CN102408346B - Preparation method of 4,5-dimethoxy-1-(methyl amino-methyl)-benzo-cyclobutane - Google Patents
Preparation method of 4,5-dimethoxy-1-(methyl amino-methyl)-benzo-cyclobutane Download PDFInfo
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- CN102408346B CN102408346B CN201110338196.1A CN201110338196A CN102408346B CN 102408346 B CN102408346 B CN 102408346B CN 201110338196 A CN201110338196 A CN 201110338196A CN 102408346 B CN102408346 B CN 102408346B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- SAVVFXUMMFHSJC-UHFFFAOYSA-N 1-(3,4-dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl)-n-methylmethanamine Chemical compound COC1=C(OC)C=C2C(CNC)CC2=C1 SAVVFXUMMFHSJC-UHFFFAOYSA-N 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000006722 reduction reaction Methods 0.000 claims abstract description 12
- 150000001412 amines Chemical class 0.000 claims abstract description 11
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 239000002262 Schiff base Substances 0.000 claims abstract description 5
- 150000004753 Schiff bases Chemical class 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N methyl alcohol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- 229940117975 chromium trioxide Drugs 0.000 claims description 7
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 7
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical group [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical group [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- LOLYILQTXGVBCK-UHFFFAOYSA-N 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbaldehyde Chemical compound C1=C(OC)C(OC)=CC2=C1C(C=O)C2 LOLYILQTXGVBCK-UHFFFAOYSA-N 0.000 abstract 2
- HXFIWZVHHAVKPV-UHFFFAOYSA-N (3,4-dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl)methanol Chemical compound C1=C(OC)C(OC)=CC2=C1C(CO)C2 HXFIWZVHHAVKPV-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 6
- ACRHBAYQBXXRTO-OAQYLSRUSA-N ivabradine Chemical compound C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 ACRHBAYQBXXRTO-OAQYLSRUSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229960003825 ivabradine Drugs 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- -1 100 milliliters Substances 0.000 description 2
- 0 COc1cc(CC2*)c2cc1OC Chemical compound COc1cc(CC2*)c2cc1OC 0.000 description 2
- 208000007718 Stable Angina Diseases 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- KUICPJYUIRXGJT-WUXMJOGZSA-N C/N=C/C(Cc1c2)c1cc(O)c2OC Chemical compound C/N=C/C(Cc1c2)c1cc(O)c2OC KUICPJYUIRXGJT-WUXMJOGZSA-N 0.000 description 1
- 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 1
- 239000003810 Jones reagent Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000001013 sinoatrial node Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 4,5-dimethoxy-1-(methyl amino-methyl)-benzo-cyclobutane. The preparation method comprises the following steps of: taking 4,5-dimethoxy benzo-cyclobutane-1-methanol as a raw material to synthesize 4,5-dimethoxy benzo-cyclobutane-1-formaldehyde through an oxidation reaction; allowing the 4,5-dimethoxy benzo-cyclobutane-1-formaldehyde to react with amine so as to generate Schiff base; and finally obtaining the 4,5-dimethoxy-1-(methyl amino-methyl)-benzo-cyclobutane through a reduction reaction. The preparation method has the advantages of mild reaction conditions, lower cost and higher yield, thus being applicable to large-scale industrial production.
Description
Technical field
The present invention relates to a kind of important intermediate 4 of ivabradine, the preparation method of 5-dimethoxy-1-(methylamino methyl)-benzocyclobutane, belongs to field of medicine and chemical technology.
Background technology
Hydrochloric acid Ivabradine, first sinus node If electric current that is the exploitation of French Shi Weiya company is selected specific inhibitor, the effect that it slows down merely heart rate is the most important progress of stable angina pectoris medicine in recent years, is used for the treatment of with normal sinus rhythm, to beta-blockers taboo or not tolerant chronic stable angina pectoris.This medicine is in the listing of multiple countries.Structural formula is shown in following formula (I)
Its base S 16257-2 can be obtained by following formula:
Route 1
Wherein, 4,5-dimethoxy-1-(methylamino methyl)-benzocyclobutane is the important intermediate of synthesis of ivabradine, and its structural formula is as shown in the formula (II)
In recent years, this intermediate receives increasing concern, also has the report of synthetic this compound of multiple route both at home and abroad: as EP0534859 discloses cyano group-4 with 1-, 5-dimethoxy benzo tetramethylene is raw material, prepares the method for II, and its main route is as follows:
Route 2
CN101671265 discloses cyano group-4 with 1-, and 5-dimethoxy benzo tetramethylene is raw material, through oxidation, and amidation, reduction obtains, and main route is as follows:
Route 3
CN101857549 discloses cyano group-4 with 1-, and 5-dimethoxy benzo tetramethylene is raw material, and through hydrolysis, reduction, sulfonylation, hydrocarbonylation, deprotection, prepare the method for II, and its main route is as follows:
Route 4
In above-mentioned several routes, reaction conditions is comparatively harsh, and aftertreatment difficulty, causes total recovery not high, and the yield of route 2 is lower than 10%, and the yield that route 3 is reported is at 20-25%, and the disclosed yield of route 4 is 42%, is all not suitable for the needs of scale operation.
Summary of the invention
The object of the invention is on the basis of existing technology, a kind of new preparation 4 is provided, the method for 5-dimethoxy-1-(methylamino methyl)-benzocyclobutane.
Object of the present invention can reach by following measures:
A kind of 4, the preparation method of 5-dimethoxy-1-(methylamino methyl)-benzocyclobutane, it is with 4,5-dimethoxy benzo tetramethylene-1-methyl alcohol is that raw material is through oxidizing reaction synthetic 4,5-dimethoxy benzo tetramethylene-1-formaldehyde, react with amine and generate schiff bases, finally make by reduction reaction, its reaction scheme is:
In the present invention, compound 5-1 is oxidized and obtains target compound 5-2, its method can adopt the oxidations such as potassium bichromate, potassium permanganate, chromium trioxide, Manganse Dioxide, preferably adopts chromium trioxide oxidation.The solvent of oxidizing reaction is selected from one or more in the third change ketone, tetrahydrofuran (THF), water, and preferably acetone and water is as mixed solvent, most preferably the volume ratio 1: 1 of acetone and water.
A kind of preferred concrete reaction conditions is: using acetone and water as mixed solvent, under sulfuric acid catalysis, with chromium trioxide oxidation 4,5-dimethoxy benzo tetramethylene-1-methyl alcohol.The mol ratio of chromium trioxide and 4,5-dimethoxy benzo tetramethylene-1-methyl alcohol is 1: 1-3: between 1, and preferably 1.5: 1.The temperature of oxidizing reaction is controlled at 0-10 ℃, preferably 5 ℃.
The present invention reacts compound 5-2 with amine, can obtain schiff bases.Amine wherein adopts methylamine hydrochloride, or the salt of other form of methylamine, preferably the hydrochloride of methylamine.The solvent of this step reaction can be selected from one or more in tetrahydrofuran (THF), methylene dichloride, acetone.The mol ratio of 4,5-dimethoxy benzo tetramethylene-1-formaldehyde and amine is 1.1: 1-2: between 1, and preferably 1.2: 1.Temperature of reaction is at 20 ℃-65 ℃, preferably 40 ℃.
In the present invention, the reduction of compound 5-3 schiff bases can be made to the target compound of formula II.Reduction reaction can pass into hydrogen under the pressure of 3MPa and reduces for compound 5-3 is existed and is less than at metal catalyst; Also can be for directly to use chemical reducing agent to reduce to compound 5-3.
Wherein metal catalyst is nickel catalyzator or palladium catalyst etc.; Chemical reducing agent is NaBH
4, NaBH
3cN or (CH
3cOO)
3bHNa, preferably (CH
3cOO)
3bHNa.The mol ratio of chemical reducing agent and substrate is 1.2: 1-2: 1, and preferably 1.5: 1.
The solvent of reduction reaction is selected from tetrahydrofuran (THF), methylene dichloride, 1, one or more in 2-ethylene dichloride, ethanol, methyl alcohol, Virahol, toluene, dimethylbenzene, preferably tetrahydrofuran (THF).Temperature of reaction is controlled at 5 ℃ following (5 ℃～5 ℃), preferably 0 ℃.
Compared with prior art, this technique invention have reaction temperature and, yield is high, environmental friendliness, the feature such as cost is low, suitability for mass industrializedization is produced.
Embodiment
With specific embodiment, technical scheme of the present invention is described below, but protection scope of the present invention is not limited to this:
Embodiment 1:4, the preparation of 5-dimethoxy benzo tetramethylene-1-formaldehyde
500 milliliters of round-bottomed flasks, magnetic stirs, and drops into 4,5-dimethoxy benzo tetramethylene-1-methyl alcohol (10 grams, 51.5mmol), 100 milliliters, acetone, 100 milliliters, water, is cooled to below 5 ℃, under stirring, slowly be added dropwise to 25 milliliters of the Jones reagents (sulphuric acid soln of chromium trioxide) of 3mol/l, drip and finish, remain on this thermotonus 30 minutes, rise to room temperature, add 100 milliliters of ether, 5 milliliters of Virahols, mix.Filter, filtering solid, filtrate is washed with extracted with diethyl ether (3*100 milliliter), saturated sodium bicarbonate, anhydrous sodium sulfate drying, filter, decompression steams solvent, obtains 9.2 grams of faint yellow oily matter, yield: 93%, IR:2731,2654,1737,1560,1455.
Embodiment 2:4, the preparation of 5-dimethoxy benzo tetramethylene-1-formaldehyde
500 milliliters of round-bottomed flasks, mechanical stirring, drops into 4,5-dimethoxy benzo tetramethylene-1-methyl alcohol (10 grams, 51.5mmol), 200 milliliters, water, stir, add potassium bichromate (22 grams, 75mmol), 5 milliliters of the vitriol oils in batches, control temperature and be no more than 10 ℃, finish, rise to 25 ℃, then stir 1 hour, filter, with extracted with diethyl ether (3*200 milliliter), saturated sodium bicarbonate washing, anhydrous sodium sulfate drying, filter, decompression steams solvent, obtains 6.8 grams of faint yellow oily matter, yield 70%.
Embodiment 3:4, the preparation of 5-dimethoxy-1-(methylamino methyl)-benzocyclobutane
4, (7.5 grams, 5-dimethoxy benzo tetramethylene-1-formaldehyde, 39mmol), with 100 milliliters of tetrahydrofuran (THF)s, add (2.5 grams of methylamine hydrochlorides, 32mmol), after stirring and dissolving, back flow reaction 6 hours, be cooled under zero degree stirring and add (10.25 grams of sodium triacetoxy borohydrides, 48mmol), insulation reaction 15 minutes, evaporated under reduced pressure solvent, add 50 milliliters, the sodium hydroxide of 1mol/l to residue, mix, with dichloromethane extraction, organic layer washes with water, anhydrous magnesium sulfate drying, filter evaporate to dryness, obtain 5.9 grams of faint yellow oily matter, yield: 89%.IR：3357，1560，1455。
Claims (8)
1. one kind 4,5-dimethoxy-1-(methylamino methyl) preparation method of-benzocyclobutane, it is characterized in that with 4,5-dimethoxy benzo tetramethylene-1-methyl alcohol is that raw material is through oxidizing reaction synthetic 4,5-dimethoxy benzo tetramethylene-1-formaldehyde, react with amine and generate schiff bases, finally make by reduction reaction, its reaction scheme is:
Wherein, the condition of oxidizing reaction is: using acetone and water as mixed solvent, under sulfuric acid catalysis, with chromium trioxide oxidation 4,5-dimethoxy benzo tetramethylene-1-methyl alcohol; The temperature of reaction of 4,5-dimethoxy benzo tetramethylene-1-formaldehyde and amine is 20 ℃～65 ℃, and described amine is methylamine or methylamine salt;
Described reduction reaction is compound 5-3 to be existed and is less than at metal catalyst under the pressure of 3MPa, pass into hydrogen and reduce; Or use chemical reducing agent to reduce to compound 5-3; Described metal catalyst is nickel catalyzator or palladium catalyst; Described chemical reducing agent is NaBH
4, NaBH
3cN or (CH
3cOO)
3bHNa.
2. method according to claim 1, is characterized in that the mol ratio of chromium trioxide and 4,5-dimethoxy benzo tetramethylene-1-methyl alcohol is 1:1～3:1, and oxidizing reaction temperature is 20 ℃～40 ℃.
3. method according to claim 1, is characterized in that described amine is methylamine hydrochloride; The reaction solvent of compound 5-2 and amine is selected from one or more in tetrahydrofuran (THF), methylene dichloride, acetone.
4. method according to claim 1, the mol ratio that it is characterized in that 4,5-dimethoxy benzo tetramethylene-1-formaldehyde and amine is 1.1:1～2:1.
5. method according to claim 1, is characterized in that described chemical reducing agent is (CH
3cOO)
3bHNa.
6. method according to claim 1, the mol ratio that it is characterized in that described chemical reducing agent and compound 5-3 is 1.2:1～2:1; The temperature of reduction reaction is-5 ℃～5 ℃.
7. method according to claim 1, is characterized in that the solvent of described reduction reaction is selected from tetrahydrofuran (THF), methylene dichloride, 1, one or more in 2-ethylene dichloride, ethanol, methyl alcohol, Virahol, toluene, dimethylbenzene.
8. method according to claim 7, is characterized in that the solvent of described reduction reaction is selected from tetrahydrofuran (THF).
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|---|---|---|---|
| CN201110338196.1A CN102408346B (en) | 2011-10-31 | 2011-10-31 | Preparation method of 4,5-dimethoxy-1-(methyl amino-methyl)-benzo-cyclobutane |
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|---|---|---|---|
| CN201110338196.1A CN102408346B (en) | 2011-10-31 | 2011-10-31 | Preparation method of 4,5-dimethoxy-1-(methyl amino-methyl)-benzo-cyclobutane |
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| Publication Number | Publication Date |
|---|---|
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| CN102408346B true CN102408346B (en) | 2014-07-02 |
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Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3101010A1 (en) | 2015-06-03 | 2016-12-07 | Urquima S.A. | New method for the preparation of highly pure ivabradine base and salts thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4647559A (en) * | 1983-04-29 | 1987-03-03 | William H. Rorer, Inc. | Bicyclic benzenoid aminoalkylene ethers and thioethers, pharmaceutical compositions and use |
| WO2004082586A2 (en) * | 2003-03-17 | 2004-09-30 | Affinium Pharmaceuticals, Inc. | Phamaceutical compositions comprising inhibitors of fab i and further antibiotics |
| FR2870537A1 (en) * | 2004-05-19 | 2005-11-25 | Servier Lab | NOVEL PROCESS FOR SYNTHESIZING (1S) -4,5-DIMETHOXY-1- (METHYL AMINOMETHYL) BENZOCYCLOBUTANE AND ITS ADDITION SALTS AND APPLICATION TO THE SYNTHESIS OF IVABRADINE AND ITS ADDITION SALTS PHARMACEUTICALLY ACCEPTABLE ACID |
| CN101857549B (en) * | 2010-06-22 | 2013-04-10 | 浙江美诺华药物化学有限公司 | Synthetic method of (1S)-4,5-dimethoxy-1-(aminomethyl)benzocyclobutane |
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