CN113336713B - Preparation method of alkoxy pyrazine derivative and alkoxy pyrazine derivative - Google Patents
Preparation method of alkoxy pyrazine derivative and alkoxy pyrazine derivative Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, in particular to an alkoxy pyrazine derivative and a preparation method thereof.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of an alkoxy pyrazine derivative and the alkoxy pyrazine derivative.
Background
Pyrazine is widely found in some bioactive compounds, especially some antiviral and antitubercular drugs, such as antiviral drug Pilazivir, antitubercular drug pyrazinamide, etc. Favipiravir is a broad-spectrum antiviral drug studied in Japan and used as an anti-influenza drug in 2014, and is approved by the Japanese food and drug administration. In 2020, favipiravir is used for the treatment of new coronary pneumonia due to its better in vitro anti-new coronavirus activity. However, besides influenza, fapirovir has low anti-other virus activity and large oral dosage, and is to be further structurally modified based on pyrazine.
The development of efficient and simple methods to functionalize pyrazines has attracted the attention of many pharmaceutical and synthetic scientists. The O-alkylation reaction is a conventional method for synthesizing ethers from alcohols, such as the reaction of aliphatic halogenated hydrocarbons with sodium alkoxides, sodium phenolates (Williamson reaction), the reaction of aromatic halides with sodium phenolates (Ullmann reaction), the reaction of sulfates or sulfonates with sodium alkoxides, sodium phenolates, and the like. These reactions either use highly reactive alkali metals, require higher temperatures, or involve more complicated steps, complicated processing, etc.
Therefore, in view of the above problems, the present invention is to provide a method for preparing alkoxy pyrazine derivatives and alkoxy pyrazine derivatives.
Disclosure of Invention
The invention aims to provide an alkoxy pyrazine derivative and a preparation method thereof, and the alkoxy pyrazine derivative is prepared by the method, so that the problems that high-activity alkali metal is required or higher temperature, more complicated steps, complex treatment and the like are required in the conventional O-alkylation reaction in the prior art are solved.
The invention provides a preparation method of an alkoxy pyrazine derivative, which comprises the following steps:
6-X-3-hydroxy-2-R 1 -pyrazine and R 2 OH reaction, introducing acid, acidic gas or acidic solution, heating to 20-100 ℃, and reacting for 3-10h to obtain alkoxy pyrazine derivatives;
wherein R is 1 Is an amide group or a cyano group; x is halogen or nitro;
R 2 comprises one of alkyl, alkoxy substituted alkyl, cyclic alkyl, aryl substituted alkyl or aryl substituted alkyl with a substituent group, phenyl or substituted phenyl.
Preferably, the acid comprises at least one of sulfuric acid, phosphoric acid, methanesulfonic acid, chlorosulfonic acid, or trifluoroacetic acid; the acid solution comprises at least one of hydrogen chloride dioxane solution, hydrogen chloride ether solution, hydrogen chloride cyclopentyl methyl ether solution or hydrogen chloride ethyl acetate solution; the acid gas includes at least one of hydrogen chloride, hydrogen bromide, or hydrogen iodide.
Preferably, the acid or the acidic solution is introduced, and the molar ratio of the 6-X-3-hydroxy-2-R1-pyrazine to the acid or the acidic solution is 1:1-10.
Preferably, 6-X-3-hydroxy-2-R 1 -pyrazine and R 2 And (3) performing an OH reaction, adding a hydrogen chloride dioxane solution, heating to 60 ℃, and reacting for 4 hours to obtain the alkoxy pyrazine derivative, wherein the yield of the alkoxy pyrazine derivative is more than 75%.
Preferably, when the acid gas is introduced, the molar ratio of the 6-X-3-hydroxy-2-R1-pyrazine to the acid gas is 1:1-10.
Preferably, 6-X-3-hydroxy-2-R 1 -pyrazine and R 2 And (3) OH reaction, introducing hydrogen chloride gas, heating to 60 ℃, and reacting for 3h to obtain the alkoxy pyrazine derivative, wherein the yield of the alkoxy pyrazine derivative is more than 75%.
The invention also provides an alkoxy pyrazine derivative obtained based on the preparation method of the alkoxy pyrazine derivative, wherein the structural formula of the alkoxy pyrazine derivative is shown as the formula (I);
wherein R is 1 Is an amide group or a cyano group; r 2 Comprises one of alkyl, alkoxy substituted alkyl, cyclic alkyl, aryl substituted alkyl or aryl substituted alkyl with a substituent group, phenyl or substituted phenyl.
Preferably, the substituent group in the aryl-substituted alkyl group with the substituent group comprises one of alkoxy, alkyl, cycloalkyl, halogen, nitro, nitrile, hydroxyl or amino;
the substituent group in the substituted phenyl comprises one of alkoxy, alkyl, cyclic hydrocarbon, halogen, nitro, nitrile group, hydroxyl or amino; the substituent in the substituted phenyl group is an alkoxy group.
Preferably, the cycloalkyl group is a saturated or unsaturated C3-12 cycloalkyl group; alkoxy is alkyl-O-, and alkyl is C1-10; alkyl is C1-8 alkyl; the cycloalkyl is a saturated or unsaturated C3-6 cycloalkyl; the cycloalkyl is cyclobutyl, cyclopentyl or cyclohexyl.
Preferably, alkoxy is methoxy or ethoxy; a monovalent aromatic carbocyclic group of 6 to 12 carbon atoms having a single ring or multiple condensed rings wherein, when the point of attachment is aryl, the condensed rings are aromatic or non-aromatic; the alkyl group comprises one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl or n-octyl; the cyclic hydrocarbon group comprises one of adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl or cyclohexenyl; the alkoxy comprises one of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy or n-pentoxy; the aryl is one of phenyl, thienyl, thiazolyl or pyridyl.
Preferably, the alkoxypyrazine derivative is
6-methoxy-3-hydroxypyrazine-2-carboxamide,
6-ethoxy-3-hydroxypyrazine-2-carboxamide,
6-propoxy-3-hydroxypyrazine-2-formamide,
6-isopropoxy-3-hydroxypyrazine-2-carboxamide,
6-butoxy-3-hydroxypyrazine-2-carboxamide,
6-n-pentyloxy-3-hydroxypyrazine-2-carboxamide,
6-isopentyloxy-3-hydroxypyrazine-2-carboxamide,
6-n-octyloxy-3-hydroxypyrazine-2-formamide,
6- (2-hydroxyethoxy) -3-hydroxypyrazine-2-carboxamide,
6- (2-methoxyethoxy) -3-hydroxypyrazine-2-carboxamide,
6- (2-chloroethoxy) -3-hydroxypyrazine-2-formamide,
6-cyclobutoxy-3-hydroxypyrazine-2-carboxamide,
6-cyclopentyloxy-3-hydroxypyrazine-2-carboxamide,
6-cyclohexyloxy-3-hydroxypyrazine-2-carboxamide,
6-cyclohexylmethoxy-3-hydroxypyrazine-2-formamide,
6-benzyloxy-3-hydroxypyrazine-2-carboxamide,
6-phenethyloxy-3-hydroxypyrazine-2-formamide,
6-phenylpropyloxy-3-hydroxypyrazine-2-carboxamide,
6-phenylbutoxy-3-hydroxypyrazine-2-carboxamide or
6-ethoxy-3-hydroxypyrazine-2-carbonitrile.
Compared with the prior art, the preparation method of the alkoxy pyrazine derivative and the alkoxy pyrazine derivative provided by the invention have the following advantages that:
1. according to the preparation method of the alkoxy pyrazine derivative, acid, acidic gas or acidic solution is introduced, the reaction temperature can be performed at low temperature, the obtained alkoxy pyrazine derivative is few in by-products and high in purity, and the yield is more than 75%.
2. The preparation method of the alkoxy pyrazine derivative provided by the invention is simple in process and convenient to synthesize, the obtained alkoxy pyrazine derivative is few in by-products and high in purity, and the yield is more than 75%.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be apparent that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
A preparation method of alkoxy pyrazine derivatives comprises the following steps:
6-X-3-hydroxy-2-R 1 -pyrazine and R 2 OH reaction, introducing acid, acid gas or acid solution, heating to 20-100 ℃, and reacting for 3-10h to obtain alkoxy pyrazine derivatives;
wherein R is 1 Is an amide group or a cyano group; x is halogen or nitro;
R 2 comprises one of alkyl, alkoxy substituted alkyl, cyclic alkyl, aryl substituted alkyl or aryl substituted alkyl with a substituent group, phenyl or substituted phenyl.
Specifically, the acid includes at least one of sulfuric acid, phosphoric acid, methanesulfonic acid, chlorosulfonic acid, or trifluoroacetic acid; the acid solution comprises at least one of hydrogen chloride dioxane solution, hydrogen chloride ether solution, hydrogen chloride cyclopentyl methyl ether solution or hydrogen chloride ethyl acetate solution; the acid gas includes at least one of hydrogen chloride, hydrogen bromide, or hydrogen iodide.
Specifically, acid or acid solution is introduced, and the molar ratio of the 6-X-3-hydroxy-2-R1-pyrazine to the acid or acid solution is 1:1-10.
Specifically, 6-X-3-hydroxy-2-R 1 -pyrazine and R 2 And (3) performing an OH reaction, adding a hydrogen chloride dioxane solution, heating to 60 ℃, and reacting for 4 hours to obtain the alkoxy pyrazine derivative, wherein the yield of the alkoxy pyrazine derivative is more than 75%.
Specifically, when the acid gas is introduced, the molar ratio of the 6-X-3-hydroxy-2-R1-pyrazine to the acid gas is 1:1-10.
Specifically, 6-X-3-hydroxy-2-R 1 -pyrazine and R 2 And (3) OH reaction, introducing hydrogen chloride gas, heating to 60 ℃, and reacting for 3h to obtain the alkoxy pyrazine derivative, wherein the yield of the alkoxy pyrazine derivative is more than 75%.
The invention also provides an alkoxy pyrazine derivative obtained based on the preparation method of the alkoxy pyrazine derivative, which is characterized in that: the structural formula of the alkoxy pyrazine derivative is shown as a formula (I);
wherein R is 1 Is an amide group or a cyano group; r 2 Comprises one of alkyl, alkoxy substituted alkyl, cyclic alkyl, aryl substituted alkyl or aryl substituted alkyl with a substituent group, phenyl or substituted phenyl.
Specifically, the substituent group in the aryl-substituted alkyl group with a substituent group comprises one of alkoxy, alkyl, cycloalkyl, halogen, nitro, nitrile, hydroxyl or amino;
the substituent group in the substituted phenyl comprises one of alkoxy, alkyl, cyclic hydrocarbon, halogen, nitro, nitrile group, hydroxyl or amino; the substituent in the substituted phenyl group is an alkoxy group.
Specifically, the cycloalkyl group is a saturated or unsaturated C3-12 cycloalkyl group; alkoxy is alkyl-O-, and alkyl is C1-10; alkyl is C1-8 alkyl; the cycloalkyl is a saturated or unsaturated C3-6 cycloalkyl; the cycloalkyl is cyclobutyl, cyclopentyl or cyclohexyl.
In particular, the alkoxypyrazine derivatives are
6-methoxy-3-hydroxypyrazine-2-carboxamide,
6-ethoxy-3-hydroxypyrazine-2-formamide,
6-propoxy-3-hydroxypyrazine-2-formamide,
6-isopropoxy-3-hydroxypyrazine-2-carboxamide,
6-butoxy-3-hydroxypyrazine-2-carboxamide,
6-n-pentyloxy-3-hydroxypyrazine-2-carboxamide,
6-isopentyloxy-3-hydroxypyrazine-2-formamide,
6-n-octyloxy-3-hydroxypyrazine-2-formamide,
6- (2-hydroxyethoxy) -3-hydroxypyrazine-2-carboxamide,
6- (2-methoxyethoxy) -3-hydroxypyrazine-2-carboxamide,
6- (2-chloroethoxy) -3-hydroxypyrazine-2-formamide,
6-cyclobutoxy-3-hydroxypyrazine-2-carboxamide,
6-cyclopentyloxy-3-hydroxypyrazine-2-formamide,
6-cyclohexyloxy-3-hydroxypyrazine-2-carboxamide,
6-cyclohexylmethoxy-3-hydroxypyrazine-2-carboxamide,
6-benzyloxy-3-hydroxypyrazine-2-carboxamide,
6-phenethyloxy-3-hydroxypyrazine-2-formamide,
6-phenylpropyloxy-3-hydroxypyrazine-2-carboxamide,
6-phenylbutoxy-3-hydroxypyrazine-2-carboxamide or
6-ethoxy-3-hydroxypyrazine-2-carbonitrile.
The reaction mechanism is as follows:
the method is a nucleophilic aromatic ring substitution reaction, halogen ions are easier to leave under the action of acid ions, and nucleophilic oxygen atoms in alcohol attack carbon atoms connected with the halogen atoms to form an intermediate; after the halogen ion leaves, an aromatic system is formed again, and finally, the hydrogen ion leaves to form a final product.
Example one
Preparing 6-methoxy-3-hydroxypyrazine-2-formamide;
adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous methanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, concentrating under reduced pressure to dryness, and recrystallizing with ethanol to obtain the compound A1, wherein the weight of the compound A1 is 0.95g, and the yield is 87%.
On the compound A1 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(600MHz,DMSO-d 6 )δ12.78(s,1H),8.52(s,1H),8.37(s,1H),8.15(s,1H),3.92(s,4H)。
13 C NMR(151MHz,DMSO-d 6 )δ54.08,120.36,137.91,153.30,157.11,169.90。
HR-MS(ESI)m/z C 6 H 6 N 3 O 3 (M-H) - theoretical value 168.0415 and measured value 168.0413.
Example 2
Preparation of 6-ethoxy-3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of absolute ethanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 50 ℃, reacting for 3h, cooling to room temperature, concentrating under reduced pressure to dryness, and recrystallizing with ethanol to obtain A2, wherein the weight of A2 is 1.01g, and the yield of A2 is 85%.
On compound A2 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(600MHz,Chloroform-d)δ11.88(s,1H),8.10(s,1H),7.41(d,J＝7.7Hz,1H),5.86(s,1H),4.30(q,J＝7.1Hz,2H),1.41(d,J＝7.2Hz,3H)。
13 C NMR(151MHz,Chloroform-d)δ14.32,62.70,119.51,139.79,153.43,157.62,169.99。
HR-MS(ESI)m/z C 7 H 8 N 3 O 3 (M-H) - theoretical value 182.0571, measured value 182.0568.
EXAMPLE III
Preparation of 6-propoxy-3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into anhydrous propanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃ after adding, reacting for 3h, cooling to room temperature, concentrating under reduced pressure to dryness, and recrystallizing with ethanol to obtain A3, wherein the weight of the A3 is 0.99g, and the yield of the A3 is 77%.
On compound A3 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(600MHz,Chloroform-d)δ11.91(s,1H),8.09(s,1H),7.45(s,1H),6.52(s,1H),4.17(d,J＝6.6Hz,2H),1.84–1.74(m,2H),1.01(d,J＝7.2Hz,3H)。
13 C NMR(151MHz,Chloroform-d)δ10.41,22.04,68.49,119.56,139.63,153.62,157.49,170.24。
HR-MS(ESI)m/z C 8 H 10 N 3 O 3 (M-H) - theoretical value 196.0728, measured value 196.0725.
Example four
Preparation of 6-isopropoxy-3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous isopropanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, concentrating under reduced pressure to dryness, and recrystallizing with ethanol to obtain 1.03g of a compound A4, wherein the yield of A4 is 81%.
On the compound A1 1 H NMR、 13 C NMR and HR-MS analyses were carried out,
1 H NMR(600MHz,Chloroform-d)δ11.88(s,1H),8.04(s,1H),7.41(s,1H),6.46(s,1H),5.25–4.85(m,1H),1.34(d,J＝6.2Hz,6H)。
13 C NMR(151MHz,Chloroform-d)δ21.70,69.69,119.53,140.16,152.95,157.29,170.30。
HR-MS(ESI)m/z C 8 H 10 N 3 O 3 (M-H) - theoretical value 196.0728, measured value 196.0724.
EXAMPLE five
Preparation of 6-butoxy-3-hydroxy-2-pyrazinecarboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous n-butanol, adding 0.3mL of sulfuric acid at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, concentrating under reduced pressure to dryness, and recrystallizing with ethanol to obtain the compound A5, wherein the weight of the A5 is 1.13g, and the yield is 0.83%.
On compound A5 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(600MHz,Chloroform-d)δ11.92(s,1H),8.05(s,1H),7.48(s,1H),6.85(s,1H),4.20(t,J＝6.6Hz,2H),1.75–1.67(m,2H),1.47–1.38(m,2H),0.92(t,J＝7.4Hz,3H)。
13 C NMR(151MHz,Chloroform-d)δ13.69,19.09,30.69,66.68,119.58,139.54,153.60,157.42,170.30。
HR-MS(ESI)m/z C 9 H 12 N 3 O 3 (M-H) - theoretical value 210.0884, measured value 210.0883.
EXAMPLE six
Preparation of 6-n-pentyloxy-3-hydroxy-2-pyrazinecarboxamide
To 20mL of anhydrous n-pentanol was added 1g of 6-fluoro-3-hydroxypyrazine-2-carboxamide, 0.5mL of phosphoric acid was added at room temperature, the temperature was raised to 60 ℃ for reaction for 3 hours, after cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure, and column separation (dichloromethane: methanol 10: 1) was performed to obtain compound A6, A6 weight was 1.16g, and an A6 yield was 80%.
On compound A6 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(600MHz,Chloroform-d)δ11.89(s,1H),8.08(s,1H),7.44(s,1H),6.48(s,1H),4.21(t,J＝6.6Hz,2H),1.79–1.72(m,2H),1.44–1.31(m,4H),0.90(d,J＝7.2Hz,3H)。
13 C NMR(151MHz,Chloroform-d)δ13.91,22.35,28.08,28.38,67.01,119.56,139.66,153.62,157.50,170.24。
HR-MS(ESI)m/z C 10 H 14 N 3 O 3 (M-H) - theoretical value 224.1041, measured value 224.1038.
EXAMPLE seven
Preparation of 6-isopentyloxy-3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous isoamyl alcohol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, concentrating under reduced pressure to dryness, and recrystallizing with ethanol to obtain a compound A7, wherein the weight of the compound A7 is 1.15g, and the yield is 79%.
On compound A7 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(600MHz,DMSO)δ11.39(s,1H),8.57(s,1H),8.37(s,1H),8.14(s,1H),4.36(t,2H,J＝6Hz),1.82-1.73(m,1H),1.63-1.59(m,2H),0.98-0.90(m,6H)。
13 C NMR(150MHz,DMSO)δ169.94,157.07,153.03,137.86,120.43,65.06,37.12,24.51,22.36。
HR-MS(ESI)m/z C 10 H 15 N 3 NaO 3 (M+Na) + theoretical value 248.1006, measured value 248.1017.
Example eight
Preparation of 6-octyloxy-3-hydroxypyrazine-2-formamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous n-octanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, distilling under reduced pressure to dryness, and recrystallizing with ethanol to obtain the compound A8, wherein the weight of the compound A8 is 1.34g, and the yield of the A8 is 78%.
On the compound A8 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(600MHz,Chloroform-d)δ11.88(s,1H),8.10(s,1H),7.41(s,1H),5.90(s,1H),4.21(t,J＝6.6Hz,2H),1.92–1.61(m,2H),1.54–1.13(m,10H),0.87(t,J＝7.0Hz,3H)。
13 C NMR(151MHz,Chloroform-d)δ14.06,22.63,25.99,28.74,29.18,29.29,31.77,67.06,119.51,139.78,153.62,157.58,170.04。
HR-MS(ESI)m/z C 13 H 20 N 3 O 3 (M-H) - theoretical value 266.1510, measured value 266.1510.
Example nine
Preparation of 6- (2-hydroxyethoxy) -3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous hydroxy ethanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, concentrating under reduced pressure to dryness, and recrystallizing with ethanol to obtain the compound A9, wherein the weight of the compound A9 is 1.05g, and the yield of the compound A9 is 82%.
On compound A9 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(600MHz,DMSO-d6)δ3.70(q,J＝5.1Hz,2H),4.36(dd,J＝5.7,4.3Hz,2H),4.81(t,J＝5.5Hz,1H),8.14(s,1H),8.35(s,1H),8.53(s,1H),12.79(s,1H)。
13 C NMR(151MHz,DMSO-d6)δ59.30,68.44,120.37,138.15,153.13,157.12,170.02。
HR-MS(ESI)m/z C 7 H 8 N 3 O 4 (M-H) - theoretical value 198.0520, measured value 198.0521.
Example ten
Preparation of 6- (2-methoxyethoxy) -3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous 2-methoxyethanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, concentrating under reduced pressure to dryness, and recrystallizing with ethanol to obtain a compound A10, wherein the weight of the A10 is 1.08g, and the yield of the A10 is 79%.
On compound A10 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(600MHz,Chloroform-d)δ11.91(s,1H),8.17(s,1H),7.38(s,1H),5.82(s,1H),4.46–4.23(m,2H),3.74(t,J＝4.2Hz,2H),3.43(s,3H)。
13 C NMR(151MHz,Chloroform-d)δ59.22,65.99,70.49,119.43,139.90,153.14,157.85,169.89。
HR-MS(ESI)m/z C 8 H 10 N 3 O 4 (M-H) - theoretical value 212.0677, measured value 212.0676.
EXAMPLE eleven
Preparation of 6- (2-chloroethoxy) -3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous 2-chloroethanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, concentrating under reduced pressure to dryness, and recrystallizing with ethanol to obtain the compound A11, wherein the weight of the compound A11 is 1.13g, and the yield of the compound A11 is 81%.
On the compound A11 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(400MHz,DMSO-d 6 )δ12.87(s,1H),8.65(s,1H),8.39(s,1H),8.22(s,1H),4.65(t,2H，J＝4),3.97(t,2H，J＝4)。
13 C NMR(100MHz,DMSO-d 6 )δ170.35,157.88,152.84,138.44,120.94,67.08,43.45。
HR-MS(ESI)m/z C 7 H 8 ClN 3 NaO 3 (M+Na) + theoretical value 240.0146, measured value 240.0157.
EXAMPLE twelve
Preparation of 6- (cyclobutoxy) -3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of cyclobutanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, distilling under reduced pressure to dryness, and recrystallizing with ethanol to obtain the compound A12, wherein the weight of the compound A12 is 1.05g, and the yield of the compound A12 is 78%.
On the compound A12 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(600MHz,DMSO-d 6 )δ12.81(s,1H),8.42(d,2H,J＝18),8.12(s,1H),5.29-5.24(m,1H),2.49-2.44(m,2H),2.07-2.00(m,2H),1.81-1.76(m,1H),1.65-1.57.(m,1H)。
13 C NMR(150MHz,DMSO-d 6 )δ169.87,157.05,152.00,137.85,120.50,69.87,29.84,12.79。
HR-MS(ESI)m/z C 9 H 11 N 3 NaO 3 (M+Na) + theoretical value 232.0693, measured value 232.0663.
EXAMPLE thirteen
Preparation of 6-cyclopentyloxy-3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous cyclopentanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, distilling under reduced pressure to dryness, and recrystallizing with ethanol to obtain the compound A13, wherein the weight of the A13 is 1.43g, and the yield of the A13 is 76%.
On compound A13 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(600MHz,DMSO-d 6 )δ12.79(s,1H),8.48(s,1H),8.37(s,1H),8.09(s,1H),5.51-5.49(m,1H),2.00-1.96(m,2H),1.73-1.65(m,4H),1.62-1.58(m,2H)。
13 C NMR(150MHz,DMSO-d 6 )δ169.95,156.83,152.64,138.25,120.42,78.36,32.00,23.46。
HR-MS(ESI)m/z C 10 H 13 N 3 NaO 3 (M+Na) + theoretical value 246.0849, measured value 246.0816.
Example fourteen
Preparation of 6-cyclohexyloxy-3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous cyclohexanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, concentrating under reduced pressure to dryness, and recrystallizing with ethanol to obtain the compound A14, wherein the weight of A14 is 1.14g, and the yield of A14 is 75%.
On compound A14 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(400MHz,DMSO-d6)δ12.81(s,1H),8.52(s,1H),8.37(s,1H),8.09(s,1H),5.19-5.13(m,1H),1.92-1.89(m,2H),1.73-1.67(m,2H),1.50-1.39(m,4H),1.30-1.21(m,2H)。
13 C NMR(100MHz,DMSO-d6)δ170.51,157.39,152.87,138.91,120.94,73.90,31.67,25.55,23.66。
HR-MS(ESI)m/z C 11 H 15 N 3 NaO 3 (M+Na) + theoretical value 260.1006, measured value 260.0957.
Example fifteen
Preparation of 6-cyclohexylmethoxy-3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous cyclohexylmethanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, distilling under reduced pressure to dryness, and recrystallizing with ethanol to obtain a compound A15, wherein the weight of the A15 is 1.34g, and the yield of the A15 is 83%.
On compound A15 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(600MHz,DMSO-d6)δ12.80(s,1H),8.54(s,1H),8.36(s,1H),8.14(s,1H),4.17(d,2H,J＝6Hz),1.80-1.64(m,6H),1.28-1.15(m,3H),1.08-1.01(m,2H)。
13 C NMR(150MHz,DMSO-d6)δ169.92,156.96,153.22,137.90,120.29,71.37,36.82,29.12,25.92,25.12。
HR-MS(ESI)m/z C 12 H 17 N 3 NaO 3 (M+Na) + theoretical value 274.1162, measured value 274.1142.
Example sixteen
Preparation of 6-benzyloxy-3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous benzyl alcohol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, distilling under reduced pressure to dryness, and recrystallizing with ethanol to obtain a compound A16, wherein the weight of A16 is 1.23g, and the yield of A16 is 78%.
On compound A16 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(600MHz,DMSO-d6)δ12.83(s,1H),8.64(s,1H),8.42(s,1H),8.22(s,1H),7.50(d,2H,J＝6Hz),7.41(t,2H,J＝6Hz),7.35(t,1H,J＝6Hz),5.45(s,2H)
13 C NMR(150MHz,DMSO-d6)δ169.86,157.19,152.64,138.10,136.60,128.33,128.19,127.92,120.26,67.92.
HR-MS(ESI)m/z C 12 H 11 N 3 NaO 3 (M+Na) + theoretical value 268.0693, measured value 268.0694.
Example seventeen
Preparation of 6-phenethyloxy-3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous phenethyl alcohol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, distilling under reduced pressure to dryness, and recrystallizing with ethanol to obtain the compound A17, wherein the weight of the compound A17 is 1.33g, and the yield is 90%.
On compound A17 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(400MHz,DMSO-d6)δ12.83(s,1H),8.58(s,1H),8.36(s,1H),8.13(s,1H),7.34-7.29(m,4H),7.24-7.20(m,1H),4.57(t,2H，J＝8),3.04(t,2H，J＝8)。
13 C NMR(100MHz,DMSO-d6)δ170.46,157.64,153.39,138.65,138.44,129.48,128.77,126.75,120.98,67.51,35.13。
HR-MS(ESI)m/z C 13 H 13 N 3 NaO 3 (M+Na) + theoretical value 282.0849, measured value 282.0851.
EXAMPLE eighteen
Preparation of 6-phenylpropyloxy-3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous benzene propanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, distilling under reduced pressure to dryness, and recrystallizing with ethanol to obtain the compound A18, wherein the weight of the compound A18 is 1.32g, and the yield of the A18 is 75%.
On compound A18 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(400MHz,DMSO-d6)δ12.82(s,1H),8.49(s,1H),8.38(s,1H),8.17(s,1H),7.31-7.17(m,5H),4.36(t,2H，J＝8),2.74(t,2H，J＝8),2.06-1.99(m,2H)。
13 C NMR(100MHz,DMSO-d6)δ170.89,158.02,153.95,142.31,138.93,129.21,126.72,121.33,66.82,32.40,31.02。
HR-MS(ESI)m/z C 14 H 15 N 3 NaO 3 (M+Na) + theoretical value 296.1006, measured value 296.1002.
Example nineteen
Preparation of 6-phenylbutoxy-3-hydroxypyrazine-2-carboxamide
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-formamide into 20mL of anhydrous benzene butanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, distilling under reduced pressure to dryness, and recrystallizing with ethanol to obtain the compound A19, wherein the weight of the compound A19 is 1.42g, and the yield of the compound A19 is 77%.
On compound A19 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(400MHz,DMSO-d6)δ12.81(s,1H),8.55(s,1H),8.39(s,1H),8.15(s,1H),7.30-7.15(m,5H),4.36(brs,2H),2.65(brs,2H),1.72(brs,4H)。
13 C NMR(100MHz,DMSO-d6)δ170.48,157.54,153.58,142.46,138.48,128.77,128.73,126.17,120.88,66.85,35.17,28.41,27.84。
HR-MS(ESI)m/z C 15 H 17 N 3 NaO 3 (M+Na) + theoretical value 310.1162, measured value 310.1113.
Example twenty
Preparation of 6-ethoxy-3-hydroxy-2-pyrazinecarbonitrile
Adding 1g of 6-fluoro-3-hydroxypyrazine-2-carbonitrile into 20mL of absolute ethanol, adding 2mL of 4mol/L hydrogen chloride dioxane solution at room temperature, heating to 60 ℃, reacting for 3h, cooling to room temperature, concentrating under reduced pressure to dryness, and recrystallizing with ethanol to obtain a compound A20, wherein the weight of A20 is 0.94g, and the yield of A20 is 81%.
On compound A20 1 H NMR、 13 C NMR and HR-MS analysis:
1 H NMR(400MHz,DMSO-d6)δ12.78(brs,1H),8.18(s,1H),4.25-4.23(m,2H),1.32(t,3H,J＝8Hz)。
13 C NMR(100MHz,DMSO-d6)δ170.48,158.89,153.85,138.43,120.96,63.11,14.66。
HR-MS(ESI)m/z C 7 H 7 N 3 NaO 2 (M+Na) + theoretical value 166.0611, measured value 166.0611.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and these modifications or substitutions do not depart from the spirit of the corresponding technical solutions of the embodiments of the present invention.
Claims (3)
1. A method for preparing alkoxy pyrazine derivatives is characterized in that: the method comprises the following steps:
6-X-3-hydroxy-2-R 1 -pyrazine and R 2 OH reaction, introducing an acidic substance, heating to 20-100 ℃, and reacting for 3-10h to obtain an alkoxy pyrazine derivative;
the mol ratio of the 6-X-3-hydroxy-2-R1-pyrazine to the acidic substance is 1:1-10;
wherein X is halogen, R 1 is-CO-NH 2 Or CN;
the acidic substance is phosphoric acid, sulfuric acid, hydrogen chloride dioxane or hydrogen chloride gas;
R 2 OH is one of methanol, ethanol, propanol, isopropanol, n-butanol, n-pentanol, isoamyl alcohol, n-octanol, cyclobutanol, cyclopentanol, cyclohexanol, benzyl alcohol, phenethyl alcohol, phenylpropyl alcohol or phenylbutanol.
2. A method for producing an alkoxypyrazine derivative according to claim 1, which comprises: 6-X-3-hydroxy-2-R 1 -pyrazine and R 2 And (3) performing an OH reaction, adding a hydrogen chloride dioxane solution, heating to 60 ℃, and reacting for 4 hours to obtain the alkoxy pyrazine derivative, wherein the yield of the alkoxy pyrazine derivative is more than 75%.
3. A method for producing alkoxypyrazine derivatives according to claim 1, characterized in that: 6-X-3-hydroxy-2-R 1 -pyrazine and R 2 And (3) OH reaction, introducing hydrogen chloride gas, heating to 60 ℃, and reacting for 3h to obtain the alkoxy pyrazine derivative, wherein the yield of the alkoxy pyrazine derivative is more than 75%.
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