CN104262265A - Preparation method for tetrahydro quinazoline derivative - Google Patents
Preparation method for tetrahydro quinazoline derivative Download PDFInfo
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- CN104262265A CN104262265A CN201410353285.7A CN201410353285A CN104262265A CN 104262265 A CN104262265 A CN 104262265A CN 201410353285 A CN201410353285 A CN 201410353285A CN 104262265 A CN104262265 A CN 104262265A
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- 0 CCCC(C(CCC1=O)CC1=C*(C)C)=O Chemical compound CCCC(C(CCC1=O)CC1=C*(C)C)=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention discloses a preparation method for a tetrahydro quinazoline derivative, and particularly relates to a preparation method for 2-(penta-3-yl)-5,6,7,8-tetrahydro quinazoline-6-carbaldehyde. The target product is prepared by adopting cyclohexanone ethyl formate ethyl 4-oxocyclohexanecarboxylate as a starting material, and carrying out carbon-carbon double bond forming, cyclization, reduction and oxidation. The compound in the present invention is an important pharmaceutical intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, particularly a kind of preparation method of 2-(penta-3-base)-5,6,7,8-tetrahydro quinazoline-6-formaldehyde.
Technical background
Compound 2-(penta-3-base)-5,6,7,8-tetrahydro quinazoline-6-formaldehyde, English 2-(pentan-3-yl)-5,6,7,8-tetrahyd roquinazoline-6-carbaldehyde by name, structural formula is:
This compound 2-(penta-3-base)-5,6,7,8-tetrahydro quinazoline-6-formaldehyde and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 2-(penta-3-base)-5,6,7,8-tetrahydro quinazoline-6-formaldehyde 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 one and prepare 2-(penta-3-base)-5,6,7, the method of 8-tetrahydro quinazoline-6-formaldehyde, with to pimelinketone ethyl formate for starting raw material, pass through into carbon-carbon double bond, Guan Huan, reduction, oxidation obtain target product 5, synthetic route is as follows.
Synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) with to pimelinketone ethyl formate for starting raw material, pass through into carbon-carbon double bond and be obtained by reacting 2;
(2) carry out ring closure reaction 2 with 2-ethyl fourth amidine, obtain 3;
(3) carry out reduction reaction 3 and obtain 4;
(4) carry out oxidizing reaction 4 and obtain target product 5,
One preferred embodiment in, described one-tenth carbon-carbon double bond reaction is prepared compound 2 reagent used and is selected from DMF dimethylacetal; The alkali that described ring closure reaction prepares compound 3 used is selected from sodium methylate; The reductive agent used that described reduction substitution reaction prepares compound 4 used is selected from Lithium Aluminium Hydride; Described oxidizing reaction is prepared compound 5 oxygenant agent used and is selected from Dai Si-Ma Ting oxygenant.
One preferred embodiment in, described one-tenth carbon-carbon double bond reacts the solvent preparing compound 2 used and is selected from DMF; Described ring closure reaction prepares compound 3 solvent selected from methanol used; The solvent that described reduction reaction prepares compound 4 used is selected from tetrahydrofuran (THF); The solvent that described oxidizing reaction prepares compound 5 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 one-tenth carbon-carbon double bond reaction; Described ring closure reaction prepares the reflux temperature that compound 3 temperature used is solvent; It is 0 DEG C that described reduction reaction prepares compound 4 temperature used; Described oxidizing reaction prepare compound 5 used be room temperature.
The present invention relates to the preparation method of a kind of 2-(penta-3-base)-5,6,7,8-tetrahydro quinazoline-6-formaldehyde, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound 2-(penta-3-base)-5,6,7,8-tetrahydro quinazoline-6-formaldehyde.
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)-ethyl 3-((dimethylamino) methylene radical)-4-oxocyclohex alkane carboxylic acid
22g is joined 580ml N to pimelinketone ethyl formate, in dinethylformamide, add 15gN, N-dimethyl methyl reflux stirs 6 hours, be cooled to room temperature, add water to extract, separatory, drying, concentrated, residuum upper prop is separated and obtains 25g (Z)-ethyl 3-((dimethylamino) methylene radical)-4-oxocyclohex alkane carboxylic acid.
(2) synthesis of ethyl 2-(penta-3-base)-5,6,7,8-tetrahydro quinazoline-6-carboxylic acid, ethyl ester
24g (Z)-ethyl 3-((dimethylamino) methylene radical)-4-oxocyclohex alkane carboxylic acid is joined in 150ml methyl alcohol, adds 12g sodium methylate, then add 18g2-ethyl fourth amidine, heated overnight at reflux, is cooled to room temperature, concentrated, add water and methylene dichloride again, extraction separatory, collects organic phase, separatory, drying, concentrated, on residuum, silicagel column is separated to obtain 18g ethyl 2-(penta-3-base)-5,6,7,8-tetrahydro quinazoline-6-carboxylic acid, ethyl ester.
(3) synthesis of (2-(penta-3-base)-5,6,7,8-tetrahydro quinazoline-6-base) methyl alcohol
15g ethyl 2-(penta-3-base)-5,6,7,8-tetrahydro quinazoline-6-carboxylic acid, ethyl ester enters in 120ml tetrahydrofuran (THF), is cooled to 0 DEG C, slowly adds 3g Lithium Aluminium Hydride, 0 DEG C is stirred 5 hours, add water, filter, filtrate concentrates, obtain 12g (2-(penta-3-base)-5,6,7,8-tetrahydro quinazoline-6-base) crude product of methyl alcohol.
(4) synthesis of 2-(penta-3-base)-5,6,7,8-tetrahydro quinazoline-6-formaldehyde
12g (2-(penta-3-base)-5,6,7,8-tetrahydro quinazoline-6-base) crude product of methyl alcohol joins in 110ml methylene dichloride, add 18g Dai Si-Ma Ting oxygenant, stirring at room temperature 24 hours, filters, and filtrate concentrates, on residuum, silicagel column is separated and obtains 2-(penta-3-base)-5,6,7,8-tetrahydro quinazoline-6-formaldehyde.
Claims (6)
1. prepare tetrahydro quinazoline derivative 2-(penta-3-base)-5,6,7 for one kind, the method of 8-tetrahydro quinazoline-6-formaldehyde, with to pimelinketone ethyl formate for starting raw material, pass through into carbon-carbon double bond, Guan Huan, reduction, oxidation obtain target product 5, synthetic route is as follows.
2. method according to claim 1, it is characterized by 4 described step reactions is,
(1) with to pimelinketone ethyl formate for starting raw material, pass through into carbon-carbon double bond and be obtained by reacting 2;
(2) carry out ring closure reaction 2 with 2-ethyl fourth amidine, obtain 3;
(3) carry out reduction reaction 3 and obtain 4;
(4) carry out oxidizing reaction 4 and obtain target product 5,
3. according to the method for claim 1-2, it is characterized in that, described one-tenth carbon-carbon double bond reaction is prepared compound 2 reagent used and is selected from DMF dimethylacetal; 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, lithium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus, sodium methylate, sodium ethylate; Described reduction substitution reaction is prepared compound 4 reductive agent used used and is selected from the mixture of one or more in sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine; Described oxidizing reaction is prepared compound 5 oxygenant agent used and is selected from the mixture of one or more in Manganse Dioxide, tin anhydride, pyridinium chlorochromate, pyridinium dichromate, chromium trioxide, Dai Si-Ma Ting oxygenant.
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 one-tenth carbon-carbon double bond reaction, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described ring closure reaction is prepared compound 3 solvent used and is selected from methylene dichloride, trichloromethane, ethyl acetate, tetrahydrofuran (THF), toluene, tetrahydrofuran (THF), toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, methyl alcohol, ethanol, Virahol; Described reduction reaction prepares compound 4 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; Described oxidizing reaction prepares compound 5 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, trichloromethane, ethyl acetate, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide.
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 one-tenth carbon-carbon double bond reaction; Described ring closure reaction prepares the reflux temperature that compound 3 temperature used is 0 DEG C ~ solvent; It is 0 DEG C ~ room temperature that described reduction reaction prepares compound 4 temperature used; Described oxidizing reaction prepare compound 5 used be 0 DEG C ~ room temperature.
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 one-tenth carbon-carbon double bond reaction; Described ring closure reaction prepares the reflux temperature that compound 3 temperature used is solvent; It is 0 DEG C that described reduction reaction prepares compound 4 temperature used; Described oxidizing reaction prepare compound 5 used be room temperature.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107162990A (en) * | 2017-06-01 | 2017-09-15 | 湖南华腾制药有限公司 | A kind of synthetic method of tetrahydro quinazoline class compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1835931A (en) * | 2003-08-12 | 2006-09-20 | 弗·哈夫曼-拉罗切有限公司 | Tetrahydroquinazolines and dihydrocyclopentapyrimidines as CFR antagonists |
| WO2012085167A1 (en) * | 2010-12-22 | 2012-06-28 | Merz Pharma Gmbh & Co. Kgaa | Metabotropic glutamate receptor modulators |
| WO2012085166A1 (en) * | 2010-12-22 | 2012-06-28 | Merz Pharma Gmbh & Co. Kgaa | Metabotropic glutamate receptor modulators |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1835931A (en) * | 2003-08-12 | 2006-09-20 | 弗·哈夫曼-拉罗切有限公司 | Tetrahydroquinazolines and dihydrocyclopentapyrimidines as CFR antagonists |
| WO2012085167A1 (en) * | 2010-12-22 | 2012-06-28 | Merz Pharma Gmbh & Co. Kgaa | Metabotropic glutamate receptor modulators |
| WO2012085166A1 (en) * | 2010-12-22 | 2012-06-28 | Merz Pharma Gmbh & Co. Kgaa | Metabotropic glutamate receptor modulators |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107162990A (en) * | 2017-06-01 | 2017-09-15 | 湖南华腾制药有限公司 | A kind of synthetic method of tetrahydro quinazoline class compound |
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Denomination of invention: Preparation method for tetrahydro quinazoline derivative Effective date of registration: 20200318 Granted publication date: 20160413 Pledgee: Bank of Changsha Limited by Share Ltd science and Technology Branch Pledgor: HUNAN HUATENG PHARMACEUTICAL Co.,Ltd. Registration number: Y2020980000827 |
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