CN106432195B - Method for preparing (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide - Google Patents
Method for preparing (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide Download PDFInfo
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- CN106432195B CN106432195B CN201510493069.7A CN201510493069A CN106432195B CN 106432195 B CN106432195 B CN 106432195B CN 201510493069 A CN201510493069 A CN 201510493069A CN 106432195 B CN106432195 B CN 106432195B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to a method for preparing (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide, which not only avoids using strong acid such as trifluoroacetic acid and the like, but also simplifies the prior preparation process, reduces pollution, lowers cost and improves product purity and yield.
Description
Technical Field
The invention relates to the synthesis of pharmaceutical raw materials, in particular to a method for preparing (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide.
Background
(R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide, the structural formula of which is shown as the following formula I, is abbreviated as ABT-888,
the dihydrochloride salt is shown in the structural formula II. ABT-888 is a novel oral poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor with Ki values of 5.2 and 2.9nmol when it acts on PARP-1 and PARP-2, respectively. ABT-888 inhibited C41 cells with an EC50 of 2nmol, and showed strong anti-cancer efficacy when used in combination with other cytotoxic agents on MX-1 transplant tumor models. Can reduce the survival rate of cloned genes in lung cancer H460 cells and inhibit DNA repair. ABT-888 delays tumor growth in the NCI-H460 transplant tumor model. ABT-888 inhibits PARP in B16F10 and 9L transplant tumor models, thereby potentiating the anticancer activity of temozolomide. ABT-888 in combination with radiation reduces tumor vascularization. More than 95% of PARP inhibition within the tumor was seen in the A375 and Colo829 transplantable tumor models, with 3 and 12.5mg ABT-888, respectively, per kilogram. ABT-888 is undergoing clinical trials with multiple tumors, with ABT-888 in combination with standard chemotherapeutic drugs in the treatment of triple negative breast cancer and non-small cell lung cancer in a third stage clinical trial. It is expected to become a new targeted antitumor drug with remarkable curative effect.
Chinese patent application CN101155797A, provides two synthetic routes for ABT-888:
1. taking pyrrolidine-1, 2-dicarboxylic acid-1-benzyl ester and 2-methyl ester as starting raw materials, hydrolyzing methyl iodide on 2 position, coupling with 2, 3-diaminobenzamide, closing ring with acetic acid, and removing benzyl ester by hydrogenation to obtain racemic 2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide; after ring closure, chiral column resolution is carried out, and then (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide is obtained by hydrogenation.
(R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide may be further salified with HCl.
2. Taking L-benzyl alanine ester as an initial raw material, carrying out condensation on 1-bromo-3-chloropropane, BOC protection, ring closure and benzyl removal to obtain R- (2-methyl-1-BOC-pyrrolidine) -2-formic acid, removing BOC, reacting with benzyl chloroformate, coupling with 2, 3-diaminobenzamide, and carrying out acetic acid ring closure to obtain 2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide with EE of about 97%. If a product with chiral purity not less than 99.5% is required, chiral column resolution is also required in the middle to obtain (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide.
3. Lutianxiang et al provide a chiral synthesis process of ABT888 in "improvement of PARP inhibitor veliparb synthesis process" (China journal of pharmaceutical chemistry, Vol.23, No. 6)
However, neither purity nor yield was satisfactory.
Disclosure of Invention
We have studied the synthesis of ABT-888 and surprisingly found that: directly taking R- (2-methyl-1-BOC-pyrrolidine) -2-formic acid as a raw material, coupling with 2, 3-diaminobenzamide, refluxing a refined product (R) -tert-butyl-2- (2-amino-3-formylbenzoyl) -2-methylpyrrolidine-1-carboxylic ester (the structure of which is shown in a formula III) in an acetic acid solution for more than 2 hours, or refluxing the refined product with 100 percent glacial acetic acid for 2 hours, adding 5 to 95 percent of water into the refluxed solution, refluxing the refluxed solution for more than 2 hours, and directly obtaining the (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide after treatment.
The process has the following remarkable advantages:
1. the prior art needs secondary feeding reaction, and needs two treatment processes to obtain a product; the invention simplifies the production process, and the product can be obtained only by one-time feeding reaction and treatment. The process is simplified, the treatment process is reduced, and the yield is greatly improved.
2. The product purity is high, and the prior process mainly adopts trifluoroacetic acid or hydrochloric acid solution to remove BOC protecting group, so that formamido is hydrolyzed, which not only can generate impurities, but also can reduce yield. The process of the invention uses weak acid-acetic acid aqueous solution, thus avoiding the hydrolysis of formamide, improving the purity and yield of the product, and refining the product to ensure that the purity is not less than 99 percent and the chiral purity is not less than 99.5 percent.
3. The process of the invention can completely recycle the acetic acid solution and remove BOC without using severe-pollution strong acids such as trifluoroacetic acid, hydrochloric acid and the like.
4. The step of removing the carbobenzoxy protecting group on the pyrrolidine N by the catalytic pressure hydrogenation of palladium carbon in the original patent process is omitted.
5. The chiral column is not needed for resolution, and the advantages are obvious.
The R- (2-methyl-1-BOC-pyrrolidine) -2-formic acid used in the patent can be prepared by the following method:
A. the chiral intermediate (R) -2-methyl pyrrole formic acid-1-tert-butyl formate is synthesized by a method similar to the synthesis process improvement of PARP inhibitor veliparb in Lutianxiang et al
B. Synthesis of intermediates by the method of patent CN101155797A
C. Analogous procedure for the Synthesis of racemic intermediate (2-methyl-1-BOC-pyrrolidine) -2-carboxylic acid
Then (R) -2-methyl pyrrole carboxylic acid-1-tert-butyl formate or 2-methyl pyrrole carboxylic acid-1-tert-butyl formate is used for synthesizing the initial intermediate of the patent
Meanwhile, we found that the racemate, or the (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide with low chiral purity can be obtained by using chiral reagent L- (-) -di-p-methylbenzoyl tartaric acid or L- (-) -di-p-methoxybenzoyl tartaric acid or L- (-) -di-p-benzoyl tartaric acid, adopting a resolving agent with the molar ratio of (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide being about 2 times that of (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide, salifying in an alcohol solvent such as methanol and the like, resolving once or more, and then alkalifying to obtain the qualified (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-methyl formamide An amide. The use of chemical resolving agents to improve chiral purity or resolution has incomparable advantages over the use of chiral column resolution or purification, especially for large doses of drug up to 200 mg.
Detailed Description
EXAMPLE one preparation of (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide with 80% acetic acid
6.0 g of (R) -tert-butyl-2- (2-amino-3-formylbenzoyl) -2-methylpyrrolidine-1-carboxylate (0.016mol), adding 60ml of 80% acetic acid, heating and refluxing for about 6 hours, detecting the completion of the raw material reaction, distilling off the solvent in vacuum, adding 30ml of water to dissolve out, neutralizing with an alkali solution (ammonia water or 4N sodium hydroxide) to a pH value of more than 8 while stirring, precipitating a white product, stirring for about 2 hours, filtering, washing a filter cake with water, washing with ethyl acetate, drying in vacuum, and refining the product with 25ml of anhydrous methanol to obtain 3.1 g of the product (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide, 99.7 percent of HPLC and 99.8 percent of chiral purity. The yield thereof was found to be 77.5%.
EXAMPLE two preparation of (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide using 90% acetic acid
6.0 g of (R) -tert-butyl-2- (2-amino-3-formylbenzoyl) -2-methylpyrrolidine-1-carboxylate (0.016mol), adding 60ml of 90% acetic acid, heating and refluxing for about 6 hours, detecting the completion of the raw material reaction, distilling off the solvent in vacuum, adding 30ml of water to dissolve out, neutralizing with an alkali solution (ammonia water or 4N sodium hydroxide) while stirring until the pH is more than 8, precipitating a white product, stirring for about 2 hours, filtering, washing a filter cake with water, washing with ethyl acetate, drying in vacuum, and refining the product with 25ml of anhydrous methanol to obtain 3.0 g of the product (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide, 99.4% of HPLC and 99.9% of chiral purity. The yield thereof was found to be 75.0%.
EXAMPLE three preparation of (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide using 50% acetic acid
6.0 g of (R) -tert-butyl-2- (2-amino-3-formylbenzoyl) -2-methylpyrrolidine-1-carboxylate (0.016mol), adding 60ml of 50% acetic acid, heating and refluxing for about 8 hours, detecting the completion of the raw material reaction, distilling off the solvent in vacuum, adding 30ml of water to dissolve out, neutralizing with an alkali solution (ammonia water or 4N sodium hydroxide) while stirring until the pH is more than 8, precipitating a white product, stirring for about 2 hours, filtering, washing a filter cake with water, washing with ethyl acetate, drying in vacuum, and refining the product with 20ml of anhydrous methanol to obtain 2.4 g of the product (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide, 99.5 percent of HPLC and 99.7 percent of chiral purity. The yield thereof was found to be 60.0%.
EXAMPLE four preparation of (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide with recovered acetic acid
6.0 g of (R) -tert-butyl-2- (2-amino-3-formylphenylcarbamoyl) -2-methylpyrrolidine-1-carboxylate (0.016mol), 70ml of the 80% acetic acid recovered in example was added, and the mixture was refluxed for about 6 hours, detecting the completion of the reaction of the raw materials, distilling the solvent out in vacuum, adding 30ml of water for dissolving, neutralizing with an alkali solution (ammonia water or 4N sodium hydroxide) while stirring until the pH is more than 8, separating out a white product, stirring for about 2 hours, filtering, washing a filter cake with water, washing with ethyl acetate, drying in vacuum, and refining the product with 25ml of anhydrous methanol to obtain the product (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide 3.05 g, 99.6 percent of HPLC and 99.8 percent of chiral purity. The yield thereof was found to be 76.2%.
EXAMPLE five resolution of racemate 2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide with L- (-) -p-methylbenzoyltartaric acid (anhydrate)
6.0 g of 2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide (0.0246mol), adding 80ml of absolute methanol, stirring, heating and dissolving, cooling to about 40 ℃, adding 80ml of absolute methanol solution dissolved with 9.6 g (0.0246mol) of L- (-) -p-methylbenzoyltartaric acid (anhydride), quickly precipitating a white product, stirring for about 2 hours, filtering, washing a filter cake with absolute methanol, adding the filter cake into 60ml of water without drying, stirring, neutralizing with alkali, starting to clear until the pH is higher than 9, then precipitating a solid product, stirring for 4 hours, carrying out suction filtration, washing the filter cake for three times, and carrying out vacuum drying to obtain 2.15 g of a product (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide, HPLC 99.7%, chiral purity greater than 98.0%. The yield thereof was found to be 70.0%.
EXAMPLE sixthly purification of (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide with L- (-) -p-methylbenzoyltartaric acid (anhydrate)
6.0 g of 98% (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide (0.0240mol), adding 80ml of absolute methanol, stirring and heating for dissolving, cooling to about 40 ℃, adding 120ml of absolute methanol solution in which 18.6 g (0.0246mol) of L- (-) -p-methylbenzoyl tartaric acid (anhydride) is dissolved, quickly precipitating a white product, stirring for about 2 hours, filtering, washing a filter cake with the absolute methanol, adding the filter cake into 90ml of water without drying, stirring, neutralizing with alkali, starting to clear until the pH is more than 9, then precipitating a solid product, stirring for 4 hours, carrying out suction filtration, washing the filter cake for three times, and carrying out vacuum drying to obtain 4.0 g of (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide, HPLC 99.7%, chiral purity 99.7%. The yield thereof was found to be 68.0%.
EXAMPLE seventhly, resolution of 2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide with L- (-) -p-methylbenzoyltartaric acid (anhydrate)
6.0 g of 2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide (0.0246mol), adding 400ml of anhydrous methanol, stirring, heating, dissolving, cooling to about 40 ℃, adding 80ml of anhydrous methanol solution dissolved with 9.6 g (0.0246mol) of L- (-) -p-methylbenzoyltartaric acid (anhydride), quickly precipitating white products, heating, refluxing, dissolving, crystallizing at low temperature for 24 hours, filtering, washing filter cakes with anhydrous methanol, adding the filter cakes without drying into 60ml of water, stirring, neutralizing with alkali, starting to clear until the pH is more than 9, then precipitating solid products, stirring for 4 hours, filtering, washing the filter cakes three times, and drying in vacuum to obtain 1.9 g of the product (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide, HPLC 99.8%, chiral purity 99.9%. The yield thereof was found to be 63.3%.
EXAMPLE eighthly resolution of 2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide with L- (-) -p-methoxydibenzoyltartaric acid (anhydrate)
6.0 g of 2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide (0.0246mol), adding 80ml of absolute methanol, stirring, heating and dissolving, cooling to about 40 ℃, adding 80ml of absolute methanol solution dissolved with 10.30 g (0.0246mol) of L- (-) -p-methoxydibenzoyltartaric acid (anhydride), quickly precipitating a white product, stirring for about 2 hours, filtering, washing a filter cake with the absolute methanol, adding the filter cake into 60ml of water without drying, stirring, neutralizing with alkali, starting to clear until the pH is higher than 9, then precipitating a solid product, stirring for 4 hours, carrying out suction filtration, washing the filter cake for three times, and carrying out vacuum drying to obtain 2.3 g of the product (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide, HPLC > 99.9%, chiral purity 99.8%. The yield thereof was found to be 76.7%.
EXAMPLE nine resolution of 2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide with L- (-) -dibenzoyltartaric acid (anhydrate)
6.0 g of 2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide (0.0246mol), adding 80ml of absolute methanol, stirring and heating to dissolve, cooling to about 40 ℃, adding 80ml of absolute methanol solution dissolved with 8.9(0.0246mol) of L- (-) -dibenzoyltartaric acid (anhydride), quickly precipitating a white product, stirring for about 2 hours, filtering, washing a filter cake with the absolute methanol, adding the filter cake into 60ml of water without drying, stirring, neutralizing with alkali, starting to clear until the pH is more than 9, then precipitating a solid product, stirring for 4 hours, carrying out suction filtration, washing the filter cake for three times, and carrying out vacuum drying to obtain 2.2 g of the product (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide, HPLC 99.6%, chiral purity 99.8%. The yield thereof was found to be 73.3%.
EXAMPLE ten purification of (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide with L- (-) -p-methylbenzoyltartaric acid (anhydrate)
6 g of 2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide (0.0246mol), which was found to contain 70% of 2- ((R) -2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide, 80ml of absolute methanol was added, the mixture was stirred and heated to dissolve it, the mixture was cooled to about 40 ℃, 100ml of an aqueous methanol solution in which 13.5 g (0.0,345mol) of L- (-) -p-methylbenzoyltartaric acid (anhydrate) was dissolved was added, a white product precipitated quickly, the mixture was stirred for about 2 hours, the filter cake was washed with absolute methanol, the filter cake was not dried, the mixture was added to 80ml of water, stirred, neutralized with a base to start clearing, a solid product precipitated and stirred for 4 hours, and (3) carrying out suction filtration, washing a filter cake for three times, and carrying out vacuum drying to obtain 3.6 g of (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide, wherein HPLC (high performance liquid chromatography) is 99.7% and chiral purity is 99.8%. The yield thereof was found to be 85.7%.
EXAMPLE eleventh preparation of (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide by adding 100% acetic acid and Water
6.0 g of (R) -tert-butyl-2- (2-amino-3-formylphenylcarbamoyl) -2-methylpyrrolidine-1-carboxylate (0.016mol), 60ml of 100% acetic acid was added thereto, and the mixture was refluxed for about 2 hours, detecting the completion of the reaction of the raw materials, adding 12ml of water, refluxing for 4 hours, distilling the solvent out in vacuum, adding 30ml of water to dissolve the solvent, neutralizing with an alkali solution (ammonia water or 4N sodium hydroxide) while stirring until the pH is more than 8, separating out a white product, stirring for about 2 hours, filtering, washing a filter cake with water, washing with ethyl acetate, drying in vacuum, and refining the product with 25ml of anhydrous methanol to obtain 2.5 g of the product (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide, wherein the HPLC (high performance liquid chromatography) content is 99.2 percent, and the chiral purity is 99.5 percent. The yield thereof was found to be 64.0%.
Claims (8)
1. A process for the preparation of (R) -2- (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide characterized by comprising the steps of: refluxing the intermediate (R) -tert-butyl-2- (2-amino-3-formyl phenylcarbamoyl) -2-methyl pyrrolidine-1-carboxylic ester in an acetic acid solution to obtain a product, wherein the concentration range of the acetic acid solution is 5-95%; wherein the mass of (R) -tert-butyl-2- (2-amino-3-formylphenylcarbamoyl) -2-methylpyrrolidine-1-carboxylate and the volume ratio of acetic acid solution are 1 g: 2-30 ml.
2. The method according to claim 1, wherein the concentration of the acetic acid solution is in the range of 10% to 90%; wherein the mass of (R) -tert-butyl-2- (2-amino-3-formylphenylcarbamoyl) -2-methylpyrrolidine-1-carboxylate and the volume ratio of acetic acid solution are 1 g: 5-15 ml.
3. The method according to claim 2, wherein the concentration of the acetic acid solution is 80%.
4. A method for preparing (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide is characterized in that racemate or 2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide with chiral purity of less than 99.5% is subjected to resolution by a resolving agent to obtain a product with chiral purity of not less than 99.5%, wherein the resolving agent is L- (-) -di-p-methylbenzoyl tartaric acid, L- (-) -di-p-methoxybenzoyl tartaric acid or L- (-) -di-p-benzoyl tartaric acid, and the molar ratio of the resolving agent to the 2- (R) - (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide is 1-3: 1; the temperature is 0-100 ℃; the solvent is one of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, water, ethylene glycol dimethyl ether, DMF, DMSO, and pyridine.
5. The preparation method according to claim 4, wherein the molar ratio of the resolving agent to the 2- (R) - (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-formamide is 1-3: 1; the temperature is 25-60 ℃.
6. The process according to claim 4, wherein the molar ratio of resolving agent to 2- (R) - (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide is 2: 1; the temperature is 25-60 ℃.
7. The process according to claim 4, wherein the molar ratio of resolving agent to 2- (R) - (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide is 2: 1; the temperature was 40 ℃.
8. The process according to claim 4, wherein the molar ratio of resolving agent to 2- (R) - (2-methylpyrrolidin-2-yl) -1H-benzimidazole-4-carboxamide is 2: 1; the temperature was 40 ℃ and the solvent was methanol.
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| CA3021507A1 (en) | 2017-10-24 | 2019-04-24 | Apotex Inc. | Processes for the preparation of veliparib and intermediates thereof |
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| CN101155797A (en) * | 2005-04-11 | 2008-04-02 | 艾博特公司 | 1h-benzimidazole-4-carboxamides substituted with a quaternary carbon at the 2-position are potent parp inhibitors |
| CN102863428A (en) * | 2011-07-09 | 2013-01-09 | 广东东阳光药业有限公司 | Spiro-compounds taken as hepatitis c virus (HCV) inhibitor |
| CN103396405A (en) * | 2013-08-21 | 2013-11-20 | 中国药科大学 | Benzimidazole-4-formamide derivate with PARP (poly-ADP-ribose polymerase) inhibiting effect |
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| CN101155797A (en) * | 2005-04-11 | 2008-04-02 | 艾博特公司 | 1h-benzimidazole-4-carboxamides substituted with a quaternary carbon at the 2-position are potent parp inhibitors |
| CN102863428A (en) * | 2011-07-09 | 2013-01-09 | 广东东阳光药业有限公司 | Spiro-compounds taken as hepatitis c virus (HCV) inhibitor |
| CN103396405A (en) * | 2013-08-21 | 2013-11-20 | 中国药科大学 | Benzimidazole-4-formamide derivate with PARP (poly-ADP-ribose polymerase) inhibiting effect |
| CN103483322A (en) * | 2013-08-21 | 2014-01-01 | 中国药科大学 | 5-fluoro-1H-benzimidazole-4-formamide derivatives, as well as preparation method and medical application thereof |
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| 新型PARP抑制剂veliparib;徐春秀等;《现代药物与临床》;20130131;第28卷(第1期);第69-73页 * |
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