CN111848521A - Preparation method of 2-substituted-4-alkoxy imidazole compound - Google Patents
Preparation method of 2-substituted-4-alkoxy imidazole compound Download PDFInfo
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- CN111848521A CN111848521A CN202010872569.2A CN202010872569A CN111848521A CN 111848521 A CN111848521 A CN 111848521A CN 202010872569 A CN202010872569 A CN 202010872569A CN 111848521 A CN111848521 A CN 111848521A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/70—One oxygen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides a preparation method of a 2-substituted-4-alkoxy imidazole compound, which comprises the following steps: (1) reacting 2-cyanoethylamine shown in a compound 1 or hydrochloride thereof with a compound 2, or reacting 2-cyanoethylamine hydrochloride with a compound 3 or a compound 4 to generate a compound 5 or a compound 6; (2) and reacting the compound 5 or the compound 6 with sodium alkoxide shown in the formula I to obtain a 2-substituted-4-alkoxy imidazole compound shown in a compound 7. The method for synthesizing the 2-substituted-4-alkoxy imidazole compound by using the simple and novel synthesis method has the advantages of short route, high yield, avoidance of use of azide, stable process and easiness in industrialization.
Description
Technical Field
The invention belongs to the technical field of synthesis of drug intermediates, and relates to a preparation method of a 2-substituted-4-alkoxy imidazole compound.
Background
2-substituted-4-alkoxy imidazole compounds are a very important pharmaceutical intermediate, however. However, the existing synthesis method has the problems of long route, low yield, unfavorable environmental protection and the like.
A process for the preparation of 2-substituted-4-alkoxyimidazole compounds is reported in SYUICHI FURUYA, KIYOSHI OMURA, YOSHIYASU FURUKAWA, Addition of 4-acetoxyimidazole to Dimethyl acrylonitrile carboxylate and Transformation of the additives to pyridine-5-yl Acetates, Chemical and Pharmaceutical Bulletin,1988 vol, 36, #5, p.1669-1675, and the synthetic route is as follows:
this route requires the use of sulphides which have a very pronounced odour and although the final product is sulphur-depleted, it is not easy to remove the odour completely by post-treatment. The intermediate is an azide compound, and has certain danger. The whole route is unfavorable for environmental protection, and gives very harsh experimental environment to experimental operators, thereby influencing mood and physical health.
Molina1, C.L Lopez-Leonardo, J.Llamas-Botii, C.Foces-Foces2, A.L.Llamas-Saiz, Preparation of high hly Functionalized Imidazoles from α -Azidoacetic acid, X-ray Crystal Structure of 4-Methoxy-2-methyl-5-methyl arylamid, Synthesis,1995, #4, p.449-452 and Chemical and pharmaceutical Bulletin,1988, vol.36, #5, p.1669-1675 disclose the following routes:
the Meerwein reagent is needed in the route, the reagent is dangerous to synthesize, dangerous ether is needed in the reagent synthesis process, the reagent is difficult to synthesize, and only 2-substituted-4-ethoxyimidazole compounds can be synthesized, so that the method has limitations. The whole route is unstable in process and high in operation difficulty.
Therefore, in the art, it is desired to develop a method for synthesizing a 2-substituted-4-alkoxyimidazole compound having a short synthetic route, a high yield, and a stable process.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a preparation method of a 2-substituted-4-alkoxy imidazole compound. The invention synthesizes the 2-substituted-4-alkoxy imidazole compound by using a simple and novel synthesis method, which has short route and high yield, avoids using azide and has stable process.
In order to achieve the purpose, the invention adopts the following technical scheme:
in one aspect, the present invention provides a method for preparing a 2-substituted-4-alkoxyimidazole compound, the method comprising the steps of:
(1) reacting 2-cyanoethylamine shown in a compound 1 or hydrochloride thereof with a compound 2, or reacting 2-cyanoethylamine hydrochloride with a compound 3 or a compound 4 to generate a compound 5 or a compound 6, wherein the reaction formula is as follows:
(2) reacting the compound 5 or the compound 6 with sodium alkoxide shown in formula I and formula II to obtain a 2-substituted-4-alkoxy imidazole compound shown in a compound 7, wherein the reaction formula is as follows:
wherein R is1Is substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl; r2Is a substituted or unsubstituted alkyl group.
Preferably, the substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C6 (e.g., C1, C2, C3, C4, C5, or C6) alkyl group.
Preferably, the heteroaryl group is a pyridyl, furyl or thienyl group.
In the present invention, when the group has a substituent, the substituent is a halogen (fluorine, chlorine, bromine, iodine), an alkyl group of C1 to C6 (e.g., C1, C2, C3, C4, C5, or C6), an alkoxy group of C1 to C6 (e.g., C1, C2, C3, C4, C5, or C6).
Preferably, R1Is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, pyridyl, substituted pyridyl, furyl or thienyl.
Preferably, R2Is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl.
Preferably, the molar ratio of 2-cyanoethylamine or hydrochloride salt thereof to compound 2 in step (1) is 1:1 to 3, such as 1:1, 1:1.3, 1:1.5, 1:1.8, 1:2, 1:2.3, 1:2.5, 1:2.8 or 1: 3.
Preferably, the molar ratio of 2-cyanoethylamine hydrochloride to compound 3 or compound 4 in step (1) is 1:1-3, such as 1:1, 1:1.3, 1:1.5, 1:1.8, 1:2, 1:2.3, 1:2.5, 1:2.8, or 1: 3.
Preferably, the compound 1 or hydrochloride thereof in the step (1) reacts with the compound 2 in the presence of concentrated sulfuric acid as a catalyst and anhydrous sodium sulfate as a dehydrating agent.
Preferably, the reaction temperature of the 2-cyanoethylamine or hydrochloride thereof with the compound 2 in the step (1) is 100 ℃ to 140 ℃, for example, 100 ℃, 105 ℃, 110 ℃, 115 ℃, 120 ℃, 130 ℃, 140 ℃.
Preferably, the reaction time of the 2-cyanoethylamine or hydrochloride thereof with the compound 2 in step (1) is 0.3 to 1 hour, such as 0.3 hour, 0.5 hour, 0.8 hour, 1 hour.
Preferably, the temperature for reacting the 2-cyanoethylamine hydrochloride salt with the compound 3 or the compound 4 in the step (1) is 20 to 25 ℃, for example, 20 ℃, 22 ℃, 24 ℃, 25 ℃.
Preferably, the 2-cyanoethylamine hydrochloride salt is reacted with compound 3 or compound 4 in step (1) for a period of 5 to 24 hours, for example 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 22 hours or 24 hours.
Preferably, the molar ratio of the compound 5 or the compound 6 in the step (2) to the sodium alkoxide shown in the formula I is 1:1.2-1.8, such as 1:1.2, 1:1.25, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7 or 1: 1.8.
Preferably, the solvent for the reaction in step (2) is methanol, ethanol, tetrahydrofuran, 1, 4-dioxane.
Preferably, the reaction of step (2) is carried out under reflux.
Preferably, the reaction time in step (2) is 5 to 10 hours, such as 5 hours, 6 hours, 7 hours, 8 hours, 9 hours or 10 hours.
Compared with the prior art, the invention has the following beneficial effects:
the method for synthesizing the 2-substituted-4-alkoxy imidazole compound by using the simple and novel synthesis method has the advantages of short route, high yield of 70-80%, no use of azide, stable process and easy industrialization.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Example 1
In this example, compound 7a was prepared by the following preparative route:
the preparation method specifically comprises the following steps:
(1) preparation of Compound 5a (4-methoxy-4-phenyl-3-azabut-3-enenitrile):
250mL of water and compound 1(100g, 1eq, 1.08mol) were added to a 500mL single-neck flask, and 82.1g of potassium carbonate (0.55eq, 0.59mol) was added in portions at 20 to 25 ℃, stirred for 0.5 hour, extracted with ethyl acetate (100 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain an oil 1 in a free state. A500 mL three-necked flask is charged with compound 2a (300g, 3.8eq, 1.59mol), 15 drops of concentrated sulfuric acid and 58.1g of sodium sulfate (1eq, 0.41mol), heated to 120 ℃, externally connected with a condensing device to receive the by-product methanol, after the temperature is stabilized, the free state of the compound 1 is added dropwise, the reaction is carried out for 0.5 hour, TLC is used for monitoring the completion of the reaction, 200mL of ethyl acetate is added for cooling, 50mL of water is washed, anhydrous sodium sulfate is dried, the filtration is carried out, and the reduced pressure distillation is carried out, so that 174g of oily matter 5a is obtained. The yield thereof was found to be 92%. MS (EI) 174.1.
(2) Preparation of Compound 7a (4-Methoxy-2-phenylimidazole)
In a 500mL three-necked flask, 200mL of methanol, 10.8g of sodium methoxide (1.2eq, 0.2mol), and compound 5a (28.5g, 1eq, 0.163mol) were added and heated to reflux, and the mixture was reacted for 6 hours, TLC reaction was completed, methanol was evaporated under reduced pressure, 50mL of water was added, pH was adjusted to 8 with 6N hydrochloric acid, and the mixture was extracted with a dichloromethane/methanol mixed solvent at a volume ratio of 10:1 (30mL × 3), dried over anhydrous sodium sulfate, decolorized with activated carbon, filtered, concentrated under reduced pressure to a small volume, and filtered to obtain 24.2g of white powder 7 a. The yield thereof was found to be 85%. MS (ESI +) 175.0.1H NMR (300MHz, CDCl 3): 12.14(br, 1H), 7.2-7.86(m, 2H), 7.30-7.44(m, 3H), 6.57(s, 1H), 3.73(s, 3H). The total yield was 78.2%.
Example 2
In this example, compound 7b was prepared by the following preparative route:
the preparation method specifically comprises the following steps:
(1) preparation of Compound 5b (4-methoxy-3-azaoct-3-enenitrile)
In a 500mL single neck flask, 250mL of water was added, compound 1(100g, 1eq, 1.08mol), potassium carbonate (82.1g, 0.55eq, 0.59mol) was added in portions at 20-25 ℃, stirred for 0.5 hour, extracted with ethyl acetate (100 mL. times.3), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give free form of oil 1. Adding the compound 2b (145.1g, 3eq, 0.894mol), 9 drops of concentrated sulfuric acid and anhydrous sodium sulfate (29.2g, 1eq, 0.298mol) into a 500mL three-necked flask, heating to 120 ℃, connecting a condensing device externally to receive a byproduct methanol, dropwise adding the free state of the compound 1 after the temperature is stable, reacting for 0.5 hour, monitoring the reaction by TLC to be complete, cooling and distilling to obtain 151g of oily substance 5 b. The yield thereof was found to be 90.6%. MS (EI) 154.2.
(2) Preparation of Compound 7b (2-Butyl-4-methoxy-1H-imidazole)
In a 500mL three-necked flask, 400mL of methanol, 21.6g of sodium methoxide (1.5eq, 0.4mol), and 41g of compound 5b (1eq, 0.265mol) were refluxed for 5 hours, and the reaction was monitored by TLC, methanol was removed by rotation, 50mL of water was added, pH was adjusted to 8 with 6N hydrochloric acid, and the mixture was extracted with a dichloromethane/methanol mixed solvent at a volume ratio of 10:1 (30mL × 3), dried over anhydrous sodium sulfate, decolorized with activated carbon, filtered, concentrated under reduced pressure to a small volume, and filtered to obtain 36.2g of yellow powder 7 b. The yield thereof was found to be 88.2%. MS (ESI +): 155.2.1H NMR (300MHz, CDCl 3): 8.90(br, 1H), 6.17(s,1H), 3.79(s,3H), 2.61-2.67(t,2H), 1.63-1.74(m,2H), 1.31-1.44(m,2H), 0.90-0.95(t, 3H). The total yield was 79.9%.
Example 3
In this example, compound 7c was prepared by the following preparative route:
the preparation method specifically comprises the following steps:
(1) preparation of Compound 5c (4- (2-furyl) -4-methoxy-3-azabut-3-enenitrile)
Into a 2L three-necked flask, 700mL of methyl tert-butyl ether and potassium carbonate (75.3g, 1eq, 0.544mol) as compound 3c (88g, 1eq, 0.544mol) were added and stirred at 20 ℃ for 5 minutes, 400mL of an aqueous solution of compound 1(50.4g, 1eq, 0.544mol) was added dropwise, the mixture was reacted at 20 ℃ overnight after completion of the dropwise addition, the aqueous phase (100 mL. times.2) was separated, extracted with methyl tert-butyl ether, and the combined organic phases were dried and distilled under reduced pressure to give 82g of oil 5 c. The yield thereof was found to be 91.7%. MS (ESI +) 165.1.
(2) Preparation of Compound 7c (2- (2-Furyl) -4-methoxyimidazole)
To a 250mL three-necked flask, 90mL of anhydrous methanol was added, sodium methoxide (4.8g, 1.7eq, 0.09mol) and compound 5c (8.7g, 1eq, 0.053 mol) were added, the mixture was refluxed for 6 hours, the reaction was monitored by TLC, and the pressure was reduced to complete the reactionMethanol was distilled off, 100mL of water was added, the pH was adjusted to 8 with 6N hydrochloric acid, and the mixture was extracted with a dichloromethane/methanol mixed solvent at a volume ratio of 10: 1(50 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to a small volume, and filtered to obtain 7.1g of yellow powder 7 c. The yield thereof was found to be 81.6%. MS (ESI +) 165.2.1H NMR (300MHz, CDCl 3): 9.16(br, 1H), 7.41-7.42(d, 1H), 6.82-6.83(d, 1H), 6.48-6.50(dd, 1H), 6.36(s,1H),3.84(s, 3H). The total yield was 74.8%.
Example 4
In this example, compound 7d was prepared by the following preparative route:
the preparation method specifically comprises the following steps:
(1) preparation of Compound 5d (4-cyclopropy-4-ethoxy-3-aza-3-enenitrile)
3L of methyl tert-butyl ether, compound 4d (408g, 1eq, 2.72mol), potassium carbonate (377.1g, 1eq, 2.72mol) were added to a 10L three-necked flask, stirred at 25 ℃ for 5 minutes, 3L of 1(252.4g, 1eq, 2.72mol) aqueous solution was added dropwise, reacted at 25 ℃ overnight, separated, the aqueous phase (1L. times.3) was extracted with methyl tert-butyl ether, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give 361g of oil 5 d. The yield thereof was found to be 87%. MS (EI) 152.1.
(2) Preparation of Compound 7d (2-Cyclopropyl-4-methoxyimidazole)
A5L three-necked flask was charged with 2.3L of anhydrous methanol, 124g (1.7eq, 2.29mol) of sodium methoxide and 5d (202.8g, 1eq, 1.33mol) of compound were added thereto, and the mixture was heated under reflux to react for 9 hours. TLC was monitored for completion of the reaction, methanol was evaporated under reduced pressure, 1000mL of water was added, the pH was adjusted to 7 with 6N hydrochloric acid, the mixture was extracted with a 10:1 volume dichloromethane/methanol mixed solvent (500mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated to a small volume under reduced pressure, and filtered to obtain 156.6g of yellow powder 7 d. The yield thereof was found to be 85.1%. MS (ESI +) 139.3.1H NMR (300MHz, CDCl 3): 9.61(br, 1H), 6.14(s, 1H), 3.75(s, 3H), 1.81-1.90(m, 1H), 0.85-0.98(m, 4H). The total yield was 74.0%.
Example 5
In this example, compound 7e was prepared by the following preparative route:
the preparation method specifically comprises the following steps:
(1) compound 5a was prepared as in example 1.
(2) Preparation of Compound 7e (4-Ethoxy-2-phenylimidazole)
To a 500mL three-necked flask, 200mL of absolute ethanol, sodium ethoxide (10.8g, 1.2eq, 0.2mol), and compound 5a (28.5g, 1eq, 0.163mol) were added and heated to reflux, the reaction was carried out for 6 hours, TLC was monitored for completion of the reaction, methanol was distilled off under reduced pressure, 50mL of water was added, pH was adjusted to 8 with 6N hydrochloric acid water, a dichloromethane/methanol mixed solvent at a volume ratio of 10:1 was used for extraction (30mL × 3), anhydrous sodium sulfate was dried, activated carbon was decolorized, and the mixture was filtered and concentrated under reduced pressure to a small volume, and 24.7g of white powder 7e was obtained by filtration. The yield thereof was found to be 80.1%. MS (ESI +): 189.1.1H NMR (300MHz, CDCl 3): 12.11(br, 1H), 7.83-7.85(m, 2H), 7.39-7.44(m, 2H), 7.29-7.32(m, 1H), 6.55(s, 1H), 3.97-4.04(q, 2H), 1.28-1.33(t, 3H). The total yield was 73.6%.
The applicants state that the present invention is illustrated by the above examples of the preparation of the 2-substituted-4-alkoxyimidazole compounds of the present invention, but the present invention is not limited to the above examples, i.e., it is not meant that the present invention must be practiced by relying on the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. A method for producing a 2-substituted-4-alkoxyimidazole compound, characterized by comprising the steps of:
(1) reacting 2-cyanoethylamine shown in a compound 1 or hydrochloride thereof with a compound 2, or reacting 2-cyanoethylamine hydrochloride with a compound 3 or a compound 4 to generate a compound 5 or a compound 6, wherein the reaction formula is as follows:
(2) Reacting the compound 5 or the compound 6 with sodium alkoxide shown in the formula I to obtain a 2-substituted-4-alkoxy imidazole compound shown in a compound 7, wherein the reaction formula is as follows:
wherein R is1Is substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl; r2Is a substituted or unsubstituted alkyl group.
2. The method according to claim 1, wherein the substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C6 alkyl group;
preferably, the heteroaryl group is a pyridyl, furyl or thienyl group.
3. The method according to claim 1 or 2, wherein R is1Is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, pyridyl, substituted pyridyl, furyl or thienyl.
4. The method of any one of claims 1-3, wherein R is2Is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl.
5. The process according to claims 1 to 4, wherein the molar ratio of the 2-cyanoethylamine or hydrochloride thereof to the compound 2 in the step (1) is 1: 1-3;
preferably, the molar ratio of 2-cyanoethylamine hydrochloride to compound 3 or compound 4 in step (1) is 1: 1-3.
6. The process for preparing the compound of formula I according to claims 1 to 5, wherein the reaction of the compound 1 or its hydrochloride salt of step (1) with the compound 2 is carried out in the presence of concentrated sulfuric acid as a catalyst and anhydrous sodium sulfate as a dehydrating agent.
7. The process of formula I as claimed in claims 1 to 6, wherein the reaction of the 2-cyanoethylamine or hydrochloride salt thereof with the compound 2 in step (1) is carried out at a temperature of 100 ℃ to 140 ℃;
preferably, the reaction time of the 2-cyanoethylamine or hydrochloride thereof with the compound 2 in the step (1) is 0.3 to 1 hour;
preferably, the temperature for reacting the 2-cyanoethylamine hydrochloride with the compound 3 or the compound 4 in the step (1) is 20-25 ℃;
preferably, the 2-cyanoethylamine hydrochloride salt is reacted with the compound 3 or the compound 4 in the step (1) for 5 to 24 hours.
8. The method according to any one of claims 1 to 7, wherein the molar ratio of the compound 5 or the compound 6 in the step (2) to the sodium alkoxide represented by the formula I is 1:1.2 to 1.8.
9. The method according to any one of claims 1 to 8, wherein the solvent for the reaction in step (2) is any one of methanol, ethanol, tetrahydrofuran, or 1, 4-dioxane, or a combination of at least two thereof.
10. The production method according to any one of claims 1 to 9, wherein the reaction of step (2) is carried out in a reflux state;
preferably, the reaction time in step (2) is 5 to 10 hours.
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