CN102936220A - BOC protection method for aminopyridine - Google Patents
BOC protection method for aminopyridine Download PDFInfo
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- CN102936220A CN102936220A CN2012104641335A CN201210464133A CN102936220A CN 102936220 A CN102936220 A CN 102936220A CN 2012104641335 A CN2012104641335 A CN 2012104641335A CN 201210464133 A CN201210464133 A CN 201210464133A CN 102936220 A CN102936220 A CN 102936220A
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Abstract
The invention discloses a BOC protection method for aminopyridine. The BOC protection method includes steps of dissolving aminopyridine and (BOC) 2O in solvent on presence of EDCI, HOBT and alkali to react to obtain BOC protected aminopyridine, wherein the amino group of the aminopyridine is positioned on optional carbon atom on the pyridine ring, the R is the donor substituent group on the pyridine ring, the solvent can be one of tetrahydrofuran, dichloromethane, methyl alcohol or 1,4-dioxane. By the BOC protection method, technical problems such as difficulty in synthesis reaction, poor selectivity and low yield in the prior art are solved, and the BOC protected aminopyridine can be obtained with high yield and high selectivity, and can be applied to organic synthesis widely.
Description
Technical field
The present invention relates to a kind of method of aminopyridine BOC protection.
Background technology
The aminopyridine of BOC protection has widespread use in organic synthesis.The synthetic great majority of general this compounds are that 2O, DMAP react under alkaline condition with (BOC) 2O or aminopyridine and (BOC) by aminopyridine.But there is following defective in existing technique: the part aminopyridine does not react or reaction yield is very low or the product of two BOC replacements is arranged.
Summary of the invention
The objective of the invention is to develop the method for a kind of simple process, yield height, good reaction selectivity.
Technical scheme:
The method of aminopyridine BOC protection may further comprise the steps: with aminopyridine and (BOC) 2O in the presence of EDCI, HOBT and alkali, be dissolved in solvent and react, obtain the aminopyridine that BOC protects, reaction formula is as follows:
In the above-mentioned reaction formula, the amino in the described aminopyridine is on the pyridine ring on any one carbon atom, and described R is the electron donating group on the pyridine ring, and described solvent is tetrahydrofuran (THF), methylene dichloride, a kind of in methyl alcohol or the Isosorbide-5-Nitrae-dioxane.
The preferred technical scheme of the present invention is:
The mol ratio of described An base Bi Ding ︰ (BOC) 2O ︰ EDCI ︰ HOBT ︰ alkali is 1 ︰ 1.5-2 ︰ 1.5-3 ︰ 0.05-0.1 ︰ 1.5-3.
Described alkali is triethylamine.
Described BOC protective reaction is reacted to terminal under room temperature, whipped state, and aftertreatment makes straight product.
Described reaction end is followed the tracks of with TLC, and disappearing to raw material is terminal point.
Described aftertreatment technology is: reaction solution is through washing, and organic layer is dry, filtering and concentrating, and column chromatography gets straight product.
The described reaction times is 0.5-2 hour.
Described R is methyl.
Temperature of reaction of the present invention is room temperature, and yield can be stablized and reaches 80-90%.
Beneficial effect of the present invention: the invention solves reaction difficulty that present existing synthetic method exists, reaction yield is low and the shortcoming such as poor selectivity.With aminopyridine and (BOC) 2O in the presence of EDCI, HOBT and alkali, react and prepares the aminopyridine that BOC protects.This technique easy handling, yield are high, selectivity is good.
Embodiment
Embodiment 1
The 2-(t-butoxycarbonyl amino) pyridine is synthetic
At room temperature, PA (1g, 10.6mmol) is dissolved in the methylene dichloride (10mL), adds respectively EDCI(3g under the whipped state, 16mmol), HOBT(0.07g, 0.5mmol), TEA(1.6g, 16mmol) and (BOC) 2O(3.5g, 16mmol).Room temperature continues to stir 2h.TLC follows the tracks of, and raw material disappears, reaction solution washing (20mL * 2), organic layer is dry, filtering and concentrating, and column chromatography gets straight product 1.85g, 1HNMR DMSO δ: 1.52 (s, 9H), 7.18-7.19 (m, 1H), 7.24 (m, 1H), 7.52 (m, 1H), 8.18-8.19 (m, 1H); Yield: 90%.Single two BOC compound ratio is 20:1.
Embodiment 2
The 3-(t-butoxycarbonyl amino) pyridine is synthetic
At room temperature, 3-aminopyridine (1g, 10.6mmol) is dissolved in the methylene dichloride (10mL), adds respectively EDCI(6.1g under the whipped state, 31.8mmol), HOBT(0.14g, 1.0mmol), TEA(3.2g, 31.8mmol) and (BOC) 2O(4.6g, 21.2mmol).Room temperature continues to stir 1h.TLC follows the tracks of, and raw material disappears, reaction solution washing (20mL * 2), and organic layer is dry, filtering and concentrating, column chromatography gets straight product 1.75g, 1HNMR DMSO δ: 1.53 (s, 9H), 7.26-7.27 (m, 1H), 7.40 (m, 1H), 8.23 (m, 1H), 8.53 (m, 1H); Yield: 85%.Single two BOC compound ratio is 50:1.。
Example 3
The 4-(t-butoxycarbonyl amino) pyridine is synthetic
At room temperature, 4-aminopyridine (1g, 10.6mmol) is dissolved in the methylene dichloride (10mL), adds respectively EDCI(4.6g under the whipped state, 23.8mmol), HOBT(0.1g, 0.8mmol), TEA(2.4g, 23.8mmol) and (BOC) 2O(4.0g, 18.5mmol).Room temperature continues to stir 0.5h.TLC follows the tracks of, and raw material disappears, reaction solution washing (20mL * 2), and organic layer is dry, filtering and concentrating, column chromatography gets straight product 1.85g, 1HNMR DMSO δ: 1.53 (s, 9H), 7.34-7.35 (m, 2H), 8.42-8.44 (m, 2H); Yield: 90%.Single two BOC compound ratio is 20:1.
Example 4
The 4-(t-butoxycarbonyl amino)-3-picoline synthetic
At room temperature, amino-3 picolines (1g, 9mmol) of 4-are dissolved in the tetrahydrofuran (THF) (15mL), add respectively EDCI(2.6g under the whipped state, 13.5mmol), HOBT(0.06g, 0.45mmol), TEA(1.87mL, 13.5mmol) and (BOC) 2O(2.9g, 13.5mmol).Room temperature continues to stir 2h.TLC follows the tracks of, and raw material disappears, and reaction solution adds water (30mL), ethyl acetate (30mL * 3) extraction, it is dry to merge organic layer, filtering and concentrating, column chromatography gets straight product 1.5g, 1HNMR DMSO δ: 1.53 (s, 9H), (2.21 s, 3H), 7.98-7.99 (m, 1H), 8.26 (m, 1H), (8.33-8.35 m, 1H); Yield: 80%.Single two BOC compound ratio is 10:1.
Embodiment 5
The 3-(t-butoxycarbonyl amino)-4-picoline synthetic
At room temperature, with amino-4 picolines (1g, 9mmol) of 3-, be dissolved in the tetrahydrofuran (THF) (15mL), add respectively EDCI(5.2g, 27mmol under the whipped state), HOBT(0.12g, 0.9mmol), TEA(2.7g, 27mmol) and (BOC) 2O(3.9g, 18mmol).Room temperature continues to stir 2h.TLC follows the tracks of, and raw material disappears, and reaction solution adds water (30mL), ethyl acetate (30mL * 3) extraction, it is dry to merge organic layer, filtering and concentrating, column chromatography gets straight product 1.6g, 1HNMR DMSO δ: 1.45 (s, 9H), (2.20 s, 3H), 7.02 (m, 1H), 8.16-8.18 (m, 1H), (8.79 m, 1H); Yield: 85%.Single two BOC compound ratio is 20:1.
The comparative example 1
The 2-(t-butoxycarbonyl amino) pyridine is synthetic
At room temperature, with PA (1g, 10.6mmol), be dissolved in the methylene dichloride (10mL), add respectively DMAP (0.01g) under the whipped state, TEA(2.2mL, 16mmol) and (BOC) 2O(3.5g, 16mmol).Room temperature continues to stir 8h.TLC follows the tracks of, and still has raw material, reaction solution washing (20mL * 2), organic layer is dry, filtering and concentrating, and column chromatography gets straight product 1.2g, 1HNMR DMSO δ: 1.52 (s, 9H), 7.18-7.19 (m, 1H), 7.24 (m, 1H), 7.52 (m, 1H), 8.18-8.19 (m, 1H); Yield: 60%.Single two BOC compound ratio is 4:1.
The measured data of comparative example 1-5 is as shown in the table, and wherein the processing step of comparing embodiment 2-4 is with comparing embodiment 1.
Claims (10)
1. the technical problems such as the present invention mainly solves in the present building-up reactions and is difficult to react, and selectivity is bad, and yield is low, the aminopyridine that obtains the BOC protection of high yield, highly selective.
2. the aminopyridine of the BOC protection of the present invention's acquisition has widespread use in organic synthesis.
3. the method for aminopyridine BOC protection is characterized in that may further comprise the steps: with aminopyridine and (BOC)
2O is dissolved in solvent and reacts in the presence of EDCI, HOBT and alkali, obtain the aminopyridine of BOC protection, and reaction formula is as follows:
In the above-mentioned reaction formula, the amino in the described aminopyridine is on the pyridine ring on any one carbon atom, and described R is the electron donating group on the pyridine ring, and described solvent is tetrahydrofuran (THF), methylene dichloride, a kind of in methyl alcohol or the Isosorbide-5-Nitrae-dioxane.
4. the method for aminopyridine BOC protection according to claim 1 is characterized in that, described An base Bi Ding ︰ (BOC)
2The mol ratio of O ︰ EDCI ︰ HOBT ︰ alkali is 1 ︰ 1.5-2 ︰ 1.5-3 ︰ 0.05-0.1 ︰ 1.5-3.
5. the method for aminopyridine BOC protection according to claim 1 and 2 is characterized in that described alkali is triethylamine.
6. according to claim 1 the method for aminopyridine BOC protection is characterized in that described BOC protective reaction is reacted to terminal under room temperature, whipped state, and aftertreatment makes straight product.
7. the method for the aminopyridine BOC protection of stating according to claim 4 is characterized in that described reaction end is followed the tracks of with TLC, and disappearing to raw material is terminal point.
8. the method for the aminopyridine BOC protection of stating according to claim 4 is characterized in that described aftertreatment technology is: reaction solution is through washing, and organic layer is dry, filtering and concentrating, and column chromatography gets straight product.
9. the method for the aminopyridine BOC protection of stating according to claim 4 is characterized in that the described reaction times is 0.5-2 hour.
10. according to claim 1 the method for aminopyridine BOC protection is characterized in that described R is methyl.
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| CN201210464133.5A CN102936220B (en) | 2012-11-15 | 2012-11-15 | BOC protection method for aminopyridine |
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| CN201210464133.5A CN102936220B (en) | 2012-11-15 | 2012-11-15 | BOC protection method for aminopyridine |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1428824A1 (en) * | 1999-05-21 | 2004-06-16 | Abbott Laboratories | Heterocyclic substituted aminoazacycles useful as central nervous system agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1428824A1 (en) * | 1999-05-21 | 2004-06-16 | Abbott Laboratories | Heterocyclic substituted aminoazacycles useful as central nervous system agents |
Non-Patent Citations (1)
| Title |
|---|
| ATUL CHASKAR ET AL: "Practical and Green Approach for N-Boc Protection of Amines Catalyzed by Indion 190 Resin", 《JOURNAL OF THE KOREAN CHEMICAL SOCIETY》 * |
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