CN106632302A - Synthesis method of 1-(thiazole-2-yl)piperidine-4-ol - Google Patents
Synthesis method of 1-(thiazole-2-yl)piperidine-4-ol Download PDFInfo
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- CN106632302A CN106632302A CN201611159395.5A CN201611159395A CN106632302A CN 106632302 A CN106632302 A CN 106632302A CN 201611159395 A CN201611159395 A CN 201611159395A CN 106632302 A CN106632302 A CN 106632302A
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- piperidines
- thiazol
- synthetic method
- alcohol
- alcohol according
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- 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
Abstract
The invention discloses a synthesis method of 1-(thiazole-2-yl)piperidine-4-ol. The synthesis method comprises the following steps: adding an alkali A into a reaction container filled with 4-hydroxypiperidine, 2-bromothiazole and a solvent and stirring and reacting at 50 DEG C-120 DEG C for 6-16 hours to obtain a crude product; and carrying out post-treatment on the crude product to obtain the 1-(thiazole-2-yl)piperidine-4-ol. According to the method disclosed by the invention, a product does not need to be purified by column chromatography; a synthesis route is short; and the product purity is high and the yield is high.
Description
Technical field
The invention belongs to the synthesis field of organic compound, and in particular to a kind of conjunction of 1- (thiazol-2-yl) piperidines -4- alcohol
Into method.
Background technology
1- (thiazol-2-yl) piperidines -4- alcohol is a kind of important organic intermediate, its extensive drug application chemical field.
First, in the medicine treated or adjust diabetes, g protein coupled receptor 40 (GPR40) is a kind of potential treatment diabetes
Drug target, and GPR40 be also believed to it is relevant with some mental disorders and cancer.Therefore, 1- (thiazol-2-yl) piperazine
Pyridine -4- alcohol molecule has important using value as the important skeleton of GPR40 in above-mentioned field of medicaments.Secondly, stearoyl-coa
Dehydrogenase (SCD) is to participate in the key enzyme that metabolism is adjusted, in having been applied to many relevant metabolic diseases, bag
Include the metabolic syndrome disease such as type ii diabetes, obesity.And changing comprising 1- (thiazol-2-yl) piperidines -4- alcohol fragments in molecule
Entering type SCD can effectively improve its pharmacokinetics, therefore 1- (thiazol-2-yl) piperidines -4- alcohol and its derivative in treatment generation
There is important using value in the medicine for thanking to Syndrome disease.
The synthesis of 1- (thiazol-2-yl) piperidines -4- alcohol is rarely reported at present.Known method 1) produced using column chromatography purifying
Thing, operation inconvenience, produces the solid wastes such as substantial amounts of silica gel, is difficult industrialized production；2) yield is low, and yield is generally 24%-
50%).
The content of the invention
The technical problem to be solved in the present invention is the defect for overcoming prior art, there is provided a kind of 1- (thiazol-2-yl) piperidines-
The synthetic method of 4- alcohol, without the need for column chromatography purified product, product purity is high, and yield is high for the method.
To solve above-mentioned technical problem, the technical solution used in the present invention is：
A kind of synthetic method of 1- (thiazol-2-yl) piperidines -4- alcohol, comprises the following steps：To equipped with 4- hydroxy piperidines, 2-
In the reaction vessel of bromo thiazole and solvent, add alkali A, the stirring reaction 6-16 hour at 50-120 DEG C to obtain crude product, then will
Crude product is post-processed, and obtains 1- (thiazol-2-yl) piperidines -4- alcohol.
Raw materials used and related reagent can be commercially available by commercial means in the present invention.The wherein knot of 4- hydroxy piperidines
Structure formula is：The structural formula of 2- bromo thiazoles isAlleged by the present invention the step of " post processing " in
Column chromatography purification step is not included.
Preferably, the post-processing step of the crude product includes adjusting PH：It is 5-7 first to adjust PH with acid, then molten with alkali B again
It is 10-12 that liquid adjusts PH.
Preferably, post processing is additionally included in the washing adjusted before PH, and the extraction after PH is adjusted, drying and mistake
Filter.
Preferably, the acid is watery hydrochloric acid, and the alkali B solution is unsaturated carbonate potassium solution or saturated sodium carbonate solution.
Preferably, the watery hydrochloric acid concentration is 2M/L.
Preferably, the solvent is selected from toluene, acetonitrile, DMF, DMA
Plant or several.
Preferably, the alkali A selected from the -5- alkene of 1,5- diazabicylos [5.4.0] 11, pyridine, sodium carbonate, potassium carbonate,
One or more in cesium carbonate, caustic alcohol.
Preferably, the 4- hydroxy piperidines and the mol ratio of 2- bromo thiazoles are 1.2～2.0:1.
Preferably, the 2- bromo thiazoles and the mol ratio of alkali A are 1:1.5～3.0.
The beneficial effect that the present invention is reached：
The low in raw material price that the method is used, is readily available, and only needs to single step reaction, easy to operate, yield and
Chemical purity is high, it is easy to industrialized production.And reaction is not required to special producing equipment, without (pole) low-temperature operation, it is to avoid existing side
The operations such as low, the purifying trouble of yield of method, have a good application prospect.
Description of the drawings
Fig. 1 is the synthetic route chart of 1- (thiazol-2-yl) piperidines -4- alcohol.
Specific embodiment
Below in conjunction with the accompanying drawings the invention will be further described.Following examples are only used for clearly illustrating the present invention
Technical scheme, and can not be limited the scope of the invention with this.
Embodiment 1
81 grams of 2- bromo thiazoles, 123 grams of sodium carbonate and 81 milliliters of N, N- dimethyl are added in the reaction bulb with agitator
Formamide, 60 grams of 4- hydroxy piperidines are added under room temperature in gained mixture, control interior temperature 70-80 DEG C, react 10 hours.So
Afterwards reactant mixture is added into 400 milliliters of ethyl acetate and 200 milliliters of saturated aqueous common salts, separate organic phase, continued with 200 milliliters
Twice, gained organic phase is adjusted to pH=6 to saturated common salt washing organic phase with 2M/L aqueous hydrochloric acid solutions, separates organic phase, organic phase
Washed once with 2M/L aqueous hydrochloric acid solutions again.Then gained water is adjusted to pH=12 under ice bath with unsaturated carbonate aqueous solutions of potassium, plus
Enter dichloromethane extraction, sodium sulphate is dried, and filters, and filter cake is washed with a small amount of dichloromethane, concentration is dry after organic phase merges, and obtains
69 grams of light yellow oil 1- (thiazol-2-yl) piperidines -4- alcohol, yield 76%.
1H NMR(400MHz,CDCl3)：7.46(d,1H),6.58(d,1H),3.99(m,1H),3.87(m,2H),3.28
(m, 2H), 1.99 (m, 2H), 1.68 (m, 2H).
Embodiment 2
81 grams of 2- bromo thiazoles, 123 grams of cesium carbonates and 81 milliliters of acetonitriles are added in the reaction bulb with agitator, under room temperature
60 grams of 4- hydroxy piperidines are added in gained mixture, interior temperature 80-90 DEG C is controlled, 7 hours are reacted.Then by reactant mixture
Filter, filter cake is washed with a small amount of ethyl acetate, after organic phase concentration 400 milliliters of ethyl acetate, resulting solution 2M/L salt are added
Aqueous acid is adjusted to pH=6, separates organic phase, and organic phase is washed again once with 2M/L aqueous hydrochloric acid solutions.Then gained water is in ice
PH=12 is adjusted to unsaturated carbonate aqueous solutions of potassium under bath, adds dichloromethane extraction, sodium sulphate to be dried, filtered, filter cake is used a small amount of
Dichloromethane is washed, and concentration is dry after organic phase merges, and obtains 73.7 grams of light yellow oil 1- (thiazol-2-yl) piperidines -4- alcohol,
Yield 81%.
Embodiment 3
8100 grams of 2- bromo thiazoles, 12300 grams of sodium carbonate and 10 liters of N, N- diformazans are added in the reaction bulb with agitator
Base formamide, 6000 grams of 4- hydroxy piperidines are added under room temperature in gained mixture, control interior temperature 50-60 DEG C, and reaction 15 is little
When.Then reactant mixture is added into 40 liters of ethyl acetate and 20 liters of saturated aqueous common salts, separates organic phase, continued with 20 liters of saturations
Twice, gained organic phase is adjusted to pH=6 to salt washing organic phase with 2M/L aqueous hydrochloric acid solutions, separates organic phase, and organic phase is used again
2M/L aqueous hydrochloric acid solutions are washed once.Then gained water is adjusted to pH=12 under ice bath with unsaturated carbonate aqueous solutions of potassium, adds two
Chloromethanes is extracted, and sodium sulphate is dried, and is filtered, and filter cake is washed with a small amount of dichloromethane, and concentration is dry after organic phase merges, and obtains 7370
Gram light yellow oil 1- (thiazol-2-yl) piperidines -4- alcohol, yield 81%, purity is more than 99%.
Embodiment 4
16.2 kilograms of 2- bromo thiazoles, 25 kilograms of sodium carbonate and 21 liters of acetonitriles, room are added in the reaction bulb with agitator
12.3 kilograms of 4- hydroxy piperidines are added in gained mixture under temperature, interior temperature 110-120 DEG C is controlled, 6 hours are reacted.Then will
Reactant mixture is filtered, and filter cake is washed with a small amount of ethyl acetate, adds 70 liters of ethyl acetate, resulting solution to use after organic phase concentration
2M/L aqueous hydrochloric acid solutions are adjusted to pH=6, separate organic phase, and organic phase is washed again once with 2M/L aqueous hydrochloric acid solutions.Then water obtained by
PH=12 is adjusted to unsaturated carbonate aqueous solutions of potassium under ice bath, adds dichloromethane extraction, sodium sulphate to be dried, filtered, filter cake
Washed with a small amount of dichloromethane, concentration is dry after organic phase merges, and obtains 15.11 kilograms of light yellow oils 1- (thiazol-2-yl)
Piperidines -4- alcohol, yield 83%, purity is more than 99%.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, on the premise of without departing from the technology of the present invention principle, some improvement and deformation can also be made, these improve and deform
Also should be regarded as protection scope of the present invention.
Claims (9)
1. a kind of synthetic method of 1- (thiazol-2-yl) piperidines -4- alcohol, it is characterised in that comprise the following steps：To equipped with 4- hydroxyls
In the reaction vessel of phenylpiperidines, 2- bromo thiazoles and solvent, alkali A is added, stirring reaction 6-16 hour, obtains slightly at 50-120 DEG C
Product, then post-process crude product, obtain 1- (thiazol-2-yl) piperidines -4- alcohol.
2. the synthetic method of 1- (thiazol-2-yl) piperidines -4- alcohol according to claim 1, it is characterised in that the crude product
Post-processing step include adjust PH：It is 5-7 first to adjust PH with acid, and it is 10-12 then to adjust PH with alkali B solution again.
3. the synthetic method of 1- (thiazol-2-yl) piperidines -4- alcohol according to claim 2, it is characterised in that post processing is also
The washing being included in before regulation PH, and extraction, drying and the filtration after PH is adjusted.
4. the synthetic method of 1- (thiazol-2-yl) piperidines -4- alcohol according to claim 2, it is characterised in that the acid is
Watery hydrochloric acid, the alkali B solution is unsaturated carbonate potassium solution or saturated sodium carbonate solution.
5. the synthetic method of 1- (thiazol-2-yl) piperidines -4- alcohol according to claim 4, it is characterised in that dilute salt
Acid concentration is 2M/L.
6. the synthetic method of 1- (thiazol-2-yl) piperidines -4- alcohol according to any one of claim 1-5, it is characterised in that
One or more of the solvent in toluene, acetonitrile, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide.
7. the synthetic method of 1- (thiazol-2-yl) piperidines -4- alcohol according to any one of claim 1-5, it is characterised in that
The alkali A is in -5- the alkene of 1,5- diazabicylos [5.4.0] 11, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, caustic alcohol
One or more.
8. the synthetic method of 1- (thiazol-2-yl) piperidines -4- alcohol according to any one of claim 1-5, it is characterised in that
The 4- hydroxy piperidines are 1.2～2.0 with the mol ratio of 2- bromo thiazoles:1.
9. the synthetic method of 1- (thiazol-2-yl) piperidines -4- alcohol according to any one of claim 1-5, it is characterised in that
The 2- bromo thiazoles are 1 with the mol ratio of alkali A:1.5～3.0.
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| CN201611159395.5A CN106632302A (en) | 2016-12-15 | 2016-12-15 | Synthesis method of 1-(thiazole-2-yl)piperidine-4-ol |
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| CN201611159395.5A CN106632302A (en) | 2016-12-15 | 2016-12-15 | Synthesis method of 1-(thiazole-2-yl)piperidine-4-ol |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201309639A (en) * | 2011-02-17 | 2013-03-01 | Lg Life Sciences Ltd | Oxime derivatives as GPR119 agonists |
| CN104918935A (en) * | 2012-11-16 | 2015-09-16 | 百时美施贵宝公司 | Dihydropyrazole gpr40 modulators |
| WO2016107832A1 (en) * | 2014-12-30 | 2016-07-07 | F. Hoffmann-La Roche Ag | Novel tetrahydropyridopyrimidines and tetrahydropyridopyridines for the treatment and prophylaxis of hepatitis b virus infection |
-
2016
- 2016-12-15 CN CN201611159395.5A patent/CN106632302A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201309639A (en) * | 2011-02-17 | 2013-03-01 | Lg Life Sciences Ltd | Oxime derivatives as GPR119 agonists |
| CN104918935A (en) * | 2012-11-16 | 2015-09-16 | 百时美施贵宝公司 | Dihydropyrazole gpr40 modulators |
| WO2016107832A1 (en) * | 2014-12-30 | 2016-07-07 | F. Hoffmann-La Roche Ag | Novel tetrahydropyridopyrimidines and tetrahydropyridopyridines for the treatment and prophylaxis of hepatitis b virus infection |
Non-Patent Citations (2)
| Title |
|---|
| 安德森著，胡文浩等译: "《实用有机合成工艺研发手册》", 31 January 2011, 科学出版社 * |
| 施韦特利克等编著，万均等译: "《有机合成实验手册》", 30 June 2010, 化学工业出版社 * |
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