CN101029044A - Method for preparing 3-(imidazole-4) pyridine - Google Patents

Abstract

A process for preparing 3-(imidazole-4-yl) pyridine from 3-acetylpyridine includes such steps as oximating, acylating by toluenesulfonyl chloride, acting on alkali, opening ring by acid to become amine, cyclizing with potassium thiocyanate and removing mercapto radical.

Description

A kind of method for preparing 3-(imidazol-4 yl) pyridine

Technical field:

The present invention relates to the method for a kind of 3-of preparation (imidazol-4 yl) pyridine, this compound can be used for synthetic Macrocyclolactone lactone kind medicine such as Ketek etc. as organic synthesis intermediate at field of medicaments.

Background technology:

People such as George are at J.Chem.Soc.1938, and 753-755 has reported the synthetic route of 3-(imidazol-4 yl) pyridine:

In this route, one step of oximate uses triethylamine, need increase the recycling operation when producing amplification; Become the amine step to use potassium metal, operational danger is big, and the cost height also is unfavorable for suitability for industrialized production; When taking off sulfydryl, produce a large amount of toxic gases rapidly, also have the danger of dashing the material blast, amplify reaction and be difficult to control with 10% nitric acid oxidation.

People such as Yi Hong are at Chinese Journal of Pharmaceuticals, and 2004,35 (2): people's unanimities such as synthetic route George that 69-70 describes, becoming the ring step to increase Catalyzed by p-Toluenesulfonic Acid, all the other operate no significant improvement.

People such as You Qidong have adopted following synthetic route in CN200610037850:

In this route, bromination uses toxicity and the strong liquid bromine of corrodibility; Become the amine step need use expensive sodium iodide; Take off the sulfydryl step and have uppity problem equally.

Summary of the invention:

The objective of the invention is at the deficiencies in the prior art, a kind of processing method of preparation 3-(imidazol-4 yl) pyridine is provided, make technology more meet the suitability for industrialized production requirement.

The objective of the invention is to solve by following technical solution:

Reaction formula of the present invention is as follows:

Wherein:

(II) be the compound 3-acetylpyridine

(III) be compound 3-acetylpyridine oxime

(IV) be compound O-tolysulfonyl-3-acetylpyridine oxime

(V) be compound salt 3-(Norleucyl base) pyridine hydrochloric acid

(VI) be compound 3-(2-mercaptoimidazole-4-yl) pyridine hydrochloride

(I) be The compounds of this invention-3-(imidazoles 4-yl) pyridine

The present invention includes the following step:

(a), raw material (II) is dissolved in the alcoholic solvent, add oxammonium hydrochloride, drop into supercarbonate in batches, suitable temperature reaction for some time, cooling;

(b), filter, filtrate is concentrated into dried, add entry stir diffusing, ethyl acetate extraction, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying;

(c), the concentrating under reduced pressure crystallization, product vacuum-drying gets (III);

(d), (III) dissolved cooling in pyridine, add Tosyl chloride in batches, stir for some time, in the impouring mixture of ice and water.Filter crude product;

(e), crude product recrystallization in 50% ethanolic soln, vacuum-drying gets (IV);

(f), (IV) is dissolved in the dehydrated alcohol adding highly basic, stirring, ice bath cooling, the sour excessive alkali that neutralizes of adding;

(g), add isopropyl ether, filter, add hydrochloric acid in the solution to neutral, the alcoholic solution that adds hydrogenchloride is to pH2～3;

(h), filter, solid vacuum-drying gets product (V);

(i), (V) is dissolved in the hot water, the noble gas protection adds potassium sulfocyanate, catalyzer down, reacting by heating for some time, cooling;

(j), filter, solid vacuum-drying gets (VI);

(k), (VI) is dissolved in the water, add oxygenant, stir for some time, add alkaline solution to pH10～12, stirring at room for some time;

(l), be evaporated to driedly, add isopropyl ether and extract, concentrate, vacuum-drying gets product (I).

The present invention compared with prior art has following advantage and effect:

In the present invention, replace triethylamine, and need not to use ammoniacal liquor, reduced three wastes generation, reduced production cost with mineral alkali; Become the amine step to use the excessive alkali of acid neutralization earlier, add sour open loop again, stable reaction, yield improves, and purifying is realized easily; One-tenth ring step is used catalyzer and is carried out under protection of inert gas, yield is obviously improved, the product purity height; Oxidation step has been avoided the toxic gas generation, and can eliminate the unsafe factor that dashes the material blast, has guaranteed to produce the feasibility of amplifying.

Embodiment:

The invention will be further described below in conjunction with specific embodiment, but the present invention is not subjected to the qualification of these embodiment.

The 3-acetylpyridine that the present invention uses provides by rising state auspicious first spices company limited; Gas bomb is contained by Guangzhou and is full of Gas Plant and provides; Potassium ethylate is provided by your chemical company limited of the rich happiness in Zibo; All the other raw materials are analytical pure or chemical pure.

Melting point compound is measured by WRS-1B numeral fusing point instrument, and temperature is not calibrated. ¹HNMR spectrum is measured by Bruker AVANCE AV 400 types or Varian INOVA 500Nb type nuclear magnetic resonance spectrometer.Mass spectrum is measured by Finnigan LCQDECA XP high performance liquid phase-GC-MS.

Embodiment 1:

1) preparation 3-acetylpyridine oxime (III)

3-acetylpyridine (II) 50.0g (0.413mol) is dissolved in the 200ml ethanol, adds oxammonium hydrochloride 43.1g (0.612mol) and drop into sodium bicarbonate 59.0g (0.702mol) in batches, produce a large amount of gases, be heated to 50 ℃, stirring reaction 4 hours.Be cooled to room temperature, filter, filtrate is concentrated into dried, adds 80ml water and stirs diffusing solid, use the 80ml ethyl acetate extraction, water layer is used the 50ml ethyl acetate extraction once again, and the combined ethyl acetate layer is with saturated nacl aqueous solution 2 * 50ml washing, anhydrous sodium sulfate drying, be evaporated to dried, compound (III) 52.2g (yield 92.6%), mp114～117 ℃.

MS-ESI(m/z)：137(M+1)

2) preparation O-tolysulfonyl-3-acetylpyridine oxime (IV)

According to document J.Chem.Soc.1938,753-755 is synthetic: compound (III) 85g (0.625mol), add in the 225ml pyridine and dissolve, be cooled to 0～5 ℃, slowly add Tosyl chloride 125.1g (0.656mol), kept 0～5 ℃ of stirring reaction 6 hours, stirred in the impouring 13000ml mixture of ice and water 0.5 hour, filter white solid, solid is with 350ml ethanol heating for dissolving, stir in the following impouring 400ml water, separate out white solid, filter 30 ℃ of vacuum-dryings, compound (IV) 173.6g (yield 95.7%), mp81～83 ℃.

MS-ESI(m/z)：291(M+1)

3) preparation 3-(Norleucyl base) pyridine hydrochloride (V)

Compound (IV) 73.8g (0.254mol) adds in the absolute dehydrated alcohol of 120ml, drips 25%

Potassium ethylate ethanolic soln 120.0g (0.356mol), stirring reaction is 3.5 hours under the room temperature, is cooled to below 10 ℃, add tosic acid 17.2g (0.100mol), stir, add the 800ml isopropyl ether, stirred 1 hour below 10 ℃, filter, filter cake washs with the 100ml isopropyl ether, and merging filtrate adds the 17ml concentrated hydrochloric acid and transfers to neutrality in the filtrate, add 30% ethanol solution of hydrogen chloride 55ml to pH2～3 again, separate out orange-yellow

Solid stirred 0.5 hour below 10 ℃, filters, and filter cake 50ml absolute ethanol washing, 50 ℃ of vacuum-dryings get compound (V) 51.7g (yield 97.3%), mp180 ℃ (decomposition).

4) preparation 3-(2-mercaptoimidazole-4-yl) pyridine hydrochloride (VI)

Method A

Dissolve in compound (V) 34.2g (0.164mol) the adding 150ml water; under the nitrogen protection; add potassium sulfocyanate 24.0g (0.246mol), trifluoroacetic acid 0.75g (6.6mmol) is heated to 90 ℃ of reactions 3.5 hours; being cooled to 0～5 ℃ stirred 2 hours; filter filter cake absolute ethanol washing, 50 ℃ of vacuum-dryings; get compound (VI) 35.4g (yield 86.3%), mp241-243 ℃.

MS-ESI(m/z)：178(M+1)

Method B

Dissolve in compound (V) 25.0g (0.120mol) the adding 110ml water; under the nitrogen protection; add potassium sulfocyanate 17.6g (0.180mol), hydrochloric acid 1.0ml (12mmol) is heated to 90 ℃ of reactions 3.5 hours; being cooled to 0～5 ℃ stirred 2 hours; filter filter cake absolute ethanol washing, 50 ℃ of vacuum-dryings; get compound (VI) 21.5g (yield 71.7%), mp241-243 ℃.

Method C

Dissolve in compound (V) 25.0g (0.120mol) the adding 110ml water; under the argon shield; add potassium sulfocyanate 17.6g (0.180mol), phosphatase 11 .77g (18mmol) is heated to 90 ℃ of reactions 3.5 hours; being cooled to 0～5 ℃ stirred 2 hours; filter filter cake absolute ethanol washing, 50 ℃ of vacuum-dryings; get compound (VI) 19.9g (yield 66.3%), mp241-243 ℃.

5) preparation 3-(imidazoles 4-yl) pyridine (I)

Compound (VI) 20.0g (80mmol) is dissolved in the 250ml water, be cooled to 10 ℃, drip 30% superoxol 22.5g (200mmol) in 1 hour, rise to room temperature, drip saturated sodium bicarbonate sodium solution 180ml, stirred 1 hour, add the 0.5g gac and add heat decoloring, filter, filtrate is concentrated into dried, add isopropyl ether 100ml in the solid and extract, solution concentration to do light yellow oil, get compound (I) 7.3g (yield 62.9%) with isopropyl ether/sherwood oil (1: 3) recrystallization, mp117～118 ℃.

MS-ESI(m/z)：146(M+1)

¹HNMR(CDCl ₃)ppm：7.31(m，1H，H5，)，7.44(s，1H，H’2)，7.77(s，1H，H’5)，8.07(d，J＝8Hz，1H，H4)，8.45(dd，J＝4、2Hz，1H，H6)，9.00(s，1H，H ₂)。

It only is preferred embodiment of the present invention that above institute is chatted, thus all according to described feature of the present patent application claim and method, be included in the present patent application claim.

Claims (8)

1, a kind of method for preparing 3-(imidazol-4 yl) pyridine, it is characterized in that: described method comprises the following steps:

3-acetylpyridine (II) and oxammonium hydrochloride generate compound 3-acetylpyridine oxime (III) under the effect of mineral alkali; Obtain compound O-tolysulfonyl-3-acetylpyridine oxime (IV) with the Tosyl chloride effect; After the alkali effect, earlier with the excessive alkali of acid neutralization, again through sour open loop and then obtain compound salt 3-(Norleucyl base) pyridine hydrochloric acid (V); With potassium sulfocyanate under protection of inert gas, obtain compound 3-(2-mercaptoimidazole-4-yl) pyridine hydrochloride (VI) through catalyst action; Oxidation obtains compound-3-(imidazoles 4-yl) pyridine (I).

2, a kind of method for preparing 3-(imidazol-4 yl) pyridine according to claim 1 is characterized in that: during compound (II) preparation compound (III), the mineral alkali that uses is yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus.

3, a kind of method for preparing 3-(imidazol-4 yl) pyridine according to claim 1 is characterized in that: during compound (IV) preparation compound (V), use the excessive alkali of acid neutralization; The acid of using comprises sulfuric acid, tosic acid, hydrogenchloride.

4, a kind of method for preparing 3-(imidazol-4 yl) pyridine according to claim 1 is characterized in that: during compound (IV) preparation compound (V), use the alcoholic solution open loop of hydrogenchloride; The alcoholic solution of hydrogenchloride comprises hydrogenchloride-methanol solution, hydrogenchloride-ethanolic soln, hydrogenchloride-aqueous isopropanol, hydrogenchloride-isobutanol solution.

5, a kind of method for preparing 3-(imidazol-4 yl) pyridine according to claim 1 is characterized in that: during compound (V) preparation compound (VI), making blanketing with inert gas gas is nitrogen or argon gas.

6, a kind of method for preparing 3-(imidazol-4 yl) pyridine according to claim 1 is characterized in that: during compound (V) preparation compound (VI), use the catalyst reaction; Catalyzer comprises hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid and their salt; The amount of the catalyzer that uses is 1～15% of compound (V).

7, a kind of method for preparing 3-(imidazol-4 yl) pyridine according to claim 1 is characterized in that: during compound (VI) preparation compound (I), the oxygenant that uses is hydrogen peroxide; The consumption of oxygenant is 2～4 times of molar weights of compound (VI).