CN106565467B - A kind of preparation method of antiallergic bilastine intermediate - Google Patents
A kind of preparation method of antiallergic bilastine intermediate Download PDFInfo
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- CN106565467B CN106565467B CN201610961880.8A CN201610961880A CN106565467B CN 106565467 B CN106565467 B CN 106565467B CN 201610961880 A CN201610961880 A CN 201610961880A CN 106565467 B CN106565467 B CN 106565467B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a kind of preparation method of antiallergy new drug bilastine intermediate, more difficult quaternary carbon atom is built using gentle addition reaction, carboxylic group is introduced at room temperature with very cheap and easily-available raw material, purify the research of progress to it using distinctive two phasic property of carboxylic acid simultaneously, so that the expensive metallic catalyst avoided in building-up process, it it also avoid the implementation condition of harshness, it is gentle so as to provide a reaction condition, it is easy to operate, synthesis cost is cheap, is adapted to the preparation method of the Bilastine intermediates of large-scale production.
Description
Technical field
The present invention relates to a kind of medicine intermediate, more particularly to a kind of preparation side of antiallergy new drug bilastine intermediate
Method.
Background technology
Bilastine (also known as pyrrole Lars spit of fland bilastine) raw material and tablet " is the exploitation of FAES drugmakers of Spain
2nd generation histamine H 1 receptor antagonist, bilastine in August in 2012 21 days by European Union ratify to be used for treat allergia nose's film it is scorching and
Nettle rash, while carry out the clinical research of II phase in the U.S..
The great difficulty of synthesis of bilastine, is mainly reflected in as shown in structure I I in compound, and its unique quaternary carbon is former
Son is very difficult to build, at present document patent report (WO2009/102155A2,2009；US2011/9636A1,2011 conjunction)
Into the silyl enol ether that unstable TMS protections are built under isobutyrate, low temperature, then with 4- bromophenethyl alcohols in absolute nothing
The coupling reaction of metal catalytic is carried out under conditions of water anaerobic, then hydrolysis obtains corresponding structure I I.
Although above-mentioned route successfully realizes the preparation of II structures, need to build unstable silyl enol ether under low temperature,
Need expensive metallic catalyst to realize coupling simultaneously, although yield is medium on the upper side, needs and its exacting terms is (exhausted
To anhydrous and oxygen-free, prolonged high temperature) and treatment conditions (removing removing heavy metals), once in addition, crucial metal coupling reaction reality
Apply scale and exceed hectogram, yield drastically declines.Although many factors, which combine, make it that this route yield in lab scale is very high, its
Implementation cost, energy consumption is all very high, and implementation condition is also very harsh, can not amplify in addition so that can not be turned into by changing route by one
Good technology route.
The content of the invention
It is an object of the invention to shortcoming be present for the preparation method of existing Bilastine intermediates, there is provided Yi Zhongkang
The preparation method of allergy new drug bilastine intermediate, the present invention build more difficult quaternary carbon original using gentle addition reaction
Son, carboxylic group is introduced at room temperature with very cheap and easily-available raw material, at the same it is pure to its using distinctive two phasic property of carboxylic acid
Change the research carried out so that the expensive metallic catalyst avoided in building-up process, the implementation condition of harshness is it also avoid, from
Easy to operate and it is gentle to provide a reaction condition, synthesis cost is cheap, and most critical is to be adapted to large-scale production
The preparation method of Bilastine intermediates.
The technical solution adopted for the present invention to solve the technical problems is：
A kind of preparation method of antiallergy new drug bilastine intermediate, bilastine intermediate are chemical combination shown in Formula II
Thing, preparation method step are as follows：
Wherein, P1 is hydroxyl protecting group；X is halogen；R1 and R2 is C1-C6 alkyl, or R1 and R2 and the carbon that is linked
Atom forms 5 yuan of rings or 6 yuan of rings together；
(1) compound V additions after the exchange of halogen carbanion obtain compound IV；
(2) compound IV obtains compound III through electrophilic cyanogenation；
(3) compound II is obtained after compound III hydrolysis.
Wherein compound V synthesis refers to document Organic Letters, 2012, vol.14, #
3p.696–699。
Preferably, the hydroxyl protecting group is TBS protection groups.
Preferably, X is one kind in halogen Cl, Br, I.
Preferably, R1 and R2 are methyl.
Preferably, step (1) compound V obtains compound IV after the exchange of halogen carbanion with acetone addition.
Preferably, halogen carbanion clearing house is n-BuLi, s-butyl lithium or isopropyl using reaction reagent
Grignard reagent, reaction temperature are -78 DEG C or -20 DEG C~0 DEG C.Isopropyl grignard reagent is specially isopropyl magnesium bromide or different
Propyl group magnesium chloride.
Preferably, cyanating reagent used in electrophilic cyanogenation is potassium cyanide, Cymag or front three in step (2)
Base cyanoalkysilane, the catalyst used are ferric trichloride, stannous chloride, butter of tin or zinc dichloride, and the solvent used is
Dichloromethane, dichloroethanes, chloroform or toluene.Eliminating hydroxide obtains carbonium ion to compound IV in the presence of a lewis acid,
Generation compound III is combined with the cyano group in system again.
Preferably, obtain compound II after step (3) compound III alkaline hydrolysis：Used alkali be potassium hydroxide,
Sodium hydroxide or lithium hydroxide, the reaction medium of hydrolysis is methanol, ethanol, isopropanol, ethylene glycol, glycol dimethyl ether or
Glycol monoethyl ether, reaction temperature are 80-140 DEG C.
The beneficial effects of the invention are as follows：Reaction condition is gentle, easy to operate, and synthesis cost is cheap, is adapted to large-scale production.
Embodiment
Below by specific embodiment, technical scheme is described in further detail.
In the present invention, if not refering in particular to, used raw material and equipment etc. are commercially available or commonly used in the art.
Method in following embodiments, it is the conventional method of this area unless otherwise instructed.
Bilastine intermediate is that compound, process route shown in Formula II are as follows：
Wherein, P1 is hydroxyl protecting group；X is halogen；R1 and R2 is C1-C6 alkyl, or R1 and R2 and the carbon that is linked
Atom forms 5 yuan of rings or 6 yuan of rings together；
Preparation method step is as follows：
(1) compound V additions after the exchange of halogen carbanion obtain compound IV；
(2) compound IV obtains compound III through electrophilic cyanogenation；
(3) compound II is obtained after compound III hydrolysis.
In a particularly preferred scheme, the invention provides following synthetic route：
The synthetic method comprises the following steps：
1) compound as shown in Formula V a, carbanion exchange after addition obtain the compound as shown in formula IV a；
2) compound as shown in formula IV a, electrophilic cyaniding obtain the compound as shown in formula III a；
3) compound as shown in formula III a, hydrolysis obtain the compound as shown in Formula II.
Term used herein, in addition to having opposite statement, there is following implication.
" alkyl " refers to the aliphatic hydrocarbon group of saturation, includes the straight chain and branched group of 1-10 carbon atom, preferably include 1 to
6 carbon atoms.Non-limiting embodiments include but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary fourth
Base, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyls, 1- ethyl propyls, 2-
Methyl butyl, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyl propyl group, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl,
1,2- dimethylbutyl, 2,2- dimethylbutyls, 1,3- dimethylbutyl, 2- ethyl-butyls, 2- methyl amyls, 3- methylpents
Base, 4- methyl amyls, 2,3- dimethylbutyls etc..Alkyl can be substitution or unsubstituted, when substituted, substituent
It can be substituted on any workable tie point, be preferably one or more following groups, independent is selected from alkyl, alkene
Base, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, epoxy radicals, Heterocyclylalkyl, aryl,
Heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo.
" hydroxyl protecting group " is known in the art the appropriate group for hydroxyl protection, referring to document
(" Protective groups in Organic Synthesis ", 5th Ed.T.W.Greene＆P.G.M. Wuts) in
Hydroxy-protective group.As an example, preferable, described hydroxyl protecting group can be (C1-C10 alkyl or aryl)3Silane
Base, such as triethyl group silicon substrate, triisopropylsilyl, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate etc..Can be C1-C10
Alkyl or substitution alkyl, such as methyl, the tert-butyl group, pi-allyl, benzyl, methoxy, ethoxyethyl group, 2- oxinanes
Base, can be C1-C10 alkyl or aromatic radical acyl group, such as formoxyl, acetyl group, benzoyl etc..The abbreviation TBS tert-butyl groups
Dimethyl silicon substrate, TMSCN trimethyl cyanoalkysilanes.
Embodiment：
1：Compound Va synthesis
4- bromophenethyl alcohols (1.0kg, 5.0mol) are added in reactor, the dichloromethane dissolving of 10 times of volumes, add three second
The DMAP of amine (1.01kg, 10.0mol) and catalytic amount, TBSCl (0.9kg, 6.0mol) is added in batches.React at room temperature to original
Material disappears, washing, saturated salt washing, be concentrated to give after anhydrous sodium sulfate drying colourless oil liquid compound Va (1.5kg,
95.5%), direct plunge into and react in next step.
2：Compound IVa synthesis
Above-claimed cpd Va (1.5kg, 4.78mol) is added in reactor, anhydrous THF (10V) dissolving, is cooled to -78 DEG C,
N-BuLi (2.5M, 2.3L) is slowly added dropwise, is added dropwise, maintains the thermotonus 2 hours.Anhydrous propanone is slowly added dropwise
(0.55kg), take 1 hour.It is added dropwise, is slowly warmed to room temperature reaction to raw material and disappears, saturated ammonium chloride is quenched rear EA and carried
Take, wash, saturated salt is washed, and the compound IVa (1.40kg, crude product) concentrated after anhydrous sodium sulfate drying, can be direct plungeed into down
Single step reaction. 3：Compound IIIa synthesis
Above-claimed cpd IVa (1.40kg, crude product) is added in reactor, anhydrous DCM (5V) dissolving, adds TMSCN
(1.41kg), the anhydrous DCM solution that butter of tin (0.86kg, 3.33mol) is slowly added dropwise after 0 DEG C is cooled to, is finished, reacted
Disappeared to raw material.Reaction system is evacuated in configured sodium hydroxide and potassium fluoride mixed solution, control temperature is less than 30 DEG C,
1kg diatomite is added into system, stirs 30 minutes and filters, organic phase is concentrated after liquid separation, and filter residue is washed with ethyl acetate, water
Mutually it is extracted with ethyl acetate, and after concentrate merging is washed twice with clear water, saturated aqueous common salt washes twice, and is concentrated to give after drying
Required compound IIIa (1.35kg, crude product), it can direct plunge into and react in next step.
4：Compound II synthesis
Compound IIIa (1.35kg, crude product) is added in reactor, adds ethylene glycol 4L, adds 50% potassium hydroxide solution
(1.92kg), it is heated to 140 DEG C of reactions to raw material and disappears.It is cooled to after room temperature plus water quenching is gone out, with the tertiary ether washing reaction system of first
Twice, aqueous phase is tuned into acidity by liquid separation with 6N hydrochloric acid, is dried after ethyl acetate extraction, the grey-brown powder shape solid of concentration, PE/
EA=3/1 mashing can obtain white powdery solids compound II (0.72kg, 70%, 4 step) of the purity more than 99%.1H-NMR
(400MHz, CDCl3) δ 7.35 (d, J=8.0Hz, 2H), 7.20 (d, J=8.0Hz, 2H), 3.86 (t, J=6.4Hz, 2H),
3.74 (brs, 2H), 2.86 (t, J=6.4Hz, 2H), 1.59 (s, 6H).
Embodiment described above is a kind of preferable scheme of the present invention, not the present invention is made any formal
Limitation, there are other variants and remodeling on the premise of without departing from the technical scheme described in claim.
Claims (4)
1. a kind of preparation method of antiallergic bilastine intermediate, it is characterised in that bilastine intermediate is Formula II institute
Show compound, preparation method step is as follows：
Wherein, P1 is hydroxyl protecting group；X is halogen；R1 and R2 is C1-C6 alkyl, or R1 and R2 and the carbon atom that is linked
5 yuan of rings or 6 yuan of rings are formed together；
(1) compound V additions after the exchange of halogen carbanion obtain compound IV；
(2) compound IV obtains compound III through electrophilic cyanogenation；
(3) compound II is obtained after compound III hydrolysis；
The hydroxyl protecting group is TBS protection groups；X is one kind in halogen Cl, Br, I；Electrophilic cyanogenation institute in step (2)
The cyanating reagent used is potassium cyanide, Cymag or trimethyl cyanoalkysilane, and the catalyst used is ferric trichloride, dichloride
Tin, butter of tin or zinc dichloride, the solvent used are dichloromethane, dichloroethanes, chloroform or toluene；Step (3) is changed
Compound II is obtained after compound III alkaline hydrolysis：Used alkali is potassium hydroxide, sodium hydroxide or lithium hydroxide, is hydrolyzed
Reaction medium be methanol, ethanol, isopropanol, ethylene glycol, glycol dimethyl ether or glycol monoethyl ether, reaction temperature is
80-140℃。
2. preparation method according to claim 1, it is characterised in that R1 and R2 is methyl.
3. preparation method according to claim 1, it is characterised in that step (1) compound V exchanges in halogen carbanion
Afterwards compound IV is obtained with acetone addition.
4. preparation method according to claim 3, it is characterised in that halogen carbanion clearing house is using reaction reagent
N-BuLi, s-butyl lithium or isopropyl grignard reagent, reaction temperature are -78 DEG C or -20 DEG C~0 DEG C.
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| CN112110811A (en) * | 2019-06-20 | 2020-12-22 | 北京万全德众医药生物技术有限公司 | Preparation method of bilastine intermediate |
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