CN110804026B - Synthesis method of 1- (3- (3- (4-chlorphenyl) propoxy) propyl) piperidine hydrochloride - Google Patents
Synthesis method of 1- (3- (3- (4-chlorphenyl) propoxy) propyl) piperidine hydrochloride Download PDFInfo
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- CN110804026B CN110804026B CN201911128318.7A CN201911128318A CN110804026B CN 110804026 B CN110804026 B CN 110804026B CN 201911128318 A CN201911128318 A CN 201911128318A CN 110804026 B CN110804026 B CN 110804026B
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Abstract
The invention discloses a method for synthesizing 1- (3- (3- (4-chlorphenyl) propoxy) propyl) piperidine hydrochloride, which comprises the following processing steps: s1, preparing a 3- (4-chlorphenyl) propane-1-alcohol solution and a 3- (piperidine-1-yl) propionic acid solution respectively; s2, respectively feeding a 3- (4-chlorphenyl) propyl-1-alcohol solution and a 3- (piperidine-1-yl) propionic acid solution into a reactor through a metering pump at a certain temperature, and simultaneously adding solid superacid for reaction to prepare a 3- (4-chlorphenyl) propyl 3- (piperidine-1-yl) propionate toluene solution; s3, evaporating the solvent of the toluene solution of the 3- (4-chlorphenyl) propyl 3- (piperidine-1-yl) propionate to obtain 3- (4-chlorphenyl) propyl 3- (piperidine-1-yl) propionate; s4, adding a reducing agent and a catalyst into 3- (4-chlorphenyl) propyl 3- (piperidine-1-yl) propionate, heating to 50-70 ℃, and reacting for 4-8 hours to obtain the target product 1- (3- (3- (4-chlorphenyl) propoxy) propyl) piperidine hydrochloride. The invention has low cost and high yield.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of 1- (3- (3- (4-chlorphenyl) propoxy) propyl) piperidine hydrochloride.
Background
1- (3- (3- (4-chlorophenyl) propoxy) propyl) piperidine hydrochloride having the formula:
tiolliro was developed by Bioprojet, Inc., approved for sale by European EMA on 31/3/2016 under the trade name Wakix®(ii) a Pitolisant hydrochloride is a histamine H3 receptor antagonist/inverse agonist approved for the treatment of hypersomnia. On day 8, 14, united states Food and Drug Administration (FDA) approved wakix (pitolisant) by Harmony Biosciences, llc (Harmony) for the treatment of excessive daytime sleepiness in adult patients with narcolepsy. Wakix is the first and only therapeutic drug approved by the FDA and not listed as a controlled substance by the U.S. drug administration (DEA) for use in patients with hypersomnia.
Wakix is an innovative drug, a selective histamine 3 (H3) receptor antagonist/inverse agonist, acting through a new mechanism of action, increasing the synthesis and release of histamine, a promoting neurotransmitter that awakens the brain. Wakix was administered once daily on waking in the morning.
The efficacy of Wakix in treating EDS in adult hypersomnia patients was evaluated in two multicenter, randomized, double-blind, placebo-controlled studies (harm 1 and harm 1 bis). A total of 261 patients enrolled in these studies, randomized to Wakix, placebo or active control patients; the median age of the patients was 37 years (HARMONY 1) and 40 years (HARMONY 1 bis). The duration of treatment was 8 weeks, a three week dose titration phase followed by a 5 week stable dose phase; 75% to 80% of patients in these studies had a history of cataplexy. In both studies, WAKIX demonstrated a statistically significant improvement in EDS measured by Epworth Somnolence Scale (ESS) score.
Current synthetic routes are either prohibitively expensive as starting materials or are synthesized via sulfonate esters. In recent years, the drug inspection department has more and more seriously examined the substances with genotoxicity, and the sulfonate has potential genotoxicity. The drug synthesized by the sulfonic acid ester has the toxic substance residue which affects the safety and reliability of the drug.
Disclosure of Invention
The invention aims to provide a synthesis method of 1- (3- (3- (4-chlorphenyl) propoxy) propyl) piperidine hydrochloride, which has the advantages of simple process, high automation degree, low cost, small pollution and high yield.
In order to achieve the purpose, the invention adopts the technical scheme that: a method for synthesizing 1- (3- (3- (4-chlorphenyl) propoxy) propyl) piperidine hydrochloride comprises the following processing steps:
s1, preparing a 3- (4-chlorphenyl) propane-1-alcohol solution and a 3- (piperidine-1-yl) propionic acid solution respectively;
s2, respectively feeding a 3- (4-chlorphenyl) propyl-1-alcohol solution and a 3- (piperidine-1-yl) propionic acid solution into a reactor through a metering pump at a certain temperature, and simultaneously adding solid superacid for reaction to prepare a 3- (4-chlorphenyl) propyl 3- (piperidine-1-yl) propionate toluene solution;
s3, evaporating the solvent of the toluene solution of the 3- (4-chlorphenyl) propyl 3- (piperidine-1-yl) propionate to obtain 3- (4-chlorphenyl) propyl 3- (piperidine-1-yl) propionate;
s4, adding a reducing agent and a catalyst into 3- (4-chlorphenyl) propyl 3- (piperidine-1-yl) propionate, heating to 50-70 ℃, and reacting for 4-8 hours to obtain the target product 1- (3- (3- (4-chlorphenyl) propoxy) propyl) piperidine hydrochloride.
The technical scheme of further improvement in the technical scheme is as follows:
1. in the above embodiment, the 3- (4-chlorophenyl) propan-1-ol solution in step S1 is a 10-90wt% toluene solution prepared from 3- (4-chlorophenyl) propan-1-ol, preferably a 50wt% toluene solution.
2. In the above scheme, the solution of the step S13- (piperidin-1-yl) propionic acid is a 10-90wt% toluene solution prepared from 3- (piperidin-1-yl) propionic acid, and preferably a 50wt% toluene solution.
3. In the scheme, the reaction temperature in the step S2 is 20-50 ℃, and preferably 40 ℃.
4. In the scheme, the material molar ratio of the 3- (4-chlorophenyl) propan-1-ol solution to the 3- (piperidin-1-yl) propionic acid solution in the step S2 is 1: 1-1.2.
5. In the above scheme, the molar ratio of the 3- (4-chlorophenyl) propan-1-ol solution to the 3- (piperidin-1-yl) propionic acid solution in the step S2 is 1: 1.
6. In the above scheme, the solid super acid in step S2 is acid strength H0Metal oxide super strong acid SO of = -8.2 to-124 2-/MXOY。
7. In the above scheme, the metal oxide super acid SO4 2-/MXOYIs SO4 2-/TiO2、SO4 2-/ZrO2Or SO4 2-/Fe2O3。
8. In the foregoing embodiment, the reducing agent in step S4 is NaBH4、LiAlH4Borane dimethyl sulfide, and AlCl as catalyst3、ZnCl2、H2SO4、I2。
9. In the above scheme, the reducing agent in step S4 is NaBH4The catalyst is I2。
The chemical reaction formula of the synthetic method is as follows:
due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
1. the synthesis method of the invention uses the 3- (4-chlorphenyl) propyl-1-alcohol solution and the 3- (piperidine-1-yl) propionic acid solution as raw materials to prepare the 1- (3- (3- (4-chlorphenyl) propoxy) propyl) piperidine hydrochloride, and has the advantages of high yield, simple process, high automation degree, low cost, small pollution, no sulfonic ester and no potential genotoxicity risk.
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FIG. 1 is a sample chromatographic analysis of 1- (3- (3- (4-chlorophenyl) propoxy) propyl) piperidine hydrochloride prepared in example 1 of the present invention.
Detailed Description
In the description of this patent, it is noted that the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc., indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings, and are only for convenience in describing the present invention and simplifying the description, but do not indicate or imply that the device or element being referred to must have a particular orientation, be constructed and operated in a particular orientation, and thus should not be construed as limiting the present invention; the terms "first," "second," and "third" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance; furthermore, unless expressly stated or limited otherwise, the terms "mounted," "connected," and "connected" are to be construed broadly, as they may be fixedly connected, detachably connected, or integrally connected, for example; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The meaning of the above terms in this patent may be specifically understood by those of ordinary skill in the art.
The invention is further described below with reference to the following examples:
example 1: preparing 3- (4-chlorphenyl) propane-1-alcohol solution: 5kg of 3- (4-chlorphenyl) propane-1-alcohol is prepared into 50wt% of toluene solution, and the raw material is I;
preparing a 3- (piperidine-1-yl) propionic acid solution: 4.61kg of 3- (piperidine-1-yl) propionic acid is prepared into 50wt% toluene solution, and the raw material is ②;
preparation of a reactor: filled catalyst SO4 2-/Fe2O3And the temperature is raised to 40 ℃.
Feeding after the temperature is stable, controlling the flow rate of the raw material I to be 6 g/min, controlling the flow rate of the raw material II to be 5.53 g/min, obtaining a toluene solution of an intermediate in a collector, and evaporating the solvent to obtain 9.0kg of the intermediate;
9kg of 3- (4-chlorophenyl) propyl 3- (piperidin-1-yl) propionate were dissolved in 40kg of THF, and NaBH was added44.4kg, 0.18kg I is dripped in a water bath with the temperature controlled by about 25 DEG C2The THF solution is dripped, the temperature is raised to 60 ℃, and the reaction is finished for 6 hours. Saturated NH is dropwise added in ice bath4And (3) quenching the Cl aqueous solution, after bubbling is stopped, centrifuging, adding water and EA into the centrifugate for extraction, washing with water, drying, dropwise adding an ethyl acetate hydrochloride solution at a controlled temperature, salifying, crystallizing, centrifuging to obtain a product, drying 7.1kg, and drying by using an HPLC (high performance liquid chromatography) method with the yield of 82%.
Example 2: preparing 3- (4-chlorphenyl) propane-1-alcohol solution: 5kg of 3- (4-chlorphenyl) propane-1-alcohol is prepared into 50wt% of toluene solution, and the raw material is I;
preparing a 3- (piperidine-1-yl) propionic acid solution: 4.61kg of 3- (piperidine-1-yl) propionic acid is prepared into 50wt% toluene solution, and the raw material is ②;
preparation of a reactor: filled catalyst SO4 2-/Fe2O3And the temperature is raised to 40 ℃.
Feeding after the temperature is stable, controlling the flow rate of the raw material I to be 6 g/min and the flow rate of the raw material II to be 5.53 g/min, obtaining a toluene solution of an intermediate in a collector, and evaporating the solvent to obtain 8.99kg of the intermediate;
8.99kg of 3- (4-chlorophenyl) propyl 3- (piperidin-1-yl) propionate were dissolved in 40kg of THF, and NaBH was added44.4kg, 0.18kg I is dripped in a water bath with the temperature controlled by about 25 DEG C2The THF solution is dripped, the temperature is raised to 60 ℃, and the reaction is finished for 6 hours. Saturated NH is dropwise added in ice bath4Quenching with Cl aqueous solution, centrifuging, extracting centrifugate with water and EA, washing with water, drying, and controllingAnd (3) dropwise adding an ethyl acetate hydrochloride solution at a low temperature, salifying, crystallizing and centrifuging to obtain a product, drying 7.07kg, wherein the yield is 81.7% and the purity is 99.9%.
Example 3: preparing 3- (4-chlorphenyl) propane-1-alcohol solution: 5kg of 3- (4-chlorphenyl) propane-1-alcohol is prepared into 50wt% of toluene solution, and the raw material is I;
preparing a 3- (piperidine-1-yl) propionic acid solution: 4.61kg of 3- (piperidine-1-yl) propionic acid is prepared into 50wt% toluene solution, and the raw material is ②;
preparation of a reactor: filled catalyst SO4 2-/Fe2O3And the temperature is raised to 40 ℃.
Feeding after the temperature is stable, controlling the flow rate of the raw material I to be 6 g/min, controlling the flow rate of the raw material II to be 5.53 g/min, obtaining a toluene solution of an intermediate in a collector, and evaporating the solvent to obtain 9.2kg of the intermediate;
9.2kg of 3- (4-chlorophenyl) propyl 3- (piperidin-1-yl) propionate were dissolved in 40kg of THF, and NaBH was added44.4kg, 0.18kg I is dripped in a water bath with the temperature controlled by about 25 DEG C2The THF solution is dripped, the temperature is raised to 60 ℃, and the reaction is finished for 6 hours. Saturated NH is dropwise added in ice bath4And (3) quenching the Cl aqueous solution, after bubbling is stopped, centrifuging, adding water and EA into the centrifugate for extraction, washing with water, drying, dropwise adding an ethyl acetate hydrochloride solution at a controlled temperature, salifying, crystallizing, and centrifuging to obtain a product, drying 7.15kg, wherein the yield is 82.5%, and the purity is 99.9%.
Then, a sample of 1- (3- (3- (4-chlorophenyl) propoxy) propyl) piperidine hydrochloride prepared by the synthesis method of example 1 of the present invention was sampled and detected by liquid chromatography.
Detection conditions are as follows: the instrument comprises the following steps: agilent 1100 hplc;
a chromatographic column: luna C18,4.6mm × 250mm,5 μm;
column temperature: 25 ℃;
flow rate: 1.0 ml/min;
detection wavelength: 210 nm;
sample introduction volume: 5 ul;
mobile phase: acetonitrile: 0.1% aqueous phosphoric acid =60:40 (v/v);
operating time: and (3) 30 min.
The liquid chromatogram and the analysis result of the detected sample are shown in FIG. 1.
FIG. 1: the chromatographic analysis result of the 1- (3- (3- (4-chlorophenyl) propoxy) propyl) piperidine hydrochloride sample prepared by the synthetic method of the invention case 1 was used.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (10)
1. A method for synthesizing 1- (3- (3- (4-chlorphenyl) propoxy) propyl) piperidine hydrochloride is characterized in that: the method comprises the following processing steps:
s1, preparing a 3- (4-chlorphenyl) propane-1-alcohol solution and a 3- (piperidine-1-yl) propionic acid solution respectively;
s2, respectively feeding a 3- (4-chlorphenyl) propyl-1-alcohol solution and a 3- (piperidine-1-yl) propionic acid solution into a reactor through a metering pump at a certain temperature, and simultaneously adding solid superacid for reaction to prepare a 3- (4-chlorphenyl) propyl 3- (piperidine-1-yl) propionate toluene solution;
s3, evaporating the solvent of the toluene solution of the 3- (4-chlorphenyl) propyl 3- (piperidine-1-yl) propionate to obtain 3- (4-chlorphenyl) propyl 3- (piperidine-1-yl) propionate;
s4, adding a reducing agent and a catalyst into 3- (4-chlorphenyl) propyl 3- (piperidine-1-yl) propionate, heating to 50-70 ℃, and reacting for 4-8 hours to obtain the target product 1- (3- (3- (4-chlorphenyl) propoxy) propyl) piperidine hydrochloride.
2. The method for synthesizing 1- (3- (3- (4-chlorophenyl) propoxy) propyl) piperidine hydrochloride according to claim 1, wherein: the 3- (4-chlorophenyl) propan-1-ol solution in the step S1 is a 10-90wt% toluene solution prepared from 3- (4-chlorophenyl) propan-1-ol.
3. The method for synthesizing 1- (3- (3- (4-chlorophenyl) propoxy) propyl) piperidine hydrochloride according to claim 1, wherein: the step S13- (piperidine-1-yl) propionic acid solution is a toluene solution prepared by preparing 3- (piperidine-1-yl) propionic acid into 10-90 wt%.
4. The method for synthesizing 1- (3- (3- (4-chlorophenyl) propoxy) propyl) piperidine hydrochloride according to claim 1, wherein: the reaction temperature in the step S2 is 20-50 ℃.
5. The method for synthesizing 1- (3- (3- (4-chlorophenyl) propoxy) propyl) piperidine hydrochloride according to claim 1, wherein: in the step S2, the material molar ratio of the 3- (4-chlorphenyl) propane-1-alcohol solution to the 3- (piperidine-1-yl) propionic acid solution is 1: 1-1.2.
6. The method for synthesizing 1- (3- (3- (4-chlorophenyl) propoxy) propyl) piperidine hydrochloride according to claim 5, wherein: the material molar ratio of the 3- (4-chlorophenyl) propan-1-ol solution to the 3- (piperidin-1-yl) propionic acid solution in the step S2 is 1: 1.
7. The method for synthesizing 1- (3- (3- (4-chlorophenyl) propoxy) propyl) piperidine hydrochloride according to claim 1, wherein: the solid super acid in the step S2 is acid strength H0Metal oxide super strong acid SO of = -8.2 to-124 2-/MXOY。
8. The method for synthesizing 1- (3- (3- (4-chlorophenyl) propoxy) propyl) piperidine hydrochloride according to claim 7, wherein: the metal oxide super acid SO4 2-/MXOYIs SO4 2-/TiO2、SO4 2-/ZrO2Or SO4 2-/Fe2O3。
9. The method for synthesizing 1- (3- (3- (4-chlorophenyl) propoxy) propyl) piperidine hydrochloride according to claim 1, wherein: the reducing agent in the step S4 is NaBH4、LiAlH4Borane dimethyl sulfide, and AlCl as catalyst3、ZnCl2、H2SO4、I2。
10. The method for synthesizing 1- (3- (3- (4-chlorophenyl) propoxy) propyl) piperidine hydrochloride according to claim 9, wherein: the reducing agent in the step S4 is NaBH4The catalyst is I2。
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