CN107176906A - A kind of synthetic method of substitution indone - Google Patents
A kind of synthetic method of substitution indone Download PDFInfo
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- CN107176906A CN107176906A CN201610133494.XA CN201610133494A CN107176906A CN 107176906 A CN107176906 A CN 107176906A CN 201610133494 A CN201610133494 A CN 201610133494A CN 107176906 A CN107176906 A CN 107176906A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/04—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid halides
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- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to a kind of synthetic method that a kind of substitution indone is 5- hydroxide radical-1-indenones (compound IV), mainly solve that the reaction condition that current synthetic method is present is more harsh, accessory substance is more, and post processing is difficult, the technical problem such as raw material is difficult to obtain.The present invention obtains compound II, II with 2,6- chlorophenesic acids (compound I) and the reaction of 3- chlorpromazine chlorides and reacted in the presence of a lewis acid obtaining compound III, III dechlorination and obtaining IV.
Description
Technical field
Replace the synthetic method that indone is 5- hydroxide radical-1-indenones the present invention relates to a kind of.
Background technology
5- hydroxide radical-1-indenones and the derivative of correlation collect in pharmaceutical chemistry and organic synthesis to be had a wide range of applications.Such change at present
The synthesis of compound mainly has following three kinds of methods synthesis 5- hydroxide radical-1-indenones：
Method one is that, using a hydroxy phenylpropionic acid as raw material, intramolecular cyclization is accordingly produced in alchlor-sodium chloride of melting
Thing (J.Med.Chem.1994,1275-1281), obtains 5- hydroxide radical-1-indenones and 7- hydroxide radical-1-indenones, is difficult while this method
Separation；Reaction needs high-temperature heating, high energy consumption；Bigger shortcoming is to be difficult post processing, and being often had to after the completion of reaction will be anti-
Bottle is answered to break processing reaction into pieces.The synthetic route of this method is as follows：
Method two is, using 5- amino -1- indones as raw material, corresponding amino to be converted into hydroxyl by Sandermyer reactions
There is raw material and be difficult to obtain, it is necessary to be synthesized by multistep in (J.Org.Chem.1962,70-76), this method.The synthesis road of this method
Line is as follows：
Method three be using 5- methoxyl group -1- indones as raw material, by hydrolyze methoxyl group as hydroxyl (J.Org.Chem.2002,
6406-6414), this method raw material 5- methoxyl groups -1- indones be also required to multistep synthesis obtain.The synthetic route of this method is as follows：
In summary, the synthetic method raw materials of the 5- hydroxide radical-1-indenones being currently known exist be difficult to obtain, selectivity not in high yield
It is low, the shortcomings of post processing is difficult.
The content of the invention
The purpose of the present invention is that a kind of high selectivity of exploitation prepares the new preparation method of 5- hydroxide radical-1-indenones.Mainly solve existing conjunction
It is difficult to obtain into method raw material, post processing is difficult, the low technical problem of the low yield of selectivity.
Technical scheme：
The present invention obtains compound II with 2,6- chlorophenesic acids (compound I) and the reaction of 3- chlorpromazine chlorides, and II is deposited in lewis acid
Compound III, III debrominate is obtained in lower reaction and obtains IV, and reaction equation is as follows：
In above-mentioned technique, first step reaction condition is that 2,6- chlorophenesic acids are dissolved in acetonitrile, and 1 eq of triethylamine of addition does alkali, 3-
The addition equivalent of chlorpromazine chloride is 1.1 equivalents, is stirred 1 hour at 0 DEG C, then be stirred at room temperature 2 hours；Second step reacts
Condition is that II is dissolved in dichloromethane, adds 2 equivalent butyl titanates and does lewis acid；Three-step reaction condition is that III is added
Into methanol, and palladium catalyst is added, be passed through hydrogen reaction.
Beneficial effects of the present invention：
The present invention solves the preparation method raw material being currently known and is difficult to obtain, the low shortcoming of the low yield of reaction selectivity.With industry
Conventional raw material 2,6- chlorophenesic acids obtain compound II, II reaction in the presence of a lewis acid with the reaction of 3- chlorpromazine chlorides
Compound III, III dechlorination obtains 5- hydroxide radical-1-indenones, i.e. IV.Technique second step ring closure reaction selectivity is high, high income, easily
In amplification, it is possible to achieve the efficient quick preparation of 5- hydroxide radical-1-indenones.
Embodiment
Specific embodiment of the invention presented below, to show possible implementation process, but is not intended to limit the present invention.
Embodiment 1
(1) compound II preparation：
It is that 2,6- chlorophenesic acids (22g, 0.1mol) are dissolved in 250ml acetonitriles by compound I, adds triethylamine (0.1mol),
0 DEG C is cooled to, 3- chlorpromazine chlorides (12.6g, 0.1mol) are added dropwise, 0 DEG C is stirred 1 hour, is stirred at room temperature 2 hours, TLC points
Plate detection reaction is finished, and reaction solution is successively by washing, and 1M NaOH are washed, and washes, saturated common salt washing, anhydrous slufuric acid
Sodium is dried, and is filtered to remove drier, is concentrated under reduced pressure to give compound II 29.6g, yield 87%.
(2) compound III preparation：
Compound II (27g, 0.085mol) is added in 400ml dichloromethane, add butyl titanate (57.8g,
0.17mol), 40 DEG C are heated to, stirring reaction 14 hours, TLC points plate detection reaction is finished, add water, extraction is quiet
Put, be layered, separate organic phase, with anhydrous sodium sulfate drying, be filtered to remove drier, be concentrated under reduced pressure to give compound III
Crude product, crude product re-crystallizing in ethyl acetate obtains white solid III22.2g, yield 86%.
(3) preparation of 5- hydroxide radical-1-indenones
Compound III (21g, 0.072mol) is added in 420ml methanol, 10% palladium charcoal 1.8g is added, argon gas is protected,
Be heated to 40 DEG C of stirring reactions 6 hours, the detection reaction of TLC points plate is finished, and reaction solution is cooled to room temperature, add water and
Ethyl acetate, is extracted, and is stood, and layering separates organic phase, washed respectively with saturated aqueous common salt and saturated sodium bicarbonate aqueous solution
Three times, with anhydrous sodium sulfate drying, drier i is filtered to remove, compound IV i.e. 5- hydroxide radical-1-indenones are concentrated under reduced pressure to give
9.8g, yield 92%.
1H NMR (400MHz, DMSO-d6)：δppm7.66(d,1H),6.98(s,1H),6.85(d,1H),6.40(s,1H),
3.08(t,2H),2.57(m,2H)；M/z=149 (M+H)+.
Claims (3)
- The synthetic method of 1.5- hydroxide radical-1-indenones, it is characterized in that comprising the following steps：Compound II, II are obtained with 2,6- chlorophenesic acids (compound I) and the reaction of 3- chlorpromazine chlorides and react in the presence of a lewis acid obtaining compound III, III dechlorination and obtaining IV, reaction equation is as follows：。
- 2. the preparation method of 5- hydroxide radical-1-indenones according to claim 1, is dissolved in acetonitrile it is characterized in that first step reaction condition is 2,6- chlorophenesic acids, and adds 1 eq of triethylamine and do alkali, the addition equivalent of 3- chlorpromazine chlorides is 1.1 equivalents；Second step reaction condition is that II is dissolved in dichloromethane, adds 3 equivalent tetraethyl titanates and does lewis acid；Three-step reaction condition adds palladium catalyst for III is added in methanol, is passed through hydrogen reaction.
- 3. the preparation method of 5- hydroxide radical-1-indenones according to claim 1, it is characterized in that first step reaction is first stirred 1 hour at 0 DEG C, then is stirred at room temperature 2 hours, second step reaction temperature is 30~40 DEG C, and three-step reaction temperature is 25~40 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610133494.XA CN107176906A (en) | 2016-03-09 | 2016-03-09 | A kind of synthetic method of substitution indone |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610133494.XA CN107176906A (en) | 2016-03-09 | 2016-03-09 | A kind of synthetic method of substitution indone |
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| CN201610133494.XA Withdrawn CN107176906A (en) | 2016-03-09 | 2016-03-09 | A kind of synthetic method of substitution indone |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108558627A (en) * | 2018-05-04 | 2018-09-21 | 山西大学 | A method of preparing 5- hydroxide radical-1-indenones |
| CN110845475A (en) * | 2019-12-25 | 2020-02-28 | 深圳市祥根生物科技有限公司 | Preparation method of loratadine impurity |
| CN113121495A (en) * | 2020-01-10 | 2021-07-16 | 深圳市九明药业有限公司 | Preparation method of desloratadine |
-
2016
- 2016-03-09 CN CN201610133494.XA patent/CN107176906A/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108558627A (en) * | 2018-05-04 | 2018-09-21 | 山西大学 | A method of preparing 5- hydroxide radical-1-indenones |
| CN110845475A (en) * | 2019-12-25 | 2020-02-28 | 深圳市祥根生物科技有限公司 | Preparation method of loratadine impurity |
| CN113121495A (en) * | 2020-01-10 | 2021-07-16 | 深圳市九明药业有限公司 | Preparation method of desloratadine |
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Application publication date: 20170919 |