CN103664697B - For preparing the chemical method of aromatic ring propionitrile and cyclopropylamine - Google Patents
For preparing the chemical method of aromatic ring propionitrile and cyclopropylamine Download PDFInfo
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- CN103664697B CN103664697B CN201210327691.7A CN201210327691A CN103664697B CN 103664697 B CN103664697 B CN 103664697B CN 201210327691 A CN201210327691 A CN 201210327691A CN 103664697 B CN103664697 B CN 103664697B
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Abstract
The present invention relates to a kind of trans aryl cyclopropyl nitrile preparing lower formula (IV) structure, reacted by the substituted oxirane of aryl and the substituted phosphate ester of cyano group and prepare；And further relate to be prepared cyclopropylamine by this trans aryl cyclopropyl nitrile, and it is used for preparing medicine, the method especially preparing Ticagrelor.
Description
Technical field
The present invention relates to aromatic ring propionitrile, for the method preparing described cyclopropylniitrile, and they are preparing medicine
Or the application in pharmaceutical intermediate.
Background technology
Ticagrelor (Ticagrelor), belongs to cyclopenta triazolopyrimidines, chemistry entitled (1S, 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, is public by U.S.'s AstraZeneca (AstraZeneca)
Department's research and development a kind of novel, there is selective little molecule anticoagulant.Need to be after carrying out anticoagulant therapy in advance for those
The patient of row operation is especially suitable again.WO0034283 and WO9905143 discloses Ticagrelor with and the like knot
Structure, wherein Ticagrelor has a chemical constitution shown in following formula:
Ticagrelor with and the like synthetically prepared typically by the splicing of three intermediate fragments, the most trans virtue
Fragrant race cyclopropylamine, has the compound shown in formula (I ') structure as follows, is the important centre preparing Ticagrelor and the like
Body
(I’)。
Have various kinds of document at present and report the synthesis of trans aromatic ring propylamine.CN1211344C discloses with 3,4-bis-
Fluorobenzaldehyde and malonic acid condensation, be converted into acyl chlorides and be esterified with MENTHOL, the method preparing cyclopropylamine by chirality auxiliary law,
Its synthetic route is as follows:
Method disclosed in other prior aries is also adopted by above-mentioned similar route synthesis cyclopropylamine, wherein uses different chiralitys
Auxiliary reagent introduces chiral source, such as L-(10,2)-camphorsultam and (4R)-4 phenyl-2-oxazolidone.This kind of reaction.This
The chiral reagent of class method needs a large amount of use costliness is as raw material, in synthesis, in order to avoid chiral centre generation racemization,
Require harsher for operating condition.
CN101495442 discloses following synthetic route, with adjacent benzene difluoro as raw material, middle through asymmetric reduction ketone group
Again through the esterification of phosphoryl ethyl acetate and Hofmann degraded preparation.But, in this route, some intermediate becomes oily, does not allows
Easily crystallisation solidification, therefore the purity of intermediate is difficult to control to, and purity and productivity for reaction final products all create necessarily
Impact；Or need the complicated mode refined product crossing column chromatography, virtually add production cost.
Summary of the invention
The invention aims to overcome prior art to prepare cost present in the method for trans aromatic ring propylamine
Too high, the defects such as products collection efficiency is relatively low, it is provided that a kind of method preparing trans aromatic ring propylamine being different from prior art.
It is an aspect of the present invention to provide the compound shown in a kind of formula IV
(IV)
Wherein R is preferably 3,4-by the phenyl of one or more halogen substiuted, such as chlorophenyl, difluorophenyl etc., R
Difluorophenyl；I.e. compound shown in formula (IV) preferably has a compound of following structure:
(IV-1).
Another aspect of the present invention is to provide the preparation method of a kind of formula (IV) compound, including by formula V compound,
(V)
With formula (a) compoundProcess, wherein R1And R2Independent selected from alkoxyl or aryl, preferably C1-
C6Alkoxyl or C6-C10Aryl, more preferably C1-C3Alkoxyl, such as methoxyl group, ethyoxyl or propoxyl group etc..Preferably formula
A () compound is cyanogen methyl acid phosphate diethylester.Described R is identical with in above-mentioned definition, preferably 3,4-difluorophenyl；I.e. formula
(V) compound shown in has elects the compound with following structure as:
(V-1).
Described reaction, in atent solvent, is carried out under the conditions of alkalescence.Described atent solvent preferably include benzene, toluene,
Chloroform, dichloromethane, N-Methyl pyrrolidone, acetone, acetonitrile, ethyl acetate, the tert-butyl alcohol, oxolane, ether, butyl ether, second
Glycol dimethyl ether, diisopropyl ether, ethylene glycol diethyl ether, 1,4-dioxane, DMF etc.；More preferably toluene, glycol dimethyl ether, second
One or more of glycol diethyl ether or oxolane.
Described alkali includes the hydride (such as sodium hydride, lithium hydride, calcium hydride etc.) of alkali metal or alkaline-earth metal, alkali gold
Alcoholates (such as Sodium ethylate, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide etc.), alkali metal or the halogenide (example of alkaline-earth metal belonged to
Such as lithium chloride or magnesium chloride etc.), DBU, alkali amide or amino bases earth metal (such as Sodamide., Lithamide., diisopropylaminoethyl
Magnesium etc.), triethylamine, organolithium (such as n-BuLi, tert-butyl lithium, phenyl lithium etc.) etc..Preferably alkali is alkali metal or alkaline earth
The hydride (such as sodium hydride, lithium hydride, calcium hydride etc.) of metal or alkali-metal alcoholic compound.The consumption of described alkali is preferred
For 1-5 times of the mole of compound (a), more preferably 1-3 times.
In described reaction, the consumption mol ratio of formula V compound and formula (a) compound is 1:1-1:5, preferably 1:1-
1:3。
Described reaction is typically carried out at a temperature of 20 DEG C-solvent boiling point, preferably reacts in the range of 40-80 DEG C.
The described compound shown in formula V can be prepared by the disclosed method of prior art preparation, for example with
Method disclosed in CN101495442, is acylated through Friedel-Crafts with o-difluoro-benzene, then warp (S)-diphenylprolinol,
Asymmetric reduction, processes through parlkaline condition and is converted into the compound shown in formula (V).
Another aspect of the present invention, is to provide the preparation method of a kind of formula (III) compound, including by above-mentioned formula (IV) institute
The compound hydrolysis shown
(III).
Wherein, R is as defined above described.Described hydrolysis is ordinary skill in the art means, it is common that in acidity
Or under the conditions of alkalescence, the solvent containing water is carried out.Such as it is referred to Organic Syntheses, Vol. 76, p.
169 (1999)；Organic Syntheses, Vol. 35, p. 6 (1955)；Organic Syntheses, Vol.
The disclosed methods such as 37, p. 47 (1957) are prepared, and at this, citation is as reference.
Another aspect of the present invention, is to provide a kind of by preparation of compounds of formula (II) compound shown in above-mentioned formula (IV)
Method
(II)。
Wherein, R is as defined above described.Described method includes preparing formula (IV) compound hydrolysis；
Or described method includes the compound shown in formula (IV) is converted into formula (III) compound, then through amidatioon
Reaction preparation formula (II) compound.
The described reaction that formula (IV) compound direct hydrolysis is prepared formula (II) is ordinary skill in the art means, example
As being referred to: Organic Syntheses, Vol. 32, p. 92 (1952)；Organic Syntheses, Vol.
37, p. 47 (1957)；The disclosed method such as Organic Syntheses, Vol. 33, p. 7 (1953) is prepared,
At this, citation is as reference.
The described reaction that formula (III) compound amidatioon is prepared formula (II) compound is ordinary skill in the art hands
Section, such as, be referred to WO2008018823；Organic Syntheses, Vol. 70, p. 101 (1992)；Organic
Syntheses, Vol. 37, p. 50 (1957)；Organic Syntheses, Vol. 85, p.72 (2008)；
Prepared by the disclosed method such as Organic Syntheses, Vol. 25, p. 95 (1945), at this, citation is as reference.
Another aspect of the present invention, is to provide the preparation method of the compound shown in a kind of formula (I), including by formula (IV) institute
The compound shown is converted into the compound shown in formula (III), then is converted into the change shown in formula (II) by compound shown in formula (III)
Compound, then by the way of Hoffmann rearrangement, prepare compound shown in formula (I)；
Or, it is converted into the compound shown in formula (II) including by the compound shown in formula (IV), then is retaken by Huffman
Mode prepare compound shown in formula (I)；
Or, it is converted into the compound shown in formula (III) including the just compound shown in formula (IV), then by formula (III) institute
Show that compound prepares compound shown in formula (I) by the way of Curtius resets
(I),
Wherein R is as defined above described.
Described Hoffmann rearrangement is ordinary skill in the art means.Such as it is referred to WO2008018823；
Organic Syntheses, Vol. 66, p. 132 (1988)；Organic Syntheses, Vol. 78, p. 234
Etc. (2002) prepared by disclosed method, and at this, citation is as reference.In Hoffmann rearrangement reaction, suitable halogen reagent includes halogen
Compound, such as N-chlorosuccinimide, N-bromosuccinimide；Hypohalite, such as sodium hypochlorite, sodium hypobromite etc..Excellent
Select sodium hypobromite.
It is ordinary skill in the art means that described Curtius resets, and is reacted by carboxylic acid and azido compound and generates
Acyl azide, and through heating mode be prepared.Such as, CN1211344C is referred to；Organic
Syntheses, Vol. 59, p. 1 (1979)；J. Prakt. Chem. 1894, 50, 275；Organic
Syntheses, Coll. Vol. 6, p.910 (1988)；J. Am. Chem. Soc. 1972,94,6203-6205 etc.
Prepared by disclosed method, at this, citation is as reference.
It is to prepare medicine by the trans aromatic ring propylamine shown in the formula (I) that the compound shown in formula (IV) prepares
Thing, especially prepares the important intermediate sheet of the Ticagrelor as disclosed in WO0034283 and WO9905143 and derivant thereof
Section.Therefore another aspect of the present invention, is to provide a kind of use preparing medicine with the compound shown in formula (IV) for intermediate
On the way, in particular for preparing the purposes of Ticagrelor and the like
(IV),
Wherein, described R is as defined above.
Further, the invention provides a kind of is prepared by intermediate with preferred compound as shown in following formula (IV-1)
The purposes of Ticagrelor
(IV-1).
It is high that the method for trans cyclopropylamine provided by the present invention has stereo selectivity, and productivity is high, and intermediate is easily processed.
The method of the cyclopropylamine shown in preparation formula (I) of the present invention, can represent by following synthetic route, in route
Shown R, R1, R2As defined above:
Route 1
。
Accompanying drawing explanation
Compound shown in Fig. 1 formula (IV-1)1H-NMR:(CDCl3) collection of illustrative plates.
Compound shown in Fig. 2 formula (IV-1)13C-NMR:(CDCl3) collection of illustrative plates.
Detailed description of the invention
Hereinafter the present invention will be expanded on further by specific embodiment, but be not limited to protection scope of the present invention.
In following embodiment, except as otherwise noted, described test method actual conditions is generally built according to normal condition or manufacturer
The condition of view is implemented；Described raw material, reagent are all obtained by commercially available purchase；Described percentage ratio, ratio, ratio or number etc.
Calculate according to weight.
Embodiment 1
Formula (V-1) compound (2S)-2-(3,4-difluorophenyl) preparation method of oxirane
(V-1)
By chloro-for (1S)-2 1-(3,4-difluorophenyl)-1-ethanol (50g is prepared according to method disclosed in CN10149544),
Toluene (128ml), sodium hydroxide (11g) and water (106ml) mixing, stirring reaction 1 hour at 40 DEG C, Separation of Organic,
Washing, removes solvent under reduced pressure, it is thus achieved that the compound 38.16g(productivity of formula (V-1): 94%).
1H-NMR:(CDCl3): δ 2.71-2.73 (1H, dd), 3.13-3.15(1H, m), 3.82-3.83(1H, m), 7.01-
7.27(4H, m).
Embodiment 2
Formula (IV-1) compound (1R, 2R)-2-(3,4-difluorophenyl) preparation method of cyclopropane nitrile
(IV-1).
By NaH(45g, 60%, 1.13mol) and glycol dimethyl ether (300ml) mixing, stirring.At 0 DEG C, hanging to gained
Supernatant liquid drips glycol dimethyl ether (120ml) solution of cyanogen methyl acid phosphate diethylester (166.4g, 0.94mol).In 40-60 DEG C
Under be slowly added dropwise (2S)-2-(3,4-difluorophenyl) glycol dimethyl ether (200ml) of oxirane (38g, 244mmol) is molten
Liquid, after dropping, in 60 DEG C of reactions, TLC monitors, and reaction in about 10 hours is completely.It is cooled to room temperature, separates organic layer, water
Wash, concentrate, separate out solid 40.5g, productivity 92.8%, HPLC purity 98%, ee value is more than 99.9%.
This compound1H-NMR and13C-NMR is the most as depicted in figs. 1 and 2.
Embodiment 3
Compound (1R, 2R)-2-(3,4-difluorophenyl) preparation method of ethylene-acetic acid
(1R, 2R)-2-(3,4-difluorophenyl that embodiment 2 is prepared) cyclopropylniitrile (20g) is water-soluble with sodium hydroxide
Liquid (10%, 100ml), is heated to reflux stir about extremely reaction in 4 hours complete.Being cooled to room temperature, concentrate, ether extracts.Dropping 15%
HCl acidifying, ether extract, concentrate prepare 21.0g(1R, 2R)-2-(3,4-difluorophenyl) ethylene-acetic acid, productivity
95%。
Embodiment 4
Compound (1R, 2R)-2-(3,4-difluorophenyl) preparation method of cyclopropyl carboxamide
Method one
(1R, 2R)-2-(3,4-difluorophenyl that embodiment 2 is prepared) cyclopropylniitrile (20g) and 80ml 35% salt
Acid mixing, stir about 1.5 hours at 40 DEG C.In 15-20 DEG C of cooling, it is gradually added into 100ml frozen water, is sufficiently stirred for, in ice bath
Cooling crystallization, is dried, and obtains (1R, 2R)-2-(3,4-difluorophenyl) cyclopropyl carboxamide 20.4g, productivity 91%.
Method two
Thionyl chloride (15g) is added (1R, 2R)-2-(3, the 4-difluorophenyl prepared containing embodiment 3) ring third
In the toluene solution of base formic acid (20g), at 35 DEG C, stir about 6 hours, concentrating under reduced pressure, prepare acyl chlorides.Less than 10 DEG C, to
The ammonia (2.5g) of 28%, water (50ml) and ethyl acetate (130ml) mixed liquor are slowly added to above-mentioned acyl chlorides.After dropping
Complete in 10 DEG C of about 1 hour stirred below question responses.Reactant liquor is neutralized with the hydrochloric acid of 35%, separates organic layer, concentrate crystallize,
Obtain (1R, 2R)-2-(3,4-difluorophenyl) cyclopropyl carboxamide 17.9g, productivity 90%.
Embodiment 5
(1R, 2S)-2-(3,4-difluorophenyl) preparation of-cyclopropylamine
Method one:
(1R, 2R)-2-(3,4-difluorophenyl that embodiment 4 is prepared) cyclopropyl carboxamide (20g) and 125g dense
The sodium hydrate aqueous solution mixing of degree 30%, adding concentration at 30 DEG C in mixed liquor is the NaOBr(115g of 20%) aqueous solution, in
After stirring 5 hours at 30 DEG C, heat the mixture to stir at 60 DEG C 30min.After question response terminates, it is cooled to 5 DEG C, 35%
Salt acid for adjusting pH value, to about 8.5, adds suitable quantity of water, is extracted with ethyl acetate, and concentrates, and obtains (1R, 2S)-2-(3,4-difluorobenzene
Base)-cyclopropylamine 15.2g(productivity about 87%).
Method two
(1R, 2R)-2-(3,4-difluorophenyl that embodiment 3 is prepared) ethylene-acetic acid (20g) in nitrogen protect
Under, add in the tert-butyl alcohol (200ml), under stirring, be slowly added to triethylamine (10.2g) and DPPA(33.3g), reactant mixture liter
Temperature is reacted about 2 hours to 85 DEG C, and TLC monitoring reaction completely, is cooled to room temperature, is spin-dried for solvent, adds ethyl acetate, washing, rotation
Do to obtain solid.By the solid of gained in the lower ethyl acetate aqueous solution (3.9mol/L, 80ml) adding hydrochloric acid of nitrogen protection, room temperature
Stirring, separates out solid, obtains (1R, 2S)-2-(3,4-difluorophenyl)-cyclopropylamine 15.7g(productivity 75%).
Claims (2)
1. a preparation method for formula (IV) compound, including by Formula V compound,
With formula (a) compoundProcess, wherein R1And R2Independent selected from C1-C3Alkoxyl；R is by one or many
The phenyl of individual halogen substiuted,
Method the most according to claim 1, it is characterised in that R is 3,4-difluorophenyl.
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| CN104311432B (en) * | 2014-10-23 | 2016-05-11 | 浙江永太科技股份有限公司 | ADZ6140 important intermediate (1R, 2S)-2-(3,4-difluoro-benzene base) preparation method of cyclopropylamine |
| CN106749133B (en) * | 2015-11-23 | 2019-01-29 | 浙江京新药业股份有限公司 | A method of preparing Ta Simeiqiong |
| CN105671099A (en) * | 2016-01-26 | 2016-06-15 | 中国科学院成都生物研究所 | Method for preparing optical pure difluorophenyl ethylene oxide |
| CN105924360A (en) * | 2016-05-10 | 2016-09-07 | 浙江工业大学 | synthesis method of (1R,2S) -2- (3, 4-difluorophenyl) cyclopropylamine |
| CN105949153B (en) * | 2016-05-10 | 2018-03-02 | 浙江工业大学 | synthesis method of tasimelteon |
| CN106565503B (en) * | 2016-10-19 | 2018-04-24 | 华北理工大学 | The method for synthesizing (1R, 2S) -1- amino-(3,4- difluorophenyls)-cyclopropane |
| CN106631887B (en) * | 2016-10-19 | 2018-03-20 | 杨绮红 | A kind of preparation technology of (1R, 2S) 1 cyano group 2 (3,4 difluorophenyl) cyclopropane |
| CN106631824B (en) * | 2016-12-30 | 2019-04-16 | 上海毕得医药科技有限公司 | A kind of synthetic method of (1- cyclopropyl -1- methyl) ethylamine hydrochloride |
| CN107556301B (en) * | 2017-08-31 | 2019-11-29 | 浙江工业大学 | Synthesis method of tasimelteon intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101495444A (en) * | 2006-08-05 | 2009-07-29 | 阿斯利康(瑞典)有限公司 | A process for the preparation of optically active cyclopropylamines |
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| GB0615619D0 (en) * | 2006-08-05 | 2006-09-13 | Astrazeneca Ab | Chemical process for preparation of intermediates |
| WO2013144295A1 (en) * | 2012-03-30 | 2013-10-03 | Sandoz Ag | Synthesis of 2-(3,4-difluorophenyl)cyclopropanamine derivatives and salts |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101495444A (en) * | 2006-08-05 | 2009-07-29 | 阿斯利康(瑞典)有限公司 | A process for the preparation of optically active cyclopropylamines |
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