CN109320485B - Method for synthesizing Tegolazan chiral alcohol - Google Patents
Method for synthesizing Tegolazan chiral alcohol Download PDFInfo
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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Abstract
The invention relates to a method for preparing Tegoprazan (Tegoprazan) chiral alcohol, in particular to (S) -5, 7-difluoro-3, 4-dihydro-2HA process for the preparation of (E) -chromen-4-ol. The method takes 5, 7-difluoro-4H-benzopyran-4-ketone as a starting material, and realizes (S) -5, 7-difluoro-3, 4-dihydro-2-by asymmetric reduction of ketone carbonyl by a chiral reagent and subsequent conventional hydrogenation reactionHPreparation of-chromen-4-ol.
Description
Technical Field
The invention belongs to the technical field of synthesizing chiral fragments of raw material medicines, and particularly relates to preparation of Tegolrazan chiral fluoroalcohol.
Background
Tegolrazan, also known as tegorazagen, Tegoprazan, CJ-12420, was approved by the korean food and drug safety department (MFDS) in 7 months of 2018 for the treatment of gastroesophageal reflux disease and erosive esophagitis.
Tegolrazan was originally developed by the company picui, was granted to RaQualia Pharma (divorced from picui) for cooperative development in 2008, was granted to CJ Health Care by RaQualia Pharma in 2014, and was finally successfully developed and marketed in korea by CJ Health Care. Tegolazan is a competitive potassium acid blocker (P-CAB) and a hydrogen/potassium ion exchange ATPase (H)+/K+ATPase) inhibitor, which was first marketed in korea, is a completely new drug for the treatment of gastric feedingMedicine for treating reflux disease of trachea and erosive esophagitis.
The gastric proton pump hydrogen/potassium ion exchange atpase is a major pharmacological target for the treatment of gastric acid related diseases. Potassium competitive acid blocker (P-CAB) capable of reacting with K+Competitive binding H+/K+-ATPases to inhibit gastric acid secretion. Tegoprazan is found to be one of the potassium competitive acid blockers and is considered to be the most advanced drug for treating gastroesophageal reflux disease at present, because a proton pump inhibitor is the most commonly used drug for treating gastroesophageal reflux disease, and Tegoprinum can just overcome the defects of the proton pump inhibitor. The effectiveness and safety of tegolazan is mainly based on two phase III clinical trials. One of them was a double-blind, actively controlled phase III study (NCT02456935) conducted in korea, with 280 erosive esophagitis patients as subjects and the cumulative healing rate of erosive esophagitis at week 8 as the primary endpoint, comparing the safety and efficacy of tegolazan with that of the proton pump inhibitor esomeprazole. Another phase III clinical trial was a double-blind, randomized, placebo-controlled trial (NCT 02556021). The test was conducted in 324 patients in korea, the primary endpoint being the percentage of patients with complete regression of the primary symptoms (heartburn and reflux) at 4 weeks as determined using the Reflux Disease Questionnaire (RDQ), to assess the safety and effectiveness of once daily tablets of tegrazan (50mg and 100mg) in non-erosive reflux patients. The approval of the medicine on the market provides a new choice for treating the diseases, and the defects of other medicines are compensated to a certain extent, so that the diseases can be better treated.
The chemical name of Tegolrazan is (S) -4- ((5, 7-difluoro chroman-4-yl) oxygen) -N, N, 2-trimethyl-1H-benzo [ d ] imidazole-6-formamide, the chemical structure contains a benzimidazole structure and a chiral 5, 7-difluoro chroman-4-oxyl structure, and the specific chemical structure is as follows:
patent CN101341149B discloses a preparation method of Tegolazan, specifically, 4-hydroxy-N, N, 2-trimethyl-1- [ (4-methylphenyl) sulfonyl ] -1H-benzimidazole-6-formamide and (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol are subjected to condensation reaction under the action of tributylphosphine/ADDP to prepare an intermediate of (-) -4- [ ((4S) -5, 7-difluoro-3, 4-2H-chromen-4-yl) oxy ] -N, N, 2-trimethyl-1- [ (4-methylphenyl) sulfonyl ] -1H-phenylimidazole-6-formamide, the latter removes the protecting group under the action of alkali to complete the preparation of Tegolazan, and the specific synthetic route is as follows:
based on the description of the above patent, the preparation of tegolazan mainly involves two fragments, one of which is a chiral fluoroalcohol fragment, i.e. (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol. cJ Health Care patents CN101341149B and CN107849003A disclose methods for preparing (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol, but the method described in CN101341149B has a relatively poor chiral purity (86% ee) (recrystallization yields are only 58% although the ee value of the product can be increased), CN107849003A relates to a chiral Ru reagent (which is expensive) which is difficult to purchase commercially, and the methods described in patents CN101341149B and CN107849003A are as follows:
in view of the shortcomings of the two methods for preparing (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol disclosed at present, the development of a new method for synthesizing (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol, which is suitable for industrialization and has superior cost, will make Tegarazan more competitive in the market.
Disclosure of Invention
The invention aims to provide a novel method for preparing (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol, aiming at avoiding the defects of expensive chiral reagent, low chiral purity of products and low yield in the prior patent. Patents CN101341149B and CN107849003A both use 5, 7-difluoro-2, 3-dihydro-4H-chromen-4-one as hydrogenation precursor, and although such substrate can achieve a certain asymmetric hydrogenation effect under the action of a special chiral reagent, since the oxetane of chromene does not have special rigidity, some conventional chiral reagents induce poor asymmetric reduction effect of ketone carbonyl group.
The synthetic route of the invention is as follows:
the starting material 5, 7-difluoro-4H-benzopyran-4-one of the present invention can be obtained by oxidation of 5, 7-difluoro-2, 3-dihydro-4H-chromen-4-one (Chemcomm., 2016, 52, 14314-one 14317) or synthesized in a similar manner as reported in the literature (Org.Lett., 2016, 18, 4986-one 4989).
The first step of the reaction involves asymmetric reduction of the ketone carbonyl group with borane-dimethylsulfide complex in the presence of a chiral reagent to give (S) -5, 7-difluoro-4H-chromen-4-ol in high selectivity.
The chiral reagent used in the first step of the reaction includes (S) -tetrahydro-1-methyl-, 3, 3-diphenyl-1H, 3H-pyrrolo [1,2-c ] [1, 3, 2] oxazoleborane, (S) -tetrahydro-1, 3, 3-triphenyl-1H, 3H-pyrrolo [1,2-c ] [1, 3, 2] oxazoleborane.
The second step of the reaction involves hydrogenation of (S) -5, 7-difluoro-4H-chromen-4-ol in the presence of a catalyst and a solvent to obtain (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol.
The second step of the reaction is carried out using a catalyst comprising Pd/C, Pd (OH)2。
The solvent used in the second step of the reaction includes methanol and ethanol.
The method for synthesizing the starting material is simple, the used reagent is easy to purchase, the process operation is simple, the chiral selectivity is high, and the method is suitable for industrial preparation of (S) -5, 7-difluoro-3, 4-dihydro-2H-chromene-4-ol.
Detailed Description
The following exemplary embodiments are provided to illustrate the present invention, and simple replacement and modification of the present invention by those skilled in the art are within the technical scheme of the present invention.
The first embodiment is as follows: preparation of (S) -5, 7-difluoro-4H-benzopyran-4-ol
To a 3L reaction flask were added anhydrous THF (400mL) and a solution of (S) -tetrahydro-1-methyl-, 3, 3-diphenyl-1H, 3H-pyrrolo [1,2-c ] [1, 3, 2] oxazaborole in Toluene (1M in Toluene, 55mL, 55mmol) under nitrogen. After the addition, the temperature of a system ice salt bath is reduced to 0 +/-2 ℃, then borane dimethyl sulfide complex (1M in THF, 575mL, 0.575mol) is added into the system, the system is stirred for 10min at the temperature of 0 +/-2 ℃, then THF (500mL) solution of 5, 7-difluoro-4H-benzopyran-4-one (100g, 0.549mol) is added, the reaction temperature of the system is maintained at 0 +/-2 ℃ in the adding process, and the system reacts until TLC tracing starting material 5, 7-difluoro-4H-benzopyran-4-one disappears after the addition. After the reaction was complete, the system was quenched by addition of MeOH (200mL) and allowed to warm to room temperature naturally and stir vigorously for 1 h. The organic solvent was removed under high vacuum and the residue was purified by column chromatography on silica gel (n-heptane/EA 5: 1) to give (S) -5, 7-difluoro-4H-benzopyran-4-ol (83.9g, 83%, 98.5% ee).
Example two: preparation of (S) -5, 7-difluoro-4H-benzopyran-4-ol
To a 500mL reaction flask, under nitrogen, was added anhydrous THF (80mL) and a solution of (S) -tetrahydro-1, 3, 3-triphenyl-1H, 3H-pyrrolo [1,2-c ] [1, 3, 2] oxazaborole in Toluene (1M in Toluene, 11.0mL, 11.0 mmol). After the addition, the temperature of the ice salt bath of the system is reduced to 0 +/-2 ℃, and then borane dimethyl sulfide complex (1M in THF, 121mL, 121mmol) is added into the system. Stirring the system at 0 +/-2 ℃ for 10min, adding a THF (100mL) solution of 5, 7-difluoro-4H-benzopyran-4-one (20.0g, 109.8mmol), maintaining the reaction temperature of the system at 0 +/-2 ℃ in the adding process, and reacting the system until TLC tracing material 5, 7-difluoro-4H-benzopyran-4-one disappears after the adding is finished. After the reaction was complete, the system was quenched by addition of MeOH (50mL) and allowed to warm to room temperature naturally and stir vigorously for 1 h. The organic solvent was removed under high vacuum and the residue was purified by column chromatography on silica gel (n-heptane/EA 5: 1) to give (S) -5, 7-difluoro-4H-benzopyran-4-ol (17.7g, 87.6%, 99.1% ee).
Example three: preparation of (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol
To a reaction flask were added (S) -5, 7-difluoro-4H-chromen-4-ol (5.0g, 27.15mmol) and ethanol (100mL), the system was stirred, then 5% Pd/C (water content 65%, 5.8g) was added under nitrogen. After the addition is finished, the nitrogen in the system is replaced for three times, and then the hydrogenation is carried out at room temperature and normal pressure until the HPLC traces the disappearance of the reaction raw materials. Filtration, removal of organic solvent under high vacuum and column chromatography purification of the residue (n-heptane/EA ═ 5: 1) gave (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol (4.65g, 92%).
Claims (1)
1. A process for preparing (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol, according to the formula:
wherein the chiral reagent used in the method is selected from (S) -tetrahydro-1-methyl-3, 3-diphenyl-1H, 3H-pyrrolo [1,2-c ]][1,3,2]Oxazaborolidines or (S) -tetrahydro-1, 3, 3-triphenyl-1H, 3H-pyrrolo [1,2-c ] S][1,3,2]Oxazaborolidine; the catalyst used is selected from Pd/C or Pd (OH)2。
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| CN112851646B (en) * | 2019-11-12 | 2023-06-13 | 中国医学科学院药物研究所 | Preparation method of tergolian prazan |
| UY39094A (en) * | 2020-02-27 | 2021-07-30 | Hk Inno N Corp | PHARMACEUTICAL COMPOSITION INCLUDING BENZIMIDAZOLE DERIVATIVE COMPOUND |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101341149A (en) * | 2005-12-19 | 2009-01-07 | 辉瑞大药厂 | Chromane substituted benzimidazoles and their use as acid pump inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101341149A (en) * | 2005-12-19 | 2009-01-07 | 辉瑞大药厂 | Chromane substituted benzimidazoles and their use as acid pump inhibitors |
Non-Patent Citations (3)
| Title |
|---|
| Efficient and general asymmetric syntheses of (R)-chroman-4-amine salts;E. A. Voight et al.;《Tetrahedron Letters》;20100908;第51卷;第5904-5907页 * |
| Enantioselective Oxazaborolidine Reduction of Ketones Containing Heteroatoms;George J. Q.,et al;《Tetrahedron Letters》;19931231;第34卷(第5期);第785-788页 * |
| Total Synthesis of (+)-trans-195A;Nicole Holub,et al;《Org. Lett.》;20050403;第7卷(第7期);第1227-1229页 * |
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Address after: 226123 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Patentee after: Jiangsu Huiju Pharmaceutical Co.,Ltd. Address before: 226123 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Patentee before: Jiangsu Huiju Pharmaceutical Co.,Ltd. |