mono-N-tert-butoxycarbonyl base-2 with the oxalic acid salify; the oxalate of 6-diazaspiro [3,3] heptane.
Concrete synthesis route of the present invention is as follows:
Described hydrogenation and Boc protective reaction are: with intermediate 2; 6-ditan-2; 6-diazaspiro [3; 3] heptane is a raw material; in etoh solvent or methyl alcohol, be catalyzer with 5% palladium carbon; pressure 15～20psi, 10～50 ℃ of temperature are directly added tert-Butyl dicarbonate and are carried out single Boc protection in the solution.2 of the mono-N-tert-butoxycarbonyl base protection that obtains; 6-diazaspiro [3; 3] heptane comes out by becoming oxalate purifying from system; again through methyl alcohol or ethanol making beating; filtration obtains mono-N-tert-butoxycarbonyl base-2,6-diazaspiro [3,3] heptane oxalate white solid; purity＞95%, yield 80～90%.
Beneficial effect of the present invention: sharpest edges of the present invention are that step is short, and aftertreatment technology is simple.Directly in system, add the tert-Butyl dicarbonate protection and be convenient to remove ditane,, directly obtain the oxalate product of purity＞95% by becoming oxalate from system, to separate out product.
This technical process easy handling, less demanding to production unit; The required production time is shorter, has saved production cost; Both be fit to laboratory short run preparation, be fit to carry out large-scale industrial production again.
Embodiment:
Following embodiment illustrates content of the present invention better.But the present invention is not limited to following embodiment.
Embodiment 1
Mono-N-tert-butoxycarbonyl base-2,6-diazaspiro [3,3] heptane synthetic
With 2,6-ditan-2,6-diazaspiro [3,3] heptane (50g 0.116mol) is dissolved in the 750ml ethanol, adds 5% palladium carbon (10g) of water content 50%, in reaction solution, add then tert-Butyl dicarbonate (25.37g, 0.116mol).Whole system hydrogen pressure is 15psi, and temperature is elevated to 30 ℃, stirs 15 hours.Reduce to about 10 ℃, filter palladium carbon, be evaporated to volume and be approximately 250ml.Oxalic acid (10.0g) is dissolved in the 700ml ethanol, then above-mentioned 250ml reaction solution is slowly dripped, a large amount of white solids are separated out.Filtration obtains white solid, then white solid is pulled an oar with about 200ml ethanol, cleans, and refilters, and oven dry promptly obtains white solid (25g, yield 89%).
Embodiment 2
Mono-N-tert-butoxycarbonyl base-2,6-diazaspiro [3,3] heptane synthetic
With 2,6-ditan-2,6-diazaspiro [3,3] heptane (50g 0.116mol) is dissolved in the 750ml ethanol, adds 5% palladium carbon (10g) of water content 50%, in reaction solution, add then tert-Butyl dicarbonate (25.37g, 0.116mol).Whole system hydrogen pressure is 20psi, and control reaction temperature stirred 15 hours about 10 ℃.Filter palladium carbon, be evaporated to volume and be approximately 250ml.Oxalic acid (10.0g) is dissolved in the 700ml ethanol, then above-mentioned 250ml reaction solution is slowly dripped, a large amount of white solids are separated out.Filtration obtains white solid, then white solid is pulled an oar with about 200ml ethanol, cleans, and refilters, and oven dry promptly obtains white solid (24g, yield 86%).
Embodiment 3
2 of mono-N-tert-butoxycarbonyl base protection, 6-diazaspiro [3,3] heptane synthetic
With 2,6-ditan-2,6-diazaspiro [3,3] heptane (50g 0.116mol) is dissolved in the 750ml methyl alcohol,
Add 5% palladium carbon (10g) of water content 50%, in reaction solution, add then tert-Butyl dicarbonate (25.37g, 0.116mol).Whole system hydrogen pressure is 20psi, and temperature is elevated to 50 ℃, stirs 5 hours.Reduce to about 10 ℃, filter palladium carbon, be evaporated to volume and be approximately 250ml.Oxalic acid (10.0g) is dissolved in the 700ml methyl alcohol, then above-mentioned 250ml reaction solution is slowly dripped, a large amount of white solids are separated out.Filtration obtains white solid, then white solid is pulled an oar with about 200ml methyl alcohol, cleans, and refilters, and oven dry promptly obtains white solid (24g, yield 86%).
Embodiment 4
2 of mono-N-tert-butoxycarbonyl base protection, 6-diazaspiro [3,3] heptane synthetic
With 2,6-ditan-2,6-diazaspiro [3,3] heptane (50g 0.116mol) is dissolved in the 750ml methyl alcohol, adds 5% palladium carbon (10g) of water content 50%, in reaction solution, add then tert-Butyl dicarbonate (25.37g, 0.116mol).Whole system hydrogen pressure is 15psi, and temperature is elevated to 50 ℃, stirs 5 hours.Reduce to about 10 ℃, filter palladium carbon, be evaporated to volume and be approximately 250ml.Oxalic acid (10.0g) is dissolved in the 700ml methyl alcohol, then above-mentioned 250ml reaction solution is slowly dripped, a large amount of white solids are separated out.Filtration obtains white solid, then white solid is pulled an oar with about 200ml methyl alcohol, cleans, and refilters, and oven dry promptly obtains white solid (23g, yield 82%).
Embodiment 5
2 of mono-N-tert-butoxycarbonyl base protection, 6-diazaspiro [3,3] heptane synthetic
With 2,6-ditan-2,6-diazaspiro [3,3] heptane (50g 0.116mol) is dissolved in the 750ml ethanol, adds 5% palladium carbon (10g) of water content 50%, in reaction solution, add then tert-Butyl dicarbonate (25.37g, 0.116mol).Whole system hydrogen pressure is 15psi, and temperature is elevated to 50 ℃, stirs 5 hours.Reduce to about 10 ℃, filter palladium carbon, be evaporated to volume and be approximately 250ml.Oxalic acid (10.0g) is dissolved in the 700ml ethanol, then above-mentioned 250ml reaction solution is slowly dripped, a large amount of white solids are separated out.Filtration obtains white solid, then white solid is pulled an oar with about 200ml ethanol, cleans, and refilters, and oven dry promptly obtains white solid (25g, yield 89%).
Embodiment 6
2 of mono-N-tert-butoxycarbonyl base protection, 6-diazaspiro [3,3] heptane synthetic
With 2,6-ditan-2,6-diazaspiro [3,3] heptane (50g 0.116mol) is dissolved in the 750ml methyl alcohol, adds 5% palladium carbon (10g) of water content 50%, in reaction solution, add then tert-Butyl dicarbonate (25.37g, 0.116mol).Whole system hydrogen pressure is 20psi, and temperature is elevated to 30 ℃, stirs 15 hours.Reduce to about 10 ℃, filter palladium carbon, be evaporated to volume and be approximately 250ml.Oxalic acid (10.0g) is dissolved in the 700ml methyl alcohol, then above-mentioned 250ml reaction solution is slowly dripped, a large amount of white solids are separated out.Filtration obtains white solid, then white solid is pulled an oar with about 150ml methyl alcohol, cleans, and refilters, and oven dry promptly obtains white solid (23g, yield 82%).
Claims (5)
1. mono-N-tert-butoxycarbonyl base-2, the synthetic method of 6-diazaspiro [3,3] heptane oxalate; it is characterized in that may further comprise the steps: with 2,6-diphenyl methyl-2,6-diazaspiro [3; 3] heptane is a raw material; in the presence of tert-Butyl dicarbonate, carry out hydrogenation and single Boc protective reaction, obtain mono-N-tert-butoxycarbonyl base-2,6-diazaspiro [3; 3] heptane; again by obtaining mono-N-tert-butoxycarbonyl base-2 with the oxalic acid salify, 6-diazaspiro [3,3] heptane oxalate.
2. mono-N-tert-butoxycarbonyl base-2 according to claim 1; 6-diazaspiro [3; 3] synthetic method of heptane oxalate; it is characterized in that: with the method for the treatment of different things alike with intermediate 2; 6-ditan-2; 6-diazaspiro [3,3] heptane directly carries out hydrogenation and removes ditane group and single Boc protective reaction in the presence of tert-Butyl dicarbonate, then by becoming oxalate to obtain the finished product.
3. single tertbutyloxycarbonyl-2 according to claim 2, the synthetic method of 6-diazaspiro [3,3] heptane oxalate is characterized in that: catalyzer is added in reaction, and catalyzer is 5% palladium carbon, and hydrogenation reaction pressure is 15～20psi, and temperature of reaction is 10～50 ℃.
4. single tertbutyloxycarbonyl 2 according to claim 2, the synthetic method of 6-diazaspiro [3,3] heptane oxalate, it is characterized in that: hydrogenation carries out in solvent, and solvent for use is methyl alcohol or ethanol.
5. 2 of single tertbutyloxycarbonyl protection according to claim 2, the synthetic method of 6-diazaspiro [3,3] heptane oxalate is characterized in that: hydrogenation utilizes oxalate crystallization in methyl alcohol or ethanol to obtain the finished product after finishing.
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| CN105315287A (en) * | 2014-08-04 | 2016-02-10 | 杭州沙力医药科技有限公司 | Synthetic method for mono-N-t-butyloxycarbonyl-2,6-bisazaspiro[3,3] heptane hydrochloride |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315287A (en) * | 2014-08-04 | 2016-02-10 | 杭州沙力医药科技有限公司 | Synthetic method for mono-N-t-butyloxycarbonyl-2,6-bisazaspiro[3,3] heptane hydrochloride |
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Application publication date: 20101013 |