CN101265201B - Method for synthesizing tramadol hydrochloride - Google Patents
Method for synthesizing tramadol hydrochloride Download PDFInfo
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- CN101265201B CN101265201B CN2008100607343A CN200810060734A CN101265201B CN 101265201 B CN101265201 B CN 101265201B CN 2008100607343 A CN2008100607343 A CN 2008100607343A CN 200810060734 A CN200810060734 A CN 200810060734A CN 101265201 B CN101265201 B CN 101265201B
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- tramadol hydrochloride
- dimethyl aminomethyl
- pimelinketone
- methyltetrahydrofuran
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- 229960003107 tramadol hydrochloride Drugs 0.000 title claims abstract description 50
- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 title claims abstract description 38
- 230000002194 synthesizing effect Effects 0.000 title 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims abstract description 81
- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 39
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 35
- 239000002904 solvent Substances 0.000 claims abstract description 29
- 239000012043 crude product Substances 0.000 claims abstract description 22
- 230000001476 alcoholic effect Effects 0.000 claims abstract description 9
- QARVLSVVCXYDNA-UHFFFAOYSA-N phenyl bromide Natural products BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 23
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000010189 synthetic method Methods 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000009413 insulation Methods 0.000 claims description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 238000001953 recrystallisation Methods 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 239000007789 gas Substances 0.000 claims description 8
- 230000000977 initiatory effect Effects 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 5
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 4
- -1 Grignard reagent m-methoxyphenyl magnesium bromide Chemical class 0.000 claims description 4
- 238000003747 Grignard reaction Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000000047 product Substances 0.000 abstract description 5
- 238000001308 synthesis method Methods 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 3
- QDHLEFBSGUGHCL-UHFFFAOYSA-N 2-[(dimethylamino)methyl]cyclohexan-1-one Chemical compound CN(C)CC1CCCCC1=O QDHLEFBSGUGHCL-UHFFFAOYSA-N 0.000 abstract 1
- 238000003912 environmental pollution Methods 0.000 abstract 1
- FKUUDDGRDRPAQQ-UHFFFAOYSA-M magnesium;methoxybenzene;bromide Chemical group [Mg+2].[Br-].COC1=CC=C[C-]=C1 FKUUDDGRDRPAQQ-UHFFFAOYSA-M 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 230000035484 reaction time Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical class O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
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. 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 described Grignard reagent of step (2) (II) and the hybrid mode of 2-dimethyl aminomethyl pimelinketone (III) are: 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: add saturated NH under the ice bath
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.
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Non-Patent Citations (4)
| Title |
|---|
| David F. Aycock.Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions.Organic Process Research & Development.2007,11(1),156-159. |
| David F. Aycock.Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions.Organic Process Research & * |
| Development.2007,11(1),156-159. * |
| 张锁庆 等.盐酸曲马多的合成.河北化工.2005,(05),第36、78页. * |
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