CN105693603B - The maleic acid datro preparation process of improvement - Google Patents
The maleic acid datro preparation process of improvement Download PDFInfo
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- CN105693603B CN105693603B CN201410682500.8A CN201410682500A CN105693603B CN 105693603 B CN105693603 B CN 105693603B CN 201410682500 A CN201410682500 A CN 201410682500A CN 105693603 B CN105693603 B CN 105693603B
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Abstract
The invention discloses the maleic acid datro preparation processes of improvement, comprising steps of step 1) is by compound 2 and compound 3, the ring-opening reaction under the first solvent obtains compound 4, compound 4 after the second solvent obtains compound 4HA salt at salt with organic acid HA by crystallization treatment by being precipitated, step 2) by compound 4HA salt first pass through catalytic hydrogenation in the presence of a catalyst go it is Benzylation after, then with maleic acid obtain maleic acid datro at salt.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, and in particular to the improvement of bronchiectasis medicine-maleic acid datro
Preparation process.
Background technique
Maleic acid datro (Indacaterol Maleate) is that a kind of bronchus developed by Novartis Co., Ltd, Switzerland expands
Drug is opened, novel ultralong effect β 2 receptor agonist is belonged to, U.S. FDA approval listing, trade name are obtained on July 1st, 2011
Arcapta.It is also that first and currently the only acquisition U.S. SFDA approval is used for stationary phase Adult chronic obstructive disease of lung
(COPD) the long-acting sucking β 2 receptor agonist (LABA) of patient's maintenance therapy.As all new generation LABA, which has daily
Once, in 5 minutes quick acting remarkable advantage, the maintenance suitable for the COPD adult patients stationary phase with airflow obstruction controls
It treats.
The chemical name of maleic acid datro is 5- { (1R) -2- [(5,6- diethyl -2,3- dihydro -1H- indane -2-
Base) ammonia] -1- hydroxyethyl } -8- hydroxyl -1H- quinoline-2-one maleate, structural formula is as follows:
The synthetic method of datro is disclosed in the prior art.As patent WO2004/76422, WO2005/123684,
In the method for the reports such as US6878721, US2011/118469, with compound 5- (2R) -2- Oxyranyle -8- benzyloxy -
2 (1H)-quinolinones (2) and 5,6- diethyl -2,3- dihydro -1H- indenes -2- amine (3) are condensed to yield intermediate 4, then through de- benzyl at
Maleic acid datro (1) is made in salt, and reaction route is as follows:
In above-mentioned route 1, step 1) ring-opening reaction is using diethylene glycol dimethyl ether as reaction dissolvent, at 120 DEG C instead
It answers 15 hours and completes, the time is long, and energy consumption is high；Furthermore reaction also while generating a large amount of isomeric by-products (formula a) and two takes
For by-product (formula b), this two by-product account for about 8% and 12% respectively, and structure is as follows:
There are mainly two types of methods for purifying document report in relation to intermediate 4: one is patent WO2000/075114 to be used
Column chromatographic purifying, but waste a large amount of solvent, increase cost.Used by another kind is patent WO2004/076422
It being purified with benzoic acid at salt, this method is novel, but its yield is lower, and only 60%, it is improved up for further process optimization.
The present invention is directed to improve the preparation process of the maleic acid datro of above-mentioned route 1, especially two present in it
A problem: one is the first step reaction time is long and inefficient, the second is due to the side reaction of first step reaction obtain it is miscellaneous
Matter is excessive, so that the purification process of intermediate 4 is difficult.
Summary of the invention
To solve deficiency present in above-mentioned technique, the present invention provides a kind of systems of new improvement maleic acid datro
Standby technique, comprising steps of step 1) is by compound 2 and compound 3, the ring-opening reaction under appropriate solvent obtains compound 4, chemical combination
Object 4 is precipitated after obtaining compound 4HA salt at salt with organic acid HA by crystallization treatment, and step 2) is by compound 4HA
Salt first pass through catalytic hydrogenation in the presence of a catalyst go it is Benzylation after, then with maleic acid obtain maleic acid datro at salt.
The technical problem to be solved in the present invention first is that shorten step 1) ring-opening reaction time, improve efficiency.To understand
Certainly this technical problem, the present invention have screened the solvent of step 1) ring-opening reaction.It is found through experiment that the step ring-opening reaction can be in nothing
It is reacted in medium system, also can choose dipole solvent, preferably reaction medium is dimethyl sulfoxide, n,N-Dimethylformamide, second
Nitrile, N-Methyl pyrrolidone, C3-C6 ketones solvent, more preferable reaction dissolvent be dimethyl sulfoxide.In addition, the dosage of solvent is excellent
Selecting v/w ratio, (v, solvent volume mL, w are that the quality g) of compound 2 is 1~3 times of amount, more preferable 1 times of amount.Reaction temperature is preferably
80~120 DEG C, more preferable 110 DEG C.
The problem to be solved in the present invention second is that the purifying of the intermediate 4 in step 1), in being formed with organic acid HA
The acylate (compound 4HA) of mesosome 4 is avoided and is carried out in organic solvent as the compound 4 of unstable free alkali
Separation；Compound 4HA salt can pass through recrystallization purifying.
Above-mentioned intermediate 4 and organic acid HA in salt, the preferred paratolunitrile of organic acid, paranitrobenzoic acid, to first
Oxybenzoic acid, more preferably to methoxy benzoic acid.At salt and the acylate is precipitated with corresponding acylate in above-mentioned intermediate 4
Solvent is preferably C1‐C4Alcohols, such as methanol, ethyl alcohol, esters solvent, such as ethyl acetate, ether solvent, chlorinated hydrocarbon solvent is such as
One kind of methylene chloride or its mixed solvent, more preferable ethyl alcohol is as precipitation solvent.The equivalent of organic acid is preferably 1~2 equivalent,
More preferable 1.2 equivalent.
Present invention solves the technical problem that third is that being directly deprotected to methoxy benzoic acid salt by intermediate 4, and and horse
Come sour at salt.
In above-mentioned reaction, the preferred method for removing the benzyl on acylate is to pass through catalytic hydrogenation in the presence of a catalyst
Handle the salt.Preferred catalyst is selected from palladium, palladium dydroxide, palladium/charcoal (Pd/C), the palladium on attached aluminium oxide, on the activated carbon
Platinum and Raney Ni.Also the mixture of catalyst can be used.It is furthermore preferred that catalyst is palladium/charcoal.
Catalytic hydrogenation solvent for use is to have selected from alkyl acetate, such as ethyl acetate；Alcohol, such as C1-6 alkylol, such as first
Alcohol, ethyl alcohol, propyl alcohol, butanol and amylalcohol；Aliphatic C6-12 hydrocarbon；Dimethylformamide；Aromatic hydrocarbons, such as toluene and benzene；Acetonitrile；Heterocycle,
Such as tetrahydrofuran；Dialkyl ether；Dimethyl sulfoxide；Dialkyl carbonate, such as dimethyl carbonate；Acid, such as acetic acid, trifluoroacetic acid；Water
Property solvent, such as water；Ion type liquid and chlorinated solvent, such as methylene chloride.The mixture of solvent also can be used.More preferably second
Acid.
The applicable temperature of catalytic hydrogenation is preferably from about 0 DEG C to about 70 DEG C.More preferably 30 DEG C to about 50 DEG C.
With maleic acid at the preferred C1-6 alkylol of solvent of salt, such as methanol, ethyl alcohol, propyl alcohol, butanol and amylalcohol, more preferable second
Alcohol.Maleic acid is excessive, preferably 1~2 equivalent, more preferable 1.5 equivalent.
The present invention is in -2 (1H)-quinolinone of compound 5- (2R) -2- Oxyranyle -8- benzyloxy and 5,6- diethyl
Using dimethyl sulfoxide as solvent in base -2,3- dihydro -1H- indenes -2- amine condensation course, the reaction time is substantially reduced, by 15 hours
It shortens to 7 hours, while yield being kept to significantly improve.On the other hand, screening organic acid is purified with intermediate 4 at salt, is sent out
Now with to methoxy benzoic acid, paranitrobenzoic acid at salt, compared with prior art, yield with higher and purity, convenient for behaviour
Make, is suitable for industrialization.
Accordingly, the preparation process provided by the invention for improving maleic acid datro, when on the one hand substantially reducing reaction
Between, on the other hand, the maleic acid datro product yield with higher and purity of acquisition；Therefore integrated artistic operation letter
Just, it is suitable for industrialization.
Specific embodiment
Further illustrate that the present invention, following embodiment are only used for the more specific description present invention preferably by the following examples
Embodiment, be not used in and technical solution of the present invention be defined.The scheme of aforementioned present invention is that the present invention can be achieved
The technical solution of purpose.The used temperature of following embodiment and reagent, can be with above-mentioned relevant temperature and reagent substitution with reality
The purpose of the existing present invention.
Below by the embodiment further instruction present invention.
Embodiment 1.5- [(R) -2- (5,6- diethyl-indane -2- base amino) -1- hydroxy-ethyl] -8- phenylmethoxy
Base-(1H)-preparation of the quinoline-2-one to methoxy benzoic acid salt
5.0g 5,6- diethyl is added in the four-necked bottle equipped with magnetic agitation, thermometer, charging hopper and reflux condensing tube
The dimethyl sulfoxide of base -2,3- dihydro -1H- indenes -2- amine and 7mL, to the solution in be added 7.0g 5- (2R) -2- Oxyranyle -
Resulting suspension is heated to 110 DEG C, and stirs 7h at such a temperature by 8- benzyloxy -2 (1H)-quinolinone, and TLC is shown instead
It should be complete.Resulting brown solution is cooled to 60 DEG C, 80mL ethyl alcohol is added, is kept for 60 DEG C, 4.4g is then added to methoxy benzene
Formic acid is completely dissolved, and solution is cooled to 40 DEG C or so, crystal seed is added, and is placed cooling in ice bath.It is isolated by filtration to methoxy
Benzoate crude product 11.4g obtains 10.6g 5- [(R) -2- (5,6- diethyl-indane -2- base amino)-with ethyl alcohol recrystallization
1- hydroxy-ethyl] -8- Phenylmethoxy-(1H)-quinoline-2-one is to methoxy benzoic acid salt sterling, for white crystalline powder (production
Rate 70.1%, purity 98.79%).1HNMR(400MHz,CDCl3): δ 9.50 (br, 1H), 8.10 (d, 1H, 8Hz), 7.92 (d,
2H, 8Hz), 7.41-7.38 (m, 5H), 7.33 (d, 1H, J=8Hz), 6.97 (d, 1H, J=8Hz), 6.94 (d, 2H, J=
8Hz), 6.83 (d, 2H, J=8Hz), 6.50 (d, 2H, J=8Hz), 5.66 (d, 1H, J=10Hz), 5.15 (s, 2H), 3.93-
3.85 (m, 1H), 3.83 (s, 2H), 3.28-3.06 (m, 6H), 2.62-2.48 (m, 4H), 1.15 (q, 6H, J=8Hz)
Embodiment 2.5- [(R) -2- (5,6- diethyl-indane -2- base amino) -1- hydroxy-ethyl] -8- phenylmethoxy
The preparation of base-(1H)-quinoline-2-one paratolunitrile salt
It is being furnished with magnetic agitation, 5.0g 5,6- diethyl is added in the four-necked bottle of charging hopper and reflux condensing tube in thermometer
The dimethyl sulfoxide of base -2,3- dihydro -1H- indenes -2- amine and 7mL, to the solution in be added 7.0g 5- (2R) -2- Oxyranyle -
Resulting suspension is heated to 110 DEG C, and stirs 7h at such a temperature by 8- benzyloxy -2 (1H)-quinolinone, and TLC is shown instead
It should be complete.Resulting brown solution is cooled to 60 DEG C, the ethyl alcohol of 80mL is added, is kept for 60 DEG C, 3.9g is then added to toluene
Formic acid is completely dissolved, and solution is cooled to 40 DEG C or so, crystal seed is added, and is placed cooling in ice bath.It is isolated by filtration to toluene
Formates crude product 10.0g obtains 9.4g 5- [(R) -2- (5,6- diethyl-indane -2- base amino) -1- hydroxyl with ethyl alcohol recrystallization
Base-ethyl] -8- Phenylmethoxy-(1H)-quinoline-2-one paratolunitrile salt sterling is white crystalline powder (yield
63.5%, purity 97.06%).1HNMR(400MHz, CDCl3): δ 9.500 (br, 1H), 8.102 (d, 1H, J=10Hz),
7.902 (d, 2H, J=8Hz), 7.431-7.357 (m, 5H), 7.294 (d, 1H, J=8.8Hz), 7.185 (d, 2H, J=
7.6Hz), 7.001 (d, 1H, J=8.4Hz), 6.960 (d, 2H, J=3.6Hz), 6.574 (d, 1H, J=10Hz), 5.459 (d,
1H, J=8.8Hz), 3.815 (m, 5H), 3.235-2.957 (m, 6H), 2.574 (q, 4H, J=7Hz), 2.390 (s, 3H),
1.165 (t, 6H, J=7.6Hz)
Embodiment 3.5- [(R) -2- (5,6- diethyl-indane -2- base amino) -1- hydroxy-ethyl] -8- phenylmethoxy
The preparation of base-(1H)-quinoline-2-one paranitrobenzoic acid salt
It is being furnished with magnetic agitation, 5.0g 5,6- diethyl is added in the four-necked bottle of charging hopper and reflux condensing tube in thermometer
The dimethyl sulfoxide of base -2,3- dihydro -1H- indenes -2- amine and 7mL, to the solution in be added 7.0g 5- (2R) -2- Oxyranyle -
Resulting suspension is heated to 110 DEG C, and stirs 7h at such a temperature by 8- benzyloxy -2 (1H)-quinolinone, and TLC is shown instead
It should be complete.Resulting brown solution is cooled to 60 DEG C, the ethyl alcohol of 80mL is added, is kept for 60 DEG C, 4.8g is then added to nitro
Benzoic acid is completely dissolved, and solution is cooled to 40 DEG C or so, crystal seed is added, and is placed cooling in ice bath.It is isolated by filtration to first
Oxybenzoic acid salt crude product 11.2g obtains 9.8g 5- [(R) -2- (5,6- diethyl-indane -2- base amino)-with ethyl alcohol recrystallization
1- hydroxy-ethyl] -8- Phenylmethoxy-(1H)-quinoline-2-one paranitrobenzoic acid salt sterling is Light yellow crystals powder.
(yield 63%, purity 98.61%)1HNMR(400MHz,CDCl3): δ 9.63 (br, 1H), 8.13 (d, 1H, 12Hz), 8.08 (d,
2H, 8Hz), 7.98 (d, 2H, J=8Hz), 7.39-7.35 (m, 5H), 7.32 (d, 1H, J=8Hz), 6.93 (d, 3H, J=
8Hz), 6.49 (d, 2H, J=8Hz), 5.81-5.78 (m, 1H), 5.15 (q, 2H, J=12Hz), 4.01-3.94 (m, 1H),
3.33‐3.17(m,6H),2.59‐2.47(m,4H),1.16‐1.11(m,6H).
Embodiment 4.5- [(R) -2- (5,6- diethyl-indane -2- base amino) -1- hydroxy-ethyl]-hydroxyl-(1H)-quinoline
The preparation of quinoline -2- ketone maleate
8.0g 5- [(R) -2- (5,6- diethyl-indane -2- base amino) -1- hydroxy-ethyl]-is added in hydriding reactor
8- Phenylmethoxy-(1H)-quinoline-2-one is added 10% palladium carbon (0.8g), is flushed with hydrogen to the acetic acid of methoxy benzoic acid salt and 80mL
Gas is heated to 50 DEG C or so, and overnight, TLC detects fully reacting for reaction.Mother liquor is concentrated under reduced pressure in filtering, and 80mL ethyl alcohol is added, and
50~60 DEG C of heating is added maleic acid (2.3g), after stirring 0.5h, is down to 30 DEG C, crystal seed is added, cooling in ice bath, white
Crystal is precipitated.Filtering, obtains 5- [(R) -2- (5,6- diethyl-indane -2- base amino) -1- hydroxy-ethyl]-hydroxyl-(1H) -
Quinoline-2-one maleate crude product 5.6g.Ethyl alcohol recrystallization twice, obtains 4.9g 5- [(R) -2- (5,6- diethyl-indane -
2- base amino) -1- hydroxy-ethyl]-hydroxyl-(1H)-quinoline-2-one maleate is white powder (yield 73%, efficient liquid
Mutually detection purity 99.65%).1HNMR (400MHz, DMSO): δ 10.54 (s, 1H), 10.46 (br, 1H), 8.93 (br, 2H),
8.15 (d, 1H, J=12Hz), 7.18 (d, 1H, J=8Hz), 7.03 (s, 2H), 6.99 (d, 1H, J=8Hz), 6.61 (d, 1H, J
=8Hz), 6.20 (s, 1H), 6.02 (s, 2H), 5.31 (d, 1H, J=8Hz), 4.06 (t, 1H, J=8Hz), 3.35-3.20 (m,
3H), 3.20-3.04 (m, 3H), 2.57 (q, 4H, J=8Hz), 2.50 (s, 1H), 1.13 (t, 6H, J=8Hz)
Embodiment 5.5- [(R) -2- (5,6- diethyl-indane -2- base amino) -1- hydroxy-ethyl]-hydroxyl-(1H)-quinoline
The preparation of quinoline -2- ketone maleate
8.0g 5- [(R) -2- (5,6- diethyl-indane -2- base amino) -1- hydroxy-ethyl]-is added in hydriding reactor
8- Phenylmethoxy-(1H)-quinoline-2-one paratolunitrile salt and 80mL acetic acid is added 10% palladium carbon (0.8g), is flushed with hydrogen
Gas is heated to 50 DEG C or so, and overnight, TLC detects fully reacting for reaction.Mother liquor is concentrated under reduced pressure in filtering, and 80mL ethyl alcohol is added, and
50~60 DEG C of heating is added maleic acid (2.25g), after stirring 0.5h, is down to 30 DEG C, crystal seed is added, cooling in ice bath, white
Crystal is precipitated.Filtering, obtains 5- [(R) -2- (5,6- diethyl-indane -2- base amino) -1- hydroxy-ethyl]-hydroxyl-(1H) -
Quinoline-2-one maleate crude product 5.4g.Ethyl alcohol recrystallization twice, obtains 4.4g 5- [(R) -2- (5,6- diethyl-indane -
2- base amino) -1- hydroxy-ethyl]-hydroxyl-(1H)-quinoline-2-one maleate is white powder (yield 68%, efficient liquid
Mutually detection purity 99.60%).1HNMR (400MHz, DMSO): δ 10.54 (s, 1H), 10.46 (br, 1H), 8.93 (br, 2H),
8.15 (d, 1H, J=12Hz), 7.18 (d, 1H, J=8Hz), 7.03 (s, 2H), 6.99 (d, 1H, J=8Hz), 6.61 (d, 1H, J
=8Hz), 6.20 (s, 1H), 6.02 (s, 2H), 5.31 (d, 1H, J=8Hz), 4.06 (t, 1H, J=8Hz), 3.35-3.20 (m,
3H), 3.20-3.04 (m, 3H), 2.57 (q, 4H, J=8Hz), 2.50 (s, 1H), 1.13 (t, 6H, J=8Hz)
Embodiment 6.5- [(R) -2- (5,6- diethyl-indane -2- base amino) -1- hydroxy-ethyl]-hydroxyl-(1H)-quinoline
The preparation of quinoline -2- ketone maleate
8.0g 5- [(R) -2- (5,6- diethyl-indane -2- base amino) -1- hydroxy-ethyl]-is added in hydriding reactor
8- Phenylmethoxy-(1H)-quinoline-2-one paranitrobenzoic acid salt and 80mL acetic acid is added 10% palladium carbon (0.8g), is flushed with hydrogen
Gas is heated to 50 DEG C or so, and overnight, TLC detects fully reacting for reaction.Mother liquor is concentrated under reduced pressure in filtering, and 80mL ethyl alcohol is added, and
50~60 DEG C of heating is added maleic acid (2.14g), after stirring 0.5h, is down to 30 DEG C, crystal seed is added, cooling in ice bath, white
Crystal is precipitated.Filtering, obtains 5- [(R) -2- (5,6- diethyl-indane -2- base amino) -1- hydroxy-ethyl]-hydroxyl-(1H) -
Quinoline-2-one maleate crude product 5.5g.Ethyl alcohol recrystallization twice, obtains 4.3g 5- [(R) -2- (5,6- diethyl-indane -
2- base amino) -1- hydroxy-ethyl]-hydroxyl-(1H)-quinoline-2-one maleate is white powder (yield 69%, efficient liquid
Mutually detection purity 99.45%).1HNMR (400MHz, DMSO): δ 10.54 (s, 1H), 10.46 (br, 1H), 8.93 (br, 2H),
8.15 (d, 1H, J=12Hz), 7.18 (d, 1H, J=8Hz), 7.03 (s, 2H), 6.99 (d, 1H, J=8Hz), 6.61 (d, 1H, J
=8Hz), 6.20 (s, 1H), 6.02 (s, 2H), 5.31 (d, 1H, J=8Hz), 4.06 (t, 1H, J=8Hz), 3.35-3.20 (m,
3H), 3.20-3.04 (m, 3H), 2.57 (q, 4H, J=8Hz), 2.50 (s, 1H), 1.13 (t, 6H, J=8Hz).
Claims (9)
1. maleic acid datro preparation process, comprising steps of by compound 2 and compound 3 in the presence of dimethylsulfoxide solvent
Ring-opening reaction obtains compound 4, and compound 4 and organic acid HA pass through after obtaining compound 4HA salt in the second solvent at salt
Crystallization be precipitated, then by compound 4HA salt first pass through catalytic hydrogenation in the presence of a catalyst go it is Benzylation after, then with maleic acid
Maleic acid datro is obtained at salt,
Wherein, HA is selected from P-methoxybenzoic acid.
2. maleic acid datro preparation process according to claim 1, the volume of dimethyl sulfoxide and the quality of compound 2
Than for 1~3ml/g.
3. maleic acid datro preparation process according to claim 1, wherein intermediate 4 and organic acid HA are at salt
Second solvent is selected from C1-C4Alcohols, esters solvent, ether solvent or chlorinated hydrocarbon solvent.
4. maleic acid datro preparation process according to claim 1, wherein the equivalent of the organic acid HA is 1~2
Equivalent, second solvent are selected from methanol, ethyl alcohol, ethyl acetate, one kind of methylene chloride or its mixed solvent.
5. maleic acid datro preparation process according to claim 1, wherein the equivalent of the organic acid HA is 1.2
Equivalent, second solvent are ethyl alcohol.
6. maleic acid datro preparation process according to claim 1, wherein the catalyst is selected from palladium, hydroxide
Palladium, palladium/charcoal, the palladium on attached aluminium oxide, platinum and Raney Ni on the activated carbon.
7. maleic acid datro preparation process according to claim 1, wherein the solvent of the catalytic hydrogenation is selected from second
Acetoacetic ester, methanol, ethyl alcohol, propyl alcohol, butanol, amylalcohol, aliphatic C6-12Hydrocarbon, dimethylformamide, toluene, benzene, acetonitrile, tetrahydro furan
It mutters, or mixtures thereof dimethyl sulfoxide, dimethyl carbonate, acetic acid, trifluoroacetic acid, water, methylene chloride；The temperature of catalytic hydrogenation is 0
DEG C to 70 DEG C.
8. maleic acid datro preparation process according to claim 7, wherein the catalyst is palladium/charcoal.
9. maleic acid datro preparation process according to claim 1, wherein the solvent of the catalytic hydrogenation is second
Acid；Methanol, ethyl alcohol, propyl alcohol, butanol and amylalcohol are selected from the solvent of salt with maleic acid.
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| CN107021921A (en) * | 2016-02-02 | 2017-08-08 | 常州爱诺新睿医药技术有限公司 | A kind of salt of QAB-149 intermediate and preparation method thereof |
| CN107868045A (en) * | 2016-09-28 | 2018-04-03 | 四川海思科制药有限公司 | A kind of preparation method of QAB-149 intermediate |
| CN108264483A (en) * | 2016-12-31 | 2018-07-10 | 天津金耀集团有限公司 | A kind of preparation method of maleic acid datro |
| CN111808021B (en) * | 2019-04-10 | 2021-08-31 | 上海谷森医药有限公司 | Preparation method of indacaterol and salt thereof |
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