CN113372344B - Synthesis method of chloro-hexatomic nitrogen-containing heterocyclic imidazole compound - Google Patents
Synthesis method of chloro-hexatomic nitrogen-containing heterocyclic imidazole compound Download PDFInfo
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a synthesis method of chloro-hexatomic nitrogen-containing heterocyclic imidazole compounds, and particularly discloses a method for reacting a compound I with phosphorus oxychloride and organic base in the presence or absence of a solvent to obtain a compound shown as a formula II; wherein X is N or C (R)3) (ii) a Y is N or C (R)2) (ii) a Z is N or C (R)1)；R1、R2And R3Independently hydrogen, halogen or C1‑C6Alkyl group of (1). The synthesis method is simple and convenient to operate, the ring closing and the chlorination steps are completed in a one-pot method, the pollution of the used reagents is small, the traditional reagents such as chloroacetaldehyde or sulfuric acid are removed, and the product yield and purity are obviously improved.
Description
Technical Field
The invention relates to a synthesis method of chloro-hexatomic nitrogen-containing heterocyclic imidazole compounds.
Background
Heterocyclic compounds are an extremely important branch in chemical molecules, and numerous drug molecules contain a parent nucleus with a heterocyclic structure. The chloro-hexatomic nitrogen-containing heterocyclic imidazole compound is used as a common synthetic intermediate, and has attracted more and more attention because the chloro-hexatomic nitrogen-containing heterocyclic imidazole compound has unique biological activity in the fields of tumor resistance, inflammation resistance, virus resistance and cardiovascular disease.
The existing synthesis method of the chloro-hexatomic nitrogen-containing heterocyclic imidazole compound mainly comprises the following two methods:
the method comprises the following steps: heating the hexabasic nitrogen-containing heterocyclic ring and chloroacetaldehyde to react and close the ring, and then chlorinating to obtain the target product. Such as patents WO2020163193 and WO 2013064984. The route has the disadvantages that toxic chloroacetaldehyde is used in the reaction, the method is not environment-friendly, the reaction is carried out in two steps, the yield is low, and impurities are more.
The second method comprises the following steps: intermediate A1 is subjected to ring closure in sulfuric acid and then chlorinated to obtain the target compound, such as patents WO2013012915 and CN110156786A. The disadvantage of this route is that the reaction dehydration uses a large amount of sulfuric acid for ring closure, resulting in severe acid contamination. Furthermore, substituents on the nitrogen-containing heterocycle, such as iodine, methylthio, mercapto, cyano and the like, are unstable in sulfuric acid and are not suitable for synthesis by this method. Isothermal and conditional ring closure with acetic acid/xylene was reported in patent WO2020097389, but the yield was very low (16%).
Disclosure of Invention
In order to solve a plurality of problems in the synthesis method of chloro-hexatomic nitrogen-containing heterocyclic imidazole compounds in the prior art, the invention provides a synthesis method of chloro-hexatomic nitrogen-containing heterocyclic imidazole compounds. The method has simple operation, less pollution of used reagents, elimination of traditional reagents such as chloroacetaldehyde or sulfuric acid, and obvious improvement of product yield and purity.
The invention provides a synthesis method of chloro-hexatomic nitrogen-containing heterocyclic imidazole compounds, which comprises the following steps: reacting the compound I with phosphorus oxychloride and organic alkali in the presence or absence of a solvent to obtain a compound shown as a formula II;
wherein X is N or C (R)3) (ii) a Y is N orC(R2) (ii) a Z is N or C (R)1)；
R1、R2And R3Independently hydrogen, halogen or C1-C6Alkyl group of (1).
In one embodiment, when R1、R2And R3Independently, when halogen is a halogen, the halogen is Cl, br or I.
In one embodiment, when R1、R2And R3Independently is C1-C6Alkyl of (2), C1-C6Alkyl of (A) is C1-C4For example, alkyl of (b) is methyl.
In one embodiment, X, Y and Z are defined as being selected from 1) or 2):
1) X is C (R)3) (ii) a Y is C (R)2) (ii) a Z is N or C (R)1)；
2) X is C (R)3) (ii) a Y is N; z is C (R)1)；
In a certain embodiment, R1Is hydrogen or C1-C6Alkyl group of (1).
In a certain embodiment, R2Is hydrogen or C1-C6Alkyl group of (1).
In a certain embodiment, R3Is hydrogen or halogen, preferably R3Is hydrogen, bromine or chlorine.
In a certain embodiment, compound I is selected from one of the following compounds:
in a certain embodiment, compound II is selected from one of the following compounds:
in the method for synthesizing the chloro-hexabasic nitrogen-containing heterocyclic imidazole compound, preferably, the raw materials of the reaction system only contain the compound I, phosphorus oxychloride and the organic base, or the raw materials of the reaction system only contain the compound I, phosphorus oxychloride, the organic base and the solvent.
In the method for synthesizing the chloro-six-membered nitrogen-containing heterocyclic imidazole compound, the method preferably comprises the following steps: in the presence or absence of a solvent, the compound I and phosphorus oxychloride are subjected to a first-stage reaction, and then a second-stage reaction is performed under the action of the organic base to obtain the compound shown in the formula II.
In the synthesis method of the chloro-six-membered nitrogen-containing heterocyclic imidazole compound, when the compound is solvent-free, the method preferably comprises the following steps: firstly, mixing the compound I with phosphorus oxychloride, carrying out a first-stage reaction, and then adding the organic base to carry out a second-stage reaction.
In the synthesis method of the chloro six-membered nitrogen-containing heterocyclic imidazole compound, when a solvent is present, the method preferably comprises the following steps: and mixing the compound I with the solvent, adding phosphorus oxychloride to perform a first-stage reaction, and then adding the organic base to perform a second-stage reaction.
In the synthesis method of the chloro six-membered nitrogen-containing heterocyclic imidazole compound, the molar ratio of the phosphorus oxychloride to the compound I is preferably (3-25): 1, more preferably (16-25): 1, for example, 20.
In the synthesis method of the chloro-hexatomic nitrogen-containing heterocyclic imidazole compound, the organic base can be conventional in the field, and preferably, the organic base is one or more of diisopropylethylamine, triethylamine and N, N-dimethylaniline.
In the synthesis method of the chloro six-membered nitrogen-containing heterocyclic imidazole compound, the molar ratio of the organic base to the compound I is preferably (1.5-10): 1, more preferably (2-8): 1, for example, 8.
In the method for synthesizing the chloro-hexabasic nitrogen-containing heterocyclic imidazole compound, the organic base is preferably added dropwise, and more preferably, the dropwise adding speed is controlled so that the reaction temperature does not exceed 100 ℃.
In the synthesis method of the chloro-hexabasic nitrogen-containing heterocyclic imidazole compound, the temperature of the first-stage reaction is preferably conventional in the art, and is, for example, 80-95 ℃, and further is, for example, 90-95 ℃ or 80-85 ℃.
In the synthesis method of the chloro six-membered nitrogen-containing heterocyclic imidazole compound, preferably, the reaction time of the first stage can be conventional in the art, for example, 1 to 8h, and further for example, 2h, 3h, 4h, 6h or 8h.
In the synthesis method of the chloro six-membered nitrogen-containing heterocyclic imidazole compound, preferably, the time of the second-stage reaction can be conventional in the art, for example, 1 to 4 hours, and further, for example, 1 hour, 2 hours, 3 hours or 4 hours.
In the method for synthesizing the chloro-hexabasic nitrogen-containing heterocyclic imidazole compound, preferably, the temperature of the second-stage reaction is the same as the temperature of the first-stage reaction.
In the synthesis method of the chloro-hexatomic nitrogen-containing heterocyclic imidazole compound, when a solvent exists, the phosphorus oxychloride is preferably added dropwise.
In the synthesis method of the chloro six-membered nitrogen-containing heterocyclic imidazole compound, when a solvent exists, the solvent can be conventional in the field, and preferably, the solvent is toluene and/or acetonitrile.
In the synthesis method of the chloro six-membered nitrogen-containing heterocyclic imidazole compound, when a solvent is present, the amount of the solvent used can be conventional in the art, and preferably, the mass ratio of the volume of the solvent to the compound I is 5mL/g-20mL/g, for example, 10mL/g.
In the synthesis method of the chloro-hexatomic nitrogen-containing heterocyclic imidazole compound, a post-treatment step is preferably further included.
In the synthesis method of the chloro-hexabasic nitrogen-containing heterocyclic imidazole compound, preferably, the post-treatment step is as follows: removing phosphorus oxychloride, regulating pH value with alkali, separating and drying.
In the post-treatment step, preferably, the method for removing phosphorus oxychloride comprises replacing the reaction solution with a solvent a, concentrating the reaction solution to obtain a crude product, and quenching the reaction.
In the post-treatment step, preferably, the solvent a may be conventional in the art, such as toluene.
In the post-treatment step, preferably, the quenching reaction may be performed in a conventional manner in the art, and more preferably, the quenching reaction is performed by adding the crude product into a solvent B to dilute the crude product to obtain a solution B phase, and adding the solvent B phase into ice water.
In the post-treatment step, the solvent B phase is preferably added dropwise to the ice water.
In the post-treatment step, preferably, the solvent B may be conventional in the art, such as dichloromethane.
In the post-treatment step, the temperature of the quenching reaction may be conventional in the art, and more preferably, not higher than 25 ℃.
In the post-treatment step, the base is preferably in the form of an aqueous base solution, such as sodium hydroxide solution.
In the post-treatment step, the mass fraction of the alkali in the aqueous solution of alkali may be conventional in the art, and is, for example, 3% to 20%, and is, for example, 10%.
In the post-treatment step, the pH may be adjusted in a range conventional in the art, for example, in the range of 5 to 6.
In the post-treatment step, preferably, the isolation may be conventional in the art, such as extraction with solvent C.
In the post-treatment step, preferably, the solvent C is conventional in the art, such as dichloromethane.
In the synthesis method of the chloro six-membered nitrogen-containing heterocyclic imidazole compound, the monitoring method (such as LC-MS, HPLC or TLC) which is conventional in the art can be preferably adopted for monitoring, and the reaction is generally stopped by taking disappearance or no longer reaction of the compound I as a reaction endpoint.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the operation is simple, the ring closing and the chlorination are finished by a one-pot method, the pollution of the used reagent is small, the traditional reagents such as chloroacetaldehyde or sulfuric acid are removed, and the product yield and purity are obviously improved.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. Experimental procedures without specifying specific conditions in the following examples were selected in accordance with conventional procedures and conditions, or in accordance with commercial instructions.
In the following examples, "eq.
EXAMPLE 1 Synthesis of 5-Chloroimidazo [1,2-a ] pyridine
Adding the compound I-1 (10 g) into phosphorus oxychloride (161g, 1ieq.), heating to 90-95 ℃, stirring for reacting for 4h, then dropwise adding diisopropylethylamine (51g, 6eq.) at the temperature, controlling the temperature not to exceed 100 ℃, continuing the reaction for 1h after the addition is finished, and detecting the complete conversion of the reaction by LCMS. And concentrating the reaction solution, replacing the toluene for two times, and finally concentrating the dry toluene to obtain a crude product. Adding dichloromethane into the crude product for dilution, slowly dropwise adding a dichloromethane phase into ice water for quenching, and keeping the temperature not higher than 25 ℃. After quenching was complete, 10% sodium hydroxide was added dropwise to adjust the pH to 5-6. The layers were separated and the aqueous layer was extracted twice more with dichloromethane and the organic layers were combined, dried and spin dried to give compound II-1 (7.2 g). Yield: 72%, purity 97%, LCMS: m +1=153, 155.
Example 2 Synthesis of 5-chloro-7-methylimidazo [1,2-a ] pyridine
Adding the compound I-2 (10 g) into phosphorus oxychloride (148g, 1ieq.), heating to 90-95 ℃, stirring for reaction for 4 hours, then dropwise adding diisopropylethylamine (47g, 6eq.) at the temperature, controlling the temperature not to exceed 100 ℃, continuing the reaction for 2h after the addition is finished, and detecting complete conversion by LCMS. And concentrating the reaction solution, replacing the toluene for two times, and finally concentrating the dry toluene to obtain a crude product. Adding dichloromethane into the crude product for dilution, slowly dropwise adding a dichloromethane phase into ice water for quenching, and keeping the temperature not higher than 25 ℃. After quenching was complete, 10% sodium hydroxide was added dropwise to adjust the pH to 5-6. The layers were separated and the aqueous layer was extracted twice more with dichloromethane and the organic layers were combined, dried and spin dried to give compound II-2 (7.8 g). Yield: 78%, purity 97%, LCMS: m +1=167, 169.
Example 3-bromo-5-chloroimidazo [1,2-a ] pyridine
Adding the compound I-3 (10 g) into phosphorus oxychloride (106g, 1ieq.), heating to 90-95 ℃, stirring for reaction for 3h, then dropwise adding diisopropylethylamine (34g, 6eq.) at the temperature, controlling the temperature not to exceed 100 ℃, continuing the reaction for 1h after the addition is finished, and detecting the complete conversion of the reaction by LCMS. And concentrating the reaction solution, replacing the toluene for two times, and finally concentrating the dry toluene to obtain a crude product. Adding dichloromethane into the crude product for dilution, slowly dropwise adding a dichloromethane phase into ice water for quenching, and keeping the temperature not higher than 25 ℃. After quenching was complete, 10% sodium hydroxide was added dropwise to adjust the pH to 5-6. The phases were separated and the aqueous phase was extracted twice more with dichloromethane, the organic phases were combined, dried and spin dried to give compound II-3 (6.5 g). Yield: 65%, purity 96%, LCMS: m +1=231, 233.
EXAMPLE 4 Synthesis of 5-Chloroimidazo [1,2-c ] pyrimidine
Adding the compound I-4 (10 g) into phosphorus oxychloride (160g, 16eq.), heating to 90-95 ℃, stirring for reacting for 4h, then dropwise adding diisopropylethylamine (51g, 6eq.) at the temperature, controlling the temperature not to exceed 100 ℃, continuing to react for 2h after the addition is finished, and detecting complete reaction conversion by LCMS. And concentrating the reaction solution, replacing the toluene for two times, and finally concentrating dry toluene to obtain a crude product. Adding dichloromethane into the crude product for dilution, slowly dropwise adding a dichloromethane phase into ice water for quenching, and keeping the temperature not higher than 25 ℃. After quenching was complete, 10% sodium hydroxide was added dropwise to adjust the pH to 5-6. The layers were separated and the aqueous layer was extracted twice more with dichloromethane and the organic layers were combined, dried and spin dried to give compound II-4 (7.0 g). Yield: 70%, purity 96%, LCMS: m +1=154, 156.
Example 5 Synthesis of 5-chloro-7-methylimidazo [1,2-c ] pyrimidine
The only difference from example 4 is that compound I-4 was replaced with compound I-5 to give compound II-5 in yield: 62%, purity 96%, LCMS: m +1=154, 156.
EXAMPLE 6 Synthesis of 5, 8-dichloroimidazo [1,2-c ] pyrimidine
The only difference from example 4 is that compound I-4 was replaced with compound I-6 to give compound II-6 in yield: 69%, purity 97%, LCMS: m +1=188, 190.
EXAMPLE 7 Synthesis of 8-bromo-5-chloroimidazo [1,2-c ] pyrimidine
The only difference from example 4 is that compound I-4 was replaced with compound I-7 to give compound II-7 in yield: 75%, purity 96%, LCMS: m +1=232, 234.
EXAMPLE 8 Synthesis of 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine
The only difference from example 4 is that compound I-4 was replaced with compound I-8 to give compound II-8 in yield: 46%, purity 95%, LCMS: m +1=280, 282.H-NMR (400mhz, cd3od) δ 8.28 (s, 1H), 8.16 (d, J =1.6hz, 1h), 7.81 (d, J =1.6hz, 1h).
Example 9-chloro-8-bromo-7-methylimidazo [1,2-c ] pyrimidine
The only difference from example 4 is that compound I-4 was replaced with compound I-9 to give compound II-9, yield: yield: 51%, purity 96%, LCMS: m +1=246, 248.
EXAMPLE 10 Synthesis of 5-chloroimidazo [1,2-a ] pyrazine
Adding the compound I-10 (10 g) into phosphorus oxychloride (160g, 16eq.), heating to 90-95 ℃, stirring for reaction for 3h, then dropwise adding diisopropylethylamine (51g, 6eq.) at the temperature, controlling the temperature not to exceed 100 ℃, continuing the reaction for 1h after the addition is finished, and detecting the complete conversion of the reaction by LCMS. And concentrating the reaction solution, replacing the toluene for two times, and finally concentrating the dry toluene to obtain a crude product. Adding dichloromethane into the crude product for dilution, slowly dropwise adding a dichloromethane phase into ice water for quenching, and keeping the temperature not higher than 25 ℃. After quenching was complete, 10% sodium hydroxide was added dropwise to adjust the pH to 5-6. Separating, extracting the water phase twice with dichloromethane, combining the organic phases, drying and spin-drying to obtain a compound II-10 with the yield: 80%, purity 97%, LCMS: m +1=154, 156.
Example 11 Synthesis of 5-chloro-6-methylimidazo [1,2-a ] pyrazine
The only difference from the examples is that compound I-10 was replaced with compound I-11, and the reaction was carried out as in example 10 to give product C-11, yield: 72%, purity 97%, LCMS: m +1=168, 170.
EXAMPLE 12 Synthesis of 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine
Adding the compound I-8 (10 g) into toluene (100 mL), dropwise adding phosphorus oxychloride (88g, 1ieq.), heating to 90-95 ℃, stirring for reaction for 8 hours, then dropwise adding diisopropylethylamine (28g, 6eq.) at the temperature, controlling the temperature not to exceed 100 ℃, continuing the reaction for 4 hours after the addition, and detecting complete reaction conversion by LCMS. And concentrating and drying the reaction liquid to obtain a crude product. Adding dichloromethane into the crude product for dilution, slowly dropwise adding a dichloromethane phase into ice water for quenching, and keeping the temperature not higher than 25 ℃. After quenching was complete, 10% sodium hydroxide was added dropwise to adjust the pH to 5-6. The layers were separated and the aqueous layer was extracted twice more with dichloromethane and the organic layers were combined, dried and spin dried to give compound II-8 (5.0 g). Yield: 50%, purity 95%, LCMS: m +1=280, 282.
EXAMPLE 13 Synthesis of 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine
Adding the compound I-8 (10 g) into toluene (100 mL), dropwise adding phosphorus oxychloride (44g, 8eq.), heating to 90-95 ℃, stirring for reaction for 8h, dropwise adding diisopropylethylamine (28g, 6eq.) at the temperature, controlling the temperature not to exceed 100 ℃, continuing the reaction for 4h after the addition, and detecting complete reaction conversion by LCMS. And concentrating and drying the reaction liquid to obtain a crude product. Adding dichloromethane into the crude product for dilution, slowly dropwise adding a dichloromethane phase into ice water for quenching, and keeping the temperature not higher than 25 ℃. After quenching was complete, 10% sodium hydroxide was added dropwise to adjust the pH to 5-6. The layers were separated and the aqueous layer was extracted twice more with dichloromethane and the organic layers were combined, dried and spin dried to give compound II-8 (4.1 g). Yield: 41%, purity 94%, LCMS: m +1=280, 282.
EXAMPLE 14 Synthesis of 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine
Adding the compound I-8 (10 g) into acetonitrile (100 mL), dropwise adding phosphorus oxychloride (44g, 8eq.), heating to 80-85 ℃, stirring for reaction for 8h, then dropwise adding diisopropylethylamine (28g, 6eq.) at the temperature, controlling the temperature to be not more than 100 ℃, continuing the reaction for 4h after the addition, and detecting complete reaction conversion by LCMS. And concentrating and drying the reaction liquid to obtain a crude product. Adding dichloromethane into the crude product for dilution, slowly dropwise adding a dichloromethane phase into ice water for quenching, and keeping the temperature not higher than 25 ℃. After quenching was complete, 10% sodium hydroxide was added dropwise to adjust the pH to 5-6. The layers were separated and the aqueous layer was extracted twice more with dichloromethane and the organic layers were combined, dried and spin dried to give compound II-8 (3.6 g). Yield: 36%, purity 95%, LCMS: m +1=280, 282.
EXAMPLE 15 Synthesis of 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine
Adding the compound I-8 (10 g) into phosphorus oxychloride (88g, 8eq.), heating to 90-95 ℃, stirring for reaction for 4h, then dropwise adding triethylamine (22g, 6eq) at the temperature, controlling the temperature to be not more than 100 ℃, continuing the reaction for 2h after the addition is finished, and detecting complete reaction conversion by LCMS. And concentrating the reaction solution, replacing the toluene for two times, and finally concentrating dry toluene to obtain a crude product. Adding dichloromethane into the crude product for dilution, slowly dropwise adding a dichloromethane phase into ice water for quenching, and keeping the temperature not higher than 25 ℃. After quenching was complete, 10% sodium hydroxide was added dropwise to adjust the pH to 5-6. The layers were separated and the aqueous layer was extracted twice more with dichloromethane and the organic layers were combined, dried and spin dried to give compound II-8 (4.2 g). Yield: 42%, purity 94%, LCMS: m +1=280, 282.
EXAMPLE 16 Synthesis of 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine
Adding the compound I-8 (10 g) into phosphorus oxychloride (88g, 16eq.), heating to 90-95 ℃, stirring for reaction for 4h, then dropwise adding N, N-dimethylaniline (26g, 6eq.) at the temperature, controlling the temperature to be not more than 100 ℃, continuing to react for 2h after the addition is finished, and detecting complete conversion by LCMS. And concentrating the reaction solution, replacing the toluene for two times, and finally concentrating the dry toluene to obtain a crude product. Adding dichloromethane into the crude product for dilution, slowly dropwise adding a dichloromethane phase into ice water for quenching, and keeping the temperature not higher than 25 ℃. After quenching was complete, 10% sodium hydroxide was added dropwise to adjust the pH to 5-6. The phases were separated and the aqueous phase was extracted twice more with dichloromethane, the organic phases were combined, dried and spin dried to give compound II-8 (4.9 g). Yield: 49%, purity 93%, LCMS: m +1=280, 282.
EXAMPLE 17 Synthesis of 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine
Adding the compound I-8 (10 g) into phosphorus oxychloride (22g, 4eq.), heating to 90-95 ℃, stirring for reaction for 8h, then dropwise adding diisopropylethylamine (9.3g, 2eq.) at the temperature, controlling the temperature not to exceed 100 ℃, continuing the reaction for 4h after the addition is finished, and detecting complete reaction conversion by LCMS. And concentrating the reaction solution, replacing the toluene for two times, and finally concentrating the dry toluene to obtain a crude product. Adding dichloromethane into the crude product for dilution, slowly dropwise adding a dichloromethane phase into ice water for quenching, and keeping the temperature not higher than 25 ℃. After quenching was complete, 10% sodium hydroxide was added dropwise to adjust the pH to 5-6. The layers were separated and the aqueous layer was extracted twice more with dichloromethane and the organic layers were combined, dried and spin dried to give compound II-8 (3.2 g). Yield: 32%, purity 90%, LCMS: m +1=280, 282.
EXAMPLE 18 Synthesis of 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine
Adding the compound I-8 (10 g) into phosphorus oxychloride (44g, 8eq.), heating to 90-95 ℃, stirring for reaction for 6h, then dropwise adding diisopropylethylamine (18.5g, 4eq.) at the temperature, controlling the temperature to be not more than 100 ℃, continuing the reaction for 3h after the addition is finished, and detecting complete reaction conversion by LCMS. And concentrating the reaction solution, replacing the toluene for two times, and finally concentrating the dry toluene to obtain a crude product. Adding dichloromethane into the crude product for dilution, slowly dropwise adding a dichloromethane phase into ice water for quenching, and keeping the temperature not higher than 25 ℃. After quenching was complete, 10% sodium hydroxide was added dropwise to adjust the pH to 5-6. The layers were separated and the aqueous layer was extracted twice more with dichloromethane and the organic layers were combined, dried and spin dried to give compound II-8 (3.9 g). Yield: 39%, purity 94%, LCMS: m +1=280, 282.
EXAMPLE 19 Synthesis of 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine
Adding the compound I-8 (10 g) into phosphorus oxychloride (110g, 20eq.), heating to 90-95 ℃, stirring for reaction for 2h, then dropwise adding diisopropylethylamine (37g, 8eq.) at the temperature, controlling the temperature to be not more than 100 ℃, continuing the reaction for 1h after the addition is finished, and detecting complete reaction conversion by LCMS. And concentrating the reaction solution, replacing the toluene for two times, and finally concentrating dry toluene to obtain a crude product. Adding dichloromethane into the crude product for dilution, slowly dropwise adding a dichloromethane phase into ice water for quenching, and keeping the temperature not higher than 25 ℃. After quenching was complete, 10% sodium hydroxide was added dropwise to adjust the pH to 5-6. The layers were separated and the aqueous layer was extracted twice more with dichloromethane and the organic layers were combined, dried and spin dried to give compound II-8 (4.9 g). Yield: 48%, purity 95%, LCMS: m +1=280, 282.
Comparative example 1: synthesis of 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine
The starting material A2 (11 g) and 80mL of concentrated sulfuric acid are sequentially added into a 250mL three-neck flask, stirred and heated to 65 ℃ under the protection of nitrogen, and the temperature is kept for 2h for reaction (purple iodine is generated). After the reaction was completed, it was cooled to room temperature, and the mixture was slowly poured into ice water, then the pH was adjusted to 6.0 with 4M sodium hydroxide solution, extracted with ethyl acetate, washed with water, and dried. Filtration and concentration of the organic phase to dryness gave a mixture of B1 and B2, LCMS showed both ratio (B1: B2= 2.
Adding 110mL of phosphorus oxychloride into a three-neck bottle, adding the mixture while stirring, dropwise adding diisopropylethylamine 2mL under the protection of nitrogen, reacting for 4 hours at 120 ℃, concentrating the reaction liquid to dryness, adding ethyl acetate and saturated sodium bicarbonate, extracting, separating, drying and concentrating the organic phase, and purifying the crude product by silica gel column chromatography to obtain a compound C-8 (0.9 g, the total yield of the two steps is 10%, LCMS: M +1=280, 282) and a compound C-8-IM (0.7 g, the yield is 14%, LCMS: M +1=154, 156).
Claims (17)
1. A synthesis method of chloro-hexatomic nitrogen-containing heterocyclic imidazole compounds is characterized by comprising the following steps: in the presence or absence of a solvent, carrying out the following reaction on the compound I, phosphorus oxychloride and organic alkali to obtain a compound shown as a formula II;
wherein X is N or C (R)3) (ii) a Y is N or C (R)2) (ii) a Z is N or C (R)1)；
R1、R2And R3Independently hydrogen, halogen or C1-C6Alkyl group of (1).
2. The method for synthesizing chloro-six-membered nitrogen-containing heterocyclic imidazole compounds according to claim 1, wherein the raw materials of the reaction system only contain said compound I, phosphorus oxychloride and said organic base, or the raw materials of the reaction system only contain said compound I, phosphorus oxychloride, said organic base and said solvent;
and/or the molar ratio of the phosphorus oxychloride to the compound I is (3-25): 1;
and/or the organic base is one or more of diisopropylethylamine, triethylamine and N, N-dimethylaniline;
and/or the molar ratio of the organic base to the compound I is (1.5-10): 1;
and/or, when a solvent is present, the solvent is toluene and/or acetonitrile;
and/or, when a solvent is present, the mass ratio of the volume of the solvent to the compound I is 5-20 mL/g;
and/or when R1、R2And R3Independently is halogen, the halogen is Cl, br or I;
and/or when R1、R2And R3Independently is C1-C6Alkyl of (2), C1-C6Alkyl of (A) is C1-C4Alkyl group of (1).
3. The method for synthesizing chloro-substituted six-membered heterocyclic nitrogen-containing imidazoles as claimed in claim 2, wherein C is1-C6The alkyl group of (b) is a methyl group.
4. The method for synthesizing a chloro-substituted six-membered nitrogen-containing heterocyclic imidazole compound according to claim 1, comprising the steps of: in the presence or absence of a solvent, the compound I and phosphorus oxychloride are subjected to a first-stage reaction, and then a second-stage reaction is performed under the action of the organic base to obtain the compound shown in the formula II.
5. The method for synthesizing a chloro-substituted six-membered nitrogen-containing heterocyclic imidazole compound according to claim 1, wherein the method for synthesizing the chloro-substituted six-membered nitrogen-containing heterocyclic imidazole compound comprises the following steps: firstly, mixing the compound I with phosphorus oxychloride, carrying out a first-stage reaction, and then adding the organic base to carry out a second-stage reaction;
and/or, when the solvent is available, the synthesis method comprises the following steps: and mixing the compound I with the solvent, adding phosphorus oxychloride to perform a first-stage reaction, and then adding the organic base to perform a second-stage reaction.
6. The synthesis method of chloro six-membered nitrogen-containing heterocyclic imidazole compounds according to claim 1, characterized in that the molar ratio of said phosphorus oxychloride to said compound I is (16-25): 1;
and/or the molar ratio of the organic base to the compound I is (2-8): 1;
and/or, when a solvent is present, the mass ratio of the volume of the solvent to the compound I is 10mL/g;
and/or, X, Y and Z are defined as being selected from 1) or 2) below:
1) X is C (R)3) (ii) a Y is C (R)2) (ii) a Z is N or C (R)1)；
2) X is C (R)3) (ii) a Y is N; z is C (R)1)；
And/or, R1Is hydrogen or C1-C6Alkyl groups of (a);
and/or, R2Is hydrogen or C1-C6Alkyl groups of (a);
and/or, R3Is hydrogen or halogen.
7. The method for synthesizing chloro-six-membered heterocyclic nitrogen-containing imidazoles compound according to claim 1, wherein R is3Is hydrogen, bromine or chlorine.
8. The method for synthesizing a chloro-six-membered nitrogen-containing heterocyclic imidazole compound according to claim 1, wherein the molar ratio of the phosphorus oxychloride to the compound I is 20;
and/or the molar ratio of the organic base to the compound I is 8;
and/or, the compound I is selected from one of the following compounds:
the compound II is selected from one of the following compounds:
9. the method for synthesizing chloro-six-membered nitrogen-containing heterocyclic imidazoles compound according to claim 4, wherein the temperature of the first stage reaction is 80-95 ℃;
and/or the time of the first stage reaction is 1-8h;
and/or the temperature of the second stage reaction is the same as the temperature of the first stage reaction;
and/or the reaction time of the second stage is 1-4h.
10. The method for synthesizing chloro-six-membered nitrogen-containing heterocyclic imidazoles compound according to claim 9, wherein the temperature of the first stage reaction is 90-95 ℃ or 80-85 ℃;
and/or the time of the first stage reaction is 2h, 3h, 4h, 6h or 8h;
and/or the time of the second stage reaction is 1h, 2h, 3h or 4h.
11. The method for synthesizing a chloro-six-membered nitrogen-containing heterocyclic imidazole compound according to claim 5, wherein the manner of adding the organic base is dropwise;
and/or, when the solvent exists, the mode of adding the phosphorus oxychloride is dropwise adding.
12. The method for synthesizing a chloro-six-membered nitrogen-containing heterocyclic imidazole compound according to claim 11, wherein the organic base is added dropwise at a rate that the reaction temperature is controlled not to exceed 100 ℃.
13. The method for synthesizing a chloro-substituted six-membered nitrogen-containing heterocyclic imidazole compound according to claim 1, further comprising the following post-treatment steps: removing phosphorus oxychloride, regulating pH value with alkali, separating and drying.
14. The method for synthesizing chloro-six-membered nitrogen-containing heterocyclic imidazoles compounds according to claim 13, wherein in the post-treatment step, the method for removing phosphorus oxychloride comprises the steps of displacing the reaction solution with a solvent a, concentrating the reaction solution to obtain a crude product, and quenching the reaction;
and/or, in the post-treatment step, the base is in the form of an aqueous base solution;
and/or, in the post-treatment step, the pH is adjusted to be in the range of 5-6;
and/or, in the post-treatment step, the separation mode is extraction by using a solvent C.
15. The method for synthesizing a chloro-six-membered nitrogen-containing heterocyclic imidazole compound according to claim 14, wherein the solvent a is toluene;
and/or, the alkali is sodium hydroxide solution;
and/or the mass fraction of the alkali in the alkali aqueous solution is 3-20%;
and/or the solvent C is dichloromethane.
16. The method for synthesizing chloro-substituted six-membered nitrogen-containing heterocyclic imidazole compounds according to claim 14, wherein the quenching reaction is to add a crude product into a solvent B for dilution to obtain a solution B phase, and add the solvent B phase into ice water;
and/or the mass fraction of the alkali in the alkali water solution is 10%.
17. The method for synthesizing chloro-six-membered nitrogen-containing heterocyclic imidazoles compound according to claim 16, wherein the temperature of the quenching reaction is not higher than 25 ℃;
and/or the solvent B is dichloromethane;
and/or the solvent B phase is added into the ice water dropwise.
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