CN108794451A - A kind of synthesis of chiral Iprazole method - Google Patents
A kind of synthesis of chiral Iprazole method Download PDFInfo
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- CN108794451A CN108794451A CN201710283548.5A CN201710283548A CN108794451A CN 108794451 A CN108794451 A CN 108794451A CN 201710283548 A CN201710283548 A CN 201710283548A CN 108794451 A CN108794451 A CN 108794451A
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- chiral
- iprazole
- synthesis
- molybdate
- thioether
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- UZPBWOXACJHIMZ-UHFFFAOYSA-N Cc1c(C[S@@](c2nc3cc(-[n]4cccc4)ccc3[nH]2)=[U])nccc1OC Chemical compound Cc1c(C[S@@](c2nc3cc(-[n]4cccc4)ccc3[nH]2)=[U])nccc1OC UZPBWOXACJHIMZ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
A kind of synthesis of chiral Iprazole method, the invention belongs to pharmaceutical technology fields.Report very few about Iprazole chipal compounds at present.The method of the present invention：Under nitrogen protection; phase transfer catalyst and isopropyl ether are sequentially added into thioether; then central metal is added, adds oxidant, after being reacted 8 hours under the conditions of 0 DEG C; it is quenched with sodium sulfite aqueous solution; then liquid separation, organic phase precipitation use ethyl alcohol recrystallization; white crystal is obtained, chiral Iprazole is obtained.The present invention can be used for the study of pharmacy of chiral Iprazole to industrial production.With the features such as new technology, step is few, and reaction condition is mild.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of new technology route of optical activity Iprazole.
Background technology
Iprazole is a kind of proton pump inhibitor of Li Zhu groups exploitation listing, and it is new to belong to 1 class for trade name " one beautiful peace "
Medicine, for treating duodenal ulcer.
Other proton pump inhibitor types of drug, as Omeprazole, Lansoprazole, Pantoprazole and Rabeprazole have
Corresponding single chiral compound listing, the entitled esomeprazole of difference, R-lansoprazole, left Pantoprazole and right Lei Beila
Azoles.However Iprazole is used for medicine with racemate form at present, and its single chiral compound form is there is not yet report.
When a chipal compounds enter life entity, its two enantiomters would generally show different biologies
Activity.For chiral drug, an isomers may be effective, and another isomers may be invalid even harmful
, if world-shaking " reaction stops event " is caused by ignoring the difference of enantiomter.Take the hand of enantiomer-pure
Property drug can not only exclude the toxic side effect caused by invalid (bad) enantiomer, moreover it is possible to reduce pharmaceutical quantities and human body pair
The metabolism burden of invalid enantiomer, has better control to pharmacokinetics and dosage, improves the specificity of drug.Therefore, it opens
It sends out and the Iprazole for studying Chiral forms has very great significance for the health tool for improving duodenal ulcer patients.
At present in the production technology of esomeprazole, R-lansoprazole, left Pantoprazole and right Rabeprazole, mainly by
Under Sharpless oxidizing conditions, is prepared at chiral sulfoxide by sulfide oxidation, also there is resolution process report.However, resolution process is wanted
Waste at least half of raw material；The oxidation reaction of titanium catalysis needs the last one chemical step in technique to use metal, control
Metal residual processed is more difficult, and oxidation step by-product is more, it is difficult to isolate and purify.
In conclusion Iprazole does not have chipal compounds report, and other existing proton pump inhibitor classes at present
There is certain defect in the fractionation scheme of type compound, develop the new method of chiral Iprazole, in terms of existing process exploitation
Meaning more has the meaning in terms of new drug research.
Invention content
A kind of method of organic catalysis synthesis of chiral Iprazole of the present invention, which is characterized in that with achirality sulfoxide as
Key intermediate occurs substitution reaction, obtains chiral Iprazole by the effect of chiral biguanides catalyst.Specifically include with
Lower reaction step：
(1) synthesis of chiral Iprazole：
Using corresponding thioether as raw material, the metal centered on tungstates or molybdate, with chiral bicyclic guanidine salt or
Person's chiral quaternary ammonium salt, as oxidant, can be synthesized as phase transfer catalyst, hydrogen peroxide or other water-soluble peroxides
Chiral Iprazole.
A kind of the step of synthesis of chiral Iprazole method, is as follows：
Under nitrogen protection, phase transfer catalyst and isopropyl ether are sequentially added into thioether, and central metal is then added, then
Oxidant is added to be quenched with sodium sulfite aqueous solution, liquid separation after reacting 8 hours under the conditions of 0 DEG C, then organic phase precipitation is used
Ethyl alcohol recrystallization obtains white crystal, obtains chiral Iprazole.
Phase transfer catalyst is chiral Guanoctine or chiral quaternary ammonium salt.The structural formula of phase transfer catalyst is：
Ar groups are phenyl, p-methylphenyl, 3,5- 3,5-dimethylphenyls, p-methoxyphenyl, 3,5- di-t-butyl base benzene
Base, 1- naphthalenes, 2- naphthalenes, R group be benzyl, to methylbenzyl, 3,5- dimethyl benzyls, to methoxy-benzyl, 3,5-, bis- uncles
Butyl benzyl, 1- naphthals, 2- naphthals, tertiary butyl, isopropyl.
Central metal is tungstates and its hydrate or molybdate and its hydrate；Tungstates is sodium tungstate, potassium tungstate,
Tungstate lithium, wolframic acid caesium, one kind in wolframic acid silver；Molybdate is sodium molybdate, potassium molybdate, lithium molybdate, cesium molybdate, one in silver molybdate
Kind.
Oxidant is water-soluble peroxide；Such as hydrogen peroxide, sodium peroxydisulfate, ammonium persulfate, Peracetic acid, the tertiary fourth of peroxide
Alcohol or cumyl hydroperoxide.
The present invention solves the composition problem of chiral Iprazole, can be used for the study of pharmacy of chiral Iprazole to industry
Production.With the features such as new technology, step is few, and reaction condition is mild.
Specific implementation mode
Embodiment 1
1. the synthesis of chiral Iprazole
A 100mL three-neck flask is taken, sequentially adds thioether (10mmol) thereto under nitrogen protection, Guanoctine phase turns
Shifting catalyst A (0.1mmol) and isopropyl ether (40mL).Then sodium tungstate (0.2mmol) is added, adds peroxide acetate aqueous solution
(12mmol).After being reacted 8 hours at 0 degree, it is quenched with sodium sulfite aqueous solution, liquid separation.Then organic phase precipitation is tied again with ethyl alcohol
Crystalline substance, obtains white crystal, 90% total recovery, and 99%ee values are left-handed.
Catalyst A structures and product structure are as follows：
Embodiment 2
1. the synthesis of chiral Iprazole
A 100mL three-neck flask is taken, sequentially adds thioether (10mmol) thereto under nitrogen protection, Guanoctine phase turns
Shifting catalyst B (0.1mmol) and isopropyl ether (40mL).Then sodium molybdate (0.2mmol) is added, adds aqueous hydrogen peroxide solution
(12mmol).After being reacted 8 hours at 0 degree, it is quenched with sodium sulfite aqueous solution, liquid separation.Then organic phase precipitation is tied again with ethyl alcohol
Crystalline substance obtains white crystal, 90% total recovery, 99%ee values, dextrorotation.
Catalyst A structures are as follows：
Claims (9)
1. a kind of synthesis of chiral Iprazole method, it is characterised in that the synthetic method carries out in the steps below：
Under nitrogen protection, phase transfer catalyst and isopropyl ether are sequentially added into thioether, central metal is then added, and are added
Oxidant is quenched, liquid separation after being reacted 8 hours under the conditions of 0 DEG C with sodium sulfite aqueous solution, then organic phase precipitation uses ethyl alcohol
Recrystallization, obtains white crystal, obtains chiral Iprazole.
2. a kind of synthesis of chiral Iprazole method according to claim 1, it is characterised in that the thioether and phase transfer
The molar ratio of catalyst is 100：1 thioether mole is 10mmol with the volume ratio of isopropyl ether：40mL, thioether and central metal
Molar ratio is 100：2, the molar ratio of thioether and oxidant is 10：12.
3. a kind of synthesis of chiral Iprazole method according to claim 1, it is characterised in that phase transfer catalyst is hand
Property Guanoctine or chiral quaternary ammonium salt.
4. a kind of synthesis of chiral Iprazole method according to claim 1, it is characterised in that the knot of phase transfer catalyst
Structure formula is：
Ar groups are phenyl, p-methylphenyl, 3,5- 3,5-dimethylphenyls, p-methoxyphenyl, 3,5- di-t-butyl bases phenyl, 1-
Naphthalene, 2- naphthalenes, R group be benzyl, to methylbenzyl, 3,5- dimethyl benzyls, to methoxy-benzyl, 3,5- di-t-butyl benzyls
Base, 1- naphthals, 2- naphthals, tertiary butyl, isopropyl.
5. a kind of synthesis of chiral Iprazole method according to claim 1, it is characterised in that central metal is tungstates
And its hydrate or molybdate and its hydrate.
6. a kind of synthesis of chiral Iprazole method according to claim 5, it is characterised in that tungstates is sodium tungstate, tungsten
Sour potassium, tungstate lithium, wolframic acid caesium, one kind in wolframic acid silver.
7. a kind of synthesis of chiral Iprazole method according to claim 5, it is characterised in that molybdate is sodium molybdate, molybdenum
Sour potassium, lithium molybdate, cesium molybdate, one kind in silver molybdate.
8. a kind of synthesis of chiral Iprazole method according to claim 1, it is characterised in that oxidant is water-soluble mistake
Oxide.
9. a kind of synthesis of chiral Iprazole method according to claim 8, it is characterised in that the Watersoluble peroxygen
Object is hydrogen peroxide, sodium peroxydisulfate, ammonium persulfate, Peracetic acid, tert-Butanol peroxide or cumyl hydroperoxide.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710283548.5A CN108794451A (en) | 2017-04-26 | 2017-04-26 | A kind of synthesis of chiral Iprazole method |
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| CN201710283548.5A CN108794451A (en) | 2017-04-26 | 2017-04-26 | A kind of synthesis of chiral Iprazole method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110128412A (en) * | 2019-06-21 | 2019-08-16 | 丽珠医药集团股份有限公司 | The preparation method of dextrorotation Iprazole sylvite mother liquor, dextrorotation Iprazole and preparation method thereof |
| CN113185500A (en) * | 2021-04-30 | 2021-07-30 | 中新国际联合研究院 | Industrial synthesis method of modified chiral biguanide phase transfer catalyst |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098867A (en) * | 2005-03-25 | 2008-01-02 | 丽珠医药集团股份有限公司 | Substituted sulfoxide compound and its preparing method and application |
| WO2009061529A1 (en) * | 2007-11-06 | 2009-05-14 | Tap Pharmaceutical Products, Inc. | (+)-enantiomer of 5-pyrrolyl-2-pyridylmethylsulfinyl benzimidazole and processing method eor preparing the same |
-
2017
- 2017-04-26 CN CN201710283548.5A patent/CN108794451A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098867A (en) * | 2005-03-25 | 2008-01-02 | 丽珠医药集团股份有限公司 | Substituted sulfoxide compound and its preparing method and application |
| WO2009061529A1 (en) * | 2007-11-06 | 2009-05-14 | Tap Pharmaceutical Products, Inc. | (+)-enantiomer of 5-pyrrolyl-2-pyridylmethylsulfinyl benzimidazole and processing method eor preparing the same |
Non-Patent Citations (2)
| Title |
|---|
| LILI ZONG ET AL.: "Bisguanidinium dinuclear oxodiperoxomolybdosulfate ion pair-catalyzed enantioselective sulfoxidation", 《NATURE COMMUNICATIONS》 * |
| XINYI YE ET AL.: "Enantioselective Sulfoxidation Catalyzed by a Bisguanidinium Diphosphatobisperoxotungstate Ion Pair", 《ANGEW. CHEM. INT. ED.》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110128412A (en) * | 2019-06-21 | 2019-08-16 | 丽珠医药集团股份有限公司 | The preparation method of dextrorotation Iprazole sylvite mother liquor, dextrorotation Iprazole and preparation method thereof |
| CN110128412B (en) * | 2019-06-21 | 2020-03-31 | 丽珠医药集团股份有限公司 | Preparation method of dextro-ilaprazole potassium salt mother liquor, dextro-ilaprazole and preparation method thereof |
| CN113185500A (en) * | 2021-04-30 | 2021-07-30 | 中新国际联合研究院 | Industrial synthesis method of modified chiral biguanide phase transfer catalyst |
| CN113185500B (en) * | 2021-04-30 | 2023-01-17 | 中新国际联合研究院 | Industrial synthesis method of modified chiral biguanide phase transfer catalyst |
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