CN103539677B - Preparation method of 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride - Google Patents

Abstract

The invention belongs to the technical field of synthesis of a medical immediate, and particularly relates to a synthesis method of a key intermediate 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride of indacaterol. The method comprises the following steps: by taking ethylbenzene as a raw material, preparing a compound I by propionyl chloride; preparing a compound II from the compound I by cyclization reaction; preparing a compound III by reaction of the compound II and butyl nitrite; preparing a compound IV from the compound III by palladium hydrogen reduction; finally preparing a compound V from the compound IV under protection of trifluoroacetyl; preparing a compound VI from the compound V by amino acetylation reaction; preparing a compound VII from the compound VI by reduction; carrying out deprotection, hydrolysis and acidification on the compound VII, so as to obtain the final product compound VIII, namely the 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride. The method disclosed by the invention is simple and convenient to operate, reasonable in reaction flow, low in cost, good in product quality, free of pollution to environment, and applicable to industrial production; the content is greater than 99%.

Description

A kind of preparation method of 5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate

Technical field

The present invention relates to the synthesis technical field of medicine intermediate, be specifically related to a kind of synthetic method of key intermediate 5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate of QAB-149.

Background technology

QAB-149 is that a kind of Novel ultralong developed by Novartis Co., Ltd of Switzerland imitates beta 2 receptor agonist.This medicine obtains U.S. FDA approval listing on July 1st, 2011.This medicine is used for there is chronic bronchial obstruction disease (COPD) airflow obstruction patient, comprises chronic bronchitis and/or emophysematous treatment.5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate is as the intermediate of QAB-149 most critical, and therefore its market outlook and economic benefit have very large potentiality.

5; 6-diethyl-2; 3-dihydro-1H-indenes-2-amine hydrochlorate at document (as Organic Process Research & Development 2006; 10; 135141) synthetic method reported is mainly with 2; 3-dihydro-1H-indenes-2-amine is raw material, protects amino through trifluoroacetylation, then through twice chloroacetylation and twice palladium hydrogenated carbon reduction finally goes protection salify to obtain finalization compound again.And raw material 2,3-dihydro-1H-indenes-2-amine is rare on market and expensive commodity, there is a definite limitation to the suitability for industrialized production of 5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate.

Summary of the invention

For the deficiencies in the prior art, the object of the present invention is to provide a kind of novel synthesis of compound 5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate.

Technical conceive of the present invention is: with commercial be easy to get and the ethylbenzene of cheapness instead of bibliographical information with 2,3-dihydro-1H-indenes-2-amine as starting raw material, propionating through chlorine; cyclisation; oximate, palladium hydrogenated carbon reduces, amido protecting; acetylize; reduction, goes protection and salify thus obtain the finished product, i.e. the intermediate 5 of QAB-149; 6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate.

The technical scheme realizing the object of the invention is as follows:

A kind of preparation method of 5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate, its step is as follows:

(1) ethylbenzene take methylene dichloride as solvent, and aluminum chloride is promotor, and through 3 chlorpromazine chloride acidylates under-5-25 ° of C, reactant is through extracting dry chemical compounds I, and wherein ethylbenzene, 3-chlorpromazine chloride, aluminum chloride consumption mol ratio are 1:1-2:1-2;

(2) chemical compounds I is dissolved in the vitriol oil under-5-5 ° of C, reheats 90-100oC and carries out cyclization, and then extract drying and obtain compound ii, wherein the consumption mass ratio of chemical compounds I and the vitriol oil is 1:4-6;

(3) compound ii take concentrated hydrochloric acid as promotor, methyl alcohol is solvent, under 40 DEG C of conditions, obtain compound III through nitrous acid straight butyl oximation reaction, reactant crystallization, drying, the consumption mol ratio of compound ii, nitrous acid straight butyl, concentrated hydrochloric acid (HCl wherein) three is 1:1-1.5:1-2;

(4) compound III take glacial acetic acid as solvent, and the vitriol oil is that promotor obtains compounds Ⅳ through under high pressure hydro-reduction, reactant extraction, the drying of palladium carbon, and the mass ratio of compound III, palladium charcoal, vitriol oil three is 1:0.1-0.3:1-3;

(5) compounds Ⅳ is solvent with ethyl acetate, in nitrogen, under 0-7 ° of C through Trifluoroacetic Acid Ethyl Ester trifluoroacetylation protection, room temperature reaction, cross post, dry compound V, the consumption mol ratio of compounds Ⅳ and Trifluoroacetic Acid Ethyl Ester is 1:1-2;

(6) compound V take methylene dichloride as solvent, aluminum chloride is promotor, in nitrogen, obtain compound VI under 0-5 DEG C of condition through Acetyl Chloride 98Min. acidylate, extraction, drying, recrystallization, excessively post, the consumption mol ratio of compound V, Acetyl Chloride 98Min., aluminum chloride three is 1:2-4:2-4;

(7) compound VI take trifluoroacetic acid as solvent, and through the reduction of triethyl silicane room temperature, neutralization, extraction, crystallization, dry compound VII, compound VI is 1:2-5 with the consumption mol ratio of triethyl silicane;

(8) compound VII is with after dissolve with methanol, add sodium hydroxide solution to be at room temperature hydrolyzed, through extraction, in ether solvent, logical hydrogen chloride gas is acidified after drying, after completion of the reaction suction filtration, dry compound VIII, and compound VII is 1:8-12 with the consumption mol ratio of sodium hydroxide.Reaction principle is as follows:

Compared with prior art, the advantage of technical solution of the present invention and beneficial effect are:

1, the ethylbenzene be easy to get with business instead of bibliographical information with 2,3-dihydro-1H-indenes-2-amine as starting raw material, industrializing implementation is more prone to.

2, because material ethylbenzene is cheap, the production cost of the finished product is about only about 50% of existing method cost.

Embodiment

Applicant will further illustrate method of the present invention in conjunction with specific embodiments below, but following content should not be construed as the restriction to claims of the present invention request protection domain.

Embodiment 1:

A kind of preparation method of 5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate, its step is as follows:

(1) synthesis of chemical compounds I

Aluminum chloride 780g and methylene dichloride 8L is dropped in 10L there-necked flask, be cooled to-1-1 DEG C, drip 600g3-chlorpromazine chloride, drip off rear reaction 30min, drip ethylbenzene 500g again, after dropwising, rise to room temperature (20-25 DEG C) reaction 8h, then reactant is poured into extraction in 10L1M hydrochloric acid frozen water (the frozen water mixed solution of hydrochloric acid) and go out, dichloromethane extraction, saturated sodium bicarbonate washing once, is washed once, anhydrous sodium sulfate drying, be spin-dried for, then freezing and crystallizing, dry 847g solid, fusing point 63-64 DEG C, product is confirmed through nuclear-magnetism, yield 90%.

(2) synthesis of compound ii

98% vitriol oil 1.5L drops in 3L there-necked flask, cryosel bath is cooled to-1 DEG C-1 DEG C, and slowly (within 10 minutes, adding) adds chemical compounds I 500g, goes to oil bath after adding, be warming up to 90 DEG C, reaction 2h, then reactant is poured in trash ice, extraction into ethyl acetate, saturated sodium bicarbonate washing once, once, anhydrous sodium sulfate drying, is spin-dried for obtain brown oil solid 347g in water washing.Fusing point 42-44 DEG C, yield 85%, product is confirmed through nuclear-magnetism.

(3) synthesis of compound III

Compound ii 232g is added in there-necked flask, methyl alcohol 1.5L, control temperature 23-28 DEG C, drips nitrous acid straight butyl 164g, drips off rear reaction 30min, then 36wt% concentrated hydrochloric acid 145mL is dripped, under 40 DEG C of conditions, react 3h after dripping off, screw out partial solvent to about 400mL, refrigerator freezing crystallization, suction filtration, obtains yellow solid 191g.Fusing point 177-178 DEG C, yield 70%, product is confirmed through nuclear-magnetism.

(4) synthesis of compounds Ⅳ

By 60g compound III, 15g10% palladium carbon (10%Pd/C), 80mL98% sulfuric acid, 0.8L glacial acetic acid adds hydrogenation in autoclave and, to 12bar, reacts 24h, then filter, screw out part glacial acetic acid to about 200mL, regulate pH to 11, through dichloromethane extraction with sodium hydroxide solution, anhydrous sodium sulfate drying, is spin-dried for obtain 39g oily matter.Yield 78%, product is confirmed through nuclear-magnetism.

(5) synthesis of compound V

Compounds Ⅳ 31g is added in there-necked flask, ethyl acetate 200mL, logical nitrogen, ice bath is cooled to 0-5 DEG C, drips Trifluoroacetic Acid Ethyl Ester 33g, after dripping off, 3-7 DEG C of reaction 2h, then room temperature (20-25 DEG C) is reacted 12 hours, is spin-dried for, dissolve with 100mL methylene dichloride, after filtered through silica gel, be spin-dried for obtain 44g product.Fusing point 112-114 DEG C, product is confirmed through nuclear-magnetism, yield 90%.

(6) synthesis of compound VI

In there-necked flask, add aluminum chloride 58g, methylene dichloride 400mL, cryosel bath temperature control is to 0-5 DEG C, and logical nitrogen, drips Acetyl Chloride 98Min. 41g, drip off rear reaction 30min, then drips the dichloromethane solution 100mL containing 45g compound V, drips off rear reaction 1h.Reactant is poured in 1M hydrochloric acid frozen water to extract and is gone out, through dichloromethane extraction, saturated sodium bicarbonate solution washing once, once, anhydrous sodium sulfate drying, is spin-dried for obtain 51g solid in washing, be that the methylene dichloride of 1:3 and normal hexane mixed solvent recrystallization obtain 26g pure compound VI by volume ratio, mother liquor is spin-dried for post and is separated to obtain 23g compound VI, and product is confirmed through nuclear-magnetism, productive rate 87%.

(7) synthesis of compound VII

With 320mL trifluoroacetic acid, 71g compound VI is dissolved, slowly drip triethyl silicane 160mL, under within 10 minutes, dripping off rear room temperature (20-25 DEG C), react 12h.Pour extraction in frozen water into go out, be adjusted to neutrality, extraction into ethyl acetate, add 100mL sherwood oil, freezing and crystallizing after being spin-dried for solvent with the sodium hydroxide solution of 4M, suction filtration is dry obtains 65g compound VII, and fusing point 159.0-159.5 DEG C, productive rate 96%, product is confirmed through nuclear-magnetism.

(8) synthesis of compound VIII

50g compound VII 250mL dissolve with methanol, adds 250mL5M sodium hydroxide solution, room temperature (20-25 DEG C) reaction 8h, then add water 500mL, and dichloromethane extraction, is spin-dried for solvent, add 600mL ether dissolution, then pass into hydrogen chloride gas, until TLC display reaction is complete, stop ventilation, suction filtration, is drying to obtain compound VIII 5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate 33g, productive rate 100%, purity 99.1%, fusing point more than 250 DEG C.Product is confirmed through nuclear-magnetism.

Claims (1)

1. the preparation method of diethyl-2, a 3-dihydro-1H-indenes-2-amine hydrochlorate, its step is as follows:

(1) ethylbenzene take methylene dichloride as solvent, and aluminum chloride is promotor, and through 3-chlorpromazine chloride acidylate under-5-25oC, reactant is through extracting dry chemical compounds I;

(2) chemical compounds I is dissolved in the vitriol oil under-5-5oC, reheats 90-100 ^oc carries out cyclization, then extracts drying and obtains compound ii;

(3) compound ii take concentrated hydrochloric acid as promotor, and methyl alcohol is solvent, under 40 DEG C of conditions, obtains compound III through nitrous acid straight butyl oximation reaction, reactant crystallization, drying;

(4) compound III take glacial acetic acid as solvent, and the vitriol oil is that promotor obtains compounds Ⅳ through under high pressure hydro-reduction, reactant extraction, the drying of palladium charcoal;

(5) compounds Ⅳ is solvent with ethyl acetate, in nitrogen, under 0-7oC through Trifluoroacetic Acid Ethyl Ester trifluoroacetylation protection, room temperature reaction, cross post, dry compound V;

(6) compound V take methylene dichloride as solvent, and aluminum chloride is promotor, in nitrogen, obtain compound VI under 0-5 DEG C of condition through Acetyl Chloride 98Min. acidylate, extraction, drying, recrystallization, excessively post;

(7) compound VI take trifluoroacetic acid as solvent, through the reduction of triethyl silicane room temperature, neutralization, extraction, crystallization, dry compound VII;

(8) compound VII is with after dissolve with methanol, adds sodium hydroxide solution and is at room temperature hydrolyzed, and through extraction, in ether solvent, logical hydrogen chloride gas is acidified after drying, after completion of the reaction suction filtration, dry product compound VIII;

In described step (1), ethylbenzene, 3-chlorpromazine chloride, aluminum chloride consumption mol ratio are 1:1-2:1-2;

In described step (2), the consumption mass ratio of chemical compounds I and the vitriol oil is 1:4-6, and vitriol oil concentration is 98wt%;

In described step (3), the consumption mol ratio of compound ii, nitrous acid straight butyl, concentrated hydrochloric acid three is 1:1-1.5:1-2, and the concentration of described concentrated hydrochloric acid is 36wt%;

In described step (4), the mass ratio of compound III, palladium charcoal, vitriol oil three is 1:0.1-0.3:1-3, and hydrogenation pressure is 10-12bar, and this step reaction makes solvent with glacial acetic acid, and palladium charcoal is 10% palladium charcoal, and vitriol oil concentration is 98wt%;

In described step (5), the consumption mol ratio of compounds Ⅳ and Trifluoroacetic Acid Ethyl Ester is 1:1-2;

In described step (6), the consumption mol ratio of compound V, Acetyl Chloride 98Min., aluminum chloride three is 1:2-4:2-4;

In described step (7), compound VI is 1:2-5 with the consumption mol ratio of triethyl silicane, and this step reaction makes solvent with trifluoroacetic acid;

In described step (8), compound VII is 1:8-12 with the consumption mol ratio of sodium hydroxide.