CN101928278B - (S)-4-[(4-chlorphenyl)(pyridine-2-yl)methoxyl]piperidinehydroxyphenpropionate and application thereof - Google Patents
(S)-4-[(4-chlorphenyl)(pyridine-2-yl)methoxyl]piperidinehydroxyphenpropionate and application thereof Download PDFInfo
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- 0 OC(CCNC1)C1c1cc(Cl)ccc1*c1ncccc1 Chemical compound OC(CCNC1)C1c1cc(Cl)ccc1*c1ncccc1 0.000 description 2
- OTZYADIPHOGUDN-KRWDZBQOSA-N Clc1ccc([C@@H](c2ncccc2)OC2CCNCC2)cc1 Chemical compound Clc1ccc([C@@H](c2ncccc2)OC2CCNCC2)cc1 OTZYADIPHOGUDN-KRWDZBQOSA-N 0.000 description 1
- VPVCLDJSWASGOM-RPBOFIJWSA-N O[C@H](Cc(cc1)ccc1N(CC1)CCC1O[C@@H](c(cc1)ccc1Cl)c1ncccc1)C(O)=O Chemical compound O[C@H](Cc(cc1)ccc1N(CC1)CCC1O[C@@H](c(cc1)ccc1Cl)c1ncccc1)C(O)=O VPVCLDJSWASGOM-RPBOFIJWSA-N 0.000 description 1
- RNVHEAGWIVHHNJ-JNDMAISQSA-N O[C@H](Cc1cc(C(C2)NCCC2O[C@@H](c(cc2)ccc2Cl)c2ncccc2)ccc1)C(O)=O Chemical compound O[C@H](Cc1cc(C(C2)NCCC2O[C@@H](c(cc2)ccc2Cl)c2ncccc2)ccc1)C(O)=O RNVHEAGWIVHHNJ-JNDMAISQSA-N 0.000 description 1
- VOXXWSYKYCBWHO-MRVPVSSYSA-N O[C@H](Cc1ccccc1)C(O)=O Chemical compound O[C@H](Cc1ccccc1)C(O)=O VOXXWSYKYCBWHO-MRVPVSSYSA-N 0.000 description 1
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Abstract
The invention discloses a (S)-4-[(4-chlorphenyl)(pyridine-2-yl)methoxyl]piperidinehydroxyphenpropionate and application thereof. The structure of the (S)-4-[(4-chlorphenyl)(pyridine-2-yl)methoxyl]piperidinehydroxyphenpropionate is shown as a formula (IV), and the (S)-4-[(4-chlorphenyl)(pyridine-2-yl)methoxyl]piperidinehydroxyphenpropionate can be applied to preparing (S)-4-[(4-chlorphenyl)(pyridine-2-yl)methoxyl]piperidine shown as a formula (I). The preparation method comprises the following steps of: reacting (RS)-4-[(4-chlorphenyl)(pyridine-2-yl)methoxyl]piperidine and hydroxyphenylpropionic acid shown as a formula (III) in a ketone solvent to prepare two diastereomeric salts, separating to obtain the (S)-4-[(4-chlorphenyl)(pyridine-2-yl)methoxyl]piperidinehydroxyphenpropionate, and dissociating the (S)-4-[(4-chlorphenyl)(pyridine-2-yl)methoxyl]piperidinehydroxyphenpropionate to prepare the (S)-4-[(4-chlorphenyl)(pyridine-2-yl)methoxyl]piperidine. All raw materials of the method are simple; the yield of optical resolution is high; the optical impurity content can be controlled within 0.5 percent; and the method has the characteristics of low production cost, easy obtaining of adopted raw materials, easy industrialized production and the like.
Description
(1) technical field
The present invention relates to a kind of (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate and application thereof, be specifically related to it at (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] application in piperidines preparation.
(2) background technology
Formula (V) compound is for having optically active bepotastine, chemistry (S)-4-[4-[(4-chloro-phenyl-by name) pyridine-2-ylmethoxy] piperidin-1-yl] butyric acid is histamine H
1Acceptor is picked up anti-dose, can be used for the anaphylactic diseases such as treatment of allergic rhinitis, and effect is rapid, and selectivity is high, and not having in the past, anti-allergy agent produces calm untoward reaction.The formula I compound chemistry is called (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidines is the key intermediate of preparation formula (V) compound.
CN1446812A, CN1242013A have reported a kind of preparation method of formula I compound; take the racemize piperidine compounds shown in formula II as raw material; take the phenylpropionic acid compound shown in formula (VII) or optically active N-acyl group-amino acid as the optical resolution agent; by utilizing the difference of formed two kinds of diastereoisomeric salts on solvability; separate and collect one of non-mapping salt; make the salt of generation from solution, and make the formula I compound.This method resolving agent complex structure used is difficult for suitability for industrialized production, and it is all undesirable to produce yield and optical purity and mapping dignity impurity.
(3) summary of the invention
The primary technical problem that the present invention will solve is to provide a kind of (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate, this compound can be in order to prepare (S)-4-[(4-chloro-phenyl-of high-optical-purity) (pyridine-2-yl) methoxyl group] piperidines.
(S)-4-[(4-chloro-phenyl-of the present invention) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate, its structure is as shown in formula IV:
second technical problem that the present invention will solve is with described (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate is applied to prepare the chloro-phenyl-of (S)-4-[(4-shown in formula I) (pyridine-2-yl) methoxyl group] in piperidines, provide a production cost low, raw materials used being easy to get, be suitable for (S)-4-[(4-chloro-phenyl-of suitability for industrialized production) (pyridine-2-yl) methoxyl group] preparation method of piperidines, the inventive method can obtain very high (the S)-4-[(4-chloro-phenyl-of optical purity) (pyridine-2-yl) methoxyl group] piperidine product, optical purity is more than 99.5%.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
(S)-4-[(4-chloro-phenyl-shown in a kind of formula I) (pyridine-2-yl) methoxyl group] preparation method of piperidines, comprise the steps: (the RS)-4-[(4-chloro-phenyl-shown in formula II) (pyridine-2-yl) methoxyl group] hydroxy phenylpropionic acid shown in piperidines and formula III reacts in ketone solvent and obtains two kinds of diastereoisomeric salts, separate and obtain (the S)-4-[(4-chloro-phenyl-shown in formula IV) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate, make (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate is from solution, namely obtain described (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidines,
Further, described ketone solvent is preferably C
3～C
8Ketone, more preferably acetone, butanone or pimelinketone.
Further, described (RS)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] molar ratio of piperidines and hydroxy phenylpropionic acid is 1: 0.5～3.5, preferred 1: 0.5～1.2.
Further, the consumption of described ketone solvent is in (RS)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] quality of piperidines is recommended as 5.5～7.5ml/g.
Further, described (RS)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidines and hydroxy phenylpropionic acid react under the temperature condition of-15 ℃～135 ℃ in ketone solvent, preferably react under reflux temperature.
(RS)-4-[(4-chloro-phenyl-of the present invention) (pyridine-2-yl) methoxyl group] piperidines and hydroxy phenylpropionic acid react in ketone solvent and obtain two kinds of diastereoisomeric salts, these two kinds of diastereoisomeric salts have different solvabilities in ketone solvent, utilizing their difference on solvability is separable two kinds of diastereoisomeric salts, (S)-4-[(4-chloro-phenyl-wherein) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate solubleness in ketone solvent is less, separates out from reaction system.The present invention generally adjusts temperature to 15～26 ℃ crystallize out after reacting completely.
Be to improve the purity of product, (S)-4-[(4-chloro-phenyl-that the present invention can obtain separation) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate carries out refinement treatment, and then carries out from solution.Described refinement treatment can adopt recrystallization, and recrystallization solvent can be selected ketones solvent (as acetone, butanone, pimelinketone etc.).The recrystallization number of times can be decided according to desired product purity.
Further, describedly specifically comprise the steps: in water solvent from solution, control pH and process (S)-4-[(4-chloro-phenyl-with mineral alkali under 9～14 condition) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate, then with extraction solvent A extraction, extraction liquid concentrates and namely obtains described (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidines.
Further, in dissociation processes, described mineral alkali can be sodium hydroxide, potassium hydroxide etc., preferred sodium hydroxide.
Further, in dissociation processes, described extraction solvent A is esters solvent, ethyl acetate.
further, in order to reclaim hydroxy phenylpropionic acid and further to improve product purity, describedly comprise the steps: in water solvent from solution, process (S)-4-[(4-chloro-phenyl-with salt acid for adjusting pH to 1～5 (preferred 2～3)) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate, then use organic solvent washing, the gained water layer adds mineral alkali adjusting pH to 9～14 (preferred 9～11) to process, again with extraction solvent B extraction, extraction liquid concentrates and namely obtains described (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidines.
Further, in dissociation processes, described mineral alkali can be sodium hydroxide, potassium hydroxide etc., preferred sodium hydroxide.
Further, in dissociation processes, described organic solvent or extraction solvent B independently are selected from esters solvent, ethyl acetate.
Compared with prior art, all raw materials of present method are simple, and the optical resolution yield is high, and optics impurity can be controlled in 0.5%, have production cost low, raw materials usedly be easy to get, be easy to the characteristics such as suitability for industrialized production.
(4) description of drawings
Fig. 1 is (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] infrared spectrogram of piperidinehydroxypheandopionate.
(5) embodiment
The below is described further technical scheme of the present invention with specific embodiment, but protection scope of the present invention is not limited to this:
Embodiment 1:
Add 7.3g (RS)-4-[(4-chloro-phenyl-in 250ml four-hole reaction flask) (pyridine-2-yl) methoxyl group] piperidines, 2.4g hydroxy phenylpropionic acid and 50ml acetone stir, be warming up to backflow, molten clear rear insulation reaction 2 hours, insulation is cooled to 23 ℃ of (± 2 ℃) crystallizatioies after finishing, and continues stirred crystallization 2 hours, suction filtration, filter cake acetone drip washing is filtered dry to get crude product 2.5g.
Above crude product is added in the four-hole bottle of 250ml, the acetone that adds 25 times of volumes, stir to heat up, fully molten clear after the cooling crystallization, stirred 2 hours after separating out solid, suction filtration, filter cake acetone drip washing, the wet product that is filtered dry is made with extra care again, repeats 3 times, get dry product 1.4g, be (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate.(S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] structural characterization of piperidinehydroxypheandopionate is as follows:
1H-NMR (D
2O) δ: 8.34 (d, J=4.4Hz, 1H), 7.78 (t, J=5.8Hz, 1H), 7.52 (d, J=8.0Hz, 1H), 7.27 (m, 10H), 5.64 (s, 1H), 4.17 (dd, J=4.4Hz, 1H), 3.72 (m, 1H), 3.27 (m, 2H), 2.89 (m, 3H), 2.89 (m, 1H), 1.98 (m, 2H) and, 1.85 (m, 2H).Infrared spectrogram as shown in Figure 1.
Above-mentioned dry product is added in the 100ml four-hole bottle, add the 20ml purified water, stir, the fully molten clear rear approximately dilute hydrochloric acid of 3ml 2N that drips, transfer pH=2, stir 30min, add ethyl acetate washing water layer, divide and remove organic layer, water layer goes in 100ml four-hole reaction flask, drip approximately 2.5ml of the 5N NaOH aqueous solution, transfer pH=10, stir 30min.The water layer ethyl acetate extraction, organic layer washs with saturated brine, branch vibration layer, with the dry organic layer of Sodium sulfate anhydrous.min(99), concentrated organic layer gets feed liquid 0.9g, be product (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidines, optical purity 99.7%, R enantiomorph 0.30%.
Embodiment 2:
Add 7.3g (RS)-4-[(4-chloro-phenyl-in 250ml four-hole reaction flask) (pyridine-2-yl) methoxyl group] piperidines, 4.0g hydroxy phenylpropionic acid and 50ml butanone stir, be warming up to backflow, molten clear rear insulation reaction 2 hours, insulation is cooled to 20 ℃ of (± 2 ℃) crystallizatioies after finishing, and continues stirred crystallization 2 hours, suction filtration, filter cake acetone drip washing is filtered dry to get crude product 2.3g.
Above crude product is added in the four-hole bottle of 250ml, the butanone that adds 18 times of volumes, stir to heat up, fully molten clear after the cooling crystallization, stirred 2 hours after separating out solid, suction filtration, filter cake butanone drip washing, the wet product that is filtered dry is made with extra care again, repeats 3 times, get dry product 1.3g, be (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate.
1H-NMR(D
2O)δ：8.34(d，J＝4.4Hz，1H)，7.78(t，J＝5.8Hz，1H)，7.52(d，J＝8.0Hz，1H)，7.27(m，10H)，5.64(s，1H)，4.17(dd，J＝4.4Hz，1H)，3.72(m，1H)，3.27(m，2H)，2.89(m，3H)，2.89(m，1H)，1.98(m，2H)and?1.85(m，2H).
Above-mentioned dry product is added in the 100ml four-hole bottle, adds the 20ml purified water, stir, the fully molten clear rear dilute hydrochloric acid that drips 3ml 2N is transferred pH=2, stirs 30min, add the 15ml ethyl acetate, stir the 5min layering, water layer washs with ethyl acetate, divide and go organic layer, water layer to go in 100ml four-hole reaction flask, drip 5N NaOH aqueous solution 2.5ml, transfer pH=10, stir 30min, add ethyl acetate, stir 30min, layering.The water layer ethyl acetate extraction merges organic layer, organic layer saturated salt acid elution, branch vibration layer, organic layer were used Sodium sulfate anhydrous.min(99) dry 2 hours, suction filtration, filter cake ethyl acetate drip washing, filtrate concentrated (45 ℃ ,-0.09MPa), be concentrated into dried, get raffinate 0.85g, be product (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidines, optical purity 99.6%, R enantiomorph 0.40%.。
Embodiment 3:
Add 7.3g (RS)-4-[(4-chloro-phenyl-in 250ml four-hole reaction flask) (pyridine-2-yl) methoxyl group] piperidines, 4.0g hydroxy phenylpropionic acid and 50ml acetone stir, be warming up to backflow, fully molten clear rear insulation reaction 2 hours, be cooled to 20 ℃ of (± 2 ℃) crystallizatioies after insulation finishes, stirred 2 hours suction filtration after separating out solid, filter cake acetone drip washing is filtered dry to get crude product 2.6g.
Above crude product is added in the four-hole bottle of 250ml, the acetone that adds 18 times of volumes, stir to heat up, fully molten clear after the cooling crystallization, stirred 2 hours after separating out solid, suction filtration, filter cake acetone drip washing, the wet product that is filtered dry is made with extra care again, repeats 3 times, get dry product 1.45g, be (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate.
1H-NMR(D
2O)δ：8.34(d，J＝4.4Hz，1H)，7.78(t，J＝5.8Hz，1H)，7.52(d，J＝8.0Hz，1H)，7.27(m，10H)，5.64(s，1H)，4.17(dd，J＝4.4Hz，1H)，3.72(m，1H)，3.27(m，2H)，2.89(m，3H)，2.89(m，1H)，1.98(m，2H)and?1.85(m，2H).
Above-mentioned dry product is added in the 100ml four-hole bottle, adds the 20ml purified water, stir, the fully molten clear rear dilute hydrochloric acid that drips 3ml 2N is transferred pH=2, stirs 30min, add ethyl acetate, stir the 5min layering, water layer washs with ethyl acetate, divide and go organic layer, water layer to go in 100ml four-hole reaction flask, drip 5N NaOH aqueous solution 2.5ml, transfer pH=10, stir 30min, add the 15ml ethyl acetate, stir 30min, layering.The water layer ethyl acetate extraction merges organic layer, organic layer saturated salt acid elution, branch vibration layer, organic layer were used Sodium sulfate anhydrous.min(99) dry 2 hours, suction filtration, filter cake ethyl acetate drip washing, filtrate concentrated (45 ℃ ,-0.09MPa), be concentrated into dried, get raffinate 0.93g, be product (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidines, optical purity 99.5%, R enantiomorph 0.45%.。
Claims (10)
1. (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate, its structure is suc as formula shown in (IV):
2. (S)-4-[(4-chloro-phenyl-as claimed in claim 1) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate is at (the S)-4-[(4-chloro-phenyl-shown in preparation formula (I)) (pyridine-2-yl) methoxyl group] application in piperidines, described (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] preparation of piperidines comprises the steps: (the RS)-4-[(4-chloro-phenyl-shown in formula (II)) (pyridine-2-yl) methoxyl group] hydroxy phenylpropionic acid shown in piperidines and formula (III) reacts in ketone solvent and obtains two kinds of diastereoisomeric salts, separate and obtain (the S)-4-[(4-chloro-phenyl-shown in formula (IV)) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate, make (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate is from solution, namely obtain described (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidines,
3. application as claimed in claim 2 is characterized in that described ketone solvent is C
3~ C
8Ketone.
4. application as claimed in claim 3 is characterized in that described ketone solvent is acetone, butanone or pimelinketone.
5. application as described in one of claim 2 ~ 4 is characterized in that described (RS)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] molar ratio of piperidines and hydroxy phenylpropionic acid is 1:0.5 ~ 3.5.
6. application as described in one of claim 2 ~ 4 is characterized in that the consumption of described ketone solvent is with (RS)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] quality of piperidines counts 5.5 ~ 7.5 ml/g.
7. application as described in one of claim 2 ~ 4 is characterized in that described (RS)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidines and hydroxy phenylpropionic acid react under the temperature condition of-15 ℃ ~ 135 ℃ in ketone solvent.
8. application as claimed in claim 2, it is characterized in that describedly specifically comprising the steps: in water solvent from solution, control pH and process (S)-4-[(4-chloro-phenyl-with mineral alkali under 9 ~ 14 condition) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate, then with extraction solvent A extraction, extraction liquid is removed extraction solvent and is namely obtained described (S)-4-[(4-chloro-phenyl-) (pyridine-2-yl) methoxyl group] piperidines; Described extraction solvent A is selected from esters solvent.
9. application as claimed in claim 2, it is characterized in that describedly specifically comprising the steps: in water solvent from solution, process (S)-4-[(4-chloro-phenyl-with salt acid for adjusting pH to 1 ~ 5) (pyridine-2-yl) methoxyl group] piperidinehydroxypheandopionate, then use organic solvent washing, the gained water layer adds mineral alkali to regulate pH to 9 ~ 14 to process, with extraction solvent B extraction, extraction liquid is removed extraction solvent and is namely obtained described (S)-4-[(4-chloro-phenyl-again) (pyridine-2-yl) methoxyl group] piperidines; Described extraction solvent B is selected from esters solvent.
10. application as claimed in claim 9 is characterized in that described mineral alkali is sodium hydroxide.
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| CN106188002B (en) * | 2016-07-19 | 2018-07-27 | 重庆华邦制药有限公司 | A kind of substituted piperidine base ethyl butyrate quaternary ammonium salt and preparation method thereof |
| CN106946847B (en) * | 2017-03-27 | 2019-06-21 | 福建省微生物研究所 | A kind of preparation method of bepotastine important intermediate |
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| 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 |
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Address after: 317016 Taizhou chemical raw material base, Zhejiang Patentee after: ZHEJIANG LIAOYUAN PHARMACEUTICAL Co.,Ltd. Address before: 317016 Taizhou chemical raw material base, Zhejiang Patentee before: ZHEJIANG LIAOYUAN PHARMACEUTICAL Co.,Ltd. |
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| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 317016 Zhejiang Taizhou chemical raw material base, Lin Hai Park Patentee after: ZHEJIANG LIAOYUAN PHARMACEUTICAL Co.,Ltd. Address before: 317016 Zhejiang Taizhou chemical raw material base, Lin Hai Park Patentee before: ZHEJIANG LIAOYUAN PHARMACEUTICAL Co.,Ltd. |