CN102936220B - BOC protection method for aminopyridine - Google Patents
BOC protection method for aminopyridine Download PDFInfo
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- CN102936220B CN102936220B CN201210464133.5A CN201210464133A CN102936220B CN 102936220 B CN102936220 B CN 102936220B CN 201210464133 A CN201210464133 A CN 201210464133A CN 102936220 B CN102936220 B CN 102936220B
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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 to react under alkaline condition with (BOC) 2O, DMAP with (BOC) 2O or aminopyridine by aminopyridine.But there is following defect in existing technique: part aminopyridine does not react or reaction yield is very low or the product that has two BOC to replace.
Summary of the invention
The object of the invention is to develop that a kind of simple process, yield are high, the method for good reaction selectivity.
Technical scheme:
The method of aminopyridine BOC protection comprises the following steps: with aminopyridine and (BOC) 2O under EDCI, HOBT and alkali exist, be dissolved in solvent and react, obtain the aminopyridine of BOC protection, reaction formula is as follows:
In above-mentioned reaction formula, the amino in described aminopyridine is on pyridine ring on any one carbon atom, and described R is the electron donating group on pyridine ring, and described solvent is tetrahydrofuran (THF), methylene dichloride, the one in methyl alcohol or 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.
Described aftertreatment technology is: reaction solution is through washing, and organic layer is dry, filtering and concentrating, and column chromatography obtains 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 the shortcomings such as the low and poor selectivity of reaction difficulty, reaction yield that current existing synthetic method exists.With aminopyridine and (BOC) aminopyridine of 2O reaction preparation BOC protection under EDCI, HOBT and alkali exist.This technique easy handling, yield is high, selectivity good.
Embodiment
Embodiment 1
2-(t-butoxycarbonyl amino) pyridine synthetic
At room temperature, PA (1g, 10.6mmol) is dissolved in methylene dichloride (10mL), under whipped state, adds respectively EDCI(3g, 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 obtains 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
3-(t-butoxycarbonyl amino) pyridine synthetic
At room temperature, 3-aminopyridine (1g, 10.6mmol) is dissolved in methylene dichloride (10mL), under whipped state, adds respectively EDCI(6.1g, 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), organic layer is dry, filtering and concentrating, and column chromatography obtains 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
4-(t-butoxycarbonyl amino) pyridine synthetic
At room temperature, 4-aminopyridine (1g, 10.6mmol) is dissolved in methylene dichloride (10mL), under whipped state, adds respectively EDCI(4.6g, 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 obtains 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
4-(t-butoxycarbonyl amino)-3-picoline synthetic
At room temperature, 4-amino-3 picolines (1g, 9mmol) are dissolved in tetrahydrofuran (THF) (15mL), under whipped state, add respectively EDCI(2.6g, 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, reaction solution add water (30mL), ethyl acetate (30mL × 3) extraction, merges organic layer dry, filtering and concentrating, column chromatography obtains 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
3-(t-butoxycarbonyl amino)-4-picoline synthetic
At room temperature, by 3-amino-4 picolines (1g, 9mmol), be dissolved in tetrahydrofuran (THF) (15mL), under whipped state, add respectively EDCI(5.2g, 27mmol), 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, reaction solution add water (30mL), ethyl acetate (30mL × 3) extraction, merges organic layer dry, filtering and concentrating, column chromatography obtains 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.
Comparative example 1
2-(t-butoxycarbonyl amino) pyridine synthetic
At room temperature, by PA (1g, 10.6mmol), be dissolved in methylene dichloride (10mL), under whipped state, add respectively DMAP (0.01g), 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 obtains 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 (8)
1. a method for aminopyridine BOC protection, is characterized in that comprising the following steps: with aminopyridine and (BOC)
2o is dissolved in solvent and reacts under EDCI, HOBT and alkali existence, obtains the aminopyridine of BOC protection, and reaction formula is as follows:
In above-mentioned reaction formula, the amino in described aminopyridine is on pyridine ring on any one carbon atom, and described R is the electron donating group on pyridine ring, and described solvent is tetrahydrofuran (THF), methylene dichloride, the one in methyl alcohol or Isosorbide-5-Nitrae-dioxane.
2. 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.
3. the method for aminopyridine BOC protection according to claim 1 and 2, is characterized in that, described alkali is triethylamine.
4. according to the method for the aminopyridine BOC protection of claim 1, it is characterized in that, described BOC protective reaction is reacted to terminal under room temperature, whipped state, and aftertreatment makes straight product.
5. 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.
6. 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 obtains straight product.
7. 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.
8. according to the method for the aminopyridine BOC protection of claim 1, it is characterized in that, described R is methyl.
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