CN103467376A - New method for preparation of meptazinol hydrochloride critical impurity - Google Patents

Abstract

The invention belongs to the field of pharmaceutical chemistry, relates to a new method for preparation of a meptazinol hydrochloride critical impurity, and particularly relates to the method for preparing the critical impurity 3-(3-ethoxy phenyl)-3-ethyl-1-methyl homopiperidine with 3-(3-hydroxy phenyl)-1-methyl-1H-hexahydroazepine-2-ketone (III) as a starting material and through a two-step reaction. The corresponding characterization of the compound is carried out, and the method is simple in operation.

Description

A kind of novel method for preparing the Wy-22811 critical impurities

Technical field

The present invention relates to the pharmaceutical chemistry field, be specifically related to the novel preparation method of a kind of Wy-22811 critical impurities compound (I).

Background technology

As above structural compounds (I) is a kind of Wy-22811 critical impurities, and its chemistry is by name: 3-(3-ethoxyl phenenyl)-3-ethyl-high piperidines of 1-methyl.

The Wy-22811 chemistry is by name: 3-(3-ethyl-1-methyl isophthalic acid H-six hydrogen azatropylidenes-3-yl) phenolate hydrochlorate.Within 1986, the hydrochloride with racemic modification goes on the market in Britain, and within 1998, British Pharmacopoeia records, and is to use at present the substitute of potent anodyne.Wy-22811 is one of 6 exciting antagonism analgesics of many national recommendations.The Wy-22811 chemical structure is similar to morphine, is the agonist of opium μ acceptor, is also the antagonist of μ acceptor.The anodyne of current clinical use is mostly with habituation. and by contrast, the side effect of Wy-22811 is little, without habituation, is the desirable substitutes such as morphine, dolantin, U-26225A.

Wy-22811 is at present in also not listing of China, China is for a long time to the narcotic analgesic stringent regulations, the kind of current potent anodyne is few, and the alternative medicine Wy-22811 of morphine commonly used and dolantin must have the great market requirement without habituation.This medicine went on the market in 1986, had experienced nearly 30 years in China still not listing, and possible reason: 1. the technique for preparing Wy-22811 is immature; 2. prepare Wy-22811 off quality, special impurity is arranged except not falling.

The contriver is in preparing the Wy-22811 process, obtained a new impurity of not reporting for work at British Pharmacopoeia, this impurity is very obstinate, be difficult to by methods such as recrystallizations it removal, so we has carried out the research work such as separation, preparation, sign to this impurity.

Summary of the invention

The contriver has explored and has developed a method for preparing Wy-22811 critical impurities compound (I).And this compound has been done to corresponding sign, as H-NMR, MS etc., this preparation method is simple to operate.

The present invention take that 3-(3-hydroxy phenyl)-1-methyl isophthalic acid H-six hydrogen azatropylidenes-2-ketone (III) is raw material, synthetic critical impurities (I), compound (III) is first docked with haloalkane and obtains compound (II), then lithium aluminium hydride reduction compound (II) obtains target compound (I), and syntheti c route is as follows:

This reaction scheme mainly carries out in two steps, and the first step is the docking reaction, and the use non-protonic solvent is reaction solvent, adds mineral alkali and haloalkane, and reaction at a certain temperature, by thin-layer chromatography (TLC) monitoring reaction progress.

Non-protonic solvent is chloroform, methylene dichloride, tetrahydrofuran (THF), wherein preferred chloroform.

Haloalkane is monobromethane, monochloroethane, and compound (III) is 1:1 ~ 1:3 with the equivalence ratio of monobromethane or monochloroethane, preferably 1:1.8.Preferred monobromethane.

The temperature of controlling is 20 ℃ of reflux temperatures to reaction system.

Mineral alkali is sodium carbonate, salt of wormwood, sodium hydride, sodium hydroxide, potassium hydroxide.

Second step is reduction process, uses lithium aluminum hydride as going back original reagent.

While preparing compound (I), solvent used is anhydrous tetrahydro furan, anhydrous diethyl ether, preferably anhydrous tetrahydro furan.

The boiling point that temperature of reaction while preparing compound (I) is solvent.

concrete embodiment

Following embodiment is to describe in detail the present invention, but should not be construed as limiting the invention.

Synthesizing of embodiment: 3-(3-the ethoxyl phenenyl)-high piperidines of 3-ethyl-1-methyl-2-ketone.

Embodiment one

Add 6.18 g reaction raw materials (III) in 50 mL there-necked flasks, add methylene dichloride 28 mL, add 3.18 g Na2CO3, add again monobromethane 4.90 g, start reflux, carry out situation by thin-layer chromatography (TLC) monitoring reaction, react 15 hours, raw material (III) is basic to disappear, stop heating, cooling, suction filtration, make to wash with water reaction solution, the concentrated by rotary evaporation organic phase, obtain slightly yellow solid of white, use ethyl acetate-sherwood oil mixed solvent to process and obtain white solid, this solid is placed in to dry 4 hours of 40 ℃ of air dry ovens to constant weight, be weighed as 5.85g, yield 85%, MS:276 [M+H]+.

Embodiment two

Add 6.18 g reaction raw materials (III) in 50 mL there-necked flasks, add trichloromethane 22 mL, add 3.18 g Na2CO3, add again monobromethane 4.90 g, start reflux, carry out situation by thin-layer chromatography (TLC) monitoring reaction, react 9 hours, raw material (III) is basic to disappear, stop heating, cooling, suction filtration, make to wash with water reaction solution, the concentrated by rotary evaporation organic phase, obtain slightly yellow solid of white, use ethyl acetate-sherwood oil mixed solvent to process and obtain white solid, this solid is placed in to dry 4 hours of 40 ℃ of air dry ovens to constant weight, be weighed as 6.20 g, yield 90%, MS:276 [M+H]+.

Embodiment three

Add 6.18 g reaction raw materials (III) in 50 mL there-necked flasks, add trichloromethane 22 mL, 6.62 g Na2CO3, monochloroethane 3.22 g, 0.25 g KI, start reflux, carry out situation by thin-layer chromatography (TLC) monitoring reaction, react 20 hours, raw material (III) is basic to disappear, stop heating, cooling, suction filtration, make to wash with water reaction solution, the concentrated by rotary evaporation organic phase, obtain slightly yellow solid of white, use ethyl acetate-sherwood oil mixed solvent to process and obtain white solid, this solid is placed in to dry 4 hours of 40 ℃ of air dry ovens to constant weight, be weighed as 4.95g, yield 72%, MS:276 [M+H]+.

Embodiment: the preparation of impurity 3-(3-ethoxyl phenenyl)-3-ethyl-high piperidines of 1-methyl

Embodiment four

Add anhydrous tetrahydro furan 30 mL in 50 mL there-necked flasks, add lithium aluminum hydride 1.9 g at the temperature of ice bath, after stirring for some time, add again 3-(3-ethoxyl phenenyl)-high piperidines of 3-ethyl-1-methyl-2-ketone (II) 5.5 g in batches, start reflux, carry out situation by thin-layer chromatography (TLC) monitoring reaction, react 5 hours, reaction completes substantially, raw material point disappears, stop heating, cooling, add slowly water in reaction system, destroy unreacted lithium aluminum hydride, suction filtration, washing, the filtrate water washing, separatory, dry organic phase concentrated by rotary evaporation obtain oily matter, oily matter passes through column chromatography for separation, obtain colorless oil, in 40 ℃ of drying under reduced pressure to constant weight, be 3.6 g, yield 69%, 1H-NMR (CDCl3) δ 0.58 (t, 3H), 1.40 (t, 3H), 1.54 (q, 2H), 1.61-1.75 (m, 5H), 2.13 (q, 1H), 2.38 (s, 3H), 2.42-2.59 (m, 3H), 2.83 (s, 1H), 4.02 (q, 2H), 6.68 (d, 1H), 6.68-6.89 (m, 2H), 7.2 (t, 1H). MS:262 [M+H]+.

Embodiment five

Add anhydrous diethyl ether 30 mL in 50 mL there-necked flasks, add lithium aluminum hydride 1.9 g at the temperature of ice bath, after stirring for some time, add again 3-(3-ethoxyl phenenyl)-high piperidines of 3-ethyl-1-methyl-2-ketone (II) 5.5 g in batches, start reflux, carry out situation by thin-layer chromatography (TLC) monitoring reaction, react 12 hours, reaction completes substantially, raw material point disappears, stop heating, cooling, add slowly water in reaction system, destroy unreacted lithium aluminum hydride, suction filtration, washing, the filtrate water washing, separatory, dry organic phase concentrated by rotary evaporation obtain oily matter, oily matter passes through column chromatography for separation, obtain colorless oil, in 40 ℃ of drying under reduced pressure to constant weight, be 3.4 g, yield 65%, 1H-NMR (CDCl3) δ 0.58 (t, 3H), 1.40 (t, 3H), 1.54 (q, 2H), 1.61-1.75 (m, 5H), 2.13 (q, 1H), 2.38 (s, 3H), 2.42-2.59 (m, 3H), 2.83 (s, 1H), 4.02 (q, 2H), 6.68 (d, 1H), 6.68-6.89 (m, 2H), 7.2 (t, 1H). MS:262 [M+H]+. ?

Claims (9)

1. the syntheti c route of a Wy-22811 critical impurities (I) is as follows, it is characterized in that using compound (III) is raw material, under the effect of mineral alkali, compound (III) docks in non-protonic solvent with haloalkane and prepares compound (II), in compound (II) prepares the process of compound (I), use tetrahydrofuran (THF) or ether to make solvent, lithium aluminum hydride obtains target compound (I) for going back original reagent

。

2. according to the method for claim 1, haloalkane is monobromethane, monochloroethane.

3. according to the method for claim 1, the mineral alkali while preparing compound (II) is sodium carbonate, salt of wormwood, sodium hydride, sodium hydroxide, potassium hydroxide.

4. according to the method for claim 1, non-protonic solvent is chloroform, methylene dichloride, tetrahydrofuran (THF).

5. according to the method for claim 4, non-protonic solvent is chloroform.

6. according to the method for claim 1, compound (III) is 1:1 ~ 1:3 with the equivalence ratio of haloalkane.

7. according to the method for claim 6, compound (III) is 1:1.8 with the equivalence ratio of haloalkane.

8. according to the method for claim 1, the temperature of reaction for preparing compound (II) is 20 ℃ of reflux temperatures to reaction system.

9. according to the method for claim 1, using anhydrous tetrahydro furan while preparing compound (I) is solvent.