CN104327065A - Preparation method of N-methyl(quinolyl-4-yl)methylamine - Google Patents
Preparation method of N-methyl(quinolyl-4-yl)methylamine Download PDFInfo
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- CN104327065A CN104327065A CN201410464910.5A CN201410464910A CN104327065A CN 104327065 A CN104327065 A CN 104327065A CN 201410464910 A CN201410464910 A CN 201410464910A CN 104327065 A CN104327065 A CN 104327065A
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- Prior art keywords
- compound
- reaction
- solvent
- ring closure
- xylol
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- SUXIPCHEUMEUSV-UHFFFAOYSA-N Brc1c(cccc2)c2ncc1 Chemical compound Brc1c(cccc2)c2ncc1 SUXIPCHEUMEUSV-UHFFFAOYSA-N 0.000 description 1
- ZHNCGFVDSCRVDH-UHFFFAOYSA-N CC(c1c(cccc2)c2ncc1)=O Chemical compound CC(c1c(cccc2)c2ncc1)=O ZHNCGFVDSCRVDH-UHFFFAOYSA-N 0.000 description 1
- RFPFJPRJGSDGAG-UHFFFAOYSA-N CC(c1c(cccc2)c2ncc1)N Chemical compound CC(c1c(cccc2)c2ncc1)N RFPFJPRJGSDGAG-UHFFFAOYSA-N 0.000 description 1
- JBSAUEMFOKUWTP-UHFFFAOYSA-N N#Cc1c(cccc2)c2ncc1 Chemical compound N#Cc1c(cccc2)c2ncc1 JBSAUEMFOKUWTP-UHFFFAOYSA-N 0.000 description 1
- PMZDQRJGMBOQBF-UHFFFAOYSA-N Oc1c(cccc2)c2ncc1 Chemical compound Oc1c(cccc2)c2ncc1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
Abstract
The invention discloses a preparation method of a thiazole derivative (4-2,3-dihydrobenzo[b][1,4]dioxine-6-yl)thiazole-2-yl)methanol. The method comprises the following steps: carrying out a ring closure reaction on an initial raw material o-diphenol, carrying out a Friedel-Crafts reaction, carrying out a ring closure reaction, carrying out acetal removal protection, and reducing to obtain the target product. The above compound is an important medicine 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 a kind of preparation method of (4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) thiazol-2-yl) methyl alcohol.
Technical background
Compound (4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) thiazol-2-yl) methyl alcohol, structural formula is:
This compound (4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) thiazol-2-yl) methyl alcohol and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of (4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) thiazol-2-yl) methyl alcohol is comparatively difficult at present.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 (4-(2; 3-dihydrobenzo [b] [1; 4] dioxine-6-base) thiazol-2-yl) method of methyl alcohol; take o-phenol as starting raw material; obtain target product 6 through the ring that reaches a standard, Friedel-Crafts reaction, Guan Huan, the aldehyde protection of de-institute, reduction, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) o-phenol is starting raw material, obtains 2 through ring closure reaction;
(2) carry out Friedel-Crafts reaction 2, obtain 3;
(3) carry out ring closure reaction 3 and obtain 4;
(4) carry out de-acetal protective reaction 4 and obtain target product 5,
(5) carry out reduction reaction 4 and obtain target product 6,
One preferred embodiment in, the alkali that described ring closure reaction prepares compound 2 used is selected from salt of wormwood; The Lewis acid that described Friedel-Crafts reaction prepares compound 3 used is selected from aluminum chloride; Described ring closure reaction is prepared compound 4 reagent used and is selected from 2,2-diethoxy thioacetamide; The reagent that described de-acetal protective reaction prepares compound 5 used is selected from hydrochloric acid; The reductive agent that described reduction reaction prepares compound 6 used is selected from sodium borohydride.
One preferred embodiment in, the solvent that described ring closure reaction prepares compound 2 used is selected from DMF; The solvent that described Friedel-Crafts reaction prepares compound 3 used is selected from methylene dichloride; The solvent that described ring closure reaction prepares compound 4 used is selected from tetrahydrofuran (THF); The solvent that described de-acetal protective reaction prepares compound 5 used is selected from tetrahydrofuran (THF); Described reduction reaction prepares compound 6 solvent selected from methanol used.
One preferred embodiment in, described ring closure reaction prepares the reflux temperature that compound 2 temperature of reaction used is solvent; Described Friedel-Crafts reaction prepares the reflux temperature that compound 3 temperature used is 0 DEG C ~ solvent; Described ring closure reaction prepares the reflux temperature that compound 4 temperature used is room temperature ~ solvent; Described de-acetal protective reaction prepare compound 5 used be room temperature; Described reduction reaction prepares compound 60 DEG C ~ room temperature used.
The present invention relates to the preparation method of one (4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) thiazol-2-yl) methyl alcohol, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound (4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) thiazol-2-yl) methyl alcohol.
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
The synthesis of (1) 2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine
42g o-phenol is joined 500ml N, in dinethylformamide, add 51g glycol dibromide, 39g Anhydrous potassium carbonate, reflux stirs 10 hours, the most of DMF of concentrated removing, adds water and ethyl acetate, separatory, drying, concentrated, residuum upper prop is separated and obtains 63g 2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine.
(2) synthesis of the bromo-1-of 2-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) ethane
60g 2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine is joined in 1000ml methylene dichloride, add 27g aluminum chloride, then add 35g 2-bromoacetyl bromide, heated overnight at reflux, be cooled to room temperature, concentrated, then add water, extraction separatory, collect organic phase, separatory, drying, concentrated, on residuum, silicagel column is separated to obtain the bromo-1-(2 of 39g 2-, 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) ethane.
(3) synthesis of 2-(diethoxymethyl)-4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) thiazole
Bromo-for 35g 2-1-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) ethane is joined in 190ml tetrahydrofuran (THF), add 46g 2 again, 2-diethoxy thioacetamide, stirring at room temperature 1 lab scale, reflux stirs 12 hours, add water and ethyl acetate, filter, extraction separatory, obtains 18g 2-(diethoxymethyl)-4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) thiazole.
(4) synthesis of 4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) thiazole-2-formaldehyde
17g 2-(diethoxymethyl)-4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) thiazole joins in 200ml1N hydrochloric acid, stirring at room temperature 24 hours, add sodium carbonate solution, be adjusted to neutrality, then add extraction into ethyl acetate, separatory, concentrated, on residuum, silicagel column is separated to obtain 11g 4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) thiazole-2-formaldehyde.
(5) synthesis of (4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) thiazol-2-yl) methyl alcohol
10g 4-(2,3-dihydrobenzo [b] [1,4] dioxine-6-base) thiazole-2-formaldehyde joins in 150ml anhydrous methanol, be cooled to 0 DEG C, add 7g sodium borohydride, naturally stirring at room temperature is risen to 18 hours, add saturated ammonium chloride solution, adjust and add extraction into ethyl acetate again, separatory, concentrated, on residuum, silicagel column is separated to obtain 6.8g (4-(2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-6-base) thiazol-2-yl) methyl alcohol.
Claims (6)
1. prepare (4-(2 for one kind; 3-dihydrobenzo [b] [1; 4] dioxine-6-base) thiazol-2-yl) method of methyl alcohol; take o-phenol as starting raw material; obtain target product 6 through the ring that reaches a standard, Friedel-Crafts reaction, Guan Huan, the aldehyde protection of de-institute, reduction, synthetic route is as follows.
。
2. method according to claim 1, it is characterized by 5 described step reactions is,
(1) o-phenol is starting raw material, obtains 2 through ring closure reaction;
(2) carry out Friedel-Crafts reaction 2, obtain 3;
(3) carry out ring closure reaction 3 and obtain 4;
(4) carry out de-acetal protective reaction 4 and obtain target product 5,
(5) carry out reduction reaction 4 and obtain target product 6,
。
3. according to the method for claim 1-2, it is characterized in that, described ring closure reaction is prepared compound 2 alkali used and is selected from the mixture of one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus; Described Friedel-Crafts reaction is prepared compound 3 Lewis acid used and is selected from the mixture of one or more in aluminum chloride, iron trichloride, zinc chloride; Described ring closure reaction is prepared compound 4 reagent used and is selected from 2,2-diethoxy thioacetamide; Described de-acetal protective reaction is prepared compound 5 reagent used and is selected from the mixture of one or more in hydrogenchloride, sulfuric acid, hydrochloric acid, tosic acid, trifluoroacetic acid; Described reduction reaction is prepared compound 6 reductive agent used and is selected from the mixture of one or more in sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine.
4. according to the method for claim 1-2, it is characterized in that, described ring closure reaction prepares compound 2 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 Friedel-Crafts 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, water; Described ring closure 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, water; 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 are prepared in described de-acetal protective reaction, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described reduction reaction prepares compound 6 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, described ring closure reaction prepares the reflux temperature that compound 2 temperature of reaction used is 0 DEG C ~ solvent; Described Friedel-Crafts reaction prepares the reflux temperature that compound 3 temperature used is 0 DEG C ~ solvent; Described ring closure reaction prepares the reflux temperature that compound 4 temperature used is room temperature ~ solvent; Described de-acetal protective reaction prepare compound 5 used be 0 DEG C ~ room temperature; Described reduction reaction prepares compound 60 DEG C ~ room temperature used.
6. according to the method for claim 1-2, it is characterized in that, described ring closure reaction prepares the reflux temperature that compound 2 temperature of reaction used is solvent; Described Friedel-Crafts reaction prepares the reflux temperature that compound 3 temperature used is solvent; Described ring closure reaction prepares the reflux temperature that compound 4 temperature used is solvent; Described de-acetal protective reaction prepare compound 5 used be room temperature; Described reduction reaction prepares compound 60 DEG C ~ room temperature used.
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| CN201410464910.5A CN104327065A (en) | 2014-09-15 | 2014-09-15 | Preparation method of N-methyl(quinolyl-4-yl)methylamine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108285432A (en) * | 2017-01-10 | 2018-07-17 | 湖南华腾制药有限公司 | A kind of preparation method of quinoline |
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| CN1120041A (en) * | 1994-02-25 | 1996-04-10 | 阿迪尔公司 | Novel benzobiulkyl, preparation of same and parmaceutical composition of same |
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2014
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Patent Citations (6)
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| JP2000204087A (en) * | 1999-01-12 | 2000-07-25 | Banyu Pharmaceut Co Ltd | Inhibitor against geranylgeranyl transferase, i-type protein |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108285432A (en) * | 2017-01-10 | 2018-07-17 | 湖南华腾制药有限公司 | A kind of preparation method of quinoline |
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