CN108083991A - It is a kind of to prepare 3-（1- naphthoxys）The method of -1- phenyl propanols - Google Patents
It is a kind of to prepare 3-（1- naphthoxys）The method of -1- phenyl propanols Download PDFInfo
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- CN108083991A CN108083991A CN201711223674.8A CN201711223674A CN108083991A CN 108083991 A CN108083991 A CN 108083991A CN 201711223674 A CN201711223674 A CN 201711223674A CN 108083991 A CN108083991 A CN 108083991A
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 44
- 239000002904 solvent Substances 0.000 claims abstract description 43
- -1 3 chlorobenzene propyl alcohols Chemical class 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000007788 liquid Substances 0.000 claims abstract description 17
- 239000007787 solid Substances 0.000 claims abstract description 14
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 238000012805 post-processing Methods 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 239000000376 reactant Substances 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 235000019441 ethanol Nutrition 0.000 claims description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 15
- 239000012279 sodium borohydride Substances 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 7
- 239000007795 chemical reaction product Substances 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 5
- ATQXMSAPMLWHBZ-UHFFFAOYSA-N chlorobenzene;propan-2-one Chemical class CC(C)=O.ClC1=CC=CC=C1 ATQXMSAPMLWHBZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000004519 grease Substances 0.000 claims description 5
- 238000013517 stratification Methods 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 238000004064 recycling Methods 0.000 claims description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 150000004782 1-naphthols Chemical class 0.000 abstract description 4
- XWKUHZMGQHEFGL-UHFFFAOYSA-N 1-naphthalen-1-yloxy-1-phenylpropan-1-ol Chemical class C=1C=CC2=CC=CC=C2C=1OC(O)(CC)C1=CC=CC=C1 XWKUHZMGQHEFGL-UHFFFAOYSA-N 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- VCNYPJMEQHTAHS-UHFFFAOYSA-N 1-(3-chlorophenyl)propan-2-one Chemical class CC(=O)CC1=CC=CC(Cl)=C1 VCNYPJMEQHTAHS-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 150000004780 naphthols Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to chemosynthesis technical fields, it is related to a kind of method for preparing 3 (1 naphthoxy) 1 phenyl propanols, comprise the following steps, in the organic solvent containing alkali, α naphthols is reacted with 3 chlorobenzene propyl alcohols, after reaction, it is extracted into reactant plus after water with benzene kind solvent, after benzene kind solvent layer is washed, recycle benzene kind solvent, thick liquid is obtained, above-mentioned thick liquid is placed in hexane class or heptane class solvent and is disperseed, obtains pulverulent solids 3 (1 naphthoxy) 1 phenyl propanol.This method has the advantages that post processing is simple, high income, products obtained therefrom purity is high.
Description
Technical field
The invention belongs to chemosynthesis technical field, particularly relate to a kind of prepare 3- (1- naphthoxys) -1- phenyl propanols
Method.
Background technology
3- (1- naphthoxys) -1- phenyl propanols are the intermediate in pharmaceutical synthesis, and in recent years, chemical expert prepares work to it
Skill carries out some researchs.United States Patent (USP) 5292962 participates in reacting using (S)-(+) -3- chlorobenzene propyl alcohols as starting material, by naphthols
Synthesize (S)-(+) -3- (1- naphthoxys) -1- phenyl propanols；CN1821212A passes through naphthols using 3- chlorobenzene propyl alcohols as starting material
Reaction is participated in, 3- (1- naphthoxys) -1- phenyl propanols is synthesized, still, in the last handling process of reaction dissolvent and product, still has
Many deficiencies.For example, selecting glycol dimethyl ether when preparing 3- chlorobenzene propyl alcohols, as solvent, toxicity is big, price is high, explosive
It is fried.Prepare 3- (1- naphthoxys) -1- phenyl propanols, room temperature reaction need 30 it is small when, the reaction time is longer, and during post processing, product is
It is stood by refrigerator, containing more impurity, increased burden for reaction in next step.Therefore, development is a kind of prepares 3- (1- naphthalenes
Oxygroup) methods of -1- phenyl propanols is always new problem urgently to be resolved hurrily.
The content of the invention
It is an object of the invention to provide a kind of methods for preparing 3- (1- naphthoxys) -1- phenyl propanols.This method has
Post processing is simple, and step is few, be related to solvent it is few, it is cheap be easy to get, the advantages that high income, products obtained therefrom purity is high.
To achieve the above object, the present invention adopts the following technical scheme that：It is a kind of to prepare 3- (1- naphthoxys) -1- phenyl propanols
Method, the described method comprises the following steps：
In the organic solvent containing alkali, alpha-Naphthol is reacted with 3- chlorobenzene propyl alcohols, after reaction, into reactant
It is extracted after adding water with benzene kind solvent, after benzene kind solvent layer is washed, recycles benzene kind solvent, obtain thick liquid, it will be above-mentioned
Thick liquid, which is placed in hexane class or heptane class solvent, to be disperseed, and obtains pulverulent solids 3- (1- naphthoxys) -1- phenyl third
Alcohol；
The alkali is selected from inorganic base, the one kind or several of the inorganic base in Anhydrous potassium carbonate, natrium carbonicum calcinatum
Kind；The organic solvent is selected from N,N-dimethylformamide；The molar ratio of the 3- chlorobenzene propyl alcohols and alpha-Naphthol is 1:0.9-
1:1.1；The molar ratio of the 3- chlorobenzene propyl alcohols and alkali is 1:0.5-1:1.2；The temperature of the reaction is 65-75 DEG C, described anti-
When the time answered is 4-6 small；The benzene kind solvent is selected from one or more of benzene,toluene,xylene；The hexane class is molten
Agent is selected from one or more of n-hexane, hexamethylene；The heptane class solvent is selected from normal heptane；The washing is by benzene class
Solvent layer is washed respectively with the NaOH aqueous solutions of 1-10%, water and saturation NaCl aqueous solutions, preferred NaOH aqueous solutions
Concentration be 5%；The thick liquid is placed in reaction vessel by described being separated into, and hexane class or heptan are added under stirring condition
Alkanes solvent is vigorously stirred grease in process at 15-35 DEG C and is gradually dispersed in hexane class or heptane class solvent, slowly changes
Into pulverulent solids, continue to stir at 15-35 DEG C 5-12 it is small when, preferably continue to stir at 15-35 DEG C 6-8 it is small when；It is described
The quality of 3- chlorobenzene propyl alcohols is 1 with hexane class or the volume ratio of heptane class solvent:4-8, preferably the quality of 3- chlorobenzene propyl alcohols and oneself
The volume ratio of alkanes or heptane class solvent is 1:6-7, the unit of the quality for gram, the unit of the volume is milliliter；It is described
Be vigorously stirred and refer to speed of agitator at 300-400 revs/min；The preparation method of the 3- chlorobenzene propyl alcohols includes the following steps：
In the presence of alcohols solvent, 3- chloro-benzene acetones are reacted with sodium borohydride, obtain 3- chlorobenzene propyl alcohols；The alcohols solvent is selected from
One or more of methanol, ethyl alcohol, propyl alcohol, butanol；The reaction is that sodium borohydride is added to containing 3- chloro-benzene acetones
Alcohols solvent in reacted；The temperature of the reaction is 15-35 DEG C, when the time of the reaction is 0.5-2 small, preferably
When the time of reaction is 0.5-0.8 small；The method is additionally included in the 3- chloro-benzene acetones and sodium borohydride after reaction,
The step of the step of being post-processed to reaction product, the post processing, includes：Reaction product is cooled down, it is water-soluble to add in dilute hydrochloric acid
Liquid is adjusted to pH value as 3-4, concentration, and into system plus water and dichloromethane, stratification after stirring, water mutually use dichloromethane again
After extraction, merge recycling organic phase；It is described reaction product is cooled down after temperature be 0 DEG C.
The present invention is characterized by its preparation method.Its principle is：When preparing 3- chlorobenzene propyl alcohols, with methanol, ethyl alcohol
Or acetonitrile replaces the glycol dimethyl ether in document, reaction is faster and better, and solvent is more cheap and easily-available.Prepare 3- (1- naphthalene oxygen
Base) -1- phenyl propanols when, replace potassium hydroxide with Anhydrous potassium carbonate, when 65 DEG C of -75 DEG C of reaction 5-6 are small, by-product is few, yield
89% is increased to by 55%.In addition, during post processing, product is broken up to obtain from organic solvent, removes many impurity, content
Reach 95% (HPLC).
A kind of method for preparing 3- (1- naphthoxys) -1- phenyl propanols compared with prior art, has high income, product matter
It measures, the advantages that post processing is simple, and step is few, and it is few to be related to solvent, cheap, be easy to get, and environmental pollution is small, will widely answer
For in the field of chemical synthesis.
Description of the drawings
The following describes the present invention in detail with reference to the accompanying drawings and embodiments.
Fig. 1 is the structural formula figure of 3- chlorobenzene propyl alcohols.
Fig. 2 is the structural formula figure of 3- (1- naphthoxys) -1- phenyl propanols.
Fig. 3 is the synthetic route chart that the present invention prepares 3- (1- naphthoxys) -1- phenyl propanols.
Specific embodiment
With reference to embodiment, the present invention is described further, and embodiment helps to more fully understand the present invention, but
The present invention is not limited only to following embodiments.
Room temperature of the present invention refers to 15-35 DEG C.
Embodiment one
3- chlorophenyl acetones 50g is added in 200mL ethanol solutions, is stirred in the reaction bulb of 500mL, be cooled to 0 DEG C with
Under；Add in sodium borohydride solids 6.6g.As sodium borohydride adds in, solution gradually becomes clear by muddy.After sodium borohydride adds, rise
Warm to room temperature reaction 0.5 it is small when, TLC monitoring extent of reaction, solvent use petroleum ether：Ethyl acetate=5:1 (volume ratio).Instead
After answering, 0 DEG C is cooled to, adds in the diluted hydrochloric acid aqueous solution of 2M, be adjusted to pH value as 3-4.It is concentrated under reduced pressure, adds into system
150mL water and 150mL dichloromethane, stratification after stirring 2 minutes.Water mutually again with after the extraction of 100mL dichloromethane, is associated with
Machine phase.It is dried with anhydrous sodium sulfate 30g.Dichloromethane is recovered under reduced pressure, obtains the orange-yellow liquid of 3- chlorobenzene propyl alcohols 50.4g, mole
Yield 99.6%, mass content 97.4% (HPLC).
45g Anhydrous potassium carbonates are added in 200mL DMF (n,N-Dimethylformamide), are stirred in the reaction bulb of 1000mL
3-5 minutes, then 46.5g alpha-Naphthols are added in reaction kettle, system becomes green.Oil bath heating is added dropwise to 65 DEG C into system
50g3- chlorobenzene propyl alcohols.Reaction system becomes brown-green.65 DEG C -75 DEG C of temperature and stirring is maintained, it substantially can be with when reaction 6 is small
The reaction was complete.TLC detects extent of reaction, and solvent uses petroleum ether：Ethyl acetate=6:1.Room temperature is down to after reaction, is added
Enter 300mL water, 200mL toluene is sufficiently stirred, layering, lower floor with toluene extract three times (100mL × 3), combining methylbenzene phase.Toluene
Layer is washed three times with 5% NaOH aqueous solutions (150mL × 3),；Toluene layer uses 120mL water and 120mL saturation NaCl water respectively again
Solution washs, and is dried with anhydrous sodium sulfate 50g.After being filtered to remove drier, toluene is recovered under reduced pressure and obtains reddish brown viscous fluid
Body.Obtained thick liquid is placed in the reaction kettle of 500mL, hexamethylene 300mL is added in stirring, is vigorously stirred at room temperature
Grease is gradually dispersed in hexamethylene during (rotating speed is at 300-400 revs/min), is slowly transformed into pulverulent solids.After
It is continuous be stirred at room temperature 6 it is small when.Decompression filters, and is fully washed with 70mL hexamethylenes.It is dry, obtain pale pink solid 3- (1- naphthalene oxygen
Base) -1- phenyl propanol 72.8g, molar yield 89.3%, mass content 95.0% (HPLC).
Embodiment two
3- chlorophenyl acetones 50g is added in 200mL ethanol solutions, is stirred in the reaction bulb of 500mL, be cooled to 0 DEG C with
Under；Add in sodium borohydride solids 7.2g.As sodium borohydride adds in, solution gradually becomes clear by muddy.After sodium borohydride adds, rise
Warm to room temperature reaction 0.6 it is small when, TLC monitoring extent of reaction, solvent use petroleum ether：Ethyl acetate=5:1 (volume ratio).Instead
After answering, 0 DEG C is cooled to, adds in the diluted hydrochloric acid aqueous solution of 2M, be adjusted to pH value as 3-4.It is concentrated under reduced pressure, adds into system
150mL water and 150mL dichloromethane, stratification after stirring 3 minutes.Water mutually again with after the extraction of 100mL dichloromethane, is associated with
Machine phase.It is dried with anhydrous sodium sulfate 30g.Dichloromethane is recovered under reduced pressure, obtains the orange-yellow liquid of 3- chlorobenzene propyl alcohols 50.5g, mole
Yield 99.8%, mass content 98.2% (HPLC).
20g Anhydrous potassium carbonates are added in 200mL DMF, are stirred 2-4 minutes in the reaction bulb of 1000mL, then by 38g α-
Naphthols is added in reaction kettle, and system becomes green.50g3- chlorobenzene propyl alcohols are added dropwise into system to 70 DEG C for oil bath heating.Reactant
System becomes brown-green.65 DEG C -75 DEG C of temperature and stirring is maintained, reaction 5 substantially can be with the reaction was complete when small.TLC detection reactions
Progress, solvent use petroleum ether：Ethyl acetate=6:1.Room temperature is down to after reaction, adds in 300mL water, 200mL toluene
It is sufficiently stirred, is layered, lower floor is extracted three times (100mL × 3) with toluene, combining methylbenzene phase.Toluene layer with 5% NaOH aqueous solutions
(150mL × 3) are washed three times,；Toluene layer is washed again with 120mL water and 120mL saturation NaCl aqueous solutions respectively, with anhydrous slufuric acid
Sodium 50g is dried.After being filtered to remove drier, toluene is recovered under reduced pressure and obtains reddish brown thick liquid.The thick liquid that will be obtained
It is placed in the reaction kettle of 500mL, n-hexane 325mL is added in stirring, is vigorously stirred that (rotating speed is at 300-400 revs/min at room temperature
Clock) during grease be gradually dispersed in hexamethylene, be slowly transformed into pulverulent solids.Continue to be stirred at room temperature 6.5 it is small when.Subtract
Pressure filters, and is fully washed with 70mL hexamethylenes.It is dry, pale pink solid 3- (1- naphthoxys) -1- phenyl propanol 73.5g are obtained,
Molar yield 90.1%, mass content 97.3% (HPLC).
Embodiment three
3- chlorophenyl acetones 50g is added in 200mL ethanol solutions, is stirred in the reaction bulb of 500mL, be cooled to 0 DEG C with
Under；Add in sodium borohydride solids 7.6g.As sodium borohydride adds in, solution gradually becomes clear by muddy.After sodium borohydride adds, rise
Warm to room temperature reaction 0.8 it is small when, TLC monitoring extent of reaction, solvent use petroleum ether：Ethyl acetate=5:1 (volume ratio).Instead
After answering, 0 DEG C is cooled to, adds in the diluted hydrochloric acid aqueous solution of 2M, be adjusted to pH value as 3-4.It is concentrated under reduced pressure, adds into system
150mL water and 150mL dichloromethane, stratification after stirring 2 minutes.Water mutually again with after the extraction of 100mL dichloromethane, is associated with
Machine phase.It is dried with anhydrous sodium sulfate 30g.Dichloromethane is recovered under reduced pressure, obtains the orange-yellow liquid of 3- chlorobenzene propyl alcohols 50.1g, mole
Yield 99.0%, mass content 98.6% (HPLC).
48g Anhydrous potassium carbonates are added in 200mL DMF, are stirred 5-6 minutes in the reaction bulb of 1000mL, then by 42g α-
Naphthols is added in reaction kettle, and system becomes green.50g3- chlorobenzene propyl alcohols are added dropwise into system to 75 DEG C for oil bath heating.Reactant
System becomes brown-green.65 DEG C -75 DEG C of temperature and stirring is maintained, reaction 4 substantially can be with the reaction was complete when small.TLC detection reactions
Progress, solvent use petroleum ether：Ethyl acetate=6:1.Room temperature is down to after reaction, adds in 300mL water, 200mL toluene
It is sufficiently stirred, is layered, lower floor is extracted three times (100mL × 3) with toluene, combining methylbenzene phase.Toluene layer with 5% NaOH aqueous solutions
(150mL × 3) are washed three times,；Toluene layer is washed again with 120mL water and 120mL saturation NaCl aqueous solutions respectively, with anhydrous slufuric acid
Sodium 50g is dried.After being filtered to remove drier, toluene is recovered under reduced pressure and obtains reddish brown thick liquid.The thick liquid that will be obtained
It is placed in the reaction kettle of 500mL, normal heptane 350mL is added in stirring, is vigorously stirred that (rotating speed is at 300-400 revs/min at room temperature
Clock) during grease be gradually dispersed in normal heptane, be slowly transformed into pulverulent solids.Continue to be stirred at room temperature 8 it is small when.Decompression
It filters, is fully washed with 70mL normal heptanes.It is dry, pale pink solid 3- (1- naphthoxys) -1- phenyl propanol 77.1g are obtained, are rubbed
That yield 94.6%, mass content 95.3% (HPLC).
It should be appreciated that for those of ordinary skills, can be improved or converted according to the above description,
And all these modifications and variations should all belong to the protection domain of appended claims of the present invention.
Claims (9)
- A kind of 1. method for preparing 3- (1- naphthoxys) -1- phenyl propanols, which is characterized in that the described method comprises the following steps：In the organic solvent containing alkali, alpha-Naphthol is reacted with 3- chlorobenzene propyl alcohols, after reaction, water is added into reactant It is extracted afterwards with benzene kind solvent, after benzene kind solvent layer is washed, recycles benzene kind solvent, obtain thick liquid, it will be above-mentioned sticky Liquid, which is placed in hexane class or heptane class solvent, to be disperseed, and obtains pulverulent solids 3- (1- naphthoxys) -1- phenyl propanols.
- A kind of 2. method for preparing 3- (1- naphthoxys) -1- phenyl propanols according to claim 1, which is characterized in that institute The alkali stated is selected from inorganic base, and the inorganic base is selected from one or more of Anhydrous potassium carbonate, natrium carbonicum calcinatum；Described has Solvent is selected from N,N-dimethylformamide；The molar ratio of the 3- chlorobenzene propyl alcohols and alpha-Naphthol is 1:0.9-1:1.1；The 3- The molar ratio of chlorobenzene propyl alcohol and alkali is 1:0.5-1:1.2.
- A kind of 3. method for preparing 3- (1- naphthoxys) -1- phenyl propanols according to claim 1, which is characterized in that institute The temperature of reaction is stated as 65-75 DEG C, when the time of the reaction is 4-6 small；The benzene kind solvent is selected from benzene, toluene, diformazan One or more of benzene；The hexane class solvent is selected from one or more of n-hexane, hexamethylene；The heptane class solvent Selected from normal heptane；The washing is that benzene kind solvent layer is used to NaOH aqueous solutions, water and the saturation NaCl water of 1-10% respectively Solution is washed, and the concentration of preferred NaOH aqueous solutions is 5%.
- A kind of 4. method for preparing 3- (1- naphthoxys) -1- phenyl propanols according to claim 1, which is characterized in that institute The thick liquid is placed in reaction vessel by being separated into for stating, and hexane class or heptane class solvent, 15-35 are added under stirring condition Grease in process is vigorously stirred at DEG C to be gradually dispersed in hexane class or heptane class solvent, is slowly transformed into pulverulent solids, Continue at 15-35 DEG C stir 5-12 it is small when, preferably continue at 15-35 DEG C stir 6-8 it is small when；The matter of the 3- chlorobenzene propyl alcohols Amount is 1 with hexane class or the volume ratio of heptane class solvent:4-8, the preferably quality of 3- chlorobenzene propyl alcohols and hexane class or heptane class are molten The volume ratio of agent is 1:6-7, the unit of the quality for gram, the unit of the volume is milliliter.
- A kind of 5. method for preparing 3- (1- naphthoxys) -1- phenyl propanols according to claim 4, which is characterized in that institute Being vigorously stirred for stating refers to speed of agitator at 300-400 revs/min.
- A kind of 6. method for preparing 3- (1- naphthoxys) -1- phenyl propanols according to claim 1, which is characterized in that institute The preparation method for stating 3- chlorobenzene propyl alcohols includes the following steps：In the presence of alcohols solvent, 3- chloro-benzene acetones and sodium borohydride are anti- Should, obtain 3- chlorobenzene propyl alcohols.
- A kind of 7. method for preparing 3- (1- naphthoxys) -1- phenyl propanols according to claim 6, which is characterized in that institute The alcohols solvent stated is selected from one or more of methanol, ethyl alcohol, propyl alcohol, butanol；The reaction is to be added to sodium borohydride It is reacted in alcohols solvent containing 3- chloro-benzene acetones；The temperature of the reaction is 15-35 DEG C, and the time of the reaction is When 0.5-2 is small, when the time preferably reacted is 0.5-0.8 small.
- A kind of 8. method for preparing 3- (1- naphthoxys) -1- phenyl propanols according to claim 6, which is characterized in that institute The method of stating is additionally included in the 3- chloro-benzene acetones and sodium borohydride after reaction, the step post-processed to reaction product Suddenly, the step of post processing includes：Reaction product is cooled down, adds in diluted hydrochloric acid aqueous solution, is adjusted to pH value as 3-4, concentration, to In system plus water and dichloromethane, stratification after stirring after water is mutually extracted with dichloromethane again, merge recycling organic phase.
- A kind of 9. method for preparing 3- (1- naphthoxys) -1- phenyl propanols according to claim 8, which is characterized in that institute The temperature after reaction product is cooled down is stated as 0 DEG C.
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Citations (2)
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|---|---|---|---|---|
| WO2008035358A2 (en) * | 2006-06-05 | 2008-03-27 | Cadila Healthcare Limited | Process for preparing dapoxetine |
| CN106748817A (en) * | 2016-12-06 | 2017-05-31 | 安徽省金楠医疗科技有限公司 | A kind of dapoxetine hydrochloride preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008035358A2 (en) * | 2006-06-05 | 2008-03-27 | Cadila Healthcare Limited | Process for preparing dapoxetine |
| CN106748817A (en) * | 2016-12-06 | 2017-05-31 | 安徽省金楠医疗科技有限公司 | A kind of dapoxetine hydrochloride preparation method |
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| Title |
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| 伍平华等: "盐酸达泊西汀的合成 ", 《中国现代应用药学》 * |
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Application publication date: 20180529 |