CN108689885A - A kind of preparation method of N-Boc-1,2- diaminoethanes - Google Patents
A kind of preparation method of N-Boc-1,2- diaminoethanes Download PDFInfo
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- CN108689885A CN108689885A CN201810494193.9A CN201810494193A CN108689885A CN 108689885 A CN108689885 A CN 108689885A CN 201810494193 A CN201810494193 A CN 201810494193A CN 108689885 A CN108689885 A CN 108689885A
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- diaminoethanes
- boc
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- carbonic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C68/00—Preparation of esters of carbonic or haloformic acids
- C07C68/06—Preparation of esters of carbonic or haloformic acids from organic carbonates
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of N-Boc-1, the preparation method of 2- diaminoethanes the described method comprises the following steps:1) di-tert-butyl dicarbonate is added dropwise by phenol, catalyst and alkali soluble in the first organic solvent, under low temperature and is dissolved in the prepared solution of the first organic solvent, the phenyl-carbonic acid tert-butyl ester is obtained by the reaction;2) 1,2-Diaminoethane is dissolved in the first organic solvent, the phenyl-carbonic acid tert-butyl ester is added dropwise, final product is obtained by the reaction.The method of the present invention separating-purifying is easy to operate, and range of reaction temperature is small, and reaction yield is high, and cost of material is low.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to the preparation method of N-Boc-1,2- diaminoethanes.
Background technology
In the chemical synthesis of medicine intermediate, N-Boc-1,2- diaminoethanes is widely used as bioconjugate chemistry
Structural unit.Especially this kind of mono-protected ethylene diamine derivative is usually used in preparing pharmacological activity analog and introduces ethylenediamine
Spacerarm.The method for preferably preparing this kind of mono-protected ethylene diamine derivative is just particularly important.
The synthetic method of traditional single Boc protection ethylenediamines, is all mainly anti-by quantitative Boc acid anhydrides and ethylenediamine
It answers, then qualified single Boc protection ethylenediamines is purified by the method for column chromatography.But the amount of Boc and reaction conversion ratio and receipts
Rate has a direct impact, and control is not proper to make N-Boc-1, and the content of 2- diaminoethanes is low, and the two of 1,2-Diaminoethane
A end group amino all has higher activity, it is easy to double protection products are generated with Boc anhydride reactions.In addition Xu,
Zhigang;DiCesare,John C.;Baures, Paul W. are it is proposed that by sloughing on N-Cbz-N '-Boc- ethylenediamines
Cbz protecting groups will first prepare N-Cbz-N '-Boc- second two to prepare single protection ethylenediamine although there is very high yield
Amine, this is but quite unsatisfactory in cost.
Invention content
The present invention provides a kind of N-Boc-1,2- diaminoethanes, and the N-Boc-1,2- diaminoethanes is by 1,2-
Diaminoethanes and t-butyl carbonate are constituted, and structural formula isIts molecular formula is
C8H18N2O2, molecular weight 174.24.
The phenyl-carbonic acid tert-butyl ester prepares N-Boc-1, and the method for 2- diaminoethanes, the preparation method includes following step
Suddenly:1) dropwise addition di-tert-butyl dicarbonate, which is dissolved in first, by phenol, catalyst and alkali soluble in the first organic solvent, under low temperature has
The prepared solution of solvent, is obtained by the reaction the phenyl-carbonic acid tert-butyl ester;2) that 1,2- diaminoethanes is dissolved in first is organic molten
In agent, the phenyl-carbonic acid tert-butyl ester is added dropwise, final product is obtained by the reaction, the molecular formula of wherein phenol is
Preferably, first organic solvent is one kind in ethyl alcohol, methanol, DMF.
The catalyst is 4-dimethylaminopyridine.
The alkali is one kind in triethylamine or DIPEA.
The molar ratio of phenol, 4-dimethylaminopyridine, two t-butyl carbonate of triethylamine in the step 1) is 1:
0.1:1.5:1.0, reaction temperature is -5~0 degree, reaction time 1h.
The molar ratio of 1,2- diaminoethanes and the phenyl-carbonic acid tert-butyl ester in the step 2) is 1:1, reaction temperature is
80 degree, reaction time 18h.
The process route of the preparation method is as follows:
The invention has the advantages that:
1. a kind of N-Boc-1 of the present invention, 2- diaminoethanes is often connect with n-hydroxysuccinimide and extensive
For biomedicine field.
2. a kind of N-Boc-1 of the present invention, 2- diaminoethanes and preparation method thereof, separating-purifying is easy to operate,
And range of reaction temperature controllability is strong, reaction conversion ratio is high, low raw-material cost.
Specific implementation mode
N-Boc-1,2- diaminoethanes
(1) 160g (1.7mol, 1.0eq) phenol is dissolved in 1.1L ethyl alcohol, addition triethylamine 258.3g (2.55mol,
1.5eq), 4-dimethylaminopyridine 20g (0.17mol, 0.1eq).The second of Boc2O is slowly added dropwise to -5~0 DEG C in liquid nitrogen cooling
Alcoholic solution (371.6gBoc2O is dissolved in 150ml ethyl alcohol) after being added dropwise, warms naturally to that 1h is stirred at room temperature, TLC is detected to benzene
Phenol has reacted, and stops reaction.Concentration removes solvent, and column chromatographic isolation and purification obtains light yellow liquid, yield 81.8%.Nuclear-magnetism number
According to as follows:1HNMR (400MHz, CDCl3):1.4~1.51 (s, 9H);7.26 (t, 1H);7.29 (m, 2H) 7.42 (t, 2H).
(2) 102.1g (1.7mol, 1.0eq) ethylenediamine is dissolved in ethyl alcohol, lower dropwise addition phenyl-carbonic acid uncle is stirred at room temperature
Butyl ester (1.7mol, 1.0eq) is warming up to 80 DEG C of back flow reaction 18h after being added dropwise, TLC, which is detected to raw material, has reacted rear stopping
Reaction.Concentration removes ethyl alcohol, obtains weak yellow liquid and is diluted with water, and PH=3, dichloromethane (3* are adjusted with 2N dilute hydrochloric acid
It 400ml) extracts, retains water phase.Water phase uses 2N sodium hydroxide solutions to adjust PH=12 again, and dichloromethane (5*500ml) is used in combination to extract
It takes, it is yellow oily liquid that organic phase drying, which is concentrated to give product,.1HNMR (400MHz, CDCl3):1.40 (s, 9H);3.33~
3.41 (f, 2H);3.68~3.72 (t, 2H).
Claims (5)
1. a kind of preparing N-Boc-1, the method for 2- diaminoethanes, which is characterized in that synthetic route is as follows:
Specifically include following steps:1) by phenol, catalyst and alkali soluble in the first organic solvent, two carbonic acid two are added dropwise under low temperature
The tert-butyl ester is dissolved in the prepared solution of the first organic solvent, and the phenyl-carbonic acid tert-butyl ester is obtained by the reaction;
2) 1,2-Diaminoethane is dissolved in the first organic solvent, the phenyl-carbonic acid tert-butyl ester is added dropwise, final product is obtained by the reaction,
The molecular formula of wherein phenol is
2. a kind of according to claim 1 prepare N-Boc-1, the method for 2- diaminoethanes, which is characterized in that described
One organic solvent is one kind in ethyl alcohol, methanol, DMF.
3. according to a kind of method preparing N-Boc-1,2- diaminoethanes of claim 2, it is characterised in that, the catalyst
For 4-dimethylaminopyridine, structural formula isAlkali is one kind in triethylamine or DIPEA, 1,2- diamino second
Alkane molecular formula is
4. according to claim 2 or 3 state a kind of preparing N-Boc-1, the method for 2- diaminoethanes, which is characterized in that
The molar ratio of phenol, 4- lutidines, two t-butyl carbonate of triethylamine in the step 1) is 1:0.1:1.5:1.0, instead
It is -5~0 degree to answer temperature, reaction time 1h.
5. according to claim 4 state a kind of preparing N-Boc-1, the method for 2- diaminoethanes, which is characterized in that described
The molar ratio of 1,2- diaminoethanes and the phenyl-carbonic acid tert-butyl ester is 1 in step 2):1, reaction temperature is 80 degree, and the reaction time is
18h。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810494193.9A CN108689885A (en) | 2018-05-22 | 2018-05-22 | A kind of preparation method of N-Boc-1,2- diaminoethanes |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810494193.9A CN108689885A (en) | 2018-05-22 | 2018-05-22 | A kind of preparation method of N-Boc-1,2- diaminoethanes |
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| CN108689885A true CN108689885A (en) | 2018-10-23 |
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| CN201810494193.9A Withdrawn CN108689885A (en) | 2018-05-22 | 2018-05-22 | A kind of preparation method of N-Boc-1,2- diaminoethanes |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107089928A (en) * | 2017-05-07 | 2017-08-25 | 济南同路医药科技发展有限公司 | The synthetic method of N Boc L propargylglycines |
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2018
- 2018-05-22 CN CN201810494193.9A patent/CN108689885A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107089928A (en) * | 2017-05-07 | 2017-08-25 | 济南同路医药科技发展有限公司 | The synthetic method of N Boc L propargylglycines |
Non-Patent Citations (2)
| Title |
|---|
| HELMS, BRETT 等: "Site-specific protein and peptide immobilization on a biosensor surface by pulsed native chemical ligation", 《CHEMBIOCHEM》 * |
| YUE-LONG XU 等: "Carbocatalysis: reduced graphene oxide-catalyzed Boc protection of hydroxyls and graphite oxide-catalyzed deprotection", 《TETRAHEDRON LETTERS》 * |
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Application publication date: 20181023 |