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Structure of 3731-52-0 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With bromine; isopentyl nitrite In dichloromethane
[0091] The following example explores reaction conditions and product distributions.[0092] Under reaction conditions identical to those used with Br2 in Example 1, the reaction using I2 failed to produce the corresponding iodide. Using 10 equivalents of ICl however, as the source of halogen, results in the production of the chloride in good yield without the iodide. In a further experiment, using 10 equivalents of IBr, gives again the bromide with no detectable iodide. As per the postulated mechanism, the highly reactive nitryl, and nitrosyl halides are the active intermediates, neither of which is known for the iodide.[0093] Conversion of 3-aminomethylpyridine to the bromide in THF was similar to that in CH2Cl2, but decreased in the series CH2Cl2 > CHCl3 > CCl4 with a <n="23"/>corresponding increase in the formation of the hydroxy product. Reaction in DMF or DMSO led to remaining AMP under the conditions used and also favored the formation of the 3-(hydroxymethyl)pyridine over the bromide.[0094] Using isoamyl nitrite as the nitroso source, and Br2, in water, resulted in an incomplete conversion with very little of the hydroxy product. In all solvents tried using NaNC>2 and acetic acid as the nitroso source, an increased amount of 3- (hydroxymethyl)pyridine was observed with incomplete reaction of the AMP. This latter observation is most likely due to the use of NaNO2 for the nitroso source, as in CH2CI2, increasing additions of acetic acid up to 5 equivalents with respect to AMP, favored the formation of the bromide over the hydroxy product. The stronger acid TFA, however, favored the formation of the hydroxy product over the bromide. Addition of an organic base, TEA, piperidine or DBU was well tolerated up to about 1 equivalent with respect to AMP, with higher amounts leading to less conversion of the amine to the bromide. Reaction to the bromide was concentration dependent with best conversions occurring at > 0.1 molar in AMP (variable only explored in GH2CI2).[0095] Conversion of 3-aminomethyl pyridine to 3-(bromomethyl)pyridine using 1.1 equiv. of nitrosyl agent and 5 equiv. of bromine was conducted in the solvent shown in Table 1 below. A sample of the reaction mixture was taken and quenched by high dilution into acetontrile for ESMS analysis of the products. 3- (hydroxymethyl)pyridine and 3-(isoamyloxymethyl)pyridine side products were also observed in addition to starting material and 3-(bromomethyl)pyridine product.Table 1. Product distributions based on variation in reaction conditions. <n="24"/>[0096] The gas evolved by the reaction was identified by collecting the gas in an IR cell and examining by IR Spectroscopy. The IR spectrum in Figure 2 shows the N2O gas produced by the reaction.[0097] Conversion of 3-aminomethylpyridine (AMP) and 2-(2- aminoethyl)pyrdine (AEP) is efficient, as demonstrated by the HPLC traces before and after reaction as shown in Figure 3.[0098] Titration of the addition of both isoamyl nitrite and Bτ2 to AMP shows that the amine disappears from the reaction mixture on addition of one equivalent each of isoamyl nitrite and Br2. As shown in Figure 7, the formation of the product 3- (bromomethyl)pyridine is out of phase with the disappearance of reacting amine, and in some trials was almost completely absent until greater than one equivalent of isoamyl nitrite and Br2 was added. Best yields were obtained by a total addition of about five equivalents OfBr2.in this example
79%
With bromine; isopentyl nitrite In tetrahydrofuran
[0091] The following example explores reaction conditions and product distributions.[0092] Under reaction conditions identical to those used with Br2 in Example 1, the reaction using I2 failed to produce the corresponding iodide. Using 10 equivalents of ICl however, as the source of halogen, results in the production of the chloride in good yield without the iodide. In a further experiment, using 10 equivalents of IBr, gives again the bromide with no detectable iodide. As per the postulated mechanism, the highly reactive nitryl, and nitrosyl halides are the active intermediates, neither of which is known for the iodide.[0093] Conversion of 3-aminomethylpyridine to the bromide in THF was similar to that in CH2Cl2, but decreased in the series CH2Cl2 > CHCl3 > CCl4 with a <n="23"/>corresponding increase in the formation of the hydroxy product. Reaction in DMF or DMSO led to remaining AMP under the conditions used and also favored the formation of the 3-(hydroxymethyl)pyridine over the bromide.[0094] Using isoamyl nitrite as the nitroso source, and Br2, in water, resulted in an incomplete conversion with very little of the hydroxy product. In all solvents tried using NaNC>2 and acetic acid as the nitroso source, an increased amount of 3- (hydroxymethyl)pyridine was observed with incomplete reaction of the AMP. This latter observation is most likely due to the use of NaNO2 for the nitroso source, as in CH2CI2, increasing additions of acetic acid up to 5 equivalents with respect to AMP, favored the formation of the bromide over the hydroxy product. The stronger acid TFA, however, favored the formation of the hydroxy product over the bromide. Addition of an organic base, TEA, piperidine or DBU was well tolerated up to about 1 equivalent with respect to AMP, with higher amounts leading to less conversion of the amine to the bromide. Reaction to the bromide was concentration dependent with best conversions occurring at > 0.1 molar in AMP (variable only explored in GH2CI2).[0095] Conversion of 3-aminomethyl pyridine to 3-(bromomethyl)pyridine using 1.1 equiv. of nitrosyl agent and 5 equiv. of bromine was conducted in the solvent shown in Table 1 below. A sample of the reaction mixture was taken and quenched by high dilution into acetontrile for ESMS analysis of the products. 3- (hydroxymethyl)pyridine and 3-(isoamyloxymethyl)pyridine side products were also observed in addition to starting material and 3-(bromomethyl)pyridine product.Table 1. Product distributions based on variation in reaction conditions. <n="24"/>[0096] The gas evolved by the reaction was identified by collecting the gas in an IR cell and examining by IR Spectroscopy. The IR spectrum in Figure 2 shows the N2O gas produced by the reaction.[0097] Conversion of 3-aminomethylpyridine (AMP) and 2-(2- aminoethyl)pyrdine (AEP) is efficient, as demonstrated by the HPLC traces before and after reaction as shown in Figure 3.[0098] Titration of the addition of both isoamyl nitrite and Bτ2 to AMP shows that the amine disappears from the reaction mixture on addition of one equivalent each of isoamyl nitrite and Br2. As shown in Figure 7, the formation of the product 3- (bromomethyl)pyridine is out of phase with the disappearance of reacting amine, and in some trials was almost completely absent until greater than one equivalent of isoamyl nitrite and Br2 was added. Best yields were obtained by a total addition of about five equivalents OfBr2.in this example
67%
With bromine; isopentyl nitrite In chloroform
[0091] The following example explores reaction conditions and product distributions.[0092] Under reaction conditions identical to those used with Br2 in Example 1, the reaction using I2 failed to produce the corresponding iodide. Using 10 equivalents of ICl however, as the source of halogen, results in the production of the chloride in good yield without the iodide. In a further experiment, using 10 equivalents of IBr, gives again the bromide with no detectable iodide. As per the postulated mechanism, the highly reactive nitryl, and nitrosyl halides are the active intermediates, neither of which is known for the iodide.[0093] Conversion of 3-aminomethylpyridine to the bromide in THF was similar to that in CH2Cl2, but decreased in the series CH2Cl2 > CHCl3 > CCl4 with a <n="23"/>corresponding increase in the formation of the hydroxy product. Reaction in DMF or DMSO led to remaining AMP under the conditions used and also favored the formation of the 3-(hydroxymethyl)pyridine over the bromide.[0094] Using isoamyl nitrite as the nitroso source, and Br2, in water, resulted in an incomplete conversion with very little of the hydroxy product. In all solvents tried using NaNC>2 and acetic acid as the nitroso source, an increased amount of 3- (hydroxymethyl)pyridine was observed with incomplete reaction of the AMP. This latter observation is most likely due to the use of NaNO2 for the nitroso source, as in CH2CI2, increasing additions of acetic acid up to 5 equivalents with respect to AMP, favored the formation of the bromide over the hydroxy product. The stronger acid TFA, however, favored the formation of the hydroxy product over the bromide. Addition of an organic base, TEA, piperidine or DBU was well tolerated up to about 1 equivalent with respect to AMP, with higher amounts leading to less conversion of the amine to the bromide. Reaction to the bromide was concentration dependent with best conversions occurring at > 0.1 molar in AMP (variable only explored in GH2CI2).[0095] Conversion of 3-aminomethyl pyridine to 3-(bromomethyl)pyridine using 1.1 equiv. of nitrosyl agent and 5 equiv. of bromine was conducted in the solvent shown in Table 1 below. A sample of the reaction mixture was taken and quenched by high dilution into acetontrile for ESMS analysis of the products. 3- (hydroxymethyl)pyridine and 3-(isoamyloxymethyl)pyridine side products were also observed in addition to starting material and 3-(bromomethyl)pyridine product.Table 1. Product distributions based on variation in reaction conditions. <n="24"/>[0096] The gas evolved by the reaction was identified by collecting the gas in an IR cell and examining by IR Spectroscopy. The IR spectrum in Figure 2 shows the N2O gas produced by the reaction.[0097] Conversion of 3-aminomethylpyridine (AMP) and 2-(2- aminoethyl)pyrdine (AEP) is efficient, as demonstrated by the HPLC traces before and after reaction as shown in Figure 3.[0098] Titration of the addition of both isoamyl nitrite and Bτ2 to AMP shows that the amine disappears from the reaction mixture on addition of one equivalent each of isoamyl nitrite and Br2. As shown in Figure 7, the formation of the product 3- (bromomethyl)pyridine is out of phase with the disappearance of reacting amine, and in some trials was almost completely absent until greater than one equivalent of isoamyl nitrite and Br2 was added. Best yields were obtained by a total addition of about five equivalents OfBr2.in this example
61%
With bromine; isopentyl nitrite In water
[0091] The following example explores reaction conditions and product distributions.[0092] Under reaction conditions identical to those used with Br2 in Example 1, the reaction using I2 failed to produce the corresponding iodide. Using 10 equivalents of ICl however, as the source of halogen, results in the production of the chloride in good yield without the iodide. In a further experiment, using 10 equivalents of IBr, gives again the bromide with no detectable iodide. As per the postulated mechanism, the highly reactive nitryl, and nitrosyl halides are the active intermediates, neither of which is known for the iodide.[0093] Conversion of 3-aminomethylpyridine to the bromide in THF was similar to that in CH2Cl2, but decreased in the series CH2Cl2 > CHCl3 > CCl4 with a <n="23"/>corresponding increase in the formation of the hydroxy product. Reaction in DMF or DMSO led to remaining AMP under the conditions used and also favored the formation of the 3-(hydroxymethyl)pyridine over the bromide.[0094] Using isoamyl nitrite as the nitroso source, and Br2, in water, resulted in an incomplete conversion with very little of the hydroxy product. In all solvents tried using NaNC>2 and acetic acid as the nitroso source, an increased amount of 3- (hydroxymethyl)pyridine was observed with incomplete reaction of the AMP. This latter observation is most likely due to the use of NaNO2 for the nitroso source, as in CH2CI2, increasing additions of acetic acid up to 5 equivalents with respect to AMP, favored the formation of the bromide over the hydroxy product. The stronger acid TFA, however, favored the formation of the hydroxy product over the bromide. Addition of an organic base, TEA, piperidine or DBU was well tolerated up to about 1 equivalent with respect to AMP, with higher amounts leading to less conversion of the amine to the bromide. Reaction to the bromide was concentration dependent with best conversions occurring at > 0.1 molar in AMP (variable only explored in GH2CI2).[0095] Conversion of 3-aminomethyl pyridine to 3-(bromomethyl)pyridine using 1.1 equiv. of nitrosyl agent and 5 equiv. of bromine was conducted in the solvent shown in Table 1 below. A sample of the reaction mixture was taken and quenched by high dilution into acetontrile for ESMS analysis of the products. 3- (hydroxymethyl)pyridine and 3-(isoamyloxymethyl)pyridine side products were also observed in addition to starting material and 3-(bromomethyl)pyridine product.Table 1. Product distributions based on variation in reaction conditions. <n="24"/>[0096] The gas evolved by the reaction was identified by collecting the gas in an IR cell and examining by IR Spectroscopy. The IR spectrum in Figure 2 shows the N2O gas produced by the reaction.[0097] Conversion of 3-aminomethylpyridine (AMP) and 2-(2- aminoethyl)pyrdine (AEP) is efficient, as demonstrated by the HPLC traces before and after reaction as shown in Figure 3.[0098] Titration of the addition of both isoamyl nitrite and Bτ2 to AMP shows that the amine disappears from the reaction mixture on addition of one equivalent each of isoamyl nitrite and Br2. As shown in Figure 7, the formation of the product 3- (bromomethyl)pyridine is out of phase with the disappearance of reacting amine, and in some trials was almost completely absent until greater than one equivalent of isoamyl nitrite and Br2 was added. Best yields were obtained by a total addition of about five equivalents OfBr2.in this example
57%
With bromine; isopentyl nitrite In dimethyl sulfoxide
[0091] The following example explores reaction conditions and product distributions.[0092] Under reaction conditions identical to those used with Br2 in Example 1, the reaction using I2 failed to produce the corresponding iodide. Using 10 equivalents of ICl however, as the source of halogen, results in the production of the chloride in good yield without the iodide. In a further experiment, using 10 equivalents of IBr, gives again the bromide with no detectable iodide. As per the postulated mechanism, the highly reactive nitryl, and nitrosyl halides are the active intermediates, neither of which is known for the iodide.[0093] Conversion of 3-aminomethylpyridine to the bromide in THF was similar to that in CH2Cl2, but decreased in the series CH2Cl2 > CHCl3 > CCl4 with a <n="23"/>corresponding increase in the formation of the hydroxy product. Reaction in DMF or DMSO led to remaining AMP under the conditions used and also favored the formation of the 3-(hydroxymethyl)pyridine over the bromide.[0094] Using isoamyl nitrite as the nitroso source, and Br2, in water, resulted in an incomplete conversion with very little of the hydroxy product. In all solvents tried using NaNC>2 and acetic acid as the nitroso source, an increased amount of 3- (hydroxymethyl)pyridine was observed with incomplete reaction of the AMP. This latter observation is most likely due to the use of NaNO2 for the nitroso source, as in CH2CI2, increasing additions of acetic acid up to 5 equivalents with respect to AMP, favored the formation of the bromide over the hydroxy product. The stronger acid TFA, however, favored the formation of the hydroxy product over the bromide. Addition of an organic base, TEA, piperidine or DBU was well tolerated up to about 1 equivalent with respect to AMP, with higher amounts leading to less conversion of the amine to the bromide. Reaction to the bromide was concentration dependent with best conversions occurring at > 0.1 molar in AMP (variable only explored in GH2CI2).[0095] Conversion of 3-aminomethyl pyridine to 3-(bromomethyl)pyridine using 1.1 equiv. of nitrosyl agent and 5 equiv. of bromine was conducted in the solvent shown in Table 1 below. A sample of the reaction mixture was taken and quenched by high dilution into acetontrile for ESMS analysis of the products. 3- (hydroxymethyl)pyridine and 3-(isoamyloxymethyl)pyridine side products were also observed in addition to starting material and 3-(bromomethyl)pyridine product.Table 1. Product distributions based on variation in reaction conditions. <n="24"/>[0096] The gas evolved by the reaction was identified by collecting the gas in an IR cell and examining by IR Spectroscopy. The IR spectrum in Figure 2 shows the N2O gas produced by the reaction.[0097] Conversion of 3-aminomethylpyridine (AMP) and 2-(2- aminoethyl)pyrdine (AEP) is efficient, as demonstrated by the HPLC traces before and after reaction as shown in Figure 3.[0098] Titration of the addition of both isoamyl nitrite and Bτ2 to AMP shows that the amine disappears from the reaction mixture on addition of one equivalent each of isoamyl nitrite and Br2. As shown in Figure 7, the formation of the product 3- (bromomethyl)pyridine is out of phase with the disappearance of reacting amine, and in some trials was almost completely absent until greater than one equivalent of isoamyl nitrite and Br2 was added. Best yields were obtained by a total addition of about five equivalents OfBr2.in this example
54%
With bromine; isopentyl nitrite In tetrachloromethane
[0091] The following example explores reaction conditions and product distributions.[0092] Under reaction conditions identical to those used with Br2 in Example 1, the reaction using I2 failed to produce the corresponding iodide. Using 10 equivalents of ICl however, as the source of halogen, results in the production of the chloride in good yield without the iodide. In a further experiment, using 10 equivalents of IBr, gives again the bromide with no detectable iodide. As per the postulated mechanism, the highly reactive nitryl, and nitrosyl halides are the active intermediates, neither of which is known for the iodide.[0093] Conversion of 3-aminomethylpyridine to the bromide in THF was similar to that in CH2Cl2, but decreased in the series CH2Cl2 > CHCl3 > CCl4 with a <n="23"/>corresponding increase in the formation of the hydroxy product. Reaction in DMF or DMSO led to remaining AMP under the conditions used and also favored the formation of the 3-(hydroxymethyl)pyridine over the bromide.[0094] Using isoamyl nitrite as the nitroso source, and Br2, in water, resulted in an incomplete conversion with very little of the hydroxy product. In all solvents tried using NaNC>2 and acetic acid as the nitroso source, an increased amount of 3- (hydroxymethyl)pyridine was observed with incomplete reaction of the AMP. This latter observation is most likely due to the use of NaNO2 for the nitroso source, as in CH2CI2, increasing additions of acetic acid up to 5 equivalents with respect to AMP, favored the formation of the bromide over the hydroxy product. The stronger acid TFA, however, favored the formation of the hydroxy product over the bromide. Addition of an organic base, TEA, piperidine or DBU was well tolerated up to about 1 equivalent with respect to AMP, with higher amounts leading to less conversion of the amine to the bromide. Reaction to the bromide was concentration dependent with best conversions occurring at > 0.1 molar in AMP (variable only explored in GH2CI2).[0095] Conversion of 3-aminomethyl pyridine to 3-(bromomethyl)pyridine using 1.1 equiv. of nitrosyl agent and 5 equiv. of bromine was conducted in the solvent shown in Table 1 below. A sample of the reaction mixture was taken and quenched by high dilution into acetontrile for ESMS analysis of the products. 3- (hydroxymethyl)pyridine and 3-(isoamyloxymethyl)pyridine side products were also observed in addition to starting material and 3-(bromomethyl)pyridine product.Table 1. Product distributions based on variation in reaction conditions. <n="24"/>[0096] The gas evolved by the reaction was identified by collecting the gas in an IR cell and examining by IR Spectroscopy. The IR spectrum in Figure 2 shows the N2O gas produced by the reaction.[0097] Conversion of 3-aminomethylpyridine (AMP) and 2-(2- aminoethyl)pyrdine (AEP) is efficient, as demonstrated by the HPLC traces before and after reaction as shown in Figure 3.[0098] Titration of the addition of both isoamyl nitrite and Bτ2 to AMP shows that the amine disappears from the reaction mixture on addition of one equivalent each of isoamyl nitrite and Br2. As shown in Figure 7, the formation of the product 3- (bromomethyl)pyridine is out of phase with the disappearance of reacting amine, and in some trials was almost completely absent until greater than one equivalent of isoamyl nitrite and Br2 was added. Best yields were obtained by a total addition of about five equivalents OfBr2.in this example
47%
With bromine; acetic acid; sodium nitrite In dimethyl sulfoxide
[0091] The following example explores reaction conditions and product distributions.[0092] Under reaction conditions identical to those used with Br2 in Example 1, the reaction using I2 failed to produce the corresponding iodide. Using 10 equivalents of ICl however, as the source of halogen, results in the production of the chloride in good yield without the iodide. In a further experiment, using 10 equivalents of IBr, gives again the bromide with no detectable iodide. As per the postulated mechanism, the highly reactive nitryl, and nitrosyl halides are the active intermediates, neither of which is known for the iodide.[0093] Conversion of 3-aminomethylpyridine to the bromide in THF was similar to that in CH2Cl2, but decreased in the series CH2Cl2 > CHCl3 > CCl4 with a <n="23"/>corresponding increase in the formation of the hydroxy product. Reaction in DMF or DMSO led to remaining AMP under the conditions used and also favored the formation of the 3-(hydroxymethyl)pyridine over the bromide.[0094] Using isoamyl nitrite as the nitroso source, and Br2, in water, resulted in an incomplete conversion with very little of the hydroxy product. In all solvents tried using NaNC>2 and acetic acid as the nitroso source, an increased amount of 3- (hydroxymethyl)pyridine was observed with incomplete reaction of the AMP. This latter observation is most likely due to the use of NaNO2 for the nitroso source, as in CH2CI2, increasing additions of acetic acid up to 5 equivalents with respect to AMP, favored the formation of the bromide over the hydroxy product. The stronger acid TFA, however, favored the formation of the hydroxy product over the bromide. Addition of an organic base, TEA, piperidine or DBU was well tolerated up to about 1 equivalent with respect to AMP, with higher amounts leading to less conversion of the amine to the bromide. Reaction to the bromide was concentration dependent with best conversions occurring at > 0.1 molar in AMP (variable only explored in GH2CI2).[0095] Conversion of 3-aminomethyl pyridine to 3-(bromomethyl)pyridine using 1.1 equiv. of nitrosyl agent and 5 equiv. of bromine was conducted in the solvent shown in Table 1 below. A sample of the reaction mixture was taken and quenched by high dilution into acetontrile for ESMS analysis of the products. 3- (hydroxymethyl)pyridine and 3-(isoamyloxymethyl)pyridine side products were also observed in addition to starting material and 3-(bromomethyl)pyridine product.Table 1. Product distributions based on variation in reaction conditions. <n="24"/>[0096] The gas evolved by the reaction was identified by collecting the gas in an IR cell and examining by IR Spectroscopy. The IR spectrum in Figure 2 shows the N2O gas produced by the reaction.[0097] Conversion of 3-aminomethylpyridine (AMP) and 2-(2- aminoethyl)pyrdine (AEP) is efficient, as demonstrated by the HPLC traces before and after reaction as shown in Figure 3.[0098] Titration of the addition of both isoamyl nitrite and Bτ2 to AMP shows that the amine disappears from the reaction mixture on addition of one equivalent each of isoamyl nitrite and Br2. As shown in Figure 7, the formation of the product 3- (bromomethyl)pyridine is out of phase with the disappearance of reacting amine, and in some trials was almost completely absent until greater than one equivalent of isoamyl nitrite and Br2 was added. Best yields were obtained by a total addition of about five equivalents OfBr2.in this example
22%
With bromine; isopentyl nitrite In N,N-dimethyl-formamide
[0091] The following example explores reaction conditions and product distributions.[0092] Under reaction conditions identical to those used with Br2 in Example 1, the reaction using I2 failed to produce the corresponding iodide. Using 10 equivalents of ICl however, as the source of halogen, results in the production of the chloride in good yield without the iodide. In a further experiment, using 10 equivalents of IBr, gives again the bromide with no detectable iodide. As per the postulated mechanism, the highly reactive nitryl, and nitrosyl halides are the active intermediates, neither of which is known for the iodide.[0093] Conversion of 3-aminomethylpyridine to the bromide in THF was similar to that in CH2Cl2, but decreased in the series CH2Cl2 > CHCl3 > CCl4 with a <n="23"/>corresponding increase in the formation of the hydroxy product. Reaction in DMF or DMSO led to remaining AMP under the conditions used and also favored the formation of the 3-(hydroxymethyl)pyridine over the bromide.[0094] Using isoamyl nitrite as the nitroso source, and Br2, in water, resulted in an incomplete conversion with very little of the hydroxy product. In all solvents tried using NaNC>2 and acetic acid as the nitroso source, an increased amount of 3- (hydroxymethyl)pyridine was observed with incomplete reaction of the AMP. This latter observation is most likely due to the use of NaNO2 for the nitroso source, as in CH2CI2, increasing additions of acetic acid up to 5 equivalents with respect to AMP, favored the formation of the bromide over the hydroxy product. The stronger acid TFA, however, favored the formation of the hydroxy product over the bromide. Addition of an organic base, TEA, piperidine or DBU was well tolerated up to about 1 equivalent with respect to AMP, with higher amounts leading to less conversion of the amine to the bromide. Reaction to the bromide was concentration dependent with best conversions occurring at > 0.1 molar in AMP (variable only explored in GH2CI2).[0095] Conversion of 3-aminomethyl pyridine to 3-(bromomethyl)pyridine using 1.1 equiv. of nitrosyl agent and 5 equiv. of bromine was conducted in the solvent shown in Table 1 below. A sample of the reaction mixture was taken and quenched by high dilution into acetontrile for ESMS analysis of the products. 3- (hydroxymethyl)pyridine and 3-(isoamyloxymethyl)pyridine side products were also observed in addition to starting material and 3-(bromomethyl)pyridine product.Table 1. Product distributions based on variation in reaction conditions. <n="24"/>[0096] The gas evolved by the reaction was identified by collecting the gas in an IR cell and examining by IR Spectroscopy. The IR spectrum in Figure 2 shows the N2O gas produced by the reaction.[0097] Conversion of 3-aminomethylpyridine (AMP) and 2-(2- aminoethyl)pyrdine (AEP) is efficient, as demonstrated by the HPLC traces before and after reaction as shown in Figure 3.[0098] Titration of the addition of both isoamyl nitrite and Bτ2 to AMP shows that the amine disappears from the reaction mixture on addition of one equivalent each of isoamyl nitrite and Br2. As shown in Figure 7, the formation of the product 3- (bromomethyl)pyridine is out of phase with the disappearance of reacting amine, and in some trials was almost completely absent until greater than one equivalent of isoamyl nitrite and Br2 was added. Best yields were obtained by a total addition of about five equivalents OfBr2.in this example
30%
With bromine; acetic acid; sodium nitrite In water
[0091] The following example explores reaction conditions and product distributions.[0092] Under reaction conditions identical to those used with Br2 in Example 1, the reaction using I2 failed to produce the corresponding iodide. Using 10 equivalents of ICl however, as the source of halogen, results in the production of the chloride in good yield without the iodide. In a further experiment, using 10 equivalents of IBr, gives again the bromide with no detectable iodide. As per the postulated mechanism, the highly reactive nitryl, and nitrosyl halides are the active intermediates, neither of which is known for the iodide.[0093] Conversion of 3-aminomethylpyridine to the bromide in THF was similar to that in CH2Cl2, but decreased in the series CH2Cl2 > CHCl3 > CCl4 with a <n="23"/>corresponding increase in the formation of the hydroxy product. Reaction in DMF or DMSO led to remaining AMP under the conditions used and also favored the formation of the 3-(hydroxymethyl)pyridine over the bromide.[0094] Using isoamyl nitrite as the nitroso source, and Br2, in water, resulted in an incomplete conversion with very little of the hydroxy product. In all solvents tried using NaNC>2 and acetic acid as the nitroso source, an increased amount of 3- (hydroxymethyl)pyridine was observed with incomplete reaction of the AMP. This latter observation is most likely due to the use of NaNO2 for the nitroso source, as in CH2CI2, increasing additions of acetic acid up to 5 equivalents with respect to AMP, favored the formation of the bromide over the hydroxy product. The stronger acid TFA, however, favored the formation of the hydroxy product over the bromide. Addition of an organic base, TEA, piperidine or DBU was well tolerated up to about 1 equivalent with respect to AMP, with higher amounts leading to less conversion of the amine to the bromide. Reaction to the bromide was concentration dependent with best conversions occurring at > 0.1 molar in AMP (variable only explored in GH2CI2).[0095] Conversion of 3-aminomethyl pyridine to 3-(bromomethyl)pyridine using 1.1 equiv. of nitrosyl agent and 5 equiv. of bromine was conducted in the solvent shown in Table 1 below. A sample of the reaction mixture was taken and quenched by high dilution into acetontrile for ESMS analysis of the products. 3- (hydroxymethyl)pyridine and 3-(isoamyloxymethyl)pyridine side products were also observed in addition to starting material and 3-(bromomethyl)pyridine product.Table 1. Product distributions based on variation in reaction conditions. <n="24"/>[0096] The gas evolved by the reaction was identified by collecting the gas in an IR cell and examining by IR Spectroscopy. The IR spectrum in Figure 2 shows the N2O gas produced by the reaction.[0097] Conversion of 3-aminomethylpyridine (AMP) and 2-(2- aminoethyl)pyrdine (AEP) is efficient, as demonstrated by the HPLC traces before and after reaction as shown in Figure 3.[0098] Titration of the addition of both isoamyl nitrite and Bτ2 to AMP shows that the amine disappears from the reaction mixture on addition of one equivalent each of isoamyl nitrite and Br2. As shown in Figure 7, the formation of the product 3- (bromomethyl)pyridine is out of phase with the disappearance of reacting amine, and in some trials was almost completely absent until greater than one equivalent of isoamyl nitrite and Br2 was added. Best yields were obtained by a total addition of about five equivalents OfBr2.in this example
With bromine; acetic acid; sodium nitrite In dichloromethane
[0091] The following example explores reaction conditions and product distributions.[0092] Under reaction conditions identical to those used with Br2 in Example 1, the reaction using I2 failed to produce the corresponding iodide. Using 10 equivalents of ICl however, as the source of halogen, results in the production of the chloride in good yield without the iodide. In a further experiment, using 10 equivalents of IBr, gives again the bromide with no detectable iodide. As per the postulated mechanism, the highly reactive nitryl, and nitrosyl halides are the active intermediates, neither of which is known for the iodide.[0093] Conversion of 3-aminomethylpyridine to the bromide in THF was similar to that in CH2Cl2, but decreased in the series CH2Cl2 > CHCl3 > CCl4 with a <n="23"/>corresponding increase in the formation of the hydroxy product. Reaction in DMF or DMSO led to remaining AMP under the conditions used and also favored the formation of the 3-(hydroxymethyl)pyridine over the bromide.[0094] Using isoamyl nitrite as the nitroso source, and Br2, in water, resulted in an incomplete conversion with very little of the hydroxy product. In all solvents tried using NaNC>2 and acetic acid as the nitroso source, an increased amount of 3- (hydroxymethyl)pyridine was observed with incomplete reaction of the AMP. This latter observation is most likely due to the use of NaNO2 for the nitroso source, as in CH2CI2, increasing additions of acetic acid up to 5 equivalents with respect to AMP, favored the formation of the bromide over the hydroxy product. The stronger acid TFA, however, favored the formation of the hydroxy product over the bromide. Addition of an organic base, TEA, piperidine or DBU was well tolerated up to about 1 equivalent with respect to AMP, with higher amounts leading to less conversion of the amine to the bromide. Reaction to the bromide was concentration dependent with best conversions occurring at > 0.1 molar in AMP (variable only explored in GH2CI2).[0095] Conversion of 3-aminomethyl pyridine to 3-(bromomethyl)pyridine using 1.1 equiv. of nitrosyl agent and 5 equiv. of bromine was conducted in the solvent shown in Table 1 below. A sample of the reaction mixture was taken and quenched by high dilution into acetontrile for ESMS analysis of the products. 3- (hydroxymethyl)pyridine and 3-(isoamyloxymethyl)pyridine side products were also observed in addition to starting material and 3-(bromomethyl)pyridine product.Table 1. Product distributions based on variation in reaction conditions. <n="24"/>[0096] The gas evolved by the reaction was identified by collecting the gas in an IR cell and examining by IR Spectroscopy. The IR spectrum in Figure 2 shows the N2O gas produced by the reaction.[0097] Conversion of 3-aminomethylpyridine (AMP) and 2-(2- aminoethyl)pyrdine (AEP) is efficient, as demonstrated by the HPLC traces before and after reaction as shown in Figure 3.[0098] Titration of the addition of both isoamyl nitrite and Bτ2 to AMP shows that the amine disappears from the reaction mixture on addition of one equivalent each of isoamyl nitrite and Br2. As shown in Figure 7, the formation of the product 3- (bromomethyl)pyridine is out of phase with the disappearance of reacting amine, and in some trials was almost completely absent until greater than one equivalent of isoamyl nitrite and Br2 was added. Best yields were obtained by a total addition of about five equivalents OfBr2.in this example
Reference：
[1] Chemical Science, 2016, vol. 7, # 5, p. 3432 - 3442
6
[ 100-55-0 ]
[ 3731-52-0 ]
Yield
Reaction Conditions
Operation in experiment
96%
With (carbonyl)chloro(hydrido)tris(triphenylphosphine)ruthenium(II); ammonia; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In tert-Amyl alcohol at 140℃; for 20 h; Inert atmosphere; Cooling
Example 6Direct Single-Stage Amination of Alcohols andHydroxy Acids by Means of Ammonia Over aHomogeneous Ruthenium Catalyst and Xantphos ata high V7J Vgas (according to the invention)Under an argon atmosphere, m g of starting material, mRU g of [carbonylchlorohydridotris(triphenylphosphane)ruthenium(II)] and mp g of 9,9-dimethyl-4,5-bis (diphenylphosphino)xanthene as catalyst and V07 ml of 2-methyl-2-butanol as solvent were introduced into a 50 mlsteel tube. The vessel was closed, pressurized three times with 20 bar of argon and depressurized each time. The vessel was then cooled by means of dry ice and m g of ammonia were condensed in. The reactor is heated to T° C. and maintained at this temperature for 20 hours. Afier cooling to room temperature, the reactor was depressurized and opened, the solvent was removed on a rotary evaporator and the residue was dissolved in methanol and then analysed by gas chromatography. Reaction parameters and conversions and selectivities to the desired reaction product are shown in Tab. 5. The results show that many different hydroxy-thnctionalized substrates can be aminated by the method described.
Reference：
[1] Patent: US2013/331580, 2013, A1, . Location in patent: Paragraph 0063
[2] Angewandte Chemie - International Edition, 2011, vol. 50, # 33, p. 7599 - 7603
7
[ 100-54-9 ]
[ 3731-52-0 ]
Reference：
[1] Synlett, 2001, # 10, p. 1623 - 1625
[2] Chemistry - A European Journal, 2016, vol. 22, # 14, p. 4991 - 5002
[3] Catalysis Science and Technology, 2018, vol. 8, # 2, p. 499 - 507
[4] Small, 2018, vol. 14, # 37,
[5] Journal of the American Chemical Society, 2015, vol. 137, # 28, p. 8888 - 8891
[6] Helvetica Chimica Acta, 1937, vol. 20, p. 690
[7] Journal fuer Praktische Chemie (Leipzig), 1936, vol. <2> 146, p. 88,102
[8] Journal of the American Chemical Society, 1956, vol. 78, p. 3693
[9] Journal of the American Chemical Society, 1944, vol. 66, p. 876,877
[10] Chemicke Listy, 1951, vol. 45, p. 451[11] Chem.Abstr., 1953, p. 8068
[12] Journal of the American Chemical Society, 1941, vol. 63, p. 490
[13] Journal of the American Chemical Society, 1944, vol. 66, p. 1293
[14] Patent: US2615896, 1950, ,
[15] Helvetica Chimica Acta, 1937, vol. 20, p. 690
[16] Journal fuer Praktische Chemie (Leipzig), 1936, vol. <2> 146, p. 88,102
[17] Chemistry - A European Journal, 2008, vol. 14, # 31, p. 9491 - 9494
[18] Medicinal Chemistry Research, 2011, vol. 20, # 7, p. 1091 - 1101
[19] Catalysis Science and Technology, 2014, vol. 4, # 3, p. 629 - 632
[20] Chemical Communications, 2016, vol. 52, # 9, p. 1812 - 1815
[21] Catalysis Science and Technology, 2016, vol. 6, # 13, p. 4768 - 4772
[22] Journal of the American Chemical Society, 2016, vol. 138, # 28, p. 8781 - 8788
[23] Journal of the American Chemical Society, 2016, vol. 138, # 28, p. 8809 - 8814
[24] ChemSusChem, 2017, vol. 10, # 5, p. 842 - 846
[25] Journal of Medicinal Chemistry, 2017, vol. 60, # 19, p. 7965 - 7983
[26] Synlett, 2017, vol. 28, # 20, p. 2855 - 2858
[27] Patent: CH244837, 1945, ,
Reference：
[1] Journal of the American Chemical Society, 1944, vol. 66, p. 1293
[2] Journal of the American Chemical Society, 1944, vol. 66, p. 1293
[3] Chemicke Listy, 1951, vol. 45, p. 451[4] Chem.Abstr., 1953, p. 8068
10
[ 33252-28-7 ]
[ 3731-52-0 ]
[ 23100-12-1 ]
[ 97004-04-1 ]
Reference：
[1] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[2] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[3] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[4] Bulletin of the Chemical Society of Japan, 2000, vol. 73, # 5, p. 1227 - 1231
Reference：
[1] Journal fuer Praktische Chemie/Chemiker-Zeitung, 1994, vol. 336, # 8, p. 695 - 697
[2] Journal of the American Chemical Society, 1931, vol. 53, p. 4367,4370
Reference：
[1] Journal of Medicinal Chemistry, 1993, vol. 36, # 3, p. 320 - 330
[2] Tetrahedron Letters, 1985, vol. 26, # 48, p. 5863 - 5866
22
[ 3731-52-0 ]
[ 67-56-1 ]
[ 20173-04-0 ]
[ 2055-21-2 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 21, p. 6166 - 6170[2] Angew. Chem., 2018, vol. 130, p. 6274 - 6278,5
23
[ 33252-28-7 ]
[ 3731-52-0 ]
[ 23100-12-1 ]
[ 97004-04-1 ]
Reference：
[1] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[2] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[3] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[4] Bulletin of the Chemical Society of Japan, 2000, vol. 73, # 5, p. 1227 - 1231
24
[ 3731-52-0 ]
[ 142643-29-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 23, p. 3889 - 3901
25
[ 3731-52-0 ]
[ 75-44-5 ]
[ 97004-04-1 ]
Yield
Reaction Conditions
Operation in experiment
87%
With sodium hydroxide; dihydrogen peroxide; trimethylamine In hydrogenchloride; chloroform; water
EXAMPLE 7 Manufacturing of 3-(aminomethyl)-6-chloropyridine starting from 3-(aminomethyl)pyridine: STR18 To a suspension consisting of 3-pyridine methane amine in an amount of 21.6g (0.2 mol), 80 ml aqueous solution of sodium hydroxide in an amount of 8.8g and chloroform in a volume of 60 ml, was fed dropwise isopropoxycarbonyl chloride in an amount of 25.7 g (0.21 mol) at a temperature of from 5° to 10° C. while stirring and spending 30 minutes, and thereaction mixture was further stirred for 30 minutes. After separating the mixture, the organic layer was concentrated under reduced pressure and wasthen dissolved in 20 ml water together with sodium tungstate in an amount of 0.58 g and 35percent hydrochloric acid in an amount of 1.0 g. To this solution, 34.5percent hydrogen peroxide solution in an amount of 27.6 g was fed dropwise at 100° C. while spending 30 minutes. After adjusting the pH of the solution to 5 and allowing the solution to proceed a reaction for 3.5 hours at 100° C., the solution was then cooled down to a room temperature and added with hypo to an extent that an iodo-starch reaction in the solution changes to the negative one. The reaction mixturewas then repeatedly extracted with chloroform in a volume of 100 ml, and all of the chloroform solution collected together was subjected to an azeotropic dehydration. To 250 ml chloroform solution obtained as described above, was added trimethylamine in an amount of 30.0 g (0.51 mol), and the resultant solution was added phosgene in an amount of 24.0 g(0.24 mol) at -5° C. while stirring and spending 1 hour. The reaction mixture was then transferred into an autoclave, whereto hydrogen chloride gas in an amount of 67.0 g was subsequently introduced, and the solution was allowed to a reaction for 5 hours at 50° C. under a pressure of 5 kgf/cm2 while stirring. After cooling the solution to aroom temperature, the solution was then extracted with 35percent hydrochloric acid in a volume of 160 ml. The aqueous solution of hydrochloric acid obtained was then heated for 3.5 hours at a temperature of from 90°to 65° C. After cooling the solution to a room temperature, the reaction mixture was then added with 28percent aqueous solution of sodium hydroxide to adjust the pH of the solution to 13.5. The solution was then extracted with 150 ml chloroform, and the aqueous layer was further repeatedly extracted with chloroform. All chloroform layers were collectedtogether to dry it with magnesium sulfate and the solvent therein was removed by distillation, thereby affording 3-(aminomethyl)-6-chloropyridine in an amount of 24.8 g in a crystalline form The yield was 87percent.
4-(3-bromo-8-chloro-6,11-dihydro-5<i>H</i>-benzo[5,6]cyclohepta[1,2-<i>b</i>]pyridin-11-yl)-1-(3-phenyl-propionyl)-piperazine-2-carboxylic acid (pyridin-3-ylmethyl)-amide[ No CAS ]
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 25℃; for 72h;
To a solution of the compound prepared in Preparative Example 123 (0.25 g, 1.3 MMOL) in dioxane (5 mL) was added IPR2NET (0.47 mL, 2.0 eq. ) and 3- aminomethylpyridine (0.15 ml, 1.1 eq. ). The resulting solution was stirred at room temperature 72 hours. The reaction mixture was diluted with H20 and extracted with EtOAc. The combined organics were washed with H20 and saturated NACI, dried over NA2S04, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography using a 5% MeOH in CH2CI2 solution as eluent (0.29 g, 83% yield). MS: MH+=260.
5-bromo-thiophene-2-sulfonic acid (pyridin-3-ylmethyl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 16h;
To a stirred solution of 4-aminomethyl-pyridine (1.24 g, 11.5 mmol) in THF (8 ml) was added at 0 C. (ice water bath) commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) dissolved in THF (8 ml) and triethylamine (0.59 ml, 4.21 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (dichloromethane/methanol) and crystallization from dichloromethane/hexane to yield the title compound (1.21 g, 95%) as a white solid. MS (ISN) 330.8 [(M-H)-], mp 159 C.
With sodium hydroxide; dihydrogen peroxide; trimethylamine; In hydrogenchloride; chloroform; water;
EXAMPLE 7 Manufacturing of 3-(aminomethyl)-6-chloropyridine starting from 3-(aminomethyl)pyridine: STR18 To a suspension consisting of 3-pyridine methane amine in an amount of 21.6g (0.2 mol), 80 ml aqueous solution of sodium hydroxide in an amount of 8.8g and chloroform in a volume of 60 ml, was fed dropwise isopropoxycarbonyl chloride in an amount of 25.7 g (0.21 mol) at a temperature of from 5° to 10° C. while stirring and spending 30 minutes, and thereaction mixture was further stirred for 30 minutes. After separating the mixture, the organic layer was concentrated under reduced pressure and wasthen dissolved in 20 ml water together with sodium tungstate in an amount of 0.58 g and 35percent hydrochloric acid in an amount of 1.0 g. To this solution, 34.5percent hydrogen peroxide solution in an amount of 27.6 g was fed dropwise at 100° C. while spending 30 minutes. After adjusting the pH of the solution to 5 and allowing the solution to proceed a reaction for 3.5 hours at 100° C., the solution was then cooled down to a room temperature and added with hypo to an extent that an iodo-starch reaction in the solution changes to the negative one. The reaction mixturewas then repeatedly extracted with chloroform in a volume of 100 ml, and all of the chloroform solution collected together was subjected to an azeotropic dehydration. To 250 ml chloroform solution obtained as described above, was added trimethylamine in an amount of 30.0 g (0.51 mol), and the resultant solution was added phosgene in an amount of 24.0 g(0.24 mol) at -5° C. while stirring and spending 1 hour. The reaction mixture was then transferred into an autoclave, whereto hydrogen chloride gas in an amount of 67.0 g was subsequently introduced, and the solution was allowed to a reaction for 5 hours at 50° C. under a pressure of 5 kgf/cm2 while stirring. After cooling the solution to aroom temperature, the solution was then extracted with 35percent hydrochloric acid in a volume of 160 ml. The aqueous solution of hydrochloric acid obtained was then heated for 3.5 hours at a temperature of from 90°to 65° C. After cooling the solution to a room temperature, the reaction mixture was then added with 28percent aqueous solution of sodium hydroxide to adjust the pH of the solution to 13.5. The solution was then extracted with 150 ml chloroform, and the aqueous layer was further repeatedly extracted with chloroform. All chloroform layers were collectedtogether to dry it with magnesium sulfate and the solvent therein was removed by distillation, thereby affording 3-(aminomethyl)-6-chloropyridine in an amount of 24.8 g in a crystalline form The yield was 87percent.
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 25℃; for 20h;
Step C. N-(3-Pyridylmethyl)-1-tert-butoxycarbonyl-4-piperidinepropanamide 1-tert-Butoxycarbonyl-4-piperidinepropionic acid (2g, 7.77mmoles), 3-(aminomethyl)pyridine (1.029ml, 10.1mmoles), DEC.HCl (1.937g, 10.1 mmoles), HOBT (1.365g, 10.1 mmoles) and NMM (1.111 ml, 10.1 mmoles) are dissolved in anhydrous DMF (25ml) and the mixture is stirred under argon at 25C for 20h. The solution is evaporated to dryness and the residue is taken up in dichloromethane, washed with 0.3N NaOH, dried over magnesium sulfate, filtered and evaporated to dryness. The residue is chromatographed on silica gel using 1.5%-2.5% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give the title compound (2.555g, 95%), ESIMS: m/z 348.1 (MH+).
N-[2-(N-tert-butoxycarbonylamino)phenyl]-4-[N-[3-[(pyridin-3-yl)methylamino]cyclobuten-1,2-dion-4-yl]aminomethyl]benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
In tetrahydrofuran; water;
(144-1) To a solution of 0.073 g of 3,4-di-n-butoxy-3-cyclobuten-1,2-dione (0.323 mmol) in 2 mL of THF was added 0.1 g of the compound from Example 1, the process (1-4) (0.293 mmol), and the solution was stirred for 4 hours. After adding 0.033 mL of 3-aminomethylpyridine (0.327 mmol), the solution was reacted for a day. After completion of the reaction, water was added to the solution, and the mixture was extracted twice with methyl ethyl ketone. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with methanol to give 0.12 g of N-[2-(N-tert-butoxycarbonylamino)phenyl]-4-[N-[3-[(pyridin-3-yl)methylamino]cyclobuten-1,2-dion-4-yl]aminomethyl]benzamide (Yield: 78%) 1H NMR(270 MHz, DMSO-d6) delta ppm: 1.44(9H, s), 4.75-4.81(4H, m), 7.15(1H, dt, J=2.2, 7.4 Hz), 7.20(1H, dt, J=2.2, 7.4 Hz), 7.40(1H, dd, J=2.2, 7.4 Hz), 7.47(2H, d, J=8.1 Hz), 7.54(2H, dd, J=2.2, 7.4 Hz), 7.73(1H, m), 7.94(2H, d, J=8.1 Hz), 8.50(1H, m), 8.55(1H, d, J=1.5 Hz), 8.67(1H, s), 9.82(1H, s)
2-methylthio-4-(pyridin-3-ylmethylamino)-pyrazolo[1,5-a]-1,3,5-triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; chloroform;
Example 31 2-methylthio-4-(3-pyridylmethylamino)pyrazolo[1,5-a]-1,3,5-triazine 3-aminomethylpyridine (3.0 g) is added to a solution of 4-chloro-2-methylthiopyrazolo[1,5-a]-1,3,5-triazine (2.0 g) in 40 ml of chloroform and 14 ml of methanol. The mixture obtained is stirred overnight at ambient temperature. After evaporation of the solvents to dryness under vacuum, the residue is divided between chloroform and the water. The organic phase is dried over MgSO4 and the solvents are evaporated to dryness under vacuum. The residual mixture is subjected to chromatography on silica gel using a chloroform/methanol (19:1) mixture as eluent. The appropriate portions are isolated and the solvents are eliminated by evaporation to dryness under vacuum. 1.47 g of a white solid is obtained. TLC (silica gel; chloroform/methanol mixture=19/1): Rf=0.58. Mass spectrometry (Electrospray): 273.1.
In methanol; chloroform;
Example 100 2-methylthio-4-(3-pyridylmethylamino)pyrazolo[1,5-a]-1,3,5-triazine 3-aminomethylpyridine (3.0 g) is added to a solution of 4-chloro-2-methylthiopyrazolo[1,5-a]-1,3,5-triazine (2.0 g) in 40 ml of chloroform and 14 ml of methanol. The mixture obtained is stirred overnight at ambient temperature. After evaporation of the solvents to dryness under vacuum, the residue is divided between chloroform and water. The organic phase is dried over MgSO4 and the solvents are evaporated to dryness under vacuum. The residual mixture is subjected to chromatography on silica gel using a chloroform/methanol mixture (19:1) as eluent. The appropriate portions are isolated and the solvents are eliminated by evaporation to dryness under vacuum. 1.47g of a white solid is obtained. TLC (silica gel; chloroform/methanol mixture=19/1): Rf=0.58. Mass spectrometry (Electrospray): 273.1.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
B. To a stirred mixture of <strong>[38239-45-1]5-bromo-3-methylthiophene-2-carboxylic acid</strong> (1.70 g, 7.69 mmol), 1-hydroxybenzotriazole (1.56 g, 11.54 mmol) and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (2.21 g, 11.54 mmol) in anhydrous N,7V-dimethylformamide (30 mL) was added lambdaf,iV-diisopropylethylamine (4.10 mL, 23.54 mmol), followed by the addition of 3-(aminomethyl)pyridine (0.78 mL, 7.69 mmol). The <n="80"/>resulting reaction mixture was stirred at ambient temperature for 16 h, and diluted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (3 x 100 mL) and water (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 7% methanol in dichloromethane to afford 5-bromo-3-methyl-iV-(pyridin-3- ylmethyl)thiophene-2-carboxamide as an off-white solid (1.92 g, 80%): MS (ES+) m/z 311.1 (M + l), 313.1 (M + 1).
B. To a solution of <strong>[67899-00-7]2-amino-4-methylthiazole-5-carboxylic acid</strong> (8.30 g, 52.0 mmol). l -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( 13.01 g, 68.00 mmol) and N,N-diisopropylethylamine ( 12.90 mL, 68.00 mmol) in N1N- dimethylfo?namide ( 150 mL) was added 1 -hydroxybenzotriazole ( 18.34 g. 136.0 mmol). The resulting mixture was stirred at ambient temperature for 15 minutes followed by the addition of 3-(aminomethyl)pyridine (6.30 mL, 63.00 mmol). The reaction mixture was stirred at ambient temperature for 17 hours. The solvent was removed in vacuo at 60 0C and the residue was partition between water and ethyl acetate. The organic layer was washed once with saturated sodium bicarbonate, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was triturated with mixture of ethyl acetate and methanol (99/1 ) to afford a white solid (4.60 g). The aqueous layer was left to stand at ambient temperature for 24 hours. The precipitated solid was collected by filtration and dried to afford a white solid (4.00 g). Both solids were combined to afford the title compound as a white solid in 67% yield (8.60 g); 1H NMR (300 MHz. CDCI3) delta 8.47 (s. I H). 8.41 (s. I H). 8.04 (t. J = 5.9 Hz. I H). 7.67-7.61 (m. I H). 7.36 (s. 2H). 7.34- 7.28 (m. I H). 4.32 (d. J = 5.9 Hz. 2H). 2.30 (s. 3H); 1 3C NMR (75 MHZ. CDCI3) delta 167.73. 162.03. 153.79. 148.74. 147.88. 135.47. 135.05. 123.42. 1 1 1.74. 40.30. 17.21 ; MS (ES+) m 'z 249.2 (M + 1 ).
Reaction of 3 -aminomethylpyridine with 4,6-dichloro- 1 -methyl- 1 H-pyrazolo [3,4- d]pyrimidine 5 by General Procedure B gave (6-chloro-l-methyl-lH-pyrazolo[3,4-d]pyrimidin-4-yl)-pyridin-3-ylmethyl-amine. ; General Procedure B[00186] To a 4,6-dichloro pyrazolo[3,4-d]pyrimidine intermediate 27 in a solvent such as ethanol is added a primary or secondary amine (R10R13NH, 1.1 equiv.) and a non-nucleophilic base such as triethylamine (NEt3, 1.5 eq, 63 mul). Alternatively, acetonitrile may be used as the solvent and potassium carbonate may be used as the base. The reaction mixture is stirred at room temperature for about 1 hour or overnight, volatiles removed in vacuo and residue partitioned between DCM and brine. If the mixture is insoluble it may be sonicated and the solid product was collected by filtration. Drying with magnesium sulphate and evaporation of the solvent gives N'-(6-chloro pyrazolo[3,4-d]pyrimidin-4-yl)-amine substituted intermediate 28, <n="63"/>often as a crystalline solid, or by trituration. Substituents R1 and R2 may be R1 and R as defined, or protected forms or precursors thereof.
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 60℃; for 20h;
A mixture of 4,6-Dichloronicotinamide (1, 950 mg, 5 mmoles), 3-picolylamine (756 mg, 7 mmoles) and DIEA (12 mmoles) in NMP (5 mL) was stirred at 60 0C for 20 hrs. The reaction mixture was concentrated under an oil pump. The residue was washed with water and dried under an oil pump. The desired 6-chloro-4-(pyridin-3-ylmethylamino)nicotinamide (2, 1.085 g) was obtained. MS+: 263.1, UV: lambda = 220.9; 260.9 nm. 1H NMR: (CDCl3) delta8.96(s,lH), delta8.60(s,lH), delta8.57(d,J=3.2 Hz,lH), delta8.30(s,lH), delta7.64(d,J=7.6Hz,lH), 67.31 (dd,Jl=7.6Hz,J2=3.2Hz,lH), delta6.51(s,lH), delta5.80(b,2H), delta4.47(s, IH), delta4.45(s, IH).
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 60℃; for 20h;
A mixture of 4,6-Dichloronicotinamide (28.1, 950 mg, 5 mmol), 3-picolylamine (756 mg, 7 mmol) and DIPEA (12 mmol) in NMP (5 mL) was stirred at 60 C. for 20 hrs. The reaction mixture was concentrated under an oil pump. The residue was washed with water and dried under an oil pump. The desired 6-chloro-4-(pyridin-3-ylmethylamino)nicotinamide (28.2, 1.085 g) was obtained. MS+: 263.1, UV: lambda=220.9; 260.9 nm. 1H NMR: (CDCl3) delta8.96 (s, 1H), delta8.60 (s, 1H), delta8.57 (d, J=3.2 Hz, 1H), delta8.30 (s, 1H), delta7.64 (d, J=7.6 Hz, 1H), delta7.31 (dd,J1=7.6 Hz,J2=3.2 Hz, 1H), delta6.51 (s, 1H), delta5.80 (b, 2H), delta4.47 (s, 1H), 84.45 (s, 1H).
General procedure: Neat secondary aromatic or aliphatic amine (5.0 mmol) was introduced at rt to a solution of imidazole-2-carboxaldehyde (1) (0.48 g, 5.0 mmol) in MeOH (100 mL) and the reaction was stirred at reflux for 1 h. After that time, solvent was evaporated under reduced pressure affording crude imines 2 that were used directly in the next step. The crude imine (5.0 mmol) was dissolved in dry toluene (50 mL) and diethyl phosphite (0.65 mL, 5.0 mmol) or ethyl phenylphosphinate (0.75 mL, 5.0 mmol) was added. The mixture was heated to reflux for 2 h and then concentrated under reduced pressure affording crude esters 3 as thick oils or semi-solids. The phosphinate esters 3c,d were recrystallized from a mixture of toluene/hexane. The phosphonate esters 3a,b were characterized as oxalate salts. The oxalates were obtained in the following way; the crude ester (1.0 equiv) was dissolved in acetone (10 mL) and oxalic acid (COOH)2·2H2O (2.0 equiv) in acetone (10 mL) was added and the mixture was refrigerated. The separated precipitate was filtered, washed with cold acetone (10 mL) and dried on air.
With poly(ethylene glycol)sulfonic acid; In toluene; at 40 - 50℃; for 4h;
General procedure: In a 50 mL round bottom flask a mixture of 4-(Pyridin-4-yl) benzaldehyde (1) (0.0025 mol, 0.46 g), aniline (2) (0.0025 mol, 0.23 mL) and triethyl phosphite (3) (0.0030 mol, 0.52 mL) were taken in toluene (10 mL) as solvent and stirred for 15 min in the presence of PEG-SO3H (0.1 mol) for a duration of 2 h at 40-50 C. The reaction progress was monitored with Thin Layer Chromatography by using ethyl acetate, hexane mixture (1:9) as mobile phase. After completion of the reaction the reaction mixture was allowed to settle for 15 min the catalyst was separated by filtration washed with toluene and dried, for its reuse. The solvent from filtrate was removed in rotaevaporator. The crude compound obtained was purified by column chromatography using neutral silica gel as an absorbent, ethyl acetate, hexane mixture (3:7) as an eluant. Finally the collected product is recrystallized from hot ethanol to get the pure diethyl(phenylamino) (4-(pyridine-4-yl)phenyl)methyl phosphonate 4a (Yield 96%; mp: 155-157 C) (Fig. 4).
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In dichloromethane; acetonitrile; at 20℃;
General procedure: A mixture of 1 mmol (1 equiv.) of carboxylic acids, 1.4 mmol (1.4 equiv.) of amine, 552 mg (1.8 equiv.) of PyBOP and 2 mL of triethylamine was stirred overnight at room temperature in 40 ml of a 1:1 mixture of CH2Cl2 and CH3CN. After solvent evaporation, the crude product was purified by column chromatography on silica (CHCl3:CH3CH2OH = 9:1) resulting in yellow thick oil that slowly crystallized.
With triethylamine; In butan-1-ol; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation;
2-Chloro-9-methyl-A^pyridin-3-ylmethyl)-9H-purin-6-amine (16n). To a solution of 15b (72.0 mg, 0.355 mmol) in n-BuOH (1.0 mL) was added 3-(aminomethyl)pyridine (39.7 mg, 0.367 mmol) and triethylamine (57.5 mg, 0.568 mmol) under an N2 atmosphere. The reaction mixture was heated under microwave irradiation at 120 C for 30 min. n-BuOH was evaporated, and the residue was dissolved in EtOAc and washed with water. The aqueous phase was further extracted with EtOAc, and the combined organic extracts were dried (MgS04) and concentrated to yield a colorless solid. The solid was resuspended (hexanes/Et20, 1 : 1), filtered, triturated (hexanes/Et20, 1: 1), and dried under high-vacuum to yield 16n (76.0 mg, 0.277 mmol, 78%) contaminated with a small amount (-10%) of EtOAc and Et20 as a fine yellow amorphous solid that was used for the next reaction without further purification: IR (ATR, neat) 3076, 2401, 1603, 1579, 1313, 1232 cnr NMR (CDCI3/CD3OD, 9/1, 600 MHz) delta 8.50 (bs, 1 H), 8.35 (bs, 1 H), 7.71 (d, 1 H, / = 7.8 Hz), 7.65 (s, 1 H), 7.25-7.20 (m, 1 H), 4.70 (bs, 2 H), 3.68 (s, 3 H); 13C NMR (CDCI3/CD3OD, 9/1, 150 MHz) delta 154.6, 154.3, 148.6, 147.9, 140.7, 136.2, 134.1, 123.6, 117.8, 41.6, 29.8.
General procedure: To a solution of palmitic acid (300mg, 1.17mmol) in dichloromethane (DCM, 10mL) was added 1,1?-carbonyldiimdazole (209mg, 1.29mmol). The reaction was stirred at room temperature for 2h. The reaction mixture was slowly added to a solution of benzylamine (153muL, 1.40mmol) and 4-dimethylaminopyridine (14mg, 0.12mmol) in dichloromethane (5mL). The solution was stirred at room temperature for 18h. DCM (100mL) and saturated aqueous NaHCO3 (30mL) were added to the reaction mixture. The organic layer was separated and washed with H2O (30mL), brine (30mL), dried over anhyd sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude was purified by flash chromatography on silica gel eluting with hexane/EtOAc (3:1, v/v) to give the title compound as a white solid (578mg, 86%). Mp 85-87 [lit.45 mp 94.5-95, and46 fp 95.1]; 1H NMR (400MHz, CDCl3) delta 7.32-7.36 (m, 2H), 7.26-7.30 (m, 3H), 5.72 (br s, 1H), 4.45 (d, J=6.0Hz, 2H), 2.21 (t, J=7.2Hz, 2H), 1.61-1.67 (m, 2H), 1.25-1.34 (m, 24H), 0.88 (t, J=6.8Hz, 3H); 13C NMR (CDCl3, 100MHz) delta 173.21, 138.66, 128.92, 128.05, 127.71, 43.80, 37.06, 32.16, 29.92, 29.89, 29.84, 29.73, 29.59, 29.56, 26.01, 22.93, 14.36; LCMS, C23H39NO, [M+H]: 346.
With diphenyl phosphoryl azide; triethylamine; In N,N-dimethyl acetamide; at 20℃;Darkness; Inert atmosphere;
Example 9 Synthesis of Amide 9: (3-pyridylamide) of AmB In another preferred embodiment the present invention provides the analogue of AmB denominated amide 9, represented by formula IX; using amphotericin B, N,N-dimethylacetamide, triethylamine, 3-aminomethylpyridine and diphenizphosphorylazide as starting materials. In a 100 mL flask ball 462 mg (0.5 mmol) amphotericin B were weighed and dissolved in 10 mL de N,N-dimethyl acetamide. The flask was wrapped in aluminum foil as amphotericin B decays in the presence of sunlight; the reaction was performed under nitrogen atmosphere. Subsequently 0.7 mL (5.0 mmol) of triethylamine, 5.0 mmol of 3-aminomethylpyridine and 1.08 mL (5.0 mmol) of diphenizphosphorylazide were added. The reaction was left at room temperature with constant stirring until disappearance of the raw material (amphotericin B). The progress of the reaction was measured by thin layer chromatography in the system chloroform:methanol:water (20:10:1). Subsequently, the reaction was precipitated in 150 mL of anhydrous ethyl ether and let to stand until the product precipitated completely, which is normally associated with the clearance of the ether solution. Ethyl ether was decanted and the precipitate formed was dissolved in 1-butanol and washed twice with 50 mL of distilled water. Subsequently, 1-butanol was evaporated under reduced pressure (10 mmHg) at 25 C. Finally, the derivative was precipitated with 50 mL of ethyl ether and washed three times with 50 mL of ethyl ether and once with 50 mL of hexane. The product was vacuum dried. In this reaction, the analogue 9 was obtained with a 95.09% yield after product purification.
6-bromo-N-(pyridin-3-ylmethyl)thieno[2,3-d]pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
In isopropyl alcohol; at 80℃; for 1h;Inert atmosphere;
General procedure: Compound 1 (1.00 g, 4.01 mmol) was mixed with the benzylamine (2-3 eq.) and i-PrOH (2-10 mL) and agitated at 80 C for 1-50 h, under nitrogen atmosphere. Then the mixture was cooled to rt, concentrated in vacuo, diluted with water (50 mL) and diethyl ether (100 mL) or EtOAc (100 mL). After phase separation, the water phase was extracted with more diethyl ether (2×50 mL) or EtOAc (2×50 mL). The combined organic phases were washed with saturated aq NaCl solution (25-50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude oil was purified by drying under reduced pressure to constant weight, by silica-gel column chromatography or crystallized as specified for each individual compound.
(E)-3-(2-fluorophenyl)-N-(3-pyridylmethyl)-2-propenamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 3h;
Example 2 Production of (E)-3-(2-Fluorophenyl)-N-(3-pyridylmethyl)-2-propenamide (Compound 2). 3-Aminomethylpyridine (2.0 g, 19 mmol) and WSC·HCl (3.8 g, 20 mmol) were added to a methylene chloride (60 mL) suspension of <strong>[451-69-4]2-fluorocinnamic acid</strong> (3.0 g, 18 mmol) at 0C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water, and an organic layer was then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvents under a reduced pressure was purified with silica gel column chromatography (n-hexane : ethyl acetate = 1:1), to give the captioned compound (3.9 g, 85%) as crystals.
3-[((pyridin-3-yl)methyl)carbamothioyl]thio}propanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
General procedure: To a mixture of pyridin-3-ylmethanamine 18 (108 mg, 1 mmol),TEA (100 mg, 1 mmol) in water (10 mL), CS2 (91 mg, 1.2 mmol) was added dropwise. After stirring for 5 min, the corresponding halide19 (1 mmol) or Michael acceptor 20 (1 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then extracted with ethyl acetate (30 mL 3). The organic phase was combined and dried over Na2SO4, concentrated under vacuum and purified by column chromatography on silica gel or recrystallization (ethyl acetate/petroleum ether) to afford the corresponding compound 17
3-(benzylamino)-3-oxopropyl ((pyridin-3-yl)methyl)carbamodithioate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
General procedure: To a mixture of pyridin-3-ylmethanamine 18 (108 mg, 1 mmol),TEA (100 mg, 1 mmol) in water (10 mL), CS2 (91 mg, 1.2 mmol) was added dropwise. After stirring for 5 min, the corresponding halide19 (1 mmol) or Michael acceptor 20 (1 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then extracted with ethyl acetate (30 mL 3). The organic phase was combined and dried over Na2SO4, concentrated under vacuum and purified by column chromatography on silica gel or recrystallization (ethyl acetate/petroleum ether) to afford the corresponding compound 17
N-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-N’-(pyridin-3-ylmethyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
Over a solution of <strong>[285984-25-0]3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-amine</strong>(50 mg, 1 eq) in DIPEA (28.4 mg, 1 eq) and THF (2 mL), theisoproprenyl chloroformate (26.5 mg, 1 eq) was added slowly. The reaction mixture was stirred at room temperature 12 h. Afterwards, pyridin-3-ylmethanamine (23.8 mg, 1 eq) was added and stirred under reflux during 3 h. After extracting with ethylacetate, the organic phase was washed subsequently with NaHCO3 and saturated NaC1 solutions. The organic phase was dried over magnesium sulfate, and chromatographed on silica gel column using dichlorometane:MeOH (95:5) as eluents. Yield: 47 mg, 59%. 1H RMN (300 MHz, CDC13) 6: 8.69 (m, 2H), 7.98 (m, 1H), 7.77 (m,5H), 5.54 (s, 1H), 4.66 (m, 2H), 2.38 (s, 3H), 1.34 (5, 3H) . 13C RMN (75 MHz, CDC13) 6: 169.4, 155.5, 150.1, 149.3, 148.4, 137.6, 136.8, 135.9, 135.1, 130.2, 127.3, 122.8, 92.4, 45.9, 32.1,30.1, 22.3 HPLC/MS: purity>99%. ESI-MS m/z = 365 (M+2H)
2-(benzo[d]isoxazol-3-yl)-N-(pyridin-3-ylmethyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
General procedure: To an ice cold solution of <strong>[4865-84-3]1,2-benzisoxazol-3-acetic acid</strong> 8 (1.0 mmol, 1.0 eq.), N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (1.5 mmol, 1.5 eq.), and 1-hydroxybenzotriazole (1.0 mmol, 1.0 eq) in DCM (25 mL) was added solution of TFA salt of proline derivative/3-aminomethyl pyridine/compound 10 (1.0 mmol, 1.0 eq.) and triethylamine (2.5 mmol, 2.5 eq.) in DCM (5 mL). The reaction mixture was stirred at 0-5 C for 30 min and at room temperature for overnight. The completion of the reaction was monitored using TLC analysis using pet.ether:ethyl acetate (1:1). The reaction mixture was concentrated on a rotavapor to give crude residue. The residue was dissolved in ethyl acetate (50 mL) and was washed with water (225 mL), 0.5N HCl solution (210 mL), saturated NaHCO3 (215 mL), and brine (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound. The compounds were purified by column chromatography using petether: ethyl acetate from 9:1 to 2:8 to give pure compounds 9a-d and 11a-e solid.
1-(5-(4-bromophenyl)furan-2-yl)-N-(pyridin-3-ylmethyl)methanamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; trifluoroacetic acid; In dichloromethane; at 45℃;Molecular sieve;
General procedure: To a solution of substituted 5-phenylfuran-2-carbaldehydes (3a and 3i, 1.5 mmol), dierent amines(1.8 mmol) and diethyl 2,6-dimethyl- 1,4-dihydropyridine-3,5-dicarboxylate (hantzschester, 1.8 mmol)in DCM (25 mL), catalytic amount of molecular sieve and trifluoroacetic acid were added at room temperature, and the reaction was warmed to 45 C and reacted for 6-12 h. After completion (monitoredby TLC), the reaction was filtered, and the crude residue was obtained by concentrating the filtratein vacuo. Finally, the crude residue was purified by column chromatography to give the desiredcompounds 31-34 in high yields.
General procedure: A solution of isoxazole acid derivative 1 (1mmol), EDCI (1.1mmol), and HOBt (1mmol) in dry acetonitrile (10mL) was stirred at room temperature for 30min. Then, 3-picolylamine 2a or 4-picolylamine 2b (1mmol) was added drop wise to the mixture and the reaction was continued at room temperature for 24h. After completion of the reaction, the solvent was reduced under vacuum and the residue was dissolved in dichloromethane and washed with sodium carbonate (10%, 3×20). The organic phase was dried over Na2SO4 and the solvent was evaporated under vacuum to give compound 3 which was completely pure. Finally, the mixture of compound 3 (1mmol) and benzyl halide derivative 4 (1.2mmol) in dry acetonitrile (10mL) was heated at reflux for 10-15h. After completion of the reaction which was monitored by TLC, the mixture was allowed to be cool and the precipitates were filtered off to afford products 5a-q in good yields.
General procedure: A solution of isoxazole acid derivative 1 (1mmol), EDCI (1.1mmol), and HOBt (1mmol) in dry acetonitrile (10mL) was stirred at room temperature for 30min. Then, 3-picolylamine 2a or 4-picolylamine 2b (1mmol) was added drop wise to the mixture and the reaction was continued at room temperature for 24h. After completion of the reaction, the solvent was reduced under vacuum and the residue was dissolved in dichloromethane and washed with sodium carbonate (10%, 3×20). The organic phase was dried over Na2SO4 and the solvent was evaporated under vacuum to give compound 3 which was completely pure. Finally, the mixture of compound 3 (1mmol) and benzyl halide derivative 4 (1.2mmol) in dry acetonitrile (10mL) was heated at reflux for 10-15h. After completion of the reaction which was monitored by TLC, the mixture was allowed to be cool and the precipitates were filtered off to afford products 5a-q in good yields.
4-(4-(4-fluorophenyl)-1-(pyridin-3-ylmethyl)-1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%
General procedure: To a solutionof the corresponding aldehyde (1.2 eq.; unless stated otherwise) in DMF (2 inL per 0.3 mmol of aldehyde; unless stated otherwise) was added the corresponding amine (2.5 eq.; unless stated otherwise) and the resulting solution was stirred at 25 C to form the corresponding inline. Then, the corresponding isocyano(tosyl)methyl)arene reagent (1 eq.; unless stated otherwise) and K2CO3 (1.5 eq.; unless stated otherwise*) were added and the reaction mixture was stirred at 25 C (unless stated otherwise). The reaction was stopped after the time indicated for each particular reaction. The reaction progress was monitored by TLC. (0083) A saturated aqueous solution of NH4CI (10 mL per 1 mmol of aldehyde) was added to the reaction mixture, which was then extracted with EtOAc (2 x 30 mL per 1 mmol of aldehyde). The combined organic extracts were washed with H2O (2 x 25 mL per 1 mmol of aldehyde), dried over MgSCC, filtered, and the solvent was evaporated in vacuo to provide the crude product. The residue obtained after the workup was purified using column chromatography or preparative TLC (unless stated otherwise). (0084) * note: in cases when the amine was used as HC1 salt, 4 eq. of K2CO3 were used
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