A kind of preparation method of ADZ6140 intermediate
(1) technical field
The present invention relates to medication chemistry synthetic field, particularly a kind of preparation method of ADZ6140 intermediate.
(2) background technology
ADZ6140, English name ticagrelor, chemistry (1S by name, 2S, 3R, 5s)-3-[7-[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamino]-5-(thiopropyl)-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) pentamethylene-1,2-glycol, Shi You U.S. AstraZeneca (AstraZeneca) company research and development a kind of novel, there is optionally small molecules anticoagulant.The platelet aggregation that this medicine causes ADP has obvious restraining effect, and it is rapid to orally use rear onset, therefore can effectively improve acute coronary patient's symptom.
Trans-(1R, 2S)-2-(3,4-difluorophenyl)-cyclopropylamine is the important intermediate of synthetic ADZ6140, and structural formula is
Announce at present trans-preparation method of (1R, 2S)-2-(3,4-difluorophenyl)-cyclopropylamine mainly comprises following several routes:
Patent CN1431992A has adopted following route:
This route, reacts with propanedioic acid for starting raw material with 3,4-difluorobenzaldehyde, adds thermal decarboxylation and obtains 3,4-cinnamic acid difluoride, then makes acyl chlorides, then with MENTHOL esterification, then with sulfur ylide ring third, change, then through hydrolysis, diazotization, finally by Ku Ertisi, reset to obtain target product.This route reaction step is long, and complex operation has increased raw materials cost and production cost, is also difficult to obtain good yield.In reaction process, to use the larger or inflammable and explosive hazardous substance of toxicity such as pyridine, sulfur oxychloride, hydrogenation are received, sodiumazide, increase the difficulty of operation.
In patent wo2011017108A, adopt following route:
This route for starting raw material, is first made acyl chlorides with 3,4-cinnamic acid difluoride, then, with sultam esterification, then encircles the third change, then under alkaline condition, is hydrolyzed, then uses azido-phosphonic acid diphenyl ester azide, then through Ku Ertisi, resets to obtain target product.This route also can be used hazardous substance sulfur oxychloride and trinitride, and will be through two step column purification, and complex operation is not suitable for amplifying and produces.
In United States Patent (USP) us20080132719, adopt following route:
This route be take difluorobenzene as starting raw material, first chloroacetyl chloride and difluorobenzene generation electrophilic substitution reaction under Louis acid catalysis, then carbonyl obtains a chiral alcohol through chiral reduction, with phosphorus ylide feed liquid ring third, changes reaction, and then ammonia solution and the hofmann rearrangement through ester obtains target product.This route side reaction is more, and product purification difficulty, needs column purification, has increased the complicacy of operation, has limited it in the application of amplifying in producing.
In patent wo2011/132083, adopted following route:
This route be also with 3,4-difluorobenzene for starting raw material, 3-chlorpromazine chloride under Louis acid catalysis with difluorobenzene generation electrophilic substitution reaction, then chlorine is replaced by nitro, carbonyl obtains chiral alcohol through chiral reduction, with diethyl azodiformate ring third, changes reaction, finally nitroreduction is obtained to target product.In the chiral reduction of carbonyl, used expensive chiral reagent, increased cost, the method that the ring third providing in patent is changed, yield is lower, and last reduction also will be used expensive palladium carbon.
In Chinese patent CN101495444A, take following route:
This route is also to encircle the third change reaction with phosphonoacetic acid triethyl, then in basic solution, carries out the hydrolysis of ester, then reacts to obtain acyl chlorides with sulfur oxychloride, then obtains acid amides with ammoniacal liquor, finally by hofmann rearrangement, obtains target product.This reaction will be used sulfur oxychloride, has increased the dangerous and corrosion to equipment of operation, has strengthened the pollution to environment.
In Chinese patent CN102249929A, adopt following route:
It is starting raw material that this route be take the acid encircling after the third change, uses diphenyl phosphate azide azide, then through Ku Ertisi, resets to obtain target product.This route has also been used trinitride, the most important thing is that this route does not relate to the Focal point and difficult point in this intermediate building-up process, and the asymmetric ring third of ethylene linkage is changed.
Patent wo2012001531A adopts following route:
This route with 3,4-difluorobenzaldehyde for starting raw material, react with phosphorus ylide feed liquid 3,4-difluorobenzene ethene, the expensive hydrogen reagent 1 that pulls out of this step reaction, 8-diazabicyclo (5.4.0) 11 carbon-7-alkene, has increased cost.Route is used ethyl diazoacetate to make ring the third change reagent, and then the ester of gained is hydrolyzed under alkaline condition, then uses diphenyl phosphate azide azide, finally by Ku Ertisi, resets to obtain target product.The use of diazonium and triazo-compound has increased the danger of operation undoubtedly.
Be not difficult to find out, announced trans-(1R, 2S)-2-(3,4-difluorophenyl) although-synthetic route of cyclopropylamine is more, also has a lot of weak points: step is longer, cause productive rate not high, or side reaction is too many, product needs column purification; Used the expensive reagent being hard to buy; Used the more serious reagent of inflammable and explosive hazardous agents and environmental pollution etc., these unfavorable factors make these synthetic routes not be suitable for the large-scale industrial production of product.
(3) summary of the invention
The present invention is in order to make up the deficiencies in the prior art, provide that a kind of preparation method is simple, easy to operate, the gentle easy control of reaction conditions, raw material are cheap and easy to get, product yield and product purity is high, the i.e. trans-(1R of the ADZ6140 intermediate that is suitable for large-scale industrial production, the preparation method of 2S)-2-(3,4-difluorophenyl)-cyclopropylamine.
The present invention is achieved through the following technical solutions:
A preparation method for ADZ6140 intermediate, comprises the steps:
(1) with 3,4-difluorobenzaldehyde (I) for starting raw material, through there is wittig-horner with phosphorus ylide feed liquid, react and obtain (E)-3-(3,4-difluorophenyl)-2-esters of acrylic acid (II);
(2) (E)-3-(3,4-difluorophenyl)-2-esters of acrylic acid (II) is changed reaction through the asymmetric ring third of Xi Mengsi-Smith and is obtained trans-(1R, 2R)-2-(3,4-difluorophenyl) cyclopropane formic ether (III);
(3) trans-(1R, 2R)-2-(3,4-difluorophenyl) cyclopropane formic ether (III) solves trans-(1R, 2R)-2-(3,4-difluorophenyl) cyclopropane carboxamide (IV) through ammonia;
(4) trans-(1R, 2R)-2-(3,4-difluorophenyl) cyclopropane carboxamide (IV) obtains i.e. trans-(1R, 2S)-2-(3,4-the difluorophenyl)-cyclopropylamine (V) of ADZ6140 intermediate through Hoffmann rearrangement reaction.
The concrete preparation method of this ADZ6140 intermediate, comprises the steps:
(1) with 3,4-difluorobenzaldehyde (I) is starting raw material, in the first organic solvent, react and obtain (E)-3-(3 with phosphorus ylide feed liquid generation wittig-horner, 4-difluorophenyl)-2-esters of acrylic acid (II), temperature of reaction is-10 ℃-30 ℃, 3,4-difluorobenzaldehyde (I) is 1 with mole proportioning of phosphorus ylide feed liquid: 1.0-1.3;
(2) in the second organic solvent, (E)-3-(3, under the effect of zinc ethyl and chiral ligand, there is the asymmetric ring third of Xi Mengsi-Smith and change to react and obtain trans-(1R in 4-difluorophenyl)-2-esters of acrylic acid (II) and methylene iodide, 2R)-2-(3,4-difluorophenyl) cyclopropane formic ether (III), temperature of reaction is 30 ℃-60 ℃, (II): methylene iodide: zinc ethyl: mole proportioning of chiral ligand is 1: 2-3: 1.5-2: 0.05-0.2;
(3) under temperature is the condition of 40 ℃, to trans-(1R, 2R)-2-(3,4-difluorophenyl) in the alcoholic solution of cyclopropane formic ether (III), lead to ammonia 15 hours, through ammonia solution, generate trans-(1R, 2R)-2-(3,4-difluorophenyl) cyclopropane carboxamide (IV);
(4) by trans-(1R, 2R)-2-(3,4-difluorophenyl) to add massfraction be in 30% sodium hydroxide solution to cyclopropane carboxamide (IV), wherein (IV) is 1: 3 with mole proportioning of sodium hydroxide, drip again massfraction and be 10% chlorine bleach liquor, wherein (IV) is 1: 1.5 with mole proportioning of clorox, at 40 ℃, stirring reaction obtains the i.e. trans-(1R of ADZ6140 intermediate for 10 hours, 2S)-2-(3,4-difluorophenyl)-cyclopropylamine (V).
In step (1), (II) is (E)-3-(3,4-difluorophenyl)-2-ethyl propenoate, (E)-3-(3,4-difluorophenyl)-2-propyl acrylate, (E)-3-(3,4-difluorophenyl)-2-n-butyl acrylate, (E)-3-(3,4-difluorophenyl)-2-isobutyl acrylate or (E)-3-(3,4-difluorophenyl)-2-vinylformic acid menthyl ester, preferred (E)-3-(3,4-difluorophenyl)-2-ethyl propenoate.
In step (1), preferable reaction temperature is 15 ℃; 3,4-difluorobenzaldehyde (I) is 1: 1.2 with preferred mole of proportioning of phosphorus ylide feed liquid.
In step (1) phosphorus ylide feed liquid be triethyl-phosphite with alpha-halogen acetic ester occur meter Xie Er-A Erbuzuofu react (Michaelis-Arbuzov reacts) must acetate groups phosphonic acids diethyl ester, and then acetate groups phosphonic acids diethyl ester is reacted to original position generate and get final product with highly basic, the phosphorus ylide feed liquid of gained is directly used in next step reaction.
In step (1), the first organic solvent is tetrahydrofuran (THF), ether or dioxan, preferably tetrahydrofuran (THF).
In step (2), preferable reaction temperature is 50 ℃; (II): methylene iodide: zinc ethyl: preferred mole of proportioning of chiral ligand is 1: 2.5: 1.6: 0.1.
In step (2), chiral ligand is anti-form-1,2-cyclohexanediamine and 2-hydroxyl-3, the schiff base ligand that 5-di-t-butyl benzaldehyde forms.
In step (2), the second organic solvent is tetrahydrofuran (THF) or dioxan, preferably tetrahydrofuran (THF).
Alcohol in step (3) in alcoholic solution is methyl alcohol, ethanol or Virahol, particular methanol.
The syntheti c route of this ADZ6140 intermediate is as follows:
The preparation method's of ADZ6140 intermediate of the present invention beneficial effect is: preparation method is simple, easy to operate, the gentle easily control of reaction conditions, raw material is cheap and easy to get and without the reagent of inflammable and explosive or contaminate environment, product yield and product purity are high, are suitable for large-scale industrial production.
(4) embodiment
By following examples, further illustrate the present invention, following examples are only for illustration, and do not limit the present invention.
The preparation method of this ADZ6140 intermediate, adopts following steps:
The preparation of (1) 3,4-cinnamic acid difluoride ethyl ester:
A) preparation of phosphorus ylide feed liquid:
In the first reaction flask, add triethyl-phosphite 16.6g, tetrahydrofuran (THF) 80ml, alpha-bromo ethyl acetate 12.2ml successively, stir, heating, back flow reaction 2h, stops heating, is naturally cooled to room temperature, then 0 ℃ of left and right of ice-water bath temperature control adds sodium tert-butoxide 12.5g in the first reaction flask in batches, stirring reaction 1h, is directly used in the reaction of preparation 3,4-cinnamic acid difluoride ethyl ester;
B) 3, the preparation of 4-cinnamic acid difluoride ethyl ester:
In the second reaction flask, add 3, 4-difluorobenzaldehyde (I) 12.8g, tetrahydrofuran (THF) 60ml, stir, 15 ℃ of left and right of temperature control, in 30min, in the second reaction flask, drip the phosphorus ylide feed liquid reaction solution that step a) makes, then insulation reaction 3h, in the second reaction flask, add 50ml water again, 50ml ethyl acetate, stir, separatory, water layer is washed by 20ml ethyl acetate, merge organic phase, then the salt washing (30ml * 3) that organic phase is 10% with massfraction, add 3g activated carbon decolorizing, 10g anhydrous magnesium sulfate drying, be evaporated to dry 3, 4-cinnamic acid difluoride ethyl ester,
(2) preparation of trans-(1R, 2R)-2-(3,4-difluorophenyl) cyclopropane-carboxylic acid ethyl ester:
In the 3rd reaction flask, add dioxan 60ml, anti-form-1,2-cyclohexanediamine 1.15g, 2-hydroxyl-3,5-di-t-butyl phenyl aldehyde 4.7g, is heated to 50 ℃ of stirring reaction 0.5h, under 50 ℃ of conditions, in the 3rd reaction flask, add zinc ethyl 19.7g, methylene iodide 67g, continue reaction 20min; By the step b in step (1)) make 3,4-cinnamic acid difluoride ethyl ester dissolves with 20ml dioxan, in 20min, drip in the 3rd reaction flask, be incubated 50 ℃ of reaction 3h, be cooled to room temperature, in the 3rd reaction flask, add ethyl acetate 60ml, saturated aqueous common salt 50ml, stir separatory after 5min, the salt that organic phase is 10% with massfraction is washed (30ml * 3), is evaporated to dry trans-(1R, 2R)-2-(3,4-difluorophenyl) cyclopropane-carboxylic acid ethyl ester;
(3) preparation of trans-(1R, 2R)-2-(3,4-difluorophenyl) cyclopropane carboxamide:
By gained trans-(1R, 2R)-2-(3,4-difluorophenyl) cyclopropane-carboxylic acid ethyl ester joins the 4th reaction flask and dissolves with 50ml anhydrous methanol, stir, 40 ℃ of logical ammonias 15 hours, detection reaction is complete; In the 4th reaction flask, add saturated brine 50ml, ethyl acetate 50ml, vigorous stirring, adjusts PH to 6.8 with the hydrochloric acid of concentration 5%, separatory, the salt washing (30ml * 3) that ethyl acetate layer is 10% with massfraction, decompression steams ethyl acetate 30ml, in the 4th reaction flask, drip isopropyl ether 300ml, separate out solid, 0 ℃ of crystallization 1h, filter, filter cake is washed with a small amount of isopropyl ether, and vacuum-drying obtains trans-(1R, 2R)-2-(3,4-difluorophenyl) cyclopropane carboxamide 13.9g;
(4) preparation of trans-(1R, 2S)-2-(3,4-difluorophenyl)-cyclopropylamine:
To adding massfraction in the 5th reaction flask, be 30% sodium hydroxide solution 40ml, add again trans-(1R, 2R)-2-(3, 4-difluorophenyl) cyclopropane carboxamide 10g, vigorous stirring, in 40 ℃, in 30min, drip massfraction and be 10% chlorine bleach liquor 110g, insulation reaction 10h, in the 5th reaction flask, add ethyl acetate 50ml, separatory after stirring 5min, the salt washing (30ml * 3) that ethyl acetate layer is 10% with massfraction, pass through anhydrous magnesium sulfate drying, concentrating under reduced pressure obtains the i.e. trans-(1R of ADZ6140 intermediate, 2S)-2-(3, 4-difluorophenyl)-cyclopropylamine.