CN104447620B - 1-[3-[3-(4-chlorphenyl) propoxyl group] propyl group] preparation method of-piperidine hydrochlorate - Google Patents
1-[3-[3-(4-chlorphenyl) propoxyl group] propyl group] preparation method of-piperidine hydrochlorate Download PDFInfo
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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
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Abstract
The present invention relates to a kind of 1-[3-[3-(4-chlorphenyl) propoxyl group] propyl group] preparation method of-piperidine hydrochlorate, step is: (1) is by piperidines and 1,3-dihalopropane is placed in water miscible polar aprotic solvent, under alkali compounds effect, condensation reaction obtains N-(3-halogen propyl group) piperidines; (2) N-(3-halogen propyl group) piperidines and 3-(4-chlorphenyl) propyl alcohol, in solvent, carry out etherificate under alkali compounds effect, obtain compound 1-[3-[3-(4-chlorphenyl) propoxyl group] propyl group]-piperidines; (3) 1-[3-[3-4-chlorphenyl) propoxyl group] propyl group]-piperidines reacts and obtains product with HCl. Processing step of the present invention is simple, easy to operate, and raw material is easy to get, low price, and the product yield of preparation is high, and purity is high, and cost is low, is applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to a kind of 1 ?[3 ?[3 ?(4 ?chlorphenyl) propoxyl group] propyl group] ?the preparation method of piperidine hydrochlorate, belong to technical field of medicine synthesis.
Background technology
1 ?[3 ?[3 ?(4 ?chlorphenyl) propoxyl group] propyl group] ?piperidine hydrochlorate, formula (I), also referred to as replacing Luo Lisheng (tiprolisant), be by Bioprojet ?the receptor antagonist of Biotech company exploitation, it shows the affinity stronger to histamine H 3 receptor and selective. Be used for the treatment of at present the three phases clinical research of transitional sleep in the daytime (EDS) symptom of the various diseases such as hypnosia, parkinsonism. It has the features such as oral, potent, side effect is little, potential applicability in clinical practice optimism.
Patent WO2007/006708 adopts 1 ?piperidinepropanol and the preparation of 3 ?(4 ?chlorphenyl) propyl group methanesulfonates for Luo Lisheng, expensive raw material price, and be not easy to obtain, cost is higher. 3 ?for patent CN101155793 (1 ?piperidines) sodium propoxide reacts preparation for Luo Lisheng with 3 ?(4 ?chlorphenyl) propyl group methanesulfonates, expensive raw material price, and be not easy to obtain, cost is higher, used catalyst that toxicity is large 15 ?Guan ?5, column chromatography and 200 DEG C of above fractionation operation have been used in post processing, are unfavorable for suitability for industrialized production. Patent CN103435575 taking 3 ?(4 ?chlorphenyl) propionic acid as raw material, through reduction, esterification obtain 3 ?(4 ?chlorphenyl) propyl group methanesulfonates, taking piperidines as raw material, through N ?alkylation obtain 1 ?piperidinepropanol, after 3 ?(4 ?chlorphenyl) propyl group methanesulfonates reacts with 1 ?piperidinepropanol, salify obtains for Luo Lisheng, the method step is oversize, complicated operation, and cost is high. All synthetic for Luo Lisheng by 3-(4-chlorphenyl) propyl group methanesulfonates in prior art, methanesulfonates compounds is genotoxicity impurity or potential genotoxicity impurity, in medicine, the genotoxicity limit of impurities needs strict control, has improved technique controlling difficulty.
Summary of the invention
The invention provides a kind of 1-[3-[3-(4-chlorphenyl) propoxyl group] propyl group] preparation method of-piperidine hydrochlorate, avoid synthetic for Luo Lisheng as intermediate by methanesulfonates compounds, processing step of the present invention is simple, easy to operate, raw material is easy to get, low price, and the product yield of preparation is high, purity is high, and cost is low.
Of the present invention 1 ?[3 ?[3 ?(4 ?chlorphenyl) propoxyl group] propyl group] ?the preparation method of piperidine hydrochlorate, comprise the following steps:
(1) by piperidines and 1,3 ?dihalopropane be placed in water miscible polar aprotic solvent, under alkali compounds effect, condensation reaction obtain N ?(3 ?halogen propyl group) piperidines;
(2) N ?(3 ?halogen propyl group) piperidines and 3 ?(4 ?chlorphenyl) propyl alcohol in solvent, under alkali compounds effect, carry out etherificate, obtain compound 1 ?[3 ?[3 ?(4 ?chlorphenyl) propoxyl group] propyl group] ?piperidines;
(3) 1 ?[3 ?[3 ?4 ?chlorphenyl) propoxyl group] and propyl group] ?piperidines react with HCl obtain 1 ?[3 ?[3 ?(4 ?chlorphenyl) propoxyl group] propyl group] ?piperidine hydrochlorate.
In described step (1) 1,3 ?1 halogen in dihalopropane be fluorine, chlorine, bromine or iodine, 3 halogens are fluorine, chlorine, bromine or iodine.
Described step (1) adopts a kind of metal iodide to complete as reaction promoter.
Described metal iodide is KI or sodium iodide.
In described step (1), water miscible polar aprotic solvent is acetone, methyl ethyl ketone, oxolane, formamide, N, N ?dimethyl formamide or N, N ?in dimethylacetylamide any one or multiple.
In described step (1) piperidines and 1,3 ?the mol ratio of dihalopropane formula be 1:1 ?6. In preferred steps (1) piperidines and 1,3 ?the mol ratio of dihalopropane formula (II) be 1:1 ?1.5.
In described step (1) reaction temperature be 20 ?150 DEG C, condensation reaction time be 3h ?30h; In described step (2) reaction temperature be 20 ?150 DEG C, the etherification reaction time be 3h ?30h. Preferably, in step (1) reaction temperature be 20 ?100 DEG C, condensation reaction 3h ?30h; In preferred steps (2) reaction temperature be 20 ?100 DEG C, etherification reaction 3h ?30h.
The described solvent of described step (2) is lower alcohol, ketone, ether, aromatic hydrocarbons, acetonitrile, DMF, DMA, any in DMSO or HPT or two or more mixing arbitrarily.
Lower alcohol is methyl alcohol, ethanol or isopropyl alcohol, and ketone is acetone or MEK, ether Wei diox or diethylene glycol dimethyl ether, and aromatic hydrocarbons is toluene or dimethylbenzene.
In described step (2), N ?(3 ?halogen propyl group) piperidines formula and 3 ?the mol ratio of (4 ?chlorphenyl) propyl alcohol formula be 0.5 ?2:1. The described N of preferred steps (2) ?(3 ?halogen propyl group) piperidines formula and 3 ?(4 ?chlorphenyl) propyl alcohol formula mole be 0.7 ?1.5:1.
Alkali compounds in described step (1) and (2) is inorganic alkaline compound, alkali alcoholate or organic basic compound. Alkali compounds is as a kind of dehydrohalogenation reagent.
Described inorganic alkaline compound is potassium hydroxide, NaOH, sodium carbonate, potash, sodium hydride, metallic potassium or Sodamide, described alkali alcoholate is sodium methoxide, caustic alcohol or potassium ethoxide, and organic basic compound is tertiary amine, pyridine, quinoline, triethylamine or tripropylamine.
Reaction equation of the present invention is as follows:
1 ?[3 ?[3 ?(4 ?chlorphenyl) propoxyl group] propyl group] the ?piperidine hydrochlorate that above-mentioned preparation method makes, 1 ?[3 ?[3 ?(4 ?chlorphenyl) propoxyl group] propyl group] ?piperidine hydrochlorate is for Luo Lisheng.
Compared with prior art, the present invention has following beneficial effect:
The present invention avoids synthesizing for Luo Lisheng as intermediate by methanesulfonates compounds, and processing step of the present invention is simple, easy to operate, and raw material is easy to get, and low price is simple, and the product yield of preparation is high, and purity is high, and cost is low, is applicable to suitability for industrialized production.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further, the following example is only for the present invention is described, and should not be considered as limiting scope of the present invention. Unreceipted actual conditions person in embodiment, carries out according to the condition of normal condition or manufacturer's suggestion. The unreceipted manufacturer person of agents useful for same or instrument, being can be by the product of commercial acquisition.
Embodiment 1
N ?(3 ?bromopropyl) piperidines synthetic
By oxolane (200ml), piperidines (17.2g, 0.2mol), 1,3 ?dibromopropane (60.6g, 0.3mol), sodium carbonate (11.1g, 0.105mol) add successively reaction bulb, 67 DEG C of back flow reaction 12 hours. Be cooled to room temperature, filter, filtrate is concentrated, residue 2N dissolving with hydrochloric acid, and ethyl acetate washing 2 times, water is adjusted pH to 10 with 2NNaOH solution, is extracted with ethyl acetate 3 times, merges organic phase, anhydrous magnesium sulfate drying. Filter, reduced pressure concentration obtains faint yellow grease 39.1g, yield 94.9%.
1 ?[3 ?[3 ?(4 ?chlorphenyl) propoxyl group] propyl group] ?piperidine hydrochlorate
By 3 ?(4 ?chlorphenyl) propyl alcohol (17.1g, 0.1mol) join in DMF (170ml), at 0 DEG C, slowly add 60% NaH (3g, 0.1mol), stir 30 minutes, then add N ?(3 ?bromopropyl) piperidines (22.6g, 0.11mol) solution in DMF (30mL). Mixture is stirred 2 hours at 0 DEG C, then 20 DEG C of reactions 8 hours. Then dilute with the water of 400ml, by ethyl acetate 400ml extracting twice, merge organic phase, by 2N NaOH and salt solution washed twice, by dried over mgso, filter, under room temperature, pass into HCl gas, stir and separate out solid, filter, dry, obtain obtaining faint yellow solid product 30.7g, yield 92.5%.
The HPLC:99.7% of product. Mp:117～120 DEG C.1H‐NMR(400MHz，D2O)δ：1.20～1.31(1H,br),1.42～1.57(2H,br),1.58～1.80(7H,br),2.44(2H,t),2.65(2H,t),2.86(2H,t),3.22～3.36(6H,br),7.02(2H,d),7.12(2H,d)。MSm/z：296[M‐HCl]。IR(KBr)：2936cm‐1，2868cm‐1，2647cm‐1，2551cm‐1，1492cm‐1，1455cm‐1，1112cm‐1，1101cm‐1，802cm‐1。
Embodiment 2
N ?(3 ?bromopropyl) piperidines synthetic
By DMF (200ml), piperidines (17.2g, 0.2mol), 1,3 ?dibromopropane (60.6g, 0.3mol), potash (14.5g, 0.105mol) sodium iodide (4.5g, 0.03mol) add successively reaction bulb, 150 DEG C are reacted 4 hours. Be cooled to room temperature, filter, filtrate is concentrated, residue 2N dissolving with hydrochloric acid, and ethyl acetate washing 2 times, water is adjusted pH to 10 with 2NNaOH solution, is extracted with ethyl acetate 3 times, merges organic phase, anhydrous magnesium sulfate drying. Filter, reduced pressure concentration obtains faint yellow grease 37.2g, yield 90.4%.
1 ?[3 ?[3 ?(4 ?chlorphenyl) propoxyl group] propyl group] ?piperidine hydrochlorate
By 3 ?(4 ?chlorphenyl) propyl alcohol (17.1g, 0.1mol) join in DMA (170ml), at 0 DEG C, slowly add 60% NaOH (3g, 0.1mol), stir 30 minutes, then add N ?(3 ?bromopropyl) piperidines (22.6g, 0.11mol) solution in DMA (30mL). Mixture is stirred 2 hours at 0 DEG C, be then warming up to 150 DEG C of reactions 4 hours. Mixture is cooled to room temperature, then dilutes with the water of 400ml, by ethyl acetate 400ml extracting twice, merge organic phase, by 2N NaOH and salt solution washed twice, by dried over mgso, filter, under room temperature, pass into HCl gas, stir and separate out solid, filter, dry, obtain obtaining faint yellow solid 29.6g, yield 89.2%, HPLC:99.5%.
Embodiment 3
N ?(3 ?bromopropyl) piperidines synthetic
By acetone (200ml), piperidines (17.2g, 0.2mol), 1,3 ?dibromopropane (60.6g, 0.3mol), potash (14.5g, 0.105mol) KI (5g, 0.03mol) add successively reaction bulb, 56 DEG C of back flow reaction 10 hours. Be cooled to room temperature, filter, filtrate is concentrated, residue 2N dissolving with hydrochloric acid, and ethyl acetate washing 2 times, water is adjusted pH to 10 with 2NNaOH solution, is extracted with ethyl acetate 3 times, merges organic phase, anhydrous magnesium sulfate drying. Filter, reduced pressure concentration obtains faint yellow grease 37.9g, yield 92.1%.
1 ?[3 ?[3 ?(4 ?chlorphenyl) propoxyl group] propyl group] ?piperidine hydrochlorate
By 3 ?(4 ?chlorphenyl) propyl alcohol (17.1g, 0.1mol) join in oxolane (170ml), at 0 DEG C, slowly add 60% NaH (3g, 0.1mol), stir 30 minutes, then add N ?(3 ?bromopropyl) piperidines (22.6g, 0.11mol) solution in DMA (30mL). Mixture is stirred 2 hours at 0 DEG C, then 25 DEG C of reactions 10 hours. Then dilute with the water of 400ml, by ethyl acetate 400ml extracting twice, merge organic phase, by 2N NaOH and salt solution washed twice, by dried over mgso, filter, under room temperature, pass into HCl gas, solid is separated out in stirring, filter, dry, obtain obtaining faint yellow solid 30.0g, yield 90.4%, HPLC:99.6%.
Embodiment 4
N ?(3 ?chloropropyl) piperidines synthetic
By acetone (200ml), piperidines (17.2g, 0.2mol), 1,3 ?bromo-chloropropane (47.2g, 0.3mol), sodium carbonate (11.1g, 0.105mol) add successively reaction bulb, 20 DEG C of reactions 30 hours. Filter, filtrate is concentrated, residue 2N dissolving with hydrochloric acid, and ethyl acetate washing 2 times, water is adjusted pH to 10 with 2NNaOH solution, is extracted with ethyl acetate 3 times, merges organic phase, anhydrous magnesium sulfate drying. Filter, reduced pressure concentration obtains faint yellow grease 28.6g, yield 88.3%.
1 ?[3 ?[3 ?(4 ?chlorphenyl) propoxyl group] propyl group] ?piperidine hydrochlorate
By 3 ?(4 ?chlorphenyl) propyl alcohol (17.1g, 0.1mol) join in DMF (170ml), at 0 DEG C, slowly add 60% NaH (3g, 0.1mol), stir 30 minutes, then add N ?(3 ?bromopropyl) piperidines (22.6g, 0.11mol) solution in DMA (30mL). Mixture is stirred 2 hours at 0 DEG C, then at 20 DEG C, react 8 hours. Then dilute with the water of 400ml, by ethyl acetate 400ml extracting twice, merge organic phase, by 2N NaOH and salt solution washed twice, by dried over mgso, filter, under room temperature, pass into HCl gas, solid is separated out in stirring, filter, dry, obtain obtaining faint yellow solid 30.4g, yield 91.7%, HPLC:99.6%.
Embodiment 5
N ?(3 ?chloropropyl) piperidines synthetic
By DMF (200ml), piperidines (17.2g, 0.2mol), 1,3 ?bromo-chloropropane (47.2g, 0.3mol), sodium carbonate (11.1g, 0.105mol), sodium iodide 1g adds reaction bulb successively, 150 DEG C of back flow reaction 3 hours. Be cooled to room temperature, filter, filtrate is concentrated, residue 2N dissolving with hydrochloric acid, and ethyl acetate washing 2 times, water is adjusted pH to 10 with 2NNaOH solution, is extracted with ethyl acetate 3 times, merges organic phase, anhydrous magnesium sulfate drying. Filter, reduced pressure concentration obtains faint yellow grease 28.8g, yield 89.1%.
1 ?[3 ?[3 ?(4 ?chlorphenyl) propoxyl group] propyl group] ?piperidine hydrochlorate
By 3 ?(4 ?chlorphenyl) propyl alcohol (17.1g, 0.1mol) join in DMA (170ml), at 0 DEG C, slowly add 60% NaH (3g, 0.1mol), stir 30 minutes, then add N ?(3 ?bromopropyl) piperidines (22.6g, 0.11mol) solution in DMA (30mL). Mixture is stirred 2 hours at 0 DEG C, then 20 DEG C of reactions 8 hours. Then dilute with the water of 400ml, by ethyl acetate 400ml extracting twice, merge organic phase, by 2N NaOH and salt solution washed twice, by dried over mgso, filter, under room temperature, pass into HCl gas, solid is separated out in stirring, filter, dry, obtain obtaining faint yellow solid 29.7g, yield 89.6%, HPLC:99.7%.
Embodiment 6
N ?(3 ?chloropropyl) piperidines synthetic
By oxolane (200ml), piperidines (17.2g, 0.2mol), 1,3 ?bromo-chloropropane (47.2g, 0.3mol), sodium carbonate (11.1g, 0.105mol) add successively reaction bulb, 66 DEG C of back flow reaction 15 hours. Be cooled to room temperature, filter, filtrate is concentrated, residue 2N dissolving with hydrochloric acid, and ethyl acetate washing 2 times, water is adjusted pH to 10 with 2NNaOH solution, is extracted with ethyl acetate 3 times, merges organic phase, anhydrous magnesium sulfate drying. Filter, reduced pressure concentration obtains faint yellow grease 30.2g, yield 93.4%.
1 ?[3 ?[3 ?(4 ?chlorphenyl) propoxyl group] propyl group] ?piperidine hydrochlorate
By 3 ?(4 ?chlorphenyl) propyl alcohol (17.1g, 0.1mol) join in DMF (150ml), add successively N ?(3 ?chloropropyl) piperidines (17.8g, 0.11mol), potash (6.9g, 0.05mol), KI 1g, be heated to 95 DEG C, stirring reaction 12 hours. Mixture is cooled to room temperature, then dilutes with the water of 300ml, by ethyl acetate 400ml extracting twice, merge organic phase, by 2N NaOH and salt solution washed twice, by dried over mgso, filter, under room temperature, pass into HCl gas, stir and separate out solid, filter, dry, obtain obtaining faint yellow solid 29.8g, yield 89.7%, HPLC:99.6%.
Claims (10)
1. 1-[3-[3-(4-chlorphenyl) propoxyl group] propyl group] preparation method of-piperidine hydrochlorate, it is characterized in that, comprise the following steps:
(1) piperidines and 1,3-dihalopropane are placed in to water miscible polar aprotic solvent, under alkali compounds effect, condensation reaction obtains N-(3-halogen propyl group) piperidines;
(2) N-(3-halogen propyl group) piperidines and 3-(4-chlorphenyl) propyl alcohol, in solvent, carry out etherificate under alkali compounds effect, obtain compound 1-[3-[3-(4-chlorphenyl) propoxyl group] propyl group]-piperidines;
(3) 1-[3-[3-4-chlorphenyl) propoxyl group] propyl group]-piperidines reacts with HCl and obtains 1-[3-[3-(4-chlorphenyl) propoxyl group] propyl group]-piperidine hydrochlorate.
2. preparation method according to claim 1, is characterized in that, 1 in described step (1), and 1 halogen in 3-dihalopropane is fluorine, chlorine, bromine or iodine, 3 halogens are fluorine, chlorine, bromine or iodine.
3. preparation method according to claim 1, is characterized in that, described step (1) adopts a kind of metal iodide to complete as reaction promoter.
4. preparation method according to claim 3, is characterized in that, described metal iodide is KI or sodium iodide.
5. preparation method according to claim 1, it is characterized in that, in described step (1) water miscible polar aprotic solvent be in acetone, methyl ethyl ketone, oxolane, formamide, DMF or DMA any one or multiple.
6. preparation method according to claim 1, is characterized in that, in described step (1), the mol ratio of piperidines and 1,3-dihalopropane formula is 1:1-6.
7. preparation method according to claim 1, is characterized in that, in described step (1), reaction temperature is 20-150 DEG C, and condensation reaction time is 3h-30h; In described step (2), reaction temperature is 20-150 DEG C, and the etherification reaction time is 3h-30h.
8. preparation method according to claim 1, is characterized in that, the described solvent of described step (2) is lower alcohol, ketone, ether, aromatic hydrocarbons, acetonitrile, DMF, DMA, any in DMSO or HPT or two or more mixing arbitrarily.
9. preparation method according to claim 1, is characterized in that, in described step (2), the mol ratio of N-(3-halogen propyl group) piperidines and 3-(4-chlorphenyl) propyl alcohol is 0.5-2:1.
10. preparation method according to claim 1, is characterized in that, the alkali compounds in described step (1) and (2) is inorganic alkaline compound or organic basic compound.
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