CN109320485A - Method for synthesizing tegolazan chiral alcohol - Google Patents
Method for synthesizing tegolazan chiral alcohol Download PDFInfo
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- CN109320485A CN109320485A CN201811461589.XA CN201811461589A CN109320485A CN 109320485 A CN109320485 A CN 109320485A CN 201811461589 A CN201811461589 A CN 201811461589A CN 109320485 A CN109320485 A CN 109320485A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- 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
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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- C07—ORGANIC CHEMISTRY
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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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 synthesis material medicine chirality segment technical fields, and in particular to Te Gelazan (Tegoprazan) is chiral
The preparation of fluorine alcohol.
Background technique
Te Gelazan, also known as Ge Lasheng, Tegoprazan, CJ-12420 are replaced, Korean foods drug peace is obtained in July, 2018
All (MFDS) approval listings, for treating the treatment of gastroesophageal reflux disease and erosive esophagitis.
Tegoprazan is initially researched and developed by Pfizer, licenses within 2008 RaQualia Pharma (being detached from from Pfizer)
Cooperative development, licenses to CJ Health Care by RaQualia Pharma in 2014, finally by CJ Health Care in Korea Spro
State researches and develops successfully simultaneously list marketing.Tegoprazan be a kind of competitive potassium ion acid retarding agent (P-CAB) and hydrogen ion/potassium from
Son exchange ATP enzyme (H+/K+ATPase) inhibitor, the medicine are a completely new anti-for treating stomach oesophagus first in Korean market
The drug of stream disease and erosive esophagitis.
Stomach proton pump hydrogen ion/potassium ion exchange ATP enzyme is the main pharmacological target spot for treating gastric acid related disorder.Potassium competition
Property acid blocking agent (P-CAB), can by with K+Competitive binding H+/K+ATP enzyme carrys out gastric acid secretion inhibiting.Research is found
Tegoprazan is exactly the competitive sour blocking agent of such a potassium, it is considered to be treats gastroesophageal reflux disease at first at present
Into drug because proton pump inhibitor is the drug of most common treatment gastroesophageal reflux disease, and the lucky energy of Tegoprazan
The shortcomings that overcoming proton pump inhibitor.The validity of Tegoprazan and safety are based primarily upon two III clinical trial phases.Its
In one be double blind, the III phase of active control studies (NCT02456935), the research South Korea carry out, with 280 erosives
Esophagitis patient is research object, and the accumulation healing rate of the 8th week erosive esophagitis compares Tegoprazan as Primary Endpoint
With the safety and validity of proton pump inhibitor esomeprazole.An other III clinical trial phase is double blind, random, peace
Console agent check experiment (NCT02556021).The test carries out in 324 patients of South Korea, and Primary Endpoint is using reflux disease
Cardinal symptom (heartburn and reflux) patient's percentage for subsiding completely at questionnaire (RDQ) determine 4 weeks, to assess daily one
Safety and validity of the secondary Tegoprazan tablet (50mg and 100mg) in Non-erosive reflux disease patient.Batch of the medicine
Quasi- listing for the treatment of such disease provides new selection, and the shortcomings that compensate for other medicines to a certain degree, makes such
Disease can be treated preferably.
Entitled (the S) -4- of Tegoprazan chemistry ((5,7- difluoro chroman -4- base) oxygen)-N, N, 2- trimethyl -1H- benzo
[d] imidazoles -6- formamide, containing benzimidazole structure and 5,7- of chirality difluoro chroman -4- oxygroup structure in chemical structure, specifically
Chemical structure is as follows:
Patent CN101341149B discloses the preparation method of Tegoprazan, specially 4- hydroxy-n, N, 2- trimethyl-
1- [(4- tolyl) sulfonyl] -1H- benzimidazole -6- formamide and the fluoro- 3,4- dihydro -2H- chromogen alkene -4- of (S) -5,7- two
Under tributylphosphine/ADDP effect condensation reaction occurs for alcohol, and (-) -4- [(fluoro- 3,4-2H- chromogen of (4S) -5,7- bis- is prepared
Alkene -4- base) oxygroup]-N, N, 2- trimethyl -1- [(4- tolyl) sulfonyl] -1H- phenylimidazole -6- carboxamide intermediate, after
Person's deprotection base under alkali effect completes the preparation of Tegoprazan, and specific synthetic route is as follows:
Based on the description of above-mentioned patent, the preparation of Tegoprazan is mainly concerned with two segments, one of them is chirality
Fluorine alcohol segment, i.e. fluoro- 3, the 4- dihydro -2H- chromogen alkene -4- alcohol of (S) -5,7- bis-.CJ Health Care patent
CN101341149B and CN107849003A discloses the preparation side of the fluoro- 3,4- dihydro -2H- chromogen alkene -4- alcohol of (S) -5,7- two
Method, the method chiral purity poor (86%ee) of CN101341149B description is (although recrystallization can be improved product ee
Value, but recrystallize yield and only have 58%), CN107849003A is related to the chiral Ru reagent (price that commercialization is difficult to purchase
It is expensive), the method for patent CN101341149B and CN107849003A description is as follows:
The method for preparing the fluoro- 3,4- dihydro -2H- chromogen alkene -4- alcohol of (S) -5,7- two in view of presently disclosed two is all deposited
In certain defect, therefore develop new suitable industrialization, fluoro- 3, the 4- dihydro-of advantageous synthesis (S) -5, the 7- bis- of cost
The method of 2H- chromogen alkene -4- alcohol will make Tegoprazan with more the market competitiveness.
Summary of the invention
The new of the fluoro- 3,4- dihydro -2H- chromogen alkene -4- alcohol of (S) -5,7- two is prepared the purpose of the present invention is to provide a kind of
Method, it is intended to current original be avoided to grind the defect that chiral reagent is expensive, product chiral purity is low and yield is low in patent.Patent
CN101341149B and CN107849003A is before being used as hydrogenation using the fluoro- 2,3- dihydro -4H- chromogen alkene -4- ketone of 5,7- bis-
Body, although such substrate can reach certain asymmetric hydrogenation effect under special chiral reagent effect, due to
The oxa- ring of chromogen alkene does not have special rigidity also, so the ketone carbonyl for causing some conventional chiral reagents to induce is asymmetric
Reduction effect is poor.
Synthetic route of the invention is as follows:
The fluoro- 4H- benzopyran-4-one of starting material 5,7- bis- of the invention can pass through the fluoro- 2,3- dihydro-of 5,7- bis-
The oxidation of 4H- chromogen alkene -4- ketone obtains (ChemComm., 2016,52,14314-14317) or according to document
The similar approach of (Org.Lett., 2016,18,4986-4989) report is synthesized.
The reaction first step is related to the fluoro- 4H- benzopyran-4-one of 5,7- bis- and uses borine-diformazan in the presence of chiral reagent
Thioether complex compound carries out asymmetric reduction to ketone carbonyl, obtains the fluoro- 4H- chromene -4- alcohol of (S) -5,7- bis- with high selectivity.
The chiral reagent that the reaction first step uses includes (S)-tetrahydro -1- methyl -, 3,3- diphenyl -1H, 3H- pyrrolo-
[1,2-c] [1,3,2] oxazaborolidine, (S)-tetrahydro -1,3,3- triphenyl -1H, 3H- pyrrolo- [1,2-c] [1,3,2] oxazole boron
Alkane.
Reaction second step is related to the fluoro- 4H- chromene -4- alcohol of (S) -5,7- two and carries out hydrogen in the presence of catalysts and solvents
Change reaction, obtains fluoro- 3, the 4- dihydro -2H- chromogen alkene -4- alcohol of (S) -5,7- bis-.
Reaction second step be using catalyst include Pd/C, Pd (OH)2。
The solvent that reaction second step uses includes methanol, ethyl alcohol.
The starting material synthetic method that the present invention uses is simple, and the reagent used is easy to purchase, and technological operation is simple, chiral
Selectivity is high, is suitble to the industrialization preparation of fluoro- 3, the 4- dihydro -2H- chromogen alkene -4- alcohol of (S) -5,7- bis-.
Specific embodiment
Following exemplary embodiments are used to illustrate that the present invention, technical staff in the art are simply replaced to what the present invention was done
It changes and improves etc. and belong within the technical solution that the present invention is protected.
Embodiment one: the preparation of the fluoro- 4H- chromene -4- alcohol of (S) -5,7- two
Anhydrous THF (400mL) and (S)-tetrahydro -1- methyl -, 3,3- hexichol is added under nitrogen protection into the reaction flask of 3L
The toluene solution (1M in Toluene, 55mL, 55mmol) of base -1H, 3H- pyrrolo- [1,2-c] [1,3,2] oxazaborolidine.Add
System ice salt bath is cooled to 0 ± 2 DEG C after entering, then into system be added borane dimethylsulfide ether complexes (1M in THF,
575mL, 0.575mol), be added after 0 ± 2 DEG C of stirring 10min of system the fluoro- 4H- benzopyran-4-one of 5,7- bis- (100g,
THF (500mL) solution 0.549mol), 0 ± 2 DEG C of adition process maintenance system reaction temperature, after addition system react to
The fluoro- 4H- benzopyran-4-one of TLC tracking initiation material 5,7- bis- disappears.After completion of the reaction, system is added MeOH (200mL) and quenches
It goes out, system warms naturally to room temperature and is vigorously stirred 1 hour.High vacuum removes the organic solvent of system, residue silica gel column chromatography
Purifying (normal heptane/EA=5:1) purifies the fluoro- 4H- chromene -4- alcohol (83.9g, 83%, 98.5%ee) of (S) -5,7- two.
Embodiment two: the preparation of the fluoro- 4H- chromene -4- alcohol of (S) -5,7- two
Anhydrous THF (80mL) and (S)-tetrahydro -1,3,3- triphenyl-is added under nitrogen protection into the reaction flask of 500mL
The toluene solution (1M in Toluene, 11.0mL, 11.0mmol) of 1H, 3H- pyrrolo- [1,2-c] [1,3,2] oxazaborolidine.
System ice salt bath is cooled to 0 ± 2 DEG C after addition, and borane dimethylsulfide ether complexes (1M in is then added into system
THF,121mL,121mmol).After 0 ± 2 DEG C of stirring 10min of system be added the fluoro- 4H- benzopyran-4-one of 5,7- bis- (20.0g,
THF (100mL) solution 109.8mmol), 0 ± 2 DEG C of adition process maintenance system reaction temperature, system is reacted after addition
It disappears to the TLC tracking fluoro- 4H- benzopyran-4-one of material 5,7- bis-.After completion of the reaction, system is added MeOH (50mL) and is quenched,
System warms naturally to room temperature and is vigorously stirred 1 hour.High vacuum removes the organic solvent of system, the purifying of residue silica gel column chromatography
(normal heptane/EA=5:1) purifies the fluoro- 4H- chromene -4- alcohol (17.7g, 87.6%, 99.1%ee) of (S) -5,7- two.
Embodiment three: the preparation of the fluoro- 3,4- dihydro -2H- chromogen alkene -4- alcohol of (S) -5,7- two
The fluoro- 4H- chromene -4- alcohol (5.0g, 27.15mmol) of (S) -5,7- two and ethyl alcohol are added into reaction flask
(100mL), system stirring, is then added 5%Pd/C (water content 65%, 5.8g) under nitrogen protection.System nitrogen after addition
Gas is replaced three times, and then room temperature normal pressure hydrogenation to HPLC tracking reaction raw materials disappears.Filtering, high vacuum removes organic solvent, residual
Excess column chromatographic purifying (normal heptane/EA=5:1) the fluoro- 3,4- dihydro -2H- chromogen alkene -4- alcohol of (S) -5,7- two (4.65g,
92%).
Claims (5)
1. the method for preparing the fluoro- 3,4- dihydro -2H- chromogen alkene -4- alcohol of (S) -5,7- two, reaction equation are as follows:
2. the preparation method with the fluoro- 4H- chromene -4- alcohol of (S) -5,7- bis- as shown in claim 1, it is characterised in that
The fluoro- 4H- benzopyran-4-one of 5,7- bis- carries out ketone carbonyl using borane methyl sulfide ether complexes in the presence of chiral reagent
Asymmetric reduction obtains the fluoro- 4H- chromene -4- alcohol of (S) -5,7- bis- with high selectivity.
3. in claim 2, reacting the chiral reagent used is (S)-tetrahydro -1- methyl -3,3- diphenyl -1H, 3H- pyrrolo-
[1,2-c] [1,3,2] oxazaborolidine, (S)-tetrahydro -1,3,3- triphenyl -1H, 3H- pyrrolo- [1,2-c] [1,3,2] oxazole boron
Alkane.
4. the preparation method with fluoro- 3, the 4- dihydro -2H- chromogen alkene -4- alcohol of (S) -5,7- bis- as shown in claim 1,
It is characterized in that carrying out hydrogenation to the fluoro- 4H- chromene -4- alcohol of (S) -5,7- bis- in the presence of catalysts and solvents, obtain
(S) the fluoro- 3,4- dihydro -2H- chromogen alkene -4- alcohol of -5,7- two.
5. in claim 4, reacting the catalyst used includes Pd/C, Pd (OH)2, reacting the solvent used includes methanol, second
Alcohol.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811461589.XA CN109320485B (en) | 2018-12-02 | 2018-12-02 | Method for synthesizing Tegolazan chiral alcohol |
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| CN201811461589.XA CN109320485B (en) | 2018-12-02 | 2018-12-02 | Method for synthesizing Tegolazan chiral alcohol |
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| CN109320485B CN109320485B (en) | 2021-06-18 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112851646A (en) * | 2019-11-12 | 2021-05-28 | 中国医学科学院药物研究所 | Preparation method of Tegolrazan |
| CN115209875A (en) * | 2020-02-27 | 2022-10-18 | 怡诺安有限公司 | Pharmaceutical composition for oral administration |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101341149A (en) * | 2005-12-19 | 2009-01-07 | 辉瑞大药厂 | Chromane substituted benzimidazoles and their use as acid pump inhibitors |
-
2018
- 2018-12-02 CN CN201811461589.XA patent/CN109320485B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
|---|
| E. A. VOIGHT ET AL.: "Efficient and general asymmetric syntheses of (R)-chroman-4-amine salts", 《TETRAHEDRON LETTERS》 * |
| GEORGE J. Q.,ET AL: "Enantioselective Oxazaborolidine Reduction of Ketones Containing Heteroatoms", 《TETRAHEDRON LETTERS》 * |
| NICOLE HOLUB,ET AL: "Total Synthesis of (+)-trans-195A", 《ORG. LETT.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112851646A (en) * | 2019-11-12 | 2021-05-28 | 中国医学科学院药物研究所 | Preparation method of Tegolrazan |
| 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 |
| CN115209875A (en) * | 2020-02-27 | 2022-10-18 | 怡诺安有限公司 | Pharmaceutical composition for oral administration |
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| CN109320485B (en) | 2021-06-18 |
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Address after: 226123 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Applicant after: Jiangsu Huiju Pharmaceutical Co.,Ltd. Address before: 226123 No. 18 Qinghua Road, three Factory Street, Haimen City, Nantong, Jiangsu Applicant before: WISDOM PHARMACEUTICAL Co.,Ltd. |
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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. |