CN107849003A - Prepare the new method of chromanol derivative - Google Patents
Prepare the new method of chromanol derivative Download PDFInfo
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- CN107849003A CN107849003A CN201680044642.9A CN201680044642A CN107849003A CN 107849003 A CN107849003 A CN 107849003A CN 201680044642 A CN201680044642 A CN 201680044642A CN 107849003 A CN107849003 A CN 107849003A
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/46—Ruthenium, rhodium, osmium or iridium
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
Abstract
The present invention relates to a kind of new method for preparing chromanol derivative.Different from conventionally known optical activity reduction technique, the method with optically active chromanol derivative of the present invention for preparing has the advantage that：Because chromanol to be prepared shows high-optical-purity, therefore extra purifying technique is not needed；Due to the reaction condition without harshness and without using the reagent of danger, therefore be advantageous to produce in batches；And prepare yield with excellent.
Description
This application claims the korean patent application No.10-2015- submitted in Korean Intellectual Property Office on the 4th of August in 2015
0110248 priority, the entire disclosure are incorporated herein by reference.
Technical field
The present invention relates to a kind of new method for preparing the chromanol derivative with chiral acti ve.
Background technology
In pharmacy and chemical field, chiral chromanol derivative compound (chiral chromanol
Derivatives compound) be it is a kind of there are various active materials, and have in the pharmaceuticals being currently being deployed
Largely there is the compound of chiral chromanol structure.However, the even if identical chromanol derivative with identical molecular formula
Compound, its drug effect also change because of three-dimensional structure.Therefore the stereoselective syntheses of chiral chromanol derivative compound
It is extremely important in medical science and organic synthesis.However, even if the importance of chiral chromanol derivative compound is very high, synthesis
The straightforward procedure of chiral chromanol derivative compound is not also fully reported.
International publication WO 2007/072146 is disclosed one kind and is used as by using 5,7- difluoro chromogen alkane -4- ketone
The method that beginning raw material prepares 5,7- difluoro chromogen alkane -4- alcohol.However, the method disclosed in text disclosed above is pointed out, first
There is 86%ee low chiral stereoselectivity in crystallization process, and purge process for increase chiral stereoselectivity be must
Need.For these reasons, although the production cost of the method disclosed in text disclosed above is high and in the presence of additional purifying
Process, but yield is also very low, is 58%.It is additionally, since it and silica gel column chromatography, the party is used in first time Purify
Method is not suitable for mass producing.
Therefore, the very important pharmacophore in medical science and chemical field is acknowledged as one kind, there is chiral acti ve
Chromanol derivative need a kind of new preparation method, for its high chiral purity and the industrialized mass production of high yield
In.
[prior art]
[patent document]
WO2007/072146
The content of the invention
Technical problem
The invention provides a kind of method for preparing chromanol derivative, because its chiral purity is high, it is not necessary to extra
Purifying technique, without using hazardous agents in preparation process, and good yields.
Technical scheme
The invention provides a kind of method for preparing compound shown in formula I, it includes：
By the way that the compound as shown in Formula II is carried out into chiral reduction in the presence of the catalyst as shown in formula III or IV
Reaction, prepares compound shown in formula I：
[Formulas I]
[Formula II]
[formula III]
[formula IV]
* represents chiral centre in Formulas I.
The preparation method of the present invention is advantageous to mass produce, and has excellent yield, because, different from known
Chiral acti ve reduction technique, high chiral purity is shown by the chromanol that is prepared of method of the present invention, so as to it not
Extra purification process is needed, the reaction condition not comprising harshness, also without using hazardous agents.
The preparation of compound shown in formula I is to carry out chiral reduction by using the catalyst as shown in formula III or IV
Reaction, i.e., by the way that the compound as shown in Formula II is reacted in the presence of the catalyst as shown in formula III or IV with hydrogen donor
Optionally to prepare the compound shown in formula I with chiral acti ve.
Now, the reaction mol ratio between the compound as shown in Formula II and the catalyst as shown in formula III or IV can be with
It is 1:0.0001~1:0.1, can be preferably 0.005~0.001.
In the present invention, the reaction dissolvent for preparing the compound shown in formula I can be extensive in this area
The organic solvent used.For example, the reaction dissolvent can be halogenated hydrocarbon such as dichloromethane, chloroform and 1,2- dichloroethanes；
Ethers such as ether, diisopropyl ether, tetrahydrofuran and dioxane；Aromatic hydrocarbons such as benzene, toluene and nitrobenzene；Sulfoxide type such as dimethyl
Sulfoxide；Benzamide type such as dimethylformamide；Alcohols such as methanol, ethanol, 2- propyl alcohol and butanol；Or its mixed solvent, but it is unlimited
In this.In the present invention, make extensively for preparing the reaction dissolvent of the compound shown in formula I and being preferably in this area
Non-polar organic solvent, it is more preferably tetrahydrofuran.
The hydrogen donor of the present invention can be selected from formic acid, dithiocarbamates, formic acid ammonium salt and the mixture of formic acid and amine.Compared with
Goodly, the hydrogen donor can be the mixture of formic acid and amine, and more preferably, hydrogen donor can be triethylamine (TEA) and formic acid, or
Diisopropylethylamine (DIPEA) and formic acid.
In the preparation of compound shown in formula I, the compound as shown in Formula II is in the catalysis as shown in formula III or IV
Chiral reduction reaction in the presence of agent can be carried out at 25 DEG C~80 DEG C, preferably 30 DEG C to 50 DEG C.If temperature is less than
Said temperature, reaction time can excessively extend, if temperature is higher than said temperature, chiral purity will be reduced excessively.Therefore, this
By unsuitable industrial production.
The preparation of compound shown in formula I can further include the step of being crystallized by recrystallisation solvent.Institute
The crystallization that recrystallisation solvent is used for the compound is stated, it can use C6-7Aliphatic hydrocarbon such as hexane and heptane, ethers such as diethyl ether and
Diisopropyl ether, or its mixed solvent.It is preferred that the recrystallisation solvent can use C6-7Aliphatic hydrocarbon such as hexane and heptane.
The invention provides a kind of method for preparing compound shown in formula I, it includes：
By the way that the compound as shown in Formula II is carried out in the presence of the catalyst as shown in formula III or IV with hydrogen donor
Reaction, prepares compound shown in formula I：
[Formulas I]
[Formula II]
[formula III]
[formula IV]
* represents chiral centre in Formulas I.
According to an aspect of the present invention, the invention provides a kind of method for preparing the compound as shown in Formulas I -1, institute
The method of stating includes, by the way that the compound as shown in Formula II is carried out in the presence of the catalyst as shown in formula III
Chiral reduction reacts, and prepares the compound as shown in Formulas I -1.
[Formulas I -1] (R) -5,7- difluoro chromogen alkane -4- alcohol
According to another aspect of the present invention, the invention provides a kind of method for preparing the compound as shown in Formulas I -2,
Methods described includes, by the way that the compound as shown in Formula II is carried out in the presence of the catalyst as shown in formula IV
Chiral reduction reacts, and prepares the compound as shown in Formulas I -2.
[Formulas I -2] (S) -5,7- difluoro chromogen alkane -4- alcohol
As described above, have high chiral active chromanol compound can be according to this hair as shown in Formulas I -1 or I-2
Bright disclosed method, with hydrogen donor by the compound hand as shown in Formula II in the presence of the catalyst as shown in formula III or IV
Property was also prepared originally.
For example, the method for the compound of preparation of the present invention shown in formula I can be represented by formulas below I.
[reaction equation I]
As shown in reaction equation I, compound shown in formula I can by by the compound shown in Formula II in organic solvent
Reacted with the hydrogen donor in the presence of the ruthenium catalyst as shown in formula III or IV to prepare.
According to an aspect of the present invention, the compound as shown in Formulas I -1 can be by by the compound as shown in Formula II
Reacted with hydrogen donor in the presence of the ruthenium catalyst as shown in formula III to prepare, as shown in formulas below I-1.
[reaction scheme I-1]
According to another aspect of the present invention, the compound as shown in Formulas I -2 can be by by the chemical combination as shown in Formula II
Thing is reacted to prepare with hydrogen donor in the presence of the catalyst as shown in formula IV, as shown in formulas below I-2.
[reaction scheme I-2]
Beneficial effect
It is of the present invention to prepare the chromanol derivative with chiral acti ve different from former chiral reduction technology
Method, because the chromanol of preparation shows high-optical-purity, therefore extra purifying technique is not needed, not comprising harshness
Reaction condition and without using the reagent of danger, therefore be advantageous to mass produce, and there is excellent yield.
In addition, the final product prepared according to methods described can be used for preparation another kind to have chiral chromanol structure
Compound, it especially can be used as preparing the intermediate for the compound that can be used as antimicrobial, antiulcer agent and antiinflammatory.
Embodiment
The present invention is more fully described below below according to appended embodiment and EXPERIMENTAL EXAMPLE.However, the present invention can be with
Many different forms are implemented, and should not limit the present invention among embodiments described herein scope.
Unless otherwise indicated, reagent as disclosed below and solvent are purchased from Sigma Aldrich.1H-NMR passes through
Bruker NMR 270MHz are measured, and chiral acti ve is measured by Rudolph research analytical autoV.
Embodiment 1：(R) preparation of -5,7- difluoros chromogen alkane -4- alcohol
30g triethylamines are put into reactor, are cooled to -10 DEG C.27g first is slowly added at a temperature of less than 10 DEG C
Acid.56mg ruthenium catalysts RuCl (p-cymene) [(R, R)-Ts-DPEN] is added in reactor.By 33g 5,7- difluoro colors
Former alkane -4- ketone is dissolved in 87g tetrahydrofurans, is added at a temperature of less than 10 DEG C in reactor.Reaction temperature rises to 40 DEG C.Instead
Room temperature is cooled to after should terminating, lower addition 293g ethyl acetate and 163g pure water is stirred, separates organic layer.In the temperature less than 40 DEG C
It is concentrated under reduced pressure under degree, adds 222g heptane, stirred at 25 DEG C, filter the solid of generation.Then it is dried in vacuo, obtains at 40 DEG C
(R) -5,7- difluoro chromogen alkane -4- alcohol (30g, 91% and 100%ee).
1H-NMR(270MHz,CDCl3)δ:6.47-6.36(m,2H),5.05-4.97(m,1H),4.36-4.20(m,2H),
2.16-1.92(m,3H)ppm
Chiral optical activity：[α]D 24=+143.6 ° (c=1.00, methanol)
Embodiment 2：(S) preparation of -5,7- difluoros chromogen alkane -4- alcohol
30g triethylamines are put into reactor, are cooled to -10 DEG C.27g first is slowly added at a temperature of less than 10 DEG C
Acid.56mg ruthenium catalysts RuCl (p-cymene) [(S, S)-Ts-DPEN] is added in reactor.By 33g 5,7- difluoro colors
Former alkane -4- ketone is dissolved in 87g tetrahydrofurans, is added at a temperature of less than 10 DEG C in reactor.Reaction temperature rises to 40 DEG C.Instead
Room temperature is cooled to after should terminating, lower addition 293g ethyl acetate and 163g pure water is stirred, separates organic layer.In the temperature less than 40 DEG C
It is concentrated under reduced pressure under degree, adds 222g heptane, stirred at 25 DEG C, filter the solid of generation.Then it is dried in vacuo, obtains at 40 DEG C
(S) -5,7- difluoro chromogen alkane -4- alcohol (28g, 85% and 100%ee).
1H-NMR：Spectrum data is identical with the data of (R) -5,7- difluoro chromogen alkane -4- alcohol (i.e. embodiment 1).
Chiral optical activity：[α]D 24=+143.6 ° (c=1.00, methanol).
Claims (9)
1. a kind of method for preparing compound shown in formula I, it includes：
It is anti-by the way that the compound as shown in Formula II to be carried out to chiral reduction in the presence of the catalyst as shown in formula III or IV
Should, prepare compound shown in formula I：
[Formulas I]
[Formula II]
[formula III]
[formula IV]
* represents chiral centre in Formulas I.
2. the method as described in claim 1, it is characterised in that methods described includes：Existed by compound shown in the Formula II
Chiral reduction reaction is carried out in the presence of catalyst shown in the formula III, prepares the compound as shown in Formulas I -1：
[Formulas I -1]
3. the method as described in claim 1, it is characterised in that methods described includes：By by the change as shown in Formula II
Compound chiral reduction reaction as described in progress in the presence of the catalyst shown in formula IV, prepares the change as shown in Formulas I -2
Compound：
[Formulas I -2]
4. the method as described in any one of claims 1 to 3, it is characterised in that the compound as shown in Formula II and described
Catalyst reaction mol ratio be 1:0.0001~1:0.1.
5. the method as described in any one of claims 1 to 3, it is characterised in that it further comprises passing through C6-7Aliphatic hydrocarbon,
The crystallisation step that ethers or its mixed solvent are carried out.
6. the method as described in any one of claims 1 to 3, it is characterised in that the chiral reduction reaction uses a hydrogen donor
Carry out, wherein any of the hydrogen donor in formic acid, dithiocarbamates, formic acid ammonium salt and the mixture of formic acid and amine
Kind.
7. method as claimed in claim 6, it is characterised in that the hydrogen donor is formic acid and triethylamine.
8. the method as described in any one of claims 1 to 3, it is characterised in that the compound as shown in Formula II is described
The chiral reduction reaction carried out in the presence of catalyst as shown in formula III or IV is carried out at 25 DEG C~80 DEG C.
9. the method as described in any one of claims 1 to 3, it is characterised in that the compound as shown in Formula II is described
The chiral reduction reaction carried out in the presence of catalyst as shown in formula III or IV is carried out in presence of organic solvent.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020150110248A KR101769204B1 (en) | 2015-08-04 | 2015-08-04 | New method for preparation of chiral chromanol derivatives |
| KR10-2015-0110248 | 2015-08-04 | ||
| PCT/KR2016/008580 WO2017023124A1 (en) | 2015-08-04 | 2016-08-03 | Novel method for preparing chromanol derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107849003A true CN107849003A (en) | 2018-03-27 |
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ID=57943342
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201680044642.9A Pending CN107849003A (en) | 2015-08-04 | 2016-08-03 | Prepare the new method of chromanol derivative |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP6676146B2 (en) |
| KR (1) | KR101769204B1 (en) |
| CN (1) | CN107849003A (en) |
| WO (1) | WO2017023124A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113237970A (en) * | 2021-04-23 | 2021-08-10 | 上海应用技术大学 | High performance liquid chromatography separation method of R, S isomer of 5,7-difluorochroman-4-ol |
| CN114222734A (en) * | 2020-07-20 | 2022-03-22 | 杭州杜易科技有限公司 | Method for preparing substituted chromanone derivative |
Citations (4)
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| CN1926083A (en) * | 2004-03-29 | 2007-03-07 | 财团法人名古屋产业科学研究所 | Manufacturing method of optical activity alcohol |
| CN1968927A (en) * | 2004-06-22 | 2007-05-23 | 诺瓦提斯公司 | Enantioselektive preparation of quinoline derivative |
| WO2007072146A1 (en) * | 2005-12-19 | 2007-06-28 | Pfizer Japan Inc. | Chromane substituted benzimidazoles and their use as acid pump inhibitors |
| KR20080108129A (en) * | 2006-03-17 | 2008-12-11 | 라퀄리아 파마 인코포레이티드 | Chromane derivatives |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR101130465B1 (en) | 2005-12-30 | 2012-03-27 | 엘지전자 주식회사 | Overheating prevention apparatus for scroll compressor |
| WO2008059373A1 (en) * | 2006-11-17 | 2008-05-22 | Raqualia Pharma Inc. | Imidazo [1, 2-a] pyrazine derivatives and their use as acid pump antagonists |
| WO2008151927A2 (en) * | 2007-06-15 | 2008-12-18 | Nycomed Gmbh | 6-n-substituted benz imidazole derivatives as acid pump antagonists |
| AR082472A1 (en) * | 2010-08-04 | 2012-12-12 | Janssen Pharmaceutica Nv | COMPOUNDS WITH ANTIBACTERIAL ACTIVITY AGAINST CLOSTRIDIUM |
-
2015
- 2015-08-04 KR KR1020150110248A patent/KR101769204B1/en active IP Right Grant
-
2016
- 2016-08-03 CN CN201680044642.9A patent/CN107849003A/en active Pending
- 2016-08-03 JP JP2018505683A patent/JP6676146B2/en active Active
- 2016-08-03 WO PCT/KR2016/008580 patent/WO2017023124A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1926083A (en) * | 2004-03-29 | 2007-03-07 | 财团法人名古屋产业科学研究所 | Manufacturing method of optical activity alcohol |
| CN1968927A (en) * | 2004-06-22 | 2007-05-23 | 诺瓦提斯公司 | Enantioselektive preparation of quinoline derivative |
| WO2007072146A1 (en) * | 2005-12-19 | 2007-06-28 | Pfizer Japan Inc. | Chromane substituted benzimidazoles and their use as acid pump inhibitors |
| KR20080108129A (en) * | 2006-03-17 | 2008-12-11 | 라퀄리아 파마 인코포레이티드 | Chromane derivatives |
Non-Patent Citations (1)
| Title |
|---|
| ROSARIO FERNÁNDEZ ET AL.: "Enantioselective synthesis of cis-a-substituted cycloalkanols and trans-cycloalkyl amines thereof", 《TETRAHEDRON》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114222734A (en) * | 2020-07-20 | 2022-03-22 | 杭州杜易科技有限公司 | Method for preparing substituted chromanone derivative |
| US11377434B2 (en) | 2020-07-20 | 2022-07-05 | Hangzhou Duyi Technology Co. Ltd. | Methods for preparing substituted chromanone derivatives |
| CN114222734B (en) * | 2020-07-20 | 2023-12-08 | 杭州杜易科技有限公司 | Method for preparing substituted chromanone derivative |
| CN113237970A (en) * | 2021-04-23 | 2021-08-10 | 上海应用技术大学 | High performance liquid chromatography separation method of R, S isomer of 5,7-difluorochroman-4-ol |
Also Published As
| Publication number | Publication date |
|---|---|
| KR101769204B1 (en) | 2017-08-17 |
| KR20170016756A (en) | 2017-02-14 |
| JP6676146B2 (en) | 2020-04-08 |
| JP2018525376A (en) | 2018-09-06 |
| WO2017023124A1 (en) | 2017-02-09 |
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