CN101265201A - Method for synthesizing tramadol hydrochloride - Google Patents
Method for synthesizing tramadol hydrochloride Download PDFInfo
- Publication number
- CN101265201A CN101265201A CNA2008100607343A CN200810060734A CN101265201A CN 101265201 A CN101265201 A CN 101265201A CN A2008100607343 A CNA2008100607343 A CN A2008100607343A CN 200810060734 A CN200810060734 A CN 200810060734A CN 101265201 A CN101265201 A CN 101265201A
- Authority
- CN
- China
- Prior art keywords
- tramadol hydrochloride
- dimethyl aminomethyl
- pimelinketone
- methyltetrahydrofuran
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of tramadol hydrochloride. The synthesis method comprises the steps as follow: Grignard reagent that is m-methoxy phenyl magnesium bromide is manufactured in 2-methyltetrahydrofuran that is green solvent, then the Grignard reagent reacts with 2-dimethylamino methyl cyclohexanone to obtain crude products which are salified in hydrochloric alcoholic solution, so as to manufacture the tramadol hydrochloride. Compared with the traditional technology, the synthesis method has the advantages that the 2-methyltetrahydrofuran that is green solvent is adopted in the Grignard reaction, the reaction yield rate is higher, products are easy to separate and purify, the solvent consumption is less and easy to be recycled and reused, the environmental pollution is small, and the synthesis method is suitable for industrialized production.
Description
(1) technical field
The present invention relates to a kind of synthetic method of tramadol hydrochloride, belong to field of medicine and chemical technology.
(2) background technology
Tramadol hydrochloride (Tramadol Hydrochloride, I), chemistry (±)-(E)-2-(dimethylamino) methyl isophthalic acid by name-(3-p-methoxy-phenyl) hexalin hydrochloride, by the research and development of German Gruenenthal company, from 1977 since Germany listing, obtained clinical application widely.Tramadol hydrochloride is a kind of non-morphine class central analgesics, belongs to part opiate receptor excitomotor.Analgesia effect and Pethidine are suitable, are 1/10～1/6 of morphine.
The document synthetic method of tramadol hydrochloride mainly is: preparation Grignard reagent---m-methoxyphenyl magnesium bromide in ether or tetrahydrofuran (THF) (THF), with the reaction of 2-dimethyl aminomethyl pimelinketone, gained intermediate product salify in the alcoholic solution of hydrogenchloride promptly gets (US3830934, US2005215821, US2003065221 and WO9961405 etc.) again.Because the ether boiling point is low, very easily fire explosively, and anesthetic action is arranged, dangerous big, be unsuitable for suitability for industrialized production; Tetrahydrofuran (THF) is because miscible with water, must add another kind of solvent in the aftertreatment such as toluene extracts product, causes difficult solvent recovery, and usually causes the layering difficulty owing to emulsion; In addition, also blast easily, thereby cause the post-reaction treatment trouble, increased production cost simultaneously because of generating superoxide.Therefore, be used for the focus that grignard reaction is research always with a kind of safety, environmental protection, energy-conservation, economic alternative ether of green solvent or THF.
(3) summary of the invention
The technical problem to be solved in the present invention is the defective at prior art, and a kind of green synthesis method of tramadol hydrochloride is provided.
The technical solution used in the present invention is as follows:
A kind of synthetic method suc as formula the tramadol hydrochloride shown in (I) comprises the steps:
(1) meta-methoxy bromobenzene and MAGNESIUM METAL make in 2-methyltetrahydrofuran (2-MeTHF) suc as formula the Grignard reagent m-methoxyphenyl magnesium bromide shown in (II);
(2) Grignard reagent that obtains (II) with suc as formula the 2-dimethyl aminomethyl pimelinketone shown in (III) in the 2-methyltetrahydrofuran in 0～60 ℃ of insulation reaction 0.5～12 hour, must be through aftertreatment suc as formula the 1-m-methoxyphenyl shown in (IV)-2-dimethyl aminomethyl hexalin;
(3) with under 1-m-methoxyphenyl-2-dimethyl aminomethyl hexalin (IV) condition of ice bath in the alcoholic solution of hydrogenchloride salify get salt love song Thomas crude product, salt love song Thomas crude product promptly gets tramadol hydrochloride (I) behind recrystallization.
Its chemical equation is:
The amount of substance that feeds intake of the present invention is than 2-dimethyl aminomethyl pimelinketone: the meta-methoxy bromobenzene: MAGNESIUM METAL is 1.0: 1.0～1.5: 1.0～1.6.
Further, described step (1) preparation Grignard reagent m-methoxyphenyl magnesium bromide can adopt following steps: N
2Protection down; in reaction flask, add magnesium rod and 2-MeTHF; add a spot of 1; 2-ethylene dibromide or the initiation reaction of iodine grain; at 0～80 ℃ of 2-MeTHF solution that slowly drips the meta-methoxy bromobenzene down; dripped complete insulation reaction 0.5～12 hour, and made Grignard reagent (II), the total mass of the 2-methyltetrahydrofuran that the preparation Grignard reagent is used is 1.5～4.0 times of 2-dimethyl aminomethyl pimelinketone quality.So-called " total mass " is meant amount that adds reaction flask 2-MeTHF and the summation of measuring in order to the 2-MeTHF that dissolves the meta-methoxy bromobenzene.
The hybrid mode of the described Grignard reagent of step (2) (II) and 2-dimethyl aminomethyl pimelinketone (III) is: the 2-MeTHF solution of 2-dimethyl aminomethyl pimelinketone (III) splashed into step (1) reaction under 0～60 ℃ and finish in the grignard reagent solution that obtains; Perhaps under 0～60 ℃ step (1) being reacted the grignard reagent solution that obtains that finishes splashes in the 2-MeTHF solution of 2-dimethyl aminomethyl pimelinketone (III).It in order to the 2-MeTHF quality of dissolving 2-dimethyl aminomethyl pimelinketone 0.5～3.0 times of 2-dimethyl aminomethyl pimelinketone quality.
The described aftertreatment of step (2) is: ice bath adds saturated NH down
4Cl solution termination reaction, the organic layer anhydrous Na of telling
2SO
4Drying, reclaim under reduced pressure 2-MeTHF, residue are 1-m-methoxyphenyl-2-dimethyl aminomethyl hexalin (IV).
Above-mentioned steps (3) preparation tramadol hydrochloride crude product can adopt following steps: 1-m-methoxyphenyl-2-dimethyl aminomethyl hexalin (IV) is dissolved in the alcoholic solvent, slowly feeds the exsiccant hydrogen chloride gas under the ice bath, and stirred crystallization, suction filtration gets the tramadol hydrochloride crude product.It is one of following that described alcohol can be selected for use: methyl alcohol, ethanol, Virahol.
It can be one of following that salt love song Thomas crude product carries out recrystallization solvent that recrystallization selects for use: acetone, acetonitrile, Virahol.
The concrete synthetic method of described tramadol hydrochloride of recommending is carried out according to following steps:
(1) N
2Protection adds magnesium rod and 2-MeTHF down in reaction flask, add a spot of glycol dibromide or the initiation reaction of iodine grain, at 0～80 ℃ of 2-MeTHF solution that slowly drips the meta-methoxy bromobenzene down, drips complete insulation reaction 0.5～12 hour, obtains grignard reagent solution;
(2) under 0～60 ℃, the 2-MeTHF solution of 2-dimethyl aminomethyl pimelinketone (III) splashed in the grignard reagent solution that step (1) makes; Perhaps the grignard reagent solution that under 0～60 ℃ step (1) is made splashes in the 2-MeTHF solution of 2-dimethyl aminomethyl pimelinketone (III), drips complete insulation reaction 0.5～12 hour, and ice bath adds saturated NH down
4Cl solution termination reaction, the organic layer anhydrous Na of telling
2SO
4Drying, reclaim under reduced pressure 2-MeTHF, residue are 1-m-methoxyphenyl-2-dimethyl aminomethyl hexalin (IV);
(3) the 1-m-methoxyphenyl that step (2) is made-2-dimethyl aminomethyl hexalin (IV) is dissolved in the alcoholic solvent, slowly feed the exsiccant hydrogen chloride gas under the ice bath, stirred crystallization, suction filtration get the tramadol hydrochloride crude product, and crude product obtains salt love song Thomas (I) through recrystallization.
Innovation part of the present invention is with the solvent of green solvent 2-methyltetrahydrofuran (2-MeTHF) as grignard reaction.Compare with traditional solvent THF, 2-MeTHF has following advantage:
1) 2-MeTHF solubleness in water is less, easily and product separation and help the recovery of solvent;
2) the 2-MeTHF boiling point is higher, can carry out grignard reaction under higher temperature, shorten the reaction times, and solvent loss is less in the reaction process;
3) can form azeotrope with water, thereby can dewater intermediate or product;
4) be difficult for forming emulsification, help layering;
5) magnesium bromide is a lot of greatly than THF in 2-MeTHF solubleness, can prepare the high density Grignard reagent, thereby has reduced the consumption of solvent;
6) compare with THF, 2-MeTHF is difficult for forming superoxide.
In sum, beneficial effect of the present invention is embodied in: adopt green solvent 2-MeTHF in grignard reaction, reaction yield is higher, the easily separated purification of product, and solvent load is few and easy to recovery of applied, and is low in the pollution of the environment, is suitable for suitability for industrialized production.
(4) embodiment:
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
Embodiment 1
The amount of substance that feeds intake ratio is 2-dimethyl aminomethyl pimelinketone: the meta-methoxy bromobenzene: MAGNESIUM METAL is 1.0: 1.0: 1.0, the dropwise reaction mode is under 0 ℃ in the 2-MeTHF drips of solution Ru Geshi reagent solution with 2-dimethyl aminomethyl pimelinketone (III), and solvent is 2-MeTHF.
In reaction flask, add magnesium rod (2.4g, 0.1mol) and 2-MeTHF (8.6g, 10mL), N
2Protection down adds an amount of glycol dibromide initiation reaction, and (18.6g, (30.15g, 35mL), 80 ℃ of following stirring reactions 2 hours make Grignard reagent (II) to 2-MeTHF solution 0.1mol) slowly to drip the meta-methoxy bromobenzene.Be cooled to 0 ℃, (15.5g, (23.25g 27mL) slowly splashes in the above-mentioned reaction flask 2-MeTHF solution 0.1mol), drips complete insulation reaction 4 hours with 2-dimethyl aminomethyl pimelinketone.Use saturated NH
4Cl cancellation reaction, the organic layer anhydrous Na of telling
2SO
4Drying, reclaim under reduced pressure 2-MeTHF, residue are 1-m-methoxyphenyl-2-dimethyl aminomethyl hexalin (IV) crude product.Above-mentioned (IV) is dissolved in the 20mL methyl alcohol, slowly feeds the exsiccant hydrogen chloride gas under the ice bath, stirred crystallization, suction filtration gets the tramadol hydrochloride crude product, uses acetone recrystallization again, promptly gets tramadol hydrochloride (I) 22.2g, and yield is 74.2%.HPLC detects: contain (E)-tramadol hydrochloride 99.1%, (Z)-tramadol hydrochloride 0.4%.
Embodiment 2
The amount of substance that feeds intake ratio is 2-dimethyl aminomethyl pimelinketone: the meta-methoxy bromobenzene: MAGNESIUM METAL is 1.0: 1.5: 1.6, the dropwise reaction mode is under 0 ℃ in the 2-MeTHF drips of solution Ru Geshi reagent solution with 2-dimethyl aminomethyl pimelinketone (III), and solvent is 2-MeTHF.
In reaction flask, add magnesium rod (3.84g, 0.16mol) and 2-MeTHF (8.6g, 10mL), N
2Protection down adds an amount of glycol dibromide initiation reaction, and (27.9g, (30.15g, 35mL), 80 ℃ of following stirring reactions 2 hours make Grignard reagent (II) to 2-MeTHF solution 0.15mol) slowly to drip the meta-methoxy bromobenzene.Be cooled to 0 ℃, (15.5g, (23.25g 27mL) slowly splashes in the above-mentioned reaction flask 2-MeTHF solution 0.1mol), drips complete insulation reaction 4 hours with 2-dimethyl aminomethyl pimelinketone.Use saturated NH
4Cl cancellation reaction, reclaim under reduced pressure 2-MeTHF, residue are 1-m-methoxyphenyl-2-dimethyl aminomethyl hexalin (IV) crude product.Above-mentioned (IV) is dissolved in the 20mL methyl alcohol, slowly feeds the exsiccant hydrogen chloride gas under the ice bath, stirred crystallization, suction filtration gets the tramadol hydrochloride crude product, uses the acetonitrile recrystallization again, promptly gets tramadol hydrochloride (I) 25.4g, and yield is 84.9%.HPLC detects: contain (E)-tramadol hydrochloride 99.2%, (Z)-tramadol hydrochloride 0.4%.
Embodiment 3
The amount of substance that feeds intake ratio is 2-dimethyl aminomethyl pimelinketone: the meta-methoxy bromobenzene: MAGNESIUM METAL is 1.0: 1.2: 1.2, the dropwise reaction mode is under 0 ℃ in the 2-MeTHF drips of solution Ru Geshi reagent solution with 2-dimethyl aminomethyl pimelinketone (III), and solvent is 2-MeTHF.
In reaction flask, add magnesium rod (2.88g, 0.12mol), 2-MeTHF (8.6g, 10mL), N
2Protection down adds an amount of iodine initiation reaction, and (22.32g, (30.15g, 35mL), 80 ℃ of following stirring reactions 2 hours make Grignard reagent (II) to 2-MeTHF solution 0.12mol) slowly to drip the meta-methoxy bromobenzene.(15.51g, (23.25g 27mL) slowly splashes in the above-mentioned reaction flask 2-MeTHF solution 0.1mol), drips complete insulation reaction 4 hours with 2-dimethyl aminomethyl pimelinketone under 0 ℃.Use saturated NH
4Cl cancellation reaction, the 2-MeTHF layer anhydrous Na of telling
2SO
4Drying, reclaim under reduced pressure 2-MeTHF, residue are 1-m-methoxyphenyl-2-dimethyl aminomethyl hexalin (IV) crude product.Above-mentioned (IV) is dissolved in the 20mL methyl alcohol, slowly feeds the exsiccant hydrogen chloride gas under the ice bath, stirred crystallization, suction filtration gets the tramadol hydrochloride crude product, uses the Virahol recrystallization again, promptly gets tramadol hydrochloride (I) 24.4g, and yield is 81.4%.HPLC detects: contain (E)-tramadol hydrochloride 99.1%, (Z)-tramadol hydrochloride 0.4%.
Embodiment 4
The amount of substance that feeds intake ratio is 2-dimethyl aminomethyl pimelinketone: the meta-methoxy bromobenzene: MAGNESIUM METAL is 1.0: 1.2: 1.3, the dropwise reaction mode is under 0 ℃ in the 2-MeTHF drips of solution Ru Geshi reagent solution with 2-dimethyl aminomethyl pimelinketone (III), and solvent is 2-MeTHF.
In reaction flask, add magnesium rod (3.12g, 0.13mol), 2-MeTHF (8.6g, 10mL), N
2Protection down adds an amount of iodine initiation reaction, and (22.32g, (30.15g, 35mL), 80 ℃ of following stirring reactions 2 hours make Grignard reagent (II) to 2-MeTHF solution 0.12mol) slowly to drip the meta-methoxy bromobenzene.(15.51g, (23.25g 27mL) slowly splashes in the above-mentioned reaction flask 2-MeTHF solution 0.1mol), drips complete insulation reaction 4 hours with 2-dimethyl aminomethyl pimelinketone under 0 ℃.Use saturated NH
4Cl cancellation reaction, the 2-MeTHF layer anhydrous Na of telling
2SO
4Drying, reclaim under reduced pressure 2-MeTHF, residue are 1-m-methoxyphenyl-2-dimethyl aminomethyl hexalin (IV) crude product.Above-mentioned (IV) is dissolved in the 20mL methyl alcohol, slowly feeds the exsiccant hydrogen chloride gas under the ice bath, stirred crystallization, suction filtration gets the tramadol hydrochloride crude product, uses the Virahol recrystallization again, promptly gets tramadol hydrochloride (I) 25.6g, and yield is 85.6%.HPLC detects: contain (E)-tramadol hydrochloride isomer 99.3%, (Z)-tramadol hydrochloride isomer 0.4%.
Embodiment 5
The amount of substance that feeds intake ratio is 2-dimethyl aminomethyl pimelinketone: the meta-methoxy bromobenzene: MAGNESIUM METAL is 1.0: 1.2: 1.3, the temperature of reaction of preparation Grignard reagent is 0 ℃, reaction times is 12 hours, the dropwise reaction mode is under 0 ℃ in the 2-MeTHF drips of solution Ru Geshi reagent solution with 2-dimethyl aminomethyl pimelinketone (III), reaction times is 12 hours, react other operations with embodiment 4, yield 79.6%, HPLC detects: contain (E)-tramadol hydrochloride 99.1%, (Z)-tramadol hydrochloride 0.5%.
Embodiment 6
The amount of substance that feeds intake ratio is 2-dimethyl aminomethyl pimelinketone: the meta-methoxy bromobenzene: MAGNESIUM METAL is 1.0: 1.2: 1.3, the temperature of reaction of preparation Grignard reagent is 80 ℃, reaction times is 0.5 hour, the dropwise reaction mode is under 60 ℃ in the 2-MeTHF drips of solution Ru Geshi reagent solution with 2-dimethyl aminomethyl pimelinketone (III), reaction times is 0.5 hour, react other operations with embodiment 4, yield 78.7%, HPLC detects: contain (E)-tramadol hydrochloride 99.0%, (Z)-tramadol hydrochloride 0.5%.
Embodiment 7
The amount of substance that feeds intake ratio is 2-dimethyl aminomethyl pimelinketone: the meta-methoxy bromobenzene: MAGNESIUM METAL is 1.0: 1.2: 1.3, the dropwise reaction mode is for to splash into grignard reagent solution in the 2-MeTHF solution of 2-dimethyl aminomethyl pimelinketone (III) under 0 ℃, react other operations with embodiment 4, yield 82.4%, HPLC detects: contain (E)-tramadol hydrochloride isomer 99.2%, (Z)-tramadol hydrochloride isomer 0.4%.
Embodiment 8
The amount of substance that feeds intake ratio is 2-dimethyl aminomethyl pimelinketone: the meta-methoxy bromobenzene: MAGNESIUM METAL is 1.0: 1.2: 1.3, solvent is 2-MeTHF, wherein preparing the used 2-MeTHF quality of Grignard reagent and be 4 times of 2-dimethyl aminomethyl pimelinketone quality, is 3 times of 2-dimethyl aminomethyl pimelinketone quality in order to the 2-MeTHF quality of dissolving 2-dimethyl aminomethyl pimelinketone.The temperature of reaction of preparation Grignard reagent is 30 ℃ in the step (I), and the reaction times is 6 hours; The dropwise reaction mode was reacted 2 hours under 30 ℃ grignard reagent solution is splashed in the 2-MeTHF solution of 2-dimethyl aminomethyl pimelinketone (III) in the step (II).React other operations with embodiment 4, yield 84.5%, HPLC detects: contain (E)-tramadol hydrochloride isomer 99.1%, (Z)-tramadol hydrochloride isomer 0.4%.
Embodiment 9
The amount of substance that feeds intake ratio is 2-dimethyl aminomethyl pimelinketone: the meta-methoxy bromobenzene: MAGNESIUM METAL is 1.0: 1.2: 1.3, solvent is 2-MeTHF, wherein preparing the used 2-MeTHF quality of Grignard reagent and be 1.5 times of 2-dimethyl aminomethyl pimelinketone quality, is 0.5 times of 2-dimethyl aminomethyl pimelinketone quality in order to the 2-MeTHF quality of dissolving 2-dimethyl aminomethyl pimelinketone.The temperature of reaction of preparation Grignard reagent is 60 ℃ in the step (I), and the reaction times is 3 hours; The dropwise reaction mode was reacted 3 hours under 20 ℃ grignard reagent solution is splashed in the 2-MeTHF solution of 2-dimethyl aminomethyl pimelinketone (III) in the step (II).The used solvent of salt-forming reaction is an ethanol, reacts other operations with embodiment 4, yield 83.7%, and HPLC detects: contain (E)-tramadol hydrochloride 99.0%, (Z)-tramadol hydrochloride 0.5%.
Embodiment 10
The amount of substance that feeds intake ratio is 2-dimethyl aminomethyl pimelinketone: the meta-methoxy bromobenzene: MAGNESIUM METAL is 1.0: 1.2: 1.3, solvent is 2-MeTHF, wherein prepare the used 2-MeTHF quality of Grignard reagent and be 2.5 times of 2-dimethyl aminomethyl pimelinketone quality, in order to the 2-MeTHF quality of dissolving 2-dimethyl aminomethyl pimelinketone 1.5 times of 2-dimethyl aminomethyl pimelinketone quality, used alcoholic solvent is a Virahol, react other operations with embodiment 4, yield 86.1%, HPLC detects: contain (E)-tramadol hydrochloride isomer 99.4%, (Z)-tramadol hydrochloride isomer 0.3%.
Claims (10)
1, a kind of synthetic method suc as formula the tramadol hydrochloride shown in (I) is characterized in that described synthetic method is:
(1) meta-methoxy bromobenzene and MAGNESIUM METAL make in the 2-methyltetrahydrofuran suc as formula the Grignard reagent m-methoxyphenyl magnesium bromide shown in (II);
(2) Grignard reagent that obtains (II) with suc as formula the 2-dimethyl aminomethyl pimelinketone shown in (III) in the 2-methyltetrahydrofuran in 0～60 ℃ of insulation reaction 0.5～12 hour, must be through aftertreatment suc as formula the 1-m-methoxyphenyl shown in (IV)-2-dimethyl aminomethyl hexalin;
(3) with under 1-m-methoxyphenyl-2-dimethyl aminomethyl hexalin (IV) condition of ice bath in the alcoholic solution of hydrogenchloride salify get salt love song Thomas crude product, salt love song Thomas crude product promptly gets tramadol hydrochloride (I) behind recrystallization;
2, the synthetic method of tramadol hydrochloride as claimed in claim 1, it is characterized in that the described amount of substance that feeds intake is than 2-dimethyl aminomethyl pimelinketone: the meta-methoxy bromobenzene: MAGNESIUM METAL is 1.0: 1.0～1.5: 1.0～1.6.
3, the synthetic method of tramadol hydrochloride as claimed in claim 1 or 2 is characterized in that the step of described step (1) preparation Grignard reagent m-methoxyphenyl magnesium bromide is: N
2Protection down; in reaction flask, add magnesium rod and 2-methyltetrahydrofuran; add a spot of 1; 2-ethylene dibromide or the initiation reaction of iodine grain; at 0～80 ℃ of 2-methyltetrahydrofuran solution that slowly drips the meta-methoxy bromobenzene down; dripped complete insulation reaction 0.5～12 hour, and made Grignard reagent (II), the described 2-methyltetrahydrofuran total mass of using in preparation Grignard reagent (II) is 1.5～4.0 times of 2-dimethyl aminomethyl pimelinketone quality.
4, the synthetic method of tramadol hydrochloride as claimed in claim 1 or 2 is characterized in that the hybrid mode of the described Grignard reagent of step (2) (II) and 2-dimethyl aminomethyl pimelinketone (III) is: the 2-methyltetrahydrofuran solution of 2-dimethyl aminomethyl pimelinketone (III) splashed into step (1) reaction under 0～60 ℃ and finish in the grignard reagent solution that obtains; Perhaps under 0～60 ℃ step (1) being reacted the grignard reagent solution that obtains that finishes splashes in the 2-methyltetrahydrofuran solution of 2-dimethyl aminomethyl pimelinketone (III).
5, the synthetic method of tramadol hydrochloride as claimed in claim 4 is characterized in that 2-methyltetrahydrofuran quality in order to dissolving 2-dimethyl aminomethyl pimelinketone is 0.5～3.0 times of 2-dimethyl aminomethyl pimelinketone quality.
6, the synthetic method of tramadol hydrochloride as claimed in claim 1 or 2 is characterized in that the described aftertreatment of step (2) is: ice bath adds saturated NH down
4Cl solution termination reaction, the organic layer anhydrous Na of telling
2SO
4Drying, reclaim under reduced pressure 2-methyltetrahydrofuran, residue are 1-m-methoxyphenyl-2-dimethyl aminomethyl hexalin (IV).
7, the synthetic method of tramadol hydrochloride as claimed in claim 1 or 2, the step that it is characterized in that described step (3) preparation tramadol hydrochloride crude product is: 1-m-methoxyphenyl-2-dimethyl aminomethyl hexalin (IV) is dissolved in the alcoholic solvent, slowly feed the exsiccant hydrogen chloride gas under the ice bath, stirred crystallization, suction filtration get the tramadol hydrochloride crude product.
8, the synthetic method of tramadol hydrochloride as claimed in claim 1 or 2 is characterized in that the described alcohol of step (3) is one of following: methyl alcohol, ethanol, Virahol.
9, the synthetic method of tramadol hydrochloride as claimed in claim 1 or 2 is characterized in that the described recrystallization solvent of step (3) is one of following: acetone, acetonitrile, Virahol.
10, the synthetic method of tramadol hydrochloride as claimed in claim 1 is characterized in that described synthetic method carries out according to following steps:
(1) N
2Protection adds magnesium rod and 2-methyltetrahydrofuran down in reaction flask, add a spot of 1,2-ethylene dibromide or the initiation reaction of iodine grain, at 0～80 ℃ of 2-methyltetrahydrofuran solution that slowly drips the meta-methoxy bromobenzene down, dripped complete insulation reaction 0.5～12 hour, obtain grignard reagent solution;
(2) under 0～60 ℃, the 2-methyltetrahydrofuran solution of 2-dimethyl aminomethyl pimelinketone (III) splashed in the grignard reagent solution that step (1) makes; Perhaps the grignard reagent solution that under 0～60 ℃ step (1) is made splashes in the 2-methyltetrahydrofuran solution of 2-dimethyl aminomethyl pimelinketone (III), drips complete insulation reaction 0.5～12 hour, and ice bath adds saturated NH down
4Cl solution termination reaction, the organic layer anhydrous Na of telling
2SO
4Drying, reclaim under reduced pressure 2-methyltetrahydrofuran, residue are 1-m-methoxyphenyl-2-dimethyl aminomethyl hexalin (IV);
(3) the 1-m-methoxyphenyl that step (2) is made-2-dimethyl aminomethyl hexalin (IV) is dissolved in the alcoholic solvent, slowly feed the exsiccant hydrogen chloride gas under the ice bath, stirred crystallization, suction filtration get the tramadol hydrochloride crude product, and crude product obtains salt love song Thomas (I) through recrystallization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100607343A CN101265201B (en) | 2008-04-16 | 2008-04-16 | Method for synthesizing tramadol hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100607343A CN101265201B (en) | 2008-04-16 | 2008-04-16 | Method for synthesizing tramadol hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101265201A true CN101265201A (en) | 2008-09-17 |
| CN101265201B CN101265201B (en) | 2011-11-23 |
Family
ID=39987920
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008100607343A Active CN101265201B (en) | 2008-04-16 | 2008-04-16 | Method for synthesizing tramadol hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101265201B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104211559A (en) * | 2014-09-18 | 2014-12-17 | 哈尔滨工业大学（威海） | Preparation method of tetramethylbiphenyl isomers |
-
2008
- 2008-04-16 CN CN2008100607343A patent/CN101265201B/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104211559A (en) * | 2014-09-18 | 2014-12-17 | 哈尔滨工业大学（威海） | Preparation method of tetramethylbiphenyl isomers |
| CN104211559B (en) * | 2014-09-18 | 2016-08-24 | 哈尔滨工业大学（威海） | A kind of preparation method of tetramethyl biphenyl isomer |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101265201B (en) | 2011-11-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106279074B (en) | A kind of compound and preparation method thereof and the purposes in Bu Waxitan is synthesized | |
| CN101654445B (en) | Compound for preparing ramelteon, preparation method thereof and application thereof | |
| CN104130188B (en) | The preparation method of 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzazepine | |
| CN101671352A (en) | Method for preparing fluoride-bearing phenyloboric acid | |
| CN113896674B (en) | Synthesis method of apremilast | |
| CN105646285B (en) | One kind dimension Lactel sieve intermediate and its preparation method and application | |
| CN105566368A (en) | Synthesis method of N-substituted piperidine-4-borate | |
| CN103804232B (en) | A kind of 1-cyano group-1-(7-methoxyl-3,4-dihydro-1-naphthyl) methanol esters compounds and its preparation method and application | |
| CN101265201B (en) | Method for synthesizing tramadol hydrochloride | |
| CN102875340B (en) | Sarpogrelate intermediate and preparation method thereof | |
| CN107602399A (en) | A kind of preparation method of enkephalinase inhibitor intermediate | |
| CN103923058B (en) | A kind of method synthesizing Wei Lanteluo intermediate and salt thereof | |
| CN114031505B (en) | Method for preparing pentazocine intermediate | |
| CN102050748B (en) | Method for preparing expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol | |
| CN101973897B (en) | Synthesis method of valdoxan intermediate 2-(7-methoxy-1-naphthyl)ethylamine | |
| CN103183680A (en) | Method for preparing asenapine | |
| WO2017177715A1 (en) | Method for preparing chiral ferrocene p, p ligand | |
| CN103787921B (en) | A kind of method preparing trans 1, the 2-ring diamines of high-optical-purity | |
| US20100152489A1 (en) | New phosphine-borane compound and method for producing the same, and method for producing hydrogen-phosphine-borane compound | |
| CN102321045A (en) | Method for preparing high morphine hydrochloride | |
| CN102336676A (en) | New preparation method of dopexamine hydrochloride by ArCHR protection strategy | |
| CN100451025C (en) | Cobaltocene cation monophosphine ligand and its synthesis and uses | |
| TW200405809A (en) | Process for preparing (S)-(+)-2-(substituted phenyl)-2-hydroxy-ethyl carbamates | |
| CN102746182B (en) | Preparation method of Aliskiren | |
| CN102617528B (en) | Tricyclic acetate compound with optical activity, and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170828 Address after: 407, room 5, No. 999, Lane 315040, sailing Road, hi tech Zone, Zhejiang, Ningbo Patentee after: Ningbo Da Da Technical Service Co., Ltd. Address before: City Zhejiang University of Technology Hangzhou Zhaohui six districts of 310014 cities in Zhejiang Province under the Patentee before: Zhejiang University of Technology |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170913 Address after: 154007 Anqing street, Dongfeng District, Heilongjiang, China, No. 477, No. Patentee after: Duoduo Pharmaceutical Co., Ltd. Address before: 407, room 5, No. 999, Lane 315040, sailing Road, hi tech Zone, Zhejiang, Ningbo Patentee before: Ningbo Da Da Technical Service Co., Ltd. |