CN108250140A - A kind of preparation method of maleic acid datro - Google Patents
A kind of preparation method of maleic acid datro Download PDFInfo
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- CN108250140A CN108250140A CN201611236438.5A CN201611236438A CN108250140A CN 108250140 A CN108250140 A CN 108250140A CN 201611236438 A CN201611236438 A CN 201611236438A CN 108250140 A CN108250140 A CN 108250140A
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- 0 CCc1c(C*)cc(CC(C2)N(CCc3c(C=CC(N4)=*)c4c(*)cc3)CC(c(cc3)c(C=CC(N4)=O)c4c3OCc3ccccc3)O)c2c1 Chemical compound CCc1c(C*)cc(CC(C2)N(CCc3c(C=CC(N4)=*)c4c(*)cc3)CC(c(cc3)c(C=CC(N4)=O)c4c3OCc3ccccc3)O)c2c1 0.000 description 3
- FAOAQSVNWSHGRW-UHFFFAOYSA-N CCc1cc(CC(C2)NC(CO)c(cc3)c(C=CC(N4)=O)c4c3OCc3ccccc3)c2cc1CC Chemical compound CCc1cc(CC(C2)NC(CO)c(cc3)c(C=CC(N4)=O)c4c3OCc3ccccc3)c2cc1CC FAOAQSVNWSHGRW-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
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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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to pharmaceutical synthesis field, in particular to a kind of preparation method of maleic acid datro.The preparation method step is brief, easy to operate, safety and environmental protection, addition without aqueous slkali, heating reaction can obtain the product of step 1) coupling, and the by-products such as the region isomer generated and dimer are few, yield is higher, reaches 93%, HPLC purity more than 97.8%, post processing is simple, is advantageously implemented industrialized production, finally obtains the higher maleic acid datro of optical purity.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, in particular to a kind of preparation method of maleic acid datro.
Background technology
Maleic acid datro (Indacaterol Maleate) is that a kind of novel long-acting beta-2-adrenoreceptor swashs
Dynamic agent (LABA) locally plays the effect of bronchodilator in intrapulmonary after sucking and increases to cardia β2-adrenergic
The selectivity of receptor.The product is a kind of bronchiectasis medicine developed by Novartis Co., Ltd of Switzerland, is obtained on July 1st, 2011
U.S. FDA approval listing, trade name Arcapta, suitable for suffering from the adult patient of Chronic Obstructive Pulmonary Disease (COPD).Make
For all new generation LABA, the medical instrument have once a day, in 5 minutes quick acting remarkable advantage, suitable for having airflow obstruction
COPD adult patients stationary phases maintaining treatment.
The chemical name of maleic acid datro be 5- [(R) -2- (5,6- diethyl-indane -2- bases amino) -1- hydroxyls -
Ethyl] -8- Hydroxy-quinolins -2 (1H) -one maleate, structural formula is shown in formula I：
The synthetic method of a variety of datro is disclosed in the prior art.As WO200476422, WO2005123684,
In the method for the reports such as US6878721, US2011118469, with compound (R) -5- Oxyranyles -8- benzyloxies-quinoline
(1H) -one of quinoline -2 and 5,6- diethyl -2,3- dihydro -1H- indenes -2- amine are condensed to yield intermediate (route 1), using de- benzyl into
Maleic acid datro is made in salt.Above-mentioned synthetic method can generate more di-substituted and position isomer impurity, account for about
20%.
WO2013132514 reports synthetic method as shown in Scheme 2, and step 1 is in organic solvent (DMSO) and alkali (three
Ethamine, K2CO3, NaI etc.) it is existing under the conditions of coupled reaction occurs, wherein when using triethylamine and NaI mixed bases, yield is
76%；When using K2CO3During with NaI mixed bases, yield 82%；As alkali selected as NaI, yield 84%.
Invention content
On the one hand the application provides a kind of Formula II compound or the preparation method of its acid-addition salts, including：
In the presence of alcohol and/or ether solvents, Formula II B compounds or its acid-addition salts and Formula II A compounds are reacted, and are obtained
Formula II compound or its acid-addition salts, wherein reaction temperature are 60 DEG C~130 DEG C.
Wherein, R is H or hydroxyl protection base, and the example of hydroxyl protection base includes but not limited to for silicon substrate, alkyl, aryl, alkane
Oxygroup, alkenyl, aralkyl, halogenated alkyl and benzyl；In some embodiments, R is benzyl.
X is leaving group, including but not limited to methanesulfonates, tosylate, bromine, chlorine and iodine；In some embodiments
In, X is bromine.
Alcoholic solvent includes C1-6Alkylol, including but not limited to methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutyl
The mixture of one or more of alcohol, sec-butyl alcohol, the tert-butyl alcohol, n-amyl alcohol, n-hexyl alcohol, it is in some embodiments, described
Alcohol is n-butanol；The ether solvents include but not limited to dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, methyl tertbutyl
The mixture of one or more of ether.
In some embodiments, reaction temperature is 80 DEG C~110 DEG C, in some embodiments, reaction temperature 90
DEG C~115 DEG C, in some embodiments, reaction temperature is 100 DEG C~110 DEG C.
The application second aspect provides a kind of datro (formula IV compound) or the preparation method of its salt, including with
Lower step：
1) in the presence of alcoholic solvent and/or ether solvents, Formula II B compounds or its acid-addition salts and Formula II A compounds are reacted,
Formula II compound or its acid-addition salts are obtained, wherein reaction temperature is 60 DEG C~130 DEG C；
2) Formula II compound or its salt reacts in the presence of a reducing agent, obtains formula III or its salt；
3) protecting group of formula III compound or its salt optionally, is removed, obtains formula IV compound or its salt；
4) optionally, formula IV compound obtains Formula V compound in the presence of solvent with acid processing, and wherein HA is acid.
Wherein, R is H or hydroxyl protection base, and the example of hydroxyl protection base includes but not limited to for silicon substrate, alkyl, aryl, alkane
Oxygroup, alkenyl, aralkyl, halogenated alkyl and benzyl；In some embodiments, R is benzyl.
X is leaving group, including but not limited to tosylate, mesylate, bromine, chlorine and iodine；In some embodiments,
X is bromine.
In step 1), alcoholic solvent includes C1-6Alkylol, including but not limited to methanol, ethyl alcohol, normal propyl alcohol, isopropanol, positive fourth
The mixture of one or more of alcohol, isobutanol, sec-butyl alcohol, the tert-butyl alcohol, n-amyl alcohol, n-hexyl alcohol, in some embodiments,
The alcohol is n-butanol；The ether solvents include but not limited to dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, methyl
The mixture of one or more of tertbutyl ether.In some embodiments, the reaction temperature of step 1) is 80 DEG C~110
DEG C, in some embodiments, reaction temperature be 90 DEG C~115 DEG C, in some embodiments, reaction temperature for 100 DEG C~
110℃。
Wherein, step 2) can be reacted in the presence of the mixture of one or more of following solvents, described molten
Agent include but not limited to ether solvent (such as tetrahydrofuran, Di Iso Propyl Ether, 2- methoxy ethyls ether, methyl tertiary butyl ether(MTBE) and 1,
4- dioxanes), acetic acid C1-C6Arrcostab (such as ethyl acetate, isopropyl acetate and butyl acetate), alkylamine (such as C1-C6Alkyl
Amine), C1-C6Alkylol (such as methanol, ethyl alcohol, propyl alcohol, isopropanol, butanol and amylalcohol), C6-C12Aliphatic hydrocarbon (such as isooctane, heptan
Alkane；Dimethylformamide), aromatic hydrocarbons (such as toluene and benzene), chlorinated solvent (such as dichloromethane).In some embodiments, it is described
Solvent is ether solvent, such as tetrahydrofuran, methyl tertiary butyl ether(MTBE)；In some embodiments, the solvent is tetrahydrofuran.
Reducing agent described in step 2) includes asymmetric reduction agent, in some embodiments, in chiral catalyst and
Asymmetric reduction is carried out in the presence of reducing agent, wherein chiral catalyst includes chiral oxazaborolidine, such as CBS catalyst, packet
Include methyl CBS and phenyl CBS, in some embodiments, chiral catalyst for (R) -2- methyl-CBS- oxazaborolidines and (R) -
2- phenyl-CBS- oxazaborolidines, most preferably (R) -2- methyl-CBS- oxazaborolidines；Reducing agent can be borane reagent, including but
It is not limited to borine-tetrahydrofuran compound, borine-DMS compounds, borine-N, N- diethylbenzene amine compound or borine-diformazan
Sulfur compound, in some embodiments, reducing agent are borine-tetrahydrofuran compound.In some embodiments, step 2)
It protects in nitrogen, is reacted at 0~5 DEG C.The reduction reaction of step 2) also can be in DIP-Cl, diethylmethoxyborane, hydroboration
It is reacted in the presence of sodium, Lithium Aluminium Hydride etc..
It wherein, can be according to method deprotection base well known in the art in step 3).In some embodiments, it is being catalyzed
Benzyl is removed by catalytic hydrogenation in the presence of agent.Wherein, the catalyst used in catalytic hydrogenation includes palladium, palladium dydroxide, in work
Property charcoal on palladium, palladium on alumina, palladium, platinum on powdered carbon, platinum and Raney nickel on the activated carbon and theirs is mixed
Close object；Most preferably, catalyst is palladium on the activated carbon.
Wherein, the sour HA described in step 4) includes but not limited to inorganic acid (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphur
Acid, nitric acid, phosphoric acid) and organic acid (such as maleic acid, fumaric acid, oxalic acid, citric acid, salicylic acid, acetylsalicylic acid), it is described
Solvent includes but not limited to C1-C6Alkylol, such as methanol, ethyl alcohol, propyl alcohol, butanol and amylalcohol, it is in some embodiments, described
Solvent is methanol.In some embodiments, using excessive acid, such as the acid of 1~2 equivalent.In some embodiments, instead
Temperature is answered to be selected from 50~70 DEG C, preferably 55~65 DEG C.
In some embodiments, this application provides a kind of preparation method of -1 compound of Formula II, including：
In the presence of alcohol and/or ether solvents, Formula II B-1 compounds and the reaction of Formula II A compounds obtain -1 chemical combination of Formula II
Object, wherein reaction temperature are 60 DEG C~130 DEG C.
Wherein, alcoholic solvent includes C1-6Alkylol, including but not limited to methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol,
The mixture of one or more of isobutanol, sec-butyl alcohol, the tert-butyl alcohol, n-amyl alcohol, n-hexyl alcohol, in some embodiments, institute
The alcohol stated is n-butanol；The ether solvents include but not limited to dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, methyl- tert
The mixture of one or more of butyl ether.In some embodiments, reaction temperature is 80 DEG C~110 DEG C, in some realities
It applies in scheme, reaction temperature is 90 DEG C~115 DEG C, and in some embodiments, reaction temperature is 100 DEG C~110 DEG C.
In some embodiments, this application provides a kind of datro (formula IV compound) or the preparation sides of its salt
Method includes the following steps：
1) in the presence of alcoholic solvent and/or ether solvents, Formula II B-1 compounds and the reaction of Formula II A compounds obtain Formula II -1
Compound, wherein reaction temperature are 60 DEG C~130 DEG C；
2) -1 compound of Formula II is reacted in the presence of a reducing agent, -1 compound of formula III is obtained, optionally, in alkaline condition
Under be changed into -2 compound of formula III；
3) protecting group of -2 compound of -1 compound of formula III or formula III is removed, obtains formula IV compound or its salt；
4) the formula IV compound or its salt of step 3) is handled in the presence of solvent with maleic acid, obtains compound of formula I.
In step 1), alcoholic solvent includes C1-6Alkylol, including but not limited to methanol, ethyl alcohol, normal propyl alcohol, isopropanol, positive fourth
The mixture of one or more of alcohol, isobutanol, sec-butyl alcohol, the tert-butyl alcohol, n-amyl alcohol, n-hexyl alcohol, in some embodiments,
The alcohol is n-butanol；The ether solvents include but not limited to dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, methyl
The mixture of one or more of tertbutyl ether.In some embodiments, the reaction temperature of step 1) is 80 DEG C~110
DEG C, in some embodiments, reaction temperature be 90 DEG C~115 DEG C, in some embodiments, reaction temperature for 100 DEG C~
110℃。
Wherein, step 2) can be reacted in the presence of the mixture of one or more of following solvents, described molten
Agent include but not limited to ether solvent (such as tetrahydrofuran, Di Iso Propyl Ether, 2- methoxy ethyls ether, methyl tertiary butyl ether(MTBE) and 1,
4- dioxanes), acetic acid C1-C6Arrcostab (such as ethyl acetate, isopropyl acetate and butyl acetate), alkylamine (such as C1-C6Alkyl
Amine), C1-C6Alkylol (such as methanol, ethyl alcohol, propyl alcohol, isopropanol, butanol and amylalcohol), C6-C12Aliphatic hydrocarbon (such as isooctane, heptan
Alkane；Dimethylformamide), aromatic hydrocarbons (such as toluene and benzene), chlorinated solvent (such as dichloromethane).In some embodiments, it is described
Solvent is ether solvent, such as tetrahydrofuran, methyl tertiary butyl ether(MTBE)；In some embodiments, the solvent is tetrahydrofuran.
Reducing agent described in step 2) includes asymmetric reduction agent, in some embodiments, in chiral catalyst and
Asymmetric reduction is carried out in the presence of reducing agent, wherein chiral catalyst includes chiral oxazaborolidine, such as CBS catalyst, packet
Include methyl CBS and phenyl CBS, in some embodiments, chiral catalyst for (R) -2- methyl-CBS- oxazaborolidines and (R) -
2- phenyl-CBS- oxazaborolidines, most preferably (R) -2- methyl-CBS- oxazaborolidines；Reducing agent can be borane reagent, including but
It is not limited to borine-tetrahydrofuran compound, borine-DMS compounds, borine-N, N- diethylbenzene amine compound or borine-diformazan
Sulfur compound, in some embodiments, reducing agent are borine-tetrahydrofuran compound.In some embodiments, step 2)
It protects in nitrogen, is reacted at 0~5 DEG C.The reduction reaction of step 2) also can be in DIP-Cl, diethylmethoxyborane, hydroboration
It is reacted in the presence of sodium, Lithium Aluminium Hydride etc..
It can be according to method deprotection base well known in the art in step 3).In some embodiments, in catalyst
In the presence of benzyl removed by catalytic hydrogenation.Wherein, the catalyst used in catalytic hydrogenation includes palladium, palladium dydroxide, in activated carbon
On palladium, palladium on alumina, palladium, platinum on powdered carbon, platinum and Raney nickel on the activated carbon and their mixing
Object；Most preferably, catalyst is palladium on the activated carbon.
Herein, the acid-addition salts (such as hydrochloride) of Formula II A compounds can first be changed into Formula II A compounds, Ran Houzai
With Formula II B compounds or its acid addition salt reaction, Formula II compound or its acid-addition salts are prepared.In some embodiments
In, in the presence of sodium hydroxide, the hydrochloride of IIA compounds is changed into free Formula II A compounds.It is specific real at some
It applies in scheme, Formula II A compounds are obtained by the reaction in the presence of organic solvent and alkali in the salt of Formula II A compounds；It is wherein described
Organic solvent can be C1-C4Alkylol (such as methanol, ethyl alcohol, isopropanol, butanol), acetonitrile, ethyl acetate, dichloromethane, tetrahydrochysene furan
It one or more of mutters with ether, preferably methanol；The alkali is selected from organic base and/or inorganic base, and wherein organic base selects
From C1To C6It is cyclic annular or without cyclammonium (such as isopropylamine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N- methyl piperidines, N-
Methyl piperazine, N- picolines, DBU, DABCO and triethylamine), inorganic base include but not limited to alkali metal (such as sodium, potassium, lithium),
Alkali carbonate (such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate), alkali metal hydrogencarbonate (such as sodium bicarbonate, bicarbonate
Potassium, lithium bicarbonate, caesium bicarbonate), alkali metal hydroxide (such as sodium hydroxide, calcium hydroxide, potassium hydroxide), metal alkoxide
(such as alkoxide of sodium, lithium, potassium, sodium tert-butoxide) and sodium hydride.In some embodiments, alkali is sodium hydrate aqueous solution, concentration
For 15~35g/L；In some embodiments, alkali is 32g/L sodium hydrate aqueous solutions.Free Formula II A compounds also can be used
Well known to a person skilled in the art other methods to be prepared.
Herein, " alkyl " refers to the aliphatic hydrocarbon of the saturation for the linear chain or branch chain being made of carbon atom and hydrogen atom
Group is connected by the rest part of singly-bound and molecule.Such as the alkyl can have 1-6 carbon atom (with C1-C6Alkyl
Represent), preferably with 1-4 carbon atom.The non-limiting examples of alkyl include but not limited to methyl, ethyl, propyl, 2- third
Base, normal-butyl, isobutyl group, tertiary butyl, n-pentyl, 2- methyl butyls, neopentyl, n-hexyl.
" halogenated alkyl " refers to the alkyl replaced by one or more halogens selected from chlorine, bromine, iodine, wherein alkyl
Definition with it is defined above identical.
" alkoxy " refers to-O- alkyl, wherein alkyl with it is defined above identical.The alkoxy can have 1-
6 carbon atoms, preferably comprise 1-4 carbon atom.The non-limiting examples of alkoxy include but not limited to methoxyl group, ethyoxyl,
Propoxyl group, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, 2- methyl butoxies, neopentyl oxygen, just
Hexyloxy.
" aryl " refer to the pi-electron system with conjugation full carbon is monocyclic or the aromatic group of fused polycycle,
It is preferred that with 6-14 carbon atom, more preferably there is 6-12 carbon atom, most preferably with 6 carbon atoms.Aryl it is unrestricted
Property example includes but not limited to phenyl, naphthalene and anthryl.
" aralkyl " refers to the alkyl of aryl substitution, wherein the definition of " aryl " and " alkyl " and definition above
It is identical.
The preparation method step of the application is brief, easy to operate, safety and environmental protection, without the addition of aqueous slkali, heating reaction
The product of step 1) coupling is can obtain, and the by-products such as the region isomer generated and dimer are few, yield is higher, reaches
93%, HPLC purity are more than 97.8%, and post processing is simple, is advantageously implemented industrialized production, and it is higher to finally obtain optical purity
Maleic acid datro.
Specific embodiment
The application is described further with reference to embodiments, it should be noted that following embodiments cannot function as pair
The limitation of the application protection domain.
The preparation of 1 compound IIA of embodiment
NaOH aqueous solutions are configured 1.：32g sodium hydroxides are added in 1000ml purified waters, stirring and dissolving, placed spare.Match
Put NaOH aqueous solutions 2.：16g sodium hydroxides are added in 1000ml purified waters, stirring and dissolving, placed spare.By 90g compounds
1. hydrochloride, 50ml methanol and the NaOH aqueous solutions of IIA is added in reaction bulb, stir 30min, be averaged with 1600ml dichloromethane
It extracts in two times, merges organic phase；It 2. washed once with NaOH aqueous solutions, washed in two times with 2000ml level of purification；Have
Machine mutually stirs dry 1h with anhydrous sodium sulfate；Drier is filtered out, filtrate is evaporated.
The preparation of 2 datro intermediate II hydrobromate of embodiment
Remaining compounds IIA, 125g compound IIB-1 and the 1300ml n-butanol that embodiment 1 is evaporated is molten
Liquid is added in 5L reaction bulbs, is stirred evenly, and is heated to 100~110 DEG C, and reaction 3h starts TLC detections, until compound IIA reacts
Stop heating after completely.50~60 DEG C of evaporated under reduced pressure, are transferred in 3L reaction bulbs, add in 1000ml ethyl acetate, are heated to 70
~78 DEG C, reflux mashing 1.5h；It filters, filter cake is dried under reduced pressure 5h in 50 DEG C, obtains the hydrobromate of 174.4g Formula II, is dark brown
Solid powder, yield 93%, liquid phase purity are 97.82%.Its Elemental analysis data is：C31H33BrN2O3Measured value is (theoretical
Value) %：C 66.25 (66.31), H 5.93 (5.92), O 8.56 (8.55), N 4.99 (4.99), Br 14.22 (14.23).
The preparation of 3 datro intermediate III -2 of embodiment
Datro intermediate II -1, tetrahydrofuran are added in reaction bulb, stirred evenly, nitrogen protection, ice-water bath will
Reaction temperature is down to 0~3 DEG C, adds in (R) -2- methyl-CBS- oxazaborolidines, tetrahydrofuran Borane solution is then added dropwise, about
30min drops finish.Continue to keep 0~3 DEG C of 6~8h of reaction of temperature in reaction, until the reaction was complete for TLC monitoring.Methanol solution is added dropwise to be quenched
Reaction solution pressurization is evaporated off solvent, is beaten 3h with 1M dilute hydrochloric acid, filters to obtain off-white powder by reaction.60 DEG C of forced air drying 6h, obtain
The hydrobromate (formula III -1) of 7.5g formula IIIs, for off-white powder, liquid phase purity 97.86%.
The hydrobromate (formula III -1,11g) of datro intermediate III is added in reaction bulb, adds in methanol 20ml,
Water 80ml；It stirs evenly, adds in potassium carbonate/aqueous solution (2.7g/20ml), stir 1h；Add in 80ml ethyl acetate, stirring
30min, liquid separation, water phase 40ml ethyl acetate backwashes；Merge organic phase, washed twice with saturated salt solution.Organic phase nothing
Aqueous sodium persulfate is dried, and is concentrated to give -2 9g of datro intermediate III, is pale solid.
The preparation of 4 datro of embodiment (formula IV compound)
1L glacial acetic acid, 1L methanol and 160g datro intermediate III -2 are added in reaction bulb, stirring and dissolving, cooling
To 0~5 DEG C, add in 10% palladium carbons of 3.2g, nitrogen replace 3 times, hydrogen replace 3 times, control Hydrogen Vapor Pressure 0.1~0.2MPa, 2
~8 DEG C, reaction 6h starts TLC monitoring, until the reaction was complete for raw material.Filtering, filtrate are concentrated under reduced pressure into about 1/5 body in 35~45 DEG C
Product adds in 639ml methanol, is stirred and heated to 55~65 DEG C, adds in 16g activated carbons, and insulated and stirred 45min is filtered while hot, filters
The not concentrated direct participation the next step of liquid.
The preparation of 5 maleic acid datro I of embodiment
47.4g maleic acids are added in into 227ml methanol, maleic acid methanol solution is configured in stirring and dissolving, places spare.Xiang Shi
Addition maleic acid methanol solution in the filtrate of example 4 is applied, is heated to 60 ± 5 DEG C of stirring 30min, cooled to room temperature, then cool down
To 0~5 DEG C of stirring and crystallizing 5h, filtering, filter cake is washed with 227ml absolute ethyl alcohols, is filtered dry, and filter cake is dried under reduced pressure in 45~55 DEG C
5h obtains 128g white solid powders, and 4,5 liang of step yields of embodiment are 76%.
Claims (10)
1. the preparation method of a kind of Formula II compound or its acid-addition salts, including：In the presence of alcohol and/or ether solvents, Formula II B
Compound or its acid-addition salts and the reaction of Formula II A compounds, obtain Formula II compound or its acid-addition salts, wherein reaction temperature is
60 DEG C~130 DEG C；
Wherein, R is H or hydroxyl protection base；X is leaving group.
2. preparation method according to claim 1, wherein R are benzyl；X is bromine.
3. preparation method according to claim 1 or 2, wherein the alcoholic solvent is methanol, ethyl alcohol, normal propyl alcohol, isopropyl
The mixture of one or more of alcohol, n-butanol, isobutanol, sec-butyl alcohol, the tert-butyl alcohol, n-amyl alcohol, n-hexyl alcohol, preferably positive fourth
Alcohol.
4. according to the preparation method described in any one in claim 1-3, wherein 80 DEG C~110 DEG C of the reaction temperature,
Preferably 90 DEG C~115 DEG C, most preferably 100 DEG C~110 DEG C.
5. a kind of preparation method of formula IV compound or its salt, includes the following steps：
1) in the presence of alcoholic solvent and/or ether solvents, Formula II B compounds or its acid-addition salts and Formula II A compounds are reacted, and are obtained
Formula II compound or its acid-addition salts, wherein reaction temperature are 60 DEG C~130 DEG C；
2) Formula II compound or its salt reacts in the presence of a reducing agent, obtains formula III or its salt；
3) protecting group of formula III compound or its salt optionally, is removed, obtains formula IV compound or its salt；
4) optionally, formula IV compound obtains Formula V compound in the presence of solvent with acid processing, and wherein HA is acid；
Wherein, R is H or hydroxyl protection base；X is leaving group.
6. preparation method according to claim 5, wherein R are benzyl；X is bromine.
7. the alcoholic solvent described in preparation method according to claim 5 or 6, wherein step 1) is methanol, ethyl alcohol, positive third
The mixture of one or more of alcohol, isopropanol, n-butanol, isobutanol, sec-butyl alcohol, the tert-butyl alcohol, n-amyl alcohol, n-hexyl alcohol, it is excellent
It is selected as n-butanol.
8. according to the preparation method described in claim 5-7 any one, wherein 80 DEG C~110 DEG C of the reaction temperature, excellent
It is selected as 90 DEG C~115 DEG C, most preferably 100 DEG C~110 DEG C.
9. preparation method according to claim 5, the wherein reducing agent described in step 2) they are asymmetric reduction agent, including
Chiral catalyst and reducing agent, chiral catalyst are selected from (R) -2- methyl-CBS- oxazaborolidines and (R) -2- phenyl-CBS- oxazoles
Borine, preferably (R) -2- methyl-CBS- oxazaborolidines；It is compound that reducing agent is selected from borine-tetrahydrofuran compound, borine-DMS
Object, borine-N, N- diethylbenzene amine compound or borane-methyl sulfide complex, preferably borine-tetrahydrofuran compound.
10. preparation method according to claim 5, the wherein sour HA described in step 4) are selected from hydrochloric acid, hydrobromic acid, hydrogen iodine
Acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, fumaric acid, oxalic acid, citric acid, salicylic acid, acetylsalicylic acid, preferably maleic acid.
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| CN109721534A (en) * | 2018-09-25 | 2019-05-07 | 四川海思科制药有限公司 | A kind of maleic acid datro intermediate and its preparation method and application |
| CN109721534B (en) * | 2018-09-25 | 2022-05-20 | 四川海思科制药有限公司 | Indacaterol maleate intermediate and preparation method and application thereof |
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| CN108250140B (en) | 2021-06-25 |
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