CN111646945A - Synthetic method of 4-bromo-2-nitro-1H-imidazole - Google Patents
Synthetic method of 4-bromo-2-nitro-1H-imidazole Download PDFInfo
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- CN111646945A CN111646945A CN202010474876.5A CN202010474876A CN111646945A CN 111646945 A CN111646945 A CN 111646945A CN 202010474876 A CN202010474876 A CN 202010474876A CN 111646945 A CN111646945 A CN 111646945A
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- 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
- C07D233/91—Nitro radicals
Abstract
The invention provides a synthesis method of 4-bromo-2-nitro-1H-imidazole, relates to the field of pharmaceutical chemistry, provides a new scheme for synthesizing 4-bromo-2-nitro-1H-imidazole by adopting 2-nitroimidazole through a three-step method, and provides a new synthesis route for the preparation and synthesis of 4-bromo-2-nitro-1H-imidazole; in addition, in the synthetic scheme, the reactants adopt common raw materials, the reaction conditions are proper, the overall yield of the product is high, the preparation process is simple, the cost is low, the large-scale production can be realized, and a synthetic thought is provided for the synthesis of the derivatives of the product.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a synthesis method of 4-bromo-2-nitro-1H-imidazole.
Background
4-bromo-2-nitro-1H-imidazole is an important heterocyclic compound, is present in a variety of biologically active compounds, and is used as a starting material for further functionalization. For example: it is an important parent for synthesizing new radioactive tracer precursor 3- (4-bromo-2-nitroimidazole-1-yl) -2- (tetrahydropyran-2-acyloxy) -propyltoluene sulfonic acid (4-Br-NITTP for short) and 1- (4-bromo-2-nitroimidazole-1-yl) -3- [18F ] fluoropropane-2-ol (4-Br- [18F ] FMISO for short), and when this tracer is used for curing apoplexy, it can be used for drawing stroke diagram with higher sensitivity in human body, and is non-toxic for human body.
For the synthesis of 4-bromo-2-nitro-1H-imidazole, its synthetic routes are reported in the American society for chemistry and the related literature of pharmaceutical chemistry, and the synthetic routes are respectively:
in the 2 synthesis routes, the hazardous reagent n-butyllithium is used in the second step of the first synthesis route, the number of byproducts is large, the purification is not suitable, and the yield is low. The second synthesis route adopts a direct N-bromosuccinimide bromination method, only 4, 5-dibromo-2-nitroimidazole can be obtained by trying, and finally 4, 5-dibromo-2-nitroimidazole is selectively debrominated by trying, so that a large number of reaction side reactions are generated, one bromine cannot be accurately debrominated, a pure product cannot be obtained, and the product purity is extremely low.
Disclosure of Invention
The invention aims to provide a method for synthesizing 4-bromo-2-nitro-1H-imidazole, which adopts a three-step method to synthesize the 4-bromo-2-nitro-1H-imidazole under appropriate reaction conditions, ensures the position of a substituent, has few reaction steps and has higher yield.
In order to achieve the above purpose, the invention provides the following technical scheme: a synthetic method of 4-bromo-2-nitro-1H-imidazole comprises the following steps:
the specific synthesis steps comprise: 1) reacting the compound (1), namely 2-nitroimidazole with sodium hydride in a THF (tetrahydrofuran) solvent for 15 min-1 h at the temperature of-5 ℃, then heating the reaction solution to room temperature, and reacting with 2- (trimethylsilyl) ethoxymethyl chloride for 1-3 h; after the reaction is finished, obtaining a product compound (2), namely 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole; 2) compound (2) 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole in DMF/CHCl3Reacting the mixed solvent with NBS for 10 to 24 hours at room temperature; after the reaction is finished, obtaining a product compound (3), namely 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole; 3) reacting a compound (3), namely 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole with trifluoroacetic acid in a DCM solvent for 1-3H at room temperature; after the reaction is finished, the final product is obtainedThe compound (4) is 4-bromo-2-nitro-1H-imidazole.
Further, in the step 1), the molar ratio of the compound (1) 2-nitroimidazole, sodium hydride and 2- (trimethylsilyl) ethoxymethyl chloride in the THF solvent is 1: (1-1.5): (1 to 1.5), preferably 1: 1.2: 1.2.
further, in the step 1), the concentration of the compound (1), 2-nitroimidazole, in the solvent of THF is 30g/L to 70g/L, preferably 50 g/L.
Further, in the step 2), the compound (2) 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole, NBS is in DMF/CHCl3The molar ratio in the mixed solvent of (1): (1 to 1.5), preferably 1: 1.1.
further, in said step 2), the compound (2), 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole, is in DMF/CHCl3The concentration of the mixed solvent (2) is 30 to 70g/L, preferably 50 g/L.
Further, in the step 2), DMF/CHCl3The volume ratio of the mixed solvent (2) is 0.8 to 1.2, preferably 1.
Further, in the step 3), the molar ratio of the compound (3) 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole and trifluoroacetic acid in the DCM solvent is 1: (4-7), preferably 1: 5.
further, in the step 3), the concentration of the compound (3), 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole in DCM solvent is 30 g/L-70 g/L, preferably 50 g/L.
According to the technical scheme, the synthesis method of the 4-bromo-2-nitro-1H-imidazole provided by the technical scheme of the invention has the following beneficial effects:
the invention discloses a synthesis method of 4-bromo-2-nitro-1H-imidazole, and provides a scheme for synthesizing 4-bromo-2-nitro-1H-imidazole from 2-nitroimidazole under appropriate reaction conditions by a three-step method, so that a synthetic route is provided for the preparation and synthesis of 4-bromo-2-nitro-1H-imidazole; the synthetic scheme of the 4-bromo-2-nitro-1H-imidazole has proper reaction conditions, the steric hindrance of the alpha position of the nitrogen atom is increased by protecting one nitrogen atom on the imidazole ring, the reaction is selectively carried out at the beta position during bromination, the target product 4-bromo-2-nitro-1H-imidazole is obtained by deprotection, the total yield of the product 4-bromo-2-nitro-1H-imidazole can reach 67.5%, and the reactants adopt common raw materials, so that the preparation process is simple, the cost is low, and the industrial production can be realized. The invention adopts the synthesis method of the 4-bromo-2-nitro-1H-imidazole with high yield and low cost to prepare the drug intermediate 4-bromo-2-nitro-1H-imidazole, thereby reducing the production cost for preparing the stroke drug and further promoting the popularization and the generalization of the treatment of stroke.
It should be understood that all combinations of the foregoing concepts and additional concepts described in greater detail below can be considered as part of the inventive subject matter of this disclosure unless such concepts are mutually inconsistent.
The foregoing and other aspects, embodiments and features of the present teachings can be more fully understood from the following description taken in conjunction with the accompanying drawings. Additional aspects of the present invention, such as features and/or advantages of exemplary embodiments, will be apparent from the description which follows, or may be learned by practice of specific embodiments in accordance with the teachings of the present invention.
Drawings
The drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. Embodiments of various aspects of the present invention will now be described, by way of example, with reference to the accompanying drawings, in which:
FIG. 1 is a nuclear magnetic hydrogen spectrum of 4-bromo-2-nitro-1H-imidazole.
Detailed Description
In order to better understand the technical content of the present invention, specific embodiments are described below with reference to the accompanying drawings.
In this disclosure, aspects of the present invention are described with reference to the accompanying drawings, in which a number of illustrative embodiments are shown. Embodiments of the present disclosure are not intended to include all aspects of the present invention. It should be appreciated that the various concepts and embodiments described above, as well as those described in greater detail below, may be implemented in any of numerous ways, as the disclosed concepts and embodiments are not limited to any one implementation. In addition, some aspects of the present disclosure may be used alone, or in any suitable combination with other aspects of the present disclosure.
Based on the phenomenon that bromine is substituted at a plurality of positions on a ring in the synthesis method of 4-bromo-2-nitro-1H-imidazole in the prior art, the yield of the synthesized product 4-bromo-2-nitro-1H-imidazole is low, and the reaction conditions are high, so that the drug cost for producing 4-bromo-2-nitro-1H-imidazole and 4-bromo-2-nitro-1H-imidazole as an intermediate is high. The invention aims to provide a method for synthesizing 4-bromo-2-nitro-1H-imidazole under appropriate reaction conditions, so that the yield of 4-bromo-2-nitro-1H-imidazole is improved, and the synthesis cost of 4-bromo-2-nitro-1H-imidazole is reduced.
In addition, the starting materials and reagents used in the present invention are commercially available, wherein the chemical reagents THF are tetrahydrofuran, DMF is N, N-dimethylformamide, CHCl3Chloroform, NBS is N-bromosuccinimide, DCM is dichloromethane, EA is ethyl acetate, and the 'room temperature condition' in the technical scheme of the invention refers to the temperature range of 10-30 ℃.
The synthesis method of 4-bromo-2-nitro-1H-imidazole according to the present invention is further described in detail with reference to the accompanying drawings and examples.
A synthetic method of 4-bromo-2-nitro-1H-imidazole comprises the following steps:
the specific synthesis steps comprise:
1) reacting the compound (1), namely 2-nitroimidazole with sodium hydride in a THF (tetrahydrofuran) solvent for 15 min-1 h at the temperature of-5 ℃, then heating the reaction solution to room temperature, and reacting with 2- (trimethylsilyl) ethoxymethyl chloride for 1-3 h; after the reaction is finished, obtaining a product compound (2), namely 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole; wherein, the molar ratio of the compound (1), the 2-nitroimidazole, the sodium hydride and the 2- (trimethylsilyl) ethoxymethyl chloride in the THF solvent is 1: (1-1.5): (1-1.5), wherein the concentration of the compound (1), 2-nitroimidazole in a THF solvent is 30-70 g/L.
2) Compound (2) 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole in DMF/CHCl3Reacting the mixed solvent with NBS for 10 to 24 hours at room temperature; after the reaction is finished, obtaining a product compound (3), namely 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole; wherein, the compound (2) is 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole, NBS in DMF/CHCl3The molar ratio in the mixed solvent of (1): (1-1.5) Compound (2) 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole in DMF/CHCl3The concentration of the mixed solvent is 30 g/L-70 g/L, and DMF/CHCl3The volume ratio of the mixed solvent is 0.8-1.2.
3) Reacting a compound (3), namely 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole with trifluoroacetic acid in a DCM solvent for 1-3H at room temperature; after the reaction is finished, obtaining a final product compound (4), namely 4-bromo-2-nitro-1H-imidazole; wherein, the mol ratio of the compound (3), 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole and trifluoroacetic acid in DCM solvent is 1: (4-7), and the concentration of the compound (3), 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole in DCM solvent is 30-70 g/L.
EXAMPLE 1 preparation of the Compound (2) 2-Nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole
Firstly, adding the compound (1), namely 2-nitroimidazole (35g, 1eq), into 700ml of THF, cooling to 0 ℃, slowly adding sodium hydride (14.7g,1.2eq), stirring at 0 ℃ for 30min, then dropwise adding 2- (trimethylsilyl) ethoxymethyl chloride (61.6g, 1.2eq), and stirring at room temperature for 2 h; after the reaction is finished, flushing, EA extracting, backwashing saturated saline solution, drying sodium sulfate, and purifying by a spin-drying column to obtain 67g of compound (2), namely 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole, with the yield of about 89%.
Examples 2 to 5 were prepared in the same manner as in example 1 except that the molar ratio, mass concentration and reaction time of the compound (1), 2-nitroimidazole, sodium hydride and 2- (trimethylsilyl) ethoxymethyl chloride in a THF solvent were changed, and the yield of the compound (2), 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole, was measured at room temperature as shown in Table 1.
From the examples shown in Table 1, it can be seen that when the compound (1), 2-nitroimidazole, sodium hydride and 2- (trimethylsilyl) ethoxymethyl chloride, are present in a THF solvent in a molar ratio of 1: 1.2: when the concentration of 2-nitroimidazole in a THF solvent is 50g/L and the reaction time is 2 hours, the yield of the product compound, namely (2), 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole is highest.
TABLE 1
EXAMPLE 6 preparation of the Compound (3) 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole
The compound (2), 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole (67g, 1eq) was added to 1340ml DMF/CHCl3Adding NBS (54g, 1.1eq) slowly into the mixed solvent with the volume ratio of 1/1, and reacting at room temperature overnight; after the reaction is finished, ice water is poured, DCM is used for extraction, saturated sodium chloride is used for backwashing, drying and spin-drying are carried out, 54g of compound (3), 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole is obtained after column chromatography purification, and the yield is about 88.5%.
EXAMPLES 7-10 Synthesis methods as in example 6, the reactant compounds (2) 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole and NBS were varied in DMF/CHCl3The yields of 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole, compound (3), measured as molar ratio, reaction time, mass concentration and volume ratio of DMF/CHCl3 in the mixed solvent at room temperature, are shown in table 2.
From the yields of the example compound (3) shown in table 2, when the molar ratio of the reactant compound (2), 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole and NBS in the DMF/CHCl3 mixed solvent was 1: 1.1, when the concentration of the compound (2), 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole, in the mixed solvent of DMF/CHCl3 was 50g/L, the reaction time was 24H, and the volume ratio of DMF/CHCl3 was 1, the yield of the product compound, 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole, was the highest.
TABLE 2
EXAMPLE 11 preparation of Compound (4) 4-bromo-2-nitro-1H-imidazole
Compound (3), 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole (54g, 1eq) was added to 1LDCM, trifluoroacetic acid (96g, 5eq) was added, and RT reacted overnight; after the reaction, water was applied, filtered, washed with water, and dried to obtain 21.6g of the compound (4), 4-bromo-2-nitro-1H-imidazole, with a yield of about 67.5%.
EXAMPLES 12-14 were prepared as in example 11, and the molar ratio of the reactant compound (3), 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole and trifluoroacetic acid in DCM solvent, reaction temperature and reaction time were varied, and the yields of the compound (4), 4-bromo-2-nitro-1H-imidazole, were determined as shown in Table 3.
From the yields of the example compound (4) shown in table 3, when the reactant (3), 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole and trifluoroacetic acid, were in a molar ratio of 1: 5. the compound (3), 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole, has the highest yield when the concentration is 50g/L in DCM solvent and the reaction time is 24H, the product, 4-bromo-2-nitro-1H-imidazole.
TABLE 3
The nuclear magnetic hydrogen spectrum of the final product compound (4), 4-bromo-2-nitro-1H-imidazole, is shown in figure 1: 1H NMR (600 MHz, DMSO)7.76(s, 1H).
The invention discloses a method for synthesizing 4-bromo-2-nitro-1H-imidazole by adopting low-cost and easily-obtained 2-nitroimidazole under appropriate reaction conditions through a three-step method, and provides a new synthetic route for preparing 4-bromo-2-nitro-1H-imidazole; according to the invention, firstly, a nitrogen atom on an imidazole ring is protected, so that the steric hindrance of the alpha position of the nitrogen atom is increased, when bromination is carried out, reaction is selectively carried out on the beta position, and deprotection is carried out, so that a target product 4-bromo-2-nitro-1H-imidazole is obtained, wherein the total yield of the product 4-bromo-2-nitro-1H-imidazole is about 61.1%, the preparation process is simple, and industrial production can be carried out; and the production cost of preparing the stroke medicament by taking the 4-bromo-2-nitro-1H-imidazole as an intermediate can be further improved by improving the yield of the final product 4-bromo-2-nitro-1H-imidazole and reducing the cost, so that the popularization and the popularization of the stroke medicament are promoted.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, the protection scope of the present invention should be determined by the appended claims.
Claims (10)
1. A synthetic method of 4-bromo-2-nitro-1H-imidazole is characterized in that the synthetic route is as follows:
the specific synthesis steps comprise:
1) reacting the compound (1), namely 2-nitroimidazole with sodium hydride in a THF (tetrahydrofuran) solvent for 15 min-1 h at the temperature of-5 ℃, then heating the reaction solution to room temperature, and reacting with 2- (trimethylsilyl) ethoxymethyl chloride for 1-3 h; after the reaction is finished, obtaining a product compound (2), namely 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole;
2) compound (2) 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole in DMF/CHCl3Reacting the mixed solvent with NBS for 10 to 24 hours at room temperature; after the reaction is finished, obtaining a product compound (3), namely 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole;
3) reacting a compound (3), namely 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole with trifluoroacetic acid in a DCM solvent for 1-3H at room temperature; after the reaction is finished, the final product compound (4), namely 4-bromo-2-nitro-1H-imidazole, is obtained.
2. The method for synthesizing 4-bromo-2-nitro-1H-imidazole according to claim 1, wherein in step 1), the molar ratio of compound (1) 2-nitroimidazole, sodium hydride, and 2- (trimethylsilyl) ethoxymethyl chloride in THF solvent is 1: (1-1.5): (1-1.5).
3. The method for synthesizing 4-bromo-2-nitro-1H-imidazole according to claim 1, wherein in step 2), compound (2), 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole, NBS, is in DMF/CHCl3The molar ratio in the mixed solvent of (1): (1-1.5).
4. The method for synthesizing 4-bromo-2-nitro-1H-imidazole according to claim 1, wherein in step 3), the molar ratio of compound (3) 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole and trifluoroacetic acid in DCM solvent is 1: (4-7).
5. The method for synthesizing 4-bromo-2-nitro-1H-imidazole according to claim 1, wherein in step 1), the molar ratio of compound (1) 2-nitroimidazole, sodium hydride, and 2- (trimethylsilyl) ethoxymethyl chloride in THF solvent is 1: 1.2: 1.2.
6. the combination of 4-bromo-2-nitro-1H-imidazole according to claim 1The method is characterized in that in the step 2), the compound (2) is 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H imidazole, NBS is in DMF/CHCl3The molar ratio in the mixed solvent of (1): 1.1.
7. the method for synthesizing 4-bromo-2-nitro-1H-imidazole according to claim 1, wherein in step 1), the concentration of compound (1), 2-nitroimidazole in THF solvent is 30g/L to 70 g/L.
8. The method for synthesizing 4-bromo-2-nitro-1H-imidazole according to claim 1, wherein in step 2), compound (2), 2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole is in DMF/CHCl3The concentration of the mixed solvent of (3) is 30 to 70 g/L.
9. The method of claim 3, wherein in step 2), DMF/CHCl is used as a starting material for the synthesis of 4-bromo-2-nitro-1H-imidazole3The volume ratio of the mixed solvent is 0.8-1.2.
10. The method for synthesizing 4-bromo-2-nitro-1H-imidazole according to claim 1, wherein in step 3), the concentration of compound (3), 4-bromo-2-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole in DCM solvent is 30g/L to 70 g/L.
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| WO2007124316A1 (en) * | 2006-04-20 | 2007-11-01 | Janssen Pharmaceutica N.V. | Heterocyclic compounds as inhibitors of c-fms kinase |
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| WO2011149874A2 (en) * | 2010-05-26 | 2011-12-01 | Schering Corporation | N-phenyl imidazole carboxamide inhibitors of 3-phosphoinositide-dependent protein kinase-1 |
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