CN106946847B - A kind of preparation method of bepotastine important intermediate - Google Patents
A kind of preparation method of bepotastine important intermediate Download PDFInfo
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- CN106946847B CN106946847B CN201710189163.2A CN201710189163A CN106946847B CN 106946847 B CN106946847 B CN 106946847B CN 201710189163 A CN201710189163 A CN 201710189163A CN 106946847 B CN106946847 B CN 106946847B
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
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Abstract
The invention discloses a kind of preparation methods of bepotastine important intermediate, that is the preparation method of (S)-(-) -4- [(4- chlorphenyl) (2- pyridyl group) methoxyl group] piperidines, raceme ((±) -4- [(4- chlorphenyl) (2- pyridyl group) methoxyl group] piperidines) is reacted into salt with S- dinaphthol phosphate, it is free with alkali again, (S)-(-) -4- [(4- chlorphenyl) (2- pyridyl group) methoxyl group] piperidines can be obtained after beating, optical purity can reach 99.0% or more.Chiral separation method process disclosed by the invention is simple, has good industrial production prospect, while also having great significance to industrialized production bepotastine.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of preparation method of bepotastine important intermediate.
Background technique
Benzene sulphur bepotastine (Bepotastine Besilate, structure are shown in formula I) is a day Honda side (Tanabe
Seiyaku) -1 receptor antagonist of histamine H that company and Ube (Ube Industries) company develop jointly, can quickly,
Effectively inhibit 3 cardinal symptoms of allergic rhinitis: sneezing has a running nose and has a stuffy nose.The chinesization of bepotastine besilate
Scientific name claims: 4- [4- [(S)-[(4- chlorphenyl) pyridine -2- base] methoxyl group] piperidin-1-yl] butyric acid list benzene sulfonate, molecular formula
C21H25ClN2O3·C6H6O3S.Benzene sulphur 4-[(S)-(4-chlorophenyl)-2-pyridinylmethoxy is effective to the more existing drug of inflammatory reaction for alleviating schneiderian membrane, separately
Outside, benzene sulphur bepotastine seldom enters intracerebral, no sedation, and cholinolytic effect is mutually separated with antihistamine effect, other bad
React minimum, have excellent pharmacodynamic action and clinical effectiveness, action intensity better than Ketotifen, RMI 9918, alerlisin,
Epinastine, therefore potential applicability in clinical practice is wide.
(S)-(-) -4- [(4- chlorphenyl) (2- pyridyl group) methoxyl group] piperidines (structure is as shown in Formula II) is synthesis Beta
The key intermediate of sting, it is reacted with the halogenated n-butyric acie ester of 4-, then can obtain bepotastine after hydrolyzing, being acidified, this intermediate
Optical purity determines the pharmacological activity of bepotastine, thus (±) -4- [(4- chlorphenyl) (2- pyridyl group) methoxyl group] piperidines
It splits extremely important.
Currently, CN97181039.7, CN201610215787, Rajesh etc. report chiral resolution (±) -4- [(4- chlorine
Phenyl) (2- pyridyl group) methoxyl group] method of piperidines prepares this intermediate (see Table 1), but generally existing following problems: it tears open
Cumbersome step by step, yield is low, needs crystal seed induction crystallization, obtained (S)-(-) -4- [(4- chlorphenyl) (2- pyridyl group) methoxy
Base] piperidines is just able to satisfy optical purity and requires (> 99.0%) after needing to recrystallize once or several times, and this patent uses S- for the first time
Dinaphthol phosphate splits the intermediate, and high income is easy to operate, and the production of high-optical-purity can be obtained through being beaten for crude product
Product.
The method for splitting reported in the literature of table 1 compares
Summary of the invention
The invention discloses a kind of chirally resolving racemics to prepare (S)-(-) -4- [(4- chlorphenyl) (2- pyridyl group) first
Oxygroup] piperidines method, (S)-(-) -4- [(4- chlorphenyl) (2- of 99.0% or more optical purity can be obtained using this method
Pyridyl group) methoxyl group] piperidines.
In order to further realize the present invention, the technical solution adopted by the present invention are as follows:
A kind of preparation method of bepotastine important intermediate, comprising the following steps:
(1) raceme is mixed with solvent, adds S- dinaphthol phosphate ester solution, is heated to reflux, cool down crystallization, takes out
Phosphate ester salt (white solid) is obtained after filter, washing and drying；
(2) phosphate ester salt obtained by step (1) is obtained into crude product after alkalization, extraction and concentration, adds alcohols solvent and beats
Slurry is primary, then obtains (S)-(-) -4- [(4- chlorphenyl) (2- pyridyl group) methoxyl group] piperidines, light after suction filtration, washing and drying
Purity is learned up to 99.0% or more.
Resolution reaction formula is as follows:
Solvent described in step (1) is acetone or ethyl acetate, preferably acetone.
In step (1), the mass volume ratio of the raceme and solvent is 1:(5 ~ 12), preferably 1:8.
The molar ratio of the raceme and S- dinaphthol phosphate is 1:(0.9 ~ 1.2), preferably 1:1.05.
The solvent of step (1) the S- dinaphthol phosphate ester solution is N,N-dimethylformamide or dimethyl sulfoxide.
The temperature of crystallization described in step (1) is 0-20 DEG C.
Alkalization alkalizing agent used is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide in step (2).
In step (2), the molar ratio of the alkalizing agent and phosphate ester salt that alkalize used is (1.0 ~ 1.6): 1.
In step (2), when extraction, organic solvent used was toluene or ethyl acetate.
In step (2), the mashing is dehydrated alcohol, isopropanol or methanol, preferably dehydrated alcohol with alcohols solvent.
The present invention has the advantages that
The invention discloses a kind of chirally resolving racemics to prepare (S)-(-) -4- [(4- chlorphenyl) (2- pyridyl group) first
Oxygroup] piperidines new method, the intermediate is split using S- dinaphthol phosphate for the first time, technology stability is good, easy to operate,
The product of high-optical-purity can be obtained through being beaten, overcome one or many in other chiral separation methods for high income, crude product
The drawbacks of recrystallization can just obtain high-optical-purity product, can preferably be applied to industrialized production.
Specific embodiment:
The present invention is described in further details by the following examples, but not the above-mentioned theme of the present invention should not be interpreted as with regard to this
Following embodiment is only limitted in range.Under the premise of not departing from above-mentioned technology of the invention, according to ordinary skill knowledge and
The corresponding modification replaced or change that customary means is made, is included within the scope of the present invention.
Embodiment 1
(1) system of the S- dinaphthol phosphate ester salt of (S)-(-) -4- [(4- chlorphenyl) (2- pyridyl group) methoxyl group] piperidines
It is standby；
30.3 g (100 mmol, 1.0 eq) raceme is put into 1 L three-necked flask, 240 ml acetone, room is added
Temperature stirring, solid are not completely dissolved.36.6 g of (S)-dinaphthol phosphate (100 mmol, 1.05 eq) is separately taken to be placed in 250
In ml single port bottle, 40 ml n,N-Dimethylformamide, 45 DEG C of water-bath stirrings, solution clarification is added, then this solution is added drop-wise to
It in acetone suspension, adds within about 10 minutes, then begins to warm up reflux, solution is gradually clarified under counterflow condition, then has white solid
Body is precipitated.It flowing back and cools down after 1 h, filter, 40 ml acetone washings, 40-50 DEG C of 2 h of vacuum drying obtain 26.0 g of white powder,
Yield 40%.
(2) preparation of (S)-(-) -4- [(4- chlorphenyl) (2- pyridyl group) methoxyl group] piperidines
26.0 g of phosphate ester salt (40 mmol, 1.0 eq) obtained by upper step is added in 1 L there-necked flask, adds 130
Ml toluene, 10% solution of potassium carbonate, 77 ml (7.7 g containing potassium carbonate, 56 mmol, 1.4 eq), stirring is warming up to 80 DEG C, white
The dissolution of color solid, the reaction was continued 1 h stop heating, are cooled to 30-40 DEG C, and 100 ml ethyl acetate and 150 ml water are added, fill
It after dividing stirring, stands, separates organic layer, water layer uses 60 ml ethyl acetate to extract 1 time again, merges organic phase, and anhydrous sodium sulfate is done
It is dry.It is filtered to remove anhydrous sodium sulfate, vacuum distillation removes solvent, obtains white blister solid.
50 ml dehydrated alcohols are added into solid, are heated to 50 DEG C, 2 h of stirring to pulp is filtered after being then down to 15 DEG C,
Dehydrated alcohol washing, 40-50 DEG C of 1 h of vacuum drying obtain 10.9 g of white powder, yield 90%, optical purity 99.5%.
Embodiment 2
(1) system of the S- dinaphthol phosphate ester salt of (S)-(-) -4- [(4- chlorphenyl) (2- pyridyl group) methoxyl group] piperidines
It is standby；
60.6 g (200 mmol, 1.0 eq) raceme is put into 2 L three-necked flasks, 450 ml acetone, room is added
Temperature stirring, solid are not completely dissolved.73.2 g of (S)-dinaphthol phosphate (210 mmol, 1.05 eq) is separately taken to be placed in 500
In ml single port bottle, 80 ml dimethyl sulfoxides, 45 DEG C of water-bath stirrings, solution clarification is added, then this solution is added drop-wise to acetone and is hanged
In supernatant liquid, adds within about 15 minutes, then begin to warm up reflux, solution is gradually clarified under counterflow condition, then has white solid precipitation.
It flows back and cools down after 1 h, filter, 40 ml acetone washings, 40-50 DEG C of 2 h of vacuum drying obtain 45.6 g of white powder, yield 35%.
(2) preparation of (S)-(-) -4- [(4- chlorphenyl) (2- pyridyl group) methoxyl group] piperidines
45.6 g of phosphate ester salt (70 mmol, 1.0 eq) obtained by upper step is added in 2 L there-necked flasks, adds 150
Ml ethyl acetate, 10% solution of potassium carbonate, 145 ml (14.5 g containing potassium carbonate, 105 mmol, 1.5 eq), stirring is warming up to
70 DEG C, white solid dissolution, the reaction was continued 1h stops heating, is cooled to 30-40 DEG C, and 150 ml ethyl acetate and 300 are added
Ml water after being sufficiently stirred, is stood, and separates organic layer, and water layer uses 80 ml ethyl acetate to extract 1 time again, merges organic phase, anhydrous
Sodium sulphate is dry.It is filtered to remove anhydrous sodium sulfate, vacuum distillation removes solvent, obtains white blister solid.
100 ml dehydrated alcohols are added into solid, are heated to 50 DEG C, 2 h of stirring to pulp is filtered after being then down to 10 DEG C,
Dehydrated alcohol washing, 40-50 DEG C of 2 h of vacuum drying obtain 18.6 g of white powder, yield 88%, optical purity 99.0%.
Embodiment 3
(1) system of the S- dinaphthol phosphate ester salt of (S)-(-) -4- [(4- chlorphenyl) (2- pyridyl group) methoxyl group] piperidines
It is standby；
15.1 g (50 mmol, 1.0 eq) raceme is put into 500 mL there-necked flasks, 150 ml acetic acid second are added
Ester is stirred at room temperature.It separately takes 19.1 g of (S)-dinaphthol phosphate (55 mmol, 1.10 eq) to be placed in single port bottle, is added 20
Ml dimethyl sulfoxide, 50 DEG C of water-bath stirrings, solution clarification, then this solution is added drop-wise in ethyl acetate suspension, about 5 minutes
It adds, then begins to warm up reflux, solution is gradually clarified under counterflow condition, then has white solid precipitation.It flows back and cools down after 2 h,
It filters, 10 ml ethyl acetate washing, 40-50 DEG C of 3 h of vacuum drying obtain 9.77 g of white powder, yield 30%.
(2) preparation of (S)-(-) -4- [(4- chlorphenyl) (2- pyridyl group) methoxyl group] piperidines
9.77 g of phosphate ester salt (15 mmol, 1.0 eq) obtained by upper step is added in there-necked flask, 40 ml second are added
Acetoacetic ester, 20% sodium carbonate liquor, 12 ml (containing sodium carbonate 2.38 g, 22.5 mmol, 1.5 eq), stirring are warming up to 80 DEG C,
White solid dissolution, the reaction was continued 1h stop heating, are cooled to 20-30 DEG C, and 30 ml ethyl acetate and 40 ml water are added, fill
It after dividing stirring, stands, separates organic layer, water layer uses 20 ml ethyl acetate to extract 1 time again, merges organic phase, and anhydrous sodium sulfate is done
It is dry.It is filtered to remove anhydrous sodium sulfate, vacuum distillation removes solvent, obtains white blister solid.
40 ml isopropanols are added into solid, are heated to 65 DEG C, 2 h of stirring to pulp is filtered after being then down to 15 DEG C, different
Propanol rinse, 40-50 DEG C of 1 h of vacuum drying, obtains 3.95 g of white powder, yield 87%, optical purity 99.3%.
The foregoing is merely presently preferred embodiments of the present invention, all equivalent changes done according to scope of the present invention patent with
Modification, is all covered by the present invention.
Claims (10)
1. a kind of preparation method of bepotastine important intermediate, which is characterized in that method includes the following steps:
(1) raceme is mixed with solvent, adds S- dinaphthol phosphate ester solution, is heated to reflux, cool down crystallization, filters, washes
It washs and obtains phosphate ester salt after drying；
(2) phosphate ester salt obtained by step (1) is obtained into crude product after alkalization, extraction and concentration, adds alcohols solvent mashing one
It is secondary, then (S)-(-) -4- [(4- chlorphenyl) (pyridine -2- base) methoxyl group] piperidines, optics are obtained after suction filtration, washing and drying
Purity is up to 99.0% or more.
2. the preparation method of bepotastine important intermediate according to claim 1, which is characterized in that institute in step (1)
Stating solvent is acetone or ethyl acetate.
3. the preparation method of bepotastine important intermediate according to claim 1, which is characterized in that in step (1), institute
The mass volume ratio for stating raceme and solvent is 1:(5 ~ 12).
4. the preparation method of bepotastine important intermediate according to claim 1, which is characterized in that the raceme with
The molar ratio of S- dinaphthol phosphate is 1:(0.9 ~ 1.2).
5. the preparation method of bepotastine important intermediate according to claim 1, which is characterized in that step (1) is described
The solvent of S- dinaphthol phosphate ester solution is N,N-dimethylformamide or dimethyl sulfoxide.
6. the preparation method of bepotastine important intermediate according to claim 1, which is characterized in that institute in step (1)
The temperature for stating crystallization is 0-20 DEG C.
7. the preparation method of bepotastine important intermediate according to claim 1, which is characterized in that in step (2), alkali
Changing alkalizing agent used is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide.
8. the preparation method of bepotastine important intermediate according to claim 1, which is characterized in that in step (2), alkali
The molar ratio for changing alkalizing agent and phosphate ester salt used is (1.0 ~ 1.6): 1.
9. the preparation method of bepotastine important intermediate according to claim 1, which is characterized in that in step (2), institute
Stating organic solvent used when extraction is toluene or ethyl acetate.
10. preparation the method for bepotastine important intermediate according to claim 1, which is characterized in that in step (2),
The mashing is dehydrated alcohol, isopropanol or methanol with alcohols solvent.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1242013A (en) * | 1996-12-26 | 2000-01-19 | 宇部兴产株式会社 | Acid-addition salts of optically active piperidine compound and process for producing the same |
| CN101928278A (en) * | 2010-08-23 | 2010-12-29 | 浙江燎原药业有限公司 | (S)-4-[(4-chlorphenyl)(pyridine-2-yl)methoxyl]piperidinehydroxyphenpropionate and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10182635A (en) * | 1996-12-26 | 1998-07-07 | Ube Ind Ltd | Optically active piperidine derivative and its production |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1242013A (en) * | 1996-12-26 | 2000-01-19 | 宇部兴产株式会社 | Acid-addition salts of optically active piperidine compound and process for producing the same |
| CN101928278A (en) * | 2010-08-23 | 2010-12-29 | 浙江燎原药业有限公司 | (S)-4-[(4-chlorphenyl)(pyridine-2-yl)methoxyl]piperidinehydroxyphenpropionate and application thereof |
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