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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- 0 COc1cc(CC2*)c2cc1OC Chemical compound COc1cc(CC2*)c2cc1OC 0.000 description 2
- 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
- SAVVFXUMMFHSJC-UHFFFAOYSA-N CNCC(Cc1c2)c1cc(OC)c2OC Chemical compound CNCC(Cc1c2)c1cc(OC)c2OC SAVVFXUMMFHSJC-UHFFFAOYSA-N 0.000 description 1
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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| CN102408346B true CN102408346B (en) | 2014-07-02 |
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| EP3101010A1 (en) | 2015-06-03 | 2016-12-07 | Urquima S.A. | New method for the preparation of highly pure ivabradine base and salts thereof |
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| 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 |
| CA2519429C (en) * | 2003-03-17 | 2013-08-06 | Affinium Pharmaceuticals, Inc. | Pharmaceutical 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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