CN107400090B - Synthesis method of benzimidazole derivative - Google Patents
Synthesis method of benzimidazole derivative Download PDFInfo
- Publication number
- CN107400090B CN107400090B CN201710814392.9A CN201710814392A CN107400090B CN 107400090 B CN107400090 B CN 107400090B CN 201710814392 A CN201710814392 A CN 201710814392A CN 107400090 B CN107400090 B CN 107400090B
- Authority
- CN
- China
- Prior art keywords
- benzo
- mercapto
- water
- filtering
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/28—Sulfur atoms
Abstract
The invention belongs to the field of medicines, and relates to a synthesis method and a purification method of benzimidazole derivatives and pharmaceutically acceptable salts thereof. The synthetic route of the invention is as follows：
Description
The technical field is as follows:
the invention belongs to the field of medicines, and relates to a synthesis method and a purification method of benzimidazole derivatives and pharmaceutically acceptable salts thereof.
Background art:
benzimidazole derivatives, namely 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid and salts thereof, and synthetic methods of the compounds have been reported.
The key step 3 is as follows:
the nitro group at the ortho position of the reaction enhances the activity of fluorine, and strong alkali NaH is adopted to remove hydrogen on naphthylamine, so that the reaction can be smoothly carried out, but after the experiment is repeated, the reaction yield is low, the activity and the danger of the adopted NaH are high, the violent reaction and the heat release are difficult to control, and the amplification and the industrial production are difficult.
For the reaction of aromatic ammonia and halogenated aromatic ring, most documents report that palladium or copper is used as the core for metal catalytic coupling reaction, such as Ullmann reaction, Buchwald-Hartwig coupling reaction, Chan-Lam coupling reaction and the like, the catalyst used in the reaction is expensive, and the aftertreatment is difficult to remove, thereby seriously affecting the heavy metal index of the final product.
Therefore, we have conducted intensive research on the intermediate, and surprisingly found in the research process that a simpler and safer inorganic base such as NaOH is adopted, a proper water absorbent such as CaO is added, an intermediate with the same structure can be obtained without using a catalyst, the reaction yield is high, the post-treatment mode is simple and convenient, the reaction route is shortened, the cost is reduced, the reaction safety is obviously improved, and the intermediate is suitable for industrial scale-up production.
The invention content is as follows:
the invention aims to provide a synthesis method of benzimidazole derivatives represented by a formula (I) and pharmaceutically acceptable salts (II) thereof.
The synthetic method of the invention has the following synthetic route:
wherein the content of the first and second substances,
R1when it is a halogen atom, R2Is amino; r1When it is amino, R2Is a halogen atom;
R3is a halogen atom or imidazole, preferably imidazole;
R4is a halogen atom, preferably Br;
R5is H or C1-3An alkyl group;
m is Na, K, Li, Ca or Mg, preferably Na;
the halogen comprises fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), mother of pear (Ts);
in the reaction process, the following reagents are respectively used:
the reagent used in step 1 is a mixture of inorganic bases and/or water absorbents or a mixture of bases.
The preferable reagent is one or more than one of NaOH, KOH, CaO or NaH.
The solvent used in step 1 is selected from: one or more of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, toluene, acetonitrile, dichloromethane and chloroform.
The reagent used in step 2 is a reducing agent selected from the group consisting of: hydrazine hydrate, palladium carbon/hydrogen, iron powder, zinc powder or stannous chloride.
The cyclization reagent used in the step 3 is N, N' -thiocarbonyl diimidazole or thiophosgene.
The solvent used in step 4 is acetonitrile.
The solvent used in step 5 is ethanol.
Specifically, the synthesis method of the benzimidazole derivatives represented by the formula (I) and the pharmaceutically acceptable salts (II) thereof comprises the following steps:
step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 2-nitroaniline, CaO, NaOH and N, N-dimethylacetamide into a three-necked flask, controlling the external temperature to be 0-150 ℃ under stirring, adding 4-bromo-1-naphthanenitrile, stirring and reacting for 1-48h, detecting no raw material residue by TLC (thin layer chromatography), stopping reaction, adding a proper amount of water, adjusting the pH value to be weakly acidic by using hydrochloric acid, filtering, and drying a filter cake to obtain a red solid.
Step 2: 4- [ (2-aminophenyl) amino ] naphthonitrile
Adding 4- [ (2-nitrophenyl) amino ] naphthanenitrile into a mixture of ethanol and water, adding ferric chloride, controlling the external temperature to be 20-120 ℃, adding hydrazine hydrate, reacting for 1-24h, detecting by TLC that no raw material remains, stopping the reaction, adding a proper amount of water, stirring, filtering, drying a filter cake, and decoloring by using activated carbon to obtain a yellow solid.
And step 3: 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthacenitrile
Adding 4- [ (2-aminophenyl) amino ] naphthanenitrile, N' -thiocarbonyl diimidazole and acetonitrile into a single-mouth bottle, controlling the external temperature to be 0-100 ℃, stirring and reacting for 1-24h, detecting by TLC (thin layer chromatography) until no raw material remains, adding a proper amount of water, filtering, and drying a filter cake to obtain a yellow solid.
And 4, step 4: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid ethyl ester
Adding 4- (2-mercapto-1H-benzo [ d ] imidazole-1-yl) naphthanenitrile, potassium carbonate and water into acetonitrile, adding ethyl 2-bromoisobutyrate under stirring, controlling the external temperature to be 20-100 ℃, reacting for 1-24H, stopping reaction, filtering, concentrating filtrate, extracting with ethyl acetate and water, separating liquid, decoloring an ethyl acetate phase with activated carbon, concentrating to dryness, adding isopropanol for recrystallization, filtering, and drying a filter cake to obtain a light yellow solid.
And 5: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid (I)
Adding ethyl 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate into ethanol, adding a sodium hydroxide solution while stirring, controlling the temperature to be 0-80 ℃, reacting for 1-24H, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, adjusting the pH to subacidity by hydrochloric acid, concentrating the system to dryness, adding the residue into water, adjusting the pH to solid full dissolution by sodium hydroxide solution, adding hydrochloric acid to adjust the pH to subacidity, separating out a large amount of solid, filtering, and drying a filter cake to obtain a white solid.
Step 6: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium (II)
Adding 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid into ethanol, adding an equivalent amount of sodium hydroxide solution while stirring, controlling the temperature to be 0-80 ℃, reacting for 1-24H, separating out a large amount of solid in a system, filtering, and drying a filter cake to obtain a white solid.
Specifically, the synthesis method of the benzimidazole derivatives represented by the formula (I) and the pharmaceutically acceptable salts (II) thereof comprises the following steps:
step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 4-amino-1-naphthalocyanine, KOH and N-methylpyrrolidone into a three-necked bottle, controlling the external temperature to be 0-150 ℃ under stirring, adding o-chloronitrobenzene, stirring for reacting for 1-48h, detecting no raw material residue by TLC, stopping the reaction, adding a proper amount of water, regulating the pH value to be weak acid by using hydrochloric acid, filtering, and drying a filter cake to obtain a red solid.
Step 2: 4- [ (2-aminophenyl) amino ] naphthonitrile
Adding iron powder into a saturated ammonium chloride solution, adding acetic acid, heating to 50-100 ℃, stirring, dissolving 4- [ (2-nitrophenyl) amino ] naphthanenitrile in ethanol, adding into an iron powder ammonium chloride system, controlling the external temperature to be 50-100 ℃, reacting for 1-24h, detecting by TLC that no raw material remains, stopping the reaction, cooling to room temperature, adding ethyl acetate, extracting, decoloring by using activated carbon, and concentrating to dryness to obtain a yellow solid.
And step 3: 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthacenitrile
Dissolving 4- [ (2-aminophenyl) amino ] naphthalocyanide in ethyl acetate, adding thiophosgene and triethylamine, controlling the external temperature to be 0-100 ℃, stirring and reacting for 1-24h, detecting no raw material residue by TLC, adding water with the same volume for extraction, washing an ethyl acetate phase twice by water, separating liquid, and concentrating to dryness to obtain a yellow solid.
And 4, step 4: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid ethyl ester
Adding 4- (2-mercapto-1H-benzo [ d ] imidazole-1-yl) naphthanenitrile, potassium carbonate and water into acetonitrile, adding 2-bromomethyl isobutyrate under stirring, controlling the external temperature to be 20-100 ℃, reacting for 1-24H, stopping reaction, filtering, concentrating filtrate, extracting with ethyl acetate and water, separating liquid, decoloring an ethyl acetate phase with activated carbon, concentrating to dryness, adding isopropanol for recrystallization, filtering, and drying a filter cake to obtain a light yellow solid.
And 5: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid
Adding 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] methyl propionate into ethanol, adding a sodium hydroxide solution under stirring, controlling the temperature to be 0-80 ℃, reacting for 1-24H, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, adjusting the pH to subacidity by hydrochloric acid, concentrating the system to dryness, adding the residue into water, adjusting the pH to solid full dissolution by sodium hydroxide solution, adding hydrochloric acid to adjust the pH to subacidity, separating out a large amount of solid, filtering, and drying a filter cake to obtain a white solid.
Step 6: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium salt
Adding 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid into ethanol, adding a proper amount of potassium hydroxide solution while stirring, controlling the temperature to be 0-80 ℃, reacting for 1-24H, separating out a large amount of solid in a system, filtering, and drying a filter cake to obtain a white solid.
Compared with the existing method, the synthesis method of the invention has the following advantages:
1) the invention adopts simpler and safer inorganic alkali such as NaOH and the like, is matched with proper water absorbent such as CaO and the like, does not use catalyst, avoids using hazardous components such as NaH and the like, and improves the safety of the production process.
2) The NaH process is characterized in that each raw material reagent is added at a lower temperature and heated to a target temperature for reaction, so that the heat release phenomenon is serious and is difficult to control; the invention adopts the mixed alkali of NaOH and CaO, can effectively control the reaction heat release in a batch feeding mode, and greatly improves the safety of the production process.
3) Through research on a reaction mechanism, the NaH is found to react with a part of solvent at a higher temperature, so that the yield is reduced, and impurities are generated; the mixed alkali of NaOH and CaO adopted by the invention can have proper alkalinity and NaH water removal capacity, KOH has the function of drying an alkaline solvent, the effect of NaH in the system can be well replaced, the side reaction is avoided, the yield of the step is effectively improved, the pressure of subsequent purification is reduced, and the overall yield is improved.
Detailed description of the invention
The present invention is further illustrated by the following specific examples, which are not intended to be limiting, and the starting materials and reagents used in the examples are known compounds and commercially available.
Example 1
Step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 2-nitroaniline (45g), CaO (24g), NaOH (26g) and N, N-dimethylacetamide (250mL) into a three-necked flask, controlling the temperature to be 80-110 ℃ under stirring, adding 4-bromo-1-naphthacenitrile (50g) in batches, stirring for reacting for 5 hours, detecting by TLC (thin layer chromatography) that no raw material is left, stopping the reaction, adding 500mL of water, adjusting the pH to be 3-4 by using hydrochloric acid, filtering, and drying a filter cake to obtain 53g of red solid with the yield of 80%.
Step 2: 4- [ (2-aminophenyl) amino ] naphthonitrile
Adding 4- [ (2-nitrophenyl) amino ] naphthalocyanine (50g) into a mixture of 250mL of ethanol and 85mL of water, adding ferric chloride, controlling the external temperature to be 70-90 ℃, adding 85% hydrazine hydrate (51g), reacting for 2h, detecting by TLC that no raw material remains, stopping the reaction, adding 170mL of water, stirring, filtering, drying a filter cake, and decolorizing with activated carbon to obtain 31.3g of yellow solid with the yield of 70%.
And step 3: 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthacenitrile
Adding 4- [ (2-aminophenyl) amino ] naphthacenitrile (30g), N' -thiocarbonyldiimidazole (23g) and acetonitrile (90mL) into a single-mouth bottle, controlling the external temperature to be 50-90 ℃, stirring for reaction for 2h, detecting by TLC (thin layer chromatography) that no raw material remains, adding 90mL of water, filtering, drying a filter cake to obtain a yellow solid (33g) with the yield of 95 percent
And 4, step 4: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid ethyl ester
Adding 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthanenitrile (30g), potassium carbonate (27.6g) and water (15mL) into acetonitrile (300mL), adding ethyl 2-bromoisobutyrate (29g) under stirring, controlling the external temperature to be 70-90 ℃, reacting for 3H, stopping the reaction, filtering, concentrating the filtrate, extracting with 300mL of ethyl acetate and 200mL of water, separating, decoloring the ethyl acetate phase with activated carbon, concentrating to be dry, adding isopropanol (90mL), recrystallizing, filtering, and drying the filter cake to obtain 37.2g of light yellow solid with the yield of 90%.
And 5: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid (I)
Reacting 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d [ ]]Imidazol-2-yl]Mercapto group]Adding ethyl propionate (35g) into 350mL of ethanol, adding 35mL of aqueous solution of sodium hydroxide (6.7g) under stirring at room temperature, reacting for 2-3 h, detecting by TLC that no raw material remains, stopping the reaction, adjusting the pH to 2-3 with hydrochloric acid, concentrating the system to dryness, adding the residue into water, adjusting the pH to 10 with 20% sodium hydroxide solution,and (3) dissolving the solid completely, adding hydrochloric acid to adjust the pH value to 2-3, separating out a large amount of solid, filtering, and drying a filter cake to obtain 27.7g of white solid with the yield of 85%. LC-MS: m/z 388.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝1.61(s,3H)，1.62(s,3H)，6.87(d,J＝8.4Hz,1H)，7.15-7.20(m,2H)，7.28-7.32(m,1H)，7.69-7.77(m,2H)，7.89-7.95(m,2H)，8.32(d,J＝8.4Hz,1H)，8.44(d,J＝7.6Hz,1H)，12.92(s,1H)。
Step 6: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium (II)
Reacting 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d [ ]]Imidazol-2-yl]Mercapto group]Propionic acid (20g) was added to ethanol (200mL), 20mL of aqueous solution of sodium hydroxide (2.1g) was added with stirring at room temperature, reaction was carried out for 1h, a large amount of solid precipitated in the system, filtration was carried out, and the filter cake was dried to obtain 17g of white solid with a yield of 80%. LC-MS: m/z 388.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝1.61(s,3H)，1.62(s,3H)，6.87(d,J＝8.4Hz,1H)，7.15-7.20(m,2H)，7.28-7.32(m,1H)，7.69-7.77(m,2H)，7.89-7.95(m,2H)，8.32(d,J＝8.4Hz,1H)，8.44(d,J＝7.6Hz,1H)。
Example 2
Step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 4-amino-1-naphthanitrile (34g), KOH (11.3g) and N-methylpyrrolidone (350mL) into a three-necked bottle, controlling the external temperature to be 70-100 ℃ under stirring, dropwise adding o-chloronitrobenzene (32g), stirring for reacting for 3 hours, detecting by TLC (thin layer chromatography) that no raw material is left, stopping the reaction, adding 700mL of water, filtering, and drying a filter cake to obtain 46.7g of red solid with the yield of 70%.
Step 2: 4- [ (2-aminophenyl) amino ] naphthonitrile
Adding iron powder (43g) into saturated ammonium chloride solution (500mL), adding acetic acid, heating to 70-100 ℃, stirring, dissolving 4- [ (2-nitrophenyl) amino ] naphthacenitrile (45g) in 100mL of ethanol, adding into an iron powder ammonium chloride system, controlling the external temperature to be 70-100 ℃, reacting for 3h, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, cooling to room temperature, adding 300mL of ethyl acetate for extraction, decoloring by using activated carbon, and concentrating to dryness to obtain 32g of yellow solid with the yield of 80%.
And step 3: 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthacenitrile
Dissolving 4- [ (2-aminophenyl) amino ] naphthacenitrile (30g) in 300mL of ethyl acetate, adding thiophosgene (20g) and triethylamine (47g), stirring and reacting for 3h at room temperature, detecting by TLC that no raw material remains, adding 300mL of water for extraction, washing an ethyl acetate phase twice (200mL x 2) by using water, separating, and concentrating to dryness to obtain a yellow solid (26g) with the yield of 75%;
and 4, step 4: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid ethyl ester
Adding 4- (2-mercapto-1H-benzo [ d ] imidazole-1-yl) naphthanenitrile (25g), potassium carbonate (23g) and water (12.5mL) into acetonitrile (250mL), adding methyl 2-bromoisobutyrate (24g) under stirring, controlling the external temperature to be 70-90 ℃, reacting for 3H, stopping the reaction, filtering, concentrating the filtrate, extracting with 300mL of ethyl acetate and 200mL of water, separating, decoloring the ethyl acetate phase with activated carbon, concentrating to be dry, adding isopropanol (75mL), recrystallizing, filtering, and drying the filter cake to obtain 30g of light yellow solid with the yield of 90%.
And 5: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid
Reacting 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d [ ]]Imidazol-2-yl]Mercapto group]Adding methyl propionate (30g) into 300mL of ethanol, adding 30mL of aqueous solution of sodium hydroxide (6g) under stirring at room temperature, reacting for 3h, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, adjusting the pH to 3-4 by hydrochloric acid, concentrating the system to dryness, adding the residue into water, adjusting the pH to 10 by 20% sodium hydroxide solution, fully dissolving the solid, adjusting the pH to 2-3 by adding hydrochloric acid, separating out a large amount of solid, filtering, and drying the filter cake to obtain 24.6g of white solid with the yield of 85%. LC-MS: m/z 388.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝1.60(s,3H)，1.62(s,3H)，6.88(d,J＝8.4Hz,1H)，7.14-7.20(m,2H)，7.27-7.33(m,1H)，7.69-7.78(m,2H)，7.89-7.94(m,2H)，8.33(d,J＝8.4Hz,1H)，8.43(d,J＝7.6Hz,1H)，12.91(s,1H)。
Step 6: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium salt
Reacting 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d [ ]]Imidazol-2-yl]Mercapto group]Propionic acid (20g) was added to ethanol (200mL), 20mL of aqueous solution of sodium hydroxide (2.1g) was added with stirring at room temperature, reaction was carried out for 1h, a large amount of solid precipitated in the system, filtration was carried out, and the filter cake was dried to obtain 17g of white solid with a yield of 80%. LC-MS: m/z 388.1[ M + H ]]+。
1H NMR(400MHz,DMSO-d6)：δ＝1.60(s,3H)，1.62(s,3H)，6.88(d,J＝8.4Hz,1H)，7.14-7.20(m,2H)，7.27-7.33(m,1H)，7.69-7.78(m,2H)，7.89-7.94(m,2H)，8.33(d,J＝8.4Hz,1H)，8.43(d,J＝7.6Hz,1H)。
Example 3 screening experiments
Screening the alkali in the step 1 to obtain the preferable alkali of the process of the embodiment 1, namely NaOH + CaO mixed alkali; the preferred base for the process of example 2 is KOH.
The following are partial screening results:
example 4 comparative experiment
Claims (4)
1. A method for synthesizing benzimidazole derivatives and pharmaceutically acceptable salts thereof is characterized by comprising the following steps:
step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 2-nitroaniline, CaO, NaOH and N, N-dimethylacetamide into a three-necked flask, controlling the external temperature to be 0-150 ℃ under stirring, adding 4-bromo-1-naphthanenitrile, stirring and reacting for 1-48h, detecting no raw material residue by TLC (thin layer chromatography), stopping reaction, adding a proper amount of water, regulating the pH value to be weak acid by using hydrochloric acid, filtering, and drying a filter cake to obtain a red solid;
step 2: 4- [ (2-aminophenyl) amino ] naphthonitrile
Adding 4- [ (2-nitrophenyl) amino ] naphthanenitrile into a mixture of ethanol and water, adding ferric chloride, controlling the external temperature to be 20-120 ℃, adding hydrazine hydrate, reacting for 1-24h, detecting by TLC that no raw material remains, stopping the reaction, adding a proper amount of water, stirring, filtering, drying a filter cake, and decoloring by using activated carbon to obtain a yellow solid;
and step 3: 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthacenitrile
Adding 4- [ (2-aminophenyl) amino ] naphthanenitrile, N' -thiocarbonyl diimidazole and acetonitrile into a single-mouth bottle, controlling the external temperature to be 0-100 ℃, stirring and reacting for 1-24h, detecting by TLC (thin layer chromatography) that no raw material remains, adding a proper amount of water, filtering, and drying a filter cake to obtain a yellow solid;
and 4, step 4: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid ethyl ester
Adding 4- (2-mercapto-1H-benzo [ d ] imidazole-1-yl) naphthanenitrile, potassium carbonate and water into acetonitrile, adding ethyl 2-bromoisobutyrate under stirring, controlling the external temperature to be 20-100 ℃, reacting for 1-24H, stopping reaction, filtering, concentrating filtrate, extracting with ethyl acetate and water, separating liquid, decoloring an ethyl acetate phase with activated carbon, concentrating to dryness, adding isopropanol for recrystallization, filtering, and drying a filter cake to obtain a light yellow solid;
and 5: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid
Adding ethyl 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate into ethanol, adding a sodium hydroxide solution while stirring, controlling the temperature to be 0-80 ℃, reacting for 1-24H, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, adjusting the pH to subacidity by hydrochloric acid, concentrating the system to dryness, adding the remainder into water, adjusting the pH to solid full dissolution by sodium hydroxide solution, adding hydrochloric acid to adjust the pH to subacidity, precipitating a large amount of solid, filtering, and drying a filter cake to obtain a white solid;
step 6: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium salt
Adding 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid into ethanol, adding an equivalent amount of sodium hydroxide solution while stirring, controlling the temperature to be 0-80 ℃, reacting for 1-24H, separating out a large amount of solid in a system, filtering, and drying a filter cake to obtain a white solid.
2. A method for synthesizing benzimidazole derivatives and pharmaceutically acceptable salts thereof is characterized by comprising the following steps:
step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 4-amino-1-naphthalocyanine, KOH and N-methylpyrrolidone into a three-necked bottle, controlling the external temperature to be 0-150 ℃ under stirring, adding o-chloronitrobenzene, stirring for reacting for 1-48h, detecting no raw material residue by TLC, stopping the reaction, adding a proper amount of water, regulating the pH value to be weak acid by using hydrochloric acid, filtering, and drying a filter cake to obtain a red solid;
step 2: 4- [ (2-aminophenyl) amino ] naphthonitrile
Adding iron powder into a saturated ammonium chloride solution, adding acetic acid, heating to 50-100 ℃, stirring, dissolving 4- [ (2-nitrophenyl) amino ] naphthanenitrile in ethanol, adding into an iron powder ammonium chloride system, controlling the external temperature to be 50-100 ℃, reacting for 1-24h, detecting by TLC that no raw material remains, stopping the reaction, cooling to room temperature, adding ethyl acetate for extraction, decoloring by using activated carbon, and concentrating to dryness to obtain a yellow solid;
and step 3: 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthacenitrile
Dissolving 4- [ (2-aminophenyl) amino ] naphthalocyanide in ethyl acetate, adding thiophosgene and triethylamine, controlling the external temperature to be 0-100 ℃, stirring and reacting for 1-24h, detecting by TLC that no raw material remains, adding water with the same volume for extraction, washing an ethyl acetate phase twice by using water, separating liquid, and concentrating to dryness to obtain a yellow solid;
and 4, step 4: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid ethyl ester
Adding 4- (2-mercapto-1H-benzo [ d ] imidazole-1-yl) naphthanenitrile, potassium carbonate and water into acetonitrile, adding 2-bromomethyl isobutyrate under stirring, controlling the external temperature to be 20-100 ℃, reacting for 1-24H, stopping reaction, filtering, concentrating filtrate, extracting with ethyl acetate and water, separating liquid, decoloring an ethyl acetate phase with active carbon, concentrating to dryness, adding isopropanol for recrystallization, filtering, and drying a filter cake to obtain a light yellow solid;
and 5: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid
Adding 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] methyl propionate into ethanol, adding a sodium hydroxide solution under stirring, controlling the temperature to be 0-80 ℃, reacting for 1-24H, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, adjusting the pH to subacidity by hydrochloric acid, concentrating the system to dryness, adding the remainder into water, adjusting the pH to solid full dissolution by sodium hydroxide solution, adding hydrochloric acid to adjust the pH to subacidity, separating out a large amount of solid, filtering, and drying a filter cake to obtain a white solid;
step 6: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium salt
Adding 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid into ethanol, adding a proper amount of potassium hydroxide solution while stirring, controlling the temperature to be 0-80 ℃, reacting for 1-24H, separating out a large amount of solid in a system, filtering, and drying a filter cake to obtain a white solid.
3. The method of synthesis according to claim 1, comprising the steps of:
step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 45g of 2-nitroaniline, 24g of CaO, 26g of NaOH and 250mL of N, N-dimethylacetamide into a three-necked flask, controlling the temperature to be 80-110 ℃ under stirring, adding 50g of 4-bromo-1-naphthanitrile in batches, stirring for reaction for 5 hours, detecting by TLC (thin layer chromatography) that no raw material is left, stopping the reaction, adding 500mL of water, adjusting the pH to be 3-4 by using hydrochloric acid, filtering, and drying a filter cake to obtain a red solid;
step 2: 4- [ (2-aminophenyl) amino ] naphthonitrile
Adding 50g of 4- [ (2-nitrophenyl) amino ] naphthalocyanine into a mixture of 250mL of ethanol and 85mL of water, adding ferric chloride, controlling the external temperature to be 70-90 ℃, adding 51g of hydrazine hydrate with the concentration of 85%, reacting for 2h, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, adding 170mL of water, stirring, filtering, drying a filter cake, and decoloring by using activated carbon to obtain a yellow solid;
and step 3: 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthacenitrile
Adding 30g of 4- [ (2-aminophenyl) amino ] naphthanenitrile, 23g N, N' -thiocarbonyl diimidazole and 90mL of acetonitrile into a single-mouth bottle, controlling the external temperature to be 50-90 ℃, stirring for reacting for 2 hours, detecting by TLC (thin layer chromatography), adding 90mL of water, filtering, and drying a filter cake to obtain a yellow solid;
and 4, step 4: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid ethyl ester
Adding 30g of 4- (2-mercapto-1H-benzo [ d ] imidazole-1-yl) naphthanenitrile, 27.6g of potassium carbonate and 15mL of water into 300mL of acetonitrile, adding 29g of ethyl 2-bromoisobutyrate under stirring, controlling the external temperature to be 70-90 ℃, reacting for 3H, stopping the reaction, filtering, concentrating the filtrate, extracting with 300mL of ethyl acetate and 200mL of water, separating, decoloring the ethyl acetate phase with activated carbon, concentrating to dryness, adding isopropanol, recrystallizing, filtering, and drying the filter cake to obtain a light yellow solid;
and 5: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid
Adding 35g of ethyl 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate into 350mL of ethanol, adding 35mL of aqueous solution containing 6.7g of sodium hydroxide under stirring at room temperature, reacting for 2-3H, detecting by TLC (thin layer chromatography) until no raw material is left, stopping the reaction, adjusting the pH to 2-3 with hydrochloric acid, concentrating the system to dryness, adding the remainder into water, adjusting the pH to 10 with 20% sodium hydroxide solution, fully dissolving the solid, adjusting the pH to 2-3 with hydrochloric acid, separating out a large amount of solid, filtering, and drying a filter cake to obtain a white solid;
step 6: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium salt
Adding 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid into ethanol, adding 20mL of aqueous solution of sodium hydroxide at room temperature under stirring, separating out a large amount of solid in the system, filtering, and drying a filter cake to obtain a white solid.
4. The method of synthesis according to claim 2, comprising the steps of:
step 1: 4- [ (2-nitrophenyl) amino ] naphthacenitrile
Adding 34g of 4-amino-1-naphthalocyanine, 11.3g of KOH and 350mL of N-methylpyrrolidone into a three-necked bottle, controlling the external temperature to be 70-100 ℃ under stirring, dropwise adding 32g of o-chloronitrobenzene, stirring for reacting for 3 hours, detecting by TLC (thin layer chromatography), stopping the reaction, adding 700mL of water, filtering, and drying a filter cake to obtain a red solid;
step 2: 4- [ (2-aminophenyl) amino ] naphthonitrile
Adding 43g of iron powder into 500mL of saturated ammonium chloride solution, adding acetic acid, heating to 70-100 ℃, stirring, dissolving 45g of 4- [ (2-nitrophenyl) amino ] naphthanenitrile in 100mL of ethanol, adding into an iron powder ammonium chloride system, controlling the external temperature to be 70-100 ℃, reacting for 3h, detecting by TLC (thin layer chromatography) that no raw material remains, stopping the reaction, cooling to room temperature, adding 300mL of ethyl acetate, extracting, decoloring by using activated carbon, and concentrating to dryness to obtain a yellow solid;
and step 3: 4- (2-mercapto-1H-benzo [ d ] imidazol-1-yl) naphthacenitrile
Dissolving 30g of 4- [ (2-aminophenyl) amino ] naphthalocyanide in 300mL of ethyl acetate, adding 20g of thiophosgene and 47g of triethylamine, stirring and reacting for 3 hours at room temperature, detecting by TLC that no raw material remains, adding 300mL of water for extraction, washing an ethyl acetate phase twice by using water, 200mL of 2, separating, and concentrating to dryness to obtain a yellow solid;
and 4, step 4: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid ethyl ester
Adding 25g of 4- (2-mercapto-1H-benzo [ d ] imidazole-1-yl) naphthanenitrile, 23g of potassium carbonate and 12.5mL of water into 250mL of acetonitrile, adding 24g of methyl 2-bromoisobutyrate under stirring, controlling the external temperature to be 70-90 ℃, reacting for 3H, stopping the reaction, filtering, concentrating the filtrate, extracting with 300mL of ethyl acetate and 200mL of water, separating the liquid, decoloring the ethyl acetate phase with activated carbon, concentrating to dryness, adding 75mL of isopropanol, recrystallizing, filtering, and drying the filter cake to obtain a light yellow solid;
and 5: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid
Adding 30g of methyl 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionate into 300mL of ethanol, adding 30mL of aqueous solution of 6g of sodium hydroxide under stirring at room temperature, reacting for 3H, detecting by TLC (thin layer chromatography) that no raw material is left, stopping the reaction, adjusting the pH to 3-4 with hydrochloric acid, concentrating the system to dryness, adding the remainder into water, adjusting the pH to 10 with 20% sodium hydroxide solution, fully dissolving the solid, adding hydrochloric acid to adjust the pH to 2-3, separating out a large amount of solid, filtering, and drying a filter cake to obtain a white solid;
step 6: 2-methyl-2- [ [1- (4-cyanonaphthalen-1-yl) -1H-benzo [ d ] imidazol-2-yl ] mercapto ] propanoic acid sodium salt
Adding 2-methyl-2- [ [1- (4-cyanonaphthalene-1-yl) -1H-benzo [ d ] imidazole-2-yl ] mercapto ] propionic acid into ethanol, adding 20mL of aqueous solution of sodium hydroxide at room temperature under stirring, separating out a large amount of solid in the system, filtering, and drying a filter cake to obtain a white solid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710814392.9A CN107400090B (en) | 2017-09-11 | 2017-09-11 | Synthesis method of benzimidazole derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710814392.9A CN107400090B (en) | 2017-09-11 | 2017-09-11 | Synthesis method of benzimidazole derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107400090A CN107400090A (en) | 2017-11-28 |
| CN107400090B true CN107400090B (en) | 2020-02-07 |
Family
ID=60388181
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710814392.9A Active CN107400090B (en) | 2017-09-11 | 2017-09-11 | Synthesis method of benzimidazole derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107400090B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110577494B (en) * | 2018-06-07 | 2021-07-16 | 华润赛科药业有限责任公司 | Polymorphic substance of benzimidazole derivative and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010090300A1 (en) * | 2009-02-03 | 2010-08-12 | 日本ケミファ株式会社 | Diazepinedione derivatives |
| CN105601571A (en) * | 2015-12-22 | 2016-05-25 | 华润赛科药业有限责任公司 | Benzimidazole derivatives as well as preparation method and application thereof |
| CN105713029A (en) * | 2016-03-02 | 2016-06-29 | 吉林奥来德光电材料股份有限公司 | Compound with heterocyclic ligand and preparation method and application thereof |
-
2017
- 2017-09-11 CN CN201710814392.9A patent/CN107400090B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010090300A1 (en) * | 2009-02-03 | 2010-08-12 | 日本ケミファ株式会社 | Diazepinedione derivatives |
| CN105601571A (en) * | 2015-12-22 | 2016-05-25 | 华润赛科药业有限责任公司 | Benzimidazole derivatives as well as preparation method and application thereof |
| CN105713029A (en) * | 2016-03-02 | 2016-06-29 | 吉林奥来德光电材料股份有限公司 | Compound with heterocyclic ligand and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107400090A (en) | 2017-11-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111423452B (en) | Intermediate of Rayleigh Lu Geli and preparation method and application thereof | |
| TWI697494B (en) | Synthesis of copanlisib and its dihydrochloride salt | |
| PT2322511E (en) | Process for the production of telmisartan | |
| CN108383749B (en) | Synthetic method of apaluamide and intermediate thereof | |
| JP7368636B2 (en) | Method for synthesizing roxadustat and its intermediates and intermediates thereof | |
| CN108623567A (en) | Ao Si replaces the preparation method of Buddhist nun | |
| CN103880830B (en) | Synthesis method of azilsartan | |
| KR101087454B1 (en) | Process for producing 1-3,4-dichlorobenzyl-5-octylbiguanide or a salt thereof | |
| CN103664912A (en) | Synthesis process of prucalopride | |
| JP6592085B2 (en) | Preparation method of revaprazan hydrochloride | |
| CN107400090B (en) | Synthesis method of benzimidazole derivative | |
| US7868183B2 (en) | Process for producing muscarine receptor antagonist and intermediate therefor | |
| JP4478140B2 (en) | Preparation of carbostyril compounds for pharmaceutical use | |
| WO2017099530A1 (en) | Preparation method of intermediate for oxazolidinone derivative | |
| CN110446704A (en) | The method for being used to prepare the kinase inhibitor of sulfonamide structure | |
| CN104829547A (en) | Substituted triazole compound preparation method | |
| CN107188888A (en) | A kind of methanesulfonic acid for preparing steps the auspicious method for Buddhist nun | |
| CN105732660B (en) | The preparation method of lavo-ofloxacin intermediate | |
| KR20210080373A (en) | Methods for preparing solid forms of BET bromodomain inhibitors | |
| CN107382968A (en) | A kind of preparation method of indoles c Met inhibitor | |
| CN106518939B (en) | Method for preparing Solithromycin compound | |
| CN108976233A (en) | Impurity and its preparation, detection method of the Ba Rui for Buddhist nun | |
| CN106866560B (en) | Lesinurad synthesis method | |
| CN103739568A (en) | Preparation method of 2-(3-cyan-4-isobutoxyphenyl)-4-methylthiazole-5-formic acid A crystal | |
| CA2957498C (en) | Process for large scale production of 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1h-indazole oxalate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |