CN104592215A - Preparation method of piperidine-substituted oxadiazole derivative - Google Patents
Preparation method of piperidine-substituted oxadiazole derivative Download PDFInfo
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- CN104592215A CN104592215A CN201510025876.6A CN201510025876A CN104592215A CN 104592215 A CN104592215 A CN 104592215A CN 201510025876 A CN201510025876 A CN 201510025876A CN 104592215 A CN104592215 A CN 104592215A
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- IZERKFFKCDMEKG-UHFFFAOYSA-N CC(C)(C)OC(N(CCC1)CC1c1n[o]c(CCl)n1)=O Chemical compound CC(C)(C)OC(N(CCC1)CC1c1n[o]c(CCl)n1)=O IZERKFFKCDMEKG-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a preparation method of piperidine-substituted oxadiazole derivative 3-(5-(chloromethyl)-1,2,4-oxadiazole-3-yl) piperidine. With N-Boc-3-cyanopiperdine as an initial raw material, the target product is obtained by addition, cyclization and Boc-off protecting reaction. The compound is an important medical intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, particularly a kind of piperidines replaces the preparation method of oxadiazoles derivative 3-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) piperidines.
Technical background
Compound 3-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) piperidines, structural formula is:
This compound 3-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) piperidines and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 3-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) piperidines is comparatively difficult.Therefore, need exploitation raw material to be easy to get, easy to operate, reaction is easy to control, the synthetic method that overall yield is suitable.
Summary of the invention
The invention discloses a kind of 3-(5-(chloromethyl)-1; 2,4-oxadiazoles-3-base) preparation method of piperidines, with N-Boc-3-cyano piperidine for starting raw material; obtain target product 4 through addition, Guan Huan, de-Boc protective reaction, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) with N-Boc-3-cyano piperidine for starting raw material, obtain 2 through addition reaction;
(2) carry out ring closure reaction 2, obtain 3;
(3) carry out de-Boc protective reaction 3 and obtain 4;
One preferred embodiment in, the reagent that described addition reaction prepares compound 2 used is selected from oxammonium hydrochloride; The alkali that described ring closure reaction prepares compound 3 used is selected from triethylamine; The reagent that described de-Boc protective reaction prepares compound 4 used is selected from hydrogenchloride.
One preferred embodiment in, compound 2 solvent selected from ethanol used is prepared in described addition reaction; The solvent that described ring closure reaction prepares compound 3 used is selected from toluene; The solvent that described de-Boc protective reaction prepares compound 4 used is selected from methylene dichloride.
One preferred embodiment in, the reflux temperature that compound 2 temperature of reaction used is solvent is prepared in described addition reaction; Described ring closure reaction prepares the reflux temperature that compound 3 temperature used is 0 DEG C ~ solvent; It is room temperature that compound 4 temperature used is prepared in described de-Boc protective reaction.
The present invention relates to the preparation method that a kind of piperidines replaces oxadiazoles derivative 3-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) piperidines, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound 3-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) piperidines.
The present invention is further described by the following embodiment, and these descriptions are not be further limited content of the present invention.One skilled in the art will understand that the equivalent replacement that technical characteristic of the present invention is done, or improve accordingly, still belong within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of (Z)-tertiary butyl-3-(N'-hydroxy formamidine base) piperidines-1-t-butyl formate
31g N-Boc-3-cyano piperidine is joined in 350ml ethanol, add 26g oxammonium hydrochloride, add 50ml water and 10g sodium hydroxide again, reflux stirs 4 hours, cooling, add water and ethyl acetate, extraction separatory, collects organic phase, dry, concentrated, obtain 27g (the Z)-tertiary butyl-3-(N'-hydroxy formamidine base) piperidines-1-t-butyl formate.
(2) synthesis of the tertiary butyl-3-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) piperidines-1-carboxylic acid tert-butyl ester
26g (the Z)-tertiary butyl-3-(N'-hydroxy formamidine base) piperidines-1-t-butyl formate is joined in 500ml toluene, is cooled to 0 DEG C, drip the chloroacetyl chloride of 40ml, stir 1 hour, then continue heated and stirred to reflux 6 hours, cooling, water and extraction into ethyl acetate separatory, collect organic phase, drying, concentrated, cross post separation and obtain the 19g tertiary butyl-3-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) piperidines-1-carboxylic acid tert-butyl ester.
(3) synthesis of 3-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) piperidines
The 18g tertiary butyl-3-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) piperidines-1-carboxylic acid tert-butyl ester joins in 180ml methylene dichloride, and pass into hydrogenchloride, stirring is spent the night, add aqueous sodium hydroxide solution, collect organic phase, dry, concentrate to obtain 11g3-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) piperidines.
Claims (6)
1. the preparation method of piperidines replacement oxadiazoles derivative 3-(5-(chloromethyl)-1,2, a 4-oxadiazoles-3-base) piperidines; with N-Boc-3-cyano piperidine for starting raw material; obtain target product 4 through addition, Guan Huan, de-Boc protective reaction, synthetic route is as follows
2. method according to claim 1, it is characterized by 3 described step reactions is,
(1) with N-Boc-3-cyano piperidine for starting raw material, obtain 2 through addition reaction;
(2) carry out ring closure reaction 2, obtain 3;
(3) carry out de-Boc protective reaction 3 and obtain 4;
3. according to the method for claim 1-2, it is characterized in that, the reagent that described addition reaction prepares compound 2 used is selected from oxammonium hydrochloride; Described ring closure reaction is prepared compound 3 alkali used and is selected from the mixture of one or more in sodium hydroxide, potassium hydroxide, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, sodium methylate, sodium ethylate, triethylamine, pyridine; The mixture of one or more in the mixture of one or more that compound 4 reagent used is selected from hydrogenchloride, hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid is prepared in described de-Boc protective reaction.
4. according to the method for claim 1-2, it is characterized in that, compound 2 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N are prepared in described addition reaction, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, triethylamine, pyridine, acetonitrile, acetic acid; Described ring closure reaction prepares compound 3 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile, water; Compound 4 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, toluene, o-Xylol, p-Xylol, m-xylene, N are prepared in described de-Boc protective reaction; the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile, phosphorus oxychloride.
5. according to the method for claim 1-2, it is characterized in that, the reflux temperature that compound 2 temperature of reaction used is 0 DEG C ~ solvent is prepared in described addition reaction; Described ring closure reaction prepares the reflux temperature that compound 3 temperature used is 0 DEG C ~ solvent; The reflux temperature that compound 4 temperature used is 0 DEG C ~ solvent is prepared in described de-Boc protective reaction.
6. according to the method for claim 1-2, it is characterized in that, the reflux temperature that compound 2 temperature of reaction used is solvent is prepared in described addition reaction; Described ring closure reaction prepares the reflux temperature that compound 3 temperature used is 0 DEG C ~ solvent; It is room temperature that compound 4 temperature used is prepared in described de-Boc protective reaction.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108299333A (en) * | 2017-01-12 | 2018-07-20 | 湖南华腾制药有限公司 | One kind 3,5- bis- replaces the preparation method of oxadiazole compound |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101663278A (en) * | 2007-02-02 | 2010-03-03 | Irm责任有限公司 | It is used as the compound and composition of GPR119 activity regulation agent |
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2015
- 2015-01-19 CN CN201510025876.6A patent/CN104592215A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101663278A (en) * | 2007-02-02 | 2010-03-03 | Irm责任有限公司 | It is used as the compound and composition of GPR119 activity regulation agent |
Non-Patent Citations (2)
| Title |
|---|
| 程忠玲: "4-(3-异丙基-1,2,4-噁二唑-5-基)哌啶的合成", 《化学试剂》 * |
| 覃宇，等: "新型哌啶类杂环化合物的设计、合成与表征", 《数理医药学杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108299333A (en) * | 2017-01-12 | 2018-07-20 | 湖南华腾制药有限公司 | One kind 3,5- bis- replaces the preparation method of oxadiazole compound |
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