CN101245072B

CN101245072B - Intermediates for the preparation of prasugrel and methods for their preparation

Info

Publication number: CN101245072B
Application number: CN2008100349958A
Authority: CN
Inventors: 吴雪松; 岑均达; 郭珩
Original assignee: Shanghai Institute of Pharmaceutical Industry
Current assignee: Shanghai Institute of Pharmaceutical Industry
Priority date: 2008-03-21
Filing date: 2008-03-21
Publication date: 2011-03-30
Anticipated expiration: 2028-03-21
Also published as: CN101245072A

Abstract

The invention discloses a new intermediate of Prasugrel, the structural formula of which is shown as the figure. The preparation of the Prasugrel by adopting the intermediate of the invention has mild reaction condition and higher yield than that of an existing preparation method, and is economical and effective, thus being suitable for large-scale industrial production.

Description

Intermediate of preparation prasugrel and preparation method thereof

Technical field

The present invention relates to a kind of intermediate and preparation method thereof technical field of prasugrel.

Background technology

Thrombus can make main organs generation ischemic and infraction, also can cause oedema and venous insufficiency, thereby causes various dysfunctions.Being used for clinical antithrombotic at present, to represent medicine be acetylsalicylic acid, clopidogrel and A Xi monoclonal antibody.The action intensity of clopidogrel is stronger than acetylsalicylic acid, side effect is little, clinical in-stent restenosis behind atheromatosis, acute coronary syndrome, the prevention coronary artery Stent and thrombotic complications etc. of being used for the treatment of.Prasugrel is and similar tetramethylene sulfide of clopidogrel and pyridine compounds and their that clinical three phases demonstrate activity, tolerance and the security that is better than clopidogrel, are expected to become a good antithrombotic reagent.The chemical name of prasugrel is: 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, and the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structural formula is as follows:

Chinese patent 92111584 discloses a kind of synthetic method of prasugrel, and its synthetic route is as follows:

This method is with 2-oxygen-2; 4; 5,6,7; 7 α-six hydrogen thieno-[3; 2-c] pyridine (formula 1 compound) and alpha-brominated adjacent luorobenzyl cyclopropyl ketone (formula 2 compounds) is raw material, reaction obtains 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-2,4 under alkaline condition; 5; 6,7,7a-six hydrogen thieno-s [3; 2-c] pyridine (formula 3 compounds); acidylate obtains 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6 then; the 7-tetramethylene sulfide is [3,2-c] pyridine (being prasugrel) also.

But the defective of aforesaid method is that formula (1) compound is as the important source material of preparation prasugrel, and not cheap industrial goods can be bought on market at present.And in U.S. Pat 470510 disclosed prior aries, its synthetic method is by 4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine obtains 5-trityl-2-oxygen-2 with n-Butyl Lithium, tributyl borate reaction at low temperatures, 4,5,6,7 α-six hydrogen thieno-s [3,2-c] pyridine, last and formic acid react and obtain.Its reaction conditions is relatively harsher, needs-40 ℃ low temperature, and n-Butyl Lithium is inflammable and explosive simultaneously, can bring danger to scale operation.

In view of the good prospect in medicine of prasugrel, therefore need the intermediate of the preparation prasugrel of a kind of economy of exploitation, safety.

Summary of the invention

One of purpose of the present invention just provides a kind of new intermediate for preparing prasugrel, uses the synthetic prasugrel of this intermediate to overcome the above-mentioned defective of prior art, be very suitable for the big production of industry, and yield is than existing method height.

Another object of the present invention provides a kind of above-mentioned intermediates preparation.

The present inventor has found a kind of suitable prasugrel intermediate through a large amount of experiments, utilizes this intermediate to prepare prasugrel, not only stable reaction, yield height, and reaction conditions gentleness.Concrete technical scheme is as follows:

The intermediate of preparation prasugrel, the i.e. compound of following formula (IV):

Wherein X represents Cl or Br.

The intermediates preparation of above-mentioned preparation prasugrel comprises

Step 1: formula (I) compound and formula (II) compound react under alkaline condition

Obtain formula (III) compound,

Step 2: the halogenation of formula (III) compound obtains formula (IV) compound,

Wherein X represents Br or Cl.

Above-mentioned step 1, used solvent is well known by persons skilled in the art during reaction, comprises alcohol, ester class, methylene dichloride, tetrahydrofuran (THF), benzene, toluene, acetonitrile, DMF etc., preferred acetonitrile and DMF, more preferably DMF.Temperature of reaction is according to used solvent, and those skilled in the art can select best temperature range.Operable alkali comprises mineral alkali and organic bases, as yellow soda ash, salt of wormwood, sodium bicarbonate, sodium hydroxide, triethylamine, diisopropylethylamine etc., and preferred mineral alkali such as yellow soda ash, salt of wormwood etc.Can also add catalyzer such as sodium iodide, potassiumiodide etc. in addition.

Above-mentioned step 2 preferably uses hydrobromic acid solution and hydrogen peroxide as halogenating agent during halogenating reaction, also can use bromine as catalyzer.

Beneficial effect of the present invention: the present invention has found a kind of new prasugrel intermediate 2-bromo-5-benzyl-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine or 2-chloro-5-benzyl-4,5 also, 6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, prepares prasugrel with it, the reaction conditions gentleness, and yield is than prior preparation method height, and economical and effective is suitable for large-scale industrial production.

Embodiment

Preferred embodiment with concrete operations with reference to the following examples.

Embodiment 1～2

5-benzyl-4,5,6,7-tetramethylene sulfide be the preparation of [3,2-c] pyridines (formula III) also:

With 4,5,6,7-tetramethylene sulfide also [3,2-c] pyridines (7.0g), salt of wormwood (7.2g) mixes with acetonitrile (50ml), adds Benzyl Chloride (6.1g), stirs after 0.5 hour and refluxes 3 hours.Cooling is filtered, and filtrate is concentrated into dried, add ethyl acetate (30ml) and water (50ml), separatory, water layer extracts with ethyl acetate (30ml * 2), merge organic layer, washing, drying, be concentrated into the dried title compound 5-benzyl-4 that obtains, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine 8.3g, yield 90.8%.

4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine (18.0g), salt of wormwood (18.6g), Benzyl Chloride (15.0g), sodium iodide (0.8g) stir in DMF (100ml) after 0.5 hour in 80 ℃ of reactions 3 hours, and cooling adds entry (150ml) and ethyl acetate (100ml), separatory, water layer extracts with ethyl acetate (50ml * 2).Merge organic layer, washing, drying is concentrated into dried title compound 23.2g, yield 98.7%.

Embodiment 3

2-bromo-5-benzyl-4,5,6, the 7-tetramethylene sulfide is the preparation of [3,2-c] pyridines (formula IV) also:

The compound (23.2g) that embodiment 2 is obtained is dissolved in acetic acid (100.0ml), 40% Hydrogen bromide (75.0ml), the methyl alcohol (100ml), and the ice-water bath cooling drips methyl alcohol (100ml) solution of 30% hydrogen peroxide (33.0ml), stirring at room 3 hours down.Drip hypo solution (150ml), dripping saturated sodium carbonate solution again is 9 to pH, and methylene dichloride (100ml * 3) extracts, and merges organic layer, washing, and drying is concentrated into dried light yellow solid 30.5g, yield 97.8%.

Embodiment 4

2-methoxyl group-5-benzyl-4,5,6,7-tetramethylene sulfide be the preparation of [3,2-c] pyridine also:

Sodium (24.0g) is dissolved in methyl alcohol (350ml), is concentrated into driedly, add dioxane (300ml), 2-bromo-5-benzyl-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridines (30.5g), cuprous bromide (1.5g) and sodium iodide (0.8g) also, stirring and refluxing 16 hours.Cooling, filter and use methanol wash, filtrate is concentrated into dried, add ethyl acetate (150ml) and water (250ml), separatory, water layer extracts with ethyl acetate (100ml * 2), merge organic layer, disodium ethylene diamine tetra-acetic acid solution (100ml * 2), salt solution (100ml * 3) are washed, and drying is concentrated into dried oily matter 29.3g.Add ethyl acetate (200ml), the ethanolic soln pH that drips hydrogenchloride is 1, and ice-water bath stirred 1 hour, filters and washes with ethyl acetate, dry light yellow solid 24.0g, yield 82.2%.

Embodiment 5

2-methoxyl group-4,5,6,7-tetramethylene sulfide be the preparation of [3,2-c] pyridine hydrochloride also:

With 2-methoxyl group-5-benzyl-4,5,6,7-tetramethylene sulfide also [3,2-c] to regulate pH be 12 to pyridine hydrochloride (20.0g) hydro-oxidation sodium solution, extracts with ethyl acetate (150ml * 3), merges organic layer, water (100ml * 3) is washed, and drying is concentrated into dried oily matter.Add toluene (240ml), diisopropylethylamine (26.5ml) and phenyl chloroformate (20ml), 70 ℃ of stirring reactions 2 hours.Cooling adds saturated sodium bicarbonate solution (180ml), layering, and organic layer is used salt solution (120ml) washing again with saturated sodium bicarbonate (120ml * 2) washing.Organic layer is concentrated into dried, adds the inferior maple (120ml) of diformazan, sodium hydroxide (12g) and water (18ml), 70 ℃ of stirring reactions 12 hours.Cooling adds frozen water (350ml), and it is 9 that the hydro-oxidation sodium solution is regulated pH.Extract with methylene dichloride (150ml * 3), washing, drying is concentrated into dried oily matter 27.5g.(200ml) dissolving that adds diethyl ether, it is 3 that the diethyl ether solution that drips hydrogenchloride is regulated pH, ice-water bath stirred 1 hour, filtered and washed with ether, dry light yellow solid 11.2g, yield 80.3%.

Embodiment 6

2-methoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the 7-tetramethylene sulfide is the preparation of [3,2-c] pyridine hydrochloride also:

With 2-methoxyl group-4,5,6, the 7-tetramethylene sulfide also [3,2-c] pyridine hydrochlorides (1.25g) hydro-oxidation sodium solution to regulate pH be 12, extract with methylene dichloride (15ml * 3), merge organic layer, water (10ml * 2) is washed, drying is concentrated into dried oily matter.Add the adjacent luorobenzyl cyclopropyl ketone (1.42g) of alpha-chloro, salt of wormwood (1.01g), sodium iodide (0.1g) and acetonitrile (30ml), refluxed 3 hours, cooling is filtered and is washed with acetonitrile.Filtrate is concentrated into dried, adds water (50ml), extracts with ethyl acetate (30ml * 3), merges organic layer, washing, and drying is concentrated into dried oily matter 2.5g.(50ml) dissolving that adds diethyl ether, it is 3 that the diethyl ether solution that drips hydrogenchloride is regulated pH, ice-water bath stirred 1 hour, filtered and washed with ether, dry light yellow solid 2.15g, yield 92.6%.

Embodiment 7

5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-2,4,5,6,7, the preparation of 7a-six hydrogen thieno-s [3,2-c] pyridine hydrochloride:

2-methoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine hydrochlorides (2.15g), 1M hydrochloric acid (20ml) reacted 3 hours in 80 ℃.Cooling, with the sodium carbonate solution neutralization, ethyl acetate (30ml * 3) is extracted, and merges organic layer, and water (10ml * 2) is washed, and drying is concentrated into dried.(50ml) dissolving that adds diethyl ether, it is 3 that the diethyl ether solution that drips hydrogenchloride is regulated pH, ice-water bath stirred 1 hour, filtered and washed with ether, dry light yellow solid 1.55g, yield 74.8%.

Embodiment 8

2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the 7-tetramethylene sulfide is the preparation of [3,2-c] pyridine hydrochloride (being prasugrel) also:

5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-2,4,5,6,7,7a-six hydrogen thieno-s [3,2-c] pyridine hydrochlorides (0.3g), adding sodium carbonate solution adjusting pH value is 7～8, extract with ethyl acetate (15ml * 3), merge organic layer, water (10ml * 2) is washed, drying, is concentrated into dried.Add N, dinethylformamide (2ml), acetic anhydride (1ml), the frozen water cooling adds 60% sodium hydrogen (0.1g), stirring at room 3 hours.Add ethyl acetate (40ml), salt solution (10ml * 3) is washed, and drying is concentrated into dried.(20ml) dissolving that adds diethyl ether, it is 3 that the diethyl ether solution that drips hydrogenchloride is regulated pH, ice-water bath stirred 1 hour, filtered and washed with ether, dry white solid 0.22g, yield 65.8%.

Claims

1. prepare the intermediate of prasugrel, i.e. the compound (IV) of following formula:

wherein X represents Cl or Br.

2. the preparation method of the intermediate for preparing prasugrel according to claim 1, comprising

Step 1: Formula (I) compound and formula (II) compound react under alkaline conditions

The compound of formula (III) is obtained,

Step 2: the compound of formula (III) is halogenated to obtain the compound of formula (IV),

wherein X represents Br or Cl.

3. the preparation method of the intermediate of preparing prasugrel as claimed in claim 2 is characterized in that: used solvent during step one reaction comprises alcohol, esters, methylene dichloride, tetrahydrofuran (THF), benzene, toluene, acetonitrile, DMF .

4. the preparation method of the intermediate of preparing prasugrel as claimed in claim 3 is characterized in that: the solvent used during step one reaction is acetonitrile or DMF.

5. the preparation method of the intermediate of preparing prasugrel as claimed in claim 2 is characterized in that: the alkali that step 1 uses is sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydroxide, triethylamine or diiso Propylethylamine.

6. the preparation method of the intermediate of preparing prasugrel as claimed in claim 5 is characterized in that: the alkali that step one uses is sodium carbonate or potassium carbonate.

7. the preparation method of the intermediate of preparing prasugrel as claimed in claim 2 is characterized in that: step 1 also comprises a step of adding catalyst sodium iodide or potassium iodide.

8. The preparation method of the intermediate for preparing prasugrel as claimed in claim 2, characterized in that: hydrobromic acid solution and hydrogen peroxide are used as the halogenating agent during the step dihalogenation reaction.